COVID-19 Resource Newsletters

The IARS COVID-19 Scientific Advisory Board (SAB) continually screens newly published peer-reviewed articles from respected journals to identify those of greatest clinical and scientific relevance to anesthesiologists, intensivists, related specialists and investigators. Our open-access newsletter provides a link to each highlighted article along with a short summary of key points. The SAB does not include any information from news media, social media, or scientific articles lacking full peer-review such as pre-prints.

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Current Newsletter: Issue 109, November 22, 2021

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Previous COVID-19 Resource Newsletters

Newsletter Issue 108, November 15, 2021:

  • Association Between COVID-19 Diagnosis and In-Hospital Mortality in Patients Hospitalized With ST-Segment Elevation Myocardial Infarction. 10/29/21. Saad M. JAMA.
    This is an outcome study of propensity matched cohorts (80,449 patients) with STEMI pre-admission and during admission prior to and during the COVID-19 pandemic (time periods January-December 2019 and 2020 with final follow up in January 2021). Pre-admission STEMI mortality 15.2% +’ve COVID Vs. 11.2% -ve COVID(p=.007); in-hospital developed STEMI mortality 78.5% +’ve COVID Vs. 46.1% -“veCOVID (p<.001). Mortality was the highest in 50-75-year-old Hispanic men. Pre-admission STEMI appears to have similar rates of interventional treatment in both time periods but the 2020 STEMI cohort was treated with fibrinolytics with fewer invasive interventions. The accompanying editorial provides context and adds an interesting perspective.
  • The immunology of asymptomatic SARS-CoV-2 infection: what are the key questions? 10/20/21. Boyton RJ. Nat Rev Immunol.
    This article is a well-referenced analysis of the often-contradictory data regarding SARS-CoV-2 asymptomatic infection (AI). Prevalence of AI vs. symptomatic infection (SI) vary widely from 20-80% of total cases, higher in younger populations. In Wuhan, even without symptoms, one-third had computer tomography lung changes. The immune basis of AI vs. SI remains unclear: viral and neutralizing antibody titers appear equivalent. AI viral-shedding is shorter and antibody titers decline more rapidly. AI is not “benign”; up to 19% result in “long COVID.” AI-adaptive immunity appears strong and primes immune memory. Additionally, silent viral carriage can result in future variants of concern.

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Newsletter Issue 107, November 8, 2021:

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Newsletter Issue 106, October 25, 2021:

  • SAB Comment: The SAB is awaiting publication of peer-reviewed data regarding the efficacy of Merck’s oral antiviral molnupiravir prior to evaluating this potentially effective therapy for our newsletter.
  • Administration of Monoclonal Antibody for COVID-19 in Patient Homes. 10/14/21. Malani AN. JAMA Netw Open.
    In this research letter, during the spring 2021 COVID-19 surge with peak counts of 1,300 cases per day, a Michigan healthcare system introduced successful in-home IV administration of monoclonal antibodies by paramedics to 144 high-risk COVID-19 patients with mild symptoms. This resulted in decompression of hospital facilities with only 8 patients requiring hospital admissions and no intubations or mortalities. Triage was accomplished by 3 nurses and prime risk factors were obesity, cardiovascular disease, and diabetes.
  • REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. 9/29/21. Weinrich D. NEJM.
    This report represents the phase 3 portion of Regeneron’s adaptive trial to demonstrate the efficacy of a combination of two monoclonal antibodies (imdevimab and casirivimab) in outpatients with COVID-19 and risk factors for severe disease in comparison to placebo. The phase 1-2 portion of this trial published one year ago showed a reduction of viral load and medical visits in 275 symptomatic patients. This phase compared 3 larger groups of patients, each receiving the antibody combination in two different doses or placebo. A highly significant relative risk reduction of 71% for hospitalization or death over placebo and a 4-day reduction in resolution of symptoms underlined the value of this treatment modality. In addition, the authors conclude that effectiveness does not depend on baseline serum antibody status.
  • Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial. 10/11/21. Connors JM. JAMA.
    Dosing strategy for inpatient COVID-19 patients remains controversial and anticoagulation benefits for stable outpatients has not been established. The ACTIV-4B was designed as minimal contact, adaptive, randomized, double-blind, placebo-controlled study to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but stable outpatients without comorbidities. Random 1:1:1:1 allocation ratio was applied to aspirin 81mg QD (164); prophylactic apixaban 2.5mg BID; therapeutic apixaban 5mg BID (164); or placebo (164) for 45 days. Primary endpoint composite was for all-cause mortality, symptomatic venous or arterial thromboembolism, MI, stroke or hospital admission for CV or pulmonary cause. The trial was terminated by the monitoring board for lower event rate than predicted and no therapeutic difference was noted.
  • Antithrombotic Therapy for Outpatients With COVID-19: Implications for Clinical Practice and Future Research. 10/11/21. Berwanger O. JAMA.
    This editorial review provides a comparison of multiple studies on antithrombotic therapy for inpatients and outpatients with specific review of the ACTIV-4B trial. The discussion provides insight into the studies and suggests the use of aspirin or apixaban for symptomatic but stable outpatients is not justified. Additional comments support the importance of appropriately structured and controlled clinical trials despite the difficulties associated with such studies during a pandemic.
  • Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. 10/7/21. Spyropoulos AC. JAMA Intern Med.
    This multicenter US study of 253 hospitalized adults with COVID-19 and evidence of coagulopathy reinforces findings in previous publications. After randomizing those with a D-dimer greater than 4x the upper limit of normal or a sepsis-induced coagulopathy score of greater than 4, to (1) standard prophylactic or intermediate-dose low-molecular-weight heparin (LMWH) or unfractionated heparin or (2) therapeutic-dose LMWH throughout hospitalization, the primary efficacy outcome of venous thromboembolism, arterial thromboembolism, or all-cause mortality was significantly reduced with therapeutic-dose anticoagulation in the non–ICU patients only (29 vs. 42%).
  • Anticoagulant Therapy in Patients Hospitalized With COVID-19. 10/7/21. Wahid L. JAMA Intern Med.
    This well-written accompanying editorial to the previous article discusses these findings along with those from several other major related studies, and points out coagulation management issues, such as antiplatelet therapy and extended prophylaxis, which remain unanswered.
  • Bacterial Superinfection Pneumonia in Patients Mechanically Ventilated for COVID-19 Pneumonia. 8/17/21. Pickens CO. ATS.
    This Northwestern University single-center study examined the prevalence and etiology of bacterial superinfection (bacterial infection in addition to SARS-CoV-2) in severe SARS-CoV-2 pneumonia at intubation and subsequent ventilator-associated pneumonia (VAP). All patients had bronchoalveolar lavage (BAL) analyzed by quantitative cultures and multiplex PCR. In 179 patients, initial superinfection was detected in 21%; 44.4% developed 1 or more VAP episode(s). Initial VAP pathogens were usually CAP-type and not requiring broad spectrum coverage. Clinical criteria could not distinguish patients with or without superinfections. BAL-based management resulted in significantly reduced antibiotic use. Current guidelines, which advocate empirical antibiotics in severe SARS, results in antibiotic overuse at intubation. Forty-four percent VAPs suggests widespread under-recognition yet overtreatment with unnecessarily broad antibiotics.

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Newsletter Issue 105, October 18, 2021:

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Newsletter Issue 104, October 11, 2021:

  • Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions – United States, March-August 2021. 9/23/21. Self WH. MMWR Morb Mortal Wkly Rep.
    This CDC study compared the real-life vaccine effectiveness (VE) against hospitalization of patients who had the three vaccines which were approved in the US. The vaccination status of 1,682 patients hospitalized with COVID-19 was compared with the vaccination status of 2,007 control patients admitted without COVID-19 during March to August 2021. VE against COVID-19 hospitalization was slightly lower for the Pfizer vaccine (88%) than the Moderna vaccine (93%), with this difference driven by a decline in VE after 120 days for the Pfizer but not for the Moderna vaccine. The Janssen (Johnson and Johnson) VE was 71%.
    SAB Comment: As viral variants were not determined in this study, and time since vaccination is increasing, the VE of various vaccines may be changing. Note that in the first week of May 2021, 1.6% of all COVID-19 infections in the US were thought to be caused by Delta, whereas in the last week of September, 99% of US cases were Delta.
  • Myocarditis With COVID-19 mRNA Vaccines. 8/10/21. Bozkurt B. Circulation.
    This report summarizes the available information regarding myocarditis occurring after mRNA vaccination against SARS-CoV-2. The CDC reports an incidence of 12.6 per million of those between ages 12 and 39, mostly men. The FDA will add a warning label to both mRNA vaccines. Case definition, symptoms, treatment, and course are presented, as well as a chart listing published cases. Rapid resolution usually occurred. The mechanism of development is unclear, but proposed mechanisms are discussed. It includes an illustration of the risk-benefit which favors vaccination for all people older than 12.
  • Fostamatinib for the treatment of hospitalized adults with COVID-19: A randomized trial. 9/1/21. Strich JR. Clin Infect Dis.
    Fostamatinib is an oral tyrosine kinase inhibitor that is FDA-approved for the treatment of chronic idiopathic thrombocytopenic purpura. Its active metabolite inhibits both the release of proinflammatory cytokines and platelet mediated thrombus formation provoked by anti-spike immune complexes. In this NIH-led pilot study, fostamatinib was given to 30 patients with advanced COVID-19 requiring oxygen and receiving remdesivir and corticosteroids. Compared to the placebo group, lung injury appeared to resolve more quickly, serious side effects were significantly reduced, and several biomarkers improved significantly. Larger confirmatory trials are needed to establish the drug’s role in advanced SARS-CoV-2 infections.
  • Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study. 9/16/21. Hatzl S. Crit Care.
    This retrospective, observational study reviewed the clinical course of all 132 consecutive patients admitted between September 1, 2020, and May 1, 2021, 75 of whom received antifungal prophylaxis (98% posaconazole). Antifungal prophylaxis was recommended in this medical center, but ordering it was left up to the discretion of individual intensivists. The authors noted that COVID-19-associated pulmonary aspergillosis (CAPA) was diagnosed in 17.5% of patients who did not receive antifungal prophylaxis, versus only in 1.4% of those receiving prophylaxis. They also noted that despite the efficacy shown for antifungal prophylaxis against aspergillosis infection in these patients, this prophylaxis did not have a significant impact on overall survival.
  • Machine Learning Prediction of Death in Critically Ill Patients With Coronavirus Disease 2019. 9/3/21. Churpek MM. Crit Care Explor.
    This observational study (67 US ICUs, N=5075, March-June 2020) addressed the variable mortality of ICU/COVID-19 patients with a machine learning tool ~eXtreme Gradient Boosting (XGBM) on 28-day mortality. XGBM had the highest discrimination and calibration of all the machine learning models tested including, SOFA Score, NEWS and CURB-65. It is a simple bedside tool that provides pertinent information for goals of care discussions, triage decisions and for prognostic clinical trials. The area under the receiver operating curve was 0.81 (CI 79-85) with a discrimination power X 10 fold. Mortality was 36.4% at day 28 from day of ICU admission. Age, number of ICU beds, creatinine, and lactate were important contributions to mortality.

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Newsletter Issue 103, October 4, 2021:

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Newsletter Issue 102, September 27, 2021:

  • Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. 9/15/21. Bar-On YM. N Engl J Med.
    More than 1.1 million (1,137,804) fully vaccinated Israelis older than 60 years were studied during the rollout of a program to provide 3rd shots of the Pfizer vaccine during the Delta surge. Data was analyzed from 5 million person-days at risk in the nonbooster group compared with 10 million person-days in the booster group. “At least 12 days after the booster dose, the rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of 11.3 (95% confidence interval [CI], 10.4 to 12.3); the rate of severe illness (cases diagnosed Aug 10-26, 2021) was lower by a factor of 19.5 (95% CI, 12.9 to 29.5).” A second analysis showed that the reduction after 12 days post 3rd shot was 5.4 times greater than the reduction after 4 to 6 days post-3rd shot. (95% CI, 4.8 to 6.1). A bar graph shows clearly that it takes 2-3 weeks for additional protection to peak.
  • Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. 9/16/21. Choi A. Nat Med.
    In an open-label ongoing phase 2a study, Moderna examined whether their current vaccine (mRNA-1273) booster 6 months after the second dose, shows decreased neutralization vs. three Beta-variant vaccines. Interim analysis of 4 booster groups (n = 20/group) is: Pre-booster dose: neutralizing antibodies against wild-type D614G waned vs. peak titers 1-month post-primary series. Neutralization titers against Beta, Gamma and Delta VOCs were low/undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe. Both boosters increased neutralization titers against wild-type D614G vs. peak titers 1 month after the primary series, and importantly, against VOCs; both were equivalent or superior to titers measured post-primary series against wild-type virus.
  • SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3. 9/15/21. Falsey AR. N Engl J Med.
    This research letter discusses what amounts to a pilot study looking at neutralizing antibody responses in a small group of subjects who received a third Pfizer vaccine dose, providing data that may be used to argue for a booster. Increases were greater in participants older than 65 years compared with adults younger than 55. Increases were greater to Beta and Delta variants than to wild type.
  • Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy. 9/8/21. Kharbanda EO. JAMA.
    In this Research Letter of 105,446 pregnancies with 13,160 spontaneous abortions, vaccination for COVID-19 did not increase the risk for spontaneous abortion as compared to unvaccinated pregnancies.
  • Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy. 9/8/21. Dagan N. Nat Med.
    A pre-Delta, observational study from researchers in Tel Aviv and at Harvard investigating the BNT162b2 messenger RNA vaccine during pregnancy in Israeli women older than 16 years found the vaccine to be of comparable effectiveness to the general population and that it reduced the infection rate by nearly 50% (see data in Figure 1) when compared to the unvaccinated pregnant control group. It should be noted there were no deaths in either group and only 1 severe infection in the unvaccinated group. The authors hypothesize the vaccination is safe and might provide protection in newborns, although they offered no evidence.
  • Surveillance for Adverse Events After COVID-19 mRNA Vaccination. 9/3/21. Klein NP. JAMA.
    This is a Vaccine Safety Datalink study from 8 participating US health plans. “In this interim analysis of surveillance data from 6.2 million persons who received 11.8 million doses of an mRNA vaccine, event rates for 23 serious health outcomes were not significantly higher for individuals 1 to 21 days after vaccination compared with similar individuals at 22 to 42 days after vaccination,…although CIs were wide for some rate ratio estimates and additional follow-up is ongoing.” Outcomes included MI, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré, myocarditis, pericarditis, PE, CVA, and thrombosis with thrombocytopenia. Follow-up is expected for at least 2 years.
  • Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. 9/15/21. Thomas SJ. N Engl J Med.
    This article updates the 2-month data from the ongoing randomized, placebo controlled study of 44,165 participants older than 16 years and 2,264 participants 12-15 years old who received 2 doses of BNT162b2 or placebo. Vaccinations were pre-Delta.

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Newsletter Issue 101, September 20, 2021:

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Newsletter Issue 100, September 13, 2021:

  • Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study. 8/27/21. Twohig KA. Lancet Infect Dis.
    All English National Health System patients diagnosed with COVID-19 by PCR from March 29 – May 23, 2021, and found by whole-genome sequencing to have alpha or delta variants, were studied. Delta grew from 0.1% to 45.8% during the study. The adjusted risk (aHR) of an emergency care visit or hospital admission within 14 days of a first positive test was 1.45 in those with delta (n=8,682) compared with alpha (n=34,656). For hospital admission, aHR for delta vs. alpha was 2.26. Median age was 31 years old; 74% were unvaccinated in both variant groups. Patients seen in emergency care or admitted on the day of their first COVID-positive test were excluded to reduce bias of screening tests at the time of presentation for non-COVID related illness.
  • 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. 8/28/21. Huang L. Lancet.
    This extensive study reports the condition at 12 months of a cohort of 1,307 COVID-19 patients discharged January-May 2020 from a single hospital in China. Patients in nursing or care homes, immobile or with osteoarthritis, and with psychiatric disorders or dementia were excluded from the study. A review of the report of their condition at 6 months appears in Newsletter 51. Intensive evaluations included multiple standardized questionnaires, physical exam, blood tests, pulmonary evaluation, use of healthcare resources and work status. Patients with at least one persistent symptom decreased from 68% at 6 months to 49% at 12 months. The most common problem, fatigue and muscle weakness decreased from 52% to 20%. The proportion with dyspnea and anxiety or depression worsened slightly. Of those who were employed prior to hospitalization, 88% had returned to work. Outcome with regard to severity of initial disease, males vs. females and patients vs. matched community controls is characterized.
  • Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial. 8/23/21. Ehrmann S. Lancet Respir Med.
    In this multicenter, international, randomized, open-label meta-trial, awake prone positioning (APP) decreased the incidence of intubation in patients with acute severe hypoxemic respiratory failure due to COVID-19 supported with high-flow nasal cannula. From April 2020 through January 2021, 1,121 patients from six countries were randomized to APP as long as possible, or to standard care. The number needed to treat with APP to prevent one intubation was 14. Though not designed to evaluate the duration of APP on outcomes (median daily duration was 5 hours), patients achieving longer durations had better outcomes. Adverse effects were mild, infrequent, and occurred at similar rates between the APP and standard care groups.
    SAB Comment: This is the first large, randomized study of APP, commonly used empirically during the pandemic. The results reinforce the safety and utility of APP for averting intubations. Other randomized studies are underway, as discussed in the accompanying Comment.
  • COVID-19 Vaccine Safety in Adolescents Aged 12-17 Years – United States, December 14, 2020-July 16, 2021. 8/5/21. Hause AM. MMWR Morb Mortal Wkly Rep.
    A statistical analysis of the Pfizer COVID-19 vaccine in children 12 years or older in the US demonstrated its safety. Reactions to the vaccine are uncommon and mostly mild. Myocarditis is one rare but severe reaction more common in boys after the second vaccination and that resulted in no deaths.
  • COVID-19 Vaccination-Associated Myocarditis in Adolescents. 8/14/21. Jain SS. Pediatrics.
    This article reviews the clinical presentation and early prognosis of the rare complication of acute myocarditis following COVID-19 vaccination in adolescents. The authors pool data from 63 patients from 16 US institutions. Using cardiac MR imaging, the authors are able to characterize this entity with exquisite detail in the figures. The authors demonstrate the favorable short-term outcomes of this subset. This article represents some of the largest dataset examining this particular entity in this age group.
  • Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. 8/25/21. Barda N. N Engl J Med.
    This Israeli study compared the occurrence of adverse events in 884,828 recipients of the Pfizer/BioNTech COVID-19 vaccine to a like number of controls matched for risks on the day of vaccination. Vaccine recipients and controls were followed for 21 days after each injection. Vaccination was not associated with an elevated risk of most of the adverse events examined. Vaccination was associated with an elevated risk of myocarditis (risk ratio, 3.24 but absolute event rate only 2.23 per 100,000), lymphadenopathy (risk ratio, 2.43), appendicitis (risk ratio, 1.40), and herpes zoster infection (risk ratio, 1.43). From a second set of data, they showed that actual SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28) and with additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia.
    SAB Comment: To make meaning of a comparison of adverse events associated with vaccination to those associated with COVID-19 infection, one must assume a cumulative incidence level. The accompanying editorial adds context and assumes that, “given the current state of the global pandemic, however, the risk of exposure to SARS-CoV-2 appears to be inevitable.”
  • Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance – Eight U.S. Locations, December 2020-August 2021. 8/26/21. Fowlkes A. MMWR Morb Mortal Wkly Rep.
    Data from the prospective frontline worker HEROES-RECOVER Cohorts showed that from 12/24/20-4/10/21 the Pfizer-BioNTech and Moderna vaccines were ~90% effective in preventing symptomatic and asymptomatic SARS-CoV-2 infection. Adjusted efficacy was 80%. The estimate was 85% among participants for whom less than 120 days had elapsed since full vaccination and 73% among those for whom 150 or more days had elapsed. Once Delta became the predominant variant, adjusted efficacy decreased from 91% to 66%. However, this trend should be interpreted with caution as effectiveness might also have declined due to greater time since vaccination. In addition, there were few weeks of observation and low numbers of infections.
  • Early Convalescent Plasma for High-Risk Outpatients with Covid-19. 8/18/21. Korley FK. N Engl J Med.
    While prior studies using convalescent plasma have failed to demonstrate improved outcomes over placebo for inpatients, this randomized study examined its use in outpatients. Patients older than 50 years old were initially seen in the emergency room and diagnosed with COVID-19. Five hundred and eleven patients from 48 hospitals in 21 states in the US were included in this blinded study funded by the NIH, 257 received convalescent plasma and 254 received placebo. The primary outcome was disease progression defined by either hospital admission, seeking emergency or urgent care, or death. The study showed no significant difference between the two groups (i.e., those receiving convalescent plasma and those that did not).

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Newsletter Issue 99, September 8, 2021:

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Newsletter Issue 98, August 30, 2021:

Author’s Note on today’s Special Edition summary on “The Virus, The Vaccines and The Variants”: This review cites published peer-reviewed articles or official governmental websites only. The information is current as of August 27, 2021. Given the fluid, constantly developing nature of the pandemic and its management, we intend to provide regular updates to this summary for our readers. 

The Virus, The Vaccines and The Variants
Robert N. Sladen MBChB, FCCM, IARS Scientific Advisory Board

The Virus

The coronavirus SARS-CoV-2 shares 80% of the genome sequence of SARS-CoV-1 (responsible for the SARS epidemic in 2002-3) and in its original, “wild” form is less lethal but far more transmissible1. Each spherical virion incorporates four structural proteins: a central nucleocapsid containing single-stranded RNA, a membrane, an envelope and a corona of spike (S) proteins. A short 25-amino acid sequence on the S1 subunit, the outer component of the S-protein, forms the viral receptor binding domain (RBD) that binds with ACE2 receptors and triggers cellular entry and viral replication. ACE2 is ubiquitous in multiple organs, converts angiotensin I to angiotensin (1-7), and provides endothelial protection. Viral blockade of the ACE2 receptor contributes to many of the vascular, coagulopathic and cytopathologic manifestations of COVID-192.

The Vaccines

Vaccines in current use against SARS-CoV-2 induce neutralizing antibodies (nAbs) that bind to the viral RBD and block its interaction with the ACE2 receptor (Table 1). Vaccine efficacy is determined by randomized controlled trials but these do not always predict effectiveness under nonrandom field conditions in heterogenous populations and geographic zones3. Levels of nAbs are often used as a surrogate for outcomes but their relationship with vaccine effectiveness is still incompletely understood. Although all vaccines currently in use in the USA remain highly effective in preventing severe illness, hospitalization and death, there is increasing evidence that asymptomatic or presymptomatic vaccinated individuals can become infected, shed and transmit active virus2.

Table 1: Vaccines Currently in Use or in Phase III Trials in the USA

Vaccines Currently in Use or in Phase III Trials in the USA

The FDA granted emergency use authorization (EUA) to the Pfizer-BioNTech, Moderna and Johnson & Johnson (J&J) vaccines for the duration of the COVID-19 pandemic. None have been approved for children younger than 12 years. Only the Pfizer-BioNTech vaccine has been approved for adolescents younger than 18 years of age, and on August 23, 2021, it received full FDA approval for use in individuals aged 16 years or older. The AstraZeneca vaccine is used widely in countries outside the US but received a major setback by reports of the rare but potentially fatal complication of vaccine-induced immune thrombotic thrombocytopenia (VITT); the J&J vaccine was briefly suspended in the US during investigation of similar reports. The unique NovaVax vaccine is undergoing Phase III trials that have been set back by FDA concerns regarding its manufacturing process.

The Variants

Mutations and Variant Categories

All viruses constantly undergo adaptive mutations to their genome to form variants. Coronaviruses are singular in having the largest genome of all RNA-based viruses2, although they mutate five-fold more slowly than influenza viruses4. A variant may have multiple or even a single mutation in the S-protein sequence and although most are of little clinical or public health consequence, minimal genomic sequence alterations of the small RBD can lead to immune escape. Important variants may emerge in a single individual, especially those who are immunocompromised and maintain high viral loads over a protracted length of time4. Stochastic modeling predicts that the highest risk of emergence of resistant variants occurs when there is a combination of high infection with low vaccination rate, but also when a high proportion of the population is vaccinated but transmission is not controlled because of a reversion to prepandemic behavior5. New variants that are more transmissible and virulent are constantly evolving and “pushing out” older strains.

The highly complex systems of nomenclature attempt to group clades of variants by their genome and lineage on the phylogenetic tree. The PANGOLIN classification (Phylogenetic Assignment of Named Global Outbreak Lineages) has become well established (, but the World Health Organization (WHO) has attempted to simplify nomenclature by grouping variant strains by letters of the Greek alphabet. The US Government SARS-CoV-2 Interagency Group (SIG) has defined three phenotypical categories of variants.

Variants of concern (VOCs) (Table 2) are strains associated with an established detriment to human health through increased transmissibility, immune evasion/escape and virulence. They may evade detection by RT-PCR testing and potentially cause reinfection and vaccine breakthrough6. Variants that increase the affinity of the viral spike protein for ACE2 receptors enhance viral attachment, cellular entry and create faster replication rates. Some mutations exist in several VOCs. The E484K “escape” mutation involves an S-protein side chain charge change, and has been observed in the alpha, beta and gamma variants and markedly increases immune resistance7.

Table 2: Current Variants of Concern (VOCs) in the USA

Current Variants of Concern in the USA


Variants of Interest (VOI) have some of the characteristics of VOCs but limited prevalence at present and include epsilon, zeta, eta, iota, theta, kappa and lambda. The epsilon variant (B.1.427) was first detected in the US in June 2020 and declared a VOC but de-escalated to VOI on June 29, 2021 because of vaccine effectivity and a marked decline in its prevalence. The lambda variant (C.37) was first described in Peru in December 2020, now dominates in South America and provides concern for its high virulence and immune escape from current vaccines.

Variants of High Consequence (VOHC) are variants with even greater virulence and immune escape than existing VOCs. Currently no variants are listed in this class in the US.

Variant Outbreaks

In late 2020 and early 2021, variants caused severe resurgent outbreaks in many parts of the world including the UK, India, South Africa and Peru8. In April-May 2021, the delta variant emerged in India and contributed to a massive second wave9. Subsequently it has triggered a major resurgence of COVID-19 cases in the US, particularly in states with low proportions of vaccinated individuals10. It is more than twice as contagious as previous strains and appears to cause more rapidly progressive disease and hospitalizations in unvaccinated patients, including young adults and children. Vaccinated individuals are at a greatly decreased risk of contracting severe disease but there is increasing recognition of their susceptibility to asymptomatic COVID-19, and even though their viral load declines rapidly, they may thereby infect susceptible persons.

The Centers for Disease Control and Prevention (CDC) website11 provides an informative link to its genomic surveillance program. It also has a model (Nowcast) that calculates the rapidly changing proportion of variants causing COVID-19 infection by geographic region. For example, in the first week of May 2021 1.6% of all COVID-19 infections in the US were projected to be caused by the delta variant. By the first week of August this had increased to 96.8%.

Variant Vaccine Resistance

Initial studies showed high effectiveness of mRNA and virus vector vaccines versus the wild type virus, and the AstraZeneca vaccine was shown to decrease viral load and duration of shedding of the alpha variant12. However, efficacy changes with geographic variant predominance. In 2020, the AstraZeneca vaccine had 74% efficacy in the UK13, but only 22% in South Africa, where the beta variant had become dominant14. Studies from Qatar with the Pfizer-BioNTech vaccine showed decreased effectiveness against infection by the alpha (95% to 89.5%) and beta variants (95% to 75%), but high protection (97.4%) persisted against severe, critical or fatal disease 14 days or more after a second dose15. In a UK observational study of almost 20,000 symptomatic genome sequenced cases, effectiveness of one dose of the Pfizer-BioNTech and AstraZeneca vaccines was 48.7% against the alpha variant but only 30.7% against the delta variant16. After two doses, the effectiveness of the Pfizer-BioNTech against the alpha and delta variants increased to 93.7% and 88.0% respectively, and for the AstraZeneca vaccine 74.5% and 67.0% respectively.

Vaccine Breakthrough Infections and Boosters

Breakthrough infections were first reported in two fully mRNA vaccinated individuals in New York in March 2021 despite a brisk neutralizing antibody response17. An epidemiologic study in Washington state prior to the delta surge revealed that 24 of 1547 US Military Health System beneficiaries – mostly healthy young healthcare workers – had positive RT-PCR 14 days or later after full vaccination18. Most had mild symptoms but some had considerable viral shedding.

By mid-March 2021, more than 80% of the adult population of Israel had been given at least one dose of the Pfizer-BioNtech vaccine and national surveillance data revealed 95% effectiveness against SARS-CoV-2 infection and 97% effectiveness against hospitalization or death19. Shortly after a winter surge when the alpha variant occurred in 94.5% of isolates, breakthrough infections were detected in 2.6% of fully vaccinated health care workers. Although the majority had no or mild symptoms, in 19%, symptoms persisted more than 6 weeks20. There is evidence that nAbs decline with duration after vaccination with Pfizer-BioNTech regimen, especially in older individuals21. After detecting an increasing number of delta variant breakthrough infections in fully vaccinated individuals, on August 13, 2021 the Israel Ministry of Health approved a third vaccine for persons 50 years old or older, healthcare workers and other high-risk groups22. On the same day, the CDC recommended a third dose for moderately to severely immunocompromised individuals23 and the Biden Administration has recommended a third dose of the Pfizer-BioNTech or Moderna vaccine starting this autumn.

Future Directions: Can We Bring the Pandemic to an End?

High transmission with low vaccination rates continually creates opportunities for the emergence of new variants with unpredictable degrees of immune escape. This emphasizes the importance of genomic sequencing to detect and quantify the predominance of variants. It is suggested that the pandemic will likely end only when vaccines against circulating variants are delivered equitably around the world24.

On the other hand, vaccines active only against the S-protein RBD may promote the emergence of more virulent escape-mutations by natural selection25. Infection of a vaccinated individual by mutated and nonmutated virions could foster selective replication of the mutated virions. This suggests that second generation vaccines should be polyvalent and act on multiple epitopes of the SARS-CoV-2 virus. For example, the VXA-CoV2-1 (Vaxart) vaccine that is currently undergoing Phase II trials in the US is being developed as an oral vaccine directed against the viral nucleocapsid (N-protein), making it potentially less susceptible to mutations.

All zoonotic sarbecoviruses use human ACE2 as the entry receptor, so it is suggested that third generation vaccines should inhibit the RBD-ACE2 interaction without blocking beneficial ACE2 activity. In SARS survivors, who continue to have detectable nAbs to SARS-CoV-1 17 years after infection, the Pfizer-BioNTech vaccine induced potent cross-clade pan-sarbecovirus nAbs, capable of neutralizing known VOCs as well as sarbecoviruses that exist in bats and pangolins with the potential for human infection1. A humanized ACE2 monoclonal targeted nAb (h11B11) provides protection against SARS-CoV-2 and escape variants in animal models26, which have also suggested that a cocktail combining ACE2 protecting peptides and S-protein neutralizing peptides may be safe and effective27.


  1. Tan CW, Chia WN, Young BE, Zhu F, Lim BL, Sia WR, et al. Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors. N Engl J Med. 2021. 10.1056/NEJMoa2108453.
  2. Forchette L, Sebastian W, Liu T. A Comprehensive Review of COVID-19 Virology, Vaccines, Variants, and Therapeutics. Curr Med Sci. 2021. 10.1007/s11596-021-2395-1.
  3. Hodgson SH, Mansatta K, Mallett G, Harris V, Emary KRW, Pollard AJ. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect Dis. 2021;21:e26-e35. 10.1016/S1473-3099(20)30773-8.
  4. Otto SP, Day T, Arino J, Colijn C, Dushoff J, Li M, et al. The origins and potential future of SARS-CoV-2 variants of concern in the evolving COVID-19 pandemic. Curr Biol. 2021;31:R918-R29. 10.1016/j.cub.2021.06.049.
  5. Rella SA, Kulikova YA, Dermitzakis ET, Kondrashov FA. Rates of SARS-CoV-2 transmission and vaccination impact the fate of vaccine-resistant strains. Sci Rep. 2021;11:15729. 10.1038/s41598-021-95025-3.
  6. Vasireddy D, Vanaparthy R, Mohan G, Malayala SV, Atluri P. Review of COVID-19 Variants and COVID-19 Vaccine Efficacy: What the Clinician Should Know? J Clin Med Res. 2021;13:317-25. 10.14740/jocmr4518.
  7. Wise J. Covid-19: The E484K mutation and the risks it poses. BMJ. 2021;372:n359. 10.1136/bmj.n359.
  8. Chadha J, Khullar L, Mittal N. Facing the wrath of enigmatic mutations: A review on the emergence of SARS-CoV-2 variants amid COVID-19 pandemic. Environ Microbiol. 2021. 10.1111/1462-2920.15687.
  9. Kunal S, Aditi, Gupta K, Ish P. COVID-19 variants in India: Potential role in second wave and impact on vaccination. Heart Lung. 2021;50:784-7. 10.1016/j.hrtlng.2021.05.008.
  10. Centers for Disease Control and Prevention. Delta Variant: What We Know About the Science. Updated August 26, 2021. Access August 30, 2021.
  11. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions. Updated August 24, 2021. Accessed August 30, 2021.
  12. Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021;397:1351-62. 10.1016/S0140-6736(21)00628-0.
  13. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397:99-111. 10.1016/S0140-6736(20)32661-1.
  14. Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AL, Fairlie L, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021;384:1885-98. 10.1056/NEJMoa2102214.
  15. Abu-Raddad LJ, Chemaitelly H, Butt AA, National Study Group for C-V. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. N Engl J Med. 2021;385:187-9. 10.1056/NEJMc2104974.
  16. Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021. 10.1056/NEJMoa2108891.
  17. Hacisuleyman E, Hale C, Saito Y, Blachere NE, Bergh M, Conlon EG, et al. Vaccine Breakthrough Infections with SARS-CoV-2 Variants. N Engl J Med. 2021;384:2212-8. 10.1056/NEJMoa2105000.
  18. Pollett SD, Richard SA, Fries AC, Simons MP, Mende K, Lalani T, et al. The SARS-CoV-2 mRNA vaccine breakthrough infection phenotype includes significant symptoms, live virus shedding, and viral genetic diversity. Clin Infect Dis. 2021. 10.1093/cid/ciab543.
  19. Haas EJ, Angulo FJ, McLaughlin JM, Anis E, Singer SR, Khan F, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet. 2021;397:1819-29. 10.1016/S0140-6736(21)00947-8.
  20. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med. 2021. 10.1056/NEJMoa2109072.
  21. Wall EC, Wu M, Harvey R, Kelly G, Warchal S, Sawyer C, et al. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet. 2021;397:2331-3. 10.1016/S0140-6736(21)01290-3.
  22. Ministry of Health. The Ministry of Health Director General Has Approved the Recommendation to Administer a Third Vaccine Doe to 50-Year-Olds and Older and to Other Populations. Updated August 13, 2021. Accessed August 30, 2021.
  23. Centers for Disease Control and Prevention. Media Statement from CDC Director Rochelle P. Walensky, MD, MPH, on Signing the Advisory Committee on Immunization Practices’ Recommendation for an Additional Dose of an mRNA COVID-19 Vaccine in Moderately to Severely Immunocompromised People. Updated August 13, 2021. Accessed August 30, 2021.
  24. Fontanet A, Autran B, Lina B, Kieny MP, Karim SSA, Sridhar D. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet. 2021;397:952-4. 10.1016/S0140-6736(21)00370-6.
  25. Galili U. COVID-19 variants as moving targets and how to stop them by glycoengineered whole-virus vaccines. Virulence. 2021;12:1717-20. 10.1080/21505594.2021.1939924.
  26. Du Y, Shi R, Zhang Y, Duan X, Li L, Zhang J, et al. A broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants. Nat Commun. 2021;12:5000. 10.1038/s41467-021-25331-x.
  27. Chen J, Li S, Lei Z, Tang Q, Mo L, Zhao X, et al. Inhibition of SARS-CoV-2 pseudovirus invasion by ACE2 protecting and Spike neutralizing peptides: An alternative approach to COVID19 prevention and therapy. Int J Biol Sci. 2021;17:2957-69. 10.7150/ijbs.61476.

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Newsletter Issue 97, August 23, 2021:

  • Surviving Covid-19 with Heparin? 8/4/21. Ten Cate H. N Engl J Med.
    This editorial attempts to reconcile the differences in outcomes of the two studies below between critically ill and moderately ill COVID-19 patients who received heparin at therapeutic vs. thromboprophylactic doses. It is fairly clear that therapeutic anticoagulation does not provide increased benefit over thromboprophylaxis for critically ill patients; however, the degree of benefit of full anticoagulation over prophylaxis for patients with moderate disease remains an open question.
  • Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. 8/5/21. REMAP-CAP Investigators. N Engl J Med.
    This randomized study of 1098 patients was stopped early because “In critically ill patients with COVID-19…therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.” Major bleeding occurred in 3.8% of patients receiving therapeutic-dose anticoagulation vs. 2.3% receiving usual-care thromboprophylaxis. These data are the result of harmonized protocols of 3 international adaptive platform trials (REMAP-CAP, ACTIV-4A, and ATTACC). A limitation is that the majority of patients were in the UK where usual care changed from low-dose to intermediate dose prophylaxis during the study period, April-December 2020.
  • Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. 8/5/21. ATTACC Investigators. N Engl J Med.
    This companion study reports outcomes following initial treatment with therapeutic vs. prophylactic heparin anticoagulation for 2,219 COVID-19 patients with moderate disease. Survival until hospital discharge without receipt of organ support during the first 21 days was 76.4% (801/1048) for those in usual-care thromboprophylaxis vs. 80.2% (939/1171) for those in the therapeutic anticoagulation group. Neither age, level of respiratory support at enrollment, nor thromboprophylaxis dose affected outcomes. The final posterior probability for superiority of therapeutic-dose anticoagulation vs. usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the cohort with an unknown d-dimer level. A table summarizes secondary outcomes, including major bleeding in 1.9% receiving therapeutic dose vs. 0.9% receiving thromboprophylaxis.

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Newsletter Issue 96, August 16, 2021:

  • SAB Comment: The following two studies on vaccine-induced immune thrombocytopenia (VITT) provide two different views of a complex therapeutic question that remains unresolved. What is the appropriate dose (therapeutic versus prophylactic) and timing of anticoagulant therapy in the treatment of COVID-19 and what is the incidence of VITT in the general population stratified by age and sex following vaccination?
    • Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis. 8/11/21. Pavord S. N Engl J Med.
      A study of 294 patients presenting to UK hospitals (03/22-06/06 2021) found incidence of vaccine-induced immune thrombocytopenia and thrombosis (VITT) following ChAdOx1 nCoV-19 (AstraZeneca) vaccination among individuals younger than 50 years at least 1:50,000 which is consistent with previous reports. The study details diagnosis, patient demographics and common timeline for vaccination to symptomatology. Useful tables detail definition criteria (definite, probable, possible, unlikely) and clinicopathological findings. Age stratification notes incidence in older than 60 years at least 1/100,000. The authors conclude “The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management.”
    • Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study. 8/9/21. Perry RJ. Lancet.
      Investigators studied 95 patients from 43 UK hospitals with image-confirmed cerebral venous thrombosis following vaccination for COVID-19 looking for vaccine-induced immune thrombotic thrombocytopenia (VITT), which was defined as acute thrombosis accompanied by D-dimer greater than 2,000 along with a minimum platelet count less than 150,000. Seventy-six (80%) of 95 patients were investigated for anti-PF4 antibodies, a reliable marker for VITT. Seventy in 96 had VITT, all following AstraZeneca vaccine. Of 26 without VITT, 21 had received AstraZeneca vaccines, and four had received Pfizer vaccines. VITT patients were younger (mean 47 vs. 57), more likely to have multiple venous thromboses (14% vs. 0) or hemorrhages (33% vs. 14%), and more disabled at discharge compared with non-VITT patients. Mortality was 29% in the VITT cohort vs. 4% in the non-VITT cohort. One non-VITT patient had serious extra-cerebral thrombosis. Non-heparin anticoagulant and intravenous immunoglobulin treatments were associated with an improved outcome. Diagnosis criteria are proposed.
  • Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome. 8/10/21. Fogarty H. J Thromb Haemost.
    Findings of pulmonary endotheliopathy and microvascular immunothrombosis have been highlighted in autopsies in acute COVID, but their contributions to Long-COVID are unknown. Long-COVID patients (n=50, age 50 + 17 years, medium post-COVID =68 days) showed that prothrombic markers (endogenous thrombin potential, peak thrombin, etc.) and endothelial activation markers (VWF:Ag, Factor VIII, etc.) and plasma soluble thrombomodulin were significantly elevated vs. controls (nonhospitalized asymptomatic, n=17, mean age 47 ± 12 years), especially in elderly, hospitalized and patients with co-morbidities. Typical acute phase markers (e.g., CRP, neutrophil counts, IL-6) were normal. Endotheliopathy assays (e.g., VWF) correlated inversely with the 6-Minute Walk Test.

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Newsletter Issue 95, August 9, 2021:

  • Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. 7/28/21. Bergwerk M. N Engl J Med.
    At the largest Israeli medical center, healthcare workers with COVID-19 exposure or symptoms underwent extensive evaluations from 1/20/21 – 4/28/21 to investigate infectivity and breakthrough infections. Breakthrough cases with neutralizing antibody (nAb) titers within a week before documented infection were matched with 4-5 uninfected controls. Among 1,497 healthcare workers fully vaccinated with BNT162b2 for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented (0.4%). Eighty-five percent were B.1.1.7. (Alpha). Most were asymptomatic or mild, yet 19 had persistent symptoms at 6 weeks. nAb titers during the peri-infection period were lower in patients than in controls (ratio, 0.36). Higher nAb levels were associated with lower viral load. No secondary infections were documented. In all 37 patients for whom the suspected source of infection was identified, it was an unvaccinated person, mostly household members.
  • Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. 7/21/21. Bernal JL. N Engl J Med.
    British investigators used a test-negative case-control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant alpha variant (B.1.1.7) over the period that the delta variant began circulating. With the Pfizer vaccine, the effectiveness of two doses was 93.7% among persons with the alpha variant (N=14,837) and 88.0% among those with the delta variant (N=4,272). Data ran up to 5/16/21. With the AstraZeneca vaccine, the effectiveness of two doses was 74.5% among persons with the alpha variant and 67.0% among those with the delta variant. Effectiveness was only 31% for alpha and 49% for delta after just one dose of either vaccine.
  • Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination. 7/26/21. Schmidt T. Nature Med.
    Heterologous priming with a single dose of the AstraZeneca ChAdOx1 nCoV-19 adeno vector vaccine followed by boosting with either the Pfizer or the Moderna mRNA vaccine is currently recommended in Germany. This study compares multiple aspects of immune response (spike-specific IgG, neutralizing antibodies, spike-specific CD4 T cells, and spike-specific CD8 T cell levels) in subjects receiving this heterologous regimen to the responses in subjects receiving two-dose homologous regimens with AstraZeneca vaccine or with an mRNA vaccine. All regimens were similarly well tolerated. Immune response levels were significantly higher with the heterologous regimens than after a two-dose AstraZeneca regimen and higher or comparable in magnitude to homologous mRNA vaccine regimens.
    SAB Comment: Heterologous vaccine strategies were initially pioneered in HIV and Ebola. Currently, at least 5 EU countries have recommended it as a means of producing fewer side effects than a two-dose AstraZeneca regimen.
  • Efficacy and safety of remdesivir in hospitalised COVID-19 patients: a systematic review and meta-analysis. 7/31/21. Angamo MT. Infection.
    This is a meticulous review of pooled data taken from 4 RCTs and 3 controlled observational trials covering a 12-month span starting December 2019 comparing remdesivir treatment to placebo or standard care. Remdesivir significantly accelerated recovery at day 7 (21%) and day 14 (29%), lowered the incidence of high oxygen flow therapy by 27% and mechanical ventilation by 47%, and decreased mortality on day 14 by 39% but not on day 28. Serious adverse effects were less common in the remdesivir group and the authors conclude that remdesivir treatment is effective and safe early in SARS-CoV-2 infections.
  • Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients. 8/6/21. Kooistra EJ. Crit Care.
    This prospective observational study from a single Dutch medical center compares the established predictive value of inflammatory biomarkers C-reactive protein (CRP) and procalcitonin (PCT) in identifying secondary bacterial infections in severe COVID-19 patients admitted between March and April 2020. A second patient cohort was treated in their ICU after August 2020 which received dexamethasone with or without a single dose of tocilizumab 8mg/kg IV. Results showed marked blunting of the CRP and PCT response during and a rebound after cessation of immunosuppression which could be falsely interpreted as a signal of secondary infection, while the blunted response may mask ongoing secondary infection.
  • Endothelium-associated biomarkers mid-regional proadrenomedullin and C-terminal proendothelin-1 have good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia: A prospective cohort study. 8/3/21. van Oers JAH. J Crit Care.
    This observational cohort study assessed baseline levels of two inflammatory markers, midregional proadrenomedullin (MR-proADM) and C-terminal proendothelin-1 (CT-proET-1) as predictors of 28-day mortality in 105 critically ill COVID-19 pneumonia patients. The area under the curve for prediction of 28-day mortality for MR-proADM and CT-proET-1 were 0.84 and 0.79 respectively. An MR-proADM level of d≥1.57 nmol/L or a CT-proET-1 level of ≥ 111 pmol/L at baseline were significant predictors for 28-day mortality (HR 6.80 and HR 3.72 respectively) and were significantly better predictors than other, more common, inflammatory markers.
  • Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. 7/30/21. Tummino TA. Science.
    Many drugs are reported to have in vitro activity against SARS-Co-V-2. Some of these “repurposed” drugs including hydroxychloroquine, azithromycin and amiodarone are already in trials. This investigation discovered a shared mechanism of many “repurposed” drugs: phospholipidosis, which is a phospholipid storage disorder induced by cationic amphiphilic drugs. For all 23 drugs tested, development of intracellular phospholipidosis correlated with antiviral “efficacy.” Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis does not reflect specific target-based activities, but is a toxic confound. Early detection of phospholipidosis could eliminate screening artifacts, steering focus on molecules with real potential. The accompanying editorial points out that that “mechanism-informed” strategy for drug repurposing can work (e.g., remdesivir) and may result in clinically useful results. Conversely, repurposing drugs based on hypothesis-free cellular screens “has not yet yielded any effective treatments for COVID-19, nor for any disease.” These latter mass screenings are not shortcuts, but rather costly, scientific “dead-ends.”

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Newsletter Issue 94, July 26, 2021:

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Newsletter Issue 93, July 19, 2021:

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Newsletter Issue 92, July 12, 2021:

  • Risk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study. 7/2/21. Osmanov IM. Eur Respir J.
    This is a study of 518 COVID-19 infected children admitted to a pediatric hospital in Moscow and followed for 5-12 months — the largest follow-up pediatric study to date. Parents were interviewed using an internationally designed and accepted protocol. Average age was 10.4 years (<1-18 years range) and near equal distribution between sexes. Long COVID was found in 24.3% of children. Fatigue and sleep disturbance were the most common complaints followed by loss of smell. Symptoms declined over time. Risk factors for persistent symptoms were patients older than 6 years old and a history of allergic disease. Psycho-social issues were uncommon and no deaths were reported.
  • Efficacy and safety of remdesivir in COVID-19 caused by SARS-CoV-2: a systematic review and meta-analysis. 6/25/21. Singh S. BMJ Open.
    Investigators reviewed and analyzed 4/52 RCTs with a total of 7324 patients to evaluate the efficacy of remdesivir for COVID-19 patients. The results indicated that there is no benefit with mortality rate. A benefit favoring remdesivir over control does exist in terms of rates of clinical improvement and faster time to clinical improvement. No difference was shown in respiratory failure in two (flawed) studies. All outcomes except mortality were influenced by two studies which were riddled with high risk of bias and low quality evidence. In a cost to benefit analysis, remdesivir has a limited role in poor countries.

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SPECIAL EDITION: Newsletter Issue 91, July 7, 2021:

  • Variants of concern are overrepresented among post-vaccination breakthrough infections of SARS-CoV-2 in Washington State. 6/24/21. McEwen AE. Clin Infect Dis.
    In an effort to determine mRNA vaccine efficacy against SARS-CoV-2 variants of concern (VOC), the University of Washington performed genetic sequencing of the SARS-CoV-2 virus on all positive PCR samples between February 23 and April 27, 2021. Of the 5,174 unvaccinated cases, 68% were VOC compared to 100% of the 20 breakthrough cases in vaccinated patients. Most breakthrough cases were symptomatic (~80%) but none were hospitalized. No single VOC was significantly more common in the breakthrough cases compared with unvaccinated cases. This is consistent with previous reports that mRNA vaccines provide excellent protection to all current strains of the virus, though there is a rare VOC breakthrough.
    SAB Comment: As the pandemic continues, more VOC that could be a problem even for vaccinated people may evolve. This emphasizes the importance of the current vaccination effort and world-wide control of the pandemic.
  • The SARS-CoV-2 mRNA vaccine breakthrough infection phenotype includes significant symptoms, live virus shedding, and viral genetic diversity. 6/12/21. Pollett SD. Clin Infect Dis.
    This pilot report from the US Military Health System examined 24 PCR confirmed infections more than 14 days after full Pfizer (92%) and Moderna (8%) vaccination. Sixty-seven percent had no co-morbidities, 63% were health care workers, and 71% were White. Five were asymptomatic, and none required hospitalization; however, symptoms lasted up to 2 weeks and were reported as severe in 3. Viral cultures and complete genomic sequencing were performed in many cases. Strains included wild type as well as variants of concern. Some were shedding live virus 7 days after symptom onset. Authors recommend larger, prospective studies of vaccine breakthrough infections.
    SAB Comment: The CDC recently reported 4,115 cases from 47 states of breakthrough infections in fully vaccinated individuals who were hospitalized or died (mortality 18%) as of 6/21/21. Seventy-six percent were older than 65 years. Twenty-six percent of hospital admissions were not initiated for COVID-19. One hundred forty-two in 750 fatalities (19%) were not attributed to COVID-19. “The number of COVID-19 vaccine breakthrough infections reported to CDC likely are an undercount of all SARS-CoV-2 infections among fully vaccinated persons. National surveillance relies on passive and voluntary reporting, and data might not be complete or representative.”
  • Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. 6/23/21. Kamar N. N Engl J Med.
    This letter documents the humoral antibody response to 3 doses of the Pfizer-BioNTec vaccine in 101 solid organ transplant recipients 97 months post transplant, none of whom have become infected. The second dose was given 30 days after the first, and the third, 60 days after the second. Titers for spike protein antibodies were obtained before the first, second and third doses and one month after the third dose. Before the second dose, only 4 patients had antibodies, increasing to 40% before the third dose. After the third dose, 68% had antibodies. 33 patients (who were older, with a higher degree of immunosuppressive and a lower GFR) presumably remained at risk for infection.
    SAB Comment: Besides antibodies, the immune system has redundant lines of defense including T-cells (e.g., cellular immunity) that may be protective though not easily assessed. We await further “real world” studies on actual numbers and severity of infections in solid organ transplant patients, regardless of antibody levels.
  • Mortality after surgery with SARS-CoV-2 infection in England: a population-wide epidemiological study. 6/21/21. Abbott TEF. IBr J Anaesth.
    This retrospective British NHS database study addresses surgical mortality associated with SARS-CoV-2 from 1/1/2020 to 2/28/2021. Of 2.5 million surgeries, 1.0% of patients died and 1.1% of patients were infected. The mortality was 21% in patients with SARS-CoV-2 and 0.8% in those uninfected (OR 5.7). With elective surgery, 1% were infected, and mortality was 7.1%, compared to 0.1% (OR 25.8). Emergency procedure mortalities were 25.1% compared to 3.4% (OR 5.5). Statistics include data for procedure types and disease severity, and demonstrate the safety of elective procedures, with precautions, in healthy patients with no SARS-CoV-2 history. The authors estimate about one-half of 4.5 million expected surgical procedures were postponed.

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Newsletter Issue 90, June 28, 2021:

  • Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. 6/16/21. Guimarães PO. N Engl J Med.
    This randomized, double-blind, placebo-controlled and industry-sponsored trial (“STOP COVID”) involving 289 hospitalized patients with Covid-19 pneumonia in Brazil showed tofacitinib superior to placebo in reducing the incidence of death or respiratory failure (18 vs 29% – HR 0.63). Overall mortality was 2.8% in the tofacitinib group vs. 5.5% for placebo. Standard therapy (antivirals, glucocorticoids, anticoagulation) was comparable between groups, as were adverse events. This study corroborates the findings of the NIH funded ACTT-2 trial and the value of JAK inhibition for the treatment of Covid-19 pneumonia in patients who are not yet receiving invasive mechanical ventilation.
    SAB Comment: NIH COVID-19 treatment guidelines recommend against the use of JAK inhibitors other than baricitinib for the treatment of COVID-19, except in a clinical trial.
  • Underlying Medical Conditions Associated With Severe COVID-19 Illness Among Children. 6/7/21. Kompaniyets L. JAMA Netw Open.
    A data rich CDC review studying 43,465 children 18 years old and younger hospitalized with COVID-19 infection through January 2021. After a complete description on data retrieval and analysis, results revealed children with diabetes, obesity and those with cardiac anomalies were more commonly hospitalized than previously healthy children. Overall children with any chronic disease were hospitalized 3 times more frequently. Asthma was a risk for severe infection. Children younger than 2 years old and born prematurely were prone to hospitalization. Finally, Hispanic and Black children suffered severe infection more frequently than Whites.
  • Awake prone positioning in patients with hypoxemic respiratory failure due to COVID-19: the PROFLO multicenter randomized clinical trial. 6/15/21. Rosén J. Crit Care.
    In this small, randomized, controlled study from Sweden, the efficacy of awake prone positioning (APP) was evaluated in 75 patients with COVID-19 in moderate to severe respiratory failure. Compared with standard care, implementation of a 16 hour/day protocol for APP increased the duration of prone positioning but did not affect the rate of intubation. The study was halted early due to futility. When secondary outcomes were analyzed, the only difference between groups was a reduction of pressure sores in the APP group.
    SAB Comment: Though small, this is a well-designed prospective and randomized trial of APP in COVID-19 patients and confirms retrospective studies that question the efficacy of APP.
  • Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis. 6/23/21. Verweij PE. Intensive Care Med.
    This is a thorough and lengthy review by an international group of 28 experts prompted by the relatively high incidence of COVID-associated pulmonary aspergillosis (CAPA) seen in severely ill COVID-19 patients. The prevalence of CAPA varied between 0 and 33%. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL-positive patients, while the authors recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients.

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Newsletter Issue 89, June 21, 2021:

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Newsletter Issue 88, June 14, 2021:

  • The year in review: mechanical ventilation during the first year of the COVID-19 pandemic. 5/7/21. Kallet R. Respiratory Care.
    This thoughtful, well-written, and thorough narrative review of COVID-19 ARDS (C-ARDS) includes 201 references and covers the evolution of best respiratory care practices to date. The overarching question is whether C-ARDS is significantly different from ARDS. Longstanding debates regarding phenotypes and taxonomy are discussed. The evolution of C-ARDS management and physiologic evidence for respiratory care are presented. Topics include phenotypic differences, mechanisms of hypoxia, noninvasive ventilation, timing of intubation, ventilation practices, PEEP, pathologic and radiologic findings, self-inflicted lung injury, lung mechanics, and cross infection. The author concludes that from a respiratory management perspective, C-ARDS differs little from ARDS of other etiologies.
  • Closed-Loop Versus Conventional Mechanical Ventilation in COVID-19 ARDS. 6/8/21. Wendel Garcia PD. J Intensive Care Med.
    Closed-Loop (C-Loop) is an automated/autopilot ventilation mode which integrates key patient respiratory parameters into automatic ventilator adjustments that provide a high degree of lung protective ventilation (LPV) and result in a reduced frequency of hypoxemic episodes. This randomized, prospective study compares ventilator support for COVID-19 ARDS patients using either C-Loop (n= 23) or conventional mechanical ventilation (Con-V, n= 17). The C-Loop group showed a statistically significant improvement in the dynamic mechanical power necessary, higher total lung compliance and PF ratio and lowered VD/ VT, PEEP, and Fio2 while maintaining adequate PaO2. This suggests that C-Loop ventilation may decrease the risk of ventilator induced lung injury while reducing the number of necessary human ventilator adjustments. The paper describes an impressive tool with a convincing radar graph for its practical utility but provides limited outcome data.
    SAB Comment: This is a small, futuristic, innovative, and intriguing pilot study of the feasibility of an automated ventilator-adjustment device to better provide lung protective ventilation.
  • Rehabilitation post-COVID-19: cross-sectional observations using the Stanford Hall remote assessment tool. 5/27/21. O’Sullivan O. BMJ Mil Health.
    These authors report the development and use (April to Nov 2020) of a video teleconferencing tool to evaluate rehabilitation needs for patients with ongoing post-COVID-19 symptoms and included patients with COVID syndromes who never had a confirmatory COVID-19 viral test. They found that the initial severity of symptoms did not predict the level of ongoing disability. They conclude that post-COVID-19 symptoms should be considered in all patients, regardless of the acute illness severity and whether they have had laboratory confirmation. They find that a significant proportion of patients require assessment and management, with symptoms such as shortness of breath, fatigue, and mood disorders impacting activities of daily living and return to work.
  • Hospitalization of Adolescents Aged 12-17 Years with Laboratory-Confirmed COVID-19 – COVID-NET, 14 States, March 1, 2020-April 24, 2021. 6/10/21. Havers FP. MMWR Morb Mortal Wkly Rep.
    In the US, “Most COVID-19-associated hospitalizations occur in adults, but severe disease occurs in all age groups, including adolescents aged 12–17 years. COVID-19 adolescent hospitalization rates from COVID-NET peaked at 2.1 per 100,000 in early January 2021, declined to 0.6 in mid-March, and rose to 1.3 in April. Among hospitalized adolescents, nearly one third required intensive care unit admission, and 5% required invasive mechanical ventilation; no associated deaths occurred. Recent increased hospitalization rates in spring 2021 and potential for severe disease reinforce the importance of continued COVID-19 prevention measures, including vaccination and correct and consistent mask wearing among persons not fully vaccinated or when required.” –MMWR Summary

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Newsletter Issue 87, June 7, 2021:

  • COVID-19 Vaccine Breakthrough Infections Reported to CDC – United States, January 1-April 30, 2021. 5/27/21. CDC COVID-19 Vaccine Breakthrough Case Investigations Team. MMWR Morb Mortal Wkly Rep.
    In this brief weekly report, the CDC provides an important glimpse into the post-vaccination scenario in the US. During the 4 months ending April 30, 2021, a total of 10,262 breakthrough infections have been reported. Of those, 63% were female, median age 58 years, of which 27% were asymptomatic, 10% hospitalized and 2% died. By the end of the study, although 100 million individuals had been vaccinated in the US, SARS-CoV-2 transmission was still in full swing with 355,000 new cases daily. Variants were detected at a similar rate among vaccinated and non-vaccinated patients. Underreporting of asymptomatic cases and limited RNA sequencing represent current and future limitations to these statistics. Notably, beginning May 1, 2021, the CDC transitioned from monitoring all reported COVID-19 vaccine breakthrough infections to investigating only those among patients who are hospitalized. Monthly reports and additional information on vaccination breakthrough initiatives by the CDC can be found here.
  • Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. 5/27/21. Frenck RW Jr. N Engl J Med.
    The BNT162b2 COVID-19 RNA vaccine (Manufacturer: Pfizer, Inc., and BioNTech) was proven effective with few side effects in 12-15 year old recipients (n=1131) who received 2 injections 21 days apart versus controls (n=1129). Among participants without evidence of previous SARS-CoV-2 infection, no COVID-19 cases with an onset of 7 or more days after dose 2 were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients. The observed vaccine efficacy was 100% (95% CI, 75.3 to 100).
  • The characteristics and outcomes of critically Ill patients with COVID-19 who received systemic thrombolysis for presumed pulmonary embolism: an observational study. 5/9/21. So M. J Thromb Thrombolysis.
    This article reviews the clinical outcome of the use of systemic tissue plasminogen activator (tPA) for suspected pulmonary embolism (PE) in 57 critically ill COVID-19 patients from 5 hospitals in NYC during March and April 2020. All of the patients were suspected to have pulmonary embolization based upon echocardiography (16%) or clinical findings but were too unstable to have CT confirmation. Forty-nine percent demonstrated short-term improvement with tPA. However, 89% died in the hospital.
    SAB Comment: This study is the largest cohort reported that we have seen for this problem, and demonstrates the poor outcomes of patients suspected of PE with or without tPA.
  • Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort. 5/26/21. Wendel Garcia PD. Crit Care.
    Propensity matching was performed on an initial group of 1,421 COVID-19 ARDS patients from the large European RISC-19-ICU cohort resulting in propensity matched patients in cohorts treated initially in the ICU with standard O2 therapy (SOT) (n=85), high-flow oxygen therapy (HFNC) (n=87), non-invasive ventilation (NIV) (n=87) and invasive mechanical ventilation (IMV) (n=92). The ICU intubation rate was lower in patients initially supported with HFNC and NIV compared to those who received SOT. Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). The authors recommend a closely observed trial of HFNC for ICU patients not immediately requiring IMV.
    SAB Comment: This retrospective analysis may best be thought of as a recommendation to perform an RCT to support or challenge these conclusions.

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Newsletter Issue 86, June 2, 2021:

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Newsletter Issue 85, May 24, 2021:

  • Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. 5/17/21. RECOVERY Collaborative Group. Lancet.
    In this randomized open-label study, 5795 hospitalized patients received high-titer convalescent plasma (CP) plus usual care and 5763 received usual care alone in 177 UK National Health Service hospitals. Ninety-two percent received corticosteroids. The study was halted prematurely, as there were no significant differences between groups in all-cause 28-day mortality (24%), progression to invasive ventilation (12-13%), renal replacement therapy (4%) or the proportion discharged from hospital within 28 days (66%). Mean age was 63, nearly 2/3 were male, and 77% were white. Median number of days since symptom onset was 9. Only 5% required mechanical ventilation at randomization. A well-written editorial reviewing this study and findings of other studies of CP can be found here.
    SAB Comment: The RECOVERY trial includes the largest randomized study thus far of CP therapy for COVID-19. Although some retrospective observational studies of CP were encouraging, randomized controlled studies have not confirmed benefit. Questions remain about whether the average timing of CP therapy in this study was beyond the window of potential efficacy and whether selected patients may benefit from CP, particularly those with immune deficiencies.
  • A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes. 5/11/21. Guo Y. Nature.
    The current monoclonal antibodies (mAb) from Regeneron and Lilly are based on the Hunan strain Spike sequence present prior to the emergence of mutants. Chinese scientists now report the development of a mAb called P4A1 that inhibits the Spike Receptor Binding Motif of the Spike Receptor-Binding Domain and acts against wild type and mutant Spike proteins. Also, P4A1 was engineered for safety, to extend its half-life and to reduce risk for Antibody-Dependent Enhancement of infection. In a rhesus monkey COVID model, a single infusion resulted in complete viral clearance. These data suggest P4A1’s potential against SARS-CoV-2 related diseases.
  • Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study. 5/17/21. Drake TM. Lancet Rheumatol.
    This prospective, multicenter cohort study shows convincingly that patients who take NSAIDs before and in the early stages of a SARS-CoV-2 infection are not at a higher risk of dying or experiencing more severe disease. Using a proven data mining protocol, 72,179 hospitalized patients in 255 hospitals in the UK, with confirmed COVID-19, were enrolled and analyzed. Of those patients, 4,211 or 5.8% used NSAIDS (but not aspirin) before their illness. Propensity score matching resulted in balanced, well matched treatment groups and matched odds ratios for mortality, ICU admission, invasive ventilation, acute kidney injury, among others, showed no statistical difference. The authors urge policy makers to review advice issued early in the course of the pandemic regarding the use of NSAIDs and disease severity.

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Newsletter Issue 84, May 17, 2021:

  • Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. 5/8/21. Haas EJ. Lancet.
    This is a prospective, longitudinal cohort study of 83 severe COVID-19 patients (admitted February and March). This data-rich study demonstrates graphically and convincingly the effectiveness of 2 doses of the Pfizer-BioNTech vaccine against a range of SARS-CoV-2 outcomes in Israel using surveillance data from the first 4 months of the vaccination campaign which began in December 2020. By April 3, 2021, 72% of 6.5 million people over age 16 had been vaccinated and the incidence rate dropped from 91.5 in unvaccinated individuals to 3.1 per 100,000 person-days in those fully vaccinated. Effectiveness against critical illness and death was 97.5% and 96.7% respectively. Widespread testing revealed effectiveness of the vaccine against the predominant B.1.1.7. (British) variant. Aspects of the Israeli health care system, concomitant lockdown measures as well as cultural and ethnic influences vis-à-vis the goal of achieving herd immunity are discussed. The Israeli Ministry of Health and Pfizer collaborated on this project.
  • Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. 5/5/21. Abu-Raddad LJ. New Engl J.
    This letter to the editor reports effectiveness of the Pfizer-BioNTech vaccine against UK and S. African variants that represented 50% and 44.5% of infections, respectively, in the Qatari research cohort community at the time of study. Estimated vaccine effectiveness against any documented B.1.1.7 variant infection was 89.5% (95% CI 85.9-92.3) and 75% against B.1.351 (CI (70.5–78.9) at 14 or more days after second doses in nearly 400,000 people. Effectiveness against severe, or fatal disease due to any SARS-CoV-2 variant was 97.4% (95% CI, 92.2-99.5). Although effectiveness against the B.1.351 variant was ~20% below previous reports from the clinical trial or real-world conditions in Israel and the US, protection from hospitalization or death was >90%. Effectiveness was found to be significantly improved after second dose.
  • SARS-CoV-2 vaccine and thrombosis: Expert opinions. 5/4/21. Elalamy I. Thromb Haemost.
    This article reviews the status of 4 COVID-19 vaccines (Pfizer, Moderna, Johnson & Johnson and AstraZeneca) with respect to thrombosis from an international viewpoint. Not only is it current and timely, but reviews:
    1. What is known about the pathophysiology;
    2. Goes over the risk/benefit ratio of vaccination;
    3. What to do if there is a concern for thrombosis after vaccination; and
    4. What not to do.

    Overall, this comprehensive article focuses on clinically relevant issues in a concrete fashion.

  • Association of Maternal SARS-CoV-2 Infection in Pregnancy With Neonatal Outcomes. 4/29/21. Norman M. JAMA.
    To determine the outcome in newborn infants of mothers testing positive for SARS-CoV-2 in pregnancy, this prospective cohort study looked at the outcomes of 88,159 infants born in Sweden during the first 10 months of the pandemic. After matching infants by maternal characteristics, the 2,323 infants of SARS-CoV-2-positive mothers were found to have more respiratory problems (2.8% vs 2.0%, OR 1.42), mostly explained by a more preterm birth. Mortality, breastfeeding rates at discharge, length of stay in neonatal care, hypoxic-ischemic encephalopathy, meconium aspiration, pneumonia, sepsis, and hypoglycemia did not differ significantly between the two groups. Twenty-one (0.9%) of the 2,323 infants of SARS-CoV-2-positive mothers had positive PCR tests, most with no morbidity and none with pneumonia. View a pertinent accompanying editorial here.

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Newsletter Issue 83, May 10, 2021:

  • 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. 5/8/21. Wu X. Lancet Respir Med.
    This is a prospective, longitudinal cohort study from China of 83 severe COVID-19 patients (admitted February and March 2020, so none received glucocorticoids) who did not require IMV, yet still had 29-day hospital stays. Patients with HTN, DM, CVD, cancer, any pulmonary disease or tobacco use had been excluded. At 3-, 6-, 9- and 12-months post admission, they underwent pulmonary function testing, documenting abnormalities with gradual improvement even after 9 months. Radiological abnormalities (24%) and DLCO less than 80% of predicted (33%) persisted at 12 months despite near normal lung volumes, 6M walk and dyspnea assessment.
    SAB Comment: These results indicate that even previously healthy patients who have recovered from COVID-19 may warrant pulmonary evaluation and consideration of timing regarding elective surgery.
  • Mortality after In-Hospital Cardiac Arrest in Patients with COVID-19: A Systematic Review and Meta-Analysis. 5/8/21. Ippolito M. Resuscitation.
    This is a well-performed meta-analysis of resuscitation (CPR) following in-hospital cardiac arrest, confirming bleak survival statistics. The article includes an interesting debate regarding universal do not resuscitate orders for COVID-19 arrest resuscitation and comparison with ICU resuscitation of comparably ill patients without COVID-19. The authors suggest further discussion and data analysis is necessary following improved results for in-hospital cardiac arrest (IHCA) over time. Conclusion: Although one of three COVID-19 patients undergoing IHCA may achieve return of spontaneous circulation, 90% are not expected to survive 30 days or to hospital discharge.
  • Trends in Patient Characteristics and COVID-19 In-Hospital Mortality in the United States During the COVID-19 Pandemic. 5/3/21. Roth GA. JAMA Netw Open.
    This analysis of mortality trends in the US among 20,736 patients in 107 hospitals in 31 states comes from the American Heart Association COVID-19 cardiovascular disease registry. In comparison with March/April patients, the odds ratio of mortality decreased approximately one-third later in the year, after adjusting for age, sex, medical history, and COVID-19 severity. ICU length of stay, use of mechanical ventilation, and mortality in age groups over 50 decreased, although mortality remained highly associated with age. Use of corticosteroids and remdesivir increased. Reasons and other independent risk factors are discussed.
  • Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. 5/2/21. RECOVERY Collaborative Group. Lancet.
    This long-awaited trial assessing the effectiveness of tocilizumab differentiated itself from several earlier attempts in two important aspects:
    1. It enrolled 4,116 of 21,550 adults at 131 sites in the UK as part of the RECOVERY trial between April 23, 2020 and January 24, 2021 and is therefore adequately powered and statistically sound.
    2. It demonstrated a small but significant benefit across a spectrum of disease severity and various degrees of respiratory support. Results included an improvement in mortality from 35% to 31% (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028) and an impressive drop in median time to being discharged from more than 28 days to 19 days.

    In addition, patients who were not receiving invasive mechanical ventilation at randomization were less likely to progress to invasive mechanical ventilation or death. An accompanying editorial that addresses the still unacceptably high mortality figures and the urgent need for additional therapies can be found here.

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Newsletter Issue 82, May 3, 2021:

  • Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. 4/21/21. Shimabukuro TT. N Engl J Med.
    Early results of mRNA COVID-19 vaccination of pregnant women between 12/14/2020 and 2/28/2021 were obtained from v-safe after-vaccination health checker, v-safe pregnancy registry (patients enrolled by identification through v-safe participation), and VAERS, the vaccine adverse event reporting system. Comparison was to nonpregnant v-safe participants and historical pregnancy outcome statistics. The 35,691 pregnant v-safe participants (94% healthcare workers) reported reactions to vaccination similar to those who were not pregnant. In the registry, 827 pregnancies were completed, 86% with a live birth, and 9% with preterm births. There were 104 spontaneous abortions among the 92 preconception and 1132 first trimester participants. These frequencies are comparable to historical rates. The most common VAERS pregnancy report was spontaneous abortion, reported in 46 patients out of at least 35,691 (0.16%), a rate far lower than published, probably because of underreporting. Although more longitudinal follow-up is necessary, no problems regarding the administration of mRNA COVID-19 vaccine during pregnancy were revealed.
  • Hospital-Level Variation in Death for Critically Ill Patients with COVID-19. 4/23/21. Churpek MM. Am J Respir Crit Care Med.
    This multicenter cohort study utilized the STOP-COVID database to explore the wide variation in published mortality rates for critically ill COVID-19 patients. Data were evaluated on 4019 adult ICU patients admitted to 70 US hospitals between March-June 2020. Thirty-eight percent of patients died within 28 days, with an unadjusted interhospital mortality range of 12-91% (OR 2.06). After mixed-effect regression adjustment for patient- and hospital-level domains, the interhospital range attenuated to 32-44% (OR 1.22). In individual patients, acute physiology contributed 49%, demographics, comorbidities and socioeconomic status 32%, hospital strain and quality 17%, and treatments 3% to mortality risk. The authors emphasized that lower socioeconomic status of the community served by the hospital (characterized by a high percentage of patients who traveled more than 45 min to get to work) is an important contributor to interhospital variability, suggesting that COVID-19 exacerbates disparities in US healthcare. Individual mortality is also impacted by hospital ICU-bed capacity and strain, but treatments had the least impact on outcome variability. [Readers should note that the study reflects an early stage of the pandemic, prior to the positive evidence of steroid therapy on outcome in ventilated patients.]

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Newsletter Issue 81, April 28, 2021:

SPECIAL EDITION: Open Critical Care COVID-19 Resources Hub

This is a comprehensive, well-organized, web-based compendium of COVID-19 care and epidemic response guidelines along with learning modules. It summarizes and provides links to COVID-19-care recommendations from the WHO, CDC, NIH, IDSA, SCCM, NEJM, UpToDate, and Partners In Health, among others. The site is led by the UCSF Center for Health Equity in Surgery & Anesthesia with support of the United States Agency for International Development (USAID) and STAR Program, and aims to provide healthcare workers with coordinated, high-quality information and learning tools regarding the care of critically ill COVID-19 patients that are open-access and continuously updated. Each section is also available in Spanish, and some material is available in multiple additional languages.

Sections include the following, along with many more resources:

  • Adaptable (though not fully peer-reviewed) protocols for the management of COVID-19 patients was created through a collaboration of Brigham & Women’s Hospital, UCSF’s Institute for Global Health Services, Partners in Health, and Open Critical Care. Content is relevant to all practice settings. Topics include testing, infection prevention and control, PPE, patient assessment, outpatient, inpatient and critical care management, obstetrics, pediatrics, and post-COVID care, among others. Features include frequent updates and an “Ask an Expert” chat service. The Spanish language version is here.
  • COVID-19 Guidelines Dashboard: This reference tool provides practitioners a quick, intuitively navigable look at current care and pharmacotherapy guidelines from leading healthcare authorities. Stop-light color coding indicates the level of concordance among authorities for each therapy. Date lines and hyperlinked references are included. It promises to be expandable and updated frequently. The Spanish language version is available here.
  • Respiratory Care Pocket Card: This link downloads the latest version of a printable, concise summary of oxygen and ventilator therapies, a collaboration of multiple institutions including the UCSF Anesthesia Division of Global Health Equity and USAID. The easy-to-use table format reviews commonly required respiratory care management including non-invasive forms of oxygen delivery, how to calculate ideal body weight, key ventilator modes and settings, how to assess and treat ventilator/patient dyssynchrony, and much more. Relevant references and links are embedded, many (including the card itself) via QR codes that may be useful after printing. The Spanish language version is available here.
  • Oxygen Supply and Demand Calculator: This valuable tool for clinicians and administrators balances individual patient use with facility requirements to help maintain a safe O2 supply. It provides an estimate of total facility hourly oxygen consumption and calculates reserves after the user provides the number of hypoxic patients, modes of treatment, and a few details about the oxygen supply infrastructure. Imputed individual patient PO2, PF ratio, and the nonlinear SpO2:FiO2 ratio can be estimated by selecting a patient’s FiO2 and O2 saturation. The Spanish language version is available here.

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Newsletter Issue 80, April 26, 2021:

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Newsletter Issue 79, April 21, 2021:

SPECIAL EDITION: Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)
Robert N. Sladen, MBChB, FCCM on behalf of the IARS Scientific Advisory Board

In recent weeks a great deal of attention has been directed to cases, some of them fatal, of major venous thrombosis associated with thrombocytopenia occurring within 1-3 weeks after initial immunization with the AstraZeneca modified adenovirus vaccine for COVID-19. Although extremely rare relative to the large numbers vaccinated, cases have been more prominent in younger (less than 50 years old), previously healthy patients in Germany and the United Kingdom. In the United States, six similar cases have been reported after immunization with the Johnson & Johnson modified adenovirus vaccine, which has been put on pause pending investigation by the FDA.

In an observational study published in the New England Journal of Medicine (NEJM) on April 16, Dr. Marie Scully and her colleagues report finding pathologic antibodies to platelet factor 4 (PF4) in 22 of 23 patients who suffered thromboembolism and thrombocytopenia after receiving the AstraZeneca vaccine1. Patients also had highly elevated levels of D-dimer with low or normal fibrinogen. The unexpected finding of anti-PF4 antibodies is identical to that of heparin-induced thrombocytopenia (HIT), but in the absence of administered heparin, and is referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). The mechanism of induction of anti-PF4 antibodies is as yet unknown.  As with HIT, use of heparin to treat the thromboses or platelet transfusion for thrombocytopenia worsens thrombosis. Instead, the authors recommend avoidance of platelet transfusions together with a combination of nonheparin anticoagulation and intravenous immunoglobulin and consideration for high-dose glucocorticoids. If there is evidence of thrombosis and thrombocytopenia with elevated D-dimer (>4000 FEU), low or normal fibrinogen and no evidence of an alternate diagnosis, they advocate early treatment as above pending results of anti-PF4 antibody testing by HIT ELISA testing or functional HIT assay.

In an accompanying editorial2, Drs. Cines and Bussel review this and two other reports previously published in the NEJM3,4, a total of 39 patients with cerebral venous sinus, portal, splanchnic or hepatic vein thrombosis who had a 40% mortality. At the current time, a total of 223 possible cases of cerebral venous sinus or splanchnic vein thrombosis have been reported among 34 million recipients of the AstraZeneca vaccine, but not all of these cases have been subjected to rigorous review or tested for anti-PF4 antibodies. The authors point out that we do not yet know how the vaccine elicits the production of anti-PF4 antibodies, nor whether these antibodies are directly responsible for platelet activation and thrombus formation. Anti-PF4 antibodies are detected in 25-50% of patients after cardiovascular surgery, but the incidence of HIT is very uncommon and even then is rarely associated with cerebral venous sinus or abdominal venous thrombosis. The low prevalence of this serious complication must be weighed against the benefits of preventing COVID-19 in the larger population.

On April 16, the American Society of Hematology (ASH) published new guidelines, which will be regularly updated, on the diagnosis and recommended therapy of VITT5. Their recommendation is that urgent evaluation for VITT should be commenced on patients with severe, recurrent or persistent symptoms of headache, abdominal pain, nausea and vomiting, vision changes, shortness of breath, and/or leg pain and swelling that have an onset 4-20 days after vaccination. While VITT has not been reported following the mRNA Pfizer or Moderna vaccines, the ASH recommends immediate evaluation for VITT in any patient presenting with this constellation of symptoms following any COVID-19 vaccination. If initial evaluation reveals thrombocytopenia or thrombosis, an urgent hematology consultation is recommended with avoidance of heparin until VITT has been ruled out.

  1. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. April 2021.
  2. Cines DB, Bussel JB. SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia. N Engl J Med. April 2021.
  3. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. April 2021.
  4. Schultz NH, Sorvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. April 2021.
  5. Bussell J, Connors JM, DCines DB, Dunbar CE, Michaelis LC, Kreuziger LB, Lee AYY, Pabinger I. Vaccine-induced Immune Thrombotic Thrombocytopenia: Frequently Asked Questions. American Society of Hematology. Updated April 19, 2021. Accessed April 21, 2021.

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Newsletter Issue 78, April 19, 2021:

  • Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. 4/12/21. Ramakrishnan S. Lancet Respir Med.
    This is a prospective, randomized, open-label, phase-2, parallel-group, age-stratified, 146-patient UK study from July 16 to December 2, 2020 testing inhaled budesonide within 7 days of early symptom development versus standard care. Participants were self-monitored (temperature, pulse oximetry), contacted daily to record symptoms (O2 saturation and temperature), and intermittently self-collected nasopharyngeal swab specimens for analysis. Primary endpoints compared urgent care and emergency room visits and hospitalizations for worsening symptoms, which occurred in 1% of budesonide treated participants, and 14% of the usual care treated group. The study was terminated early with positive results for budesonide inhalant use. Authors concluded that budesonide was effective in treating early COVID-19 infection, could be applicable to global healthcare systems, and that further validation was required.
  • Editorial: Early treatment with inhaled budesonide to prevent clinical deterioration in patients with COVID-19. 4/12/21. Agusti A. Lancet Respir Med.
    This editorial, accompanying the article above, gives perspective to the study and discusses the implications of terminating the study early. The rationale for and use of budesonide (and potentially other inhaled corticosteroids) encourages further trials to confirm the value of this readily available therapy, with significant implications for a cost-effective and easily accessible disease mitigation strategy that could be used globally.
  • Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation. 4/12/21. Grandone E. J Thromb Thrombolysis.
    Prior data has been conflicting with the utility of prophylactic low-molecular weight heparin (LMWH) with COVID-19. This group from Padua retrospectively examined the mortality of 264 non-ventilated inpatients with COVID-19 with respect to the prophylactic use of LMWH enoxaparin. One hundred fifty-six patients (87.7%) received standard LMWH prophylaxis during hospitalization. LMWH was significantly and independently associated with a reduction in mortality in these patients, (OR 0.31, 95% CI 0.13–0.85), as compared to patients who did not receive anticoagulation. Although transfusion or bleeding complications were not higher in these patients, the number of transfusions were significantly and independently associated with mortality. The median fatalities age was 80.5 years. These data suggest that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

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Newsletter Issue 77, April 14, 2021:

  • 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. 4/6/21. Taquet M. Lancet Psychiatry.
    This study provides a rich source of data covering a multitude of neurological and psychiatric symptoms in the wake of COVID-19. Using anonymized records from 62, mostly US healthcare organizations, from 3 patient cohorts, one with COVID-19 and two with other contemporaneous illnesses, the authors identify a COVID-specific incidence of neurologic and psychiatric diagnoses of 34% overall, with 13% receiving their first such diagnosis. They convincingly show a link to severity of illness with an incidence of 46% among all patients admitted to ICUs and to a diagnosis of delirium and encephalopathy where the overall incidence rose to 62%. The long-term impact of prolonged recovery due to neurological or psychiatric sequelae of COVID-19 represents a global public health challenge.
  • Secondary Bacterial Pneumonias and Bloodstream Infections in Patients Hospitalized with COVID-19. 4/6/21. Adelman MW. Ann Am Thorac Soc.
    These authors examined the secondary bacterial pneumonias and bloodstream infections (BSI) in 774 patients hospitalized with COVID-19 from February to May 2020. The most common bacteria grown was Staphylococcus aureus. Mortality did not differ between intubated patients with an identified bacterial respiratory pathogen and those without. Overall, mortality was 50% in patients with BSI versus 13.8% without (p<0.0001). These results suggest that hospitalization and central lines are more important than are COVID-19-specific effects in conferring susceptibility to specific pathogens. BSIs in their cohort were also largely related to risk factors, especially central lines, and pathogens associated with hospitalization and did not appear significantly different from the non-COVID data.
  • Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic. 4/6/21. Belay ED. JAMA Pediatr.
    A Center for Disease Control study of patients younger than 21 years old presenting with multisystem inflammatory syndrome in children demonstrating that, although rare (1733 patients countrywide), the presenting symptoms were constant including a rash and conjunctival hyperemia. Half of the affected patients progressed to hypotension and intensive care. These patients tended to be the older of the age range. Most patients were either Hispanic or Black with a median age of 9. The good news was a mortality of only 1.4%.

View the full issue.

Robert N. Sladen, MBChB, FCCM on behalf of the IARS Scientific Advisory Board

One of the most challenging yet enigmatic aspects of the COVID-19 pandemic is the increasing recognition of prolonged impairment of functional capacity for weeks or months after the initial illness. Like many a “new” entity, it is categorized by a plethora of descriptors, including Long COVID, Long-haul COVID, post-acute COVID-19 Syndrome (PACS) or post-acute sequelae of SARS-CoV-2 infection (PASC). Others simply describe “persistent poor health” or “long-term symptoms.”

Early in the pandemic information on “long-haulers” was spread via social media in the lay community who often met with skepticism from their primary care providers1. Self-reporting by respected physicians has changed attitudes,2, 3 together with published case reports and multiple retrospective studies. Reports from Italy and China revealed symptoms in nearly 90% of discharged hospitalized patients at 60 days4 and 75% at six months,5 but it is now recognized that these symptoms may occur in up to 30% of nonhospitalized patients.6-8 No association has been found between persistent respiratory symptoms in COVID-19 survivors and initial disease severity.9

Reported symptoms run the entire gamut of pathophysiology, the most prominent being chronic fatigue (similar to myalgic encephalomyelitis ME/CFS10), “brain fog,” insomnia, depression, altered mood, dyspnea on exertion, cardiac arrhythmias, anosmia, tinnitus and alopecia among others.11 Physician-sufferers have drawn attention to a myriad chronic or relapsing conditions, including myocarditis, thromboembolic disease, new onset diabetes, thyroiditis and allergies, and autonomic dysfunction such as postural orthostatic tachycardia syndrome (POTS).12

In the US, there is increasing recognition of the impact of Long COVID on healthcare and many clinics have opened to provide support for patients. In May 2020, Mount Sinai Medical Center opened its Center for Post-COVID Care,13 and others have followed. In the United Kingdom, the National Health Service has posted a list of common symptoms14 and provides considerable supportive information on “Your COVID Recovery” on its website. Recently, the Centers for Disease Control (CDC) held a webinar on Clinician Experience with Post-Acute COVID-19 Care.15

Many questions regarding the etiology of Long COVID remain. One of the most perplexing aspects is that many patients with Long COVID have had very mild or even asymptomatic infection.6, 7 Why do some patients develop it and others do not? A large study based on a mobile app suggests that early multisystem symptoms, older age and female sex are predictors of Long COVID.16 Could some long-term symptoms simply represent the lingering physical effects of severe illness and multiorgan injury17 and their psychological consequences such as postintensive care syndrome or PTSD?18, 19 How might these differ from long-term effects after SARS or MERS20 or other historic influenza epidemics?21 Could they be due to persistence of a host viral reservoir even if SARS-CoV-2 testing is negative, or viral fragments that stimulate a persistent aberrant auto-immune response?

A host of published studies have examined aspects of Long COVID, including respiratory, neurologic, auditory and other manifestations. Some even tie in previously unclear syndromes such as POTS.22 Most recently, an extraordinarily comprehensive multidisciplinary review was published in Nature Medicine.11 It provides extensive discussion on available evidence and knowledge for every organ system, a list of relevant studies and publications and also a series of simple, clear graphics that provide an easily understandable overview of the problem. On a practical level, there is increasing awareness that COVID-19 survivors may need ongoing medical and community support, especially in the light of stigma, discrimination, depression and PTSD, akin to cancer survivors.23, 24  Support groups and digital communities for sufferers of Long COVID are forming on social media.25 The UK National Institute for Health and Care Excellence (NICE) has established guidelines for managing the long-term effects of COVID-19.26 The World Health Organization (WHO) has called upon countries to offer more rehabilitation and has developed a clinical platform case report form for “post COVID-19 condition.”27

A number of large-scale research endeavors are being developed to explore Long COVID. The NIH recently announced a $1.15 billion initiative to study PASC.28 In the UK, the Post-Hospitalization COVID Study (PHOSP-COVID) is being led by a national consortium to gather long-term prospective data on 10,000 patients after hospital discharge.29 A 42-country multinational open access study linked to the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) is being developed to specifically focus on the long-term consequences of COVID-19.30

In sum, there is still much to be learned about the long-lasting effects of COVID-19. What has become abundantly clear is that the personal and public health impact of Long COVID will linger long after the acute pandemic has subsided.


  1. Editorial. Long COVID: let patients help define long-lasting COVID symptoms. Nature. 2020;586:170.
  2. Garner P. Paul Garner: For 7 weeks I have been through a roller coaster of ill health, extreme emotions, and utter exhaustion. thebmjopinion. 2020.
  3. Garner P. Paul Garner: on his recovery from long covid. thebmjopinion. 2021.
  4. Carfi A, Bernabei R, Landi F. Gemelli Against COVID-19 Post Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020;324:603.
  5. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397:220-32.
  6. Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers”. Ann Clin Transl Neurol. 2021.
  7. Jacobson KB, Rao M, Bonilla H, et al. Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic. Clin Infect Dis. 2021.
  8. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw Open. 2021;4:e210830.
  9. Townsend L, Dowds J, O’Brien K, et al. Persistent poor health Post-COVID-19 is not associated with respiratory complications or initial disease severity. Ann Am Thorac Soc. 2021.
  10. Nath A. Long-Haul COVID. Neurology. 2020;95:559-60.
  11. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021.
  12. Gorna R, MacDermott N, Rayner C, et al. Long COVID guidelines need to reflect lived experience. Lancet. 2021;397:455-7.
  13. Center for Post-COVID Care at Mount Sinai. COVID-19 Facts and Resources. 2020. Accessed April 12, 2021.
  14. NHS. Long-term effects of coronavirus (long COVID). 2021. Accessed April 12, 2021.
  15. Kahn I, COCA, CDC. COCA Call: Treating Long COVID: Clinician Experience with Post-Acute COVID-19 Care. 2021. Accessed April 12, 2021.
  16. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021.
  17. Marshall M. The lasting misery of coronavirus long-haulers. Nature. 2020;585:339-41.
  18. Sykes DL, Holdsworth L, Jawad N, Gunasekera P, Morice AH, Crooks MG. Post-COVID-19 Symptom Burden: What is Long-COVID and How Should We Manage It? Lung. 2021.
  19. Naidu SB, Shah AJ, Saigal A, et al. The high mental health burden of “Long COVID” and its association with on-going physical and respiratory symptoms in all adults discharged from hospital. Eur Respir J. 2021.
  20. Vittori A, Lerman J, Cascella M, et al. COVID-19 Pandemic Acute Respiratory Distress Syndrome Survivors: Pain After the Storm? Anesth Analg. 2020;131:117-9.
  21. Stefano GB. Historical insight into infections and disorders associated with neurological and psychiatric sequelae similar to Long COVID. Med Sci Monit. 2021;27:e931447.
  22. Johansson M, Stahlberg M, Runold M, et al. Long-Haul Post-COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience. JACC Case Rep. 2021.
  23. Ernst M, Brahler E, Beutel ME. How can we support COVID-19 survivors? Five lessons from long-term cancer survival. Public Health. 2021.
  24. Iqbal FM, Lam K, Sounderajah V, Elkin S, Ashrafian H, Darzi A. Understanding the survivorship burden of long COVID. EClinicalMedicine. 2021;33:100767.
  25. Yan W. Understanding the Long-Term Impacts of COVID-19 in Survivors. IEEE Pulse. 2021;12:19-23.
  26. Sivan M, Taylor S. NICE guideline on long covid. BMJ. 2020;371:m4938.
  27. Wise J. Long covid: WHO calls on countries to offer patients more rehabilitation. BMJ. 2021;372:n405.
  28. Subbaraman N. US health agency will invest $1 billion to investigate ‘long COVID’. Nature. 2021;591:356.
  29. The Post-hospitalisation COVID-19 study (PHOSP-COVID). Accessed April 12, 2021.
  30. Sigfrid L, Cevik M, Jesudason E, et al. What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19? A harmonised, global longitudinal observational study protocol. BMJ Open. 2021;11:e043887.

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Newsletter Issue 75, April 7, 2021:

  • Mortality and Readmission Rates Among Patients With COVID-19 After Discharge From Acute Care Setting With Supplemental Oxygen. 4/1/21. Banerjee J. JAMA Netw Open.
    A retrospective study of 621 adult COVID-19 pneumonia patients (65% male) who were discharged from inpatient care (76%) or ED (24%) from 2 large urban public hospitals with a carefully executed, patient-focused discharge and follow-up plan showed excellent outcomes. 76% were insured by Medicaid and 84% were Spanish-speaking. Interventions included pre-discharge patient education, non-automated daily telephone contact 7 days/week until not needed, facility-dispensed equipment (pulse oximeter, O2 tank, concentrator), and vendor support. All-cause mortality was low – 1.3% (95% CI, 0.6%-2.5%) with none outside hospital, and 30-day hospital readmission rate was 8.5% (95% CI, 6.2%-10.7%). Median follow-up time was 26 days. Readmission rates were lower than the overall post-acute care 30-day readmission rate (15.2%) for California Dept. of Health Care Services patients in 2020, and compare favorably to privately insured pre-COVID patients in an earlier, referenced report.
  • New Decade, Old Debate: Blocking the Cytokine Pathways in Infection-Induced Cytokine Cascade. 3/31/21. Rizvi MS. Crit Care Explor.
    Providing deep perspective, this narrative review summarizes literature beginning in 1994 evaluating the efficacy and safety of anticytokine therapy for dysregulated immune responses to infectious pathogens. The longstanding idea of neutralizing “cytokine storm” induced by bacterial sepsis and/or ARDS, using cytokine pathway inhibitors or nonpharmacologic cytokine removal has a “grim history.” Severe COVID-19 causes less cytokine release than either condition; however, anticytokine therapy is being used. Discussions include potential reasons for failure, such as the complexity and variation of cytokine cascades, and future directions.
  • The role of antirheumatics in patients with COVID-19. 4/5/21. Nissen CB. Lancet Rheumatol.
    This review, written by an international panel of rheumatologists, nicely summarizes current knowledge of COVID-19 therapy targeting the immune system. Topics include evidence for potentially useful immune modulators (steroids and baricitinib), those under active investigation (tocilizumab, colchicine and anakinra), undergoing early trials (TNF blockade, anti-complement therapy and intravenous immunoglobin) and disproven treatments (hydroxychloroquine). Authors stress that the timing, dosing and interaction of these therapies is incompletely understood, and the hope that studies now underway will provide more clarity.
  • Toxicity of herbal medications suggested as treatment for COVID-19: A narrative review. 4/5/21. DiPietro MA. J Am Coll Emerg Physicians Open.
    The lack of a proven COVID-19 remedy has led to a host of recommendations promoting the use of various plant-based therapeutics, particularly traditional Chinese medicines. Authored by two emergency medicine physicians, this well-researched review of the major characteristics and toxicities of herbal preparations currently in use and sometimes recommended as treatments for COVID-19 provides valuable information on the symptomatology of “toxidromes” caused by mismanagement or overdoses of potentially toxic extracts including oleander and Datura species.
  • Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study. 4/4/21. Aveyard P. Lancet Respir Med.
    This retrospective review of medical records from late January through April 2020 of 8,256,161 people registered in 1205 primary care practices in the English NHS showed that people with some respiratory diseases were at an increased risk of hospitalization or death due to COVID-19 compared with those without these diseases with hazard ratios for hospitalization or death respectively as follows: asthma 1·18, 0.99; severe asthma 1·29, 1.08; COPD 1·54, 1.54; bronchiectasis 1·34, 1.12; sarcoidosis 1·36, 1.41; idiopathic pulmonary fibrosis 1·59, 1.47; and lung cancer 2·24, 1.77. The study also provides evidence that the use of inhaled corticosteroids is not associated with a substantially increased risk of severe COVID-19, but nor does it appear to be associated with reduced risk.
  • COVID-19 Treatment Guidelines
    Updated NIH COVID-19 treatment guidelines can be found at this website.

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Newsletter Issue 74, April 5, 2021:

  • Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. 4/1/21. Ayoubkhani D. BMJ.
    This is a study of post-COVID syndrome in 47,000+ hospitalized COVID-19 patients individually matched to United Kingdom NHS controls. Patients were discharged by 8/31/2020 and followed for a mean of 140 days, with the study ending on 9/30/2020. The readmission rate was 29% (3.5 times that of controls), and mortality was 12% (7.7 times that of controls). New respiratory disease was 27% more frequent than controls. The risk of diabetes increased 1.5 times, and that of a major cardiovascular event by three times. Younger and ethnic minority patients had greater relative risk than those over age 70. There is an accompanying editorial expressing a need for adjustment of the NHS patient follow-up practices.
  • ABCDEF Bundle and Supportive ICU Practices for Patients With Coronavirus Disease 2019 Infection: An International Point Prevalence Study. 3/31/21. Liu K. Crit Care Explor.
    This is an international, 2-day (June 3 and July 1) survey on the compliance of nutrition, sleep hours and ABCDEF Bundles for 262 COVID-19 patients in 212 ICUs. The authors reported that 47.3% of patients were on mechanical ventilation and 4.6% were on ECMO. Each element of the ABCDEF Bundle was implemented at alarmingly low percentages (16% to 52% compliance), while nutritionally recommended protein was provided to only 50% of ICU patients. Because these supportive measures are known to prevent ICU patients from developing the physical, cognitive and mental disabilities of post-intensive care syndrome, authors strongly suggest that efforts be made to adhere to all evidence-based gold standards of the ABCDEF Bundles including protein supplements and avoiding sleep deprivation in ICU patients.
  • Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. 3/29/21. Cele S. Nature.
    Using a live virus-neutralizing assay, investigators tested the effectiveness of convalescent plasma collected from donors during the first (original) and second (S. African variant) waves of COVID-19 against both types of virus. First-wave plasma was effective against first-wave virus, however showed a 15-fold decrease in effectiveness against S. African variant virus. Second-wave plasma was effective against the then-predominant variant strain and, although it demonstrated a 2.3 fold decrease in activity against the original strain, it was still effective. This provides preliminary evidence that vaccines based on variant-of-concern sequences could retain effective activity against other SARS-CoV-2 lineages.

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Newsletter Issue 73, March 31, 2021:

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Newsletter Issue 72, March 29, 2021:

  • Post-acute COVID-19 syndrome. 3/23/21. Nalbandian A. Nat Med.
    This comprehensive review of current literature divides post-acute COVID-19 into 2 categories: subacute, lasting 4-12 weeks, and chronic, lasting over 12 weeks. Concise discussions cover post-acute epidemiology, prevention and management of thromboemboli, pulmonary, cardiovascular, neurologic, renal, endocrine, and inflammatory complications as well as race/ethnicity factors, organ system involvement and potential interdisciplinary clinic management, findings from studies of post-acute COVID-19 prevalence, and active research. The need to include rehabilitation in multidisciplinary clinics is reinforced. Links to prominent patient advocacy groups are provided.
  • Predictors of clinical deterioration in patients with suspected COVID-19 managed in a ‘virtual hospital’ setting: a cohort study. 3/24/21. Francis NA. BMJ Open.
    The authors actively followed up on 900 UK COVID-19 patients to determine rates of overnight hospitalization or death over a median period of 21 days from outpatient diagnosis (n=455) or hospital discharge (n=445). 76 patients (8.4%) experienced clinical deterioration. 15 previously hospitalized patients and 3 never-hospitalized patients died, and 58 others required COVID-related hospitalization. Of 35 clinical and laboratory features examined, including O2 saturation, the only predictors of clinical deterioration were increased age (OR 1.04 per year of age), severe renal insufficiency (OR 9.1 for eGFR <30), a history of cancer (OR 2.9), or mental health problems (OR 1.76).
  • Hospital load and increased COVID-19 related mortality in Israel. 3/26/21. Rossman H. Nature.
    An analysis of all 22,636 Israeli COVID-19 inpatients from mid-July 2020 – mid-January 2021 determined that in-hospital mortality increased significantly when >62.5% of the national capacity for severely ill patients (800 beds) was occupied. A validated model using Monte-Carlo methods and a set of Cox regressions was used to predict mortality. Two high-occupancy periods had 22% (SE 3.1%) and 27% (SE 3.3%) greater mortality. Authors postulate that excess mortality during periods of high caseload was most likely due to “an insufficiency of health-care resources.”
  • Racial and Ethnic Disparities in COVID-19 Incidence by Age, Sex, and Period Among Persons Aged <25 Years – 16 U.S. Jurisdictions, January 1-December 31, 2020. 3/18/21. Van Dyke ME. MMWR Morb Mortal Wkly Rep.
    This is a data-rich CDC report on nearly 700,000 COVID-19 cases in young people from jurisdictions representing 23% of the US population. (Included cases represent 77% of total cases due to absent ethnicity data in the remainder.) Incidences among multiple minorities ranged from 0.77 to 4.57 relative to non-Hispanic Whites and disparities evolved during 2020. Large disparities January–April generally decreased May–December, primarily due to higher incidence among Whites. Children <10 rarely tested positive, however incidence increased stepwise from ages 10-24. The largest persistent disparities involved Native Hawaiian and Pacific Islanders, Native Americans, and Hispanics. Ethnic minorities often live in multigenerational homes and include essential workers unable to shelter at home. Equitable and timely access to testing, prevention, and vaccination is urged.
  • Incidence and mortality due to thromboembolic events during the COVID-19 pandemic: Multi-sourced population-based health records cohort study. 3/12/21. Aktaa S. Thromb Res.
    This unique dataset examined the thromboembolic events (TE) in the United Kingdom during a 3-year period. As expected, TE increased with the COVID-19 pandemic and the mortality of TE with COVID-19 was increased as compared to pre-COVID-19. However, the rates of TE deaths in the community also increased. These data suggest that some patients may have avoided the hospital evaluation and that the outpatient evaluation and treatment of patients with COVID-19 may need further investigation.
  • CHA2DS2-VASc score and modified CHA2DS2-VASc score can predict mortality and intensive care unit hospitalization in COVID-19 patients. 3/17/21. Gunduz R. J Thromb Thrombolysis.
    This manuscript examined 1000 Turkish patients admitted with COVID-19 and calculated the CHAD2DS2-VASc score for each patient. They found that this simple score (previously used to assess risk of thromboembolization with atrial fibrillation) was significantly correlated with mortality and the need for ICU admission. The sensitivity and specificity of the original score were 81.7% and 83.9%, respectively. For the modified score sensitivity and specificity were 85.4% and 84.1%. The potential strength of these data lie in the simplicity of the score and the ease of obtaining it.
    SAB Comment: These retrospective data would need to be investigated in a prospective fashion before being applied.

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Newsletter Issue 71, March 24, 2021:

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Newsletter Issue 70, March 22, 2021:

  • Changes in Stress and Workplace Shortages Reported by U.S. Critical Care Physicians Treating Coronavirus Disease 2019 Patients. 3/17/21. Gray BM. Crit Care Med.
    This article discusses questionnaire responses from 1356 (57%) of polled critical care attending physicians who reported stress graded moderate-high by 67.6% in spring 2020 and 50.7% in fall 2020. Staff shortages were reported by 48.3% in spring with nearly no decrease (46.5%) by fall. Medication and equipment shortages largely improved by fall. However, PPE often remained in short supply; N95 respirator supply was short for 42.5% despite altered practices. Physical and emotional exhaustion rates were high. Elevated patient mortality rates, potential risk of SARS-CoV-2 exposure to personal contacts, risk of personal exposure, patient isolation from their families, and ethical challenges were among the most important drivers.
    SAB Comment: For interested readers, detailed results are available in the PDF available via a link in the article or here ( We await updated studies following vaccination of most hospital workers and elderly persons that will likely show further evolution of the incidence of stress in ICU physicians and its drivers.
  • Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method. 3/17/21. Nasa P. Crit Care.
    This article discusses the Delphi structured communication process used with 39 international experts, which yielded strong suggestions for use of systemic corticosteroids for critical COVID-19. The suggestions include awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16–24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator desynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end-expiratory pressure titration or the choice of personal protective equipment.

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Newsletter Issue 69, March 17, 2021:

  • Reinfection Rates among Patients who Previously Tested Positive for COVID-19: a Retrospective Cohort Study. 3/15/21. Sheehan MM. Clin Infect Dis.
    In a retrospective cohort study, PCR testing in the Cleveland Clinic Health System from March 2020 to February 2021 was analyzed to detect repeat SARS-CoV-2 infection. Of 8,845 individuals with initially positive PCR tests, 62 had reinfections, defined as a positive PCR test at least 90 days following the first positive PCR. Half were asymptomatic, few were hospitalized, and none required intensive care. Protection offered against reinfection was 82%. Risk of reinfection declined with time after initial infection. The authors suggest that the protection afforded by infection with SARS-CoV-2 is adequate to delay vaccination of these people, if vaccine is in short supply.
    SAB Comment: A negative PCR test after the first infection was not part of their definition of reinfection therefore, the authors acknowledge that persistent shedding of virus could account for some reinfections.
  • Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. 3/8/21. Davies NG. Nature.
    The B.1.1.7 “UK” variant is known to be more infectious. This British study shows it is more lethal. B.1.1.7 is identified with PCR, as the S gene is not amplified: S gene target failure = SGTF. Based on 4,945 deaths within 28 days of community testing of 1,146,534 patients with known SGTF status, authors estimate that the associated adjusted hazard of death is significantly increased across age groups. For example, in 55-69 year old subjects, estimated absolute risk of death within 28 days after a positive test in the community for males increased from 0.6% to 0.9% (95% CI 0.8–1.0%); for females it increased from 0.18% to 0.28% (0.25–0.31%).
    SAB Comment: In a separate retrospective British study with similar results ~55,000 adults >30 years old with the B.1.1.7 variant were matched with an equivalent number of controls. It was highlighted in our Newsletter Issue 68, and can be found here.
  • Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. 3/8/21. Wang P. Nature.
    These investigators report that the “UK variant” (B.1.1.7) remains sensitive to both convalescent plasma and serum collected from vaccinated individuals during Moderna phase I trials (both collected Spring 2020), but refractory to neutralization by most monoclonal antibodies (mAbs) to the spike N-terminal domain (NTD), and relatively resistant to a few mAbs to the receptor-binding domain (RBD). The “South African variant” (B.1.351), containing the E484K mutation is more resistant to neutralization by convalescent plasma (9.4x) and serum from vaccinated individuals (10.3-12.4x). The virus is refractory to most NTD mAbs and multiple individual mAbs to the RBD. This study reinforces concerns about emergent variants and the need for vaccines and mAbs that target them.
  • Severe covid-19 pneumonia: pathogenesis and clinical management. 3/11/21. Attaway AH. BMJ.
    The authors reviewed COVID-19 publications from 1/2020 to 2/2021 and collated the conclusions into a succinct review of major topics descriptive of the disease and its treatment. Concise overviews by topic include mechanism of infection, immunology, pulmonary injury, treatment, outcomes, etc. A table summarizes results of 27 studies regarding respiratory support including high flow nasal cannula, non-invasive ventilation, and invasive mechanical ventilation. Long-term morbidity is also discussed.

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Newsletter Issue 68, March 15, 2021:

  • Transpulmonary pressure measurements and lung mechanics in patients with early ARDS and SARS-CoV-2. 3/7/21. Baedorf Kassis E. J Crit Care.
    To further explore respiratory mechanics in COVID-ARDS, this cohort study from Boston analyzed 40 ventilated patients with chest wall and transpulmonary pressures measured using esophageal pressure monitoring. Lung and respiratory system compliance varied widely over the entire cohort. Elevated basal pleural pressures correlated with increased BMI. Respiratory system and lung mechanics were similar to known existing ARDS cohorts. The wide range of respiratory system mechanics illustrates the inherent heterogeneity that is consistent with typical and COVID-19 ARDS. This information reinforces the practice of treating patients individually, rather than trying to treat with general algorithms.
    SAB Comment: Esophageal pressure monitoring, not usually part of routine ventilator care, provides an indirect measurement of intrapleural pressure, which allows one to determine the compliance/elastance of the chest wall separately from transpulmonary pressure.
  • Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study. 3/10/21. COVIDSurg Collaborative. Anaesthesia.
    This prospective cohort study included 140,000 patients undergoing surgery in 1647 hospitals in 116 countries during October 2020. Thirty-one hundred twenty-seven patients with SARS-CoV-2 diagnosed, 0-2, 3-4, 5-6, and >7 weeks prior to surgery were compared with those without SARS-CoV-2. Mortality was increased in all SARS-CoV-2 groups except the >7-week group, as were pulmonary complications. Patients with symptoms lasting >7 weeks also had increased mortality. Mortality in all patients from 0-6 weeks was increased from 1.5% up to 4%. Even asymptomatic patients in the 0-6 week group had increased mortality. Deferring elective surgery for seven weeks, and even longer in the presence of ongoing symptoms is recommended. The report explains statistical methods and includes many graphs.
  • Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. 3/10/21. Challen R. BMJ.
    The authors gauged the mortality and future healthcare needs resulting from the new COVID-19 infection variant, B.1.1.7 (VOC-202012/1, from southeast UK in late 2020). The absence of the S gene was found to be a proxy for the B.1.1.7 variant. Patients with this variant were matched for age, sex, ethnicity, and region, with patients with the prior common variants to produce 54,906 pairs. The mortality hazard ratio associated with infection with VOC-202012/1 compared with infection with previously circulating variants was 1.64 in patients who tested positive for COVID-19 in the community. In this comparatively low-risk group, this represents an increase in deaths from 2.5 to 4.1 per 1,000 detected cases.
  • Attributes and predictors of long COVID. 3/11/21. Sudre CH. Nat Med.
    This letter addresses cases of so-called “long COVID” that are rising. These authors examine prevalence and early predictive risk factors. Starting when they were pre-symptomatic, individuals prospectively self-reported symptoms between 3/2020-9/2020 using the COVID Symptom Study app. In 558/4,182 (13.3%) incident cases, symptoms lasted ≥4 weeks; 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Symptoms of fatigue, headache, dyspnea and anosmia increased with age, BMI and female sex. Experiencing >5 symptoms in week 1 predicted long COVID (odds ratio = 3.53 (2.76–4.50)). A simple model identifies at-risk individuals with early symptom patterns for trials of prevention or treatment and plan education and rehabilitation.
  • Association between ABO blood types and coronavirus disease 2019 (COVID-19), genetic associations, and underlying molecular mechanisms: a literature review of 23 studies. 3/9/21. Zhang Y. Ann Hematol.
    International reports generally agree that blood type O is a protective factor. Most, but not all, report that the blood type conferring greatest risk for infection is A. One of the largest retrospective cohort studies indicated risk ratios for infection of 0.87, 1.09, 1.06, and 1.15 for O, A, B, and AB individuals, respectively. Although some report no correlation between blood type and COVID-19 severity or mortality, most studies found that types A and AB had higher risk of severe illness or death, while type O was protective against severe outcomes or death. Potential molecular mechanisms are discussed.
  • Association of State-Issued Mask Mandates and Allowing On-Premises Restaurant Dining with County-Level COVID-19 Case and Death Growth Rates — United States, March 1–December 31, 2020. 3/5/21. Guy GP. MMWR Morb Mortal Wkly Rep.
    During March 1-December 31, 2020, state-issued mask mandates applied in 2,313 (73.6%) of the 3,142 U.S. counties. Mandating masks was associated with a decrease in daily COVID-19 case and death growth rates within 20 days of implementation. During the study period, states allowed restaurants to reopen for on-premises dining in 3,076 (97.9%) U.S. counties. This was associated with an increase in daily COVID-19 case growth rates 41–100 days after implementation and an increase in daily death growth rates 61–100 days after implementation. The study did not distinguish between indoor and outdoor on-premises dining.

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Newsletter Issue 67, March 10, 2021:

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Newsletter Issue 66, March 8, 2021:

  • Comparison of Saliva and Nasopharyngeal Swab Nucleic Acid Amplification Testing for Detection of SARS-CoV-2: A Systematic Review and Meta-analysis. 1/15/21. Butler-Laporte G. JAMA Internal Med.
    This systematic review and meta-analysis compared PCR testing (here called “nucleic acid amplification testing – NAAT”) on saliva samples versus nasopharyngeal samples using data from 16 studies. In ambulatory patients with minimal or mild symptoms the pooled saliva NAAT sensitivity (83.2%) and specificity (99.2%) were comparable to the nasopharyngeal swab NAAT sensitivity (84.8%) and specificity (98.9%). Secondary analysis restricted to the 10 peer-reviewed articles gave essentially identical results. Given greater ease and lesser cost of saliva sample collection, the authors propose that saliva NAAT should be prioritized for larger-scale deployment with prospective studies conducted by clinical microbiology laboratories and public health authorities.
  • Baricitinib Therapy in Covid-19 Pneumonia – An Unmet Need Fulfilled. 3/3/21. Goletti D. N Engl J Med.
    This clinically valuable editorial interprets the results of three therapeutic studies. By looking at a scoring system for disease severity the optimal timing for peak benefit from treatment with remdesivir, dexamethasone and baricitinib is defined and an algorithm for therapy is offered. In the ACCT-1 trial, remdesivir was most effective in patients not receiving oxygen or receiving low-flow oxygen. In the RECOVERY trial patients receiving invasive ventilation benefitted most from dexamethasone, however those receiving oxygen also benefitted. In the ACCT-2 trial, the combination of remdesivir and baricitinib was most effective for those receiving high-flow oxygen or noninvasive ventilation. An excellent, clinically useful, graphic defines stages of severity and optimal treatment windows along with a typical timeline of days since symptom onset.
  • Predictors of failure with high-flow nasal oxygen therapy in COVID-19 patients with acute respiratory failure: a multicenter observational study. 3/6/21. Mellado-Artigas R. J Intensive Care.
    The authors developed a simple online tool to predict the eventual need for intubation and mechanical ventilation in patients treated with high-flow nasal oxygen (HFNO) based on the outcome of 259 patients from 36 Spanish and Andorran intensive care units. Inputs required include those from the SOFA score (platelet count, bilirubin, mean arterial pressure, Glasgow Comma Scale, creatinine, and FiO2) plus SpO2 and respiratory rate. Performance measured by area under the curve was 0.88, (95% CI 0.80-0.96).
  • Altered pulmonary blood volume distribution as a biomarker for predicting outcomes in COVID-19 disease. 2/26/21. Morris MF. Eur Respir J.
    This group examined the CT scans of 313 COVID-19 patients and used an automated program to obtain the percentage of blood vessels with a cross-sectional area 1.25–5 mm2 (BV5%). If the (BV5%) was < 25 %, the data suggested odds ratio (OR) 5.58 for death, and OR 3.20 for intubation. Decreased BV5% has been noted in prior literature in patients with COPD and ARDS. While the decrease in BV5% may represent a change associated with ARDS, this novel marker is noteworthy and merits further investigation.
    SAB Comment: This is a tool we have not seen before, and if validated, may become clinically relevant due to the high-observed odds ratio for mortality and death.

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Newsletter Issue 65, March 3, 2021:

  • Acute Respiratory Distress Syndrome: Contemporary Management and Novel Approaches during COVID-19. 2/4/21. Williams GW. Anesthesiology.
    This is a concise yet comprehensive review of 25 years of ARDS intervention trials, primarily supported through the US ARDS and the Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks and the RECOVERY trial in the UK. Although outcomes and understanding of ARDS has improved significantly, not all interventions studied resulted in clinical benefit and some were potentially harmful. In addition to the discussion, figures and a table nicely summarize findings from pre-COVID-19 and recent reports.
  • Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. 2/25/21. The REMAP-CAP Investigators. New Engl J.
    Focusing on therapeutic success for COVID-19 patients requiring organ support measures, 895 patients were randomly assigned to receive one of two IL-6 receptor antagonists and were compared to a 402-patient control group receiving standard care, including glucocorticoids and antivirals. Tocilizumab was given to 366 patients starting in April, and sarilumab, available only since June, to 49 patients. Statistical criteria for efficacy were met in October 2020 and demonstrated significant therapeutic benefit for the primary outcome, expressed in more organ-support free days and lower in-hospital mortality. Both drugs also improved secondary outcomes, including 90-day survival, time to ICU and hospital discharge, among others. Authors link the success of IL-6 antagonists in this series to their use in the sickest patients while organ dysfunction is still reversible.
  • “Silent” Presentation of Hypoxemia and Cardiorespiratory Compensation in COVID-19. 2/4/21. Bickler PE. Anesthesiology.
    This well-written review discusses variability in the human response to hypoxemia from any cause, based upon longstanding research in both normal subjects and patients with pathologic conditions. The theory that COVID-19 is unique in its ability to cause hypoxemia without dyspnea (so-called “happy hypoxia”) is refuted, and the physiologic basis for this somewhat surprising condition is explained. When oxygen concentration falls, the most important compensatory mechanism to preserve oxygen delivery is augmentation of cardiac output. If cardiac reserve is compromised, patients experiencing profound hypoxemia are at increased risk for hypoxic organ damage and death.
  • Development of Severe COVID-19 Adaptive Risk Predictor (SCARP), a Calculator to Predict Severe Disease or Death in Hospitalized Patients With COVID-19. 3/1/21. Wongvibulsin S. Ann Intern Med.
    This article presents a simple web-based calculator for the risk of developing severe disease (requiring high-flow nasal oxygen, non-invasive or mechanical ventilation) or of death in the following day or in the following week. The input values include only the worst O2 saturation, and highest O2 flow rate in the last 6 hours and in the last 24 hours, plus, for milder cases, the absolute neutrophil and lymphocyte count. Development was facilitated by a machine learning tool used to analyze 105 parameters from 3294 patients hospitalized from May to December in Baltimore area hospitals. The final calculator requiring only the above few measures showed an area under the curve (AUC) of 0.89 for one-day predictions and 0.83-0.87 for one-week predictions.
  • Acute covid-19 and multisystem inflammatory syndrome in children. 3/2/21. Rubens JH. BMJ.
    This is a clinical summary of children with acute COVID-19 and the associated multiple inflammatory syndrome in children (MIS-C). A small proportion of children go on to develop severe acute COVID-19 disease and require hospitalization because of respiratory compromise or complications of SARS-CoV-2 infection. Clinicians should consider MIS-C in children presenting with fever and abdominal symptoms, particularly if they develop conjunctivitis or rash, and refer to a pediatric emergency department for evaluation. MIS-C can have overlapping symptomatology with disease processes that require prompt treatment, such as sepsis, toxic shock syndrome, myocarditis, and meningitis.

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Newsletter Issue 64, March 1, 2021:

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Newsletter Issue 63, February 24, 2021:

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Newsletter Issue 62, February 22, 2021:

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Newsletter Issue 61, February 17, 2021:

  • Perspectives of Ketamine Use in COVID-19 Patients. 1/1/21. Weinbroum A. J Korean Med Sci.
    This article is a brief review from Israel of the use of ketamine sedation in the context of COVID-19. It includes the rationale, practical aspects and potential benefits such as evidence of reduced IL-6 and CRP following infusion. Advantages include minimal hemodynamic suppression, bronchodilation, and lack of respiratory depression during spontaneous or assisted ventilation. Authors also discuss a potentially lower incidence compared with other sedatives of psychological complications including acute anxiety and post-traumatic stress and depression following illness.
  • Association of chronic anticoagulant and antiplatelet use on disease severity in SARS-COV-2 infected patients. 2/2/21. Ho G. J Thromb Thrombolysis.
    This article reviews data from Kaiser Permanente Northern California, which covers 4.4 million patients, and examined the records of the 28,076 patients with confirmed positive SARS-CoV-2 infection. 1% were prescribed anticoagulants within 3 months prior to diagnosis and 3% were taking antiplatelet agents. Neither was associated with a reduced risk of hospitalization, venous thromboembolism, emergency department visit, ICU stay, invasive ventilation or death. Based upon these data, authors do not recommend broad institution of anticoagulation or antiplatelet therapy for patients testing positive for SARS-CoV-2 infection.
  • Neutralizing Monoclonal Antibody for Mild to Moderate COVID-19. 1/21/21. Malani PN. JAMA.
    This editorial compares the BLAZE-1 trial results published in January 2021 with an interim analysis published online in October 2020. Because final data resulted in changes in the effect sizes for all 5 cohorts, earlier results indicating that one dose cohort made a significant difference had to be overturned. Authors note that in normal times an interim analysis of an ongoing clinical trial would not have been published. The FDA has issued emergency use authorizations for both bamlanivimab (Lilly) and for the combination of casirivimab and imdevimab (Regeneron) for outpatients with mild to moderate symptoms of COVID-19 and risk factors for progression to severe disease (such as advanced age, obesity, diabetes, chronic kidney disease, and immunosuppression).
  • Cardiopulmonary Resuscitation in the Prone Position in the Operating Room or in the Intensive Care Unit: A Systematic Review. 2/1/21. Anez C. Anesth Analg.
    The discussion section in this article provides an excellent, practical “how-to,” including diagrams, for prone CPR and defibrillation. This review is based on 52 selected pre-COVID-19 articles including case reports of 14 intubated patients (13 during surgery). The data presented confirms that CPR in the prone position is a reasonable alternative to supine CPR when the latter cannot be immediately implemented, and the airway is already secured. Defibrillation in the prone position is also possible.
  • Mortality and renal outcomes of patients with severe COVID-19 treated in a provisional intensive care unit. 1/21/21. Hittesdorf E. J Crit Care.
    This study involves 116 COVID-19 patients who required mechanical ventilation and were cared for in an OR-ICU. The patients were followed for 90 days for mortality and renal outcomes. 30.2% died (n=35). Mortality among 45 patients receiving continuous replacement therapy (CRRT) was 40% (n=18) vs. 23.4% (n=17) in 71 patients who did not receive CRRT. The stage of AKI did not affect mortality compared with no AKI. However, those with stage 3 were more likely to require CRRT and to die during hospitalization. Only two survivors required dialysis at 90 days and outcomes did not differ from those cared for in a regular ICU.

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Newsletter Issue 60, February 15, 2021:

  • Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study. 2/2/21. Marks M. Lancet Infect Dis.
    In an attempt to identify variables that affect the transmission dynamics of SARS-CoV-2, these investigators from Spain analyzed contact tracing data associated with a randomized control trial. Quantitative RT-PCR and clinical data was analyzed on 282 adult, non-hospitalized index cases with a total of 753 contacts. The viral load of the index case was the leading determinant of the risk of PCR positivity among contacts and viral load significantly influenced the risk of developing the symptomatic disease in a dose-dependent manner. No association of risk of transmission was found with reported mask usage by contacts, with the age or sex of the index case, or with the presence of respiratory symptoms in the index case.
  • Occurrence and Timing of Subsequent Severe Acute Respiratory Syndrome Coronavirus 2 Reverse-transcription Polymerase Chain Reaction Positivity Among Initially Negative Patients. 2/5/21. Long DR. Clin Infect Dis.
    The authors compared the occurrence of a discordant result of RT- PCR in two health systems. They assessed the conversion rate to a new positive in less than 7 days. They noted the conversion rate was at 3.5% (4.1% at the University of Washington, 2.8% at Stanford). Retesting was done based on clinical symptoms of patients. These observations suggest that false-negative RT-PCR results do occur, but at a low frequency. Neither team was able to calculate a true clinical sensitivity or false-negative proportion due to the lack of a gold-standard.
  • Rapid decline of neutralizing antibodies against SARS-CoV-2 among infected healthcare workers. 2/8/21. Marot S. Nature Communications.
    Serological testing is used to identify individuals who are immunized and potentially “protected” against re-infection. From 28 January to 21 March 2020, 26 healthcare workers from Pitié-Salpêtrière University Hospital in France were enrolled in this study. Healthcare workers with mild COVID-19 were tested three weeks (D21), two months (M2) and three months (M3) after the onset of symptoms. All healthcare workers displayed seroconversion at D21 after symptom onset, and elicited a neutralizing antibodies response to SARS-CoV-2 correlated with the anti-receptor binding domain antibody levels. However, this neutralizing activity declines, and may even be completely lost, in association with a decrease in systemic IgA antibody levels from 2 months after disease onset.
  • SAB Comment: The SAB policy is to only review articles that have undergone peer review for inclusion in this newsletter. We are making an exception for the following two studies due to their therapeutic implications for COVID-19 patients. Final versions of these studies will be presented as they become available.
    • ATTACC, ACTIV-4a & REMAP-CAP multiplatform RCT: Results of interim analysis. 1/28/21. NHLBI.
      This is new, exciting RCT data for decreasing morbidity and mortality for COVID-19 with therapeutic anticoagulation. This interim data from NHLBI examines 3 international trials, suggesting decreased morbidity and mortality for COVID-19 patients with therapeutic anticoagulation for patients not in the ICU.
    • Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial. 2/8/21. Ramakrishnan S. medRxiv.
      This open label trial from Oxford, UK, convincingly showed that a steroid inhaler used twice daily within 7 days of onset of mild COVID-19 significantly improves outcome measured primarily in hospitalization and secondarily in days to recovery from symptoms, fever and low oxygen saturation. Statistically, the difference in proportions was 0.131, 95% CI (0.043, 0.218), p=0.004, indicating a relative risk reduction of 90% for patients using the budesonide inhaler compared to usual care.
      SAB Comment: This study has not yet been peer reviewed, was partially funded by Astra Zeneca and was halted early due to the December surge in COVID-19 cases in the study area. However, the authors plead convincingly that this ubiquitous treatment modality can influence the course of illness and possibly avoid prolonged recovery from SARS-CoV-2.

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Newsletter Issue 59, February 10, 2021:

  • Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. 2/5/21. RECOVERY Collaborative Group. Lancet.
    As part of the British RECOVERY trial which includes 176 hospitals, 2582 hospitalized patients with COVID-19 were randomized to receive azithromycin 500 mg daily for 10 days and compared to 5181 patients receiving standard care. The 28-day all-cause mortality for both patient groups was 22% indicating that azithromycin has no benefit for COVID-19 and should be used for antimicrobial indications only.
    SAB Comment: The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an investigator-initiated, individually randomized, controlled, open-label, adaptive platform trial to evaluate the effects of potential treatments in patients admitted to hospital with COVID-19. After completing work on azithromycin, dexamethasone, hydroxychloroquine, lopinavir–ritonavir, convalescent plasma, and tocilizumab, study into the effects of REGN-COV2 (a combination of two monoclonal antibodies directed against SARS-CoV-2 spike glycoprotein), aspirin, and colchicine are still underway.
  • Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19. 2/2/21. Shaefi S. Intensive Care Med.
    This article reports the results of a study on the use of V-V ECMO in selected COVID-19 patients treated in experienced centers with mortality reduction (66.8% survival at 60 days). The study represents ECMO patients admitted across all participating ICUs during the trial period (190/5122). The article includes detailed analysis and an interesting use of an emulation cohort to support conclusions, eliminate confounders and immortal time bias and provide comparator between ECMO and non-ECMO patients to provide a non-ECMO control group lacking in prior studies. The author emphasizes the importance of early initiation in carefully selected patients treated in experienced centers to maximize outcomes.
  • Evolution of antibody immunity to SARS-CoV-2. 1/18/21. Gaebler C. Nature.
    SARS-CoV-2 neutralizing antibody levels eventually decrease post-illness or vaccination. It is unknown how well memory B cells produce antibodies many months later. Eighty-seven individuals were assessed at 1.3- and 6.2-months post-infection. As expected, IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decreased significantly. Functionally, plasma viral killing activity decreased fivefold. However, at 6.2 months, memory B-cells remained unchanged and continued evolving antibodies showing antibody sequence changes with increased potency and resistance to RBD mutation. Following up on known stool SARS-CoV-2 persistence, the authors related ongoing memory B-cell evolution to lingering antigen immunoreactivity shown in intestinal biopsies 4 months post-infection.
  • Global absence and targeting of protective immune states in severe COVID-19. 1/25/21. Combes A. Nature.
    This fascinating study shows that immune response to COVID-19 is complex and differs between severe systemic effects in some patients and milder symptoms in others. Authors exposed the differences by studying whole blood analysis identifying individual cellular elements and expression in samples of severe and mild disease. Examination of serum in mild disease shows production of interferon-stimulated genes which blunt overproduction of anti-SARS-CoV-2 antibodies which in severe disease are higher and associated with lower viral titers than seen in mild disease. The authors make research suggestions to study modification of this response.
  • SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. 2/4/21. Müller JA. Nat Metab.
    These investigators show that SARS-CoV-2 can cause diabetes in the absence of autoantibodies and other pancreatic disorders by directly infecting human exocrine (enzyme-producing) and endocrine (hormone-producing) pancreatic cells. Beta-cells (insulin-producing) express ACE-2, and TMPRSS2 allowing entry and then viral replication, inhibitable by remdesivir. The reduction in insulin-secretory granules in beta-cells results in reduced glucose-stimulated insulin secretion. The nucleocapsid protein was detected in four post-mortems in exocrine cells, beta-cells and in close proximity to the islets of Langerhans. These data suggest that SARS-CoV-2 targeting the pancreas leads to endocrine dysregulation (hyperglycemia, DKA, new onset Type-1 diabetes) and pancreatitis (up to 33%).

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Newsletter Issue 58, February 8, 2021:

  • The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. 1/19/21. Chaccour C. eClin Med.
    Ivermectin has been shown to inhibit SARS-CoV-2 replication in vitro. This 24-patient pilot randomized, double-blind, placebo-controlled trial was launched in Spain to determine whether a single 400mcg/kg dose of ivermectin could provide a public health benefit by limiting viral spread when administered early to young patients attending the emergency room with symptoms compatible with COVID-19 and with no more than 72 h of fever or cough. No difference in the proportion of PCR positives were found but a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers was noted. A significantly faster recovery from anosmia (76 v 158 days) is among the results and – along with multiple retrospective studies showing favorable outcomes – calls for further investigations into the potential benefits of this widely available drug.
  • SARS-CoV-2 viral load is associated with increased disease severity and mortality. 10/30/20. Fajnzylber J. Nature Communications.
    The authors quantified SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. Amongst participants hospitalized with COVID-19, the authors report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation. Forty-four percent of those on a ventilator had detectable viremia compared to 19% of those receiving supplemental oxygen by nasal cannula and 0% of individuals not requiring supplemental oxygen. Compared to individuals who were discharged from the hospital, those who eventually died had significantly higher levels of plasma viremia at the time of initial sampling.
  • The Association of Preinfection Daily Oral Anticoagulation Use and All-Cause in Hospital Mortality From Novel Coronavirus 2019 at 21 Days: A Retrospective Cohort Study. 2/1/21. Harrison RF. Crit Care Explor.
    Of 1027 patients 60 years old or older admitted for COVID-19, the 28 who were on warfarin upon admission did not have a significantly different mortality at 28 days than the 894 patients who were on no anticoagulation. However, the 104 patients taking a direct oral anticoagulant had improved mortality (14.4% vs 23.8%; odds ratio, 0.57) prior to adjustment and after controlling for age, gender, and comorbidities. They had a mortality odds ratio of 0.44 when compared to patients on no oral anticoagulant on admission. No statistical difference was noted between the groups in the prevalence of bleeding events. The authors recommend an RCT to better evaluate this possible effect.
  • Assessment of Maternal and Neonatal Cord Blood SARS-CoV-2 Antibodies and Placental Transfer Ratios. 1/29/21. Flannery DD. JAMA Pediatr.
    This data rich article is from a single institution describing a study in which 6% of 1714 women became infected with COVID-19 during pregnancy. This multi-ethnic/race study revealed that of the 83 women infected, 72 (87%) passed igG antibodies to the fetus offering neonatal protection from infection.
    SAB Comment: Maternal infections during pregnancy (HIV) can alter IgG transfer to the fetus. Reference: Immunohorizons. 2018 Jan 1; 2(1): 14–25.
  • A rapid review of the pathoetiology, presentation, and management of delirium in adults with COVID-19. 12/25/20. Hawkins M. J Psychosomatic Res.
    In this in-depth literature review of delirium in COVID-19, the authors initially identified 10,000 publications and after removing duplicates and screening abstracts, 229 studies were included in the review. This review serves as a source of reference for intensivists dealing with various aspects of diagnosing and treating delirium. After reviewing current information on prevalence, symptoms and etiology, prevention and management are highlighted in a summarizing table. In the absence of randomized clinical trials on this topic, the discussion is limited to reporting diverse empirical management with and without pharmacological intervention, stressing the fact that delirium can be a core symptom at presentation and may be under-recognized and under-diagnosed.

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Newsletter Issue 57, February 3, 2021:

  • Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. 1/19/21. Lopes RD. JAMA.
    This article discussed the BRACE CORONA trial, a registry-based open label clinical trial of 659 participants admitted to 29 Brazilian hospitals with mild to moderate COVID-19 disease. The results corroborated that discontinuing ACEI or ARB therapy for 30 days did not affect the number of days alive and out of the hospital in patients hospitalized with mild to moderate COVID-19.
    SAB Comment: This trial is characterized by a single-country design and a notably younger (mean age 55 years) patient population with less comorbid disease (33% with diabetes; 5% with cardiovascular diseases) than the REPLACE COVID trial and had fewer total deaths despite the larger sample size (3% mortality in the BRACE CORONA trial vs 14% mortality in the REPLACE COVID trial).
  • Information on Respiratory Protection
    For readers interested in respiratory protection including N95 filtering facepiece respirators (FFR), our special sections at the end of the newsletter and on our website have been updated with 2 new publications, including summaries and direct links, and a spreadsheet of testing information of hundreds of new FFR manufactured in various countries, performed by NIOSH and ECRI, a health quality institute.
  • Vaccine Updates
    • Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. 12/31/20. Baden LR. NEJM.
      This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the US. Persons at high risk for SARS-CoV-2 infection or its complications (with locations or circumstances that put them at an appreciable risk of SARS-CoV-2 infection, a high risk of severe COVID-19, or both) were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (Moderna) (100 μg) or placebo 28 days apart. Site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial. The mRNA-1273 vaccine showed 94.1% efficacy at preventing COVID-19 illness, including severe disease. All the severe COVID-19 cases were in the placebo group. Aside from transient local and systemic reactions, no safety concerns were identified.
    • Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. 12/31/20. Polack FP. NEJM.
      In this ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, the authors randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 (BioNTech-Pfizer) vaccine candidate. Forty-three thousand four hundred forty-eight (43,448) individuals received injections. Eight patients who received the vaccine developed COVID-19 compared to 162 patients who received placebo, i.e., the vaccine was 95% effective. None of the eight vaccinated patients who developed COVID-19 required hospitalization. The safety profile included short-term, mild-to-moderate pain at the injection site, fatigue, and headache. Although the vaccine can be stored for up to 5 days at standard refrigerator temperatures once ready for use, very cold temperatures are required for shipping and longer storage.

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Newsletter Issue 56, February 1, 2021:

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Newsletter Issue 55, January 27, 2021:

  • Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study. 1/11/21. Gupta R. Lancet Resp Med.
    ISARIC4C is a global initiative with the purpose of preventing illness and death from infectious disease outbreaks. This article presents information on development and validation of a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalized adults with suspected or confirmed COVID-19 prospectively recruited to ISARIC4C study across 260 hospitals in England, Scotland, and Wales. The authors contend that the 4C Deterioration model, designed to be used on admission, has strong potential for clinical utility and generalizability to predict clinical deterioration and inform decision-making among adults hospitalized with COVID-19. The Mortality and Deterioration calculator can be accessed with the following link:
    SAB Comment: While the SAB does not endorse management strategies or interventions, its members believe this manuscript and accompanying calculator to evaluate risk of disease progression or death MAY be useful in supplementing case management decisions.
  • Improving clinical management of COVID-19: the role of prediction models. 1/11/21. Wynants L. Lancet Resp Med.
    This is an editorial indicating that the main clinical advantage of the ISARIC4C predictive model is that required patient specific data is available from daily routine care and may help inform stratification of patients on the basis of clinical severity. In combination, the 4C Deterioration and Mortality models could be utilized in creating an evidence-based clinical pathway for patients with COVID-19. Validated predictive models may improve clinical management and resource utilization.

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Newsletter Issue 54, January 25, 2021:

  • Renin-angiotensin system inhibitors in hospitalised patients with COVID-19. 1/10/21. Williams B. Lancet Respir Med.
    This editorial provides a commentary on the ACEI/ARB controversy. While highlighting the REPLACE COVID trial which examined the impact of continuing or withdrawing chronic ACEIs or ARB treatment in 152 patients hospitalized with COVID-19 across 20 international centers which resulted in no difference in outcome, it stresses the global collaboration, scale and speed with which investigators conducted observational cohort studies with similar results which made this small RCT’s results convincing. In addition, the authors refer to the larger BRACE CORONA RCT with identical yet unpublished results and refer to recent literature showing that there is no increase in ACE2 expression caused by ACEIs and ARBs in pulmonary or renal tissue.
  • The Association of Low Molecular Weight Heparin Use and In-hospital Mortality Among Patients Hospitalized with COVID-19. 1/4/21. Shen L. Cardiovasc Drugs Ther.
    This paper examines 525 COVID-19 hospitalized patients from Wuhan. Twenty-three percent were treated with low molecular weight heparin (LMWH). These patients were likely to be older, have more co-morbidities and had more severe COVID-19 parameters. Compared with non-LMWH group, LMWH group had a higher unadjusted in-hospital mortality rate (21.70% vs. 11.10%; p = 0.004), but a lower adjusted mortality risk (adjusted odds ratio [OR], 0.20; 95% CI, 0.09–0.46). These retrospective data suggest that LMWH use was associated with lower all-cause in-hospital mortality. The survival benefit was particularly significant among more severely ill patients.
    SAB Comment: This retrospective study suggests benefits of LMWH on mortality and contributes to the ongoing debates about the use of anticoagulants in these patients. This further highlights the need for the upcoming RCTs.
  • Venous thromboembolism and major bleeding in patients with COVID-19: A nationwide population-based cohort study. 1/5/21. Dalager-Pedersen M. Clin Infect Dis.
    This review from 6 Danish hospitals examines 30-day VTE and bleeding risks in 9,460 PCR+ patients for SARS-CoV-2, 226,510 SARS-CoV-2 negative patients and 16,281 patients with influenza. One thousand five hundred and forty of the COVID-19 patients were hospitalized. Overall 30-day risk for VTE was 0.4% (40/9,460) among COVID-19 positive patients compared with 0.3% (649/226,510) for COVID-19 negative patients and 1.0% (158/16,281) among influenza patients. Among hospitalized patients, risks for VTE were 1.5% (23/1,540) in COVID-19 positive patients compared with 1.8% (483/26,131) in COVID-19 negative patients and 1.5% (147/9,599) in hospitalized influenza patients. No differences were noted in major bleeding events. In this nationwide survey, the data demonstrate a low rate of VTE and bleeding for outpatients with SARS-CoV-2.
  • Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis. 12/8/20. Kruse JM. Crit Care.
    While this review only has 40 ICU COVID-19 patients, the data suggest that a severe decrease in clot breakdown is a cause of the coagulopathy associated with COVID-19. Maximum lysis, especially following stimulation of the extrinsic coagulation system using rotational thromboelastometry (ROTEM), was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction (area under curve of 0.92).
  • Neutralizing antibody titres in SARS-CoV-2 infections. 1/4/21. Lau E. Nature Communications.
    SARS-CoV-2 infection elicits effective neutralizing antibody titers in most individuals. Using plaque reduction neutralization (PRNT) assays, a “gold-standard,” kinetics of virus neutralizing antibody responses were examined from a cohort of 195 infections collected days 0 to 209 after symptom onset. Of 115 sera collected ≥61 days after onset of illness tested, 99.1% remained seropositive for both 90% (PRNT90) and 50% (PRNT50) neutralization endpoints. Investigators estimated it takes at least 372, 416 and 133 days for PRNT50 titers to drop to the detection limit for severe, mild, and asymptomatic patients, respectively. Results were uninfluenced by age or corticosteroid use.
  • Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. 1/11/21. Grant RA. Nature.
    In this basic science article, using flow cytometry and transcriptomic profiling these investigators compared bronchoalveolar lavage (BAL) samples from 88 patients with SARS-CoV-2 respiratory failure to 211 patients with non-SARS-CoV-2 failure. In 10 SARS-CoV-2 BALs they analyzed single-cell RNA-seq. In SARS-CoV-2, the alveolar space was enriched in T cells (CD4+ and CD8+) and monocytes; only 31% had neutrophilia. Transcriptomes suggested that SARS-CoV-2 directly infects alveolar macrophages (AM), which produce T-cell chemo-attractants. T-cells then produce interferon-gamma. Feedback to AM promotes further T-cell activation. In contrast to non-SARS-CoV-2, SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis. Infected AM and T cells form a positive feedback circuit.

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Newsletter Issue 53, January 20, 2021:

  • Stability of SARS-CoV-2 on critical personal protective equipment. 1/13/21. Kasloff SB. Nature Scientific Reports.
    Persistence of viable virus was measured on eight PPE materials. Viable SARS-CoV-2 persisted for 21 days on plastic, 14 days on stainless steel, 7 days on nitrile gloves and 4 days on chemical resistant gloves, though at significantly reduced levels compared to the initial inoculum. Viable SARS-CoV-2 was nearly undetectable, but could still be recovered from N-95 and N-100 materials for up to 21 days. On 100% cotton, the virus underwent rapid degradation and was not detectable within 24 hours. These findings underline the importance of appropriate handling of contaminated PPE and a potential advantage of cotton.
    SAB Comment: Many of the results in this study differ from other often-quoted reports. This is not surprising as experimental conditions including contaminating load, medium, ambient temperature and humidity have a large influence on the time viruses remain viable and vary among studies.
  • Persistent Post-COVID-19 Inflammatory Interstitial Lung Disease: An Observational Study of Corticosteroid Treatment. 1/12/21. Myall KJ. Ann Am Thorac Soc.
    This is a well-written narrative following 837 COVID-19 patients seen between February and May 2020 in metropolitan London, UK hospitals. Four weeks after discharge, 39% had not returned to baseline and underwent further study. Thirty patients with persistent respiratory symptoms and interstitial lung disease received an initial maximal dose of prednisolone 0.5mg/kg with rapid weaning over a 3-week period which improved diffusion capacity by 31.6% and FVC by 9.6% which resulted in symptomatic and radiological improvement. This preliminary data requires further study into the natural history and potential treatment for patients with persistent inflammatory interstitial lung disease following SARS-CoV2 infection.
  • Ventilator-associated pneumonia in critically ill patients with COVID-19. 1/12/21. Maes M. Crit Care.
    This retrospective observational study from the UK studied ventilator-associated pneumonia (VAP) in mechanically ventilated COVID-19 (n=81) and non-COVID-19 (n=144) patients at a single hospital. All patients were studied between March and August 2020, and VAP was defined by the European Center for Disease Control using clinical and microbiological criteria. COVID-19 was associated with an increased risk of VAP (28 per 1,000 ventilator days) compared with non-COVID-19 patients (13 per 1,000 ventilator days). Although the distribution of organisms causing VAP was similar between the two groups, aspergillosis was only found in COVID-19 patients (n=3, none on steroids), though one patient without COVID-19 was borderline positive and met clinical criteria.
  • Lung ultrasound score predicts outcomes in COVID-19 patients admitted to the emergency department. 1/11/21. de Alencar JCG. Ann Intensive Care.
    Lung ultrasound (LUS) was performed in the emergency department (ED) on 180 patients who were PCR positive for COVID-19. The protocol involved the examination of 12 lung regions, was performed at bedside by experienced ED physicians, and typically required five minutes. LUS scores correlated with findings from chest commuted tomography (CT) (when performed) and predicted the estimated extent of parenchymal involvement, death, endotracheal intubation, and ICU admission. The authors believe that LUS is more sensitive than chest radiography, requires less resource and infection risk than CT, and could be used as an effective evaluation tool, particularly in resource-constrained settings.
  • Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19). 1/12/21. van Kampen JJA. Nat Commun.
    The CDC currently uses a minimum disease duration of 10 days in their symptom-based strategy as the statistically estimated likelihood of recovering a replication-competent virus approaches zero after ten days of symptoms. In a study of 129 hospitalized patients, duration and key determinants of infectious SARS-CoV-2 shedding in patients with severe and critical COVID-19 was assessed. Median time for infectious virus shedding was 8 days post-symptom onset; ≤5% probability for isolating infectious SARS-CoV-2 when duration of symptoms was ≥ 15.2 days. Median viral load was significantly higher in culture + samples than culture – samples. Probability of isolating infectious virus was < 5% when neutralizing antibody titer was 1:80 or higher. Detection of subgenomic RNAs outlasted detection of infectious virus. Based on their findings, a longer disease duration could be considered for severely-ill patients.

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Newsletter Issue 52, January 18, 2021:

  • COVID-19, Personal Protective Equipment, and Human Performance. 1/6/21. Ruskin KJ. Anesthesiology.
    This article addresses the issue of the varieties of PPE worn by healthcare workers. The authors discuss how various varieties of PPE may cause increased work of breathing, reduced field of vision, communication mishaps, thermoregulation derangements, limitations of physical dexterity and mental, physical, and psychological fatigue and stress which lead to decreased human performance. These effects are not individual weaknesses. Here the authors suggest some helpful remedies to address the physiologic and psychologic challenges imposed by non-standardized PPE. There is a need for a new, standardized, integrated design for PPE to improve the safety of patients and healthcare workers.
  • SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. 1/7/21. Johansson MA. JAMA Netw Open.
    A decision analytical model was used including multiple scenarios for the infectious period and the proportion of transmission from individuals who never have COVID-19 symptoms. Baseline assumptions were taken from meta-analyses and included an incubation period of a median of 5 days. In the various analyses peak infectiousness was varied between 3 and 7 days. Under a broad range of values for each of these assumptions, at least 50% of new SARS-CoV-2 infections were estimated to have originated from exposure to individuals who were asymptomatic at the time of transmission (combining those who never develop symptoms with those who are pre-symptomatic).
    SAB Comment: This highlights the importance of mask-wearing and social distancing even as vaccines are rolled out.
  • Facial Pressure Injuries from Prone Positioning in the COVID-19 Era. 1/3/21. Shearer SC. Laryngoscope.
    This study highlights the high frequency (48%) of facial pressure injuries associated with intubated COVID-19 patients placed in the prone position at a single US institution. Most of these patients were continuously in the prone position. Of 143 intubated ICU patients proned for an average of 123 hours, cheek and ear injuries accounted for the majority of damage, with the likelihood of injury increasing as proning times increased. A particular problem seemed to be pressure caused by commercial endotracheal tube fasteners. Suggestions for reducing these injuries are made. The study did not address injuries to the eye or elsewhere on the body.
  • Impact of cardiovascular disease and risk factors on fatal outcomes in patients with COVID-19 according to age: a systematic review and meta-analysis. 12/18/20. Bae S. Heart.
    This is a retrospective meta-analysis to investigate the impact of cardiovascular disease (CVD) and associated risk factors (hypertension, diabetes) on age-related mortality in COVID-19 patients. Fifty-one studies, including 48,171 patients were included, along with PRISMA diagrams and tables. Unsurprisingly, CVD, hypertension and diabetes increased mortality across all groups. However, when present in younger ages, the odds ratio of mortality compared with same age patients without the risk factors was disproportionately higher than the same age ratio in the elderly. While young patients had lower prevalence rates of cardiovascular comorbidities than elderly patients, relative risk of fatal outcome in young patients with hypertension, diabetes and CVD was higher than in elderly patients.
  • Early corticosteroids are associated with lower mortality in critically ill patients with COVID-19: a cohort study. 1/5/21. Monedero P. Crit Care.
    This is a prospective, multicenter, observational, cohort study in 882 critically ill adult patients with COVID-19 admitted to 36 critical care units in Spain. Beginning in early March to the end of June 2020, patients receiving corticosteroids within 48 hours of ICU admission had a lower mortality compared to those receiving steroids later (30 vs. 40% – HR 0.71) or not at all. Patients treated early did better overall with shorter ICU stays, fewer ventilator days and a lower incidence of organ dysfunction. Higher dosages were found to be more effective. Corticosteroid administration occurred on average 12 days after symptom onset. The authors recommend corticosteroids as early as day 7 provided inflammatory markers are elevated.

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Newsletter Issue 51, January 13, 2021:

  • Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers. 12/28/20. Lumley SF. N Engl J Med.
    This is an original article from 4 Oxford University Hospitals that followed its employees for SARS-CoV-2 infection. Testing was performed every 2 weeks or if symptomatic. 10% of 12,541 staff tested positive from March through November 2020. Polymerase chain reaction assays of both anti-spike IgG and anti-nucleocapsid IgG demonstrated that healthcare workers who tested positive suffered mild disease and were afforded immunity for the length of the study, 31 weeks.
  • 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. 1/8/21. Huang C. Lancet.
    175-199 days after symptom onset, 1733 of 2469 discharged Wuhan COVID-19 patients (median age 57) completed questionnaires to evaluate symptoms and quality of life along with physical examinations, a 6-min walking test, and blood tests. Reduced 6-min walk, fatigue, pulmonary abnormalities, and anxiety or depression were prevalent. 73% of men and 81% of women reported at least one symptom (76% overall). Most common were fatigue or muscle weakness (63%), sleep difficulties (26%), and anxiety or depression (23%). Symptoms were positively correlated with previous COVID-19 illness severity.
    SAB Comment: Many with mobility or neurologic issues were excluded, therefore accurate percentages may be higher.
  • Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. 1/6/21. Libster R. N Engl J Med.
    This article describes an Argentine randomized, double-blind, placebo-controlled trial of convalescent plasma (CP) with IgG titers >1:1000 against SARS-CoV-2 within 72 hours following the onset of mild COVID-19. CP reduced disease progression in adult patients older than 75 years or 65-74 years old with co-morbidities. Severe respiratory disease developed in 13/80 patients (16%) who received 250 ml of CP and 25/80 (31%) who received 250 ml normal saline (relative risk, 0.52). Benefit was more frequent following units with higher IgG titers, indicating a dose-dependent effect. Deaths were 2/80 in the CP group vs. 4/80 in the placebo group.
  • Hypercoagulopathy in Severe COVID-19: Implications for Acute Care. 12/28/20. Waite AAC. Thromb Haemost.
    This is a review of the coagulopathy associated with COVID-19. This is a good summary of the early literature up to current papers. It includes clinically relevant data and upcoming trials. This paper is a useful update.
  • Incidence of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up. 12/22/20. Salisbury R. Blood Adv.
    This paper presents new data examining venous thromboembolism (VTE) after discharge for patients with COVID-19. 303 patients were treated at Oxford University Hospitals. 5.9% were diagnosed with VTE in the hospital. Data were collected in 205 patients post discharge up to 90 days or until death if earlier. Based upon the national registry, 2.6% had VTE, all pulmonary emboli. The authors suggest that this needs to be further investigated as there may be a beneficial role for post-discharge anticoagulation in some patients.

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Newsletter Issue 50, January 11, 2021:

  • Adaptation of an Obstetric Anesthesia Service for the Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic: Description of Checklists, Workflows, and Development Tools. 12/14/20. Li Y. Anesth Analg.
    In this pragmatic report from Boston, authors share their revised workflows and checklists for all aspects of obstetric anesthesia care in the COVID-19 era. A cyclical improvement methodology was used to design each new workflow. Challenges include simultaneous care of infected patients alongside noninfected patients, inherent uncertainties regarding the course of labor and delivery, and need for coordination with other departments such as neonatology. Authors developed independent workflows and procedure-specific material kits that may be used alone or in sequence without extensive staff training to facilitate care and conserve resources.
  • Update to living systematic review on drug treatments for covid-19. 12/18/20. Siemieniuk RAC. BMJ.
    First 6-month follow-up and therefore “living” review of randomized trials examining COVID-19 treatment options were discussed, specifically their comparative effectiveness that have not been tested head-to-head. Leading off with a uniquely designed interactive infographic diagram (available on the web but not featured on the PDF download) that links therapeutics to 11 different outcomes, the review tabulates and discusses results and allows for a quick search as well as in-depth sourcing using extensive tables and bibliographic links sorted by outcome modality. This encyclopedic review originated from 20 institutions in 13 countries, including 3 in China, and in its conclusions highlights the beneficial effect of glucocorticoids on mortality and mechanical ventilation, while questioning other drugs, including tocilizumab and remdesivir.
  • A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. 12/28/20. ACTIV-3/TICO LY-CoV555 Study Group. N Engl J Med.
    The antiviral drug remdesivir has been shown to decrease the time to recovery in hospitalized patients with COVID-19. However, the preliminary results of a study involving a single infusion of the neutralizing monoclonal antibody LY-CoV555 when co-administered with remdesivir, did not demonstrate efficacy, among hospitalized patients (sample size 300) who had COVID-19 without end-organ failure, measured at day 5 vs those who received placebo. LY-CoV555 met the pre-specified criteria for futility and further enrollment was stopped.
  • Factors Associated with Positive SARS-CoV-2 Test Results in Outpatient Health Facilities and Emergency Departments Among Children and Adolescents Aged <18 Years – Mississippi, September-November 2020. 12/17/20. Hobbs CV. MMWR Morb Mortal Wkly Rep.
    This investigation included children and adolescents younger than 18 years who received RT-PCR testing for presence of SARS-CoV-2 in nasopharyngeal swab specimens at outpatient testing health care centers or the ED during September 1–November 5, 2020. Of 397 participants, children and adolescents who received positive test results for SARS-CoV-2 were more likely than were similarly aged participants who had negative test results to have had close contact with persons with COVID-19. Exposure was attributed to gatherings with persons outside the household, and a lack of consistent mask use in school. However, attending school or childcare was not associated with receiving positive SARS-CoV-2 test results.
  • SARS-CoV-2 Variant – United Kingdom of Great Britain and Northern Ireland. 12/21/20. WHO.
    UK scientists sequenced a SARS-CoV-2 variant (VUI 202012/01) now representing >50% of isolates in South East England. The variant shows 14 mutations resulting in amino acid changes and three deletions. Significant mutations in the receptor binding domain are N501Y and P681H. A deletion at position 69/70 affects the Spike (S)-gene. The variant increases transmissibility between 40-70%, adding 0.4 to R0 bringing it to 1.5-1.7. Investigations are ongoing to determine if this variant will change symptom severity, antibody responses or vaccine efficacy. Most PCRs target multiple sequences and therefore the impact of the variant on diagnostics is not anticipated to be significant.
    SAB Comment: In order to understand the epidemiology of any variant, widespread and frequent genetic sequencing of viral testing samples is needed. Currently, the US lags far behind the UK in this regard, sequencing ~1% of samples vs. >10% in the UK. Therefore, relatively little is known about the spread of the “UK variant” in the US.
  • Genetic mechanisms of critical illness in Covid-19. 12/11/20. Pairo-Castineira E. Nature.
    Oriented towards research, this genome-wide association study (GWAS) examined 2,244 critical COVID-19 patients in 208 UK ICUs to uncover gene variants that are severity markers and potential treatment targets. GWAS findings implicated antiviral restriction enzyme activators (OAS1/OAS2/OAS3), high tyrosine kinase-2 (TYK2), dipeptidyl peptidase- 9 (DPP9) and low interferon receptor gene IFNAR2. Mendelian randomization techniques implicated as “causal” low IFNAR2 and high TYK2 expression. Lung tissue transcriptome-wide association implicated high monocyte/macrophage chemotactic receptor CCR2. These gene alterations implicating early anti-viral defense (IFNAR2, OAS) and late inflammation (DPP9, TYK2, CCR2) can be evaluated in clinical trials using licensed drugs (interferons, JAK inhibitors, CCR2 inhibitors, etc.).

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Newsletter Issue 49, January 6, 2021:

  • Variation in US Hospital Mortality Rates for Patients Admitted With COVID-19 During the First 6 Months of the Pandemic. 12/22/20. Asch DA. JAMA Intern Med.
    This cohort study from a US-managed health company evaluated outcomes for 38,517 adults with COVID-19 admitted to 955 US hospitals during two time periods (January to April and May to June). The primary outcome was the hospitals’ risk-standardized event rate (RSER) of 30-day in-hospital mortality or referral to hospice, adjusted for patient-level characteristics. RSERs declined from 16.6% to 9.3%. Individual hospitals did better when the prevalence of COVID-19 in their surrounding communities was lower. The article speculates on possible causes for this improvement, including fewer overwhelmed hospitals, improved knowledge and medical care, and possibly smaller infective inoculums as mask-wearing became more common.
  • Factors Associated With Severe SARS-CoV-2 Infection. 12/16/20. Ouldali N. Pediatrics.
    This 60-hospital French national study used an established meningitis surveillance network to study demographics of COVID-19 pediatric patients. Data collection was from February 15-June 1, with 397 children and included an estimated 38.5% of the total cases in France. The primary outcome was the proportion of patients with disease progression, and secondary outcomes were defined by age groups. The median age was 16 months. Three percent of children (4/135) <90 days old developed severe disease. MIS-C increased with age. There was severe disease overall in 11% (23/306). Of the 6 mortalities only one was entirely due to COVID-19. Findings suggested that the rate of severe forms was the lowest in very young children and was the highest for children ≥ 10 years.
  • Corticosteroids for Patients With Coronavirus Disease 2019 (COVID-19) With Different Disease Severity: A Meta-Analysis of Randomized Clinical Trials. 12/10/20. Pasin L. J Cardiothorac Vasc Anesth.
    In this meta-analysis of 5 studies involving treatment with steroids of 7,692 COVID patients, the authors note that the effect of corticosteroids therapy on survival with COVID patient varies with different respiratory support. The use of corticosteroids may be detrimental to patients who do not require oxygen support (NNH/number needed to harm=29) and increases mortality. Its effectiveness for mechanically ventilated patients was (NNT/number needed to treat=19). The majority of COVID-19 patients not requiring oxygen/mechanical ventilation will have a better survival benefit without steroids.
  • Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. 12/15/20. van Paassen J. Crit Care.
    This well-conducted systematic review and meta-analysis to evaluate safety and effectiveness of corticosteroids in COVID-19 included 44 studies and 20,197 patients collected between December 1, 2019 and October 1, 2020. Primary outcomes were short-term mortality and viral clearance (based on RT-PCR in respiratory specimens). Secondary outcomes were need for mechanical ventilation, other oxygen therapy, length of hospital stay and secondary infections. Non-peer reviewed and pre-published manuscripts were excluded from analysis. Findings from observational studies and RCTs confirm beneficial effect of corticosteroids on short-term mortality and reduction in mechanical ventilation. A possible signal of delayed viral clearance and an increase in secondary infections was noted. Optimal timing, dose and duration of corticosteroids, in relation to safety, remain subjects for further investigation.
  • COVID-19 Convalescent Plasma Treatment of Moderate and Severe Cases of SARS-CoV-2 Infection: A Multicenter Interventional Study. 12/7/20. Alsharidah S. Int J Infect Dis.
    SAB Comment: This is a non-randomized observational study from Kuwait. Research is needed to determine patient groups that benefit.
    One hundred and thirty-five patients with moderate-severe COVID-19 disease who received 2 units of convalescent plasma (CP) within 3 days of hospital admission had an earlier and higher rate of clinical improvement compared with 233 control patients. Moderate disease was found in 86.5% of CP group (n=89) who had a time to clinical improvement of 7 days versus 68% of controls with time to clinical improvement of 8 days (p=0·006). Severe disease was found in 61% of CP group (n=46) with time to clinical improvement of 7 days vs. 35% of controls with time to clinical improvement of 15.5 days (p=0·003). Overall 30-day mortality was 18% CP group vs. 39% controls. Moderate disease patients had a significantly lower mortality following CP (11% vs. 30%, p= 0.001).
  • Masking the 6 Minutes-Walking-Test in the COVID-19 Era. 12/14/20. Salles-Rojas A. Ann Am Thorac Soc.
    A small study of 77 COVID-19 pneumonia survivors who each performed the 6-Minute Walking Test twice, once with a surgical or an N-95 mask and once without a mask. No differences were observed between wearing or not wearing a mask in the meters walked, SpO2, HR, dyspnea or fatigue.

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Newsletter Issue 48, January 4, 2021:

  • A Year in Review and Brief Survey

    The IARS COVID-19 Resource Newsletter is a unique resource for anesthesiologists, intensivists, and other front-line healthcare providers. Since launch of the newsletter last March, the COVID-19 Scientific Advisory Board (SAB) has screened more than 85,000 peer-reviewed journal articles to identify the information most useful for our intended audience. More than 1,750 articles have undergone thorough review by the SAB members, and 641 have been summarized by the SAB for the 88 issues of the newsletter we published in 2020. Unlike other society newsletters, the IARS newsletter pulls content from dozens of peer-reviewed journals to identify the information deemed most useful for physicians on the front lines and summarizes the key takeaways.

    We hope you are one of the thousands of physicians who are benefitting from this resource. We would appreciate you taking just a few minutes to complete a brief survey about our COVID-19 initiative. We also welcome your comments and questions at any time. Please direct them to Meghan Whitbeck, [email protected].

    Thank you for your interest.


    The COVID-19 Scientific Advisory Board

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Newsletter Issue 47, December 28, 2020:

  • Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. 12/11/20. Kalil AC. N Engl J Med.
    This article provides the encouraging outcome of a randomized trial enrolling 1033 patients in 8 countries, led by the team that conducted ACTT-1, the remdesivir randomized control trial. The oral anti-inflammatory drug baricitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, in combination with remdesivir, proved safe and superior to remdesivir alone for the treatment of hospitalized patients with COVID-19. While the primary outcome, time to recovery, improved by one day only, patients with impending respiratory failure benefitted most with progression to death or invasive ventilation being 31% lower in the combination group. The discussion includes a detailed review of the drugs’ potential dual action as an anti-inflammatory and antiviral and makes a pertinent comparison with dexamethasone and the RECOVERY trial.
    The incidence of side effects of JAK inhibitors (immunosuppression, secondary infections, and thrombosis) were not significantly higher when baricitinib was added.
  • On the whereabouts of SARS-CoV-2 in the human body: A systematic review. 10/30/20. Trypsteen W. PLOS Pathogens.
    This article is a well-presented review of available literature through June 2020. The strength of this paper resides in its focus on viral presence and evidence of replication and infectivity in different organ systems. It acknowledges the fact that the presence of an ACE2 receptor does not control viral cell entry per se. It concludes that while we have a good understanding of the presence and replication mechanisms in the respiratory system, a full understanding of the underlying mechanism of organ toxicity – direct viral, micro-vascular or inflammatory – in other systems (heart, kidney, CNS) remains inconclusive.
  • Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. 12/8/20. Diorio C. Blood Adv.
    This study, designed for researchers, examined 50 COVID-19 pediatric hospitalized patients for soluble C5b9 and thrombotic microangiopathy. C5b9 were found to correlate with the severity of disease and serum creatinine. Thrombotic microangiopathy was found in 17 of the 19 patients examined. These data help characterize COVID-19 disease in the pediatric population and help form the building blocks for further study.

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Newsletter Issue 46, December 21, 2020:

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Newsletter Issue 45, December 16, 2020:

  • Decontamination and Reuse of N95 Filtering Facepiece Respirators: Where Do We Stand? 12/15/20. Cassorla L. Anesth Analg.
    Interest in decontamination methods for N95 respirators increased during the COVID-19 pandemic along with shortages and altered practices in health care facilities. This is a well-referenced review of available science. Best-supported methods are based upon time, heat, microwave-generated steam, hydrogen peroxide, or UV-C (ultraviolet germicidal irradiation, UVGI). Many require special equipment and most require procedures to prevent cross-contamination and return each respirator to its original user due to the potential for residual organisms other than SARS-CoV-2. Tables include reference websites, a summary of methods, and current FDA emergency use authorizations.
  • Cardiac complications in patients hospitalised with COVID-19. 11/23/20. Linschoten M. Eur Heart J Acute Cardiovasc Care.
    This article shows results from a 3011 patient multi-national/institutional study designed to determine the role of cardiovascular (CV) disease in COVID-19 patients admitted to the hospital enrolled between April and June. Eleven and a half percent (349) of the patients had CV complications with AF 4.7% (142) being the most common. Eight hundred thirty-seven patients required ICU/high dependency unit, of which 87% required mechanical ventilation; overall mortality was 19.8%. Patients with pre-existing cardiac disease (ischemia, heart failure) were more likely to develop complications. Pulmonary embolism was reported in 6.6% of patients overall but was found in 18.9% of those who were admitted to the ICU. These results suggest that elevated troponin levels in absence of electro- or echocardiography abnormalities should be interpreted cautiously and may more likely be related to demand ischemia. The authors conclude that incidence of cardiac complications during hospital admission is low, despite frequent patient histories of pre-existing cardiovascular disease.
    SAB Comment: This article highlights difficulty in diagnosing primary cardiac complications from biomarkers alone. While not diagnostic, elevated troponin levels have been associated with increased mortality in COVID-19 patients as well as in other ARDS-associated conditions (e.g. septic shock, post-traumatic injury).
  • COVID-19 Associated Thrombosis and Coagulopathy: Review of the Pathophysiology and Implications for Antithrombotic Management. 11/24/20. Ortega-Paz L. J Am Heart Assoc.
    This is a comprehensive, well-written, albeit lengthy, review of COVID-19 pathophysiology and therapies. Cardiovascular, thrombotic, and coagulopathic manifestations are emphasized along with the importance of individual risk assessment for venous thromboembolism (VTE). Multiple validated VTE risk assessment tools are enumerated. A theory of imbalanced ACE/ACEII receptors as a risk factor for SARS-CoV-2 infection is discussed. Useful summary figures and tables include knowledge gaps and ongoing areas of research.
  • The ADAMTS13-von Willebrand factor axis in COVID-19 patients. 11/23/20. Mancini I. J Thromb Haemost.
    This study examines the VWF antigen to ADAMTS13 activity ratio in 50 COVID-19 hospitalized patients and demonstrates that this ratio was strongly associated with COVID-19 severity. Three groups of patients were studied, namely those receiving nasal oxygen, CPAP treatment, or intubation with ventilatory support. The authors suggest that these data represent potential new markers of disease severity and further support the concept of micro thrombogenesis in patients with severe COVID-19.
    SAB Comment: This is new scientific information to help understand pathophysiology of micro thrombosis but routine ADAMTS13 testing isn’t recommended.
  • Association of inhaled and systemic corticosteroid use with Coronavirus Disease 2019 (COVID-19) test positivity in patients with chronic pulmonary diseases. 12/4/20. Liao SY. Respir Med.
    This study of 928 patients tested at National Jewish Health respiratory hospital for COVID-19 found 113 (12%) were positive. Retrospective analysis showed that using inhaled corticosteroids was not associated with a change in the likelihood of testing positive for COVID-19. Being treated with systemic corticosteroids was actually associated with a slight decrease in the likelihood of testing positive for COVID-19, especially in patients with chronic pulmonary disease or airway diseases (asthma or COPD).
  • Controversies in airway management of COVID-19 patients: updated information and international expert consensus recommendations. 12/1/20. Wei H. Br J Anaesth.
    This editorial by a panel of international experts summarizes the COVID-19 airway management literature on the effectiveness of personal protective equipment (PPE), transmission of the virus during high flow nasal oxygen therapy (HFNO), and the debate over early vs. late intubation. Tables nicely summarize the examined literature. Their consensus includes:
    • The higher the PPE level, the better the protection.
    • There is no convincing evidence that HFNO increases the risk of COVID-19 cross-infection to healthcare workers.
    • Timing of intubation will depend upon individual pathophysiology, the trajectory of the illness, and the response to trials of noninvasive airway management.
    • More study is needed.
  • Tissue-specific Immunopathology in Fatal COVID-19. 11/20/20. Dorward DA. Am J Respir Crit Care Med.
    In eleven post-mortems these authors investigated whether inflammation is primarily a direct reaction to SARS-CoV-2 or an independent organ-specific immunopathologic reaction. Using multiplex PCR and in situ viral spike protein detection, SARS-CoV-2 organotropism was mapped. Multiple virus-independent aberrant immune responses mostly in lungs and reticuloendothelial system were found. These viral-independent immunopathologic features included monocyte/myeloid-rich pulmonary artery vasculitis, pulmonary parenchymal expansion of monocytes/macrophage-lineages and in the reticuloendothelial system, iron-laden macrophages and plasma cell responses. They concluded that a disconnect between viral presence and inflammation implicates immunopathology as a primary mechanism of organ injury in severe COVID-19.

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Newsletter Issue 44, December 14, 2020:

  • Loneliness, Mental Health, and Substance Use among US Young Adults during COVID-19. 10/28/20. Horigian VE. J Psychoactive Drugs.
    Frequently discussed in mass media, this paper presents the psychologic issues associated with the COVID-19 pandemic. In addition, intensivists and anesthesiologists should be aware of possible alcohol and drug use intended by the patient to relieve depression associated with this illness and its treatment.
  • Characteristics of Adults aged 18-49 Years without Underlying Conditions Hospitalized with Laboratory-Confirmed COVID-19 in the United States, COVID-NET – March-August 2020. 12/3/20. Owusu D. Clin Infect Dis.
    This article describes a Center for Disease Control-funded, cross-country study of non-pregnant adults younger than 50 years old providing the causes of hospital admissions due to COVID-19. While fever was a common presenting symptom, the illness primarily affected the pulmonary system. 22% were admitted to ICU although death occurred in <1%. 74% of patients were male and authors discuss the possibility of genetics linked to ACE2 receptor as a cause of infection severity.
    Of note, 42% of patients were Hispanic/Latino; treatment was not controlled; obesity and the use of steroids were not reported; 20% of patients were healthy prior to infection; 12% received remdesivir.
  • Repurposed Antiviral Drugs for Covid-19 – Interim WHO Solidarity Trial Results. 12/2/20. WHO Solidarity Trial Consortium. N Engl J Med.
    Beginning in March 2020, the WHO Solidarity trials enrolled 11,330 patients in 405 hospitals in 30 countries representing all six WHO regions and randomly assigned them to receive either remdesivir, lopinavir, hydroxychloroquine or interferon beta-1a regimens or to receive hospital-specific standard care. None of these drugs achieved the desired goal of a reduction in 28-day mortality. Except for remdesivir, all trials have since been discontinued.
    SAB Comment: Despite a negative outcome, this work is encouraging as it shows WHO’s capability to direct a rigorous global study protocol and a complex data collection and report it in a timely manner.
  • Early Percutaneous Tracheostomy in Coronavirus Disease 2019: Association With Hospital Mortality and Factors Associated With Removal of Tracheostomy Tube at ICU Discharge. A Cohort Study on 121 Patients. 11/17/20. Rosano A. Critical Care Medicine.
    This single-center Italian study reviewed outcomes of 121 COVID-19 patients treated with early percutaneous tracheostomy between 4 and 12 days (median 6) following ICU admission. Includes detailed discussion of rationale, inclusion criteria, methods, decannulation strategies and rehabilitation. Outcomes include procedural safety and efficacy for providers and patients, ability to decannulate survivors in ICU and trend to improved survival. Also discussed are improved/earlier weaning, and easier management and discharge from ICU. A useful comparison with other relevant studies is provided.
  • Early Percutaneous Tracheostomy During the Pandemic “As Good as It Gets”. 11/19/20. Auzinger G. Critical Care Medicine.
    This related editorial discusses percutaneous tracheostomy risk/benefit related to COVID-19 as well as other ICU conditions including ARDS and MERS. Strengths of the related article, the largest single-center study of percutaneous tracheostomy for COVID-19 disease, include a pragmatic approach relating to timing and choice of percutaneous vs. surgical approach based on well-described protocols for management and decannulation extant prior to the pandemic. This editorial compares the study’s strengths to others in literature and notes that while early tracheostomy may be considered a risk to the procedural team, the incidence of subsequent +COVID tests in participants was lower than in other ICU staff. This editorial amplifies Rosano’s manuscript and understanding regarding timing and potential benefits of early tracheostomy in COVID-19 patients.
  • SAB Comment: The following two articles address right ventricular dysfunction.
    • Pulmonary embolism in COVID-19 patients: Prevalence, predictors and clinical outcome. 12/3/20. Scudiero F. Thromb Res.
      This retrospective database study from 7 Italian hospitals looked over the echocardiogram results of 224 patients with COVID-19 of whom 14% had PE confirmed by CTA. The purpose was to identify which echocardiographic findings best predict pulmonary embolism. PE patients were hospitalized a longer time after symptom onset, showed higher D-dimer level and a higher prevalence of myocardial injury. At multivariable analysis, tricuspid annular plane systolic excursion (TAPSE) and systolic pulmonary arterial pressure were the only parameters independently associated with PE. Mortality rates (50% vs 27%; p = 0.010) and cardiogenic shock (37% vs 14%; p = 0.001) were significantly higher in PE patients.
    • Right ventricular dysfunction in critically ill COVID-19 ARDS. 11/26/20. Bleakley C. Int J Cardiol.
      Interesting observational study/retrospective analysis of RV echocardiographic data collected on 90 patients requiring invasive ventilation revealed that RV dysfunction was under-diagnosed with long axis views of the RV. Analysis noted radial measurement of RV dysfunction correlated with elevations in hs-Tn1 and NT pro-BNP, indicators of myocardial injury possibly related to high afterload. The authors suggest a new phenotype of RV dysfunction in COVID-19 not seen in other ARDS diagnoses. Of note, 42% of patients were receiving vino-venous ECMO. The authors suggest that findings that indicate hyperdynamic results on longitudinal views may represent a response to radial dysfunction. Excellent descriptions and tables are included.
  • No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2. 11/25/20. van Dorp L. Nat Commun.
    SARS-CoV-2 is not becoming more transmissible or virulent. In jumping from animal to human, SARS-CoV-2 might evolve or adapt toward higher transmissibility. This study examined whether viral changes have emerged repeatedly and independently (homoplasies) and if repeated mutations in human lineages made the virus more transmissible. Using a 99-country dataset of 46,723 SARS-CoV-2 genomes compared to the reference Wuhan-Hu-1, investigators did not identify a single recurrent mutation convincingly associated with increased viral transmission. So far, as an endemic human pathogen, recurrent mutations appear to be evolutionary neutral, single lineage and primarily induced via RNA editing, rather than being signatures of adaptive pressure and a new separate phenotype.

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Newsletter Issue 43, December 7, 2020:

  • Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients. 11/23/20. Jonmarker S. Crit Care.
    This is a retrospective analysis for 2 ICUs in Stockholm. In March, patients received low-dose LMWH and in April, all got medium- or high-doses. The baseline characteristics for these 152 COVID-19 patients were similar. For patients who received high-dose prophylaxis, 28-day mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low-dose (38.8%), p = 0.02. Hazard ratio was 0.33 among those who received high-dose prophylaxis. There were fewer thromboembolic events in the high- (2.7%) vs medium- (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. Bleeding rates were similar.
  • Incidence of venous thromboembolism and bleeding among hospitalized patients with COVID-19: a systematic review and meta-analysis. 11/17/20. Jiménez D. Chest.
    This is a systematic review with meta-analysis of the world’s incidence of DVT, PE and bleeding with COVID-19. The paper offers a snapshot but also analyzes the data and points to the way forward. Forty-eight studies were selected with 18,093 patients with VTE in 17% (2/3 with DVT) and any bleeding event in 7.8%. The authors point out that this varies with whether VTE was detected by duplex screening or clinical diagnosis, percentage of ICU patients and the degree of anticoagulation. The authors point out the lack of optimal strategies and the need for controlled trials.
  • A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. 11/24/20. Simonovich VA. N Engl J Med.
    Convalescent plasma with a median titer of 1:3200 of total SARS-CoV-2 antibodies was administered a median of 8 days after the onset of symptoms to 228 hospitalized patients with severe COVID-19 pneumonia. Placebo was administered to 105 patients. Other therapy was not standardized. After 30 days there was no significant difference in outcome. Adverse effects of plasma transfusion could not be evaluated. This also suggests that passive immune therapy with monoclonal antibodies may not be beneficial to such a population.
    SAB Comment: Other studies indicate that antibodies administered early after onset of symptoms to patients with mild disease are beneficial.
  • Association Between ABO and Rh Blood Groups and SARS-CoV-2 Infection or Severe COVID-19 Illness: A Population-Based Cohort Study. 11/24/20. Ray JG. Ann Intern Med.
    This population-based study of adults and children who had previous ABO blood group assessed, and who subsequently had SARS-CoV-2 testing found that O (adjusted odds ration 0.89) and Rh− (adjusted odds ration 0.80) blood groups may be associated with a slightly lower risk for SARS-CoV-2 infection and severe COVID-19 illness. Data came from 225,556 persons with a + PCR test for SARS-CoV-2 between 15 January and 30 June 2020 of 2,659,328 who had ABO/Rh measured during 2007-2019 in Ontario, Canada, a province with universal health care.
  • SARS-CoV-2 analysis on environmental surfaces collected in an intensive care unit: keeping Ernest Shackleton’s spirit. 11/23/20. Escudero D. Intensive Care Med Exp.
    This study analyzed environmental contamination by SARS-CoV-2 of surfaces in a Spanish intensive care unit dedicated exclusively to the care of patients with COVID-19 and equipped with negative pressure of – 10Pa and an air change rate of 20 cycles per hour. None of 102 surface samples collected at different times of day over 2 weeks were positive by RT-PCR nor did any of the 237 ICU workers become infected by the virus. The ICU was cleaned with detergent and sodium hypochlorite twice daily. Authors discuss the contrast with studies sampling surfaces in other institutions.
  • Assessment of 135,794 Pediatric Patients Tested for Severe Acute Respiratory Syndrome Coronavirus 2 Across the United States. 11/23/20. Bailey LC. JAMA Pediatr.
    This is an epidemiologic, retrospective study of 135,794 patients younger than 25 years old tested for SARS-CoV-2 during the first 9 months of 2020 — 3% of the nation’s 2.5 million children — in a country-wide study of a consortium of children’s hospitals admissions. An overall low positive COVID-19 rate of 4% was found. Black, Hispanic and Asian youth were underrepresented yet produced higher positive results. Of the 5374 children testing positive, only 359 were hospitalized and 8 died. Six of the deaths had complex preexisting comorbidities.
    Preexisting respiratory and cardiac morbidity was not a significant issue in those hospitalized. Endocrine, metabolic and malignancy-associated illnesses were linked to hospitalizations from COVID-19. Obesity was not defined.
  • SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. 11/19/20. Cevik M. Lancet.
    This meta-analysis of 79 COVID-19 articles characterized viral load kinetics and dynamics, duration of viral RNA shedding, and viable virus shedding. Despite evidence of prolonged SARS-CoV-2 RNA shedding (mean 17 days) in respiratory samples, viable virus shedding appears to be short-lived (9 days maximum). Therefore, RNA detection cannot be used to infer infectiousness. High titers of SARS-CoV-2 RNA are detected from symptom onset to day 5 of illness, which probably explains the efficient spread of SARS-CoV-2 compared with SARS-CoV and MERS-CoV. These findings emphasize the importance of early case finding and prompt isolation.
  • Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. 11/30/20. Meinhardt J. Nature Neurosci.
    Viral penetrance of the CNS is likely through diverse routes. These investigators demonstrate in 33 autopsies morphological changes associated with SARS-CoV-2 neurotropism, such as thromboembolic ischemic infarction of the CNS and the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. By exploiting the proximity of olfactory mucosal, endothelial and nervous tissue, including olfactory and sensory nerve endings, virus can cross into the olfactory CNS. Subsequently, SARS-CoV-2 appears to penetrate other areas of the CNS, including the primary respiratory and cardiovascular control centers in the medulla oblongata.

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Newsletter Issue 42, December 2, 2020:

  • Decline in SARS-CoV-2 Antibodies After Mild Infection Among Frontline Health Care Personnel in a Multistate Hospital Network – 12 States, April-August 2020. 11/27/20. Self WH. MMWR Morb Mortal Wkly Rep.
    In this MMWR/CDC regarding 156 (median age 38, 94% female) frontline health care personnel who had a positive COVID-19 antibodies test result, 94% experienced a decline at repeat testing 60 days later and 28% sero-reverted to below the threshold of positivity. Health care workers with robust antibody responses were more likely to have a slower antibody decay. Whether the slimmer response of the antibody increases risk for reinfection remains unanswered. These results suggest that serology testing at a single point in time is likely to underestimate infection and a negative serologic test result might not reliably exclude prior infection.
  • Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020. 11/24/20. Bajema KL. JAMA Intern Med.
    Residuals of 177,919 serum samples collected for non-COVID-19 tests by two US national commercial clinical labs were retested for antibodies to SARS-CoV-2. Four sets of samples from every state were tested from periods in late July to late September 2020. Seroprevalence varied from 23% for New York State to less than 1% for several states and was less than 10% for the vast majority of states. Nowhere was seroprevalence close to the 60% to 80% estimated to be necessary to achieve herd immunity. An excellent figure summarizes the results for each period in all 50 states.
  • Comprehensive health assessment three months after recovery from acute COVID-19. 11/21/20. van den Borst B. Clin Infect Dis.
    This is a well-performed and conducted study on 124 mild (not admitted), moderate and severe (ICU survivors) COVID-19-positive patients at 3-month follow-up. The comprehensive (anthropometric, psycho-social, exercise tolerance, frailty, social coping, PTSD, etc.) study indicates that significant abnormalities persisted in majority of patients irrespective of initial illness severity. Improvement in lung radiography was present in severe cases, but pulmonary function remained mildly depressed including decreasing pulse oximetry on 6-minute walk test. The conclusion is that COVID-19, as previously noted, presents long-term health care challenges including physical, psychological, neurologic and quality of life which could lead to significant future personal and societal health care burden.
  • Aerosol Retention Characteristics of Barrier Devices. 10/30/20. Fidler RL. Anesthesiology.
    Investigators studied 6 barriers designed to protect health care professionals from potentially infectious aerosolized particles during airway interventions. Particle counters and mass spectrometry were used to evaluate particle spread following experimental aerosol generation and simulated cough. Performance varied widely, with closed devices performing best. Some increased exposure to the operator compared with no device. Addition of smoke evacuation techniques (e.g. suction) was also evaluated. All barriers should be used in conjunction with appropriate PPE.
    An accompanying editorial discusses the importance of bioaerosol science to mitigate disease transmission in health care settings. Current experimental aerosol models remain imperfect surrogates for airborne viral disease transmission. Collaboration with bioaerosol scientists is lauded.
  • Veno-venous extracorporeal membrane oxygenation allocation in the COVID-19 pandemic. 11/21/20. Murugappan KR. J Crit Care.
    This is a well-researched and referenced discussion regarding appropriate allocation and utilization of VV-ECMO based on institutional practice. It includes ethical, practical and decision-maker considerations as well as preemptive end-of-life care discussions in severe cases. It introduces the concept of a “bridge to nowhere,” i.e., when the decision to prolong life mechanically has no future alternative/resolution. The article discusses the importance of clear communication between the health care team and patient/family consortium. It highlights the importance of clear understanding of ethical and practical implications of initiation and utilization of a scarce resource.

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Newsletter Issue 41, November 30, 2020:

  • SAB Comment: Interferon (IFN) gets its name because it “interferes” with viral replication. Suspecting that interferon is inadequately produced and/or its actions blocked, two important Science papers (below) examined possible mechanisms. Zhang et al, reports finding loss of function gene variants in 3.5% of severe COVID-19 patients that control induction and amplification of Type I IFNs. The effects of these lifelong inborn variants, not found in mild disease or healthy controls, are only exposed with development of severe viral pneumonia. In the other paper, Bastard, et al, found (presumed preexisting) high-titer IgG neutralizing autoantibodies against Type I IFNs-alpha and -omega only in severe COVID-19. The autoantibodies occur in at least 2.6% of women and 12.5% of men. The defects identified by Zhang, et al, if discovered early on, could be treated with Type I IFNs, and by Bastard et al, treated with Type I IFN-beta in particular, as autoantibodies against IFN-beta are rare.
    • Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. 10/23/20. Zhang Q. Science.
      These authors examined 659 severe COVID-19 patients for mutations in genes involved in the regulation of type I and III interferon (IFN) immunity. Following exome or genome sequencing examining rare variants at 13 candidate loci they found genetic defects in 3.5% of severe patients at eight of the 13 candidate loci involved in the TLR3- (double stranded RNA-responsive) and Interferon-regulatory factor-7 (IRF7)-dependent induction and amplification of type I IFNs. These variants resulted in enrichment of loss of function variants not found in mild COVID-19 patients or healthy individuals. Early type I IFN administration may benefit patients with these inborn variants.
    • Autoantibodies against type I IFNs in patients with life-threatening COVID-19. 10/23/20. Bastard P. Science.
      In COVID-19 pneumonia, at least 101/987 patients had low or undetectable serum IFN-α and high-titer neutralizing IgG autoantibodies (auto-Abs) against interferon-omega (IFN-ω) (13 patients), against the 13 types of IFN-α2 (n=36), or against both (n=52). In vitro, auto-Abs blocked IFNs inhibition of SARS-CoV-2. Auto-Abs were not present in asymptomatic or mild SARS-CoV-2 infection (n=663) and in only 4/1227 healthy individuals; 95/101 with auto-Abs were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity (seen in Zhang) accounts for life-threatening COVID-19 in at least 2.6% of women and 12.5% of men who could be treated with IFN-beta.
  • COVID-19-associated Non-Occlusive Fibrin Microthrombi in the Heart. 11/16/20. Bois MC. Circulation.
    This study represents new data in autopsy results from patients with COVID-19 (n=15), influenza A/B (n=6), and non-virally mediated deaths (n=6). There were 12 COVID-19 cases with non-occlusive microthrombi and 2 cases each in the other groups. Focal myocarditis was seen in 4 active COVID-19 patients limited in extent. Direct invasion of the virus into myocardial cells was not seen. The authors conclude that the high incidence of microthrombi in the cardiac vascular system is a potential reason to use anticoagulants in these patients. A higher risk of complications including death may be seen in patients with cardiac disease, particularly those with amyloidosis.
  • Delirium in Older Patients With COVID-19 Presenting to the Emergency Department. 11/19/20. Kennedy M. JAMA Netw Open.
    Delirium at presentation occurred in 28% of patients older than 65 years presenting to 7 US Emergency Departments. In this retrospective chart review, a total of 817 patients (mean age 78) with COVID-19 were analyzed and 16% presented with delirium as a primary symptom. Associated conditions and multivariant risk factors were identified, and impaired consciousness was listed as the predominant symptom occurring in 54% of patients with a delirium diagnosis. Delirium as a leading symptom is frequently underreported but associated with adverse outcomes and hence an important marker for poor patient outcomes (ICU stay, intubation and hospital death).
  • Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. 10/29/20. COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators. Intensive Care Med.
    In this multi-center (149 ICUs) European cohort study, the results of 4244 COVID-positive patients admitted 02/25-05/04 with ICU and 90-day follow-up were reported; ARDS severity, ventilator management and outcome at 90 days. Detailed demographic information, ventilator management, laboratory findings, ICU LOS, additional interventions and 90 day outcome reported. Overall mortality was 31% with a decrease in overall mortality noted during study; mortality was higher in older, immunocompromised, obese, diabetic patients and those with increasing ARDS severity. Higher mortality was noted in patients with shorter time between first symptoms and ICU admission.
  • SARS-CoV-2 has displaced other seasonal respiratory viruses: results from a prospective cohort study. 11/15/20. Poole S. J Infect.
    This is a study performed in a county in South East England on the English Channel coast of viral PCR results of tests done from March through May on patients with respiratory symptoms in the emergency department or acute care ward in most of years from 2015 through 2020. Before 2020, a non-SARS-CoV-2 virus was detected in 54% patients (202/371) compared to only 4.1% (20/485) in 2020. SARS-CoV-2 was associated with asthma or COPD exacerbations in a smaller proportion of infected patients compared to other viruses (1.0% vs 37%).

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Newsletter Issue 40, November 23, 2020:

  • SAB Comment: These two studies used data from the same database.
  • Diaphragm Pathology in Critically Ill Patients With COVID-19 and Postmortem Findings From 3 Medical Centers. 11/16/20. Zhonghua S. JAMA Internal Med.
    This research letter describes evaluation of autopsy specimens of diaphragm muscle obtained from 26 consecutive deceased COVID-19 patients, 24 of whom had been on mechanical ventilation for a mean of 12 days. Specimens from 8 deceased non-COVID-19 patients mechanically ventilated for a similar amount of time were used as a control group. ACE-2 receptors were present on diaphragm myofiber membranes in all patients. Viral RNA was found in the myofibers of 4 of the 26 COVID-19 patients. Significantly more fibrosis was present in the diaphragms of the deceased COVID-19 patients than in the diaphragms of the control patients predicting more diaphragmatic weakness in the COVID-19 patients.
  • Influence of room ventilation settings on aerosol clearance and distribution. 11/16/20. Sperna Weiland NH. Br J Anaesth.
    This study from the Netherlands used actual hospital rooms and ventilation systems to measure the clearance of aerosols after a simulated aerosol generating procedure. Higher air exchange rates were much more effective than manipulating the pressure gradient (i.e. negative or positive pressure rooms). A freestanding air purification unit also markedly improved aerosol removal. In positive pressure rooms, small amounts of aerosol were detected in adjacent hallways. This information could be useful when deciding on the best location for aerosol-generating procedures in SARS-CoV-2 infected patients.
  • Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. 11/15/20. Monk PD. Lancet Respir Med.
    A small company-sponsored pilot study comparing the clinical course of 48 patients treated for 14 days with a daily dose of nebulized interferon beta-1a to the clinical course of 50 placebo-treated patients as assessed by 9-point WHO Ordinal Scale for Clinical Improvement [OSCI]. Patients receiving the medication had greater odds of improvement on the OSCI scale (odds ratio 2.32) and a higher percentage of recovered patients (58% vs 35%) at the end of the observation period (day 28). The medication was well tolerated compared with placebo. Larger studies are planned. These results contrast with the absence of effect noted in a prior trial of interferon beta-1a given subcutaneously.
  • Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. 11/6/20. Ng K. Science.
    Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, these investigators examined preexisting humoral immunity to the novel and older coronaviruses in humans. Using flow cytometry, predominately IgG class cross-reacting antibodies particularly targeting the S2 subunit of the spike glycoprotein were detectable in the SARS-CoV-2-uninfected, especially children and adolescents. SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies, targeting both proteolytically-cleaved S1 (attachment) and S2 (entry) subunits, along with contemporaneous IgM and IgA. Notably, SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Cross-reacting immunological memory may be critical to understand susceptibility to SARS-CoV-2 infection.
  • Immune suppression in the early stage of COVID-19 disease. 11/18/20. Tian W. Nat Commun.
    Using elegant quantitative advanced mass spectrometry proteomics and integrated data analysis with hierarchical clustering and functional correlational network strategies, these authors analyzed urine samples from COVID-19 (n=14), non-COVID-19 pneumonia cases (n=13) and healthy donors (n=10). A total of 5991 proteins were identified; 1986 proteins were significantly changed in the COVID-19 vs the other groups. More than 10 pathways significantly changed and 10x were more down-regulated than up-regulated. Showing heatmaps and protein interaction diagrams, the molecular signatures suggested a two-stage pathogenesis: immunosuppression and tight junction/cell-cell adhesion impairments early on and an activated immune response in late stages of severe COVID-19 pneumonia.

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Newsletter Issue 39, November 18, 2020:

  • Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe. 11/9/20. Valverde I. Circulation.
    A European multi-institutional study of 287 children admitted with COVID-19 demonstrated a high incidence of cardiac involvement. Most children admitted suffered GI symptoms, rash and conjunctival changes in addition to cardiac involvement. Forty percent presented with cardiac shock. Markers of cardiac involvement were present on admission including D-dimers. Treatment was not controlled. 286 were eventually discharged. Twenty-five percent had a diagnosis of coronary artery dilation by echocardiography, requiring follow-up.
  • Review of Cardiac Involvement in Multisystem Inflammatory Syndrome in Children. 11/9/20. Alsaied T. Circulation.
    Though the prevalence of multisystem inflammatory syndrome in children is unknown, there have been more than 300 cases now reported in the literature. It is more common in the US in Black and Hispanic children; typically occurs a few weeks after acute infection and the putative etiology is a dysregulated inflammatory response to SARS-CoV-2 infection. Persistent fever and gastrointestinal symptoms are the most common symptoms. Cardiac manifestations are common and include ventricular dysfunction, coronary artery dilation and aneurysms, arrhythmia and conduction abnormalities, vasodilatory or cardiogenic shock requiring fluid resuscitation, inotropic support, and in the most severe cases mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Most patients recover within days to a couple of weeks and mortality is rare. Long-term cardiovascular complications are not yet known.
  • Comparison of Clinical Features and Outcomes in Critically Ill Patients Hospitalized with COVID-19 versus Influenza. 11/13/20. Cobb NL. Ann Am Thorac Soc.
    This is a retrospective cohort analysis “case matching” 74 seasonal influenza with 65 COVID-19 patients from 01/01/19 to 04/15/20. Diagnoses were confirmed by RT-PCR and ICU courses studied. COVID-19 patients had different demographics, longer prodrome, increased numbers of presenting symptoms and co-morbidities, higher incidence of ARDS, longer duration of mechanical ventilation and higher mortality. Includes an interesting discussion with tables.

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Newsletter Issue 38, November 16, 2020:

  • Prone position in ARDS patients: why, when, how and for whom. 11/10/20. Guérin C. Intensive Care Med.
    This is a thorough and excellent review of the use of prone position in ARDS including a detailed explanation of its effects on pulmonary physiology, gas exchange and hemodynamics. The significant benefits in mortality are discussed. As noted in many studies, the improvement in mortality does not correlate with the degree of oxygenation improvement but appears more likely to be related to a decrease in ventilator-induced lung injury. Specific recommendations and cautions for practical application are provided. The use of prone positioning in spontaneously breathing, non-intubated patients is commonly used with COVID-19, and studies are planned to verify if this strategy can reduce the rate of intubation and improve survival.
  • Current and evolving standards of care for patients with ARDS. 11/6/20. Menk M. Intensive Care Med.
    Written by an international group of experts, this narrative review is a succinct and up-to-date review of caring for ARDS and COVID-ARDS patients, and is very useful for a frontline worker wanting a broad overview. It briefly explains the studies that establish the current standards and discusses therapies of promising interest (evolving standards). Nicely summarized in a table and discussed in the text are: ventilatory management (tidal volume, PEEP, driving pressure, mechanical power, etc.), ventilation adjuncts (proning, neuromuscular blockade, ECMO, etc.) and pharmacotherapy (steroids, fluid therapy, etc.).
  • Neutrophil extracellular traps and thrombosis in COVID-19. 11/5/20. Zuo Y. J Thromb Thrombolysis.
    Forty-four patients with COVID-19 had blood collected for neutrophil extracellular traps (NETs) and neutrophil activation. Eleven of these patients developed thrombosis despite at least prophylactic heparin. Thrombosis in COVID-19 was associated with higher levels of circulating NETs and calprotectin (neutrophil activation). These data further add to the characterization of COVID-19 and the stepwise understanding of how to combat the epidemic.
  • Frequency of venous thromboembolism in 6513 patients with COVID-19: a retrospective study. 11/2/20. Hill JB. Blood Adv.
    This single health-system venous thromboembolism (VTE) study described the use of standard heparin or LMWH prophylaxis in most of the 6513 COVID-19 patients. Dose was increased if BMI >40 and decreased if creatinine clearance < 30. Ninety-day VTE rate was 2.2% (n=86) when receiving prophylaxis vs. 11% without. Eighty-four of 86 VTE patients had received prophylaxis. PADUA Score was high in 89%. Including arterial thrombosis in 7 patients, the overall incidence of VTE was 3.1% and 7.2% if mechanically ventilated. Fifty percent inpatient VTEs met the definition of prophylaxis failure. Only three of 2075 hospitalized patients (0.14%) without VTE surviving to discharge had VTE after discharge. The authors conclude these data support a traditional approach to VTE prophylaxis both during and following hospitalization.
    SAB Comment: We note a surprisingly low rate of VTE in this large, retrospective study, equally divided between DVT and PE. It did not include thrombosis in the microcirculation or ECMO circuit. Most were failures or breakthroughs on VTE prophylaxis. One may question the use of so few risk factors for modification of standard dosing and the conclusion that the data support a traditional approach.

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Newsletter Issue 37, November 11, 2020:

  • SAB Comment: The following two articles confirm what was previously summarized in an earlier editorial.
    • Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. 10/16/20. Leisman. Lancet.
      The hypothesis that a “cytokine storm” occurring later in severe COVID-19 disease may be causative for the excess inflammatory response noted in terminal disease has provoked studies of anti-cytokine therapies, specifically interleukin-6 antagonists. This systematic review and meta analysis of studies published between November 1, 2019 and April 14, 2020, including interleukin-6 levels in the results, compared cytokine levels in four disease categories associated with elevated levels: sepsis (5,320); cytokine release syndrome (72); ARDS unrelated to COVID-19 (2,767); and COVID-19 (1,245). While COVID-19 levels were raised, the mean interleukin-6 levels in all three other conditions were statistically higher than noted in COVID (e.g. 27 times higher in sepsis and 12 times higher in non-COVID ARDS while over 1,000 times in CRS). The authors question the impact of a “cytokine storm” in COVID-19 organ dysfunction. Other arguments offered a detailed, well-presented discussion.
    • Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions. 9/3/20. Kox. JAMA.
      This retrospective, single-center study admitted 204 patients between 2010 and 2020 with sampling recorded plasma concentrations of proinflammatory cytokines TNF, IL-6 and IL-8 and determined (2020) in consecutively ventilated COVID-19 patients (49) with ARDS. Previously recorded levels in patients with bacterial septic shock with ARDS (51), septic shock without ARDS (15), out-of-hospital cardiac arrest (30), and multiple traumas (62) were compared with those from the COVID-19 population. COVID-19 patients had higher BMI, co-morbidities and cardiac dysfunction; however, cytokine levels were lower than in other diseases mentioned questioning the importance of a “cytokine storm” as a primary therapeutic target in COVID-19 disease.
  • Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients. 11/4/20. Zotzmann V. J Thromb Thrombolysis.
    This article presents the results of a retrospective evaluation of 20 ICU COVID-19 patients who had all undergone CT pulmonary angiography and lung ultrasound for suspected pulmonary emboli in a tertiary referral ARDS/ECMO center. The study showed that subpleural consolidations ≥ 1cm detected in lung ultrasound were found frequently in COVID-19 ARDS patients with pulmonary embolism. By combining a Wells score ≥ 2 and a lung ultrasound showing subpleural consolidations, PE could be predicted with a sensitivity of 100% and a specificity of 80% in these 20 patients, 12 of whom were found to have pulmonary emboli by CT pulmonary angiography.
  • Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy – SET-NET, 16 Jurisdictions, March 29-October 14, 2020. 11/5/20. Woodworth KR. MMWR Morb Mortal Wkly Rep.
    The authors of this article about pregnant women with SARS-CoV-2 state, “Among 3,912 infants with known gestational age born to SARS-CoV-2 infected women, 12.9% were preterm (<37 weeks), higher than a national estimate of 10.2%. Among 610 (21.3%) infants with testing results, 2.6% had positive SARS-CoV-2 results, primarily those born to women with infection at delivery.” Half of positive infants were preterm. Median maternal age was 28.9 years. Forty-six percent were Hispanic/Latina. One or more underlying medical condition was reported for 45.1%. Pre-pregnancy obesity was the most common (35.1%). Eight-four point four percent had infection identified in the third trimester. None had neonatal IgM, placental tissue or amniotic fluid testing; thus, routes of transmission could not be assessed.

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Newsletter Issue 36, November 9, 2020:

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Newsletter Issue 35, November 4, 2020:

  • Characterization of Myocardial Injury in Patients With COVID-19. 10/30/20. Giustino G. J Am Coll Cardiol.
    This retrospective, international, multicenter cohort study (7 hospitals in NYC and Milan) reviewed 305 patients with documented RT-PCR COVID-19 diagnosis with myocardial injury diagnosed at admission or during hospitalization. Inclusion criteria included elevated cardiac troponins, EKG abnormalities and full TTE examination. Findings indicated that severity of cardiac disease indicated by serial increases in troponins associated with graded TTE abnormalities (none, moderate, severe) was a useful prognostic indicator of outcome. Of 305 patients, myocardial injury was documented by elevated troponins in 190 (62.3%). When compared with patients with no myocardial injury, increasing severity of myocardial injury was associated with increased mortality with discrimination noted between “no” and minor TTE abnormalities versus significant abnormalities and increased inflammatory biomarkers and troponins. Effects of co-morbidities and BMI were noted as additional risk factors for myocardial damage and TTE abnormalities.
  • Cardiac Injury in COVID-19-Echoing Prognostication. 10/30/20. Lavie CJ. J Am Coll Cardiol.
    This editorial is best summarized in the following direct quote underlining the importance of the Giustino et al manuscript. “The current recommendations of the American College of Cardiology (ACC) endorse the measurement of cTn levels when a diagnosis of acute myocardial infarction is being considered in patients with SARS-CoV-2 infection. This indication seems somehow inadequate according to the information collected by Giustino et al. (above), (12), whereby there is now evidence that Tn-positive COVID-19 patients may benefit from routine TTE, which would allow practitioners to garner useful prognostic information and to establish specific therapeutic options in patients with cardiac injury.” An excellent discussion and table are included in the editorial.
  • Characteristics of cardiac injury in critically ill patients with COVID-19. 10/24/20. Doyen D. Chest.
    This prospective study of 43 consecutive COVID-19 positive patients admitted to two French ICUs was designed to characterize incidence and time course of cardiac injury by serial measurements of cardiac biomarkers (troponin), EKGs and echocardiographic investigations. Extensive cardiac involvement documented with 49% demonstrating injury on ICU admission and 70% experiencing injury within the 14-day observation window. New atrial dysrhythmias, and RV and LV systolic as well as diastolic dysfunction noted with greater RV systolic dysfunction associated with increased disease severity. Conclusion: Cardiac injury is common in COVID-19, occurs early in disease, and patients with injury exhibit more RV than LV systolic dysfunction.

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Newsletter Issue 34, November 2, 2020:

  • Venous Thromboembolism in COVID-19. 10/25/20. Schulman S. Thromb Haemost.
    This is an excellent review regarding the mechanisms and pathogenesis of the disease biomarkers and their clinical usefulness. Risk assessment models are discussed as well as the type and strength of prophylaxis based on available evidence. Recommendations or position statements from 10 sources are discussed along with treatment recommendations according to current guidelines. Thrombosis prophylaxis with low molecular weight heparin is recommended for most hospitalized patients along with a recommendation against escalating anticoagulant doses. Therapeutic anticoagulation is advised only in response to a very high suspicion or in the presence of documented venous thromboembolism. An excellent algorithm regarding VTE treatment is presented.
  • Aspirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19. 10/23/20. Chow JH. Anesth Analg.
    This multi-center cohort study of 412 COVID-19 patients explored the theory that aspirin’s anti-platelet and anti-inflammatory properties might be beneficial in lowering the risk of serious outcomes. Ninety-four patients who had taken aspirin within 7 days of admission were compared with 314 patients who had not. Aspirin use was independently associated with decreased hazard ratio (HR) of mechanical ventilation (HR 0.56), ICU admission (HR 0.57), and in-hospital mortality (HR 0.53). There were no differences in major bleeding (p=0.69) or overt thrombosis (p=0.82) between aspirin users and non-aspirin users and confounding variables were carefully controlled. Potential mechanisms are discussed including aspirin’s ability to lower interleukin-6, C-reactive protein, and macrophage stimulation. Randomized controlled trials are necessary to confirm these results.
  • Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomized controlled trial (PLACID Trial). 10/22/20. Argwal A. BMJ.
    A randomized, controlled trial of convalescent plasma (CP) in 227 treated and 224 control hospitalized patients with moderate COVID-19 from 39 hospitals in India. Patients who received 200 ml of CP x 2 had less dyspnea and fatigue and a 24% higher rate of negative PCR on day 7 (P<0.05). No difference in the levels of inflammatory markers such as ferritin, C-reactive protein, D-dimer, or LDH was observed. However, there was no difference in progression to severe disease or mortality at 28 days between groups, including a subgroup of patients who received plasma with neutralizing antibody titers >1:80.
  • Convalescent plasma is ineffective for covid-19. Lessons from the Placid Trial. 10/22/20. Pathak EB. BMJ.
    In light of the prevalence of micro-thrombosis and the large number of thrombotic complications in COVID-19 patients, authors of this accompanying editorial highlight the pro-thrombotic properties of plasma and recommend that future blinded convalescent plasma (CP) trials exclude plasma without detectable neutralizing antibodies or treatment of control groups with other plasma. They point out that coagulation-related events in previous CP trials were not rigorously screened for their potential relationship to the treatment.
  • SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. 10/28/20. Chen P. N Engl J Med.
    This BLAZE-1 phase 2 interim safety analysis involved 452 mild or moderate COVID-19 outpatients within three days of diagnosis. In a study funded by Eli Lilly, patients received a single infusion of spike-protein-RBD neutralizing antibody LY-CoV555 in one of three doses (700, 2800 or 7000 mg) or placebo. Change from baseline viral load by quantitative RT-PCR at day 11 was the primary outcome and decreased in all groups. Only the middle, 2800 mg dose significantly diminished load more than placebo at day 11. All doses reduced symptoms on days 2-6, and hospitalizations (1.6% vs. 6.3%), particularly in high-risk cohorts. Although 70% had high-risk co-morbidities, no deaths occurred.
  • Awake prone positioning for COVID-19 hypoxemic respiratory failure: A rapid review. 10/23/20. Weatherald J. J Crit Care.
    Using a “rapid review” technique, these authors from Calgary synthesize 35 studies (none randomized) evaluating the effect of awake proning in 414 COVID-19 patients with respiratory failure. All but one study showed improvement in oxygenation while prone, but generally not sustained when returned to the supine position. 29% of patients went on to require intubation. The authors conclude that “many questions remain unanswered when considering the use of awake prone positioning.”
  • COVID-19 Gastrointestinal Manifestations Are Independent Predictors of PICU Admission in Hospitalized Pediatric Patients. 10/26/20. Gonzalez Jimenez D. Pediatr Infect Dis J.
    This multicenter Spanish brief report describes 91 patients with an average age of 10. GI symptoms were the initial cause for reporting ill in 10% of children. 40% were found to have elevated LFTs. Children overall were less ill than adults; however, all 11 severely ill children suffered GI symptoms.
    SAB comment: Although pediatric cases are uncommon compared to adults with multi-system illness, GI symptoms might be overlooked in children and are significant in the progress of the disease.
  • Improving Survival of Critical Care Patients With Coronavirus Disease 2019 in England: A National Cohort Study, March to June 2020. 10/26/20. Dennis JM. Crit Care Med.
    This retrospective, observational study of COVID-19 inpatients reviewed mortality by week of admission. High dependency unit (n = 15,367) survival went from 71.6% in March/April to 92.7% in May/June while ICU (n = 5,715) went from 58% to 80.4% in the same time period. The authors attributed this to the introduction of effective treatments as part of the RECOVERY trial, improved physician understanding of the disease process, and a falling critical care burden rather than to any changes in age, sex, ethnicity or major comorbidity burden in the patient population.

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Newsletter Issue 33, October 28, 2020:

  • Sensible Medicine—Balancing Intervention and Inaction during the COVID-19 Pandemic. 10/15/20. Seymour CW. JAMA.
    This article, which contains a discussion relevant for all practitioners engaged in clinical care cautions against abandoning clinical experience and consultation for early adoption of unproven and potentially harmful therapies. The authors urge that practitioners use sensible medicine, a blend between doing nothing and going all in. Their argument is well illustrated and supports the current therapeutic state in which good clinical care in well-managed ICUs following established protocols appears to be effective management strategy. No therapeutic agent has demonstrated significant mortality benefit with the exception of dexamethasone administered appropriately. The discussion supports the decision to steer a middle course with elegance and logic and is refreshing, timely and relevant.
  • Time to Reassess Tocilizumab’s Role in COVID-19 Pneumonia. 10/20/20. Parr JB. JAMA Intern Med.
    The author’s conclusions in this excellent editorial are informed by three studies (two are randomized prospective) reported in this issue of JAMA Internal Medicine and by two additional randomized prospective studies (not including the NEJM study cited below). Although observational studies by the STOP-COVID investigators and others report mortality benefit and other positive outcomes, findings from the randomized prospective trials described herein (total of 542 patients treated) do not support routine tocilizumab use in COVID-19. A well-constructed summary table of the five studies is provided.
  • Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. 10/21/20. Stone JH. N Engl J Med.
    This is a prospective, randomized, placebo-controlled study where treated patients received a single dose of 8mg/kg of tocilizumab (161 of 243 enrolled patients). The results showed that tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19.
  • Physiological and quantitative CT-scan characterization of COVID-19 and typical ARDS: a matched cohort study. 10/21/20. Chiumello D. Intensive Care Med.
    This detailed Italian physiologic study compared 32 COVID-19 ARDS (CARDS) patients with two other matched historical groups of typical ARDS patients; one matched with the CARDS patients by SpO2/FiO2, and one matched by respiratory compliance. As noted previously by this group (but not some studies by other groups), they found CARDS patients to have higher compliance than the group of non-COVID ARDS patients who were matched for SpO2/FiO2. They also found the CARDS patients had lower SpO2/FiO2 than non-COVID ARDS patients who were matched for compliance. Increasing PEEP from 5 to 15 improved oxygenation in CARDS patients but did not improve respiratory mechanics or CO2 clearance as usually seen in ARDS. These authors continue to recommend low PEEP and low driving pressure in early CARDS.
  • What have we learned ventilating COVID 19 patients? 10/12/20. Trahtemberg U. Intensive Care Med.
    These leaders in ARDS research provide a crisp review of ventilatory management of COVID-19-induced ARDS (CARDS), based on the underlying pathophysiology and contend that the similarities in the spectrum of CARDS versus that of non-COVID ARDS outweigh the differences. They find a paucity of data exists to justify early intubation. They favor lung protective ventilation for all patients, and they argue for prone positioning for patients with moderate-to-severe ARDS (PaO2/FiO2 ratio < 150 mmHg). In summary they write, “ventilatory management of patients with COVID-19 ARDS should be similar to that for other causes of ARDS, tailored to the specific patient.”
  • Aspergillosis Complicating Severe Coronavirus Disease. 10/21/20. Marr KA. Emerg Infect Dis.
    Mounting evidence suggests that severe respiratory virus infections, especially influenza and coronavirus 2 infections, can be complicated by Aspergillus airway overgrowth with pulmonary infection characterized by mixed airway inflammation and bronchial invasion. This article reviews these issues succinctly and adds data on 20 COVID-19 patients to the growing world literature. The authors note that the syndromes of pulmonary aspergillosis complicating severe viral infections are distinct from classic invasive aspergillosis. They state that combined with severe viral infection, aspergillosis in COVID-19 pneumonia comprises a constellation of airway-invasive and angio-invasive disease and see an urgent need for strategies to improve diagnosis, prevention, and therapy.
    SAB comment: An article previously highlighted in the Newsletter clarifies some of the important issues specific to diagnosing and treating pulmonary aspergillosis in COVID-19 patients.
  • Characteristics Associated With Racial/Ethnic Disparities in COVID-19 Outcomes in an Academic Health Care System. 10/21/20. Gu T. JAMA Netw Open.
    In this cohort study of 5698 University of Michigan Health System patients tested for or diagnosed with COVID-19, preexisting type 2 diabetes or kidney diseases and living in high–population density areas were associated with higher risk for COVID-19 hospitalization. Adjusting for covariates, non-Hispanic Black patients were 1.72-fold more likely to be hospitalized than non-Hispanic White patients, though the reasons for hospitalization were not defined. However, no significant race differences were observed in intensive care unit admission and mortality.

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Newsletter Issue 32, October 26, 2020:

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Newsletter Issue 31, October 21, 2020:

  • Treatments Considered for COVID-19. 10/15/20. The Medical Letter.
    This latest edition of The Medical Letter’s “Treatments Considered for COVID-19” was released on October 15, 2020 and included comprehensive (over 100 pages) up-to-date tables of drug, vaccine and other treatment classes. The columns include “Drug and Dosage,” “Efficacy,” “Adverse Effects/Interactions” and “Comments,” all with thorough referencing.
    Updates added to this edition include:
    • remdesivir – new guidelines from NIH and IDSA,
    • convalescent plasma – new guidelines from IDSA,
    • monoclonal antibodies, mesenchymal stem cell therapy, corticosteroids – new guidelines from NIH and IDSA,
    • IL-6 Inhibitors – new guidelines from IDSA; JAK inhibitors – data from NIH’s ACTT-2 trial on baricitinib, and
    • antimalarials – results from the RECOVERY trial, PPIs, vaccines and SSRIs.
  • Acute Respiratory Distress Syndrome: Contemporary Management and Novel Approaches during COVID-19. 10/5/20. Williams GW. Anesthesiology.
    This is a succinct, well-written review of best practice treatment strategies for non-COVID-19 ARDS with research-based updates on appropriate strategies for COVID-19 associated-ARDS treatments. Figures and brief descriptions are provided on the research supporting low tidal volumes, PEEP levels, prone positioning, PaO2 targets, steroid treatment, fluid management, ECMO and early neuromuscular blockade.
  • Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized COVID-19 Patients from a Large Healthcare System. 10/15/20. Yeramaneni S. Gastroenterology.
    This large retrospective study from HCA Healthcare repudiates 2 smaller studies from Columbia and Hartford which reported a two-fold reduction in risk of death or intubation for COVID-19 inpatients. One thousand one hundred twenty-seven patients (15.7%) received famotidine and 6031 (84.3%) did not. Applying multivariable logistic regression within a carefully matched cohort showed no association between in-hospital famotidine use and 30-day mortality after adjustment for WHO severity, smoking status, and listed medications.
    SAB Comment: Due to famotidine’s ability to inhibit a protease essential for SARS-CoV-2 virus replication in vitro, it is under intense study in many centers. A clinical trial administering high-dose IV treatment (120 mg IV q8h) is currently under way at Columbia.
  • Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. 10/5/20. RECOVERY Collaborative Group. Lancet.
    This article reports results of a prospective, controlled, open-label adaptive platform trial designed to test effectiveness of lopinavir-ritonavir (1616) against usual care (3424) in patients admitted to hospital with COVID-19 between March 19 and June 29. Lopinavir-ritonavir treatment was not associated with any primary endpoint benefit, including 28-day mortality, hospital length of stay, risk of progressing to mechanical ventilation or death. The results do not support use of lopinavir-ritonavir to treat COVID-19 patients.
  • Antiviral monotherapy for hospitalised patients with COVID-19 is not enough. 10/5/20. Cao B. Lancet.
    Commentary on accompanying article findings from the RECOVERY trial that lopinavir-ritonavir addition to usual care in managing COVID-19 patients admitted to hospital conveyed no outcome benefit for the primary endpoints of death at 28 days, hospital length of stay or progression to mechanical ventilation. The authors suggest that despite negative trial results, future research in this area should continue and that evaluation and efficacy of antiviral and immunomodulator combination therapy be continued.
  • Convalescent plasma for patients with severe COVID-19: a matched cohort study. 10/10/20. Rogers R. Clin Infect Dis.
    This small study from 3 hospitals compared 64 recipients of 1-2 units of CP (median 7 days after symptom onset) with 177 matched controls. Neither in-hospital mortality (~15%) nor overall rate of hospital discharge differed significantly, although the rate of hospital discharge among patients older than 65 years who received convalescent plasma (CP) was significantly higher (RR 1.86, 95% CI 1.03 – 3.36). There was a greater than expected frequency of transfusion reactions in the CP group (2.8% per unit transfused). Authors suggest adequately powered randomized studies should target patients older than 65 years when assessing CP treatment efficacy.
  • Transmission Dynamics by Age Group in COVID-19 Hotspot Counties – United States, April-September 2020. 10/15/20. Oster AM. MMWR Morb Mortal Wkly Rep.
    CDC analyzed temporal trends in percent test positivity by age group in COVID-19 hotspot counties before and after their identification as hotspots. Among 767 U.S. hotspot counties identified during June and July 2020 (24% of counties, 63% of population) early increases in the percent positivity among persons 24 years old and younger were followed by several weeks of increasing percent positivity in persons 25 years old and older, particularly those in the South and West. Addressing transmission among young adults is an urgent public health priority.
  • The duration of infectiousness of individuals infected with SARS-CoV-2. 10/13/20. Walsh KA. J Infect.
    The potential duration of patient infectiousness, as derived from virus culture and contact tracing studies, for those individuals in whom SARS-CoV-2 RNA is detected is summarized. Thirteen various quality studies and 2 large contact tracing studies were included. The data suggests that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious beyond 10 days from symptom onset. Evidence from a limited number of studies indicates that patients with severe-to-critical illness, and/or those who are immunocompromised, may be infectious for a prolonged period, possibly for 20 days or more. Research is needed to confirm these findings and to provide information on the duration of infectiousness in subgroups such as children, and asymptomatic and immunosuppressed patients.

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Newsletter Issue 30, October 19, 2020:

  • A quantitative evaluation of aerosol generation during tracheal intubation and extubation. 10/6/20. Brown J. Anaesthesia.
    This is a pertinent report on measurement of 0.3-10 nm aerosolized particles using real-time, high-resolution environmental monitoring in ultraclean ORs with laminar flow ventilation and 500–650 air changes / hour. Tracheal intubation sequences including face-mask ventilation produced very low particle quantities (average concentration, 1.4 particles/L, n = 14, p < 0·0001 vs. cough). Tracheal extubation, particularly when the patient coughed, produced a detectable aerosol (21 particles/L, n = 10), 15-fold greater than intubation (p = 0.0004) but 35-fold less than a volitional cough (p < 0.0001). The study does not support the designation of elective tracheal intubation as an aerosol-generating procedure.
  • Aerosolisation during tracheal intubation and extubation in an operating theatre setting. 10/12/20. Dhillon RS. Anaesthesia.
    This study reports measurements and size characterization of aerosols generated and spread throughout a standard positive pressure operating room (with 26 room volume air exchanges per hour) during intubation and extubation of 3 study patients. Face-mask ventilation, tracheal tube insertion and cuff inflation generated small particles 30–300 times above background noise that remained suspended in airflows and spread from the patient’s facial region throughout the confines of the operating room. The authors believe that these findings support careful use of PPE throughout standard ventilation operating rooms.
  • The Effect of Temperature on Persistence of SARS-CoV-2 on Common Surfaces. 10/7/20. Riddel S. Virology.
    In this study, SARS-CoV-2 viability was measured on polymer and paper bank notes, stainless steel, glass, vinyl and cotton cloth at 20, 30, and 40°C. High titer virus was applied, and samples stored in the dark at 50% relative humidity. Half-lives were a few days on all surfaces at 20°C and reduced to a few hours at 40°C. Hard surfaces support viable virus longer than absorbent ones. Some remained detectable for 28 days on nonabsorbent surfaces at ambient temperature. Fomite transmission may be more important than previously thought. Concerns regarding bank notes, touchscreens and mobile phones are of particular importance.
  • COVID-19 Transmission in US Child Care Programs. 10/1/20. Gilliam WS. Pediatrics.
    This is an analysis of a survey completed in late May 2020 by 57,335 childcare providers from all 50 states that were asked about their exposure, their transmission mitigation efforts and whether or not they had ever tested positive for having COVID-19. While 427 (0.7%) of the respondents had tested positive, there was no association found between exposure to childcare and contracting COVID-19. The authors note that results may depend upon the mitigation efforts taken (outlined in the article) and on the relatively low prevalence rates across the United States at the time of the study. Transmission home to parents or siblings was not evaluated.
  • Duration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectivity: When Is It Safe to Discontinue Isolation? 10/8/20. Rhee C. Clin Infect Dis.
    In the review, SARS-CoV-2 is most contagious right before and immediately after symptom onset, and contagiousness rapidly decreases to near-zero about 10 days from symptom onset in mild-moderately ill patients and 15 days in critically ill and immunocompromised patients. The longest duration of viral viability reported is 20 days from symptom onset. Persistently positive SARS-CoV-2 RNA PCR does not indicate replication-competent virus and is not associated with contagiousness. Chain reaction assays that alternate between positive and negative results in recovered patients from COVID-19 most likely reflect sampling variability. The infection confers at least short-term immunity in most cases, but duration of immunity is unclear and several cases of re-infection have now been confirmed.
  • The impact of protocol-based high-intensity pharmacological thromboprophylaxis on thrombotic events in critically ill COVID-19 patients. 10/12/20. Atallah B. Anaesthesia.
    This study was conducted to discover if high-intensity thromboprophylaxis would lead to fewer thrombotic events in COVID-19 positive patients. These patients were selected for high-intensity thromboprophylaxis when the D-dimer level was > 2ug/ml, and for therapeutic anticoagulation when the level was >3ug/ml. High-intensity thromboprophylaxis (enoxaparin 40 milligrams bid), but not therapeutic anticoagulation was associated with fewer thromboembolic events. Low D-dimer levels were independently associated with fewer venous thromboembolism events. Bleeding events in the high intensity thromboprophylaxis group were 2.7% compared to 16.5% using therapeutic anticoagulation. The authors conclude that high intensity thromboprophylaxis may reduce the incidence of thrombotic events without a significant increase in bleeding.

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Newsletter Issue 29, October 14, 2020:

  • Clinical Outcomes of In-Hospital Cardiac Arrest in COVID-19. 9/28/20. Thapa S. JAMA Int Med.
    This research letter reports single-center results of CPR in 60 COVID-19 patients out of 1309 admitted between March 15 and April 3 who developed cardiac arrest (4.6%). Non-shockable rhythms presented in 52 (96.3%) with no patients surviving to discharge. The discussion notes results of CPR with those previously reported for in-hospital cardiac arrest (25% with 86% presenting non-shockable) and provides potential consequences of COVID-19. The authors suggest the importance of further research and consideration of guidelines for CPR in COVID-19.
  • Outcomes of Cardiopulmonary Resuscitation in Patients With COVID-19—Limited Data but Further Reason for Action. 9/28/20. Modes M. JAMA Int Med.
    Important discussion based on dismal post-CPR outcomes in accompanying research letter. While recognizing the difficulties of performing CPR in COVID-19 patients, the importance of developing a clearly defined care plan following a detailed, continuing discussion on outcome prognosis between the healthcare team and patient-family unit is emphasized. The concept of initiating an informed assent with the family in which the care team makes real-time decisions on DNAR (do not attempt resuscitation) is raised. Additionally, healthcare disparities and associated availability of advanced care directives highlight need for healthcare systems to adopt clearly defined protocols and emphasizes “goals of care” discussion between patients and families. Resource links provided.
  • In-hospital cardiac arrest in critically ill patients with covid-19: multicenter cohort study. 9/30/20. Hayek S. BMJ.
    This article discusses a multicenter (68 sites) US study which followed 5019 admitted COVID-19 patients, 701 (14%) of whom had in-hospital cardiac arrest. The influence of patient demographics, co-morbidities and critical care facilities on outcome are also described. Patients younger than 45 years were more likely to receive CPR with 21.2% (11/52) surviving to hospital discharge with normal or mild neurocognitive deficit compared to 2.9% in patients 80 years or older. The article confirms generally poor results of CPR in COVID-19 but provides interesting discrimination between age, ICU size and co-morbidities. It raises key questions regarding triage and informed assent discussions.
  • Remdesivir for Adults With COVID-19: A Living Systematic Review for an American College of Physicians Practice Points. 10/5/20. Wilt TJ. Ann Intern Med.
    Of the 89 pertinent articles that these authors reviewed, only 4 fit their strict criteria and were chosen for this review. They concluded that from the best evidence available so far, remdesivir probably improves recovery, reduces serious adverse events and may reduce mortality and time to clinical improvement in hospitalized adults with COVID-19. For patients not on a ventilator, a 5-day course may provide similar benefits to, and fewer harmful effects, than a 10-day course. The review is titled “Living” because these authors, from the VA system, plan to update their literature search every 2 months through December 2021.
  • Remdesivir for the Treatment of Covid-19 — Final Report. 10/8/20. Beigel JH. N Engl J Med.
    This article is a follow-up to the initial “preliminary report” that was published May 22, 2020 and was included as 47% of the patients in the review above. This “final report” of the ACTT-1 study provides later outcomes and analysis of the same 1062 patients in the “preliminary” report, randomized between February 21 and April 19 to receive 10 days of remdesivir or placebo. Similar to the analysis in the first report, those who received remdesivir had a median recovery time of 10 days compared with 15 days among those who received placebo. Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and estimates of mortality by day 29 (new in this report) were 11.4% with remdesivir and 15.2% with placebo.
  • Compassionate Use of Remdesivir in Pregnant Women with Severe Covid-19. 10/8/20. Burwick RM. Clin Infect Dis.
    This is a multicenter review of the outcomes for 67 pregnant and 19 immediate post-partum patients with moderate to severe COVID-19 treated with remdesivir. Outcomes were generally good, but there was no comparison to a control group. Remdesivir was well tolerated, with a low incidence of serious adverse events (16%). Most adverse events were related to pregnancy and underlying disease; most laboratory abnormalities were Grades 1 or 2. There was one maternal death attributed to COVID-19 and no neonatal deaths.
  • Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020). 10/6/20. Bai C. Eur Respir Rev.
    In this article, the Task Force (American Thoracic Society/European Respiratory Society coordinated International Task Force 29 July 2020) make consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but not with hydroxychloroquine except in the context of a clinical trial. COVID-19 patients with a venous thromboembolic event can be treated with therapeutic anticoagulant therapy for 3 months. Routine screening of patients for depression, anxiety and post-traumatic stress disorder was also suggested by the task force.

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Newsletter Issue 28, October 12, 2020:

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Newsletter Issue 27, October 7, 2020:

  • The US Strategic National Stockpile (SNS) Ventilators in COVID-19: A Comparison of Functionality and Analysis regarding the Emergency Purchase of 200,000 devices. 9/14/20. Branson R. Chest.
    Recognized disaster experts reviewed the capabilities of the ventilators available in the Strategic National Stockpile (SNS) before COVID-19, and those ordered by the US government under an Emergency Use Authorization. About half of these are not designed to support the sickest COVID-19 patients, and many have important limitations, such as lack of pediatric capability, lack of flow-volume loops, missing parts, difficult user learning curves, lack of maintenance availability, etc. Each of the currently available ventilators in the SNS is described, and suggestions for updates to the ventilator SNS stockpiles are made.
  • Cardiopulmonary exercise and the risk of aerosol generation while wearing a surgical mask. 9/11/20. Helgeson SA. Chest.
    The authors quantified the number of various-sized airborne particles 6 feet from exercising normal volunteers wearing type II procedural surgical masks. They found there was a minimal increase of particle number at low and moderate exercise but a doubling of the ambient baseline of small respirable particles (0.3–0.5 micrometer) with very hard exercise. Larger droplet sized particles were not significantly increased during any stage of exercise. These results may be applicable to gyms and health clubs if all participants wear surgical masks.
  • Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection. 9/23/20. Foy BH. JAMA Netw Open.
    Review of 1641 COVID-19 patients from the Boston Partners Health System found that increased red blood cell distribution width (RDW) at admission was associated with increased in-hospital mortality by multivariate analysis (ROR of 2.7) and correlated with the presence and degree of increased RDW. This effect was increased with age and an increase in RDW over the hospitalization also correlated with mortality. This finding is not novel but is simple, easily accessible and useful. This test is part of the routine complete blood count with differential that is available worldwide.
  • Convalescent Plasma for the Treatment of COVID-19: Perspectives of the National Institutes of Health COVID-19 Treatment Guidelines Panel. 9/25/20. Pau AK. Ann Intern Med.
    Data are currently insufficient for the NIH to recommend for or against convalescent plasma (CP) for COVID-19. Enrollment in adequately powered US RCTs is slow.
    FDA analysis (4330 patients):
    • 7-day mortality following high-titer vs. low-titer plasma
      • No difference overall.
      • Intubated patients (~1/3) – No difference.
      • Non-intubated patients: 11% high-titer vs. 14% low-titer.
    • Non-intubated patients <80 years treated w/in 72 hrs. of diagnosis, 6.3% high-titer vs. 11.3% low-titer (P = 0.0008).

    Analysis of 3082 patients / 35,322 who received plasma by 4 July 2020 via Mayo Clinic’s parallel Expanded Access Program, developed to provide broader access to CP yet NOT designed to generate definitive safety or efficacy data as no untreated control group.

    • 30-day mortality 29.1% in low-titer group vs. 24.7% in the high-titer group (not statistically significant).
    • Suggestion that high-titer plasma beneficial when administered within 72 hours of Dx.
  • High Frequency of SARS-CoV-2 RNAemia and Association With Severe Disease. 9/23/20. Hogan CA. Clin Infect Dis.
    Paired nasopharyngeal and plasma samples from 85 COVID-19 patients, median age 55, revealed plasma RNAemia in 28/85 (32.9%), including 22/28 (78.6%) who required hospitalization, and older age (63 vs. 50 years; P = .04). In models adjusted for age, RNAemia was more frequent in individuals who developed severe disease including ICU admission (32.1% vs 14.0%; P = .04), invasive mechanical ventilation (21.4% vs. 3.5%; P = .02), and all 4 deaths. Plasma RNA persisted for a maximum of 10 days. Authors suggest potential utility as a prognostic indicator.
  • COVACTA trial raises questions about tocilizumab’s benefit in COVID-19. 9/9/20. Furlow B. Lancet Rheumatol.
    IL-6 has both pro-inflammatory (e.g. “cytokine storm”) and anti-inflammatory effects. Retrospective studies suggested that the IL-6 antagonist tocilizumab reduced mortality. On July 29, 2020, Hoffmann-La Roche announced results of COVACTA, a Phase 3 tocilizumab randomized controlled trial in severe COVID-19 pneumonia. Tocilizumab failed to meet the primary endpoint of improved clinical status or mortality. However, treated patients spent a week less in the hospital. The full results await publication. Proper timing of administration assessing clinical signs of hyperinflammation may prove crucial. The results of the much larger tocilizumab RECOVERY trial are pending.
  • Portable pocket-sized ultrasound scanner for the evaluation of lung involvement in COVID-19 patients. 9/21/20. Bennett D. Ultrasound in Medicine & Biology.
    No significant differences were found between lung ultrasound scores obtained with a high-end or a portable pocket-sized ultrasound scanner on 437 paired readings in 34 LUS evaluations of hospitalized patients, including patients with mild (n=7), moderate (n=11) and severe (n=16) disease. The tested pocket-sized scanner has a single silicon chip containing a 2D array of 9000 capacitive micromachined ultrasound transducers instead of the standard piezoelectric crystal-based transducers. The chip emulates curved, linear, or phased transducers in M-mode, B-mode or color Doppler with a 2–30 cm scan depth.
  • Reduced Monocytic Human Leukocyte Antigen-DR Expression Indicates Immunosuppression in Critically Ill COVID-19 Patients. 9/14/20. Spinetti T. Anesth Analg.
    Major histocompatibility complex (MHC) Class II molecules present processed extracellular proteins and are only expressed on the surface of “professional” antigen presenting cells such as dendritic cell and macrophages/monocytes. As such, there are clear implications for SARS-CoV-2. This small monocentric prospective study examined CD14+ monocytic HLA-DR (mHLA-DR) expression in 9 ICU vs. 7 non-ICU hospitalized COVID-19 patients. The investigators found on flow cytometry significant downregulation of surface expression of this marker indicating immunosuppression. The decrease found on ICU admission persisted on days 3 and 5. The authors suggest that immune monitoring in the ICU could indicate who might benefit from immunological intervention (e.g. GM-CSF, IFNγ).

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Newsletter Issue 26, October 5, 2020:

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Newsletter Issue 25, September 30, 2020:

  • New Studies on COVID-19 Epidemiology
    The following four articles examine risk factors for developing COVID-19, for having severe disease and for death. Common findings include an increased risk of infection and hospitalization in Blacks but no increase in mortality. It should be noted that the mentioned hospitalization rates may depend on socio-economic factors and may not be a clear indicator of severity of disease.
    • Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: A nationwide cohort study. 9/22/20. Rentsch CT. PLoS Med.
      This article presents a nationwide VA data set study (~6 million patients, February 8 to July 22) comparing positive COVID-19 test results with 30-day mortality. Healthcare disparities were explored by evaluating “associations between race/ethnicity and receipt of COVID-19 testing, a positive test result, and 30-day mortality, with multivariable adjustment for demographic and clinical characteristics including comorbid conditions, health behaviors, medication history, site of care, and urban versus rural residence.” The study confirms prior reports indicating that “Black and Hispanic individuals experience excess burden of SARS-CoV-2 infection” but not increased mortality and notes that these disparities “are not entirely explained by underlying medical conditions or where they live or receive care.” The article contains interesting distinctions and reinforces the importance of designing “strategies to contain and prevent further outbreaks in racial and ethnic minority communities.”
    • Risk Factors for Hospitalization, Mechanical Ventilation, or Death Among 10 131 US Veterans With SARS-CoV-2 Infection. 9/23/20. Ioannou GN. JAMA Netw Open.
      This large study showed no increase in mortality associated with Black or Hispanic race, obesity, COPD, hypertension or smoking (contrary to what has been found in smaller, prior studies). It did find the expected association of increased severity and mortality with older age (≥50) and multiple comorbidities.
    • Association of Race and Ethnicity With Comorbidities and Survival Among Patients With COVID-19 at an Urban Medical Center in New York. 9/25/20. Kabarriti R. JAMA Netw Open.
      Among 5902 patients with positive COVID-19 diagnosis treated at a single academic center in urban New York, non-Hispanic Black and Hispanic patients had a higher proportion of more than 2 medical comorbidities and were more likely to require inpatient hospitalization, but had outcomes including mortality that were at least as good as, and maybe even marginally superior to, their non-Hispanic White counterparts when controlling for age, sex, and comorbid conditions at presentation.
    • Racial Disparities in Incidence and Outcomes Among Patients With COVID-19. 9/25/20. Muñoz-Price LS. JAMA Netw Open.
      This article investigates the goal-described patterns and outcomes of COVID-19 by race, controlling for age, sex, socioeconomic status, and comorbid conditions among 2595 urban patients. COVID-19 positivity was associated with Black race. Among patients with COVID-19, both race and poverty were associated with higher risk of hospitalization, but only poverty was associated with higher risk of intensive care unit admission. The findings also imply that adverse outcomes and greater population mortality associated with Blacks early in the course of the US pandemic were primarily attributable to greater incidence of COVID-19 among African American residents rather than worse survival once hospitalized.
  • Stroke Risk, phenotypes, and death in COVID-19: Systematic review and newly reported cases. 9/15/20. Fridman S. Neurology.
    This is a complex study of stroke characteristics in COVID-19 patients by an international team of neurologists who pooled results from 10 studies with their own case series for a total of 160 patients. Their goal is to estimate overall incidence of stroke (1.8%) and mortality (34.4%), determine risk factors, particularly in patients under age 50, and identify clinical phenotypes and associated mortality separating all strokes from ischemic etiology. Large vessel occlusion contributed to a high percentage of strokes in younger patients and occurred before the onset of COVID-19 symptoms in 49% of those cases, while pulmonary involvement correlated with strokes in older patients and poor outcomes.
  • Association of Daily Wear of Eyeglasses With Susceptibility to Coronavirus Disease 2019 Infection. 9/16/20. Zeng W. JAMA Ophthalmol.
    While the public has not received guidance to wear eye protection to decrease the risk of COVID-19, Zeng raised the question of whether ordinary eyeglasses may help prevent infection, as in their observational study of 276 COVID-19 inpatients of which only 5.8% wore glasses vs. 31.5% in a reference population. This editorial highlights the study’s weaknesses, including that the “local population” data were from another region of China and another time period altogether. Although the data are unlikely to be by chance alone, an inference of cause requires additional study.
  • Probative Value of the D-Dimer Assay for Diagnosis of Deep Venous Thrombosis in the Coronavirus Disease 2019 Syndrome. 9/15/20. Gibson CJ. Crit Care Med.
    The authors tested the utility of the D-dimer assay for the diagnosis of deep vein thrombosis. Despite the excellent correlation between the D-dimer and the presence of DVT, the positive predictive value was 21.8%. DVT is only one aspect of the thrombotic problems in these patients. Many do not recommend leg duplex scanning using the sole criteria of D-dimer. One interesting aspect of this study was that all ICU patients received therapeutic anticoagulation. That may have been reflected in the low incidence of DVT discovered in these patients. Unfortunately, there are no data presented regarding the incidence of bleeding in these patients.
  • COVID-19 concerns aggregate around platelets. 9/10/20. Battinelli EM. Blood.
    This is a well-written, useful editorial which describes the essence of the following two papers, including its limitations and future steps.
  • Platelet gene expression and function in patients with COVID-19. 9/10/20. Manne B. Blood.
    Using platelet RNA sequencing, this group profiles gene expression in the platelets of COVID-19 patients (n= 41) and finds altered gene expression profiles in pathways associated with ubiquitination, antigen presentation, and mitochondrial dysfunction. Patients with COVID-19 have higher levels of platelet activation at rest and increased interactions with neutrophils, monocytes, and T cells compared with healthy donors. Platelet functionality studies demonstrate hyperactivity, as evidenced by increased aggregation, spreading on fibrinogen and collagen through upregulation of the MAPK pathway, and increased thromboxane generation. These new data help extend prior data into the basic science of the hypercoagulable state of COVID-19.
  • Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. 9/10/20. Hottz E. Blood.
    This group demonstrates that COVID-19 is associated with increased platelet activation. They show that the platelets of critically ill COVID-19 patients exhibit increased platelet aggregation and platelet-monocyte aggregation. Further, these changes correlate with a worse outcome. Changes in platelet activation were associated with increased platelet expression of P-selectin and CD63. Platelets from patients with severe COVID-19 infection induce monocyte-derived tissue factor (TF) expression that is diminished by pretreating COVID-19 patient platelets with an anti–P-selectin neutralizing antibody or the clinically approved anti-αIIb/β3 monoclonal antibody, abciximab. These data are new and add to the understanding of the role that platelets play in the hypercoagulable state of COVID-19.

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Newsletter Issue 24, September 23, 2020:

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Newsletter Issue 23, September 21, 2020:

  • Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. 6/25/20. Varatharaj A. Lancet Psychiatry.
    Report on a nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19 in the UK combined with a call for similar initiative to collect data on short- and long-term neurological and psychiatric sequelae of COVID-19 worldwide. The authors used a secure rapid-response case report notification portal that was made available to all pertinent professional organizations and obtained valuable and timely data to be reviewed by clinicians, researchers and funders.
  • Racial/Ethnic Variation in Nasal Gene Expression of Transmembrane Serine Protease 2 (TMPRSS2). 9/10/20. Bunyavanich S. JAMA.
    Nasal epithelium contains a protease (transmembrane serine protease 2 – TMPRSS2) which facilitates SARS-CoV-2 virus entry into the body. In a racially diverse cohort participating in an asthma study between 2015 – 2018, Black individuals exhibited a significantly higher expression of TMPRSS2 in nasal epithelium compared with other self-identified races/ethnicities. This finding may shed further light on the observed higher burden of COVID-19 among Black individuals. Protease inhibitors, like camostat mesylate, are undergoing clinical trials to test their utility for COVID-19 treatment via TMPRSS2 inhibition.
  • Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients. 9/9/20. Mouhat B. Eur Respir J.
    This article reviews 162 patients who had computed tomography pulmonary angiography (CTAP) with clinical pulmonary deterioration taken from 349 patients with COVID-19 in a French hospital. Twenty-seven percent had pulmonary embolism (PE). Review of their data with multivariate analysis demonstrates lack of anticoagulation and D-dimer > 2590 ng/ml to be predictive of PE. A D-dimer level >2590 ng/mL−1 was associated with a 17-fold increase (!), and lack of anticoagulation with a 4-fold increase in the risk of PE. Linearity was verified for D-dimers in the study population (test of linearity <0.001). This paper adds more details to the literature and helps guide the clinician.
  • Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation. 9/8/20. Shah GL. J Clin Invest.
    From Sloan Kettering, a retrospective study of 77 COVID-19 PCR+ recipients of allogeneic and autologous hematopoietic cell transplant and chimeric antigen receptor T cell therapy (44% admitted). Of the 77 cellular therapy recipients, the results were: Allo = 35, Auto = 37, CAR-T = 5. The median time from cellular therapy was 782 days. Overall survival at 30 days was 78%. Clinical variables significantly associated with more severe disease (greater than non-rebreathing mask oxygen) or death were number of comorbidities, infiltrates and neutropenia. Worsening graft-versus-host-disease was not identified. The authors observed rapid recovery in lymphocyte populations across lymphocyte subsets which are critical to anti-viral responses and immune reconstitution.
  • The coronavirus is mutating – does it matter? 9/8/20. Callaway E. Nature.
    In an article from Nature, mutations in the SARS-CoV-2 are reviewed. Mutations in RNA viruses such as SARS-CoV-2 containing “proofreading” enzymes occur slowly. One distinct mutation in the spike protein gene occurs at the 614th amino-acid position: the aspartate (D, in biochemical shorthand) is replaced by glycine (G) in the virus’s 29,903-letter RNA code. The “D614G mutation” became the dominant SARS-CoV-2 lineage in Europe and the US. Despite early alarm, it does not enhance spread or affect antibody defense. More than 12,000 mutations in SARS-CoV-2 are catalogued. The author speculates that worrisome mutations could arise especially if antibody therapies producing selection pressure are not used wisely.

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Newsletter Issue 22, September 16, 2020:

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Newsletter Issue 21, September 14, 2020:

  • Anticipating and managing coagulopathy and thrombotic manifestations of severe COVID-19. 8/16/20. Godoy LC. CMAJ.
    This is an interesting, informative, and well-written review. The explanation of the pathology beginning with the viral spike protein invading the cells facilitated by ACE2 followed by a cascade of reactions involving inflammatory and immunological pathways resulting in widespread endotheliitis is well stated. The clarity of the authors’ approach is refreshing. A summary of current recommendations is presented along with interesting individual studies that stimulate the reader and the researcher to pursue additional studies. It’s interesting to note that the reported bleeding rate using full anticoagulation is not much different than using lower doses.
  • Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19. 8/17/20. Rauch A. J Thromb Haemost.
    This well-done study from Lille, France of 234 patients admitted with COVID-19 presents new data. von Willebrand factor (VWF) levels were associated with severity and oxygen need in COVID-19 at admission; low factor VIII (FVIII)/VWF ratio at admission is predictive of increased oxygen requirements; and coagulation biomarkers predict outcome independently of major comorbidities in COVID-19. Furthermore, FVIII is predictive of early thrombotic events irrespective of BMI in COVID-19.
  • Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. 6/29/20. Paranjpe I. JACC.
    The authors studied 2,773 hospitalized patients with COVID-19. Therapeutic anticoagulation was administered to 28% of these patients and survival between those who received prophylactic versus therapeutic anticoagulation was similar. In patients who required mechanical ventilation who received treatment doses of anticoagulation, in-hospital mortality rates were lower. Bleeding was more common for intubated patients. Prospective randomized trials will be needed to confirm these findings but the results in this study are very encouraging. These preliminary results provide some guidance for selecting therapeutic heparin in critical situations.
  • Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. 7/19/20. Joyner MJ. Mayo Clin Proc.
    This was a study based on a collaborative effort of the FDA, Mayo Clinic and the national blood banking community. Over 20,000 patients received convalescent plasma in the US. In this report of 20,000 patients, the one week mortality was 13%; transfusion reactions were <1% (n=78). This is important data supporting the use of convalescent plasma. However, these data examined the safety of its use not the efficacy. While these data are important, we will be looking forward to further information in the future.
  • Humoral Immune Response to SARS-CoV-2 in Iceland. 9/1/20. Gudbjartsson DF. N Engl J Med.
    Fifty-six percent of all SARS-CoV-2 infections in Iceland had been diagnosed with quantitative polymerase-chain-reaction (qPCR) assay, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR. Despite extensive screening by qPCR, a substantial fraction of infections were not detected, which indicates that many infected persons did not have substantial symptoms. But due to the low SARS-CoV-2 antibody seroprevalence, the Icelandic population is vulnerable to a second wave of infection.
  • Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19. 8/21/20. Spinner C. JAMA.
    In this international study (United States, Europe, and Asia) of COVID-19 patients with pulmonary infiltrates but oxygen saturation above 94% (moderate COVID-19 pneumonia), patients who received a 5-day course of remdesivir did better on day 11 than a comparable group of patients who received standard care only. However, a 10-day course of remdesivir failed to show clinical improvement compared to standard care. The results suggest that remdesivir works when given early and may not have additional benefit once patients progress to more severe illness.
  • Perspective of the Surviving Sepsis Campaign on the Management of Pediatric Sepsis in the Era of Coronavirus Disease 2019. 9/4/20. Weiss SL. Pediatr Crit Care Med.
    The authors provide a framework for the early recognition and initial resuscitation of children with sepsis or septic shock caused by all pathogens. The emphasis of COVID-19 has more in common with other forms of sepsis than was originally appreciated; 6 key managements are listed: IV (if necessary, intraosseous); blood culture; broad spectrum antimicrobials; measure lactate, fluid boluses for shock if needed; and start vasoactive drugs if shock persists.
  • COVID-19: more than a cytokine storm. 9/5/20. Riva G. Crit Care.
    This commentary from Modena, Italy cites the current overemphasis on therapies combating the cytokine storm of the innate COVID-19 immune response and “neglect” of fighting the adaptive immune response. Lymphocyte dysregulations in COVID-19 include lymphopenia (CD4+ and CD8+), T cell exhaustion and a skewing toward a low IFN-Ɣ CD4+ tolerogenic balance. Some of these adaptive deficiencies also are evident in cancer and with aging. The authors advocate trials with immunotherapeutic drugs that may reverse T cell impairment. Trials to determine appropriate immunomodulatory drugs, antibodies, biomarkers and their optimal timing are beginning.
  • Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. 7/31/20. Brann DH. Science Advances.
    The authors examined human and mouse olfactory epithelial cells and found ACE2 is expressed not in olfactory neurons but in dorsally located olfactory epithelial sustentacular cells and olfactory bulb pericytes support cells, goblet and ciliated cells, stem cells, and perivascular cells. Hence, neurons are not injured and the findings suggest that sensory damage is unlikely to be permanent and should usually recover within a few weeks.
  • The Effect of Ultraviolet C Radiation Against Different N95 Respirators Inoculated with SARS-CoV-2. 8/28/20. Ozog DM. Int J Infect Dis.
    This study from Michigan provides new data regarding the ability of ultraviolet (UV)-C to inactivate SARS-CoV-2 on specific N95 respirator models. A dose of 1.5 J/cm2 to each mask side was adequate for 3M 1860 and Moldex 1511. Straps of 3M 1860 required secondary decontamination. Three other models tested had residually detectable virus when cultured, confirming model-dependent heterogeneity and need for secondary strap decontamination found in previous studies. No fit testing was done. Implementation of UV-C decontamination of N95 respirators requires careful consideration of model, material type, design, and fit-testing following irradiation.

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Newsletter Issue 20, September 9, 2020:

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Newsletter Issue 19, September 2, 2020:

  • Sex differences in immune responses that underlie COVID-19 disease outcomes. 8/26/20. Takahashi T. Nature.
    Preliminary data show different immune capabilities and responses for males and females, with implications for disease prevention and treatment strategies. Viral loads, antibody levels, plasma cytokines/chemokines, and blood cell phenotypes were measured in 98 COVID-19 inpatients and 43 healthy controls. Forty-eight patients had longitudinal analysis. Multiple pro-inflammatory immune chemokine and cytokine levels were higher in males, while females demonstrated a more robust baseline T-cell response. T-cell response was negatively correlated with age in males only. Disease progression was inversely associated with T-cell response in males and positively associated with innate immune cytokine levels in females.
  • Role for Anti-Cytokine Therapies in Severe Coronavirus Disease 2019. 8/25/20. Buckley LF. Crit Care Explor.
    This is an excellent detailed review summarizing existing knowledge of the immune response (cytokine injuries) to coronavirus infection and highlights the current and potential future roles of therapeutic strategies to combat the hyper-inflammatory response of patients with COVID-19. Here, details regarding immunopathogenesis, pharmacodynamics, pharmacokinetics with illustrations are provided for available anti-cytokines pertaining to their success and failure in 3 groups (IL1, IL6 and other cytokine modulators). The authors conclude by advising to look for approximately a dozen future clinical trials to answer questions regarding the dose, timing, biomarkers and other issues of anti-cytokines. Both IL1 and IL6 cytokine blockers have a role in the first wave of inflammation (< 7 days of symptoms), while IL1 blockers are slightly superior having no black box warning for secondary infection as do IL6 and TNF blockers.
  • Viral dynamics and immune correlates of COVID-19 disease severity. 8/28/20. Young BE. Clin Infect Dis.
    One hundred COVID-19 patients from Singapore underwent prospective study of infectivity and immune response on days 1, 3, 7,14, 21 and 28 after enrollment. No positive viral cultures were found in respiratory samples (n=21) obtained more than 14 days after symptom onset and all positive viral cultures occurred in patients with PCR cycle threshold values <30. Disease severity was associated with earlier seroconversion, higher peak IgM and IgG levels, and higher levels of inflammatory markers, but not duration of viral shedding by PCR. Results have implications for duration of isolation/quarantine and from whom to potentially obtain convalescent plasma.
  • Anakinra in COVID-19: important considerations for clinical trials. 5/21/20. King A. Lancet Rheumatol.
    This comment is of interest for clinicians and researchers working with the Interleukin IL-1α and IL-1β inhibitory agent anakinra in COVID-19 patients with evidence of hyperinflammation. The authors review and critique 10 ongoing trials with anakinra and suggest using worsening lymphopenia as a marker of disease progression and severity and increasing C-reactive protein as evidence of worsening inflammation. They also favor subcutaneous administration due to the drug’s short half-life and implore the trial gate keepers to ensure collection of core outcome measures, like ferritin levels for current and future trials.
  • Cardiac Injury Patterns and Inpatient Outcomes Among Patients Admitted With COVID-19. 7/23/20. Raad M. Am J Cardiol.
    This is a retrospective analysis of 1020 patients with confirmed COVID-19 disease of which 390 (38%) had cardiac injury on presentation diagnosed by hs-cTnI levels >99% tile; primary endpoint was mortality and secondary were intensive care requirement and length of stay. Patients were older (median 70), higher cardiac co-morbidities (hypertension, diabetes) and all had BMI >30. Higher troponin levels associated with mortality and ICU requirements including mechanical ventilation. Results confirm previous studies associating cardiac involvement due to COVID-19 with increasing severity associated with cardiac related co-morbidities.
  • Transthoracic Echocardiography in Prone Patients With Acute Respiratory Distress Syndrome: A Feasibility Study. 8/25/20. Gibson LE. Crit Care Explor.
    Gibson et al. describe the technique, views and utility of performing bedside transthoracic cardiac ultrasound exams on 27 prone, intubated COVID-19 patients in Boston. They found the views obtained prone were sometimes improved over supine images, allowing avoidance of TEE. There are excellent images, videos, and tables.
  • Respiratory physiology of COVID-19-induced respiratory failure compared to ARDS of other etiologies. 8/28/20. Grieco DL. Crit Care.
    This article provides a detailed comparison of the respiratory mechanics of 30 COVID-19 ARDS patients measured within 24 hours of initial intubation with 30 non-COVID matching ARDS patients based on PaO2/FiO2, FiO2, PEEP, and tidal volume. The average compliance and ventilatory ratio were slightly higher in COVID-19 patients. Inter-individual variability of compliance was similar in both groups. In COVID-19 patients, PaO2/FiO2 was linearly correlated with respiratory system compliance. High PEEP improved PaO2/FiO2 in both cohorts, but more remarkably in COVID-19 patients. Recruitability was not different between cohorts. The authors conclude that overall the respiratory mechanics were similar in the two groups but were marked by prominent intra-group variability in both.

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Newsletter Issue 18, August 31, 2020:

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Newsletter Issue 17, August 26, 2020:

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Newsletter Issue 16, August 19, 2020:

  • Association Between Anxiety and New Organ Failure, Independently of Critical Illness Severity and Respiratory Status: A Prospective Multicentric Cohort Study. 7/30/20. Mazeraud A. Crit Care Med.
    Interesting, multi-center prospective study evaluating patient’s admission anxiety level on new organ system failure within seven days following ICU admission. While not directly related to COVID-19 (or any specific admission diagnosis), patients identified with moderate to severe anxiety (State anxiety-assessed using state component of State-Trait Anxiety Inventory State) associated with disease severity (Simplified Acute Physiology Score II and Sequential Organ Failure Assessment) associated with increased risk for further deterioration when compared to lower stress comparators. Interesting with obvious implications for current pandemic given long prodrome with variable symptomatology and outcome increasing general anxiety in population with some estimates indicating a recent reported 25% incidence of suicidal ideation in younger age groups.
  • Infection Prevention Precautions for Routine Anesthesia Care During the SARS-CoV-2 Pandemic. 8/3/20. Bowdle A. Anesth & Analg.
    Authors promote precautions that are practical, affordable, and efficient to adjust routine anesthesia care to the current and near-future environment. Consideration for asymptomatic and pre-symptomatic SARS-CoV-2 infection, and the potential for false-negative tests inform recommendations to reduce the risk of transmission via anesthesia care behaviors. Universal N95 or higher respiratory protection is proposed for anesthesia providers with consideration given to whether the entire surgical team should use equivalent respiratory protection. Tables provide a useful summary of PPE, hand hygiene and other recommendations.
  • A physiological approach to understand the role of respiratory effort in the progression of lung injury in SARS-CoV-2 infection. 8/10/20. Cruces P. Crit Care.
    A thorough, well-written review of the physiology of patient-induced lung injury and of ventilator-induced lung injury adding information from the authors’ detailed CT scan profiles of lung injury in animal models. The article concludes with a balanced discussion of when to support Covid-19 pneumonia patients with non-invasive measures such as high flow nasal cannula versus when to intubate and support with mechanical ventilation. While no new approaches are provided, their recommendations support a complete evaluation of the patient’s condition and show clear consideration for the consequences of patient-induced lung injury.
  • Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients. 8/8/20. Helms J. Crit Care.
    Following up on the concept that neurotropism of the SARS-CoV-2 virus has been confirmed, French investigators focused on the neurological status of 140 consecutive patients with COVID-19 linked ARDS (mean age 62, 71% male) to determine the incidence of delirium and abnormal neurological exams. 84% developed delirium and of those, 69% presented with agitation and 63% had long-tract signs. Of 28 patients who underwent lumbar puncture and MRI, 65% had perfusion abnormalities and 61% had signs of a disturbed blood brain barrier, 64% showed inflammatory signs in CSF and one was PCR positive for SARS-CoV-2 in CSF. Delirium associated with ARDS and COVID-19 is a distinct entity caused by the corona virus which prolongs and complicates recovery, both short term and possibly in the long term as well.
  • Prominent coagulation disorder is closely related to inflammatory response and could be as a prognostic indicator for ICU patients with COVID-19. 8/8/20. Liu Y. J Thromb Thrombolysis.
    Interesting discussion highlighting interrelationship between inflammatory and coagulation systems; suggests coagulation abnormalities (PT, D-Dimer, FDP and AT III) can predict deterioration and mortality; also notes the neutrophil/lymphocyte ratio is a potential inflammatory marker in disease. Recognizes importance of prophylactic thromboprophylaxis and accurate timing of systemic anticoagulation.
  • Convalescent plasma for COVID-19. 8/8/20. Mucha SR. Cleve Clin J Med.
    While convalescent plasma has yet to be proven effective, it has generated great interest as a possible COVID-19 therapy and clinical trials are underway. For those interested in a well-written review of the questions and potential risks that must be taken into consideration, this report is a worthwhile read. Potential downsides include TACO, TRALI, antibody dependent enhancement of infection and attenuated immune response. Current limitations include obstacles to effective testing of donor neutralizing antibody levels. This topic is at the center of the current controversy surrounding a potential FDA emergency use authorization for convalescent plasma, (now on hold).
  • Late Onset Infectious Complications and Safety of Tocilizumab in the Management of COVID-19. 8/14/20. Pettit NN. J Med Virol.
    Tocilizumab while previously showing some positive results in treating COVID-19, in this controlled study demonstrated higher complication rates, especially infectious, and death.
  • Extracorporeal membrane oxygenation for refractory COVID-19 acute respiratory distress syndrome. 7/31/20. Le Breton C. J Crit Care.
    A brief single center report stating that 11 of 13 patients treated with ECMO were successfully weaned from ECMO (medium treatment of 13 days) and eventually from mechanical ventilation (median treatment 29 days). The authors support ECMO use in carefully selected cases.
  • Unspecific post-mortem findings despite multiorgan viral spread in COVID-19 patients. 8/12/20. Remmelink M. Crit Care.
    The authors found in this study of 17 patients, a great heterogeneity of COVID-19-associated organ injury and the remarkable absence of any specific viral lesions, even when RT-PCR identified the presence of the virus in many organs. Pulmonary findings revealed early-stage diffuse alveolar damage 15/17; microthrombi in small lung arteries in 11 patients and no evidence of myocarditis, hepatitis, or encephalitis. Onset of symptoms and death ranged from 2 to 40 days.

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Newsletter Issue 15, August 17, 2020:

  • SARS-CoV-2 viral load in the upper respiratory tract of children and adults with early acute COVID-19. 8/6/20. Baggio S. Clin Infect Dis.
    Click here to take this CME activity.

    This prospective cohort study from Switzerland compared the viral load in patients of all ages during the first 5 days of COVID-19 symptoms. Viral loads as measured by cycle thresholds of RT-PCR testing were similar across all age groups (0-82 years old). This study of viral load in symptomatic patients helps clarify confusing results from other studies and may be especially pertinent as schools try to reopen.

  • Systematic SARS-CoV-2 screening at hospital admission in children: a French prospective multicenter study. 7/25/20. Poline J. Clin Infect Dis.
    In a small French study of consecutive children admitted to the hospital, 45% were not able to be diagnosed with COVID-19 on symptoms alone. A pre-existing underlying condition did not alter the rate of infection. This study demonstrates that routine symptom screening for COVID-19 frequently fails.
  • Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2: A Systematic Review. 8/4/20. Abrams JY. J Pediatr.
    This article is a comprehensive description of multisystem inflammatory syndrome in children (MIS-C) authored by Centers for Disease Control scientists.
  • The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation. 8/5/20. Wang J. AAPS PharmSciTech.
    This article is an in-depth review of vaccine development and delivery strategies, particularly as they apply to SARS-CoV-2. The proper choice of the type of vaccine, carrier or vector, adjuvant, excipients (other ingredients), dosage form, and route of administration can directly impact not only the immune responses and efficacy against COVID-19, but also the logistics of manufacturing, storing, distributing the vaccine and mass vaccination. The 13 vaccines under development (as of May 29, 2020) are nicely compared. The tables and graphics are excellent.
  • Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. 7/2/20. Korber B. Cell.
    Herd immunity and vaccines for SARS-CoV-2 are likely to be effective due to low mutation rates. D614 was the original spike protein form. G614 is now dominant, although there are other mutations. G614 is ~10x more infectious and leads to higher viral loads but does not cause more severe clinical disease. It is being targeted for the development of vaccines and therapeutics.
  • COVID-19: pharmacology and kinetics of viral clearance. 8/8/20. Farina N. Pharmacol Res.
    In addition to critically reviewing the results of currently available therapeutic options, investigators examined viral clearance dynamics in a cohort of 1000+ patients enrolled in a COVID-19 hydroxy-chloroquine and lopinavir/ritonavir research protocol at a single center in Milan. Viral clearance was assessed as time to negative RT-PCR as well as determining the proportion of patients with a negative test within 14 and 28 days. Significantly, persistence of the virus did not identify patients with higher mortality risk.
  • Cerebrovascular Complications of COVID-19. 8/8/20. Katz JM. Stroke.
    Retrospective case review focusing on imaging confirmed stroke incidence among COVID-19 inpatients treated in a largely metropolitan health care system. 86 stroke patients were identified and compared to 499 stroke patients admitted a year earlier. COVID-19 patients were significantly more likely to have a stroke while hospitalized (48% vs 5%). Additional important findings among the COVID-19 group includes a predominance of ischemic stroke and a high frequency (67%) of non-focal neurologic presentations and a higher incidence among racial minorities.
    In-hospital stroke among COVID-19 patients is a strong independent risk factor and deserves a high grade of suspicion when patients develop neurologic symptoms.
  • Impact of the Coronavirus Infection in Pregnancy: A Preliminary Study of 141 Patients. 7/7/20. Nayak AH. J Obstet Gynaecol India.
    They studied 141 pregnant COVID positive women and 836 pregnant controls in Mumbai, India from April 1, 2020 to May 15, 2020. COVID-19 did not have a major adverse effect on maternal or newborn outcomes. Mortality was 2% and morbidity was low among COVID-positive mothers. Out of a total of 131 babies tested, only 3 tested positive on first swab and all tested negative on day 5. Vertical transmission of COVID-19 infection from mother to newborn was rare. This study reports fewer adverse outcomes than some others.
  • Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK. 6/8/20. Knight M. BMJ.
    At all 194 obstetric units in the United Kingdom, 4.9 per 1000 pregnant women (n=427) were hospitalized with confirmed SARS-CoV-2 infection between March 1, 2020 and April 14, 2020. Sixty-nine percent were overweight or obese. Fifty-eight percent had symptom onset >32 weeks gestational age. By study end, 62% (n=266) had completed pregnancy with 259 live births, 3 still births and 4 lost pregnancies. Of those, 74% (n=196) were term births,16% (n=42) had C/section “due to COVID-19,” and 44% (n=114) had C/section for other reasons. Among all hospitalized, 10% needed ICU, 1% were placed on ECMO, and 1% died. Five percent of 265 infants were RNA+ for SARS-CoV-2. Results resemble USA reports.
  • COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection. 7/30/20. Stauffer WM. JAMA.
    Dexamethasone is recommended for critically ill COVID-19 patients. One of its uncommon preventable complications is strongyloides hyperinfection caused by a nematode (roundworm). Seroprevalence of strongyloides ranges from 10-15% among migrants from less developed countries. The infection can last a lifetime. Hyperinfection appears to be independent of dose or duration of steroid. Its possibility should be considered if the patient deteriorates acutely. For outpatients, the authors recommend screening for strongyloides and treating with ivermectin if positive. For inpatients, they recommend presumptive treatment with ivermectin for patients not previously tested or treated for strongyloides.
  • Therapeutic plasma exchange in adult critically ill patients with life-threatening SARS-CoV-2 disease: A pilot study. 7/31/20. Faqihi F. J Crit Care.
    This article reports preliminary data on total plasma exchange as rescue therapy for 10 consecutive eligible adult COVID-19 ICU patients. (Technique using Spectra Optia™ Apheresis System w/ Depuro D200 Adsorption Cartridge and volume replacement w/ 5% albumin or fresh frozen plasma if PT>37 sec.) All patients were mechanically ventilated and had life-threatening illness and cytokine release syndrome (average PaO2/FiO2 ratio 110, SOFA 11, APACHE II 22.5). After 5-7 treatments P/F >250 in all and vasopressors weaned. One on ECMO, 2 had PE, and there was 1 sudden death during ventilator weaning. Nine patients were discharged from hospital. No reported adverse effects. Confounding factors include steroid and other concurrent treatments.
    (Note: this is not convalescent plasma treatment.)

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Newsletter Issue 14, August 12, 2020:

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Newsletter Issue 13, August 10, 2020:

  • CORRECTION: In Issue 12 of the IARS COVID-19 Resource Newsletter, the summaries were inadvertently flipped for two articles: “Outcomes in COVID-19 Positive Neonates and Possibility of Viral Vertical Transmission: A Narrative Review,” and “COVID-19 Lung Injury and High-Altitude Pulmonary Edema. A False Equation with Dangerous Implications.” Those articles and summaries are provided in their correct format in this issue below.
  • Reopening Primary Schools during the Pandemic. 7/29/20. Levinson M. N Engl J Med.
    This is a narrative summary and commentary on the literature and debate around reopening primary schools in the US, written by educators and medical epidemiologists. Primary schools in many other countries have re-opened successfully for in-person classes, but that success hinged on low community transmission rates, and extensive testing and surveillance. The authors believe that there is time in the US to achieve successful reopening in some areas if resources and effort are increased. The argument is made that primary schools are essential services, and “whether (or how) to reopen primary schools is not just a scientific and technocratic question. It is also an emotional and moral one.”
  • Reprocessing filtering facepiece respirators in primary care using medical autoclave: prospective, bench-to-bedside, single-centre study. 8/4/20. Harskamp RE. BMJ Open.
    Dutch investigators studied standard autoclave machines for decontamination of FFP2 and FFP3 respirators. They found that one model of FFP2 (the closest European Standard to US N95 respirators) tolerated up to 3 decontamination cycles at 121°C x 17 min. without significant change in filtration, resistance, or fit. Others, including the tested FFP3 model (higher filtration), did not. Referenced published studies support efficacy of this temperature to kill SARS-CoV-2. This study corroborates great variation between mask models observed in other studies and the critical importance of careful fit testing with each donning when considering decontamination and reuse of filtering facepiece respirators.
  • To Toci or Not to Toci for COVID-19: Is That Still the Question? 7/31/20. Cheng GS. Clin Infect Dis.
    This is a very well written editorial describing the emergence of inflammatory inhibitors, such as tocilizumab, as potential treatment choices for COVID-19, and how the recent University of Michigan study adds credence to that choice.
  • Post-discharge venous thromboembolism following hospital admission with COVID-19. 8/3/20. Roberts LN. Blood.
    These authors identified 1,877 patients with COVID-19 discharged from the hospital, and noted that there were nine episodes of Hospital Associated Venous Thromboembolism (HA-VTE) diagnosed within 42 days compared with 2019 hospital discharge data. The authors calculated an odds ratio of 1.6 compared to historically “similar” groups of patients. They concluded that hospitalization of patients with COVID-19 does not appear to increase the risk of post-discharge HA-VTE compared to hospitalization with other acute medical illnesses. Their data suggests empiric post-discharge thromboprophylaxis is not necessary, thereby supporting the ACCP recommendations to not offer post-discharge thromboprophylaxis.
  • Determination of brain death/death by neurologic criteria: the World Brain Death Project. 8/30/20. Sung GY. JAMA.
    Published by a panel of 40+ international experts, this is a thorough and comprehensive guideline aiming to establish worldwide recognized brain death criteria and testing methods.

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Newsletter Issue 12, August 5, 2020:

  • Outcomes in COVID-19 Positive Neonates and Possibility of Viral Vertical Transmission: A Narrative Review. 8/1/20. Sheth S. Am J Perinatol.
    Click here to take this CME activity.

    This is an international review, mostly from China, of transmission from COVID-19 infected pregnant women to newborns. Of the 39 published reports, it includes only 326 COVID-19 positive women. Despite the small numbers, newborns were infrequently infected with COVID-19 at birth. Of the 23 COVID-19-positive neonates reported, no deaths resulted.

  • Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection. 8/4/20. Lala A. JACC.
    This is a retrospective analysis of troponin-I levels taken within 24 hours of admission from 2,736 patients admitted to Mount Sinai Health System hospitals between February 27 and April 12. Thirty-six percent of patients showed elevated levels (normal <0.03 ng/ml). After correction for co-morbidities and clinical severity, small elevations were associated with increased morbidity and mortality. Elevations greater than three times normal (>0.09ng/ml) were associated with significantly higher risk. Troponin may be a useful indicator of cardiac involvement and may aid disease stratification.
  • EDITORIAL: Myocardial Injury in COVID-19 Patients: The Beginning or the End? 8/1/20. Uriel N. J Am Coll Cardiol.
    This editorial accompanies the article by Lala et al entitled, “Prevalence and Impact of Myocardial Injury in Patients Hospitalized with COVID-19 Infection,” and suggests pathophysiological pathways of cardiac involvement and underscores the importance of troponin-I elevations as markers of disease severity and outcome. The editorial reinforces the importance of cardiac involvement in COVID-19 disease and suggests troponin elevations could be a useful adjunct in disease stratification.
  • Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). 7/27/20. Puntmann VO. JAMA Cardiol.
    This is a report of 100 cardiac magnetic resonance (CMR) imaging studies on recovered COVID-19 patients compared with 50 healthy age- and sex-matched controls and 50 risk-factor matched, non-COVID-19 patients. Seventy-eight percent of recovered patients had CMR abnormalities, while 60% had findings consistent with ongoing myocardial inflammation independent of preexisting conditions, disease severity and course of acute illness and recovery. Ongoing investigation is needed to determine course and long-term cardiac morbidity of COVID-19.
  • Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. 7/27/20. Lindner D. JAMA Cardiol.
    Despite reports of fulminant myocarditis in patients with SARS-CoV-2 infection, this study of cardiac tissue from 39 consecutive autopsies of patients who died from confirmed disease demonstrates the presence of the virus in cardiac tissue but does not suggest an inflammatory reaction consistent with clinical myocarditis. The authors suggest further studies and clinical correlations are necessary to determine long-term consequences of SARS-CoV-2-specific myocardial infections.
  • EDITORIAL: Coronavirus Disease 2019 (COVID-19) and the Heart-Is Heart Failure the Next Chapter? 7/27/20. Yancy CW. JAMA Cardiol.
    This editorial raises the question of prevalence of cardiac involvement in COVID-19 disease and its impact on mortality and long-term morbidity. It discusses two relevant manuscripts and raises awareness of an important disease manifestation, the long-term implications of which are unknown and require investigation.
  • Characteristics and Strength of Evidence of COVID-19 Studies Registered on 7/27/20. Pundi K. JAMA Intern Med.
    As an indication of how difficult it is to obtain quality data, this evaluation of 1,551 clinical studies of COVID-19 patients listed on up to May 19, 2020 found that only 29.1% were designed in a way that the results could possibly change clinical practice (i.e., be classified as Level 2 evidence by the Oxford Centre for Evidence-Based Medicine level of evidence framework). In the 664 randomized clinical studies included, only 14% included mortality as a primary or composite outcome (arguably the most important research question). The authors state that, “Even before results are known, most studies likely will not yield meaningful scientific evidence at a time when rapid generation of high-quality knowledge is critical.”
  • COVID-19 Lung Injury and High-Altitude Pulmonary Edema. A False Equation with Dangerous Implications. 8/1/20. Luks AM. Ann Am Thorac Soc.
    This is a well written opinion piece responding to the claim (now seen frequently on social media) that the pathophysiology of COVID pneumonia and high-altitude pulmonary edema (HAPE) are similar and may respond to similar therapies. The striking differences between the pathophysiologies of the two diseases are well described as are the expected responses of each to standard therapies for HAPE. The significant risk for adverse effects treating COVID pneumonia as HAPE are elucidated.
  • EDITORIAL: COVID-19: a complex multisystem disorder. 6/30/20. Roberts CM. Br J Anaesth.
    COVID-19 has extensive effects on virtually all the organs. The virus binds to angiotensin converting enzyme 2 (ACE2) receptors present in vascular endothelial cells, lungs, heart, brain, kidneys, intestines, liver, pharynx, and other tissue. It can directly injure these organs. In addition, systemic disorders caused by the virus lead to organ malfunction. It can cause cytokine storm which can culminate in death. It causes inflammation, endotheliitis, vasoconstriction, hypercoagulability, and edema. Lymphocytopenia, elevated D-dimer, elevated fibrin degradation products (FDPs), and disseminated intravascular coagulation (DIC) are observed. Deep vein thrombosis (DVT), venous thromboembolism, pulmonary embolism (PE), systemic and pulmonary arterial thrombosis and embolism, and ischemic stroke are reported. In the heart, it can cause acute coronary syndrome, congestive heart failure, myocarditis, and arrhythmias. Kidney injury is usually secondary to systemic abnormalities. Stroke occurs even in young patients. Delirium and seizures are common. Anosmia and impaired sense of taste are reported. Psychological problems are common among patients as well as providers. Stool may contain virus. Lactate dehydrogenase may be elevated. Various skin manifestations including patchy erythematous rash are reported. Injury to an organ may become apparent long after the acute infection has subsided. Different organs may be affected at different times. Chronic injury may occur. Rehabilitation can be long and difficult.

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Newsletter Issue 11, August 3, 2020:

  • Remdesivir for Severe COVID-19 versus a Cohort Receiving Standard of Care. 7/25/20. Olender SA. Clin Infect Dis.
    Pharma-sponsored proof of benefit of remdesivir in patients with severe COVID-19 is demonstrated by comparing patients’ clinical status on day 14 during two parallel studies. One is an international, 16-site retrospective cohort study of clinical outcomes in 800+ patients receiving standard-of-care treatment for severe COVID-19 infection; the other is an international, 45-center, phase 3, randomized, open-label trial comparing two courses of remdesivir in 312 patients. Remdesivir was associated with significantly greater recovery (74 vs 59%) and 62% reduced odds of death versus standard-of-care treatment.
  • Age-Related Differences in Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Levels in Patients With Mild to Moderate Coronavirus Disease 2019 (COVID-19). 7/30/20. Heald-Sargent T. JAMA Pediatrics.
    Although published only as a letter, the article contains timely data regarding the potential infectivity of children lacking significant symptoms. Nasal viral load as measured by nasopharyngeal swab PCR demonstrated higher levels in young children when compared to adults. At issue is that the study was performed in a pediatric center yet describes adult testing without elaborating how those samples were obtained. Timely article with the start of school approaching.
  • NIH Launches Platform to Serve as Depository for COVID-19 Medical Data. 7/29/20. Rubin R. JAMA.
    Though not a research article, the news report, based on an NIH news release, summarizes an NIH effort to store and study medical record data from people across the country who have been diagnosed with coronavirus disease 2019. Certainly, research articles will be published in the future that will be based on this effort. For more information for institutions on how to contribute data, visit
  • Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System. 7/20/20. Bilaloglu S. JAMA.
    This research letter reports retrospective data analysis from 3,334 consecutive hospitalized COVID-19 patients from four NYC hospitals. “Most” received low-dose thromboprophylaxis. Sixteen percent experienced thrombotic events defined as DVT, PE, MI, or CVA (no screening). ICU patients: 13.6% venous, 18.6% arterial. Ward points: 3.6% VTE, and 8.4% arterial. Mortality with event was 43% vs. 21% without. Age, male sex, Hispanic ethnicity, CAD, prior MI, and higher D-dimer at hospital presentation were associated with a thrombotic event, but not BMI or current smoking Hx.
  • COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. 6/16/20. Bikdeli B. J Am Coll Cardiol.
    This article is an excellent clinically relevant review of thrombotic complications of COVID-19. Systemic and pulmonary venous and arterial thrombosis and thromboembolism are common in COVID-19. Thrombi are observed in virtually every organ. This is caused by inflammation, platelet activation, hypercoagulability, endothelial dysfunction, constriction of blood vessels, stasis, hypoxia, muscle immobilization, and disseminated intravascular coagulation (DIC).
    Fever and inflammation cause hypercoagulability and impair fibrinolysis. Cytokine interleukin-6 (IL-6) levels correlate with hypercoagulability and disease severity.
    Elevated antiphospholipid antibodies are associated with thrombosis. The liver increases production of procoagulant substances. Prothrombin time and activated partial thromboplastin time are moderately prolonged. Moderate thrombocytopenia is observed. C-reactive protein is elevated. Cytokine storm and excessive systemic inflammation are associated with lymphocytopenia, elevated D-dimer, elevated fibrin degradation products (FDP), and DIC. D-dimer levels and DIC are prognostic.
    Guidelines recommend thromboprophylaxis. Prophylaxis with low-molecular weight or regular heparin, fondaparinux, or a direct oral anticoagulant such as apixaban or rivaroxaban should be considered. Heparins bind tightly to COVID-19 spike proteins impeding the entry of the virus into cells. Heparins also downregulate IL-6 and reduce immune activation. A non-randomized study suggests that among patients requiring mechanical ventilation, systemic anticoagulation may be associated with reduced mortality without increasing major bleeding. However, systemic anticoagulation has not proven to be beneficial in ARDS due to other etiologies. After hospital discharge prolonged prophylaxis may be beneficial.
  • Genomewide association study of severe Covid-19 with respiratory failure. 6/17/20. Ellinghaus D. N Engl J Med.
    Genetic differences may in part explain the difference in response of different persons to SARS-CoV-2. They compared hospitalized patients with respiratory failure with controls. They studied 835 patients and 1255 controls from Italy and 775 patients and 950 controls from Spain.
    They found 3p21.31 gene cluster is a genetic susceptibility locus. Patients with blood group A were found to be at a higher risk of infection (odds ratio, 1.45) and develop more severe symptoms. Patients with blood type O were found to be at a lower risk of infection (odds ratio, 0.65). Although the results are statistically significant, the effect size is small. Results on the association with blood group has been reviewed by the SAB in several articles previously.
  • Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. 5/15/20. Grifoni A. Cell.
    To be effective, a COVID-19 vaccine has to elicit strong T cell immunity. Vaccines stimulate B cells to make antibodies against the virus. Helper T cells promote this. Those antibodies join with the virus, preventing it from entering a host cell and mark the virus for destruction. Once the virus infiltrates the host cell, antibodies are not effective. However, cytotoxic T cells can destroy infected host cells.
    T cell immunity does not prevent re-infection but reduces the severity of symptoms. Among patients recovered from COVID-19, CD4+ T cells were observed in all and CD8+ T cells were observed in about 70%. CD4+ responses to spike antigen correlated with IgG and IgA antibody titers. Each of M, spike, and N antigens accounted for 11%–27% of the total CD4+ response. The remaining responses were against other SARS-CoV-2 antigens. This suggests that vaccines that target multiple antigens may be more effective than the ones targeting only the spike antigen.
    T cell immunity is observed in persons infected and in about one-half of persons uninfected with SARS-CoV-2. The latter may have been previously infected with a virus such as one of the four human coronaviruses that cause colds. Thus, there is cross reactivity with other corona viruses. This may be a reason for variability in severity of clinical illness after infection.
    Many of the vaccine candidates lead to production of the spike protein and antibodies against it. If the vaccine does not produce the spike protein with correct confirmation, the generated antibodies may be binding but not neutralizing antibodies. This can promote viral replication or form complexes that trigger more inflammation. Memory B and T cells that recognize the virus can provide protective immunity for years although the antibody titers may decline within months. Efforts are being made to genetically modify certain immune cells to target the virus.
  • Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis. 6/11/20. Parasa S. JAMA.
    Gastrointestinal (GI) symptoms of COVID-19 include loss of appetite, nausea, vomiting, diarrhea, and abdominal discomfort. These symptoms might start before or occur with or without other symptoms such as fever, myalgias, and cough. Lower gastrointestinal tract is rich in ACE2 receptors.
    About 40% of the patients’ stool tests positive for SARS-CoV-2 RNA. This is primarily due to RNA fragments of the virus. One study showed live virus on electron microscopy in a small percentage of patients. These patients’ stools are infectious. Patients who have virus in the stool take longer to clear it. Although a small percentage of patients have GI symptoms, up to one-half shed virus in the stool. Virus protein shell is also found in gastric, duodenal, and rectal cells.
    More than one-half of COVID-19 hospitalized patients have elevated lactate dehydrogenase and other liver enzymes indicating injury to the liver or bile ducts. This is likely to be due to an overactive immune system or due to drugs causing liver damage.
  • COVID-19 pandemic and the skin: what should dermatologists know? 3/24/20. Darlenski R. Clin Dermatol.
    Skin manifestations of COVID-19 are like those of other viruses and chronic inflammatory diseases like acne, eczema, psoriasis, and rosacea. Vascular problems associated with skin manifestations can be neurogenic, microthrombotic, or immune complex-mediated.
    Of the patients with skin manifestations, a majority have patchy erythematous rash. Some have widespread urticaria or hives. A few also have chickenpox-like fluid-filled vesicles or blisters. They can have measles-like rashes. The most affected area is the trunk. Itching is mild or absent. Some patients have skin eruptions at symptom onset, and others after hospitalization. Lesions usually heal in a few days. Skin manifestations do not correlate with the severity of COVID-19.
    Patients may develop livedo reticularis. It is a purplish net-like discoloration of the skin, often a result of blood clotting abnormalities. Lacy, dusky rashes, including dead skin cells are observed on the arms, legs, and buttocks. They are associated with hypercoagulability. Petechiae are present. Nonpruritic blanching livedoid vascular eruption, possibly due to vaso-occlusion may be present. They appear as mottled, netlike red or pink patches. Also present are chilblains, which are purplish, slightly firm and often tender. COVID toes and fingers have frostbite-like areas with red or purple rash or hive-like eruption.

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Newsletter Issue 10, July 29, 2020:

  • Strategies to Optimize ICU Liberation (A to F) Bundle Performance in Critically Ill Adults With Coronavirus Disease 2019. 7/23/20. Devlin JW. Crit Care Explor.
    Click here to take this CME activity.

    Multi-institutional panel reviews option to modify and apply the ICU Liberation Bundle to COVID-19 scenarios in the ICU. They strongly recommend applying the Bundle to effectively deal with pain, agitation and delirium wherever possible and offer a number of valuable suggestions, among those dealing with lack of resources, like PPE and utilizing non-critical care trained clinicians. 

  • Considering the potential for an increase in chronic pain after the COVID-19 pandemic. 7/24/20. Clauw DJ. Pain.
    An International panel reviews the underlying factors likely to lead to or exacerbate chronic pain in individuals during a pandemic whether or not an infection actually takes place. Addressing both chronic pain management professionals and acute care providers, this synopsis reminds us of post-SARS syndrome and urges us to prepare for post-COVID-symptomatology which includes chronic debilitating illnesses, like chronic fatigue, irritable bowel syndrome and interstitial cystitis and other conditions marked by a chronic pain experience. Registries, awareness and multidisciplinary teams will be required to deal with this likely scenario.
  • Outcomes from intensive care in patients with COVID‐19: a systematic review and meta‐analysis of observational studies. 6/30/20. Armstrong B. Anaesthesia.
    Fascinating meta-analysis of 10,150 adult patients in 24 studies (enrollment was December 16, 2019 until May 28, 2020) from 11 countries with ICNARC (UK) database (national, rapidly updated registry) accounted for most cases in the study (results were unchanged when removed) with ICU death as primary endpoint. Mortality trended down from ~50% to 41.6% over time with confirmed by meta regression analysis by publication date indicating decreasing mortality. Discussion includes possibility of increasing sophistication of care outside ICU and despite likely increasing severity of ICU patients, therapeutic sophistication improvement was likely responsible for better outcome.
    Excellent analysis with interesting discussion and conclusions emphasizing need for better national data reporting in real time to better follow disease progression and resource utilization.
  • Design for Implementation of a System-Level ICU Pandemic Surge Staffing Plan. 7/23/20. Thakur N. Crit Care Explor.
    Authors provide a comprehensive description of the design, dissemination, and implementation of an algorithm for multidisciplinary critical care staffing during surge demand, as implemented by a 40-hospital multi-state healthcare system. Staff is tiered according to skills and experience with team leadership roles for the most appropriate. On-site and telemedicine supervision are employed to optimally leverage oversight and scaling of patient loads. The plan provides for doubling of 750 ICU beds out of a total 5,500 beds. Consistent terminology and role-definition facilitate redeployment and allocation of human resources to meet changing local needs across diverse hospitals.
  • Pulmonary embolism in hospitalised patients with COVID-19. 7/10/20. Whyte MB. Thromb Res.
    A single center retrospective review of the results of 214 computer tomography pulmonary angiography studies performed on hospitalized Covid-19 patients with suspected pulmonary emboli. 31% of studies were positive for pulmonary emboli which represents 5.4% of all patients admitted during the study’s time interval. Elevated Wells score greater or equal to 4 did not predict results. Median D-dimer was 8000 ng/ml for patients with a positive study versus 2060 ng/ml for patients with a negative study, but low D-dimer had limited utility excluding patients with pulmonary emboli.
  • Pulmonary immune responses against SARS-CoV-2 infection: harmful or not? 7/19/20. Guillon A. Intensive Care Med.
    A brief, well written review of the literature on COVID-19 immune responses claiming that the critical processes occur primarily in the lung and that the immune injury phase of the disease is not well described as a generalized “cytokine storm.” A T-cell subpopulation called innate T-cells appears to be diminished and have impaired function in peripheral blood but is found in increased numbers and activation in the airways of these patients.
  • A proposal for staging COVID-19 coagulopathy. 7/21/20. Thachil J. Res Pract Thromb Haemost.
    Authors from three continents propose a framework within which to stage COVID-19 associated hemostatic abnormalities, and potentially guide treatment. A theory that infected lung epithelium acts as the epicenter of coagulation with early stages that are difficult to diagnose is described, along with a 3-stage disease model. Currently there are no reliable markers to guide treatment; however patterns and questions for researchers are outlined. A table outlines 11 current international clinical trials on approaches to coagulopathy and are listed on
  • Characterization of experimental and clinical bioaerosol generation during potential aerosol-generating procedures. 7/15/20. Doggett N. Chest.
    This prospective study from Toronto quantified aerosol production pre and post two presumed aerosol generating procedures (AGPs); intubations in pigs (n=16) and elective bronchoscopies in human adults (n=39). Though overall, there was a significant reduction in larger particle aerosols during the procedures, and no significant increase in small particle aerosolization during the procedures, some bronchoscopies did produce significantly increased small particle aerosols. The authors conclude that the variability of aerosol generation reinforces the need for PPE during AGPs, and that more research is needed, especially in the more uncontrolled environments typical of a COVID-19 surge.
  • Review of Viral Testing (Polymerase Chain Reaction) and Antibody/Serology Testing for Severe Acute Respiratory Syndrome-Coronavirus-2 for the Intensivist. 7/23/20. Motley MP. Crit Care Explor.
    A nice review of nucleic acid amplification technology (PCR) and serological assays to diagnose, treat, and limit the spread of SARS-Cov-2 and it includes a discussion of the strengths and limitations of individual assays.
  • Personalized Ventilation to Multiple Patients Using a Single Ventilator: Description and Proof of Concept. 7/17/20. Han JS. Crit Care Explor.
    A proof of concept: the authors used components readily available in their hospital to assemble two “bag-in-a-box” breathing circuits. This shared ventilator function is proposed as a “last ditch” ventilatory assist device and not as a preferred ventilation mode. In a time of crisis where resources are limited, they introduced a system of multiple secondary breathing circuits driven by a ventilator in preference to that of simply splitting the breathing circuits. The authors hope, though, that this will not be needed. But these were all test conditions, not actually used on a patient.

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Newsletter Issue 9, July 27, 2020:

  • Prospective study in 355 patients with suspected COVID-19 infection. Value of cough, subjective hyposmia, and hypogeusia. 7/21/20. Martin-Sanz E. Laryngoscope.
    Click here to take this CME activity.

    Review by the SAB
    By Dr. Lance Lichtor, on behalf of the SAB
    Of 355 patients who were healthcare personnel, there was a significant association between positive PCR and subjective hyposmia. If cough was added, the odds of having a positive RT-PCR increased significantly. The measurement of fever as the only method for screening of COVID-19 infection resulted in a poor association.

  • Excess Deaths From COVID-19 and Other Causes, March-April 2020. 7/1/20. Woolf, SH. JAMA.
    The initial symptomatology, prodromal infective potential, anticipated course/severity, value of PPE and myriad additional variables were unknown when COVID-19 began its international journey. Early optimism in terms of containing and controlling the virus rapidly deteriorated as disease progression was recognized, the ability of asymptomatic carriers were known to be highly infectious and the initially unexpected benefit of universal face mask adoption created uncertainly about not only the viral spread but also the safety and reliability of the health system. Death is usually categorized accurately and reliable “death rate” statistics have been accumulated; the authors use seasonally adjusted U.S. death rates from December 29, 2013 to February 29, 2020 and compare historical to actual death rates reported between March 1, 2020 and April 2020 and include a secondary analysis in the five states most severely affected by the virus during the collection period. Careful data analysis was used to determine all-cause mortality and how COVID-19 influenced the total. The results attribute 65% of excess deaths to COVID-19-related causes and suggest that the total number is likely higher. Analysis was able to distinguish significant increases in other diseases during the period.
    Also included is an insightful discussion underscoring importance of accurate determination of COVID-19’s true impact on not only death but also on hidden morbidity (including COVID-19 delayed treatment and/or resource constraints) which is still being elaborated.
  • EDITORIAL: Mortality and Morbidity: The Measure of a Pandemic. 7/1/20. Zylke JW. JAMA.
    This editorial accompanying “Excess Deaths” further elaborates on the importance of, and difficulties associated with, estimating impact of COVID-19 on health systems and society. Peripheral effects are included and discussed. Together, the articles underscore the importance of classification and clarification in estimating disease impact, prevalence and spread in vulnerable populations and on society at large.
  • Association Between Universal Masking in a Health Care System and SARS-CoV-2 Positivity Among Health Care Workers. 7/14/20. Wang X. JAMA.
    This research letter from the Mass General Brigham healthcare system reports an association between the requirement for universal masking for their healthcare workers and a reduction in their percent positive COVID-19 PCR test results during a period of time when the disease continued to increase in the general population. The decrease in healthcare worker infections could have been confounded by other interventions inside and outside of the health care system, such as restrictions on elective procedures, social distancing measures, and increased masking in public spaces. However, the authors contend these results support universal masking as part of a multi-pronged infection reduction strategy in healthcare settings.
  • Race, Postoperative Complications, and Death in Apparently Healthy Children. 7/1/20. Nafiu OO. Pediatrics.
    In a retrospective article of over 170,000 healthy children with care provided by anesthesiologists, African American children suffered more postsurgical complications, especially bleeding and death.
  • The Structural and Social Determinants of the Racial/Ethnic Disparities in the U.S. COVID-19 Pandemic: What’s Our Role? 7/17/20. Thakur N. Am J Respir Crit Care Med.
    A call to arms for critical care and pulmonary specialists: black, Latinx, and Native Americans test positive for and die from coronavirus at higher proportion than other racial and ethnic groups. Their mortality rates far exceed the proportion of the population that these groups represent. Historically disadvantaged communities have reduced capacity to adopt preventive measures. Minority communities with low socioeconomic status (SES) and/or limited English proficiency receive less public communication during crisis and pandemics; access to testing and care is greatly limited in low-SES and minority communities. This article advocates for under-represented minority patients, who are becoming critically ill and dying at disproportionate rates.
  • Nutrition of the COVID-19 patient in the intensive care unit (ICU): a practical guidance. 7/19/20. Thibault R. Crit Care.
    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    French authors propose a flow chart and identify ten key issues for optimizing the nutrition management of COVID-19 patients in the ICU. Prominent among those is a preference for enteral nutrition whenever possible, attention to avoid the refeeding syndrome and awareness of the propofol infusion syndrome. Existing guidelines like GLIM* are valuable and their application encouraged. The use and limitations of indirect calorimetry during Covid-19 is discussed.
    * Global Leadership Initiative on Malnutrition
  • COVID-19 and the kidney: what we think we know so far and what we don’t. 7/22/20. Farouk SS. J Nephrol.
    Review by the SAB
    These authors are troubled by existing data related to true incidence, etiopathology, and its management with Covid-19. A heterogeneous report, with respect to population size, location, severity of illness, and definitions of acute kidney injury (AKI), show a wide range of rates of AKI occurrence in patients, from 1-46% and an equally wide percentage range of patients who were treated with kidney replacement therapy (KRT) (10-35%). Most patients with KRT were in the ICU (data was from the UK, Ireland, Italy, China, and the USA) and it has overwhelmed the nephrology services the world over. Potential explanations for these differences include the prevalence of co-morbid conditions and heterogeneity along racial and ethnic lines, local institutional policies about KRT timing, the use of extracorporeal KRT beyond classical “nephrological” indications. Using AKI as defined by “the 2019 Kidney Diseases: Improving Global Outcomes Consensus Conference” may standardize the whole process (a work in progress?). Mode of injury is also noted to be multifactorial. Though the link between AKI and poor outcomes is clear, prevalence and outcomes of COVID-19 in patients with chronic kidney disease and end-stage kidney disease has not yet been reported. In patients on immunosuppression like those with kidney transplants or glomerular disease, COVID-19 has presented a management dilemma.

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Newsletter Issue 8, July 22, 2020:

  • Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. 7/17/20. The RECOVERY Collaborative Group. N Engl J Med.
    Click here to take this CME activity.

    Review by the SAB
    These authors (Nuffield /Oxford) provide preliminary results (recruitment ended on June 8) of the controlled, open-label-randomized evaluation of COVID-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with COVID-19. The primary outcome was mortality within 28 days after randomization.
    In patients hospitalized with COVID-19, the use of dexamethasone (6mg either IV or PO up to 10 days) resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support (may harm). In a 2:1 randomization, 2,104 patients received dexamethasone and 4,321 received the usual care. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82). There was a trend showing the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (11.5 by chi square test for trend). Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days (rate ratio, 1.10; 95%). It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on a selection of the right dose, at the right time, in the right patient. Viral replication peaks in the second week of illness in SARS, while viral shedding in SARS-CoV-2 appears to be higher early in the illness and declines, thereafter when dexamethasone is most effective. At that stage, the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.

  • Therapeutic Plasma Exchange: A potential Management Strategy for Critically Ill COVID-19 Patients. 7/16/20. Tabibi S. J Intensive Care Med.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    This report briefly discusses various approaches currently being investigated to treat SARS-CoV-2 with a focus on potential benefits of therapeutic plasma exchange (TPE). TPE may alleviate the need for polypharmacy to combat various cytokines along with their associated side effects and necessary adjustments for comorbidities. TPE has been used to treat H1N1-associated ARDS, myasthenia gravis, Kawasaki disease, early septic shock, and various multi-organ dysfunction syndrome phenotypes including thrombocytopenia purpura. Reports of its use to treat severe COVID-19 are reviewed. TPE appears generally safe. Concerns involve blood supply, availability, and potentially cost. A proposed set of criteria that overlap with those for convalescent plasma and Spectra Optia Apheresis System is outlined, including early ARDS, severe disease, and life-threatening disease. Clinical trials are underway.
  • Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. 7/15/20. Mathew D. Science.
    Review by the SAB
    By Dr. Uday Jain, on behalf of the SAB
    Previously uncharted role of lymphocytes in COVID-19 is discussed. A wide variability in immune response was observed among hospitalized COVID-19 patients. Responses were barely detectable in about one-fifth of the patients. This was associated with pathology due to the virus and reduced survival. Remaining patients had CD8 and/or CD4 T lymphocyte and plasmablast responses that were heterogeneous among the patients and were divided into immunotypes. In many patients who became seriously ill with Covid-19, helper and killer cells do not work well cooperatively. An overabundance of helper cells is proinflammatory. An overabundance of killer T cells is not ideal but consistent with survival.
  • Protecting healthcare workers from SARS-CoV-2 infection: practical indications. 4/3/20. Ferioli M. Eur Respir Rev.
    Review by the SAB
    By Dr. Jay Przybylo, on behalf of the SAB
    A “how to” based on oxygen therapy and dispersed exhaled breath. The importance of the article concerns exhaled breaths dispersion which depends on the mode of oxygen therapy. The remainder of the article is not scientifically based.
  • CPR in the COVID-19 Era – An Ethical Framework. 7/9/20. Kramer DB. N Engl J Med.
    Review by the SAB
    By David Clement, on behalf of the SAB
    This opinion paper provides important reading on the ethics of how the surge of patients with COVID-19 complicate standard CPR practices. An ethical framework of three crisis standards is proposed: acknowledge resource limitations, forgo CPR in certain circumstances, and impose selective constraints on CPR to ensure the safety of healthcare personnel. Hospitals need to develop such explicit crisis standards for CPR to help clinicians and the public understand when strict adherence to established resuscitation protocols may no longer be appropriate.
  • Hospitalization and Mortality among Black Patients and White Patients with Covid-19. 6/25/20. Price-Haywood EG. N Engl J Med.
    Review by the SAB
    By Heinrich Wurm, on behalf of the SAB
    This retrospective cohort study takes a critical look at incidence, mortality and concomitant risk factors among black and white non-Hispanic members of the Ochsner integrated delivery health system.
    Black patients far exceeded white non-Hispanics in getting infected (70 vs. 30% of enrolled patients were PCR positive), requiring hospital admission (77%) and dying (71%). But black race was not independently associated with a higher mortality (HR death vs. white race 0.89; 95 CI, 0.68-1.17) when adjustments for differences in socio-demographic and clinical characteristics were made.
    Blacks had a greater prevalence of underlying disease (obesity, diabetes, hypertension, chronic kidney disease), presented with higher levels of inflammatory markers, elevated creatinine and were more likely to live in low-income areas and receive public insurance. Greater occupational exposure in service industries and higher incidence of morbid obesity and chronic kidney disease were also discussed.
  • Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. 7/6/20. Pollan M. Lancet.
    Review by the SAB
    By Dr. Robert Coffey, on behalf of the SAB
    This article reports the results of antibody testing of 61,000 individuals across Spain, from April 27 to May 11, showing an overall national seropositive rate of only 5% (the majority of new diagnoses in Spain’s severe epidemic were made by May 1). Regions that experienced a more intense epidemic such as Madrid did have a seropositive rate of greater than 10%. Approximately one-third of the seropositive subjects reported having had no symptoms suggestive of COVID-19 infection. While specific locales such as Bergamo, Italy and some neighborhoods in Queens, NY may have seropositive rates high enough to confer local herd immunity, this does not seem to be occurring at a national level after severe epidemic episodes.
  • Impact of delays on effectiveness of contact tracing strategies for COVID-19: a modelling study. 7/16/20. Kretzschmar ME. Lancet Public Health.
    Review by the SAB
    By Dr. Lance Lichtor, on behalf of the SAB
    The authors used a mathematical model that describes the different steps of a symptomatic contact tracing strategy for COVID-19. They found reducing the testing delay (i.e., shortening the time between symptom onset and a positive test result, assuming immediate isolation) is the most important factor for improving contact tracing effectiveness. Reducing the tracing delay (i.e., shortening the time to trace contacts, assuming immediate testing and isolation if found positive) might further enhance contact tracing effectiveness, though this additional effect rapidly declines with increasing testing delay.
  • Individualizing Risk Prediction for Positive COVID-19 Testing: Results from 11,672 Patients. 6/20/20. Jehi L. Chest.
    Review by the SAB
    By Dr. Lance Lichtor, on behalf of the SAB
    The authors of this article developed an online risk calculator that can identify individualized risk of a positive COVID-19 test. All patients from Cleveland Clinic in Ohio and Florida were tested, not just those who had the disease. Findings included: lower risk for Asians vs whites; lower risk for those who had pneumococcal polysaccharide vaccine and flu vaccine; higher risk with poor socioeconomic status; and reduced risk of testing positive in patients who were on melatonin, carvedilol, and paroxetine.
  • Neurobiology of COVID-19. 6/30/20. Fotuhi H. J Alzheimer’s Dis.
    Review by the SAB
    By Heinrich Wurm, on behalf of the SAB
    This review by a panel of U.S. experts goes beyond analyzing neurological manifestations of COVID-19 and provides us with plausible and well-illustrated pathophysiological theories and a 3-stage evolution of a condition termed Neuro-COVID. A synopsis of worrisome post-COVID-19 neurological sequelae, ranging from poor memory and slow processing speed to lasting depression, Parkinson’s, multiple sclerosis and Alzheimer’s, concludes this remarkable publication and points us towards a future of COVID-related sequelae.
  • SARS-CoV-2 infection protects against rechallenge in rhesus macaques. 5/20/20. Chandrashekar A. Science.
    Review by the SAB
    By Dr. Uday Jain, on behalf of the SAB
    Nine adult rhesus macaques infected with SARS-CoV-2 developed humoral and cellular immune responses leading to protective immunity. On re-challenge by SARS-CoV-2, there was a major attenuation of viral load in nasal mucosa and bronchoalveolar lavage in all of them. As the virus was still detectable, the protection was not sterilizing and the macaques could infect others. These results in primates suggest that patients who have COVID-19 may develop immunity to it. This is also essential for the development of a vaccine and determination of herd immunity.

View full issue.

Newsletter Issue 7, July 20, 2020:

  • COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy. 7/16/20. Bellino S. Pediatrics.
    Click here to take this CME activity.

    Review by the SAB
    By Dr. Jay Pryzbylo, on behalf of the SAB
    This large pediatric study demonstrates that infection by COVID-19 increases with age (severe illness in the youngest) is uncommon in the pediatric age group with only 1.8% of total infections over all ages. The study reported only 4 deaths, all in children with complex underlying medical issues.

  • The Impact of Coronavirus Disease 2019 Pandemic on U.S. and Canadian PICUs. 7/8/20. Sachdeva R. Pediatr Crit Care Med.
    Review by the SAB
    By Dr. Philip Lumb, on behalf of the SAB
    This report is from a large pediatric ICU registry (Virtual Pediatric Systems, Los Angeles, CA), with data from over 200 hospital units and >1.5 million patient admissions. In order to determine the manner in which COVID-19 was affecting PICU’s, VPS expanded data collection related to COVID-19 to all Canadian and US PICU’s regardless of prior VPS membership to provide a near real-time dashboard including admissions, patient demographics and comorbidities, therapeutic interventions, deaths and length of stay. Data collection, from March 4 to May 20, represented 3,228 bed capacity comprising most US and Canadian resources from major teaching institutions to smaller hospitals with multifunctional PICU’s. At the peak of the admissions in late April, ~40% of admissions >18yo and ~12% >30yo indicating unusual age disparity than normally seen and providing insight into future PICU adjustments. Detailed description of analysis and future research directions are provided, demonstrating the value of high reliability registry with capability to provide rapid resource allocation and patient demographic, therapeutic and outcome information.
  • An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. 7/14/20. Jackson LA. N Engl J Med.
    EDITORIAL: The Covid-19 Vaccine-Development Multiverse. 7/14/20. Heaton PM. Cardiovasc Res.
    Review by the SAB
    By Dr. David Clement, on behalf of the SAB
    This paper and the associated editorial report the Phase 1 trial of a SARS-CoV-2 vaccine developed by the National Institute of Allergy and Infectious Disease and the private company, Moderna. In a dose escalation, 2 injection trial in 45 adults using a spike RNA viral antigen, the vaccine induced anti-SARS-CoV-2 immune responses in all participants, similar to the immune responses of recovered COVID-19 patients. Adverse events were common, but none were serious.
    The accompanying editorial gives an overview of traditional vaccine development, how the current efforts have accelerated this usual process, and describes hurdles yet to be overcome.
  • Covid-19: What do we know about “long covid”? 7/14/20. Mahase E. BMJ.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    This non-peer reviewed article discusses “Long COVID,” a term used for lasting effects after recovering from COVID-19 infection or symptoms that persist longer than expected.
    Ongoing health problems may include “breathing difficulties, enduring tiredness, reduced muscle function, impaired ability to perform vital everyday tasks, and mental health problems such as post-traumatic stress disorder, anxiety, and depression.”
    HNS England will be launching an online portal for those with long-term effects of COVID-19 to communicate with nurses, physiotherapists, and mental health specialists.
    A Facebook “long Covid Support group” has >7000 members, and the hashtag “longcovid” enables personal experiences to be shared on social media.
    Research on the long-term effects of COVID-19 infection is needed. The Post-hospitalization COVID-19 Study plans to follow 10,000 UK patients for a year, but it will not include milder cases that didn’t require hospital care.
  • Palliative care for patients with severe covid-19. 7/14/20. Ting R. BMJ.
    Review by the SAB
    By Dr. Lance Lichtor, on behalf of the SAB
    We usually think about a cure, but not everyone can be saved. This is a good article about managing patients with distressing symptoms, explaining the importance of having a strategy to manage patient deterioration and death, and stressing the importance of communication with the family with the sensitivity of noting that their loved one may soon die.
  • Neurological manifestations of COVID-19: a systematic review. 7/15/20. Nepal G. Crit Care.
    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    This well-organized review of the world literature up to May 20, 2020 analyses 37 articles, many of them case reports. The authors critically review each neurological symptom or disease entity currently known to exist with the intent to provide practitioners with an overview of a host of manifestations ranging from mild headaches to taste and smell disorders to strokes, hemorrhage and central and peripheral nervous system inflammatory reactions like encephalo-myelits and Guillain-Barré syndrome.

ABO Blood Phenotypes and COVID-19
Below are articles on data on the infection rate and potential comorbidities of COVID-19 associated with ABO blood phenotypes.

  • ABO Phenotype and Death in Critically Ill Patients with COVID-19. 7/1/20. Leaf RK. Br J Haematol.
    Review by the SAB
    By Lydia Cassorla, on behalf of the SAB
    In this Letter to the Editor, ABO blood type data from adults admitted to ICUs over 38 days in the 67-center Study of the Treatment and Outcomes in critically ill Patients from COVID-19 (STOP-COVID) study were analyzed. Patients were followed until hospital discharge, death, or May 8, 2020 – a date that included a minimum of 28 days follow-up for those still hospitalized. 2033/3239 (62.8%) had ABO data available. 799/2033 (39.3%) died within 28 days. Death rates were similar across ABO phenotypes in all race/ethnicity categories, as well as Rh status. Among White patients, the observed distribution of ABO phenotypes differed from expected, primarily due to blood type A being over-represented (45.1% observed vs. 39.8% expected) and blood type O being under-represented (37.8% observed versus 45.2% expected). Among Black and Hispanic patients the observed and expected distributions of ABO phenotypes were similar.
  • Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. 6/21/20. Wu Y. Clin Chim Acta.
    Review by the SAB
    By Lydia Cassorla, on behalf of the SAB
    Retrospective case controlled study of Wuhan patients admitted to a single Chinese hospital 1/20/20 – 3/5/20. 187 study patients were admitted with COVID-19 while 1991 control patients were COVID negative individuals admitted during the same time period. The proportion of patients with type A blood in the COVID-19 group was significantly higher than that in the control group (36.90% vs. 27.47%, P = 0.006), while the proportion of patients with type O blood in the COVID-19 group was significantly lower than that in the control group (21.92% vs. 30.19%, P = 0.018). Blood group A patients had a higher risk of COVID-19 than non-A blood group patients. (OR = 1.544, 95% CI = 1.122–2.104, P = 0.006). Blood group O patients had a lower risk of COVID-19 than non-O blood group patients (OR = 0.649, 95% CI = 0.457–0.927, P = 0.018).

View full issue.

Critical Care Edition, July 16, 2020:

  • Inhalational volatile-based sedation for COVID-19 pneumonia and ARDS. 6/25/20. Jerath A. Intensive Care Med.
    Click here to take this CME activity.

    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    In light of a growing shortage of sedatives and intravenous anesthetics, this narrative review from Toronto highlights the benefits and technical details of volatile anesthetics for sedation in the critical care unit during the COVID-19 pandemic.
    Spearheaded in Europe – volatile anesthetics using in-line vaporizers may provide added benefits, like bronchodilatation and an anti-inflammatory effect, but safe use requires trained teams familiar with volatile anesthetics administration in the ICU. The authors provide a comprehensive and realistic review of available options and alternatives.

  • Cardiopulmonary Resuscitation in Intensive Care Unit Patients With Coronavirus Disease 2019. 7/1/20. Cheruku S. J Cardiothorac Vasc Anesth.
    Review by the SAB
    By Dr. Philip Lumb, on behalf of the SAB
    Interesting discussion involving practical, ethical and medical (physicians, ICU staff and ancillary personnel) decisions and preparations to perform cardiac resuscitation in terminally ill COVID-19 patients. Focuses on planning and preparing appropriate patients for potential resuscitation by informed discussion with patient/family, insertion of central venous access lines with long IV connections for access and infusion outside patient care area. CPR performed with automated chest compressor. Other safety elements described to protect staff and value of simulation in preparation emphasized. Novel approach to preparing for and performing CPR in COVID-19 patients.
  • Original Article: Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. 3/30/20. Gattinoni. American Thoracic Society.
    Review by the SAB
    Excellent discussion based upon 16 ventilated COVID-19 patients that the virus does not cause a typical ARDS and these patients may benefit from low PEEP and prone positioning.
  • Reply to: Hedenstierna et al, Haouzi et al, Maley et al, Fowler et al, Bhatia and Mohammed, Bos, & Koumbourlis and Motoyama. 6/24/20. Gattinoni L. Am J Respir Crit Care Med.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Response to correspondence regarding previously reviewed letter to the Am J Respir Crit Care Med by Gattinoni et al on COVID-19 and ARDS. The response reiterates two phenotypes of COVID-19 pneumonia:
    • Early L phenotype — atypical ARDS with lower elastance, lower Va/Q, lower recruit ability and lower lung weight.
    • Late H phenotype — typical ARDS with higher elastance, higher R->L shunt, higher recruit ability, and higher lung weight.

    They suggest the “contradictory results” reported by others may be due to the time of observation and reflect progression to the late H phenotype of the disease. They reiterate that the important feature of the L phenotype is not the high respiratory system compliance per se but the Va/Q mismatch induced hypoxia with a lung gas volume greater than is seen with ARDS “baby lung.”
    They re-discuss mechanical ventilation management for the different phenotypes and suggest that the wide global disparity in COVID-19 ICU mortality rate may reflect the impact of “standard ARDS” treatment.

  • Improved Clinical Symptoms and Mortality on Severe/Critical COVID-19 Patients Utilizing Convalescent Plasma Transfusion. 6/23/20. Xia X. Blood.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    This article may be of interest to those looking to learn from the Chinese experience with convalescent plasma (CP). 138/1568 COVID-19 patients from this retrospective single-center Chinese cohort study received CP. Death (2.1% vs. 4.1%) and requirement for ICU care (2.4% vs. 5.1%) in the CP group were close to half of that in the untreated patients. Patients with higher initial lymphocyte counts and those who received CP treatment within 7 wks. from onset of clinical disease were more likely to respond.
  • Anesthesiologists’ and intensive care providers’ exposure to COVID-19 infection in a New York City academic center: a prospective cohort study assessing symptoms and COVID-19 antibody testing. 6/11/20. Morcuende M. Anesth Analg.
    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    A prospective cohort study from Columbia University Irving Medical Center based on an email-based survey mailed on April 15, 2020. The survey asked for symptoms and COVID-19 antibody testing after work-related COVID-19 exposures, among anesthesiologists and critical care doctors in a large NYC academic medical center at the height of the pandemic.
    The survey’s goal was to differentiate community from professional exposure and to evaluate the degree of protection PPE affords clinicians. The study achieved a 51% response rate and detected a 58% incidence of work-related exposure, 54% of which were high-risk exposures (e.g. intubation with inadequate PPE) and 26% reported symptoms suggesting COVID-19 infection.
    Antibody testing revealed an almost identical 12% positive result among those with work-related exposure and those who did not report such an event. Antibody positive respondents were more likely to use NYC subway to commute to work and report COVID-19-like symptoms in the last 90 days.
  • Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. 6/22/20. Verweij PE. Intensive Care Med.
    Review by the SAB
    Although the number of COVID-19-associated aspergillosis (CAPA) cases that have been reported is a small number, in two series, similarities and differences with Influenza with Invasive Aspergillosis (IAP) and COVID-19 are pointed out. Here a group of authors (EU, USA and Taiwan) are seeking to change the definition of IAP (inclusive of clinical and radiological signs). They make a point that an under-estimation of IAP requires a need for vigilance for IAP in the ICU, an early diagnosis, holding steroids, judicious use of antiviral to avoid a fatal outcome due to an IAP patient in comparison to Influenza with IAP.
    For CAPA:
    • 85% host factors are -ve but Lymphopenia/monocyte hyperimmune response is present
    • IPA tracheobronchitis is not known
    • The entry point ACE 2 – anti-fungal immunomodulation by antifungal not likely?
    • Serum GM + ve – need a study in COVID-19 to understand the implication.
    • No specificity of secondary infection organism types.
  • Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. 6/29/20. Arshad S. Int J Infect Dis.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Multi-center retrospective observational study of 2,541 consecutive RT-PCR confirmed COVID-19 admissions from March 10 to May 2 in Detroit to determine impact of hydroxychloroquine +- azithromycin on inpatient mortality.
    Standard, uniform treatment guidelines established by a system-wide interdisciplinary COVID-19 task force also included corticosteroids and tocilizumab, which were used in 68% and 4.5% respectively.
    In hospital mortality:
    • Overall 18%
    • No hydroxychloroquine or azithromycin 26%
    • Azithromycin alone 22%
    • Hydroxychloroquine + azithromycin 20%
    • Hydroxychloroquine alone 13.5%
    • Mortality predictors were age > 65, CKD, decreased O2 sat on admit, ventilator use, and in contrast to previous studies, white race.

    Propensity matched regression analysis showed a mortality hazard ratio of .49 for patients who received hydroxychloroquine.
    Of note, no deaths due to major cardiac arrhythmias, such as torsades, were seen with hydroxychloroquine treatment.
    The authors suggest that early medication treatment (91% within 48 hours of admission), standardized dosing, and inpatient telemetry with electrolyte protocols may have accounted for the positive results seen with hydroxychloroquine.

  • Long-Term ACE Inhibitor/ARB Use Is Associated with Severe Renal Dysfunction and Acute Kidney Injury in Patients with severe COVID-19: Results from a Referral Center Cohort in the North East of France. 7/5/20. Oussalah A. Clin Infect Dis.
    Editorial: ACE inhibitors/ARB use and COVID-19. Time to change practice or keep gathering data?. 7/4/20. de Feria A. Clin Infect Dis.
    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    This well-designed retrospective longitudinal cohort study on patients admitted for severe COVID-19 to a tertiary referral university hospital in France finds that chronic ACE inhibitor and ARB use was associated with an increased risk of acute kidney injury as well as a potential interaction with the occurrence of acute respiratory failure. Although retrospective, this study stands out in its use of large amounts of high quality data and their sophisticated analysis allowing identification of potential groups of patients at higher risk for poor outcomes.
    The accompanying editorial poses the question whether and when this and similar studies will impact clinical decision making.

View full issue.

Newsletter Issue 6, July 15, 2020:

  • Tocilizumab for treatment of mechanically ventilated patients with COVID-19. 7/11/20. Somers EC. Clin Infect Dis.
    Click here to take this CME activity.

    Review by the SAB
    By Dr. David Clement, on behalf of the SAB
    An observational, controlled study of 154 adult, ventilated COVID-19 patients, half of whom received tocilizumab. Tocilizumab-treated patients had a 45% reduction in hazard of death, improved status on some secondary outcomes, and twice as many superinfections. Extensive tables, figures and statistical analysis provide insight.  A randomized study is needed to confirm these findings.

  • Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis. 7/11/20. Lecronier M. Crit Care.
    Review by the SAB
    By Dr. Lance Lichtor, on behalf of the SAB
    In critically ill patients admitted for SARS-CoV-2-related pneumonia, no difference was found between hydroxychloroquine or lopinavir/ritonavir as compared to patients who received standard of care only on the proportion of patients who needed treatment escalation at day 28.
  • Risk factors for myocardial injury and death in patients with COVID-19: insights from a cohort study with chest computed tomography. 7/8/20. Ferrante G. Cardiovasc Res.
    Review by the SAB
    By Dr. Philip Lumb, on behalf of the SAB
    Interesting study reporting admission CT Scan results on 332 consecutive patients with documented COVID-19 disease. Of these, 123 had myocardial injury defined as high-sensitivity troponin I above 20 ng/ml. Included patients had a median follow up of 12 days with 20.5% (68) deaths. Co-morbidities and course are well described; however, CT findings are consistent with lung involvement in COVID-19.
    The study concludes that “myocardial injury, as assessed by cardiac troponins, occurs in approximately one third of COVID-19 cases and is associated with an adjusted two-fold mortality increase. An increased PA diameter, as assessed on chest CT, is an independent predictor of both myocardial injury and death.”
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Discussion of risks and benefits of percutaneous tracheostomy versus surgical tracheostomy, with strategies for safely performing percutaneous tracheostomies in COVID-19 settings. However, they recommend that a surgical tracheostomy is the first choice in the case of goiter, obesity, pneumomediastinum, difficult anatomy, coagulopathy, hemodynamic or respiratory instability.
  • Is clinical effectiveness in the eye of the beholder during the COVID-19 pandemic? 7/9/20. Sandoval JL. BMJ Evid Based Med.
    Review by the SAB
    By Dr. Philip Lumb, on behalf of the SAB
    Editorial noting the importance of maintaining clinical practice based on sound scientific evidence despite the current data overload from multiple poorly controlled or prematurely reported studies. Notes the importance of scientific balance in the media influenced public response to frequently incomplete, unsubstantiated, or erroneous data.
  • Factors affecting stability and infectivity of SARS-CoV-2. 7/6/20. Chan KH. J Hosp Infect.
    Review by the SAB
    Authors from a Chinese laboratory report the results of several (virus strain line, temperature, tissue infectivity dose, humidity, pH, etc.) experiments for the COVID-19 virus and its survival under different environmental situations. COVID-19 was able to retain viability for 3-5 days in dried form or 7 days in solution at room temperature, could be detected under a wide range of pH (2-13) conditions for several days and also 1-2 days in stool at room temperature but lost 5 logs infectivity. Common fixatives, nucleic acid extraction methods, and heat inactivation were found to significantly reduce viral infectivity. That will likely ensure hospital and laboratory safety during the COVID-19 pandemic but transmission related to food handlers and workers in meat and poultry processing facilities is possible. The presence of the virus on high-risk hospital surfaces should lead to concern about cleaning on other surfaces. It is estimated that 18% of infections are asymptomatic. With its propensity to cause milder infections, COVID-19 spreads more efficiently in communities in the absence of rigorous social distancing and environmental cleaning measures.

COVID-19 and Obstetrics
Below are previously reviewed articles on the management of pregnant women during the COVID-19 pandemic. Despite their publication dates, these articles continue to remain relevant.

  • Clinical Implications of SARS-CoV-2 Infection in the Viable Preterm Period. 7/3/20. Gulersen M. Am J Perinatol.
    Review by the SAB
    The authors in this article conducted a retrospective, logistic regression analysis for preterm birth (PTB) from boroughs in New York of patients diagnosed with COVID-19 infection with pregnancy between 23 and 37 weeks of gestation during March and April of 2020. PTB was noted to be in two groups: 23 to 33 weeks (n = 7/36) and the other one was 34+ (n = 18/29) with p= 0.0001. Most women with COVID-19 infection in the early preterm period recovered and were discharged home. The majority of PTB were indicated and not due to spontaneous preterm labor. Delivery during the current admission was noted as statistically significant for the group of patients with 34+ weeks. No correlation was noted with severity of the COVID-19 disease grade or treatment regimes (antibiotics and antimalarial) but no interleukins or steroids were given to the late group. Gestational age at diagnosis of COVID-19 infection had an odds ratio of 2.9.
  • The Relationship between Status at Presentation and Outcomes among Pregnant Women with COVID-19. 5/20/20. London V. Am J Perinatol.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    This is a single-center retrospective cohort study of pregnant women who tested positive for COVID-19 at one Brooklyn hospital from March 15 to April 15, 2020. Fifty-five SARS-CoV-2 positive pregnant women were followed to term and 1 had fetal demise at 17 weeks. Among parturients with COVID-19 symptoms at presentation (n = 33), 16 (48.5%) had Cesarean delivery, 9 (27.3%) had preterm birth <37 weeks of whom 7 were C/Section for maternal respiratory distress. Twelve (26%) required respiratory support including 1 who required mechanical ventilation. Among those who were asymptomatic at presentation (n = 22), 6 (27%) had Cesarean delivery, and there were no preterm births. Pregnant women who present without symptoms remained asymptomatic to a greater degree than has been reported from cohorts of older individuals. Initially, patients were only tested because of symptoms of potential exposure. Universal testing began during the study period and 13.3% of 76 asymptomatic patients tested after that date were COVID-19 positive. Of 48 neonates tested on day 0 by PCR, none tested positive for COVID-19. Conclusion: Pregnant women with COVID-19-related symptoms have a high rate of severe disease and preterm birth due to Cesarean delivery to treat maternal respiratory distress.
  • Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study. 5/12/20. Pierce-Williams RAM. Am J Obstet Gynecol MFM.
    Review by the SAB
    By Dr. Jay Pryzbylo, on behalf of the SAB
    Data-rich, multicenter study of COVID-19 severe and critically ill women in third trimester pregnancy. Of the many findings, critically ill women required intubation, delivered prematurely mostly for maternal risk, the newborns were COVID-19 negative, 1 of 64 women required a tracheostomy. Matched to a non-pregnant control group, pregnancy did not alter outcome.

View full issue.

Newsletter Issue 5, July 14, 2020:

  • Managing Anxiety in Anesthesiology and Intensive Care Providers during the Covid-19 Pandemic: An Analysis of the Psychosocial Response of a Front-Line Department. 7/8/20. Fleisher LA. NEJM Catalyst.
    Click here to take the CME activity.

    Review by the SAB
    A survey about “anxiety / stress induced crisis of health care provider – HCP” conducted by Dr. Lee Fleisher of 242 MDs and CRNAs in the anesthesia and critical care medicine departments at University of Pennsylvania comes up with the best guidelines to follow for healthcare workers’ emotional well being during this pandemic.

    1. Covid-19 Task Force
    2. Development of a protocol
    3. Simulation training
    4. PPE training for all – addressing comfort level.
    5. Communication through a town hall meeting regarding the root of anxiety, identification of symptoms (insomnia, appetite, living situation).
    6. Complementing weakness and strength of traits, culture, gender, experience, psychology, age-related burnout while addressing shared expertise of healthcare workers in the field.

    Leadership should render the necessary training, psychological support, and clinical support, with acknowledgement of value of their work, to improve emotional health. The author stresses the role of meditation, maintaining routine including sleep, exercise, friends, and psychological assistance, and training.

  • How to Quantify and Interpret Treatment Effects in Comparative Clinical Studies of COVID-19. 7/7/20. McCaw ZR. Ann Intern Med.
    Review by the SAB
    By Dr. Jay Pryzbylo, on behalf of the SAB
    Concise but in depth explanation using the example of two previously published articles to demonstrate that the statistical techniques used do not necessarily accurately describe the outcomes achieved. At issue is that negative outcomes (e.g., deaths) are not adequately accounted for in positive outcome statistical evaluation (days to recovery). The authors advance a method to do so that alters the outcomes of the studies.
  • COVID-19 Clinical Trials: Unravelling a Methodological Gordian Knot. 7/7/20. Mathioudakis AG. J Thromb Thrombolysis.
    Review by the SAB
    By Dr. Lance Lichtor, on behalf of the SAB
    During a pandemic, in part because of the limit in a patient population that might shrink in the coming months, clinical trials might need to enroll a patient for more than 1 trial. In addition, because of the need to get information out quickly, interim data meta-analyses (or network meta-analyses) powered to evaluate key outcomes, may be useful. At least, strategies and methodologies need to be developed to allow the best use of data collected.
  • Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring. 6/19/20. Susen S. Crit Care.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    Authors of this practical review article from a multinational European working group recommend a strategy to categorize thrombotic risk level and to increase anticoagulation above standard prophylactic doses for hospitalized COVID-19 patients with additional risk factors including obesity (BMI>30), respiratory failure, findings of major inflammation (D-dimer>3mcg/ml. or fibrinogen >8 g/L) or evidence of consumptive coagulopathy. They propose baseline testing repeated q48 hrs. and include a color-coded chart to quickly determine the risk category for individual patients. Not discussed: management of consumptive coagulopathy, thrombolysis, antiplatelet therapy, and arterial thrombosis. Their management strategy is based upon previously published international data.
  • Thromboelastography Profiles of Critically Ill Patients With Coronavirus Disease 2019. 6/26/20. Yuriditsky E. Crit Care Med.
    Review by the SAB
    By Dr. Philip Lumb, on behalf of the SAB
    Interesting retrospective study of 64 critically ill COVID-19 patients with available/reported thromboelastograph studies within 72 hours of ICU admission; 50% showed hypercoagulable profile defined as a Clotting Index (CI) >3. It is noted that D-Dimer > 2,000 ng/ml associated with median CI 3.4 while D-Dimer <2,000 ng/ml median CI 2.1. Discussion indicates TEG profiles consistent with fibrinogen and platelet effect and authors suggest further studies evaluating platelet aggregation profiles. While value of TEG evaluation in COVID-19 patients has not been confirmed, nonetheless further investigation is warranted as results consistent with clinical severity markers, D-Dimer elevations and requirements for appropriate and timely anticoagulation.
  • Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis. 6/29/20. Mestre-Gómez B. J Thromb Thrombolysis.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Retrospective review of EMR data of 452 consecutive patients admitted to the general ward with COVID-19 (based on WHO clinical criteria and/or RT-PCR) in Madrid to determine the incidence of PE in non-critically ill COVID-19 patients and identify predictive factors.
    • 91 of these patients had CT pulmonary angiography (CTPA) to rule out PE, with 29 (32%) positive for acute PE.
    • Incidence of PE was 6.4% — 29/452 patients.
    • Of note, 79% were receiving prophylactic LMWH at the time PE was diagnosed
    • PE was not associated with a significantly increased risk of ICU admission or mortality
    • Multivariate analysis showed lack of history of dyslipidemia and elevated D-dimer were independent predictors of PE.
    • D-Dimer peak median was 2x higher in PE patients. Cut off predictor was > 5000 ug/dl.
    • Patients with history of dyslipidemia had a 9x lower risk of PE. It is not known if this is due to statin use prior to admission. Hospital statin administration was not significantly different among the two groups.

    While the study concludes that an elevated D-Dimer > 5000 ul/dl and lack of dyslipidemia history are independent predictors of COVID-19 related PE risk, it is limited by small sample size, retrospective nature, and lack of DVT studies.

  • Rate of venous thromboembolism in a prospective all-comers cohort with COVID-19. 7/2/20. Rieder M. J Thromb Thrombolysis.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    This German prospective single-center study analyzed 190 ED patients with suspected COVID-19 March-April 2020. 49 SARS-CoV-2 positive (25.8%). 141 SARS-CoV-2-negative patients served as a control group. After 30-day follow-up, VTE was diagnosed in 3 SARS-CoV-2-positive patients (6.1%, including 2 ICU patients) vs. 5 SARS-CoV-2-negative (3.5%), however the difference was not statistically significant (p = 0.427). 30-day mortality was similar (6.1% vs. 5%, p = 0.720). COVID-19 disease severity correlated with the maximum D-dimer level during follow-up, but not D-dimer at admission.
    Dyspnea was more common in the SARS-CoV2 negative group (41.7% vs. 52.4%, p = 0.002), whereas cough (58.3% vs. 37.6%, p < 0.0001) and fever (75% vs. 48.2%, p < 0.0001) were more frequent in COVID-19 patients. The rate of hospital admission was higher in the SARS-CoV-2 positive group (81.6% vs. 66.7%, p = 0.068) D-Dimers at admission did not differ between both groups (1.1 ± 1.4 mg/l vs. 0.8 ± 1.7 mg/l, p = 0.3).
  • Extracorporeal Membrane Oxygenation During the Coronavirus 2019 Pandemic. 6/26/20. Mikkelsen ME. Crit Care Med.
    Review by the SAB
    By Dr. Jay Przybylo, on behalf of the SAB
    An editorial addressing the use of ECMO in COVID-19 elaborating on an article describing ECMO for critically ill patients and demonstrating that survival was minimally better than conventional treatment of mechanical ventilation.

View full issue.

Newsletter Issue 4, July 13, 2020:

  • Original Article: Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. 3/30/20. Gattinoni. American Thoracic Society.
    Review by the SAB
    Excellent discussion based upon 16 ventilated COVID-19 patients that the virus does not cause a typical ARDS and these patients may benefit from low PEEP and prone positioning.
  • Reply to: Hedenstierna et al, Haouzi et al, Maley et al, Fowler et al, Bhatia and Mohammed, Bos, & Koumbourlis and Motoyama. 6/24/20. Gattinoni L. Am J Respir Crit Care Med.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Response to correspondence regarding previously reviewed letter to the Am J Respir Crit Care Med by Gattinoni et al on COVID-19 and ARDS. The response reiterates two phenotypes of COVID-19 pneumonia:
    • Early L phenotype — atypical ARDS with lower elastance, lower Va/Q, lower recruit ability and lower lung weight.
    • Late H phenotype — typical ARDS with higher elastance, higher R->L shunt, higher recruit ability, and higher lung weight.

    They suggest the “contradictory results” reported by others may be due to the time of observation and reflect progression to the late H phenotype of the disease. They reiterate that the important feature of the L phenotype is not the high respiratory system compliance per se but the Va/Q mismatch induced hypoxia with a lung gas volume greater than is seen with ARDS “baby lung.”
    They re-discuss mechanical ventilation management for the different phenotypes and suggest that the wide global disparity in COVID-19 ICU mortality rate may reflect the impact of “standard ARDS” treatment.

  • Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. 6/29/20. Arshad S. Int J Infect Dis.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Multi-center retrospective observational study of 2,541 consecutive RT-PCR confirmed COVID-19 admissions from March 10 to May 2 in Detroit to determine impact of hydroxychloroquine +- azithromycin on inpatient mortality.
    Standard, uniform treatment guidelines established by a system-wide interdisciplinary COVID-19 task force also included corticosteroids and tocilizumab, which were used in 68% and 4.5% respectively.
    In hospital mortality:
    • Overall 18%
    • No hydroxychloroquine or azithromycin 26%
    • Azithromycin alone 22%
    • Hydroxychloroquine + azithromycin 20%
    • Hydroxychloroquine alone 13.5%

    Mortality predictors were age > 65, CKD, decreased O2 sat on admit, ventilator use, and in contrast to previous studies, white race.
    Propensity matched regression analysis showed a mortality hazard ratio of .49 for patients who received hydroxychloroquine.
    Of note, no deaths due to major cardiac arrhythmias, such as torsades, were seen with hydroxychloroquine treatment.
    The authors suggest that early medication treatment (91% within 48 hours of admission), standardized dosing, and inpatient telemetry with electrolyte protocols may have accounted for the positive results seen with hydroxychloroquine.

  • Improved Clinical Symptoms and Mortality on Severe/Critical COVID-19 Patients Utilizing Convalescent Plasma Transfusion. 6/23/20. Xia X. Blood.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    This article may be of interest to those looking to learn from the Chinese experience with convalescent plasma (CP). 138/1568 COVID-19 patients from this retrospective single-center Chinese cohort study received CP. Death (2.1% vs. 4.1%) and requirement for ICU care (2.4% vs. 5.1%) in the CP group were close to half of that in the untreated patients. Patients with higher initial lymphocyte counts and those who received CP treatment within 7 wks. from onset of clinical disease were more likely to respond.
  • EDITORIAL: SARS-CoV-2 viral load and antibody responses: the case for convalescent plasma therapy. 7/8/20. Casadevall A. J Clin Invest.
    Review by the SAB
    By Dr. David Clement, on behalf of the SAB
    Using a study on the kinetics of viral load and antibody response as an introduction, this article summarizes what is known about convalescent plasma therapy for COVID-19. The case is made for using sera from patients who recovered from severe COVID-19 disease (because of higher antibody titers), certainly giving therapeutic sera earlier (less than 10 days from symptom onset), and possibly giving therapeutic sera to patients with severe disease later in the course of their disease.
  • Characteristics and serological patterns of COVID-19 convalescent plasma donors: optimal donors and timing of donation. 7/6/20. Li L. Transfusion.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Study from Wuhan, China of 49 blood donors who recovered from mild-moderate COVID-19 to determine optimum convalescent plasma donor strategy.
    Nucleocapsid (N) and Spike protein receptor-binding domain (S-RBD) antibodies were measured by ELISA assay. S-RBD ELISA results were correlated with a SARS-CoV-2 viral neutralization assay, as the authors state that recent studies suggest that S-RBD antibodies may provide immunity.
    N specific IgM declined 3 weeks after infection and reached low levels after 6 weeks. S-RBD and N specific Ig G increased after 4 weeks from symptom onset.
    Those who donated > 28 days from symptom onset, and whose fever > 38.5°C or lasted longer than 3 days, had higher levels of S-RBD IgG.
    Further studies with larger sample size, plasma from asymptomatic donors, and clinical validation are needed.
  • Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. 6/22/20. Verweij PE. Intensive Care Med.
    Review by the SAB
    Although the number of COVID-19-associated aspergillosis (CAPA) cases that have been reported is a small number, in two series, similarities and differences with Influenza with Invasive Aspergillosis (IAP) and COVID-19 are pointed out. Here a group of authors (EU, USA and Taiwan) are seeking to change the definition of IAP (inclusive of clinical and radiological signs). They make a point that an under-estimation of IAP requires a need for vigilance for IAP in the ICU, an early diagnosis, holding steroids, judicious use of antiviral to avoid a fatal outcome due to an IAP patient in comparison to Influenza with IAP.
    For CAPA:
    1. 85% host factors are -ve but Lymphopenia/monocyte hyperimmune response is present
    2. IPA tracheobronchitis is not known
    3. The entry point ACE 2 – anti-fungal immunomodulation by antifungal not likely?
    4. Serum GM + ve – need a study in COVID-19 to understand the implication.
    5. No specificity of secondary infection organism types.

View full issue.

Newsletter Issue 3, July 9, 2020:

View full issue.

Newsletter Issue 2, July 8, 2020:

  • Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. 6/30/20. Feldstein LR. N Engl J Med.
    Click here to take this CME activity.

    Review by the SAB
    By Dr. Jay Przybylo, on behalf of the SAB
    One hundred eighty-six patients, up to 21 years old in age, were studied for COVID-19. GI symptoms were more common than respiratory. Only 8% demonstrated cardiac vessel abnormalities. Authors conclude this is not Kawasaki-related disease and thus label it MIS-C.

  • Revisiting the Protein C Pathway: An Opportunity for Adjunctive Intervention in COVID-19? 6/10/20. Mazzeffi M. Anesth Analg.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Discussion of hypercoagulability in COVID-19 with a focus on the anticoagulant and anti-inflammatory properties of Protein C. The authors suggest that two modulators of the Protein C pathway — recombinant thrombomodulin and 3K3A-APC — may be beneficial in the treatment of severe COVID-19 as they are not associated with an increased risk of bleeding.
  • Drug-Induced Liver Injury and COVID-19 Infection: The Rules Remain the Same. 6/8/20. Olry A. Drug Saf.
    Review by the SAB
    By Dr. Philip Lumb, on behalf of the SAB
    Editorial noting that patients have been discontinued/withdrawn from studies because of suspected drug-induced liver damage that does not meet international guidelines for association. A summary of currently used drugs in COVID-19 and possible interactions that may cause liver damage is listed. However, the authors state that since many drugs used in therapeutic interventions may be related to liver damage, it is important to discuss acute liver injury on internationally defined biologic criteria “on the Upper Limit of Normal of serum alanine aminotransferase activity (ALT), serum alkaline phosphatase activity (ALP) and serum concentration of total bilirubin,” which are provided in the editorial as well as a severity grading score to include in association. Internationally recognized criteria for DILI should be satisfied to confirm the diagnosis prior to premature removal of patients from potentially important clinical trials.
  • Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia. 6/23/20. Jordan SC. Clin Infect Dis.
    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    Single center review by a multidisciplinary team from Cedars-Sinai following 27, mostly intubated, patients with confirmed SARS-CoV-2 pneumonia who received a single dose of 400 mg tocilizumab intravenously under a compassionate use protocol. Decreasing vasopressor support and oxygen requirements as well as lower C-reactive protein levels and temperature were observed in a majority of subjects monitored to assess anti-inflammatory effectiveness and clinical improvement.
    Tocilizumab proved beneficial in reducing inflammation and improving clinical outcome including mortality. Final proof of the drug’s efficacy awaits a placebo-controlled trial, now underway.
  • SARS-CoV-2-induced Acute Respiratory Distress Syndrome: Pulmonary Mechanics and Gas Exchange Abnormalities. 6/24/20. Barbeta E. Ann Am Thorac Soc.
    Review by the SAB
    By Dr. David Clement, on behalf of the SAB
    This study from a single center in Spain describes in detail the gas exchange, pulmonary mechanics and ventilatory management of 50 consecutive ventilated patients with COVID-19 ARDS. On average, COVID-19 patients had a similar presentation as non-COVID-19 ARDS patients, though pulmonary compliance was remarkably more heterogeneous in those with COVID-19. Several tables and figures displaying physiologic data will be of interest to critical care physicians caring for COVID-19 ARDS.
  • Extracorporeal Membrane Oxygenation for Critically Ill Patients with COVID-19 Related Acute Respiratory Distress Syndrome: Worth the Effort? 6/16/20. Falcoz PE. Am J Respir Crit Care Med.
    Review by the SAB
    By Dr. David Clement, on behalf of the SAB
    A prospective, single-center study from France following 17 COVID-19 patients who met defined criteria and were placed on ECMO. The endpoints at 60 days were death (6 patients, 35%), discharge from hospital (9 patients, 41%), inpatients off the ventilator (3 patients, 17%) and still ventilated (1 patient, 6%). Nearly half of the patients had major bleeding or thrombotic complications. The authors conclude that “Considering the high frequency of severe adverse events, ECMO should probably remain a rescue therapy and therefore be undertaken only in ECMO-expert centers with adequate resources.”

View the full issue.

Newsletter Issue 1, July 2, 2020:

  • Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study. 6/9/20. El-Boghdadly K. Anaesthesia.
    Click here to take this CME Activity.

    Review by the SAB
    By Dr. Heinrich Wurm, on behalf of the SAB
    The “intubateCOVID project” is an ongoing prospective multicenter cohort study using a web-based, self-reporting registry for providers involved in endotracheal intubations. Over 1700 providers in 500 hospitals and 17 countries are registered and as of June 2 performed over 5000 intubations. Of the 184 providers (10.7%) that became infected, only two required hospitalization. Multiple procedural and epidemiological aspects were tracked and statistically evaluated. There was an unexplained higher incidence among women and considerable variation among countries. The authors list a number of serious limitations of this study, among those infection from other sources, self-reporting bias and asymptomatic seroconversion. As the study is ongoing, we will report updates as they become available.

  • Prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19: CHEST Guideline and Expert Panel Report. 5/26/20. Moores LK. Chest.
    Click here to take this CME activity.

    Review by the SAB
    By Dr. Jay Przybylo, on behalf of the SAB
    The vast majority of data over the years support combination antiplatelet and anticoagulant prophylaxis. In summary, this is a very important document that will be used by the medical authorities, the legal profession, hospitals, and societies to be a reference for clinical behavior.

  • COVID and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection. 6/3/20. Al-Samkari H. Blood.
    Review by the SAB
    This is a retrospective observational study of data from 400 COVID-19 in-patients with D-dimer on admission to 5 affiliated Boston area hospitals between March 1 – April 5, 2020 with a data cutoff of April 8, 2020. All received prophylactic anticoagulation except one who was fully anticoagulated. Incidence of thrombosis and bleeding was similar to that reported in non-COVID-19 patients with equivalent illness severity. (9.5% had thrombosis and 4.8% hemorrhage w/ higher fractions in the critically ill.) There were no deaths from thrombosis and 1 from intracerebral hemorrhage. D-dimer on admission was predictive of thrombosis, bleeding, illness severity and death. The authors recommend that clinicians await the results of randomized clinical trials before increasing thromboprophylaxis dosages for COVID-19 patients, including the critically ill.
  • The association of lung ultrasound images with COVID-19 infection in an emergency room cohort. 6/11/20. Bar S. Anaesthesia.
    Review by the SAB
    For emergency room patients with suspected COVID-19 disease, the delay in RT-PCR testing results can cause unnecessary isolation of patients and a strain on hospital resources. This prospective study of 100 ER patients from France found that a POCUS protocol (BLUE) in conjunction with the quick SOFA score accurately predicted RT-PCR positive patients and worse outcomes.
  • Occurrence and Timing of Subsequent SARS-CoV-2 RT-PCR Positivity Among Initially Negative Patients. 6/7/20. Long DR. Clin Infect Dis.
    Review by the SAB
    By Dr. Barry Perlman, on behalf of the SAB
    Detailed, retrospective electronic medical record data analysis showing that a small percentage of symptomatic patients who initially test negative for SARS-CoV-2 may have a positive result on repeat testing.
    A combined 21,000 patients underwent nasopharyngeal swab testing at Stanford and University of Washington. Testing was performed for either clinical reasons (symptoms with pertinent risk factors or clinical judgement) or universal asymptomatic preoperative screening.
    • 91% of the patients initially tested negative.
    • 96% of those who initially tested negative did not have a repeat test within 7 days and did not require subsequent care.
    • Of the remaining 626 patients who were initially negative and underwent repeat testing within 7 days for persistent or worsening symptoms, 14 of 338 (4.1%) UW and 8 of 288 (2.6%) Stanford patients were positive on repeat testing.
    • Subgroup analysis excluding UW asymptomatic preop patients yielded similar results.

    Overall occurrence of testing discordance for patients who had persistent or worsening symptoms was 3.5%, suggesting that the initial test was false negative.
    Nasopharyngeal swab RT-PCR testing sensitivity or specificity cannot be determined from this analysis due to:

    • lack of a gold standard confirmatory test to determine whether initial or subsequent results were false positive or false negative.
    • not all patients with an initial negative result were retested
    • incomplete clinical information regarding patients who had a negative result but did not undergo retesting.
    • possibility of newly acquired infection during the 7-day interval.
    • lack of complementary serology or RT-PCR testing of samples from other sites.

    However, it does support retesting of patients with a negative RT-PCR test who have persistent symptoms, although the optimal method of retesting needs to be determined.

  • The Laboratory Diagnosis of COVID-19 – Frequently Asked Questions. 6/8/20. Fang FC. Clin Infect Dis.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    This review from the clinical laboratories of the University of Washington breaks down information about testing for COVID-19 in a useful question-and-answer format. Subjects include PCR, serology, point-of-care testing, correlation with clinical disease, and biomarkers.
  • Wearing an N95 Respiratory Mask: An Unintended Exercise Benefit? 6/1/20. Davis BA. Anesthesiology.
    Review by the SAB
    By Dr. Lydia Cassorla, on behalf of the SAB
    The authors of this letter to the editor discuss the physiologic effects of N95 FFR use.  They review data from previous studies, particularly one by Sinkule in 2013 that measured the potential physiologic effects of using an N95 respirator with and without a surgical mask in front of it.  The data were generated using an automatic breathing and metabolic simulator.  Effects are largely due to increased work of breathing due to the resistance of the respirator, and increased dead space ventilation.  Vvaries with mask design (folded models have more VD than molded models) and tidal volume (lower tidal volumes increase % VD).  At 2 METs energy expenditure (~walking quietly) average inspired O2 is estimated to be 16.1-17.5% and CO2 is estimated to be 2.5-3.5%.  With increased efforts and associated ventilation, minute ventilation increases, along with the work of breathing. However, effects of dead space decrease.  Consequently, N95 users may experience multiple symptoms, even with minimal activity. Associated work of breathing and more marked thoracic pressure swings also generate cardiopulmonary training, a potential benefit.

View the full issue.

June 8, 2020 Newsletter:

  • Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study
    May 29. CovidSurg Collaborative. The Lancet.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Joseph Anthony Caprini
    AH: 30-day results of an international cohort study assessing postoperative outcomes in 1128 adults with COVID-19 who were undergoing a broad range of surgeries. SARS-CoV-2 infection was diagnosed postoperatively in more than two-thirds of the patients (806 [71·5%]). The primary outcome was overall postoperative mortality at 30 days, and the rate was high at 23·8% (268 of 1128 patients). Pulmonary complications occurred in 577 (51·2%) patients and 30-day mortality in these patients was 38·0% (219 of 577).
    JC: This represents a very important study demonstrating a high incidence of relatively severe complications including death postoperatively. There are obvious flaws in this study as expressed by both the authors and in the subsequent editorial. Nevertheless, these data emphasize the importance of improved preventative measures including the vaccine as well as a multimodal therapeutic approach involving drugs representing hematologic immunologic and inflammatory pathways.
  • Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study
    May 27. Tremblay D. Blood.
    Opinion from SAB Member: Dr. Joseph Anthony Caprini, Dr. Anil Hingorani
    JC: This is a very clever analysis looking at patients who did or did not have therapeutic anticoagulation prior to developing the viral infection as a result of their underlying condition. The same analysis was done in patients on antiplatelet therapy. The results showed no benefit of either anticoagulation or antiplatelet therapy in changing all-cause mortality, mechanical ventilation, and hospital admission. They comment that the results of this study do not rule out the possibility that among some groups of patients suffering from the virus therapeutic anticoagulation following diagnosis may be important and beneficial. They further comment that their findings agree with the current recommendations of the American Society of Hematology that state that the benefit of therapeutic anticoagulation in patients with COVID-19 is unknown.
    AH: These data are from Mount Sinai. The authors use retrospective propensity matching for anticoagulation usage before COVID-19 diagnosis. No benefit of any single anticoagulation type was noted. The article suggests we may need multiple types of treatment. This paper is novel and raises good questions.
  • Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review
    June 3. Oran DP. Annals of Internal Medicine.
    Opinion from SAB Member: Dr. David M. Clement
    A well-written, concise review of 16 studies describing the prevalence and significance of asymptomatic persons infected with SARS-CoV-19. Four of five of the studies that included longitudinal serial testing to distinguish asymptomatic vs. presymptomatic persons showed otherwise healthy asymptomatic persons rarely (0-10%) became symptomatic. On the other hand, 89% of RT-PCR + nursing home patients were presymptomatic. Their conclusion is that asymptomatic infection is a significant factor in the rapid progression of the SARS-CoV-2 pandemic, and that current medical practice and public health measures should be modified to address this challenge.
  • Effectiveness of N95 Respirator Decontamination and Reuse against SARS-CoV-2 Virus
    June 3. Fischer RJ. Emerging Infectious Diseases.
    Opinion from SAB Member: Dr. Lydia Cassorla
    Using SARS-CoV-2, this study sponsored by the US government builds on the knowledge needed to evaluate the efficacy of decontamination methods that are being used around the world to extend the life of N95 masks due to shortages of new masks. N95 fabric discs and some whole masks were studied following treatments with ethanol, vaporized hydrogen peroxide (VHP), UV-C irradiation (UVGI), and dry heat. Data was modeled and extrapolated to calculate expected 3-log (threshold considered decontamination) and 6-log (threshold considered sterilization) reductions in viral load. For 3-log reduction, dry heat at 70°C took 46.3 min and UVGI took a dose of 2J/cm2, delivered to one side only. SARS-CoV-2 virus was undetectable after the initial treatment time for VHP, so no modeling was done. Mask fit and filtration performance was tested on 6 whole N95 masks per method for 3 cycles using a quantitative fit test that results in a fit score. Mask fit and filter function (tested in 6 masks/method after wearing for 2 hours) was good following 3 cycles of VHP and UVGI, but began to decline following the 3rd cycle of heat (note: their conditions were drier than some recommend). While ethanol sterilized well, it caused mask function failure and is not recommended. Control data with no treatment showed a median viral half-life of 78.5 min at 21-23°C with 40% relative humidity and a calculated 3-log reduction in 13 hrs. Despite limitations, this work adds important data regarding SARS-CoV-2 viability on N95 fabric along with measures of N95 fit and function under control and after test conditions. VHP provided the best combination of effectiveness and speed with good retention of fit and filtration function for 3 cycles (all that was tested) but requires proprietary equipment (note, some companies providing VHP equipment have received Emergency Use Authorizations from the FDA during the pandemic). UVGI and heat require care to take the time required to achieve the desired reduction in viral load and ensure procedures are followed to prevent cross-contamination, as they are not necessarily sterilizing techniques. Readers will also find data regarding stainless steel surfaces (not discussed in this summary). The CDC continues to provide some guidance regarding this issue on its website, where the publication is currently posted in pre-print form.


  • Category: Retraction
    Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
    The Lancet. Jun 5, 2020.
    Mandeep R Mehra; Frank Ruschitzka; Amit N Patel
    The Lancet retracted an article previously cited and summarized by this Scientific Advisory Board in the 26MAY2020 Newsletter.
    “After publication of our Lancet Article, several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication. We launched an independent third-party peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.
    Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements. As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.”
  • Category: Retraction
    Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621.
    The New England Journal of Medicine. Jun 4, 2020.
    Mandeep R. Mehra; Sapan S. Desai; SreyRam Kuy; Timothy D. Henry; Amit N. Patel
    The New England Journal of Medicine retracted an article previously cited and summarized by this Scientific Advisory Board in the 5MAY2020 Newsletter.
    ‘Because all the authors were not granted access to the raw data and the raw data could not be made available to a third-party auditor, we are unable to validate the primary data sources underlying our article, “Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19.” We therefore request that the article be retracted. We apologize to the editors and to readers of the Journal for the difficulties that this has caused.’

June 5, 2020 Newsletter:

  • SARS-CoV-2 Antibody Testing – Questions to be asked
    May 25. Ozcurumez MK. Journal of Allergy and Clinical Immunology.
    Opinion from SAB Member: Dr. Barry Perlman
    Informative article by the COVID-19 Task Force of the German Society for Clinical Chemistry and Laboratory Medicine addressing the interpretation of antibody testing. Topics discussed include:
    • Possible indications for COVID-19 serology
    • Value of antibody testing in diagnosis
    • Does presence of antibodies indicate end of infectivity?
    • Does presence of antibodies indicate immunity?
    • Comparison of different assay technologies
    • Ensuring assay quality
    • Baseline samples from asymptomatic or healthy individuals
    • Estimating demand for antibody testing

    The paper points out that in a low prevalence setting, even a high specificity test can result in an unacceptable false positive rate, leading to an overestimate of population immunity and a lower estimate of viral mortality. False positive results may be minimized by selecting for higher prevalence with symptom screening or contact tracing.

  • Respiratory Mechanics of COVID-19 vs. Non-COVID-19 Associated Acute Respiratory Distress Syndrome
    Apr 20. Haudebourg AF. American Journal of Respiratory and Critical Care Medicine.
    Opinion from SAB Member: Dr. Robert L. Coffey
    A prospective, observational study comparing the respiratory mechanics and lung recruitability of 30 consecutive COVID-19 ARDS patients and 30 consecutive non-COVID-19 ARDS patients of similar severity. In contrast to other reports, compliance, while ranging widely, was similar in the two groups and did not appear to worsen in COVID patients over the 15 days after their initial symptoms. The lung recruitment measure (R/I ratio) was significantly higher in the COVID-19 ARDS patients. The authors could not discern subgroup phenotypes within these 30 COVID pneumonia patients.
  • Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis
    June 1. Chu DK. The Lancet.
    Opinion from SAB Member: Dr. Barry Perlman
    Meta-analysis published in Lancet and featured in the NYT 6/2/20 reporting that physical distancing > 1 m and use of face mask and eye protection decrease transmission of virus. However, a variety of issues limit the strength of their conclusions.
    2 m distance was more effective than 1 m. As compared with no mask use, N95 or similar respirators were more effective than surgical or cotton masks in decreasing risk of infection. Of note, no intervention provided complete protection from infection. The authors suggest the findings from this review of 172 observational (44 comparative) studies from 16 countries regarding COVID-19, SARS, and MERS transmission can be used to guide protection policies for the public and health-care workers.
    However, the analysis was based on non-randomized studies, most involved SARS and MERS, the impact of duration or setting (e.g. ward, ER, OR, ICU) of exposure was not addressed, most studies reported on bundled interventions, the need for appropriate fit and proper use of N95 masks to achieve maximum effectiveness was not considered, only three non-health-care setting studies were included, there was no direct effectiveness comparison of N95 or similar masks to surgical or cotton masks, and the conclusions were rated at a low to moderate degree of certainty.
    Therefore, further research is required to determine optimal protection from COVID-19 infection, and which are most appropriate for health-care versus non-health-care settings.

Corrections / Retractions:

  • Category: Retraction
    Notice of Retraction: Effectiveness of Surgical and Cotton Masks in Blocking SARS-CoV-2. A Controlled Comparison in 4 Patients
    Jun 2. Bae S. Annals of Internal Medicine. Jun 2, 2020.
    The Annals of Internal Medicine retracted an article previously cited and summarized by this Scientific Advisory Board in the 11APR2020 Newsletter.
    ‘According to recommendations by the editors of Annals of Internal Medicine, we are retracting our article, “Effectiveness of Surgical and Cotton Masks in Blocking SARS-CoV-2. A Controlled Comparison in 4 Patients,” which was published on on 6 April 2020.
    We had not fully recognized the concept of limit of detection (LOD) of the in-house reverse transcriptase polymerase chain reaction used in the study (2.63 log copies/mL), and we regret our failure to express the values below LOD as “<LOD (value).” The LOD is a statistical measure of the lowest quantity of the analyte that can be distinguished from the absence of that analyte. Therefore, values below the LOD are unreliable and our findings are uninterpretable. Reader comments raised this issue after publication. We proposed correcting the reported data with new experimental data from additional patients, but the editors requested retraction.
    This article was published at on 2 June 2020.’
  • Category: Retraction
    The following two articles were retracted after an expression of concern was posted on June 2.
  • Category: Expression of Concern
    Expression of Concern: Mehra MR et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621.
    June 2. Mehra MR. The New England Journal of Medicine.
    The Lancet published the following Expression of Concern about an article previously cited and summarized by this Scientific Advisory Board in the 5MAY2020 Newsletter.
    ‘On May 1, 2020, we published “Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19,” a study of the effect of preexisting treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) on Covid-19. This retrospective study used data drawn from an international database that included electronic health records from 169 hospitals on three continents. Recently, substantive concerns have been raised about the quality of the information in that database. We have asked the authors to provide evidence that the data are reliable. In the interim and for the benefit of our readers, we are publishing this Expression of Concern about the reliability of their conclusions.
    Studies of ACE inhibitors and ARBs in Covid-19 can play an important role in patient care. We encourage readers to consult two other studies we published on May 1, 2020, that used independent data to reach their conclusions.’
  • Category: Correction
    Department of Error: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
    May 29. Mehra MR. The Lancet.
    The Department of Error from the Lancet published the above statement about an article previously cited and summarized by this Scientific Advisory Board in the 26MAY2020 Newsletter.
    “In this Article, in the first paragraph of the Results section, the numbers of participants from Asia and Australia should have been 8101 (8·4%) and 63 (0·1%), respectively. One hospital self-designated as belonging to the Australasia continental designation should have been assigned to the Asian continental designation. The appendix has also been corrected. An incorrect appendix table S3 was included, originally derived from a propensity score matched and weighted table developed during a preliminary analysis. The unadjusted raw summary data are now included. There have been no changes to the findings of the paper. These corrections have been made to the online version as of May 29, 2020, and will be made to the printed version.”

June 2, 2020 Newsletter:

  • The role of SARS-CoV-2 antibodies in COVID-19: Healing in most, harm at times
    May 20. French MA. Respirology.
    Opinion from SAB Member: Dr. Edward S. Schulman
    This is an excellent commentary that all should read. Though some antibodies to the spike glycoprotein promote virus neutralization and other protective antibody functions, particular IgG antibodies might enhance the infection of immune cells and/or disease progression. One example is antibody‐dependent enhancement of virus uptake by macrophages by enhancing antibodies as described in dengue virus infection that has also been demonstrated for SARS‐CoV‐1. Therefore, current development of antibody-dependent strategies, whether human monoclonal antibodies, convalescent plasma or choosing the right target for vaccine is complex. Depending on the peptide targeted on the spike glycoprotein by the human immune system or the vaccine lab, neutralizing or enhancing activity may result. Simply having a “positive SARS-CoV-2 antibody” on a serological test may not be a license for a “passport.”
  • The Spectrum of Cardiac Manifestations in Coronavirus Disease 2019 (COVID-19) – a Systematic Echocardiographic Study
    May 29. Szekely. Circulation.
    Opinion from SAB Member: Dr. Paul D. Scanlon
    This is a prospective survey of echocardiographic findings in 100 patients admitted with COVID-19–20% had repeat echo during clinical deterioration. At baseline, 61 had mild disease (no O2), 29 had moderate disease (non-inv O2), and 10 had severe disease (intubated). 32 had normal baseline echos, 39 had RV dilatation and dysfunction, 16 had LV diastolic dysfunction only, 10 had LV systolic dysfunction. Of the 20 who deteriorated, 12 (60%) had RV deterioration, of whom 5 (25%) had DVT (possible PE?). 5 (25%) had decrease in LVEF. Lung US was c/w ARDS, without evolution to cardiogenic pulmonary edema.
  • ICU and Ventilator Mortality Among Critically Ill Adults With Coronavirus Disease 2019
    May 26. Auld SC. Critical Care Medicine.
    Opinion from SAB Member: Dr. Philip Lumb, Dr. Jagdip Shah
    PL: Results of an observational cohort study of 217 patients admitted to Emory Healthcare System ICUs between March 6th and April 17th with RT-PCR confirmed COVID-19 disease, 165 of whom required invasive ventilation with a reported mortality rate of 33.9% (56/165) and a hospital mortality of 35.7%. Patient demographics, other supportive therapies (ECMO, RRT, Etc.), laboratory values and pulmonary characteristics well described with clear delineation between survivors and non-survivors. Authors discuss ICU preparation and pre-peak awareness as characteristics promoting more favorable outcomes than previously reported under surge conditions.
    JS: Authors form Emory conducted a retrospective cohort study of critically ill patients with COVID-19 in 6 designated ICUs which were adequately staffed and stocked. 217 patients were admitted to the ICU and 165 were treated with mechanical ventilation in the ICU. A total of 59 died (in the ICU or in hospital) and 88 were discharged out of the hospital. Statistically significant baseline parameters associated with non-survivors were: age > 75, BMI > 40, pre-existing chronic kidney disease. The ICU parameters associated with non-survival were: SOFA score on the day of admission > 7, rise of d Dimer > 1600 ng/dl, C-reactive protein > 183, PaO2:FiO2 < 144, use of mechanical ventilation, use of vasopressors, use of continuous renal replacement therapy, and hospital stay > 11 days. The authors claim that timely start of mechanical ventilation with lung protective strategy likely improves the outcome (the overall mortality in this study was 31%).
  • Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults
    May 20. Bunyavanich S. JAMA.
    Nasal ACE2 Levels and COVID-19 in Children
    May 20. Patel AB. JAMA.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Why do children seem to have a lower incidence of COVID-19 infection? The authors Bunyavanich, et al studied nasal epithelium samples obtained between 2015-2018 from 305 individuals 4-60 years both with and without asthma as part of a research study on nasal biomarkers of asthma to examine ACE2 gene expression. They found a positive association between ACE2 gene expression and age that was independent of sex and asthma. In the accompanying editorial, the authors note that since ACE2 binds to the receptor binding domain of SARS-CoV-2, by decreasing ACE2 gene expression, that might help mitigate transmission of COVID-19. Patel et al provide a nice editorial on the topic that references the Bunyavanich, et al study.

May 30, 2020 Newsletter:

  • Remdesivir for the Treatment of Covid-19 – Preliminary Report
    May 22. Beigel JH. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. Philip Lumb
    Results from the Adaptive COVID-19 Treatment Trial (ACTT-1), an international, double-blind, placebo-controlled trial of IV remdesivir in adults with documented COVID-19 disease hospitalized with evidence of lower respiratory tract involvement sponsored by the National Institutes of Allergy and Infectious Diseases (NIAID). Patients were randomly assigned to remdesivir or placebo for up to 10 days. It is important to note that “the initial primary outcome measure was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient satisfied categories 1, 2, or 3 on the eight-category ordinal scale.”
    Patients were enrolled from February 21 until April 19 at 60 trial sites in the US, Denmark, UK, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. Eligible patients were randomized to either study drug or placebo in a 1:1 ratio stratified by study site and disease severity at enrollment; routine therapy in place at the institution was continued. On March 22, the primary outcome was amended by trial statisticians (unaware of the treatment assignments or outcome data) and approved on April 2 prior to any outcome data being available. This change led to the early observation that is now widely recognized as the statement presented by the NIAID sponsors that “remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection.” It is important to read the trial details to understand the reasons for the change and the validity of the results as reported.
    This is an example of a well conducted, adaptive platform clinical trial conducted under difficult circumstances across multiple institutions with appropriate Data Safety Monitoring Board (DSMB) oversight and interim analyses. On April 27, the DSMB reviewed results and because patient enrollment had been completed (patient follow up continuing) at the time of what had been intended to be an interim review, and it was noted that the remdesivir group had a shortened time to recovery when compared to placebo, these results were reported to the NIAID and subsequently made public.
    Hidden in the press coverage but of clinical concern is the now secondary outcome indicating the “odds of improvement were higher in the remdesivir group…than in the placebo group.” The discussion is particularly illuminating regarding the complexities of the study, the enrollment supervision complexity given travel restrictions (lack of study monitors), local and environmental controls and the nature of the study itself; the addition of an experimental therapy supported by routine care across all institutions involved. The authors conclude: “The full statistical analysis of the entire trial population must occur in order to fully understand the efficacy of remdesivir in this trial. These preliminary findings support the use of remdesivir for patients who are hospitalized with COVID-19 and require supplemental oxygen therapy. However, given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient.”
    I found this manuscript a fascinating description of an adaptive trial undertaken in difficult circumstances that produced interesting, clinically relevant results that await further analysis for final determination of the remdesivir’s efficacy. However, it stimulated the inclusion of the drug into routine management of COVID-19 patients and suggests that early administration is likely to be of greater benefit.
  • How did we rapidly implement a convalescent plasma program?
    May 25. Budhai A. Transfusion.
    Opinion from SAB Member: Dr. Louis McNabb
    Impressive example of how all interested parties came rapidly together to provide convalescent plasma. Useful tables on their process.
  • High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients
    Apr 22. Llitjos JF. Journal of Thrombosis and Haemostasis.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Lydia Cassorla
    AH: This French paper is a short communication where the authors describe venous duplex exams in 26 patients in the ICU with COVID-19. 8 patients were on prophylactic heparin doses and 18 were on therapeutic doses. All patients were intubated. The rate of VTE was 100% for the patients on prophylactic doses and 56% for those on therapeutic doses. 8 patients had PE. The authors do not mention the location of lower extremity DVT. This paper is novel and raises questions. It confirms data from a 48 patient series with 84% VTE incidence from China (Extremely High Incidence of Lower Extremity Deep Venous Thrombosis in 48 Patients with Severe COVID-19 in Wuhan).
    LC: This is a French retrospective study from March 19 to April 11, 2020 of 26 consecutive ICU patients from 2 units with severe COVID‐19 who were screened for VTE on ICU admission and at least every 7 days. 8 (31%) were treated with prophylactic anticoagulation, and 18 (69%) were treated with therapeutic anticoagulation. The overall rate of VTE in patients was 69%. The proportion of VTE was significantly higher in patients treated with prophylactic anticoagulation when compared with therapeutic anticoagulation (100% vs 56%, respectively, P = .03) 6 (23%) had PE. This documents a high incidence of VTE despite prophylaxis and supports trends towards more aggressive anticoagulation.
  • Extremely High Incidence of Lower Extremity Deep Venous Thrombosis in 48 Patients with Severe COVID-19 in Wuhan
    May 15. Ren B. Circulation.
    Opinion from SAB Member: Dr. Anil Hingorani
    AH: The duplex exam were performed in 48 ICU patients in China. 84% were positive for DVT. All but one was on LWMH. 10% of lower extremity DVTs were proximal. This is not a bad paper but the series is small.
  • Understanding the COVID-19 coagulopathy spectrum
    May 21. Thachil J. Anaesthesia.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Lydia Cassorla
    AH: This editorial is a summary article covering the link of the immune system to thrombosis. The paper asks clinical questions concerning the use of additional anticoagulants (beyond heparin) for certain patients and raises the use of thromboelastography for clinical guidance.
    LC: This is a useful editorial that summarizes current trends in management and proposes an algorithm for management of COVID-19 related hypercoagulability. If no contraindications, inpatients should receive prophylaxis with LMWH, or unfractionated heparin if indicated. They propose a low bar for imaging (but not a screening regimen) and ramping up anticoagulation according to findings and potentially thrombolysis if the situation continues to worsen. The potential role of point-of-care TEG or ROTEM viscoelastic testing and questions for the future are addressed. While consideration of antiplatelet therapy and the results of more clinical trials are pending, perhaps the most important message is that each center should have a plan.
  • Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
    May 21. Ackermann M. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Louis McNabb
    AH: This is an autopsy study of 7 COVID-19 patients compared to 7 H1N1 patients, age and gender matched with 10 controls. Tests performed: histology, electron microscopy and gene array. Widespread thrombosis with microangiopathy were seen. COVID-19 patients had more alveolar capillary microthrombi and new vessel growth–predominantly through a mechanism of intussusceptive angiogenesis. Gene analysis also showed more angiogenesis.
    LM: This study compared lung histology of 7 patients dying of COVID-19 vs. 7 patients dying of influenza. Key Points: 1) COVID-19 patients had 9 times more capillary micro-thrombi, 2) Disrupted capillary cell membranes with intracellular virus were seen, 3) Perivascular t-cell infiltration was seen, and 4) COVID-19 patients had 2.7 more times new vessel growth through the mechanism of intussusceptive angiogenesis.
  • Covid-19, Angiogenesis, and ARDS Endotypes
    May 21. Hariri L. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Louis McNabb
    AH: Editorial points out limitations of the Ackermann paper: n=7, none intubated, only 20% with noninvasive ventilation. Exact correlation with the time course of the disease and the findings are not clear.
    LM: Complimentary article to Ackermann’s paper suggesting that the small vessel disruption in COVID-19 may represent a specific ARDS histologic phenotype.
  • Coagulation changes and thromboembolic risk in COVID-19 pregnant patients
    May 11. Benhamou D. Anaesthesia Critical Care & Pain Medicine.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Joseph Anthony Caprini
    AH: A good review of the literature for prophylaxis for pregnant COVID-19 patients.
    JC: This article contains important information for the anesthesiologist including hematologic changes that reflect thrombosis more than an increased incidence of bleeding. I don’t agree with the authors opinion that only selective patients admitted to the hospital should receive prophylactic anticoagulation. Pregnancy is associated with a mild hypercoagulable state, and combining the effects of the virus one would logically conclude that prophylaxis is indicated unless there is an increased risk of bleeding. In my opinion the number one priority is to prevent the patient from developing a thrombotic complication. I would place less emphasis on neuraxial anesthesia. The incidence of thrombosis post discharge in these patients is significant particularly if they have comorbidities. Many of these patients may benefit from prophylaxis for a period of time during the convalescence. A careful detailed thrombosis risk assessment on admission, during hospitalization and updated upon discharge in my opinion should be a standard part of the workup of these patients. The choice of assessment can be whatever is a commonly used in the hospital and may vary widely according to countries.
  • COVID-19 and NSAIDS: A Narrative Review of Knowns and Unknowns
    May 24. Pergolizzi Jr. JV. Pain and Therapy.
    Opinion from SAB Member: Dr. Robert L. Coffey
    A brief commentary article reviewing the possible mechanisms for an increase in susceptibility to COVID-19 or for a worsened prognosis in patients taking NSAIDs. The possibility that the anti-inflammatory effects might in fact be helpful is noted. The previously reported association of NSAID use and poor outcome is described, but this may be due to the association of higher NSAID use with increasing age. The review of the literature presented here indicates that “to date there is no strong evidence in favor or disputing the use of NSAIDs in patients diagnosed with COVID-19.”
  • RAAS inhibitors do not increase the risk of COVID-19
    May 22. Fernández-Ruiz I. Nature Reviews Cardiology.
    Opinion from SAB Member: Dr. David M. Clement, Dr. Jay Przybylo
    DC: This editorial briefly reviews 5 recent retrospective studies that all confirm prior speculation that pre-COVID-19 use of ACE2 inhibitors and ARBs is not associated with increased susceptibility to COVID-19 and does not have harmful effects in patients with COVID-19. These results justify prior guideline advice to continue ACE2is and ARBs in the COVID-19 era.
    JP: An editor for Nature combined the results of multiple papers investigating the effect of ACEi and ARB therapy on the susceptibility to COVID-19, concluding that despite the lack of controlled studies, the aggregate of the cited studies provides proof that these drugs do not provide an entry portal for the infection and are safe to continue. This easily understood paper serves as a valuable resource for physicians of any specialty caring for patients on RAAS therapy who are infected with COVID-19.
  • Incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease 2019 in California and Washington: prospective cohort study
    May 12. Lewnard JA. BMJ.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    For the practicing clinician, this study represents an epidemiological deep dive using the Kaiser Permanente database of 1840 patients (as of April 22, 2020) in a prospective cohort study aimed to:
    1. Assess population-based rates of COVID-19 disease over time in three distinct geographic areas (Southern CA: 15.6, Northern CA 23.3, WA 14.7)
    2. Model
      • estimated hospital length of stay for survivors (9.3 days) and non-survivors (12.7 days)
      • ICU admission rates and median length of stay for males (48.5% and 10.6 days) and females (32% and 14.9 days)
      • Fatality risk by age group (median 18.9%; >80yrs: 37.3)
    3. Study transmission dynamics by following the effective reproduction number over the study period within each region.

    The authors conclude that hospitalizations have substantial lengths of stay, that probability of ICU stay is high, and that the effective reproduction number has fallen over time, coincident with social isolation regulations.

  • Training and Fit Testing of Health Care Personnel for Reusable Elastomeric Half-Mask Respirators Compared With Disposable N95 Respirators
    Mar 25. Pompeii LA. JAMA.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    In this research letter, the authors showed that health care workers can be rapidly fit tested and trained to use the reusable Elastomeric Half-Mask Respirators. These have the advantage over N95 respirators in that they are reusable. They cost about $30-$40 and they are used currently in about four major U.S. health systems.

May 28, 2020 Newsletter:

  • Predicting infectious SARS-CoV-2 from diagnostic samples
    May 22. Bullard. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Barry Perlman
    Many studies have assumed that “viral shedding” based on positive RT-PCR testing suggests presence of infectious virus. This is a retrospective cross-sectional Canadian study to determine whether presence of SARS-CoV-2 RNA by RT-PCR predicts infectivity. 26/90 (29%) samples positive by RT-PCR targeting the 122nt portion of the envelope gene incubated on Vero cells demonstrated viral growth. Only samples with RT-PCR cycle threshold (Ct) < 24 and symptom to test time (STT) < 8 days showed growth. Specificities for the thresholds of Ct > 24 and STT > 8 days were 97% and 96%, respectively. If confirmed by larger studies utilizing additional RT-PCR targets, these results suggest that Ct and STT can predict duration of infectivity with high specificity and would avoid the unnecessary isolation resulting from policies based upon 2 negative RT-PCR results.
  • Chronological Changes of Viral Shedding in Adult Inpatients with COVID-19 in Wuhan, China
    May 23. Huang. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Barry Perlman
    This is a retrospective study of 308 COVID-19 inpatients at one hospital in Wuhan between 1/11/20 and 2/21/20 who received > 5 ORF1ab gene RT-PCR tests. Viral loads (based upon cycle threshold) peaked 2-4 days after admission and then decreased with treatment. A rebound seen around 7, 16, and 22 days after admission was more common in non-severely ill patients. 43% of patients had positive tests after 2 negative tests. On day 30 of treatment most patients had undetectable virus by RT-PCR tests. High viral loads (cycle threshold < 30) correlated with critical illness, mortality, decreased serum albumin, decreased Th and Ts cells, lower lymphocyte, eosinophil, and basophil counts, and increased neutrophil counts, serum glucose, corrected calcium, LDH, CKMB, myoglobin, ultra TnI, and NT-proBNP. Sputum viral loads were higher than in nasopharyngeal samples, and respiratory loads were higher than in GI samples. The authors suggest that positive RT-PCR test rebound reflects surviving coronavirus particles.
  • Features of 20‚133 UK patients in hospital with Covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study
    May 22. Docherty. BMJ.
    Opinion from SAB Member: Dr. David M. Clement
    This is a somewhat different twist on the numerous studies describing symptoms, co-morbidities and outcomes with COVID-19 inpatients. It is a prospective, observational cohort study from the UK of 20,100 inpatients who were tracked with a pandemic protocol written before the SARS-CoV-2 pandemic in response to the H1N1 and MERS epidemics. An army of 2,468 research nurses, administrators and medical students collected data using a pre-pandemic standardized form and protocol in 208 hospitals on about a third of RT-PCR positive patients. Of note, symptoms were present in overlapping clusters reflecting organ systems involved (lung, GI, musculoskeletal and musculo-cutaneous). Overall, symptoms, comorbidities and outcomes were somewhat similar to previous studies: 41% of patients were discharged alive, 26% died and 34% were still inpatients. In ICU patients, 32% died and 41% were still admitted. The utility of pre-pandemic preparation for many facets of care was apparent.
  • Critically ill patients with COVID-19 in New York City
    May 19. Grasselli. The Lancet.
    Opinion from SAB Member: Dr. Jagdip Shah
    This editorial describes the study by Matthew J. Cummings, et al (below) as a high-quality example of research even when facing an overwhelming clinical workload. The authors claim that further studies are required to improve and personalize patient treatment, with particular attention to the role of initial non-invasive respiratory support strategies, timing of intubation, optimal setting of mechanical ventilation, and efficacy and safety of immunomodulating agents and anticoagulation strategies.
  • Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study
    May 19. Cummings. The Lancet.
    Opinion from SAB Member: Dr. Jagdip Shah
    1150 adults were admitted in this prospective study from 2 hospitals (Columbia, New York). Both hospitals were able to utilize more than double the ICU surge capacity. 257 were critically ill with confirmed COVID-19. The median age of patients was 62 years, 67% were men, 82% of patients had at least one chronic illness, (HTN, DM, BMI > 30). A high incidence of critical illness among racial and ethnic minorities in this pandemic is noted. 39% of patients had died and 37% remained hospitalized, 79% patients had to be mechanically ventilated for 18 days, 66% of 257 patients received vasopressors and 31% RRT. The authors present extensive respiratory and critical illness parameters on the first day of critical illness (medians): SOFA = 11, lowest PaO2:FiO2 = 129 mmHg, plateau airway pressure = 27 cmH2O, highest PEEP = 15 cmH2O.
    In the multivariable Cox model, older age (HR 1.31 per 10-year increase), chronic cardiac disease (HR 1.76), chronic pulmonary disease (HR 2.94), higher concentrations of interleukin-6 (HR 1.11 per decile increase), and higher concentrations of D-dimer (HR 1.10 per decile increase) were independently associated with in-hospital mortality. Univariate and multivariate HRs being somewhat similar suggest a higher confidence in the study and the group composition.
    Patients hospitalized with COVID-19 had a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality.
  • Therapy with agents acting on the renin-angiotensin system and risk of SARS-CoV-2 infection
    May 22. Gnavi. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Jay Przybylo
    This is a study with controls demonstrating that patients treated with ACE inhibitors (ACEi) or Angiotensin II Receptor Blockers (ARBs), in particular those with diabetes or cardiovascular disease, were not more susceptible to SARS-CoV-19 infection due to drug therapy.
  • Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study
    May 22. Jung. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Jay Przybylo
    In a Korean population of patients taking Renin-angiotensin-aldosterone system (RAAS) inhibitors, the risk of death was higher compared with non-users. However, after adjustment for age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type, the use of RAAS inhibitors was not associated with higher mortality.
  • A proposed lung ultrasound and phenotypic algorithm for the care of COVID-19 patients with acute respiratory failure
    May 21. Denault. Canadian Journal of Anesthesia/Journal canadien d’anesthésie.
    Opinion from SAB Member: Dr. Robert L. Coffey
    This is an opinion piece from a group of physicians in Quebec based on a literature review and patient care experience that recommends the use of lung ultrasound and the previously validated ROX index [(SpO2/FiO2)/RR] to better distinguish between the proposed Type L and Type H COVID-19 pneumonia phenotypes. A guide to differentiated ventilator support strategies is offered, but no patient outcome data is presented. While the concepts are interesting and bedside lung ultrasound offers a low risk imaging technique, it is not clear to me that the ventilator strategies suggested differ significantly from standard high quality lung protective ARDS care.

May 26, 2020 Newsletter:

  • Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019
    Apr 2020. Villar. Critical Care Explorations.
    Opinion from SAB Member: Dr. Barry Perlman
    This is an opinion piece advocating for the use of corticosteroids in severe COVID-19 outside of trials. The occurrence rate of ARDS with COVID-19 is 17-41%. There is an association between ARDS and dysregulated systemic inflammation, and corticosteroids have been used to down-regulate systemic and pulmonary inflammation in non-viral ARDS due to bacterial pneumonia and sepsis. The 2017 Corticosteroid Guideline Task Force of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, based on 9 RCTs, found moderate quality/certainty of evidence that corticosteroids decrease duration of conventional mechanical ventilation and improve survival. A subsequent RCT also showed corticosteroid benefit in patients receiving low tidal volume ventilation. The authors opine that the WHO recommendation against the routine use of corticosteroids for viral pneumonia outside of clinical trials is based on incomplete evidence and flawed studies. 2 large studies showing benefit with SARS and H1N1 pneumonia, and small observational studies showing benefit with COVID-19 ARDS, support the viewpoint that there is currently no evidence to “deny the use” of corticosteroids outside of RCTs in COVID-19 patients with life threatening cytokine storm.
  • Category: Retraction
    The following article was retracted after an expression of concern was posted on June 2.
    • Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. June 5. The Lancet
    • Read additional information about the retractions. 6/4/2020. Retraction Watch.
    • Category: Correction
      Department of Error: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
      May 29. Mehra MR. The Lancet.
      The Department of Error from the Lancet published the above statement about an article previously cited and summarized by this Scientific Advisory Board in the 26MAY2020 Newsletter.
      “In this Article, in the first paragraph of the Results section, the numbers of participants from Asia and Australia should have been 8101 (8·4%) and 63 (0·1%), respectively. One hospital self-designated as belonging to the Australasia continental designation should have been assigned to the Asian continental designation. The appendix has also been corrected. An incorrect appendix table S3 was included, originally derived from a propensity score matched and weighted table developed during a preliminary analysis. The unadjusted raw summary data are now included. There have been no changes to the findings of the paper. These corrections have been made to the online version as of May 29, 2020, and will be made to the printed version.”
    • Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
      May 22. Mehra. The Lancet.
      Opinion from SAB Member: Dr. Barry Perlman
      This is a multinational cloud based registry (Surgical Outcomes Collaborative) analysis of 96,032 confirmed COVID-19 patient data from 671 hospitals on 6 continents that explores the effects of hydroxychloroquine or chloroquine with or without macrolide treatment between 12/20/19 and 4/14/20. An additional 2230 patients who received remdesivir, or whose treatment started more than 48 hours after diagnosis or while mechanically ventilated, were excluded.
      • 1868 received chloroquine
      • 3783 received chloroquine with macrolide
      • 3016 received hydroxychloroquine
      • 6221 received hydroxychloroquine with macrolide
      • 81114 were in control group

      The hospital death rate was 11.1%. Age, BMI, being black or hispanic, having coronary artery disease, CHF, a history of arrhythmia, diabetes, HTN, hyperlipidemia, COPD, smoking and immunocompromise were associated with a higher risk of death. Being female, of Asian origin, and ACE inhibitor or statin use were associated with decreased risk of in-hospital mortality. Coronary artery disease, CHF, h/o arrhythmias, and COPD were independently associated with increased risk of ventricular arrhythmias. After using a propensity score matching analysis to control for comorbidities, age, sex, race, ethnicity, cardiac and other antiviral medications, and baseline disease severity, all treatment groups independently had significantly higher (1.5-2.5 x) mortality and > 10x increased risk of de-novo ventricular arrhythmias during hospitalization. The treatment groups also had an approximately 3x incidence of mechanical ventilation as compared with the control group which was not addressed in the discussion but, according to personal communication with the author, reflects the fact that the patients who received the treatment medications got sicker, requiring ventilation. While the discussion does point out that “…a cause-and-effect relationship between drug therapy and survival should not be inferred”, the study does strongly suggest that benefit from these medications could not be confirmed.

  • Factors Associated With Intubation and Prolonged Intubation in Hospitalized Patients With COVID-19
    May 19. Kur. Otolaryngology–Head and Neck Surgery.
    Opinion from SAB Member: Dr. David M. Clement
    A retrospective, observational study from Chicago of 486 adult inpatients with COVID-19 that is nicely written and provides a wealth of clinical data. The focus of the study was on demographics and risk factors associated with intubation and time to extubation. 28% (138) of patients were intubated and of those, 56% were extubated, 15% died and 28% were still intubated. Age, male sex and a history of diabetes were independent risk factors associated with intubation. Age and BMI>30 predicted a longer time to extubation. Among the data are some interesting findings, such as 1/3 of patients were intubated in the ED, SpO2 was below 90 in 12% of non-intubated patients, only one non-intubated patient died, and 4% were treated with ECMO. There are limitations acknowledged (e.g. criteria for intubation), but overall the study provides a useful window into a COVID-19 surge. We feel this paper pairs nicely with a previous paper reviewed by the SAB that covered the timing and indications for tracheostomy Tracheostomy in the COVID-19 era: global and multidisciplinary guidance.
  • Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019-Induced Acute Respiratory Distress Syndrome: A Multicenter Descriptive Study
    May 18. Yang. Critical Care Medicine.
    Opinion from SAB Member: Dr. David M. Clement, Dr. Jagdip Shah
    DC: Though ECMO was shown to be an effective management choice in H1N1 ARDS, the utility of ECMO in COVID-19 is unclear. This study helps us to understand the use of ECMO with COVID-19 respiratory failure. This is a descriptive, retrospective, uncontrolled study from China of 59 ventilated patients, 21 of whom received ECMO for worsening respiratory failure. Of the 21 treated with ECMO, 12 died (57%), 9 were weaned off ECMO, and 6 were discharged. Of patients ventilated without ECMO, 63% died (NS compared with ECMO). This shows that ECMO is not a hopeless endeavor in certain circumstances with COVID-19 respiratory failure.
    JS: Here, Chinese authors retrospectively review the outcomes from 21 patients (2 hospitals) who received extracorporeal membrane oxygenation support (ECMO). When the optimal lung-protective strategy and prone position were both proven to be ineffective, patients would be considered for ECMO if any one of these criteria were met:
    1. PaO2/FiO2 less than 50 mm Hg over 3 hours;
    2. PaO2/ FiO2 less than 80 mm Hg over 6 hours;
    3. arterial blood gas pH less than 7.25 and PaCO2 greater than 60 mm Hg over 6 hours, as well as RR greater than 35 breaths per minute;
    4. RR greater than 35 breaths per minute, arterial blood gas pH less than 7.2, and Pplat greater than 30 cm H2O;
    5. complicated with cardiogenic shock or cardiac arrest.

    They adopted these doctrine from the H1N1 experience. The results showed a tendency of decline in mortality but with no significant difference. No ECMO 63.2% vs ECMO 57.1%; p=0.782. Noted in the study, 12 patients died and nine survived. The authors imply “we should have started earlier.”

  • Technologies to optimize the care of severe COVID-19 patients for healthcare providers challenged by limited resources
    May 19. Rubulo. Anesthesia & Analgesia.
    Opinion from SAB Member: Dr. Lydia Cassorla
    This excellent and comprehensive summary from multinational European and North American authors reviews techniques and approaches that may be of particular utility in limited-resource settings. Topics discussed: ETT positioning, processed EEG for drug conservation, neuromuscular monitoring, paperless documentation in isolation settings, adaptation of anesthesia machines for the ICU, point-of-care diagnostics including testing for infection, point-of-care US, and thromboelastography. One might think of every medical center as limited in resources, therefore, I suspect most readers will find useful information here.
  • Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID-19
    May 15. Joly. Intensive Care Medicine.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Joseph Anthony Caprini
    AH: This review of the literature of COVID-19 and its effects on coagulation is complete and bridges into the clinical effects of this knowledge.
    JC: This paper describes a number of interesting observations regarding the pathophysiology and clinical manifestations of this disease. The focus of this paper on heparin, while important, does not adequately reflect to the reader what is involved in the correlation between pathophysiology and various treatment modalities. The Becker paper (below) captures more fully the myriad of pathophysiologic mechanisms, and provides a good source for the interested reader regarding these interactions in COVID-19. The bottom line for the treating physician is there is going to be a combination of therapeutic modalities including heparin at various stages of the disease needed to blunt the pathophysiologic changes described in this paper. Thromboelastography is mentioned in this paper as a possible way to measure the sum total of these effects using a global test. I’m a strong proponent of this method, having worked with it for many years, but it is not quite ready for clinical application except in prospective studies correlating the results with known hemostatic tests. Reminding us that evidence-based data is not available for full anticoagulation isn’t very helpful, especially since there are a number of reports showing a variety of beneficial effects with these treatment doses.
  • COVID-19 update: Covid-19-associated coagulopathy
    May 15. Becker. Journal of Thrombosis and Thrombolysis.
    Opinion from SAB Member: Dr. Anil Hingorani, Dr. Lydia Cassorla, Dr. Joseph Anthony Caprini
    AH: This article contains very detailed data on COVID-19 and its effects on coagulopathy that includes basic science.
    LC: This comprehensive and detailed analysis of COVID-19 associated coagulopathy (bleeding and thrombosis phenotypes) is a deep dive into both what is known and speculation about pathophysiology. Overlapping and distinguishing features relative to DIC and thrombotic microangiopathies (including TTP, HUS, pre/eclampsia) are reviewed. Lab features of COVID coagulopathy more resemble DIC, with the exception of the absence of low platelet count. A useful table for comparison is provided. Virchow’s triad of pro-thrombotic factors holds strong. (Abnormal blood flow, vascular injury and abnormalities within the circulating blood). US and international guidelines regarding thromboprophylaxis are reviewed as the world awaits more definitive data from ongoing clinical trials.
    JC: This is an incredibly important paper describing the sophisticated array of changes associated with this viral infection. It is must reading for those interested in learning more about the pathophysiology of the disease. There are too many important points in this paper to repeat otherwise we would rewrite the paper. Most sentences are packed with information. What is important for all of us to understand is that this viral infection is much more than the coagulation system gone wild. In addition, no amount of heparin anticoagulation will be the answer to controlling the morbidity and mortality associated with this disease. The important take away is a concept introduced nearly 50 years ago by the famous hematologist Oscar Ratnoff. He described a “tangled hemostatic web” where contact activation pathways of the blood beginning with factor XII (Hageman factor) resulted in a triggering of platelet, coagulation, fibrinolysis, complement, and kallikrein pathways. The clinical result was not only thrombosis but also systemic vascular changes consistent with activation of both the inflammatory and immunologic pathways. The implications of this work quite clearly involved therapeutic approaches not only involving anticoagulation but also perhaps antiplatelet, anti-fibrinolytic, anti-inflammatory, and anti-immunologic therapy. We know there are various stages of the disease and introducing these modalities at different times may also be important. I personally feel that this knowledge intensifies my zeal for providing early and adequate anticoagulation to these patients along with anti-inflammatory and anti-immunologic therapy to prevent the progression of the disease.
  • Neurologic complications of COVID-19
    May 10. Bridwell. American Journal of Emergency Medicine.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    Announced by the authors as, “A practical review of the literature aimed at the emergency medicine clinician”, this review of 60 recent papers dealing with the neurological impact of COVID-19 adds value for the clinician without being superficial. The avenues of direct viral assault via endothelial ACE-2 receptors, retrograde migration via the nasopharynx into the olfactory system, or via transsynaptic transmission, are highlighted, as well as the impact of secondary events like the systemic inflammatory response evoked by the virus and its impact on the blood brain barrier or the effect hypoxia may exert on cerebral autoregulation.
    In addition to highlighting clinical presentations, this review points to pre-existing neurological disease like stroke and Parkinson’s as an important risk factor not only for added neurological complications, but for severity of illness and mortality. A table listing the side effects of various pharmaceuticals used to treat COVID-19 provides another helpful addition for the practitioner.
  • Pulmonary fibrosis secondary to COVID-19: a call to arms?
    May 15. Spagnolo. Lancet Respir Med.
    Opinion from SAB Member: Dr. Louis McNabb
    This is a short article pointing out the potential for a large population of COVID-19 survivors with residual pulmonary fibrosis and its consequences.
  • Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy
    May 15. George. Lancet Respir Med.
    Opinion from SAB Member: Dr. Louis McNabb, Dr. Edward S. Schulman
    LM: This is an opinion article raising the issue of long-term pulmonary fibrosis in survivors of severe COVID-19 pneumonia/ARDS. The authors discuss the logic for considering anti-fibrotic drugs such as: pirfenidone and nintedanib. They also discuss many other experimental anti-fibrotic drugs and their potential mechanism of action in COVID-19.
    ESS: While it may eventually become pertinent to consider the theoretical role of anti-fibrotic agents in the treatment of COVID-19, it must be noted that we do not yet know the natural history of lung injury in survivors and whether fibrosis is a persistent feature. With regards to pirfenidone and nintedanib, these agents carry significant side-effect profiles including nausea, vomiting, diarrhea and liver injury that may preclude their use in critically ill COVID-19 patients. Furthermore, the authors of this paper acknowledge relationships including “personal fees with the companies marketing pirfenidone and nintedanib.”
  • Cardiovascular implications of the COVID-19 pandemic: a global perspective
    May 10. Boukhris. Canadian Journal of Cardiology.
    Opinion from SAB Member: Dr. Jagdip Shah
    Cardiologists from across the world provide a holistic review of the present and future of their acute and chronic issues with clinical practice in this article. The article provides a comprehensive overview with evidence-based input of the pathophysiology and the dynamic cardiovascular implications of COVID-19. The authors have made an excellent effort to explain pathophysiology for noncardiac conditions, drug implication and their interactions as well. They noted that the information in references here is contemporary and relevant. It offers a detailed recommendation of existing pathways of care, the role of modern technologies (AI, social media, smartphones, telemedicine, etc.) to tackle the patient care issues in this pandemic, which other specialties can adopt. This is a practical, realistic proposal of novel management algorithms for the most common acute cardiac conditions with excellent tables and figures that are easy to read and follow.
    Although respiratory symptoms dominate the clinical presentation, COVID-19 is known to have potentially serious cardiovascular consequences, including myocardial injury, myocarditis, acute coronary syndrome, pulmonary embolism, stroke, arrhythmias, heart failure, and cardiogenic shock. The cardiac manifestations of COVID-19 may be related to the adrenergic drive, systemic inflammatory milieu and cytokine-release syndrome caused by SARS-CoV-2, direct viral infection of myocardial and endothelial cells, hypoxia due to respiratory failure, electrolytic imbalances, fluid overload, and side effects of certain COVID-19 medications known to be in practice currently.
  • Nurturing Morale
    May 8. Vinson. Anesthesia & Analgesia.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    An “Open Mind” contribution focusing on current pandemic related stressors, but also on the personal impact the “Great Catch-up” phase that we are entering now will have on individual anesthesiologists’ morale. Daily challenges are identified, and remedies suggested. The role compassionate, honest and servient leadership plays under these circumstances is highlighted and leaders are urged to become aware of their crucial role in stressful situations. The author is a pediatric anesthesiologist and chair of the ASA Committee on Physician Well-being.
  • Olfactory Dysfunction in COVID-19: Diagnosis and Management
    May 20. Whitcroft. JAMA.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    This is a study that examines olfactory dysfunction both with and without COVID-19. The basis of olfactory dysfunction, as the authors explain, may be due to disruption of cells in the olfactory neuroepithelium, and that the virus may actually penetrate the brain and then have downstream effects on brain regions that may adversely affect olfactory function. The authors explain also how olfactory dysfunction should be assessed and how it might be treated.

May 21, 2020 Newsletter:

  • Simulated Sunlight Rapidly Inactivates SARS-CoV-2 on Surfaces
    May 20. Ratnesar-Shumate. The Journal of Infectious Diseases.
    Opinion from SAB Member: Dr. Jay Przybylo
    This is a biodefense research article proving that simulated sunlight inactivates SARS-CoV-2. 90% of the virus on different surfaces became inactivated in between 7-14 minutes. Lower intensity light containing UV spectra took longer to achieve effect. Different than the article (below) describing the effect of UV light on large populations in geographic regions investigating natural effects of the sun and climate, this article is specific to the actual virucidal effect of the light.
  • Higher solar irradiance is associated with a lower incidence of COVID-19
    May 19. Guasp. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Jay Przybylo
    This is an interesting study using statistical evaluation of population density and solar and weather influences on COVID-19 spread that correlates high urban population density and low UV radiation to increased COVID-19 infection rates. The graphs are difficult to interpret.
  • Tracheostomy in the COVID-19 era: global and multidisciplinary guidance
    May 15. McGrath. Lancet Respir Med.
    Opinion from SAB Member: Dr. Jay Przybylo
    Presented by an international, multidisciplinary team, this article attempts to limit “conflicting recommendations” that have arisen in this pandemic regarding tracheostomies. Using COVID-19 as the example, the paper reviews the history of pandemics, searches the literature for guidance, and describes the issues of tracheostomy–in non-COVID-19 patients less than 50% of trached patients survive to leave the hospital and 12% are functional at 1 year while in COVID-19 the statistics are worse, suggesting a longer wait prior to tracheostomy. Using data on the infectious nature of COVID-19, the wait allows the detectable virus to drop below 50% of patients while allowing antibodies to become detectable in most. With this timing, the incidence of trach is 0.5%. The location of the procedure and the optimal procedure are discussed. The care of patients with emphasis on healthcare provider safety is discussed. The paper contains multiple, easily interpretable tables and graphs. Not a science paper with statistics and errors supplied, this paper promotes standards that can (should) be met worldwide.
  • The Relationship between Status at Presentation and Outcomes among Pregnant Women with COVID-19
    Apr 27. London. American Journal of Perinatology.
    Opinion from SAB Member: Dr. Lydia Cassorla
    This is a single-center retrospective cohort study of pregnant women who tested positive for COVID-19 at one Brooklyn hospital from March 15 to April 15, 2020. 55 SARS-CoV-2 positive pregnant women were followed to term and 1 had fetal demise at 17 wks. Among participants with COVID-19 symptoms at presentation (n=33), 16 (48.5%) had cesarean delivery, 9 (27.3%) had preterm birth <37 weeks of whom 7 were cesarean sections for maternal respiratory distress. 12 (26%) required respiratory support, including 1 who required mechanical ventilation. Among those who were asymptomatic at presentation (n=22), 6 (27%) had cesarean delivery, and there were no preterm births. Pregnant women who present without symptoms remained asymptomatic to a greater degree than has been reported from cohorts of older individuals. Initially, patients were only tested because of symptoms of potential exposure. Universal testing began during the study period and 13.3% of 76 asymptomatic patients tested after that date were COVID-19 positive. Of 48 neonates tested on day 0 by PCR, none tested positive for COVID-19. Conclusion: Pregnant women with COVID-19-related symptoms have a high rate of severe disease and preterm birth due to cesarean delivery to treat maternal respiratory distress.
  • Smell and taste alterations in Covid-19: a cross-sectional analysis of different cohorts
    May 14. Paderno. Allergy & Rhinology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    In this study of a little over 500 patients who were either hospitalized or in quarantine with laboratory confirmed SARS-CoV-2 disease, whose data was collected between March 27 and April 1 via survey, the prevalence of olfactory and gustatory dysfunction was greater than 50%. There was a higher prevalence in home-quarantined patients (79% vs 72%). Hospitalized patients, though, had more dyspnea and a lower rate of flu-like syndrome. Indeed, because of a severe clinical condition and a decrease in oral intake, the perception of olfactory and gustatory dysfunction in the inpatient setting was likely lower than for outpatients. Outpatients were also younger, healthier, were less likely to smoke, and were more likely female.
  • Cardiovascular Safety of Potential Drugs for the Treatment of Coronavirus Disease 2019
    May 20. Aggarwal. The American Journal of Cardiology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Any drug might have an effect on the heart. The authors have provided a nice summary of the cardiac safety of various drugs used to treat patients with COVID-19, including chloroquine/hydroxychloroquine, azithromycin, remdesivir and lopinavir/ritonavir, interferon-alpha, and briefly concerning some other therapies.
  • Cardiovascular phenotypes in ventilated patients with COVID-19 acute respiratory distress syndrome
    May 18. Evrard. Critical Care.
    Opinion from SAB Member: Dr. Philip Lumb
    This is a comparison of TEE findings in 18 COVID-19 patients with 23 seasonal flu (A-H1N1) patients ventilated for flu-associated ARDS from previous 2 years. While COVID-19 patients were older, disease was less severe (SAPSII, SOFA, less vasopressor support). Cardiac findings indicated that left ventricular failure, acute and severe cor pulmonale were higher in flu. Interestingly, the authors report, “Hypovolemic and hyperkinetic phenotypes were similarly observed in both groups. Despite similar tidal volume and PEEP level, COVID-19 patients had significantly higher P/F ratio and respiratory-system compliance, and lower driving pressure than flu patients.” The manuscript includes illustrative tables. This is a preliminary study requiring further investigation to elucidate cardiac phenotypes during COVID-19 disease.
  • Angiotensin II infusion in COVID-19-associated vasodilatory shock: a case series
    May 15. Zangrillo. Critical Care.
    Opinion from SAB Member: Dr. Philip Lumb
    This research letter details a trial of angiotensin II (ANGII) in 16 patients with vasodilatory shock resistant to high dose catecholamine (norepinephrine > 0.25 mcg/kg/min) as either first line or rescue infusion in a compassionate use protocol. Patients demonstrated improvement in oxygenation parameters associated with ANGII infusion; catecholamines were withdrawn or significantly reduced after 24 hours. Small series with interesting and favorable results.

May 20, 2020 Newsletter:

  • Below are three recent literature reviews on neurological manifestations and complications of COVID-19 as well as possible psychiatric and neuropsychiatric effects on patients that are now available. Relying primarily on case reports and pre COVID-19 coronavirus research there is strong suspicion that SARS-CoV-2 gains access to both the central and peripheral nervous system directly and possibly to a larger extent than observed in SARS or MERS. While the etiological mechanisms of anosmia remain unclear, this early sign may be a clue to the neurotropism of the SARS-CoV-2 virus. Separating primary neurologic injury from secondary effects of severe illness, hypoxia, hyper-inflammatory state and multi-organ failure, represents an additional hurdle. While new onset psychiatric illness is unlikely to follow COVID-19 recovery, patients are prone to suffer post-traumatic stress disorder and its complex symptomatology.
    • Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review
      Apr 28. Montalvan. Clinical Neurology and Neurosurgery.
      Opinion from SAB Member: Dr. W. Heinrich Wurm
      This is a systematic review of 67 studies dealing with neurological manifestations of COVID-19, including encephalitis, Guillain Barre, multiple sclerosis, and stroke, but also reviewing available evidence of neurotropism of CoV observed during SARS and MERS. Direct viral access to the CNS through the cribriform plate and olfactory bulb and dissemination via trans-synaptic transfer to the peripheral nervous system remains under investigation, as is the invasion of the medullary cardiorespiratory center as a postulated cause of refractory respiratory failure observed in COVID-19. Future research into the expression of ACE2 receptors in neurological tissues could be the key to some of these questions.
    • Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic
      May 18. Rogers. The Lancet Psychiatry.
      Opinion from SAB Member: Dr. W. Heinrich Wurm
      This systematic review and meta-analysis of 70+ papers deals primarily with psychiatric sequelae of SARS-CoV and MERS-CoV and suggests that among patients admitted to hospital for severe SARS or MERS coronavirus infections, delirium is common acutely, whereas post-traumatic stress disorder, depression, anxiety, and fatigue are common in the following months. COVID-19 patients are likely to experience delirium, confusion, agitation, and altered consciousness, as well as symptoms of depression, anxiety, and insomnia but at this point there is not enough data to determine the overall extent and impact of such sequelae. Based on their review, the authors believe there is no indication that COVID-19 results in new onset mental illness.
    • Neurological manifestations and complications of COVID-19: A literature review
      Apr 24. Ahmad. Journal of Clinical Neuroscience.
      Opinion from SAB Member: Dr. W. Heinrich Wurm
      Narrative review covering the neurological manifestations of COVID-19 based on an English language literature search which at the time of submission (April 24th) consisted of only two series: one retrospective chart review from China (245 patients, 45% neurologic involvement), and one observational study from France (58 patients, 84% neurological involvement). Following a brief discussion of SARS-CoV2’s access to central and peripheral neurons, the authors postulate the two prime mechanisms responsible for neurological injury to be hypoxia and the COVID-19 immune response. What follows are a series of case reports of central and peripheral nervous system effects, including encephalopathies, encephalitis, and strokes, as well as anosmia, myelitis, Guillian Barre syndrome and a poorly defined but not infrequently seen syndrome of skeletal muscle damage accompanied by CPK elevations, severe muscle pain and signs of concomitant kidney and liver injury. The authors conclude with a call for clinicians to track and report more detailed information on neurological manifestations of COVID-19.
  • Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19?
    May 13. Qaseem. Annals of Internal Medicine.
    Opinion from SAB Member: Dr. Barry Perlman
    Practice points based on evidence review concluded on 4/17/20 by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and developed by the Scientific Medical Policy Committee of the ACP.
    1. Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis against COVID-19 due to known harms and no available evidence of benefits in the general population.
    2. Do not use chloroquine or hydroxychloroquine alone or in combination with azithromycin as a treatment of patients with COVID-19 due to known harms and no available evidence of benefits in patients with COVID-19.
    3. In light of known harms and very uncertain evidence of benefit in patients with COVID-19, using shared and informed decision making with patients (and their families), clinicians may treat hospitalized COVID-19–positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial.

    Additional issues considered:

    1. Chloroquine and hydroxychloroquine are used to manage other major ailments, such as rheumatic diseases, with a known benefit and are in short supply in the United States.
    2. Inappropriate and overuse of antibiotics (e.g., azithromycin) is an important contributor to the antibiotic resistance, an immediate public health threat.
  • Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure
    May 13. Kucirka. Annals of Internal Medicine.
    Opinion from SAB Member: Dr. Barry Perlman
    This analysis illustrates that the predictive value of a negative SARS-CoV-2 RT-PCR test result depends on both pre test probability and test timing relative to exposure or symptom onset. Therefore, it applies more to “ruling out” infection in exposed patients and health care workers, rather than “clearing” asymptomatic patients for elective surgery. Using results from 7 previous studies reporting SARS-CoV-2 RT-PCR results, a Bayesian hierarchical model was created to estimate the false-negative rate by day since symptom onset or virus exposure. The model assumed a typical 5-day incubation period to symptom onset. The probability of RT-PCR false negative decreased from 100% on day 1 of exposure to 20% on day 8 (3 days after typical symptom onset), and then increased again to 66% on day 21. Therefore, the lowest post test probability from 1 negative RT-PCR test is achieved when the test is done on day 8, 3 days after symptoms onset. However, the post test probability from a negative day 8 sample varied from 1.2% to 14% depending on the pretest probability. The model suggests that negative RT-PCR tests early or late in infection should not be used to rule out COVID-19 if suspicion is high based on clinical and epidemiologic information.
  • Antibody Testing For Covid-19
    May 15. Mathur. American Journal of Clinical Pathology.
    Opinion from SAB Member: Dr. Barry Perlman
    Accurate antibody tests can help with diagnosis, identify those with asymptomatic infections, determine prevalence in a population, aid in contact tracking, and measure progression to herd immunity. The 10 antibody tests that are currently FDA-approved have, on average, a sensitivity of 84.9% and a specificity of 98.6%. Sensitivities of these tests range from 58% to 94%. 90 additional tests are available for use, but are not yet FDA approved and don’t have sensitivity and specificity established. Table 2 demonstrates that positive predictive value varies widely depending on both the accuracy of the tests and local disease prevalence. When prevalence is high, such as in the greater NY area, antibody tests with specificity and sensitivity of 98% or better can be used as reliable screening tools. In areas of low prevalence, a test would need 100% specificity to avoid false positive results that could incorrectly indicate that someone is immune to COVID-19. The authors warn against using serologic tests not yet FDA approved with unknown accuracy to guide decision making.
  • Clinically Applicable AI System for Accurate Diagnosis, Quantitative Measurements, and Prognosis of COVID-19 Pneumonia Using Computed Tomography
    May 17. Zhang. Cell.
    Opinion from SAB Member: Dr. Barry Perlman
    A variety of projects are investigating how artificial intelligence (AI) tools can be utilized during the COVID-19 pandemic. In this report, CT results from 4154 patients and clinical information from 843 patients in China were used to develop an AI system to diagnose COVID-19 pneumonia and differentiate it from other common (viral, bacterial, and mycoplasma) pneumonias. Data from retrospective and pilot prospective studies were used to validate the system, with sensitivities of 87-95% and specificities of 82-89%. System performance was superior to that of junior radiologists and comparable to mid-senior radiologists. It was found that lung CT findings correlated with clinical and biochemical evidence of disease severity in other organs systems. This AI system may assist in early diagnosis, prognosis prediction, management, evaluation of drug treatment efficacy, and follow up of COVID-19 patients.
  • Anticipating and curtailing the Cardiometabolic toxicity of social isolation and emotional stress in the time of COVID-19
    Apr 20. Oren. American Heart Journal.
    Opinion from SAB Member: Dr. David M. Clement
    “Individuals experiencing sustained deficiencies in social interaction attributable to quarantine or physical distancing should be considered at higher risk of cardiovascular disease.” “Understanding social isolation and its public health consequences is key to minimizing the late cardiometabolic burden of COVID-19.” In a well referenced opinion paper, the authors briefly explain this increased risk, and encourage health care providers to address this increased risk by paying more attention to risk modification in individual patients: risk assessment, hypertension, and healthy living habits (diet, exercise, smoking reduction). Though far from flashy, these recommendations are important.
  • A care pathway for the cardiovascular complications of COVID-19: Insights from an institutional response
    Apr 28. Loungani. American Heart Journal.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Cardiovascular complications may be common in the sickest patients with COVID-19. To that end, the authors present a framework for addressing cardiac complications associated with COVID-19. What’s shown is what to do with myocardial injury, ST segment elevation, heart failure, arrhythmias, and drug considerations.
  • Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic
    May 17. Belhadjer. Circulation.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    A summary of 35 children from France admitted for acute heart failure in febrile cardiogenic shock or left ventricular dysfunction and inflammatory state (all with fever (>38.5°C) and asthenia) that was temporally related to previous exposure to SARS-CoV-2. SARS-Cov-2 infection was confirmed in 31/35 patients (88.5%). 80% of patients were in cardiogenic shock requiring the use of intravenous inotropic drugs. Ten/35 patients (28%) required mechanical circulatory assistance with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) which was weaned and removed in all. All but one patient left the hospital after a median stay of 8 days. The point: not all children have a mild COVID-19 disease.
  • Thoracic Anesthesia of Patients With Suspected or Confirmed 2019 Novel Coronavirus Infection: Preliminary Recommendations for Airway Management by the European Association of Cardiothoracic Anaesthesiology Thoracic Subspecialty Committee
    May 17. Senturk. Journal of Cardiothoracic and Vascular Anesthesia.
    Opinion from SAB Member: Dr. Lydia Cassorla, Dr. Joseph Anthony Caprini
    LC: This report is the result of an opinion based survey of anesthesiologists experienced in thoracic surgery (TS) cases regarding management of patients for TS who are known or suspected of being SARS-CoV-2 positive. It is the result of 21 responses from Europe and Canada out of 28 survey requests sent to members of the European Association of Cardiothoracic Anaesthesiology. The report covers all aspects of care. Of interest, it shows a trend towards the choice of a bronchial blocker (BB) over double lumen endotracheal tube (DLT) for lung isolation in both previously intubated and non intubated TS patients. This is related to the potential for reduced aerosolization and reduced tube-changing procedures if the patient is already intubated or is to remain intubated post-op. The flow charts are useful. A nice review of the issues, albeit not data-based. A word of caution: while these practitioners may be rather experienced with the use of BBs, they can be more difficult to place and keep in place than a DLT.
    JC: This publication outlines the consensus recommendations of a group of expert anesthesia specialists who were surveyed regarding the overall approaches to general and specific aspects of airway management, preparations for anesthesia, lung isolation/separation procedures and ventilation itself. It is a very detailed analysis. The authors are quick to point out that the recommendations contained in this document are not claimed to be evidence-based or comprehensive. They do represent the opinion of experts regarding conducting routine daily practice and patience with this serious viral infection.

May 18, 2020 Newsletter:

  • Editorial: Is the Prone Position Helpful During Spontaneous Breathing in Patients With COVID-19?
    May 15. Telias. JAMA.
    Opinion from SAB Member: Dr. Philip Lumb
    This is an intelligent discussion and summary of related articles (below) that demonstrates interesting observations regarding prone positioning despite small sample sizes, lack of controls and limited outcome benefits in clinical studies. Taken in context of related case studies, this editorial stimulates discussion and further clinical trials.
  • Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure
    May 15. Elharrar. JAMA.
    Opinion from SAB Member: Dr. Philip Lumb
    This research letter includes 24 patients entered into a spontaneous breathing prone positioning trial. Reported outcomes: 1) ability to tolerate position for specified and increasing times; 2) PaO2 increase in prone position (PP); 3) sustained PaO2 increase on resupination; 4) progression of disease. The article notes that of 5 patients requiring intubation, 4 did not tolerate prone position for > 1 hour. Out of 24 patients, 15 (63%) tolerated PP > 3 hours, oxygenation increased in 6 (25%), and sustained following resupination in 3 (12%). As authors note, the study had several limitations–the sample was small, a single episode of PP was evaluated, the follow-up was short, clinical outcomes were not assessed, and causality of the observed changes cannot be inferred.
  • Respiratory Parameters in Patients With COVID-19 After Using Noninvasive Ventilation in the Prone Position Outside the Intensive Care Unit
    May 15. Sartini. JAMA.
    Opinion from SAB Member: Dr. Philip Lumb
    This is a research letter describing observations on non-invasive ventilation (FiO2 0.6; 10 cm H2O CPAP) in the prone position (PP) on April 2nd, 2020. Measured outcomes of proning during the observation period included SPO2, respiratory rate, and comfort and tolerance of PP, before, during and after proning. Fifteen patients were identified and during proning, all demonstrated increased oxygenation, decreased RR, and adequate comfort. The clinical status of patients followed up at day 14 (April 16, 2020) included: 9 discharged home, 1 improved, 3 continued pronation, 1 intubated and in ICU, and 1 died. As the authors state, “Limitations include the small number of patients, short duration of NIV in the prone position, and lack of a control group. Comparisons of NIV in the prone position with oxygen by face mask or NIV in the standard position are needed. Importantly, selection bias is possible.”
  • Mechanical Ventilation in COVID-19: Interpreting the Current Epidemiology
    Apr 26. Wunsch. American Journal of Respiratory and Critical Care Medicine.
    Opinion from SAB Member: Dr. Jay Przybylo
    A plea for action using COVID-19, ARDS and ventilatory support for the example of demonstrating the differences in care that exist internationally and regionally. No aspect of the choice to ventilate exists in a rational, prescribed manner. As evidence, the author cites the JAMA article with 88% New York mortality in mechanically ventilated patients, the difference between the 29% mechanically ventilated patients cited in China compared to 89.9% in the U.S., and the difference in ventilatory assistance between 18.6% and 42.0% in California alone. The author cautions that differences in care resulted in differences in outcomes, publications and conclusions. COVID-19 has amplified these differences in care.
  • AGA Institute Rapid Review of the GI and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19
    May 1. Sultan. Gastroenterology.
    Opinion from SAB Member: Dr. David M. Clement
    This is an excellent paper from the American Gastroenterological Association for frontline workers wanting to understand and care for patients with GI disease during the COVID-19 pandemic. It starts with a detailed meta-analysis (47 studies with 10,890 patients) of GI symptoms and abnormal LFTs in patients with COVID-19. Overall, 10% of COVID-19 patients had GI symptoms and 15% had elevations of AST and/or ALT. Both GI symptoms and elevated LFTs were more common outside China. Occasionally, GI symptoms presented before other COVID-19 symptoms. Though fecal RT-PCR testing is commonly positive, culture of SARS-CoV-2 is rarely successful. Numerous tables are included, such as the GI side effects of commonly used COVID-19 drugs. Based on all pooled information, guidelines are presented for frontline providers dealing with GI symptoms in the COVID-19 era. These include, among others, checking for other etiologies of GI symptoms in outpatients, following LFTs on COVID-19 inpatients, not testing stool, and following outpatients with GI symptoms alone in case they develop COVID-19.
  • An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study
    May 13. Verdoni. The Lancet.
    Opinion from SAB Member: Dr. Jay Przybylo
    A study of Kawasaki-like illness comparing children presenting over a five-year period prior to SARS-CoV-2 to a group of children presenting in a two-month period after SARS-CoV-2. The disease is further broken down into children presenting with circulatory dysfunction vs immune system disorder. An included table describes in depth all possible variables of the COVID-19 patients. Compared with adults, children have a more benign respiratory illness, yet suffer from vasculitis and cytokine storm. All received immunoglobulin in addition to aspirin. Steroids were administered to a minority of patients. No children were reported to die. The report contains a discussion of Kawasaki Syndrome and links the probable cause to a virus.
  • Interferon beta-1b for COVID-19
    May 8. Shalhoub. The Lancet.
    Opinion from SAB Member: Dr. Barry Perlman
    Studies of interferons alpha and beta have shown variable results with SARS-CoV and no significant benefit with MERS-CoV. This comment discusses the accompanying study of triple drug therapy ( including interferon beta-1b for patients with mild-moderate COVID-19 by Hung et al. While combination therapy with interferon showed benefit as compared to lopinavir-ritonavir alone, further studies with larger patient numbers and use of placebo controls are needed to determine: 1) whether patients with severe disease would benefit; 2) if interferon beta-1b has efficacy alone or in combination with other medications; 3) how best to treat patients when therapy is started more than 7 days after symptom onset; and 4) the optimum number of interferon beta-1b doses.
  • COVID Activated Emergency Scaling of Anesthesiology Responsibilities (CAESAR) ICU
    May 7. Verdiner. Anesthesia & Analgesia.
    Opinion from SAB Member: Dr. Jagdip Shah
    Practitioners from the American Society of Anesthesiologists (ASA), the Society of Critical Care Anesthesiologists (SOCCA), the Society of Critical Care Medicine (SCCM), and the Anesthesia Patient Safety Foundation (APSF), representing more than a dozen universities in the USA, created the COVID Activated Emergency Scaling of Anesthesiology Responsibilities (CAESAR) ICU working group. The specific goal is to address the shortage of critical care medicine (CCM) MDs in this current COVID-19 pandemic when supply is mismatched with demand, by fast-tracking anesthesiologists with short notice. This long article is formatted as a knowledge-based guideline. It addresses all possible potential areas of weaknesses in anesthesiology knowledge as it pertains to practicing in the ICU on day #1. The authors have provided state of the art information about the pathophysiology of COVID-19, pertaining to all the disciplines (respiratory, cardiovascular, renal, inflammation cascades, central nervous system, infection control, endocrinology, coagulation dichotomy, etc.) in a dynamic fashion. The article is a well referenced and complete effort to inform non-ICU physicians in simple formats of an inner working of the ICU regarding: multi-specialty involvement, scoring systems for patients, the ABCDEF Bundle (Assess, prevent, and manage pain, Both spontaneous awakening trials and spontaneous breathing trials, Choice of analgesia and sedation, Delirium: assess, prevent, and manage, Early mobility and exercise, and Family engagement and empowerment), drug therapy / interactions, supply shortages and their implications, managing codes, interpretation of monitors, ventilator synchronizations, proning, CPR, ARDS, glucose control, ECHO, ECMO, CRRT/dialysis/ultrafiltration, ethical philosophy, the role of the triage committee, and role of palliative care and hospice. The authors explain clearly that COVID-19 is a very different disease regarding its transmissibility to the caregivers, and stresses the need for adaptability of the healthcare system for a huge surge of ICU demand while optimizing the patients for greater benefit and greater good without wasting time, effort and resources.

May 16, 2020 Newsletter:

  • Potential for Lung Recruitment and Ventilation-Perfusion Mismatch in Patients With the Acute Respiratory Distress Syndrome From Coronavirus Disease 2019
    Apr 28. Mauri. Critical Care Medicine.
    Opinion from SAB Member: Dr. Louis McNabb
    In this article, ventilated patients with COVID-19 were given PEEPs of 5 and 15 cmH2O. The degree of lung recruitment was variable among the participants and most of the V/Q mismatch was attributed to increased dead space ventilation.
  • Dealing With the CARDS of COVID-19
    May 13. Marini. Critical Care Medicine.
    Opinion from SAB Member: Dr. Louis McNabb
    This is an editorial response to above article that describes different phases of COVID-19 lung involvement, which require different ventilator strategies. The author describes the potential pathophysiologic causes of V/Q mismatch.
  • Medically Vulnerable Clinicians and Unnecessary Risk During the COVID-19 Pandemic
    May 13. Janvier. The American Journal of Bioethics.
    Opinion from SAB Member: Dr. Philip Lumb
    This is an intellectually provocative discussion on appropriate tasks for retired physician volunteers in COVID-19 areas. The article entertains appropriate conflict between “wishing to be in the front line” versus more appropriate and potentially intellectually valuable activities that entertain less risk for volunteers and the health system.
  • The electronic medical record and COVID-19: is it up to the challenge?
    May 2. Pryor. American Journal of Infection Control.
    Opinion from SAB Member: Dr. Barry Perlman
    This is a discussion of existing EMR barriers during the COVID-19 pandemic. Currently, hospital infection prevention (IP) teamwork and communication with caregivers and other hospital staff involve too many manual processes. Identified areas in need of more EMR assisted automation include: notification and identification of suspected and positive COVID-19 patients, tracking infected and suspected inpatients and inter-facility transfers, and ensuring proper isolation orders are executed. For example, EMR screens should be more standardized across disciplines, improved EMR communication between health systems is needed, and IPs should receive more automated alerts regarding testing and patient disposition.
  • A serological assay to detect SARS-CoV-2 seroconversion in humans
    May 12. Amanat. Nature Medicine.
    Opinion from SAB Member: Dr. Jay Przybylo
    A dense, technical Brief Communication stating in the first sentence that the authors developed “a serological enzyme-linked immunosorbent assay” that then proceeds to describe the purpose and method culminating in the assay to assess the presence of SARS-CoV-2 spike protein antibody.
  • Asymptomatic Seroconversion of Immunoglobulins to SARS-CoV-2 in a Pediatric Dialysis Unit
    May 14. Hains. JAMA.
    Opinion from SAB Member: Dr. Jay Przybylo
    This is a Research Letter describing the futility of limiting the spread of SARS-CoV-2 using a pediatric dialysis unit as an example. A single patient presented to the unit and was isolated for therapy. This initiated testing on everyone, patients and staff, in the unit. 38% of patients and healthcare workers who presented repeatedly to this unit seroconverted positive to the virus by serum evaluation over a two-week period, proof that this virus is rapidly spreading in unrecognized ways.
  • Real-time tracking of self-reported symptoms to predict potential COVID-19
    May 11. Menni. Nature Medicine.
    Opinion from SAB Member: Dr. Lydia Cassorla
    This interesting report may represent a sign of the future of disease prediction models. 2.6M users reported symptoms on a smartphone-based app during a 4 week period beginning 24 March 2020. 93.6% in GB (balance in US). 15,638 UK and 2,763 US app users reported having had an RT-PCR SARS-CoV-2 test, and having received the result. Of the UK cohort with a (+) COVID PCR test, 65% reported a loss of smell and taste, compared with 23% of those with a (-) test result. “We re-ran logistic regressions adjusting for age, sex and BMI to identify other symptoms besides anosmia that might be associated with being infected by SARS-CoV-2. All ten symptoms queried (fever, persistent cough, fatigue, shortness of breath, diarrhea, delirium, skipped meals, abdominal pain, chest pain and hoarse voice) were associated with testing positive for COVID-19 in the UK cohort…In the US cohort, only loss of smell and taste, fatigue and skipped meals were associated with a positive test result.” A prediction model was created including factors of age, sex, loss of smell/taste, cough, fatigue, and skipped meals. “In the UK test set, the prediction model had a sensitivity of 0.65 (0.62–0.67), a specificity of 0.78 (0.76–0.80), an area under the curve (AUC) of the receiver operating characteristic curve (ROC) (that is, ROC-AUC) of 0.76 (0.74–0.78), a positive predictive value of 0.69 (0.66–0.71) and a negative predictive value of 0.75 (0.73–0.77).” Application of the model to the US cohort showed similar sensitivity and increased specificity of 0.83. Limitations include self-selection of cohorts, self-reporting, testing selection bias, and in GB the influence of media reports. The authors recommend adding loss of smell/taste to WHO symptom list for COVID-19.
  • Corona Viruses and the Chemical Senses: Past, Present, and Future
    May 14. Pellegrino. Chemical Senses.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    In this review of chemosensory ability in patients with COVID-19, the authors sought to determine whether chemosensory dysfunction is the same with COVID-19 as it is with other pandemics including SARS and MERS and whether COVID-19 represents a special case of viral infection attacking the olfactory system. They also discussed whether the taste disturbances with COVID-19 are a misrepresentation of olfactory disturbances rather than the direct impact of SARS-CoV-2 on taste and chemical sensitivity of skin and mucous membrane pathways. First, whether taste disturbance is olfactory-dependent or instead reflects true taste loss in COVID-19 is currently unclear. Second, olfactory disturbances may not be as prominent in SARS and MERS as with COVID-19. Third, the reduction in sensitivity being associated with reduced ability to promote the clearing of pathogenic agents from the nasal cavities can only be speculated. Certainly, distinguishing each aspect of chemo-sensation in patients with confirmed and suspected COVID-19 diagnosis as well as with other respiratory illnesses is needed to determine whether the chemical senses are uniquely affected by COVID-19 infection.
  • A primer on viral-associated olfactory loss in the era of COVID-19
    Apr 9. Soler. Allergy & Rhinology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    A nice summary of olfactory loss associated with COVID-19 that helps to answer questions that include presentation and evaluation, natural history, mechanisms of disease and viral pathogens, pharmacologic treatment, olfactory training. The authors then conclude with some practical recommendations including the fact that COVID-19 should be considered if a patient has a sudden loss of smell and/or taste, patients with an acute loss of smell and taste after COVID-19 should assume smell loss is virally associated, oral or topical steroids should not be used to treat acute loss of smell with active COVID-19, olfactory training should be started sooner rather than later, and for persistent loss of smell, consult an otolaryngologist.
  • A Game Plan for the Resumption of Sport and Exercise After Coronavirus Disease 2019 (COVID-19) Infection
    May 13. Phelan. JAMA Cardiology.
    Opinion from SAB Member: Dr. Barry Perlman
    Expert consensus opinion from members of the American College of Cardiology’s Sports & Exercise Cardiology Council, with input from national leaders in sports cardiology, regarding when those recovered from COVID-19 can return to recreational or competitive sports. Acute cardiac injury, based on elevated troponin, EKG changes, or ECHO abnormalities, occur in up to 22% of hospitalized COVID-19 patients. After myocarditis, return to play should require “normalization of ventricular function, absence of biomarker evidence of inflammation, and absence of inducible arrhythmias.” ECHO, stress testing, and rhythm monitoring are used to determine risk stratification after 3-6 months of exercise restriction. An algorithm is provided based on COVID-19 testing and symptoms: 1) Asymptomatic COVID-19 positive athletes or those who have detected antibodies indicating prior infection can slowly resume activity after 2 weeks; 2) If mild or moderate symptoms, a minimum of 2 weeks cessation of exercise training after symptoms resolve is recommended, and if cardiovascular evaluation including cardiac biomarkers and imaging reveal evidence of cardiac involvement, myocarditis return-to-play guidelines should be followed; 3) For those who were hospitalized or had more severe COVID-19, myocarditis return-to-play guidelines should be followed, and if cardiac biomarkers and imaging are normal after cardiac reevaluation graded, resumption of exercise can start at a minimum of 2 weeks after symptom resolution.

May 15, 2020 Newsletter:

  • ORIGINAL ARTICLE: Incidence of thrombotic complications in critically ill ICU patients with COVID-19
    Apr 13. Klok. Thrombosis Research.
    UPDATE: Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis
    May 9. Klok. Thrombosis Research.
    Opinion from SAB Member: Dr. Louis McNabb, Dr. Anil Hingorani
    LM: This article reported on 184 COVID-19 patients in the ICU. The initial evaluation demonstrated a thrombotic rate of 31%. Follow up 17 days later showed a thrombotic rate of 49%. The PE rate was 65/184, and most patients were on prophylactic anticoagulation. Given the high risk of VTE in COVID-19 patients, we need immediate trials on regimens of anticoagulation to reduce thrombotic complications. AH: A review of 184 ICU COVID-19 patients in the Netherlands. The patients had a high incidence of VTE despite prophylaxis and 3% had arterial thrombosis. Patients with thrombotic complications had five-fold increased risk of all-cause death.
  • Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia
    May 11. Pavoni. Journal of Thrombosis and Thrombolysis.
    Opinion from SAB Member: Dr. Lydia Cassorla, Dr. Joseph Anthony Caprini, Dr. Anil Hingorani
    LC: While perhaps not available or familiar to many, ROTEM, a form of thromboelastography (TEG), is a clinically useful point-of-care tool that can help evaluate coagulopathy. It extends diagnostic capability beyond traditional coagulation studies by providing an evaluation of platelet function, clot strength, and fibrinolysis. The test takes about an hour to complete and requires user training. This Italian single center retrospective observational study evaluated ROTEM in 40 consecutive COVID-19 patients admitted to the ICU with multiple measurements over 10 days. In many, hypercoagulability without consumptive coagulopathy or secondary hyperfibrinolysis was detected. The article provides discussion of the potential value of ROTEM over conventional coagulation studies in COVID-19 to guide therapy and calls for prospective studies. JC: This is an interesting article introducing the concept of using viscoelastic measurements to correlate with clinical events in patients with a severe viral infection. This study is small but it does demonstrate the concept of hypercoagulability. I am not sure at this point given the widespread vascular damage associated with this disease how this unique technique is going to be clinically helpful. I’m not discouraging the use of this technique which I have used extensively in the past for other purposes, but realize that we need more work. One interesting thought is that we know many patients following hospitalizations are still at high risk of developing thrombotic complications. Furthermore, there have been attempts to identify patients who would benefit from extended anticoagulation based on risk factors including laboratory parameters such as D dimer. It would be interesting to learn whether this technique might be useful in deciding the length of extended anticoagulant prophylaxis based on the return of the thrombelastographic parameters to normal. AH: This is an evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia (n=40). This is a point-of-care test to assess hypercoaguability for COVID-19, and is NEW data worth reviewing.
  • The tug-of-war between coagulopathy and anticoagulant agents in patients with COVID-19
    May 8. Canonico. European Heart Journal – Cardiovascular Pharmacotherapy.
    Opinion from SAB Member: Dr. Lydia Cassorla, Dr. Anil Hingorani
    LC: This brief report from the pharmacology literature outlines possible drug-drug interactions between anticoagulants and experimental drugs for COVID-19 patients including antivirals and anti-cytokine Rx. Most are due to hepatic metabolism. The interaction with cytochrome P450s and P-glycoprotein are the principal mechanism involved in DDIs. It includes a summary table that pretty much says it all. AH: Useful for listing drug to drug interactions of anticoagulants and other agents used for COVID-19, though I am not sure why they are using the older term NOAC rather than the safer term DOAC.
  • An Update on Current Therapeutic Drugs Treating COVID-19
    May 11. Wu. Current Pharmacology Reports.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    A review of common and not-so-common therapeutic agents in current use or under consideration to treat COVID-19 patients, collated by a group from Rutgers School of Pharmacy. Grouped into antivirals, supportive, miscellaneous and traditional herbal medicine, the discussion spans across a wide array of therapies currently used around the globe to deal with COVID-19. Mechanism action and logistics of use in COVID-19 as well as other viral illnesses is addressed, and pros and cons according to recent studies are reviewed. Ongoing trials worldwide are listed. Along with 175 citations, this paper represents a valuable reference for clinicians and investigators.
  • Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients
    May 6. Klopfenstein. Medecine et Maladies Infectieuses.
    Opinion from SAB Member: Dr. Philip Lumb
    Retrospective case-control study demonstrating possible benefit of Tocilizumab prescription (TCZ: recombinant humanized anti-interleukin-6 receptor [IL-6R] monoclonal antibody used in the treatment of rheumatoid arthritis) when combined with standard care. The article describes a small number of cases, but contains a well-referenced discussion that considers the theoretical basis for use; the methodology and results are clearly presented.
  • Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID-19
    Apr 29. Patel. Journal of Clinical Virology.
    Opinion from SAB Member: Dr. David M. Clement
    This paper is a good overview of the current literature on GI disease with COVID-19. A well written, concise review of the GI symptoms, laboratory abnormalities, outcomes, possible mechanisms of GI disease, and outcomes in COVID-19 patients with GI disease are included. The prolonged Rt-PCR positivity of fecal samples is discussed, concluding that this could be a significant mode of viral transmission, and should be taken into account.
  • Taste Changes (Dysgeusia) in COVID-19: A systematic review and metaanalysis
    May 1. Aziz. Gastroenterology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    The authors performed a retrospective analysis of published articles that reported on ageusia/dysgeusia as a symptom in laboratory-confirmed COVID-19 patients and found that almost half of the patients (49.8%) with COVID-19 have altered taste sensation. Though it is not certain that taste or smell changes can predict COVID-19, certainly the clinical feature can raise the suspicion of COVID-19 and lead to early testing and diagnosis.
  • COVID-19 and Racial/Ethnic Disparities
    May 11. Hooper. JAMA.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    In this viewpoint article, the authors highlight the health disparities among African Americans and Latinos. The incidence of COVID-19 disease is higher, and the number of patients who die from the disease is greater in these groups of patients. It’s hard to know why, but social and structural determinants of health, racism and discrimination, economic and educational disadvantages, health care access and quality, individual behavior, and biology may be determinants. This is not the first time, in that pulmonary tuberculosis, for example, disproportionately affects persons of lower socioeconomic status. As the authors note, the “pandemic presents a window of opportunity for achieving greater equity in the health care of all vulnerable populations.”
  • Multidisciplinary guidance for safe tracheostomy care during the COVID-19 pandemic: the NHS National Patient Safety Improvement Programme (NatPatSIP)
    May 12. McGrath. Anaesthesia.
    Opinion from SAB Member: Dr. David M. Clement
    Prolonged ventilation necessitating tracheostomy is not uncommon with the COVID-19 pandemic. To address most questions about tracheostomies, UK stakeholder organizations involved in tracheostomy care developed consensus guidelines based on the available literature, expert opinion, and existing multidisciplinary guidelines. These guidelines address infectivity of patients with respect to tracheostomy, indications and timing, aerosol-generating procedures, risks to staff, insertion procedures, and management following tracheostomy. The paper is long but well organized, and starts out with the key points, such as recommending an apnea test, the use of full muscle paralysis for tracheostomy insertion, and plans to define and limit trach care post-insertion to reduce virus exposure to staff.
  • Subphenotyping ARDS in COVID-19 Patients: Consequences for Ventilator Management
    May 12. Bos. Annals of the American Thoracic Society.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    As the authors note, there are phenotypes that can be used as a basis to treat patients with ARDS. For example, patients with focal lung pathology respond better for ventilation to prone positioning, though their lungs are not as recruitable. The authors in a retrospective sequential analysis of 70 patients in The Netherlands tried to see if the same was true in patients with COVID-19 and found that that was not the case.
  • Recruitability and effect of PEEP in SARS-Cov-2-associated acute respiratory distress syndrome
    May 12. Beloncle. Annals of Intensive Care.
    Opinion from SAB Member: Dr. Jay Przybylo
    A follow-up to a previous case report prospective study demonstrating the effect of high vs low PEEP on two groups of mechanically ventilated SARS-CoV-2 patients divided into highly vs poorly recruitable lung mechanics. Determining the R/I ratio, the ratio between the recruited lung compliance and CRS at a PEEP of 5 cmH2O, might lead to better ventilatory management.

May 13, 2020 Newsletter:

  • Cutaneous Signs in COVID-19 Patients: A Review
    May 10. Wollina. Dermatologic Therapy.
    Opinion from SAB Member: Dr. Barry Perlman
    Detailed review describing reported cutaneous symptoms of COVID-19. ACE2 receptors are found in skin and adipose tissue. SARS-CoV-2 associated pulmonary and cutaneous fibrosis both involve transdifferentiation of adipocytes or lipo-fibroblasts into myofibroblasts. Adipocytes can act as a viral reservoir. The different cutaneous manifestations are described, along with differential diagnosis and associated COVID-19 presentation. Chilblain-like acral eruptions, purpuric and erythema multiforme-like lesions have been seen in children and young adult patients with asymptomatic or mild COVID-19. Acro-ischemic lesion and maculopapular rash are often seen in adult patients with more severe disease. Urticaria with pyrexia can be an early symptom of SARS-CoV-2 infection. Attention to cutaneous signs may aid in diagnosis, triage, and risk stratification of COVID-19 patients.
  • Clinical and histological characterization of vesicular COVID-19 rashes: A prospective study in a tertiary care hospital
    May 8. Fernandez‐Nieto. Clinical and Experimental Dermatology.
    Opinion from SAB Member: Dr. Barry Perlman
    There are now many reports of COVID-19 patients presenting with or having associated cutaneous lesions. This is a prospective observational study of vesicular lesions in 24 COVID-19 patients in Spain. 29% had prior history of dermatologic conditions. 75% had a disseminated pattern with the rest having a more localized one. Median rash duration was 10 days. Rashes developed a median 14 days after COVID-19 diagnosis, prior to COVID-19 treatment in 71%. Skin biopsy in 2 patients showed histology consistent with viral infection. PCR tests performed on vesicular fluid in 4 patients were negative in 4/4 for SARS-CoV-2 and herpes virus.
  • Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State
    May 11. Rosenberg. JAMA.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Among 1438 hospitalized patients with a diagnosis of COVID-19 in metropolitan New York, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. Although randomized double-blind clinical trials are the optimal study design, given the urgent need to respond to the COVID-19 pandemic in New York, this study was designed as an observational multi-center retrospective cohort study using data from the State Health Information Network for NY (SHIN-NY), the state’s public health information exchange network connecting New York State hospitals, supplemented by medical record reviews by trained chart abstractors to evaluate the clinical outcomes and adverse effects associated with hydroxychloroquine and azithromycin therapies for COVID-19. Of course, the interpretation of these findings may be limited by the observational design.
  • EDITORIAL: Hydroxychloroquine, Coronavirus Disease 2019, and QT Prolongation
    May 1. Bonow. JAMA Cardiology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Hydroxychloroquine has been advocated and even politicized as a promising therapy because of its anti-inflammatory and potential antiviral properties. However, hydroxychloroquine prolongs the QT interval because of blockade of inward cellular potassium current and is known to be proarrhythmic, especially in the setting of other drugs that also prolong the QT interval. Azithromycin has also been increasingly recognized for risks of QT interval prolongation and sudden death. Excessive prolongation of QTc was observed in 14 of 40 patients (36%) in an intensive care unit, and 37 of 40 patients (93%) manifested an increase in QTc with hydroxychloroquine alone or in combination with azithromycin. In another study, 18 of 90 patients (20%) treated with hydroxychloroquine alone or in combination with azithromycin developed QTc prolongation of 500 milliseconds or more. As noted in the editorial, there’s a potential risk associated of QT prolongation with widespread use of hydroxychloroquine and the combination of hydroxycholoquine and azithromycin in ambulatory patients with known or suspected COVID-19.
  • Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study
    American Journal of Obstetrics & Gynecology MFM. Apr 27, 2020.
    Rebecca A.M.Pierce-Williams; Julia Burd; Laura Felder; Rasha Khoury; et al
    Opinion from SAB Member: Dr. Jay Przybylo
    This is a data-rich, multicenter study of COVID-19 severe and critically ill women in third trimester of pregnancy. Of the many findings: critically ill women required intubation and delivered prematurely mostly for maternal risk; the newborns were COVID-19 negative; 1 of 64 women required a tracheostomy. Matched to a non-pregnant control group, pregnancy did not alter outcome.
  • Adult ICU Triage During the Coronavirus Disease 2019 Pandemic: Who Will Live and Who Will Die? Recommendations to Improve Survival
    May 6. Sprung. Critical Care Medicine.
    Opinion from SAB Member: Dr. Jagdip Shah
    The authors review 3 methods of triage (Andorran Model, Medical Benefit, and Manchester Triage System), in 3 countries (Spain, Ecuador, and the Netherlands). They then compared results with current COVID-19 pandemic ICU care profiles. The Netherlands ICU was able to increase capacity 4-fold and was able to decrease mortality while other ICUs in Ecuador and Spain more than doubled ICU bed capacity and experienced an increased mortality of almost 2- to 3-fold. Triage is to be used only in crisis mode, not in contingency mode (e.g. when demand for ICU bed is increased >100%). Here the authors make an appeal for a flexible, simple and powerful tool implemented by a triage committee that may include doctors with relevant experience (palliative care, critical care, administration), nurses, social workers, and ethicists for ICU admission and discharge. The authors recommend a triage algorithm based on clinical estimations of the incremental survival benefit (saving the most life-years) with “first come, first served” being applied for patients with otherwise equal priorities/benefits. Prognosis is an important factor to consider with emphasis on biologic age being needed for COVID-19, specifically. Fairness by age, gender, race ethnicity, sex preference, financial status, social worth is also recommended. The triage model proposed here is based on the priority (1 to 4) label of all ICU seeking patients. The triage committee will make color coding of each patient seeking ICU based on: 1. performance score (The premorbid baseline condition using the Eastern Cooperative Oncology Group Performance Score + the Clinical Frailty Score + the Karnofsky Performance Scale), 2. ASA class, 3. SOFA score, 4. predicted survival. The triage committee reviews all ICU admitted patients Q24 hrs and also Q14 days for discharge from the ICU. The authors make a plea for health workers to get priority for treatment with a blessing from the government/communities that they serve. Administrators in the committee are likely to guide space, staff and supplies. An excellent graphic clearly written for the current pandemic is included.
  • Understanding Observational Treatment Comparisons in the Setting of Coronavirus Disease 2019 (COVID-19)
    May 5. Thomas. JAMA Cardiology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    In this editorial, concerning patients with COVID-19, hypertension, diabetes, and cardiovascular disease may be vulnerable and are more likely to be taking angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Based on the Mehta study (below), patients taking those drugs can continue taking the drugs given the current pandemic given the fact that these patients are not more likely to be susceptible to the disease, though based on a secondary analysis, the severity of disease might be greater in terms of need for hospitalization and ICU admission. Yet, it’s possible also that the presence of cardiovascular disease and other comorbidities lowers the threshold on the part of referring clinicians to hospitalize and move to the ICU those individuals considered to be at higher risk than the general population. These secondary findings, though real, should not be considered as causal.
  • Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)
    May 5. Mehta. JAMA Cardiology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    As has been discussed in previous articles this newsletter has referenced, SARS-CoV-2 binds to the extracellular domain of the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor to gain entry into host cells; patients who are taking angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers are theoretically at an increased risk for becoming infected with SARS-CoV-2 or may have worse outcomes; upregulation of angiotensin-converting enzyme 2 may improve outcomes in infection-induced acute lung injury in patients with SARS-CoV or SARS-CoV-2 infections; and in certain high-risk patients, the withdrawal of ACEIs or ARBs may be harmful. In this retrospective analysis of 18,472 patients tested for SARS-CoV-2, taking either an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers was not associated with an increase in the likelihood of testing positive for SARS-CoV-2 infection.

May 12, 2020 Newsletter:

  • COVID-19 and acute myocardial injury: the heart of the matter or an innocent bystander?
    Apr 30. Cheng. Heart.
    Opinion from SAB Member: Dr. Philip Lumb
    Short but valuable review of myocardial involvement in COVID-19 with relevant literature reviews, and a useful table of potential mechanism and diagnostic limitations in myocardial injury. Recognizes the current therapeutic dilemmas facing clinicians in order to maximize myocardial preservation and/or recovery.
  • Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic
    Mar 17. Driggen. JACC.
    Opinion from SAB Member: Dr. Jay Przybylo
    An exhaustive State-of-the-Art Review with complete recommendations concerning every phase of COVID-19 cardiac involvement from presentation by phone through hospitalization and including all forms of cardiac pathology to healthcare worker precautions. Multiple tables with reviews from previous studies and 100+ references included.
  • Misinformation During the Coronavirus Disease 2019 Outbreak: How Knowledge Emerges From Noise
    Apr 1, 2020. Rochwerg. Critical Care Explorations.
    Opinion from SAB Member: Dr. Lydia Cassorla
    This well articulated narrative review by authors from Canada, New Zealand, and the US outlines the challenges and opportunities for both the media and researchers to develop knowledge in the face of an information storm. Much of the media is driven by corporate interests rather than a desire to meticulously vet sources and research quality, fanning hysteria. There are important benefits to the “live update” culture, however, consumers are advised to carefully consider the reliability of their sources in both lay press and medical publications. During a pandemic, conventional research and publishing practice are out of synch with the need for rapid information and dissemination, as they require months to years. Major publications have prioritized and made accessible COVID-19 related work to help overcome barriers to rapid, peer-reviewed work and combat misinformation. Nonetheless, some reports remain questionable. The concept of “living guidelines”, frequently updated as evidence emerges, is discussed. The authors highlight the benefit of advance planning to accelerate clinical trials, governmental support, targeted funding and collaboration with industry to optimize the reliability of research output when pandemics occur.

  • In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, China
    Apr 2. Shao. Resuscitation.
    Opinion from SAB Member: Dr. David M. Clement
    This study documents the poor outcomes for in-hospital cardiac arrest (IHCA) in severe COVID-19 patients. It is a retrospective, observational study from China, of 136 patients with IHCA. Most were monitored, had witnessed arrests, and received CPR in under a minute. Most IHCA had respiratory causes, 94% had asystole or PEA, and only 6% had shockable rhythms. Return of spontaneous circulation was achieved in 13%, with 3% surviving at least 30 days and only one patient surviving with an acceptable neurologic outcome at 30 days.
  • Acute Physiology and Chronic Health Evaluation II Score as a Predictor of Hospital Mortality in Patients of Coronavirus Disease 2019
    May 7. Zou. Crit Care Med.
    Opinion from SAB Member: Dr. David M. Clement, Dr. Jagdip Shah
    DC: Especially in healthcare settings with overextended resources, accurately predicting mortality may or may not be useful for frontline providers. In this retrospective, single referral hospital study from China of 154 ICU patients with COVID-19, an admitting Acute Physiology and Chronic Health Evaluation (APACHE) II score of equal to or greater than 17 predicted mortality with a sensitivity of 96% and a specificity of 86%, better than other predictive indices.
    JS: This single, tertiary center, retrospective, small study (N= 154) in China compared three ICU scoring systems on day one of ICU admission to decide which one is a better predictive tool for survival (e.g. a futility index) with COVID-19 patients with MOF. The three scoring systems compared were APACHE II (age, Glasgow Coma Scale, vital signs, oxygenation, chemistry values, hematology values & organ insufficiency [0 to 71]; used for general critical illness), Sequential Organ Failure Assessments (PaO2:fiO2 ratio, mean arterial pressure, creatine, GCS, platelet count, bilirubin [0 – 24]; used for general critical illness), and Confusion, Urea, Respiratory rate, Blood pressure, Age 65 (CURB65; used for pneumonia). Their aim was to describe the difference of epidemiologic and clinical characteristics between survivors and deaths in an attempt to provide an effective clinical tool to predict the probability of death among patients with COVID-19 based on data about admission and the first day in the ICU. The APACHE II score performed better to predict hospital mortality in patients with COVID-19 compared with SOFA and CURB65 scores. APACHE II scores greater than or equal to 17, serve as an early warning indicator of death, which may help to provide guidance for making further clinical decisions. The authors’ conclusion is useful and applicable when you have a tremendous surge of ICU admissions in a short time, shortage of equipment, manpower (DRs & RNs), and patients with comorbidities. The authors capture a few hallmark comorbidities: hypoxic encephalopathy, abnormal Na & K, abnormal hepatic panel, a higher platelet:lymphocyte ratio, (an index of inflammatory process?). ROC & AUC is a tool for sensitivity/specificity index: AUC FOR APACHE II = 0.966, SOFA = 0.867, CURB65 = 0.844.
  • A Trial of Lopinavir-Ritonavir in Covid-19: Letter Series with Author Response
    May 5. Dalerba. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    This investigation from Wuhan, China, published in early April, elicited a number of responses which culminated in the following message: Abandoning an available antiviral at this stage of the pandemic based on a statistically under-powered trial is unwise. Larger cohorts, earlier enrollment and control for secondary therapies might yet point towards a role for these drugs in the management of the SARS-CoV-2 virus. Larger studies are currently underway.

May 11, 2020 Newsletter:

  • Considerations for Assessing Risk of Provider Exposure to SARS-CoV-2 after a Negative Test
    May 8. Long. Anesthesiology.
    Opinion from SAB Member: Dr. Barry Perlman
    The SARS-CoV-2 RT-PCR test is not 100% sensitive and, therefore, can result in a false negative. It has been questioned whether 1 negative test preop can be used to guide the level of PPE needed to adequately protect an anesthesiologist during an intubation or other aerosol generating procedure. Negative predictive value (NPV) and post test probability of SARS-CoV-2 infection were calculated based upon estimated prevalence in the population and test sensitivity and specificity. Using a “most likely” prevalence estimate of 1.0%, post test probabilities ranged from 1 in 89 to 1 in 1,636 with a median of 1 in 338. Based on the results: 1) If prevalence is uncommon, 1 negative test should provide “reassurance” regarding risk of exposure from an asymptomatic patient; 2) If surgical volume is high, exposure to aerosolized SARS-CoV-2 from asymptomatic, 1 test negative patients might occur on a regular basis; 3) If prevalence is high, full PPE should be used for test negative patients; 4) Due to estimate uncertainty in prevalence and testing sensitivity, there is a wide range in the calculated negative predictive value. The authors recommend that a lower threshold of NPV to justify use of universal airborne precautions regardless of preop test results be determined but be re-evaluated if prevalence estimates change.
  • The Role of Antibody Testing for SARS-CoV-2: Is There One?
    Apr 29. Theel. Journal of Clinical Microbiology.
    Opinion from SAB Member: Dr. W. Heinrich Wurm, Dr. Barry Perlman
    WHW: This well-written correspondence presents a deep dive into the state-of-the-art SARS-CoV-2 serology as of mid-April 2020. While outlining the usefulness and applicability of serologic testing, the authors shed light on the absence of FDA oversight of a burgeoning industry of 91 manufacturers. This is a must read for anyone looking for: 1) A tutorial on the optimal use and interpretation of currently available serological testing; 2) verification studies used by laboratories; or 3) the role serologic testing plays in: a) Developing population immunity; b) Development of vaccine; c) Identifying convalescent plasma donors; d) Monitoring the response of vaccines. BP: Richly detailed commentary regarding the current state of SARS-CoV-2 serology testing. It points out the current lack of FDA oversight for serologic testing, which has resulted in a variety of approaches that differ in assay format, antibody detected, target antigen, and specimen type. In addition, it is not yet known whether antibody detection indicates clinical immunity. While some may decide not to read the entire article, the abstract provides a nice summary and useful information.
  • Interpreting Diagnostic Tests for SARS-CoV-2
    May 6. Sethuraman. JAMA.
    Opinion from SAB Member: Dr. Barry Perlman
    Viewpoint from authors in India and Japan discusses interpretation of RT-PCR and ELISA serology testing. There are a variety of RT-PCR tests. Most target envelope, nucleocapsid, spike, RNA-dependent RNA polymerase (RdRp), or ORF1. Most have comparable sensitivities with the RdRp test showing lower sensitivity. RT-PCR nasal swab testing becomes positive as early as day one of symptom onset, peaks within the first week, and starts to decline by week 3. Sputum and fecal sample positivity persists longer than for nasopharyngeal samples. Of note, a positive result reflects presence of viral RNA and does not necessarily mean viable virus. IgM and IgG ELISA testing may be positive as early as day 4 of symptom onset, and rises in weeks 2 and 3. IgM declines by week 5 and disappears by week 7, while IgG persists beyond week 7. Antibody detection to NC protein is most sensitive, while antibody testing to the S receptor-binding domain is more specific and might indicate neutralizing antibodies. Paired testing with initial RT-PCR and then 2 weeks later can increase diagnostic accuracy. It is not known how long neutralizing antibodies will persist and provide protection.
  • COVID-19 Convalescent Plasma; Phase 2
    May 6. Knudson. Transfusion.
    Opinion from SAB Member: Dr. Louis McNabb
    This article discusses methodological issues in using convalescent plasma for COVID-19 patients, such as: donor selection, the fact that some donors have over ten times the antibody level of other donors, the existence of many different antibody tests, factoring in the weights of recipients, and pre- and post-antibody measurements in recipients.
  • Convalescent Plasma To Treat Coronavirus Disease 2019 (Covid-19): Considerations For Clinical Trial Design
    May 6. Barone. Transfusion.
    Opinion from SAB Member: Dr. Louis McNabb
    This article discusses many of the issues in collecting and administering convalescent plasma, and outlines the clinical trials in the USA currently in progress.
  • The following 4 articles provide evidence that COVID-19 infection is Kawasaki Disease in an exceptionally small number of children. Regardless of the diagnosis terminology, the treatment of all COVID-19 patients regardless of age includes the administration of immunoglobulin.
  • Should COVID-19 take advice from rheumatologists?
    May 7. Kernan. Lancet Rheumatology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Anakinra is a drug that has had success treating patients with auto-inflammatory diseases and now, there is evidence that the drug may also be useful in managing patients with COVID-19 disease who also have acute respiratory distress syndrome. The authors summarized the results seen in the study “Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study” (below). As the authors note: “these and other emerging data rightly focus more attention on the host inflammatory response and might herald a shift in how we approach the host-virus relationship.”
  • Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study
    May 7. Cavalli. Lancet Rheumatology.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    The authors first noted that of 16 patients treated between March 10 and March 17, 2020 with COVID-19, ARDS, and hyper-inflammation who were managed with CPAP outside of the ICU, that 21-day survival was 56%. Another similar group of patients receive low dose anakinra (100 mg twice a day) and did not do much better. But when instead high-dose intravenous anakinra (5 mg/kg twice daily) was used, survival increased to 90% at 21 days.
  • Respiratory advice for the non-respiratory physician in the time of COVID-19
    May 4. Bennett. Clinical Medicine Journal.
    Opinion from SAB Member: Dr. David M. Clement
    A pre-print review from the British Thoracic Society mostly describing one approach to the pre-ICU respiratory care of hospitalized COVID-19 patients. The emphasis is on coordinated assessments, cooperation between personnel, and the systematic alteration of respiratory treatments as patient parameters hit certain thresholds. Healthcare worker safety and efficiency, do-not-intubate preferences (“ceilings of care”), proning before intubation, oxygen therapy (esp. CPAP) and triggers for transfer to the ICU are reviewed. Several tables and diagrams help explain this strategy.
  • Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions
    Apr 26. Jamilloux. Autoimmunity Reviews.
    Opinion from SAB Member: Dr. Philip Lumb
    Reviews current literature and knowledge of COVID-19 pathophysiology and focuses on following question: “How can antiviral immunity be reinforced and hyperinflammatory damages be avoided?” The authors provide a detailed overview of the immunopathology of various presentations of COVID-19 from mild to progressive respiratory and multi-organ system failure, and death. Subsequently, the authors discuss the rationale for targeted and non-targeted, supportive therapies. They conclude with, “Therefore, factors to predict progression toward severe forms of the disease are, at present, the most urgently needed and awaited determinants. A highly-structured approach, which includes immune monitoring, would thus be of utmost importance.”

May 8, 2020 Newsletter: 

  • Coagulopathy associated with COVID-19
    May 4. Lee. CMAJ.
    Opinion from SAB Member: Dr. Louis McNabb
    5 key points in a concise one-page summary on where we are in our understanding of coagulopathy issues for COVID-19.

  • Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study
    May 6. Wichmann. Annals of Internal Medicine.
    Opinion from SAB Member: Dr. Lydia Cassorla, Dr. Joseph Anthony Caprini
    LC: This fascinating report from Hamburg Germany describes the findings of complete autopsy reports, as mandated by law, of the first 12 consecutive known COVID-19 deaths in their city. “In all cases the cause of death was in the lungs or the pulmonary vascular system”. Unsurprisingly, patients were older (10/12 >60 yrs) and all had pre-existing co-morbidities and pneumonia at death. They trended obese with BMI of >30 in 5 and nearly 30 in a sixth. The focus of the report is on the high incidence (7/12 or 58%) of venous thrombosis with 4/12 dying of PE. D-dimer was measured in 5 patients on admission, all elevated. 3/5 of those with elevated D-dimer had venous thrombosis including 2 PE deaths. 3 patients had some form of anticoagulation therapy, including 2 PE deaths. There is a trove of additional information in this report as each death resulted in a full autopsy, a post mortem total body CT in all but 2, histopathology and virology. SARS–CoV-2 RNA was present in high titers in the lungs in all, and in the blood in 6/10. The authors suggest that their findings support proactive anticoagulant therapy for hospitalized patients as well as potentially for outpatients. JC: In this autopsy study of 12 consecutive patients who died of COVID-19, we found a high incidence of deep venous thrombosis (58%). One third of the patients had a pulmonary embolism as the direct cause of death. Furthermore, diffuse alveolar damage was demonstrated by histology in 8 patients (67%). The CT images of the ground glass appearance in the lungs is chilling. They indicate the need for more than heparin and some have raised the possibility of steroids. The association between fatal outcomes and pre-existing risk factors, particularly CV disease is also striking.
  • Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19
    May 5. Bowles. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. Philip Lumb
    Authors note that while a prolonged aPTT may indicate caution in prescribing anticoagulants, they report a coagulation screening series of 216 patients positive for COVID-19 of which 44 (20%) had a prolonged aPTT. Lupus anticoagulant assays were performed in 34 patients and 31 (91%) tested positive. Authors suggest that a persistent presence of Lupus anticoagulant can be associated with a “thrombotic tendency within the antiphospholipid syndrome” and that a prolonged aPTT in the presence of COVID-19 should not “withhold use of anticoagulants for thrombosis while awaiting further investigation of a prolonged aPTT, nor withhold thrombolytic therapy in the face of high risk PE on the basis of a prolonged aPTT alone.”
  • High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study
    May 4. Helms. Intensive Care Medicine.
    Opinion from SAB Member: Dr. Louis McNabb, Dr. Joseph Anthony Caprini
    LM: Study of 150 patients in an ICU setting. The main clinical threat was PE at 16%. There was a high incidence of catheter clotting, particularly for patients on dialysis (28/29). Most of patients were on at least prophylactic anticoagulation. 67% of patients were still intubated at time of data analysis, which may have led to underestimation of thrombotic risk, Lupus anticoagulant was found in 50/57 patients. No DIC was noted, but this result may reflect early termination of the study. Curiously, non-COVID-19 patients with ARDS had higher D-dimer levels. JC: In a prospective cohort study, we have shown that sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients with COVID-19 ARDS during their ICU stay, mainly pulmonary embolisms (25 patients, 16.7%). Despite anticoagulation, a high number of patients with COVID-19 ARDS developed life-threatening thrombotic complications, meaning that higher anticoagulation targets than in usual critically ill patients should probably be considered.
  • Incidence of venous thromboembolism in hospitalized patients with COVID-19
    May 5. Middeldorp. Journal of Thrombosis and Haemostasis.
    Opinion from SAB Member: Dr. Louis McNabb
    This is an article describing 198 hospitalized patients of which 38% were in the ICU. 20% were diagnosed with VTE, of which 13% were symptomatic. Most patients were on prophylactic anticoagulation in the medical units. Patients in the ICU received BID prophylactic anticoagulation (double standard regimen). The key point to this paper is that clinicians need to be vigilant looking for VTE in patients with less severe COVID-19 disease.
  • Venous thromboembolism and heparin use in COVID-19 patients: juggling between pragmatic choices, suggestions of medical societies
    May 4. Profidia. Journal of Thrombosis and Thrombolysis.
    Opinion from SAB Member: Dr. Lydia Cassorla, Dr. Joseph Anthony Caprini
    LC: This editorial states that while most guidelines are currently recommending antithrombotic prophylaxis for all hospitalized COVID-19 patients, and full anticoagulation for a subset, questions remain about which population may benefit from therapeutic doses of anticoagulation. It is a call to share data via registries and arrive at a consensus at a time when randomized controlled clinical trials may not be able to answer the question in a timely manner. JC: This is a very good discussion from the data driven point of view including extrapolation of pre-existing data to the clinical presentation and course of patients with COVID-19. Unfortunately, it is a whole new ball game and we need to learn on the job.
  • Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy
    Apr 23. Lodigiania. Thrombosis Research.
    Opinion from SAB Member: Dr. J. Lance Lichtor, Dr. Joseph Anthony Caprini
    JLL: Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. The study is based on retrospective data for 388 admitted hospitalized patients with COVID-19. All ICU patients received thromboprophylaxis and 75% of those admitted to general wards also had thromboprophylaxis. Thromboembolic events occurred in almost 8% of patients which included pulmonary embolism. A little over half of the patients with PE did not receive anticoagulant treatment. Hospital mortality was associated with a high rate of thromboembolic complications. Rapidly increasing D-dimer levels were observed in non-survivors. A true incidence is difficult to determine since, as the reader is told in the discussion, a low number of specific imaging tests were performed. JC: The low incidence of thrombotic events on the ward compared to the ICU is one feature of this series. The fact that 58% of thrombotic events were not on anticoagulation is telling. We know all patients should be on anticoagulation. That has not been their routine practice in the past in many medical patients not in ICU. The paper sends the wrong message advocating for more tests which exposes scanners and machines to risks that may be avoided. Giving everyone anticoagulation and adjusting the dose based on co-morbidities and when the D-dimers skyrocket using full dose anticoagulation. We are learning as we go along but more heparin or LMWH is the developing trend.

May 7, 2020 Newsletter: 

  • Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: a closer look at angiotensin-converting enzyme 2 (ACE2)
    May 5. Zemlin. Annals of Clinical Biochemistry: International Journal of Laboratory Medicine.
    Opinion from SAB Member: Dr. Barry Perlman
    In depth review of SARS-CoV-2, COVID-19, the renin-angiotensin system, the relationship between ACE2 and COVID-19, use of ACE-I and ARB with COVID-19, and possible RAS related targets for COVID-19 treatment.

  • Utility of Tracheostomy in Patients with COVID-19 and Other Special Considerations
    May 5. Mecham. Laryngoscope.
    Opinion from SAB Member: Dr. Jay Przybylo
    A concise prepublication article describing the options for prolonged airway support in COVID-19. Begins with statistics on this pandemic vs earlier SARS-CoV. Provides pros and cons of OR vs bed space, positive pressure vs negative pressure rooms, and percutaneous vs open tracheostomy. The authors imply a percutaneous tracheostomy at the bedside prevents transporting the patient and exposing many people to the virus and might be the best solution in complex patients who are likely to require an artificial airway for a prolonged time.
  • Application of Lung Ultrasound during the COVID-19 Pandemic: A Narrative Review
    Apr 30. Convissar. Anesthesia & Analgesia.
    Opinion from SAB Member: Dr. David M. Clement
    An excellent review of the literature on the use of point of care ultrasound (POCUS) with the current COVID-19 pandemic and previous viral epidemics. Typical POCUS findings (thick irregular pleural lines, B lines, A lines during recovery) are as good or better for diagnosis and followup compared with CXR or CT, and are nicely shown on accompanying videos. “Lung ultrasound may be preferred over chest radiography or computed tomography in the diagnosis and monitoring of COVID-19 patients due to its ease of bedside use, low associated cost, and reduced risk of infectious spread.”
  • Can N95 Respirators Be Reused after Disinfection? How Many Times?
    May 5. Liao. ACS Nano.
    Opinion from SAB Member: Dr. Lydia Cassorla
    Due to shortages of PPE, individuals and groups are seeking effective methods to decontaminate N95 masks designed for single use. While this report in the basic science literature from the Stanford-4C Air group does not include confirmatory testing of SARS-CoV-2 decontamination, it adds to current information about the effects of decontamination methods on the fabric of N95 masks. Based on their work, heat in a range of 70-85 degrees C in a static air oven for 30 min with varying degrees of relative humidity does not degrade the structure and function of the filter layer of masks up to 50 cycles. These are temperatures that have been shown in referenced work to be effective in inactivating SARS-CoV-2. The authors suggest that this is a potentially safe and relatively simple technique to decontaminate N95 masks for re-use by the same individual during the current pandemic. UVGI was a secondary option, with adequate retention of function for up to 10 cycles. Their work mostly involved fabric samples, using only a few whole masks due to shortages, and highlights the importance of ongoing fit evaluation, especially after 5 rounds of donning and doffing.
  • COVID-19 and Trauma Care: Improvise, Adapt and Overcome!
    May 1. Dutton. Anesthesia & Analgesia.
    Opinion from SAB Member: Dr. Jagdip Shah
    This article outlining the approach to trauma care in the era of COVID-19 emphasizes: PPE for the whole anesthesia team, use of negative pressure ORs, blood conservation, video laryngoscopy and safety precautions during extubation, the role of lung protective ventilation strategies–frequent manual breaths, a need to expand use of multimodal analgesia (regional techniques), care for multi-organ failure intra op, restrictive goal-directed fluid therapy, standard ASA monitoring and frequent laboratory values–especially the coagulation profile to guide patient care, guidelines that address the shortage of drug and equipment on the horizon, healthcare worker protection including donning and doffing, and the current chaos surrounding emergency and acute care surgery. It has guidelines on when to operate in the ER. It references useful resources for those practicing trauma care, including the COVID-19 Global DocMatter Community, the Trauma Anesthesiology Society DocMatter Community, and — a website for like-minded trauma anesthesiologists. The authors wish lung ultrasound would be more frequently included in acute surgery / trauma, with less emphasis on CT scans in emergency care.
  • Olfactory and Gustatory Dysfunction in Coronavirus Disease 19 (COVID-19)
    May 1. Luers. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    72 patients with polymerase chain reaction confirmed COVID-19 agreed to participate and were enrolled in this study. Reduced olfaction was noted in 74% and a reduced sense of taste was noted in 69%. 68% reported both symptoms. Both symptoms occurred on average on the 4th day after first symptoms were noted, though 13% noted reduced olfaction and taste on the first day of COVID-19 symptoms.

May 6, 2020 Newsletter: 

  • Management of acute ischemic stroke in patients with COVID-19 infection: Report of an international panel
    May 3. Qureshi. International Journal of Stroke.
    Opinion from SAB Member: Dr. Barry Perlman
    Multinational expert consensus for management of acute ischemic stroke in COVID-19 patients. 5% incidence of acute ischemic stroke is noted in COVID-19 patients, and such events are associated with older age, hepatic and renal dysfunction, HTN, DM, cerebrovascular disease, and elevated D-dimers. Mortality rate of 38% dependent on severity of COVID-19 infection. Possible undiagnosed COVID-19 infection should be suspected in patients with acute stroke, as some may have difficulty communicating due to the stroke. Since renal insufficiency is common with COVID-19 infection, risk of contrast-induced nephropathy should be considered prior to neuroimaging. Coagulation assessment can help determine risk benefit of IV rt-PA. Mechanical thrombectomy with low threshold for intubation and general anesthesia may be considered on case-by-case basis. Single or dual antiplatelet therapy may be considered for patients who do not receive IV rt-PA or mechanical thrombectomy. Risk of healthcare provider infection and mitigation strategies are also discussed.

  • Inhibitors of the Renin-Angiotensin-Aldosterone System and Covid-19
    May 1. Jarcho. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. David M. Clement
    Editorial reviewing the theoretical concerns for the use of ARB/ACEI drugs during the COVID-19 epidemic, and three observational clinical studies that conclude these drugs seem not to influence the course of the disease. This is consistent with other studies and guidelines from pertinent organizations; that ARB/ACEI drugs should be continued if a patient develops COVID-19 disease.
  • Randomized Clinical Trials and COVID-19: Managing Expectations
    May 4. Bauchner. JAMA.
    Opinion from SAB Member: Dr. Jagdip Shah
    Today there are more than 1,000 studies addressing various aspects of COVID-19 registered on, including more than 600 interventional studies and randomized clinical trials (RCTs). It has become common practice to report the glimpses of preliminary results in social media and the popular press. The authors question how we (clinicians, press, public, politicians) should understand the results. The authors appeal to investigators to be strict on control groups, statistical power, proper selection of clinical endpoints, and blinding methods, and strongly advocates merging smaller trials for better robust outcomes. This article was open for comments and an excellent comment from Bhatt A. from Oxford points out that the International Committee of Medical Journal Editors (ICMJE) should be firmer in its proactive stance and guidance to ethics committee verdicts than simply relying on ethics approvals, which all small and uncontrolled studies will have, but which may not have meaning or purpose.
  • An Italian programme for COVID-19 infection in multiple sclerosis
    Apr 30. Sormani. The Lancet Neurology.
    Opinion from SAB Member: Dr. Barry Perlman
    This article describes a program developed by the Italian MS Society, Italian MS Foundation, and MS Study Group of the Italian Neurological Society to help guide management of patients with multiple sclerosis during the COVID-19 pandemic. Case report forms were sent to >200 neurologists in Italy and data was collected on 232 patients with known or suspected COVID-19. 96% had mild infection. Of the 3% with critical infection, 1 recovered and 5 died. Further data collection is needed to determine if MS disease or treatment impacts COVID-19 infection.
  • When the game changes: Guidance to adjust sarcoidosis management during the COVID-19 pandemic
    Apr 27. Sweiss. Chest.
    Opinion from SAB Member: Dr. Jay Przybylo
    An international Rheumatology panel makes recommendations regarding sarcoidosis care including lowering the dose of most medications as necessary to protect against viral infection. The Hydroxychloroquine dose should be maintained if the drug is available. Patients should be followed closely and medication doses adjusted as needed.
  • COVID-19 patients with respiratory failure: what can we learn from aviation medicine?
    May 5. Ottestad. British Journal of Anaesthesia.
    Opinion from SAB Member: Dr. Jay Przybylo
    A short editorial with an interesting observation that the symptoms of hypoxia of COVID-19 might be masked by hypocapnia, as demonstrated by previous flight altitude experiments.
  • The Use of Bronchoscopy during the COVID-19 Pandemic: CHEST/AABIP Guideline and Expert Panel Report
    Apr 29. Wahidi. Chest.
    Opinion from SAB Member: Dr. Louis McNabb
    Lengthy article with very little data summarized in a table at end of article. There is a nice table detailing which patients need emergency vs. elective bronchoscopies. Unsurprisingly, the article recommends that operators and health care workers should wear PAPR or N-95 masks with eye shields, gloves, and gowns for most if not all bronchoscopy situations.

May 5, 2020 Newsletter:

  • Antibody Detection and Dynamic Characteristics in Patients with COVID-19
    Apr 19. Xiang. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Barry Perlman
    Serologic study of 85 SARS-CoV-2 RT-PCR test confirmed COVID-19 patients, 24 patients with symptoms but negative RT-PCR testing, and 60 controls. Serologic test was an ELISA for IgM and IgG against the SARS-CoV-2 nucleocapsid N protein. COVID-19 patients showed IgM by 4 days after symptom onset with peak by day 9. IgG increased sharply 12 days after symptom onset, with all COVID-19 patients positive for both IgG and IgM by day 30. For symptom positive but test negative patients, 88% had IgM and 71% had IgG, demonstrating false negative RT-PCR results. 3 controls had IgG but not IgM, which represent either false positives or asymptomatic infection. For RT-PCR confirmed patients: IgM sensitivity 77%, specificity 100%, PPV 100%, NPV 80%. IgG sensitivity 83%, specificity 95%, PPV 95%, NPV 84%. The authors suggest that IgG can be used to diagnose COVID-19 in pneumonia patients, and if negative, serology testing should be repeated 10 days after onset.
  • Role of serology in the COVID-19 pandemic
    May 1. Stowell. Clinical Infectious Diseases.
    Opinion from SAB Member: Dr. Barry Perlman
    Editorial of serologic study by Xiang et al. which demonstrated ability to measure IgG and IgM in COVID-19 patients with good sensitivity and specificity. The editorial points out that variability in kinetics and magnitude of the serologic response, especially early in infection, can result in false negative results, and IgM results may be false positive. In addition, it is not known if positive serology correlates with disease immunity. Suggested uses for serologic testing: 1) COVID-19 symptoms but RT-PCR negative; 2) Populations to determine degree of community exposure; 3) Frontline healthcare workers; 4) Convalescent plasma donation.
  • Category: Retraction
    The following article was retracted after an expression of concern was posted on June 2.
    • Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621. June 4. NEJM.
    • Read additional information about the retractions. 6/4/2020. Retraction Watch.
    • Category: Expression of Concern
      Expression of Concern: Mehra MR et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621.
      June 2. Mehra MR. The New England Journal of Medicine.
      The Lancet published the following Expression of Concern about an article previously cited and summarized by this Scientific Advisory Board in the 5MAY2020 Newsletter.
      ‘On May 1, 2020, we published “Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19,” a study of the effect of preexisting treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) on Covid-19. This retrospective study used data drawn from an international database that included electronic health records from 169 hospitals on three continents. Recently, substantive concerns have been raised about the quality of the information in that database. We have asked the authors to provide evidence that the data are reliable. In the interim and for the benefit of our readers, we are publishing this Expression of Concern about the reliability of their conclusions.
      Studies of ACE inhibitors and ARBs in Covid-19 can play an important role in patient care. We encourage readers to consult two other studies we published on May 1, 2020, that used independent data to reach their conclusions.’
    • Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19
      May 1. Mehra. The New England Journal of Medicine.
      Opinion from SAB Member: Dr. David M. Clement, Dr. Jagdip Shah
      DMC: This study, with data from many institutions and three different continents, provides an excellent summary of the patient characteristics most associated with mortality in COVID-19 patients. JS: The authors provide a multivariate, logistical regression model that describes a few independent predictors and their corresponding odds ratios of in-hospital death from COVID-19. The population (N= 8910) comes from 169 hospitals located in 11 countries in Asia, Europe, and North America. Inclusion criteria were that patients must be hospitalized with COVID-19 positive swab test with a reported outcome (discharged alive v. dead) by March 20, 2020. 1536 patients (17.2%) were from North America, 5755 (64.6%) were from Europe, and 1619 (18.2%) were from Asia. The significant, independent predictors (odds ratio for death [>1=more likely to die; <1=less likely to die]) of in-hospital death included: 1) >65 yr of age (1.93); 2) Female (0.79); 3) Coronary Artery Disease (2.7); 4) Congestive Heart Failure (2.48); 5) Arrhythmia (1.95); 6) COPD (2.96); 7) Current Smoker (1.79); 8) Receiving ACEi (0.33); 9) Receiving statin (0.35). Of note, the authors were not able to confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital mortality in this clinical context.
  • Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19
    May 1. Mancia. The New England Journal of Medicine.
    Opinion from SAB Member: Dr. David M. Clement
    This is the first large study confirming smaller studies and various recommendations on ACEI and ARBs use in COVID-19 patients. A case-control study from Italy of 6,272 COVID-19 patients looking for an association between ACEI or ARB use and the risk of COVID-19 disease. No association was found between pre-infection ARB/ACEI use and susceptibility or severity of SARS-CoV-2 infection. Starting ACEI or ARB drugs during infection was not studied.
  • Cardiac considerations in patients with COVID-19
    May 1. Calvillo-Argüelles. CMAJ.
    Opinion from SAB Member: Dr. Louis McNabb
    Five key points on cardiac considerations for COVID-19 in a convenient one-page summary.
  • Acute myocardial injury is common in patients with Covid-19 and impairs their prognosis
    Apr 6. Wei. Heart.
    Opinion from SAB Member: Dr. Philip Lumb
    101 patient prospective study from January to March 10, 2020 in Sichuan, China with primary endpoints including cardiac injury defined by above normal high-sensitivity troponin T (hs-TnT) levels. Study confirms that myocardial involvement in COVID-19 is common and that elderly and patients with underlying cardiovascular disease at increased risk.

May 2, 2020 Newsletter: 

  • Current perspectives on Coronavirus 2019 (COVID-19) and cardiovascular disease: A white paper by the JAHA editors
    Apr 29. Gupta. Journal of the American Heart Association.
    Opinion from C19SAB: Dr. David M. Clement
    A “White Paper” from the international editorial board of the Journal of the American Heart Association, thoroughly addressing the important aspects of cardio-vascular disease during the COVID-19 pandemic. Very long, but well organized to highlight the important conclusions on troponin elevations, hypertension (RAS), vascular events (including hypercoagulability), arrhythmias (i.e. long QT with some drugs), myocardial injury, ECMO, healthcare worker protection and ethics. Of note, explanations of the pathophysiology of CV disease usually circle back to the inflammatory response to COVID-19. Statins and antiplatelet therapy recommended. A thorough overview of the current knowledge.

  • COVID-19 and its implications for thrombosis and anticoagulation
    Apr 27. Connors. Blood.
    Opinion from C19SAB: Dr. Anil Hingorani, Dr. Louis McNabb
    AH: This article reviews the worldwide literature regarding the effects of COVID-19 on the hematologic system and proposes prophylaxis and treatment options for these patients that is clinically relevant and well organized. LM: Good overview on mechanisms of sepsis-induced coagulopathy. Concludes no data at this time for full anticoagulation of COVID-19 patients in the ICU setting unless proven or suspected VTE. The authors note that COVID-19 do not have propensity to bleed. Many centers are using moderate dosing of anticoagulation, i.e., BID LMWH in the ICU.
  • Incidence of thrombotic complications in critically ill ICU patients with COVID-19
    Apr 13. Kloka. Thrombosis Research.
    Opinion from C19SAB: Dr. Anil Hingorani, Dr. Lydia Cassorla
    AH: This paper presents real world data on thromboembolism with COVID-19 patients in the ICU. It gives the clinician realistic expectations of the incidence of thromboembolism in these critically ill patients and explores prophylaxis strategies. LC: The incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital was observed for 4 weeks. (March 7-April 5, 2020). Among 184 ICU patients with proven COVID-19 pneumonia, 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still in the ICU at the conclusion of the observation period. All patients received at least standard doses of thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CT pulmonary angiography and/or ultrasonography confirmed venous thrombosis in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio 1.05/per year) and coagulopathy were independent predictors of thrombotic complications. None developed DIC. The findings were all the more striking given that ¾ of the study patients were still in ICU at the end of the observation period. The authors recommend low molecular weight heparin prophylaxis in higher dose ranges in all ICU patients, vigilance, and a low bar for diagnostic tests to confirm thrombosis but not full therapeutic anticoagulation for all ICU patients with COVID-19 illness “even in the absence of randomized evidence”. There have been many other reports regarding the high incidence of thrombotic complications in COVID-19 patients. The question of when to use prophylactic or therapeutic anticoagulation in severely ill patients that will likely be further clarified as data and studies emerge.
  • COVID-19: ICU delirium management during SARS-CoV-2 pandemic
    Apr 28. Kotfis. Critical Care.
    Opinion from C19SAB: Dr. W. Heinrich Wurm
    Well referenced review of central nervous system effects of the corona virus with special focus on current available data on delirium–direct and indirectly caused by SARS-CoV-2 infection. While direct CNS invasion is likely originating from the nasopharynx, there is insufficient data on CNS pathophysiology and resulting delirium in severely ill patients. Secondary neural pathology caused by inflammatory mediators affecting the blood brain barrier may be contributing as are metabolic factors secondary to organ dysfunction, social isolation, sedation and pre-existing disease. These concepts are summarized in a well-organized graph and management advice is given using the Society of Critical Care Medicine’s ABCDEF Safety Bundle framework.
  • Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study
    Apr 16. Ziehr. American Journal of Respiratory and Critical Care Medicine.
    Opinion from C19SAB: Dr. Jay Przybylo
    A small study submitted as a letter to the editor that describes the characteristics of patients presenting with respiratory failure requiring mechanical ventilation. The study demographics confirm other reports and further describes ventilatory management using measurements of oxygenation and compliance. Prone positioning improved the pulmonary status of patients in this study.
  • Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation
    Apr 28. Leisman. Intensive Care Medicine.
    Opinion from C19SAB: Dr. W. Heinrich Wurm
    A literature review aiming to classify COVID-19 as a vascular disease characterized by “a confluence of vascular dysfunction, thrombosis and dysregulated inflammation.” The author’s argument is based on the divergence of lung injury seen in the early stages of COVID-19 from typical ARDS, the elevation of pro-thrombotic markers and histopathological findings of endothelial injury. They consider the evidence of a cytokine storm as an underlying mechanism weak and propose “vasculopathy and dysregulated inflammation” to be the underlying cause leading to thrombotic microangiopathy in pulmonary, renal and other organ systems. A graphic demonstration of the SARS-CoV-2 infection of an endothelial cell initiating a cascade of ACE-2 mediated events, strengthens the argument: loss of angiotensin 2 results in loss of autoregulation and vasoconstriction leading to the hypoxic compliant lung injury described by Gattinoni.
    The author’s closing argument is to focus less on cytokine modulation and more on anticoagulation as a therapeutic measure and to investigate the use of angiotensin 2 therapy.
    This paper created a lively discussion among the members of the SAB as to its clinical relevance and applicability. It is hoped that it will do the same among our readers. Most importantly, we look forward to future multi-disciplinary research leading to a consensus on the mechanisms of COVID-19’s attack on multiple organ systems.
  • Clinical phenotypes of SARS-CoV-2: Implications for clinicians and researchers
    Apr 11. Rello. European Respiratory Journal.
    Opinion from C19SAB: Dr. Barry Perlman
    Discussion of COVID-19 clinical experience in Italy and Spain. Lymphocytopenia, low procalcitonin, and elevated LDH and CRP are characteristic. Hypercoagulability is common, with increased risk of thrombotic and embolic events. Severe cases have elevated D-Dimer and INR, and low fibrinogen and platelet count. Use of prophylactic unfractionated heparin is suggested for all hospitalized COVID-19 patients. 5 phenotypes of COVID-19 infection are described to guide individualized therapy (Table 2): 1. Most common is benign, with fever, headache, mild respiratory symptoms, malaise. Normal CXR and no hypoxemia; 2. 80% of hospitalized patients. Hypoxemia or small CXR opacities. Should be monitored closely due to risk of rapid deterioration. Typically hypovolemia and hyper-inflamed. Good candidates for clinical trials of anti-virals, anti-inflammatories, or anti-fibrotics; 3. 15% of China hospitalizations. Greater hypoxemia and high respiratory rates. High IL6. Also candidates for clinical trials. Prone position may help avoid intubation. Consider intubation if respiratory alkalosis with increasing hyperventilation on high O2; 4. Severe hypoxemia requiring intubation. Pulmonary hypoxic vasoconstriction with normal lung compliance. Probably due to pulmonary microvascular thrombosis. Advise no delay in intubation, especially when BB coalescent lines are present in more than 3 fields. Nitric oxide or prostacyclin may be helpful. PEEP typically should be 8-10 cm H2O with tidal volumes 6-9 mL/kg. Avoid recruitment maneuvers, prone positioning; 5. Less common. Advanced disease with acute lung injury or co-infection causing high procalcitonin. More common when intubation is delayed by non-invasive ventilation treatment. Low lung compliance < 40 mL/cm H2O. Suggest ARDS strategy with high PEEP and prone positioning.
  • Cardiovascular Consequences and Considerations of Coronavirus Infection – Perspectives for the Cardiothoracic Anesthesiologist and Intensivist During the Coronavirus Crisis
    May 1. Augoustides. Journal of Cardiothoracic and Vascular Anesthesia.
    Opinion from C19SAB: Dr. Barry Perlman
    Editorial discussing causes of cardiovascular collapse in patients with severe COVID-19, focusing on Cardiogenic shock, vasoplegic shock, acute coronary ischemia, and right ventricular failure.
  • COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options
    Apr 30. Guzik. Cardiovascular Research.
    Opinion from C19SAB: Dr. Philip Lumb, Dr. Lydia Cassorla
    PL: Detailed, research-oriented discussion on cardiovascular implications of COVID-19 infection. Mechanisms of infection described with experimental justification for potential interventions; recognizes supportive care required for most cases. Discusses (albeit briefly) progression to invasive therapies including ECMO. Basic science oriented with clearly described mechanisms and exhaustive review of available literature with references to match. LC: This comprehensive review of COVID-19 illness with a particular eye toward cardiovascular ramifications may raise more questions than it answers. However, it is well written and thoroughly referenced to be consumed when time permits careful reading. Regarding CV complications: “The most common cardiac complications include arrhythmia (AF, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury (elevated hs-cTnI and CK), fulminant myocarditis, and heart failure.” The authors point out that since cardiac manifestations often occur >15 d after onset of symptoms, they are possibly a result of host-driven phenotypes and/or secondary effects of medications. They mention that inclusion bias may result from specific factors in the area where a pandemic begins and expect data to differ as the disease population changes. Surprisingly, a history of smoking or chronic lung disease is less of a risk for poor outcomes than with SARS-CoV (2003) or MERS. HTN/CV disease are risk factors for advanced disease and death but not for infection and may partly be a proxy for age. When acute myocardial injury occurs, PCI may not always benefit patients as their ischemia may be due to Type 2 MI or myocarditis.
  • Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases
    Apr 29. Casas. British Journal of Dermatology.
    Opinion from C19SAB: Dr. Barry Perlman
    Description of 5 clinical patterns of cutaneous lesions associated with 375 COVID-19 cases in Spain, in order of associated severity of disease: 1. Acral areas of erythema with vesicles or pustules (Pseuo-chilblain). Appears late, more common in younger patients; 2. Other Vesicular eruptions. More common in middle aged patients; 3. Urticarial lesions; 4. Maculopapular eruptions. Most common; 5. Livedo or Necrosis. Consistent with occlusive vascular disease.
  • Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia
    Apr 30. Pei. Journal of the American Society of Nephrology.
    Opinion from C19SAB: Dr. Barry Perlman
    Retrospective study of EMR data from 333 COVID-19 patients hospitalized with pneumonia in China. Patients with CKD or on dialysis were excluded. 75% had hematuria, proteinuria, or acute kidney injury. 82% had suspected intrinsic AKI. Severity of pneumonia was an independent risk factor for AKI. 46% with AKI had complete recovery of kidney function within 3 weeks of illness onset. Renal involvement correlated with a 9X increased rate of mortality. No deaths occurred in patients with pre-renal AKI, or in whom hematuria or proteinuria resolved.
  • COVID-19 Pandemic ARDS Survivors: Pain after the Storm?
    Apr 27. Vittori. Anesthesia & Analgesia.
    Opinion from C19SAB: Dr. W. Heinrich Wurm
    A look beyond the acute phase of COVID-19 by an international panel of specialists in pediatric critical care, pain management and anesthesiology, alerting us of the challenges ahead as survivors will have to deal with the after effects of ARDS, severe illness, isolation, PTSD, and the altered reality of post-COVID-19 society. Specifically, the panel calls for a multidisciplinary commission of experts to issue recommendations on monitoring symptoms, create best practices to prevent sequelae, establish a registry for survivors (both patients and care givers), and embark on multicenter studies to track chronic pain and other physical and psychological sequelae of the disease and the impact it has on health care workers and families.
  • COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids
    Mar 27. Peters. American Journal of Respiratory and Critical Care Medicine.
    Opinion from C19SAB: Dr. Louis McNabb, Dr. Jay Przybylo
    LM: African Americans, males, and diabetics have increased expression of ACE2 and TMPRSS2 which might theoretically explain why these groups are at increased risk for COVID-19. Inhaled corticosteroids decreased expression of ACE2 and TMPRSS2 and theoretically might favorably modify the risk from COVID-19. JP: Thorough study demonstrating asthmatics taking inhaled corticosteroids might be at lower risk of significant COVID-19 infection via activity on the ACE2 receptor.
  • Patients with cancer appear more vulnerable to SARS-COV-2: a multi-center study during the COVID-19 outbreak
    Apr 29. Dai. Cancer Discovery.
    Opinion from C19SAB: Dr. J. Lance Lichtor
    Based on a retrospective analysis of patient information collected from 14 hospitals in Hubei Province, China, patients affected by the SARS-CoV-2 coronavirus for 105 hospitalized patients with cancer and 536 patients without cancer were compared. Patients with hematological cancer (1st), lung cancer (2nd), and cancers in metastatic stages demonstrated higher rates of severe events compared to patients without cancer. In addition, patients who underwent cancer surgery showed higher death rates and higher chances of having critical symptoms. In addition, patients on immunotherapy had the highest death rate and the most severe illness. It is expected that people with systemic disease should do less well. Unfortunately, the authors did not compare the two groups to hospitalized patients with cancer but without COVID-19.

April 30, 2020 Newsletter: 

  • Innovative ICU Physician Care Models: Covid-19 Pandemic at New York-Presbyterian
    Apr 28. Kumaraiah. NEJM Catalyst.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    Stunning description of the strategy, innovation, collaboration and compassion that propelled NYC health care providers to rise to the challenge of creating and staffing 550 additional critical care beds as the COVID-19 pandemic surged. The ingredients for success were flexibility, sharing best practices and deploying teams across a vast enterprise. A must read for all of us.

  • Battle Buddies: Rapid Deployment of a Psychological Resilience Intervention for Healthcare Workers during the COVID-19 Pandemic
    Apr 24. Albott. Anesthesia & Analgesia.
    Opinion from SAB Member: Dr. David M. Clement
    A very detailed overview of a program implemented at the University of Minnesota, designed to preserve “the psychological health of the medical workforce” through “pre-emptive resilience-promoting strategies” during the COVID-19 pandemic. Their program included three levels of support: 1. A “Battle Buddy” peer support strategy based on a US Army program. 2. A mental health consultant assigned to every clinical unit. 3. Confidential one-on-one additional help for HCW with additional needs. Excellent tables and graphic support. No outcome information.
  • Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young
    Apr 28. Mocco. NEJM.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    Report of 5 patients under 50 presenting with large vessel arterial occlusion and stroke symptoms and testing positive for COVID-19. Clinical characteristics are presented and delay in seeking medical care due to fear of contracting the virus is highlighted.
  • Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China
    Apr 10. Mao. JAMA.
    Opinion from SAB Member: Dr. Jay Przybylo
    This article lists some of the neurologic findings that occur in 36+% of patients admitted in China. Includes disrupted mentation and vascular insults and adds musculoskeletal injury caused by the disease.
  • Objective evaluation of anosmia and ageusia in COVID-19 patients: a single-center experience on 72 cases
    Apr 27. Vaira. Head & Neck.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    Among 72 COVID-19 patients, almost 75% had chemosensory dysfunctions during the course of their COVID-19 disease, with taste disorders in 12%, 14% with olfactory dysfunction, and 41% with combined dysfunction. 66% had recovery of chemosensitive dysfunction, with recovery in <5 days in 19 patients. Using an objective test, 80% of these patients still revealed a certain degree of residual hypoosmia or hypogeusia after resolution of their illness.
  • How Could This Happen? Narrowing Down the Contagion of COVID-19 and Preventing Acute Respiratory Distress Syndrome (ARDS)
    Apr 25. Alaerts. Acta Biotheor.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    A biologist’s deeply scientific but also philosophical review of the history, epidemiology and the viral genomics of the Corona virus family. The author provides a helpful template for understanding the present pandemic outbreak and focuses on the role of the renin-angiotensin system in acute lung injury and ARDS and SARS-CoV action during infection. His suggestions for future research list: 1) The correlation and interaction with previous medication, particularly ACE-inhibitors; 2) Creating immunologic profiles, particularly for patients at risk for ARDS; and 3) The influence of viral genomic differences on infectivity, virus reproduction and shedding and biochemical entry routes with host cells. In addition, the range of immunological reactions to the virus by the host deserves further scrutiny and will be of great importance in the vaccine development. A valuable contribution to both clinician scientists and investigators searching to contribute to solve the COVID-19 puzzle.
  • Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study
    Apr 27. Bi. The Lancet Infectious Diseases.
    Opinion from SAB Member: Dr. Barry Perlman
    Retrospective epidemiologic analysis demonstrating the benefits of contact surveillance, adequate availability of testing, and quarantines. There were 391 confirmed cases of COVID-19 Jan 14-Feb 12 and 1286 close contacts confirmed before Feb 9 in Hubei province. Suspected cases and contacts were tested by RT-PCR nasal swabs. Asymptomatic close contacts who tested positive were quarantined at central facilities, while those who tested negative were quarantined at home or a central facility. Infection rate did not differ significantly by age, with on average 7% of close contacts becoming infected, 77% of these contacts having any symptoms, and 3% of infections having severe disease at initial assessment. Median time to recovery was 22 days with older patients and those with severe disease having a longer time to recovery. Contact-based surveillance reduced the duration an infected person could spread disease in the community by 2 days as compared with symptom-based surveillance.
  • Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial
    Apr 24. Borba. JAMA.
    Opinion from SAB Member: Dr. Jay Przybylo
    Data from Brazilian researchers previously discussed now published. Study stopped when high dose chloroquine was found to result in more deaths in a group of patients with concurrent heart disease and associated other diseases. Of great interest is the accompanying editorial that addresses multiple issues associated with COVID-19 and chloroquine use.
  • Caution Needed on the Use of Chloroquine and Hydroxychloroquine for Coronavirus Disease 2019
    Apr 24. Fihn. JAMA.
    Opinion from SAB Member: Dr. Jay Przybylo
    Data from Brazilian researchers previously discussed now published. Study stopped when high dose chloroquine was found to result in more deaths in a group of patients with concurrent heart disease and associated other diseases. Of great interest is the accompanying editorial that addresses multiple issues associated with COVID-19 and chloroquine use.
  • Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia
    Apr 26. Zhang. Clinical Drug Investigation.
    Opinion from SAB Member: Dr. Jagdip Shah
    Key Points: 1) Cytokine storm is an important factor in the rapid deterioration of patients with COVID-19, 2) Tocilizumab, an IL-6 receptor antagonist, is hypothesized to be used in the treatment of cytokine storm caused by COVID-19 and is recommended as an immunotherapy drug for critical COVID-19 patients in China, 3) Tocilizumab should be used cautiously in patients with serious infections, neutropenia, thrombocytopenia, and liver damage, 4) Clinical studies are ongoing, making use outside of clinical studies premature for recommendation. This article includes a nice graphical representation of the cytokine storm pathways and potential mechanism of action for IL-6 receptor antagonists.
  • Use of tocilizumab for COVID-19 infection-induced cytokine release syndrome: A cautionary case report
    Apr 20. Radbel. CHEST.
    Opinion from SAB Member: Dr. Philip Lumb
    The article reviews experimental rationale for use of tocilizumab (IL-6 receptor antagonist) as COVID-19 therapy based on cytokine release syndrome (CRS) and subsequent secondary hemophagocytic lymphohistiocytosis which may add/cause to lung pathologies. Syndromes characterized by production of inflammatory cytokines including IL-6, IL-10 and TNF alpha providing therapeutic rationale for tocilizumab which is commonly used to treat CRS secondary to CAR T-cell therapy. 2 case reports detailing patient deterioration and death following tocilizumab therapy despite a decrease in CRP (IL-6 surrogate) following therapy. While no direct correlation to tocilizumab and mortality is suggested, authors caution against use.
  • Understanding the Renin-Angiotensin-Aldosterone-SARS-CoV-Axis: A Comprehensive Review
    Apr 18. Ingraham. European Respiratory Journal.
    Opinion from SAB Member: Dr. Jay Przybylo
    “Comprehensive Review” is an understatement. A basic science article that ties together the RAS to COVID-19 clinical implications. Addresses the infection and many of the symptoms that result. The article needs time to consume.
  • Troponin and BNP Use in COVID-19
    Mar 18. Januzzi. American College of Cardiology.
    Opinion from SAB Member: Dr. Barry Perlman
    Discussion of troponin and BNP elevations in COVID-19 patients. While increased levels of both biomarkers are common in these patients and are associated with an unfavorable course, the mechanism is not clear as severe respiratory illness can cause both to rise. Cardiomyocytes have abundant distribution of ACE2, which suggests that the troponin rise may be due to direct, nonischemic myocardial damage due to myocarditis. It is recommended that troponin and BNP be measured in COVID-19 patients only if acute MI or heart failure are suspected clinically. ECHO or coronary angiography should only be performed if results are expected to impact outcome.
  • COVID-19-related myocarditis in a 21-year-old female patient
    Apr 13. Kim. Eur Heart J.
    Opinion from SAB Member: Dr. Barry Perlman
    Report of 21-year-old South Korean patient with COVID-19 and elevated Troponin I of 1.26 ng/ml and NT-proBNP of 1929 pg/ml. Chest CT showed multifocal consolidation and bilateral peripheral lower lobe ground-glass opacification. EKG showed NSIVCD and multiple PVCs. ECHO showed severe LV systolic dysfunction. Cardiac CT showed normal coronary arteries but myocardial edema and hypertrophy with lateral LV subendocardial perfusion defect. Cardiac MRI was also consistent with myocardial edema with extensive transmural late gadolinium enhancement. Her treatment or clinical course were not discussed.
  • The role of extracorporeal life support for patients with COVID-19: Preliminary results from a statewide experience
    Apr 25. Sultan. Journal of Cardiac Surgery.
    Opinion from SAB Member: Dr. Jagdip Shah
    Preliminary report of ECMO from Pittsburgh/Pennsylvania describing their experience of the first 10 patients on ECMO. All patients were cannulated in a venovenous configuration. As of 9Apr2020, 2 patients were successfully liberated from ECMO support after 7 and 10 days, 1 patient was on a weaning course, 1 death occurred after 9 days on ECMO due to multiorgan dysfunction, and all other patients were still on ECMO with a median time of support of 11 days (IQR, 4‐14).
  • Regional Planning for Extracorporeal Membrane Oxygenation Allocation During COVID-19
    Apr 20. Prekker. CHEST.
    Opinion from SAB Member: Dr. Lydia Cassorla
    This pre-proof review from the University of Minnesota and the Mayo Clinic provides a well thought out and succinctly described framework for regional ECMO resource planning and operational deployment. Their approach involves regional situation awareness, a high degree of coordination between centers with ECMO capability, clinical decision support tools, involvement of expert clinicians in decision making and triage of resources to those most likely to benefit. It also addresses the ethical and practical aspects of not continuing to offer ECMO during a disaster, a decision best based upon a pre-existing framework. Priority for ECMO, which is described as a “trial of support rather than an indefinite resource assignment”, is based upon probability of survival, expected duration of ECMO, illness severity and patient age. A table outlines their framework for prioritization. Acute respiratory failure due to infection including flu and corona viruses is expected to require a “long” duration of >5 days with anticipated survival >60% if all other organ systems are intact. The authors anticipate that when more data of sufficient quality is available for COVID-19 patients treated with ECMO, it may become clearer how to optimally leverage this limited resource.

April 28, 2020 Newsletter: 

  • Personal protective equipment (PPE) for both anesthesiologists and other airway managers: principles and practice during the COVID-19 pandemic
    Apr 23. Lockhart. Canadian Journal of Anesthesia/Journal canadien d’anesthesie.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    A call to arms from several Canadian anesthesia departments stressing the fact that protecting health care personnel from infection is the most important factor determining the success of a prolonged campaign against COVID-19. Their exhaustive recommendations exceed WHO standards in the area of high risk aerosol generating medical procedures (AGMPs) like endotracheal intubation and include head, neck and wrist protection. A sobering table highlights the odds-ratio of transmission for a number of anesthesia related procedures including AGMPs, but a reminder to avoid self-contamination during the doffing procedure is of equal importance. This guide is a valuable reference for practitioners, students and instructors.

  • Updated diagnosis, treatment and prevention of COVID-19 in children: experts’ consensus statement (condensed version of the second edition)
    Apr 24. Shen. World Journal of Pediatrics.
    Opinion from SAB Member: Dr. Lydia Cassorla
    This review provides guidance in the form of an updated consensus statement regarding COVID-19 in children. In early February 2020, an expert committee with more than 30 Chinese experts from 11 academic medical organizations formulated the first edition of consensus statement on diagnosis, treatment and prevention of coronavirus disease 2019 (COVID-19) in children. According to the 28 February 2020 WHO COVID-19 situation report, pediatric cases in China accounted for 2.4% of 55,924 confirmed cases. Close contact with infected persons with or without symptoms is the main transmission route of SARS-CoV-2 to children, resulting in mostly clustered cases. “There is no direct evidence of vertical mother-to-child transmission, but newborns can be infected through close contact.”
    Risk factors, diagnosis, severity classifications, early warning indicators, differential diagnosis, and treatment are discussed. Risk factors for severe disease include underlying diseases, immunosuppressant Rx and age<3 months. Most manifestations and laboratory findings are similar to adults, with atypical symptoms such as GI manifestations and listlessness noted. The group recommends antipyretics such as ibuprofen and acetaminophen if T>38.5 degrees C, and nebulizer treatments to manage mucus plugs. “Antiviral drugs without clear evidences of safety and efficiency are not recommended to be used in pediatric patients. The revised antiviral drug therapy remains interferon-alpha (IFN-alpha) sprays and aerosol inhalation. We do not recommend using lopinavir/ritonavir, ribavirin or chloroquine phosphate in pediatric patients.” Intubation and controlled ventilation is recommended if non-invasive mechanical ventilation does not result in clinical improvement after 2 hours. Plasma exchange to treat cytokine storm, immunoglobulin and anticoagulation are mentioned. 27 references provided, including the group’s initial statement.
  • Determining risk factors for mortality in liver transplant patients with COVID-19
    Apr 24. Webb. The Lancet Gastroenterology & Hepatology.
    Opinion from SAB Member: Dr. Barry Perlman
    A previous correspondence of liver transplant patients in Italy reported that 3 of their 111 long-term liver transplant survivors (on minimal immunosuppression) died from severe COVID-19, while 3 of 40 more recent liver transplant patients (on full immunosuppression) who had COVID-19 experienced an “uneventful course.” The long-term survivors were older, and had significantly higher incidence of obesity, DM, HTN, kidney disease, cardiovascular disease, and hyperlipidemia. Asymptomatic patients were not tested, so the incidence of SARS-CoV-2 in each group was not known. To address whether co-morbidities contributed to the higher death rate in the long-term transplant patients, the current correspondence reports the outcome of 39 liver transplant recipients with COVID-19 submitted to the COVID-Hep and SECURE Cirrhosis international registries. 9 (23%) died of respiratory failure. Frequency of co-morbidities between fatal and non-fatal cases was not significantly different. A study with larger case numbers will be needed to identify risk factors for severe COVID-19 in liver transplant patients.
  • SARS-Cov-2 (human) and COVID-19: Primer 2020
    Apr 24. Ramakrishna. Hepatology International.
    Opinion from SAB Member: Dr. J. Lance Lichtor 
    This is a pictorial original paper that illustrates basics concerning where the disease came from, what the virus looks like, how it enters the body, disease prognosis, how it replicates in the lung and the liver, and generally how it replicates.
  • Management of COVID-19 Respiratory Distress
    JAMA. Apr 24, 2020.
    John J. Marini; Luciano Gattinoni
    Opinion from SAB Member: Dr. Louis McNabb
    Discusses the differences in the lung mechanics and approaches to treatment in the early vs. the late phase of lung injury in COVID-19. Primary goal is to prevent patient self-induced lung injury from increased transpulmonary pressures from patient’s hypoxic drive.
  • Prevalence and Characteristics of Gastrointestinal Symptoms in Patients with SARS-CoV-2 Infection in the United States: A Multicenter Cohort Study
    Apr 20. Redd. Gastroenterology.
    Opinion from SAB Member: Dr. Jay Przybylo
    A brief but substantial article constructing a link between SARS-CoV-2, angiotensin converting enzyme 2 receptors as the cellular entry portal, and the abundance of the receptor in the GI tract. GI symptoms were associated with taste and smell disorders but not associated with blood, liver or heart involvement.
  • Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial
    June 3, 2019. Ham. Annals of Intensive Care.
    Opinion from SAB Member: Dr. Jay Przybylo
    This extends beyond a case report in an 88y/o who died. Angiotensin II provided stabilization of blood pressure and allowed decrease of other vasopressors.

April 27, 2020 Newsletter: Special Report from the SAB

  • 95 Mask Decontamination Information
    Apr 27. Cassorla L; Przybylo JH; Clement DM; Perlman B. IARS Coronavirus (COVID-19) Resources.
    Opinion from SAB Member: Dr. Lydia Cassorla
    Interest in decontamination and re-use of N95 and similarly rated particle filtering masks (e.g. Filtering Face Piece grades 2,3 [FFP2, FFP3]–Euro standards for N95 type masks) designed for single use has skyrocketed due to extraordinary demand that cannot be met during the current COVID-19 pandemic. For a decontamination technique to be considered worthy it must satisfy at least 4 criteria: 1) Effective in inactivating the targeted pathogen; 2) Preserve desired particle filtration after decontamination; 3) Preserve mask fit; 4) Be safe for reuse. The most promising techniques appear to involve heat (wet or dry), hydrogen peroxide, and ultraviolet light. Other decontamination techniques such as alcohols, high heat, and bleach were shown by multiple investigators to destroy the filtering properties of the masks. Readers should note constraints and limitations for each study. Not all assessed masks fit after processing. Decontamination was assessed using established norms or by the inactivation of pathogens other than SARS-CoV-2, due to tests being performed before the current pandemic or the risks that would have been incurred. How many times the fabric or whole masks were re-sterilized also varies. Some websites, such as those from the Centers for Disease Control and the industry-academic consortium are being continuously updated with new information and potential recommendations as they become available. We have assembled potentially useful resources and references on this topic.

April 25, 2020 Newsletter:

  • All Hands on Deck: How UW Medicine Is Helping Its Staff Weather a Pandemic
    Apr 24. Kim. NEJM Catalyst.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    University of Washington Medicine was one of the first U.S. health systems to treat COVID-19 patients in large numbers. The article describes how they helped their workforce during the crisis by providing free testing for COVID-19 infection, that included liberalizing history and symptom elements so that more employees would be free to ask for the test; counseling on how to quarantine and when to return to work safely; and then open communication through regular community-wide virtual (Zoom) Friday afternoon town hall meetings and facilitation of peer-to-peer support both emotional and practical.

  • What the Great Pandemic Novels Teach Us
    Apr 23. Pamuk. The New York Times.
    Opinion from SAB Member: Dr. J. Lance Lichtor, Dr. David M. Clement
    JLC: Though not really a science paper, this piece shows, based on literary history, how eerily similar the current pandemic is compared to what has happened over the last 400 years in terms of initial response (denial); the carelessness, incompetence and selfishness of those in power that infuriates the masses; how institutions are unsure how to deal with many of the issues; how rumor and the spread of false information has been a universal and unprompted response, including how the disease is foreign, and is brought in with malicious intent; the intensity of suffering; and finally the terror all of us feel which shows how fragile our lives are and how we all share the same humanity. Fear may cause us to withdraw, but it also teaches us to be humble and practice solidarity.
    DC: One may question the historical accuracy of novels. During the current pandemic some countries (New Zealand, Australia and Taiwan for example) have largely avoided baseless rumors and false information. But the human tendency for such dysfunctional approaches to pandemics are wonderfully illustrated in this article.
  • Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility
    Apr 24. Arons. NEJM.
    Opinion from SAB Member: Dr. W. Heinrich Wurm
    Second epidemiological analysis of institutional spread of COVID-19 in a Kings County, WA Skilled Nursing Facility. Triggered by just one symptomatic patient who came in contact with an infected health care worker, this meticulous study highlights the spread of the virus over the next 23 days resulting in 57 (65%) additional infections. Most notably, 89% of asymptomatic residents testing positive one week into the outbreak, were symptomatic 4-7 days later. These findings underscore the role asymptomatic and pre-symptomatic patients play in spreading the virus, as well as the need for low threshold serial institutional testing.
  • Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D-Dimer Levels
    Apr 23. Leonard-Lorant. Radiology.
    Opinion from SAB Member: Dr. Philip Lumb, Dr. Louis McNabb
    PL: Reports 32/106 (30% [95%CI 22-40%]) COVID-19 positive patients were diagnosed positive for acute PE on pulmonary CT angiography between March 1st and March 31st. Noted in this series incidence correlated with increased D-dimer levels; sensitivity 32/32 positive PE with D-dimer >2660 mcg/L (100% [95%CI 88-100]) with a specificity of 49/74 (67% [95%cI 52-79]) on CT angiography. Authors confirm higher incidence of PE in COVID-19 patients with elevated D-dimer, suggested secondary to COVID induced activation of blood coagulation secondary to systemic inflammatory response and recommend increased awareness of and surveillance for PE complications. LM: The results of this article give a theoretical basis for routine use of full dose anticoagulation in COVID-19 patients. The efficacy of such a practice should be explored in controlled studies with prophylactic anticoagulation as a comparator.
  • Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED’s Experience during the COVID-19 Pandemic
    Apr 22. Caputo. Academic Emergency Medicine.
    Opinion from SAB Member: Dr. J. Lance Lichtor
    In patients with non-COVID-19 related ARDS, having a patient in the prone position while awake while also using high-flow nasal cannula (HFNC) can decrease the risk of intubation and improve outcome. After 50 patients with hypoxia (SpO2<90%) were asked to position themselves in the prone position, before treatment but with supplemental oxygen (not with HFNC), SpO2 was 84% and increased to 94% after 5 minutes in the prone position. 13 patients were intubated within 24 hours in the ED and 5 more were intubated more than 24 hours after arrival in the ED. Interesting, and though the study did not have a control group, the initial effect was significant.
  • Patient Self-Proning with High-Flow Nasal Cannula Improves Oxygenation in COVID-19 Pneumonia
    Apr 21. Slessarav. Canadian Journal of Anesthesia.
    Opinion from SAB Member: Dr. Philip Lumb
    Single case report of successful patient management utilizing HFNC on 68 year old patient instructed to self-prone in a negative pressure room. Discussion includes concept of two types of respiratory failure in COVID-19 paralleling the work of Gattinoni and others.

April 24, 2020 Newsletter:

  • Sonographic signs and patterns of COVID-19 pneumonia
    Apr 21. Volpicelli. The Ultrasound Journal.
    Opinion from SAB Member: Dr. Barry Perlman
    This paper describes the use of lung ultrasound (LUS) for diagnosis of COVID-19 pneumonia, and discusses signs that distinguish it from classic ARDS. Sonographic signs with COVID-19 are similar to those seen with ARDS–clusters of B lines and small peripheral consolidations. More particular to early COVID-19 pneumonia is “a shining band-form artifact spreading down from a large portion of a regular pleural line, often appearing and disappearing with an on–off effect in the context of a normal A-lines lung pattern visible on the background.” It is important to also consider clinical presentation, symptom timing, laboratory findings and co-morbid diseases when using LUS for diagnosis or following progression of COVID-19. The use of LUS in the pediatric COVID-19 population is not discussed, but at the time of this review one small preliminary study of 8 pediatric patients showed LUS utility for both diagnosing and following the resolution of disease. 

  • COVID-19 therapeutic options for patients with kidney disease
    Apr 23. Izzedine. Kidney International.
    Opinion from SAB Member: Dr. Jay Przybylo
    An editorial, but one of significance. Contains a table of antiviral drugs that might currently be used. For international use.
  • Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2
    Pediatric Infectious Diseases Society. Apr 22, 2020.
    Kathleen Chiotos; Molly Hayes; David W Kimberlin; Sarah B Jones; et al
    Opinion from SAB Member: Dr. Barry Perlman
    Recommendations from a multidisciplinary panel of infectious disease physicians and pharmacists from 18 North American institutions regarding the use of antiviral treatment for severe COVID-19 infection in children.
    The panel addressed the following questions:
    1. Are antiviral agents indicated in children with COVID-19?
    2. What criteria define the pediatric population in whom antiviral use may be considered?
    3. Does presence of any underlying medical condition or characteristic warrant different criteria for antiviral use based on increased risk of COVID-19-related morbidity or mortality?
    4. What agents are preferred if antiviral therapy is offered to children with COVID-19?
    The panel concluded that most pediatric COVID-19 patients have mild disease and just require supportive care. A small proportion develop severe illness requiring respiratory support. Most of these, and some children with critical illness, also only require supportive care. In the absence of available data, possible risk factors for severe COVID-19 in children were discussed–cardiovascular or pulmonary disease, diabetes, cancer, obesity, young age, immunocompromise. On a case by case basis, if antiviral medication is used, remdesivir is recommended as the preferred agent, with hydroxychloroquine as an alternative if remdesivir is contraindicated or not available. Hydroxychloroquine/azithromycin combination and lopinavir-ritonavir are not recommended. Preferably, antivirals should be used as part of a clinical trial, but as of 4/14/20 no US trials are enrolling children < age 12. Of note, subsequent to acceptance of this manuscript, preliminary results from a hydroxychloroquine retrospective analysis and a remdesivir clinical trial, both involving adult COVID-19 patients, did not show benefit. Additional studies are ongoing.
  • Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
    medRxiv. Apr 23, 2020.
    Joseph Magagnoli; Siddharth Narendran; Felipe Pereira; Tammy Cummings; et al
    Opinion from SAB Member: Dr. Jay Przybylo
    Non-peer reviewed study. Hydroxychloroquine (HC) failed to reduce the need for mechanical ventilation but did result in more deaths when compared to a control group. This correlates with a study from Brazil stopped early because HC resulted in heart rhythm abnormalities.

April 23, 2020 Newsletter:

  • Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized with COVID-19 in the New York City Area
    Apr 22. Richardson. JAMA.
    Opinion from SAB Member: Dr. David M. Clement, Dr. J. Lance Lichtor
    DC: This is a case review of a 12 hospital system in New York City, detailing the characteristics and outcomes of 5,700 patients admitted between March 1 and April 4. Besides the usual co-morbidities (hypertension, obesity and diabetes), only 31% of patients were febrile at triage, 14% needed ICU admission, 12% were intubated and of those intubated, 88% died. This provides an early window into the US experience. The supplementary tables provide a wealth of clinical data. JLL: In this review of 5700 patients admitted between March 1, 2020, and April 4, 2020 to any of 12 Northwell Health acute care hospitals, some clinical characteristics and outcomes were described. The median time to obtain polymerase chain reaction testing results was 15.4 hours, and common morbidities included hypertension, obesity and diabetes. 30% were febrile, almost 20% had a respiratory rate greater than 24 and almost 30% needed supplemental oxygen. The overwhelming majority had a positive COVID-19 test result on the first attempt. About 15% were treated in the ICU; 12% were treated with mechanical ventilation and 3% were treated with kidney replacement. About 20% died. Patients between 18 and 65 were more likely to be treated in the ICU, receive mechanical ventilation, compared to patients older than 65 years. Mortality rates were lower than reported in China.