COVID-19 Newsletter

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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Disclaimer
The material on this website is provided for informational purposes and does not constitute medical advice. New knowledge is added daily and may change over time. Opinions expressed should not be construed as representing IARS policy or recommendations. References and links to third parties do not constitute an endorsement or warranty by IARS.

Current Newsletter: Issue 163, May 22, 2023

Following the recent declarations from the US Department of Health and Human Services and World Health Organization ending the COVID-19 Public Health Emergency, the IARS COVID-19 Scientific Advisory Board (SAB) is pausing its review of the scientific literature about SARS-CoV-2. Although COVID-19 remains a concern for frontline healthcare providers, it has taken a back seat to more pressing concerns. Moreover, the publication of new COVID-19 information relevant to frontline providers has waned significantly. The SAB will reconvene in three months to reassess the future of this endeavor more permanently. In the meantime, today’s issue of the COVID-19 newsletter will be the last one you will see for at least awhile. The articles and summaries compiled on our COVID-19 resource website will continue to be available should you need access to that content.

With the publication of the two article summaries in this issue of the newsletter, the SAB has reviewed more than 3,100 journal articles and published 1,076 article reviews over the past 39 months. It has been an enormous commitment from the SAB, and the IARS owes our dedicated physician volunteers a huge debt of gratitude for their unwavering participation in this initiative. It’s time for us to allow them to return to their well-earned retirement lives unencumbered by the responsibility of reviewing articles, drafting summaries, and meeting regularly to discuss and debate the relevance to frontline care providers.

We hope you have found the COVID-19 newsletter to be an informative, reliable, and valuable resource during this very difficult period for clinicians, patients and healthcare. Although in healthcare there is no such thing as “business as usual,” we look forward to being able to focus on the challenges of clinical care and research discovery without the additional burdens of COVID-19.

As always, we welcome your feedback on this newsletter and initiative. Please email [email protected] with any comments.

  • Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. 3/30/23. Selvakumar J. JAMA Netw Open.
    This study calls into question the usefulness of the WHO definition of post-COVID condition (PCC). The goal of this prospective Norwegian study conducted during the Alpha-dominant wave was to define the prevalence and risk of post-COVID condition (PCC) in young outpatients, a little-studied population. “This cohort study included 382 SARS-CoV-2–positive individuals and a control group of 85 SARS-CoV-2–negative individuals aged 12 to 25 years who were assessed at the early convalescent stage and at 6-month follow-up.” At inclusion and follow-up participants underwent a clinical interview, complete physical exam, measurement of vital signs, spirometry, electrocardiogram (ECG) including heart rate variability, cognitive function tests, blood tests including viral antibodies, cytokines and inflammatory markers, and questionnaires. Results: “When applying the World Health Organization case definition of PCC, prevalence at 6 months was 49%, but was also comparably high (47%) in the control group. PCC was not associated with biological markers specific to viral infection, but with initial symptom severity and psychosocial factors.” The main risk factor for PCC was symptom severity at baseline (RR, 1.41), and correlated with personality traits. Female sex, low physical activity, recent negative life events and loneliness were also factors.
    SAB Comment: Our group found this study of interest, despite weaknesses that include a relatively small control group, and a question of whether self-selection may have played a role, given the number of hours required for the two evaluations. Additionally, although neuropsychiatric factors may be implied, we note that thorough neuropsychiatric testing was not part of the study. On the other hand the design was prospective and testing relatively complete compared with many if not most studies of post-COVID conditions. We hope it comes to the attention of the WHO.
  • Expert consensus statement on venovenous extracorporeal membrane oxygenation ECMO for COVID-19 severe ARDS: an international Delphi study. 5/2/23. Rabie AA. Ann Intensive Care.
    The modified Delphi technique was used by 22 international extracorporeal membrane oxygenation (ECMO) experts worldwide to reach consensus on 14 general statements based on the most recent findings of the evolving published research. These 14 statements were in four domains (clinical, operational, and logistic ECMO management and ethics) and were formulated to guide next-generation ECMO providers during future pandemic situations. Two example statements are, 1) “The duration of invasive mechanical ventilation (IMV) before considering ECMO should not be used as a primary determinant for ECMO candidacy,” and 2) “There is no validated evidence-based scoring system to predict the outcome for COVID-19 patients receiving ECMO. Therefore, available scoring systems previously used for non-COVID-19 patients should not be used for COVID-19 patients as a prognostic tool.”
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

View the full issue.

Disclaimer
The material on this website is provided for informational purposes and does not constitute medical advice. New knowledge is added daily and may change over time. Opinions expressed should not be construed as representing IARS policy or recommendations. References and links to third parties do not constitute an endorsement or warranty by IARS.

Previous COVID-19 Newsletters

Newsletter Issue 162, April 25, 2023:

  • Claim CME ButtonEffectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system. 3/18/23. Lewnard JA. Lancet Infect Dis.
    This is an observational outpatient study using electronic record analysis of the Southern California Kaiser Permanente HCS to further determine the effectiveness of nirmatrelvir–ritonavir (Paxlovid) in preventing hospital admissions and death within 30 days of a positive SARS-CoV-2 PCR test. Between April and October 2022, cases were matched by vaccination history, comorbidities, health care seeking trends and BMI in addition to age, sex and clinical status and patients who were tested within 5 days of symptom onset were analyzed separately. A total of 7,274 Paxlovid recipients were matched with 125,152 non-recipients and demonstrated an overall effectiveness in preventing hospital admission of 54% which increased to 80% among a smaller cohort treated within 5 days of symptom onset and to 90% when Paxlovid was dispensed on the day of a positive PCR test result. The authors discuss the etiology of 7 recently published observational studies conducted in the USA, Israel and Hong Kong, where Paxlovid effectiveness ranged from 21-79% in outpatients, and conclude that in a setting with high levels of vaccine uptake, Paxlovid is highly effective, particularly when given early.
  • Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study. 2/13/23. Aggarwal NR. Lancet Infect Dis.
    A retrospective cohort study examined the real-world effectiveness of nirmatrelvir–ritonavir among high-risk outpatients with COVID-19 during the Omicron BA.2 and BA.2.12.1 (from March 26 to June 18, 2022) and BA.4 and BA.5 (from June 19 to Aug 25, 2022) waves in Colorado, USA. After propensity-score matching, 7168 patients treated with nirmatrelvir–ritonavir and 9,361 untreated controls were included for analysis. Outpatient use of nirmatrelvir–ritonavir reduced the odds of 28-day all-cause hospitalization from 1.4 to 0.9%, a clinical benefit that was consistently observed during both Omicron BA.2 and BA.2.12.1 and BA.4 and BA.5 predominant periods. All-cause mortality following treatment with nirmatrelvir–ritonavir was 5 times lower in the treatment group (2 deaths vs.15 in the non-treatment group or 0.03% vs. 0.16% in the non-treatment cohort). Fewer emergency department visits following treatment suggests that clinically significant rebound requiring urgent medical care was not observed more frequently among users of oral antivirals.
    An accompanying editorial from Hong Kong stresses the ongoing need for real-world studies for two major reasons: 1. Recombinant variants of Omicron – especially XBB.1.5 and BQ.1.1 – continue to emerge posing an imminent threat to public health, due their even greater immune evasion capabilities than BA.5. 2. Such studies remain relevant when assessing cost-effectiveness for different therapeutic strategies and their prioritization among various patient populations, as the number needed to treat to prevent one case of severe COVID-19 might also increase as population immunity grows.
    SAB Comment: Using the author’s results, the number of patients necessary to treat to prevent one hospitalization is 200, which is consistent with an absolute risk reduction of 0.5%.
  • Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition. 3/23/23. Xie Y. JAMA Intern Med.
    A Veterans Administration cohort study, consisting of 87% men, to examine whether nirmatrelvir in the acute phase of SARS-CoV-2 infection lowers the risk of post-COVID-19 condition (PCC) or long COVID, defined as persistence of symptoms beyond 90 days past the acute episode. The authors identified 35,717 veterans who had been treated in 2022 with nirmatrelvir within 5 days of a positive COVID-19 test and 246,076 controls who had not received any antiviral or antibody treatment and who had at least one risk factor for progression to severe COVID-19. Using inverse probability weighting, the authors determined that nirmatrelvir reduced the relative risk of developing 10 of 13 prespecified symptoms of PCC by 26% (relative risk, 0.74; 95% CI, 0.72-0.77) at 180 days. Nirmatrelvir was also associated with decreased risk of death (47%) and hospitalization (24%). These results were independent of vaccination status or prior infection or re-infection.
    SAB Comment: This study strongly supports nirmatrelvir administration during acute COVID-19 for at risk patients to mitigate PCC.
  • Maternal third dose of BNT162b2 mRNA vaccine and risk of infant COVID-19 hospitalization. 3/24/23. Lipschuetz M. Nat Med.
    This is a retrospective analysis of all live-born infants delivered in Israel between 24 August 2021 and 15 March 2022 to estimate the effectiveness of the third maternal Pfizer COVID-19 booster dose versus the second dose against infant COVID-19-related hospitalizations. Among 48,868 live-born infants included in the analysis, rates of COVID-19 hospitalization during the first 4 months of life were 0.7%, 0.6% and 0.4% in the unvaccinated, two-dose and three-dose groups, respectively, supporting clinical and public health guidance for maternal booster vaccination to prevent infant COVID-19 hospitalization.
  • Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection. 2/21/23. Deo R. Ann Intern Med.
    This retrospective analysis of 563 placebo recipients (enrolled in ACTIV-2/A5401 randomized control trials of treatments for mild/moderate COVID-19) sought to characterize symptom and viral rebound in an untreated population. Patients, enrolled between November 2020 and July 2021 (pre-Omicron), were mostly unvaccinated. Patients reported daily scores for 13 symptoms over 28 days, and nasal swab quantitative viral RNA measurements were taken for days 1-14, 21, and 28. Symptom rebound occurred in 26%, was brief, and was associated with female sex, high risk factors for severe COVID, short time since symptom onset, and higher symptom score at study onset. Viral rebound occurred in 31%, was also brief, was not associated with high risk for severe COVID, but was associated with a high viral load at study onset. Both symptom and viral rebound occurred in only 3% of subjects.
  • COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation. 1/23/23. Patton MJ. Crit Care.
    A multicenter (UAB and Ochsner-LSU Shreveport systems), demographically diverse, cohort study of adult community-acquired bacteremic co-infection to date is lacking. This retrospective study evaluated bacteremic co-infection using 48-h post-admission blood cultures. Groupings: (1) confirmed (positive blood cultures), (2) suspected (negative culture with 2 or more doses antimicrobials administered), and (3) no evidence (no blood cultures obtained). The primary outcomes were in-hospital mortality, ICU admission, and mechanical ventilation. Cohorts:13,781 COVID-19 inpatients (2020 to 2022). Results: confirmed (2.5%), suspected (46%), no evidence (51.5%). The comparison cohort: 99,170 pre-COVID inpatients (2010-2019). An easily available elevated neutrophil-to-lymphocyte ratio greater than or equal to 15 (+ or – steroids) within 48-h of admission was a key marker of co-infection. Co-infection posed the greatest risk for in-hospital mortality, ICU admission and mechanical ventilation. Co-infection mortality (24%) with COVID far exceeds pre-pandemic inpatients (5.9%) and is consistent across alpha, delta, and omicron.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

View the full issue.

Newsletter Issue 161, March 27, 2023:

  • Risk of venous thromboembolism in non-respiratory and respiratory presentations of COVID-19 in critically ill patients. 2/14/23. Roubinian NH. Chest.
    This research letter reports a retrospective cohort study of adult Kaiser Permanente patients who were PCR tested for SARS-CoV-2 before admission to 21 ICUs between December 1, 2020 and April 30, 2022. Authors assessed the incidence of venous thromboembolism (VTE) within 90 days of hospital admission, comparing those who presented with respiratory versus nonrespiratory diagnoses. Of these 11,143 cases, 5,440 (49%) were admitted with respiratory diagnoses. 2,983 (27%) had COVID-19, of whom 2,428 (81%) were admitted with respiratory diagnoses. ICU patients admitted with respiratory diagnoses has a higher 90-day incidence of VTE compared with those with nonrespiratory diagnoses (13.4% vs. 7.4%). SARS-CoV-2 infection was not associated with an increased risk of VTE among patients with nonrespiratory diagnoses, regardless of vaccination status. In contrast, the relative risk (RR) of VTE was increased in those admitted to ICU with respiratory diagnoses, including unvaccinated COVID-19 patients (RR 2.9), vaccinated COVID-19 patients (RR 2.0) and those without COVID-19 (RR 1.3). The increased risk of VTE in unvaccinated and vaccinated COVID-19 patients persisted during the period of Omicron variant predominance.
    SAB Comment: This dataset helps further characterize the risk of VTE for patients with COVID-19 based upon symptoms at presentation. This study may act as a basis for further studies to better target prophylaxis for VTE in critically ill COVID-19 patients.
  • Early Treatment with Pegylated Interferon Lambda for Covid-19. 2/13/23. Reis G. N Engl J Med.
    In this randomized, controlled, adaptive platform, Phase III, outcome based trial, vaccinated adult outpatients who presented with COVID-19 acute respiratory symptoms within 7 days of onset were treated either with pegylated interferon lambda (n=931, single subcutaneous injection, 180 μg) or placebo (n=1,018). The primary outcome of a COVID-19-related emergency department visit or hospitalization within 28 days of randomization occurred in 2.7% following the drug vs. 5.6% following placebo (OR of 0.49). These authors concluded that early treatment with Interferon conveyed a > 50% reduction risk of ER visit or hospitalization, irrespective of vaccine status (0, 1, 2, or 3 shots) and was also effective against multiple variants (Alpha, Delta and Omicron). The authors noted an additional benefit in lowering the viral load. The benefit differed amongst SARS-CoV-2 variants with Omicron > Delta > Alpha.
  • Claim CME ButtonDeterminants of Professional Fulfillment and Burnout Among Intensivists: A National Survey by the Society of Critical Care Anesthesiologists in 2022. 2/15/23. Siddiqui S. Anesth Analg.
    This is a cross-sectional survey of Society of Critical Care Anesthesiologists members in ICU practices in the US using the Stanford Personal Fulfillment Index. Response rate was 29%, 175 of 606. Several factors were associated with higher levels of personal fulfillment (likely to be an inverse of “burnout”) including age >45 years, ≤15 weeks per year of full time ICU coverage, and nighttime on-call supervision from home rather than in hospital. Adequate staffing allowed the coverage from home and was deemed better for clinician well-being. A favorable public perception of intensivists may have contributed positively and eventually provided additional emotional reward. The survey was comprehensive and assessed personal fulfillment, work exhaustion and interpersonal disengagement. This study sheds light on important underlying causes of healthcare worker loss and reinforces the need for further study.
  • Infection-induced immunity is associated with protection against SARS-CoV-2 infection and decreased infectivity. 2/12/23. Frutos AM. Clin Infect Dis.
    Investigators present data from an ongoing household cohort study between March 2020-November 2022 in Nicaragua to determine transmission after one household member tests positive for SARS-CoV-2. There were 2,399 active participants in the cohort with 87 new/re-enrollees, 394 withdrawn, and 27 deaths. Within this subsidy of SARS-CoV-2 transmission, a total of 228 households (51.9% of all cohort houses) were activated (some multiple times) with 349 total activations. Of activated household contacts, 81.5% consented to intensive monitoring. Transmission occurred in 70% of households, with 41% of household contacts becoming infected. The secondary attack risk ranged from 8% to 14% depending on the time period. Symptomatic infected individuals were more infectious (RR 21.2) and participants with a prior infection were half as likely to be infected compared to naïve individuals (RR 0.52). While young children were less infectious, neither prior infection nor asymptomatic presentation reduced their infectivity (as was seen for adults). Authors comment that as SARS-CoV-2 becomes endemic, children may become more important in transmission dynamics.
  • Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis. 2/16/23. Stein M. Lancet.
    This meta-analysis of 65 studies (up to September 31, 2022) provides a comprehensive review of the effectiveness of past infection on outcomes (infection, symptomatic disease and severe disease), variant, and time since previous infection. The analysis shows high levels of protection against reinfection from all pre-Omicron variants (82%), but significantly reduced protection against reinfection from Omicron BA.1 (42%). Levels of protection against severe disease remained high for all variants (pooled protection of 78%), including Omicron BA.1. When analyzed as a function of time since previous infection, pre-Omicron infections afforded initially high protection (85%) which waned to 79% at 40 weeks. By contrast, protection from the Omicron BA.1 variant declined more rapidly, decreasing to 36% at 40 weeks. Although protection from reinfection by all variants wanes over time, the level of protection afforded by previous infection is at least as high, if not higher, than that provided by two-dose vaccination using mRNA vaccines.
    SAB Comment: The number of studies on vaccine efficacy far exceeds the number of studies on the protection against COVID-19 by previous infection, yet protection afforded by previous infection is likely to be at least as important as vaccination status, and could be factored into public health approaches to COVID-19. This study provides the information needed to address protection from previous infections, at least through Omicron BA.1.
  • Early Estimates of Bivalent mRNA Booster Dose Vaccine Effectiveness in Preventing Symptomatic SARS-CoV-2 Infection Attributable to Omicron BA.5- and XBB/XBB.1.5-Related Sublineages Among Immunocompetent Adults – Increasing Community Access to Testing Program, United States, December 2022-January 2023. 2/2/23. Link-Gelles R. MMWR Morb Mortal Wkly Rep.
    This is a CDC report on the bivalent mRNA vaccine effectiveness (VE) against symptomatic infection by recent SARS-CoV-2 variants BA.5 and XBB/XBB1.5. Using data from the Increasing Community Access to Testing Program during December 1, 2022 to January 13, 2023, the authors used a test negative control format to evaluate 29,175 immunocompetent adult patients with COVID-19-like symptoms who had received two or more monovalent mRNA vaccine/booster doses. In persons 18-49 years of age who had additionally received a bivalent mRNA booster 2 to 3 months earlier compared with no bivalent booster, VE was 52% against symptomatic BA.5 infection and 48% against symptomatic XBB/XBB1.5 infection. Other age groups also had modest but real VE with a bivalent booster.
    SAB Comment: As featured in two articles in Newsletter Issue 159 (“Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years – IVY Network, 18 States, September 8-November 30, 2022” and “Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022“) bivalent boosters reduced the incidence of hospitalizations and urgent care or emergency department evaluations. This is the first evaluation of VE of the bivalent booster against symptomatic infections with the most recent BA.5 and XBB/XBB1.5 lineages and suggests that all persons should stay up to date with recommended COVID-19 vaccines.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

Read the full issue.

Newsletter Issue 160, February 27, 2023:

  • Reports of Guillain-Barré Syndrome After COVID-19 Vaccination in the United States. 2/1/23. Abara WE. JAMA Netw Open.
    Relying on the Vaccine Adverse Event Reporting System (VAERS), this CDC and FDA-authored retrospective cohort study analyzes the occurrence of Guillain-Barré Syndrome (GBS) within 21-42 days following 3 different COVID-19 vaccines administered between December 2020 and January 2022. Among 488 million vaccinations, there were 295 verified cases of GBS and a 9-12 times higher incidence following vaccination with Ad26.COV2.S (Janssen) compared to BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). While contributing cause and associate risk factors remain unclear, the authors identify a number of potential mechanisms related to the immune response elicited by the vaccine on a molecular level. The Advisory Committee on Immunization Practices recommends the mRNA COVID-19 vaccine rather than Ad26.COV2.S when both are available but bases this recommendation primarily on the increased risk of developing thrombosis with thrombocytopenia syndrome in addition to the risk of developing GBS.
  • Claim CME ButtonLong COVID: major findings, mechanisms and recommendations. 1/13/23. Davis HE. Nat Rev Microbiol.
    This literature review summarizes the current knowledge about most aspects of long COVID. Starting with epidemiology (an estimated incidence of 10-30% of nonhospitalized cases, 50-70% of hospitalized cases and 10-12% of vaccinated cases), the authors move through the known and postulated etiologies of long COVID, including immunologic dysregulation, reactivation of SARS-CoV-2 and other associated viruses, clotting and endothelial abnormalities, dysfunctional neurological signaling and other etiologies. Long COVID of the commonly affected organ systems is reviewed, as well as the diagnostic tools and treatments currently in use. Some of the “miscues” about long COVID are briefly mentioned. The impact of vaccination and re-infection on established long-COVID patients is discussed. Particular attention is paid to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia, especially postural orthostatic tachycardia syndrome (POTS). The authors clearly state that much more research is needed to understand and treat long COVID.
    SAB Comment: This exhaustive review packs a huge amount of information into just a few pages, with useful tables and graphs. Some of the authors are members of the Patient-Led Research Collaborative, a team of long-COVID patients with a wide range of research, policy, design and medical backgrounds.
  • Adherence to Healthy Lifestyle Prior to Infection and Risk of Post-COVID-19 Condition. 2/6/23. Wang S. JAMA Intern Med.
    The role of a healthy lifestyle before infection in reducing post-COVID condition (PCC) was the focus of this substudy within the Nurses’ Health Study II, a prospective cohort which enrolled participants in 1989. The substudy enrolled 32,249 nurses for whom lifestyle data from 2017 was available. They completed monthly and quarterly surveys beginning in April 2020, reporting testing positive for SARS-CoV-2 (1,981), and the presence of symptoms for at least 4 weeks (871 or 44%). The 2017 lifestyle parameters (BMI, smoking, alcohol consumption, diet, physical activity and sleep) were individually and collectively compared between those with and without PCC. As the number of healthy lifestyle factors increased, the likelihood of PCC decreased; those with 5-6 healthy parameters had a 49% lower risk of PCC. The most significant factors were BMI (risk ratio [RR] 0.85) and sleep (RR 0.83).
    SAB Comment: This report contains a great deal of data, and includes 10 sensitivity analyses, as well as population attributable risk (PAR) information. The authors posit that the anti-inflammatory effect of a healthy lifestyle mitigates PCC. It must be kept in mind that the population was 97% white and limited to women aged 55-75, who were willing to share their health information for more than 30 years.
  • VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19. 12/28/22. Cao Z. N Engl J Med.
    VV116 is an orally effective antiviral remdesivir analogue developed in China and undergoing multicenter, observer blinded, randomized controlled trial on symptomatic patients at high risk for progression to severe COVID-19. To compare duration of symptoms and time to clinical recovery, SARS-CoV-2 infected patients with a median age of 53 and mostly vaccinated, were recruited from 7 Shanghai hospitals during the month of April 2022 and assigned to receive either the study drug (n=384) or nirmatrelvir-rotinavir (Paxlovid) (n=387) orally twice a day. The result showed that among symptomatic adults hospitalized with mild to-moderate COVID-19 with risk factors including age older than 50 years, cardiac disease and obesity, a 5-day course of oral treatment with VV116 was noninferior to nirmatrelvir–ritonavir in shortening the time to sustained clinical recovery (HR 1.17, [CI 1.01 to 1.35]). Among the limitations listed in this industry-funded study is the inability to draw conclusions about the efficacy of VV116 for the prevention of progression to severe or critical COVID-19 or death, because no events occurred in either group.
    SAB Comment: This is one of several recent studies exploring oral antiviral alternatives to Paxlovid and remdesivir. Worldwide shortages, high costs and the need for parenteral administration of remdesivir are of concern for currently approved antivirals, as well as a high percentage of contraindications due to impaired renal and hepatic function and drug-drug interactions among patients who would otherwise be prime candidates for these treatments based on their risk category.
  • Physical interventions to interrupt or reduce the spread of respiratory viruses. 1/30/23. Jefferson T. Cochrane Reviews.
    This Cochrane Review metanalysis has generated significant press controversy despite the clearly stated concerns of its authors that more and better studies are essential to gaining an adequate understanding of the effects of these interventions. This review is an update of one last published in 2020 and only 2 of the 9 studies used to develop the updated first and primary conclusion concerned COVID-19 infection. That conclusion was that wearing masks in the community probably makes little or no difference to the outcome of influenza‐like illness or COVID‐19 like illness compared to not wearing masks (risk ratio (RR) 0.95, 9 trials, 276,917 participants); or in the outcome of laboratory‐confirmed influenza/SARS‐CoV‐2 (RR 1.01, 6 trials, 13,919 participants). However, it’s worth noting that both COVID-19 studies used were designed to test a mask encouraging strategy, not mask wearing, and both showed a small decrease in infection rate in the intervention group which was statistically significant in the larger of the two studies (but not the smaller).
    Two additional conclusions are presented: 1) The use of a N95/P2 respirators compared to medical/surgical masks probably makes little or no difference for the objective outcome of laboratory‐confirmed influenza infection (RR 1.10, 5 trials, 8407 participants), and 2) Pooled data showed that hand hygiene may be beneficial with an 11% relative reduction of respiratory illness (RR 0.89, low‐certainty evidence with high heterogeneity).
    The authors state that, “The high risk of bias in the trials, variation in outcome measurement, and relatively low adherence with the interventions during the studies hampers drawing firm conclusions.”
    SAB Comment: We’re impressed, as are the authors, that there are so few randomized controlled trials published to date of the effectiveness of mask wearing during the COVID-19 epidemic but wonder, given the lethality of the virus, whether researchers have been hesitant to define a control group.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

View the full issue.

Newsletter Issue 159, January 23, 2023:

  • SAB Comment for the following three studies summarized below: The two well-done clinical studies provide much anticipated bivalent vaccine effectiveness data as Omicron variants continue to evolve and many infections are uncounted. Despite lab data that suggest viral neutralization after the bivalent vaccine is poor (lab study below titled “Alarming Antibody Evasion…), these clinical studies document real but moderate protection against visits to urgent care or emergency departments and hospitalization. This protection seems to be most prominent in older adults and the time since the previous monovalent vaccine dose was of greater significance. These studies do not address the durability of bivalent booster effectiveness. This information suggests that all eligible persons should stay up to date with recommended COVID-19 vaccinations despite indications that we may be headed for a period of increased breakthrough infections.
    • Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022. 12/29/22. Tenforde MW. MMWR Morb Mortal Wkly Rep.
      This is a bivalent vaccine effectiveness (VE) study from the VISION Network (nine US states) during September 13 to November 18, 2022, specifically looking at effectiveness against Emergency Department (ED) and Urgent Care (UC) encounters as well as hospitalizations. Among 78,303 ED/UC encounters in immunocompetent adults (over 18 years old), VE of the bivalent vaccine was 56% compared to no vaccination, 31% compared with receipt of last monovalent dose 2-4 months earlier, and 50% compared with receipt of last monovalent dose 11 months or more earlier. Among 15,527 hospitalizations of immunocompetent adults, the booster VE was similar to that in ED/UC patients.
    • Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years – IVY Network, 18 States, September 8-November 30, 2022. 12/29/22. Surie D. MMWR Morb Mortal Wkly Rep.
      These IVY Network investigators from 18 US states sought to define vaccine effectiveness of the bivalent COVID-19 vaccine against hospitalization in elderly patients. Between September 8 and November 30, 2022, 798 patients hospitalized with a COVID-like illness were enrolled in this test-negative analysis. Among immunocompetent adults aged ≥65 years, a bivalent booster dose received after ≥2 monovalent mRNA doses provided good protection (73%) against COVID-19-associated hospitalization during this period of Omicron BA.5 or BQ.1/BQ.1.1 predominance. Compared to unvaccinated patients, the bivalent vaccine effectiveness was 84%. Substantial additional protection from a bivalent booster dose was observed when compared with remote monovalent-only mRNA vaccination.
    • Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. 12/29/22. Wang Q. Cell.
      This is a detailed in-vitro study of antibody resistance and viral receptor binding affinity of SARS-CoV-2 Omicron BQ.1, BQ.1.1, XBB, and XBB.1 subvariants, that are now prevalent and rapidly expanding globally. Sera from 5 cohorts (n=14-21 each) with the following histories were tested: 1) 3 doses of an original COVID-19 mRNA vaccine, 2) 4 doses of an original COVID-19 mRNA vaccine, 3) a fourth vaccination with a bivalent COVID-19 mRNA vaccine, 4) breakthrough BA.2 infection post-vaccination, and 5) breakthrough BA.4 or BA.5 infection. Results showed BQ.1.1 is approximately 6-fold more resistant to serum neutralization than its predecessor BA.5. XBB.1 is ∼63-fold more resistant to serum neutralization than its predecessor, or ∼49-fold more resistant than BA.4/5. SARS-CoV-2 breakthrough infection induced somewhat better antibody responses than vaccination. In addition, the clinically authorized monoclonal antibodies bebtelovimab and Evusheld could not neutralize BQ or XBB variants, leaving no effective preventative treatments for immunocompromised patients. The publication includes illustrative graphs, tables, and structural analysis. Analysis of cellular immunity and clinical studies are called for; however previous in-vitro studies have been predictive of in vivo outcomes.
  • SAB Comment for the following two articles summarized below: The two studies below are among those that assess the real-world effect of Paxlovid during the Omicron era. They show similar reductions in hospitalization rate which are not nearly as large as that seen in the Paxlovid phase 2-3 trial done with unvaccinated patients during the Delta variant surge in 2021 (87.8% reduction of combined death or hospitalization). In these recent studies the rates of hospitalization or mortality are significantly reduced in all patients (Paxlovid treated or untreated) compared to the original phase 2-3 study likely related to a combination of vaccinations, prior infections and decreasing virulence of evolving viral strains. It’s interesting that as a consequence, both of the studies below show that the number of patients needed to treat to achieve a single improved outcome (NNT) in hospitalization or combined hospitalization/mortality exceeds 200 patients.
    • Claim CME ButtonPaxlovid Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022. 12/2/22. Shah M. MMWR Morb Mortal Wkly Rep.
      This study reviewed electronic medical records to show that of 699,848 adults aged ≥18 years who were eligible for Paxlovid during April-August 2022, 28.4% received a Paxlovid prescription within 5 days of COVID-19 diagnosis (of whom 68.8% previously had received two or more doses of mRNA vaccine). Being prescribed Paxlovid was associated with a lower hospitalization rate among the overall study population (adjusted hazard ratio [aHR] = 0.49). The reduction was similar among those who had received ≥3 mRNA COVID-19 vaccines (aHR = 0.50) and across all age groups. The proportion of persons with in-hospital death was also lower among persons who received Paxlovid (0.01%) than among those who did not (0.04%). The authors state that Paxlovid should be prescribed to eligible adults to reduce the risk of COVID-19-associated hospitalization.
      SAB Comment: This study shows a significant real-world effect of Paxlovid during the Omicron era but with a reduction in hospitalization rate that is not nearly as large as that seen in the Paxlovid phase 2-3 trial done with unvaccinated patients during the Delta variant surge in 2021 (87.8% reduction of combined death or hospitalization).
    • Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System : A Population-Based Cohort Study. 12/12/22. Dryden-Peterson S. Ann Intern Med.
      This study was designed to assess the real-world efficacy of nirmatrelvir plus ritonavir (Paxlovid) for early outpatient COVID-19 during the first 6 months of 2022 in an era of prevalent SARS-CoV-2 immunity and immune-evasive Omicron subvariants. It attempts to emulate a clinical trial using observational data from 117,000 patients diagnosed with COVID-19 to determine the drug combination’s efficacy in preventing hospitalization within 2 weeks of diagnosis and death of any causes within 28 days. Of 44,000 outpatients receiving Paxlovid, 69 (0.55%) were hospitalized compared to 310 (.97%) among the 32,000 patients who were not, resulting in an adjusted risk ratio for Paxlovid of 0.56 (CI, 0.42-0.75), confirming the drug combination’s effectiveness among vaccinated and unvaccinated patients aged 50 and older.
      An accompanying editorial compliments the author’s attempt to minimize bias in a retrospective data evaluation, lends perspective to the value of recent trials and reviews current literature.
      SAB Comment: This is a high-profile retrospective real-world study corroborating Paxlovid’s effectiveness.
  • Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease. 11/15/22. Hoertel N. JAMA Netw Open.
    Nirmatrelvir-ritonavir (Paxlovid) reduces COVID-related morbidity and mortality. Hospitalized patients may have contraindications to its use. Ritonavir may elevate drug concentrations if dependent on hepatic cytochrome P-450-3A (CYP3A) metabolism. Coadministration with CYP3A inducers can significantly reduce nirmatrelvir concentrations with loss of drug response. Severe kidney and liver disease patients were excluded from clinical trials. In 36 Parisian University Hospitals, the authors studied records from January 24, 2020 to November 30, 2021, a period before patients received nirmatrelvir-ritonavir. Of 62,500 PCR-proven patients; 9,136 (14.6%) had a medical contraindication (men 18%, women 11%; older (>65)- 27%; co-morbidities-37%). Among 4,861 patients who died, 50.7% had a contraindication. The authors conclude that published nirmatrelvir-ritonavir hospital studies may overestimate treatment efficacy by avoiding patients with contraindications. A large unmet need remains for effective COVID treatments.
  • Diaphragm Muscle Weakness Might Explain Exertional Dyspnea Fifteen Months After Hospitalization for COVID-19. 1/3/23. Regmi B. Am J Respir Crit Care Med.
    The etiology of long COVID/Post-COVID Condition (PCC) remains an enigma. Recent studies consider multiple causes which remain under investigation. Additional questions remain whether invasive ventilation increases the incidence or severity of symptoms. Many COVID-19 survivors report dyspnea that cannot be explained by routine clinical diagnostic measures, including pulmonary function tests and cardiac evaluation. This study investigated 50 patients previously hospitalized with COVID-19 (14 female, age 58±12 years), half were treated with mechanical ventilation and the remaining outpatients using pulmonary function testing, 6-minute walk test, echocardiography, twitch transdiaphragmatic pressure following cervical magnetic stimulation of the phrenic nerve roots, and diaphragm ultrasound. Diaphragm function data were compared with values from a healthy control group. Testing evaluated both voluntary and involuntary (magnetic phrenic nerve stimulation) measurements of inspiratory and expiratory power at FRC. Dyspnea was equally experienced between survivors who required invasive ventilation (including ECMO) and those managed without. Diaphragmatic inspiratory strength reflected in voluntary and magnetically induced twitch pressures generated at functional residual capacity (FRC) and diaphragmatic thickening noted on ultrasound were reduced. Expiratory values similarly measured showed minimal disruption of expiration. The study demonstrated diaphragm muscle weakness underlying otherwise unexplained exertional dyspnea in patients previously hospitalized for COVID-19 and suggested specific interventions, such as inspiratory muscle training, could be an effective approach to mitigate COVID-19 exertional dyspnea.
  • Two masks can be worse than one: N95 respirator failure caused by an overlying face mask. 12/20/22. Mueller JT. Infection Control & Hospital Epidemiology.
    Adding an external procedure mask in front of a filtering face-piece respirator (FFR), such as an N95, has been suggested at times, largely to protect the FFR from soiling and to extend its use. One hundred healthcare workers from Mayo Clinic in Arizona, who successfully passed quantitative fit testing of an N95 respirator (3M 1870 Aura FFR), were immediately re-evaluated to assess the effect of adding a procedure mask (Halyard 47117) in front of their N95. Thirteen out of 100 participants failed the quantitative fit test following the addition of the procedure mask. Authors review potential causes as well as limitations of the study with regard to testing a single combination of face protection devices. Guidance on the use of N95 FFRs should consider the potential risk of increased fit failure when they are worn with an overlying face mask. Further research including other FFR + face-mask combinations is needed.
  • Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo. 12/7/22. Torchia JA. Science Advances.
    These investigators report the development of recombinant soluble forms of the cell surface ACE-2 protein to act as a therapeutic decoy receptor. The decoys show no loss of potency with recent variants. The decoy receptors engage the viral receptor-binding domain (RBD) and are thought to outcompete cell-surface ACE2 for viral binding. The authors state the decoy is in theory, identical to the cell-surface receptor. Therefore, viral mutations which would weaken binding to the decoy would weaken binding to the cell surface receptor and reduce infectivity. The optimized ACE2 decoy triggers irreversible structural changes in the critical viral RBD S-protein. These studies show how ACE2 decoys function and support therapeutic development for emerging ACE-2-dependent coronaviruses.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

View the full issue.

Best of 2022 Newsletter

As we begin this new year, we would like to reflect on all that has been accomplished with the IARS COVID-19 Resource Initiative as well as highlight some of the trending articles and CME activities that were featured in 2022. Now more than two years since this initiative was launched, the IARS COVID-19 Scientific Advisory Board remains dedicated to this important effort and continues to screen the peer-reviewed literature to identify and disseminate the most pertinent information to help frontline professionals navigate this ever-evolving pandemic via this newsletter and a resource website. At this current stage of the pandemic, articles relevant for clinical care for anesthesiologists and intensivists have begun to decrease. In response to this change, we will now deliver the COVID-19 Newsletter on a monthly basis to ensure each issue continues to provide the most critical information. As this pandemic continues to adapt so will this initiative. Learn more below.

COVID Newsletter By the Numbers 2022

  • Claim CME ButtonWellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey. 10/27/22. Burns KEA. Crit Care.
    This survey supported by the American Thoracic Society assessed ICU attending physician wellness and coping during the COVID-19 pandemic. The results reflect a 43% response rate to 1,080 questionnaires, using four validated instruments from physicians in 62 US and Canadian sites, conducted February-April 2021. About 60% reported moral distress (conflict with internal ethical values) and burnout (emotional exhaustion, depersonalization, reduced personal accomplishment). Moral distress, correlated with increased workload (patient volume, days worked, unscheduled in-house night shifts), was exacerbated by adverse institutional organization, was greater in women and physicians of color, and contributed to a desire to leave their position in a quarter of respondents. Despite this, most physicians experienced moderate professional fulfillment (satisfaction from attaining career goals). The survey revealed four coping profiles: active planning/social interaction (20%), avoidance/self-distraction (45%), mixed (5%) or infrequent (30%).
    SAB Comment: The phenomenon of pandemic-induced healthcare provider burnout is widely understood, but this survey provides new information on the extent and consequence of moral distress among intensivists. It also quantifies different work stress coping mechanisms, although ironically those who used them infrequently had less moral distress and burnout and more professional fulfilment. This group was older and could represent less intense “front-line” activity, a question not addressed by the authors. This point highlights that this survey quantitates problems but merely hints at solutions. Nonetheless, it provides an important database for future studies on interventions to ameliorate moral distress, burnout and work changes among intensivists.
  • The Next Next Wave: How Critical Care Might Learn From COVID in Responding to the Next Pandemic. 11/1/22. Tung A. Anesth Analg.
    The Open Mind is an Anesthesia & Analgesia forum for “…proposing new approaches or solutions to an important issue facing the anesthesiology community.” In this article, “front-line” anesthesiology intensivists were asked how the critical care response to the next pandemic might be informed by their experience during COVID-19. Each section reflects provider experience at different institutions as follows: (1) managing hospital-wide critical care response to a new disease (NYU Langone Health); (2) converting operating rooms to ICUs (New York Presbyterian-Columbia); (3) evolving airway management of the COVID patient (University of Chicago); (4) adapting extracorporeal membrane oxygenation to COVID-associated acute respiratory failure (Emory University) and (5) the impact of COVID on provider wellness (Beth Israel Deaconess). Lessons learned include that the rapid, unpredictable evolution of pathogens requires nimble adaptability, collaboration and discovery; that published clinical guidance may lag behind empiric adaptation; and that provider stress must be recognized and supported.
    SAB Comment: This is a unique overview based on the first-hand experience and contributions of anesthesiology intensivists over the almost three years of the COVID-19 pandemic. Given the pandemic’s enormous physical, emotional, economic and political toll, the lessons learned are germane to all intensivists, regardless of specialty, as well as hospital administrators and leadership. Readers are encouraged to also review the superb overview provided by the accompanying editorial.
  • Long-term neurological sequelae of SARS-CoV-2 infection. 10/3/22. Nat Med.
    This is a research briefing by the senior author of a number of studies examining long-term sequelae of COVID-19 using the US Department of Veteran Affairs database. It highlights the fact that patients who survive the first 30 days of acute SARS-CoV-2 infection have a 42% increased risk of developing various neurological disorders during the subsequent year compared with uninfected contemporaries. Although the absolute burden of developing any neurological disorder might seem small (7% at 1 year), given the large scale of the pandemic, this translates into a large number of affected individuals. The authors used a cohort of 154,068 infected patients and 5,638,795 uninfected controls in addition to a prepandemic historical control of almost 6 million patients. Risk correlated with acute COVID severity. They emphasize the need for early recognition and treatment instead of dismissal of nonspecific symptoms, provide a number of references, and urge further investigation.
    SAB Comment: A more detailed account of this research can be found below.
    Claim CME ButtonLong-term neurologic outcomes of COVID-19. 9/22/22. Xu E. Nat Med.
  • COVID-19 and Acute Neurologic Complications in Children. 8/11/22. Antoon JW. Pediatrics.
    This study is based upon data provided to the Pediatric Health Information System database from 52 pediatric academic centers during a 2-year period beginning March 2020. It focused on prevalence, risk factors and outcomes associated with neurological complications in hospitalized children. Among 15,137 children aged 2 months to 18 years, the overall incidence of acute neurological complication was 7%. Febrile seizures, nonfebrile seizures, and encephalopathy combined accounted for 85% of neurologic complications. Identified risk factors included preexisting chronic neurologic conditions, older age, race, and ethnicity. Lower odds occurred during the period of Delta-variant dominance, and in patients treated with remdesivir and dexamethasone. Neurologic complications were associated with increased mortality (1.8% vs. 0.6%, p<0.001), ICU admission, longer hospitalization, and higher cost of care. These results are comparable to children hospitalized with influenza and other viral illnesses and emphasize the importance of COVID-19 immunization, especially in a high-risk population.
  • Long-term cardiovascular outcomes of COVID-19. 2/8/22. Xie Y. Nat Med.
    In this Veteran’s Administration database study, COVID-19 survivors who survived 30 days or more after their first positive test, exhibited increased risks and 12-month burdens of cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease and other cardiac disorders. Two key findings: (1) the risks and associated burdens were evident among those who were not hospitalized during the acute phase of the disease; and (2) complications and associated burdens were correlated with the severity of the acute phase of COVID-19. This finding suggests that care pathways of people who survived the acute episode of COVID-19 should include attention to cardiovascular health and disease. Excellent description of methods accompanied by helpful tables.
    SAB Comment: This VA study has important implications for the risk of perioperative major adverse cardiac events (MACE) in COVID-19 survivors. In comparing more than 150k COVID-19 survivors with more than 11 million controls, the risk of postacute cardiovascular manifestations was significantly higher in patients who had an ICU admission or were hospitalized than for those who were not hospitalized. These factors should be taken into consideration in the preoperative cardiovascular workup of COVID-19 survivors subsequently presenting for moderate or high-risk surgery.
  • Claim CME ButtonUse of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis. 10/12/22. Durstenfeld MS. JAMA Netw Open.
    This systematic review and meta-analysis examines changes in cardiopulmonary exercise testing (CPET) for patients with long COVID (LC). A total of 38 studies were identified that performed CPET on 2,160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1,228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies that compared a total of 464 LC patients with prevalent symptoms to 359 others without, the mean peak V̇O₂ was lowered by 4.9 mL/kg/min in symptomatic individuals. While cardiopulmonary exercise testing is not readily available and there are limitations including selection bias, limited data sets and variability in definitions, this study represents a compilation of the present understanding in this field and helps identify future areas of research.
  • Timing of elective surgery and risk assessment after SARS-CoV-2 infection: an update: A multidisciplinary consensus statement on behalf of the Association of Anaesthetists, Centre for Perioperative Care, Federation of Surgical Specialty Associations, Royal College of Anaesthetists, Royal College of Surgeons of England. 2/23/22. El-Boghdadly K. Anaesthesia.
    This multidisciplinary update of the guidelines for surgery after SARS-CoV-2 infection comes from several United Kingdom medical organizations, focusing on the Omicron variant. The authors emphasize there is no data yet available regarding surgery after Omicron, and the previous need to wait 7 weeks to avoid any increase in risk stands. Avoiding surgery during active infection, vaccination, preoperative prevention measures, exercise, and hospital prevention measures are emphasized. Risk assessment with a tool such as Surgical Outcome Risk Tool v2 (SORT-2) is recommended along with an instructive example of how to calculate individual patient risk. The possibility that use of local or regional anesthesia may lower risk compared with general anesthesia is also discussed.
  • Claim CME ButtonCovid-19 Vaccination and the Timing of Surgery Following Covid-19 Infection. 7/15/22. Le S. Annals of Surgery.
    Kaiser Permanente investigators reviewed 228,913 adult elective inpatient and outpatient surgeries, prepandemic and after vaccination availability, to assess whether vaccination status or type of anesthesia affected postoperative complication rates following SARS-CoV-2 infection. Postoperative emergency room visits and unscheduled hospitalizations were increased only for patients not fully vaccinated at the time of surgery, and if it occurred less than 30 days following a COVID diagnosis (n=373, adjusted HR 1.55). The increased risk was fully accounted for in those who had general anesthesia (adjusted HR 1.84). Risks were not elevated when surgery occurred more than 4 weeks following a COVID diagnosis. Authors note “Current guidelines recommend deferring elective surgery for at least 7 weeks after Covid-19 diagnosis among patients who are asymptomatic at the time of surgery.” They recommend further study and liberalizing guidelines for those fully vaccinated or for whom general anesthesia can be avoided.
    SAB Comment: This article prompted SAB review of a key cited reference, summarized below, that analyzed data from unvaccinated patients undergoing major elective surgery earlier in the pandemic. It contributed to guidelines suggesting a 7-8 week preoperative delay following a positive PCR. SARS-2-CoV continues to evolve with multiple variants and the specter of long COVID-19, and the concomitant evolution of vaccines and therapeutics. As a consequence, decisions regarding timing of elective surgery following a COVID diagnosis are best individualized to each patient. We anticipate ongoing studies regarding the important question of how to assess and minimize perioperative risks following COVID.
  • Claim CME ButtonExtended prone positioning duration for COVID-19-related ARDS: benefits and detriments. 7/8/22. Walter T. Crit Care.
    This retrospective observational study in France from March 2020-April 2021 evaluated 81 COVID-19 patients using a strategy, originally implemented for organizational and human resources purposes. It was based on extending the duration of proning sessions (PP) up to 48 hours in patients ventilated for COVID-19-related ARDS. The primary objective, the occurrence of pressure injury was observed in 26% of patients and was equivalent to patients who had PP sessions of shorter duration for non-COVID-19-related ARDS. The presence of skin injury, the most common complication of PP, correlated with cumulative duration of PP sessions and length of ICU stay, not the duration of each session. Extended PP significantly reduced staff viral exposure and workload, allowing for most position changes during the daytime. Longer proning sessions were also associated with continued improvements in ventilatory parameters over the extended time.
  • N95 respirators: quantitative fit test pass rates and usability and comfort assessment by health care workers. 5/29/22. Ng I. Medical Journal of Australia.
    Healthcare workers (n = 2,161) at the Royal Melbourne Hospital underwent quantitative fit testing of N95 respirators per Australian Infection Control Expert Group protocol, each with at least three of four types: semi-rigid cup, flat-fold cup, duckbill, and three-panel flat-fold. Images are available here. The overall fit test pass rates were 65% for the semi-rigid cup respirators, 32% for the flat-fold respirator, 59% for the duckbill respirators, and 96% for the three-panel flat-fold respirator. Three hundred seventy-eight participants completed a detailed comfort and usability survey. Overall comfort and assessment ratings differed significantly by type. Median overall comfort and overall assessment values were highest for the three-panel flat-fold model and lowest for the semi-rigid cup model. These results may inform institutional procurement decision-makers as well as individuals who may not have access to quantitative testing to enhance respiratory protection.
  • Best COVID-19 Activities:

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Newsletter Issue 157, December 19, 2022:

  • Claim CME ButtonA population-based serological study of post-COVID syndrome prevalence and risk factors in children and adolescents. 11/29/22. Dumont R. Nat Commun.
    This report is from a Swiss population study of 1,034 children, aged 6 months to 17 years, who were tested for anti-SARS-CoV-2 N antibodies December 2021-February 2022. Pediatric vaccinations were not available to participants until early January 2022. Their parents filled in a questionnaire on symptoms compatible with post-COVID syndrome lasting over 12 weeks. Of the 1,034 children tested, 570 (55.1%) were seropositive. Overall, 24% has a prior test confirming SARS-CoV-2 infection, and 19% had had clinical symptoms consistent with COVID-19. Both were far more prevalent in the seropositive cohort, (by a factor of ~8x). The sex- and age-adjusted prevalence of children with persistent symptoms was 9.1% among seropositive children and 5.0% among seronegative children, with an adjusted prevalence difference (ΔaPrev) = 4.1%. Stratifying by age group, only those 12-17 years of age displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%). Identified risk factors for post-COVID syndrome were older age, lower socioeconomic status and chronic health conditions, especially asthma.
    SAB Comment: This study is useful in estimating the population’s prevalence of long COVID in young children (0%) and in adolescents (8.3%) of all those with positive serologies but does not estimate a symptomatic COVID-infected adolescent’s risk of long COVID (which may be significantly higher). Because pediatric vaccinations began in Switzerland in January 2022, the study could not assess the effect of prior vaccination on persistent symptoms, as not enough participants were vaccinated.
  • Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and Molnupiravir. 12/6/22. Wong GL. JAMA Netw Open.
    To better understand the much-discussed rebound phenomena when COVID-19 patients receive oral antiviral medication (molnupiravir (Lagevrio) or nirmatrelvir-rotinavir (Paxlovid)), 12,629 adult COVID-19 inpatients in Hong Kong were followed with RT-PCR testing during the first three months of 2022. Serial cycle threshold (Ct) values were used to measure rebound, defined as a Ct value that increased to > 40, followed by a decrease to 40 or less. Viral rebound was uncommon, occurring in 0.6% of patients who did not receive an antiviral (n=11,688), 0.8% in molnupiravir patients (n=746), and 1% in nirmatrelvir-rotinavir patients (n=195). Viral rebound was not associated with an increased risk of mortality.
    SAB Comment: It’s important to note that this study evaluates viral and not symptom rebound in hospitalized patients. Clinical symptoms were not studied. This study is similar to a research letter previously presented in newsletter 148. Both show a low incidence of viral rebound in treated as well as untreated patients. One study of the mechanism of rebound suggests that a more robust immune response rather than uncontrolled viral replication is the cause of clinical rebound.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

View the full issue.

Newsletter Issue 156, December 5, 2022:

  • Trends in Clinician Burnout With Associated Mitigating and Aggravating Factors During the COVID-19 Pandemic. 11/23/22. Linzer M. JAMA Health Forum.
    Presented are the results of 204 ongoing surveys regarding burnout administered to 56,000 physicians and advanced caregivers by members of the AMA partner healthcare systems, between February 2019 and December 2021, with 21,000 responses. Using the Mini Z work-life measure, topics included clinician outcomes (stress, satisfaction, burnout and intent to leave), and mitigating or aggregating factors (feeling valued, teamwork, work pace, work control, chaos, electronic health record factors, time pressure, and values alignment). Burnout occurred with 45% of respondents in 2019 and by late 2021, it was 60%. Intent to leave rose from 24% to greater than 40%. Mitigating factors that reduced burnout significantly were a calm vs chaotic environment 42%, good work control 36%, good teamwork 39% and feeling valued 32%. The authors concluded that monitoring and improving factors of providers’ working conditions may aid workforce retention.
  • Claim CME ButtonIncidence of Epilepsy and Seizures Over the First 6 Months After a COVID-19 Diagnosis: A Retrospective Cohort Study. 11/17/22. Taquet M. Neurology.
    To find the incidence of new-onset seizures and epilepsy after COVID-19 infection, these authors used data from a network of linked electronic health records that included over 81 million patients, mostly in the USA. Between January 2020 and May 2021, 152,754 patients with COVID-19 were compared to a matched cohort of 152,754 patients with influenza. The incidence of seizures within six months of COVID-19 was 0.81% (hazard ratio (HR) compared to influenza 1.55) and the incidence of epilepsy was 0.3% (HR compared to influenza 1.87). The incidence of epilepsy after COVID-19 compared to influenza was greater in people who had not been hospitalized and in individuals younger than 16 years old.
    SAB Comment: An associated editorial discussed the clinical implications of these findings. Though the incidence of seizures or epilepsy is low, the large number of COVID-19 cases over the pandemic and the finding that milder cases are more at risk means that there may be many additional seizure and epilepsy patients presenting to providers after COVID-19. The etiology of the seizures and the long-term natural history for these patients is presently unknown.
  • Omicron sublineage BQ.1.1 resistance to monoclonal antibodies. 11/21/22. Arora P. Lancet Infect Dis.
    This correspondence was submitted by a group of scientists working in a German primate center. They demonstrated on color charts how monoclonal antibodies (mAbs) suffer from increasing resistance and lack of effectiveness against several omicron sublineages. In particular, BQ.1.1, which is currently spreading in Europe and the US, is completely resistant to all mAbs in the authors’ model which consists of pseudovirus particles exposed to subclinical serum levels of a series of 16 mAbs, administered individually or in combination. Although this model awaits clinical confirmation, the findings indicate that novel, broadly active mAbs are urgently needed.
    SAB Comment: The result of this lab study parallels clinical evidence of waning efficacy of monoclonal antibodies, including Evusheld, among patients exposed to omicron BQ.1.1 subvariants, currently responsible for roughly 50% of US infections. The study does not consider secondary resistance conferred by infection or vaccination.
  • Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial. 11/11/22. Ben Abdallah S. Clin Infect Dis.
    This prospective, randomized, double-blind, placebo-controlled, multicenter trial included both COVID-19 positive outpatients (n= 190) and inpatients (n= 280). Patients received 25mg of oral zinc (Zn) twice a day or placebo for 15 days. Mortality was 6.5% in the Zn group vs. 9.2% in the placebo group (OR 0.68, p=0.27, not statistically significant). ICU admission was 5.2% in the Zn group vs. 11.3% for the placebo group (OR 0.43. p=0.01). For inpatients, hospital length of stay was significantly shorter in the Zn group vs. the placebo group by 3.5 days. In outpatients, the duration of symptoms decreased by 1.9 days amongst the Zn treated group. Consistent results were observed in subgroups of patients based on age, comorbidities and oxygen therapy.
    SAB Comment: The article didn’t mention serum Zn levels, so we cannot comment as to whether Zn prescription was for a Zn deficiency or used as a supplement. Larger studies should be done before Zn is considered a magic bullet for COVID-19 infection.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

View the full issue.

Newsletter Issue 155, November 21, 2022:

View the full issue.

Newsletter Issue 154, November 14, 2022:

  • Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in critically ill French patients with COVID-19. 10/12/22. de Prost N. Nat Commun.
    This prospective, multicenter observational study from France studied 259 patients with severe COVID-19 requiring ICU admission between December 6, 2021 and May 1, 2022. Extensive viral genomic sequencing was done and Delta and several early Omicron subvariants were identified. Mortality at 28 days in Delta and Omicron patients was not significantly different. The clinical phenotype of patients infected with Omicron was different from that in those infected with Delta. Omicron patients were older, frailer with more comorbidities (especially immunosuppression), and had higher severity of illness scores, reflecting more extrapulmonary organ failure. Among Omicron-infected patients, 43% were immunocompromised and these patients had a higher mortality compared with other Omicron-infected patients (47% vs 26%). Most immunocompromised Omicron-infected patients had been vaccinated (86%) but displayed a poor humoral response to vaccination.
    SAB Comment: Continued deaths from COVID-19 during the Omicron period suggest that severe Omicron is a problem, even if general population studies suggest Omicron is not as severe as Delta. This study confirms that ICU patients have as poor a prognosis with Omicron as with Delta, and that the elderly, frail and immunocompromised population is particularly vulnerable. People with such risk factors may want to adopt strategies to avoid getting COVID-19 in the first place.
  • Claim CME ButtonEffectiveness of Evusheld in Immunocompromised Patients: Propensity Score-Matched Analysis. 10/31/22. Najjar-Debbiny R. Science Trans Med.
    This is a real-world efficacy assessment of preexposure prophylactic intramuscular Evusheld administered to a cohort of immunosuppressed patients belonging to Israel’s largest healthcare system. On February 15, 2022, 703 patients were identified to be eligible and received 300 mg of the two-component monoclonal antibody (150 mg of tixagevimab and 150 mg of cilgavimab). This group was propensity matched with a 2,812 patient control group and followed through June 30 or up to 90 days focusing on COVID-19 related illness and hospitalization.
    Results identified a reduced risk for SARS-CoV-2 infection and COVID-19-related hospitalization with a hazard ratio of 0.75 and 0.41, respectively. The reasons for the less promising results in this study compared to other recent studies were discussed. The need of a dosage increase, particularly for obese patients, was discussed along with an alert to expect lower responses as new variants emerge.
    SAB Comment: This study parallels another previously reviewed paper highlighting Evusheld’s role in preexposure prophylaxis. In addition, a recent CDC fact sheet lists indication, timing and use for immunocompromised patients and those unable to be vaccinated. A higher 300 mg dose of each component (600 mg total) is to be repeated every 6 months where indicated and efficacy may decrease as variants evolve.
  • Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells. 11/3/22. Nguyenla X. Sci Rep.
    In this basic science study, these investigators conducted combinatorial high-throughput screening to find synergy of approved drugs with remdesivir to prevent SARS-CoV-2 replication in human lung epithelial cells. Of 20 approved drugs found, the strongest synergies were with the hepatitis C virus (HCV) NS5A inhibitors, velpatasvir and elbasvir, which may act on the SARS-CoV-2 exonuclease proofreader. These anti-HCV drugs are commercially available in combination with “partner” drugs, Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir). When velpatasvir and elbasvir were combined with their “partner” drugs, it boosted remdesivir’s potency more than 25-fold. Further fine-tuning the potency and pharmacokinetic properties of these FDA-approved HCV therapeutics, used in combination with remdesivir, could merit clinical testing.
    SAB Comment: As SARS-Co-V-2 continues to mutate, novel therapeutics will be crucial. In other viral illnesses (e.g., HIV), drug combinations yield benefits far beyond their constituents used alone. Unexpectedly, these investigators reported HCV drugs targeting a non-mutated part of the virus, the exonuclease proofreader, provide a remarkable boost to remdesivir concentrations achievable in vivo. However, much more work is needed before clinical trials can be considered. The in vitro concentrations required of the HCV drugs may not be achievable in patients and the expense of the HCV drugs may limit their usefulness. The authors also reported common generic drugs that appear to synergize with remdesivir in vitro. We await further testing.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

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Newsletter Issue 153, November 7, 2022:

  • The Next Next Wave: How Critical Care Might Learn From COVID in Responding to the Next Pandemic. 11/1/22. Tung A. Anesth Analg.
    The Open Mind is an Anesthesia & Analgesia forum for “…proposing new approaches or solutions to an important issue facing the anesthesiology community.” In this article, “front-line” anesthesiology intensivists were asked how the critical care response to the next pandemic might be informed by their experience during COVID-19. Each section reflects provider experience at different institutions, as follows: (1) managing hospital-wide critical care response to a new disease (NYU Langone Health); (2) converting operating rooms to ICUs (New York Presbyterian-Columbia); (3) evolving airway management of the COVID patient (University of Chicago); (4) adapting extracorporeal membrane oxygenation to COVID-associated acute respiratory failure (Emory University) and (5) the impact of COVID on provider wellness (Beth Israel Deaconess). Lessons learned include that the rapid, unpredictable evolution of pathogens requires nimble adaptability, collaboration and discovery; that published clinical guidance may lag behind empiric adaptation; and that provider stress must be recognized and supported.
    SAB Comment: This is a unique overview based on the first-hand experience and contributions of anesthesiology intensivists over the almost three years of the COVID-19 pandemic. Given the pandemic’s enormous physical, emotional, economic and political toll, the lessons learned are germane to all intensivists, regardless of specialty, as well as hospital administrators and leadership. Readers are encouraged to also review the superb overview provided by the accompanying editorial.
  • Claim CME ButtonWellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey. 10/27/22. Burns KEA. Crit Care.
    This survey supported by the American Thoracic Society assessed ICU attending physician wellness and coping during the COVID-19 pandemic. The results reflect a 43% response rate to 1,080 questionnaires, using four validated instruments from physicians in 62 US and Canadian sites, conducted February-April 2021. About 60% reported moral distress (conflict with internal ethical values) and burnout (emotional exhaustion, depersonalization, reduced personal accomplishment). Moral distress, correlated with increased workload (patient volume, days worked, unscheduled in-house night-shifts), was exacerbated by adverse institutional organization, was greater in women and physicians of color, and contributed to a desire to leave their position in a quarter of respondents. Despite this, most physicians experienced moderate professional fulfillment (satisfaction from attaining career goals). The survey revealed four coping profiles: active planning/social interaction (20%), avoidance/ self-distraction (45%), mixed (5%) or infrequent (30%).
    SAB Comment: The phenomenon of pandemic-induced healthcare provider burnout is widely understood, but this survey provides new information on the extent and consequence of moral distress among intensivists. It also quantifies different work stress coping mechanisms, although ironically those who used them infrequently had less moral distress and burnout and more professional fulfilment. This group was older and could represent less intense “front-line” activity, a question not addressed by the authors. This point highlights that this survey quantitates problems but merely hints at solutions. Nonetheless, it provides an important database for future studies on interventions to ameliorate moral distress, burnout and work changes among intensivists.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic and date posted on the website:

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Newsletter Issue 152, October 24, 2022:

  • Take advantage of COVID-19 Journal CME from newly published peer-reviewed articles from respected journals. The IARS COVID-19 Scientific Advisory Board (SAB) selects articles of the greatest clinical and scientific relevance to anesthesiologists, intensivists, related specialists and investigators. View the Journal CME First-Time User Guide for instructions.
  • Claim CME ButtonUse of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis. 10/12/22. Durstenfeld MS. JAMA Netw Open.
    This systematic review and meta-analysis examines changes in cardiopulmonary exercise testing (CPET) for patients with long COVID (LC). A total of 38 studies were identified that performed CPET on 2,160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1,228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies that compared a total of 464 LC patients with prevalent symptoms to 359 others without, the mean peak V̇O₂ was lowered by 4.9 mL/kg/min in symptomatic individuals. While cardiopulmonary exercise testing is not readily available and there are limitations including selection bias, limited data sets and variability in definitions, this study represents a compilation of the present understanding in this field and helps identify future areas of research.
    SAB Comment: As the importance of LC gains attention, this data summarizes prior literature and helps point the way forward. An accompanying podcast in the multimedia link summarizes the article well and adds to the clinical utility of these findings.
  • Claim CME ButtonLong-term neurological sequelae of SARS-CoV-2 infection. 10/3/22. Nat Med.
    This is a research briefing by the senior author of a number of studies examining long-term sequelae of COVID-19 using the US Department of Veteran Affairs database. It highlights the fact that patients who survive the first 30 days of acute SARS-CoV-2 infection have a 42% increased risk of developing various neurological disorders during the subsequent year compared with uninfected contemporaries. Although the absolute burden of developing any neurological disorder might seem small (7% at 1 year), given the large scale of the pandemic, this translates into a large number of affected individuals. The authors used a cohort of 154,068 infected patients and 5,638,795 uninfected controls in addition to a prepandemic historical control of almost 6 million patients. Risk correlated with acute COVID severity. They emphasize the need for early recognition and treatment instead of dismissal of nonspecific symptoms, provide a number of references, and urge further investigation.
    SAB Comment: A more detailed account of this research can be found below.
    Long-term neurologic outcomes of COVID-19. 9/22/22. Xu E. Nat Med.
  • Claim CME ButtonCirculating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms. 9/22/22. Son K. Eur Respir J.
    This longitudinal observational multi-institutional Canadian study of 106 COVID-19 patients from 8/2020 to 9/2021 examined the relationship between long COVID symptoms and antinuclear/extractable-nuclear antibodies (ANA/ENA). Patients, whose acute COVID symptoms varied, were evaluated at 3, 6, and 12 months with ANA/ENA and cytokine assays. They self-reported fatigue, coughing and dyspnea. Controls were age- and sex-matched, nonimmunized, COVID-negative volunteers (22), and non-COVID-19 positive patients with respiratory symptoms (34). At 3 months, ANA levels were increased in COVID patients compared to controls, but decreased over the year. Higher levels of tumor necrosis factor alpha, D-dimer and IL-1β predicted elevated ANA at 12 months. Tracking the increase of antibodies associated with autoimmune disease over time demonstrated potential de novo autoantibody synthesis. The authors conclude that persistently positive ANAs at 12 months post-COVID-19 are associated with continuing symptoms and inflammation in a subset of COVID survivors.
    SAB Comment: The authors present elegant immunological evidence of an autoimmune factor in the development of long COVID. However, this small study has much potential for bias. Only 57 of 106 patients were available at 12 months. Also, in a study which concluded severity of disease was important, only 1 of 34 respiratory symptom control patients was hospitalized compared to 80 of 106 COVID-19 patients.
  • Claim CME ButtonPersistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae. 9/2/22. Swank Z. Clin Infect Dis.
    This retrospective pilot study measured 3 SARS-CoV-2 antigens (using a Simoa assay) in blood samples from 63 individuals diagnosed with COVID-19, of whom 37 had postacute sequelae of COVID-19 (PASC) identified. SARS-CoV-2 spike antigen was detected several months postinfection in 60% of PASC and in none with COVID-19 only. Longitudinal blood samples were available in 12 PASC individuals and in 6 with COVID-19 only. Serial blood samples in 12 PASC individuals showed sustained or fluctuating spike antigen levels, whereas in samples of 6 with COVID-19 only, high antigen levels immediately after diagnosis dropped rapidly. The authors indicate that more study is needed and propose these results support the hypothesis that a reservoir of active virus persists within the body in individuals with PASC. Ten cytokines were also measured and were not different among the groups. The discussion further analyzes the validity of the findings.

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Newsletter Issue 151, October 17, 2022:

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Newsletter Issue 150, October 12, 2022:

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Newsletter Issue 149, October 5, 2022:

  • Claim CME ButtonCirculating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms. 9/22/22. Son K. Eur Respir J.
    This longitudinal observational multi-institutional Canadian study of 106 COVID-19 patients from 8/2020 to 9/2021 examined the relationship between long COVID symptoms and antinuclear/extractable-nuclear antibodies (ANA/ENA). Patients, whose acute COVID symptoms varied, were evaluated at 3, 6, and 12 months with ANA/ENA and cytokine assays. They self-reported fatigue, coughing and dyspnea. Controls were age- and sex-matched, nonimmunized, COVID-negative volunteers (22), and non-COVID-19 positive patients with respiratory symptoms (34). At 3 months, ANA levels were increased in COVID patients compared to controls, but decreased over the year. Higher levels of tumor necrosis factor alpha, D-dimer and IL-1β predicted elevated ANA at 12 months. Tracking the increase of antibodies associated with autoimmune disease over time demonstrated potential de novo autoantibody synthesis. The authors conclude that persistently positive ANAs at 12 months post-COVID-19 are associated with continuing symptoms and inflammation in a subset of COVID survivors.
    SAB Comment: The authors present elegant immunological evidence of an autoimmune factor in the development of long COVID. However, this small study has much potential for bias. Only 57 of 106 patients were available at 12 months. Also, in a study which concluded severity of disease was important, only 1 of 34 respiratory symptom control patients was hospitalized compared to 80 of 106 COVID-19 patients.
  • Respiratory Support in the Time of COVID-19. 9/27/22. Nichol AD. JAMA.
    This editorial reviews 6 prior randomized studies of non-invasive respiratory support for patients with COVID-19 pneumonitis along with the SOHO-COVID Randomized Clinical Trial, published in the same issue of JAMA. After discussing each study, the authors conclude that “the available evidence suggests that the initial choice of supplemental oxygen therapy for patients with COVID-19-related acute hypoxemic respiratory failure does not influence mortality. This will provide some reassurance for clinicians in times of reduced availability of certain noninvasive respiratory support strategies during surges in COVID-19 hospitalizations.” They found that the rates of intubation using high-flow nasal oxygen vs conventional oxygen therapy did not consistently favor one modality or the other in this group of studies.
  • COVID-19 mRNA Vaccine Safety Among Children Aged 6 Months-5 Years – United States, June 18, 2022-August 21, 2022. 9/1/22. Hause AM. MMWR Morb Mortal Wkly Rep.
    In the time period noted above, 1,040,230 children received Pfizer-BioNTech or Moderna vaccines. Approximately 23,266 children were enrolled in v-safe, the CDC voluntary cell phone-based monitoring system. The most frequent systemic reactions reported to v-safe after receipt of vaccines were irritability or crying in approximately one half of children aged 6 months–2 years. In children aged 3 years or older, systemic reactions after vaccination were less frequently reported; injection site pain was the most frequently reported reaction among these older children. The VAERS reporting system received a total of 1,017 reports of adverse events after Pfizer-BioNTech or Moderna vaccination, 98.1% of which were classified as nonserious. No reports of myocarditis after vaccination were reported. Health care providers and parents of young children should be aware that local and systemic reactions are expected after vaccination with Pfizer-BioNTech or Moderna vaccine and that serious adverse events are rare.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic on the website:

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Newsletter Issue 148, September 28, 2022:

  • Claim CME ButtonPersistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae. 9/2/22. Swank Z. Clin Infect Dis.
    This retrospective pilot study measured 3 SARS-CoV-2 antigens (using a Simoa assay) in blood samples from 63 individuals diagnosed with COVID-19, of whom 37 had postacute sequelae of COVID-19 (PASC) identified. SARS-CoV-2 spike antigen was detected several months postinfection in 60% of PASC and in none with COVID-19 only. Longitudinal blood samples were available in 12 PASC individuals and in 6 with COVID-19 only. Serial blood samples in 12 PASC individuals showed sustained or fluctuating spike antigen levels, whereas in samples of 6 with COVID-19 only, high antigen levels immediately after diagnosis dropped rapidly. The authors indicate that more study is needed and propose these results support the hypothesis that a reservoir of active virus persists within the body in individuals with PASC. Ten cytokines were also measured and were not different among the groups. The discussion further analyzes the validity of the findings.
  • Nirmatrelvir-Ritonavir and Viral Load Rebound in Covid-19. 9/7/22. Anderson AS. N Engl J Med.
    Using data from the EPIC-HR3 trial which compared nirmatrelvir-ritonavir (Paxlovid) to placebo in unvaccinated patients, the authors found that viral load rebound following nirmatrelvir-ritonavir is not retrospectively associated with low nirmatrelvir exposure, recurrence of moderate to severe symptoms or development of resistance to nirmatrelvir. During the recruitment period from June to December 2021 which coincided with delta variant predominance, viral load rebound occurred in 23 of 990 patients (2.3%) in the nirmatrelvir– ritonavir group and in 17 of 980 (1.7%) in the placebo group. These results – published in a research letter suggest that viral load rebound may be a natural feature of a small percentage of SARS CoV-2 infections. However, viral load as determined by PCR assay, may not explain the frequently noted clinical syndrome.
  • A Bivalent Omicron-Containing Booster Vaccine against Covid-19. 9/16/22. Chalkias S. N Engl J Med.
    This industry-sponsored study presents the interim results of Moderna’s phase 2-3 trial of their bivalent mRNA vaccine. Participants (n = 890) who had received a primary series of two doses and a single booster of Moderna’s original vaccine were divided into two groups; one received another booster of the original vaccine, and the other received the new bivalent mRNA vaccine which includes 25mcg of the original, and 25 mcg of an mRNA vaccine developed against Omicron BA-1. At 29 days, the bivalent Omicron-containing vaccine elicited neutralizing antibody responses against Omicron (including BA.4/5 subvariants) and previous variants that were superior to those of the original vaccine, without safety concerns.
    SAB Comment: These interim laboratory immune results are encouraging. In the near future we look forward to the important vaccine effectiveness and longevity results.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic on the website:

View the full issue.

Newsletter Issue 147, September 19, 2022:

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Newsletter Issue 146, September 12, 2022:

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Newsletter Issue 145, September 7, 2022:

Take advantage of COVID-19 Journal CME from newly published peer-reviewed articles from respected journals. The IARS COVID-19 Scientific Advisory Board (SAB) selects articles of the greatest clinical and scientific relevance to anesthesiologists, intensivists, related specialists and investigators. View the Journal CME First-Time User Guide for instructions.

  • Claim CME ButtonCOVID-19 and Acute Neurologic Complications in Children. 8/11/22. Antoon JW. Pediatrics.
    This study is based upon data provided to the Pediatric Health Information System database from 52 pediatric academic centers during a 2-year period beginning March 2020. It focused on prevalence, risk factors and outcomes associated with neurological complications in hospitalized children. Among 15,137 children aged 2 months to 18 years, the overall incidence of acute neurological complication was 7%. Febrile seizures, nonfebrile seizures, and encephalopathy combined accounted for 85% of neurologic complications. Identified risk factors included pre-existing chronic neurologic conditions, older age, race, and ethnicity. Lower odds occurred during the period of Delta variant dominance, and in patients treated with remdesivir and dexamethasone. Neurologic complications were associated with increased mortality (1.8% vs. 0.6%, p<0.001), ICU admission, longer hospitalization, and higher cost of care. These results are comparable to children hospitalized with influenza and other viral illnesses and emphasize the importance of COVID-19 immunization, especially in a high-risk population.
  • Claim CME ButtonThe Risk of Postoperative Complications After Major Elective Surgery in Active or Resolved COVID-19 in the United States. 2/22/22. Deng JZ. Annals of Surgery.
    Using data from the COVID-19 Research Database, investigators studied the incidence of complications following 18 common major elective surgeries in unvaccinated patients who previously had PCR-confirmed SARS-CoV-2 infection (98.7% mild-moderate). Compared with 2,621 controls who underwent equivalent surgeries at least 30 days before a COVID diagnosis, those who had surgery within 4 weeks following a COVID diagnosis (n = 780) had substantially elevated adjusted odds ratio (aOR) for pneumonia (aOR 6.5), respiratory failure (aOR 3.4), pulmonary embolus (aOR 2.4) and sepsis (aOR 3.7). For those having surgery between 4 and 8 weeks after COVID (n = 445), only the aOR for pneumonia was higher at 2.4. For those having surgery more than 8 weeks following COVID (n=1633), no increased risk of complications was observed. Following a COVID diagnosis authors recommend waiting 8 weeks prior to major elective surgery, with due consideration for malignancies.
  • Claim CME ButtonCovid-19 Vaccination and the Timing of Surgery Following Covid-19 Infection. 7/15/22. Le S. Annals of Surgery.
    Kaiser Permanente investigators reviewed 228,913 adult elective inpatient and outpatient surgeries, pre-pandemic and after vaccination availability, to assess whether vaccination status or type of anesthesia affected postoperative complication rates following SARS-CoV-2 infection. Postoperative emergency room visits and unscheduled hospitalizations were increased only for patients not fully vaccinated at the time of surgery, and if it occurred <30 days following a COVID diagnosis (n=373, adjusted HR 1.55). The increased risk was fully accounted for in those who had general anesthesia (adjusted HR 1.84). Risks were not elevated when surgery occurred more than 4 weeks following a COVID diagnosis. Authors noted “Current guidelines recommend deferring elective surgery for at least 7 weeks after Covid-19 diagnosis among patients who are asymptomatic at the time of surgery.” They recommend further study and liberalizing guidelines for those fully vaccinated or for whom general anesthesia can be avoided.
    SAB Comment: This article prompted SAB review of a key cited reference that analyzed data from unvaccinated patients undergoing major elective surgery earlier in the pandemic. It contributed to guidelines suggesting a 7-8 week preoperative delay following a positive PCR. SARS-CoV-2 continues to evolve with multiple variants, the specter of Long COVID-19, and the concomitant evolution of vaccines and therapeutics. Consequently, decisions regarding timing of elective surgery following a COVID diagnosis are best individualized to each patient. We anticipate ongoing studies regarding the important question of how to assess and minimize perioperative risks following COVID.
  • Claim CME ButtonMaternal Vaccination and Risk of Hospitalization for Covid-19 among Infants. 6/22/22. Halasa NB. N Engl J Med.
    This multicenter, case-control, test-negative study assessed the effectiveness of maternal 2-dose mRNA COVID-19 vaccination during pregnancy against hospitalization for COVID-19 disease among infants younger than 6 months. Protection was 52% overall (80% during the Delta period, and 38% during the Omicron period). Of 537 case infants hospitalized for COVID-19, only 16% were born to mothers fully vaccinated during pregnancy vs. 29% of 512 hospitalized controls. Among case infants, 21% were admitted to ICU; 12% received mechanical ventilation or vasoactive infusions. Two infants died from COVID-19 and 2 received ECMO treatment; none of these 4 infants’ mothers had been vaccinated during pregnancy. Effectiveness was greater if vaccination occurred after 20 weeks of gestational age than earlier in pregnancy (69% vs. 38%). However, due to well-documented risks of COVID-19 during pregnancy, this did not lead to a recommendation to delay vaccination. The results are discussed in a well-written accompanying editorial.
  • Claim CME ButtonExtended prone positioning duration for COVID-19-related ARDS: benefits and detriments. 7/8/22. Walter T. Crit Care.
    This retrospective observational study in France from March 2020-April 2021 evaluated 81 COVID-19 patients, using a strategy, originally implemented for organizational and human resources purposes. It was based on extending the duration of proning sessions (PP) up to 48 hours in patients ventilated for COVID-19-related ARDS. The primary objective, the occurrence of pressure injury, was observed in 26% of patients and was equivalent to patients who had PP sessions of shorter duration for non-COVID-19-related ARDS. The presence of skin injury, the most common complication of PP, correlated with cumulative duration of PP sessions and length of ICU stay, not the duration of each session. Extended PP significantly reduced staff viral exposure and workload, allowing for most position changes during the daytime. Longer proning sessions were also associated with continued improvements in ventilatory parameters over the extended time.
  • Claim CME ButtonAssociation between AZD7442 (tixagevimab-cilgavimab) Administration and SARS-CoV-2 Infection, Hospitalization and Mortality. 7/29/22. Kertes J. Clin Infect Dis.
    This retrospective, observational, “real world” study demonstrates lower rates of infection (3.5% vs. 7.2%), hospitalization (0.1 vs. 0.6%) and mortality (0 vs. 0.9%) when AZD7442 is administered pre-infection to a heterogenous group of highly immunosuppressed patients and compared to a similar group who chose not to receive the drug combination. The study coincided with an Omicron-dominated wave of COVID-19 in Israel (Dec. 2021- April 2022) and was designed to determine whether AZD7442, a human SARS-CoV-2 neutralizing monoclonal antibody combination, with the US trade name, Evusheld, was effective against the Omicron variant using a large Israeli healthcare system’s database. Among the immune suppressed patients contacted, 825 patients chose to participate and received AZD7442, while 4,299 declined and served as controls. Study results complement several ongoing and completed randomized controlled trials (PROVENT, TACKLE) and suggest the use of AZD7442 with its 90-day half-life for pre-exposure prophylaxis in individuals where immune-suppression is a concern.
  • Claim CME ButtonGood practice statements for antithrombotic therapy in the management of COVID-19: Guidance from the SSC of the ISTH. 7/29/22. J Thromb Haemost. Clin Infect Dis.
    This article is a set of best practice statements for deep vein thrombosis prophylaxis and treatment with COVID-19 from the International Society of Thrombosis and Hemostasis. It is not based upon a systematic review but expert opinion. While much of this is similar to prior guidelines, the special considerations section covering pregnancy, pediatrics, chronic kidney disease, obesity and heparin-induced thrombocytopenia without thrombosis are of value.

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Newsletter Issue 144, August 29, 2022:

  • Claim CME ButtonCOVID-19 and Acute Neurologic Complications in Children. 8/11/22. Antoon JW. Pediatrics.
    This study is based upon data provided to the Pediatric Health Information System database from 52 pediatric academic centers during a 2-year period beginning March 2020. It focused on prevalence, risk factors and outcomes associated with neurological complications in hospitalized children. Among 15,137 children aged 2 months to 18 years, the overall incidence of acute neurological complication was 7%. Febrile seizures, nonfebrile seizures, and encephalopathy combined accounted for 85% of neurologic complications. Identified risk factors included pre-existing chronic neurologic conditions, older age, race, and ethnicity. Lower odds occurred during the period of Delta variant dominance, and in patients treated with remdesivir and dexamethasone. Neurologic complications were associated with increased mortality (1.8% vs. 0.6%, p<0.001), ICU admission, longer hospitalization, and higher cost of care. These results are comparable to children hospitalized with influenza and other viral illnesses and emphasize the importance of COVID-19 immunization, especially in a high-risk population.
  • Oral Nirmatrelvir and Ritonavir in Non-hospitalized Vaccinated Patients with Covid-19. 8/20/22. Ganatra S. Clin Infect Dis.
    Though Paxlovid (nirmatrelvir plus ritonavir, NMV-r) reduces progression to severe disease in high-risk, nonhospitalized unvaccinated patients, benefits among vaccinated patients are unclear. This retrospective cohort study between December 2021 and April 2022 evaluated vaccinated adults (over 18 years), who subsequently developed COVID-19, comparing 1,130 who took NMV-r within five days of diagnosis with an equal number who did not. All-cause emergency room visits, hospitalization, or death within 30 days occurred in 89 patients (7.87%) in the NMV-r cohort, compared to 163 patients (14.4%) in the non-NMV-r cohort (p<0.005), a 45% relative risk reduction. Complications and overall resource utilization (e.g., diagnostic tests) were also decreased.
  • Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge. 8/24/22. Arbel R. N Engl J Med.
    This observational, retrospective, Israeli study of ambulatory patients, conducted January 9, 2022 – March 31, 2022 during the Omicron period, investigated early use of nirmatrelvir, a protease inhibitor. Of 105,352 eligible patients (over 40 yrs of age and considered “high risk”), 3,902 received the drug. The authors report significantly lower rates of hospitalization and death within 35 days in patients over 65 yrs who received nirmatrelvir (HR 0.27) irrespective of previous immunity status. They also noted a further reduction of hospitalization in patients over 65 who had previous immunity to COVID from vaccination, previous infection or both, and received the drug. No benefit of use was noted in patients less than 65 years of age.
  • Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections. 8/1/22. Breinholt Stærke N. Nature Communications.
    Using the Danish National Microbiology database, this observational cohort study examined whether levels of anti-spike IgG influenced rates of Delta and Omicron breakthrough infections in a fully vaccinated cohort. Anti-spike IgG levels were measured before vaccinations and at days 21–28, 90, 180 post first-vaccination, and 4 weeks post-booster. Among 6076 participants, Delta and Omicron (BA.2) infections occurred in 127 and 364, respectively. The highest vs. lower quintile of anti-spike IgG led to a 71% lower Delta breakthrough infection rate (p = 0.0002). However, no significant quintile differences were observed for Omicron suggesting that the level of anti-spike IgG has limited impact on Omicron breakthrough risk.
    SAB Comment: Prior to Omicron’s emergence, and consistent with the Delta variant data in the above study, increasing levels of anti-spike IgG were associated with reduced risk of breakthrough infections. This observation is not valid with Omicron breakthrough infection and does not address T- and B-cell immune function post-vaccination.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic on the website:

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Newsletter Issue 143, August 22, 2022:

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Newsletter Issue 142, August 15, 2022:

  • Claim CME ButtonAssociation between AZD7442 (tixagevimab-cilgavimab) Administration and SARS-CoV-2 Infection, Hospitalization and Mortality. 7/29/22. Kertes J. Clin Infect Dis.
    This retrospective, observational, “real world” study demonstrates lower rates of infection (3.5% vs. 7.2%), hospitalization (0.1 vs. 0.6%) and mortality (0 vs. 0.9%) when AZD7442 is administered pre-infection to a heterogenous group of highly immunosuppressed patients and compared to a similar group who chose not to receive the drug combination. The study coincided with an Omicron-dominated wave of COVID-19 in Israel (Dec. 2021- April 2022) and was designed to determine whether AZD7442, a human SARS-CoV-2 neutralizing monoclonal antibody combination, with the US trade name, Evusheld, was effective against the Omicron variant using a large Israeli healthcare system’s database. Among the immune suppressed patients contacted, 825 patients chose to participate and received AZD7442, while 4,299 declined and served as controls. Study results complement several ongoing and completed randomized controlled trials (PROVENT, TACKLE) and suggest the use of AZD7442 with its 90-day half-life for pre-exposure prophylaxis in individuals where immune-suppression is a concern.
  • Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. 6/10/22. Montgomery H. Lancet Respir Med.
    This human SARS-CoV-2-neutralizing monoclonal antibody (NMA) combination, also referred to as AZD7442 or Evusheld, has an extended half-life of 90 days and is subject to an Astra Zeneca-funded, multicenter, international trial which began enrolling unvaccinated patients with seven days or less of mild COVID-19 symptoms and at least one major risk factor in January 2021. By July 2021, 910 patients (average age 46) had received either placebo (n = 454) or an intramuscular injection of 300 mg each of tixagevimab and cilgavimab (n = 456). Progression to severe illness or death from any cause through day 29 occurred in 18 patients receiving the NMA combination, compared to 36 who received placebo, resulting in a relative risk reduction of 50.5%.
    In the pre-Omicron era, this NMA combination provided significant protection from severe disease without major side effects. As the trial is ongoing, future results may confirm in-vitro effectiveness to the Omicron variant.
    SAB Comment: An associated editorial, titled “Early treatment to prevent progression of SARS-CoV-2 infection,” highlights the evolving role antivirals and monoclonal antibodies like Evusheld may play in the prevention and management of SARS-CoV-2 and its variants, and the protection of vulnerable populations from severe disease.
  • Association of nirmatrelvir/ritonavir treatment on upper respiratory SARS-CoV-2 RT-PCR negative conversion rates among high-risk patients with COVID-19. 7/23/22. Li H. Clin Infect Dis.
    Nirmaltrelvir/ritonavir (Paxlovid) given orally within 5 days of symptom onset to high-risk patients hospitalized with mild to moderate COVID-19, accelerated the RT-PCR conversion rate from positive to negative significantly. Median conversion time for a 258-patient cohort receiving the drug between March and April 2022 was day 10 (7-12 days) while a control cohort of 241 patients converted 7 days later on day 17 (12-21 days). Secondary outcomes included lingering PCR positivity on day 15 among untreated patients, resulting in a hazard ratio of 4.33 in favor of patients receiving the drug combination. Delayed negative conversion were also observed in patients with lower cycle threshold (Ct) during RT-PCR testing, suggesting the presence of greater viral loads. Although neither infectiousness nor diminishing viral loads were assessed directly, the accelerated RT-PCR conversion suggests reduced risk of viral shedding and disease transmission in patients receiving the antiviral.
  • Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants. 7/20/22. N Engl J Med.
    The efficacy of monoclonal antibodies against the circulating BA.2.12.1, BA.4 and BA.5 is unknown. Live virus neutralization laboratory testing showed the combination of casirivimab and imdevimab (REGEN-COV) inhibited all variants; however, neutralization was reduced vs. imdevimab alone. Casirivmab was inactive. The combination of tixagevimab and cilgavimab (Evusheld) was active vs all three variants as was cilgavimab. Tixagevimab only neutralized BA.2.12.1. Sotrovimab lost all inhibitory capability. Bebtelovimab neutralized all three and was the only monoclonal active at concentrations similar to the ancestral strain. Remdesivir, molnupiravir and nirmatrelvir (active component of Paxlovid) all neutralized variants at concentrations similar to ancestral stains.
    SAB Comment: To date, there has been a lack of in vitro or clinical data to help decision making in selection of monoclonals and antiviral drugs to treat current circulating variants. These in vitro data may help a treating physician formulate a rationale for such decisions.

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Newsletter Issue 141, August 8, 2022:

  • Claim CME ButtonCovid-19 Vaccination and the Timing of Surgery Following Covid-19 Infection. 7/15/22. Le S. Annals of Surgery.
    Kaiser Permanente investigators reviewed 228,913 adult elective inpatient and outpatient surgeries, pre-pandemic and after vaccination availability, to assess whether vaccination status or type of anesthesia affected postoperative complication rates following SARS-CoV-2 infection. Postoperative emergency room visits and unscheduled hospitalizations were increased only for patients not fully vaccinated at the time of surgery, and if it occurred <30 days following a COVID diagnosis (n=373, adjusted HR 1.55). The increased risk was fully accounted for in those who had general anesthesia (adjusted HR 1.84). Risks were not elevated when surgery occurred more than 4 weeks following a COVID diagnosis. Authors noted “Current guidelines recommend deferring elective surgery for at least 7 weeks after Covid-19 diagnosis among patients who are asymptomatic at the time of surgery.” They recommend further study and liberalizing guidelines for those fully vaccinated or for whom general anesthesia can be avoided.
    SAB Comment: This article prompted SAB review of a key cited reference that analyzed data from unvaccinated patients undergoing major elective surgery earlier in the pandemic. It contributed to guidelines suggesting a 7-8 week preoperative delay following a positive PCR. SARS-CoV-2 continues to evolve with multiple variants, the specter of Long COVID-19, and the concomitant evolution of vaccines and therapeutics. Consequently, decisions regarding timing of elective surgery following a COVID diagnosis are best individualized to each patient. We anticipate ongoing studies regarding the important question of how to assess and minimize perioperative risks following COVID.
  • Claim CME ButtonThe Risk of Postoperative Complications After Major Elective Surgery in Active or Resolved COVID-19 in the United States. 2/22/22. Deng JZ. Annals of Surgery.
    Using data from the COVID-19 Research Database, investigators studied the incidence of complications following 18 common major elective surgeries in unvaccinated patients who previously had PCR-confirmed SARS-CoV-2 infection (98.7% mild-moderate). Compared with 2,621 controls who underwent equivalent surgeries at least 30 days before a COVID diagnosis, those who had surgery within 4 weeks following a COVID diagnosis (n = 780) had substantially elevated adjusted odds ratio (aOR) for pneumonia (aOR 6.5), respiratory failure (aOR 3.4), pulmonary embolus (aOR 2.4) and sepsis (aOR 3.7). For those having surgery between 4 and 8 weeks after COVID (n = 445), only the aOR for pneumonia was higher at 2.4. For those having surgery more than 8 weeks following COVID (n=1633), no increased risk of complications was observed. Following a COVID diagnosis authors recommend waiting 8 weeks prior to major elective surgery, with due consideration for malignancies.
  • Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial. 7/20/22. Gusdon AM. Science Trans Med.
    OP-101, a therapeutic nanoparticle with attached “tendrils” (a dendrimer), can place high concentrations of the anti-inflammatory/antioxidant N-acetyl cysteine (NAC) into activated macrophages and microglia. This multicenter, randomized, double-blind, phase 2a pilot study tested single-escalating doses (2mg/kg: n=6, 4mg/kg: n=6, or 8 mg/kg: n=5) vs placebo (n = 7) in severe COVID-19. All received SOC/corticosteroids. OP-101 at 4 mg/kg significantly decreased inflammatory markers; 4 and 8 mg/kg reduced neurological injury markers. Risk for mechanical ventilation/death at 30 and 60 days was 71% for placebo and 18% for pooled OP-101. At 60 days, 3/7 placebo-treated patients and 14/17 OP-101–patients survived without drug-related adverse events.
    SAB Comment: Multiple ligands can be attached to injectable dendrimer nanoparticles to allow the novel targeting, treating, and even illuminating of specific inflammatory cells. In this first-in-human trial, macrophages and microglia, suspected culprits in COVID-19, were nanotherapy-targeted and “treated” with high concentration of NAC. The striking, potentially “game-changing” survival results reported here in severe, corticosteroid-treated COVID-19 requires confirmation in much larger multi-institutional studies. Neuropsychiatric exams should be included.
  • Effectiveness Associated With Vaccination After COVID-19 Recovery in Preventing Reinfection. 7/27/22. Lewis N. JAMA Netw Open.
    In this cohort study of more than 95,000 Rhode Island residents from March 2020 to December 2021, including residents and employees of long-term congregate care (LTCC) facilities, completion of the primary vaccination series after recovery from COVID-19 was associated with 49% protection from reinfection among LTCC residents, 47% protection among LTCC employees, and 62% protection in the general population during periods when wild type, Alpha, and Delta strains of SARS-CoV-2 were predominant.
    SAB Comment: The finding that in people who have recovered from COVID-19, subsequent completion of the primary vaccination series reduced the risk of reinfection by approximately half is shown here for the earlier variants, but that conclusion may not be extended to the Omicron variants without further study.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic on the website:

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Newsletter Issue 140, August 3, 2022:

  • Claim CME ButtonExtended prone positioning duration for COVID-19-related ARDS: benefits and detriments. 7/8/22. Walter T. Crit Care.
    This retrospective observational study in France from March 2020-April 2021 evaluated 81 COVID-19 patients, using a strategy, originally implemented for organizational and human resources purposes. It was based on extending the duration of proning sessions (PP) up to 48 hours in patients ventilated for COVID-19-related ARDS. The primary objective, the occurrence of pressure injury, was observed in 26% of patients and was equivalent to patients who had PP sessions of shorter duration for non-COVID-19-related ARDS. The presence of skin injury, the most common complication of PP, correlated with cumulative duration of PP sessions and length of ICU stay, not the duration of each session. Extended PP significantly reduced staff viral exposure and workload, allowing for most position changes during the daytime. Longer proning sessions were also associated with continued improvements in ventilatory parameters over the extended time.
  • The COVID-19 pandemic and its consequences for chronic pain: a narrative review. 7/18/22. Shanthanna H. Anaesthesia.
    This is a narrative review of 3,859 published reports. It succinctly reviews new onset chronic pain after SARS-CoV-2 infection, the influence of the pandemic on patients with pre-existing chronic pain, possible pain mechanisms associated with SARS-CoV-2, and treatments being considered to address post-COVID-19 pain. Both new onset post-COVID-19 pain and ongoing chronic pain increased. Risk factors were social isolation, lack of psychological support, female sex, lower level of education, reduced physical activity and disabled employment status. Tables summarize key findings on COVID-19-associated pain and headache, and the effect of the pandemic on chronic pain patients and the use of steroids for pain interventions. A diagram illustrates possible mechanisms of pain and associated symptoms with COVID-19. Finally, vaccination and the use of steroids and opioids are discussed.
  • Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5. 7/5/22. Wang Q. Nature.
    The authors performed systematic antigenic analyses of Omicron subvariants finding BA.2.12.1 only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. Serum neutralization assays used sera from persons who received three shots of mRNA vaccines, others who received mRNA vaccines before or after non-Omicron infection, vaccinated patients with BA.1 or BA.2 breakthrough infection as well as pseudoviruses containing point mutations. The Omicron SARS-CoV-2 lineage continues to evolve, successively yielding subvariants that are both more transmissible and more evasive to antibodies.
    SAB Comment: Bebtelovimab (Eli Lilly) has been authorized under EUA since 2/22 for mild-to-moderate COVID-19 in patients older than 12 years and weighing at least 40 kg who are at high risk for progression to severe disease. It is given as a single IV injection, within 7 days of symptom onset. Readers may access current NIH Therapeutic Guidelines, including use of bebtelovimab, on the IARS COVID-19 Published Guidelines and Reviews web page.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic on the website:

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Newsletter Issue 139, July 18, 2022:

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Newsletter Issue 138, July 11, 2022:

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Newsletter Issue 137, July 6, 2022:

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Newsletter Issue 136, June 27, 2022:

  • Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure. 6/14/22. Reynolds CJ. Science.
    Even in those triple vaccinated, Omicron (B.1.1.529) can evade immune defenses. These investigators studied triple mRNA-vaccinated healthcare workers (TVHCW) with diverse COVID histories. Before suffering Omicron infections, TVHCW showed robust in vitro blood antibody, B- and T-cell immunity to all variants of concern (VOC) EXCEPT Omicron. Prior Alpha infections singularly dampened Omicron response duration. Previously infection-naive TVHCW who then suffered Omicron infections showed boosted immune responses to all VOC EXCEPT Omicron. TVHCW with a history of prior COVID infection followed by Omicron infections had negligible immune boosting. Interestingly, a prior Wuhan Hu-1 infection abrogated Omicron immune defenses. Inability of Omicron to boost itself invites reinfection.
    SAB Comment: It had been assumed that SARS CoV-2 infections would boost immune defenses against SARS-CoV-2, and that “hybrid immunity” (both vaccine and infection) would provide an even greater boost. This study shows that Omicron fails to boost immune responses in TVHCWs (remember-vaccine is Wuhan strain-based). The failure was especially profound if subjects had past Wuhan or Alpha infections termed, “hybrid immune-dampening.”
    This study predicts: 1) Omicron re-infection is possible/probable, and 2) vaccination + the specific SARS CoV-2 strain (e.g., Wuhan, Alpha, Delta) infection history will shape (“imprint”) the strength and durability of responses.
    Omicron produces poor antibody, T- and B-cell immunogenicity against itself, and predicts vaccines based purely upon Omicron-sequences may produce poor immunogenicity and protection unless paired with ancestral-sequence-based vaccine.
  • Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5. 6/22/22. Hachmann N. NEJM.
    These authors evaluated the neutralizing antibody titer levels against the reference WA1/2020 (ancestral) isolate of SARS-CoV-2 along with Omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 in 27 participants who had been vaccinated and boosted with messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). As expected, the neutralizing antibody titer was lower by a factor of 6 to 21 against the Omicron variants compared with the response against the WA1/2020 isolate. As compared with the median neutralizing antibody titer against the BA.1 subvariant, the median titer against the other omicron subvariants was lower by a factor of 2.2 against the BA.2.12.1 subvariant and by a factor of 3.3 against the BA.4 or BA.5 subvariant. The authors also tested neutralizing antibodies in an additional 27 participants (only one of whom had ever been vaccinated) who had been infected with the BA.1 or BA.2 subvariant a median of 29 days earlier. As compared with the median titers against the BA.1 subvariant, the median titer was lower by a factor of 1.5 against the BA.2.12.1 subvariant and by a factor of 2.9 against the BA.4 or BA.5 subvariant.
  • Rapid, scalable assessment of SARS-CoV-2 cellular immunity by whole-blood PCR. 6/13/22. Schwarz M. Nature Biotechnology.
    Low T-cell activation measurements to SARS-CoV-2 is predictive of COVID-19 breakthrough and need for revaccination. T-cell assays are difficult and rarely performed. These investigators developed fast, high-throughput quantitative PCR assays for T-cell activation. The tests stimulate whole-blood cells with SARS-CoV-2 antigens. Viral-specific T-cells secrete IFN-γ, which then stimulate monocytes to produce the cytokine CXCL10 mRNA which correlates and proved a proxy for SARS COV-2 antigen-specific T-cells activation. These assays may allow large-scale monitoring of both the magnitude and duration of functional T-cell immunity to SARS-CoV-2. In vulnerable populations, such screening may predict breakthrough infections and help prioritize revaccination strategies.
  • Nasal Spray of Neutralizing Monoclonal Antibody 35B5 Confers Potential Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern (VOCs): A Small-scale Clinical Trial. 6/6/22. Lin Y. Clin Infect Dis.
    These investigators studied a nasal spray formulation of a SARS-CoV-2 neutralizing IgG1 monoclonal antibody (“35B5”). In 30 healthy, disease-naïve but vaccinated volunteers, nasal mucosal samples were assayed against spike proteins of the wild type (WT) and variants of concern (VOC) including Omicrib (B.1.1.529) at 0h and again at 12h-72h post-spray. Samples collected within 24 hours following a single spray neutralized WT and all VOC. Protection efficacy dropped to 60% and 20% at 48h and 72h, respectively. At a time where most monoclonals have lost efficacy especially against Omicron, the 35B5 nasal spray formulation may enhance SARS-CoV-2 prevention especially in unvaccinated and high-risk populations.
    SAB Comment: This novel means of prevention at upper airway sites of viral introduction will need assessment in large-scale clinical trials. However, if proven effective, easy-to-administer intranasal monoclonals against VOC including Omicron would fill an unmet clinical need for those anticipating potential exposure including medical settings.
  • Below you will find a list of additional articles and resources selected for the IARS COVID-19 Resource website, all of which include a summary with major takeaways and are searchable by topic:

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Newsletter Issue 135, June 22, 2022:

  • Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials. 6/1/22. Zhu F. Lancet Respir Med.
    In this randomized, single-center, double-blind, placebo-controlled trial in healthy COVID-naïve adults, these investigators published the first intranasal vaccine results in humans. The Phase 1 (n=63 subjects), phase 2 (n=724) and phase 2-extension (n=297) trial arms administered a live-attenuated influenza virus vector-based SARS-CoV-2 spray (“dNS1-RBD”), 2 doses, 14 days apart. Peripheral blood showed both weak cellular (40-46% conversion) and IgG and IgA humoral responses (10-13% conversion). Secretory IgA (nasopharynx) conversions and concentrations were also weak. “dNS1-RBD” was well tolerated and without serious adverse effects (0-12 months). Despite apparent “weak” effects, this vaccine may be effective in a real-world, phase-3 trial, which is ongoing.
  • Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination. 5/18/22. Suryawanshi RK. Nature.
    This complex study applies basic laboratory research to answer the question whether widespread infections with the Omicron variant will eventually lead to herd immunity and end the COVID-19 epidemic. After creating mouse models susceptible to various SARS CoV-2 variants (WA1, Delta and Omicron), the authors compared their impact on respiratory tract pathology and immune markers and showed that Omicron infections were less severe and resulted in a diminished inflammatory response. When collecting convalescent serum from mice and humans, a diminished humoral immune response to Omicron infections compared to other variants indicated limited cross-variant neutralization induced by Omicron in mice and humans. Sera collected from vaccinated individuals experiencing breakthrough infections with Omicron developed higher neutralization titers against all variants, demonstrating that Omicron enhances pre-existing immunity but lacks protection against non-Omicron variants in the unvaccinated. Sera collected from vaccinated individuals experiencing breakthrough infections with Omicron developed higher neutralization titers against all variants, demonstrating that Omicron enhances pre-existing immunity but lacks protection against non-Omicron variants in the unvaccinated.
  • Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. 5/14/22. Yamasoba D. Cell.
    Authors review the mechanism of infection of all SARS-CoV-2 variants and studied infectivity and immune escape of BA.2, which has over 30 mutations compared with the Wuhan strain. Data suggest that similar to BA.1, BA.2 is highly resistant to antisera induced by vaccination or infection with other SARS-CoV-2 variants as well as three therapeutic antiviral antibodies. BA.2 has a 1.4-fold higher effective reproductive rate than BA.1 as well as higher fusion potential and pathogenic potential. BA.2 was 4-fold more resistant to BA.1-infected sera from convalescents without full vaccination. Multiple studies using convalescent human, hamster, and murine sera demonstrated that BA.1-induced humoral immunity is less effective against BA.2, but not vise versa. Virologic features and proposed mechanistic consequences are reviewed.

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Newsletter Issue 134, June 13, 2022:

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Newsletter Issue 133, June 6, 2022:

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Newsletter Issue 132, May 23, 2022:

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Newsletter Issue 131, May 16, 2022:

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Newsletter Issue 130, May 4, 2022:

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Newsletter Issue 129, April 25, 2022:

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Newsletter Issue 128, April 20, 2022:

  • Dysfunctional breathing diagnosed by cardiopulmonary exercise testing in ‘long COVID’ patients with persistent dyspnoea. 3/31/22. Frésard I. BMJ Open Respir Res.
    Cardiopulmonary exercise testing (CPET) identifies mechanisms of dyspnea by simultaneously evaluating cardiovascular adaptation, ventilation and gas exchange through exercise. Dysfunctional breathing (DB) with normal PaCO2 and V̇E/V̇CO2 has been described in long COVID, particularly erratic ventilation with wide, irregular variations of tidal volume and breathing frequency over the progression of effort during CPET. DB evaluated by CPET occurred in 15 of the 51 COVID patients complaining of dyspnea. DB was associated with younger age and previous mild/moderate acute COVID and was present >200 days following infection. DB without hyperventilation with erratic breathing and deep sighs may also explain persisting dyspnea in long COVID patients. The pathophysiology is unknown. A prompt diagnosis is needed in order to offer specific respiratory training.
  • Trajectories of Neurologic Recovery 12 Months After Hospitalization for COVID-19: A Prospective Longitudinal Study. 3/22/22. Frontera JA. Neurology.
    This study reports the results of telephone psychological testing and interviews of 294 patients 12 months after symptom onset of moderately severe to severe COVID-19 infection. Patients were tested to assess functional status and cognition and given structured interviews to determine presence of anxiety, depression, fatigue and sleep impairment. Abnormal scores on cognitive testing persisted in 50% of patients without a pre-COVID history of cognitive abnormalities, irrespective of the presence or absence of a neurological complication during hospitalization. Rates of abnormal cognition were substantially higher than rates of abnormalities in other domains such as activities of daily living, anxiety, depression, fatigue or sleep. Between the 6- to 12-month evaluations, the majority of patients did not have improvements in functional status or activities of daily living; however, there were significant improvements in cognition and anxiety scores.
  • Intravenous methylprednisolone pulses in hospitalised patients with severe COVID-19 pneumonia, A double-blind, randomised, placebo-controlled trial. 4/1/22. Salvarani C. Eur Respir J.
    In this multicenter, randomized, double-blind, placebo-controlled trial, 304 hospitalized COVID-19 patients received either 3 boluses of 1 g of methylprednisolone intravenously daily for 3 days or placebo in addition to standard dexamethasone. The key outcome was overall survival in days, discharge without oxygen / ETT. The study group included patients who had < 5 days of symptoms, PaO2: FiO2>200 with O2 and C-reactive protein > 5. Outcomes were similar in both groups including % discharged without O2, duration of hospital or ICU stay, death or adverse reactions. Pulsed methylprednisolone in addition to dexamethasone was safe but redundant to treat hyper-inflammation.
  • Factors for success of awake prone positioning in patients with COVID-19-induced acute hypoxemic respiratory failure: analysis of a randomized controlled trial. 3/29/22. Ibarra-Estrada M. Crit Care.
    Although awake prone positioning (APP) may be helpful, identifying which COVID-19 patients benefit is key. This multicenter, randomized controlled trial from Mexico of 941 COVID-19 patients with respiratory failure requiring high flow nasal cannula (HFNC) between May 2020 and January 2021 identified factors associated with success of APP in preventing intubation. Predictors of APP success in these patients that already required HFNC to maintain SpO2 over 91% included an APP duration at least 8 hours per day, a respiratory rate at enrollment below 26, and improvement in objective measurements (ROX and lung ultrasound) in response to APP. The number needed to treat to prevent intubation was 8.
    SAB Comment: This is a post hoc analysis of a meta-trial featured previously in this newsletter. Though some studies do not show a benefit from APP for patients requiring simple nasal oxygen and using APP for shorter periods of time, this study clearly shows that patients with more severe respiratory failure may benefit, especially with longer APP times. Maintaining the prone position in sick, awake patients is difficult. Authors discuss their approach to this challenge.

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Newsletter Issue 127, April 11, 2022:

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Newsletter Issue 126, April 4, 2022:

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Newsletter Issue 125, March 28, 2022:

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Newsletter Issue 124, March 22, 2022:

  • NIH Therapeutics Recommendations – Updated March 2, 2022
    Based upon data generated during the Omicron variant surge, the NIH has revised its recommendations for antiviral therapeutics for nonhospitalized patients with mild-moderate COVID-19 at high risk of progression to severe disease. The drugs are ranked by order of preference. Click here to read the full NIH treatment guidelines.
    NIH
  • Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants. 3/16/22. Yu J. N Engl J Med.
    Omicron has three major sublineages: BA.1, BA.2, and BA.3, each with common and unique mutations to evade neutralizing antibodies (NAbs). Recently, BA.2 is surging. These investigators compared NAbs against Wuhan and BA.1/BA.2 strains induced post-Pfizer vaccinations (primaries + booster, n=24) vs. BA.1 natural infection (n=8). Two weeks postbooster vaccinations, NAbs to each virus rose by 10-fold vs post-primary vaccination; BA.1 NAbs =1.4x BA.2. Two weeks post-BA1 infection, BA.1 and BA.2 titers were each 3x higher vs. postbooster values. Conclusion: BA1 infection confers higher cross-reactive BA.2 NAbs than vaccination alone and the BA.2 surge is from increased infectivity, not immunological escape.
    SAB Comment: Neutralizing antibody titers were undetectable to both BA.1 and BA.2 six months postprimary series before receiving boosters. This emphasizes a critical need for the six-month booster to protect against variants. Seven of eight infected patients were previously vaccinated. The unvaccinated eighth rapidly became critically ill.
  • Efficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron. 3/17/22. Regev-Yochay G. N Engl J Med.
    This research letter from Israel examines the immune response and vaccine efficacy to a 4th dose of mRNA vaccine in 274 young, healthy healthcare workers, compared to matched controls. This non-randomized study took place in January 2022 during an Omicron surge. All subjects were tested with RT-PCR weekly. The 4th vaccine dose increased the antibody levels and viral neutralization by a factor of 10, but vaccine efficacy was low and relatively high viral loads were found, suggesting those with positive RT-PCRs were infectious. The authors conclude that a 4th vaccination of healthy people may have only marginal benefits. Older and vulnerable populations were not assessed.
    SAB Comment: Though a small study, this is hopefully the first of much more information on the utility of a second booster. Of note is the infectiousness of those who get Omicron, whether or not they received a 4th vaccine dose (masks may still play a role), and that data on an older population with more comorbidities has yet to be presented.
  • Palliative care consultation and end-of-life outcomes in hospitalized COVID-19 patients. 12/13/21. Cheruku SR. Resuscitation.
    This is a multicenter analysis of end-of-life care for 3,227 adult patients who died from COVID-19 between March 2020 and March 2021 in US hospitals without resource constraints, based on registry data of the Society of Critical Care Medicine. Cardiopulmonary resuscitation was given to 10% of patients and not given to 90%; about 20% of both groups had a palliative care consultation. However, patients who received individualized comfort care measures rather than continuation of life-sustaining treatment were significantly more likely to have had palliative care consultation (43.2% v 8.5%). The authors suggest that palliative care consultation at the end-of-life may better align the needs and values of patients with their received care.
  • The Fragility of Statistically Significant Results in Randomized Clinical Trials for COVID-19. 3/18/22. Itaya T. JAMA Netw Open.
    The objective of this study was to use the fragility index (FI) to evaluate the robustness of statistically significant findings from RCTs for COVID-19. Forty-seven English language articles published by August 7, 2021, involving 138,235 participants were included. In order to apply the index, studies must randomly assign patients 1:1 into 2 parallel groups and reported at least 1 binary outcome as significant in the abstract. In this study, many randomized clinical trials (RCTs) had a low FI, challenging confidence in the robustness of the results. The median was 4, meaning a change in outcome of only 4 participants was required to change the analysis findings from “statistically significant” (P<0.05) to not significant. In over half of the trials, the FI was less than 1% of sample size. Thirty-six were drug trials, with a median FI of 2.5. The most robust group contained 6 vaccine trials, with a median FI of 119. Authors state, “The fragility of RCT results should be considered before applying them to clinical settings,” and “Health care professionals and policy makers should not rely heavily on individual results of RCTs on COVID-19,” particularly small studies.
  • Additional articles and resources selected for the IARS COVID-19 Resource website and searchable by topic:

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Newsletter Issue 123, March 14, 2022:

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Newsletter Issue 122, March 7, 2022:

  • Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. 2/16/22. Hammond J. N Engl J Med.
    This industry-sponsored, phase 2-3, double-blind, randomized, controlled trial treated patients with either nirmatrelvir and ritonavir (Paxlovid, n=1039) or placebo (n=1046). Patients were symptomatic less than 5 days, unvaccinated, not hospitalized at enrollment and at high-risk. At 28 days, combined hospitalizations and deaths were 88% lower in the treated group. No deaths were reported in the treated group. Fewer serious adverse events and adverse events leading to discontinuation occurred with nirmatrelvir and ritonavir than with placebo. The most frequent adverse events occurring more often in recipients of nirmatrelvir plus ritonavir were dysgeusia, diarrhea and vomiting.
    SAB Comment: This is the definitive study on the use of Paxlovid. See highlights from the NIH therapeutic guidelines for possible drug interactions.
  • ‘I can’t cope with multiple inputs’: a qualitative study of the lived experience of ‘brain fog’ after COVID-19. 2/12/22. Callan C. BMJ Open.
    The authors collected and analyzed comments from 50 patients describing their sensations living with neurocognitive dysfunction resulting from “long COVID.” Qualitative analysis revealed the following themes: rich descriptions of the experience of neurocognitive symptoms (especially executive function, attention, memory and language), accounts of how the illness fluctuated — and progressed over time; the profound psychosocial impact of the condition on relationships, personal and professional identity; self-perceptions of guilt, shame and stigma; strategies used for self-management; challenges accessing and navigating the healthcare system; and participants’ search for physical mechanisms to explain their symptoms.
    SAB Comment: The analysis is supplemented with a series of direct quotes from some of the study subjects which may give valuable insight to clinicians caring for similar patients.
  • Risks of mental health outcomes in people with covid-19: cohort study. 2/16/22. Xie Y. BMJ.
    This Veterans Administration study carefully documents the mental health outcomes of 153,848 COVID-19 survivors at one year. These outcomes were compared to two control groups, contemporaneous and pre-COVID. The risks of mental health disorders was substantial and spanned several disorder categories, including anxiety, depression, stress and adjustment disorders, opioid and other substance use disorders, cognitive decline and sleep disorders. The risks were evident even among those with COVID-19 who did not require hospital admission. The authors feel that tackling mental health disorders among survivors of COVID-19 should be a priority.
    SAB Comment: The authors analyzed an enormous amount of data, and presented the results in a series of graphs and tables which succinctly and clearly summarize the scope of post-COVID mental health problems. An associated opinion by the senior author cautions against dismissing these long COVID mental health problems as psychosomatic.
  • Association of COVID-19 Acute Respiratory Distress Syndrome With Symptoms of Posttraumatic Stress Disorder in Family Members After ICU Discharge. 2/18/22. Azoulay E. JAMA.
    This is a prospective 2020 cohort study in 23 French ICUs. Family members of patients with COVID-19 ARDS had a significantly higher prevalence of symptoms of posttraumatic stress disorder (PTSD), anxiety, and depression at 90 days after patients’ discharge from the ICU than family members of patients with non–COVID-19 ARDS. Three hundred and seven patients and 602 family members participated. Twenty-six percent of patients died before the relatives had the day-90 assessment, similar for patients with and without COVID-19. PTSD symptoms were significantly higher in families of patients who died from COVID-19 compared with non-COVID-19 ARDS. Non-COVID-19 ARDS and COVID-19 ARDS survivors had rates of symptoms that were not significantly different for PTSD, anxiety, or depression. Compared with family members, ICU survivors reported fewer PTSD symptoms. The discussion addresses outcome determinants.
  • Thromboprophylaxis in Patients with COVID-19. A Brief Update to the CHEST Guideline and Expert Panel Report. 2/15/22. Moores LK. Chest.
    This article updates the CHEST guidelines for thromboprophylaxis for COVID-19. Briefly, they suggest full dose anticoagulation with heparin for acutely ill hospitalized patients not in the ICU who are at high risk for deep vein thrombosis and without high risk for bleeding. The remainder of hospitalized patients should be on prophylactic doses of heparin. They do not suggest intermediate doses of heparin. These guidelines are developed using a Delphi approach. In addition, they summarize the evidence supporting these conclusions. This concise report represents the most up-to-date guidelines and is useful for clinicians.
    SAB Comment: This manuscript is based upon the evidence (RCTs) that have demonstrated improved mortality and decreased need for organ support with these protocols. The authors do take into account the implementation of these guidelines.
  • Noninvasive respiratory support for COVID-19 patients: when, for whom, and how? 1/15/22. Sullivan ZP. J Intensive Care.
    This is a directed review of non-invasive respiratory support (NIRS) for patients with COVID-19 based upon an extensive evaluation of its literature with and without proning (57 citations). Under the NIRS rubric the authors include high flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and non-invasive ventilation (NIV) which predominantly implies bilevel positive airway pressure (BiPAP). They discuss the rationale and evidence for NIRS in enhancing outcome, particularly avoidance of invasive mechanical ventilation (IMV), in patients with COVID-19 but also compare its use in prior pandemics (SARS, MERS, H1N1) and other forms of acute respiratory failure. They use this to generate a COVID-19 NIRS decision algorithm that includes indications, contraindications, most appropriate form of NIRS, monitoring, steps to reduce health care worker viral exposure and predictors of failure. The authors conclude that judicious use of NIRS may provide an acceptable alternative to early IMV in COVID-19 patients with mild to moderate acute respiratory failure.
    SAB Comment: This is an excellent overview that provides a practical summary of the different forms of NIRS, their historic and COVID-19 evidence basis, and a coherent step-wise clinical guideline to decision-making in their application and transition to IMV. As such it provides an extremely useful resource for providers who care for hospitalized COVID-19 patients.
  • Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. 2/18/22. Afkhami S. Cell.
    Using both a human and chimpanzee adenoviral (Ad) vectored vaccine expressing three COVID antigens (spike-1, and internal/conserved nucleocapsid, and RNA-dependent-RNA-polymerase) these investigators showed marked protection in a murine model. Single-dose intranasal was much superior to IM immunization. Tripartite protective immunity was demonstrated in local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal-trained innate immunity. Intranasal immunization protected against the ancestral strain and two variants of concern (VOC): alpha (UK) and beta (S. African). Conclusion: Intranasal mucosal delivery of this Ad-vectored multivalent vaccine is a next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.
    SAB Comment: This scientific tour de force used a murine model to rigorously demonstrate the superior protective effects of their trivalent vaccine administered intranasally vs. IM. Human phase 1 trials have begun comparing immune responses to both the human and chimpanzee versions after aerosol delivery to mRNA-vaccinated humans (clinicaltrials.gov: NCT05094609).
  • Additional articles and resources selected for the IARS COVID-19 Resource website and searchable by topic:

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Newsletter Issue 121, February 28, 2022:

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Newsletter Issue 120, February 22, 2022:

SPECIAL EDITION: Mental Health and COVID-19

  • SAB Comment: Due to increasing attention to and recognition of COVID’s negative psychologic impact on all healthcare workers [including physicians, nursing staff, nursing home caregivers, first responders, etc.], survivors and survivors’ families, the SAB is presenting the following articles as a current collation of relevant articles. Further information on this topic will be forthcoming.
  • Anxiety, worry, and job satisfaction: effects of COVID-19 care on critical care anesthesiologists. 1/13/22. Siddiqui S. Can J Anaesth.
    This correspondence describes the psychological impact of the COVID-19 pandemic on intensivists in late 2020. An online survey was sent to 1,400 mostly American intensivists, 21% of whom responded. Analysis of the results indicate that the COVID-19 pandemic is associated with a high incidence of generalized anxiety disorder (42%) and an increased sense of burnout among critical care anesthesiologists, particularly in females (73%) and younger physicians. This is balanced by enhanced job satisfaction and a sense of being respected and valued for contributions during the pandemic. Seventy-five percent felt that institutional wellness resources were unhelpful.
  • The Impact of the COVID-19 Pandemic on Mental Health, Occupational Functioning, and Professional Retention Among Health Care Workers and First Responders. 12/16/21. Hendrickson RC. Journal of General Intern Med.
    The authors conducted an observational survey of 510 US health care workers and first responders at a single time-point between September 2020 and February 2021. The goal was to examine the relationships between COVID-19 occupational stressors and symptoms of posttraumatic stress disorder (PTSD), depression (and suicidality), insomnia and anxiety as well as functional impairment and likelihood to leave the current profession. Stressors included factors related to volume (intensity of patient suffering, long hours), demoralization (futile care, lack of personal protective equipment, inadequate support) and risk (to oneself or family). There was a direct relationship between the intensity of stressors (especially demoralization) and psychiatric symptoms (especially PTSD). Both were more intense in nurses than physicians and in emergency medical services than firefighters or police. More than half the health care workers reported that working in the pandemic decreased their likelihood of remaining in their current field. Based upon their data the authors suggest a number of strategies that could mitigate stressors, especially those related to demoralization.
  • Challenges for the Beleaguered Health Care Workforce During COVID-19. 1/27/22. Cutler DM. JAMA Forum.
    This is a brief review of the COVID-19 pandemic-induced challenges to the health care workforce that have culminated in burnout and widespread job resignation. The latter has been particularly prevalent in low-wage occupations such as health aides and licensed practical nurses in home health care and nursing homes. Simultaneous increase or steady health care worker demand in the face of falling supply has resulted in wage increases, but still leaves hospitals and health care workers stressed because of inadequate patient coverage and stalled throughput. The author recommends strategies to reduce burnout, including vaccine mandates, continued reimbursement for telehealth, and billing simplification.
  • Mental health symptoms in family members of COVID-19 ICU survivors 3 and 12 months after ICU admission: a multicentre prospective cohort study. 2/1/22. Heesakkers H. Intensive Care Med.
    To better understand the impact of a COVID-19 intensive care unit (ICU) admission on family members, this prospective cohort study from ICUs in 10 Dutch hospitals followed 197 family members of surviving ICU COVID-19 patients. Questionnaires were completed by family members at enrollment, 3 months and 12 months. Thirty-eight percent experienced at least one mental health symptom (anxiety, depression, or posttraumatic stress disorder) and 23% experienced two or more mental health symptoms, all significantly higher than baseline. Additionally, family members experienced a reduction in quality of life and an impaired work status. Clinicians, including non-ICU clinicians (e.g., general practitioners), should be aware of the high prevalence of mental health problems among family members of COVID-19 ICU patients, especially in family members with mental health symptoms prior to ICU admission.

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Newsletter Issue 119, February 14, 2022:

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Newsletter Issue 118, February 7, 2022:

  • Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae. 1/19/22. Su Y. Cell.
    These numerous authors present an extensively detailed, longitudinal profiling of 209 COVID-19 patients representing a broad spectrum of acute infection severities along with 457 healthy controls. Patients were studied at clinical diagnosis, during acute disease, and 2-3 months after onset of initial symptoms. Four features present at diagnosis (pre-existing type 2 diabetes, assessments of SARS-CoV-2 RNAemia, EBV viremia, and autoantibodies) predicted the likelihood of Post-Acute Sequelae of COVID-19 (PASC), a syndrome defined by the CDC as a range of new, returning, or ongoing health problems that people can experience four or more weeks following initial SARS-CoV-2 infection (called “Long COVID” by some). The authors note that each of the features associated with PASC in the study can be treated.
    SAB Comment: This study demonstrates a statistical association between the 4 features noted and the persistence of symptoms 2-3 months later, but the authors don’t claim to show a causal relationship or predict a response to treatment. They don’t attempt to distinguish these associations from those related to intensive care hospitalization or predict the persistence of the symptoms longer than 2-3 months.
  • Cardiac Dysfunction and Arrhythmias 3 Months After Hospitalization for COVID-19. 1/20/22. Ingul CB. J Am Heart Assoc.
    In this data-rich Norwegian study of 204 hospitalized COVID-19 survivors and 204 matched controls the authors conclude: “At 3 months after COVID‐19 hospitalization, patients had mildly impaired RV (right ventricular) function, reduced diastolic function, and mainly preserved left ventricular function compared with matched controls. Premature ventricular contractions and nonsustained ventricular tachycardia were common, but the relation to COVID‐19 is unknown. Patients treated in an ICU had similar cardiac function as those not admitted to an ICU. Persistent dyspnea or fatigue were not found to be associated with cardiac function.”

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Newsletter Issue 117, January 31, 2022:

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Newsletter Issue 116, January 24, 2022:

  • Perioperative Cardiovascular Considerations Prior to Elective Noncardiac Surgery in Patients With a History of COVID-19. 1/12/22. Rohatgi N. JAMA Surg.
    Risk evaluation for patients with preoperative cardiac risk factors for noncardiac surgery is standard anesthesiology practice. COVID-19 is associated with cardiovascular complications including but not limited to myocardial injury, dysrhythmias, and thromboembolism. Following symptomatic recovery, optimal timing for elective surgery is discussed with data supporting a seven-week delay. Standard clinical practice guidelines can be applied to COVID-19 patients with clinical appreciation for disease severity in individual cases. A valuable table is included for reference.
    SAB Comment: This opinion piece is timely given the current impact of the Omicron surge, high hospital occupancy and healthcare staff shortages on elective noncardiac surgery. However, its value may lie in stimulating discussion rather than providing a strict guideline. We have insufficient data on postacute cardiovascular manifestations and long COVID after Omicron. In a real-world situation, optimal timing of elective noncardiac surgery may depend on the interaction of institutional constraints, appropriate cardiovascular assessment and the relative “electiveness” of surgery, rather than a fixed delay.
  • Myocarditis and Pericarditis After Vaccination for COVID-19. 8/4/21. Diaz GA. JAMA.
    This is a report on postvaccination myocarditis or pericarditis derived from data from 40 hospitals in the Providence healthcare system based in 4 states (WA, OR, MT and CA). Out of more than 2 million individuals receiving at least one vaccination (97% Pfizer or Moderna), there were 20 cases of myocarditis and 37 of pericarditis, a rate of 1.0 and 1.8 per 100k vaccinations, respectively. These represented two distinct self-limited syndromes. Myocarditis patients were mostly young (median age 36 years), male, developing symptoms 3-10 days after the second vaccination. Nineteen of 20 were admitted to hospital and all were discharged after a median of 2 days. All patients had symptom resolution or improvement within 5-40 days of onset. Pericarditis patients were also mostly male, but older (median age 59 years) with more comorbidity, developing symptoms 6-41 days after the first or second vaccination. About half (19/37) required hospital admission with a median stay of 1 day. A minority of both groups required cardiovascular therapy in addition to anti-inflammatory medications.
    SAB Comment: This US-based report emphasizes that myocarditis and pericarditis are extremely rare, distinct entities occurring in different age groups, that are self-limited with a benign outcome. This risk should be compared with the risk of developing cardiovascular complications in unvaccinated patients with severe COVID-19.
  • Antiplatelet Therapy in Patients With COVID-19-More Is Less? 1/18/22. Spaetgens B. JAMA.
    This editorial reviews a multinational prospective trial that randomized 562 non-ICU selected patients with COVID-19 to 1) therapeutic heparin or 2) therapeutic heparin with a P2Y12 inhibitor (ticagrelor 63%, clopidogrel 37%). The number of days free of respiratory or cardiovascular organ support, incidence of death in the hospital, and bleeding complications were the same between the two groups.
    These data suggest no additional benefits with the use of P2Y12 inhibitors in the face of full therapeutic anticoagulation for non-ICU patients with COVID-19. These data are consistent with prior data failing to demonstrate benefit of the use of aspirin in COVID-19 patients.
    SAB Comment: The trial started on February 26, 2021 but was discontinued due to futility 4 months later.
  • Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. 12/22/21. Gottlieb RL. N Engl J Med.
    In this randomized, double-blinded, placebo controlled trial of 3 doses of Remdesivir (N=279 vs. placebo N=283), COVID-19 patients, ages 50+, with symptoms and one co-morbidity were studied. Remdesivir had a 87% lower risk of COVID-19–related hospitalization or death and 81% lower risk of medical visits compared to the placebo at day 28. The drug is considered to be safe in the outpatient setting. This group included patients that were unvaccinated and not on oxygen before the emergence of the Delta variant.
  • Debulking SARS-CoV-2 in saliva using angiotensin converting enzyme 2 in chewing gum to decrease oral virus transmission and infection. 11/10/21. Daniell H. Molecular Therapy.
    This study describes the development of a chewing gum containing virus-trapping proteins expressly designed to minimize oral virus transmission or reinfection. Salivary glands are primary sites of SARS-CoV-2 replication and saliva from symptomatic or asymptomatic COVID-19 patients contains a viral load proportionate to the severity of symptoms. Contagious airborne droplets are the major form of transmission of the virus, which utilizes ACE2 receptors to enter cells. The authors incorporated biomass plant-created cholera toxin B(CTB)-ACE2 powder into flavored chewing gum and tested its ability in vitro to bind to viral spike proteins, debulk virus from saliva and thus potentially reduce oral transmission. Incubation of CTB-ACE2 microparticles with infected saliva reduced SARS-CoV-2 virus count by >95%. Since the mechanism utilizes the ACE2 receptor rather than blocking specific viral antigens, it has the potential to be effective regardless of the variant genome.
    SAB Comment: This is a remarkably novel approach to the amelioration of viral transmission that if proven to be beneficial in vivo could have dramatic effects on COVID-19 contagion. It also creates the potential of allowing millions to chew gum and walk at the same time.
  • Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant. 1/18/22. Gao Y. Nat Med.
    In some cases, Omicron, despite escaping antibodies, does not lead to severe disease. These investigators examined Omicron spike-specific CD4+ and CD8+ T cell responses induced by prior infection or BNT162b2 (Pfizer) vaccination. Spike-specific CD4+ T cells that cross-recognized Omicron in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and for CD8+ T cells were 70% and 92%. The CD4+ and CD8+ T cells were functionally and phenotypically similar in response to the ancestral strain or Omicron. These data indicate that established SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses, especially after BNT162b2 vaccination, remain largely intact against Omicron.
  • Additional articles and resources selected for the IARS COVID-19 Resource website and searchable by topic:

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Newsletter Issue 115, January 19, 2022:

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Newsletter Issue 114, January 10, 2022:

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