The Daily Dose • Sunday, May 16, 2021
Hope Beyond the COVID-19 Vaccine in the Wake of the Pandemic
COVID-19 infections result in mild symptoms or asymptomatic cases in the majority of the population due to innate immunity; however, roughly five percent of cases experience a devastating multisystemic disease. Much is still unknown about the science behind that disease. Thought leaders of the “Science of COVID Symposium,” presented on May 15, who are actively exploring this mystery, shared their latest research about alternative ICU sedation, pathologic thrombosis, and innate immunity surrounding COVID-19 management that has unfolded in the wake of the pandemic.
As a result of the extraordinary number of ventilated COVID-19 patients that filled our ICU across the world, the US Federal Food and Drug Administration issued warnings for IV sedation shortages. Angela Jerath, Msc, FRCPC, FANZA, MD, BSc, from Sunnybrook Health Sciences Centre in Toronto, explained how intensivists were left with few options, and volatile anesthetics became a reasonable alternative.
Fortunately, Dr. Jerath’s institution had several years of prepandemic experience utilizing volatile agents for ICU sedation. She brought convincing research from her experiences for their use in this setting with COVID-19 patients. Her own meta-analysis, “Safety and Efficacy of Volatile Anesthetic Agents compared with standard IV midazolam/propofol sedation in Ventilated Critical Care Patients,” published in Anesthesia & Analgesia, compared volatile anesthetics with benzodiazepine and propofol and found faster awakening and extubation times with volatile anesthetics.
Volatile anesthetics offer additional benefits over IV sedation in the ICU, she explained. Real time end-tidal concentration monitoring reflects blood and brain levels. Volatile anesthetics also have limited end-organ metabolism, sparing the hepatorenal system, as they are primarily eliminated by respiration.
Not only are volatile anesthetics a great option for sedation, they may reduce the immune response by decreasing inflammation in the lung. A 2009 study by De Conno et al., “Anesthetic-induced improvement of the Inflammatory Response to One-Lung Ventilation,” published in Anesthesiology, compared inflammatory mediators of total intravenous anesthesia (TIVA) propofol versus sevoflurane groups before and after one-lung ventilation demonstrated lower inflammatory mediators (TNF-alpha, IL-6, IL-8, MCP-1) in the sevoflurane group compared to the TIVA group.
In 2017, de la Gala et al. performed a larger trial of propofol versus sevoflurane for lung resection, “Postoperative pulmonary complications, pulmonary and systemic inflammatory responses after lung resection surgery with prolonged one-lung ventilation,” which was published in the British Journal of Anaesthesia. Decreased pulmonary complications, inflammatory markers, and 1-year mortality occurred in patients in the sevoflurane group compared with those who received propofol.
Dr. Jerath and colleagues are now studying these benefits specifically in ICU COVID-19 patients in the Save-ICU trial, comparing patients who receive inhaled volatile anesthetics versus intravenous sedation. Study outcomes to be examined include ICU-free days, ventilator-free days, quality-of-life, and in-hospital mortality.
This paradigm shift of using volatile anesthetics for ICU sedation has its challenges. Adequate scavenging systems in the ICU and robust staff training on vaporizer systems and volatile management are essential. Dr. Jerath is hopeful that outcomes for long-term volatile anesthetic use in the ICU will show additional benefits with further research.
Beverley Hunt, OBE, RCP, FRCPath, from King’s College London, and a national and international expert in thrombosis, has done extensive work in hemostasis abnormalities. She has been at the forefront of solving the perplexing pathological thrombosis of COVID-19 as well as investigating the recent vaccine-induced thrombotic thrombocytopenia.
The coagulopathy of COVID-19 is the result of the proinflammatory response: high levels of interleukin-1 and interleukin-6 cause the liver to produce excessive procoagulants. Many patients already have an existing inflammatory state (diabetes, atherosclerosis, aging) but determining predisposing factors is still under study, Dr. Hunt outlined. Early in the pandemic, DIC presented with high fibrinogen levels. This causes increased blood viscosity that leads to venous thromboembolism. Two processes discovered in the lungs: pulmonary embolism resulting from embolized DVT and microvascular immunothrombosis of ARDS, causing pulmonary thrombosis.
Why do coagulopathies occur in COVID-19 patients with ARDS? The body produces excessive fibrin to wall off infectious organisms, Dr. Hunt explained. Additionally, these patients have viscous blood and hypoxia where an incredible prothrombotic state occurs.
Dr. Hunt asked the question, “Is COVID-19 the most prothrombotic state we have seen?” Her recent 2021 study, “Comparison of Thrombosis and Hemorrhagic Rates in Patients with Severe Respiratory Failure due to COVID-19 and Influenza Requiring ECMO,” published in Critical Care Medicine, found pulmonary thromboembolism and catheter-associated DVT were greater in patients requiring extracorporeal membrane oxygenation for coronavirus than for influenza. In Hunt et. al., “Prophylactic anticoagulation for patients in hospital with covid-19,“ published in the British Journal of Medicine, full dose anticoagulation in moderately ill patients proved to be potentially beneficial in improving outcomes. Antiviral properties of heparin may be responsible for this success.
Dr. Hunt concluded her presentation, describing the rare syndrome of thrombosis and thrombocytopenia seen following the adenoviral vector vaccines (AstraZeneca and Johnson & Johnson) similar to heparin-induced thrombosis. These patients have antiplatelet factor 4 antibody. Hunt advised treating with IV IgG to blunt the immune response. Other vaccine components may also be responsible for this inflammatory response.
Leon du Toit, MBChB, MMed, FCA, from University of Cape Town, discussed his work with the CROWN Coronation, a multinational platform of phase 3 trials of agents to prevent symptomatic COVID-19 illness and enhance innate immunity. Leon provides hope for preventing severity of COVID illness beyond the current COVID-19 vaccines.
The immune system is composed of both the innate and adaptive systems. The former has a rapid robust response while the adaptive system provides a slower more specialized response. Dr. du Toit proposed bolstering the rapid innate response through nonspecific modalities as a first line of defense.
A study by Netea M.G. et. al., “Defining trained immunity and its role in health and disease,” published in Nature, contributed to the growing evidence that suggests the innate immune system contributes to immune memory. Plants and invertebrates have only innate immune systems yet still exhibit immune memory and have thrived for centuries.
Dr. du Toit used Edward Jenner’s vaccinia polio vaccine as an example of vaccine off-target effects. While the vaccine led to near irradiation of polio, the off-target effects of this vaccine included decreased mortality in low-income countries and decreased asthma, melanoma, and infectious disease hospitalization in high-income countries. Oral polio vaccine has also demonstrated off-target effects such as 3.8-fold decrease in influenza mortality and 32% decrease in infant mortality in West Africa.
Off-target effects of vaccines can be explained by the innate immune system’s memory and ability to store long-term programming responses after initial immune threats, Dr. du Toit explained. These nonspecific effects could have a greater public health impact than the vaccine’s original intended effect. Studies are underway for the off-target effects of bacille Calmette-Guerin, measles, mumps & rubella, influenza, zoster, and polio against COVID-19, as described by Gonzalez-Perez et. al. in their article “The BCG vaccine for COVID-19: first verdict and future directions,” published in Frontiers in Immunology.
Why spend resources on trained immunity and nonspecific vaccines when we have effective COVID-19-specific vaccines? Reasons include limited availability of COVID-19 vaccine in some countries, limited safety data, new coronavirus variants, duration of protection, vaccine interaction, priming, and preparation for the next pandemic, according to Dr. du Toit.
In the Q&A session, moderated by Michael S. Avidan, MBBCh, from Washington University in St. Louis, the panelists referred to the recently published Lancet report from May 12, 2021 by Shaw, et al., “Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data,” in which the 2-dose COVID-19 vaccine series with patients who had the same vaccine for the 2 doses were compared with patients who received different COVID-19 vaccines for the 2 doses. The heterogenous group showed more severe systemic responses. In closing, Dr. Avidan reminded attendees that caution is needed as we move forward with vaccine research. Manipulating innate immunity is a double-edged sword − you can’t always be sure you will get the benefits you desire or avoid the inflammatory consequences you dread.