The FLARE Four
- The primary cause of death in COVID-19 is sepsis-associated acute respiratory distress syndrome (ARDS)
- ARDS probably develops because early innate immune responses are impaired, resulting in a pathogenic "inflammatory loop"
- Attempts to target early inflammation in COVID-19 have not been successful; it's not clear that all patients have the same type of inflammatory response, and the novel coronavirus has different latency periods in different individuals
- Immunomodulation for COVID-19 should be approached with caution as corticosteroid therapy has not been helpful against other diseases caused by RNA viruses and can be harmful
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It's important to apply basic pathobiology to clinical treatment, but even more so during the COVID-19 pandemic, according to speakers at Massachusetts General Hospital's virtual Medical Grand Rounds on March 26, 2020.
Rebecca M. Baron, MD, of the Department of Pulmonary and Critical Care at Brigham and Women's Hospital, and Jason Griffith, MD, PhD, of the Division of Pulmonary & Critical Care Medicine at Mass General, participated in a meeting co-sponsored by their hospitals and Beth Israel Deaconess Medical Center. In their talks, the two describe the biology of COVID-19 related acute respiratory distress syndrome (ARDS) and potential therapeutic strategies.
Background on ARDS
Dr. Baron began by describing the pathophysiology of ARDS, the primary cause of death in COVID-19. The hallmark of ARDS is a breakdown of the barrier between the alveolus (the gas-exchanging unit of the lung) and the adjacent capillary, which allows an influx of inflammatory cells and proteinaceous fluid. That material floods the lungs and patients can essentially drown.
Patients with COVID-19 develop sepsis-associated ARDS, which has higher mortality than other causes of ARDS. Fundamentally, sepsis is a dysregulated host response to a microbial pathogen. In cases of infection with SARS-CoV-2—the virus that causes COVID-19—the sepsis commonly occurs from pneumonia or direct lung injury.
COVID-19 Pathogenesis and Potential Treatment Strategies
SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the lung epithelium, which allows the virus to enter the cell. Viral binding to the receptor also releases a pro-inflammatory response out of proportion to the compensatory anti-inflammatory response, and that results in lung injury. This phenomenon has stimulated keen interest by researchers in interfering with viral entry as one approach to therapy.
Another strategy would be to target the dysregulated inflammatory response of the host. This has been thought of for decades in sepsis, but has not been effective. The reason might be that there are two subphenotypes of ARDS, one of which is characterized by hyperinflammation, shock and metabolic acidosis and has been linked to significantly worse clinical outcomes. However, sepsis can also develop in patients with ARDS who do not have a hyperinflammatory response.
There have been attempts to target early inflammation in the treatment of COVID-19, but that's a "blunt tool" and can be challenging. It's not clear that all patients with COVID-19 have the same type of inflammatory response. Moreover, SARS-CoV-2 has different latency periods in different individuals, so it's not possible to know a presenting patient's immune stage and degree of viral control.
Lessons from Influenza
Building on Dr. Baron's talk, Dr. Griffith specified that in a cohort study from China, published in JAMA Internal Medicine, ARDS in patients with COVID-19 was associated with elevated levels of interleukin-6. In patients with severe influenza, this early innate immune response is known to be critical in suppressing early viral replication. It allows activated dendritic cells to travel to the lymph node and activate adaptive immunity in the form of T and B cells.
The adaptive immune response takes time, though—seven or eight days in a mouse model of influenza. In the meantime, other innate immune cells such as neutrophils and natural killer cells try to suppress viral replication.
If early innate immune responses are impaired and viral replication is excessive, a pathogenic feedforward inflammatory loop develops. Incoming neutrophils and inflammatory monocytes produce increasing amounts of cytokines, which then recruit additional neutrophils and inflammatory monocytes, leading to an aberrant inflammation response. That results in ongoing epithelial injury as well as vascular leak, and it's thought that' is what promotes the development of ARDS.
Corticosteroids: Proceed with Caution
Elevation of inflammatory cytokines led to the idea of treating pandemic influenza with immune modulation in the form of corticosteroids. That was tried in 2009 in patients with severe H1N1 influenza, but in a study outside France, published in the American Journal of Respiratory and Critical Care Medicine, early steroid therapy was actually associated with worsening outcomes. Critical Care published a meta-analysis in 2015 and another in 2019 that also determined that steroid treatment can be harmful in patients with influenza-related pneumonia.
Similarly, a recent commentary in The Lancet points to the lack of benefit of steroids in patients with Middle East respiratory syndrome and sudden acute respiratory syndrome, which are coronavirus-related diseases.
The medical community should think carefully about immunomodulatory therapy in patients with COVID-19. It should be approached with extreme caution, preferably in the context of clinical trials.
Massachusetts General Hospital has made its guidance for treating COVID-19 outpatients and inpatients publicly available. All documents are subject to revision.
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