As we review the now over 14,000 articles published on COVID-19 we aim to draw your attention to something that has caught our eye, either clinically or scientific. This week, we focus on two articles I believe can help us better understand COVID-19 disease pathogenesis, a field that is evolving rapidly. I love Cassie’s pick in NEJM as it gives us a whole new light on pathogenesis and the role of the endothelium. My pick is a short read that gives you a deep dive into understanding the virus at the molecular level and what this understanding may mean for future therapies and vaccines. It’s complex but elegantly simplified by two of our colleagues at the Cleveland Clinic. Please reach out to us with your thoughts, questions, or clinical conundrums. That is what our effort for United Rheumatology is all about.
Drs Bergman and Silverman give us an incredible 30,000-foot view of how SARS-CoV-2, the viral pathogen, seeks out, binds, enters, reproduces, and is exocytosed from its targeted cell (see figure). Each step is a molecular bit of choreography which reveals both the power and cleverness of this pathogen to evade our own defenses but also its vulnerability to a variety of antiviral, immune-based, and vaccine strategies.
As with all RNA viruses they gain access to our cells via a receptor and in this case it’s ACE-2, an enzyme involved in down regulating the vasoconstrictive properties of angiotensin I and II. This is not a simple interaction and as they explain it involves numerous subunits and a host of both viral host enzymes to actually fuse and enter the cell. Each step is of high interest for potential drug targets. Also, as with all RNA virus, our cells respond with a vigorous counter-attack in the form of our interferon response (Type I and II) which then lead to the production of many downstream molecules which are designed to dispatch the invader. Triggering our viral detectors (those intracellular receptors designed to recognize such invaders (TOLL, RIGS, STING, etc.) also generates inflammation which serves as a focus within our integrated immunologic defense.
Here is where it gets really interesting. It appears, like with so many other viruses, that SARS-CoV-2 is well-equipped for immune evasion but COV-2 has developed some new and deadly defenses. At the molecular level it appears to have developed molecular pathways to literally shut off our interferon response, thus lowering innate immunity while at the same time ramping up our inflammatory response. As a result, the virus continues to proliferate and we suffer the ravages of unbridled inflammation, a process I described last week. Bergmann and Silverman go on to provide a rationale for subsequent drug targets. Like I said it is short with some heavy stepping but if you want the deep dive. this it. Enjoy!
As the weeks go on we continue to learn more about the natural history of COVID-19 disease, which is one of a mild-moderate, self-limiting disease in approximately 80% but more severe in the remainder with 5% or more requiring intensive care carrying a mortality of 1-2%. While in many ways what goes on at the tissue level in terms of immunopathogenesis remains a mystery, much can be learned from post-mortem studies. This week we highlight another autopsy series published in NEJM where the authors compare lung histopathology from 7 patients who died from COVID-19 to patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A (H1N1) and age-matched controls who had neither infection.
Diffuse alveolar damage is the process occurring histologically in early ARDS, and is not specific to COVID-19 as it can occur in many other viral respiratory infections (influenza, SARS, MERS, etc.) as well as secondary to non-infectious etiologies. Pulmonary inflammation at the endothelial level is felt to be a driver of morbidity and mortality in COVID-19, and something that may make it different from other respiratory viral infections.
While the lungs of these patients who died from COVID-19 or influenza did share the morphologic pattern of diffuse alveolar damage and infiltrating perivascular lymphocytes, several distinctive features were seen in the COVID-19 cases. While pulmonary and alveolar-capillary thrombi were noted in both groups, alveolar-capillary microthrombi were 9 times more prevalent in the COVID-19 cases. Scanning electron microscopy revealed severe cellular injury and intracellular virus in the COVID-19 cases (see figure below). Finally, the COVID-19 lungs demonstrated significant new vessel growth through something called intussusceptive angiogenesis.
While their sample size was small it clearly shows distinct pulmonary vascular features that differ from those of influenza. Larger studies will be needed to further elucidate what impact these findings may have on the clinical course of COVID-19.
Leonard H. Calabrese, DO, is the head of the RJ Fasenmyer Center for Clinical Immunology and Vice-Chair of the Department of Rheumatic and Immunologic Diseases at Cleveland Clinic Dr. Calabrese has lectured nationally and internationally on the subjects of immunology, rheumatology, and viral diseases. He is the author of more than 400 published peer-reviewed articles, book chapters, and reviews. @LCalabreseDO
Cassandra Calabrese, DO, is a staff physician in the Department of Rheumatic and Immunologic Diseases and the Department of Infectious Diseases at Cleveland Clinic and directs the combined Rheumatology-Infectious Disease training program. She also directs the Clinic for immune-related adverse events form cancer immunotherapy within the department of Rheumatic and Immunologic Diseases. @CCalabreseDO