MORE THAN JUST SEVERE PNEUMONIA

Back on January 26th (which seems like another age, another world) I commented on Dr. Anthony Fauci's very informative JAMA article "More than just the common cold" - http://bit.ly/2OAcAq1. That report seemed then to be very significant.

In the four months since that seminal article, we have learned a great deal -- many hard lessons. Now the world seems awash in novel and horrifying new details: from bleeding brains to Covid toes. How can one make sense of it all? Or at least to have an inkling that leads to next steps, as that fateful JAMA article helped us back then.

Yesterday, the NEJM published such an article, "Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19" (https://bit.ly/2WWJRjL). [The accompanying editorial can be found at https://bit.ly/2LSaT5q] This report, though quite technical, is important enough to share beyond just the expert medical community. Admittedly, this is not some mega-million dollar study, nor is it a groundbreaking result for some magic "antiviral" or vaccine. No--it is a simply a pathology (autopsy) study limited to examining only the lungs of just 24 subjects: 7 with Covid, 7 with influenza and 10 uninfected controls.

So why the big deal?

Looking at the big picture, it has been clear since January that SARS-CoV-2, the virus that causes Covid-19, is a very, very strange beast. It seems, in the horrifying traditions of other "Great Imitator" diseases (https://en.wikipedia.org/wiki/The_great_imitator), to have widespread effects throughout the body. For example, there are the strokes in the brain (https://bit.ly/3edxMMW). Should we study these for clues? Or Covid toes (https://www.bbc.com/news/health-52493574)? Research that? The problem with Great Imitator disease is that from both a research perspective and clinical practice these wild goose chases end up being just that: intriguing, though ultimately fruitless deadends.

Covid-19 is predominantly a pulmonary disease

While the SARS-CoV-2 virus can possibly enter the body through the eyes (conjunctiva) or perhaps the gastrointestinal tract, the predominant mode of transmission is via the respiratory tract. This has been well established. And pneumonia and acute respiratory distress syndrome (ARDS) are hallmarks of severe Covid-19 disease (https://youtu.be/qc2ZcUxV1VU & https://youtu.be/s9Zlv37Z6No). Indeed, most victims of the disease die of pulmonary complications, not, for example, of Covid toes. So while Covid-19 has turned out to be one of those "Great Imitators" it would be wise to focus on the disease's pulmonary mechanisms.

To understand disease, study pathology

There have been innumerable studies, countless field reports, clinical cases, genomic analyses and so forth on all these myriad manifestations of Covid-19. But to truly understand disease, one needs to do pathology and this NEJM report does essentially that in a very comprehensive and sophisticated manner utilizing the full spectrum of pathologic analytical tools. And, most importantly, the authors aim to answer the big question: why is Covid-19, as a respiratory infection, so different from severe influenza? As Dr. Fauci recognized early on, SARS-CoV-2 is not just the common cold (which is actually caused in about 15% of cases by similar coronaviruses) but something more serious, this NEJM article provides strong evidence regarding how Covid-19 is different than the flu. [Yes, there are some limitations to this study, beyond just the limited subject numbers, but these are not, in my mind crippling to the overall conclusions. In addition, I would have hoped that there was more analysis relative to specific pathology involving Type 2 pneumocytes and relative surfactant depletion, with the hypothesis being that this would be more of an issue with Covid-19 as compared to influenza.]

So how is Covid-19 different than severe flu?

Both influenza and Covid-19 infect the lower respiratory tract and so both diseases show "diffuse alveolar damage" which account for the severe respiratory difficulties in these patients. Also seen in both diseases is "perivascular T-cell infiltration" which essentially means there is an immune reaction going on down in the lungs. None of these pathological manifestations are unexpected. What was unusual in the lungs of these deceased Covid-19 victims was significantly increased microvascular changes including severe endothelial injury (the lining of capillaries being damaged) as well as widespread thrombosis (blood clots) with microangiopathy (again, damaged small vessels). One important background point: why do blood clots form? The main reason, of course, is as a response to damage - when you cut yourself, a clot forms to prevent bleeding. So while there are many possibilities for the propensity to clot (hypercoagulation syndromes, etc.) the simplest one (Occam's Razor) likely applies: namely, damage to the blood vessels themselves incites such clot formation. This is a well known phenomenon in diseases which involve such damage to the inner surface of blood vessel walls. To summarize: both Covid-19 and influenza cause damage to the lung, but Covid-19 is unique in also causing significant blood vessel injury.

Is Covid-19, then, a bloodborne virus?

The conventional answer: no. The more nuanced answer: probably but it depends. So now I will speculate a little. Even though Covid-19 likely begins (at least in most cases) as a respiratory infection (which has implications for public health -- like not coughing in public --, etc.) it appears to also involve the blood vessels in the target pulmonary tissues. [Endothelial cells are also known to express the virus target protein, ACE2 - https://bit.ly/2ATWGTl] This means that the virus becomes, at some point, blood borne. This is very important. Many of the most fearsome of viral pathogens such as Ebola, HIV (now controlled, though not cured), Polio, and Smallpox, are (or were) bloodborne. And so with Covid-19, what was once considered a respiratory infection, is also in the blood. It may be possible to develop blood-based Covid-19 antigen tests (as compared to the more commonly known PCR / RNA and antibody tests) which can pick up virus protein from blood samples. So while it is fairly certain that the virus enters the bloodstream and damages the blood vessels downstream (hence causing Covid toes, heart attacks brain strokes, rashes, etc.) we don't really know many details of this process, including blood borne viral load dynamics. So this is one area I believe will bear important results.

What are other implications? Who gets severe disease?

One mystery has been the very "nonlinear" nature of disease progression. Some have mild (or even no) symptoms, others have a protracted, though not serious course, and others progress inexorably to death. One hypothesis may be that presence of virus in the blood - namely an antigen test - may be a biomarker of significant progression (and risk). Right now we do oro- and/or naso-pharynx (nose and mouth) PCR tests that pick up viral RNA. But other than possible clinical correlation with viral load (faster PCR reaction = more viral load = likely more severe disease) a positive results offers no information on the probability of progression to severe disease. Combining nasal swab tests with a blood-based test (antigen or PCR slow) could be used not just for diagnosis but also for prognosis. Indeed, as Hippocrates noted at the dawn of medicine, prognosis is even more important than diagnosis. It is critical in managing this pandemic at both the individual patient and population levels.

And the prospect for a vaccine?

Bloodborne viruses sound scary. And indeed they are, having served up some terrifying examples such as Ebola which carries with it a 50% fatality rate. So viruses in the blood are bad news. Luckily, viruses that "live" in the blood are transmitted through the blood or closely related body fluids. And hence transmission of these evil pathogens is quite difficult. Unfortunately SARS-CoV-2 is primarily a respiratory virus so it is easy to transmit -- and it definitely is. That makes SARS-CoV-2 bad on both counts. Any good news, you ask, plead? Yes: bloodborne viruses are, generally speaking, more readily neutralized by the body's antibodies. That's because antibodies floating around in the bloodstream are much more effective than antibodies outside the body, such as on the respiratory surfaces. It's one reason why we don't develop very good, long-lasting antibody protection against the common cold or, in fact, influenza more generally. Viruses confined to the "outside" of the body are more difficult to fight; viruses deep "inside", namely in the blood, within the vasculature, are more vulnerable to immune clearance. So while we may never get a vaccine for the common cold, a vaccine against SARS-CoV-2, while certainly more dangerous than the common cold, may be a possibility. [Careful readers will note that HIV, as a bloodborne virus, has never had a successful vaccine. HIV, because it directly infects the immune system, is a special, and perhaps interminably intractable exception.]

In summary

· Covid-19 causes vascular injury, specifically via damage to endothelial cells

· This also causes excessive thrombosis, probably leading to other "Great Imitator" syndromes

· Covid-19 is thus likely to have a significant bloodborne component to its disease dynamics, particularly in severe cases

· Blood-based Antigen or PCR tests should be given greater emphasis in both the management of individual patients as well as in more focused public health measures

· The presence of virus in the blood raises hopes for an effective vaccine and also points to vaccine strategies, which differ as to the type of antibodies that are stimulated: those like IgG in the bloodstream as compared to IgA and other variants for "surface" pathogens.

Return to "Just the Common Cold?"

These distinctions are important, because if we are hoping for a vaccine that confers complete and utter "immunity" this may be an unattainable goal, especially since part of the disease dynamics are "external" to the body. Focusing on the more severe aspects of the Covid-19 dynamics may be more fruitful (and feasible).

In other words, what can we do to convert SARS-CoV-2 into just the "Common Cold?"