Background:
The severe acute respiratory distress syndrome-associated coronavirus-2 (SARS-CoV-2), etiologic agent of Coronavirus disease 2019 (COVID-19), was initially identified in Wuhan, Hubei, China in December 2019 and, by November 2020 there were over 50 million confirmed cases and over 1.2 million deaths. The natural reservoir is the horseshoe bat where the virus does not cause the bat to develop significant disease despite the potential severity of symptoms found in humans. The virus does not infect all mammals. For example pigs and chickens are unable to be infected while ferrets have subclinical disease resembling humans. Additional hosts such as the pangolin are possible but not confirmed as definitive intermediary host. The bat transmits the disease to humansthrough guana (fecal material) and of course if the infected bat is eaten the virus will be potentially transmitted to the human. Respiratory failure, acute renal failure, cardiovascular collapse, and a coagulopathy/procoagulant state are associated with fatal disease. Well-documented risk factors include increased age, pre-existing medical conditions including diabetes and hypertension, and an immunocompromised state; obesity is an independent risk factor for severe COVID-19 disease. The virus has many molecular similarities to its predecessor SARS-CoV. It is significantly less virulent but vastly more contagious. Understanding the biology of SARS CoV has provided an excellent framework for understanding the potential mechanisms of disease in humans as it applies to SARS-CoV-2.
While the majority of SARS-CoV-2 infections are self-limited, 20% of patients are significantly symptomatic and of those, a small percentage develop severe COVID-19 which can be fatal. In New York City the number of deaths per 1000 person-years greatly increased from a nearly flat monthly death rate, average of 7.83, in 2017 to 9.44 in April and May of 202, , a 21% increase in the death rate in all cause mortality. Serious manifestations typically begin within 7 to 14 days after the onset of symptoms, and are heralded by profound shortness of breath and then additional complications related to a hypercoagulable state including the formation of blood clots in larger vessels which may develop after the onset of acute respiratory distress syndrome.
Mechanisms of Disease:
SARS-CoV-2 is a unique virus with a proclivity to infect and or influence microvascular biology and generate varied innate and adaptive immune responses critical to disease outcome. In an ideal scenario the inception of active infective disease is met with a robust immune response that likely includes an interferon T cell and monocyte driven one that is seemingly effective in eliminating and or at least attenuating viral replication quickly before it can have a deleterious multiorgan microvascular and larger vessel effects. However the immune response cannot be so extensive that it leads to its own consequences in the form of multiorgan inflammatory disease best exemplified by the Kawasaki-like disease that children develop.
In the minority of cases of COVID-19 where the type I interferon immune response is blunted due to certain acquired or hereditary defects in the patient’s specific immunologic makeup including the immunosenescence of advancing age, the virus can replicate excessively in the lung. This excessive replication can then eventuate in significant and potentially catastrophic disease that closely recapitulates other serious microvascular injury and thrombotic syndromes such as thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome and antiphospholipid antibody syndrome. The virus has a natural tendency to bind to endothelial cells of the small vessels of the lung at the interface of gas change because those small microvessels possess the receptor for the virus called ACE2. That engagement leads to activation of a pathway called the mannan binding lectin pathway that damages the microvessels at the level of critical gas exchange. In addition, there are other microvascular beds outside the lung that express ACE2. While there is very little evidence of viral replication outside of the lung, the part of the virus that binds to the ACE2 receptor can be released into the circulation where it docks to these vessels and can activate pathways leading to vascular injury and the formation of blood clots.
To understand the varying faces of COVID-19 clinically and pathologically and explore critical mechanisms involved in the evolution of this potentially heterogenous viral syndromic complex is our mission.