The COVID-19 Pandemic, caused by SARS-CoV-2, remains a “mysterious” disease even after its arrival in the world more than nine months ago. The general consensus is—the virus is a highly transmissible pathogen that can cause a wide range of symptoms, depending on the health condition of the individual. Beyond that consensus, there has been much controversy and debate on the reading and interpretation of the data as well as the validity of the data source. For the common person who is both a rational and an emotional being, numbers will go only so far! If we are able to complement the data with known science, then we can begin to construct a helpful understanding of the virus and react with more appropriate measures both as individuals and collectively as a society.
SARS-CoV-2, in laymen terms, is a cousin of SARS-CoV that led to the SARS outbreak in 2003. Both coronaviruses bind to the receptor, Angiotensin-Converting-Enzyme-2 (ACE2) for cell entry. This is the first important fundamental fact. From studies of SARS, upon binding of the coronavirus to ACE2, ACE2 is down-regulated (i.e., ACE2 is produced less). This is the second important fundamental fact. In drug development (finding a therapy for a disease), the two most important aspects are knowing: 1) the site-of-action, i.e., the receptor and 2) the mechanism-of-action, i.e., the path of disease progression. Knowing both the site-of-action and the mechanism-of-action should have equipped us to handle COVID-19 with greater clarity and less guesswork. However, we are still left in the “fog”. Scientists and physicians are often “pigeonholed” into certain perception because of the terminologies used. When people hear words such as virus and pathogen, they could only think in the infectious disease “silo”.
COVID-19 is certainly an infectious disease because the virus infects a person. Nobody would disagree with this irrefutable fact. But looking at the science (site-of-action and mechanism-of-action) along with the collected human data, COVID-19 is a highly accelerated chronic disease—exacerbating chronic disease(s) to their final endpoint, death—for the “vulnerable” (people with pre-existing conditions). For the young and the healthy, they will experience no symptoms (asymptomatic cases) or very mild symptoms (mild cases) because of the absence of chronic disease. It is this duality of behaving like the “common cold” for the young and the healthy and like “SARS” for the vulnerable that makes COVID-19 “mysterious” unless you look at the known science. Just like the expected dismissal for calling it an “infectious chronic disease” unless you look at the known science.
ACE2 is an integral part of the “protective” axis (ACE2/Ang(1-7)/Mas) that counterbalances the “disease” axis (ACE/AngII/AT1R) in the RAS (Renin-Angiotensin-System, see below scheme). RAS is vital to cardio-pulmonary and vascular health; it is the cornerstone therapeutic modality in the treatment of hypertension and heart-related diseases. Essential heart medicines such as ACE inhibitors and ARBs work by modulating the RAS.
The systemic and local effects of RAS are summarized in the below scheme.
Deterioration of RAS (i.e., RAS dysfunction) leads to chronic diseases such as hypertension, heart disease, kidney disease, lung disease, brain disease, and metabolic disorders; these all contribute to increased mortality risk with COVID-19. The correlations between chronic diseases and COVID-19 are depicted in the below scheme.
If a person has chronic disease(s) or COVID-19 (left diagram), the RAS balance is knocked down to the disease state. There could be symptoms depending on the duration of disease and the health condition of the individual. Specifically for COVID-19, the majority of the cases are asymptomatic or mild (symptoms ranging from fever and cough to GI abnormalities to temporary loss of smell and taste). There are cases in which the patient has lingering cardiac[i] or neurological[ii] complications that are consistent with prolonged ACE2 down-regulation. If a person has chronic disease(s) and COVID-19 (right diagram), the RAS balance is doubly knocked down to a severe disease state, with an increased likelihood for death. Specifically for COVID-19, these are the moderate to severe cases requiring hospitalization and some type of oxygen support. This model is consistent with the human data collected globally. From the latest CDC analysis,[iii] only 6% died from COVID-19 alone. 94% died with comorbidities, with on average 2.6 comorbidities per death. A similar median number of 2.7 comorbidities was observed in Italy from an early epidemiological study.[iv] Also from the CDC analysis, over 90% of deaths are from people aged 55 or older. The majority of these elderly people have pre-existing conditions. A “top-level” analysis of excess deaths associated with COVID-19[v] corroborates with the science model (see below scheme). Circulatory diseases (cardio-vascular diseases) show the greatest adverse effects with COVID-19 followed by Alzheimer disease and dementia (which are neurological diseases with strong vascular dysfunction) and respiratory diseases. Within the “Other causes” category, Diabetes was also severely affected by COVID-19. These four major chronic disease groups—Circulatory (blood pressure and heart-related), Neurodegenerative, Respiratory, and Diabetes—are the major contributors to COVID-19 related deaths as predicted by the RAS balance model.
One last “top-level” analysis comes from Sweden where there was limited “lock-down” measures in place and the data fidelity is among the highest in the world. The cumulative “ALL CAUSE DEATHS” with COVID-19 did not increase from a historical perspective (last 20 years). The “ALL CAUSE DEATHS” number with COVID-19 is 66,841 that is actually below the median number of 67,696 for the previous nine years (assuming standard healthcare practices have not changed significantly over the past ten years). This finding is consistent with the prediction that COVID-19 accelerates the chronic diseases already existing in people; it does not create a significant class of new patients leading to death.
In conclusion, COVID-19 is as much a chronic disease as it is an infectious disease. The “vulnerable” are the people with multiple pre-existing conditions which a significant number of the elderly population possess. For the young and the healthy, they have minimal risk to COVID-19. If we study these facts and improve our understanding of COVID-19, then we can take a giant step to resuming our normalcy!
[i] doi:10.1001/jamacardio.2020.3575
[ii] doi:10.1093/brain/awaa240
[iii] https://www.cdc.gov/nchs/nvss/vsrr/covid_weekly/index.htm?fbclid=IwAR0fUcThh_Dn2PL3FqFmpNqJPUX1pFJKkaw5oNtwZsiOn-xr96v9gnxhmYE#Comorbidities
[iv] doi:10.1001/jama.2020.4683
[v] https://www.cdc.gov/nchs/nvss/vsrr/covid19/excess_deaths.htm