COVID-19 RISK FACTORS: Who gets them and why. You are going to ACE this one…

Now usually I don’t go and make wild conjectures and hypotheses. But Im going to discuss a pretty interesting (wild conjecture?) one that on paper seems to make sense to me. Let’s look at the COVID-19 risk factors for who gets severe disease and put them in a molecular and biological framework. If you want you can also skip down and just look at the tables because they sum everything up and then correlates risk factor to molecular basis…The rest is me just talking’. …We will start with the risk factors

Risk Factors of COVID

As with all disease there is usually a group that is particularly susceptible to a particular disease. As information becomes more available we are better able to describe this susceptible population.  In the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003 that occurred in Beijing it was noted that those with chronic medical conditions and the elderly had a significantly higher risk of developing SARS1. That outbreak was caused by the SARS-associated coronavirus (SARS-CoV).

         Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic. As more time and data accrue it is becoming more clear who may be at risk in this current outbreak of COVID-19. The data thus far is reported from China, Italy and the US, with the majority coming from the devastating effects of the pandemic in Italy. It would appear from the data thus far that once again age and comorbidities play a role in the risk factors of COVID (see Table 1). Those with hypertension (7.3%) and cardiac disease (7.2%) seem to have the highest associations and thus risk. These 2 groups are followed by Diabetes Mellitus (3.3%) (No data specifically distinguishing the two have been reported thus far). Men appear to be more affected by COVID-19 as well. Roughly a 60-40 mix in the confirmed but a 70-30 mix in the cohort from Italy that died (see Table 2 & 3). The age group (see Figure 2) most affected by COVID-19 appears to over-represented by the 70-79, and 80-89-year-old’s. As seen from the Italian data 112 of the 10,026 patients reported to have died were under the age of 50. Twenty-three of that group was less than 40 and of that group 6 were reported to have no co-morbidities.

TABLE 1. Comorbidities of reported COVID patients

Comorbidity# CasesN= 10473a%TotalCasesNumber DiedN= 10336b%Total of Deaths
Rheumatologic disease10.0NRNR
Immune Suppression/Cancer/ Organ transplant2352.22222.1
CNS disease70.1NRNR
>1 comorbidity1035c10.1890d0.8

# of Cases from references: 2–5, Italy contributed 10,026 cases of patients who died

b # Died from references: 2, 5

c of 10,272 cases reported

d of only 10,135 cases reported

NR=Not reported

Table 2. Number and Percent of Men and Women having Confirmed COVID-19 infection

confirmed ChinaConfirmed UKChina meta-analysisSum

Table 3. Number and Percent of Men and Women Died in Italian cohort

Died Italy

Figure 1. Number of patients who died by age group. This data is based solely on the Italian2 reported cohort of 10,026 patients who died. 

Now for the molecular basis!

Lets go back in time, long before anyone ever associated a corona virus with an incredibly severe pandemic. Before this, we in the medical field new it as “The common cold”. So how did something go from being a common cold to the second worst pandemic the world has ever seen? (1918-1919 Flu killed an estimated 50 million people*- as of today 4/3 COVID-19 has been confirmed in >1 Million people and has taken just over 53 thousand lives)? 

The “common cold” coronaviruses that we used to be able to test for came in such flavors HCoV-229E, HCoV-NL63, HCoV-OC43 (HCoV = Human Corona virus). They caused only self-limiting upper respiratory tract infections (about 30% of the common colds) 1. We never, really, bothered to make any treatments for the diseases they caused because as a 1994 study said “the presence of side-effects in treating such a mild illness is…unacceptable” 1.

Something has definitely changed. You might be surprised to know that we actually do understand what has changed since these OG corona viruses and the 2003 SARS (we now call SARS-CoV-1).

The “corona” of corona virus gets its name from spikes on the outer edge of the virus that give it a crown-like appearance (SEE THE FEATURED IMAGE ON THIS PAGE). Those spikes are how it gets into the cell. Now, in this rendition of SARS-CoV-2, those spikes sting…

In a paper so important it made it into NATURE, Li in 2003 found that SARS (CoV-1)  used the ACE2 receptor to facilitate viral entry into humans2. Sound familiar? ACE inhibitors have been used to control hypertension for years and ACE inhibition is key in the treatment of cardiovascular disorders.

Interestingly, although we have known about ACE for a long time, ACE2 was only discovered in 20003 and its discovery has been “noteworthy and might be categorized as a Classic”4. The reason for this is it has “changed our simplistic vertical concept about the renin-angiotensin-system (RAS) by pointing out the presence of dual functions of the RAS with opposing effects in cardiovascular biology”4. We now know A LOT about ACE2 (SEE FIGURE BELOW FOR BIOCHEMICAL PATHWAY). ACE2 prevents the formation of the vasopressor angiotensin II. Interestingly, the gene for this enzyme, ACE2, maps to the X chromosome in humans. Thus the male species have less ACE2 than women do. Also interesting to note is that we start out life with a high amount of ACE2 and then ACE2 becomes down regulated and decreases with age. Thus older males have the least amount of  ACE2 5! (Really starting to sound like a correlation here with risk factors!). We know that ACE2 is an essential regulator of heart function6. We also know that ACE2 is abundantly present in humans in the epithelia of the lung, small intestine, and vascular endothelium which may provide routes of entry for the SARS-CoV 7. With the SARS epidemic in 2003 we also learned a lot about SARS-CoV. We found that the CoV-1 bound tightly to ACE2 much more tightly than the corona viruses of old did. In fact now we know that SARS-CoV-2 even more efficiently recognizes and binds to ACE2 which may explain it enhanced ability to be transmitted from person to 8

So how does that translate into such severe disease? Well for that we dive deeper into ACE2. Crackower in his article in Nature created knock-out mice that could not express ACE2. The loss of ACE2 did not alter blood-pressure but did impair cardiac function causing:

Mild thinning of the left ventricle and severe reduction in contractility but without fibrosis or hypertrophy of the heart.  The damage was more similar to that seen with  myocardial stunning, which is reversible and also suggested a role for ACE2 in mediating a response to cardiac ischemia. 

Now it gets more interesting, because ACE2 also protects us from lung injury!9 In 2011 it was found that the development of ARDS is determined by the balance between ACE and ACE2 activity within the lung10. This study found that treating ACE2 knockout mice with either the by product of ACE2 (Ang1-7) or losartan (which in animal models has been shown to be lung protective but also causes sever drops in blood pressure in those with bp dysregulation such as the kind that occurs in sepsis), resulted in higher values of PaO2 in models of ARDS. They also found that in models of ARDS ACE activity was enhanced, whereas ACE2 activity was reduced in bronchoalveolar lavage fluid. Yang et al. found that an abundance of ACE2 enhanced disease severity in a mouse model of SARS-CoV-1 infection.  They introduced the human gene for angiotensin-converting enzyme 2 (hACE2) into these mice. The mice had more severe pulmonary lesions, interstitial hemorrhage, and replicated more efficiently in these mice. CoV-1 had more openings in these mice to enter into. They also found other changes such as desquamation, and vasculitis in these mice. 11

Thus, ACE2 is not only the entry receptor of the virus but also protects from lung injury. Because CoV-2 binds to it, it essentially becomes nonfunctional and can’t participate in lung repair. So SARS-CoV-2 may have become more infectious because the virus inhibits a lung protective pathway! SARS-CoV likely results in ACE2 downregulation through binding of SARS-CoV Spike protein to ACE2. It has been shown in many animal models that ACE2 is an inhibitor of lung injury. This scenario would explain how this family member of the common cold coronaviruses has turned into a worldwide pandemic.  Indeed, this information is all being used in looking for treatments (drugs and vaccines) to subdue this emergency12

We can even hypothesize further because all this becomes very interesting in the setting of ACEI’s and ARB in the treatment of hypertension. In a study by Burchill, the effect of Ramipril in combination with losartan was investigated. They found that despite ACE inhibition there was no down regulation of ACE2. Thus while it is still to early to tell one could hypothesize that the hypertension medications we take really shouldn’t affect CoV-2—but only time will tell. It is also interesting to consider the issue of ibuprofen. In a study by Qiao, the effects of ibuprofen on ACE2 were investigated in diabetic rats. It was found that Ibuprofen could blunt the cardiac fibrosis in diabetic rats by enhancement of the ACE2! Now obviously there have been “reports” of people saying not to take ibuprofen in CoV-2. In no way does this say one way or the other.  What this should do is remind us that CORRELATION IS NOT CAUSATION. We have animal data that suggests ibuprofen is protective by increasing ACE2 and we have small observational data that suggests ibuprofen may be associated with worse disease. This is not the first time ibuprofen has been associated with worse respiratory disease. In 2016 a study reported an ASSOCIATION between NSAIDs and empyema with an adjusted odds ratio of 2.79 (CI 1.4-5.58, P = .004) 13. Again this is an ASSOCIATION and should make us skeptical UNTIL WE SEE A RANDOMIZED CONTROLLED TRIAL to adjust for confounders. However, certainly titles like “Is It Time to Dump the Ibuprofen From Your Medicine Cabinet?” should be met with extreme skepticism. 

So to sum up here are the key points and their associated molecular mechanisms


1.COVID-19 (CoV-2) has higher transmission and higher virulenceSpike protein of CoV-2 binds ACE2 more tightly than CoV-1 and infinitely tighter than “the common cold”
2.COVID-19 occurs in men more than womenACE2 is carried on the X chromosome
3.COVID-19 occurs in older adults than younger adultsACE2 is down regulated with age
4.COVID-19 causes acute lung injury and ARDSACE2 is protective of lung injury and is unavailable because of binding to viral spike particles
5.COVID-19 causes myocardial injuryLack of ACE2 causes myocardial dysfunction without fibrosis or hypertrophy


1.      Wu J, Xu F, Zhou W et al. Risk factors for SARS among persons without known contact with SARS patients, Beijing, China. Emerg Infect Dis. 2004; 10: 210-216.

2.      Sanità ISD. Characteristics of COVID-19 patients dying in Italy Report based on available data on March 30th, 2020. 2020;

3.      Arentz M, Yim E, Klaff L et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020;

4.      Deng Y, Liu W, Liu K et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin Med J (Engl). 2020;      Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020; 101623.


1. Myint SH. Human coronaviruses: A brief review. Reviews in Medical Virology. 1994; 4: 35-46.

2. Li W, Moore MJ, Vasilieva N et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426: 450-454.

3. Donoghue M, Hsieh F, Baronas E et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87: E1-9.

4. Marian AJ. The discovery of the ACE2 gene. Circ Res. 2013; 112: 1307-1309.

5. Fernández-Atucha A, Izagirre A, Fraile-Bermúdez AB et al. Sex differences in the aging pattern of renin-angiotensin system serum peptidases. Biol Sex Differ. 2017; 8: 5.

6. Crackower MA, Sarao R, Oudit GY et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002; 417: 822-828.

7. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-637.

8. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020; 94:

9. Imai Y, Kuba K, Rao S et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436: 112-116.

10. Wösten-van Asperen RM, Lutter R, Specht PA et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011; 225: 618-627.

11. Yang XH, Deng W, Tong Z et al. Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med. 2007; 57: 450-459.

12. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine. 2020; 46: 586-590.

13. Le Bourgeois M, Ferroni A, Leruez-Ville M et al. Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. J Pediatr. 2016; 175: 47-53.e3.

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