SARS-CoV-2 has caused about millions of infections around the world with thousands of causalities. However, some people seem to be more susceptible than others; a phenomenon called differential susceptibility. Several factors including socioeconomic inequality, genetic differences (polymorphism), environmental factors, sex, age distribution, blood group type and others might be responsible for differential immune response against the virus and differential probability of being affected by the disease. Variations in ACE2 receptors amongst individuals can also be a major factor [Refer to the ‘first article of Warfare series of CONOCIMIENTO, ISSUE 2’ for more details]. While the medical system all over the world is being overburdened by the increasing number of patients, it is very essential to identify the ‘more’ vulnerable population to isolate them quickly. Various clinical studies have identified certain groups to be on the riskier edge. This article provides an analysis of how sex differences, age structure, hypertension and blood group differences act as regulating factors to determine the COVID-19 spectrum.

SEX DISPARITY IN COVID-19 SUSCEPTIBILITY

Analysis of data from different parts of the world suggests that men seem to be more hit by the virus than women and are more likely to have severe illness and die. Chinese Centre for Disease Control and Prevention reported that the fatality rate was 2.8% for men, whereas, it was only 1.7% in the case of women after studying 44,672 patients. In a study of 1,591 critical cases in Italy, 82% were reported to be men.

There are many explanations for this sex disparity in COVID-19 susceptibility as suggested by researchers across the globe. Higher smoking rate in men in China (288 million men vs 12·6 million women were smokers in 2018) might be associated with this sex pre-disposition. SARS-CoV-2 uses/ involve the ACE2 receptor (Angiotensin converting enzyme 2 receptor) to infect the host respiratory tract. It has been reported that ACE2 expression is higher in smokers as compared to nonsmokers. Tobacco smoke exposure results in inflammatory processes in the lung via increased mucosal inflammation, expression of inflammatory cytokines and tumour necrosis factor α, increased permeability in epithelial cells, mucus overproduction & impaired mucociliary clearance. Another study showed that the % of current and former smokers were higher among the severe cases: 17% and 5%, respectively, than among the non-severe cases (12% and 1%, respectively) out of 173 severe and 926 non-severe cases. The number of deaths of smokers (9%) were found to be higher than the survivors (6%).

Some of the other reasons for this disparity are as follows:
• Innate immunity is up regulated in women due to high TLR7 (recognizes foreign ss RNA) expression as compared to men.
• Triggered by TLR7, immune cells become more activated in women, leading to the production of IFN (Interferon), i.e., antiviral proteins.
• Loci coding for the genes involved in the regulation for biosynthesis of regulatory T cells (FOXP3) are located on the X-chromosome. X-chromosome encodes immune regulatory genes causing lower viral load levels and less inflammation in females, as a result, the number of CD4+ T (Helper T cells) cells increases.

Though the infection rate is almost symmetrical between men and women, the mortality rate is higher in the case of men as compared to women. The information obtained around the world varies, thus, we still do not have a complete picture of how sex is playing out as a risk factor for the disease.

COVID 19 SUSCEPTIBILITY OF PATIENTS WITH DIABETES AND CHRONIC RESPIRATORY DISEASES

Although the overall death rate due to COVID-19 is low, patients with comorbidities are more likely to have severe disease and subsequent mortality. Patients with chronic obstructive pulmonary disease (COPD) and asthma, might be expected to be at increased risk of SARSCoV-2 infection and show more severe complications of COVID-19. However, both the diseases appear to be underrepresented in the comorbidities reported for COVID-19 patients as compared with the global burden of disease estimates of the prevalence of these conditions in the general population (Table 1). A similar pattern was observed in case of SARS. On the contrary, most of the available studies have shown the high prevalence of diabetes mellitus (DM) in patients with COVID-19 or SARS and is associated with more severe acute respiratory distress syndrome and ascended mortality.

In recent data collected from Italy (March 23, 2020) diabetes was reported in 20·3% of patients but COPD was not listed as a comorbidity for any patient among 355 patients dying with COVID-19 (mean age 79·5 years). Similarly, provisional data from the USA (March 31, 2020) show that chronic respiratory diseases and diabetes were comorbidities in 8·5% and 10·2% of patients with COVID-19, respectively, compared with Global Burden of Disease figures for the population as a whole of 11·3% for chronic respiratory diseases and 10·2% for diabetes; however these data are based on only 7162 of the 74, 439 patients reported.

The lower prevalence of chronic respiratory diseases reported in COVID19 patients might be attributed to several factors. One theory is that a different immune response is elicited by the chronic disease itself which protects against COVID-19. However, this theory is not supported by the finding that among those with COVID-19, who have COPD as comorbidity, mortality is increased, as would otherwise be expected. Another possibility might be that the therapies used by patients with chronic respiratory illness can play a role in reducing the risks of getting infected and consequently develop symptoms. Studies show that nearly 75% of people in China with asthma use inhaled corticosteroids. These drugs are used to lower inflammation as well as reduce redness, swelling and other allergic reactions. In-vitro studies have shown that inhaled corticosteroids alone, or when taken along with bronchodilators (drugs which open the airways of lungs), suppress coronavirus replication and production of cytokines. Accurate collection of more data for the comorbidities and previous therapy of patients with COVID-19 is crucial to understand risk factors for becoming infected, developing symptoms, and being diagnosed, as well as finding answers to questions about possible benefits or harms of therapy for asthma and COPD during the COVID-19 pandemic.

Various explanations can be accounted for the apparent association between pre-existing Diabetes Mellitus and COVID19 severity. Patients with uncontrolled DM have highly compromised innate immunity. Even short-term hyperglycemia can transiently stun the innate immune system. Pro-inflammatory cytokine response, mainly interleukin IL-1, IL-6 and tumor-necrosis factor TNF-α, is exaggerated in the absence of appropriate immunostimulation in patients with diabetes mellitus. It may be exaggerated further in patients with COVID- 19 complicated by acute respiratory distress syndrome (ARDS). ACE2 plays a role in the association between DM and COVID-19. ACE-2 is an integral membrane glycoprotein that is constitutively expressed by the epithelial cells of the lungs, kidney, intestine and blood vessels. The normal function of ACE2 is to break down angiotensin-II, an endogenous angiogenesis (blood vessel formation) inhibitor and to a lesser extent, angiotensin-I to smaller peptides, angiotensin 1-7 (heptapeptides) and angiotensin 1- 9 (nonapeptides), respectively. ACE2/Ang 1-7 system functions as an anti-inflammatory and antioxidant system which protects the lung against ARDS.

ACE-2 expression is reduced in patients with DM possibly due to glycosylation; this might explain the increased predisposition to severe lung injury and ARDS with COVID-19. But over expression of ACE2 would be counterproductive in COVID-19 because SARS-CoV-2 enters the host pneumocytes through ACE2 receptors. ACE inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) are widely used drugs in DM. The expression of ACE2 increases significantly in patients with DM (and hypertension) on ACEi or ARBs as an adaptive response to counteract the elevated levels of Ang-II and Ang-I. Thus, use of ACE2-stimulating drugs would facilitate the entry of SARS-CoV-2 into pneumocytes and consequently might result in more complications. It can also be concluded from recent studies that ACE2 overexpression, while facilitating entry of SARS-CoV-2, is unable to protect against lung injury as the enzyme gets degraded by thevirus. The prevalence of DM in India is 7.3% thereby predisposing a large section of the community to COVID-19 and its complications.

LOWER SUSCEPTIBILITY OF CHILDREN

COVID-19 is found to be relatively uncommon in children and exploring the possible reasons can help in understanding the pathogenesis. Usually children are more susceptible to various respiratory tract infections and influenza because of the immaturity of respiratory tract and less developed immune system.

One of the possible reasons points to a smaller number of outdoor activities and international travel undertaken by children making them less susceptible to the disease. However, a lower number of cases in the start does not necessarily mean that children are less susceptible to infection as the number of cases can increase in the future.

In the outbreak of SARS the mortality rate was fairly low in people below 24 years, including children. These results could indicate towards the possibility of a specific mechanism regulating interaction between respiratory system and immune system. One possibility is of lung infiltrates which may have a protective role in pediatric SARS-CoV-2.

Another reason may be that young children have less damaged lungs due to less exposure to pollution and especially cigarette smoke and less number of underlying diseases. A more developed immune system in adults can also cause a detrimental immune response which is often associated with Acute respiratory distress symptom.

A difference in distribution, functioning and maturation of different viral receptors might also be a major reason for the age-related incidence. ACE2 expression has been found to decrease with age in rats which may not be consistent with the findings of the lesser impact on children, but studies also reveal that ACE2 is involved in protective mechanisms against various viral infections that affect the lungs. ACE2 also protects the lung from damage that can be caused due to acid aspiration, SARS, sepsis etc.

CORONA VIRUS AND THE SUSCEPTIBILITY TO VARIOUS BLOOD GROUPS

The results of an extensive study among the mass of infected patients in china showed that blood group A was associated with a higher risk for acquiring COVID19 compared with non-A blood groups, whereas blood group O was associated with a lower risk for the infection compared with non-O blood groups. This study is completely subjective to sample size and environmental conditions. The disease being in the early stages this report is based on the available numbers in clusters.

Landsteiner’s ABO blood types are carbohydrate epitopes that are present on the surface of human cells. These blood types are hereditary and also influenced by the environment, a trend as observed is susceptibility of some diseases to specific blood groups like hepatitis B, SARS.

In another study, the nasal swabs taken from the patients of an undisclosed location in Wuhan China along with certified blood test reports, were used to create a chi square table, the data received was recorded and analyzed. With the numbers mentioned (Table 2), it is pretty much clear that the blood group A is more susceptible to the disease. Though the conclusion might have several variables based on region, temperature, food habits and especially the number of samples taken.

The proposed explanation for a pattern is as follows:
Blood group A has anti A anti bodies. The proposed explanation in majority of the papers can be summed up as: Given the similarity in nucleic acid sequence & binding ability between SARS-CoV and SARS-CoV2, the lower susceptibility of blood group O and higher susceptibility of blood group A for COVID-19 could be linked to the presence of natural antiblood group antibodies, particularly anti-A antibody, in the blood.

While this article provides some details about the most vulnerable groups, at present in the absence of any vaccine, we need to ensure proper social distancing and self-isolation to stop the rapid spread of the disease. Though the older population has been found to be more vulnerable there have been cases where younger people and children were infected as well. We should never let our guard down against the pandemic we are fighting right now. To find whether it is due to genetic differences, or sex difference along with various environmental factors, more research is yet to be done, to be able to develop a comprehensive picture.

REFERENCES
1. https://www.npr.org/sections/ goatsandsoda/2020/04/10/831883664/thenew-coronavirus-appears-to-take-a-greatertoll-on-men-than-on-women
2. https://www.medicalnewstoday.com/ articles/sex-differences-in-covid-19#Whysex-disaggregated-data-are-urgent
3. https://www.biolifesas.org/ biolife/2020/04/07/coronavirus-cov-19- sars-cov-2-affects-women-less-than-menclinical-response-to-viral-infection/
4. COVID-19 and Smoking Ivan Berlin, MD, PhD, Daniel Thomas, MD, Anne-Laurence Le Faou, MD, PhD, Jacques Cornuz, MD, MPH
5. StrzelakA,RatajczakA, AdamiecA, FeleszkoW. Tobacco smoke induces and alters immune responses in the lung triggering inflammation, allergy, asthma and other lung diseases: a mechanistic review. Int J Environ Res Public Health.2018;15(5):1033. (https://www.mdpi. com/1660-4601/15/5/1033)
6. Sex differences in patients with COVID-19: Focus on severity and mortality Jian-Min Jin, MD, PhD1,2, Peng Bai, MD1,2, Wei He, MD3,2, Fei Wu, MD 2, Xiao-FangLiu, MD, PhD1, De-Min Han MD, PhD4, Shi Liu, MDandJin-Kui Yang MD,PhD (https://www.medrxiv.org/content /10.1101/2020.02.23.20026864v2)
7. Sex difference and smoking predisposition in patients with COVID-19 (https://www. thelancet.com/pdfs/journals/lanres/ PIIS2213-2600(20)30117-X.pdf)
8. Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection- www.thelancet.com/respiratory .Published online April 3, 2020 (https://doi. org/10.1016/S2213-2600(20)30167-3)
9.Are patients with hypertension and diabetes mellitus at increased risk for COVID19 infection - https://doi.org/10.1016/ S2213-2600(20)30116-8
10. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding - https:// doi.org/10.1016/ S0140-6736(20)30251-8
11. Are children less susceptible to COVID-19? Ping-Ing Lee, Ya-Li Hu, [...], and Po-Ren Hsueh doi: 10.1016/j.jmii.2020.02.011 [Epub ahead of print]
12. COVID-19 in children: the link in the transmission chain Alyson A Kelvin Scott Halperin Published:March 25, 2020 DOI:https://doi.org/10.1016/ S1473-3099(20)30236-X PlumX Metric.
13. Cheng Y, Cheng G, Chui CH, Lau FY, Chan PK, Ng MH, Sung JJ, Wong RS. ABO blood group and susceptibility to severe acute respiratory syndrome. JAMA.2005 Mar 23;293(12):1450-1.
14. Guillon P, Clément M, Sébille V, Rivain JG, Chou CF, Ruvoën-Clouet N, Le Pendu J. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histoblood group antibodies. Glycobiology. 2008 Dec;18(12):1085-9