Risk factors that affect host antiviral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and increase susceptibility to severe coronavirus disease 2019 (COVID-19)
| Risk factor | Altered physiological and immune profile |
| Age-related susceptibility: elderly people | • ACE2 expression in airway and alveolar epithelial cells increases with advancing age, affecting SARS-CoV-2 cellular entry and infection |
| • Weakened antiviral IFN-1 responses upon viral infection | |
| • Inflammaging and counter-regulation of anti-inflammatory molecules may promote pro-inflammatory cytokine secretion, leading to a hyperinflammatory milieu that can cause widespread tissue damage | |
| • Immunosenescence and decreased naïve T-cells and B-cell numbers, with involution of primary lymphoid organs, lead to reduced ability of the host to respond to new infections, allowing increased viral loads, a hyperinflammatory status and disease progression | |
| • Apoptotic priming of lung tissue decreases with age, which may lead to increased virion production due to later apoptosis induction in infected cells | |
| • Comorbidities/chronic diseases are more common with advancing age, further contributing to the enhancement of COVID-19 severity and risk of mortality | |
| Age-related susceptibility: neonates | • Increased ACE2 expression at birth (which subsequently drops and then gradually increases with time) makes infants more susceptible to infection |
| • Low expression of cytotoxic and inflammatory mediators after birth, with inefficient clearance of virally infected cells by CTLs and NK cells | |
| • Altered early Th1 functions (skewed towards a Th2 profile) leads to insufficient antiviral responses | |
| Comorbidities and chronic diseases#, an immunosuppressed status, high viral exposure | • Altered immune statuses that impair host defence mechanisms can result in inability to produce effective/timely antiviral responses, leading to higher viral loads, a hyperinflammatory status and disease progression |
| • Excessive tissue damage can trigger abnormal macrophage activation, leading to uncontrolled pro-inflammatory cytokine release with associated coagulopathy, vasculopathy and multiorgan injury | |
| • Altered atherogenic profiles may augment coagulopathy in COVID-19 | |
| • Increased tissue expression of ACE2 in several comorbidities/chronic diseases or resulting from treatment of chronic diseases (e.g. COPD, hypertension, diabetes, carcinomas and cardiac diseases) | |
| • Increased tissue expression of TMPRSS2 in COPD and hypertension | |
| Biological sex (male) bias | • The ACE gene is located on the X-chromosome and is downregulated by oestrogen, and higher ACE2 expression in male compared to female lungs, which may lead to higher infection rates in males |
| • Steroid hormones affect immune cell functions: variability of hormone expression may be implicated in the variability of immune responses and age-related sex dimorphism | |
| Pregnancy | • Strong Th1 response during implantation and placentation, followed by Th2 dominance and another Th1 wave at parturition/postpartum: gestational age-dependent dynamic immune status may promote development of severe COVID-19 due to increased pro-inflammatory cytokine production or Th1 response counteraction, or obstetric complications with adverse effects on maternal and fetal health |
| • Pregnancy is a prothrombotic state due to increased oestrogen levels and altered immune responses, and may augment coagulopathy in COVID-19 | |
| ABO blood group | • Circulating anti-A antibodies (possessed by blood group O, absent in group A) interfere with virus-cell adhesion: blood group A at higher risk of SARS-CoV-2 infection |
| • A-allele (possessed by blood group A) associated with a higher risk of cardiovascular disease and lower expression of factors that promote coagulation by blood group O (protection from complications associated with severe COVID-19 in blood group O) | |
| Genetic susceptibility and environmental factors | • Several genetic factors relating to key host antiviral defence mechanisms or mediators of inflammatory organ damage have been proposed and/or identified to influence susceptibility and severity, including IFN-1 signalling pathway dysfunction, other cytokine defects/polymorphisms, errors of the ACE2 gene, HLA locus, TLR and complement pathways, and myeloid compartments |
| • Race and ethnicity may have genetic influences, but could also have major environmental factors underlying predisposition |
#: e.g. obesity, hypertension, diabetes, cancer, respiratory, cardiovascular or autoimmune diseases. ACE2: angiotensin converting enzyme 2; CTL: cytotoxic T-lymphocyte; HLA: human leukocyte antigen; IFN-1: interferon 1; NK: natural killer; Th: T-helper cell; TLR: Toll-like receptor; TMPRSS2: transmembrane protease serine 2.