Risk factors
The emergence of new variants of SARS-CoV-2, such as Omicron and its subvariants, present a challenge for the eradication of COVID-19 as they have evolved immune escape from the neutralizing antibodies developed in previous infections and vaccinations66,67. COVID-19 breakthrough infection has become a major concern associated with the new variants68. Whole genome sequencing revealed two distinct mechanisms that can predispose an individual to life-threatening COVID-19, namely failure to control viral replication or an enhanced tendency towards pulmonary inflammation and intravascular coagulation69. Older age, male sex, cardiovascular and metabolic comorbidities, racial/ethnic disparities, chronic kidney diseases and cancer have been identified as risk factors for SARS-CoV-2 infection and worse outcomes of COVID-1935,36. Healthcare workers are at higher risk of SARS-CoV-2 infection compared to non-healthcare workers36,70. Blood levels of neutrophil elastase71 and histone-DNA72 were associated with severe and systemic and multi-organ manifestations of COVID-19. Higher levels of bacteria DNA in the system circulation were associated with severe and fatal COVID-1973. COVID-19 patients with inborn errors of immunity, except type I IFN immunity errors, exhibit an almost similar natural COVID-19 course compared to the general population74. Interestingly, individuals with blood group A are at higher risk of SARS-CoV-2 infection and severe disease, whereas blood group O may be protective against COVID-1975.
The higher expression of entry receptors ACE2 and TMPRSS2 increase the susceptibility to SARS-CoV-2 infection35. Smoking was associated with higher expression of ACE2, TMPRSS2, FURIN, and BSG in bronchial brushes8 and represents a risk factor for COVID-19 mortality when not adjusted for chronic respiratory diseases76.
Air pollution has been shown to be associated with SARS-CoV-2 infection and COVID-19 mortality77. Mechanistically, air pollutants such as nitrogen dioxide, ozone, and particulate matters (PM) may disrupt the airway epithelial barrier and impair the defense against respiratory viruses77,78. The airway epithelial barrier interacts with the respiratory microbiome to shape the immune response in the lungs79. In addition, air pollution may contribute to chronic systemic inflammation and a higher prevalence of comorbidities such as cardiovascular and respiratory diseases which have been demonstrated to be risk factors for severe COVID-1978,80,81. Air pollution is also correlated with a higher expression of ACE2 receptor in the lung82. Furthermore, fine particulate matters such as PM2.5 and PM10 may act as carriers of SARS-CoV-2 and promote the transmission of this virus80. Lockdown during COVID-19 was associated with a reduction in PM2.5 concentrations due to reduced traffic emission83. Interestingly, the concentrations of airborne pollen correlated with the infection rates of SARAS-CoV-2 in thirty-one countries across both hemispheres84. This may be attributed to the impairment of innate antiviral immunity of airway epithelia upon pollen exposure84.
As an interesting risk factor, exposure to pollution and gut barrier leakiness have been proposed to play a role on COVID-19 severity. Although further studies are needed, severity and excess death rate in northern Italy were suggested to have a link with increased air pollution78, in accordance with several other studies85-87.