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.