Protective factors
Health systems resilience is critical for the control of the COVID-19
pandemic37. A healthy diet and sufficient nutrition
have been identified as protective factors against SARS-CoV-2
infection35. Both the incidence rate and mortality of
COVID-19 were lower in Bacillus Calmette-Guerin (BCG)-vaccinated
countries than in those without vaccination
program38,39. Moreover, BCG vaccination during early
childhood seems to selectively protect against infection in the
elderly40. BCG was suggested to enhance innate immune
responses, leading to “trained immunity” and confer protection against
viral infections41. Similarly, recent administration
of the mumps-measles-rubella vaccine was observed to be associated with
a reduction in SARS-CoV-2 infection in males42 and
severity of COVID-1943, although the real correlation
between this vaccine and COVID-19 is still unclear44.
Lower levels of nasal ACE245 and airway cathepsin
L/CTSL146, a protease that cleaves and primes the
SARS-CoV-2 spike protein, may contribute to the mild disease of COVID-19
in children. Atopy and type 2 inflammation have been associated with a
decreased expression of ACE2 in airway epithelial cells and thus lower
susceptibility to SARS-CoV-247. More importantly, the
type 2 cytokine IL-13 reduced ACE2 expression47,
intracellular viral load and cell-to-cell transmission, whilst
increasing the cilial keratan sulfate coating in airway epithelial
cells, suggesting a role of IL-13 in attenuating viral shedding and thus
reducing the entry, replication, and spread of
SARS-CoV-248. Genetic variation of allergic disease
was associated with a lower risk of COVID-1949.
Most studies suggested that AR and chronic rhinosinusitis (CRS) are not
associated with a higher risk of susceptibility and severity of
COVID-1935,50,51. Reduced ACE2 expression was observed
in bronchial epithelial cells from patients with concomitant AR and
allergic asthma47, suggesting a potential protective
effect of atopy against susceptibility and severity of COVID-19. The
expression of ACE2 in nasal polyp tissues of patients with CRS was lower
than that of healthy controls52. The expression of
ACE2 and TMPRSS2 was also lower in the olfactory mucosa of patients with
chronic rhinosinusitis with nasal polys (CRSwNP) compared to healthy
controls, and the protein expression of ACE2 was negatively correlated
with eosinophils numbers in olfactory mucosa53.
Moreover, the expression of ACE2 was upregulated by interferon (IFN)-γ
and downregulated by type 2 cytokines in nasal epithelial
cells47,54,55. All these data support a protective
role of type 2 inflammation against SARS-CoV-2 infection and severe
disease.
The corticosteroid dexamethasone can increase ventilator-free
days56 and reduce the death rate57in severe and critically ill COVID-19 patients. Mechanistically,
dexamethasone treatment restrains neutrophil pathogenicity by reducing
IFNactive-neutrophils and expanding immunosuppressive
immature neutrophils58. Treatment with inhaled
corticosteroids (ICS) reduced the expression of ACE2 in induced
sputum59 from asthma patients and in bronchial
epithelia from patients with chronic obstructive pulmonary
diseases60. Clinical studies reported that inhaled
budesonide in COVID-19 patients reduced time to recovery and resulted in
less severe outcome61,62. Mechanistically, early Th2
inflammation and attenuated IFN-γ production in the nose may indicate
worse clinical outcomes, and ICS budesonide treatment inhibited Th2
inflammation in the nose63. Inhalable
SARS-CoV-2-specific siRNA and human ACE2-containing nanocatchers were
shown to reduce SARS-CoV-2 infection64,65 and lung
inflammation64, as shown in SARS-CoV-2 infected mice.