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.