SARS-CoV-2 (COVID-19) and cystic fibrosis

Abstract

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene. Although viral respiratory tract infections are, in general, more severe in patients with CF compared to the general population, a small number of studies indicate that SARS-CoV-2 does not cause a worse infection in CF. This is surprising since comorbidities including preexisting lung disease have been reported to be associated with worse outcomes in SARS-CoV-2 infections. Several recent studies provide insight into why SARS-CoV-2 may not produce more severe outcomes in CF. First, ACE and ACE2, genes that play key roles in SARS-CoV-2 infection have some variants that are predicted to reduce the severity of SARS-CoV-2 infection. Second, mRNA for ACE2 is elevated and the mRNA for TMPRSS2, a serine protease, is decreased in CF airway epithelial cells. Increased ACE2 is predicted to enhance SARS-CoV-2 binding to cells, but would increase conversion of angiotensin II, which is proinflammatory, to angiotensin-1-7, which is anti-inflammatory. Thus, increased ACE2 would reduce inflammation and lung damage due to SARS-CoV-2. Moreover, decreased TMPRSS2 would reduce SARS-CoV-2 entry into airway epithelial cells. Second, many CF patients are treated with azithromycin, which suppresses viral infection and lung inflammation, and inhibits the activity of furin, a serine protease. Finally, the CF lung contains high levels of serine protease inhibitors including ecotin and SERPINB1, which are predicted to reduce the ability of TMPRSS2 to facilitate SARS-CoV-2 entry into airway epithelial cells. Thus, a variety of factors may mitigate the severity of SARS-CoV-2 in CF.

Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases

“…In contrast, studies to date indicate that SARS-CoV-2 does not lead to a worse infection in CF patients. A culmination of factors including decreased TMPRSS2 levels in airway epithelial cells and high expressions of serine protease inhibitors such as SERPINB1 in these patients may account for this surprising finding [ 150 ].…”

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study

“…During the 2009 influenza A (H1N1) pandemic infection was associated with substantial morbidity in people with CF and a high mortality rate in those admitted to intensive care [15,16] . Conversely, other aspects of CF airway pathophysiology may mitigate against severe COVID-19 disease [17,18] . CF airway epithelial cells may be less susceptible to coronavirus infection due to altered intracellular processes involved in host defence and viral replication, for example autophagy, unfolded protein response and NOD-, LRR-and pyrin domain-containing protein 3 inflammasome.…”

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2

“…Cosgriff et al present a more detailed evaluation of the effects of COVID-19 in the cystic fibrosis population in eight countries on three continents [ 16 ]. Further commentary on this phenomenon is found in [ 33 , 40 ] and [ 45 ].…”

“… 5 Other research groups have suggested other aspects of the CF phenotype which may confer such benefit [ 33 , 40 , 45 ]. All of these phenomena may be operating to various degrees to confer survival benefit.…”