Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants

Abstract

The clinical presentation of COVID-19 is extremely heterogeneous, ranging from asymptomatic to severely ill patients. Thus, host genetic factors may be involved in determining disease presentation and progression. Given that carriers of single cystic fibrosis (CF)-causing variants of the CFTR gene—CF-carriers—are more susceptible to respiratory tract infections, our aim was to determine their likelihood of undergoing severe COVID-19. We implemented a cohort study of 874 individuals diagnosed with COVID-19, during the first pandemic wave in Italy. Whole exome sequencing was performed and validated CF-causing variants were identified. Forty subjects (16 females and 24 males) were found to be CF-carriers. Among mechanically ventilated patients, CF-carriers were more represented (8.7%) and they were significantly (p < 0.05) younger (mean age 51 years) compared to noncarriers (mean age 61.42 years). Furthermore, in the whole cohort, the age of male CF-carriers was lower, compared to noncarriers (p < 0.05). CF-carriers had a relative risk of presenting an abnormal inflammatory response (CRP ≥ 20 mg/dL) of 1.69 (p < 0.05) and their hazard ratio of death at day 14 was 3.10 (p < 0.05) in a multivariate regression model, adjusted for age, sex and comorbidities. In conclusion, CF-carriers are more susceptible to the severe form of COVID-19, showing also higher risk of 14-day death.

The genetic and evolutionary determinants of COVID-19 susceptibility

“…Yet, other studies have brought supporting evidence for the implication of type I IFN-independent genes as monogenic etiologies of COVID-19. For example, genetic variants in the CFTR gene, including those causing cystic fibrosis, have been found to be overrepresented among critically ill COVID-19 patients [ 18 – 20 ], consistent with previous associations of the gene with susceptibility to respiratory tract infections [ 21 ]. Likewise, a genetic polymorphism in the androgen receptor ( AR ) gene that correlates with low serum testosterone level has been associated with severe COVID-19 in men [ 22 ].…”

COVID-19 in a pregnant cystic fibrosis carrier with myasthenia gravis: A case report

“…Yet the recent GEN-COVID multicenter trial showed that non-pregnant CF carriers (heterozygous) are predisposed to severe COVID-19 and a higher risk of death. The authors also noted previous studies suggesting that active CF patients (homozygous) appeared to undergo a mild form of COVID-19 and postulate this discrepancy could be due to their treatment with CFTR modulators while the CF carriers (heterozygous) are not treated [ 11 ].…”

Flagellin From Pseudomonas aeruginosa Modulates SARS-CoV-2 Infectivity in Cystic Fibrosis Airway Epithelial Cells by Increasing TMPRSS2 Expression

“…Thus, whether the risk of developing severe COVID-19 is increased in pwCF because of their P. aeruginosa infection remains unresolved and will require further meta-analysis performed using international cohorts. Moreover, a recent study including 874 individuals with COVID-19 showed that carriers of CF-causing variants (N=40) may be more likely to develop severe COVID-19 ( 38 ). This reinforces the interest in studying the specific role of CFTR in the pathogenesis of COVID-19.…”