Systematic Review

Cystic Fibrosis in the SARS-CoV-2/COVID-19 Pandemic

Hannah R. Mathew; May Y. Choi; Michael D. Parkins; Marvin J. Fritzler


BMC Pulm Med. 2021;21(173) 

In This Article


COVID-19 Incidence in CF

From the cases reported in the medical literature thus far, individuals with CF appear to be contracting SARS-CoV-2 viral infection at lower rates as compared to the general population.[25] Here and below, we discuss the factors that may mitigate COVID-19 in CF (summarized in Table 4). Most authors suspected that the lower rates of SARS-CoV-2 infection observed in individuals with CF relative to the general population are reflective of increased awareness of infection prevention and control practices, such as frequent hand hygiene and mask-wearing.[26–28] In addition, others suspected that rapid implementation and continued maintenance of physical and social distancing in CF populations were due to a perceived risk of COVID-19 respiratory disease exacerbation and complications.[27,28]

COVID-19 Outcomes in CF

Despite demonstration that hospitalization rates are higher in CF than in the general population, individuals with CF also appear to have better outcomes than initially anticipated as compared to other respiratory viral infections.[19] From a pathogenic perspective, increased concentrations of neutrophil elastase are linked to enhanced lung damage and a decline in pulmonary function in CF.[29] Accordingly, neutrophil elastase inhibitors are being successfully used in trials to treat CF.[29] Of note, a pro-inflammatory imbalance of excess neutrophil elastase is involved in the development of acute respiratory distress syndrome (ARDS) associated with COVID-19.[30] Therefore, neutrophil elastase inhibitors have also been proposed as potential therapies that could be repurposed for treating ARDS and the associated lung damage.[31] Furthermore, nebulized dornase alfa, a common CF medication, is currently undergoing trials for COVID-19 treatment.[32] Its proposed protective effect relates to its clearance of neutrophil extracellular traps, which play a pathogenic role in SARS-CoV-2 infection.[33] Of interest, preliminary data suggests that dornase alfa is effective in limiting the in vitro infection of green monkey and bovine kidney cell lines by SARS-CoV-2.[33] Lastly, azithromycin, another commonly prescribed antibiotic in CF, has been suggested to potentially impact COVID-19—both by modulating the immune response and because of weak anti-viral activity.[34,35] In early studies, the administration and use of chronic nebulized dornase alfa was not mentioned, but azithromycin use was described in four of the studies,[20–23] either in regard to pre-existing use or as a treatment for COVID-19. In summation, it is possible that a CF patient exposed to SARS-CoV-2 might be on medications that may mitigate clinically severe COVID-19 (see Table 4).[36]

Since elevated interleukin-6 (IL-6) levels are associated with severe disease course and mortality in COVID-19, IL-6 is suggested to be an important cytokine in SARS-CoV-2 infection pathogenesis and 'cytokine storm'.[37,38] However, in CF, there is a localized constitutive reduction of IL-6 in the respiratory tract, which suggests that it could serve as a protective factor from severe SARS-CoV-2 infection-related cytokine storms.[37] In a cohort of 39 individuals with advanced CF and chronic Pseudomonas aeruginosa infection, on average, the collected sputa contained high interleukin-8 (IL-8) levels and extremely low IL-6 and interleukin-10 (IL-10) levels.[37] This reduction of IL-6 was localized to the sputum, whereas systemic production of IL-6 was unaffected.

Angiotensin-converting enzyme 2 (ACE2) is the host cell receptor required for binding and entry of SARS-CoV-2 via the receptor-binding domain of the spike (S) protein.[39] SARS-CoV-2 infection causes ACE2 transcriptional downregulation, resulting in an excessive synthesis of angiotensin II by angiotensin-converting enzyme (ACE),[40] a potential factor for exacerbated lung damage.[41] One study on an ACE biallelic polymorphism in 180 individuals with CF, termed "I" (insertion) and "D" (deletion), reported that subjects with the ACE D/D polymorphism were associated with an earlier appearance of clinical symptoms and higher risks of lung deterioration than those with I/I or D/I polymorphisms.[42] In another study on human coronaviruses (HCoV) in CF children, researchers did not find a significant association of HCoV infections with pulmonary exacerbations; however, those infected by HCoV-NL63, which also uses ACE2 for cell entry, had a significantly higher rate of pulmonary exacerbation than those with other coronavirus infections.[43] Taken together, the evidence suggests that a varied COVID-19 disease course in CF may in part be due to the association between ACE polymorphisms, effects on ACE2 downregulation, and resulting CF features, such as pulmonary inflammation.[44]

It is also worth noting the importance of the SARS-CoV-2 3-chymotrypsin-like cysteine proteinase (3CLpro), which is critical in controlling viral replication and life cycle.[45] The SARS-CoV-2 3CLpro shares 99.02% genomic similarity with the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro, and every residue involved in catalysis, dimerization, and substrate binding is entirely conserved.[46] As such, the 3CLpro cleavage sites of the viral polyproteins are also considerably conserved.[46] The high degree of identity between SARS-CoV 3CLpro and SARS-CoV-2 3CLpro suggests that the activities of one are reflective of the other. The SARS-CoV 3CLpro potential cleavage sites include the CFTR protein, which may be cleaved if available to the proteinase.[47] This information suggests that the cleavage of the CFTR protein may be involved in the molecular pathology of SARS-CoV-2, although the consequent effect on disease outcomes in the CF population is unclear.

It has also been postulated that thick secretions as well as the existing microbiota in the respiratory tract of individuals with CF may be protective mechanisms against viral infection.[21] Although information is limited, autophagy induction also plays direct and indirect roles in anti-viral response and is seen to be elevated in those with CF, suggesting its potential as a protective mechanism.[48,49]

According to the studies included in this review, history of solid-organ transplantation is hypothesized to be a potential determinant of COVID-19 disease outcomes. This finding is supported by another study describing 32 lung transplant recipients (transplanted for multiple aetiologies) who tested positive for COVID-19.[50] In this study, 16% developed mild disease, 44% developed moderate disease, and 41% developed severe disease. Eighty-four percent were hospitalized, and 34% of the 32 individuals died, suggesting that COVID-19 is associated with a significantly higher mortality rate in lung transplant recipients than the general population. In this small study, the authors did not find a significant association between underlying pathology that necessitated lung transplantation (including CF) and the risk of severe COVID-19. Although certain immunosuppressant therapies in transplant recipients represent potential risk factors for severe disease,[51,52] baseline immunosuppressant doses were not significantly correlated with the severity of disease in the study. Indeed, because of the severe immune dysregulation culminating in a severe inflammatory component, immunomodulation and suppression strategies may be important if we are to modify the natural history of the later stages of COVID-19.[53–55] Despite uncertainty regarding the mechanisms that elicit severe disease in this subgroup, the authors state that C-reactive protein, D-dimer, and IL-6 markers were disproportionally elevated in severe disease compared to moderate disease and may aid in determining disease prognoses in post-lung transplant individuals.

Risk of Bias Assessment

Due to the unprecedented nature of the pandemic, we are indebted to the authors of these studies for their foresight in collecting and reporting data on the effect of SARS-CoV-2 infection in the CF population. However, the pandemic presented challenges in establishing certain elements of cohort studies, such as forming a distinct non-exposed cohort. While non-exposed (non-CF) participants were not recruited, an effort was made by some studies to compare results in the CF population to local statistics on the general population.[20,21] Most studies were unable to control for factors beyond a method of defining a SARS-CoV-2 positive case, as the urgency for data on perceived at-risk populations, such as individuals with CF, prompted swift reporting.[18–23] The need for data early in the pandemic is also evidenced by the fact that, at the time of publication of the first multinational cohort study of 40 individuals, 30% of the cases were unresolved;[18] similarly, in the multinational cohort study of 105 CF children, two cases (2%) were unresolved at the time of publication.[22] The smallest study, which was a survey describing 14 children with CF who contracted COVID-19, had a low response rate; however, the results of the study were in accord with statistics reported by the larger studies included here.[23]

Limitations and Future Studies

Within the countries included in the analyzed studies, the reported cases of COVID-19 are not comprehensive and represent preliminary data. The data may be biased by the first wave of the pandemic, allowing for the possibility of the emergence of new information and trends over subsequent months. Furthermore, there is a lack of information regarding the long-term effects of COVID-19 disease in CF as well as the general population. Lastly, due to small sample sizes, univariate analyses were common among the analyzed studies and should be interpreted accordingly, especially considering univariate analysis could not be completed in the post-transplantation subgroup in the largest multinational cohort study published to date.[19]

Further studies would benefit from analyzing the use of nebulized dornase alfa in those who developed COVID-19 and clarifying the uncertain effects of azithromycin in COVID-19 treatment. As well, the effect of ACE D/I biallelic polymorphism on COVID-19 severity in CF should be considered in future studies.