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)

Abstract and Introduction

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the development of life-threatening COVID-19 are believed to disproportionately affect certain at-risk populations. However, it is not clear whether individuals with cystic fibrosis (CF) are at a higher risk of COVID-19 or its adverse consequences. Recurrent respiratory viral infections are often associated with perturbation and pulmonary exacerbations of CF as evidenced by the significant morbidity observed in CF individuals during the 2009 H1N1 pandemic. The primary goal of this review was to systematically survey published accounts of COVID-19 in CF and determine if individuals with CF are disproportionally affected by SARS-CoV-2 and development of COVID-19.

Methods: We conducted a systematic literature search using EMBASE and Medline between April 28 and December 10, 2020. Six evaluable studies reporting on a total of 339 individuals with CF who developed COVID-19 were included in this study.

Results: We found that although individuals with CF generally experience acute exacerbations of lung disease from infectious agents, COVID-19 incidence estimates in CF appear to be lower than in the general population. However, there are reports of subsets of CF, such as those who had organ transplants, that may experience a more severe COVID-19 course. Potential protective mechanisms in the CF population include pre-pandemic social isolation practices, infection prevention and control knowledge, altered expression of angiotensin-converting enzyme, and the use of certain medications.

Conclusions: Although individuals with CF are at risk of acute exacerbations often precipitated by respiratory tract viral infections, published evidence to date indicated that individuals with CF do not experience higher risks of contracting SARS-CoV-2 infection. However, there is evidence that some subsets within the CF population, including those post-transplantation, may experience a more severe clinical course. As SARS-CoV-2 variants are identified and the pandemic goes through additional waves of disease outbreaks, ongoing monitoring of the risk of COVID-19 in individuals with CF is required.

Introduction

Cystic fibrosis (CF) is a classic Mendelian autosomal recessive disorder and is the most common fatal genetic disease in North America.^[1] The predominant incidence estimate of the disorder is 1/2500 live births in Caucasians, with a mean prevalence of 0.797/10,000 in the United States of America.^[2,3] The estimated median age of survival, which denotes the estimated age that 50% of infants born in a given year will live beyond, reaches 50 years and beyond in some countries.^[4] CF has been traced to the inheritance of two abnormal copies of the CF transmembrane conductance regulator (CFTR) gene.^[1] Abnormal CFTR are associated with aberrant salt and water transport across epithelial surfaces. Within the lungs, this manifests with mucus accumulation and the inability to clear inhaled organisms, giving rise to chronic infection and inflammation leading to airway remodelling and disease.^[1] CFTR is also involved in the movement of bicarbonate; defects in its function lowers the pH of the airway surface liquid.^[1,5] Studies have shown this pH alteration in animal models impairs innate immunity by inhibiting the function of antimicrobial peptides.^[1,6,7] Data also suggests that CFTR gene variants cause epithelial cells to inherently respond in an increasingly pro-inflammatory manner.^[1]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the development of life-threatening COVID-19 are believed to disproportionately affect certain at-risk populations such as those over the age of 50 as well as those with diabetes, hypertension, cardiovascular diseases, and chronic respiratory disease.^[8–11] However, it is not clear whether individuals with CF are at a higher risk of COVID-19 or its adverse consequences. This topic has been of great concern due to the importance of recurrent respiratory viral infections in disease perturbation and pulmonary exacerbations.^[12–14] Additionally, significant morbidity was observed in individuals with CF during the 2009 H1N1 pandemic.^[15,16] The primary goal of this study was to survey published accounts of COVID-19 in CF and determine if CF constitutes an 'at risk' population with respect to morbidity or mortality from COVID-19.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
Appendix
References

Table 1. MEDLINE electronic search strategy
Number	Search term(s)
1	Cystic fibrosis/
2	(Cystic fibrosis or fibrocystic disease* or mucoviscidosis).tw,kf
3	1 or 2
4	Exp coronaviridae infections/
5	Exp coronavirus/
6	(Severe acute respiratory syndrome coronavirus 2 or severe acute respiratory syndrome coronavirus or severe acute respiratory syndrome or covid-19 or covid19 or covid or coronavir* or corona vir* or ncov or novel coronavirus or novel cov or SARS-COV-2 or SARSCOV-2 or SARS-COV2 or SARSCOV2).tw,kf
7	4 or 5 or 6
8	3 and 7

Table 2. Clinical studies of COVID-19 in CF
Citation	Countries reporting	Sample size (n)	Study design	Main findings
Cosgriff et al. [18]	Australia, Canada, France, Ireland, Netherlands, New Zealand, UK, USA	40	Multinational cohort observational	Incidence of COVID-19 in CF was 0.07%, compared to 0.15% in general population
				Clinical features of COVID-19 similar in CF and general population
				No deaths in cohort
McClenaghan et al. [19]	Argentina, Australia, Belgium, Brazil, Canada, Chile, France, Germany, Ireland, Italy, Netherlands, New Zealand, Russia, South Africa, Spain, Sweden, Switzerland, UK, and USA	181	Multinational cohort observational	Post-transplant individuals (18%) and FEV₁ < 70% were hospitalized at significantly higher rates
				7 deaths in cohort (3 post-transplant)
Corvol et al. [20]	France	31	Prospective cohort	Incidence of COVID-19 in CF was 0.41%, 93% less than general population
				Post-transplant individuals (39%) received supplemental oxygen and were hospitalized at significantly higher rates
				No deaths in cohort
Mondejar-Lopez et al. [21]	Spain	8	Retrospective descriptive cohort	Incidence of COVID-19 in CF was 0.32%, compared to 0.49% in general Spanish population
				Pediatric subset was not hospitalized, but all adults were
				No deaths in cohort
Bain et al. [22]	Argentina, Brazil, Chile, France, Germany, Italy, Russia, South Africa, Spain, Sweden, Switzerland, UK, US	105	Multinational cohort observational	29% asymptomatic
				FEV₁ of hospitalized children significantly lower than non-hospitalized
				No deaths directly attributed to COVID-19 in cohort
Moeller et al. [23]	N/A^a	14	Survey	7 individuals (50%) were hospitalized, with 3 in the PICU
				No deaths in sample

CF cystic fibrosis, FEV₁ forced expiratory volume in 1 s, PICU pediatric intensive care unit, UK United Kingdom, USA Unites States of America.
^aThe survey stratified patients by asthma, cystic fibrosis, bronchopulmonary dysplasia, and other respiratory conditions but did not specify the number of countries for each condition

Table 3. Newcastle–Ottawa Quality Assessment Scale for cohort studies
	Selection (/☆☆☆☆)	Comparability (/☆☆)	Outcome (/☆☆☆)
Cosgriff et al. [18]	☆☆☆	☆	☆☆
McClenaghan et al. [19]	☆☆☆	☆	☆☆☆
Corvol et al. [20]	☆☆☆☆	☆	☆☆☆
Mondejar-Lopez et al. [21]	☆☆☆☆	☆	☆☆☆
Bain et al. [22]	☆☆	☆	☆☆
Moeller et al. [23]	☆☆☆	☆	☆☆

Table 4. Factors that may mitigate COVID-19 in cystic fibrosis
Category	Mitigating factor
Preventative measures	Social distancing/self-isolation
	Masking
	Frequent hand-hygiene
Physiological	Lower median age
	ACE and ACE2 expression
	Localized respiratory tract reduction of IL-6
	Altered interaction between SARS-CoV 3CL^pro and CFTR
	Thick secretions in respiratory tract
	Existing microbiota
	Elevated autophagy induction
Therapeutic/Interventional	Neutrophil elastase inhibitors
	Dornase alfa
	Azithromycin

ACE Angiotensin-converting enzyme, ACE2 Angiotensin-converting enzyme 2, IL-6 Interleukin-6, 3CL^pro 3-chymotrypsin-like cysteine proteinase, CFTR CF transmembrane conductance regulator

Table 5. EMBASE electronic search strategy
Number	Search term(s)
1	Exp cystic fibrosis/
2	(Cystic fibrosis or fibrocystic disease* or mucoviscidosis).tw,kw
3	1 or 2
4	Exp coronavirinae/or exp coronavirus infection/
5	(Severe acute respiratory syndrome coronavirus 2 or severe acute respiratory syndrome coronavirus or severe acute respiratory syndrome or covid-19 or covid19 or covid or coronavir* or corona vir* or ncov or novel coronavirus or novel cov or SARS-COV-2 or SARSCOV-2 or SARS-COV2 or SARSCOV2).tw,kw
6	4 or 5
7	3 and 6

Table 6. Expanded Newcastle–Ottawa Quality Assessment Scale for Cohort Studies
	Selection				Comparability		Outcomes
	Representativeness of exposed cohort	Selection of non-exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Study controls for most important factor	Study controls for other factor	Assessment of outcome	Follow-up length	Adequacy of follow-up
Cosgriff et al. [17]	☆	–	☆	☆	☆	–	☆	–	☆
McClenaghan et al. [18]	☆	–	☆	☆	☆	–	☆	☆	☆
Corvol et al. [19]	☆	☆	☆	☆	☆	–	☆	☆	☆
Mondejar-Lopez et al. [20]	☆	☆	☆	☆	☆	–	☆	☆	☆
Moeller et al. [21]	–²	☆	☆	☆	☆	–	☆	☆	–