Cystic fibrosis (CF) is a chronic autosomal recessive condition affecting multiple systems, mainly the respiratory, gastrointestinal, and reproductive tract. The condition occurs due to mutations in the CF transmembrane conductance regulator (CFTR) gene.1 The global incidence of CF ranges from 1 in 1353 in Ireland (2001–2003)2 to 1 in 6000 in Central Europe (2010–2017),3,4 and is more prevalent in Caucasian populations.3,5 An improving trend in outcomes relating to CF has been reported owing to a better understanding of the pathophysiology, mutation-specific therapeutic options, nutritional intervention modalities, rolling out of newborn screening, and care centers with multidisciplinary approaches and support systems.3,6 However, repeated bacterial and viral respiratory infections can lead to recurrent hospitalization, reduction in pulmonary function, and, eventually, death of persons with CF.7,8
The pathophysiology of CF is based on the dysregulation of the CFTR gene, which, along with the epithelial sodium channel, essentially maintains the respiratory tract's mucociliary clearance and hydration by proper transport of chloride and sodium ions across the apical membranes of the airway. There are 6 types of mutations that alter the normal function of the CFTR gene, causing either the absence or reduction of the CFTR protein, reduced stability, altered transporting, regulation, or decreased conductance of the channel. These mutations may be nonsense, frame shift, or missense, with either amino acid deletion, change, or splicing defect, all leading to more than 2000 variants of the CFTR gene.1,5
CF can present as meconium ileus or failure to thrive in neonates; pancreatic insufficiency or nasal polyps in children and adults; recurrent long-standing respiratory infections; bronchiectasis; and malnutrition.1,9 There are various phenotypes of CF based on the differences in CFTR mutations, modifier genes, lifestyle, treatment protocol, and environmental changes.9 The core diagnostic tests for this condition are the sweat test, the CFTR mutation analysis test, and the CFTR bioassays.1,9 The susceptibility of people with CF to recurrent infections and associated comorbidities requires frequent hospitalization with a plethora of investigations for detection and targeted therapy. The chronicity of the condition, the necessity for supportive equipment, and the need for long-term prophylactic drugs have a significant socioeconomic impact on the individuals, their families, and the health care system.1,9,10 Associated mental health problems, such as depression and anxiety, have a negative impact on survival rates and quality of life of these individuals and their families.11
On December 31, 2019, the World Health Organization (WHO) was informed of an outbreak of “pneumonia of unknown origin” in Wuhan province in China.12 As of April 11, 2022, the WHO has reported 497 million cases of COVID-19 worldwide, and 6 million13 deaths, with a variable case fatality rate of approximately 0.1% to 25%.14
Early in 2020, a study from Europe reported a 0.3% incidence of COVID-19 in persons affected by CF compared with 0.49% in the general population.15 However, other studies report incidence ranging from 0.24% to 2.7% (2020),16,17 demonstrating variability, with the need to also consider mortality and hospitalization rates among people with CF who contract COVID-19.
The CFTR mutations disrupt the metabolism in cells and accentuate the inflammatory response through a chronic response facilitated by the NF-κB and upregulation of the inflammasome complex, namely, the NLRP3. In the lungs, it results in tissue damage, and with SARS-CoV-2 infection, this is exacerbated. The SARS-CoV-2 spike protein binds to the host cell angiotensin-converting enzyme 2 (ACE-2) receptor. ACE-2, which converts angiotensin II to angiotensin in the lungs, is used up by the ever-increasing viral load, resulting in the accumulation of angiotensin II, causing apoptosis and fibrosis. In addition, the infection upregulates the NLRP3 inflammasome complex synthesis of the pro-inflammatory cytokines, worsening the inflammation. Hence the pathogenesis of SARS-CoV-2 is directly entwined with that of CF, leading to a high pro-inflammatory response and accentuated lung injury.18,19
The clinical features of COVID-19 may include mild fever, cough with or without sputum, breathlessness, myalgia or fatigue, headache, hemoptysis, and diarrhea.20 Complications include acute respiratory distress syndrome, acute cardiac injury, secondary infection, and death.20,21 There is increasing evidence that people in the older age group (above 60 years) affected with COVID-19 and with comorbidities, such as chronic kidney disease, cardiovascular disease, respiratory disease, diabetes, and cancer, have higher mortality rates compared with the general population.20,21 Similarly, persons with CF, who already have a chronic airway disease or are immunocompromised, may be at risk of increased severity of COVID-19.21,22 Therefore, it is important to assess the incidence, prevalence, clinical features, and outcomes of COVID-19 in persons with CF in order to develop strategies to reduce the adverse effects of COVID-19 in this population.
A preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews, and JBI Evidence Synthesis identified one systematic review on the topic. This review was conducted in the first year of the COVID-19 pandemic, included only early literature (2020–21), and did not conduct a meta-analysis.23 Therefore, a robust review is warranted for a comprehensive and systematic analysis of the current evidence on incidence, prevalence, clinical features, and outcomes of COVID-19, such as hospitalization and mortality in persons with CF. This will provide current evidence to guide clinicians in predicting the probable burden and outcomes in this high-risk group to carefully choose the therapeutic and intervention modalities.
- i) What is the incidence and/or prevalence of COVID-19 in persons with CF?
- ii) What are the clinical features and outcomes of persons with CF who have been diagnosed with COVID-19?
Studies with persons with preexisting CF and laboratory-confirmed COVID-19 through a polymerase chain reaction, serology, or point-of-care test will be considered for inclusion, irrespective of age, race, sex, or cultural factors. Persons with known CF who are suspected of having or are symptomatic of COVID-19, but without laboratory-confirmed COVID-19, will be excluded from the review.
This review will consider studies that report on the incidence and/or prevalence, clinical features (such as fever, cough, dyspnea), or outcomes (such as hospitalization, intensive care unit admission, mortality) of COVID-19 in individuals known to have CF.
This review will consider studies that have been conducted in community or health care settings, irrespective of geographic location.
Types of studies
This review will consider observational studies, including descriptive and analytical (longitudinal, cohort, and cross-sectional) studies. Studies that include registry and census data will also be included. Experimental and quasi-experimental study designs that report on prevalence and incidence, clinical features, or outcomes will also be considered. Letters to the editor, short communications, or editorials that report incidence, prevalence, clinical features, or outcomes data of primary studies will also be included in this review. Case reports and case series will be excluded.
The proposed systematic review will be conducted in accordance with the JBI methodology for systematic reviews of prevalence and incidence.24
The search strategy will aim to locate both published and unpublished studies. An initial limited search of MEDLINE (Ovid) was undertaken to identify articles on the topic. The text words contained in the titles and abstracts of relevant articles, and the index terms used to describe the articles, were used to develop a full search strategy for MEDLINE via Ovid (see Appendix I). The search strategy, including all identified keywords and index terms, will be adapted for each included database and/or information source. The reference lists of all included sources of evidence will be screened for additional studies.
Studies published in English and available English translations will be included. Studies published since January 30, 2020, will be included as this was when COVID-19 was declared by WHO as a public health emergency of international concern.
Electronic databases will be searched and further information will be collected from authors if required. The databases to be searched include MEDLINE (Ovid), Scopus, Embase (Ovid), CINAHL (Ovid), and PsycINFO (EBSCO). The search for unpublished studies and gray literature will include Google Scholar, Dissertation Abstracts International, ProQuest Dissertations and Theses, and MedNar.
Following the search, all identified citations will be collated and uploaded into EndNote v.X8 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Potentially relevant studies will be retrieved in full and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia).25 The full text of selected citations will be assessed in detail against the inclusion criteria by two independent reviewers. Reasons for exclusion of full-text studies that do not meet the inclusion criteria will be recorded and reported in the systematic review. Any disagreements that arise between the reviewers at each stage of the study selection process will be resolved through discussion or with a third reviewer. The results of the search will be reported in full in the final systematic review and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.26
Assessment of methodological quality
Eligible studies will be critically appraised by two independent reviewers at the study level for methodological quality in the review using standardized critical appraisal instruments from JBI for prevalence studies, cohort, analytical cross-sectional, experimental, and quasi-experimental studies.27 Authors of papers will be contacted to request missing or additional data for clarification, where required. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. The results of the critical appraisal will be reported in narrative format and a table.
All studies, regardless of the results of their methodological quality, will undergo data extraction and synthesis (where possible).
Data will be extracted from the papers included in the review by two independent reviewers, using the standardized data extraction tool for prevalence and incidence available in JBI SUMARI.25 The data extracted will include specific details about the condition, populations, study methods, and proportions of interest to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data, where required.
Papers will, where possible, be pooled in statistical meta-analysis using JBI SUMARI. Effect sizes will be expressed as a proportion with 95% CI around the summary estimate. Heterogeneity will be assessed statistically using the standard χ2, τ2, and I2 tests.28 A random effects model using the double arcsine transformation approach will be used.29 Subgroup analyses will be conducted where there are sufficient data to investigate subgroups, such as adults and children, or those with or without a lung transplant. Sensitivity analyses will be conducted to test decisions by excluding studies of lower methodological quality to assess conclusion robustness/study design. Where statistical pooling is not possible, the findings will be presented in narrative format, including tables and figures to aid in data presentation, where appropriate.
The postdoctoral research work by SA is supported by a postdoctoral award from the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India (PDF/2019/003550).
SA: concept, designing analysis, collection of data, analysis and interpretation of results, writing manuscript. SSV: designing analysis, collection of data, analysis and interpretation of results, writing manuscript. RF: designing analysis, analysis and interpretation of results, editing. HG: designing analysis, collection of data, analysis and interpretation of results, editing. MJI and CSC: concept defining, editing. EM: concept defining, designing analysis, editing.
Appendix I: Search strategy
Searched: March 3, 2022
1. Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, et al. The future of CF care: a global perspective. Lancet Respir Med 2020;8:65–124.
2. Farrell P, Joffe S, Foley L, Canny GJ, Mayne P, Rosenberg M. Diagnosis of cystic fibrosis in the Republic of Ireland: epidemiology and costs. Ir Med J 2007;100:557–560.
3. Scotet V, L’Hostis C, Férec C. The changing epidemiology of cystic fibrosis: incidence, survival and impact of the CFTR gene discovery. Genes (Basel) 2020;11 (6):589.
4. David J, Chrastina P, Pešková K, Kožich V, Friedecký D, Adam T, et al. Epidemiology of rare diseases detected by newborn screening in the Czech Republic. Cent Eur J Public Health 2019;27:153–159.
5. Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet 2021;397:2195–2211.
6. Corriveau S, Sykes J, Stephenson AL. Cystic fibrosis survival: the changing epidemiology. Curr Opin Pulm Med 2018;24:574–578.
7. Patel S, Thompson MD, Slaven JE, Sanders DB, Ren CL. Reduction of pulmonary exacerbations in young children with cystic fibrosis during the COVID-19 pandemic. Pediatr Pulmonol 2021;56:1271–1273.
8. Eymery M, Morfin F, Doleans-Jordheim A, Perceval M, Ohlmann C, Mainguy C, et al. Viral respiratory tract infections in young children with cystic fibrosis: a prospective full-year seasonal study. Virol J 2019;16:1–8.
9. Hassan M, Bonafede MM, Limone BL, Hodgkins P, Sawicki GS. The burden of cystic fibrosis in the Medicaid population. Clinicoecon Outcomes Res 2018;10:423–431.
10. Angelis A, Tordrup D, Kanavos P. Socio-economic burden of rare diseases: a systematic review of cost of illness evidence. Health Policy 2015;119:964–979.
11. Schechter MS, Ostrenga JS, Fink AK, Barker DH, Sawicki GS, Quittner AL. Decreased survival in cystic fibrosis persons with a positive screen for depression. J Cyst Fibros 2021;20:120–126.
12. World Health Organization. Pneumonia of unknown cause – China [internet]. WHO; 2020 [cited 2022 Apr 11]. Available from: https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/
13. World Health Organization. WHO coronavirus (COVID-19) dashboard [internet]. WHO; 2022 [cited 2022 Apr 11]. Available from: https://covid19.who.int/
14. World Health Organization. Estimating mortality from COVID-19 [internet]. WHO; 2020 [cited 2022 Apr 11]. Available from: https://www.who.int/news-room/commentaries/detail/estimating-mortality-from-covid-19
15. Mondejar-Lopez P, Quintana-Gallego E, Giron-Moreno RM, Cortell-Aznar I, Ruiz de Valbuena-Maiz M, Diab-Caceres L, et al. Impact of SARS-CoV-2 infection in patients with cystic fibrosis in Spain: incidence and results of the national CF-COVID19-Spain survey. Respir Med 2020;170:106062.
16. Berardis S, Verroken A, Vetillart A, Struyf C, Gilbert M, Gruson D, et al. SARS-CoV-2 seroprevalence in a Belgian cohort of patients with cystic fibrosis. J Cyst Fibros 2020;19:872–874.
17. Colombo C, Alicandro G, Daccó V, Gagliano V, Morlacchi LC, Casciaro R, et al. SARS-CoV-2 infection in cystic fibrosis: a multicentre prospective study with a control group, Italy, February-July 2020. PLoS One 2021;16:e0251527.
18. Peckham D, McDermott MF, Savic S, Mehta A. COVID-19 meets cystic fibrosis: for better or worse? Genes Immun 2020;21:260–262.
19. Sarantis P, Koustas E, Papavassiliou AG, Karamouzis MV. Are CF mutation carriers a potentially highly vulnerable group to COVID-19? J Cell Mol Med 2020;24:13542–13545.
20. Shah SJ, Barish PN, Prasad PA, Kistler A, Neff N, Kamm J, et al. Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: a retrospective cohort study of patients with and without COVID-19. EClinicalMedicine 2020;27:100518.
21. Biswas M, Rahaman S, Biswas TK, Haque Z, Ibrahim B. Association of sex, age, and comorbidities with mortality in COVID-19 persons: a systematic review and meta-analysis. Intervirology 2021;64:36–47.
22. Naehrlich L, Orenti A, Dunlevy F, Kasmi I, Harutyunyan S, Pfleger A, et al. Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020. J Cyst Fibros 2021;20:566–577.
23. Mathew HR, Choi MY, Parkins MD, Fritzler MJ. Systematic review: cystic fibrosis in the SARS-CoV-2/COVID-19 pandemic. BMC Pulm Med 2021;21:173.
24. Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Chapter 5: Systematic reviews of prevalence
and incidence. In: Aromataris E, Munn Z, editors. JBI Manual for Evidence Synthesis [internet]. Adelaide: JBI; 2020 [cited 2022 Apr 11]. Available from: https://synthesismanual.jbi.global
25. Munn Z, Aromataris E, Tufanaru C, Stern C, Porritt K, Farrow J, et al. The development of software to support multiple systematic review types: The Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI). Int J Evid Based Healthc 2019;17:36–43.
26. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:241e1000097.
27. JBI. JBI critical appraisal tools. n.d. [cited 2021 Feb 22]. Available from: https://jbi.global/critical-appraisal-tools
28. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560.
29. Miller JJ. The inverse of the Freeman-Tukey double arcsine transformation. Am Stat 1978;32:138.