We conducted a retrospective chart review to characterize clinical features of CF carriers with asthma and recurrent neutrophilic inflammation. Our main findings are: i) CF carriers are overrepresented in this cohort, supporting the role of CFTR hypofunction in the predisposition of some patients with asthma to recurrent respiratory infections, ii) the dominant inflammatory type in these patients is neutrophilic bronchitis, but some have intense eosinophilic inflammation as well, and iii) hypertonic saline appears to be effective and is well tolerated in this asthmatic population.
We identified pathogenic CFTR mutations in 17% of subjects. The carrier rate of pathogenic CFTR gene mutations is approximately 4% in persons of northern European descent14, indicating a more than 4-fold higher prevalence of CF carriers in our cohort, which may be an underestimation since not all of the included patients were from high risk ethnic groups. This higher prevalence should be seen in light of previous findings in this field, challenging the dogma that CF carriers are asymptomatic. CF carriers have also been found to have a higher prevalence of chronic rhinosinusitis compared to the general population15. A large Danish population study that assessed patients specifically for the ∆F508 variant found that CF carriers were at increased risk of chronic bronchitis and bronchiectasis16. Additionally, a large American database study found that CF carriers were at increased risk of recurrent airway infections and many other manifestations of CF17. Though these reports suggest that the absolute risk is low, 3-4% of the population are CF carriers in the USA, Canada, and Northern Europe14, and the potential morbidity caused by CFTR heterozygosity in these populations is large. Our findings add further evidence that CF carriers are at increased risk of recurrent pulmonary infections and show that these patients may have significant morbidity and health care utilization with frequent hospitalizations.
Three of the 13 CF carriers had the intron 8 splice variant 5T. This variant is located at a splice acceptor site of intron 8 and causes frequent skipping of exon 9, leading to a dysfunctional CFTR protein. Compound heterozygotes with ∆F508 and 5T have significantly reduced CTFR function and a high rate of symptoms attributable to CF, including pulmonary disease and congenital bilateral absence of vas deference18. In our cohort, patient 6 was compound heterozygous for these variants and it is possible that her much more severe respiratory disease compared to the other ∆F508 carriers was due to the 5T variant. Further data are needed to determine the importance of the intron 8 polypyrimidine genotype in symptomatic adult CF carriers.
Consistent with our previous study10, neutrophilic bronchitis was the dominant sputum inflammatory subtype in CF carriers, which reflects recurrent or persistent airway infection in these patients. However, 8/13 CF carriers also had eosinophilic bronchitis, and the prevalence of eosinophilic bronchitis was similar between CF carriers and non-carriers. These patients required inhaled corticosteroids, and in some cases systemic corticosteroids and anti-eosinophil biologicals for optimal management. Therefore, even though CF carriers are at greater risk of airway infections, flares of respiratory symptoms in these patients should not be assumed to be due to infection. Sputum cell counts are needed to determine whether anti-inflammatory or antibiotic therapy is needed.
In this cohort, asthmatic CF carriers with recurrent infections were older on average compared to non-carriers at the time of diagnosis. The genetic and environmental factors that cause a small subset of CF carriers to develop pulmonary disease have yet to be fully elucidated, and it is possible these factors accumulate over time to produce disease manifestations in certain patients. Evidence supporting this hypothesis includes studies showing that CFTR hypofunction can be acquired from cigarette smoke exposure19, bacterial and viral infections20,21, and neutrophilic inflammation22. It is thus possible that a positive feedback loop ensues with worsening CFTR function caused by infection and neutrophil recruitment to the airways, leading to further infections. In addition to recurrent infections, CFTR hypofunction may also contribute to asthma by increasing airway smooth muscle contractility by modulating cellular calcium mobilization23. A longitudinal study examining respiratory symptoms and CFTR function in CF carriers is needed to test this hypothesis. However, it is important to consider CFTR mutations even in older patients presenting later in life with exacerbations of asthma associated with recurrent airway infections.
In our cohort, nebulized hypertonic saline was well tolerated in asthma patients despite reduced FEV1 and demonstrable bronchial hyperresponsiveness in some patients. This is an important finding, as there are little data on the safety of hypertonic saline in asthma and these data are limited to mild-to-moderate asthma24,25. There was also a significant reduction in the number of infective exacerbations, and some experienced up to five fewer infections in the year after initiation. Presently, pharmacologic therapy for uncontrolled, severe asthma with neutrophilia is limited to macrolide therapy3. It thus seems reasonable to trial nebulized hypertonic saline in asthmatics with recurrent respiratory infections, potentially in addition to macrolide therapy, in the absence of more definitive evidence supporting treatment choices. Given that hypertonic saline is effective in reducing the frequency of airway infections in CF26, CF carriers with asthma may benefit more than asthmatic non-carriers, but this requires further study. Recently, CFTR modulators have been approved for ∆F508 homozygous patients and such therapies may benefit CF carriers as well, though the cost is prohibitive27. Novel therapeutic strategies such as inhibition of the epithelial Na+ channel in the airway may also prove to be helpful in CF carriers in the future28.
This study has several important limitations. First, this is a single center retrospective chart review from a tertiary airway disease clinic, so the morbidity in CF carriers observed is influenced by selection bias and not generalizable to the full CF carrier population. The cohort described represents 20% of our volume, therefore selecting patients for CFTR genotyping could have influenced the results. Second, CFTR mutations were detected using a multiplex PCR panel rather than gene sequencing, so rare CFTR variants may have been missed. This could have led to misclassification of CF carriers as non-carriers or true CF patients with compound heterozygosity as CF carriers. However the genetic screen used would detect mutations in over 84% of a pan-ethnic north American population29, so this is unlikely to have affected the results. Third, for most of our cohort, a sweat chloride test was not available, so it is possible some CF carriers could have met the diagnostic criteria for CF or CF related disorder. Fourth, some CF carriers had other additional factors that contributed to airway infections such as hypogammaglobulinemia needing immunoglobulin substitution therapy and oral corticosteroid use, though these factors were not more common in the CF carriers compared to non-carriers. Fifth, though all patients in this cohort were referred with a physician-diagnosis of asthma, current asthma could not be confirmed in all patients. Most patients at the time of referral had a FEV1 below 65% predicted, so a methacholine challenge could not be performed. Sixth, since CFTR mutation analysis was obtained only in patients with recurrent neutrophilic bronchitis, this analysis is limited to those patients with patients referred for asthma who have infective exacerbations. If a broader asthma population were considered, the significance of factors such as bronchiectasis and non-tuberculous mycobacterial disease in predicting CF carrier status may have been more apparent. Finally, given the retrospective nature of the study and the small number of CF carriers studied, our conclusions regarding the safety and efficacy of nebulized hypertonic saline should be considered provisional.
In summary, CF carriers are significantly overrepresented in a cohort of asthma patients with recurrent airway infections referred to a tertiary care centre, and we recommend testing for CFTR mutations in patients with asthma with recurrent airway infections, even in older patients. Neutrophilic bronchitis is the dominant inflammatory type, but some also have concomitant eosinophilic bronchitis that may be severe enough to warrant treatment with an anti-IL5 biological. Hypertonic saline was well tolerated in most patients. Additional research is needed to assess the efficacy of hypertonic saline and other treatment strategies in asthmatics with exacerbations associated with intense neutrophilic bronchitis.