Cystic fibrosis (CF) is one of the most frequent and severe genetic diseases affecting European populations. Clinical manifestations can vary from mild to severe forms, and prognosis depends to a large extent on the severity of respiratory impairment. This associates chronic bronchial inflammation and infection, and the presence of very thick mucus, a consequence of the absence or dysfunction of the CFTR channels present on the apical surface of bronchial epithelial cells. Bronchiectasis will ensue, followed by chronic respiratory failure.

Asthma and CF are both chronic inflammatory diseases of the lung, but their pathophysiology is quite different. Airway inflammation is mostly eosinophilic in allergic asthma, whereas it is predominantly neutrophilic in CF (1, 2). Wheezing is very common in asthma. A prevalence of 30–50% has been reported in preschool children, in whom less than half will undergo persistent symptoms (1). Wheezing, whether in patients with asthma or CF, is classically the consequence of airway obstruction due to inflammation, bronchospasm, non-discharged secretions and/or small airways.

Morphologically, the bronchi of patients with asthma and CF share common features, such as the development of bronchial remodeling, including hyperplasia of the bronchial smooth muscle (3, 4). Bronchial hyperresponsiveness (BHR) is also observed in both conditions. This is usually demonstrated by the onset of bronchoconstriction induced by a specific or non-specific stimulus, and/or reversibility after exposure to a bronchodilator (5). Up to half of all patients with CF have measurable BHR, which does not appear to be related to the patient’s atopic status (6–8). According to Weinberger BHR in CF shows characteristics which are different from asthma, e.g., bronchodilation on exertion (9).

Alterations in the signaling pathways regulating airway smooth muscle (ASM) contractility in CFTR-deficient patients have been described. As an example, persistent bacterial infection, especially by Pseudomonas aeruginosa, stimulates the release of interleukin-8 from the airway epithelium, resulting in neutrophilic inflammation. Increased neutrophilia and CFTR-deficient T-helper cells create an inflammatory environment characterized by high levels of Tumor Necrosis Factor (TNF). The presence of high levels of TNFα, Interleukin-8 and Interleukin-13, may contribute to increased ASM contractility which participates in wheezing and BHR (10).

Predictive indices and scores have been proposed to identify which of the early non-CF wheezing children are at risk of persistence (of wheezing) at school age. Two of these have been validated in different populations: the PIAMA score (11, 12) and the Asthma Predictive Index (API) (13). A positive API index indicates a 2.6–9.8 greater risk of current asthma during school age (6 and 13 years) (14). According to the PIAMA score the risk of asthma from age 6 to 8 years is as follows: <5% (score 0–7); 6–22% (score 8–15); 25–60% (score 16–23) (12).

There is a lack of such data in children with CF. Our primary objective was therefore to evaluate the prevalence and characteristics of wheezing and a bronchodilatory response (BDR) to short-acting beta-agonists as a marker of airway lability in a population of children with CF followed in a single large CF center. The secondary objectives were to identify the factors associated with wheezing and a positive BDR, and to determine the impact of current wheezing at the age of 6 years.

We conducted a retrospective, analytic, single-center study in children with CF, aged less than 18 years, followed at the Regional Pediatric CF-center in Bordeaux University Hospital, France. In this retrospective study French regulatory legislation requires that the protection of personal data is ensured, and this was applied in our study (15). The Bordeaux University Hospital Institutional Research Ethics Board authorized the conduct and publication of this research (Reference CERBDX-2022-03).

The first part of the study involved children aged less than 6 years, recruited from February 2016 to June 2016. The primary objective was to determine the overall frequency of wheezing in such children. The secondary objectives were to describe the characteristics of wheezing according to the TUCSON clinical phenotypes as described by Martinez et al. (16), to determine predictive markers for the persistence of wheezing at school age (6 years), and to describe the consequences of wheezing particularly with respect to lung function at 6 years. Children were assigned to four categories according to their history of wheezing: those who had no recorded lower respiratory tract illness with wheezing during the first 3 years of life and had no wheezing at 6 years of age (NW); those with at least one lower respiratory tract illness with wheezing during the first 3 years of life but no wheezing at 6 years of age (those with transient early wheezing, TW); those who had no lower respiratory tract illness with wheezing during the first 3 years of life but who had wheezing at 6 years of age (those with wheezing of late onset, LW); and those who had at least one lower respiratory tract illness with wheezing in the first 3 years of life and had wheezing at 6 years of age (those with persistent wheezing, PW) (16).

Data collected over the first 6 years of life were the following: Demographic (age, weight, and gestational age), family (asthma and atopy, in utero and postnatal cigarette smoke exposure), respiratory function (best lung function (LFT) results between age 6 and 7 years), immunological (allergic Skin Prick Tests and total IgE or specific IgE to the most common respiratory allergens: (house dust mite, cat or dog dander)), bacteriological (pathogens found in the sputum) and therapeutic (treatments prescribed for respiratory symptoms. From these data, we scored the Asthma Predictive Index, the PIAMA score and determined the “TUCSON” wheezing phenotypes (16).

The second part of the study involved children aged 6–17 years from 2002 to 2011 and focused on the presence of a BDR. The preschool children shown in the above section were not included in this >6 years age school age study group. Three age ranges were selected: ≥6 years to <8 years, ≥10 years to <12 years, and ≥15 years to <17 years. For each patient, anthropometric, clinical, allergic (total IgE, blood eosinophils, and allergic skin tests), bacteriological, genetic, and spirometric data were collected. LFT criteria regarding bronchial obstruction and the BDR were reported according to the ATS/ERS recommendations. The criteria for a positive BDR were: improvement in ppFEV1 by at least 12%, of ppFEF_25–75 or ppFEV1 by at least 35%; decrease in ppRV (and/or ppRV/TLC) by at least 20%, decrease in R_aw by at least 35%. The BDR was analyzed either based solely on ppFEV1 criteria, or on all the above-mentioned criteria (positive BDR if at least one of the functional reversibility parameter was present).

Current wheezing at 6 years of age was defined as children who had presented at least one episode of wheezing in the previous 12 months.

Regarding continuous variables, data are presented as medians and interquartile ranges, or means and standard deviations, according to their distribution. The statistical analysis was performed using NCSS software (Kaysville, Utah). The qualitative variables were compared using the Chi² test. Quantitative variables were compared using a Student’s t-test if two groups were studied and by analysis of variance (ANOVA) in the presence of >2 groups (with a Bonferroni test to determine statistical differences between groups). A p-value < 0.05 was considered statistically significant.

One hundred and twenty-five patients aged less than 6 years of age and 69 patients above 6 years of age were included in the study.

The present study indicates that wheezing is a common phenomenon in preschool children with CF. Wheezing was not associated to p.Phe508del homozygosity, allergic factors or chronic Pseudomonas aeruginosa colonization. Persistent wheezing was associated with lower lung function at the age of 6 years. A positive BDR in older children with CF was also a common finding, and was associated with lower lung function between 6 and 8 years of age, increased BMI between 10 and 12 years of age, and a greater sum of the diameter of allergic prick test papules for three common respiratory allergens. In this study, we did not find identify allergic bronchopulmonary aspergillosis as a cause of wheezing.

The reported rate of wheezing in CF is variable. In a large population of patients with CF in the United States and Canada, the cumulative percentage of patients reaching onset of persistent wheezing was approximately 30% at the age of 6 years and 50% at the age of 15 years (17). In contrast, the European CF Epidemiologic Registry (ERCF) reported a rate of asthma of 14% in children with CF less than 6 years of age. Ren et al. showed that wheezing during the first 6 years of life was associated with lower lung function at the age of 6–8 years (18, 19). Based on the different TUCSON phenotypes (16), they reported that persistent wheezers (PW) had significantly lower FEV1 than never wheezers (NW) (19). Levine et al. showed that 39% of children aged 14.4 (4–76) years, median (range), with CF had reversible bronchial obstruction (20).

Physicians tend to extrapolate asthma treatment to the management of wheezing in CF. We and others (1, 17, 20) raise concerns regarding the abuse of inhaled steroids and bronchodilators which are too often prescribed in patients with CF. According to the French 2019 CF registry, 36.3 and 59.3% of patients received inhaled corticosteroids and bronchodilators, respectively (21). Our work confirmed the widespread use of these agents: short-acting bronchodilators were prescribed in 97.2% of PWs and 94.4% of such wheezers received inhaled corticosteroids. Ren et al. reported that 89.1% of PW received bronchodilators vs. 73.2% of NW (p < 0.05). Kent et al. (22) pointed out that there was little evidence for the efficacy of asthma therapy in CF. A Cochrane review concluded that no study has been able to demonstrate that the use of inhaled corticosteroids decreases lung inflammation in CF (23). In France, a Delphi study recommended restricting the use of inhaled corticosteroids in CF due to an insufficient level of evidence (24). According to Smith and Edwards neither long-acting beta-2 agonists nor long-acting muscarinic antagonist bronchodilators demonstrate improvement in FEV1 in CF (25). Moreover, the side effects of inhaled corticosteroids are not negligible. They can cause oral fungal infections and at high doses may negatively impact growth. Overall, under close supervision, teams caring for patients with CF may safely stop prescribing inhaled corticosteroids in these patients (26).

While wheezing is very common in children with CF, no major determinants in children below 6 years of age could be clearly identified. Current wheezing at age 6 years was significantly associated with lower lung function. In children older than 6 years, allergic factors, genetics (p.F508del homozygosity) and higher BMI were significantly associated with the presence of a positive BDR but this varied between age groups. In 6–8 years old children with a BDR, baseline lung function was significantly lower. Our results suggest that the “CF-Asthma” designation may be misleading in a vast majority of cases, and may lead to inappropriate treatment with inhaled steroids, especially in preschool wheezers.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Ethical approval was not provided for this study on human participants because not yet, processing. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

MF is affiliated (but not employed) by the INSERM, CIC 1401. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.