Asthma and inhaled corticosteroids in primary ciliary dyskinesia (PCD): a consensus from the Minneapolis PCD meeting

During the 2025 North American Primary Dyskinesia (PCD) Foundation meeting in Minneapolis (PCD On the Move), prospective new data were presented showing that over half of patients with PCD have bronchial hyperresponsiveness (BHR).1 But a strenuous objection was raised about interpreting the data to suggest that most PCD patients have asthma. Specifically, the concern was that PCD patients are being overtreated for asthma with inhaled corticosteroids (ICSs).2 After vigorous discussion, an agreement emerged. The concordant view presented here may be broadly helpful for providers caring for patients both with PCD and with asthma. Some of the results have been reported in abstract form.1 Recent evidence suggests that ICSs are among the most commonly prescribed medications for patients with PCD.3 Like our colleagues in the United Kingdom,2 we have questioned whether this should be so. There are no prospective studies testing the efficacy of ICSs in PCD. The premise supporting their use in PCD is that (1) all PCD patients have airway inflammation; (2) many have both reversable airflow limitation and asthma-like exacerbations; and (3) in T-lymphocyte type 2 predominant (T2-high) asthma, ICS use is an effective treatment. Here, we will review our concerns about the relevance of this logic, globally, to PCD. The first question to address is whether asthma in general (T2-high or not) is common among patients with PCD. As recently discussed in detail, asthma is heterogenous, but fundamentally involves airway inflammation and a history both of exacerbations and of reversable airway narrowing.4 A recent analysis of 132 million electronic health records showed that, in subjects with relatively unequivocal PCD, the odds of having an asthma diagnosis were 22-fold higher than in age- and sex-matched controls.5 However, in this study, the asthma diagnoses could not be confirmed. Several retrospective studies have shown increased BHR in PCD patients (see, eg 6). In these studies, however, subjects failed properly to be tested for BHR. Specifically, following a drug withhold, subjects must have either a 10% improvement in FEV1 with albuterol or a positive challenge test (typically using methacholine).7 In studies published to date, the drug withhold was missing, challenge testing was not performed, and the recommended FEV1 threshold was not used (all decreasing sensitivity). Note also that providers caring for patients with PCD argue that repeated forced expiratory maneuvers during spirometry may result in movement of mucus out of the distal airways, believed to account for some improvement in FEV1 after albuterol. This theory was challenged by a study of repeated spirometry efforts among PCD subjects that was presented at the Minneapolis meeting.1 The next and most important question is this: Do PCD patients with BHR have asthma that is likely to respond to ICS treatment? Is it a treatable trait? There are different asthma endotypes.4,7 Conventionally, these are broadly divided into T2-high and T2-low groups. T2-high patients, overall, have features that are not typical of PCD patients. They generally have a high fractional exhaled nitric oxide (FeNO), allergies, and airway and circulating eosinophilia. Most PCD patients with BHR likely have T2-low immune responses; they generally have very low FeNO and neutrophilic inflammation. Importantly, patients with T2-low asthma are much less likely to benefit from ICS use than are patients with T2-high asthma: ICSs are not optimal for managing neutrophilic airway inflammation.8 Further, ICSs have both local and systemic side effects, and ICS use has been identified as a risk factor for nontuberculous mycobacterial infection, which is a serious concern in patients with PCD. For this reason, we and others have taken the position that for routine PCD management, ICS treatment alone is generally not ideal. That said, long-acting β2 agonist (LABA) therapy can be associated with increased morbidity and mortality unless given with ICSs. It follows that there may be a case for using ICSs in conjunction with LABA therapy in some PCD patients with BHR, even if they have a T2-low endotype. Careful, prospective studies are needed to determine whether this is true for a subset of PCD patients. For example, do LABA/ICS combinations improve symptoms or decrease exacerbations among in PCD patients in whom T2-high asthma or bronchiectasis with eosinophilia9 may be treatable traits? Biomarkers in these studies would be highly targeted (likely not FeNO, for example). Mechanistically, one would assume that asthma and PCD are 2 separate, unrelated diseases. The association seems counterintuitive. However, antigen and irritant stasis on the airway epithelial surface in PCD leads to oxidative stress.10 Superoxide production lowers FeNO, and DUOX1 upregulation leads not only to H2O2 production but also to epithelial alarmin production.10,11 Downstream of alarmins, both T2 high- and T2-low immune responses can be signaled in the airway. This is important to understand because monoclonal antibody–based therapies directed against alarmins have been developed. There is a paucity of effective treatments for airway inflammation in PCD, and it may be that anti-alarmin therapies would be good candidates to study. Moreover, studies of BHR in PCD patients may help investigators understand T2-low asthma. One study suggests that PCD genes are enriched in a Japanese asthma population,12 and another that bronchiectasis itself may be a treatable trait in asthma.13 Fundamentally, antigen stasis, oxidative stress, and alarmins may be targets for treatment of T2-low asthma, with or without PCD. Indeed, secondary ciliopathies could also contribute to asthma through an antigen stasis-related mechanism. Providers should be alert to the possibility that some of their patients being followed for T2-low asthma could actually have PCD. In summary, we are agreed that evidence does not support the routine use of ICS monotherapy in many or most patients with PCD. True BHR is common in PCD, but it seems generally driven by a T2-low mechanism, which is less likely to respond to ICS treatment. That said, understanding PCD airway immunology and reactivity is likely to lead to needed therapies for patients with PCD, and possibly for T2-low asthma as well. Prospective therapeutic studies are required. Conception and draft preparation: B.G. and A.J.S.; Data analysis: J.P.C., E.M.M., A.T.L., A.G. and B.G.; Manuscript editing: J.P.C., E.M.M., A.T.L. and A.G. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. The authors have no conflicts of interest to declare. Please see the ICMJE disclosure forms, which have been provided as supplementary material.