Pulmonary exacerbations in patients with genetically confirmed PCD: A prospective observational multicentre study

Background Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by deficient mucociliary clearance and development of chronic lung disease. Pulmonary exacerbations (PEx) in chronic lung diseases increase morbidity and lung function decline, but their frequency in PCD has been understudied. We aimed to prospectively determine the annual frequency of PEx in PCD and identify related risk factors.

In a multicentre, observational study conducted in 11 centres from seven countries, we prospectively collected data from a well-described patient cohort with genetically confirmed PCD over a year via monthly telephone questionnaires and clinical visits. We assessed the annual PEx frequency using three definitions: i) clinical definition 1 (Def-1) when three out of seven clinical items were positive; clinical definition 2 (Def-2) if the patient started or changed antibiotic treatment; self-reported PEx by the patient). For paired statistical comparisons we used the Friedman test and the Wilcoxon matched-pairs test and tested their agreement (Cohen’s kappa statistics). We also determined related risk factors using a mixed-effects model.

We recruited 271 individuals with PCD of all ages. Among patients with complete annual records (n=248), approximately 80% experienced at least one PEx per year, as assessed by the three definitions used. Self-reported PEx per year (median 2, interquartile range (IQR) 1-5) were higher (p<0.0001) than the PEx assessed by Def-1 (median 2, IQR 0-4) and Def-2 (median 1, IQR 0.25-3). Self-reported PEx had a substantial agreement with Def-1 [kappa (SE) =0.61 (0.05)] and a moderate agreement with Def-2 [kappa (SE) =0.51 (0.05)]. Female sex and autumn season were associated with significantly higher number of PEx, independent of the definition used. Increasing age was correlated with higher annual PEx frequency by Def-1.

In this multicentre study, we prospectively assessed the annual PEx frequency in patients genetically diagnosed with PCD, demonstrating the importance of the definition used in capturing the exacerbation burden of PCD, as well as the influence of sex, age and season on exacerbation frequency. Competing Interest Statement PA, PK, DAT, SA, SB, MB, AC, HNC, RC, NE, EE, YG, SG, EH, SH, BK, DM, JKM, NM, UO, MP, JR, SR-A, FS, IT, NU, NZ, PY have nothing to disclose MAM reports grants or contracts from the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), the German Innovation Fund, Boehringer Ingelheim, Enterprise Therapeutics, and Vertex Pharmaceuticals with payments made to the institution; personal fees for advisory board participation or consulting from Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Splisense, Vertex Pharmaceuticals; lecture honoraria from Vertex Pharmaceuticals; and travel support from Boehringer Ingelheim and Vertex Pharmaceuticals. AM-G has received fees for lectures from Abbvie, Sanofi-Pasteur, Janssen and Astra-Zeneca and fees for participation in Advisory Boards sponsored by AbbVie, Sanofi-Pasteur and Astra-Zeneca, not related to this Project. KGN has received honoraria for advisory board/consulting from Parion Sciences, Insmed, Recode Therapeutics, Boehringer Ingelheim and Ethris, outside of the submitted work. JRo has received payments for lectures from Vertex Pharmaceuticals, Chiesi, Pari und Insmed outside of the submitted work. HO reports grants or contracts from the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), Ethris GmbH and ReCode Therapeutics with payments made to the institution. Funding Statement MAM was supported by grants from the German Ministry for Education and Research (82DZL009C1 and 01GL2401D) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; SFB 1449 - 431232613; JR is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation RA3522/1-1); JRoe is participant of the Case Analysis and Decision Support (CADS) program funded by the Berlin Institute of Health at Charite (BIH). HO is supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation OM6/7, OM6/8, OM6/10, CRU 326(subproject OM6/11), OM6/14, and OM6/16, the Interdisziplinaeres Zentrum fuer klinische Forschung Muenster (IZKF) (Om2/010/20 and OM2/014/24) and the German Ministry for Education and Research (BMBF) (01GM1515A; 16LW0648). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Westphalian Wilhelms University of Muenster (Muenster, Germany; AZ-2011-270-f-S) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes