Lung function from school age to adulthood in primary ciliary dyskinesia

Florian S Halbeisen, Eva S L Pedersen, Myrofora Goutaki, Ben D Spycher, Israel Amirav, Mieke Boon, Malena Cohen-Cymberknoh, Suzanne Crowley, Nagehan Emiralioglu, Eric G Haarman, Bulent Karadag, Cordula Koerner-Rettberg, Philipp Latzin, Michael R Loebinger, Jane S Lucas, Henryk Mazurek, Lucy Morgan, June Marthin, Petr Pohunek, Francesca Santamaria, Nicolaus Schwerk, Guillaume Thouvenin, Panayiotis Yiallouros, Kim G Nielsen, Claudia E Kuehni, Florian S Halbeisen, Eva S L Pedersen, Myrofora Goutaki, Ben D Spycher, Israel Amirav, Mieke Boon, Malena Cohen-Cymberknoh, Suzanne Crowley, Nagehan Emiralioglu, Eric G Haarman, Bulent Karadag, Cordula Koerner-Rettberg, Philipp Latzin, Michael R Loebinger, Jane S Lucas, Henryk Mazurek, Lucy Morgan, June Marthin, Petr Pohunek, Francesca Santamaria, Nicolaus Schwerk, Guillaume Thouvenin, Panayiotis Yiallouros, Kim G Nielsen, Claudia E Kuehni

Abstract

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

Conflict of interest statement

Conflict of interest: P. Latzin reports grants from Vertex and Vifor, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participation on a data safety monitoring board or advisory board for Polyphor, Santhera (DMC), Vertex, OM Pharma and Vifor. M.R. Loebinger reports consultancy fees from Insmed, AstraZeneca and Grifols, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Insmed and Grifols. The remaining authors disclose no potential conflicts of interest.

Copyright ©The authors 2022.

Figures

FIGURE 1
FIGURE 1
Forced expiratory volume in 1 s (FEV1) trajectories during the lung growth period compared to Global Lung Function Initiative 2012 reference values.
FIGURE 2
FIGURE 2
Forced expiratory volume in 1 s (FEV1) trajectories of primary ciliary dyskinesia patients in different countries compared to Global Lung Function Initiative 2012 reference values.

References

    1. Kouis P, Goutaki M, Halbeisen FS, et al. . Prevalence and course of disease after lung resection in primary ciliary dyskinesia: a cohort & nested case-control study. Respir Res 2019; 20: 212. doi:10.1186/s12931-019-1183-y
    1. Wallmeier J, Nielsen KG, Kuehni CE, et al. . Motile ciliopathies. Nat Rev Dis Primers 2020; 6: 77. doi:10.1038/s41572-020-0209-6
    1. Goutaki M, Halbeisen FS, Barbato A, et al. . Late diagnosis of infants with PCD and neonatal respiratory distress. J Clin Med 2020; 9: 2871. doi:10.3390/jcm9092871
    1. Behan L, Dimitrov BD, Kuehni CE, et al. . PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia. Eur Respir J 2016; 47: 1103–1112. doi:10.1183/13993003.01551-2015
    1. Noone PG, Leigh MW, Sannuti A, et al. . Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med 2004; 169: 459–467. doi:10.1164/rccm.200303-365OC
    1. Shah A, Shoemark A, MacNeill SJ, et al. . A longitudinal study characterising a large adult primary ciliary dyskinesia population. Eur Respir J 2016; 48: 441–450. doi:10.1183/13993003.00209-2016
    1. Halbeisen FS, Jose A, de Jong C, et al. . Spirometric indices in primary ciliary dyskinesia: systematic review and meta-analysis. ERJ Open Res 2019; 5: 00231-2018. doi:10.1183/23120541.00231-2018
    1. Marthin JK, Petersen N, Skovgaard LT, et al. . Lung function in patients with primary ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study. Am J Respir Crit Care Med 2010; 181: 1262–1268. doi:10.1164/rccm.200811-1731OC
    1. Speizer FE, Tager IB. Epidemiology of chronic mucus hypersecretion and obstructive airways disease. Epidemiol Rev 1979; 1: 124–142. doi:10.1093/oxfordjournals.epirev.a036206
    1. Bui DS, Lodge CJ, Burgess JA, et al. . Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. Lancet Respir Med 2018; 6: 535–544. doi:10.1016/S2213-2600(18)30100-0
    1. Miller MR, Pedersen OF, Lange P, et al. . Improved survival prediction from lung function data in a large population sample. Respir Med 2009; 103: 442–448. doi:10.1016/j.rmed.2008.09.016
    1. Marott JL, Ingebrigtsen TS, Çolak Y, et al. . Lung function trajectories leading to chronic obstructive pulmonary disease as predictors of exacerbations and mortality. Am J Respir Crit Care Med 2020; 202: 210–218. doi:10.1164/rccm.201911-2115OC
    1. Davis SD, Rosenfeld M, Lee HS, et al. . Primary ciliary dyskinesia: longitudinal study of lung disease by ultrastructure defect and genotype. Am J Respir Crit Care Med 2019; 199: 190–198. doi:10.1164/rccm.201803-0548OC
    1. Maglione M, Bush A, Nielsen KG, et al. . Multicenter analysis of body mass index, lung function, and sputum microbiology in primary ciliary dyskinesia. Pediatr Pulmonol 2014; 49: 1243–1250. doi:10.1002/ppul.22984
    1. Halbeisen FS, Goutaki M, Spycher BD, et al. . Lung function in patients with primary ciliary dyskinesia: an iPCD Cohort study. Eur Respir J 2018; 52: 1801040. doi:10.1183/13993003.01040-2018
    1. Ardura-Garcia C, Goutaki M, Carr SB, et al. . Registries and collaborative studies for primary ciliary dyskinesia in Europe. ERJ Open Res 2020; 6: 00005-2020. doi:10.1183/23120541.00005-2020
    1. Goutaki M, Maurer E, Halbeisen FS, et al. . The international primary ciliary dyskinesia cohort (iPCD Cohort): methods and first results. Eur Respir J 2017; 49: 1601181. doi:10.1183/13993003.01181-2016
    1. Lucas JS, Paff T, Goggin P, et al. . Diagnostic methods in primary ciliary dyskinesia. Paediatr Respir Rev 2016; 18: 8–17. doi:10.1016/j.prrv.2015.07.017
    1. Lucas JS, Barbato A, Collins SA, et al. . European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Eur Respir J 2017; 49: 1601090. doi:10.1183/13993003.01090-2016
    1. Strippoli MP, Frischer T, Barbato A, et al. . Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J 2012; 39: 1482–1491. doi:10.1183/09031936.00073911
    1. Halbeisen FS, Shoemark A, Barbato A, et al. . Time trends in diagnostic testing for primary ciliary dyskinesia in Europe. Eur Respir J 2019; 54: 1900528. doi:10.1183/13993003.00528-2019
    1. Quanjer PH, Stanojevic S, Cole TJ, et al. . Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012; 40: 1324–1343. doi:10.1183/09031936.00080312
    1. World Health Organization (WHO) . WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development. Geneva, WHO, 2006. Available from:
    1. Pifferi M, Bush A, Mariani F, et al. . Lung function longitudinal study by phenotype and genotype in primary ciliary dyskinesia. Chest 2020; 158: 117–120. doi:10.1016/j.chest.2020.02.001
    1. Kirkby J, Bountziouka V, Lum S, et al. . Natural variability of lung function in young healthy school children. Eur Respir J 2016; 48: 411–419. doi:10.1183/13993003.01795-2015
    1. Nakagawa S, Johnson PCD, Schielzeth H. The coefficient of determination R2 and intra-class correlation coefficient from generalized linear mixed-effects models revisited and expanded. J R Soc Interface 2017; 14: 20170213. doi:10.1098/rsif.2017.0213
    1. Yiallouros PK, Kouis P, Middleton N, et al. . Clinical features of primary ciliary dyskinesia in Cyprus with emphasis on lobectomized patients. Respir Med 2015; 109: 347–356. doi:10.1016/j.rmed.2015.01.015
    1. Maglione M, Montella S, Mollica C, et al. . Lung structure and function similarities between primary ciliary dyskinesia and mild cystic fibrosis: a pilot study. Ital J Pediatr 2017; 43: 34. doi:10.1186/s13052-017-0351-2
    1. Walker W, Harris A, Rubbo B, et al. . Lung function and nutritional status in children with cystic fibrosis and primary ciliary dyskinesia. Eur Respir J 2016; 48: Suppl. 60, PA3128. doi:10.1183/13993003.congress-2016.PA3128
    1. Kuehni CE, Goutaki M, Kobbernagel HE. Hypertonic saline in patients with primary ciliary dyskinesia: on the road to evidence-based treatment for a rare lung disease. Eur Respir J 2017; 49: 1602514. doi:10.1183/13993003.02514-2016
    1. Kobbernagel HE, Buchvald FF, Haarman EG, et al. . Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial. Lancet Respir Med 2020; 8: 493–505. doi:10.1016/S2213-2600(20)30058-8
    1. Paff T, Omran H, Nielsen KG, et al. . Current and future treatments in primary ciliary dyskinesia. Int J Mol Sci 2021; 22: 9834. doi:10.3390/ijms22189834
    1. Kuehni CE, Goutaki M, Rubbo B, et al. . Management of primary ciliary dyskinesia: current practice and future perspectives. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 282–289.
    1. Turner SW, Palmer LJ, Rye PJ, et al. . Infants with flow limitation at 4 weeks: outcome at 6 and 11 years. Am J Respir Crit Care Med 2002; 165: 1294–1298. doi:10.1164/rccm.200110-018OC
    1. Martinez FD, Morgan WJ, Wright AL, et al. . Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first three years of life. Group Health Medical Associates. Am Rev Respir Dis 1991; 143: 312–316. doi:10.1164/ajrccm/143.2.312
    1. Stocks J, Sonnappa S. Early life influences on the development of chronic obstructive pulmonary disease. Ther Adv Respir Dis 2013; 7: 161–173. doi:10.1177/1753465813479428
    1. Caley L, Smith L, White H, et al. . Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: data from the UK CF registry. J Cyst Fibros 2021; 20: 86–90. doi:10.1016/j.jcf.2020.04.008
    1. Kuehni CE, Frischer T, Strippoli MP, et al. . Factors influencing age at diagnosis of primary ciliary dyskinesia in European children. Eur Respir J 2010; 36: 1248–1258. doi:10.1183/09031936.00001010
    1. Mahut B, Bokov P, Beydon N, et al. . Longitudinal assessment of loss and gain of lung function in childhood asthma. J Asthma 2022; in press [10.1080/02770903.2021.2023176].
    1. McGeachie MJ, Yates KP, Zhou X, et al. . Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med 2016; 374: 1842–1852. doi:10.1056/NEJMoa1513737
    1. Ellerman A, Bisgaard H. Longitudinal study of lung function in a cohort of primary ciliary dyskinesia. Eur Respir J 1997; 10: 2376–2379. doi:10.1183/09031936.97.10102376
    1. Davis SD, Ferkol TW, Rosenfeld M, et al. . Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med 2015; 191: 316–324. doi:10.1164/rccm.201409-1672OC
    1. Goutaki M, Halbeisen FS, Spycher BD, et al. . Growth and nutritional status, and their association with lung function: a study from the international Primary Ciliary Dyskinesia Cohort. Eur Respir J 2017; 50: 1701659. doi:10.1183/13993003.01659-2017
    1. Earnest A, Salimi F, Wainwright CE, et al. . Lung function over the life course of paediatric and adult patients with cystic fibrosis from a large multi-centre registry. Sci Rep 2020; 10: 17421. doi:10.1038/s41598-020-74502-1
    1. Bott L, Béghin L, Devos P, et al. . Nutritional status at 2 years in former infants with bronchopulmonary dysplasia influences nutrition and pulmonary outcomes during childhood. Pediatr Res 2006; 60: 340–344. doi:10.1203/
    1. Konstan MW, Butler SM, Wohl ME, et al. . Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr 2003; 142: 624–630. doi:10.1067/mpd.2003.152
    1. Liou TG, Adler FR, Fitzsimmons SC, et al. . Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001; 153: 345–352. doi:10.1093/aje/153.4.345
    1. Schaedel C, de Monestrol I, Hjelte L, et al. . Predictors of deterioration of lung function in cystic fibrosis. Pediatr Pulmonol 2002; 33: 483–491. doi:10.1002/ppul.10100
    1. Cohen-Cymberknoh M, Weigert N, Gileles-Hillel A, et al. . Clinical impact of Pseudomonas aeruginosa colonization in patients with primary ciliary dyskinesia. Respir Med 2017; 131: 241–246. doi:10.1016/j.rmed.2017.08.028
    1. Mésinèle J, Ruffin M, Kemgang A, et al. . Risk factors for Pseudomonas aeruginosa airway infection and lung function decline in children with cystic fibrosis. J Cyst Fibros 2022; 21: 45–51. doi:10.1016/j.jcf.2021.09.017
    1. Turkovic L, Caudri D, Rosenow T, et al. . Structural determinants of long-term functional outcomes in young children with cystic fibrosis. Eur Respir J 2020; 55: 1900748. doi:10.1183/13993003.00748-2019
    1. Goutaki M, Papon JF, Boon M, et al. . Standardised clinical data from patients with primary ciliary dyskinesia: FOLLOW-PCD. ERJ Open Res 2020; 6: 00237-2019. doi:10.1183/23120541.00237-2019

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren