Abstract
Primary ciliary dyskinesia (PCD) is predominantly inherited as an autosomal recessive disorder leading to recurrent and chronic upper and lower respiratory tract infection, and in 40–50% of cases mirror-image organ arrangement and other forms of heterotaxy. To date, these disorders of dysmotile cilia have been poorly studied in children; indeed most of the therapeutic strategies used are derived from cystic fibrosis (CF) protocols, accentuating the need for more PCD research. Although unproven, it seems likely that early diagnosis is important for the preservation of pulmonary function, quality of life and life expectancy in this disease, and therefore there is a great need for more diagnostic awareness and evidence-based treatment. Ciliary dysfunction is also implicated in a broader spectrum of disease, such as polycystic liver and kidney disease, biliary atresia and central nervous system abnormalities, including retinopathy and hydrocephalus . The present consensus statement originates from a European Respiratory Society Task Force on PCD in children, which is aimed at describing diagnostic and therapeutic practices for paediatric PCD patients in Europe, assessing the number of diagnosed patients, developing a consensus statement, defining research needs and enhancing collaborative research. Genetics PCD is a genetically heterogeneous disorder, which is predominantly inherited as an autosomal recessive trait. The majority of the genes identified to date for autosomal recessive PCD variants [dynein, axonemal, intermediate chain 1 (DNAI1) and 2 (DNAI2) and heavy chain 5 (DNAH5) and 11 (DNAH11) and thioredoxin domain containing 3 (TXNDC3)] encode outer dynein arm (ODA) components, whereas only one gene [chromosome 14 open reading frame 104 (KTU)] is required for cytoplasmic pre-assembly of axonemal dyneins. Genetic analyses may help to assess the carrier status of family members and provide tools for informed reproductive choices, although this is currently possible only for a minority of families. They may also become more important diagnostically since 35% of PCD patients carry either DNAH5 or DNAI1 mutations (hot spots and founder mutations are worthy of analysis in patients with ODA defects). Further studies are required in order to identify the genes responsible for the remaining PCD patients. Children with PCD often have a clinical history of lower airway disease, manifested in a chronic wet-sounding cough and, occasionally, wheeze or shortness of breath. In addition, virtually all subjects show evidence of chronic upper airway symptoms, such as chronic rhinitis (nasal discharge, episodic facial pain and anosmia). This may be confirmed by physical examination and/or sinus imaging. Ear symptoms (recurrent otitis media and glue ear) are a frequent complication that can require multiple interventions, including repeated courses of antibiotics. Diagnosis of PCD is frequently delayed, in part because patients present with symptoms (rhinitis, secretory otitis media, cough and recurrent bronchitis) that are common in healthy children. A positive family history of PCD is an indication for performing diagnostics, since this accounted for 10% of cases, in one series. Siblings of probands should also have PCD excluded. Diagnosis The diagnosis of PCD should be based on the presence of a typical clinical phenotype and appropriate diagnostic testing. PCD is a rare disease, and diagnostic analysis and interpretation are difficult. Diagnosis should, therefore, be confirmed in a specialist centre. The clinical history and clinical observation are pivotal to diagnosis and extreme caution should be exercised in making a diagnosis if the clinical symptoms do not fit. Inflammation and infection can produce secondary ciliary defects, which may result in a misdiagnosis of PCD. If in doubt, repeat brushings should be performed following treatment of infection and inflammation. New phenotypes of PCD are still being discovered, and this will be aided by further developments in diagnostic testing Screening tests Screening tests may precede formal ciliary function analysis, thereby reducing the number of referrals for ciliary analysis. These screening tests may prevent some patients from requiring nasal biopsy/brushing, but do not obviate the need for specialist equipment and personnel. Diagnostic tests Diagnosis of PCD requires analysis of ciliate epithelial cells in order to assess function and ultrastructure. Further investigations, e.g. primary cell culture, may aid diagnosis. There is no single gold standard test, and diagnosis should be made in a specialist centre following review of the clinical history and screening test results alongside these specific ciliary tests. PCD is likely to include a small number of milder phenotypes that may be manifest in subtle or no apparent structural defects and ciliary dysfunction. Identifying these defects and their clinical implications in diagnostic testing is an area for future research. Respiratory treatment As with all chronic respiratory diseases, the aim of therapy for PCD is to restore or maintain normal lung function as far as is possible, based on early detection and vigorous treatment of complications. There are no randomised trials of PCD treatment, and, consequently, all treatment recommendations are based on a very low level evidence, or extrapolated from CF guidelines. Respiratory treatment involves aggressive treatment of upper and lower airway infections and airway clearance by combinations of physiotherapy and physical exercise. As with CF patients, it is likely that the best results will be obtained if treatment is in an experienced centre caring for a sufficient number of patients. There is no evidence to positively state how many patients such a centre needs to oversee, but, by analogy with CF (according to prevalence), probably >10-15 patients need to be under follow-up. However, in parts of Europe, geographical factors may make this impossible. By analogy with CF, PCD patients should be managed in specialised centres, in which they have regular access to respiratory paediatricians, audiology, ENT surgeons and respiratory physiotherapists. Some patients need access to clinical psychology and social work services. It is wise to establish links with specialists who are involved on a more occasional basis with PCD patients, e.g. speech therapists. Conclusion and next steps The main conclusion of the present Task Force is the urgent need for further research into PCD. Most of the published data relating to PCD are observational and derived from small case series. The natural history of PCD, and how this might be altered by treatments, is virtually unknown. Therefore, most recommendations regarding diagnosis and treatment provided in the present consensus statement are based on low-to-moderate-level evidence. The Task Force Committee has stated that the following research areas are urgent: 1) studies on the natural history of PCD, including long-term outcome in adult life, spectrum and severity of clinical disease, functional limitations and quality of life in patients of different ages, based on large and representative patient samples; 2) further development of diagnostic techniques, in order to permit a sensitive, specific and practicable approach to diagnosis; 3) the setting up of an international database for PCD patients, to permit long-term multicentric observational and interventional studies; 4) high-quality randomised controlled multicentric trials to investigate the effect of different treatments on symptoms, lung function, quality of life and long-term progression of the disease; and 5) studies on genetic mutation and its correlation with certain PCD phenotypes are required in order to sustain the diagnosis of PCD and to make prenatal counselling possible in these families.