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Primary ciliary dyskinesia

L.J. Lobo, M.A. Zariwala, P.G. Noone
DOI: http://dx.doi.org/10.1093/qjmed/hcu063 691-699 First published online: 20 March 2014

Abstract

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of cilia structure and function, leading to chronic infections of the respiratory tract, fertility problems and disorders of organ laterality. Making a definitive diagnosis is challenging, utilizing characteristic phenotypes, ciliary functional and ultra-structural defects in addition to newer screening tools such as nasal nitric oxide and genetic testing. There are 21 known PCD causing genes and in the future, comprehensive genetic testing may help diagnosis young infants prior to developing symptoms thus improving survival. Therapy includes surveillance of pulmonary function and microbiology in addition to, airway clearance, antibiotics and early referral to bronchiectasis centers. Standardized care at specialized centers using a multidisciplinary approach is likely to improve outcomes. In conjunction with the PCD foundation and lead investigators and clinicians are developing a network of PCD clinical centers to coordinate the effort in North America and Europe. As the network grows, care and knowledge will undoubtedly improve.

Overview

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of motile cilia that leads to a clinical syndrome of oto-sino-pulmonary disease.1 PCD was first clinically described by Kartagener in the 1930’s based on observation of a triad of chronic sinusitis, bronchiectasis and dextrocardia. In 1976, Afzelius reported that these patients had ‘immotile’ cilia, with defective ciliary ultrastructure and function. In the last decade or so, the term ‘immotile cilia syndrome’ has been supplanted by ‘primary ciliary dyskinesia’ as it is now clear that there is a large range of ciliary ultrastructural and functional abnormalities, with different underlying genetic bases.2

Normal cilia structure and function

Respiratory cilia are a critical component of airway host defense, helping protect the airways from inhaled material via a mucociliary ‘escalator’. Cilia are hair-like attachments (∼200 per cell) found on epithelial surfaces, composed of ∼250 proteins organized into longitudinal microtubules comprising the basic axonemal structure. Outer dynein arms (ODAs) and inner dynein arms (IDAs), ATP-ase containing proteins, traverse the length of the peripheral microtubules forming a doublet (Figure 1). Motile cilia are found in the respiratory tract, on the ependymal cells lining the ventricles of the central nervous system, in the oviducts and in the flagellum of sperm. They are organized into nine microtubule pair doublets, surrounding a central pair, in a 9+2 arrangement. The central pair is linked to the surrounding pair doublet through an array of radial spoke proteins and the surrounding pair doublets are linked to one another via nexin-linked proteins (Figure 1). Through coordinated and synchronized bending of adjacent cilia, wave-like movements occur at ∼6–12 Hz, which propel mucus and adherent particles/bacteria proximally along the surface of the airway. It can thus be readily seen that abnormalities in any component of the ciliary structure and/or function may result in clinical disease.3 Non-respiratory cilia are also important: motile cilia are functional during embryonic development, located on the embryonic node, with a 9+0 configuration (lacking a central pair). They exhibit rotational movement, important for cell signaling during the development of normal human left–right asymmetry. Defects in the structure of these cilia result in defective nodal ciliary rotation, and thus organ laterality defects, the commonest being situs inversus (SI) which occurs in ∼50% of patients with PCD.1

Figure 1.

Diagram of the basic ciliary structure.

Clinical disease

The PCD phenotype

The exact prevalence of PCD is difficult to determine. Even with improvements in diagnostic and screening tests at specialized centers, up to 30% of patients may be mis-diagnosed.4 The use of genetic testing is advancing the ability to diagnose patients with PCD and also further increase our understanding of PCD. The clinical manifestations in patients with defective ciliary structure and function are predictable, although they depend to some extent on age and organ system (Table 1).2 Symptoms may occur at birth, or in early childhood; >80% of full-term neonates with PCD have respiratory distress.5 Recurrent otitis media, radiographic abnormalities (e.g. atelectasis) or hypoxia in a child should raise the suspicion for PCD. Most patients with PCD have a daily productive cough from early life, which may partially compensate for abnormal mucociliary clearance. Bronchiectasis is seen in virtually all adults with PCD.2

View this table:
Table 1

Clinical signs and symptoms of PCD

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Airway microbiology

As with any patient with bronchiectasis, monitoring the respiratory flora on a regular basis is important. The spectrum of microorganisms in PCD generally mirrors that of patients with CF, although with a later time course. Children with PCD have airway colonization with Haemophilus influenza, Staphylococcus aureus and Streptococcus pneumoniae and, recently, there has been an increase in the isolation of Pseudomonas aeruginosa even in infants/preschoolers.6 Pseudomonas aeruginosa or other gram-negative organisms are very common in adults with PCD. Non-tuberculosis mycobacteria (NTM) may be seen in 15% of adults with PCD, emphasizing the need for vigilant monitoring.5

Pulmonary function

Patients with PCD develop progressive airway obstruction as their disease advances. While the disease progression is generally less severe than the decline seen in CF, it is nonetheless important to measure lung function serially to help guide therapy, to determine prognosis and to help referral for lung transplantation (FEV1 < 30%).6

Radiology

Using high resolution chest computed tomography scanning, bronchiectasis is usually present in the more dependent lobes such as the middle and lower lobes, in contrast to the upper lobes most affected in CF.7 Imaging in infants and children with PCD may show early changes of disease, such as sub-segmental atelectasis, peri-bronchial thickening, mucus plugging, or evidence of air trapping and ground glass opacities. Virtually all adults with PCD have some evidence of bronchiectasis on HRCT.7

Extra-pulmonary manifestations

Situs abnormalities (SI totalis, situs ambiguus, heterotaxy) occur in 60% of pediatric patients (allowing for diagnostic bias) and 50% of adults.1 Approximately 12% of patients with PCD have congenital heart disease.1 Infertility is seen in almost all males with PCD. However, some males with PCD may have a few motile sperm, and have conceived normally. Females are thought to have longer ovum transit times, with an increased incidence of ectopic pregnancies, though many have normal pregnancies. Less clear phenotypic associations observed in PCD as compared to the general population include pectus excavatum (10%), scoliosis (5–10%), retinitis pigmentosa and hydrocephalus.

Diagnostic tests (Figure 2)

The diagnosis of PCD with SI can be relatively straightforward, although a degree of awareness is required. Difficulty with diagnosis may be encountered in non-classic cases, or in diseases with overlapping phenotypes, especially CF. A history of neonatal respiratory distress, early onset ear, rhinosinusoidal and pulmonary symptoms, fertility issues or a positive family history (e.g. situs abnormalities) should trigger clinicians to consider the diagnosis. The following outlines the key tests that help with diagnosis, ignoring older, less reliable tests or those only available at specialized research centers.

Figure 2.

Diagnostic algorithm for PCD.

Nasal NO measures

Nasal nitric oxide (NO) levels have emerged as very robust, reproducible screening test in PCD. NO is produced by the para-nasal sinus epithelium via NO-synthase and low levels are seen in PCD, CF, acute/chronic sinusitis and nasal polyposis. In patients with PCD, levels of exhaled NO are extremely low (∼10% of normal value) even when compared to other etiologies for low exhaled NO. A nasal NO level <77 nl/min has a sensitivity and specificity of 0.98 and >0.999, respectively.8

Assessment of ciliary function

Microscopic analysis

Direct visualization of ciliary beat pattern and frequency can be seen with microscopic analysis of trans-nasal brushings or nasal scrapes of airway epithelia derived from the inferior turbinate. Function can be classed as qualitatively normal, dyskinetic or immotile. However, it is subjective, and neither sensitive nor specific.9

High-speed digital video imaging

Similar airway epithelial ciliated cell samples can be analysed with high-speed digital video imaging to get more quantitative measurements of the ciliary beat frequency (CBF) as well as ciliary beat patterns. CBF and beat pattern abnormalities are associated with specific ciliary ultrastructural defects (e.g. ODA, IDA or radial spokes/central apparatus defects. Pitfalls include active epithelial inflammation, which may be associated with secondary ciliary dysfunction.10

Assessment of ciliary ultrastructure

Transmission electron microscopy

As first reported in 1976, cilia can be studied in detail using transmission electron microscopy (TEM). The most common ultrastructural defect in PCD is either the absence or shortening of an ODA which is seen in ∼55% of cases, or with combined absence/shortening of both ODA and IDA11 (∼15% of cases). Less common defects include defects in the IDA alone, or in combination with defects of either radial spokes, central microtubule pairs (transposition) or central microtubular agenesis. Until recently, the identification of ultrastructural defects on TEM has been regarded as ‘gold standard’ for the diagnosis of PCD. However, it is important to note that advances in the molecular genetics of PCD has recently shown that ∼30% of patients with mutations in genes encoding for ciliary components have normal ciliary ultrastructure.12 In addition, TEM requires technical expertise in sampling, as well as image acquisition and analysis, as well as changes associated with mucosal epithelium inflammation.2

Flourescence-labeled antibodies

Immunoflourescent analysis using antibodies directed against the main axonemal components have recently been developed to identify structural abnormalities of cilia. For example, PCD patients with ODA defects have aberrant DNAH5 (ODA encoding protein) staining; whereas, patients with ODA+IDA defects have aberrant DNAH5, plus DNALI1 (IDA encoding protein) staining.13 Currently, a panel of antibodies directed toward multiple ciliary proteins is being developed, available as yet in only a few laboratories.11

Genetic testing

PCD is usually an autosomal recessive disorder, exhibiting locus and allelic heterogeneity.1 Despite this complex genetic situation, 12 different genes with pathogenic mutations for the recessive form of PCD were described between 1999 and 2011 using linkage mapping and/or a candidate gene approach. The pace of gene discovery has increased due to the wide spread use of next-generation sequencing (NGS) in addition to the previously used methods, and an additional 15 genes have been described since 2012 (Table 2). About 85% of the mutations are loss-of-function variants (nonsense, frame shift or defective splice mutations) while the other are conservative missense mutations. The majority of mutations are private but a minority occurs in multiple unrelated patients. Currently, ∼65% of the 200 PCD patients in the rare disease consortium (based in North America) have biallelic mutations. With the use of exome sequencing, mutations in ∼70% of patients with PCD can be identified. These and further advances in the molecular genetics of PCD will continue to facilitate early diagnosis and treatment.14,15 There are examples of genotype–phenotype correlations; for example some genes encode for proteins in the ODA, IDA or radial spoke, causing specific ciliary dysmotility, while others encode for proteins in the cytoplasm that are used for the preassembly of the dynein arm complexes, thus causing loss of both the ODA and the IDA, leading to ciliary immotility.12 Specific gene mutations may relate to some aspects of the clinical phenotype; for example, gene mutations that lead to loss-of-functional cilia are associated with low nasal NO levels. Similarly, mutations that affect ODA +/– IDA may randomly lead to situs abnormalities, while mutations that affect the central apparatus do not, since the nodal cilium is not affected in those cases. Overall, the more that the genetics of PCD unfold, the more is revealed about the pathophysiology of the disease, the spectrum of phenotypic variation, with the notion of classic and non-classic disease emerging.16

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Table 2

PCD-associated genes in humans showing extensive locus heterogeneitya

Human geneChromosomal locationAxonemal componentUltra-structure defectOMIM #
DNAH55p15.2ODA dynein HCODA defect608644, 603335
DNAI19p21-p13ODA dynein ICODA defect244400, 604366
DNAI217q25ODA dynein ICODA defect612444, 605483
DNAL114q24.3ODA dynein LCODA defect610062, 614017
TXNDC3 (NME8)7p14-p13ODA dynein IC/LCPartial ODA defect (66% cilia defective)610852, 607421
CCDC11419q13.32ODA DCODA defect615067, 615038
ARMC410p12.1-p11.23ODA transport componentODA defect615451, 615408
DNAAF1 (LRRC50)16q24.1Cytoplasmic DA preassembly factorODA + IDA defect613190, 613193
DNAAF2 (KTU)14q21.3Cytoplasmic DA preassembly factorODA + IDA defect612518, 612517
DNAAF3 (C19ORF51)19q13.42Cytoplasmic DA preassembly factorODA + IDA defect606763, 614566
CCDC10317q21.31Cytoplasmic DA attachment factorODA + IDA defect614679, 614677
C21orf5921q22.1Cytoplasmic DA assembly or adaptor for transportODA + IDA defect615500, 615494
DYX1C115q21.3Cytoplasmic DA preassembly factorODA + IDA defect615482, 608706, 607070
LRRC68q24Cytoplasmic DA preassembly or transportODA + IDA defect614935, 614930
HEATR27p22.3Cytoplasmic DA preassembly or transportODA + IDA defect614864, 614874
SPAG18q22Cytoplasmic DA preassembly or transportODA + IDA defect615505, 603395
ZMYND103p21.31Cytoplasmic DA assemblyODA + IDA defect615444, 607070
CCDC393q26.33N-DRCIDA defect + microtubular disorganization613807, 613798
CCDC4017q25.3N-DRCIDA defect + microtubular disorganization613808, 613799
CCDC65 (DRC2)12q13.12N-DRCMostly normal, CA defects in small proportion of cilia615504, 611088
CCDC164 (DRC1)2p23.3N-DRCNexin (N-DRC) link missing; axonemal disorganization in small proportion of cilia615294, 615288
RSPH121q22.3RS componentMostly normal, CA defects in small proportion of cilia609314, 615481
RSPH4A6q22.1RS componentMostly normal, CA defects in small proportion of cilia612649, 612647
RSPH96p21.1RS componentMostly normal, CA defects in small proportion of cilia612650, 612648
HYDIN16q22.2CA componentNormal, very occasionally CA defects608647, 610812
DNAH117p21ODA dynein HCNormal611884, 603339
DNAH8b6p21.1ODA dynein HCNot available603337
RPGRcXp21.1naMixed312610
OFD1dXq22naNot available311200
  • DA: Dynein arm; ODA: outer dynein arm; IC: intermediate chain; HC: heavy chain; LC: light chain; RS: radial spokes; IDA: inner dynein arm; CA: central apparatus; N-DRC: nexin-dynein regulatory complex; DC: docking complex.

  • aOnline Mendelian Inheritance in Man (OMIM), http://www.omim.org/

  • bCiliary ultrastructure not available (Watson et al, Hum Mutat: Dec 4, 2013 Epub); however, DNAH8 is paralogous to DNAH5.

  • cCosegregation of X-linked PCD with X-linked Retinitis Pigmentosa.

  • dCosegregation of X-linked PCD with X-linked Mental Retardation.

Therapies

The goal of the therapy is to prevent exacerbations, and slow the progression of lung disease, as there is as yet no ‘cure’ for PCD. As with most chronic genetic diseases, early diagnosis is considered to be important. As the patient population in PCD is small, there is little robust evidence to guide therapy. However, the clinical experience with the CF and bronchiectasis populations have helped guide the way.

Surveillance/preventive care

Regular clinical surveillance to establish clinical and lung function trends, to detect exacerbations early and to guide appropriate therapy is critical. Although many patients have relatively mild lung disease up to older age as compared with CF, nonetheless, a proportion of patients develop respiratory failure requiring lung transplantation.5 Microbiologic assessment should be done regularly. Periodic chest imaging is also indicated to assess the extent of the disease. Routine immunizations, as recommended regionally, are important.

Airway clearance

Regular airway clearance of various methodologies helps mobilize and clear airway secretions. There are no data to support one specific method over another. Exercise is highly recommended. Nebulized hypertonic saline modulates the liquid content of the periciliary fluid layer via increased hydration, thinning thick secretions and triggering a cough in the CF population. It has been shown to improve lung function, quality of life, and antibiotic needs in the non-CF bronchiectasis population. It seems logical that it would also help in PCD and thus is likely to beneficial in many patients.17 Deoxyribonuclease (rhDNA-ase), is an enzyme that hydrolyses eukaryotic DNA released from decaying neutrophils to reduce mucus viscosity and aids airway clearance in the CF population, but is not recommended in the non-CF population, including PCD18

Antibiotics

As with other forms of non-CF bronchiectasis, antibiotics remain a critical element of the management of PCD, especially for exacerbations. Evidence, and clinical judgment, generally shows that antibiotics improve symptoms and hasten recovery. Most importantly, antibiotic therapy (oral or intravenous) should be based on airway cultures and previous therapeutic responses. Early attempts to eradicate newly acquired bacteria, especially P. aeruginosa are recommended (as with CF). Chronic or cycling oral or inhaled antibiotics (colistemethate, tobramycin or aztreonam) may be used in patients with frequent exacerbation, in the presence of gram-negative organisms.19–22

Anti-inflammatory agents

Anti-inflammatory agents have been used in diseases with a similar pathophysiology of infection and inflammation, including oral prednisone, inhaled corticosteroids and macrolides. Prednisone has not been effective in the CF population outside of allergic bronchopulmonary aspergillosis (ABPA) and there are no studies in the PCD population. Inhaled corticosteroids have questionable benefit in non-CF bronchiectasis.2 Studies with oral macrolides have shown a reduction in exacerbation frequency in non-CF bronchiectasis. It is unclear if this benefit is from an anti-inflammatory or antimicrobial effect. Prior to initiating therapy with a macrolide, patients should be tested for NTM to prevent resistance from chronic macrolide use as a single agent in disease that may require a multi-drug regimen.23

Miscellaneous therapies

Surgery may be considered in areas of localized lung disease if symptoms, exacerbations or hemoptysis are problematic. Patients in such situations have undergone successful resection. Lung transplantation has been performed on patients with PCD with end stage disease, with good survival outcomes. Concerns include highly resistant organisms and poor nutritional status, as with CF. In patients with SI, the anatomic disorientation may be challenging, but not a contraindication.

Extra-pulmonary disease management

The management of otitis media is controversial, with long-term implications include conductive hearing loss, delayed speech and language development and cholesteatoma formation. Standard therapy is recommended for acute episodes. There are not enough data on surgical tympanostomy to make a definitive statement regarding its utility, although many individuals strongly discourage the practice. Scheduled audiology assessments should be encouraged.24 As with CF, the sinuses are frequently involved, leading to chronic rhino-sinusoidal disease. Management includes nasal steroids, nasal lavage and intermittent antibiotic lavages and systemic antibiotics. Surgery, for example, polypectomy, to promote sinus drainage may be helpful for patients refractory to medical therapy.Male infertility is secondary to sperm immotility and can be overcome by assisted fertilization techniques such as intracytoplasmic sperm injections, or artificial insemination. Female infertility may be overcome using assisted fertilization techniques.

Prognosis

The severity of the disease is generally perceived as less severe than that of CF, for probably multiple factors. A Danish study reported longitudinal lung function in 24 patients diagnosed with PCD. The patients diagnosed in adulthood had worse lung function at time of diagnosis compared to the cohort diagnosed in adolescence. However, once diagnosed, no further lung deterioration was noted as they were started on appropriate therapy.25 There is significant genetic and phenotypic heterogeneity, with wide spectrum of disease severity, and thus survival is difficult to predict. Overall, lung function appears to decline more slowly as compared to patients with CF. A minority of patients may however progress to severe lung disease, with respiratory failure and need consideration for lung transplant for continued survival.5

Summary

The body of knowledge with regard to this interesting genetic disease is growing; the diagnosis is becoming less challenging and access to specialized centers is becoming easier. Standardized care at specialized centers using a multidisciplinary approach is likely to improve outcomes. In conjunction with the PCD foundation and lead investigators and clinicians are developing a network of PCD clinical centers to coordinate the effort in North America and Europe. As the network grows, care and knowledge will undoubtedly improve.

Conflict of interest: None declared.

References

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