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INTRODUCTION — Primary ciliary dyskinesia (PCD, also called the immotile-cilia syndrome) is characterized by congenital impairment of mucociliary clearance (MCC) . The underlying cause is a defect of cilia in the airways, making them unable to beat (ciliary immotility), unable to beat normally (ciliary dyskinesia), or absent altogether (ciliary aplasia). It is an inherited disease that has been described from most parts of the world and with equal prevalence in men and women of approximately one in 10,000 to 30,000 individuals [1-4].
Because the embryonic, nodal cilia are also defective, body asymmetry occurs randomly so that approximately 50 percent of the patients have situs inversus totalis (image 1) [5-7]. When situs inversus, chronic sinusitis, and bronchiectasis occur together, an individual is said to have Kartagener's syndrome.
The genetics, clinical manifestations, diagnosis, and management of PCD are reviewed here. The evaluation and treatment of bronchiectasis are discussed separately. (See "Clinical manifestations and diagnosis of bronchiectasis in adults" and "Treatment of bronchiectasis in adults" and "Clinical manifestations and evaluation of bronchiectasis in children" and "Management of bronchiectasis in children without cystic fibrosis".)
CILIARY FUNCTION — PCD is a highly heterogeneous syndrome that can be caused by a defect in any of the many polypeptide species within the axoneme (central core) of cilia or of sperm flagella, in other proteins that are present in the ciliary membrane and matrix, or in proteins needed for the proper assembly of cilia [8-13]. Different components may be missing or defective in different patients, and different clinical manifestations may develop depending upon the nature of the lesion [14,15].
Motile cilia in the upper and lower respiratory tract epithelium have microtubules that are composed of alpha and beta monomers of tubulin and a complex axonemal structure of inner and outer dynein arms, radial spokes, and nexin links (image 2). Respiratory epithelial cells have approximately 200 cilia per cell that beat in a coordinated fashion to move respiratory secretions. Mutations in the genes encoding the axonemal structure and accessory components of cilia can result in primary ciliary dyskinesia. Some mutations result in abnormal ultrastructure and others in abnormal function, but preserved ultrastructure.
GENETICS — Primary ciliary dyskinesia (PCD) is inherited as an autosomal recessive disease (Mendelian inheritance in man [MIN] 244400) . More than 30 different PCD causing genetic variants have been described, including mutations in the axonemal outer dynein arms (DNAH5, DNAH9, DNAH12, DNAI1, ARMC4, CCDC103), inner dynein arms (DNALI1), assembly proteins (DNAAF3), and radial spokes (RSPH4A, RSPH9) (figure 1) [17-24]. Families may have different mutated genes, but identical clinical symptoms.
In some cases it has been possible to identify a specific chromosomal locus and gene product [25,26]. As an example, in patients with PCD, a mutation of DNAH5 on chromosome 5p15 is reported to be disease-causing in 28 percent and present in 53 percent of unrelated patients with associated partial or total loss of outer dynein arms . Complete absence of DNAH5 along the ciliary axoneme results in immobility, while absence of DNAH5 in the distal portion of the axoneme causes impaired mobility .
A number of other genes are associated with PCD, including the dynein arm genes DNAI1, which encodes the outer dynein arm intermediate chain, and DNAH11, which is associated with normal appearing dynein arms but impaired function [29-32]. Radial spoke head gene mutations (eg, RSPH4A, RSPH9) have been identified and appear to be associated with PCD, but not situs inversus . Mutations in DNAI1 and DNAH5 are present in approximately 30 to 38 percent of families with PCD .
The trait of situs inversus apparently has an element of random determination [1,35]. Rather than having one gene for situs solitus (organs in their normal position) and one for situs inversus, the nodal cilia of the embryo are responsible for controlling the normal position of heart and visceral organs, and without such control there is an equal chance of situs inversus and situs solitus. Two pairs of monozygotic twins with primary ciliary dyskinesia have been identified; in each pair there was one twin with situs inversus and one with situs solitus .
Compound heterozygotes can have the clinical manifestations of PCD, and a few cases of x-linked recessive PCD have been reported, but mutations associated with autosomal dominant inheritance are extremely rare .
CLINICAL MANIFESTATIONS — Considerable variation exists in the clinical presentation of primary ciliary dyskinesia (PCD), although the most common features are recurrent infections of the upper and lower respiratory tract. Most patients with PCD present in childhood (median age of diagnosis 5 to 5.5 years), but some present in adulthood (median age of diagnosis 22 years) [4,7,38]. Among adults, the age at diagnosis varies; in a series from Cyprus, the median age at presentation was 36.3 years (range 23.4 to 58.4) , while in a North American population, the median age at diagnosis was 22 years .
Pulmonary — Newborns with primary ciliary dyskinesia often suffer from mild respiratory distress, such as tachypnea or mild hypoxemia, and may require supplemental oxygen for a few hours to days after birth [4,20,39-41]. An increased incidence of respiratory infections with chronic cough and expectoration of mucopurulent sputum is commonly encountered as the infant grows . These symptoms tend to increase during the course of the day rather than peak in the morning, as they do in smoker's bronchitis. (See "Clinical manifestations and evaluation of bronchiectasis in children" and "Transient tachypnea of the newborn", section on 'Diagnosis'.)
Patients with bronchiectasis generally manifest auscultatory crackles and may have wheezes that mimic asthma, particularly in children. In one series, clubbing was not seen in children, but was seen in 8 percent of adults .
Common findings on chest radiograph and high resolution computed tomography (HRCT) are a moderate degree of hyperinflation, peribronchial thickening, atelectasis, and bronchiectasis (image 1 and image 3A-B) . Cylindrical or saccular bronchiectasis may occur, even in childhood, and usually affects the middle and lower lobes and the lingula . Bronchiectasis is reported to be present on HRCT in all adults and approximately 50 percent of children . Multiple, diffuse small centrilobular nodules up to 2 mm are sometimes seen, probably representing bronchiolitis .
Spirometry often reveals mild to moderate airway obstruction with variable responsiveness to bronchodilators . However, in contrast to patients with cystic fibrosis, forced expiratory volume in one second (FEV1) does not necessarily correlate with HRCT findings .
Sputum cultures have found that the major infecting bacteria are Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa or nontuberculous mycobacteria . Mucoid P. aeruginosa tends to appear after age 30, which is delayed compared with cystic fibrosis.
Rhinosinusitis — A constantly runny nose and year-round nasal congestion may be noted beginning in early childhood [34,49]. Uncomplicated common colds do not seem to occur more often in PCD than in normal subjects, nor do they usually have a more severe course. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis" and "Microbiology and antibiotic management of chronic rhinosinusitis" and "Chronic rhinosinusitis: Management".)
Rhinosinusitis is a cardinal feature of PCD, occurring in almost 100 percent of affected individuals . Nasal polyposis is frequently present; chronic sinusitis typically involves the maxillary (image 1) and ethmoidal sinuses, while the frontal and sphenoid sinuses are less likely affected as they often fail to develop . The absence of a frontal sinus often gives the voice a somewhat nasal tone. A sinus CT scan is usually obtained to assess for chronic sinusitis in patients with persistent mucopurulent drainage (anterior and/or posterior), nasal obstruction or blockage, and facial pain or pressure. In adults, impaired or absent sense of smell is another clue to the presence of chronic rhinosinusitis, while a chronic cough is a more common clue in children.
Otitis — The otologic complications of PCD are a consequence of defective ciliary function in the Eustachian tube and middle ear cleft, leading to poor mucociliary clearance. Chronic secretory otitis media with recurrent episodes of acute otitis media is present during childhood and adolescence, but these problems become much less frequent following puberty [34,49,52]. Conductive hearing loss is common [4,53]. (See "Acute otitis media in adults (suppurative and serous)", section on 'Otitis media with effusion' and "Acute otitis media in children: Treatment", section on 'Recurrent AOM' and "Hearing impairment in children: Evaluation".)
Situs inversus and Kartagener syndrome — Situs inversus, when present in patients with primary ciliary dyskinesia, generally occurs as a complete reversal of the circulatory system and the viscera known as situs inversus totalis (image 1). Situs inversus has no serious adverse health consequences per se, and the condition often goes undetected until a chest radiograph is obtained. Situs inversus is a very useful sign when primary ciliary dyskinesia is being considered, but as described above, is present only in approximately 50 percent of patients with primary ciliary dyskinesia. Isolated situs inversus has a prevalence of about one in 10,000 in Scandinavia .
When situs inversus, chronic sinusitis, and bronchiectasis occur together, an individual is said to have Kartagener's syndrome, which is a subgroup of primary ciliary dyskinesia that has a prevalence of around one in 20,000 to 40,000 individuals . Bronchiectasis may develop in young persons, but is never present at birth; thus, no individual is born with a fully developed Kartagener's triad.
Central nervous system — Fatigue and headaches are common complaints and may be caused by chronic sinusitis, although the headaches may persist even during infection-free periods. Hydrocephalus has been described from several persons with primary ciliary dyskinesia and two siblings with ciliary aplasia [55-58]. Impaired function of ependymal cilia may be at least partially responsible.
Fertility — Most men with PCD have living but immotile spermatozoa and are infertile, although some have motile spermatozoa but immotile cilia and others are azoospermic [4,59,60]. Women likewise have decreased fertility, with fewer than 50 percent successfully completing pregnancy [2,61]. Impaired ciliary function in the fallopian tubules can delay ovum transit leading to reduced fertility or, on very rare occasions, ectopic pregnancy .
Associated abnormalities — A number of other congenital abnormalities are occasionally associated with primary ciliary dyskinesia, including transposition of the great vessels and other cardiac abnormalities, pyloric stenosis, and epispadias. Cardiac evaluation is suggested for most patients since the incidence of congenital heart disease with heterotaxy is reported to be 200-fold higher in PCD than the general population [62,63]. (See "L-transposition of the great arteries" and "Infantile hypertrophic pyloric stenosis" and "Anatomy, clinical manifestations, and diagnosis of heterotaxy (isomerism of the atrial appendages)".)
Among patients with PCD, the frequencies of pectus excavatum (10 percent) and scoliosis (5 to 10 percent) are increased [4,45,64].
One-third of PCD patients aged 6 to 29 years are reported to exhibit substantially lower aerobic fitness compared to healthy controls .
DIAGNOSTIC EVALUATION — The crucial diagnostic feature of primary ciliary dyskinesia is an inborn error of the cilia, rendering them immotile, dysmotile, or missing. However, no "gold standard" diagnostic test has been established. A number of tests have been employed and each has advantages and disadvantages (table 1) [20,49,66,67]. A combination of tests is necessary for accurate diagnosis of PCD, as described in the guidelines published by the European Respiratory Society [24,67].
Tests measuring nasal nitric oxide and mucociliary clearance may be useful for screening, but generally require confirmation with tests of ciliary function and ultrastructure . The role of genetic testing is changing with the identification of a greater number of PCD-causing mutations and development of high-throughput testing. Referral to a specialist (eg, pediatric or adult pulmonary) is generally necessary for diagnostic evaluation.
In the absence of cystic fibrosis, a history of neonatal respiratory distress, early onset and persistent cough, chronic nasal congestion and rhinorrhea, otitis media, and a laterality defect (eg, situs inversus or ambiguous) should raise a strong clinical suspicion for PCD . In adults, the diagnosis should be suspected in males with dyskinetic spermatozoa and respiratory symptoms and females who are infertile or subfertile without other explanation, particularly in the presence of respiratory symptoms.
Nasal nitric oxide — Measuring the amount of nasal nitric oxide (nNO), which is very low or absent in patients with PCD, is a useful screening test for patients age 5 years or older with a clinical suspicion of PCD [24,68-75]. However, the specific threshold to use has not been determined and varies with the technique used [24,67,72,73].
●In a prospective study of 301 patients, using a cut-off of 30 nL/minute, the sensitivity and specificity were 91 and 96 percent, respectively .
●In a separate prospective study that included 143 patients with PCD, 146 subjects with other respiratory diseases, and 78 healthy controls, nNO accurately identified patients with PCD, although some overlap with cystic fibrosis was noted . In this study, a nNO ≥77 nL/minute was determined as a cut-off value that excludes PCD [49,76-78].
Confirmatory testing (eg, ultrastructural studies, sweat test, cystic fibrosis genetic studies) is required, however, because other respiratory conditions, such as cystic fibrosis and acute viral infection, may rarely present with low nNO . Certain genetic variants (eg, radial spoke head proteins) are associated with normal nNO levels and other testing is needed to make the diagnosis of PCD . On the other hand, nNO may be particularly helpful in atypical PCD phenotypes with normal ciliary ultrastructure, but abnormal function [4,67,80]. (See "Exhaled nitric oxide analysis and applications", section on 'Formation of NO'.)
The technique requires modification of the apparatus and procedure used for measuring exhaled nitric oxide in asthma. However easily portable and relatively cost-effective analyzers are becoming available . Measurements should be obtained at a time remote from acute nasal or respiratory infection. nNO measurements are obtained from the nose during velum closure, which is achieved by exhalation against resistance or into a party toy, to decrease dilution from the lower airways [73,74]. nNO is measured by chemiluminescence during exhalation. The nNO production (nL/min) is calculated by multiplying the nNO concentration (parts per billion) by the sampling flow rate, which varies according to the chemiluminescent analyzer used.
The reduced levels of nasal NO in patients with PCD may be related to alterations in nasal nitric oxide synthetase (NOS) activity, increased consumption of NO by superoxide anions, obstruction of the paranasal sinuses inhibiting release of NO into the nasal passages, or hypoplasia or agenesis of the paranasal sinuses reducing NO production . Gene expression studies in nasal biopsy samples from patients with PCD found reduced mRNA levels of the inducible isoform NOS2, which localizes to the apical part of nasal epithelial cells, compared with patients with secondary ciliary dysfunction . NOS2 gene expression in these biopsies correlated with nasal NO levels. Gene expression of the endothelial isoform NOS3, which is associated with the ciliary basal microtubule membrane, was not reduced. In contrast, a separate report confirmed low levels of NO in nasal and exhaled breath condensates of 15 children with PCD, but found the level of breakdown products (including nitrite) was not low, suggesting that overall NOS activity is not diminished .
Ciliary motion and ultrastructure — High speed videomicroscopy analysis (HSVA) and transmission electron microscopy (TEM) are traditional methods to examine ciliary movement and ultrastructure. The European Respiratory Society guidelines for patients with clinical features of PCD suggest performing HSVA first and proceeding to TEM, if HSVA is abnormal or equivocal . While accurate for patients with complete immotility or gross dysmotility, HSVA requires an experienced videomicroscopist to identify subtle abnormalities of ciliary motion . TEM is limited by the need for an adequate sample size and experienced readers .
Samples should be obtained at a time remote from acute nasal or respiratory infection (eg, four to six weeks after infection) [49,83,84]. In a prospective study of 654 patients referred for evaluation of possible PCD, HSVA had a sensitivity and specificity of 100 and 93 percent, respectively . TEM was 100 percent specific, but lacked sensitivity in that 21 percent of PCD patients had normal ultrastructure. Combination testing with HSVA and TEM was found to be a highly accurate (100 percent sensitive and 92 percent specific) but this was not recommended until better standardization of testing between centers is achieved.
Nasal brushing with a bronchoscopy (or similar) brush is the preferred method to obtain ciliate epithelium as it is less invasive; the inferior turbinate is brushed for two to three seconds . Flexible bronchoscopy with bronchial brushing and/or biopsy is performed if the nasal sample is not adequate.
●High speed videomicroscopy analysis – For HSVA, the respiratory epithelial cells are rapidly transferred to an isotonic saline solution and examined in the living state. HSVA with beat frequency measurement is used to determine whether cilia have normal coordination, beat frequency, and beat pattern. Slowing ciliary motion by cooling the specimen may help reveal abnormal waveforms . For equivocal or abnormal results, repeating the ciliary beat frequency and pattern assessment after air-liquid interface culture improves the accuracy of HSVA [24,85]. The clinical usefulness of these tests has increased, as their accuracy in distinguishing between primary and secondary ciliary dyskinesia has improved [67,86,87].
●Transmission electron microscopy – TEM analysis is performed when the diagnosis is uncertain after high speed video microscopy, but may also be performed to identify the type of ciliary abnormality [49,79,88]. TEM can be diagnostic if hallmark ciliary ultrastructural defects are identified . However, TEM can be normal in approximately 10 to 20 percent of patients with PCD, so TEM should not be relied upon as a single diagnostic test .
For electron microscopy, the fresh biopsy is immersed in a glutaraldehyde solution and further processed for ultrastructural investigation. Cross-sections of the cilia (at least 30 sections containing >60 high-quality cilia images is desirable) are examined to identify specific defects or normal ultrastructure (figure 1 and image 2) . The diversity in ciliary ultrastructure among different patients with the same clinical symptoms is due to the fact that the immotile-cilia syndrome is a heterogeneous disease, and the underlying defect may reside in any of a great number of ciliary genes.
A commonly observed ultrastructural defect is the absence of so-called dynein arms (dyneins are the high molecular weight motor proteins responsible for ciliary motility); other reported ultrastructural abnormalities include the absence of radial spokes and absent, or additional, microtubule assemblies (image 2). A variant form of ciliary transposition, which results in circular ciliary beating and central microtubule agenesis, has also been described . (See 'Ciliary function' above.)
When the living cilia are seen to be immotile but the ciliary ultrastructure appears quite normal (10 to 20 percent of cases), the underlying defect is likely in membrane pumps or in other proteins not visible in electron micrographs. Use of computer-based image processing algorithms can improve visualization of ultrastructural abnormalities detected using electron microscopy .
Cell culture — Cell culture is used to allow redifferentiation of ciliated epithelial cells to reduce false positive tests that mistake secondary loss or dysfunction of cilia for PCD [49,83,92]. This technique is also useful to confirm the presence of less common phenotypes, such as ciliary disorientation, ciliary aplasia, central microtubular agenesis, and inner dynein arm defects.
Epithelia from the inferior concha of the nose are obtained with a cytology brush (such as those used for endobronchial brushing during bronchoscopy) and maintained in tissue culture with antibiotics (to eliminate any epithelial bacteria) for several weeks. The culture medium is then supplemented with pronase (to separate the individual cells from the epithelium). After several days, cilia are shed and new ones emerge. Healthy cilia are then recognized by their ability to rotate the cells in the tissue medium, whereas the cells will not rotate if primary ciliary dyskinesia is present.
Genetic testing — Genetic testing for PCD mutations has not generally been part of the initial evaluation, but may be performed if specific variants are suspected . Genetic testing for PCD mutations is usually reserved for patients with normal or equivocal HSVA and TEM and a strongly suggestive history . This testing is available through specialized laboratories , and approximately 35 percent of PCD patients carry either DNAH5 or DNAI1 mutations. If biallelic mutations are present, the test is diagnostic. If only one allelic mutation is found, further testing may identify a transallelic mutation. However, genotyping only identifies 50 to 65 percent of patients with PCD . High throughput genetic technologies such as characterization of additional PCD-causing mutations and whole-genome sequencing may allow diagnostic genotyping of over 80 percent of PCD in the near future .
Measures of mucociliary transport — Methods to assess mucociliary transport are limited by availability and difficulties with specificity and, thus, are infrequently used. Cilia from the airways may be immobilized by bacterial toxins; immotility is then acquired rather than inborn and is associated with a different prognosis. Furthermore, mucociliary transport involves a two-component system, and the abnormality may reside in the mucus rather than in the cilia. As an example, patients with cystic fibrosis generate very viscous mucus, which their normal cilia are unable to propel forward. Mucus from patients with asthma also is more viscous than in healthy persons.
One method for measuring mucociliary transport in situ is to administer an inhalation aerosol of colloid albumin tagged with 99Tc [94-96]. Radioactivity within the lungs is then measured repeatedly for two hours and again at 24 hours by profile scanning of the thorax while the patient is supine. The amount of coughing must be monitored for two hours, because coughing acts as a substitute for mucociliary clearance and results in elimination of the isotope from the lungs. This test can only be performed in adults and children over the age of five. In a large series of patients with primary ciliary dysfunction and those suspected of the disease, the test had high positive and negative predictive values compared with nasal ciliary function tests (eg saccharin clearance). An absence of mucociliary clearance is a sign of ciliary immotility, dysmotility, or aplasia, which may be inborn or acquired.
A somewhat simpler, previously used technique consists of depositing small particles of saccharin or dye in the concha inferior and measuring the time required for the taste of the marker to be perceived or the dye to become visible in the throat [97,98]. However, as mentioned above, these methods are associated with major disadvantages. A "positive" test result is considered as inconsistent with PCD while a "negative" test result is of no value. However, these techniques are less reliable than other methods of diagnosis and cannot be used in small children.
Other tests — Other diagnostic tests have been proposed but have a less well-defined role. These include:
●A gel electrophoretic examination of dyneins in a biopsy from the nasal epithelium or a sample of ejaculate .
●Using a dynein gene probe to map the corresponding messenger RNA in lung or testicular tissue .
●Examining whether spermatozoa are motile or immotile, although care must be taken to differentiate dead from living, but immotile, spermatozoa. It must also be kept in mind that occasional patients have immotile cilia but normally motile spermatozoa .
MANAGEMENT — The optimal management of the sequelae of PCD is not known, so recommendations are based in part on experience treating patients with cystic fibrosis and other forms of bronchiectasis. In general, treatment must be individualized depending upon the specific clinical course of a given patient [4,49,101].
Bronchiectasis — Clearing secretions and reducing the microbial load with selective use of antibiotics form the cornerstone of preventive therapy. Daily chest physiotherapy is important in compensating for diminished or absent mucociliary clearance, and a number of airway clearance techniques are available. (See "Management of bronchiectasis in children without cystic fibrosis", section on 'Medical treatment' and "Treatment of bronchiectasis in adults", section on 'Prevention of exacerbations'.)
The effectiveness of airway hydration (eg, nebulized hypertonic saline, aerosolized mannitol) and mucolytic agents (eg, DNase, acetylcysteine) has not been fully assessed in PCD, but may be tried, particularly in patients with recurrent infections or ongoing respiratory symptoms [49,102,103]. Of note, DNase has been found to be beneficial in cystic fibrosis, but not in other forms of bronchiectasis. (See "Treatment of bronchiectasis in adults", section on 'Mucolytic agents and airway hydration' and "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Thiols and thiol derivatives'.)
Acute exacerbations of bronchiectasis due to bacterial infection are usually heralded by increased production of sputum that is more viscous and of darker color and may be accompanied by lassitude, shortness of breath, pleuritic chest pain, or hemoptysis, while fever may not be present. Such exacerbations are treated with oral antibiotics, even when the symptoms are mild. Regular sputum cultures should be obtained to identify resistant organisms and guide antibiotic therapy. Intravenous antibiotics may be required for treatment of Pseudomonas aeruginosa infection, or in cases of severe pneumonia from other bacterial etiologies . Early and definitive treatment of respiratory infections may prevent or delay the evolution of bronchiectasis and minimize the progressive loss of lung function that is otherwise noted. The management of infection in noncystic fibrosis bronchiectasis is discussed separately. (See "Treatment of bronchiectasis in adults", section on 'Treatment of acute exacerbations' and "Management of bronchiectasis in children without cystic fibrosis".)
For patients with recurrent exacerbations, preventive antibiotic therapy (usually with a macrolide) may be considered. This is based on data from studies of cystic fibrosis and noncystic fibrosis bronchiectasis; data in PCD are lacking. Sputum cultures should be checked to exclude nontuberculous mycobacteria infection, prior to initiating long-term antibiotic therapy. (See "Treatment of bronchiectasis in adults", section on 'Macrolides'.)
Vaccination against influenza and pneumococcus is advisable. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups' and "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children" and "Pneumococcal (Streptococcus pneumoniae) polysaccharide vaccines in children".)
Smoking causes a more rapid deterioration in lung function, and counseling regarding smoking cessation is essential. (See "Overview of smoking cessation management in adults".)
Surgical intervention to remove an isolated area of bronchiectasis is rarely recommended due to the risks of the procedure and likelihood of development of bronchiectasis in other areas . Bilateral lung transplantation is the therapy of choice in patients with end-stage respiratory insufficiency, although heart-lung transplantation or a modified surgical procedure is required in patients with situs inversus [105,106]. (See "Lung transplantation: General guidelines for recipient selection" and "Heart-lung transplantation".)
Chronic rhinosinusitis and nasal polyposis — While not specifically assessed in PCD, the medical management of chronic rhinosinusitis includes nasal saline lavage, intranasal glucocorticoids for nasal polyposis, and antibiotic therapy for exacerbations. (See "Chronic rhinosinusitis: Management".)
Surgical interventions to treat chronic sinusitis and nasal polyposis may be necessary in a subset of patients. Indications for functional endoscopic sinus surgery include debulking of severe polyposis, failure of intensive medical management, bony erosion due to chronic infection, or extension of disease beyond the sinus cavities. (See "Chronic rhinosinusitis: Management", section on 'Indications for sinus surgery'.)
Otitis media with effusion — Chronic otitis media with effusion (OME) is common in children and adolescents with PCD and can lead to hearing loss. The value of tympanostomy in chronic OME due to PCD has been questioned because OME tends to be chronic and recurrent [49,52]. On the other hand, some authors feel that tympanostomy tubes improve hearing, at least temporarily . The general management of OME and the decision about tympanostomy tube placement are discussed in greater detail separately. (See "Otitis media with effusion (serous otitis media) in children: Management", section on 'Tympanostomy tubes'.)
Impaired fertility — Because ciliary immotility (or dysmotility) commonly is associated with abnormal sperm motility, male patients should be informed about possible infertility, and semen analysis should be offered. In vitro fertilization techniques, particularly intracytoplasmic sperm injection, have been effective in this setting . (See "Evaluation of male infertility" and "Treatment of male infertility".)
Female patients of child-bearing age should be alerted to the possibility of reduced fertility and the extremely rare risk of ectopic pregnancy. (See "Evaluation of female infertility".)
Monitoring — Close, ongoing clinical follow-up is essential in PCD. We perform spirometry at every visit, starting at age six. Although evidence for this is lacking, we believe that it is useful to obtain an objective measure of lung function and a decrease in forced expiratory volume in one second (FEV1) may occasionally detect a subclinical exacerbation. On average, patients undergo spirometry one to three times a year. In contrast to its use in cystic fibrosis, the Lung Clearance Index (LCI) does not appear to be a sensitive test of airway disease in advanced PCD .
Chest radiographs are relatively insensitive measures of bronchiectasis, but are helpful to evaluate changes in respiratory symptoms.
High-resolution computed tomography (HRCT) is more sensitive than conventional chest radiographs for detecting early airway and parenchymal lung changes. It is typically performed to evaluate worsening symptoms or abnormalities on chest radiograph that do not respond to initial therapy As early recognition of deterioration (eg, mucus plugging, atelectasis, pneumonia) is important in patients with PCD, HRCT may be helpful in selected cases (eg, unexplained clinical deterioration, decline in spirometric values, or to determine the extent of bronchiectasis) .
The utility of HRCT for monitoring progression of lung disease was compared with spirometry in a retrospective study of 20 patients followed for a median interval of 2.3 years (range 1.3 to 3.4 years) . HRCT scans significantly worsened over time, showing an increased extent of bronchiectasis, mucus plugging, peribronchial thickening, parenchymal abnormalities, and mosaic attenuation, while spirometry remained stable. This discrepancy between HRCT and spirometry (FEV1) seems to be more attenuated in patients with PCD compared to those with CF . While HRCT appears more sensitive than spirometry, we do not obtain HRCT for routine monitoring due to concerns about radiation exposure. However, when performing a HRCT it is a good idea to do a chest x-ray simultaneously making the interpretation of subsequent chest radiographs more reliable.
PROGNOSIS — Persons with primary ciliary dyskinesia generally live an active life and have a normal lifespan. The rate of decline of lung function is much slower than with cystic fibrosis . However, repeated or chronic infections eg, sinusitis may be tiresome and influence on the ability to work full time.
The effect of PCD on lung function was evaluated in a three-decade long observational study . Seventy-four patients underwent interval pulmonary function testing over a median of 9.5 (range, 1.5 to 30.2) years. The cohort consisted mostly of children and young adults; the smoking history of these patients was not reported. There was a high degree of variation in the course of lung function after diagnosis. During the observation period, approximately 60 percent had a stable forced expiratory volume in one second (FEV1), 30 percent had a decrease of more than 10 percent, and 10 percent had a greater than 10 percent improvement. The variation in lung function was not related to age or level of lung function at the time of diagnosis.
An international registry for patients with PCD has been established .
Additional information for patients and families can be found on the PCD Foundation website.
SUMMARY AND RECOMMENDATIONS
●Primary ciliary dyskinesia (PCD), also called the immotile-cilia syndrome, includes patients with a spectrum of ciliary abnormalities, including ciliary akinesia, dyskinesia, and aplasia. It is characterized by chronic cough, bronchiectasis, chronic rhinosinusitis, and recurrent otitis media (image 1). (See 'Introduction' above.)
●The inheritance pattern of PCD is autosomal recessive. A number of different PCD causing mutations have been described, including mutations in the axonemal outer dynein arms (DNAH5, DNAH9, DNAH12, DNAI1), inner dynein arms (DNALI1), assembly proteins (DNAAF3), and radial spokes (RSPH4A, RSPH9). Situs inversus is present in about 50 percent of individuals with PCD. (See 'Genetics' above and 'Clinical manifestations' above.)
●A combination of tests is necessary for accurate diagnosis of PCD. Measuring the production of nasal nitric oxide (nNO) is a useful method to screen patients with a clinical suspicion of PCD. Measuring mucociliary clearance with inhalation of colloid albumin tagged with 99Tc is an alternative screening test of ciliary function, but is not standardized. The saccharin clearance time is not a reliable screening test for PCD. Semen analysis is an option in adult males. At present, none of these is diagnostic, so a confirmatory test is necessary. (See 'Diagnostic evaluation' above.)
●Definitive diagnosis is based on transmission electron microscopic (TEM) visualization of specific defects, such as absence of dynein arms or radial spokes and absent, or additional, microtubule assemblies. High speed videomicroscopy analysis (HSVA) in conjunction with beat frequency measurement can determine whether cilia have normal coordination, beat frequency, and beat pattern. These tests require nasal or bronchial biopsy and are only available at specialized centers. (See 'Diagnostic evaluation' above.)
●Genetic testing, although not usually part of the initial evaluation, is available for some of the variants that cause PCD and may be diagnostic. (See 'Genetic testing' above.)
●Persons with primary ciliary dyskinesia generally live an active life and have a normal lifespan. The rate of decline of lung function is much slower than that with cystic fibrosis. (See 'Management' above.)
●Smoking causes a more rapid deterioration in lung function, and counseling regarding smoking cessation is essential. (See 'Management' above.)
●Interventions to improve secretion clearance and reduce respiratory infections include daily chest physiotherapy and prompt treatment of respiratory infections. The role of nebulized DNase and other mucolytic drugs is less clear. (See 'Management' above and "Treatment of bronchiectasis in adults" and "Management of bronchiectasis in children without cystic fibrosis".)
●Surgical interventions to treat middle ear disease, maxillary sinusitis, and nasal polyposis may be necessary in a subset of patients. (See 'Management' above.)
●Bilateral lung transplantation is the therapy of choice in patients with end-stage respiratory insufficiency, although heart-lung transplantation or a modified surgical procedure is required in patients with situs inversus. (See 'Management' above.)
●Because ciliary immotility (or dysmotility) is commonly associated with abnormal sperm motility, male patients should be informed about possible infertility, and semen analysis should be offered. In vitro fertilization techniques, particularly intracytoplasmic sperm injection, have been effective in this setting. (See 'Management' above.)
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