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 with equal prevalence in males and females [1-5]. Genomic studies analyzing the frequency of defects in 29 causal genes estimate that PCD affects at least 1 in 7,500 people worldwide, doubling the prior epidemiologic estimates . However, even these studies likely underestimate the true disease prevalence, as over 50 genes are now known to cause PCD . By all accounts, most people with PCD remain undiagnosed.
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 "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations" and "Bronchiectasis in children: Clinical manifestations and evaluation" and "Bronchiectasis in children without cystic fibrosis: Management".)
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 [5,8-13]. Different components may be missing or defective in different patients, and different clinical manifestations may develop depending upon the nature of the lesion [14-16].
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 1). 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 — PCD is most often inherited as an autosomal recessive disease (eg, Mendelian inheritance in man [MIN] 244400), although autosomal dominant (FOXJ1-PCD) and X-linked inheritance (PIH1D3-PCD) have been reported [17-20]. More than 50 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) (image 1 and figure 1) [21-30]. 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 [31,32]. 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 [35-39]. 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 [1,42]. 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 .
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 [29,44-46]. 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) [4,47,48]. 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 .
Because the embryonic, nodal cilia can also be defective, body asymmetry occurs randomly so that approximately 50 percent of the patients have situs inversus totalis (image 2) [47,49,50]. When situs inversus, chronic sinusitis, and bronchiectasis occur together, an individual is said to have Kartagener syndrome.
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 [4,24,29,51-53]. Respiratory symptoms complicate the first month of life in 60 percent of patients with PCD . The great majority of adults and children with primary ciliary dyskinesia have a chronic productive cough [55,56]. Recurrent pneumonias are also common and were reported by approximately 75 percent of patients in a PCD registry [54,56]. (See "Bronchiectasis in children: Clinical manifestations and evaluation" 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) include a moderate degree of hyperinflation, peribronchial thickening, atelectasis, mucus plugging or impaction, and bronchiectasis (image 2 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 [61,62]. 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 demonstrated 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 constant, non-seasonal runny nose and year-round nasal congestion may be noted beginning in early childhood [41,64]. 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 with nasal polyposis: Management and prognosis".)
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 2) and ethmoidal sinuses, while the frontal and sphenoid sinuses are less likely affected as they often fail to develop [66-68]. 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 otitis media with effusion (serous otitis media) and recurrent episodes of acute otitis media are common during childhood and adolescence, but these problems become much less frequent following puberty [41,64,67,70]. Conductive hearing loss is common [4,71]. (See "Hearing loss in children: Screening and evaluation" and "Acute otitis media in adults", section on 'Immune dysfunction' and "Acute otitis media in children: Treatment", section on 'Recurrent episode of AOM'.)
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 2). 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. However, most individuals with situs inversus do not have PCD . Isolated situs inversus has a prevalence of about 1 in 10,000 in Scandinavia .
When situs inversus, chronic sinusitis, and bronchiectasis occur together, an individual is said to have Kartagener syndrome, which is a subgroup of primary ciliary dyskinesia that has a prevalence of around 1 in 20,000 to 40,000 individuals . Bronchiectasis may develop in young persons, but it is never present at birth; thus, no individual is born with a fully developed Kartagener 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 [18,74-78]. Impaired function of ependymal cilia that line the ventricles of the brain may be at least partially responsible .
Fertility — Most males with PCD have living but immotile spermatozoa and are infertile, although some have motile spermatozoa but immotile cilia and others are azoospermic [4,80,81]. Female patients with PCD likewise have decreased fertility, with fewer than 50 percent successfully completing pregnancy [2,82]. 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 [83,84]. (See "L-transposition of the great arteries (L-TGA): Anatomy, clinical features, and diagnosis" and "Infantile hypertrophic pyloric stenosis" and "Heterotaxy (isomerism of the atrial appendages): Anatomy, clinical features, and diagnosis".)
Among patients with PCD, the frequencies of pectus excavatum (10 percent) and scoliosis (5 to 10 percent) are increased [4,59,85].
Both aerobic and anaerobic performance are often impaired from early age [62,86,87]. One-third of PCD patients aged 6 to 29 years are reported to exhibit substantially lower aerobic fitness compared with healthy controls .
Concurrence of humoral immunodeficiency (eg, immunoglobulin [Ig] G, IgG subclass, IgM, and IgA) and PCD has been reported in 6 percent of patients with PCD . The mechanism of the association and potential contribution to recurrent sinopulmonary infections have not been fully studied.
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. In the absence of cystic fibrosis or prematurity, a history of neonatal respiratory distress (tachycardia, cough, pneumonia), early onset and persistent cough, chronic nasal congestion and rhinorrhea, chronic otitis media, and a laterality defect (eg, situs inversus or ambiguous) should raise a strong clinical suspicion for PCD . In adults, PCD should be suspected in males with dyskinetic spermatozoa and respiratory symptoms and in females who are infertile or subfertile without other explanation, particularly in the presence of respiratory symptoms.
A number of tests have been employed and each has advantages and disadvantages (table 2) [5,24,64,91,92]. A combination of tests is necessary for accurate diagnosis of PCD, as described in the guidelines published by the European Respiratory Society (algorithm 1) [28,92,93].
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.
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 five years or older with a clinical suspicion of PCD [28,93-102]. In this age group, a threshold of 77 nL/min is the standard cutoff when nNO is measured using exhalation against resistance or breathhold maneuvers [103,104]. Other cutoffs may be appropriate for younger children or measurements during tidal breathing.
Studies supporting this cutoff include:
●In a prospective study of 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 (CF) was noted . An nNO ≥77 nL/minute was determined as a cutoff value that excludes PCD.
●A retrospective study of 301 patients without CF referred for possible PCD also found that the 77nl/min cutoff was near-optimal, with a sensitivity of 92 percent and specificity of 86 percent based on subsequent testing .
Following nNO measurement, confirmatory testing (eg, ultrastructural studies, sweat test, cystic fibrosis and PCD genetic studies) is required 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) and some genotypes with dyskinetic, but motile, cilia are also associated with normal nNO levels, so other testing is needed to make the diagnosis of PCD in these cases [28,107]. On the other hand, nNO may be particularly helpful in atypical PCD phenotypes with normal ciliary ultrastructure, but abnormal function [4,92,108]. (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. It is important to conduct the measurements when there is no recent acute nasal or respiratory infection. To obtain accurate measurements, nNO is measured from the nose during velum closure. Velum closure can be achieved by exhaling against resistance or into a party toy, which reduces dilution from the lower airways [99,100,103,104].
In patients who cannot perform the velum closure maneuver, an alternative approach is to hold their breath with glottis closure and perform a valsalva maneuver. Although this method is somewhat less reliable, it can still provide an acceptable reading.
For real-time feedback of nNO plateaus, it is best to measure nNO by chemiluminescence devices during one of these maneuvers. The nNO production (nL/min) is calculated by multiplying the nNO plateau concentration (in parts per billion) by the sampling flow rate, which varies according to the chemiluminescent analyzer used.
Portable electrochemical analyzers may also be used with similar technique and interpretation, but the results are generally less consistent or reliable, and the equipment has not yet been as well-validated .
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, also called HSVM) 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 and is not sufficiently diagnostic to be used without additional testing (eg, TEM or extended genetic panel testing) [4,93]. 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) [64,111,112]. 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 [4,113]. For equivocal or abnormal results, repeating the ciliary beat frequency and pattern assessment after air-liquid interface culture improves the accuracy of HSVA [28,114]. The clinical usefulness of these tests has increased, as their accuracy in distinguishing between primary and secondary ciliary dyskinesia has improved [92,113,115,116].
●Transmission electron microscopy – TEM analysis is usually performed when the diagnosis is uncertain after high speed video microscopy or genetic testing but may also be performed to identify the type of ciliary abnormality [64,106,117,118]. If a child suspected of PCD is sedated for another reason (eg, tympanostomy, bronchoscopy), a simultaneous brushing or biopsy of nasal or bronchial mucosa is advisable to obtain respiratory cilia for TEM analysis.
TEM can be diagnostic if hallmark ciliary ultrastructural defects are identified (figure 1) . However, TEM can be normal in approximately 20 to 30 percent of patients with PCD, so TEM should not be relied upon as a single diagnostic test [28,118]. An international consensus guideline has defined Class 1 defects (diagnostic of PCD) and Class 2 defects (diagnostic of PCD when accompanied by supporting evidence [eg, HSVA, genetic analysis]) (table 3) . The guideline also describes the features that should be mentioned in a TEM report of ciliary ultrastructure, such as source of the sample, number of cross sections assessed, percentage of abnormal cilia with defects, consistency of defect across several cells, and a one-sentence summary of the specific findings. The parameters of an adequate diagnostic sample (eg, review of more than 50 axonemes with intact membranes in cross section) were also addressed in the guideline.
For electron microscopy, the fresh biopsy is immersed in a glutaraldehyde solution and further processed for ultrastructural investigation. 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 (figure 1). 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 [64,111,113,121]. 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 — In a patient with compatible clinical features, a biallelic (or X-linked) pathogenic mutation in a known PCD gene confirms the diagnosis [28,93,122]. Previously, genetic testing for PCD mutations was reserved for patients with normal or equivocal HSVA and TEM and a strongly suggestive history, due to the limited availability of testing and relatively small number of genes in the standard genetic panel (≤12 genes) [28,123]. However, the role of genetic testing for PCD diagnosis is evolving with the increasing availability of extended panel tests and/or whole exome sequencing [93,124]. The 2018 American Thoracic Society as well as the European Respiratory Society guidelines advise use of extended panel genetic testing over TEM ciliary testing and/or standard genetic panel testing for PCD diagnosis [28,93,122]. (See "Genetic testing" and 'Ciliary motion and ultrastructure' above.)
Evidence in support of extended panel testing comes from studies that show increasing diagnostic sensitivity as the number of analyzed PCD genes increases [44,93,125,126]. As an example, among 205 children (age 0 to 18 years) who were thought to have definite PCD, a standard genetic panel identified 138 pathogenic variants, while an extended panel identified 26 additional genetic variants . Approximately 35 percent of participants with "definite PCD" had pathogenic mutations in DNAH5 or DNAI1 . Even extended panel testing has limitations; in this study, testing did not find genetic variants in 41 participants with "definite" PCD.
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 [127-129]. 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, called nasal mucociliary clearance (NMCC), 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 [130,131]. However, as mentioned above, these methods are associated with major disadvantages. A "positive" test result (NMCC <60 minutes) is considered as inconsistent with PCD while a "negative" test result (NMCC >60 minutes) 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 [4,64,134].
Pneumonia without obvious bronchiectasis — Infections in the lower respiratory tract need to be treated promptly to delay the development of bronchiectasis, which occurs in most patients with PCD. Based on our clinical experience, we follow an approach similar to that used in patients with cystic fibrosis (see "Cystic fibrosis: Management of pulmonary exacerbations"):
●Review the most recent sputum cultures and history of antibiotic use; obtain a new sputum sample for culture.
●Initiate antibiotic treatment in patients with suspected pneumonia even when symptoms are mild, such as a sudden increase in the amount of colored sputum combined with a low fever.
●Select empiric antibiotics that have activity against the pathogenic bacteria identified in the patient's most recent sputum cultures. The duration of antibiotics is generally 10 to 14 days.
●Airway clearance therapy is typically intensified during treatment for pneumonia. (See 'Bronchiectasis' below.)
●Assess for clinical improvement within approximately four to five days of starting treatment. If not improving, and a bacterial infection is still likely, adjust the antibiotic regimen. Choose a new regimen either empirically or by adjusting the regimen if new culture results reveal a bacteria species not covered by the initial regimen.
Bronchiectasis — Clearing secretions and reducing the microbial load with selective use of antibiotics form the cornerstone of preventive therapy for PCD-related bronchiectasis as with bronchiectasis from other causes.
●Airway clearance therapy – Daily chest physiotherapy is important in compensating for diminished or absent mucociliary clearance, and a number of airway clearance techniques are available, as described separately. (See "Bronchiectasis in children without cystic fibrosis: Management", section on 'Airway clearance therapy' and "Bronchiectasis in adults: Maintaining lung health", section on 'Airway clearance therapy'.)
The effectiveness of airway hydration (eg, nebulized hypertonic saline [7 percent]) has not been fully assessed in PCD [64,135,136]. However, based on clinical experience and studies in noncystic fibrosis bronchiectasis, we typically add hypertonic saline twice daily to the routine airway clearance program in patients with recurrent respiratory infections or ongoing moderate or severe respiratory symptoms [137-140]. Inhaled bronchodilator is given prior to each treatment. The administration of hypertonic saline is described separately. (See "Bronchiectasis in children without cystic fibrosis: Management", section on 'Inhaled airway hydrating agents and mucolytics' and "Bronchiectasis in adults: Maintaining lung health", section on 'Mucolytic agents and airway hydration'.)
●Acute exacerbations – 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 "Bronchiectasis in children without cystic fibrosis: Management" and "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)
●Recurrent exacerbations – For patients with recurrent exacerbations who are ≥7 years of age, preventive antibiotic therapy (usually with a macrolide) may reduce the rate of exacerbations. Azithromycin preventive therapy has shown benefit in cystic fibrosis and noncystic fibrosis bronchiectasis. In addition, a multinational randomized trial (BESTCILIA) in 90 participants with PCD (age 7 to 50 years) demonstrated that azithromycin maintenance therapy (250 mg for <40 kg; 500 mg for ≥40 kg) three times a week for six months was well tolerated and halved the rate of respiratory exacerbations (rate ratio 0.45; 95% CI 0.26-0.78) .
Alternatively, it is reasonable to defer initiation of azithromycin and observe for additional exacerbations. Prior to initiating long-term antibiotic therapy, sputum cultures should be checked to exclude nontuberculous mycobacteria infection and patients should be assessed for risk of QT interval prolongation (eg, family history, other medications). The optimal duration of therapy is not known; it is reasonable to re-evaluate after six months. The potential benefits of chronic antibiotics in these patients must be balanced against the risk of developing antibiotic resistance. Referral to a specialist center is advisable in this situation. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Macrolides'.)
For patients with recurrent exacerbations and Pseudomonas aeruginosa in their sputum, a therapeutic trial of inhaled antipseudomonal antibiotics (eg, tobramycin) is reasonable alone or in combination with a course of an antipseudomonal antibiotic aimed at early eradication. In one study of 31 children with PCD and new Pseudomonas aeruginosa infection, 97 percent achieved negative culture results, and 70 percent had prolonged (one year) pseudomonas eradication after treatment with inhaled tobramycin followed by intravenous therapy for persistent culture positivity . Inhaled antibiotic therapy is discussed separately. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Inhaled antibiotics' and "Bronchiectasis in children without cystic fibrosis: Management", section on 'Chronic antibiotics'.)
●Supportive care – Age and season-appropriate vaccination against influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19), and pneumococcus is advisable. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups' and "COVID-19: Vaccines" and "Pneumococcal vaccination in children".)
Smoking causes a more rapid deterioration in lung function, and counseling regarding abstinence from smoking is essential. (See "Overview of smoking cessation management in adults".)
●Advanced disease – 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 . For patients with advanced respiratory insufficiency, bilateral lung transplantation is preferred to single lung transplantation similar to bronchiectasis from other causes, although heart-lung transplantation or a modified surgical procedure is required in patients with situs inversus [144-146]. (See "Lung transplantation: General guidelines for recipient selection" and "Heart-lung transplantation in adults".)
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 with nasal polyposis: Management and prognosis".)
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, as described separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Surgical management' and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
Otitis media with effusion — Chronic otitis media with effusion (OME) is common in children and adolescents with PCD (>80 percent) and can lead to hearing loss [137,147]. While the value of pressure equalization tubes (PET, also called tympanostomy tubes) in chronic OME has been questioned [64,70,148], consensus guidelines from the PCD Foundation advise use of PET in patients with hearing deficits or speech delay because of the persistent nature of OME in these patients [137,149,150]. PET appear to improve hearing with normalization in 80 to 100 percent of patients, at least temporarily [137,150,151]. The general management of OME and the decision about PET placement are discussed in greater detail separately. (See "Otitis media with effusion (serous otitis media) in children: Management", section on 'Tympanostomy tubes'.)
Conductive hearing loss and potential associated speech delays should be assessed regularly and hearing aids prescribed as required [70,137]. (See "Hearing loss in children: Screening and evaluation".)
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 "Approach to the male with infertility" and "Treatments for 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 "Female infertility: Evaluation".)
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 at this time to be a sensitive test of airway disease in advanced PCD .
Chest radiographs are relatively insensitive measures of bronchiectasis but may be helpful to evaluate changes in respiratory symptoms when compared with previous examinations. Longitudinal decreases in nasal nitric oxide levels, but not fractional exhaled nitric oxide levels, appear to correlate with lung function decline and increased risk of infections in some high-risk genotypes .
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 an 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 [16,61]. However, repeated or chronic infections, eg, sinusitis, may be tiresome and influence the ability to work full time. Moreover, the overall prognosis may relate to the specific gene and/or associated ultrastructural defect .
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.
Other studies have assessed clinical course in children and young adults to determine risk factors for more severe disease. In one multinational retrospective cohort of 486 patients between the ages of 6 and 24 years, there was a trend towards decreased lung function over time (FEV1 z-score change of -0.07 per year), but there was a large amount of heterogeneity in disease course between countries and between individuals . Higher BMI was associated with better baseline lung function and less decline. Different ultrastructural defects were associated with low baseline FEV1 levels versus longitudinal worsening, with combined outer and inner dynein arm defects showing the highest rate of FEV1 decline. In a separate prospective five-year study of 137 patients with PCD (age ≤19 years), those with variants leading to absent inner dynein arm, central apparatus defects, and microtubular disorganization, including individuals with CCDC39 and CCDC40 mutations, had lower growth indices and worse lung function compared with participants with outer dynein arm defects and DNAH5 mutations .
ADDITIONAL RESOURCES — An international registry for patients with PCD has been established .
Additional information for patients and families can be found on the PCD Foundation website.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary ciliary dyskinesia" and "Society guideline links: Bronchiectasis".)
SUMMARY AND RECOMMENDATIONS
●Definition – 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 2). (See 'Introduction' above.)
●Genetics – The inheritance pattern of PCD is autosomal recessive in most cases. 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.)
●Diagnostic evaluation – A combination of tests is necessary for accurate diagnosis of PCD (algorithm 1). A history of neonatal respiratory distress, early onset and persistent productive cough, chronic nasal congestion and rhinorrhea, chronic otitis media, and/or a laterality defect (eg, situs inversus or ambiguous) should raise a strong clinical suspicion for PCD in the absence of cystic fibrosis or prematurity (table 1).
Measuring the production of nasal nitric oxide (nNO) is a useful method to screen patients age five years or older with a clinical suspicion of PCD. Mucociliary clearance, another screening test, is not standardized, and the saccharin clearance time is not reliable. Semen analysis is an option in adult males. At present, none of these tests is diagnostic, so a confirmatory test is necessary. (See 'Diagnostic evaluation' above.)
●Definitive diagnosis – Definitive diagnosis is usually based on identification of ciliary abnormalities on high speed videomicroscopy analysis (HSVA) or transmission electron microscopy (TEM). These tests require nasal or bronchial biopsy and are only available at specialized centers with expertise in these tests. (See 'Diagnostic evaluation' above.)
•If HSVA is abnormal or equivocal, TEM is used to visualize specific defects, such as absence of dynein arms or radial spokes and absent, or additional, microtubule assemblies (table 3). (See 'Ciliary motion and ultrastructure' above.)
•Genetic testing has an increasing role in PCD diagnosis, particularly when extended panel testing (>12 genes) is available. (See 'Genetic testing' above.)
●Reducing respiratory infections – Interventions to improve secretion clearance and reduce respiratory infections include daily chest physiotherapy and prompt treatment of respiratory infections.
•For patients with recurrent respiratory infections or ongoing moderate or severe respiratory symptoms, we suggest regular use of nebulized (hypertonic) saline (Grade 2C). Treatments are given twice daily before airway clearance techniques; inhaled bronchodilator is administered prior to nebulized saline. A role for mucolytic drugs has not been established. (See 'Management' above and "Bronchiectasis in children without cystic fibrosis: Management" and "Bronchiectasis in adults: Maintaining lung health".)
•For patients 7 years of age and older with frequent exacerbations of bronchiectasis (eg, requiring antibiotics for at least 30 days in prior two years), we suggest azithromycin maintenance therapy (250 mg for <40 kg or 500 mg for ≥40 kg, three times a week) (Grade 2B). Alternatively, for patients with less severe baseline bronchiectasis, it is reasonable to observe and provide antibiotics as needed for flares of bronchiectasis. Infection with nontuberculous mycobacteria should be excluded prior to initiating azithromycin. (See 'Bronchiectasis' above.)
●Associated problems – Patients with PCD often have chronic otitis media with effusion (OME), recurrent episodes of acute otitis media, and concomitant hearing loss. The placement of pressure equalization tubes (PET, also called tympanostomy tubes) is often appropriate in patients with hearing loss and/or speech delay due to chronic OME and is discussed in detail separately. (See 'Otitis media with effusion' above and "Otitis media with effusion (serous otitis media) in children: Management", section on 'Tympanostomy tubes'.)
Rhinosinusitis is a cardinal feature of PCD, occurring in almost 100 percent of affected individuals, often with associated nasal polyposis; the management follows standard practices for chronic rhinosinusitis with nasal polyposis. (See 'Management' above.)
Because ciliary immotility (or dysmotility) is commonly associated with abnormal sperm motility, male patients should be informed about possible infertility and offered semen analysis. Female patients with PCD may also have reduced fertility. In vitro fertilization techniques, particularly intracytoplasmic sperm injection, have been effective in this setting. (See 'Management' above.)
●Supportive care – Smoking causes a more rapid deterioration in lung function, and counseling regarding abstinence from smoking is essential. Age and season-appropriate vaccination against influenza and pneumococcus is advised. (See 'Management' above.)
●Natural history – 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. (See 'Management' above.)
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