Primary ciliary dyskinesia (PCD) also known as immobile cilia syndrome, is an autosomal recessive disease with extensive genetic heterogeneity characterized by abnormal ciliary motion and impaired mucociliary clearance. Ultrastructural and functional defects of cilia result in the lack of effective ciliary motility, causing abnormal mucociliary clearance. This leads to recurrent or persistent respiratory infections, early-onset chronic obstructive pulmonary disease, sinusitis, otitis media, and male infertility.
Approximately 50% of patients with PCD will have situs inversus, resulting in Kartagener's syndrome (KS). Siewert first described the combination of situs inversus, chronic sinusitis, and bronchiectasis in 1904. However, Manes Kartagener recognized this clinical triad as a distinct congenital syndrome in 1933. Because Kartagener described this syndrome in detail, it bears his name.[1]
Diagnosis is often difficult and may not be confirmed for several years after the onset of symptoms or even in adulthood. In a comparative study performed by Sommer et al, 70% of patients were seen by a physician more than 50 times before the diagnosis was made at an average age of 10-14 years, although accompanying situs inversus did correlate with significantly earlier diagnosis.[2] Although respiratory signs are present in all patients, the symptoms are nonspecific, and there is no accepted gold standard for the diagnosis of PCD or KS.[3] Diagnostic guidelines for the US, Europe and Japan vary in their recommended approaches and accepted criteria, although they all concur that diagnosis requires multiple tests.[4, 5, 6]
There are no PCD-specific approved therapies that restore ciliary function, and treatment is based on treatments used for cystic fibrosis and non-CF bronchiectasis.[7] Aggressive management of infections with antibiotic therapy and disease prevention with routine vaccination (ie., pertussis, measles, Haemophilus influenzae type b, influenza, and pneumococcus) is needed to preserve lung health and minimize complications.[3] Surgical treatments such as lobectomy and lung or heart-lung transplantation are reserved for severe cases of bronchiectasis or end stage respiratory failure.[8]
Camner and coworkers[9] first suggested ciliary dyskinesia as the cause of Kartagener syndrome in 1975. They described two patients with Kartagener syndrome who had immotile cilia and immotile spermatozoa. These patients had poor mucociliary clearance because the cilia that lined their upper airways were not functioning.
Later, Afzelius[10] discovered that bronchial mucosal biopsy specimens from patients with similar respiratory complaints showed cilia that appeared abnormal and were poorly mobile. In 1977, Eliasson and coworkers[11] used the descriptive phrase “immotile cilia syndrome” to characterize male patients with sterility and chronic respiratory infections.
In 1981, Rossman and coworkers[12] coined the term primary ciliary dyskinesia (PCD) because some patients with Kartagener syndrome had cilia that were not immobile but exhibited an uncoordinated and inefficient movement pattern. Current nomenclature classifies all congenital ciliary disorders as primary ciliary dyskinesias in order to differentiate them from acquired types. Kartagener syndrome is part of the larger group of disorders referred to as primary ciliary dyskinesias.
Approximately one half of patients with primary ciliary dyskinesia have situs inversus and, thus, are classified as having Kartagener syndrome. Afzelius proposed that normal ciliary beating is necessary for visceral rotation during embryonic development. In patients with primary ciliary dyskinesia, organ rotation occurs as a random event; therefore, half the patients have situs inversus and the other half have normal situs.
Ciliated epithelium covers most areas of the upper respiratory tract, including the nasal mucosa, paranasal sinuses, middle ear, eustachian tube, and pharynx. The lower respiratory tract contains ciliated epithelium from the trachea to the respiratory bronchioles. Each ciliated cell gives rise to approximately 200 cilia that vary in length from 5-6 μm and decrease in size to 1-3 μm as the airway becomes smaller.
The typical ciliary axoneme consists of two central microtubules surrounded by 9 microtubular doublets. Each doublet has an A subunit and a B subunit attached as a semicircle. A central sheath envelops the two central microtubules, which attach to the outer doublets by radial spokes.
The outer doublets are interconnected by nexin links, and each A subunit is attached to two dynein arms that contain adenosine triphosphatase; one inner arm and one outer arm. The primary function of the central sheath, radial spokes, and nexin links is to maintain the structural integrity of the cilium, whereas the dynein arms are responsible for ciliary motion.
The cilium is anchored at its base by cytoplasmic microtubules and a basal body comprised of a basal foot and rootlet. The orientation of the basal foot indicates the direction of the effective cilial stroke. Just above the base, the cilium is composed of microtubular triplets (previously doublets) without associated structures, but at the tip, only the B subunits remain.
Cilia propel overlying mucus via a two-part ciliary beat cycle. First, the power stroke occurs when a fully extended cilium moves perpendicular to the cell surface in an arclike manner. Then, the recovery stroke follows, in which the entire cilium bends and returns to its starting point near the cell surface. Once a cilium starts to move, the complete beat cycle is obligatory.
The cycle is mediated by dynein arms from the A subunit that attach to the B subunit of the adjacent microtubule. Adenosine triphosphate is hydrolyzed by the dynein arms and the 9 microtubule doublets as they slide against each other.
Patients with primary ciliary dyskinesia exhibit a wide range of defects in ciliary ultrastructure and motility, which ultimately impairs ciliary beating and mucociliary clearance. The most common defect, first described by Afzelius, is a reduction in the number of dynein arms, which decreases the ciliary beat frequency. The image below illustrates missing dynein arms in Kartagener syndrome.
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Normal cilia (A) compared with cilia in Kartagener syndrome with missing dynein arms (B). Image courtesy of Wikimedia Commons.
Sturgess et al[13] described how the radial spoke, which serves to translate outer microtubular sliding into cilial bending, was absent in some patients with primary ciliary dyskinesia. Cilia in other patients lacked central tubules; however, instead of the central tubules, an outer microtubular doublet transposed to the cell of the axoneme was present that displayed an abnormal 8+1 doublet-to-tubule pattern. Both the radial spoke and the transposed doublet defects impaired mucociliary clearance.
Other ciliary defects include an abnormal basal cell apparatus with giant roots and double feet, cilia lacking all internal microtubular structures, and even cilia twice the normal length that beat in an uncoordinated undulating fashion. Pedersen[14] compared the type of ultrastructural defect to ciliary motility and found that dynein defects caused hypomotility and microtubular defects caused asynchrony. He also found that normal ciliary ultrastructure occasionally was associated with hypermotility or inefficient ciliary trembling.
Some patients with clinical features of primary ciliary dyskinesia have a ciliary ultrastructure that appears normal, but their arrangement and beat direction is disoriented, which causes inefficient mucociliary transport. These findings illustrate the importance of analyzing ciliary motility and ultrastructure when considering a diagnosis of primary ciliary dyskinesia.
Primary ciliary dyskinesia tissues have also been characterized by impaired chloride ion transport currents. This impaired current has been shown to persist even after application of a cAMP-elevating agonist.[15]
The cause of primary ciliary dyskinesia is genetic with a primarily autosomal recessive inheritance pattern. However, exceptions to this rule have been identified, including x-linked inheritance of gene PIH1D3 and autosomal dominant inheritance of mutations in gene FOXJ1.[16] More than 50 genes have been associated with PCD.[3] Genome analysis has found primary ciliary dyskinesia to be genetically heterogenous. Genes DNAH5 and DNA11 on bands 5p15.1 and 9p13,3 respectively, are known to cause primary ciliary dyskinesia. Both genes encode for dynein.[17] There are more than 200 genes, however, that are predicted to be involved in cilia biology and may play a role in primary ciliary dyskinesia and other ciliopathies.[18]
Recently a gene protein, CCDC40, has been characterized as playing an essential role in correct left-right patterning in mouse, zebrafish, and humans. In mouse and zebrafish, CCDC40 is expressed in tissues that contain motile cilia. Mutations in this protein result in cilia with reduced ranges of motility and likely result in a variant of primary ciliary dyskinesia characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes.[19]
Onoufriadis et al have described loss-of-function mutations in CCDC114 as causing primary ciliary dyskinesia with laterality malformations. The result of these mutations is a loss of the outer dynein arms. Fertility is apparently not greatly affected by CCDC114 deficiency.[20]
Adenylate kinase type 7 (AK7), the mediator of the reaction of ADP to ATP and AMP, is also diminished significantly in patients with primary ciliary dyskinesia compared with healthy controls. AK7 expression has also been correlated with ciliary beat frequency in this patient population.[21]
Table. Mutations in the Genes that Cause Human Primary Ciliary Dyskinesia[22]
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See Table
MIM number is from the Online Mendelian Inheritance in Man Web site, which is a continuously updated catalog of human genes, genetic disorders, and traits, with particular focus on the molecular relationship between genetic variation and phenotype expression.
The frequency of Kartagener syndrome is 1 case per 10,000-20,000 live births. Situs inversus occurs randomly in half the patients with primary ciliary dyskinesia; therefore, for every patient with Kartagener syndrome, another patient has primary ciliary dyskinesia but not situs inversus.
International frequency
A genetic database analysis by Hannah et al estimated that the overall minimum global prevalence of PCD is at least 1 in 7554 persons. The expected frequency of PCD is higher in persons of African ancestry than in most other populations with a prevalence of 1 in 9906 persons.[23]
Sex
No sex predilection exists.
Age
Clinical manifestations of chronic sinusitis, bronchitis, and bronchiectasis are more severe during the first decade of life but remit somewhat by the end of adolescence.
Chronic childhood infections can be very debilitating, but the range and severity of clinical symptoms is wide. In severe cases, the prognosis can be fatal if bilateral lung transplantation is delayed.[24] Fortunately, primary ciliary dyskinesia and Kartagener syndrome usually become less problematic near the end of the patient's second decade, and many patients have near normal adult lives. The prognosis of patients with Kartagener syndrome was outlined in a longitudinal study, which measured long-term outcomes and pulmonary function test results. Tests were conducted on an interval basis in a cohort of 74 patients. The study found that patients are at risk for decreased pulmonary function. The study did not come to a firm conclusion on age correlation with lung deterioration or disease progression.[25] However, cross-sectional data suggest that spirometry worsens in patients over time.
Clinical manifestations include chronic upper and lower respiratory tract disease resulting from ineffective mucociliary clearance. Males demonstrate infertility secondary to immotile spermatozoa.
Upper airway
Patients may exhibit chronic, thick, mucoid rhinorrhea from early in childhood. Examination usually reveals pale and swollen nasal mucosa, mucopurulent secretions, and an impaired sense of smell. Nasal polyps are noted in 30% of affected individuals.
Sinonasal disease in primary ciliary dyskinesia has been poorly studied; however, these patients often have recurrent chronic sinusitis with sinus pressure headaches in the maxillary and periorbital regions. Sinus radiographs (which largely have been supplanted by CT scans) typically demonstrate mucosal thickening, opacified sinus cavities, and aplastic or hypoplastic frontal and/or sphenoid sinuses.[26] Symptoms usually improve with antibiotic therapy but have a propensity for rapid recurrence. It appears that patients with chronic rhinosinusitis (CRS) may benefit from long-term macrolide therapy and endoscopic sinus surgery (ESS) in recalcitrant disease. Therapies targeted at improving mucociliary clearance have not been tested specifically in primary ciliary dyskinesia.[27] It has been shown that up to 59% of patients have recurring episodes of sinusitis and 69% of these patients require surgical intervention.[2]
Recurrent otitis media is a common manifestation of primary ciliary dyskinesia. Examination may reveal a retracted tympanic membrane with poor or absent mobility and a middle-ear effusion. Further testing usually demonstrates a flat tympanogram and bilateral conductive hearing loss secondary to thick middle-ear effusion. Many patients undergo repeated tympanostomy tube insertion, often complicated by chronic suppurative otitis media. Campbell et al found that ventilation tube insertion improves hearing in primary ciliary dyskinesia, but may lead to a higher rate of otorrhea when compared with the general population.[27] Other associated otologic disorders may include tympanosclerosis, cholesteatoma, and keratosis obturans.
Lower respiratory tract
Chronic bronchitis, recurrent pneumonia, and bronchiectasis are common conditions associated with primary ciliary dyskinesia. Patients presenting with bronchiectasis should be evaluated for Kartagener syndrome. Bronchiectasis usually occurs in the lower lobes in patients with Kartagener syndrome, while patients with cystic fibrosis have bronchiectasis predominantly in the upper lobes.
Chest radiographs may illustrate bronchial wall thickening (earliest manifestation), hyperinflation, atelectasis, bronchiectasis, and situs inversus (in 50% of patients with primary ciliary dyskinesia). High-resolution CT (HRCT) scanning, spirometry, and plethysmography may also be performed. Pifferi et al found that plethysmography better predicted HRCT abnormalities than spirometry by allowing recognition of different severities of focal air trapping, atelectasis, and extent of bronchiectasis in patients with primary ciliary dyskinesia.[28] Whether it might be a useful test to define populations of patients with primary ciliary dyskinesia who should or should not have HRCT scans requires further longitudinal studies. Magnin et al evaluated the longitudinal relationships between lung function tests (LFTs) and chest HRCT in children with primary ciliary dyskinesia and found significant correlation. It is possible that lung function follow-up can be used to reduce CT frequency to help minimize the radiation exposure in these children.[29]
Obstructive lung disease may be another component of Kartagener syndrome symptomatology. It probably results from elevated levels of local inflammatory mediators in a chronically irritated airway.
Other features
Other features include digital clubbing, male infertility, and diminished female fertility. Primary ciliary dyskinesia has been associated with esophageal problems and congenital cardiac abnormalities.
Patients commonly present with chronic upper and lower respiratory tract infections resulting from an ineffective mucociliary mechanism. Patients present initially in the neonatal period, suggestive of ineffective ciliary motion needed to clear fetal lung fluid. As many as 80% of newborn babies with primary ciliary dyskinesia develop respiratory distress in the first 12-24 hours of life.[30]
When taking a history, pertinent findings include chronic wet cough with unexplained respiratory distress. This cough is described as wet and productive, found in nearly 100% of infants.[22] Coupled with improper drainage of the sinonasal system, this leads to congestion, rhinorrhea, and chronic middle ear effusions with possible purulent otorrhea.
Some male patients present later in life with sterility due to immotile spermatozoa. Females may have a higher rate of ectopic pregnancy.
Lastly, situs inversus abnormalities on imaging are relatively specific for Kartagener syndrome.[31]
Primary ciliary dyskinesia is characterized by the clinical triad of chronic sinusitis, bronchiectasis, and situs inversus. The majority of patients are seen by a physician more than 50 times before the diagnosis is made at an average age of 10-14 years.[2]
Upper airway
Patients may exhibit chronic, thick, mucoid rhinorrhea from early in childhood. Examination usually reveals pale and swollen nasal mucosa, mucopurulent secretions, and an impaired sense of smell. Nasal polyps are recognized in 30% of affected individuals.[32]
The recurrent chronic pansinusitis typically produces sinus pressure headaches in the maxillary and periorbital region. Symptoms usually improve with antibiotic therapy but have a propensity for rapid recurrence.[32]
Recurrent otitis media is a common manifestation of primary ciliary dyskinesia. Examination may reveal a retracted tympanic membrane with poor or absent mobility and a middle-ear effusion. Other associated otologic disorders may include tympanosclerosis, cholesteatoma, and keratosis obturans.[32]
Middle ear symptoms in primary ciliary dyskinesia (PCD) patients tend to remain severe throughout childhood, with improvement only after age 18 years, and, in a recent study, grommet tympanostomy tube placement did not improve the middle ear condition. In this study, half the patients with a history of grommet placement eventually developed tympanic perforation, which is much more frequent than in the general pediatric population. These patients, therefore, should be closely followed and a specific treatment approach may be required, especially in the treatment of persistent middle ear effusion, as repeated grommet placement can predispose patients to chronic otitis and worsen the long-term prognosis.[33]
Lower respiratory tract
Chronic bronchitis, recurrent pneumonia, and bronchiectasis are common conditions in patients with primary ciliary dyskinesia and are often caused by pseudomonal infection.[24] Thus, upon physical examination of the patient's chest, increased tactile fremitus, rhonchi, crackles, and, occasionally, wheezes may be present.
Obstructive lung disease may be another component of Kartagener syndrome symptomatology. It probably results from elevated levels of local inflammatory mediators in a chronically irritated airway. Although, wheezing may occur, the lung examination may be normal during intercurrent periods when the airway is not actively inflamed.
Other features
Cardiovascular examination of a patient with primary ciliary dyskinesia demonstrates a point of maximal impulse, and the heart sounds are heard best on the right side of the chest.
Extremities may exhibit digital clubbing.
Chest wall abnormalities, such as pectus excavatum, may be seen.
Interstitial lung diseases, including idiopathic pulmonary fibrosis
Malignancy
Postinfectious bronchiectasis
Pulmonary sequestration
Samter triad
Severe atopy
Tracheobronchomegaly
Tumor
Yellow nail syndrome
Laboratory Studies
The initial diagnostic workup is started after suggestive findings are encountered during the history and physical examination. Diagnosis requires a combination of clinical features and supportive objective data. Multiple lab tests are often required to definitively diagnose PCD.
The only standardized definitive diagnostic tool is electron microscopy, which is used to visualize ciliary ultrastructure. The sample of these respiratory cilia is obtained from a nasal scrape or brush biopsy. Some research centers use high-speed videomicroscopy to observe ciliary beats.[31] Electron microscopy may positively identify up to 70% of PCD patients; however, in centers with lower volume or less experience interpreting electron microscopy, this number may be less. Biopsies should be obtained at least 2 weeks after acute illness in order to represent the patient's true ciliary function baseline [34]
Multiple other diagnostic tests have emerged, but none has been fully standardized. These include nasal nitric oxide measurement, functional ciliary beat analysis with high speech videomicroscopy, and immunofluorescent analysis. The stimulation tests should be conducted when patients are at a stable respiratory baseline, owing to the altered motility during illness.
Semen analysis in postpubescent males may reveal abnormal sperm motility and ultrastructure.
All of these novel diagnostic tools have caused a large expansion into the field of genetic testing and isolation of Kartagener syndrome mutations. Multiple recent studies have focused on identification of new genes related to Kartagener syndrome. New disease-causing mutations are being identified at a rapid pace, and as more genes are identified, the utility of genetic testing increases. Genetic testing is now recommended when clinical features suggest a diagnosis of PCD.[4, 5] Currently, genetic panels are able to reliably identify genetic variants in 50% of PCD cases.[34] It has been posited that in the near future, more than 80% of patients will be able to be identified by genetic testing.[35]
Sinus radiographs (which largely have been supplanted by CT scans) typically demonstrate mucosal thickening, opacified sinus cavities, and hypoplastic frontal and/or sphenoid sinuses.[26]
Chest radiographs may illustrate bronchial wall thickening as an early manifestation of chronic infection, hyperinflation, atelectasis, bronchiectasis, and situs inversus (in 50% of patients with primary ciliary dyskinesia). The presence of situs inversus strongly suggests Kartagener syndrome (KS).[36]
Bronchiectasis occurs in the lower lobes in patients with Kartagener syndrome and immunoglobulin deficiency, while bronchiectasis predominantly occurs in the upper lobes of patients with cystic fibrosis.
High-resolution CT scan of the chest is the most sensitive modality for documenting early and subtle abnormalities within airways and pulmonary parenchyma when compared to routine chest radiographs. Consideration should be given to this imaging technique early in the presentation of primary ciliary dyskinesia (PCD) syndromes, when a chest radiograph may not be sensitive enough to identify disease processes or when another differential is being considered. See the images below.
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Axial CT image showing dextrocardia and situs inversus in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
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Axial CT image showing situs inversus (liver and inferior vena cava on the left, spleen and aorta on the right) in a patient with Kartagener syndrome.....
Nitric oxide: Measuring exhaled nasal nitric oxide, which is mostly reduced in primary ciliary dyskinesia, is a good screening test for immotile-cilia syndrome with a good negative predictive value.[24] This study is generally more reliable in children older than 5 years and in adults, as they are more likely to cooperate with actions required in testing.[30] Studies have demonstrated a relationship between nasal nitric oxide levels, nasal oxide synthase mRNA expression, and ciliary beat frequency.[37] There is also a significant inverse correlation between the degree of aplasia and/or hypoplasia of the paranasal sinus and nasal nitric oxide values in primary ciliary dyskinesia patients.[26]
Functional ciliary beat/waveform analysis with high speed videomicroscopy: Using high-speed videomicroscopy, ciliary beat pattern can be analyzed for abnormal function. [38] Analysis of ciliary beat pattern requires extensive experience. While several centers in Europe regularly utilize this testing, there are no centers in the United States where this testing is performed with reliable frequency and results. [34]
Immunofluorescence testing for ciliary proteins: Immunofluorescence (IF) testing can be used identify dysfunctional cilia and is less difficulty to perform and interpret compared to gold-standard electron microscopy. In a study that compared IF testing with electron microscopy, both were found to be equivalent in identifying outer dynein arm defects. [39] Immunofluorescence is posited to be less affected by factors impacting ciliary function and as such may have more accurate results in a patient with acute or recurrent illness.
Audiologic testing usually demonstrates a flat tympanogram and bilateral conductive hearing loss secondary to thick middle-ear effusion.
Pulmonary function studies are as follows:
Spirometry often reveals an obstructive ventilatory defect with decreases in the ratio of forced expired volume in 1 second to forced vital capacity, reduced forced expired volume in 1 second, and a reduced forced expiratory flow of 25-75%.
Static lung volumes also may demonstrate hyperinflation.
The response to bronchodilators is variable in patients with primary ciliary dyskinesia
Older tests no longer recommended for diagnostic workup of PCD are as follows:
Nasal saccharin testing: Saccharin or another substance is placed in the nose, and the speed of transport into the nasopharynx is measured to calculate mucociliary clearance (used infrequently because of awkwardness and dubious reliability - high rate of false-positive and false-negative results).
Pulmonary radioaerosol mucociliary clearance: Mucociliary transport, which is reduced in these patients, can be measured in situ by administering an inhalation aerosol of colloid albumin or colloid sulfur tagged with technetium Tc 99. This test is generally not recommended owing to the high rate of false-positive results.[24, 40]
Ciliary beat frequency calculation
Visual assessment of ciliary motion with high speed recording devices
For mucosal biopsy, the specimen should come from ciliated epithelium, preferably when the patient is not acutely ill. Infectious processes can alter cilia and cause secondary ciliary dyskinesia, even in a healthy host. Tracheal biopsies require general anesthesia but provide excellent specimens. Nasal mucosa is more readily available. Although nasal brushing is least invasive, it frequently yields an inadequate specimen. Children with suspected primary ciliary dyskinesia often require an adenoidectomy. Because adenoid tissue has a ciliated surface, adequate material is available for histopathologic and electron microscope examination. Knowledge of this fact should eliminate the need for other invasive biopsies.
Nasal endoscopy is a sensitive indicator for nasal polyposis.
The mucosal biopsy specimen should be examined for ciliary movement using light microscopy. Light microscopic quantitation of ciliary beat frequency, coordination, and amplitude, although available in very few medical centers, can identify ciliary dyskinesia in patients with normal ultrastructure. Light microscopy alone offers a reliable and simple method of excluding primary ciliary dyskinesia, but light microscopy and electron microscopy in combination provide a higher degree of accuracy.
A ciliary beat frequency(CBF) of less than 11 beats per second (< 11 Hz) has been suggested as a cutoff value for patients to proceed to electron microscopy(EM).[38] However, CBF as a laboratory screening test to determine which patients should undergo EM results in a number of patients with primary ciliary dyskinesia being missed. The use of beat-pattern analysis appears to be a more sensitive and specific test, with higher positive and negative predictive values.[38]
Quantitative diagnostic criteria do not exist for EM; however, ciliary ultrastructure is examined qualitatively for abnormalities in dynein arms (inner and outer), radial spokes, central sheaths, nexin links, and ciliary transposition and orientation. The most common ultrastructural defect is an absence or decrease in the number of inner or outer dynein arms. A radial spoke deficiency commonly appears with a dynein arm deficiency. Other ultrastructural abnormalities with nexin links, central sheaths, and ciliary transposition and orientation are considered nonspecific for primary ciliary dyskinesia because they can occur in healthy people and as a consequence of recurrent respiratory infections.
Electron microscopic diagnosis of ciliary ultrastructure is expensive, time consuming, and described by some experts as inadequate. Patients with Kartagener syndrome also may have normal ultrastructure, which decreases the sensitivity of electron microscopy.[41, 42]
Efforts have been undertaken to standardize the clinical criteria for the diagnosis of Kartagener syndrome. These criteria include dextrocardia, a ciliary beat frequency of less than 10 Hz/s, and a mean cross-section dynein arm count of less than two. If the patient does not have dextrocardia, primary ciliary dyskinesia presents a much greater diagnostic challenge. Genetic testing ultimately may become the principal means of establishing this diagnosis.
Kartagener syndrome represents a wide array of patients along the clinical spectrum; accordingly, management must be tailored towards each individual patient. Continuous clinical follow up is one of the best means of providing this type of individualized care.
Medical management
Prevention of dwindling pulmonary function is the primary end goal of clinical treatment. Because of the paucity of randomized control trials involving patients with Kartagener syndrome, no firm guidelines exist for management and most of those currently used are modified from prior cystic fibrosis studies.
Barbot et al compiled existing evidence to formulate general clinical recommendations. They include patients having at least biannual clinical visits, which would involve routine spirometry, sputum culture, and, if needed, imaging studies. It was found that antibiotic treatment was effective for exacerbations.[43]
Antibiotics, intravenous or oral and continuous or intermittent, are used to treat upper and lower airway infections. Although prophylactic antibiotics should be used with great caution in this era of emerging antibiotic resistance, children with primary ciliary dyskinesia are especially good candidates for long-term low-dose preventative antibiotics. New studies have supported prophylactic therapy, with gentamicin demonstrating decreased exacerbation frequency.[22] Another RTC demonstrated decreased exacerbation with no apparent increase in antibiotic resistance with thrice weekly azithromycin dosing for PCD patients. [44]
Obstructive lung disease, if present, should be treated with inhaled bronchodilators and aggressive pulmonary toilet. Mucolytics may be helpful. Anecdotal reports indicate that inhaled antibiotics, oral and inhaled corticosteroids, and recombinant human DNAse have been used, but no large studies support the use of these agents.[45] It has been found that regular bronchodilators, recombinant human deoxyribonuclease (rhDNase), and N -acetylcysteine have not been proven to be effective, but still are used occasionally in attempts at symptomatic relief.
It has been postulated that breaking up mucosal secretions with nebulized hypertonic or normal saline could be effective. No studies have demonstrated efficacy.
Pulmonary physiotherapy and exercise also have been shown in some studies to improve respiratory quality.
The most common infectious organisms affecting children with primary ciliary dyskinesia are Haemophilus influenza and Staphylococcus aureus. All patients should have the pneumococcal vaccine and a yearly flu vaccine in addition to standard childhood immunizations. Few long-term trials to measure clinical outcomes and statistical efficacy have been conducted for most medical management strategies.[43]
Strippoli et al found a substantial heterogeneity in the management of primary ciliary dyskinesia within and between countries and poor concordance with current recommendations, demonstrating a need to standardize management in this patient population,[46] as well as better research regarding outcomes to therapy.
Smoking risk
Patients with Kartagener syndrome ultimately have an inefficient mucociliary clearance, which results in the inability to prevent toxic and irritant substances from remaining within the respiratory tract. Without this mechanism, patients are much more prone to the complications of such toxins. Patients who smoke cigarettes or have persistent exposure to second-hand smoke are much more likely to develop reactive pneumonias and respiratory distress.
Smoking has been found to have multiple deleterious effects on respiratory cilia. Baseline ciliary beat frequency is increased to clear the irritant, but when the system has an underlying dysmotility, this becomes a less effective response.[22, 31] Children exposed to cigarette smoke may develop additional structural defects to nasal mucosa, causing ciliary function to further decline.[47] Additionally, microscopic models have demonstrated that cigarette smoke also can reduce the length of respiratory cilia.[48]
Ultimately, smoking can cause a more rapid deterioration of lung function in patients with Kartagener syndrome, who lack the usual protective mechanisms. Thus, smoking cessation is critical in the Kartagener patient population, as is avoidance of second-hand smoke.
Future treatments in development
Idrevolide, an epithelial sodium channel blocker, has been identified as a potential treatment for PCD. The results of the phase two clinical trial performed by Ringshausen et al. were recently published and showed safety and improvement in pulmonary function over a 28 day period when idrevolide was added to hypertonic saline nebulizer treatments.[49]
Genetic therapies are being studied to repair or replace the affected genes in PCD. Chhin et al discovered partial recovery of ciliary function after lentivirus ex vivo gene therapy was used to restore DNAI1 genetic code and other groups performed similar classical gene therapy experiments.[50] Gene editing has also been explored as a potential future treatment option. Lai et al recently published a study which detailed their use of transcription activator-like effector nucleases to cleave and replace mutated DNAH11 gene in ex vivo epithelial cell cultures derived from patients with PCD. Using gene editing, they demonstrated partial restoration of ciliary activity in PCD cells with mutation in the DNAH11 gene.[51] These treatments remain in very early stages of development and notable concerns remains due to the risk of off-target effects of genetic therapy.[52]
Tympanostomy tubes are required to reduce conductive hearing loss and recurrent infections. Many patients undergo repeated tympanostomy tube insertions, often complicated by chronic suppurative otitis media. Chronic otorrhea may require special measures for aural hygiene, such as regular otomicroscopy, acetic acid irrigations, or culture-guided topical or systemic antibiotic therapy. Because of anticipated long-term middle-ear disease, inserting tympanostomy tubes is the most sensible method of maintaining the myringotomy because the tube can be expected to stay in the tympanic membrane longer than routine grommets.
When sinus disease is refractory to medical management, functional endoscopic sinus surgery leads to transient improvement in upper and lower respiratory tract symptoms.[53] The antiquated procedure of making a nasal antral window underneath the inferior turbinate may have a role in the management of primary ciliary dyskinesia because this procedure relies on gravitational rather than ciliary clearance of mucus.
Lobectomy may have a role in cases of severe bronchiectasis, but this is not specific to patients with Kartagener syndrome. Reports describe patients who have undergone lung transplantation for primary ciliary dyskinesia; however, no studies illustrate long-term efficacy and outcomes.[22]
Consultations from an otolaryngologist, geneticist, pulmonologist, social services agent, or obstetrician/gynecologist or urologist/male fertility specialist (infertility) may be indicated.
Early intervention should be instituted with antibiotics directed at specific organisms identified by nasal secretions and/or expectorated sputum samples. Sensitivities of these samples should be obtained because resistant microorganisms can develop. Mucolytics may be helpful in specific individuals.
Clinical Context:
This combination inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. The antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa. The dose depends on whether treatment is prophylactic or for ongoing infection.
Clinical Context:
Amoxicillin interferes with the synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.
Clinical Context:
This drug combination treats bacteria resistant to beta-lactam antibiotics. In children older than 3 months, base dosing protocol on amoxicillin content. Owing to the different amoxicillin/clavulanic acid ratios in the 250-mg tablet (250/125) versus the 250-mg chewable tablet (250/62.5), do not use the 250-mg tablet until the child weighs more than 40 kg.
Antibiotics are used to treat acute or chronic infection or for prophylaxis against infection. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Clinical Context:
Guaifenesin increases respiratory tract fluid secretions and helps loosen phlegm and bronchial secretions. Large doses are necessary. It should be used in combination with adequate hydration.
What is primary ciliary dyskinesia (Kartagener syndrome)?How was ciliary dyskinesia (Kartagener syndrome) first described?What is the pathophysiology of primary ciliary dyskinesia (Kartagener syndrome)?What causes primary ciliary dyskinesia (Kartagener syndrome)?What is the prevalence of primary ciliary dyskinesia (Kartagener syndrome) in the US?What is the sexual predilection of primary ciliary dyskinesia (Kartagener syndrome)?Which age groups have the highest prevalence of primary ciliary dyskinesia (Kartagener syndrome)?What is the prognosis of primary ciliary dyskinesia (Kartagener syndrome)?What is the morbidity associated with upper airway primary ciliary dyskinesia (Kartagener syndrome)?What is the morbidity associated with lower respiratory tract primary ciliary dyskinesia (Kartagener syndrome)?What possible complications of primary ciliary dyskinesia (Kartagener syndrome)?Which clinical history findings are characteristic of primary ciliary dyskinesia (Kartagener syndrome)?What is the clinical triad characteristic of primary ciliary dyskinesia (Kartagener syndrome)?Which upper respiratory findings are characteristic of primary ciliary dyskinesia (Kartagener syndrome)?Which lower respiratory tract findings are characteristic of primary ciliary dyskinesia (Kartagener syndrome)?What other findings may be seen in primary ciliary dyskinesia (Kartagener syndrome)?What are the differential diagnoses for Primary Ciliary Dyskinesia (Kartagener Syndrome)?What is the role of lab testing in the workup of primary ciliary dyskinesia (Kartagener syndrome)?What is the role of imaging studies in the workup of primary ciliary dyskinesia (Kartagener syndrome)?Which tests are performed for primary ciliary dyskinesia (Kartagener syndrome) screening?What pulmonary function studies are used in the workup of primary ciliary dyskinesia (Kartagener syndrome)?What is the role of biopsy in the workup of primary ciliary dyskinesia (Kartagener syndrome)?What is the role of nasal endoscopy in the workup of primary ciliary dyskinesia (Kartagener syndrome)?Which histologic findings are characteristic of primary ciliary dyskinesia (Kartagener syndrome)?How is primary ciliary dyskinesia (Kartagener syndrome) treated?How does smoking affect the treatment of primary ciliary dyskinesia (Kartagener syndrome)?What is the role of surgery in the treatment of primary ciliary dyskinesia (Kartagener syndrome)?Which specialist consultations are beneficial to patients with primary ciliary dyskinesia (Kartagener syndrome)?Which activity modifications are needed during the treatment of primary ciliary dyskinesia (Kartagener syndrome)?Which medications are used for treatment of primary ciliary dyskinesia (Kartagener syndrome)?Which medications in the drug class Expectorants are used in the treatment of Primary Ciliary Dyskinesia (Kartagener Syndrome)?Which medications in the drug class Antibiotics are used in the treatment of Primary Ciliary Dyskinesia (Kartagener Syndrome)?
Elena B Willis, MD, Resident Physician, Department of Otorhinolaryngology, Albert Einstein College of Medicine, Montefiore Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Alexandra Koontz, DO, Resident Physician, Department of Otolaryngology - Head and Neck Surgery, Oklahoma State University College of Osteopathic Medicine
Disclosure: Nothing to disclose.
Margo Rose Tanghetti, DO, Chief Resident, Department of Otolaryngology, Oklahoma State University College of Osteopathic Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director, Pulmonary Medicine General Practice Unit (F2), Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital
Disclosure: Received research grant from: Sanofi Pharmaceutical; AstraZeneca Pharaceutical; aTyr Pharmaceutical; Dompe Pharmaceutical.
Chief Editor
John J Oppenheimer, MD, Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Amgen; GSK; Aquestive; Aimmune<br/>Clinical Adjudication/Data Safety Monitoring Board for AZ, GSK, Abbvie, Sanofi; Executive Editor for Annals of Allergy, Asthma & Immunology; Editor for Medscape; Reviewer for UpToDate; Honoraria from American Board of Allergy and Immunology.
Additional Contributors
Arvind K Badhey, MD, Clinical Assistant Professor , Attending Surgeon, Head and Neck Surgical Oncology and Microvascular Reconstructive Surgery, Department of Otolaryngology, UMass Memorial Health, University of Massuchusetts Medical School
Disclosure: Nothing to disclose.
John P Bent, III, MD, Professor, Director of Pediatric Otolaryngology, Departments of Otolaryngology-Head and Neck Surgery and Pediatrics, Albert Einstein School of Medicine; Director, Airway Clinic, Cochlear Implant Program, Children's Hospital at Montefiore
Disclosure: Nothing to disclose.
Ryland P Byrd, Jr, MD, Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Matthew Olearczyk, MD and Esther X Vivas, MD, to the development and writing of this article.
References
Kartagener M. Zur pathogenese der bronchiectasien. I Mitteilung:bronchiectasien bei situs viscerum inversus. Betr Klin Tuberk. 1933. 83:498-501.
Normal cilia (A) compared with cilia in Kartagener syndrome with missing dynein arms (B). Image courtesy of Wikimedia Commons.
Axial CT image showing dextrocardia and situs inversus in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
Axial CT image showing situs inversus (liver and inferior vena cava on the left, spleen and aorta on the right) in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
Axial CT image showing dextrocardia and situs inversus in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
Axial CT image showing situs inversus (liver and inferior vena cava on the left, spleen and aorta on the right) in a patient with Kartagener syndrome. Image courtesy of Wikimedia Commons.
Normal cilia (A) compared with cilia in Kartagener syndrome with missing dynein arms (B). Image courtesy of Wikimedia Commons.
Human Gene
Human Chromosomal Location
Chlamydomonas Ortholog
Ciliary Ultrastructure in Subjects with Biallelic Mutations
Presence of Laterality Defects
Percentage of Individual with Biallelic Mutations
MIM No.
DNAH5
5p15.2
DHC ?
ODA defect
Yes
15-21% of all PCD, 27-38% of PCD with ODA defects
608644
DNAI1
9p21-p13
IC78
ODA defect
Yes
2-9% of all PCD, 4-13% of PCD with ODA defects
244400
DNAI2
17q25
IC69
ODA defect
Yes
2% of all PCD, 4% of PCD with ODA defects
612444
DNAL1
14q24.3
LC1
ODA defect
Yes
na
614017
CCDC114
19q13.32
DC2
ODA defect
Yes
6% of PCD with ODA defects
615038
TXNDC3 (NME8)
7p14-p13
LC5
Partial ODA defect (66% cilia defective)
Yes
na
610852
DNAAF1 (LRRC50)
16q24.1
ODA7
ODA + IDA defect
Yes
17% of PCD with ODA + IDA defects
613193
DNAAF2 (KTU)
14q21.3
PF13
ODA + IDA defect
Yes
12% of PCD with ODA + IDA defects
612517, 612518
DNAAF3 (C19ORF51)
19q13.42
PF22
ODA + IDA defect
Yes
na
606763
CCDC103
17q21.31
PR46b
ODA + IDA defect
Yes
na
614679
HEATR2
7p22.3
Chlre4 gene model 525994 Phytozyme v8.0 gene ID Cre09.g39500.t1
ODA + IDA defect
Yes
na
614864
LRRC6
8q24
MOT47
ODA + IDA defect
Yes
11% of PCD with ODA + IDA defects
614930
CCDC39
3q26.33
FAP59
IDA defect + axonemal disorganization
Yes
36-65% of PCD with IDA defects + Axonemal disorganization
613798
CCDC40
17q25.3
FAP172
IDA defect + axonemal disorganization
Yes
24-54% of PCD with IDA defects + Axonemal disorganization
613808
RSPH4A
6q22.1
RSP4, RSP6
Mostly normal, CA defects in small proportion of cilia
No
na
612649
RSPH9
6p21.1
RSP9
Mostly normal, CA defects in small proportion of cilia
No
na
612648
HYDIN
16q22.2
hydin
Normal, very occasionally CA defects
No
na
610812
DNAH11
7p21
DHC ß
Normal
Yes
6% of all PCD, 22% of PCD with normal ultrastructure
603339
RPGR
Xp21.1
na
Mixed
No
PCD cosegregates with X-linked retinitis pigmentosa
300170
OFD1
Xq22
OFD1
nd
No
PCD cosegregates with X-linked intellectual disability
312610
CCDC164 (C2ORF39)
2p23.3
DRC1
Nexin (N-DRC) link missing; axonemal disorganization in small proportion of cilia
No
na
312610
CA = central apparatus; IDA = inner dynein arm; MIM = Mendelian Inheritance in Man; na = not available; N-DRC = nexin–dynein regulatory complex; ODA = outer dynein arm; PCD = primary ciliary dyskinesia.
American Thoracic Society
European Respiratory Society
Japanese Rhinologic Society
Criteria used for PCD diagnosis
Confirmed biallelic pathogenic variants in PCD-associated gene or
TEM hallmark ciliary ultrastructural defect or
Low nNO level
Definitive Diagnosis:
TEM hallmark ciliary ultrastructure defects or
Confirmed bi-allelic mutations in PCD causing genes.
Probable Diagnosis:
Very low nNO plus HSVA findings consistently suggestive of PCD on three occasions or following cell culture
Definitive Diagnosis:
At least one of the six clinical features is present AND at least one of the following test results is positive:
See the list below:
Class 1 defect on TEM
iPS cells established from patients’ peripheral blood show impairment of ciliary motility and the impairment is repaired by correcting the causative gene variants, pathogenic
Likely pathogenic variants are identified in PCD related genes
Probable Diagnosis:
At least one of the six clinical features is present AND at least one of the following test results is positive:
Nasal nitric oxide production ≤77 nL/min
Class 2 defect on TEM
Missing expression of proteins related to cilia by immunofluorescence microscopy
By high-speed video analysis, cilia show characteristic defective motility such as immotility or flickering, stiff, or circular movement
Patient eligibility for testing
Patients with two of the following four clinical features should be evaluated for PCD:
Early onset chronic wet cough
Early onset chronic nasal congestion
Unexplained neonatal respiratory distress
Organ laterality defect
A combination of distinct PCD symptoms and predictive tools (e.g. PICADAR) should be used to identify patients for diagnostic testing. Any patient with several of the following clinical features should be evaluated for PCD:
Persistent wet cough
Situs anomalies
Congenital cardiac defects
Persistent rhinitis
Chronic middle ear disease with or without hearing loss
History in term infants of neonatal upper and lower respiratory symptoms or neonatal intensive care admittance
Patients with normal situs presenting with other symptoms suggestive of PCD and siblings of patients should also be evaluated for PCD
Patients with any of the following clinical features and both cystic fibrosis and primary immunodeficiency syndrome have been ruled out
should be evaluated for PCD:
Respiratory symptoms such as tachypnea and cough, pneumonia, or atelectasis in neonates OR bronchiectasis or bronchiolitis in adults
Chronic rhinosinusitis
Otitis media with effusion or its sequelae
Situs inversus or situs ambiguus
Male infertility
Family history of suspected primary ciliary dyskinesia in a sibling
Recommendations for specific testing:
Nasal nitric oxide (nNO)
nNO is preferred over TEM or genetic testing in cooperative patients ≥5 years when a diagnosis of cystic fibrosis has been excluded.
nNO should be used as part of the diagnostic work-up of patients >6 years but is not is not sufficiently accurate to rule PCD in or out in isolation
PCD is considered likely if nNO is less than 77 nL/min. In cases where PCD is strongly suspected additional tests such as electron microscopy and genetic testing should be performed even if the nNO is above the cutoff.
Ciliary ultrastructure analysis by transmission electron microscopy (TEM)
TEM is included in the diagnostic reference standard.
TEM should be used as part of the diagnostic work-up with a hallmark defect confirming diagnosis; however, it should not be used in isolation to rule out PCD and further diagnostic testing should be performed in patients with normal TEM if clinical history is strong
TEM findings can be divided into Class 1 and Class 2 defects. PCD can be diagnosed based on Class 1 defects alone. Class 2 defects alone are not sufficient and must be combined with other findings to make the diagnosis.
Genetic testing
An extended genetic panel should be used over TEM ciliary testing and/or standard (≤12 genes) genetic panel testing
At the time the guidelines were published, there was not enough evidence to recommend for or against genetic testing for PCD diagnosis.
Genetic testing is required in all cases for a definitive diagnosis.
High speed video microscopy (HSVMA)
Ciliary beat pattern (CBP) analysis by high-speed video microscopy (HSVM) should not be used as a diagnostic test for PCD
HSVA, including CBF and CBP analysis, should be used as part of the diagnostic work-up
Only used in select cases when TEM and/or genetic testing is unavailable or inconclusive.
Ciliary beat frequency (CBF)
CBF measurement alone should not be used as a diagnostic test for PCD
CBF measurement alone should not be used as a diagnostic test for PCD
CBF measurement alone should not be used as a diagnostic test for PCD
Immunofluorescence
Not evaluated by guidelines
At the time the guidelines were published, there was not enough evidence to recommend for or against immunofluorescence for PCD diagnosis
The results of immunostaining should be interpreted in combination with other laboratory findings, such as electron microscopy, ciliary movement analysis, and genetic testing.
Human iPS cells
Not evaluated by guidelines
Not evaluated by guidelines
If peripheral blood samples can be obtained, iPS cells with pathogenic variants can be established, stored, and induced to differentiate into airway epithelial cells for repeated measurement of ciliary function, thus enabling reproducible and objective analysis of ciliary function
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