Primary Ciliary Dyskinesia (Kartagener Syndrome) 

Updated: Jun 12, 2020
Author: Elena B Willis, MD; Chief Editor: John J Oppenheimer, MD 

Overview

Background

Siewert first described the combination of situs inversus, chronic sinusitis, and bronchiectasis in 1904.[1] However, Manes Kartagener[1] first recognized this clinical triad as a distinct congenital syndrome in 1933. Because Kartagener described this syndrome in detail, it bears his name. Kartagener syndrome (KS) is inherited via an autosomal recessive pattern. Symptoms result from defective cilia motility.

Also see Primary Ciliary Dyskinesia (pediatrics).

Pathophysiology

Camner and coworkers[2] 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[3] 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[4] used the descriptive phrase “immotile cilia syndrome” to characterize male patients with sterility and chronic respiratory infections. The image below illustrates missing dynein arms in Kartagener syndrome.

Normal cilia (A) compared with cilia in Kartagener Normal cilia (A) compared with cilia in Kartagener syndrome with missing dynein arms (B). Image courtesy of Wikimedia Commons.

In 1981, Rossman and coworkers[5] 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.

Sturgess et al[6] 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[7] 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.[8]

Etiology

The cause of primary ciliary dyskinesia is genetic, with an autosomal recessive inheritance pattern. 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.[9] 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.[10]

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.[11]

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.[12]

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.[13]

Table. Mutations in the Genes that Cause Human Primary Ciliary Dyskinesia [14] (Open Table in a new window)

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 mental retardation

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.

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.

Epidemiology

US frequency

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.

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.

Prognosis

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.[15] 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.[16] 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.[17] 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.[18] It has been shown that up to 59% of patients have recurring episodes of sinusitis and 69% of these patients require surgical intervention.[19]

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.[18] 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.[20] 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.[21]

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.

 

Presentation

History

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.[22]

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.[14] 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.[23]

Physical Examination

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.[19]

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.[24]

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.[24]

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.[24]

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.[25]

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.[15] 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.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

The initial diagnostic workup is started after suggestive findings are encountered during the history and physical examination. 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.[23]

Semen analysis in postpubescent males may reveal abnormal sperm motility and ultrastructure.

Multiple diagnostic tests have emerged, but none has been fully standardized. These include nasal nitric oxide measurement, mucociliary clearance, and immunofluorescent analysis. The stimulation tests should be conducted when patients are at a stable respiratory baseline, owing to the altered motility during illness.

All of these novel diagnostic tools have caused a large expansion into the field of genetic testing and isolation of Kartagener syndrome mutations. Studies have recently discovered multiple new genes related to Kartagener syndrome. These studies are motivated by the hypothesis that additional ciliary mutations may exist that do not manifest themselves as ultrastructural defects. These discoveries have created the potential for future genetic testing as part of disease diagnosis. It has been posited that in the near future, more than 80% of patients will be able to be identified by genetic testing.[26]

Imaging Studies

Sinus radiographs (which largely have been supplanted by CT scans) typically demonstrate mucosal thickening, opacified sinus cavities, and hypoplastic frontal and/or sphenoid sinuses.[17]

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).[27]

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.

Axial CT image showing dextrocardia and situs inve 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 i 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.

Other Tests

Screening tests include the saccharin test and the measurement of nasal and exhaled nitric oxide, as follows:

  • Saccharine test: 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).

  • 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.[15] 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.[22] Studies have demonstrated a relationship between nasal nitric oxide levels, nasal oxide synthase mRNA expression, and ciliary beat frequency.[28] 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.[17]

  • 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.[15, 29]

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.

Procedures

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.

Histologic Findings

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).[30] 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.[30]

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.[31, 32]

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.

 

Treatment

Medical Care

General management

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 lack of major 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.[33]

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.[14]

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.[34] 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.[33]

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,[35] 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.[14, 23] Children exposed to cigarette smoke may develop additional structural defects to nasal mucosa, causing ciliary function to further decline.[36] Additionally, microscopic models have demonstrated that cigarette smoke also can reduce the length of respiratory cilia.[37]

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.

Surgical Care

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.[38] 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.[14]

Consultations

Consultations from an otolaryngologist, geneticist, pulmonologist, social services agent, or obstetrician/gynecologist or urologist/male fertility specialist (infertility) may be indicated.

Activity

Activities can be performed as tolerated; however, patients usually experience mild limitations in physical tolerance.

 

Medication

Medication Summary

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.

Antibiotics

Class Summary

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.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra)

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.

Amoxicillin (Biomox, Trimox, Amoxil)

Amoxicillin interferes with the synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Amoxicillin and clavulanate (Augmentin)

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.

Expectorants

Class Summary

Expectorants may thin mucous secretions.

Guaifenesin (Humibid LA)

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.

 

Questions & Answers

Overview

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)?

Presentation

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)?

DDX

What are the differential diagnoses for Primary Ciliary Dyskinesia (Kartagener Syndrome)?

Workup

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)?

Treatment

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)?

Medications

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)?