Primary Ciliary Dyskinesia 

Updated: Oct 17, 2017
Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Denise Serebrisky, MD 

Overview

Background

Immotile cilia syndrome (ICS) 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, sinusitis, otitis media, and male infertility. In 50% of the patients, ICS is associated with situs inversus.

In 1933, Kartagener described a unique syndrome characterized by the triad of situs inversus, chronic sinusitis, and bronchiectasis, which was dubbed Kartagener syndrome.[1, 2] Later, patients with this condition were noted to have defects in the ultrastructure of cilia. Afzelius coined the term immotile cilia.[3] Later studies showed that disorganized motion, rather than immotile cilia, resulted in the uncoordinated and ineffective ciliary beat, hence the term ciliary dyskinesia syndrome (CDS). Because transient ciliary dyskinesia may be acquired following epithelial injury from viral respiratory tract infections or exposure to pollutants,[4, 5] the term primary ciliary dyskinesia (PCD) is used to describe the genetic defect and to differentiate it from acquired defects.

Dysfunction of the axonemal structure has been linked to the emerging class of disorders collectively known as ciliopathies, which includes PCD/Kartagener syndrome, Bardet-Biedl syndrome, hydrocephalus, polycystic kidney disease, polycystic liver disease, nephrolithiasis, Meckel-Gruber syndrome, and Joubert syndrome.[6] A report of 9 patients with PCD from an inbred Amish community reported genetic heterogeneity.[7]

Review of normal and abnormal ciliary ultrastructure

The epithelial lining of the large airways and contiguous structures, including the paranasal sinuses, middle ears, and posterior nose, consists of ciliated pseudostratified columnar epithelium. Ciliated cells are also found in the ependymal lining of the brain and fallopian tubes. In addition, the spermatozoal flagella (tail of spermatozoa) has a core structure that is identical to cilia.

Each matured ciliated cell has up to 200 cilia. Each cilium has an array of longitudinal microtubules arranged as 9 doublets formed in an outer circle around a central pair (see image below). The main structural protein of these doublets is tubulin. The microtubules are anchored by a basal body in the apical cytoplasm of the cell. Radial spokes connect the outer microtubular doublets with a central sheath of protein around the central tubules.

Diagram showing the cross-section of normal cilia Diagram showing the cross-section of normal cilia showing its ultrastructure. Important components are labeled.

Cross-section of the cilia (see image below) reveals inner and outer dynein arms, which are attached to the A subunit of each microtubule doublet. The inner dynein arms are longer and form a hook, whereas the outer dynein arms are short and straight. Dynein, a type of ATPase, provides energy for microtubule sliding and the longitudinal displacement of adjacent microtubular doublets, resulting in ciliary bending. The protein nexin links the outer microtubular doublets, creating a circumferential network as straplike bands. Because nexin links maintain axonemal relationships while the basal bodies anchor the microtubules, the sliding of the outer microtubule results in bending of the cilium.

Ciliary ultrastructure, Left, Normal cilium from a Ciliary ultrastructure, Left, Normal cilium from a healthy individual in which both inner and outer dynein arms can clearly identified. Right, the absence of outer and inner dynein arms in a patient with primary ciliary dyskinesia. Image courtesy of J. Carson, PhD, University of North Carolina.

Ciliary movement involves 2 phases: an effective stroke phase that sweeps forward and a recovery phase during which the cilia bend backward and extend into the starting position for the stroke phase. The mucous lining present on the respiratory epithelium has an inner serous layer called the sol phase, in which the cilia recover from their active beat, and an outer, more viscous layer, the gel phase. The tips of the cilia contact the gel layer during the stroke phase to propel the secretions forward, but the cilia lose contact with the gel layer of the mucus during the recovery phase.

Normal ciliary beat frequency is 1000-1500 beats per minute. The frequency is slower in the peripheral airways (eg, bronchioles) compared to the larger airways (eg, trachea). The ciliary motility is maintained in the same plane along the length of airways and results in mucociliary transport rates up to 20-30 mm/min.

Pathophysiology

Defects in the ciliary component cause abnormal ciliary movements, resulting in impaired mucociliary clearance and manifesting as recurrent and or persistent sinopulmonary infections, among other problems.

Dynein arm defects manifest as a total or a partial absence of either both inner or both outer dynein arms or involve just the inner or outer arms. Sometimes, shortened dynein arms are the only defect. Recent studies show differential functions of both inner and outer dynein arms and correlate ciliary beat frequency directly with the number of outer dynein arms. The ciliary beat frequency is not correlated with the number of inner dynein arms.

Radial spoke defects exhibit either a total absence of radial spokes or an absence of radial spoke heads. These defects are easily recognized by an eccentric position of the central pair of microtubules that are normally stabilized in a central position by radial spokes. Microtubular transposition defects occur in the form of absence of the central pair of tubules with transposition of the outer doublet to the center. Other defects, such as ciliary aplasia, ciliary disorientation,[8] malaligned central pair of microtubules in adjacent cilia, and basal body abnormalities may occur after viral infections, making it unclear if they are primary or secondary defects.

Moreover, in some patients with typical clinical manifestations of PCD and low levels of nasal nitric oxide, the ciliary ultrastructure may appear normal, suggesting functional abnormalities because of other defects in ciliary components. This includes few patients with biallelic mutations in DNAH11.[9] An association has been reported between genetic mutations and ciliary ultrastructure defects, as follows:[10]

  • Outer dynein arm (ODA) defects - DNAH5, DNA11, DNA12, DNAL1, TXNDC3, CCDC114, ARMC4

  • ODA and IDA defects -LRRC50/DNAAF1, KTU/DNAAF2, DNAAF3, CCDC103, HEATR2, LRRC6, ZMYND10,DYX1C1

  • Central microtubular pair abnormalities -RSPH4A, RSPH9, RSPH1

  • Radial spoke defects -CCDC39, CCDC40

  • Normal cilia or subtle ultrastructural abnormalities -DNAH11, HYD1N, CCDC 164, CCDC65

Studies have confirmed that ciliary beat pattern is associated with specific ultrastructural defects in PCD.[11] New high-resolution digital high-speed video (DHSV) imaging has allowed the precise beat pattern of cilia to be viewed in 3 different planes in slow motion or frame-by-frame. Using this technique, 3 patterns were identified and correlated with ultrastructural defects.

In the first pattern, the cilia are virtually immotile with occasional slow, low-amplitude, stiff flickering motion. This is associated with either a combined inner and outer dynein arm defect or isolated outer dynein arm defect. In the second pattern, the cilia have stiff planar forward-backward motion with markedly reduced amplitude, a pattern associated with either an isolated inner dynein arm defect or a radial spoke defect. In the third pattern, the cilia beat in a large circular gyrating motion about the base of the cilium. This pattern is associated with transposition defect.

In patients showing moderate alteration in ciliary beating, in contrast to the patients easily diagnosed due to demonstration of immotile cilia, quantitative analysis of ciliary beating has been proposed.[12]

Epidemiology

Frequency

United States

The prevalence of PCD is approximately 1:16,000 live births. Geographic area and consanguinity may affect the prevalence. Specific types of defects are consistent within individual families and appear to be genetically determined. Based on the autosomal recessive mode of inheritance, the probability of having subsequent children with PCD is 1:4.

International

The reported frequency is 1 per 26,000-40,000 live births. However, this is likely to be an underestimate because misdiagnosis is common.[13]

Mortality/Morbidity

Morbidity includes chronic, persistent, or recurrent sinusitis, rhinitis, pneumonia, and otitis media. Male infertility is common. Evidence of female infertility is inconclusive. Progression of lung disease varies and is affected by age at diagnosis, ability of medical treatment to control the symptoms, and prevention of complications. These factors affect the quality of life. Individuals with normal or near normal lifespan have been reported. No studies have examined the impact of current symptomatic therapies on the course of disease.

Race

No racial predilection is reported.

Sex

No sex predilection is reported.

Age

No particular age predilection is recognized; infants are born with this genetic disorder. Cases associated with dextrocardia and with respiratory symptoms are more likely to be diagnosed in early infancy.

 

Presentation

History

Clinical manifestations vary.

  • Ear, nose, and paranasal sinuses

    • Chronic persistent rhinorrhea, sensation of local fullness, and sinus pain

    • Anosmia, nasal character of speech, and halitosis

    • Recurrent acute otitis

    • Chronic otitis

    • Recurrent sinusitis

  • CNS - Hydrocephalus in a few cases

  • Reproductive system[14] - Male infertility (common)

  • Lower respiratory tract

    • Chronic productive cough and respiratory distress, especially in infants

    • Bronchospastic symptoms (eg, wheeze and cough), usually responsive to bronchodilator therapy

    • Recurrent or persistent atelectasis or pneumonia

Physical

See the list below:

  • Nose and paranasal sinuses

    • Nasal mucosal congestion

    • Mucopurulent nasal discharge

    • Nasal obstruction

    • Mouth breathing and halitosis

    • Nasal polyps

  • Ears

    • Inflammation of tympanic membranes

    • Perforation with purulent discharge

    • Hearing loss

  • Lower respiratory tract

    • Respiratory distress

    • Retractions

    • Hypoxia

    • Crackles, wheeze

  • Other

    • Apex beat and heart sounds on the right side, if associated dextrocardia is present

    • Evidence of situs inversus, such as the spleen and liver on the incorrect side

    • Digital clubbing in cases with chronic and recurrent lower respiratory infections

 

PCD remains underrecognized due to lack of awareness of the clinical features of the disease[15]

A study by Leigh et al reported that four criteria-defined clinical features were statistically predictive of PCD in children and adolescents. The four features were laterality defect; unexplained, neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough.[16]

A study by Mullowney et al concluded that when encountering term neonates with unexplained respiratory distress, clinicians should consider PCD in those with lobar collapse, situs inversus, and/or prolonged oxygen therapy (>2 days).[17]

 

Causes

Primary ciliary dyskinesia (PCD) is a genetic disorder, and it appears to follow the autosomal recessive inheritance pattern. Two genes directly implicated in autosomal recessive PCD are DNAI1 and DNAH5, which encode for components of the outer dynein arm complex.[18, 19, 20, 21] Mutations in these genes are detected in 38% of patients with PCD. Commercial testing for these mutations is available and may help with the diagnosis.

 

DDx

 

Workup

Laboratory Studies

Genetic Testing

Thirty-three disease-causing mutations have been identified[22] . All but two of these follow autosomal recessive inheritance. Eighteen of these are associated with outer dynein arm defect and nine also involve inner dynein arm defects. Nineteen of these mutations are included in the commercial PCD genetic testing panel.  

Mutations in DNAI1 and DNAH5 have been detected in 38% of patients with primary ciliary dyskinesia. Commercial testing is available for all mutations in these 2 genes.  A diagnostic yield of 69% has been reported by combining ciliary biopsy and molecular genetics.[10]

Ciliary Biopsy

In North America ciliary biopsy for electron microscopy to detect ciliary ultrastructural abnormalities is used in conjunction with genetic testing while a combination of genetic testing and high speed videomicroscopy is used in Europe.[23] Electron microscopy will detect approximately 70% of PCD cases.[22]

Imaging Studies

See the list below:

  • Chest roentgenography may reveal changes due to chronic bronchitis and pneumonia. Dextrocardia, if present, is observed on chest roentgenographs. Bronchiectasis may be observed with recurrent lower respiratory infections.

  • Direct video cinematography or oscillography is used to analyze ciliary beat frequency and waveform.

  • Digital high-speed video (DHSV) imaging allows evaluation of ciliary beat pattern in 3 different planes in slow motion or frame-by-frame. Using DHSV imaging, patients with PCD can be classified into 3 distinct groups on the basis of ciliary beat pattern (see Pathophysiology).

  • Ciliary beat pattern analysis is a more sensitive and specific test for PCD with positive predictive value.[24]

  • Santamaria et al have studied structural lung disease in patients with PCD using a modified Brody composite high-resolution CT (HRCT) scoring system to evaluate the severity and distribution of lung abnormalities; they found that bronchiectasis, peribronchial thickening, and peripheral mucous plugging were the most common changes, followed by central mucus plugging and parenchymal abnormalities.[25]

Other Tests

See the list below:

  • Mucociliary clearance studies measure the perception of sweetness after saccharin is placed on the anterior portion of the inferior turbinate. A delayed or absent response suggests impaired mucociliary clearance. However, this test is not recommended 

  • Nasal nitric oxide measurements have been tried to screen children older than 5 years.[26, 27] Extremely low levels of nitric oxide (less than 100 nL/min) may be suggestive.[28] A portable nitric oxide analyzer has been validated for screening of PCD.[22] Very low levels of nasal nitric oxide may be found during acute viral respiratory infections and in some patients with cystic fibrosis.

  • Pulmonary function testing has shown reduced values for FEV1.[7, 29] Longitudinal studies have shown a high degree of variation in the course of lung function after diagnosis that was not related to either age or lung function level at the time of diagnosis.[29]

  • A prospective study of 654 consecutive patients showed that high-speed video miscopy analysis had an excellent sensitivity and specificity (100% and 93% respectively). The transmission electromicroscopy in combination with high-speed videomicroscopy was 100% sensitive and 92% specific.[23]  

Procedures

Bronchoscopy reveals mucosal inflammation and mucopurulent secretions. It can also be used to confirm the reversal of bronchial anatomy in those patients with situs inversus.

Examination of the ciliary ultrastructure by electron microscopy in a nasal or bronchial ciliary biopsy sample can be used as a diagnostic test.

Nasal biopsy (brush or curettage) samples are obtained from inferior surface of turbinates. Electron microscopy reveals the abnormalities in the cilia.

Bronchial brush biopsy demonstrates ciliary ultrastructure abnormalities using an electron microscope. Due to the varying orientation of the cilia in a biopsy specimen and resultant technical difficulties in the full analysis of cilia, a quantitative method includes assessing axonemal defects in less than perfectly oriented cilia, with dynein arms being assessed only in those cilia in which these small structures can be discerned.

A review of quantitative transmission electron microscopy in 1182 patients referred for ciliary structure analysis reported confirmation of diagnosis of PCD in 242 (20%) cases.[30] In addition to describing an algorithm including screening tests such as exhaled nasal nitric oxide, saccharine test, light microscopy, and electron microscopy, the authors describe the use of transmission electron microscopy using a rapid quantitative method. However, electron microscopy does not always exclude the diagnosis of PCD.

 

Treatment

Medical Care

There are no specific therapies, or prospective, randomized clinical trials on monitoring or treating primary ciliary dyskinesia (PCD).[22] General principles of airway clearance, antibiotic therapy used for cystic fibrosis or No non CF bronchiectasis should be followed. However, an ex-vivo attempt at gene editing by site specific recombination using transcription activator-like effector nucleases of DNAH11  was successful to cleave 80% of mutated sequence and replace it by wild type sequence in 50% of cells,[31] thus opening new avenues for treating PCD.

In patients with PCD, monitoring pulmonary function through spirometry, lung volume determination, and oxyhemoglobin saturation measurements allows objective assessment of progression of disease. Sputum culture and sensitivity tests are useful in managing antibiotic therapy in expectorating patients; bronchoscopy may be required in ascertaining lower respiratory tract pathogens from symptomatic nonexpectorating patients. Monitoring hearing is essential to avoid speech and educational problems. Treatment of the respiratory disease is directed at aggressive airway clearance and resolving respiratory or bacterial infections.

  • Chest physical therapy (CPT)

    • Chest physical therapy and aerosolized bronchodilators assist in airway clearance and postural drainage.

    • CPT may be provided by hand percussion and postural drainage or by using a mechanical method such as high-frequency chest wall oscillation (ThAIRapy Vest), positive expiratory pressure valve, or Flutter.

  • Infections

    • Administer routine vaccination for pertussis, measles, Haemophilus influenzae type b, influenza, and pneumococcus.

    • Provide antibiotic therapy for otitis media, pneumonia, and sinusitis. In cases with recurrent respiratory infections, consider preventive long-term oral or nebulized antibiotics.

Surgical Care

See the list below:

  • Surgery may be indicated when antibiotic therapy has not helped.

  • Tympanostomy with pressure-equalizing tube placement is used for chronic persistent otitis media.

  • Functional endoscopic sinus surgery and/or nasal polypectomy promote sinus drainage and improve nasal breathing in cases of persistent symptomatic sinusitis and nasal obstruction.

  • Lobectomy is used in rare cases with persistent localized bronchiectasis that is progressive in spite of medical treatment. It is also used in cases of recurrent infection in localized nonfunctioning tissue.

Consultations

See the list below:

  • Collaboration between the primary care physician, pulmonologist, and otolaryngologist is essential to assure optimal care for affected patients.

  • Consultation with a geneticist may help to provide genetic counseling to the family.

Activity

See the list below:

  • Activity is not restricted as long as the oxygen saturation is adequate.

 

Medication

Medication Summary

Antimicrobial therapy is indicated for the treatment of pulmonary infections, otitis media, and sinusitis. Starting with the usual antibiotics, including amoxicillin or amoxicillin-clavulanate, is reasonable. In the absence of response, the choice of a different antibiotic depends on the results of bacterial cultures. Some of the drugs commonly used are listed below.

Antimicrobial agents

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Amoxicillin (Trimox, Amoxil)

A penicillin antibiotic with activity against gram-positive and some gram-negative bacteria. Binds to PBPs, inhibiting bacterial cell wall growth.

Amoxicillin and clavulanic acid (Augmentin)

Combination product that extends the antibiotic spectrum of this penicillin to include bacteria normally resistant to beta-lactam antibiotics.

Different amoxicillin/clavulanic acid ratios are recognized. (eg, 250-mg tab [250/125] vs 250-mg chewable tab [250/62.5]). Do not use products containing 125 mg of clavulanate until child weighs >40 kg. Note different product ratios for bid and tid dosing schedules.

Sulfamethoxazole and trimethoprim (Bactrim, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Erythromycin and sulfisoxazole (Pediazole)

Erythromycin is a macrolide antibiotic with a large spectrum of activity. Erythromycin binds to the 50S ribosomal subunit of the bacteria, which inhibits protein synthesis.

Sulfisoxazole expands erythromycin's coverage to include gram-negative bacteria. Sulfisoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid.

Bronchodilators

Class Summary

Inhaled bronchodilators are used to treat associated bronchospastic symptoms or before chest physical therapy to help airway clearance.

Albuterol (Proventil, Ventolin)

May be administered as either metered dose inhaler or nebulized form. Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

Glucocorticoids

Class Summary

Anti-inflammatory agents are used to treat inflammation associated with chronic and recurrent pulmonary infections. Various inhaled corticosteroids are used.

Inhaled corticosteroids are the most commonly used anti-inflammatory agents. Various preparations are available in metered dose inhaler form. Recently, a nebulized form of budesonide was approved and made available.

Budesonide inhaled (Beclovent, Vanceril)

Inhibits bronchoconstriction mechanisms. Produces direct smooth muscle relaxation. May decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

Fluticasone inhaled (Flovent)

Inhibits bronchoconstriction mechanisms. Produces direct smooth muscle relaxation. May decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

Budesonide (Pulmicort)

The nebulized form (ie, Respules) is now approved by the FDA, allowing younger children the benefit of administration. Alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as dry inhaled powder (Flexhaler - 90 mcg/actuation [delivers 80 mcg]; Turbuhaler – 200 mcg/actuation [delivers 160 mcg]) or suspension for nebulization (Respules).

 

Follow-up

Deterrence/Prevention

Recommendations from the European Respiratory Society task force on diagnostic and treatment approaches in children with PCD include exclusion of this diagnosis in children found to have situs inversus totalis or any heterotaxic syndrome, in the siblings of probands, in babies with otherwise unexplained neonatal respiratory distress other features of PCD are present, in children with chronic productive cough, and in patients with bronchiectasis of unknown cause, particularly if other features of PCD are present.[32]

Prognosis

See the list below:

  • The progression of lung disease varies and is affected by the time of diagnosis, the ability of medical treatment to control symptoms, and the prevention of complications that affect the quality of life.

  • Some individuals have a normal or near normal lifespan. No studies have examined the impact of current symptomatic therapies on the course of disease.

Patient Education

See the list below:

  • Genetic counseling should be offered to parents of newly diagnosed infants and children. The importance of regular health monitoring should be emphasized. Counsel patients to avoid smoke, allergens, environmental irritants, and exposure to respiratory pathogens.

  • For patient education resources, see the Procedures Center, as well as Bronchoscopy.