AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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.

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 Media file 1). 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.

Cross-section of the cilia (see Media file 1) 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 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,⁶ 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, the ciliary ultrastructure may appear normal, suggesting functional abnormalities because of other defects in ciliary components.

Recent studies have confirmed that ciliary beat pattern is associated with specific ultrastructural defects in PCD.⁷ 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.

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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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 system⁸ - 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

• 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

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.^{9, 10, 11, 12} 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Immunodeficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• Three genes directly implicated in autosomal recessive primary ciliary dyskinesia (PCD) are DNAI1, DNAH5, and DNAH11; these genes encode components of outer dynein complex.
• Mutations in DNAI1 and DNAH5 have been detected in 38% of patients with PCD. Commercial testing is available for all mutations in these 2 genes.

Imaging Studies

• 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).
• 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.¹³

Other Tests

• 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.
• Nasal nitric oxide measurements have been tried to screen children with PCD.^{14, 15} Extremely low levels of nitric oxide (less than 100 nL/min) may be suggestive.¹⁶

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.
• 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

In patients with primary ciliary dyskinesia (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

• 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

• 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

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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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.

Drug Category: Antimicrobial agents

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

Drug Category: Bronchodilators

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

Drug Category: Glucocorticoids

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Prognosis

• 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

• 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 excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Diagram showing the cross-section of normal cilia showing its ultrastructure. Important components are labeled.
	View Full Size Image
Media type:  Image

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

1. Kartagener M. Zur pathogene der bronkiectasein:bronkiectasein bei situs viscerum inversus. Beitr Klin Tuberk. 1933;82:489.
2. Kartagner M. Zur pathogenese der bronkiectasein. I Mittelung: Bronkiectasein bei situs viscerum invesus. Beitr Klin Tuberk. 1933;83:498-501.
3. Afzelius BA. A human syndrome caused by immotile cilia. Science. Jul 23 1976;193(4250):317-9. [Medline].
4. Carson JL, Collier AM, Hu SS. Acquired ciliary defects in nasal epithelium of children with acute viral upper respiratory infections. N Engl J Med. Feb 21 1985;312(8):463-8. [Medline].
5. Pedersen M. Ciliary activity and pollution. Lung. 1990;168 Suppl:368-76. [Medline].
6. Sturgess JM, Chao J, Turner JA. Transposition of ciliary microtubules: another cause of impaired ciliary motility. N Engl J Med. Aug 7 1980;303(6):318-22. [Medline].
7. Chilvers MA, Rutman A, O'Callaghan C. Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia. J Allergy Clin Immunol. Sep 2003;112(3):518-24. [Medline].
8. Afzelius BA, Eliasson R. Male and female infertility problems in the immotile-cilia syndrome. Eur J Respir Dis Suppl. 1983;127:144-7. [Medline].
9. Pennarun G, Escudier E, Chapelin C, et al. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet. Dec 1999;65(6):1508-19. [Medline].
10. Guichard C, Harricane MC, Lafitte JJ, et al. Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome). Am J Hum Genet. Apr 2001;68(4):1030-5. [Medline].
11. Hornef N, Olbrich H, Horvath J, et al. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. Jul 15 2006;174(2):120-6. [Medline].
12. Bush A, Ferkol T. Movement: the emerging genetics of primary ciliary dyskinesia. Am J Respir Crit Care Med. Jul 15 2006;174(2):109-10. [Medline].
13. Santamaria F, Montella S, Tiddens HA, et al. Structural and functional lung disease in primary ciliary dyskinesia. Chest. Aug 2008;134(2):351-7. [Medline].
14. Corbelli R, Bringolf-Isler B, Amacher A, Sasse B, Spycher M, Hammer J. Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia. Chest. Oct 2004;126(4):1054-9. [Medline].
15. Karadag B, James AJ, Gultekin E, Wilson NM, Bush A. Nasal and lower airway level of nitric oxide in children with primary ciliary dyskinesia. Eur Respir J. Jun 1999;13(6):1402-5. [Medline].
16. Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med. Feb 15 2004;169(4):459-67. [Medline].

Article Last Updated: Sep 25, 2008