BASICS
DESCRIPTION
- Kartagener syndrome (KS) is a rare disorder characterized by defects in the ultrastructure of cilia impairing their motility. It is also referred to as primary ciliary dyskinesia (PCD).
- Three key symptoms definitive for KS include:
- Situs inversus
- Chronic sinusitis
- Bronchiectasis
EPIDEMIOLOGY
- No gender or racial bias
- Some geographically isolated communities, such as the Amish, may have a higher incidence due to consanguinity.
- Encountered predominantly in neonates and younger children
- Median age of diagnosis: within the first 10 to 14 years of age
Incidence
Incidence of KS is ~1/15,000 to 30,000 live births. é á
Prevalence
Prevalence of situs inversus totalis occurs in >60% in the pediatric population and 50% in the adult population: é á
- Estimated 70 new cases/year
ETIOLOGY AND PATHOPHYSIOLOGY
- KS stems from a disturbance or loss of ultrastructural components of cilia, more specifically dynein arms that help motor cilia.
- It causes cilia and flagella to lose their normal and fast synchronous beat and waveform patterns, which affect ciliary-dependent areas in the body, such as respiratory epithelia, brain ependyma, embryonic node, oviduct, and sperm.
- Chronic upper and lower respiratory tract infections result from lack of mucociliary clearance of mucus and bacteria leading to chronic sinusitis, bronchitis, and permanent lung damage.
- Impairment of ependymal ciliary function within the brain may lead to decreased cerebral spinal flow and thus result in hydrocephalus that may be seen in these patients.
- 40 " ô50% of patients with PCD present with lateralization defects, such as situs inversus totalis, affecting left " ôright organogenesis due to absent or affected motility within embryonic nodal cilia, which results in random orientation of thoracoabdominal contents that is not genetically predetermined (1).
- Reduced motility of flagellated sperm as well as cilia within oviducts of the fallopian tubes in females may lead to decreased fertility and possible sterility in both genders.
RISK FACTORS
- Heterogeneous, autosomal recessive disorder (2)
- 19 genes associated with PCD to date, which fall into three categories:
- Genes that code for components of the outer or inner dynein arms: DNAH5, DNAH11, DNA11, DNA12, DNAL1, TXNDC3 (2)
- Genes that code for proteins which play a role in axonemal organization of the central pair microtubules and radial spokes: CCDC39, CCDC40, CCDC164,CCDC103,CCDC40, CCDC164 (2)
- Genes that code for cytoplasmic proteins: KTU, HEATR2, DNAAF1, DNAAF2, DNAAF3, and LRRC6 (2)
DIAGNOSIS
HISTORY
- Presentation typically includes cardinal features of upper and lower respiratory tract infections.
- Respiratory distress manifests in neonatal period and persists year round (1).
- Lower respiratory tract infections will present with chest congestion, tachypnea, cough, and ineffective airway mucociliary clearance leading to chronic bronchitis, chronic productive cough, and recurrent pneumonia.
- Although rare, neonates may present with hypoxia and possible respiratory failure:
- Careful not to confuse this with "wet lungs, " Ł neonatal pneumonia, or transient tachypnea of the newborn (1)
- Upper respiratory tract infections most commonly manifest as otitis media with effusion:
- Seen in 85% of children with PCD
- Chronic rhinitis and recurrent mucoid rhinorrhea, chronic sinusitis, and nasal polyps with nasal congestion are also noted.
- In KS cardiac defects, such as dextrocardia, with laterality abnormalities may or may not be seen; however, prevalence of heterotaxy, although rare, with and without congenital heart disease, is increased:
- Heterotaxia syndrome includes abdominal situs inversus, polysplenia (left isomerism), and asplenia (right isomerism).
- Prevalence: 6% (1,3,4)
- Postpubescent males and females may present with decreased fertility.
- Patients may state they have visited a physician many times with these recurring symptoms before an accurate diagnosis has been made.
DIFFERENTIAL DIAGNOSIS
Malignancy (bronchoalveolar carcinoma), interstitial lung disease (idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia),α1-antitrypsin deficiency and connective tissue disease, or conditions associated with bronchiectasis, such as acquired obstructions (foreign body aspiration, chronic obstructive pulmonary disease [COPD], mucoid impaction), congenital obstructions (bronchomalacia, pulmonary sequestration, pulmonary artery aneurysm, yellow-nail syndrome), immunodeficiency states with recurrent infections (IgG, IgA deficiencies, leukocyte dysfunction), or conditions that result in abnormal ciliary clearance (cystic fibrosis) é á
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Screening tests:
- Nasal nitric oxide (NO) measurements during tidal breathing:
- Very low in patients with PCD
- Poor screening test; NO is low in other similar diseases (i.e., CF, panbronchiolitis, and nasal polyposis)
- Requires confirmation with ultrasound or EM
- Poorly standardized in children <5 (3)[B]
- Saccharin test: Microtablet of saccharin is placed on the inferior turbinates and the time taken for the patient to test saccharin is recorded.
- Test unreliable in children <12 years old (3)[B]
- Diagnostic tests:
- Ciliary beat frequency (CBF) and electron microscopy (EM) may be used to detect ciliary structure (3)[A]:
- If CBF, visualized under light microscopy, is <11 beats/s (<11 Hz), further analysis with EM is required.
- EM: cilia obtained from nasal scrapes or bronchial brush biopsies examined for defects in axonemal structure and orientation
- Complete absence or "stub-like " Ł shortening of both inner and outer dynein arms; aplasia of cilia or abnormalities within radial spokes may be observed.
- Sensitivity, 87.1%; specificity, 77.2%; positive predictive value (PPV), 50.0%; negative predictive value (NPV), 95.8%
- Beat pattern analysis may be used to assess ciliary function prior to further analysis with EM (3)[A].
- Genetic studies demonstrate abnormalities in one of many mutated proteins required for normal ciliary function:
- Biallelic mutation is diagnostic; single allele mutation requires further testing.
- Additional tests:
- Sputum culture:
- May reveal source of infection or pneumonia
- Primary sources include Pseudomonas aeruginosa in adults; Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae in children
- CBC may reveal leukocytosis, particularly an increase in neutrophil count.
- Pulmonary function test:
- Compliance is limitation to this test, especially in infants. Sedation may be required.
- 65 " ô80% of preschool age children should be able to perform spirometry adequately.
- <5 years of age: diminished flow and volumes
- >6 years of age: early signs of abnormal forced expiratory volume in the first second of expiration (FEV1) and forced vital capacity (FVC) values; reduced FEV1 by 50% when diagnosed in adolescents and up to 80% when diagnosed in adulthood
- Airflow obstruction is variable: Lung function may be stable or may worsen over time.
- Situs inversus will be demonstrated on chest x-ray (CXR).
- CT images demonstrate early structural changes that include atelectasis, opacities, bronchial wall thickening, air trapping, and bronchiectasis.
TREATMENT
GENERAL MEASURES
- Limit first-hand and/or second-hand tobacco smoke exposure, as well as other environmental pollutants.
- Recommend patients to be up-to-date with their childhood immunizations and vaccines " öpneumococcal and influenza vaccinations in particular (3)[A].
- Saline nasal douches may be beneficial during episodes of rhinorrhea (3)[C].
- Exercise of active coughing is a good form of airway clearance and should be encouraged (3)[C].
- Avoid cough suppressants (3)[C].
MEDICATION
First Line
Largely supportive é á
- 2013 systematic review found a very limited database of evidence to support most treatment options; recommends developing a treatment database, and for now, using clinical discretion.
- Antibiotics can be used acutely to help treat patients with the presence of upper and lower respiratory tract infections.
- Consider chronic treatment with antibiotics when patient repeatedly grows P. aeruginosa in sputum cultures, and when young children present with chronic otitis media and sinusitis.
- Long-term azithromycin has been shown to improve clinical symptoms and radiographic signs in patients diagnosed with PCD with specific mutations in the inner dynein arms of cilia.
Second Line
- Nasal congestion and secretions may be treated with nasal douches or anticholinergics.
- Mucolytics, inhaled corticosteroids, or macrolide therapy have immunomodulatory effects and may help with mucociliary clearance:
- No published data present that state definitively for or against its use; however, can be attempted as supplemental therapy.
ISSUES FOR REFERRAL
Referral to PCD specialty centers, otolaryngologist, pulmonologist, fertility specialist or gynecologist, and geneticist is recommended when patient is first suspected to demonstrate evidence of KS or PCD. é á
ADDITIONAL THERAPIES
Future treatment options é á
- Ongoing investigations on treatments being studied include:
- Tobramycin and aztreonam for new and chronic cases of Pseudomonas
- Azithromycin and trimethoprim-sulfamethoxazole as prophylactic "immunomodulatory " Ł antibiotics in children with PCD
- "Mucoactive " Ł therapy, including hypertonic saline, rhDNase, and mannitol (3)[C]
SURGERY/OTHER PROCEDURES
- Lobectomy
- Reserved for patients with severe bronchiectasis who do not respond to medical management
- Cardiac testing must be completed prior to lobectomy, because cardiac arrest and death may result.
- Lung transplantation
- Reserved for severe end-stage lung disease with certain criteria:
- Patients presenting with disabling symptoms and bilateral disease
- Severe functional impairment
- Dependence on oxygen
- Failure to respond to medical or surgical management
- Otitis media with effusions
- Tends to resolve spontaneously by 13 years of age (3)
- Moderate to severe hearing loss noted within the first 10 years of life may benefit from surgical intervention with insertion of ventilation tubes:
- Controversial use in children with mild symptoms
- May result in progressive otorrhea
- Hearing aids for short-term periods may be considered as a better option.
- Nasal polyps, chronic rhinitis, and sinusitis may be treated with endoscopic sinus surgery. Studies regarding this form of treatment are limited.
- Should be limited to the maxillary and ethmoid sinuses; ostiomeatal complex nasal saline rinses and topical steroids to follow surgical treatment is mandatory.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Monitor for progression of lung disease is strongly recommended.
- Including spirometry to determine pulmonary function level and sputum cultures on every visit
- Irreversible lung damage occurs early on. CT imaging is superior to CXR in looking for bronchiectasis in infants or young children and should be done on every visit.
- Patients should be evaluated at least 2 times per year at centers that specialize in PCD diagnosis and treatment.
PROGNOSIS
- Leading cause of increased morbidity and mortality in patients affected with this disease is from chronic airway infection:
- Early childhood: typically caused by H. influenza, S. aureus, and S. pneumoniae
- Older adults: P. aeruginosa and non-TB mycobacteria
- Overall, with intensive therapy, decline of lung function is slow and progression of symptoms tends to decrease as patients achieve adolescence/adulthood.
- In cases of severe respiratory failure, or where early irreversible damage results in respiratory failure, results can be fatal if lung function cannot be improved.
COMPLICATIONS
- Permanent lung damage may result from early irreversible insults of lung injury. Respiratory failure and lung transplantation may be required.
- Conductive hearing loss, delayed speech and language development, atelectasis of tympanic membrane, and cholesteatoma formation may result from prolonged otitis media with effusion.
- Prolonged otorrhea, disruption of hearing, as well as inability to maintain a healthy tympanic membrane may result with surgical intervention.
REFERENCES
11 Leigh é áMW, Pittman é áJE, Carson é áJL, et al. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med. 2009;11(7):473 " ô487.22 Horani é áA, Brody é áSL, Ferkol é áTW, et al. CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia. PLoS One. 2013;8(8):e72299.33 Barbato é áA, Frischer é áT, Kuehni é áCE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J. 2009;34(6):1264 " ô1276.44 Leigh é áMW, Zariwala é áMA, Knowles é áMR. Primary ciliary dyskinesia: improving the diagnostic approach. Curr Opin Pediatr. 2009;21(3):320 " ô325.
ADDITIONAL READING
- Bush é áA, Chodhari é áR, Collins é áN, et al. Primary ciliary dyskinesia: current state of the art. Arch Dis Child. 2007;92(12):1136 " ô1140.
- Bush é áA, O 'Callaghan é áC. Primary ciliary dyskinesia. Arch Dis Child. 2002;87(5):363 " ô365.
- Kido é áT, Yatera é áK, Yamasaki é áK, et al. Two cases of primary ciliary dyskinesia with different responses to macrolide treatment. Intern Med. 2012;51(9):1093 " ô1098.
- Mener é áDJ, Lin é áSY, Ishman é áSL, et al. Treatment and outcomes of chronic rhinosinusitis in children with primary ciliary dyskinesia: where is the evidence? A qualitative systematic review. Int Forum Allergy Rhinol. 2013;3(12):986 " ô991.
- Mitchison é áHM, Schmidts é áM, Loges é áNT, et al. Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia. Nat Genet. 2012;44(4):381 " ô389, S1 " ôS2.
- Sagel é áSD, Davis é áSD, Campisi é áP, et al. Update of respiratory tract disease in children with primary ciliary dyskinesia. Proc Am Thorac Soc. 2011;8(5):438 " ô443.
- Skeik é áN, Jabr é áFI. Kartagener syndrome. Int J Gen Med. 2011;4:41 " ô43.
- Sommer é áJU, Sch â Ąfer é áK, Omran é áH, et al. ENT manifestations in patients with primary ciliary dyskinesia: prevalence and significance of otorhinolaryngologic co-morbidities. Eur Arch Otorhinolaryngol. 2011;268(3):383 " ô388.
- Stannard é áWA, Chilvers é áMA, Rutman é áAR, et al. Diagnostic testing of patients suspected of primary ciliary dyskinesia. Am J Respir Crit Care Med. 2010;181(4):307 " ô314.
- Stillwell é áPC, Wartchow é áEP, Sagel é áSD. Primary ciliary dyskinesia in children: a review for pediatricians, allergists, and pediatric pulmonologists. Pediatr Allergy Immunol Pulmonol. 2011;24(4):191 " ô196.
- Zariwala é áMA, Omran é áH, Ferkol é áTW. The emerging genetics of primary ciliary dyskinesia. Proc Am Thorac Soc. 2011;8(5):430 " ô433.
CODES
ICD10
Q89.3 Situs inversus é á
ICD9
759.3 Situs inversus é á
SNOMED
Kartagener syndrome (disorder) é á
CLINICAL PEARLS
- KS is characterized by defects in the ultrastructure of cilia impairing their motility.
- Is also referred to as PCD
- Impaired motility results in an array of abnormalities, including situs inversus, chronic sinusitis, bronchiectasis, and infertility.
- NO testing is often used for screening, but positive results must be confirmed with EM or ultrasound.
- No definitive consensus on treatment exists to date.