Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD), also known as immotile-cilia syndrome, is an autosomal recessive disorder leading to an impairment that affects mucociliary clearance. Primary ciliary dyskinesia is caused by defective ciliary function in the airways and is characterized by the loss of oscillation (immotility), abnormal oscillation (dyskinesia), or absence of cilia (aplasia). In most cases, PCD commonly presents with recurrent infections of the upper and lower respiratory tract. Clinical features include bronchiectasis, chronic rhinosinusitis, and situs inversus. There is no gold standard diagnostic test for PCD, as several tests are used in the diagnosis. Treatment is individualized, and the primary goal is to remove trapped mucus and treat infections. Patients with PCD usually have a regular lifespan.

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Overview

Definition

Primary ciliary dyskinesia (PCD) is a genetic condition in which cilia in the respiratory tract have defective functionality that leads to ineffective mucociliary clearance.

Epidemiology

  • Affects 1 in 16,000–20,000 live births 
  • Equal prevalence in men and women
  • Affects all racial and ethnic groups

Etiology

  • Autosomal recessive inheritance
  • More than 30 different PCD genetic variants have been implicated.

Pathophysiology

Normal physiology

  • Cilia are microscopic, finger-like structures projecting out of the cell surface.
  • Cilia line the airways, reproductive tissues, and other organs.
  • Normal, motile cilia in the upper and lower respiratory tract are composed of:
    • Alpha- and beta-tubulin monomers
    • A complex central core (axonemal) structure including:
      • Dynein arms
      • Radial spokes
      • Nexin links
  • Cilia usually beat in a coordinated fashion to move respiratory secretions.

Ciliary dysfunction

  • PCD is a highly heterogeneous syndrome that can be caused by a defect in:
    • 1 of the many polypeptide species in the central core of the cilia 
    • Proteins needed for the proper assembly of cilia
  • Mutations involving dynein are commonly implicated in PCD.
  • Effects:
    • Abnormal ciliary movement (ciliary dyskinesia)
    • Inability to move (ciliary immobility)
    • Absent cilia (ciliary aplasia)
  • Proper ciliary function is necessary for the rotation of organs in the abdomen and chest.
  • With dysfunction, situs inversus and/or abnormal organ positioning can occur.

Clinical Presentation

Onset

  • Commonly presents in children, but can also present in adults
  • Median age of diagnosis:
    • In children, 5–5.5 years of age
    • In adults, 22 years of age

Signs and symptoms

  • Recurrent infections of the upper and lower respiratory tract:
    • Most common symptom
    • Common causative bacteria include:
      • Haemophilus influenzae
      • Streptococcus pneumoniae
      • Staphylococcus aureus
      • Pseudomonas aeruginosa
      • Non-tuberculosis mycobacteria
  • Chronic rhinosinusitis:
    • Occurs in almost 100% of patients
    • Year-round runny nose and nasal congestion
    • Often begins in early childhood
    • Usually involves the maxillary and ethmoid sinuses
    • Can be associated with headaches
    • Can lead to nasal polyposis
  • Mild respiratory distress (in newborns):
    • Tachypnea 
    • Hypoxemia
  • Bronchiectasis: 
    • Auscultatory crackles
    • Wheezing that mimics asthma
  • Chronic secretory otitis media with recurrent bouts of acute otitis media (↓ frequency after puberty)

Other related findings

  • Situs inversus:
    • Present in about 50% of patients with PCD
    • Situs inversus presents as situs inversus totalis, which is a complete mirror-image reversal of the circulatory system and viscera, including the heart (dextrocardia).
    • Causes no apparent health problems and often remains undiagnosed until a chest radiograph is ordered
    • Can be part of Kartagener syndrome: a triad of situs inversus, chronic sinusitis, and bronchiectasis
  • Heterotaxy syndrome (situs ambiguus):
    • Defect in right-left laterality, which results in abnormalities in arrangements of the heart, liver, intestines, or spleen
    • Organs may be structurally abnormal or abnormally positioned.
    • Patients may exhibit asplenia or polysplenia.
  • Transposition of the great arteries
  • Hydrocephalus
  • Fertility issues:
    • Infertility in men due to live, but immotile sperm
    • Impaired fertility in women due to impaired ciliary function in the fallopian tubes
  • Epispadias 
  • Pyloric stenosis

Diagnosis

Evaluation of ciliary function

There is no gold standard diagnostic test for PCD, but the following evaluations aid in the diagnosis: 

  • Nasal nitric oxide (nNO) determination:
    • Measures NO levels
    • Low or absent in PCD
    • Screening tool (needs confirmation, as similar findings are noted in viral infection and cystic fibrosis in rare instances)
  • Assessment of ciliary motion and ultrastructure using high-speed video microscopy analysis (HSVA) and transmission electron microscopy:
    • Ciliated epithelium obtained via nasal brushing using bronchoscopy (at least 4–6 weeks after a respiratory infection)
    • Ciliary beat frequency and pattern observed on video
    • Structural defects of cilia determined using electron microscopy
  • Cell cultures of ciliated cells:
    • Epithelia obtained using a cytology brush
    • Cilia are regrown and their ability to rotate cells is observed.
    • PCD: cells do not rotate
  • Genetic testing is useful in individuals exhibiting characteristic clinical features.
  • Measures of mucociliary transport:
    • Low availability and low sensitivity
    • Rarely used

Electron microscope photograph of the ciliary structure in a bronchiole:
Left: diagram of the ciliary internal structures
Middle: cross-section image obtained using electron microscopy
Right: The microtubules are labeled.

Left image by Lecturio.
Middle and right images: “Bronchiolar area cilia cross-sections 1” by Louisa Howard, Michael Binder. License: Public Domain, edited by Lecturio.

Additional tests

  • Spirometry: reveals mild-to-moderate obstructive disease with variable response to bronchodilators
  • Chest X-ray and high-resolution CT (HRCT) used to evaluate worsening lung function can usually reveal:
    • Hyperinflation
    • Peribronchial thickening
    • Atelectasis
    • Bronchiectasis (present on HRCT in all adults and about 50% of children with PCD)
  • Sinus CT scan is obtained in patients with chronic sinusitis who present with the following signs and symptoms:
    • Persistent mucociliary drainage
    • Nasal obstruction or blockage
    • Facial pain or pressure

Chest X-ray diagnosing Kartagener syndrome:
Mild cardiomegaly with pulmonary congestion and dextrocardia (arrow) noted in a patient with a form of primary ciliary dyskinesia. Kartagener syndrome (primary ciliary dyskinesia: situs inversus, chronic sinusitis, and bronchiectasis)

Image: “Chest X-ray” by Madeeha Subhan, Waleed Sadiq. License: CC BY 3.0

Management and Prognosis

Management

Treatment is individualized and guided by the clinical presentation of the patient.

  • Main goals of management:
    • Control and treat all infections.
    • Remove trapped mucus from the lungs and airways.
    • Treatment techniques are based on the experience of treating cystic fibrosis and other forms of bronchiectasis.
  • Monitoring
    • Close and continuous follow-up 
    • Spirometry at every visit (average 1–3 times annually) starting at 6 years of age
  • Management depends on the clinical course of the patient:
    • Bronchiectasis:
      • Daily chest physiotherapy
      • Use of selective antibiotics (guided by sputum cultures) to help clear secretions and decrease microbial load
      • For acute exacerbation of bronchiectasis: oral antibiotics
      • For P. aeruginosa infections or severe pneumonia: IV antibiotics
      • Preventive antibiotic therapy for recurrent exacerbations in patients ≥ 7 years of age is usually using macrolides
      • Vaccination against influenza and pneumococcus
      • Smoking cessation
    • Chronic rhinosinusitis and nasal polyposis:
      • Nasal saline lavage
      • Intranasal glucocorticoids for nasal polyposis
      • Antibiotics for exacerbations
    • Chronic otitis media with effusion: 
      • Can lead to hearing loss
      • Consider the use of a tympanostomy tube.
    • Male infertility: Consider in vitro fertilization techniques.
  • End-stage respiratory insufficiency:
    • Bilateral lung transplantation
    • In case of situs inversus: heart-lung transplantation

Prognosis

  • Patients generally have a normal lifespan.
  • Slower rate of reduction in lung function than cystic fibrosis
  • Repeated and chronic infections may impact the ability to work full-time.

Differential Diagnosis

  • Cystic fibrosis: an autosomal recessive disorder caused by mutations in the CFTR gene leading to dysfunctional chloride channels. The defective chloride channels lead to hyperviscous mucus and the accumulation of secretions. Cystic fibrosis commonly presents with recurrent respiratory infections, pancreatic insufficiency, and failure to thrive. Diagnosis is using a sweat chloride test followed by genetic testing. Cystic fibrosis has a worse prognosis than PCD. 
  • IgG subclass deficiency: a decrease in 1 or more subclasses of IgG antibodies with normal levels of other immunoglobulins. Patients are often asymptomatic but may have recurrent infections of the ears, bronchi, sinuses, and lungs. Updated vaccinations and antibiotics are part of the management. Immunoglobulin therapy is an option if initial management is not successful in controlling infections.
  • Granulomatosis with polyangiitis: a type of vasculitis that results in damage to various organ systems, particularly the kidneys and respiratory tract. Granulomatosis with polyangiitis can lead to constitutional symptoms, chronic upper respiratory infections, nosebleeds, ear pain, hemoptysis, and/or hematuria. Patients can progress to kidney failure. Granulomatosis with polyangiitis demonstrates c-ANCA positivity and is treated with corticosteroids along with an immunosuppressant.

References

  1. Bergström, S. (2021). Primary ciliary dyskinesia (immotile-cilia syndrome). UpToDate. Retrieved March 2, 2020, from https://www.uptodate.com/contents/primary-ciliary-dyskinesia-immotile-cilia-syndrome
  2. Husain, A. (2021). The Lung. In Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Philadelphia, PA: Elsevier Saunders.
  3. MedlinePlus (2020). Primary ciliary dyskinesia. Retrieved March 2, 2020, from https://medlineplus.gov/genetics/condition/primary-ciliary-dyskinesia/
  4. National Heart, Lung, and Blood Institute. Primary Ciliary Dyskinesia. Retrieved March 2, 2020, from https://www.nhlbi.nih.gov/health-topics/primary-ciliary-dyskinesia.
  5. National Organization for Rare Disorders (2020). Primary Ciliary Dyskinesia. Retrieved March 2, 2020, from https://rarediseases.org/rare-diseases/primary-ciliary-dyskinesia/

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