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What is PCD?

• Also called immotile-cilia syndrome
  • Congenital impairment of mucocilliary clearance
• A highly heterogeneous syndrome
  • Caused by a defect in structural proteins
  • Mutations result in abnormal ultrastructure, but some in preserved ultrastructure
• Incidence:  1 in 20,000-30,000 live births

Clinical Presentation

• Signs and symptoms
• Neonatal respiratory distress
• Organ laterality defect (50% of PCD)
• Persistent wet cough and nasal congestion
• Recurrent upper and lower respiratory infections
• Bronchiectasis
• Pansinusitis
• Male infertility
• Associated anomalies (other than organ laterality defect)
• Polycystic kidney disease, biliary atresia, and retinitis pigmentosa

Diagnostic Criteria

EM is included in the ATS and ERS criteria!

Major Criteria (Clinical Criteria)

1. Unexplained neonatal respiratory distress (at term birth) with lobar collapse and/or need for respiratory support with CPAP and/or oxygen for >24 hr
2. Any organ laterality defect—situs inversus totalis, situs ambiguous, or heterotaxy
3. Daily, year-round wet cough starting in first year of life or bronchiectasis on chest CT
4. Daily, year-round nasal congestion starting in first year of life or pansinusitis on sinus CT

Cystic fibrosis and immunodeficiencies, and diagnostic tests performed to rule out those disorders, as clinically indicated. 

Diagnostic Criteria

Diagnostic Criteria Newborns (0–1 month of age)

• Situs inversus totalis and unexplained neonatal respiratory distress at term birth 
• Plus at least one of the following: 
  1. Diagnostic ciliary ultrastructure on electron micrographs
  2. Biallelic mutations in one PCD-associated gene
  3. Persistent and diagnostic ciliary waveform abnormalities on high-speed videomicroscopy, on multiple occasions 

Note: nasal nitric oxide for ≥ 5 yo, since it is not yet sufficiently tested

Children (1 month to 5 years)

• Two or more major PCD clinical criteria (see below) 
• Plus at least one of the following: 
  1. Diagnostic ciliary ultrastructure on electron micrographs
  2. Biallelic mutations in one PCD-associated gene
  3. Persistent and diagnostic ciliary waveform abnormalities on high-speed videomicroscopy, on multiple occasions

Note: nasal nitric oxide for ≥ 5 yo, since it is not yet sufficiently tested

Children 5-18 years and adults

• Two or more major PCD clinical criteria (see below) 
• Plus at least one of the following: 
  1. Nasal nitric oxide during plateau <77 nl/min on 2 occasions, >2 months apart (with cystic fibrosis excluded)
  2. Diagnostic ciliary ultrastructure on electron micrographs
  3. Biallelic mutations in one PCD-associated gene
  4. Persistent and diagnostic ciliary waveform abnormalities on high-speed videomicroscopy, on multiple occasions

Difference in ATS and ERS criteria

American Thoracic Society

European Respiratory Society

Advantages and Limitations of Diagnostic Tests

Electron Microscopy

Sample Adequacy

• Ideal samples
  • An appropriate number of intact ciliated respiratory cells (e.g., >20 cells) that have total >50 preserved mid-shaft cilia cross-sections
  • Taken from multiple areas
    • To decrease the risk to include damaged cilia
  • Avoid inflammation (e.g., URI) or irritation (e.g., nasal cannula)
    • Inflammation/irritation cause denudation of cilia and squamous metaplasia

• Cilial ultrastructures are only evaluated on good cross-sections of mid-shaft cilia.

Ultrastructure of Normal Cilia

• Specificity is high
• Sensitivity is low; approximately 20% of PCD shows normal EM
• Should not rely on as a single diagnostic test

• Microtubular doublets “9+2” configuration
  • A central pair
  • 9 doublets in an outer circle
• Outer doublets have:
  • Inner dynein arms (IDA)
    • Attached at repeated 96 nm interval
  • Outer dynein arms (ODA)
    • Attached at repeated 24 nm interval
  • ODAs more frequently appear on cross-sections than IDA.
• Nexin
• Radial spokes
• Central sheath

Causative Gene Mutations and EM Finding

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