Primary Ciliary Dyskinesia (PCD)

Source: PCD Sunny Template.pptx (38 slides) Author: Orna McGinley Date: October 2024 Acknowledgements: With thanks to Simona Moravcikova (Specialist PCD Physiotherapist, Royal Brompton Hospital) Learning Level: Foundation through Advanced

Overview

1. What is PCD?
2. Cilia — structure and function
3. Diagnosis
4. Clinical Presentation
5. Treatment and Management
6. Clinics
7. Service in the UK
8. Useful Resources

1. Definition and Pathophysiology

What Is PCD?

Speaker Notes: Genetic mutation leads to defects in the motile cilia. Characterised by impaired mucociliary clearance, recurrent infections and progressive upper respiratory tract (URT) and lower respiratory tract (LRT) disease.

Key clinical summary (from notes): Primary ciliary dyskinesia (PCD) is a genetically and clinically heterogeneous disease, usually inherited in an autosomal recessive pattern. Patients with PCD develop recurrent and chronic infections of upper and lower airways, invariably leading to bronchiectasis and impaired lung function. Conductive hearing impairment is common and half of people with PCD have situs abnormalities, e.g. situs inversus or situs ambiguus, which can be associated with congenital heart disease. Many, but not all men are infertile due to immotile sperm, and some women are sub-fertile because of immotile cilia in the Fallopian tubes.

Learning Level: Foundation

2. Genetics

Inheritance Patterns

Disease-Causing Genes

• Over 50 disease-causing genes have been identified to date
• Increasing number of mutations being identified: 2012 = 2 genes, 2013 = 16, 2014 = 27, 2018 = 40, 2023 ~52

4 Most Common Genes

Gene Categories

Local Caseload

• Currently 24 paediatric patients on the RLH caseload

Learning Level: Intermediate/Advanced

3. Cilia — Structure and Function

Basic Structure

• Small, slender, hair-like structures on the surface of cells
• Involved in locomotion and mechanoreception
• Can be motile or non-motile
• Line the respiratory tract and reproductive tract
• Each mature ciliated cell contains 200 cilia
• Specialised organelles that provide the force necessary to transport foreign materials

Learning Level: Foundation

Ultrastructure (Axoneme)

Learning Level: Intermediate/Advanced

Ciliary Beat

Two Phases of Ciliary Beat

• Metachronal beating — coordinated wave-like motion of cilia

Learning Level: Intermediate

4. Ciliary Defects

Beat Pattern Defects

Structural (Cilia) Defects

Learning Level: Advanced

5. Diagnosis

Principles

• Based on clinical phenotype and combination of tests
• No standalone test or combination of tests can definitively rule out PCD
• ERS recommends that PCD should be confirmed in a specialist centre using appropriate diagnostic testing

Learning Level: Intermediate

PICADAR Score

PICADAR: A Diagnostic Predictive Tool for Primary Ciliary Dyskinesia (published tool)

Used to identify patients who should be sent for diagnostic testing.

Learning Level: Intermediate

Diagnostic Tests

ERS Guidelines recommend the following diagnostic tests:

1. Nasal Nitric Oxide (FeNO)

Technique (from notes): Once the nasal olive is placed inside the child’s nostril, the test will start. The child will be asked to breathe in through a mouthpiece as deeply as possible. They will then be asked to breathe out at a steady pace for 10 seconds. An animation on the screen will help them achieve the correct speed. While breathing in and out, the nasal olive measures the nitric oxide levels. This process is repeated a few times in each nostril.

2. High Speed Video Microscopy (HSVM)

3. Transmission Electron Microscopy (TEM)

4. Immunofluorescent Assay

Speaker Notes: Immunofluorescence assay is a significant technique commonly used in immunology or molecular biology for detecting the presence and distribution of specific proteins or antigens. This process uses antibodies labelled with fluorescent molecules that bind to the target protein or antigen of interest. The immunofluorescence assay principle relies on the antibodies’ specificity for their target proteins. This specificity helps selectively label and visualise the location and distribution of specific proteins within cells, tissues, or other biological samples. Immunofluorescence can be helpful in clinical diagnostics for detecting specific antigens or markers associated with diseases or conditions.

5. Genetic Testing

• Increasing number of mutations being identified (see Genetics section above)
• Common genes by category provided above

Diagnostic Pathway

• Diagnostics are undertaken in PCD specialist centres
• If a patient is suspected to have PCD, they are referred to the Royal Brompton Hospital

Learning Level: Advanced

6. Clinical Presentation

Typical Presentation

Learning Level: Foundation

PCD Lungs

• Chronic (wet) cough
• Poorly / non-functioning mucociliary escalator leading to sputum retention
• Consistent airway inflammation +/- infection
• Recurrent exacerbations with lower airway infection / inflammation
• Areas of V/Q mismatch
• +/- Bronchiectasis — scarring / changes to the airways
  • Preventable but irreversible
• Research mostly extrapolated from CF

Learning Level: Foundation/Intermediate

PCD Sinuses

• Constantly blocked / runny nose
• Recurrent sinusitis
• Poor sense of smell and taste
• Headaches
• Facial fullness
• Nasal polyps
• Element of bronchopulmonary disease (BPD)

Learning Level: Foundation

PCD Ears

• Frequent ear infections
• Hearing loss
• Otitis media (glue ear)
• Grommets — generally unsuccessful
• Yearly ENT check-ups required

Speaker Notes: A surgical procedure that involves inserting tiny tubes into the eardrum to treat fluid build-up in the middle ear (glue ear). In healthy ears, cilia beat mucus and fluid from the middle ear to the back of the nose but in PCD this does not happen. As a result, many children with PCD have mild hearing loss and grommets will not improve this.

Learning Level: Foundation

PCD Heart

• Situs inversus
• Dextrocardia
• Congenital heart defects: TGA, ASD, VSD, TOF, etc.

Learning Level: Foundation

Other Issues

Learning Level: Intermediate

7. Treatment and Management

ERS Guidelines 2021

Airway Clearance

Strong recommendation, very low quality evidence:

• All patients should be taught and receive regular airway clearance techniques (ACT) or manoeuvres
• Individualised frequency of ACT
• Should be reviewed at least biannually by paediatric respiratory physiotherapists
• During acute exacerbations, children/adolescents should receive ACT more frequently

Inhaled Therapies

Conditional recommendation, low evidence:

• Neither inhaled mannitol nor hypertonic saline are used routinely
• SABAs should be used prior to inhaling either HS or mannitol

DNase

Strong recommendation, low evidence:

• Recombinant human DNase is NOT used routinely in PCD

Defining Exacerbations

In children/adolescents with bronchiectasis:

• Increased respiratory symptoms (cough +/- increased sputum quantity and/or purulence) for >3 days
• The presence of dyspnoea (increased work of breathing) and/or hypoxia should be considered a severe exacerbation, irrespective of duration

Learning Level: Intermediate

Paediatric Physiotherapy Guidelines 2018

Airway Clearance Techniques (ACT)

Exercise

Sinonasal Management

Learning Level: Intermediate/Advanced

Treatment Summary

Learning Level: Foundation

Things to Consider During ACT

• Normal mucociliary transport is absent/impaired
• Viscoelastic properties of the phlegm
• Sinus issues — impact on upper airway
• Element of BPD (bronchopulmonary disease)
• Hydration of the airway (many are mouth breathers)
• Positive pressure / oscillation with headaches — may exacerbate sinus symptoms
• Hearing — communication challenges during treatment
• Age — developmental appropriateness of techniques

Learning Level: Intermediate

8. Microbiology / Sampling

Common Pathogens

Learning Level: Intermediate

9. Clinic Considerations

Routine Clinic Assessments

• Lower airway sample (likely sputum in children >5 years old)
• Upper airway sample (nasal lavage in children >5 years old if swallow not a concern)
• Check ACT at least annually (biannually if bronchiectasis)

Common Challenges

• Usually poor understanding of PCD and ACT (child and parent) — education is key
• Burden of treatment — significant treatment load
• Altered perception of symptoms (when well or unwell)
• Safeguarding concerns
• Language and cultural considerations
• Stress urinary incontinence — screen and address

Clinic Frequency

Speaker Notes: Business case going in to try increase clinics to monthly. Currently 4 times a year (2 joint with RBH).

Learning Level: Intermediate

10. PCD Services in the UK

Diagnostic and Management Centres

Management Only Centres

National Adult Service

• Established August 2020

Learning Level: Foundation

11. Standards of Care

• Physiotherapy English National Standards of Care for Children with Primary Ciliary Dyskinesia (2018)
• Paediatric PCD Standards of Care — submitted April 2024, currently under review

Learning Level: Intermediate

12. Useful Contacts

Royal Brompton Hospital

Royal London Hospital

Websites

• PCD Support UK — HOME - PCD Support UK, Primary Ciliary Dyskinesia
• BEAT-PCD — BEAT-PCD (squarespace.com)

Learning Level: Foundation

13. References

1. Chang AB, Bush A & Grimwood K. Bronchiectasis in children: diagnosis and treatment. The Lancet 2018; 392(10150): 866-879.
2. Chang AB, et al. Clinical and research priorities for children and young people with bronchiectasis: an international roadmap. European Respiratory Journal 2021; 7.
3. Chang AB, et al. Task Force Report: European Respiratory Society guidelines for the management of children and adolescents with bronchiectasis. European Respiratory Journal 2021; in press.
4. Hamamy H. Consanguineous marriages: preconception consultation in primary health care settings. Journal of Community Genetics 2012; 3(3): 185-192.
5. Jackson LC, et al. Accuracy of diagnostic testing in primary ciliary dyskinesia. European Respiratory Journal 2015; 47(3).
6. Lucas JS, Burgess A, Mitchison HM, et al. Diagnosis and management of primary ciliary dyskinesia. Arch Dis Child 2014; 99: 850-856.
7. Mata M, et al. Gene mutations in primary ciliary dyskinesia related to otitis media. Current Allergy and Asthma Reports 2014; 14(420).
8. Schofield LM, et al. Physiotherapy English National Standards of Care for Children with Primary Ciliary Dyskinesia. Journal of ACPRC 2018; 50: 71-82.
9. Shapiro AJ, et al. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia. Chest 2014; 146(5): 1176-1186.
10. Walker WT, et al. Nitric oxide in primary ciliary dyskinesia. European Respiratory Journal 2012; 40: 1024-1032.
11. Wijers CDM, Chmiel J & Gaston BM. Bacterial infections in patients with primary ciliary dyskinesia: comparison with cystic fibrosis. Chronic Respiratory Disease 2017; 14(4): 392-406.
12. Wodenhouse T, et al. Nasal nitric oxide measurements for the screening of primary ciliary dyskinesia. European Respiratory Journal 2003; 21: 43-47.