Mahreen Sohail and Abi Whitehouse

Having dysfunctional cilia can really put your mucus in the wrong place at the wrong time. Primary ciliary dyskinesia (PCD) is one of the rarer chronic lung diseases in children. In the UK, we see it in about 1 in 20,000 people, although there is ethnic variation with some studies reporting 1 in 2,200 people in the UK Asian population. It is often picked up relatively late (there is no newborn screening test for it) so presentation can vary quite a lot. We hope that this article will guide you through the ins and outs of presentation, diagnosis, and management so you can identify some dodgy cilia!

A little bit of normal physiology

Cilia are little organelles projecting from the bigger cellular body in many different types of cells. Each type of cilia have their own properties – some are motile whilst some are not, some have special sensory receptors while some do not etc. 

Under an electron microscope, the basic structure of the ciliary skeleton forms a “9+2” pattern: there are two central microtubules surrounded by nine outer doublets of microtubules in a ring formation. There are various protein complexes attached to the microtubules known as dyneins and nexins as shown in the diagram below and these proteins have a role in the movement of the cilia.

Broadly, cilia can be classified based on microtubular structure and function to:

1. Motile cilia – These cilia have a classic “9+2” microtubular arrangement in electron microscopy and move in a distinct beat in a planar fashion. They are seen in cells lining the airways, sperm, fallopian tubes and brain ventricles. These motile cilia are affected in PCD and it is mainly the dysmotility of these cilia which is responsible for the clinical features seen in the patients.
2. Sensory cilia – These are non-motile cilia which are arranged in the microtubular pattern of 9+0. Their main function is to serve as sensory receptors in various organs such as renal tubules, bile and pancreatic ducts, cochlea etc. Abnormality in genes encoding for this type of cilia can causes diseases such as polycystic kidney disease, Bardt-Biedl syndrome but they are not affected in PCD.
3. Nodal cilia – These are unique cilia that are seen transiently during embryonic development. Their structure is also characterized by a 9+0 pattern seen in the sensory cilia but they spin in a clockwise manner and is responsible of left-right sidedness. Dysfunction of cilia at the node can result in situs inversus, a feature that is frequently seen in PCD.

Primary Ciliary Dyskinesia

Armed with our understanding of cilia history and physiology, we can now talk PCD! PCD is a rare, ciliopathic, autosomal recessive genetic disorder that causes defects in the action of cilia lining the respiratory tract, fallopian tube, and flagellum of sperm cells. These cilia beat in an irregular, unsynchronized pattern leading to the clinical manifestations seen.

PCD, Kartagener, immotile ciliary syndrome…. which one is which?

There’s a fair bit of overlap in the nomenclature of PCD which means you may remember some of the more complex aspects from medical school. Patients with PCD were first described by Dr A W Seiver in 1904 and Dr Kartagener in 1933, who both noticed patients with bronchiectasis and situs inversus. Later on in 1976, Dr Azfelia noticed cilia abnormalities in these patients, and subsequent research led to the name we know today as Primary Ciliary Dyskinesia.

The most important clinical feature suggestive of a PCD diagnosis is a wet sounding cough that has always been there

The clinical spectrum of the disease is quite varied for several reasons:

• There is marked heterogenicity in the symptom manifestation based on extent of ciliary dysfunction.
• There is also variability in disease presentation based on age of the child.
• The clinical symptoms are often not very striking and in the absence of a widespread screening test, it is important to have a high degree of clinical suspicion to investigate for the disease (which is unfortunately may not be the reality of the situation).

The most important clinical feature suggestive of a PCD diagnosis from a detailed history includes a wet sounding cough that has ‘always been there’ and is present every day even when the child is well. Most older children and adults will also expectorate sputum. In PCD, chronic secretion retention in the upper respiratory tract predisposes to infection in the middle ear, nose and facial sinuses. Chronic otitis media with effusion affects up to 80% of children and is often persistent, with fluctuation through adulthood and can be associated with hearing loss as well.

Children often also have chronic rhinosinusitis which can have a major impact on quality of life – the persistent runny nose, nasal congestion, chronic otitis media, difficulty hearing, speech delay can all also add to furthering the psychosocial burden of the disease on the child. Complications associated with the chronic cough can lead to pneumonias and chronic obstructive suppurative lung disease, with localised-to-diffuse bronchiectasis. In neonates, unexplained neonatal respiratory distress is observed to be a frequent clinical feature. Most of these babies often have transient tachypnea of the newborn with resolution by the fifth day of life. However, some PCD infants with TTN may require continuous supplemental oxygen for days to weeks, these infants are often retrospectively diagnosed as PCD.

So how do we diagnose it?

In the UK we have centralised services for the diagnosis of PCD. However there is often a delay in the diagnosis of the disease with a study in 2016 reporting that thirty-five percent of patients with confirmed PCD had visited their doctor on more than 40 occasions with symptoms prior to referral for PCD testing.

The problem with the current diagnostic tools is that a lot of them may be normal in PCD and there is lack of a standardised consensus of what the cut-off for abnormal is. 

Currently, a positive diagnosis of PCD requires a combined approach of investigations. The various tools used are:

1. Nasal nitric oxide – Its levels are extremely low in PCD compared to healthy and disease controls. There are many theories on why this happens and one popular explanation is that there is a reduced biosynthesis of NO by paranasal sinuses. This test is sensitive, rapid, non-invasive, and results are immediately available. Unfortunately, measuring nasal nitric oxide in younger children is challenging due to poor cooperation and this is the vital target age group to identify and diagnose PCD. Also, there is no standardised ‘cut-off’ as it can vary based on age and method of measuring nNO.
2. High speed video microscopy – Direct visualisation of ciliary beat frequency and ciliary beat pattern can be used to visualise the movement of cilia as part of the PCD diagnosis.
3. Transmission electron microscopy – EM of ciliary cross sections from a nasal respiratory epithelium sample can show a direct visual of the microtubular structure. This allows us to compare the cilia ultrastructure with that of a normal person to recognise any defects.
4. Ciliated cell culture – Ciliated epithelium can be re-analysed following the culture and re-differentiation of the epithelial cells. These specimens are then studied under electron microscopy.

A sick child with PCD in the emergency department

How does all this knowledge about PCD fit into the day-to-day practice of a general paediatrician? Consider this scenario:

MS is a 12-year-old girl who has come to the emergency department with a productive cough for the past 2 months. Her cough is ‘wet-sounding’, but she says she feels fine. Parents are concerned about her fever which is why they’ve brought her in. She’s a known case of PCD and has had multiple admissions in the past for recurrent episodes of respiratory tract infections since childhood. You review her history and you find out that:

On examination, you auscultate some crepitations bilaterally but there are otherwise no abnormal findings. MS says she’s fine and is very keen to go home

• Birth history: she was a term delivery, born in good condition but was admitted for respiratory support for a few days after which she got better on her own and was discharged with no other complications.
• Her past medical history revealed that MS has long standing problems with nasal discharge and hearing problems. She was previously seen by ENT for grommet insertions.
• In the past year, she had some chest x-rays which showed left basal consolidation with effusion. A CT chest done 2 months ago showed bronchiestasis on the left side.

The truth is…its hard! It can be difficult to evaluate the disease based on clinical assessment alone. This is because children with PCD have a persistently wet sounding cough which remains unchanged regardless of treatment and may not always give a true indication of severity or how far they are from their ‘baseline’. This places a large emphasis on monitoring changes in cough and sputum production, clinical wellbeing, lung function and culture of pathogens. In this scenario it would be best to review MS’s history in more detail on sputum frequency change, spirometry, previous sputum culture results. Deterioration in these parameters will often require antibiotic treatment and more intensive inpatient airway clearance with the physiotherapist.

Management of PCD

The aim of management for the respiratory symptoms of PCD is to improve and maintain the child’s lung function based on early detection and vigorous treatment of complications. 

It is important to keep in mind that although maintaining a good lung function is important for these children, there are lots of other options to optimise their health. The MDT team often includes, but is not limited to: PCD respiratory physicians, ear, nose and throat physicians with an interest in PCD, PCD physiotherapists, PCD nurses, and audiologists. Principles of their care involve a set of regular reviews in a specialist centre, with personalised management plans, and an aggressive approach to airway clearance and management of infections.

A big part about managing PCD is about education. PCD is lifelong and so it is important to educate carers and children to learn about the disease as well as management options present to them such as understand the importance of long term physiotherapy, using nebulisers at home, routinely sending cough swabs etc.

Although maintaining a good lung function is important for these children, there are lots of other options to optimise their health.

Below are some basic principles of respiratory management arranged in different categories.

Airway clearance	There are different techniques to airway clearance in PCD which is recommended such as manual chest physiotherapy, postural drainage, autogenic drainage, active cycle breathing, and exercise. Various combinations of modalities and routines exist tailored specifically to the child but generally a minimum of once a day physiotherapy session is advocated
Bugs in the lungs	All patients with PCD should have routine clinical visits (at least 2-4/year) for spirometry monitoring and respiratory culture checks through sputum or oropharyngeal swabs. The hot bugs children are monitored for are Pseudomonas aeruginosa and atypical Mycobacteria. They are also surveyed for Staphylococcus aureus, Streptococcus pneumonia, and Haemophilus influenza. Acute airway infection with with any of the above would warrant antibiotic treatment. The keyword here is ‘acute’ as some of these children may be chronically colonised with certain bugs.  High-dose oral antibiotics should be prescribed at the first sign of worsening respiratory symptoms or deterioration in lung function. If persistent respiratory symptoms do not respond to oral antibiotics, then intravenous therapy should be given. A small cohort of patients may even need regular 3 monthly courses. Some patients may even need long-term use of nebulised anti-pseudomonas antibiotics to reduce exacerbations.
Mucolytics	Nebulised inhaled hypertonic saline (3-7%) is a common aid to help moisten and dilute viscous airway secretions to help clear airways. Nebulised DNAse can be considered for use as well.
ENT symptoms	Chest symptoms are often considered the most important aspect of PCD management but it is often the nasal symptoms that children find most bothersome. From a psychosocial point of view children may face bullying in school due to a constant runny nose, eating with their mouth open and sniffing. Nasal douching may help with symptomatic relief. Children with PCD often have glue ear resulting in conductive hearing loss. Regular audiology is essential to assess hearing and provide hearing aids if necessary. If hearing deteriorates, they may need a grommet inserted. All children are offered a school visit to explain PCD care with special emphasis given to hearing  because of how important it is for learning.

Where Next?

• As illustrated from the article above, there’s still a lot of work needed into developing standardized cut-offs and clear guidelines for diagnosing PCD. 
• A lot of the respiratory management of PCD is based off managing children with cystic fibrosis. There is a need for developing specific gold standard guidelines for management of children with PCD.
• Genetics: PCD is associated with mutations in at least 30 separate genes (encoding for various proteins within the microtubular structure) encompassing over 700 exons. Comparatively, cystic fibrosis is a disease of mutations in one known gene (coding for the CFTR protein) and encompasses approximately 27 exons. So far, only about 60% of diagnosed PCD cases have been accounted for by gene abnormalities. There is huge potential for further research to identify more genetic mutations coding for PCD which will open possibilities for appropriate genetic counselling and extended family screening in high-risk populations.
• In the pipeline for development is a questionnaire screening tool to identify and refer people who may have PCD. This tool is known as a PICADAR tool. It’s basically a seven-question tool to be used in a non-specialist setting to determine which patients with chronic chest symptoms require PCD diagnostics. Research is still ongoing on in implementing the tool for referring to PCD centers. You can read more about it in this article here.
• The European Respiratory Society has a basic framework for management which can be found here.

Further reading

1. Robson EA, et al., Update on primary ciliary dyskinesia, Paediatrics and Child Health (2017), http://dx.doi.org/ 10.1016/j.paed.2017.03.007
2. Mirra V, Werner C, Santamaria F. Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies. Front Pediatr. 2017;5:135. Published 2017 Jun 9. doi:10.3389/fped.2017.00135
3. Fretzayas A, Moustaki M. Clinical spectrum of primary ciliary dyskinesia in childhood. World J Clin Pediatr. 2016;5(1):57-62. Published 2016 Feb 8. doi:10.5409/wjcp.v5.i1.57
4. Ware, Stephanie & Aygun, Meral & Hildebrandt, Friedhelm. (2011). Spectrum of Clinical Diseases Caused By Disorders of Primary Cilia. Proceedings of the American Thoracic Society. 8. 444-50. 10.1513/pats.201103-025SD.
5. Horani A, Ferkol TW. Advances in the Genetics of Primary Ciliary Dyskinesia: Clinical Implications. Chest. 2018;154(3):645-652. doi:10.1016/j.chest.2018.05.007
6. Laura Behan, Borislav D. Dimitrov, Claudia E. Kuehni, Claire Hogg, Mary Carroll, Hazel J. Evans, Myrofora Goutaki, Amanda Harris, Samantha Packham, Woolf T. Walker, Jane S. Lucas PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia. European Respiratory Journal 2016; DOI: 10.1183/13993003.01551-2015

Mahreen Sohail is a Junior Clinical Fellow in Respiratory Paediatrics at the Royal London Hospital and Abi Whitehouse is a NIHR Academic Clinical Lecturer at Queen Mary University London