PCD more common than currently recognised

Primary ciliary dyskinesia (PCD) is much more common than currently recognised, the Irish Thoracic Society 2025 Annual Scientific Meeting heard. 

An inherited disorder, PCD is a clinically and genetically heterogeneous condition, caused by pathogenic variants in at least 50 genes, but likely many more. 

The variants result in the congenital impairment of mucociliary clearance due to a defect in the cilia. Clinically, PCD is variably characterised by bronchiectasis, chronic rhinosinusitis, recurrent otitis media, laterality defects, and infertility.

Dr James O’Hanlon, University Hospital Galway (UHG), gave a presentation on ‘A view of PCD in a tertiary referral centre in Ireland’ to the meeting.

Dr O’Hanlon told attendees that PCD prevalence “is likely grossly underestimated”, with only 1,236 people with genetically-diagnosed PCD known to the European Reference Network (ERN)-LUNG registry and 698 included in the US registry.

He added that a 2022 Lancet study looked at the frequency of disease-causing variants in 29 PCD genes in 182,000 individuals worldwide.

The study estimated the global prevalence of PCD to be one in 7,500.

“We know that at least 50 genes are associated with PCD, with 37 deemed definitely associated,” he said.

Another 2022 study from the European Respiratory Journal found that motile ciliopathy associated genes were identified in 12 per cent of the 142 patients recruited for whole-genome sequencing who had a diagnosis of idiopathic bronchiectasis.

“The bottom line is that most people with PCD remain undiagnosed,” Dr O’Hanlon said. He added that different mutations can affect different parts of the axoneme resulting in variable clinical manifestations.

“The resultant lung disease is heterogeneous across all ultrastructural and genotype groups and some are more severe than others,” he said. They are worse in those with inner dynein arm, central apparatus, and microtubular disorganisation ultrastructural defects, Dr O’Hanlon noted.

“When we compare this to [cystic fibrosis], which is a monogenic disease, we can see that comparatively there is a huge variety in what can go wrong in PCD and how that can present.”

Traditionally, guidelines have recommended using a combination of tests to diagnose PCD.

In Ireland, however, the requirement for patients to travel abroad for these investigations has likely led to their under-utilisation, resulting in a greater reliance on clinical features for diagnosis.

This year, the European Respiratory Society and American Thoracic Society published consensus guidelines for the diagnosis of PCD for the first time. The diagnosis can be confirmed either by genetic testing or by transmission electron microscopy (TEM), but other methods can support a diagnosis in the correct clinical context.

High-speed video microscopy is the only diagnostic test that allows direct visualisation of ciliary dyskinesia. It can identify abnormalities in cilia affected by pathogenic mutations in DNAH5, the most common gene associated with PCD. Immunofluorescence is another valuable tool, particularly for clarifying genetic uncertainty related to variants of unknown significance, such as HYDIN.

“The guidelines recommend that PCD patients would have all of these investigations performed, but a more practical approach is possible where access is limited,” he said. “Immunofluorescence is much easier to analyse and perform than TEM, so we will likely see a more prominent role in diagnosis going forward.”

He emphasised the importance of obtaining a clear diagnosis, noting that patients with confirmed PCD gain access to specialised, multidisciplinary care provided through dedicated PCD referral centres. Following diagnosis and the initiation of appropriate management, stabilisation of the condition and improvements in lung function can also be achieved.

He noted that delayed diagnosis in adults with PCD is associated with reduced ‘forced expiratory volume’ at the time of diagnosis, as well as an increased likelihood of Pseudomonas aeruginosa colonisation.

“Now there are specific therapies in development targeting known pathogenic mutations, which will hopefully be a future therapy option for our patients,” he said.

While genetic diagnosis is strongly encouraged whenever possible, it is negative in about 30 per cent of cases, so often further testing is needed, the meeting heard. TEM is the only way to confirm a diagnosis where there is no pathogenetic phenotype identified. TEM is 99 per cent specific in confirming a PCD diagnosis when performed within specialist centres.

Nasal nitric oxide (nNO) testing can also support a diagnosis and is easily performed in clinic. It can be measured during velum closure or tidal breathing, with velum closure providing greater accuracy and less variability.

 Dr O’Hanlon explained that in UHG, a search was carried out of a clinic letter database for mention of PCD or related terms. Patients who had been given PCD as a primary diagnosis were identified.

Patients were further analysed with regard to previous diagnostic evaluation, clinical features, co-morbidities, and sputum microbiology. The aim of the study was to identify patients with suspected PCD, and assess their previous diagnostic evaluation. A diagnosis would then be made and formal multidisciplinary care would be instituted.

A total of 25 patients were identified, 60 per cent of whom were female, with a median age of 38. Four of these patients had a diagnosis confirmed by genetic testing or TEM.

“So, despite having typical clinical features, the vast majority of patients with suspected PCD had not had the required diagnostic work-up to confirm the diagnosis.”

Following these findings, clinicians continued to actively case-find while also identifying cases opportunistically. Once identified, these patients were referred to the specialist bronchiectasis clinic for comprehensive evaluation and management.

“Now we have five new confirmed diagnoses of PCD by genetic analysis,” he said. nNO has been performed in 12 patients and was positive in nine. One patient was referred to the UK for TEM.

Regarding the most common causative genes, five were identified, with HYDIN being by far the most frequent. The HYDIN gene encodes a protein essential for ciliary motility, but it does not affect the overall ciliary ultrastructure, meaning that TEM results appear normal.

“These patients often have preserved lung function,” he said. He also highlighted that the majority of these patients are within the Traveller community.

In terms of take-home messages, Dr O’Hanlon emphasised that clinicians should maintain a high index of suspicion for PCD in patients with typical features, as a confirmed diagnosis has important implications for care. Certain causative genetic mutations, such as HYDIN, may be more prevalent in Ireland than in other populations.

When asked why HYDIN may be more common here  than elsewhere, Dr O’Hanlon said it was known to be more common in closed ethnic groups, with consanguinity a big risk factor.

“But we would still not expect to see it as prevalent in Ireland as compared to the rest of Europe. Most of the people we have seen are members of the Traveller community, but some are not, and don’t have any risk factors. So there is more to it than that as well.” 

He stated that UHG, along with other sites in Ireland, will be designated as a PCD centre as part of the ERN-LUNG International PCD Registry.

“We then will be able to centralise care and establish a nationwide diagnostic pathway for adult and paediatric medicine, which will hopefully have important implications for these patients.”