Coordinator: Melissa Borrelli
Segretario: Adele Corcione
Primary Ciliary Dyskinesia – PCD – is a rare genetic disorder characterized by marked clinical heterogeneity and often progressive involvement of the respiratory system. Early diagnosis is essential to ensure timely specialist follow-up and prevent long-term complications. In 2025, new joint guidelines from the European Respiratory Society (ERS) and the American Thoracic Society (ATS) were published to address PCD diagnosis. The aim of the document is to provide a shared international diagnostic approach based on current scientific evidence.
Diagnostic methods assessed
The new guidelines assess the diagnostic accuracy of nasal nitric oxide measurement, high-speed video microscopy, and immunofluorescence as complementary tools to genetic analysis and transmission electron microscopy in confirming the diagnosis in subjects with a strong clinical suspicion of PCD.
1. Main diagnostic recommendations
• Nasal nitric oxide (nNO)
Measurement of nNO during velum closure is strongly recommended as an additional test to genetics and/or transmission electron microscopy (TEM), based on moderate-quality evidence. Measurement during tidal breathing is instead conditionally recommended because of its lower diagnostic accuracy. Chemiluminescence analyzers remain the reference standard, whereas portable electrochemical devices are not yet fully standardized.
• High-speed video microscopy (HSVM)
HSVM is strongly recommended in combination with genetics and/or TEM. Although the quality of evidence is considered very low, HSVM allows direct visualization of ciliary beating and confirmation of the primary nature of ciliary dyskinesia through reproducibility of abnormalities after in vitro cell culture. The absence of HSVM in the diagnostic pathway may lead to missed diagnoses in patients with normal nNO values, age < 5 years, or inconclusive genetic/TEM results.
• Immunofluorescence (IF)
The guidelines strongly recommend the use of IF in addition to TEM and/or genetic testing because of its high diagnostic accuracy. IF may be particularly useful in cases involving variants of uncertain significance (VUS), providing additional information to support diagnosis.
2. Additional aspects of diagnosis
The document also addresses three additional aspects of particular relevance in the diagnosis of PCD: age-related clinical manifestations guiding diagnostic suspicion, additional diagnostic tools, and strategies to overcome diagnostic challenges in resource-limited settings.
The PICADAR score and other symptom-based scoring systems are useful tools for identifying patients at risk. However, a high index of clinical suspicion and awareness of the broad phenotypic variability of the disease, including atypical presentations, remain essential.
Regarding additional diagnostic tools, advanced genetic techniques such as whole-exome sequencing, whole-genome sequencing, and long-read sequencing can identify variants not detected by standard panels, including deep intronic mutations and structural variants. However, these methods have limitations, including higher costs and challenges in interpreting variant pathogenicity. RNA sequencing represents another promising tool allowing the detection of complex genetic alterations and functional variants not identifiable with traditional techniques.
Among functional tests, pulmonary radio-aerosol mucociliary clearance (PRMC) — a functional imaging technique assessing mucociliary clearance efficiency by measuring the rate of elimination of radiolabeled aerosol from the airways — has demonstrated high diagnostic accuracy, although it requires patient cooperation, skilled technicians and standardized protocols. The guidelines also highlight the future potential of artificial intelligence in processing and interpreting diagnostic data.
In resource-limited settings, diagnosis remains particularly challenging because of limited availability of specialized tests, inadequate infrastructure, and lack of dedicated expertise. Effective strategies include the use of clinical screening tools, centralization of testing, collaboration with expert centers, and support from international networks.
3. Key points and diagnostic algorithm
The guidelines define that the diagnosis can be confirmed in the presence of a suggestive clinical phenotype associated with a class I defect on TEM or with pathogenic or likely pathogenic variants in genes known to be associated with PCD. Adjunctive diagnostic tests (nNO, HSVM, and IF) are considered useful tools that can be included in the diagnostic algorithm; however, none of them alone has sufficient sensitivity and specificity to be used as a standalone diagnostic test.
Diagnosis therefore requires an integrated approach based on the combination of clinical data and results from multiple investigations, without a strictly predefined sequence for performing the different tests. Not all tests are required in all circumstances, but limiting the number of tests performed may reduce diagnostic accuracy. The quality of test performance and laboratory expertise are critical to ensuring reliable results, as is the use of more extensive tests, which are generally more accurate. The guidelines emphasize the importance of referring patients with clinical suspicion of PCD to specialist centers, highlighting that early diagnosis is associated with improved respiratory outcomes and is a shared priority for both patients and their families.
The proposed diagnostic algorithm integrates clinical data and test results to define five diagnostic categories: “confirmed PCD,” “highly likely PCD,” “suspected PCD,” “unlikely PCD,” and “highly unlikely PCD.” The definition of “suspected PCD” is used for patients with compatible clinical features and inconclusive or discordant test results; these cases should be reassessed over time and, whenever possible, followed up in expert centers.
4. Conclusions and practical implications
The new 2025 ERS/ATS guidelines provide an updated diagnostic algorithm developed through international consensus. The document emphasizes the importance of early recognition of the clinical signs of PCD and prompt referral of patients with suspected disease to specialized centers. Early diagnosis enables implementation of monitoring and treatment strategies aimed at preserving respiratory function and improving patients’ quality of life. Overall, the guidelines aim to standardize the diagnostic pathway for PCD at an international level, promoting greater equity in access to care, consistency in diagnostic practice, and the development of future clinical research.
Limitations
PCD is a rare and heterogeneous disease, and the evidence supporting diagnostic tests remains limited, with considerable variability related to different genotypes and laboratory expertise. Furthermore, the ongoing identification of new disease-associated genes requires continuous updates to diagnostic pathways and interpretation strategies, particularly in cases with inconclusive or uncertain findings
References
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