The Controversies and Difficulties of Diagnosing Primary Ciliary Dyskinesia

To the Editor:

We welcome the correspondence from Lavie and Amirav (1), highlighting the difficulties diagnosing primary ciliary dyskinesia (PCD) and the role of high-speed video analysis (HSVA). As members of the European Respiratory Society (ERS) PCD Diagnostic Task Force (2) and/or large PCD Centres, we agree that HSVA has an important role that is not recognized by the American Thoracic Society (ATS) PCD Diagnostic Guideline (3). This risks a large proportion of false-negative “missed” diagnoses and a sizable number of false-positive cases; we make additional important observations.

We agree with Lavie and Amirav that nasal nitric oxide (nNO) should not be used in isolation to make a diagnosis or to exclude PCD. The risk for false-negatives is clearly described in the literature (reviewed in Reference 2). The ERS Guidelines therefore suggest that both nNO and HSVA should be entirely normal before deciding that further investigation is not warranted (2). We all have patients who proceeded to further testing because clinical history was strong or HSVA was abnormal despite normal nNO, and then had a diagnosis confirmed by transmission electron microscopy (TEM) or genetics (e.g., CCDC103, DNAH9, or RSPH1 mutations). Contrary to Lavie and Amirav, neither ATS nor ERS guidelines would exclude the diagnosis of PCD in patients with a compatible history and diagnostically low nNO despite normal HSVA, without proceeding to further tests including TEM and genetics.

Similarly to Lavie and Amirav, we were surprised that the ATS guideline specifically suggests not assessing ciliary beat pattern. Dyskinesia is a key feature of the condition and can be accurately detected by HSVA (4). According to the ERS Guidelines, repeatedly dyskinetic cilia or abnormal beat pattern following reanalysis after culture, with normal genetics and TEM, indicates PCD is “highly likely” (2), and patients should follow a PCD treatment plan (2). This recognizes that TEM and genetics will each be normal in 20–30% (2) of patients who truly have PCD (false negative), and that HSVA will detect most of these patients who require specialist PCD care. Until HYDIN, DNAH11, and GAS8 were discovered as PCD genes, the patients were recognized by abnormal HSVA, and until all genetic causes are identified, HSVA is needed. It also acknowledges that even repeatedly abnormal HSVA may be falsely positive, and therefore the ERS Guidelines recommend that patients are not labeled as definitely having PCD based on HSVA alone (2, 4). Importantly, HSVA provides an accurate result on the day of testing that can be used to counsel patients and commence treatment while awaiting confirmatory TEM and genetics (4). HSVA also has an important research value, assessing the ability of novel treatments to restore function.

There are a large number of PCD genes, and because of their size, variants are common; not infrequently, patients without PCD have biallelic variants of unknown significance in PCD-related genes. The specificity of genetic testing is severely reduced, and many individuals could be incorrectly diagnosed with PCD (false positive) unless the mutations are confirmed pathogenic. It is therefore essential to ensure that the genotype is compatible with the ciliary phenotype using HSVA, TEM, and/or immunofluorescence labeling, as well as with the clinical phenotype (2).

Importantly, there is no perfect way to identify patients for diagnostic testing based on clinical assessment. Lavie and Amirav outline the approach proposed by the ATS Guideline, using a four-point clinical symptoms score. Having two of four clinical features provides specificity (0.72), ensuring that the diagnostic service only sees the most likely cases, but we suggest it has insufficient sensitivity for screening (0.8), meaning that 20% of patients with PCD are not tested and will therefore never be correctly diagnosed (5). The ERS Guideline provides a flexible approach (“patients with several typical features” [2]), or suggests a clinical predictive score called Primary Ciliary Dyskinesia Rule (PICADAR), which has good sensitivity and specificity (cutoff, 4; 0.97, specificity, 0.48) (6). Therefore, PICADAR may correctly identify 97% of patients who require further testing, while not inappropriately overwhelming diagnostic services, as approximately 50% of patients will turn out to have PCD. Both scores need validating in primary care settings.