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The Controversies and Difficulties of Diagnosing Primary Ciliary Dyskinesia

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.

Reply to Gagnon et al.

From the Authors:
We thank Dr. Gagnon and colleagues for their interest and comments. Because of the constraints of a research letter, we were not able to provide all the details of the telehealth intervention. Briefly, each video session was designed to mimic the components of centerbased pulmonary rehabilitation (PR) and lasted 45 to 60 minutes. The sessions included stretching and breathing exercises for approximately 10 minutes; aerobic exercises using a foot peddler or walking for 10 and 20 minutes in those with low and high baseline functional capacity, respectively; and strength training with stretch bands for 10 minutes. Educational sessions were interspersed between these exercise periods. We agree with Dr. Gagnon and colleagues that the interval between the initiation of PR and 30 days is short, and thus we may not see meaningful changes in functional capacity. The 30day time point was chosen based on our primary outcome of hospital readmission (1). We disagree that the higher proportion of patients on domiciliary oxygen in the group exposed to PR may have contributed to improved outcomes, as this suggests more severe and perhaps less-responsive disease. We acknowledge that the study was not randomized and that we did not collect data on the number of patients approached and reasons for patient refusal to participate. These limitations in part underlie our call for well-conducted randomized trials to test the efficacy of our intervention. They also make a case that behavioral changes could have had a significant impact. Although we did not systematically study this in both groups, the emotional guardedness domain of the psychosocial risk factor survey did improve with telehealth PR (2). n Author disclosures are available with the text of this letter at www.atsjournals.org.  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. n