ERS and ATS diagnostic guidelines for primary ciliary dyskinesia: similarities and differences in approach to diagnosis

a) Adapted from the European Respiratory Society primary ciliary dyskinesia (PCD) diagnostic algorithm [6]. Patients do not necessarily need to go through all steps, and the order of investigations may vary depending on local resources [6]. The clinical importance of the algorithm is the summary of how the combination of tests contributes to the diagnostic outcome: positive, highly likely and highly unlikely. b) Adapted from the American Thoracic Society PCD diagnostic algorithm [7]. ^#: cystic fibrosis (CF) should be ruled out before performing nasal nitric oxide (nNO) measurement, as roughly one-third of CF patients can have nNO values below PCD diagnostic cut-offs. nNO measurements should only be performed with chemiluminescence analysers using standardised protocols at centres with specific expertise in nNO measurements. Some nNO analysers have not received approval from federal agencies worldwide (US Food and Drug Administration and Health Canada), which may have implications for clinical implementation. ^¶: genetic panel testing for mutations in >12 disease-associated PCD genes, including deletion/duplication analysis. ⁺: as nNO levels can be significantly decreased by viral respiratory tract infections, a repeat nNO measurement, at least 2 weeks after the initial low value (expert opinion), is recommended to ensure the initial low value is not secondary to a viral process. A normal nNO value upon repeat testing is not suggestive of PCD, as nNO values remain consistently low in PCD. ^§: most forms of PCD resulting in normal nNO levels have normal or non-diagnostic electron microscopy studies. Thus, genetic testing is recommended in these cases. ^ƒ: or presence of variants of unknown significance. ^##: additional corroborative testing may provide information on clinical prognosis, further disease understanding, and potential future therapeutic considerations. ^¶¶: known disease-associated transmission electron microscopy (TEM) ultrastructural defects include outer dynein arm (ODA) defects, ODA plus inner dynein arm (IDA) defects, IDA defect with microtubular disorganisation, and absent central pair, identified using established criteria [1, 6, 13]. Of note, the presence of IDA defects alone is rarely diagnostic for PCD. ⁺⁺: up to 30% of PCD cases can have normal ciliary ultrastructure on electron microscopy. Consider referral to PCD specialty centre if there is a strong clinical phenotype but all electron microscopy and genetic testing are negative. HSVMA: high-speed video microscopy analysis.