Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline

Abstract

Background: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD).

Target audience: Clinicians investigating adult and pediatric patients for possible PCD.

Methods: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript.

Results: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD.

Conclusions: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

Keywords: Kartagener syndrome; diagnosis; nitric oxide; primary ciliary dyskinesia; situs inversus.

Figure 1.

Suggested diagnostic algorithm for evaluating the patient with suspected primary ciliary dyskinesia. *Cystic fibrosis should be ruled out before performing nNO measurement, as roughly one-third of CF patients can have nNO values below PCD diagnostic cutoffs. nNO measurements should only be performed with chemiluminescence analyzers using standardized protocols at centers with specific expertise in nNO measurements. Some nNO analyzers have not received approval from federal agencies worldwide (U.S. Food and Drug Administration and Health Canada have not approved all chemiluminescence devices for clinical use), which may have implications for clinical implementation. ^†Genetic panels testing for mutations in more than 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 that the initial low value is not secondary to a viral process. A normal nNO value upon repeat testing suggests that the patient does not have PCD, as nNO values remain consistently low in PCD. ^§Most forms of PCD resulting in normal nNO levels have normal or nondiagnostic electron microscopy studies. Thus, genetic testing is recommended in these cases. ^#Or presence of variants of unknown significance. For the purposes of this algorithm, “likely pathogenic” variants and “pathogenic” variants are grouped together as pathogenic. ^¶Additional corroborative testing may provide information on clinical prognosis, further understanding of the disease, and suggest potential future therapeutic considerations. ^||Known disease-associated TEM ultrastructural defects include outer dynein arm defects, outer dynein arm plus inner dynein arm (IDA) defects, IDA defects with microtubular disorganization, and absent central pair, identified using established criteria (1, 6, 13). Of note, the presence of IDA defects alone is rarely diagnostic for PCD. ^ΔUp to 30% of PCD cases can have normal ciliary ultrastructure of electron microscopy (EM). Consider referral to PCD specialty center if there is a strong clinical phenotype but all EM and genetic testing are negative. CF = cystic fibrosis; nNO = nasal nitric oxide; PCD = primary ciliary dyskinesia; TEM = transmission electron microscopy.