Accuracy of diagnostic testing in primary ciliary dyskinesia

Abstract

Diagnosis of primary ciliary dyskinesia (PCD) lacks a "gold standard" test and is therefore based on combinations of tests including nasal nitric oxide (nNO), high-speed video microscopy analysis (HSVMA), genotyping and transmission electron microscopy (TEM). There are few published data on the accuracy of this approach.Using prospectively collected data from 654 consecutive patients referred for PCD diagnostics we calculated sensitivity and specificity for individual and combination testing strategies. Not all patients underwent all tests.HSVMA had excellent sensitivity and specificity (100% and 93%, respectively). TEM was 100% specific, but 21% of PCD patients had normal ultrastructure. nNO (30 nL·min(-1) cut-off) had good sensitivity and specificity (91% and 96%, respectively). Simultaneous testing using HSVMA and TEM was 100% sensitive and 92% specific.In conclusion, combination testing was found to be a highly accurate approach for diagnosing PCD. HSVMA alone has excellent accuracy, but requires significant expertise, and repeated sampling or cell culture is often needed. TEM alone is specific but misses 21% of cases. nNO (≤30 nL·min(-1)) contributes well to the diagnostic process. In isolation nNO screening at this cut-off would miss ∼10% of cases, but in combination with HSVMA could reduce unnecessary further testing. Standardisation of testing between centres is a future priority.

FIGURE 1

Primary ciliary dyskinesia (PCD) diagnostic pathway for patients and samples. Diagnostic tests included nasal nitric oxide (nNO), high-speed video microscopy analysis (HSVMA) and transmission electron microscopy (TEM). Not all patients underwent all tests. UHS: University Hospital Southampton.

FIGURE 2

The diagnostic investigations and outcomes of patients seen a) at the diagnostic centre at University Hospital Southampton (UHS) or b) having had samples sent by courier to UHS from a satellite respiratory clinic. Patients were diagnosed as primary ciliary dyskinesia (PCD)-positive, PCD-negative or valid-inconclusive (VI). Invalid-inconclusive (II) results due to inadequate samples or data are shown, but were subsequently excluded from accuracy analyses. Diagnostic tests included nasal nitric oxide (nNO), high-speed video microscopy analysis (HSVMA) and transmission electron microscopy (TEM).

FIGURE 3

Receiver operating characteristic (ROC) curve analysis for ciliary beat frequency (CBF) and nasal nitric oxide (nNO) for predicting a diagnosis of primary ciliary dyskinesia (PCD) (using multidisciplinary diagnosis as the reference standard). ROC curve analysis showed that nNO ≤30 nL·min⁻¹ (area under the curve (AUC) 0.97, 95% CI 0.94–1.00) was superior to CBF (AUC 0.92, 95% CI 0.79–1.00) as predictors of a PCD-positive diagnosis.