Pediatric Year in Review

PEDIATRIC YEAR IN REVIEW 13 highly experienced centers after lengthy air-liquid interface culture to regrow ciliated cells. In this retrospective analysis of 120 randomly selected HSVM patient samples from three British PCD centers, three blinded HSVM experts compare HSVM results against two reference standards: 1) ERS guideline recommendations using only TEM and/or PCD genetic testing, or 2) a multidisciplinary team (MDT) diagnostic opinion using all available diagnostic results, including previous HSVM interpretations. Importantly, disease control samples are not intentionally included in analyzed HSVM samples. Results of HSVM show high diagnostic accuracy compared to ERS guideline PCD diagnosis (sensitivity 100%, specificity 96%), but when including 42 inconclusive HSVM results (35% of the total population), results are less accurate (sensitivity 93%, specificity 68%). However, HSVM is mainly compared against TEM results alone, as only 16 subjects (13%) had PCD genetic testing. Compared against past MDT opinion, HSVM seems very accurate (sensitivity 97%, specificity 91%), but worsens considerably when counting 25 inconclusive HSVM cases (sensitivity 85%, specificity 68%). There is good inter-observer agreement between three HSVM experts on cases where HSVM is clearly diagnostic of PCD (K=0.70), but agreement worsens considerably when HSVM results are non-diagnostic (K=0.44 for “PCD highly unlikely”; K=0.11 for “PCD highly likely”; K=0.20 for “inconclusive”). Comments 1. The diagnostic accuracy of HSVM seems excellent in a highly selected population, yet this accuracy is likely substantially inflated due to several critical errors in methodology (only limited genetic testing in the ERS guideline reference standard, inclusion of HSVM in both the index test and MDT reference standard, and lack of other disease controls). 2. Accurate comparison of HSVM against a true PCD reference standard of TEM and/or genetic testing in all included subjects is lacking here, and the true diagnostic accuracy of HSVM in the era of PCD genomic sequencing remains unknown. 3. The lack of air-liquid interface culture to regrow ciliated cells prior to HSVM analysis in this study, despite a strong recommenda- tion to do so in ERS PCD guidelines, means some abnormal HSVM results may be due to secondary insults and not of primary (genetic) origin. 4. While inter-observer agreement among HSVM experts is good in definitive PCD, agreement is considerably weaker when HSVM is not definitively diagnostic of PCD. 5. HSVM remains a research-based PCD test with non-standardized sample preparations, subjective interpretation of results without established minimal diagnostic criteria, and no prospective evi- dence of successful transferability to centers lacking experience in this technique. GENOTYPE PHENOTYPE ASSOCIATIONS IN PCD Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW. Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype. Am J Respir Crit Care Med. 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC. Summary With over 40 different PCD genes, certain genotypes may result in worse clinical phenotypes. Past cross-sectional data suggests PCD patients with absent inner dynein arms, central apparatus abnormalities, and microtubule organization (IDA/CA/MTD) or corresponding CCDC39/ CCDC40 gene mutations have worse lung function and nutritional parameters. This multi-center, longitudinal study tracks children </=19 years old with PCD from mutations in 22 different genes and various ciliary ultrastructural defects, collecting annual lung function, sputum cultures, and other phenotypic information. Over 5 years, 137 participants completed 732 visits, and clinical trends of various PCD subtypes are compared against those with absent ODA or corresponding gene defects in ODA proteins (ODA controls). As a group, all PCD patients have a -0.57% predicted annual decline in FEV1 over the study period. Participants with ICA/CA/MTD and/or CCDC39/ CCDC40 mutations are diagnosed at younger ages, have worse FEV1 at enrollment (72% versus 88% predicted), and exhibit a steeper annual decline in FEV1 over 5 years (-1.1% versus -0.73% predicted) compared against ODA controls, respectively. Body mass index is worse at enrollment for patients with IDA/CA/MTD or CCDC39/ CCDC40 mutations versus ODA controls but does not decrease further over the study. There are no significant differences in pathogen prevalence per ultrastructural defect or PCD gene mutation, and persistent P. aeruginosa infection rates are low (9%) in this young PCD cohort. Comments 1. Patients with PCD from IDA/CA/MTD and/or CCDC39/CCDC40 mutations have worse pulmonary function and nutrition from early in life and may benefit from more aggressive pulmonary and nutri- tional therapies at younger ages. 2. Regular PCD therapies (daily airway clearance, sputum surveil- lance, antibiotics, etc.) after diagnosis seem to stabilize lung function over time in most forms of PCD, yet specific treatment differences and subsequent clinical benefits have not yet been examined in a longitudinal fashion. 3. Though classically considered to have milder lung disease than cystic fibrosis cohorts, PCD patients seem to have worse lung function than contemporary cystic fibrosis populations of similar age. UPDATE ON PCD AND NON-CF BRONCHIECTASIS