In preschool children with cystic fibrosis (CF), lung clearance index (LCI) is a sensitive test to detect early lung disease. Some children with CF screen positive, inconclusive diagnosis (CFSPID) may in time develop clinical features of CF. LCI has not been studied in CFSPID children. LCI and spirometry were performed in preschool age children with CF, CFSPID, and non-CF healthy controls (HCs) during two visits. Fifty-four preschool age children (HC n = 18, CFSPID n = 17, and CF n = 19) were tested. Mean LCI from the CFSPID group was not statistically different from HC (p = 0.49), but significantly different when compared to CF (p = 0.04). LCI was abnormal in 2 CFSPID children who carried potentially deleterious CFTR variants. Mean forced expiratory volume in 1 s (FEV1) was not statistically different between CFSPID and CF (p = 0.26). LCI can potentially detect early lung disease in CFSPID individuals as part of assessing their risk for reclassification to CF diagnosis.
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Newborn screening for CF in California uses a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens, (2) testing of 40 pre-selected CFTR mutations in specimens with immunoreactive trypsinogen values ≥ 62 ng/mL (top 1.6%), and (3) performing CFTR-DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥ 2 mutations/variants are screen positive and referred to CF care centers for diagnostic evaluation and follow-up .
Subbarao P, Milla C, Aurora P et al (2015) Multiple-breath washout as a lung function test in cystic fibrosis. A Cystic Fibrosis Foundation Workshop Report. Ann Am Thorac Soc 12(6):932–939
Ellemunter H, Fuchs SI, Unsinn KM et al (2010) Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease. Respir Med 104(12):1834–1842
Lahiri T, Hempstead SE, Brady C et al (2016) Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis. Pediatrics 137(4):e20151784
Aurora P, Stanojevic S, Wade A et al (2011) Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care Med 183(6):752–758
Jensen R, Stanojevic S, Klingel M et al (2016) A systematic approach to multiple breath nitrogen washout test quality. PLoS ONE 11(6):e0157523
Subbarao P, Stanojevic S, Brown M et al (2013) Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Am J Respir Crit Care Med 188(4):456–460
Ren CL, Borowitz DS, Gonska T et al (2017) Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome and cystic fibrosis screen positive, inconclusive diagnosis. J Pediatr 181S:S45–S51.e1
Robinson PD, Latzin P, Verbanck S et al (2013) Consensus statement for inert gas washout measurement using multiple- and single-breath tests. Eur Respir J 41(3):507–522
Robinson PD, Latzin P, Ramsey KA et al (2018) Preschool multiple-breath washout testing. An Official American Thoracic Society Technical Statement. Am J Respir Crit Care Med 197(5):e1–e19
Beydon N, Davis SD, Lombardi E et al (2007) An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med 175(12):1304–1345
Behar DM, Inbar O, Shteinberg M et al (2017) Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med 5(3):223–236
Keiles S, Kammesheidt A (2006) Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas 33(3):221–227
Salinas DB, Azen C, Young S, Keens TG, Kharrazi M, Parad RB (2016) Phenotypes of California CF newborn screen-positive children with CFTR 5T allele by TG repeat length. Genet Test Mol Biomark 20(9):496–503
Groman JD, Hefferon TW, Casals T et al (2004) Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet 74(1):176–179
Vilozni D, Bentur L, Efrati O et al (2007) Spirometry in early childhood in cystic fibrosis patients. Chest 131(2):356–361
Marostica PJ, Weist AD, Eigen H et al (2002) Spirometry in 3- to 6-year-old children with cystic fibrosis. Am J Respir Crit Care Med 166(1):67–71
Simon MR, Chinchilli VM, Phillips BR et al (2010) Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol 126(3):527–534.e1-8
Culver BH, Graham BL, Coates AL et al (2017) Recommendations for a Standardized Pulmonary Function Report. An Official American Thoracic Society Technical Statement. Am J Respir Crit Care Med 196(11):1463–1472
Quanjer PH, Weiner DJ, Pretto JJ et al (2014) Measurement of FEF25–75% and FEF75% does not contribute to clinical decision making. Eur Respir J 43(4):1051–1058
Aurora P, Bush A, Gustafsson P et al (2005) Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. Am J Respir Crit Care Med 171(3):249–256
Mayer OH, Jawad AF, McDonough J, Allen J (2008) Lung function in 3–5-year-old children with cystic fibrosis. Pediatr Pulmonol 43(12):1214–1223
Eigen H, Bieler H, Grant D et al (2001) Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med 163(3 Pt 1):619–623
Kharrazi M, Yang J, Bishop T et al (2015) Newborn screening for cystic fibrosis in California. Pediatrics 136(6):1062–1072
The authors thank Dr. Sally L. Davidson Ward and the Cystic Fibrosis Team at Children’s Hospital Los Angeles for supporting this study. The authors thank Whitney Gore, Cynthia Leyva, Monique Margetis, Alejandra Franquez, Amy Deblaise-Kasai, Maria Carmen Reyes, and Cathleen Salata for their help with patient recruitment. They also thank the children and families who participated in this study.
This project was supported by the Webb Family and National Institute of Health (NIH)/National Center for Research Resources Southern California Clinical and Translational Science Institute (NCRR SC-CTSI), Grant Number UL1 TR000130. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
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Kasi, A.S., Wee, C.P., Keens, T.G. et al. Abnormal Lung Clearance Index in Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) Children with Otherwise Normal FEV1. Lung 198, 163–167 (2020). https://doi.org/10.1007/s00408-019-00307-3
- Cystic fibrosis
- CFTR-related metabolic syndrome
- Lung clearance index
- Early lung disease