The Importance of Appropriate Reference Sources for Spirometry: Lessons Learned from the UK Cystic Fibrosis Gene Therapy

Davies G, Simpson AJ, Bayfield KJ, McGovern MJ, Embley MA, Sheridan HS, Saunders C, Dewar MH, Cunningham S, Alton EW, Innes JA, Davies JC

Pediatic Pulmonology, 47 S35 Abstract 387

The North American Cystic Fibrosis Conference, Orlando, 2012

Introduction: The “Run-In” was a longitudinal observational study of cystic fibrosis (CF) patients designed to assess optimal patients and outcome measures for our current multi-dose gene therapy trial. Spirometry was per- formed at each Run-In study visit and volumes converted to % predicted val- ues according to published reference sources; historically these were sepa- rate for adults and children. Here, we describe the issues arising from this approach, and highlight the benefit of using a reference source which bridges the transition from child to adulthood.

Methods: CF subjects (≥10 years; FEV1 ≥ 40% predicted) were recruit- ed from three sites in London and Edinburgh. Visits were undertaken during periods of stability every 3-6 months; data presented here are from the first 4 visits. At each visit, a series of laboratory, physiological and clinical tests were performed, one of which was spirometry using an Easyone spirometer. Volumes were converted to % predicted values according to Rosenthal1 (<18 years) and Quanjer2 (≥18 years) reference equations. The FEV1 raw data has been subsequently re-analysed using Stanojevic look-up tables3 which became available during the course of the trial. These span all age ranges.

Results: A total of 191 patients attended visit 1 (mean age 22.7 years, 55% male; 91 patients <18 years). Rosenthal and Quanjer FEV1% predict- ed values were both significantly higher than the Stanojevic values: mean differences 2.8 (95%CI 1.9-3.7) for children with Rosenthal equations (p<0.0001), and 2.4 (95%CI 2.1-2.8) for adults using Quanjer equations (p<0.0001). Ten patients transitioned between paediatric and adult reference ranges during the study period. The mean absolute drop in FEV1 % predicted val- ues across the study visits spanning a patient’s 18th birthday was 9.7 with Rosenthal to Quanjer equations in comparison to 4.1 when Stanojevic refer- ence values were used. The slope representing decline in FEV1 % predicted values over study visits 1-4 was significantly greater with Rosenthal/Quan- jer than with Stanojevic (p =0.001), largely due to an artefactual drop when switching from Rosenthal to Quanjer values at age 18. As an example, a female patient aged 17.8 years at visit 1 had a drop in absolute FEV1% pre- dicted between visits 1 and 2 of 11% when Rosenthal/Quanjer were used but only 3% with Stanojevic reference values.

Conclusions: Our results highlight issues raised when separate adult and paediatric spirometry reference sources are used in longitudinal study. They make interpretation of data in terms of change over time impossible and beyond the research setting have implications for clinical decision mak- ing. The UK CF Gene Therapy Consortium has converted to using the Stanojevic reference source for longitudinal spirometry analysis in its recently commenced multidose trial of nebulised non-viral CF gene therapy. Supported by the UK CF Trust. References: 1. Rosenthal et al. Thorax 1993;48:794-802 2. Quanjer et al. Eur Respir J 1993; 6 suppl. 16: 5-40 3. Stanojevic et al. AJRCCM 2008; 177:253-260