Long-term outcomes following early infection and inflammation in cystic fibrosis lung disease

Introduction/Aim: Infection is critical to cystic fibrosis (CF) lung disease pathogenesis. We explored the impact of lower airway infection with Staphylococcus aureus prior to age 24-months and with Pseudomonas aeruginosa prior to age 60-months on survival and rate of decline of lung function over 25-years. Methods: A birth cohort of infants newly-diagnosed with CF was established in Melbourne, Australia in 1992. Anti-staphylococcal prophylaxis was not practiced. Bronchoalveolar lavage was performed at study entry and semi-annually thereafter. A follow-up study was designed. Data were collected from hospital records and the Australian Cystic Fibrosis Data Registry. Survival analyses used Kaplan Meier curves and Cox proportional hazard models. FEV1% predicted annual rate of decline was estimated using linear mixed-effects modelling. Results: Seventy-nine of 100 original birth cohort members (45.6% male), participated in this follow-up. Lower airway samples (n=221) were collected at median 20.3-months (25th-75th%ile 9.8-30.5-months). Twenty-nine (36.7%) participants were deceased and/or underwent lung transplantation. Survivors (n=50, 63.3%) were of median age 24.9-years (25th-75th%ile 23.3-26.2-years) at the study conclusion. S. aureus prior to age 24-months was not associated with reduced survival, FEV1% predicted at age 5-years (+0.15, 95% CI -7.91-8.2) or annual rate of FEV1% predicted decline (+0.09%, 95% CI -0.81-0.99). Early P. aeruginosa infection was associated with reduced survival (p=0.015), reduced FEV1 at age 5-years (-4.37%, 95%CI 12.53-3.81) and increased rate of annual FEV1% predicted decline (-0.49, 95%CI -1.37-0.39). Conclusion: In this first birth cohort of infants with CF diagnosed by newborn screening and treated symptomatically, infection with S. aureus in the first 2-years had no impact on 25-year outcomes. Infection with P. aeruginosa was associated reduced survival and poorer longitudinal lung function. These findings, together with emerging understanding of the potential long-term benefits of microbial diversity, highlight the urgent need for careful evaluation of current approaches to anti-staphylococcal prophylaxis in newly-diagnosed infants.