A retrospective investigation of the risk factors for chronic Pseudomonas aeruginosa infections in children with cystic fibrosis in Canada from 2000 - 2020

Abstract

Rationale: Cystic Fibrosis (CF) is a genetic disorder that causes viscid mucous within the lungs, predisposing people with CF to infections. Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative bacterium that is common in people with CF. Previous research has found that early eradication with antibiotic treatment can successfully eliminate P. aeruginosa from the lungs, but eventually these infections return and can become chronic. Chronic P. aeruginosa infection is detrimental to the health of people with CF and often leads to greater morbidity and mortality. This thesis investigated three objectives: (1) What are the characteristics of children with CF who develop chronic P. aeruginosa infections; (2) What is the association between number of eradication attempts and time to chronic P. aeruginosa infection; and (3) Does the association between the number of eradication attempts and time to chronic P. aeruginosa infection differ between children diagnosed with CF clinically and those diagnosed with CF by newborn screening (NBS). Methods: This study used a retrospective paediatric cohort from prospectively collected data within the Canadian CF Registry (CCFR) from 2000 – 2020. Descriptive statistics were used to summarise the characteristics of children with chronic P. aeruginosa (Objective 1). A multivariable time dependent Cox proportional hazards regression was performed to investigate the association between number of previous infections and chronic infection (Objective 2), and the results were stratified by NBS to test effect modification (Objective 3). Results: Of the 2098 children eligible for this study, 817 (38.9%) developed a chronic P. aeruginosa infection. The risk of developing a chronic infection increases by 9% for each new infection acquired (hazard ratio (HR) 1.09; 95% confidence interval (CI) [1.07, 1.12]) and was not attenuated after adjusting for potential confounding variables (HR 1.08; 95% CI [1.06, 1.10]). A non- linear association between the number of previous infections and chronic infection was observed; there was an increased hazard of chronic infection with each additional infection, with the hazard increasing to two times the baseline level (one infection) after 4 repeated P. aeruginosa infections. Children diagnosed through NBS were less likely to develop a chronic infection compared with children clinically diagnosed with CF, but the association between number of previous infections and chronic infection was similar. In a sensitivity analysis, limited to children diagnosed after the year 2000, the hazard for chronic infection was 1.17 (95% CI [1.13, 1.21]), suggesting that either the exposure or outcome (or both) were misclassified. Discussion: With each new P. aeruginosa infection children with CF face an increased risk of developing chronic P. aeruginosa. The prevention and early eradication of infection is necessary to minimize the risk of chronic P. aeruginosa infection.