Repeated time-to-event models support that Pseudomonas aeruginosa infection increase the risk of acquiring Aspergillus in young children with cystic fibrosis
Sabariah Noor Harun,(1,2) Nicholas H. G. Holford,(2,3) Keith Grimwood,(4,5) Claire E. Wainwright,(6,7) Stefanie Hennig,(2) on behalf of the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group
1 School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia; 2 School of Pharmacy, The University of Queensland, St Lucia, QLD 4072, Australia; 3 Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. 4 School of Medicine and Menzies Health Institute Queensland, Griffith University, Southport, QLD 4222, Australia; 5 Departments of Infectious Diseases and Paediatrics, Gold Coast Health, Southport, QLD 4215, Australia; 6 Department of Respiratory and Sleep Medicine, Queensland Children’s Hospital, South Brisbane, QLD 4101, Australia; 7Child Health Research Centre, The University of Queensland, South Brisbane, QLD 4101, Australia
Objectives: Chronic P. aeruginosa infection is usually treated with long-term, inhaled antibiotic therapy in patients with cystic fibrosis (CF). However, such treatment has been associated with airway dysbiosis and acquisition of other potential pathogens, including filamentous fungi from the Aspergillus genus. While Aspergillus detection rates in adults, adolescents and older children with CF have increased, the risk of acquiring this fungal pathogen in young children is unknown.
This study aimed to determine the risk and explanatory factors of acquiring Aspergillus in children with CF within the first 5-years of life.
Methods: Clinical, bronchoalveolar lavage (BAL) and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study [1] was used to identify predictive factors for detecting Aspergillus. Infants detected by a new born screening programme and with features of classic CF (two or more of the following: two CF gene mutations, sweat chloride >60mmol/L, pancreatic insufficiency or meconium ileus) were randomised to either BAL-directed therapy or standard care where clinical judgement and oropharyngeal (OP) swabs guided treatment of pulmonary exacerbations in the first 5-years of life. When a child in either study arm had a pulmonary exacerbation, a specimen (either via BAL or OP) was obtained. Children in the BAL-directed arm had a BAL at baseline (before age 6-months), at the study end (at age 5-years), and after completion of any P. aeruginosa eradication therapy. A confirmed P. aeruginosa infection was treated identically with a course of anti-pseudomonal eradication therapy, which involving 2-weeks of intravenous antibiotics, followed by 8-weeks of tobramycin solution for inhalation. OP specimens are commonly associated with increased false positive results, therefore only BAL culture data was analysed.
A longitudinal parametric survival analysis was performed using interval-censored repeated time-to-event (RTTE) models to determine the risk of acquiring recurrent positive Aspergillus BAL cultures in the first 5-years of life. Specifically, a RTTE model for positive P. aeruginosa BAL cultures was built concurrently with an Aspergillus RTTE model from birth until age 5-years. The joint model allows for the influence of the P. aeruginosa eradication therapy on the risk of having Aspergillus positive cultures to be evaluated.
Results: The median (interquartile range) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture.
In the child’s first year of entering the study, the risk of acquiring P. aeruginosa had a hazard ratio of 0.399 (95% CI 0.181 to 0.599). After the first and second P. aeruginosa events, the risk of acquiring the subsequent P. aeruginosa infection increased with a hazard ratio of 138 (95%CI 50.6, 1236). As predicted by a Gompertz hazard model, the risk of acquiring Aspergillus event was very low during the first year of the study period. However, the risk then increased influenced by factors other than time alone. Having had the first Aspergillus event increased the risk of a second or third Aspergillus event as shown by hazard ratios of 7.29x105 (95%CI 1.99x105, 1.83x106) and 5.97x105 (95%CI 1.21x105, 2.05x106), respectively. After completing P. aeruginosa eradication therapy, the Aspergillus risk increased with a hazard ratio of 2.75 (95%CI 1.45, 5,41). Kaplan Meier visual predictive checks for P. aeruginosa events show good predictions and for Aspergillus events also indicate that the final model describes the observed data generally adequately, with some discrepancies at 4 years of age.
Conclusions: A joint RTTE model for two non-competing but interacting interval censored events was developed. Young children with CF, completing intensive Pseudomonas aeruginosa eradication treatment and having experienced a previous Aspergillus event are associated with substantially increased risk of acquiring further Aspergillus events.
References:
[1] Wainwright CE, Vidmar S, Armstrong DS, et al. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA 2011;306:163-71.
