Background While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown.
Aim To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years.
Methods Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years.
Results Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) 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. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event.
Conclusion In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.
- Pseudomonas aeruginosa eradication therapy
- repeated time-to-event analysis
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Collaborators The following investigators constitute the ACFBAL Study Investigators Group: Claire E Wainwright, Lady Cilento Children’s Hospital, Brisbane and The University of Queensland, Brisbane; Keith Grimwood, Griffith University; Joyce Cheney, Lady Cilento Children’s Hospital, Brisbane; Narelle George, Pathology Queensland; Colin F Robertson, Royal Children’s Hospital, Melbourne; Rosemary Carzino, Murdoch Children’s Research Institute, Melbourne; Marj Moodie, Deakin University, Melbourne; David S Armstrong, Monash Medical Centre, Melbourne; Peter J Cooper, The Children’s Hospital at Westmead, Sydney; A (James) Martin, Womens & Children’s Hospital, Adelaide; Bruce Whitehead, John Hunter Children’s Hospital, Newcastle; Catherine A Byrnes, Starship Children’s Hospital and University of Auckland, Auckland; Harm A Tiddens, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands; Nicholas Gailer, B Creative Industries; Katrina Jess, Lady Cilento Children’s Hospital, Brisbane; Peta Yarrow, Lady Cilento Children’s Hospital, Brisbane; Merilyn McArthur, The Children’s Hospital at Westmead, Sydney; Sam Forbes, The Children’s Hospital at Westmead, Sydney; Hiran Selvadurai, The Children’s Hospital at Westmead, Sydney; John Massie, Royal Children’s Hospital, Melbourne; Sarath Ranganathan, Royal Children’s Hospital, Melbourne; Phil Robinson, Royal Children’s Hospital, Melbourne; Jan Tate, Starship Children’s Hospital, Auckland; Els Van Der Wiel, Erasmus MC, Sophia Children’s Hospital, Rotterdam, the Netherlands.
Contributors All authors meet the criteria of authorship. SNH was responsible for collecting and analysing the data and drafting the manuscript. NHGH performed and reviewed the longitudinal analysis, reviewed and edited the manuscript. CEW developed the study concept, supported data collection, reviewed and edited the manuscript. KG provided microbiological advice, reviewed and edited the manuscript. SH participated in concept development, reviewed and supported the analyses, reviewed and edited the manuscript.
Funding The original ACFBAL study was supported by the National Health and Medical Research Council (grants 9937868 and 351541) and the Children’s Hospital Foundation Queensland, Australia. The tobramycin inhalation solution and delivery system used throughout the ACFBAL study was supplied by Pathogenesis Corporation, Chiron Corporation, and Novartis Pharmaceuticals Inc. CW was supported by a project grant from the Children’s Hospital Foundation Brisbane and a Queensland Health Research Fellowship. SH was supported by a fellowship from the Alexander von Humboldt Foundation, Germany during part of the study.
Competing interests CEW reports grants from Australian National Health and Medical Research Council and non-financial support in providing study drug from Pathogenesis, then Chiron, and then Novartis during the conduct of the ACFBAL study, reports income on a per patient basis derived from Pharmaceutical Studies—Vertex Pharmaceuticals, Boehringer-Ingelheim & Ablynx NV. Epidemiological Research Support from GlaxoSmithKline—Analysis of Bronchoalveolar lavage (BAL) fluid from children with respiratory disorders; 2010–2012 Research Grant from Novo Nordisk Pharmaceuticals P/L- CF-IDEA Study; 2012–2013 Other Reimbursement: Vertex Pharmaceuticals Inc.—Consultant on the Vertex Physician Pediatric CF Advisory Board and the Vertex Innovation Awards (VIA) Grants Committee Gilead Sciences—AZLI Advisory Board Honorarium 2010 Medscape—Consultation interview regarding CF Studies 2012 Vertex Pharmaceuticals 2013 San Francisco return flight and accommodation as Investigator in Lumacaftor study (104) Vertex Pharmaceuticals 2014 return flight and accommodation + honorarium as invited speaker at European CF Conference, Gothenburg, Sweden Vertex Pharmaceuticals (Australia) 2015 honorarium as speaker at a Vertex sponsored educational meeting series Vertex Pharmaceuticals 2015 Chicago return flight and accommodation as Investigator in Lumacaftor study (109) Vertex Pharmaceuticals (Australia) 2015 honorarium for attendance at Advisory Board meeting at Australasian CF Conference held in Sydney in August; Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings re VX15-770-123 Study and to attend the Global Medical Advisory Board Meeting in March 2016. Novartis Pharmaceuticals 2013 return travel and accommodation to give a symposium at European CF Conference in Lisbon Novartis Pharmaceuticals Australia P/L 2013 honorarium to present symposium at Australasian CF Conference in Auckland Novartis Pharmaceuticals 2014 return flight and accommodation + honorarium as invited speaker at National Pediatric Congress in Lebanon Novartis Pharmaceuticals Australia P/L 2015 honorarium to present symposium at Australasian CF Conference in Sydney in August; The University of Miami honorarium for meeting attendance. Thorax honorarium for associate editor duties Q3/Q4 2015 and BMJ honorarium for consulting work in April 2016. Current Board Positions—Thoracic Society Australia and New Zealand and International Advisory Board Vertex Pharmaceuticals P/L. (N.B. Payments for all items listed above have been made into an institutional consultancy fund account). KG reports grants from Australian National Health and Medical Research Council and non-financial support from Pathogenesis, then Chiron, and then Novartis during the conduct of the ACFBAL study.
Patient consent for publication Obtained.
Ethics approval The details of the ACFBAL study have been published previously and it was approved by the ethics committees of each of the eight participating centres.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The Australasian Cystic Fibrosis BronchoAlveolar Lavage research group - listed in the authorship - have access to the ACFBAL data. Any decisions regarding the use of the data or publications within the group and/or access to the data from outside the group have been discussed and agreed by a core panel designated by the ACFBAL researchers.
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