Maria Victoria Medeleanu ^1,2 Myrtha E Reyna ^2,3 Darlene Dai ⁴ Geof Winsor ⁵ Fiona Brinkman ⁵ Rahul Verma ⁶ Ella Nugent ² Nashita Riaz ² Elinor Simons ⁷ Piush Mandhane ^8,9 Meghan B Azad ^10,11 Stuart Turvey ^12,4 Theo Moraes ^2,6 Padmaja Subbarao ^{1,13,14,2,3,6*}

• ¹ Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ² Translational Medicine Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
• ³ Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• ⁴ Department of Pediatrics, British Columbia Children's Hospital, Vancouver, British Columbia, Canada
• ⁵ Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, British Columbia, Canada
• ⁶ Division of Respiratory Medicine, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
• ⁷ Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
• ⁸ Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
• ⁹ Faculty of Medical and Health Sciences, UCSI University, Kuala Lampur, Malaysia
• ¹⁰ Manitoba Interdisciplinary Lactation Centre (MILC), Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
• ¹¹ Department of Community Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
• ¹² Department of Microbiology and Immunology, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada
• ¹³ Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
• ¹⁴ Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Objective: Lower respiratory tract infections (LRTIs) in early life are one of the strongest risk factors for childhood asthma and are often treated with systemic antibiotics. We aimed to explore the association between early-life LRTIs and systemic antibiotics on asthma development and the potential mediating role of antibiotics in this relationship. Methods: Data were collected as part of the longitudinal, general Canadian population CHILD Study. LRTIs during the first 18 months of life were identified through parental symptom report at regular study visits. Systemic antibiotic use was defined as at least one dose of oral/intravenous antibiotics between birth and the 18-month visit and were categorized by indication as either given for a respiratory or non-respiratory indication. Asthma was diagnosed by in-study pediatricians at the 5-year study visit. Adjusted logistic regression models and mediation analyses via systemic antibiotics were performed.Results: Among 2,073 participants included in our analysis, 72 (4.9%) had asthma at age 5, and 609 (29.3%) used systemic antibiotics before the 18-month visit. Among children who had taken antibiotics, 61.6% also had an LRTI in that period compared to 49.7% among children without exposure to systemic antibiotics (p<.001). Moderate-severe LRTIs before age 18 months were associated with higher odds of 5-year asthma (aOR 4.12 [95%CI 2.04 -7.95] p<.001). Antibiotics taken for respiratory indications were associated with higher odds of asthma (p<.001). Children who received systemic antibiotics for only non-respiratory indications during the first 18 months of life were not associated with increased odds of asthma (aOR 1.08 [95%CI 0.44 -2.30] p=.851). Using mediation analysis, 21.7% of the association between LRTI and asthma is estimated to be mediated through use of early-life systemic antibiotics. However, a significant direct effect of moderate-to-severe LRTIs on asthma risk remained in adjusted mediation models (p=.014).Through mediation modeling we estimate that the increased risk of asthma at age 5 that is associated with moderate-severe LRTIs in infancy may be partially mediated by systemic antibiotics taken during the first 18 months of life. This underscores the importance of public health strategies focused on antibiotic stewardship and reducing early life LRTIs to mitigate asthma risk.