Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study.
BACKGROUND
The relationship between early-life antibiotic use and the development of wheeze and asthma has been reported in several studies but might arise as a consequence of bias rather than causal relationship. We investigated the association between antibiotic prescription and subsequent development of atopy, wheeze, and asthma exacerbations, and the relation of early life antibiotic prescription with anti-infective immunity and genetic variants on asthma susceptibility locus 17q21.


METHODS
Children in a population-based birth cohort were followed from birth to age 11 years. Information on antibiotic prescription, wheeze, and asthma exacerbations was extracted from medical records, and the effect of antibiotic prescription assessed with longitudinal analyses. We assessed immune responses of peripheral blood mononuclear cells, taken at age 11 years, to viruses (rhinovirus and respiratory syncytial virus; RSV) and bacteria (Haemophilus influenzae and Streptococcus pneumoniae) in children who either received at least one or no antibiotic prescriptions in infancy. Finally, we assessed the association of 17q21 polymorphisms with antibiotic prescription.


RESULTS
Of 984 families who gave consent, we extracted data for 916 children. We noted significantly higher risk of physician-confirmed wheezing after antibiotic prescription (hazard ratio [HR] 1·71, 95% CI 1·32-2·23; p<0·0001) and severe wheeze or asthma exacerbation after antibiotic prescription (HR 2·26, 95% CI 1·03-4·94; p=0·041). In children who wheezed, the hazards of exacerbations (2·09, 1·51-2·90; p<0·0001) and admissions to hospital (2·64, 1·49-4·70; p=0·0009) were significantly increased in the 2 years after the first antibiotic prescription. Children who received antibiotics in infancy had significantly lower induction of cytokines, which are important in host defence against virus infections to both RSV and rhinovirus; there were no differences in antibacterial responses. Variants in 17q21 were associated with an increased risk of early life antibiotic prescription.


CONCLUSIONS
The association between antibiotics and asthma might arise through a complex confounding by indication. Hidden factors that may increase the likelihood of both early life antibiotic prescription and later asthma are an increased susceptibility to viral infections consequent upon impaired antiviral immunity and genetic variants on 17q21.


BACKGROUND
Moulton Charitable Foundation and Medical Research Council.
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester & University Hospital of South Manchester, Manchester, UK.
Aida
A
Semic-Jusufagic
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester & University Hospital of South Manchester, Manchester, UK; Centre for Health Informatics, Institute of Population Health, University of Manchester, Manchester, UK.
Danielle
D
Belgrave
Department of Biostatistics, King's College London, London, UK.
Andrew
A
Pickles
Airway Disease Infection Section, National Heart & Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, and Centre for Respiratory Infection, Imperial College London, UK.
Aurica G
AG
Telcian
Airway Disease Infection Section, National Heart & Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, and Centre for Respiratory Infection, Imperial College London, UK.
Eteri
E
Bakhsoliani
Airway Disease Infection Section, National Heart & Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, and Centre for Respiratory Infection, Imperial College London, UK.
Annemarie
A
Sykes
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester & University Hospital of South Manchester, Manchester, UK.
Angela
A
Simpson
Airway Disease Infection Section, National Heart & Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, and Centre for Respiratory Infection, Imperial College London, UK.
Sebastian L
SL
Johnston
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester & University Hospital of South Manchester, Manchester, UK. Electronic address: adnan.custovic@manchester.ac.uk.
Adnan
A
Custovic
D000367:Age Factors; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001249:Asthma / Q000209:etiology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D011307:Drug Prescriptions / Q000706:statistics & numerical data; D004527:Egg Proteins / Q000235:genetics; D005500:Follow-Up Studies; D005838:Genotype; D006193:Haemophilus influenzae / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects*; D011446:Prospective Studies; D012135:Respiratory Sounds / Q000209:etiology*; D012229:Rhinovirus / Q000276:immunology; D012307:Risk Factors; D012720:Severity of Illness Index; D012882:Skin Tests; D013296:Streptococcus pneumoniae / Q000276:immunology; D011795:Surveys and Questionnaires
D000900:Anti-Bacterial Agents; D004527:Egg Proteins; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; C479482:ZPBP2 protein, human