Complex Link Between Early Antibiotics and Asthma

Veronica Hackethal, MD

May 15, 2014

Impaired antiviral immunity and genetic variants may play roles in the link between early antibiotic use and subsequent asthma, according to a UK study by Aida Semic-Jusufagic, MD, from the Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, United Kingdom, and colleagues, published online May 15 in Lancet Respiratory Medicine.

"The essence of our study [is that] antibiotics do not cause asthma. Our findings suggest that the reported association between antibiotics and childhood asthma arises through a complex confounding by indication," lead author Adnan Custovic, DM, MD, PhD FRCP, professor of allergy at the University of Manchester, told Medscape Medical News.

These confounders, according to Dr. Custovic, include increased susceptibility to viral infections resulting from impaired antiviral immunity and genetic variants on chromosome 17q21, linked to increased risk for respiratory illness and asthma. These hidden factors could increase the likelihood of antibiotic prescription in early life, as well as later asthma development.

Past studies have suggested an increased risk for asthma among children who receive antibiotics early in life, but identifying causality has proven elusive, Dr. Custovic and colleagues note. Rather than playing a causal role in asthma, antibiotic prescription in early life could indicate impaired antiviral immunity and increased susceptibility to viral infections determined partly by genes, the researchers theorize. That, in turn, could affect the risk for later asthma.

To learn more, the researchers analyzed data from children in the Manchester Asthma and Allergy Study, a population-based birth cohort in the United Kingdom, followed from birth until age 11 years (from April 20, 1995, to April 13, 2000).

To minimize recall bias and control for reverse causation bias, the authors extracted data from medical records on antibiotic prescription, wheeze, and asthma exacerbations and also used validated questionnaires to collect data on parentally reported symptoms and physician-diagnosed illnesses and treatments. The team analyzed blood samples taken at 11 years for rhinovirus and respiratory syncytial virus and bacteria (Haemophilus influenza and Streptococcus pneumonia). They also evaluated the association between 17q21 polymorphisms and antibiotic prescriptions and tested children for common allergies, using skin prick tests, at ages 3, 5, 8, and 11 years. The investigators controlled for sex, day care attendance, older siblings, and breast-feeding.

Nearly all of the 916 children (98%) had received at least 1 course of antibiotics, and most had (71%) received their first course of antibiotics within 1 year of life. After antibiotic prescription, children had a significantly higher risk for physician-confirmed wheezing (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.32 - 2.23; P < .0001) and severe wheeze or asthma exacerbation (HR, 2.26; 95% CI, 1.03 - 4.94; P = .041), with all of the statistically significant excess risk occurring in the first 2 years after the prescription.

In addition, children with wheeze had significantly higher risk for exacerbation (HR, 2.09; 95% CI, 1.51 - 2.90; P < .0001) and hospital admissions (HR, 2.64; 95% CI, 1.49 - 4.70; P = .0009) during the 2 years after antibiotic prescription.

Children with early-life antibiotic use had similar antibacterial responses but significantly lower levels of cytokines, the immune cells that play an important role in fighting viral infections. Analyses linked genetic variants on chromosome 17q21 to increased risk for antibiotic prescription in infancy. Antibiotic prescription, however, showed no effect on allergy development.

Limitations included the inability to confirm administration of antibiotics as prescribed. In addition, researchers collected blood samples only at age 11 years and could not evaluate immune responses in infancy that preceded antibiotic prescription, making it difficult to rule out the possibility of reverse causation (eg, that asthma or antibiotic use could change immune response to viruses).

In an accompanying comment, Julian Crane, MB BS, FRCP, and Kristin Wickens, PhD, from the Wellington Asthma Research Group, Otago University, Wellington, New Zealand, argue that the current study does little to reassure physicians about the lack of association between early antibiotic use and later development of asthma. They note that most studies suggest no association exists while also mentioning that the largest birth cohort study to date (252,000 births) found a small risk for later asthma development among children who received antibiotics during the first year of life. Although ethically challenging, a randomized trial, they suggest, would help settle this chicken or egg scenario.

"In view of the concerns over the rapidly waning efficacy of antibiotics, partly from overprescription, the fact that many are prescribed for disorders that they cannot benefit and the disquiet many parents express about overmedicating their children, the proposal for a randomized control trial is perhaps worthy of some consideration," the editorialists conclude.

"Whether impaired antiviral immunity predated antibiotic use, making antibiotic prescription more likely [as our data suggests], or whether it is also a consequence of antibiotic use will require further studies," Dr. Custovic agreed. "Given the inappropriate prescribing of antibiotics and the development of resistance which this may be causing, when primary care physicians are considering the need to prescribe antibiotics for respiratory infections amongst wheezy children, they can take some reassurance from our data showing that while antiviral immunity may be impaired amongst children who were prescribed antibiotics in early life, antibacterial immunity is not."

One coauthor reported receiving grants from the Medical Research Council and Moulton Charitable Foundation and has received personal fees from GlaxoSmithKline and Chiesi. Another coauthor has reported receiving grants and personal fees from Centocor, Sanofi Pasteur, GlaxoSmithKline, Chiesi, Boehringer Ingelheim, Grünenthal, Novartis, and Sinairgen and holds patents for interferon-beta and interferon-lambda in the treatment of and prevention of virally induced exacerbations of asthma and chronic obstructive pulmonary disorder. Dr. Custovic has reported receiving grants from the Medical Research Council and Moulton Charitable Trust and personal fees from Circassia, GlaxoSmithKline, Thermo Fisher Scientific, Novartis, ALK, Airsonett, and MSD. The other authors and editorialists have disclosed no relevant financial relationships.

Lancet Respir Med. Published online May 15, 2014. Article abstract, Comment extract

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