It’s been proposed and widely accepted that children who receive antibiotics before their first birthday might be at a slightly increased risk of developing asthma. However, a new study by researchers at The University of Manchester in the U.K. suggests that the relationship between early-life antibiotic use and the development of wheeze and asthma that has been reported in several studies might arise as a consequence of bias rather than causal relationship, and that it is actually impaired viral immunity and genetic variants on a region of chromosome 17 that increase the risk of both antibiotic use in early life and later asthma rather than the antibiotics themselves, as previously thought.
Importantly, findings of a population-based birth cohort study funded by the Medical Research Council and J.P. Moulton Charitable Foundation seem to contradict the prevailing theory that early antibiotic exposure, via changes in gut flora, alters the development of a child’s immune system, increasing susceptibility to allergic asthma later on.
The study results, which were reported in an article published in The Lancet on May 15 entitled “Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21” (Lancet Respir Med 2014, Published Online May 15, 2014, doi.org/10.1016/S2213-2600(14)70096-7), co-authored by Adnan Custovic, Aida Semic-Jusufagic, Danielle Belgrave, Andrew Pickles, Aurica G Telcian, Eteri Bakhsoliani, Annemarie Sykes, Angela Simpson, and Sebastian L Johnston of various U.K. universities, hospitals, institutes and agencies, found no link between early antibiotic prescription and subsequent development of allergic reactions.
A Manchester U. release notes that antibiotics are routinely used to treat pediatric respiratory infections, ear infections, and bronchitis, and several studies have reported a link between the use of antibiotics during early childhood and the subsequent development of asthma. And while the most common use of antibiotics in children is to treat respiratory tract infections, the Lancet article notes that in about 80 percent of children presenting to a physician with cough and fever have an identifiable viral cause, against which antibiotics are useless. The researchers note that systematic reviews have reported conflicting results calling for additional longitudinal studies to provide definitive answers.
The coauthors of the Lancet report further suggest that the association between antibiotics and asthma might arise through a “complex confounding by indication,” with hidden factors that may increase the likelihood of both early life antibiotic prescription and later asthma being an increased susceptibility to viral infections consequent upon impaired antiviral immunity and genetic variants on 17q21. They observe that this topic has been a subject of at least three systematic reviews, which reported conflicting results between different reports, and called for further longitudinal studies to provide definitive answers.
In this study, U.K. researchers examined data from the Manchester Asthma and Allergy Study (MAAS), which has followed over 1,000 children from birth to 11 years. Information on antibiotic prescription, wheeze and asthma exacerbations were taken from medical records. Skin reaction tests that show whether a child is hypersensitive to allergens were done at ages 3, 5, 8, and 11 years.
It is noted that at age 11, blood was collected from children who had received at least one course of antibiotics or no antibiotics in the first year of life to compare their immune-system cell response to viruses (rhinovirus; the virus responsible for the common cold, and respiratory syncytial virus; RSV) and bacteria (Haemophilus influenzae and Streptococcus pneumoniae). Genetic testing was also done to look at the links between common genetic variations on chromosome 17, known as 17q21, and antibiotic prescription.
The study’s findings are believed to be the first to show that children with wheezing who were treated with an antibiotic in the first year of life were more than twice as likely as untreated children to experience severe wheeze or asthma exacerbations and be hospitalized for asthma. Similarly, these children also showed significantly lower induction of cytokines, which are the bodies’ key defense against virus infections such as the common cold. However, no differences were noted in antibacterial responses.
The researchers also identified two genes in the 17q21 region that were associated with an increased risk of early life antibiotic prescription.
Lead author Professor Adnan Custovic, from the Institute of Inflammation and Repair based at The University of Manchester, comments: “We speculate that hidden factors which increase the likelihood of both antibiotic prescription in early life and subsequent asthma are an increased susceptibility to viral infections due to impaired antiviral immunity and genetic variants on 17q21. However, further studies will be needed to confirm that the impaired immunity was present at the time of the early childhood respiratory symptoms and predated antibiotic prescribing rather than as a consequence of the antibiotics.”
At the core of Dr. Custovic’s research activity is the aforementioned Manchester Asthma and Allergy Study. Dr. Custovic is principal investigator on this population-based birth cohort study specifically designed to determine risk factors for asthma and allergies which I commenced in 1995 and which currently follows ~1000 participants. At the national level, Dr. Custovic also leads the MRC-funded STELAR (Study Team for Early Life Asthma Research) consortium which aims to pull together all of the data from five UK-based birth cohorts looking into the development of asthma and allergies.
Together with principal investigators from birth cohorts in Bristol, Aberdeen, the Isle of Wight and Ashford, Dr. Custovic and his research colleagues will combine all of our data and create an Asthma “e-Lab,” which is a secure web-based research environment supporting consistent recording, description and sharing of data and emerging findings across all partners, thus enabling collaborative epidemiological research in near-real-time. This will create a platform that will enable and facilitate research into asthma and allergic diseases for decades to come; this will open up the research not only to investigators in bio-medicine and life sciences, but also computing, mathematics, physics etc.
Dr. Custovic notes that pulling together researchers from different areas of science is the particularly exciting aspect of this program: and the multidisciplinary/multi-institutional team includes world-leading experts in birth cohort studies, epidemiologically oriented health informatics research and machine learning pioneered by industrial partner Microsoft Research Cambridge. The consortium plans to use innovative computational statistical methods to identify novel latent endotypes of childhood asthma, with the ultimate aim to underpin new trials of asthma prevention and treatment, personalized for specific endotypes, with their ultimate objective to deliver stratified medicine in pulmonology and allergy for the benefit of their patients.
The University of Manchester, a member of the Russell Group, is one of the largest and most popular universities in the UK. It has 20 academic schools and hundreds of specialist research groups undertaking pioneering multi-disciplinary teaching and research of worldwide significance. According to results of the 2008 Research Assessment Exercise, The University of Manchester is one of the U.K.’s major research institutions, rated third in the country in terms of “research power.” The University has an annual income of £807 million and is ranked 40th in the world and fifth in the UK for the quality of its teaching and impact of its research.
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