May 15, 2014

expert reaction to antibiotic use in infants and asthma development

Research published in The Lancet Respiratory Medicine reported that a possible explanation for the association between infants who receive antibiotics before their first birthday and a greater risk of developing asthma is that they could be genetically predisposed to have low immune defences – they are therefore more likely to both develop asthma and to suffer infections for which they are prescribed antibiotics.

Prof Seif Shaheen, Clinical Professor of Respiratory Epidemiology, Blizard Institute, Queen Mary University of London (QMUL), said:

“An association between antibiotic use in early life and later childhood asthma has been found in many epidemiological studies. In recent years experts have concluded that most, if not all, of this link is likely to be explained by a tendency for young children with wheezing and respiratory infections (the commonest trigger of wheezing) to be treated with antibiotics, and for their wheezing to persist and become asthma later in childhood.  In other words antibiotic use per se was not causing asthma to develop.

“This paper backs up this idea by showing that some children may be more susceptible to getting viral respiratory infections, and hence (inappropriate) antibiotic treatment, and also to developing asthma, because of low immune defences against viruses and because they have a particular genetic make-up. However, the measurements of the children’s immune system in this study were made at 11 years of age.  Therefore we cannot be certain that altered immunity was already present very early in life and influenced whether the children were given antibiotics.”

Prof Mike Thomas, Professor of Primary Care Research, University of Southampton, said:

“Asthma has increased greatly in prevalence over the last 40 years, for reasons that are still incompletely understood. The rapidity of the increase in asthma points to environmental rather than genetic facts, but which aspect or aspects of antenatal or early life exposures are responsible is unclear. One factor that has been hypothesised as driving this change is increased antibiotic exposure in early life, particularly given to babies in the first year of life, something which has happened more until recent initiatives to restrict antibiotics to when they are really needed. Broad spectrum antibiotics can have major effects on the ‘good’ bacteria that live in our bowel, and it is plausible that altering the number and balance of these gut bacteria can have major effects on the developing immune system that make asthma and allergies more likely.

“A number of observational studies have shown that children who are given early antibiotics are more likely to subsequently be diagnosed as having asthma, but it hasn’t been clear whether this is a chicken or an egg scenario – were the children given antibiotics because they had early asthma or an abnormality in their immune system that rendered infection and asthma more likely, or was the exposure to antibiotics affecting the immune system and leading directly to subsequent asthma development.

“This paper looks at detailed information of the lung function, allergy and immune status, genetic make-up and on antibiotic receipt from within a large birth cohort. The MAAS cohort consists of almost 1,000 children in Manchester who have been followed up since birth in a detailed way by researchers. The paper did indeed find a relationship between early life antibiotics and subsequent asthma. However, the children who went on to develop asthma showed abnormal immunological responses to some viruses which can cause significant childhood respiratory infections, and a particular genetic association. They hypothesise that children who go on to develop asthma may have been born with a particular genetic make-up that makes them vulnerable to respiratory infections, and hence to asthma in later childhood. This is an important observation that needs to be confirmed in other patient populations. There is great interest in the overlap between immunity, infections and asthma, and this potentially provides an important piece of the jigsaw.”

Dr Alastair Sutcliffe, Paediatric Epidemiologist, UCL, said:

“The authors of this paper suggest that a possible reason behind the association of antibiotic usage in babies with asthma development is their genetic make-up and subsequent viral immunity – those children who are by genetic nature relatively vulnerable to viral infections (including respiratory infections) are likely to have more interaction with GPs and hospitals because they are more often ill, and are therefore more likely to be prescribed antibiotics to treat their illness (even if it is viral, rather than bacterial, in nature).  These same genetic and viral vulnerabilities could also independently be associated with asthma development.

“Thus, there is no evidence here that antibiotics in early life cause asthma, and that is not what the authors claim.  Further research is needed to explore whether the genetic and viral immunity of infants suggested by the authors could explain subsequent asthma development.

“The accompanying editorial suggests that one way of furthering research in this field could be to carry out a randomised controlled trial of antibiotic treatment versus no antibiotic treatment in infants with infections.  In my view, there is simply no way that children (in this Lancet Respiratory Medicine study, often first born children), are going to agree (via their parental proxy consent) to such a trial, which would necessarily mean some infected children would not receive antibiotics where judged to need them by their doctors.  It is unlikely that parents, knowing infections can kill, would agree to this. Not all young children get given antibiotics, indeed many do not, but what is needed (apart from more vaccines) and what is starting to come into clinical practice is more accurate diagnostics at the bedside to test for viral infections so that unnecessary antibiotics (if the infection is viral, not bacterial) can be avoided – but this is needed because of antibiotic resistance, not because antibiotics themselves increase the risk of asthma (there is no evidence of this, as is emphasised by this new study).

“At the Institute of Child Health (UCL), where I work, a birth cohort study has started (the 2014 British Birth cohort study).  This will recruit a large cohort (around 80,000 babies) – in future, therefore, this Lancet Respiratory Medicine study could be repeated using datasets such as that one which will give a more reliable indicator of whether this modest sized cohort study is reproducible using a different dataset – one of the paradigm tests of potential validity of these interesting findings.”

Kay Boycott, Chief Executive of Asthma UK, said:

“Asthma kills the equivalent of a classroom full of children every year with thousands facing a daily struggle to breathe, which is why it is so important that more funding is made available for asthma research like this. The report adds to the ongoing debate on whether antibiotic use in early life might increase risk of developing asthma for children with particular genetic differences, but does not conclusively confirm this. However, this report highlights the importance of phenotyping asthma patients in research studies and shows that we cannot apply a ‘one size fits all’ approach when it comes to treating and managing asthma.”

Paper = ‘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’ by Aida Semic-Jusufagic et al. published in the Lancet Respiratory Medicine on Thursday 15 May 2014.

Editorial = ‘Antibiotics and asthma: a tricky tributary of the hygiene theory’ by Julian Crane and Kristin Wickens published in the Lancet Respiratory Medicine on Thursday 15 May 2014. 

Declared interests

Asthma UK has contributed funding towards the MAAS (Manchester Asthma and Allergy Study) study in the past.