Dr Tom Waterfield: Wheeze And Intermittent Treatment (WAIT) trial

With winter fast approaching paediatricians, GPs and ED doctors will be bracing themselves for the inevitable surge in children presenting with wheeze. Any approach that could reduce attendances would be gratefully received and the WAIT study set out to determine if Montelukast could be used intermittently by parents to reduce unscheduled attendances with wheeze. This study published in October’s Lancet recruited 1358 children aged between 10months and 5 years over a 3 year period across 62 sites in the UK. All of the children had physician diagnosed wheeze on at least two occasions. The study set out to determine if giving Montelukast to children at the onset of cold or wheeze symptoms over a 12 month period could reduce unscheduled attendances to hospital. This double blinded, multicentre randomised control study found that intermittent Monteleukast usage did not reduce hospital attendance. The authors also performed a meta-analysis of existing studies investigating the intermittent usage of Montelukast for wheeze and again found no evidence of a benefit.

Interestingly however, the group also performed subgroup analysis based on genotyping for the arachidonate 5-lipoxygenase (ALOX5) gene promoter and found that a subgroup of childrenin the WAIT study did demonstrate a statistically significant reduction in unscheduled medical attendances for wheezing episodes.

So where does this leave us?

For this winter this study doesn’t offer any additional hope for the use of Montelukast in preventing hospital attendances but there is hope for the future. Further work to better understand how genotyping could be used to identify Montelukast responsive children could result in targeted therapy.

Dr Chin Nwokoro’s reply:

Effective treatment for preschool wheezing children remains elusive. Oral steroids do not reduce hospital admissions or length of stay (1, 2) and may cause harm. Preschool wheezers are predominantly well between attacks and chronic inhaled steroids are not justified in the absence of very frequent or clinically severe episodes. Montelukast shows promise as the only leukotriene receptor antagonist licensed in children, especially given previous work showing an increase in leukotriene axis activation during acute wheezing episodes(3). This study did not show evidence of global benefit in this age group, and the genetic subgroup effect did not in truth meet significance when the p-value for interaction is considered. The data hint at rather than firmly identify a responsive subgroup, and furthermore no link is shown between baseline leukotriene status and montelukast response(4). The success of ivacaftorin CF patients with a gating mutation is evidence that genotype-guided therapy can be transformative(5), unfortunately that evidence is lacking here. The ERS taskforce(6) suggests a role for prophylactic therapy in preschool viral wheezers with severe or frequent attacks and it is here, in the absence of steroid-modifiable pathology, where ‘preloading’ with regular (but not on this evidence intermittent) montelukast may prove of benefit.

References:

1. Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Lancet. 2003;362(9394):1433-8.
2. Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med. 2009;360(4):329-38.
3. Oommen A, Grigg J. Urinary leukotriene E4 in preschool children with acute clinical viral wheeze. Eur Respir J. 2003;21(1):149-54.
4. Nwokoro C, Pandya H, Turner S, Eldridge S, Griffiths CJ, Vulliamy T, et al. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial. Lancet Respir Med. 2014;2(10):796-803.
5. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-72.
6. Brand PL, Caudri D, Eber E, Gaillard EA, Garcia-Marcos L, Hedlin G, et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J. 2014;43(4):1172-7.