How Best to Care for Children with Allergies

The journal Archives of Disease in Childhood has recently published a supplement containing a series of articles focused on developing care pathways for children with allergies. The articles represent an effort by the Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department to develop national care pathways for these children, as requested by the UK Department of Health. The articles each focus on a different condition:

• Anaphylaxis
• Asthma and/or rhinitis
• Drug allergies
• Eczema
• Food allergy
• Latex allergies
• Urticaria, angioedema, or mastocytosis
• Venom allergies

Each article presents a pathway algorithm and a set of competences that are required to deliver high-quality care. They are intended as “a guide for training and development of services to facilitate improvements in delivery as close to the patient's home as possible.” The authors note that the pathways should be implemented by a multidisciplinary team, at a local level, and with an eye to establishing connections between primary, secondary, and tertiary care.

Council of the European Union adopts conclusions on chronic respiratory diseases in children

On December 2, the Council of the European Union adopted a set of conclusions regarding "Prevention, early diagnosis and treatment of chronic respiratory diseases in children." This topic had been identified by the Polish Presidency of the EU as one of its public health priorities. According to the press release, the conclusions urge member states “to give appropriate consideration to the prevention, early diagnosis and treatment of chronic respiratory diseases in children in their health programmes” and “to increase public awareness of these diseases, strengthen smoking prevention and cessation programmes for pregnant women and follow the Council recommendation on smoke-free environment.” In addition, the Council asks the Commission “to support member states in developing and implementing effective policies on the prevention of chronic respiratory diseases in children, improving networking among institutions responsible for the implementation of member states' programmes, and strengthening cooperation of national centres and reinforcing existing international research networks.”

Can we predict montelukast treatment failure in step-down therapy for controlled asthma?

Although many physicians and patients want to replace low dose inhaled steroids with montelukast in controlled patients with mild asthma, there are insufficient data to predict montelukast failure. A study by Drummond et al (J Asthma 2011 Oct 27 [Epub ahead of print]) provides a piece of the puzzle. Using the 165 participants in the Leukotriene or Corticosteroid or Corticosteroid-Salmeterol Study (LOCCS) trial who were stepped down from low-dose ICS to montelukast, the authors attempted to predict the risk of montelukast treatment failure during step-down. Characteristics independently associated with montelukast treatment failure included early asthma onset (<10 years), need for steroid burst in the last year, and low pre-bronchodilator FEV₁. They constructed a montelukast failure index that may prove to be helpful for clinical practice, but it needs further validation.

Another piece to the LABA debate in asthma: The age of the patient

The US Food and Drug Administration assessed the risks of LABAs in asthma using a meta-analysis of controlled clinical trials in patients 4 to 11, 12 to 17, 18 to 64, and older than 64 years old (McMahon AW et al., Pediatrics 2011;128:e1147-e1154). They studied how age affected a composite index of asthma-related deaths, intubations, and hospitalizations, as well as the effects of concomitant inhaled corticosteroid (ICS) use. For all ages, the composite event incidence difference was 6.3 events per 1000 patient-years when patients using LABAs were compared to those not using LABAs. The greatest difference in serious asthma-related events attributable to LABAs was observed among children — 30.4 events per 1000 patient-years [95% CI: 5.7-55.1] in the 4- to 11-year age group. In all age groups, results for the subgroup of patients with concomitant ICS use were similar to the overall results. The authors conclude that “Additional data are needed to assess risks of LABA use for children with simultaneous ICS use.”

Do we have biomarkers to improve control of asthma in children?

The level of asthma control incorporates current clinical control and exacerbations. Traditionally asthma treatments have been individualized using symptoms and spirometry or peak flow. Biomarkers hold promise for capturing complementary information, but need to be validated with regard to control. Two studies published online ahead of print in Thorax may help to give some guidance in clinical practice.

First, a systematic review evaluated the efficacy of tailoring asthma interventions based on inflammatory markers (sputum analysis and FeNO) as compared to clinical symptoms with or without pulmonary function tests in children and adults (Petsky et al. Thorax, 11 Oct 2010, epub ahead of print). The authors concluded that “tailoring of asthma treatment based on sputum eosinophils (3 studies in adults) is effective in decreasing asthma exacerbations in adults. However, tailoring of asthma treatment based on FeNO levels (2 studies in adults and 4 in children) has not been shown to be effective in improving asthma outcomes in children and adults.”

In the second article, a study was undertaken to investigate whether a strategy based on sputum eosinophils would be successful in 55 children with severe asthma (Fleming et al. Thorax, 8 August 2011, epub ahead of print). “Incorporating the control of sputum eosinophils into the management algorithm,” the authors concluded, “did not significantly reduce overall exacerbations or improve asthma control. Exacerbations were reduced in the short term, suggesting that more frequent measurements would be needed for a clinically useful effect and that controlling inflammation may have a role to play in subgroups of children with severe asthma.”

Do you agree that biomarkers are either not readily available or unavailable in most practice settings?

What do we really need to appraise the safety of combined long-acting ß2 agonists and inhaled corticosteroids in asthma?

The safety of LABAs has been questioned since their introduction in the early 1990s, and we do not have the answer yet. In an attempt to improve the safety of these drugs, the U.S. Food and Drug Administration (FDA) last year issued a requirement that labels for LABA-containing products should be changed with respect to asthma treatment. These changes state that LABAs are contraindicated without the concomitant use of an asthma controller medication, such as an inhaled corticosteroid. Furthermore, the revised labels recommend that LABAs are only to be used when they are necessary to achieve and maintain asthma control. While LABAs used by themselves increase the risk of serious adverse outcomes, it is still unclear whether there are similar risks when LABAs are added to inhaled corticosteroids. More studies are still needed to fully understand this key issue.

In a Perspective published in the New England Journal of Medicine (N Engl J Med 2011;364:2473-2475), Badrul Chowdhury and colleagues, from the FDA, provide some insights into the future studies that need to be carried out. This question cannot be answered through reanalysis of existing data, analyses of spontaneous reports of adverse events, or epidemiologic studies using existing databases; controlled clinical trials are necessary.

This April, the FDA issued a requirement that manufacturers of all LABAs marketed for asthma in the U.S. must conduct 5 controlled clinical trials to compare the safety of treatment with LABAs plus inhaled corticosteroids to treatment with inhaled corticosteroids alone. Even children as young as 4 will be enrolled in one of the trials. The 6-month trials will be multinational, randomized, and double-blind. The plan is to “mimic a real-world scenario,” and the FDA believes that “these clinical trials will provide data in a timely fashion that will clarify the safety risk associated with LABAs when used concurrently with inhaled corticosteroids and will inform the safe use of these medications for the treatment of asthma.”

What are your expectations for these trials? Are they going to change your practice?

The safety of tiotropium

“Safety of tiotropium: Indirect evidence suggests the Respimat inhaler is riskier than the Handihaler.” So states an editorial by Cates (BMJ 2011;342:d2970) that accompanies a recent BMJ article by Singh et al. (BMJ 2011;342:d3215). The authors systematically reviewed the risk of mortality associated with long-term use of tiotropium delivered using a mist inhaler for symptomatic improvement in COPD and found that 5 randomized controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality. The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 151, based on the average control event rate from the long term trials. There is however considerable uncertainty around this estimate (95% confidence interval: 51 to 5556). However, this point estimate is considerably larger than that found for salmeterol in asthma.

Is everything clear? No. The same authors made a previous meta-analysis on tiotropium (Singh et al. JAMA 2008;300:1439-50) and showed that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD. However, the publication of the large UPLIFT trial (Tashkin et al. N Engl J Med 2008;359:1543-54) did not confirm this meta-analysis. The FDA (Michele et al. N Engl J Med 2010;363(12):1097-9) did not support the conclusions of Singh et al. on tiotropium “because of the strengths of the UPLIFT data, the absence of a strong signal related to stroke or cardiovascular events with tiotropium and the potential methodologic limitations of the Singh meta-analysis.”
However, the conclusions of Cates are ambiguous since he wrote: “An ongoing trial will provide more certainty about the comparative safety of tiotropium inhaler devices” and concludes “if patients have a strong preference for the mist inhaler, the possible increased risk mortality will need to be shared with them.”

We therefore think that you should be warned about this new controversy and we would be delighted to know what you think.