Sublingual immunotherapy for asthma

Rebecca Normansell, Kayleigh M Kew, Amy‐Louise Bridgman

Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. However, it is not clear whether the sublingual delivery route is safe and effective in asthma. To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. We identified trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/) and reference lists of all primary studies and review articles. The search is up to date as of 25 March 2015. We included parallel randomised controlled trials (RCTs), irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. Two review authors independently screened the search results for included trials, extracted numerical data and assessed risk of bias, all of which were cross-checked for accuracy. We resolved disagreements by discussion.We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We rated all outcomes using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) and presented results in the 'Summary of findings' table. Fifty-two studies met our inclusion criteria, randomly assigning 5077 participants to comparisons of interest. Most studies were double-blind and placebo-controlled, but studies varied in duration from one day to three years. Most participants had mild or intermittent asthma, often with co-morbid allergic rhinitis. Eighteen studies recruited only adults, 25 recruited only children and several recruited both or did not specify (n = 9).With the exception of adverse events, reporting of outcomes of interest to this review was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence. Allocation procedures generally were not well described, about a quarter of the studies were at high risk of bias for performance or detection bias or both and participant attrition was high or unknown in around half of the studies.One short study reported exacerbations requiring a hospital visit and observed no adverse events. Five studies reported quality of life, but the data were not suitable for meta-analysis. Serious adverse events were infrequent, and analysis using risk differences suggests that no more than 1 in 100 are likely to suffer a serious adverse event as a result of treatment with SLIT (RD 0.0012, 95% confidence interval (CI) -0.0077 to 0.0102; participants = 2560; studies = 22; moderate-quality evidence).Within secondary outcomes, wide but varied reporting of largely unvalidated asthma symptom and medication scores precluded meaningful meta-analysis; a general trend suggested SLIT benefit over placebo, but variation in scales meant that results were difficult to interpret.Changes in inhaled corticosteroid use in micrograms per day (MD 35.10 mcg/d, 95% CI -50.21 to 120.42; low-quality evidence), exacerbations requiring oral steroids (studies = 2; no events) and bronchial provocation (SMD 0.69, 95% CI -0.04 to 1.43; very low-quality evidence) were not often reported. This led to many imprecise estimates with wide confidence intervals that included the possibility of both benefit and harm from SLIT.More people taking SLIT had adverse events of any kind compared with control (OR 1.70, 95% CI 1.21 to 2.38; low-quality evidence; participants = 1755; studies = 19), but events were usually reported to be transient and mild.Lack of data prevented most of the planned subgroup and sensitivity analyses. Lack of data for important outcomes such as exacerbations and quality of life and use of different unvalidated symptom and medication scores have limited our ability to draw a clinically useful conclusion. Further research using validated scales and important outcomes for patients and decision makers is needed so that SLIT can be properly assessed as clinical treatment for asthma. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma, so we cannot comment on the safety of SLIT for those with moderate or severe asthma. SLIT is associated with increased risk of all adverse events.