Sublingual immunotherapy for asthma

Review question

We assessed the evidence on the use of sublingual immunotherapy (SLIT) for people with asthma compared with placebo (dummy treatment) or with standard asthma care. We focused on whether SLIT is a good treatment for asthma and whether it is safe.

Background

Asthma is a long-term condition that causes breathing problems and cough, which sometimes develop into asthma attacks. This may lead to the need for patients to take extra medication, visit a clinic or a hospital for treatment, or even be admitted to the hospital. Approximately 300 million people worldwide have asthma, and allergies may be an important trigger of asthma symptoms in about half of these people (e.g. house dust mites, pollen). The aim of SLIT is to reduce the body's allergic response that causes asthma symptoms, which is done by giving repeated doses of what the person is allergic to in liquid or tablet form under the tongue. It is currently unclear whether SLIT is more helpful or safer for people with asthma, when compared with placebo or just continuation of normal asthma treatments.

Study characteristics

We included 66 studies involving 7944 people, which is 2867 more people than the last time we reviewed the evidence. The included studies lasted between one day and three years, and most people in the studies had mild asthma. Both males and females were included, and about half of the studies included only children.

Most studies involved people with house dust mites or pollen allergy. The evidence presented here is current to 29 October 2019.

Key results

Very few included studies recorded the number of people who had asthma attacks or 'exacerbations' leading to a hospital visit or the need for additional medication, possibly because most people in the studies had mild asthma, so it was difficult to tell if they can be reduced by SLIT. A few studies reported quality of life, but they used different scales, so it was unclear if SLIT had a positive effect. Some studies reported that people taking SLIT had fewer asthma symptoms and a reduced need for asthma medication compared with the control group, but studies measured this information in lots of different ways so that it was difficult to combine or assess for accuracy.

People receiving SLIT were no more or less likely to experience serious unwanted side effects, but these were generally very rare. We are not confident that this finding would apply to people with more severe asthma. People receiving SLIT were more likely to experience any unwanted side effect, but many of these were mild.

Most guidelines for asthma treatment recommend that SLIT should be used only for people with asthma that is difficult to control with standard treatments. However, many of the studies in this review included people with mild asthma, so trials looking at the effects of SLIT for people with more severe asthma are needed. It would be helpful if these studies used standard scales to report their findings, so that in the future results can be combined.

Certainty of the evidence

The evidence presented in this review is generally of moderate or low certainty, with very few studies reporting outcomes that are important to people with asthma, such as asthma attacks and quality of life. Most studies did not clearly explain how investigators decided which people would receive SLIT and which individuals would receive placebo or normal care, and in some studies, both participants and trial organisers knew which treatment participants were getting, which may have affected the results.

Authors' conclusions: 

Despite continued study in the field, the evidence for important outcomes such as exacerbations and quality of life remains too limited to draw clinically useful conclusions about the efficacy of SLIT for people with asthma. Trials mostly recruited mixed populations with mild and intermittent asthma and/or rhinitis and focused on non-validated symptom and medication scores. The review findings suggest that SLIT may be a safe option for people with well-controlled mild-to-moderate asthma and rhinitis who are likely to be at low risk of serious harm, but the role of SLIT for people with uncontrolled asthma requires further evaluation.

Read the full abstract...
Background: 

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. Fifty-two studies were identified and synthesised in the original Cochrane Review in 2015, but questions remained about the safety and efficacy of sublingual immunotherapy for people with asthma.

Objectives: 

To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma.

Search strategy: 

The original searches for trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, WHO ICTRP, and reference lists of all primary studies and review articles found trials up to 25 March 2015. The most recent search for trials for the current update was conducted on 29 October 2019.

Selection criteria: 

We included parallel randomised controlled trials, 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. We selected outcomes to reflect recommended outcomes for asthma clinical trials and those most important to people with asthma. Primary outcomes were asthma exacerbations requiring a visit to the emergency department (ED) or admission to hospital, validated measures of quality of life, and all-cause serious adverse events (SAEs). Secondary outcomes were asthma symptom scores, exacerbations requiring systemic corticosteroids, response to provocation tests, and dose of inhaled corticosteroids (ICS).

Data collection and analysis: 

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. Any disagreements were resolved 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 considered the strength of evidence for all primary and secondary outcomes using the GRADE approach.

Main results: 

Sixty-six studies met the inclusion criteria for this update, including 52 studies from the original review. Most studies were double-blind and placebo-controlled, varied in duration from one day to three years, and recruited participants with mild or intermittent asthma, often with comorbid allergic rhinitis. Twenty-three studies recruited adults and teenagers; 31 recruited only children; three recruited both; and nine did not specify.

The pattern of reporting and results remained largely unchanged from the original review despite 14 further studies and a 50% increase in participants studied (5077 to 7944). Reporting of primary efficacy outcomes to measure the impact of SLIT on asthma exacerbations and quality of life was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence; 16 studies did not contribute any data, and a further six studies could only be included in a post hoc analysis of all adverse events. Allocation procedures were generally not well described; about a quarter of the studies were at high risk of performance or detection bias (or both); and participant attrition was high or unknown in around half of the studies.

The primary outcome in most studies did not align with those of interest to the review (mostly asthma or rhinitis symptoms), and only two small studies reported our primary outcome of exacerbations requiring an ED or hospital visit; the pooled estimate from these studies suggests SLIT may reduce exacerbations compared with placebo or usual care, but the evidence is very uncertain (OR 0.35, 95% confidence interval (CI) 0.10 to 1.20; n = 108; very low-certainty evidence). Nine studies reporting quality of life could not be combined in a meta-analysis and, whilst the direction of effect mostly favoured SLIT, the effects were often uncertain and small. SLIT likely does not increase SAEs compared with placebo or usual care, and analysis by risk difference suggests no more than 1 in 100 people taking SLIT will have a serious adverse event (RD −0.0004, 95% CI −0.0072 to 0.0064; participants = 4810; studies = 29; moderate-certainty evidence).

Regarding secondary outcomes, asthma symptom and medication scores were mostly measured with non-validated scales, which precluded meaningful meta-analysis or interpretation, but there was a general trend of SLIT benefit over placebo. Changes in ICS use (MD −17.13 µg/d, 95% CI −61.19 to 26.93; low-certainty evidence), exacerbations requiring oral steroids (studies = 2; no events), and bronchial provocation (SMD 0.99, 95% CI 0.17 to 1.82; low-certainty evidence) were not often reported. Results were imprecise and included the possibility of important benefit or little effect and, in some cases, potential harm from SLIT.

More people taking SLIT had adverse events of any kind compared with control (OR 1.99, 95% CI 1.49 to 2.67; high-certainty evidence; participants = 4251; studies = 27), but events were usually reported to be transient and mild.

Lack of data prevented most of the planned subgroup and sensitivity analyses.

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