september 2020 • Cochrane Database Syst Rev.

Sublingual immunotherapy for asthma.

Fortescue R, Kew KM, Leung MST

DOI: 10.1002/14651858.CD011293.pub3

Content curated by:Paulo Faria de Sousa

Key message

#Mensagem chave: Apesar dos vários estudos publicados nesta área, não é possível retirar conclusões clinicamente significativas sobre o efeito da Imunoterapia Sublingual nas exacerbações e qualidade de vida dos doentes com asma. A evidência disponível apresenta uma qualidade baixa e resultados tão imprecisos que variam desde o benefício importante até à possibilidade de dano. #População: Adultos ou crianças com asma tratados com Imunoterapia Sublingual comparada com placebo ou cuidados habituais em contexto de consulta externa. #Métodos:a Os autores escolheram como outcomes principais exacerbações graves com necessidade de ida ao SU ou internamento, qualidade de vida e efeitos adversos graves. Como outcomes secundários figuraram avaliações em escalas de sintomas de asma, exacerbações com necessidade de corticoterapia e dose de corticóides inalados. Revisão sistemática e meta-análise realizada seguindo os métodos habituais da Cochrane. #Resultados: Foram encontrados 66 estudos dos quais 31 recrutaram apenas crianças. Os autores alertam que reporte selectivo pode ter afectado seriamente os dados, uma vez que, 16 estudos não contribuíram com dados e outros 6 foram incluídos apenas na análise de eventos adversos. Houve também motivo para preocupação com os vieses de alocação, detecção, performance e atrito. Relativamente às exacerbações graves foi encontrado um OR de 0.35 (IC 95% 0.10 a 1.20; n = 108). Não foi possível analisar os dados de qualidade de vida nesta meta-análise. Não parece existir um aumento de efeitos adversos graves atribuíveis à Imunoterapia Sublingual. Existe um aumento de Efeitos Adversos (OR de 1.99, IC 95% de 1.49 a 2.67), ainda que ligeiros e transitórios. Os sintomas de asma e utilização de medicação foram medidos com escalas não validadas na maioria dos estudos, impossibilitando uma interpretação definitiva dos dados. Ainda assim, parece existir uma tendência para melhoria com utilização de SLIT. A imprecisão dos resultados, aliada ao risco de viés levou a que apenas os outcomes de efeitos adversos pontuassem acima de moderado na certeza de evidencia de acordo com metodologia GRADE. Os restantes outcomes foram classificados como baixa ou muito baixa.

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 methods: 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 analysi: 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 effect 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. 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.