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Lin SY, Azar A, Suarez-Cuervo C, et al. The Role of Immunotherapy in the Treatment of Asthma [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Mar. (AHRQ Comparative Effectiveness Reviews, No. 196.)
In this systematic review addressing the efficacy and safety of SCIT and SLIT in the treatment of allergic asthma, we identified a total of 61 RCTs and 29 non-RCTs. Of those studies focusing on SCIT only, there were 31 RCTs focused on efficacy and 44 articles reporting data on the safety of SCIT. Patients in the included SCIT studies had mild to moderate asthma in most studies. However, in many studies the diagnosis of asthma was not specified and, in the majority, the status of asthma control prior to treatment with SCIT was not specified. Several studies described an accelerated SCIT protocol.
For asthma related outcomes, our current report abstracted data exclusively from RCTs, with 31 studies of the efficacy of SCIT meeting inclusion criteria. Of the SCIT asthma outcomes that were the focus of our current report, we found moderate strength of evidence that SCIT reduces the need for long-term control medications. We also found that SCIT may improve quality of life, reduce the use of quick-relief medication, reduce the need for systemic corticosteroids, and improve FEV1 (low SOE). We found insufficient evidence to make conclusions about the effect of SCIT on asthma symptoms, and for health care utilization. Overall, our systematic review found that SCIT was beneficial for the majority of asthma-related outcomes assessed in this report.
Regarding adverse reactions to SCIT, we found that local reactions are frequent, occurring in up to one-third of patients receiving AIT injections; however, reactions also commonly occurred with placebo injections in more than one-tenth of patients but infrequently required a change in the SCIT dosing. Systemic allergic reactions to SCIT are relatively common and were reported in up to 33 percent of adult patients. Seldom were reactions consistent with anaphylaxis requiring treatment with injectable epinephrine (of the total 180 systemic allergic reactions reported in RCTs, we determined that six cases were consistent with anaphylaxis and there was one case reported from the 165 reported in the non-RCTs.) SCIT in patients with asthma generally has a favorable safety profile; however, our review found that systemic allergic reactions do occur, some of which require treatment with injectable epinephrine. According to published practice guidelines, it is essential that patients in these studies are carefully monitored in a medically supervised setting where a trained allergist and appropriate emergency equipment are immediately available to recognize and treat systemic allergic reactions.119, 120
The efficacy of SLIT for asthma was assessed in 18 RCTs. Similar to the SCIT articles identified in our report, the patients in the SLIT studies generally had mild to moderate asthma. In several SLIT efficacy studies that were included in our review, the diagnosis of asthma and asthma control prior to treatment was not clearly stated. We found high strength of evidence that SLIT reduces asthma symptom outcomes. There was moderate grade evidence for the benefit of SLIT in reducing the use of long-term control medications (inhaled corticosteroids) and improving FEV1. SLIT may also reduce the need for quick-relief medication and improve disease-specific quality of life (low SOE). There was insufficient evidence to draw conclusions on the effect of SLIT on systemic corticosteroid use and health care utilization. Overall, our systematic review finds SLIT beneficial for the majority of asthma-related outcomes included in this systematic review.
We found that local adverse events were common with use of SLIT, occurring in up to 40 percent of patients, but that systemic and life-threatening events were reported in only a few studies. Recent alterations in grading of systemic versus local reactions, with a more liberal definition of systemic allergic reactions prior to the 2017 World Allergy Organization (WAO) update,121 may lead to an overestimation of systemic allergic reactions. It is important to note that all reported anaphylaxis events (3 case reports) occurred in patients receiving multiple-allergen therapy, perhaps signaling that this form of therapy poses higher risk for systemic adverse effects.122 Furthermore, the rate of adverse events did not show a consistent relationship with SLIT dose. Of note, the package insert for SLIT tablets approved by the FDA does recommend that an epinephrine auto-injector device be prescribed for patients taking SLIT tablets,123 and this is supported by our systematic review, which found systemic reactions can occur with SLIT.
Our current systematic review is the most up-to-date evidence report on the efficacy of AIT for asthma. Our current findings are consistent with our prior JHU EPC evidence report and other prior systematic reviews and support the efficacy of SCIT and SCIT for asthma in the allergic patient. The Cochrane review of SCIT concluded that it resulted in significant reduction in asthma symptoms and the need for asthma medications, as well as improvement in allergen-specific bronchial hyper-reactivity.8 Our prior evidence report similarly concluded that there was high strength of evidence that SCIT reduces asthma symptoms and medication use.10 Both of these reviews noted the significant heterogeneity between the studies, as we found. In contrast, we could not draw conclusions about the effect of SCIT on asthma symptoms, as we limited our review to studies that used validated tools to measure asthma symptoms and identified none. A 2015 Cochrane review found there was low quality evidence supporting the use of SLIT in changing ICS use and very low quality evidence regarding bronchial provocation.9 This Cochrane review further noted that the largely non-validated asthma symptom scores, medications scores, and available data for quality of life precluded meaningful synthesis of these outcomes. Our prior evidence report examined SLIT in aqueous form only, and concluded that SLIT reduced asthma symptoms.10 This review expanded our scope to consider SLIT in tablet form and came to similar conclusions.
Limitations
We found considerable heterogeneity in the outcomes reported, and in the measurement of outcomes, that precluded quantitative pooling of the data. Many studies did not report relevant statistical information on continuous variables (such as confidence interval, standard deviation, and standard error) and some studies did not report results between arms, also limiting our ability to synthesize the evidence. We found considerable heterogeneity in the outcomes reported, and in the measurement of outcomes, that precluded quantitative pooling of the data. Many studies did not report relevant statistical information on continuous variables (such as confidence interval, standard deviation, and standard error) and some studies did not report results between arms, also limiting our ability to synthesize the evidence. While heterogeneity of study methods and outcome precluded quantitative meta-analysis, because the general mechanism of immunotherapy is the same across targeted allergens, we pooled these results qualitatively. In addition, it was not feasible to make direct comparisons between different allergen targets due to insufficient data and lack of studies for specific allergens.
It was a challenge to align some study findings with the age categories defined in asthma guidelines. National asthma guidelines recommend distinct treatment for children 5 to 11 years of age and consider treatments for children 12 years of age and older to be the same as for adults. When we evaluated studies that included children and youth (i.e., younger than 18 years of age) we found very few studies had set enrollment criteria to restrict populations that would fit neatly into either of the groups defined by the guidelines. Furthermore, data were not reported in the studies to allow abstraction of subgroups that fit distinctly into these categories. Thus, a study that enrolled, for example, patients between 5 to 15 years of age would have findings relevant to both age groups (5 to 11 years of age and 12 years of age and older); for the purposes of this review, these studies were reported as mixed-age groups. As a result, there was some information that could inform the overall question of immunotherapy efficacy but could not be used in subgroup analyses of children only or adults only.
We found extreme variability in the dosing and treatment schedules from study to study. The doses were reported in varying units (e.g., BU, IR, SQ-U, micrograms, BAU, STU, etc.). Some studies used conventional schedules; some studies used rush or ultra-rush schedules. These variations made it very hard to compare outcomes across studies. In several studies, major allergen content was not reported and the study length varied from weeks to months. There was also variability from study to study in the use of standardized and non-standardized allergens. In addition, almost all of the SCIT and SLIT studies were performed using a single allergen; therefore, we were unable to perform an analysis of multi-allergen immunotherapy.
There was much variability across studies in methods and criteria used for asthma diagnosis, as well as grading of asthma severity and control status. Also, some studies did not provide information about baseline asthma severity or control. These issues may affect the ability to generalize the findings to certain patients with asthma and limited our ability to determine whether asthma health status at the beginning of treatment affects the observed outcomes.
Unfortunately, there were some studies of SLIT and SCIT that could not be included in the analysis, either because validated measures of outcomes were not used (e.g., use of a non-standardized “symptom score” or “medication score”), or because patients without asthma were also included in the study but results were not presented separately for those with asthma. For example, some studies enrolled patients with allergic rhinitis and/or asthma which did not allow us to assess the impact of immunotherapy specifically on asthma.
We tried to grade all adverse events using the WAO classification; however, many descriptions of the reactions (or the lack of description) significantly limited our ability to classify the adverse events. Studies reporting adverse events used different grading systems, no formal grading system at all, and, in some cases, no descriptions of events: this made classification difficult for both SCIT and SLIT. All the studies included were published before the most recent WAO classification,121 and even before the initial 2010 grading system;124 therefore, classification of what was considered as local or systemic events and severity differed greatly, and may lead to overestimation or underestimation of events.
Only a small number of articles described some of the systemic reactions as “anaphylactic” reactions. However, upon review of the systemic allergic reactions described, several of these reactions would be consistent with anaphylaxis, based on the National Institute of Allergy and Infectious Diseases (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) criteria for diagnosis of anaphylaxis.125
Applicability
The results of this review are applicable to patients with inhalant allergy (as confirmed by skin or allergen specific in vitro testing) and asthma treated with allergen-specific immunotherapy. Most studies were performed in adults or mixed-aged populations, with merely 12 studies of children only. For some outcomes in this report, a limited number of allergens were studied. The applicability of results to allergens that have not been studied is unclear. Almost all trials used a single allergen for immunotherapy; therefore, we cannot comment on the comparative effectiveness of multiple-allergen immunotherapy. These studies were done almost exclusively in patients with mild to moderate persistent asthma, with a paucity of studies in those with severe persistent asthma. The dose and duration of treatment varied considerably in these studies. Half of the studies were with HDM allergen (46 of the 89 studies); the number of studies of other allergens that met inclusion criteria for this review were limited or very diverse. Many of the studies were performed with extracts manufactured outside of the United States and subject to different standardization methods; therefore, caution does need to be applied when considering the applicability of our results to allergens that have undergone different standardization processes.
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