Allergen-Specific Immunotherapy Jessica L. Rice, DO, MHS,a​ Gregory B. Diette, MD, MHS,b​ Catalina Suarez-Cuervo, MD,​c Emily P. Brigham, MD, MHS,​b Sandrain theY. Lin, MD,d​ MurugappanTreatment Ramanathan Jr, MD, FACS,of​d KarenPediatric A. Robinson, PhD,e​ Antoine Azar, MDf Asthma: A Systematic Review CONTEXT: abstract Treatment options for allergic asthma include allergen avoidance, pharmacotherapy, OBJECTIVES: and allergen immunotherapy. Summarize and update current evidence for the efficacy and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in pediatric DATA SOURCES: allergic asthma. PubMed, Embase, Cochrane Central Register of Controlled Trials (January 1, 2005, through May 8, 2017), ClinicalTrials.gov, and the US Food and Drug Administration STUDY SELECTION: Adverse Event Reporting System. We reevaluated≤ trials from our 2013 systematic review. We included studies with children 18 years of age in which researchers reported on prespecified outcomes and had an intervention arm receiving aeroallergen SCIT or SLIT. Only randomized controlled trials (RCTs) were included for efficacy. RCTs and non- DATA EXTRACTION: RCTs were included for safety outcomes. Two reviewers extracted data. We included 40 studies (17 SCIT trials, 11 SLIT RESULTS: trials, 8 non-RCTs for SCIT safety, and 4 non-RCTs for SLIT safety). We found moderate-strength evidence that SCIT reduces long-term asthma medication use. We found low-strength evidence that SCIT improves asthma-related quality of life and forced expiratory volume in 1 second. There was also low-strength evidence that SLIT improves medication use and forced expiratory volume in 1 second. There was LIMITATIONS: insufficient evidence on asthma symptoms and health care use. There were no trials in which researchers evaluated asthma symptoms using a CONCLUSIONS: validated tool. Study characteristics and outcomes were reported heterogeneously. In children with allergic asthma, SCIT may reduce long-term asthma medication use. Local and systemic allergic reactions are common, but anaphylaxis is reported rarely.

aDepartment of Pediatrics, Pediatric Pulmonology, bDepartment of Medicine, Pulmonary and Critical Care Medicine, eGeneral Internal Medicine, and fAllergy and Clinical Immunology, dDepartment of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and cEvidence-based Practice Center, Department of Health Policy and Management, Johns Hopkins School of Public Health, Baltimore, Maryland

Dr Suarez-Cuervo drafted the protocol with contributions by each author, conducted the search, screened studies, developed tables and flowcharts, assisted with drafting the review manuscript, and coordinated contributions from the coauthors; Dr Robinson drafted the protocol with contributions by each author; Dr Rice drafted the initial manuscript and reviewed and revised the manuscript; and all authors assessed studies for inclusion, extracted data, assessed the risk of bias, critically reviewed the manuscript for important intellectual content, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

To cite: Rice JL, Diette GB, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy in the Treatment of Pediatric Asthma: A Systematic Review. Pediatrics. 2018;141(5):e20173833

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018:e20173833 REVIEW ARTICLE Asthma is a chronic respiratory Healthcare7 Research and Quality for efficacy and RCTs, observational disease characterized by lower (AHRQ). studies, case series, and case reports airway inflammation, bronchial METHODS in which researchers examined hyperreactivity, and airflow safety. 1 Trial Selection obstruction. As of 2015, over 6 million or 8.4% of children2 in the We developed a protocol for the United States had asthma,​ and review with guidance from a approximately half of these3 cases technical expert panel and input Abstracts and full-text articles were attributable to atopy. The from representatives from both the were screened independently by majority of children with allergic3 AHRQ and the NHLBI. The protocol 2 reviewers. Any disagreements asthma are polysensitized. was registered in PROSPERO regarding inclusion were resolved Treatment options for allergic (http://​www.​crd.york.​ ​ac.​uk/​ through discussion, and unresolved asthma include allergen avoidance, PROSPERO), registration number conflicts were adjudicated during meetings. pharmacotherapy, and allergen CRD42016047749, and was posted Data Extraction and Quality immunotherapy (AIT). The goal of on the AHRQ Web site (https://​ Assessment AIT is to induce allergen-specific effectivehealthca​re.ahrq.​ ​gov/​ehc/​ – immune tolerance, and it is the only products/​644/2311/​ asthma-​ ​ allergic disease modifying therapy immunotherapy-​protocol-​160913.​ 4 Two reviewers extracted data and available. AIT can be given via a pdf). Detailed methods are7 available subcutaneous immunotherapy (SCIT) Datain the Sources full evidence and Searches report. assessed risk of bias (ROB). Efficacy or sublingual immunotherapy (SLIT) outcomes that were graded per our route. At this time, there are only 4 protocol included the following: – asthma symptoms as reported by US Food and Drug Administration We conducted a search of PubMed, asthma control composite scores, (FDA) approved SLIT tablets Embase, and the Cochrane Central QoL, medication use, health care use, available in the United States (house Register of Controlled Trials from and pulmonary physiology (forced dust mite [HDM], 5-grass, Timothy January 1, 2005, through May 8, expiratory volume in 1 second grass, and ragweed) for treatment of 2017. We requested scientific [FEV1]). Safety outcomes included allergic rhinitis; treatment of asthma information packages from– industry 5 anaphylaxis, local effects, systemic is off-label. representatives, searched previous 8 11 effects, and deaths. Details regarding reviews and guidelines,​ ‍ ‍ searched In preparation for an update to the immunotherapy including allergen, 1 ClinicalTrials.gov, and reviewed asthma management guidelines,​ formulation, dose, and treatment the FDA Adverse Event Reporting a National Heart, Lung, and Blood duration were extracted. System. We also reevaluated all of Institute (NHLBI) working group the included studies in our previous ’ identified the efficacy and safety of 6 For RCTs, the ROB was assessed by 2013 systematic review to confirm SCIT and SLIT in asthma management using the Cochrane Collaboration s eligibility for this review. 12 as an important topic for an updated tool. Overall ROB was graded systematic review. Our objective in For the main report, we included as low, moderate, or high. For this review is to provide an update studies of patients of any age with observational trials, ROB was ≤ to our previous 2013 systematic diagnosis of allergic asthma. For this assessed by using the Risk Of review (efficacy outcomes included review, only studies of children 18 Bias In Nonrandomized Trials of13 symptoms and medication use for years of age in which researchers Interventions, or ROBINS-I tool,​ children with asthma and allergic reported on prespecified outcomes and overall ROB was graded as rhinoconjunctivitis) and summarize were included. Trials were required low, medium, or high. For case the current evidence for the efficacy to have an intervention arm receiving reports and case series, we used the (symptoms, quality of life [QoL], SCIT or SLIT (tablet or aqueous). We World Health Organization (WHO) medication use, health care use, and excluded studies on food allergies criteria to judge the likelihood lung function) and safety of SCIT and if aeroallergens were not related to that the intervention was causally

SLIT, specifically6 in pediatric allergic asthma, if the type of allergen was not related (dose and time related) to asthma. This report is derived specified, or if the study population the observed14 serious adverse event from a larger review in which the did not report data separately for (AE). Following this guidance, efficacy and safety of SCIT and SLIT patients with asthma. Study inclusion we reported causality as certain or in adults and children with allergic was not restricted by language probable, likely or possible, unlikely asthma was evaluated, which was of publication. We included only or conditional, unclassified or commissioned by the US Agency for randomized controlled trials (RCTs) unassessable, or unclassifiable. Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 RICE et al Data Synthesis and Analysis

characteristics are summarized in on 2 small trials with medium and – Supplemental Table 5 and 6. high ROB. We completed a qualitative synthesis Efficacy Outcomes of SCIT Medication Use for all questions (Tables 1 4). We considered meta-analyses but determined that the trials were The efficacy of SCIT was reported in In 2 RCTs of HDM SCIT including 70 not sufficiently homogenous for 8 trials that included 644 children children, authors reported on quick- aged 5 to 14 years (Supplemental quantitative synthesis because relief medication19,23​ use (Supplemental of marked variability in patient Table 5). Asthma– severity was graded Table 8). ‍ One of these revealed characteristics, allergen and as mild to moderate17 20 persistent a significant decrease in the days of dose, trial duration, and outcome in most trials. ‍ ‍ Only 2 trials salbutamol used per year over the definitions. included21, those22​ with severe persistent 3-year trial period in the SCIT arm asthma,​ ‍ and researchers did The strength of evidence (SOE) versus the23 control arm (results in a not specify asthma severity in 1 was graded for each outcome as 23 figure). Researchers in the other trial. Most authors did not specify specified in our protocol. We used trial did not find a difference within the level of asthma control, but in 1 the grading scheme recommended in arms after 8 months and did not 19 trial, children were considered not the Evidence-based Practice Center 18 report a comparison between arms. 15,16​ well controlled. In 5 of the trials, Methods Guide. ‍ Five domains These 2 small trials with medium and patients were monosensitized and were considered when grading the high ROB had inconsistent and direct received a single allergen (HDM SOE for an outcome: trial limitations 17,19,​ 20,​ 22,​ 23​ results, providing low SOE that SCIT was evaluated in 4,​ ‍ ‍ ‍ mold (called ROB in this review), 18 improves quick-relief medication use. was evaluated in 1 ); in 2 trials, directness, consistency, precision, 15 polysensitized patients received In 4 trials, authors reported on long- and reporting bias. SOE was 21,24​ multiple allergens ‍ ; and in 1 term control medication use. Two of classified into 1 of 4 grades: (1) high trial, it was unclear if patients were these trials (both low ROB) included grade (indicating high confidence monosensitized or polysensitized, children with mild to moderate that the true effect is reflected in and these patients were treated with persistent asthma, and researchers the evidence, and further research 17 HDM. The maintenance-dosing found a significant decrease in the is unlikely to change our confidence interval varied from biweekly to dose of inhaled corticosteroids in the estimate of the effect), (2) every 6 weeks, and duration of (ICSs) used between17,20​ treatment and moderate grade (indicating moderate therapy ranged from 3 months to 3 comparator arms. ‍ In 1 of the confidence that the true effect is years. SCIT dosing and dosing units trials with 88 children, blinded study reflected in the evidence, but further wereAsthma variable. Control investigators adjusted controller research could change our confidence medications per a protocol based in the estimate of the effect and on symptom control every 1 to 3 may change the estimate), (3) low months and found that the dosage µ grade (indicating low confidence There were no trials in which of budesonide in the SCIT arm µ that the true effect is reflected in researchers reported on asthma decreased from 196.7 g at baseline the evidence, and further research QoLcontrol using a validated tool. to 71.3 g at 3-year follow-up, and the is likely to change our confidence final dosage was significantly lower in the estimate of the effect and is than the comparator arm, which µ likely to change the estimate), and In 2 RCTs including 57 children, received a desensitization vaccine 20 ± (4) insufficient grade (indicating authors reported on asthma-specific (101.3 g). Researchers in the other evidence is unavailable, or the QoL using a validated tool (Asthma trialn evaluated SCIT vitamin D (650 body of evidence has unacceptable Quality of Life Questionnaire 18,19​ IU per day) versus pharmacotherapy deficiencies, precluding reaching a [AQLQ]) (Supplemental Table 7). ‍ ( = 50); ICS doses were only conclusion). Researchers in both trials compared expressed in a figure, but SCIT + RESULTS single allergen SCIT (HDM and mold) vitamin D had a significantly lower to pharmacotherapy in children with ICS dose than the pharmacotherapy mild to moderate persistent asthma arm. Researchers in this trial also had In the full report, we identified 91 and found a significant improvement blinded investigators and patients trials in which researchers addressed in AQLQ scores in the SCIT arm but record their doses of ICSs on daily SCIT and SLIT. Of these, 40 included no difference between study arms. diary cards that were monitored children: 17 trials of SCIT, 11 trials Although these trials had consistent at each study visit. Authors of both of SLIT, 8 non-RCTs for SCIT safety, results, there is low SOE that SCIT trials also reported that significantly and 4 non-RCTs for SLIT safety. Trial improves asthma-related QoL based more patients in the SCIT arm Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 3 TABLE 1 SCIT Efficacy Summary Outcome No. Studies, Allergen Comparators Summary of Findings SOE Participants (n Studies) (n Studies) Asthma symptoms 0 — — Unable to draw conclusions. Insufficient QoL 2, 57 Dust mite (1), Alternaria (1) SCIT versus The SCIT arm improved in Low SOE that SCIT pharmacotherapy (2) both trials. Control arm improves asthma- also improved in 1 trial. related QoL In 1 trial, researchers measured difference between arms and found no difference Quick-relief 2, 70 Dust mite (2) SCIT versus placebo (1) 1 study revealed significant Low SOE that SCIT medication use versus control (1) reduction in No. d with reduces short- salbutamol treatment term medication in the SCIT arm when use compared with control. The second study did not reveal any significant difference for either arm Long-term control 4, 300 Dust mite (3), multiple (1) SCIT versus placebo 2 studies revealed significant Moderate SOE that medication use (1) versus reductions in medication SCIT reduces long- pharmacotherapy (1) use for SCIT versus term medication versus vitamin D + comparator arm. In use pharmacotherapy (1) 1 study, researchers versus desensitization didn’t compare arms, vaccine (1) and researchers in 1 study found no difference between arms. 2 studies revealed significant decrease in medicine use for SCIT arm at follow-up compared with baseline but not in the comparator arm Systemic 2, 150 Dust mite (1), multiple (1) SCIT versus placebo (1) The study on dust mite Low SOE that SCIT corticosteroids versus control (1) revealed significant reduces systemic decrease in No. d with steroid use systemic steroid use in the SCIT group when compared with control. The study on multiple allergens revealed no difference between groups Health care use 2, 161 Dust mite (1), multiple (1) SCIT versus placebo 1 study in which researchers Insufficient (1) versus report increase in clinic pharmacotherapy (1) visits but do not explain the reason or if study related. The second study revealed no difference Pulmonary 5, 378 Dust mite (3), mold (1), SCIT versus 1 study in which researchers Low SOE that SCIT

physiology: FEV1 multiple (1) pharmacotherapy (3) found significant difference improves FEV1 versus vitamin D + in the proportion of pharmacotherapy (1) patients with improved

versus control (1) FEV1 in the SCIT arm when compared with pharmacotherapy. 3 studies revealed no significant difference between arms. Researchers in 1 study reported that 100% of patients in the SCIT arm

had FEV1 >80% at follow-up —, not applicable.

Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 RICE et al TABLE 2 SLIT Efficacy Summary Outcome No. Studies, Allergen (n Comparators (n Findings SOE Participants Studies) Studies) Asthma symptoms 0 NA NA NA Insufficient QoL 0 NA NA NA Insufficient Health care use 0 NA NA NA Insufficient Quick-relief 2, 218 Dust mite (2) SLIT versus placebo Neither study revealed a significant difference Low SOE that medication use (2) between arms SLIT does not affect quick- relief asthma medication use Long-term control 2, 218 Dust mite (2) SLIT versus placebo Neither study revealed a significant difference Low SOE that SLIT medication use (2) between arms does not affect long-term asthma medication use Systemic 1, 110 Dust mite (1) SLIT versus placebo 1 study revealed significant reduction in Insufficient corticosteroids (1) medication consumption in the SLIT group when compared with placebo Pulmonary 6, 375 Dust mite (5); SLIT versus placebo 1 study revealed a significant improvement in Low SOE that SLIT

physiology: FEV1 grass (1) (6) FEV1 in SLIT versus placebo. 4 studies revealed improves FEV1 no difference between study arms. 3 studies revealed a significant improvement in SLIT arm only NA, not applicable.

discontinued ICS treatment versus 4 trials had low (3 trials) to high (1 health care use (Supplemental ± 21,22​ the comparator arm (20% and 35% trial) ROB and presented inconsistent Table 9). ‍ A significant difference vs 0% for SCIT vitamin D versus but direct results. There is moderate in hospitalizations or emergency pharmacotherapy; 29% vs 20% SOE that SCIT may improve long-term department (ED) visits was not controller medication use. found in either trial, but researchers for SCIT versus17,​20 desensitization in 1 trial of HDM SCIT did note a vaccine). Researchers in the In 2 RCTs, researchers evaluated significant increase in the number of remaining 2 trials found a significant systemic corticosteroid use. In 1 trial, office visits in the SCIT arm versus decrease in controller medication researchers evaluating HDM SCIT the pharmacotherapy arm (12.4 vs use in only the SCIT arm 19,at21​ follow-up in 29 children over 3 years found 17.25 visits in the previous 6 months compared with baseline. ‍ In 1 of a significant decrease in the mean for pharmacotherapy and SCIT these,n researchers evaluated HDM number of days of treatment required 22 arms, respectively). The authors SCIT versus pharmacotherapy in the previous year in the SCIT arm did not provide an explanation for ( = 41) for 8 months, and noted that versus controls (22 days at baseline this increase. Although these results at baseline, 7 (33%) patients in the decreased to 1 day at follow-up in the P are consistent and direct, there are SCIT arm and 4 (20%) in the control SCIT group versus 25 days decreased to 23 only 2 small trials with low and arm required ICSs, and at follow-up 12 days in the control group; < .01). P medium ROB, so we conclude that this decreased to 2 (10%) versus In the other trial, researchers did not there is insufficient evidence to draw no change, respectively ( value find a significant change within or 19 conclusions. not reported). In the final trial, between arms in the number of days Pulmonary Physiology researchers compared multiple- of children needing systemic steroids allergen SCIT to placebo in 121 in the previous 60 days between 21 children with moderate to severe baseline and 30-month follow-up. In 5 trials, researchers– evaluated asthma for 30 months and found that From these 2 small trials in which 1 FEV in 37817 children19,23,​ 24​ (Supplemental only patients in the SCIT arm had researchers presented inconsistent Table 10). ‍ ‍ ‍ Researchers significantly decreased use of ICSs at but direct results with low and in 1 evaluated multiple-allergen follow-up (mean of 21 out of 60 days medium ROB, we conclude that SCIT for 12 months in 242 children at baseline and 11.3 out of 60 days there is low SOE that SCIT improves and noted that significantly more at follow-up versus 20 out of 60 days systemicHealth Care corticosteroid Use use. patients in the SCIT arm versus at baseline and 14.7 out of 60 days the pharmacotherapyP arm had 1 at follow-up in the SCIT and placebo improvement in 24their FEV (60% vs arms, respectively). There21 was no In 2 trials with 161 children, 19%, = .0001). In another trial of difference between arms. These researchers evaluated SCIT and HDM SCIT, authors reported that all Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 5 TABLE 3 SCIT Safety Summary Type of Reaction No. Studies and Allergen (n Studies) No. AEs or Affected Patients/Total No. Description Design Treatment Arm Comparator Arm Local reaction 7 RCTs; Reported as Dust mite (7) 0/36 patients; 15/65 0/30 patients; 0/50 Local reaction not specified; patients patients; 26/97 patients; 0/70 patients Urticaria; Local edema, patients pruritus, and pain 5 RCTS; Reported as Dust mite (2); Grass 793 events/124 262 events/43 patients Redness, swelling, pain events (1); Dog (1); Mold patients (1) 1 non-RCT; Reported Pollen (1) 1/1 NA Erythema, swelling ≥5 cm as patients Systemic reactions General reactions 5 RCTS; Reported as Dust mite (4); Multiple 22/132 patients 4/128 patients Unspecified systemic reactions patients allergens (1) 2 RCTS; Reported as Dust mite (1); Mold (1) 46 events/61 patients NR Unspecified systemic reactions events Respiratory 6 RCTS; Reported as Dust mite (4); Grass 13/224 patients 3/217 patients Asthma, cough, dyspnea reactions patients (1) Multiple (1) 1 RCT; Reported as Dust mite (4) 14 events/20 patients 8 events/10 patients Asthma, cough, dyspnea events Cutaneous 1 RCT; Reported as Multiple allergens (1) 8/105 0/137 Skin rash reactions patients Other reactions 1 RCT; Reported as Grass (1) 21 events/18 patients 9 events/17 patients Eczema, urticaria, events rhinoconjunctivitis General reactions 3 non-RCTs; Multiple allergens (2); 37/161; 1/NR 0/52 Unspecified systemic reactions Reported as Dust mite (1) patients 2 non-RCTs; 1 Dust mite (1); Multiple 2/NR; 2/NR; 2 events/ NA Hives, wheezing; Rhinorrhea, reported as (1) NR; 4 events/NR ocular itching; Asthma, patients; 1 dyspnea; Congestion, reported as rhinorrhea, sneezing events Anaphylaxis 4 RCTS Dust mite (3), grass 2/96 0/69 Systemic reactions requiring (1) epinephrine 1 non-RCT Dust mite (1) 0/67 NA Death 5 non-RCTs Dust mite (3); Multiple 0/NR; 1/1 NA Death; 1 case report of death (3); Pollens (1) NA, not applicable; NR, not reported.

Asthma Control – patients in the SCIT arm had an FEV1 on the clinical efficacy of SLIT 25 30 >80% predicted at 8 month follow-up (Supplemental Table 6). ‍ ‍ Asthma No authors reported on asthma (19 out of 21 patients had FEV1 severity was graded as mild or mild QoLcontrol by using a validated tool. >80% at baseline), but comparator19 to moderate persistent in all trials. arm results were not reported. Control status was only specified in In the remaining 3 trials (2 HDM 2 trials; authors of 1 mentioned that and 1 mold), researchers found no 30 No authors reported on asthma- patients had controlled symptoms,​ Medicationrelated QoL. Use significant differences 17,between18,​ 23​ SCIT and comparator arms. ‍ In 1 of and authors of the other reported that patients had ongoing respiratory these (mold), researchers did find18 a n significant increase in both arms. symptoms despite ICSs and allergen In 2 trials in which HDM SLIT 26 Overall, inconsistent results were avoidance. Only monosensitized (aqueous and tablet) ( = 218) was – reported in 5 trials with low to high patients were included, and HDM used, researchers reported on asthma ROB; therefore, there is low SOE that 25,26,​ 28​ 30 medication use (Supplemental SLIT was evaluated in 5,​ ‍ ‍ ‍ 25,29​ SCIT improves FEV1. 27 Table 11). ‍ No significant Efficacy Outcomes of SLIT and grass was evaluated in 1 trial. difference between arms for quick- Maintenance dosing ranged from relief or long-term control medication daily to 2 days per week for 6 to 18 use was found in either trial. In 1 In 6 RCTs including 392 children months, and the maintenance dose trial, researchers evaluated the use aged 5 to 18 years, authors reported was variable between trials. of systemic corticosteroids and did Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 RICE et al TABLE 4 Safety Summary SLIT Type of Reaction No. Studies and Allergen (n studies) No. AEs or Affected Patients/Total No. Description Design Treatment Arm Comparator Arm Local reactions 3 RCTs Grass (1) 35%/20 patients 20%/15 patients Oral itching Reported as Dust mite (2) 5%/20 patients 6.6%/15 patients Stomach ache patients 0/55 0/46 No local AEs 2 RCTs Dust mite (2) 561 events/108 patients 10 events/73 patients Oral itching, ear itching, stomatitis, throat irritation Reported as events 19 events/54 patients 2 events/55 patients Unspecified GI events 1 non-RCT Dust mite (1) 1 event/1 patient NA Eosinophilic esophagitis Reported as patients Systemic reactions Respiratory 1 RCTs Multiple (1) 1/46 patients 1/22 patients Worsening asthma Reported as patients 4 RCTs Dust mite (3) 82 events/352 patients 73 events/152 patients Rhinitis and/or asthma, dyspnea Reported as events Grass (1) Other 10 RCTs Dust mite (6) 50%–68%/46 patients 32%–46%/22 patients Unspecified AEs Reported as Multiple (1) 115/236 patients 117/236 patients Headache patients Grass (2) 0/20 patients 6.6%/15 patients No systemic AEs Tree (1) 0/200 0/156 2 non-RCTs Dust mite (2) 3 events/1 patient NA Wheezing Reported as events 0 event/39 patients NA No systemic reactions Anaphylaxis 3 RCTs Dust mite (2) 0/266 0/183 Anaphylaxis Reported as Multiple (1) patients 1 non-RCT Tree (1) 1/1 NA Anaphylactic shock after overdose Reported as Dust mite (1) patients Death 1 RCT Grass (1) 0/55 0/50 Death Reported as patients GI, gastrointestinal; NA, not applicable.

1 not find any significant difference29 a significant improvement in FEV For SCIT, local reactions, including between arms at follow-up. percent predicted for SLIT compared urticaria, swelling, and redness or Evidence is low on the basis of only with placebo P(mean at follow-up = pain at the injection site, occurred 2 small trials with consistent results 100.4 vs 88.2 for SLIT and27 placebo, in 0% to 27% of trial patients in the and low to medium ROB that SLIT respectively; = .005). In 3 other treatment arm or 6.4 events per does not reduce quick-relief or long- HDM SLIT trials, researchers noted patient. In the comparator arms, such term control medication use. There is a significant improvement in FEV1 events occurred in 0% of patients or insufficient evidence about the effect at 6-month follow-up compared 0 to 6 events per patient. In the SLIT of SLIT on systemic corticosteroid use with baseline in only the SLIT arm trials, local reactions, including oral 1 toHealth draw Care conclusions. Use P(predicted FEV of 83.4% at baseline itching, stomatitis, throat irritation, improved to 92.6% at follow-up;– stomach ache, and unspecified GI

< .001; results for the other28 trials30 complaints occurred in 0% to 35% No authors reported on health care were presented in a figure). ‍ ‍ or 0.35 to 5.2 events per patient Pulmonaryuse. Physiology Overall, there is low SOE that SLIT in the treatment arms versus 0% improves FEV1 on the basis of results to 20% or 0.04 to 0.14 events per from 6 trials with inconsistent results patient in the comparator arms. Of the 6 trials in which authors andSafety low of to SCIT medium and SLIT ROB. There was 1 episode of eosinophilic reported on FEV1 (5 HDM and esophagitis reported in a patient 1 grass mix), only 1 revealed a treated with SLIT that resolved after difference between arms at follow-up In our review, we found that local discontinuation of SLIT (non-RCT). (Supplemental Table 12). In this and systemic reactions to both SCIT trial, researchers evaluated the and SLIT occurred more frequently In the SCIT trials, systemic reactions – efficacy of grass SLIT (ultra-rush) in the treatment than the comparator (cough, dyspnea, asthma, hives, for 2 years in 35 children and found arms (Supplemental Tables 13 21). rhinoconjunctivitis, eczema, and Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 7 unspecified reactions) occurred in per patient in the treatment arms for outcomes relating to asthma 6% to 17% or 0.7 to 1.1 events per versus 4.5% or 0.48 events per symptoms was limited to RCTs in patient in the treatment arms versus patient in the comparator arms. which researchers used validated 0% to 3% or 0.5 to 0.8 events per Unspecified adverse reactions measurement tools, which we did patient in the comparator arms. occurred in 0% to 68% of patients not find, so we do not have an update Anaphylaxis was reported in 2% of receiving SLIT versus 0% to 46% in for this outcome. Although we did patients receiving SCIT in trials (2 of the comparator arms. A researcher not include medication scores as an 96 patients) versus no events in the in 1 non-RCT described wheezing outcome, we similarly found that comparator arms (0 of 69 patients). that occurred 3 times in 1 patient. SCIT may decrease medication use. In 1 non-RCT, researchers specifically There was 1 episode of anaphylaxis Our review found that adverse local reported no anaphylactic events in in 267 patients receiving SLIT. In and systemic reactions to both SCIT 67 children treated with HDM SCIT. this case report, a 16-year-old girl and SLIT occurred more frequently Unspecified systemic reactions were with well-controlled intermittent in the treatment arms than the also reported in 23% of patients asthma receiving HDM SLIT had 2 comparator arms. Similar to previous receiving SCIT in non-RCTs. Other episodes of self-resolving wheezing reviews, local reactions were reactions including hives, wheezing, during maintenance therapy, and commonly reported in both SCIT and rhinorrhea, asthma, and congestion then in her third year of SLIT, after a SLIT trials. For SCIT, local reactions were also reported in the non-RCTs. 3-week break in maintenance dose, included urticaria, swelling, redness, the patient (for unknown reasons) There was 1 case report of death or pain at the injection site, and in administered herself 60 drops of 100 occurring in a 17-year-old girl with SLIT trials, local reactions included IR/mL instead of 10 drops and had moderate persistent asthma who 32 oral itching and gastrointestinal an episode of anaphylactic shock. had received SCIT in childhood for complaints. Similar to previous No deaths were reported for SLIT. 4 years and stopped because of a reviews, we found rare reports of skin reaction. The authors report DISCUSSION anaphylaxis associated with SCIT, that 12 hours after initiation of and although rarely reported, we a new regimen, she complained are including a case report of death of abdominal pain, vomiting, In this systematic review of the associated with SCIT as well as a and diarrhea without fever. Two evidence for the clinical efficacy case report of anaphylactic shock days later, she developed acute and safety of SCIT and SLIT for associated with an overdose of HDM respiratory failure and was referred pediatric allergic asthma, we found SLIT. Per the practice guidelines, AIT to the ICU. She had markedly elevated moderate-strength evidence that should be administered in a setting creatine kinase, elevated troponin, SCIT reduces long-term asthma that can monitor for and manage leukopenia, thrombocytopenia, controller medication use. We adverse reactions, and patients and bilateral interstitial markings otherwise found either low or should be monitored for 30 minutes on chest radiograph. On day 4, she insufficient evidence for the other after therapy (this includes the first developed a hypoxic coma leading outcomes, including asthma-related dose of SLIT). After the first dose, to intubation and mechanical QoL, quick-relief medication and SLIT can be administered at home. ventilation, followed by shock and systemic corticosteroid use (SCIT), Patients administering SLIT at home acute renal impairment. By day 5, asthma-related medication use should, however, be instructed on she developed multiorgan failure (SLIT), lung function (FEV1), and how to manage adverse reactions and died. The authors considered health care use. We did not identify and situations34 when SLIT should be immunologic mechanisms secondary any trials in which researchers held. For patients with asthma, AIT to manipulation or the way the used validated symptom scales, and should not be given to patients with dose was escalated and considered therefore we were unable to evaluate severe, unstable,11,34​ or poorly controlled causality probable. Following WHO this outcome. symptomsChallenges. and‍ Trial Limitations criteria for assessing case reports, we In our 2013 systematic review also determined that the likelihood of AIT for pediatric asthma and of SCIT causing this death (causality) rhinoconjunctivitis that included 34 The trials included in our review was possible, as the event was trials, we found moderate-strength were heterogeneous in patient and related to intervention but was not 31 evidence that SCIT improves intervention characteristics and dose related. asthma symptoms and low-strength in how outcomes were measured.

In the SLIT trials, systemic reactions evidence that SCIT improves33 Because of this heterogeneity, we (asthma, dyspnea) were rare, asthma medication scores. Unlike were only able to synthesize the data occurring in 2% or 0.23 events this previous review, our search qualitatively. Downloaded from www.aappublications.org/news by guest on September 25, 2021 8 RICE et al ≤ The studies in this review included future trials. We also did not find of Medicine, Baltimore, MD), who only children 18 years of age. Other any trials in which researchers assisted in the screening of search studies in the full report included reported asthma symptoms using results. children and adults but did not report a validated scale, and we would This topic was nominated by the results forn children separately; encourage this in future trials so the NHLBI and was selected therefore, they could not be used in that this important outcome can by AHRQ for systematic review this review ( = 9). Additional studies be more easily compared across by an evidence-based practice that we were not able to include trials. None of the researchers in clinic. A representative from the ’ had mixed populations of children the efficacy trials directly compared AHRQ served as a contracting with asthma and allergic rhinitis but different lengths of treatment or officer s technical representative did not report outcomes separately followed patients for an extended and provided technical assistance for those with asthma. Although period of time after completion of during the conduct of the full researchers in several trials reported therapy, so the question of how long evidence report and provided asthma symptoms as an outcome, we AIT must be given to see a lasting comments on draft versions did not find any that reported this effect on asthma symptoms remains of the full evidence report. Applicability outcome by using a validated tool. an important unanswered clinical The AHRQ did not directly question. Because there are only 4 participate in the literature FDA-approved SLIT tablets at this search, determination of trial Our results are applicable to children time, the use of other sublingual eligibility criteria, data analysis and adolescents with allergic asthma drops or tablets would be considered or interpretation, or preparation, due to inhalant allergens. The off-label. There is a need for rigorous review, or approval of the article majority of SCIT trials and all of the trials to evaluate these SLIT products34 for publication. SLIT trials used a single allergen ’ in United States populations. ABBREVIATIONS (HDM) AIT in monosensitized CONCLUSIONS patients, and it s possible that results may not be generalizable to AE: adverse event patients with allergic asthma who In children with allergic asthma, AHRQ: Agency for Healthcare are polysensitized, patients treated SCIT may reduce the need for asthma Research and Quality with multiple allergens, or other medication, improve FEV1, and AIT: allergen immunotherapy inhalant allergen AIT. Finally, most improve asthma-related QoL. SLIT AQLQ: asthma quality of life of the trials included children and may improve FEV1, but does not questionnaire adolescents with mild to moderate seem to improve asthma medication ED: emergency department persistent asthma. Patients with use. Local and systemic allergic FDA: US Food and Drug severe, uncontrolled asthma are at reactions to SCIT and SLIT are Administration increased risk for systemic reactions, common. Life-threatening events FEV1: forced expiratory volume therefore AIT should not be initiated11 such as anaphylaxis and death were in 1 second Future Research Needs unless asthma symptoms are stable. reported rarely. HDM: house dust mite ACKNOWLEDGMENTS ICS: inhaled corticosteroid NHLBI: National Heart, Lung, Future researchers should consider and Blood Institute evaluating multiple-allergen AIT QoL: quality of life as well as other inhalant allergens This trial is based on research RCT: randomized controlled trial in polysensitized patients. In our conducted at the Johns Hopkins ROB: risk of bias review, we did not find studies in University Evidence-based SCIT: subcutaneous which researchers evaluated the Practice Center under contract immunotherapy effect of single versus multiple- 290-2015-00006I. SLIT: sublingual immunotherapy allergen AIT in patients who are We acknowledge Jessica Gayleard, SOE: strength of evidence polysensitized, which is an important BS (Department of Medicine, WHO: World Health Organization clinical question to address in Johns Hopkins University School DOI: https://​doi.​org/​10.​1542/​peds.​2017-​3833 Accepted for publication Feb 5, 2018 Address correspondence to Jessica L. Rice, DO, MHS, Pediatric Pulmonology, Johns Hopkins University School of Medicine, Rubenstein Child Health Building, 200 N Wolfe St, Baltimore, MD 21287. E-mail: [email protected]

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 9 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Funded under contract 290-2015-00006I from the Agency for Healthcare Research and Quality (AHRQ) from the US Department of Health and Human Services. The authors of this article are responsible for its content. Statements in the article should not be construed as endorsement by the AHRQ or the US Department of Health and Human Services. The AHRQ retains a license to display, reproduce, and distribute the data and the report from which this article was derived under the terms of the agency’s contract with the author. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 11 Allergen-Specific Immunotherapy in the Treatment of Pediatric Asthma: A Systematic Review Jessica L. Rice, Gregory B. Diette, Catalina Suarez-Cuervo, Emily P. Brigham, Sandra Y. Lin, Murugappan Ramanathan Jr, Karen A. Robinson and Antoine Azar Pediatrics 2018;141; DOI: 10.1542/peds.2017-3833 originally published online March 23, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/141/5/e20173833 References This article cites 27 articles, 2 of which you can access for free at: http://pediatrics.aappublications.org/content/141/5/e20173833#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Allergy/Immunology http://www.aappublications.org/cgi/collection/allergy:immunology_s ub Asthma http://www.aappublications.org/cgi/collection/asthma_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 25, 2021 Allergen-Specific Immunotherapy in the Treatment of Pediatric Asthma: A Systematic Review Jessica L. Rice, Gregory B. Diette, Catalina Suarez-Cuervo, Emily P. Brigham, Sandra Y. Lin, Murugappan Ramanathan Jr, Karen A. Robinson and Antoine Azar Pediatrics 2018;141; DOI: 10.1542/peds.2017-3833 originally published online March 23, 2018;

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