Risk factors for fatal and nonfatal reactions to immunotherapy (2008-2018): postinjection monitoring and severe asthma.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is highly effective but risks exist. OBJECTIVE: To identify practices that influence systemic allergic reactions (SRs) to SCIT and SCIT-associated infections. METHODS: Members of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology completed an annual survey of SCIT-related SRs of varying severity (2008-2018). Injection-related infections were queried (2014-2018). Strategies to enforce postinjection waiting times and to reduce risks from asthma/severe asthma were queried (2016-2018). RESULTS: Data were gathered on 64.5 million injection visits. Ten confirmed fatalities occurred since 2008, including 3 new fatalities since 2017. One fatal reaction occurred per 7.2 million injection visits (2008-2018). No infections occurred. Practices that tracked the time after injections, and required checking out with office personnel, had significantly lower total (P < .001), grade 3 (severe) (P < .001), and grade 4 (very severe) SRs (P < .001). Having more individuals with asthma on SCIT was associated with more grade 3 SRs (P < .02). Not prescribing SCIT in individuals with uncontrolled asthma was associated with fewer grade 3 SRs (P = .02). Having individuals with more severe asthma on SCIT was associated with more total, grade 1, and grade 2 SRs (P < .001); 50% of grade 3 and 4 SRs occurred in individuals with severe asthma. CONCLUSION: SCIT-related fatalities have declined since 2008, with a slight increase in recent years. SCIT is not associated with an increased risk of infections. Tracking the time after injections and checking out with office staff confer significantly lower risks of severe SRs. Asthma, especially severe asthma, is a major risk factor for severe and fatal SRs. Strategies that reduce risks for individuals with asthma, such as not prescribing SCIT to patients with uncontrolled asthma, may lower the risks.

Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013).

BACKGROUND: In 2008, an annual surveillance study of systemic reactions (SRs) from subcutaneous immunotherapy (SCIT) injections was initiated in North America. OBJECTIVE: To define the incidence of SRs to SCIT. METHODS: From 2008 to 2013, 27% to 51% of American Academy of Allergy, Asthma, and Immunology and American College of Asthma, Allergy, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. From 2012 to 2013, data were collected regarding SRs with off-label sublingual immunotherapy (SLIT), selection of patients with asthma for SCIT, and strategies for dose adjustment during pollen seasons. RESULTS: From 2008 to 2013, data were gathered on 28.9 million injection visits, including 344,480 patients for 2012 to 2013. Since 2008, a total of 2 confirmed fatalities were directly reported that occurred under the care of allergists. Two additional fatalities occurred under the care of nonallergists. The rate of SRs from SCIT remained stable, occurring in 1.9% of patients, with 0.08% and 0.02% experiencing grade 3 and 4 SRs. SRs occurred in 1.4% of patients receiving off-label SLIT, including 0.03% with grade 3 SRs. There were no SLIT-related grade 4 SRs or fatalities. Practices that never administered SCIT in patients with uncontrolled asthma (Asthma Control Test score <20) had significantly fewer grade 3 and 4 SRs (odds ratio, 0.7; 95% confidence interval, 0.5-1.0, and odds ratio, 0.3; 95% confidence interval, 0.1-0.8, respectively). Lowering doses during pollen seasons for patients with highly positive skin tests reduced SRs of all severity grades (P < .05). CONCLUSIONS: SCIT-related fatality rates may be decreasing, but continued vigilance regarding modifiable risk factors, including careful patient selection, is needed. Dose adjustment during pollen seasons for highly sensitive patients may reduce risks. Potential risk for SRs from off-label SLIT exists.

AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008-2012: an update on fatal and nonfatal systemic allergic reactions.

BACKGROUND: Before 2002, there were an estimated 3.4 fatal reactions per year to subcutaneous allergen immunotherapy (SCIT). Recent incidences of SCIT-related systemic allergic reactions (SR) and fatal reactions are not well defined. OBJECTIVE: To define the incidence of and clinical practices associated with SRs to SCIT and skin testing. METHODS: From 2008 to 2012, 27% to 49% of the American College of Allergy, Asthma, and Immunology and American Academy of Allergy, Asthma, and Immunology members completed an annual survey of SCIT-related fatal and nonfatal SRs of varying severity. A shortened version of the World Allergy Organization (WAO) classification system for SRs was adopted in 2011 (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, very severe). From 2011 to 2012, data were collected regarding nonfatal SRs to skin testing and strategies to lower the risk of SRs from SCIT. RESULTS: Between 2008 and 2012, data were gathered on 23.3 million injection visits. One confirmed fatality occurred in 2009. Overall SR rates remained stable at 0.1%. The rate of very severe, WAO grade 4, SRs was similar to previously reported rates of near-fatal reactions (1 in 1 million injections). Although almost one-third of practices experienced at least 1 SR from skin testing, no WAO grade 3 or 4 SRs from skin testing were reported. A lower target dose during cluster buildup before transitioning to maintenance may be associated with a lower risk of WAO grade 3 SRs (P = .07). Dose adjustment during pollen seasons was associated with fewer WAO grade 3 or 4 SRs (P < .001). CONCLUSIONS: Although SR rates have remained stable and fatalities appear to be declining, continued vigilance regarding SCIT safety is recommended. Additional surveillance and study regarding methods to decrease the risk of severe SRs is warranted.

AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions?

OBJECTIVE: To define the incidence of and clinical practices associated with subcutaneous immunotherapy (SCIT)-related systemic reactions (SRs). METHODS: From 2008-2011, American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma & Immunology members completed an annual survey of SCIT-related SRs of varying severity (with grade 1 indicating mild; grade 2, moderate; and grade 3, severe anaphylaxis). From 2010-2011 (year 3) data were collected regarding SCIT-related procedures, including screening of patients with asthma, dose adjustment during peak pollen seasons, build-up regimens (conventional, cluster, or rush), and premedication. RESULTS: No fatal reactions were directly or indirectly reported from 2008-2011. The SR rates were similar for all 3 years (0.1% of injection visits; 83% of practices), as were severity grades. On average, for all 3 years, there were 7.1 grade 1, 2.6 grade 2, and 0.4 grade 3 SRs per 10,000 injection visits. Screening for worsening asthma symptoms was highly prevalent (86% always screened). Practices that always reduced doses during peak pollen season were significantly less likely to report grade 2 or 3 SRs (44% vs 65%; P = .04). Cluster and rush build-up were associated with significantly more SRs (P < .001). Practices that premedicated were significantly more likely to report grade 2 and 3 SRs (P < .01). CONCLUSION: Fatal reactions to SCIT appear to be declining, possibly related to almost universal screening of asthmatic patients. Adjusting doses during the pollen season may be associated with decreased risk for severe SRs. Cluster and rush immunotherapy were associated with increased risk for SRs. Premedication by practices reporting SRs likely reflects past experience with SRs.

Immediate and delayed-onset systemic reactions after subcutaneous immunotherapy injections: ACAAI/AAAAI surveillance study of subcutaneous immunotherapy: year 2.

BACKGROUND: Incidences of subcutaneous immunotherapy (SCIT) related systemic reactions (SRs) and fatal reactions (FRs) are not well defined, nor are delayed-onset SRs and their treatment. OBJECTIVES: To estimate SCIT-related SRs/FRs, and the incidence and treatment of delayed-onset SRs. METHODS: In 2008 and 2009, American Academy of Allergy, Asthma & Immunology (AAAAI) and American College of Allergy Asthma & Immunology (ACAAI) members completed a survey about SCIT-related SR severity (grade 1 = mild; grade 2 = moderate; grade 3 = severe anaphylaxis). In 2009, members reported the time of onset and use of epinephrine (EPI), with early onset defined as beginning ≤30 minutes, and delayed onset beginning more than 30 minutes after injections. RESULTS: As in year 1, no FRs were reported during year 2 (630 total practices responded). Among 267 practices providing data on the timing of SRs, 1,816 early-onset SRs (86%) and 289 (14%) delayed-onset SRs were reported. Fifteen percent (226/1,519) of grade 1, 10% (54/538) of grade 2, and 12.5% (9/72) of grade 3 SRs were delayed-onset. Among early-onset SRs, EPI was given for 71% of grade 1, 93% of grade 2, and 94% of grade 3s. Among delayed-onset SRs, EPI was given for 56% of grade 1, 67% of grade 2, and 100% of grade 3s (P = .0008 for difference in EPI administration based on severity; P = .07 based on time of onset). CONCLUSIONS: Delayed-onset SRs are less frequent than previously reported. Epinephrine was given less frequently for grades 1 and 2 (but not grade 3) delayed-onset SRs compared with early-onset SRs. Further study of prescribing self-injectable EPI for SCIT patients in the event of delayed-onset SRs may be warranted.

Surveillance of systemic reactions to subcutaneous immunotherapy injections: year 1 outcomes of the ACAAI and AAAAI collaborative study.

BACKGROUND: Although systemic reactions (SRs) to subcutaneous immunotherapy (SCIT) injections are not uncommon, life-threatening and fatal reactions are rare. The annual incidence of injection-related SRs of varying severity is not well-defined. OBJECTIVE: To determine the annual frequencies of SCIT reactions in North America via a longitudinal surveillance program initiated among practicing allergists in 2008. METHODS: Physicians were asked to complete a Web-based survey reporting numbers of injections administered, injection- and skin test-related fatal reactions, and all nonfatal SRs in their clinical practices during the previous 12 months. The SR events were classified as mild (grade 1: cutaneous or upper respiratory symptoms), moderate (grade 2: asthma with reduced lung function), or severe (grade 3: life-threatening airway compromise or hypotension). RESULTS: In the initial year of the program, 806 physicians responded, representing 1,922 SCIT prescribers. No fatal reactions to SCIT injections were identified during the first 12 months, although 6 SCIT fatal reactions were reported retrospectively between 2001 and 2007. Eighty-two percent of practices reported 8,502 SRs to SCIT (10.2 SRs per 10,000 = 0.1% of injection visits). Most were grade 1 (74%) or grade 2 (23%) SRs. However, 3% (n = 265) were grade 3 anaphylactic events (3 severe reactions for every 100,000 injection visits). CONCLUSIONS: We demonstrated the feasibility of annual surveillance of SRs associated with SCIT injections. This surveillance study will continue to monitor SCIT adverse events in parallel with vigorous efforts instituted by members of professional organizations aimed at reducing the risk of severe reactions.