Anaphylaxis knowledge gaps and future research priorities: A consensus report.

BACKGROUND: Despite a better understanding of the epidemiology, pathogenesis, and management of patients with anaphylaxis, there remain knowledge gaps. Enumerating and prioritizing these gaps would allow limited scientific resources to be directed more effectively. OBJECTIVE: We sought to systematically describe and appraise anaphylaxis knowledge gaps and future research priorities based on their potential impact and feasibility. METHODS: We convened a 25-member multidisciplinary panel of anaphylaxis experts. Panelists formulated knowledge gaps/research priority statements in an anonymous electronic survey. Four anaphylaxis themed writing groups were formed to refine statements: (1) Population Science, (2) Basic and Translational Sciences, (3) Emergency Department Care/Acute Management, and (4) Long-Term Management Strategies and Prevention. Revised statements were incorporated into an anonymous electronic survey, and panelists were asked to rate the impact and feasibility of addressing statements on a continuous 0 to 100 scale. RESULTS: The panel generated 98 statements across the 4 anaphylaxis themes: Population Science (29), Basic and Translational Sciences (27), Emergency Department Care/Acute Management (24), and Long-Term Management Strategies and Prevention (18). Median scores for impact and feasibility ranged from 50.0 to 95.0 and from 40.0 to 90.0, respectively. Key statements based on median rating for impact/feasibility included the need to refine anaphylaxis diagnostic criteria, identify reliable diagnostic, predictive, and prognostic anaphylaxis bioassays, develop clinical prediction models to standardize postanaphylaxis observation periods and hospitalization criteria, and determine immunotherapy best practices. CONCLUSIONS: We identified and systematically appraised anaphylaxis knowledge gaps and future research priorities. This study reinforces the need to harmonize scientific pursuits to optimize the outcomes of patients with and at risk of anaphylaxis.

Early Introduction of Food Allergens and Risk of Developing Food Allergy.

There is increasing evidence that early introduction of allergenic foods may decrease the risk of developing IgE-mediated food allergy. Patterns of food introduction before the 2015 publication of the Learning Early about Peanut Allergy (LEAP) trial are not well-studied, but are important as a baseline for evaluating subsequent changes in infant feeding practices and potentially food allergy. We performed a retrospective longitudinal study using data from a multicenter cohort of infants hospitalized with bronchiolitis between 2011-2014. The primary outcomes were IgE-mediated egg or peanut allergy by age 3 years. Of 770 participants included in the analysis, 635 (82%) introduced egg, and 221 (27%) introduced peanut by age 12 months per parent report. Four participants had likely egg allergy, and eight participants had likely peanut allergy by age 3 years. Regular infant egg consumption was associated with less egg allergy. The association was suggestive for infant peanut consumption with zero peanut allergy cases. Overall, our results suggest that early introduction of peanut was uncommon before 2015. Although limited by the small number of allergy cases, our results suggest that early introduction of egg and peanut are associated with a decreased risk of developing food allergy, and support recent changes in practice guidelines.

Emergency department revisits and rehospitalizations among infants and toddlers for acute allergic reactions.

Background and Objective: Allergic reactions, including anaphylaxis, are rising among children. Little is known about health care utilization among infants and toddlers. Our objective was to characterize health care utilization and charges for acute allergic reactions (AAR). Methods: We conducted a retrospective cohort study of trends in emergency department (ED) visits and revisits, hospitalizations and rehospitalizations, and charges among infants and toddlers (ages < 3 years), with an index ED visit or hospitalization for AAR (including anaphylaxis). We used data from population-based multipayer data: State Emergency Department Databases and State Inpatient Databases from New York and Nebraska. Multivariable logistic regression was used to identify factors associated with ED revisits and rehospitalizations. Results: Between 2006 and 2015, infant and toddler ED visits for AAR increased from 27.8 per 10,000 population to 35.2 (Ptrend < 0.001), whereas hospitalizations for AAR remained stable (Ptrend = 0.11). In the one year after an index AAR visit, 5.1% of these patients had at least one AAR ED revisit and 5.9% had at least one AAR rehospitalization. Factors most strongly associated with AAR ED revisits included an index visit hospitalization and receipt of epinephrine. Total charges for AAR ED visits (2009-2015) and hospitalizations (2011-2015) were more than $29 million and $11 million, respectively. Total charges increased more than fourfold for both AAR ED revisits for AAR rehospitalizations during the study period. Conclusion: Infants and toddlers who presented with an AAR were at risk for ED revisits and rehospitalizations for AAR within the following year. The charges associated with these revisits were substantial and seemed to be increasing.

Emerging Therapies in Anaphylaxis: Alternatives to Intramuscular Administration of Epinephrine.

PURPOSE OF REVIEW: Anaphylaxis is a severe, life-threatening, systemic allergic reaction that should be recognized and treated promptly. Intramuscular (IM) epinephrine is the first-line treatment for anaphylaxis and there are no absolute contraindications to its use. Despite its established track record of efficacy and safety, physicians and patients face barriers in the recognition and treatment of anaphylaxis, including the maintenance and appropriate use of epinephrine auto-injectors. This has led to investigation into potential alternatives to IM epinephrine administration in anaphylaxis. RECENT FINDINGS: This review investigates the current standard of care in the treatment of anaphylaxis, barriers to IM epinephrine use, and alternative therapies under investigation for administration in anaphylaxis. Alternative routes under investigation include intranasal, sublingual, inhaled, and needle-free intramuscular administration of epinephrine. There are currently numerous investigational alternatives to IM epinephrine therapy which could hold promise as future effective treatments in the emergent management of anaphylaxis.

Severity grading system for acute allergic reactions: A multidisciplinary Delphi study.

BACKGROUND: There is no widely adopted severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions, thus limiting the ability to optimize and standardize management practices and advance research. OBJECTIVE: The aim of this study was to develop a severity grading system for acute allergic reactions for use in clinical care and research. METHODS: From May to September 2020, we convened a 21-member multidisciplinary panel of allergy and emergency care experts; 9 members formed a writing group to critically appraise and assess the strengths and limitations of prior severity grading systems and develop the structure and content for an optimal severity grading system. The entire study panel then revised the grading system and sought consensus by utilizing Delphi methodology. RESULTS: The writing group recommended that an optimal grading system encompass the severity of acute allergic reactions on a continuum from mild allergic reactions to anaphylactic shock. Additionally, the severity grading system must be able to discriminate between clinically important differences in reaction severity to be relevant in research while also being intuitive and straightforward to apply in clinical care. Consensus was reached for all elements of the proposed severity grading system. CONCLUSION: We developed a consensus severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions. Successful international validation, refinement, dissemination, and application of the grading system will improve communication among providers and patients about the severity of allergic reactions and will help advance future research.

Trends in US hospitalizations for anaphylaxis among infants and toddlers: 2006 to 2015.

BACKGROUND: Anaphylaxis is a potentially fatal acute allergic reaction. Its overall prevalence appears to be rising, but little is known about US hospitalization trends among infants and toddlers. OBJECTIVE: To identify the trends and predictors of hospitalization for anaphylaxis among infants and toddlers. METHODS: We used the nationally representative National Inpatient Sample (NIS), from 2006 to 2015, to perform an analysis of trends in US hospitalizations for anaphylaxis among infants and toddlers (age, <3 years) and other children (age, 3-18 years). For internal consistency, we identified patients with anaphylaxis by the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code and excluded those with the International Classification of Diseases, Tenth Revision, Clinical Modification (late 2015). We calculated trends in anaphylaxis hospitalizations over time by age group and then used multivariable logistic regression to describe anaphylaxis hospitalizations among infants and toddlers. RESULTS: Among infants and toddlers, there was no significant change in anaphylaxis hospitalizations during the 10-year study period (Ptrend = .14). Anaphylaxis hospitalization among infants and toddlers was more likely in males, with private insurance, in the highest income quartile, with chronic pulmonary disease, who presented on a weekend day, to an urban teaching hospital, located in the Northeast. In contrast, anaphylaxis hospitalizations among older children (age, 3-<18 years) rose significantly during the study (Ptrend < .001). CONCLUSION: Anaphylaxis hospitalizations among infants and toddlers in the United States were stable from 2006 to 2015, whereas hospitalizations among older children were rising. Future research should focus on the trends in disease prevalence and health care utilization in the understudied population of infants and toddlers.

Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study.

BACKGROUND: The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts. OBJECTIVE: Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis. METHODS: Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as "consensus reached." If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate de-identified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as "no consensus reached." RESULTS: The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system. CONCLUSION: Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research aimed at development of an anaphylaxis severity grading system.

Epinephrine in the Management of Anaphylaxis.

Epinephrine is life-saving and the only first-line medication in the management of anaphylaxis. At therapeutic doses, it acts rapidly to reverse nearly all symptoms of anaphylaxis, and stabilize mast cells. The standard approved doses administered intramuscularly in the lateral thigh have a long track record for safe and effective use, but more information is needed on epinephrine pharmacokinetics and pharmacodynamics to ensure that current dosing strategies are optimal. Epinephrine should be administered promptly once anaphylaxis is suspected, to minimize morbidity and mortality. Providers on the front-line for managing patients with life-threatening allergic reactions need clear parameters and tools to guide the appropriate use of epinephrine, which take into account the potential evolution of symptoms and signs over time. All patients at risk for anaphylaxis should carry 2 epinephrine autoinjectors and be taught and able to demonstrate how to use them. Epinephrine autoinjectors need to be affordable, readily available, and easy for patients with allergies to carry and use. Furthermore, these devices should be available to meet the needs of all patients, from small infants through large or obese adults. The ideal means for storing and delivering epinephrine in prehospital and hospital environments warrants further study, to determine how to best balance efficiency, safety, and costs.

Utility of ICD-9-CM Codes for Identification of Allergic Drug Reactions.

BACKGROUND: The epidemiology of allergic drug reactions is poorly understood due, in large part, to difficulty in identifying true cases in population data sets. Use of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes is a potentially valuable approach that requires formal evaluation. OBJECTIVE: To better understand the utility of ICD-9-CM codes for identification of allergic drug reactions, including the validation of specific codes by chart review. METHODS: We reviewed randomly sampled medical records of patients treated in the emergency department (ED) between January 1, 2001, and December 31, 2006, with ICD-9-CM codes for drug allergy and E codes (E930-949) for adverse drug reactions. RESULTS: During the 6-year period, 11,130 charts were identified by ICD-9-CM and E codes and 1,634 were reviewed. Allergic drug reactions were found in 444 (27%) of the reviewed ED visits. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0; 87%), adverse reaction to drug (995.2; 52%), and anaphylaxis (995.0; 38%). Patients with both an ICD-9-CM code and an E code had a high likelihood of having an allergic drug reaction (76%). Most allergic drug reactions were attributed to antibiotics (42%), intravenous contrast (7%), and nonsteroidal anti-inflammatory drugs (6%). The estimated frequency of allergic drug reactions increased from 0.49% of ED visits in 2001 to 0.94% in 2012. CONCLUSIONS: Specific ICD-9-CM and E codes can be used in combination to identify allergic drug reactions. Further study of these codes in the inpatient and outpatient settings is necessary to better understand the utility of diagnosis codes for improving epidemiologic research on drug allergy.

Topical Review: Pediatric Food Allergies Among Diverse Children.

OBJECTIVE: To present a brief review of the literature regarding potential racial/ethnic disparities in pediatric food allergy (FA). METHODS: Topical review considering data regarding FA prevalence, asthma comorbidity, epinephrine access/use, and psychosocial impact (e.g., burden, quality of life). RESULTS: Methodological variation precludes firm conclusions regarding disparities in prevalence; however, some data suggest Black children may be at particular risk. The comorbidity of FA and asthma among urban populations may increase risk of negative outcomes. There are clear racial/ethnic and socioeconomic disparities in epinephrine access and use. Psychosocial measures are frequently validated on samples that are not racially or ethnically diverse. Studies investigating FA's psychosocial impact are often composed of mostly White, non-Hispanic participants (>85% of study sample). CONCLUSIONS: Further research is needed to clarify prevalence patterns by race/ethnicity, to investigate the sources of disparity in epinephrine use, and to evaluate the differential impact of FA on diverse children.

Sunlight, vitamin D and food allergy.

PURPOSE OF REVIEW: The role of vitamin D in the development of food allergy is unclear. We summarize recent data on the epidemiologic link between sunlight (UVB) and food allergy, and evidence for and against a specific role for vitamin D status. RECENT FINDINGS: Since 2007, most epidemiologic studies have supported low sunlight (as measured by season of birth and latitude) as a risk factor for food allergy. Investigators have also looked directly at vitamin D status (as measured by serum 25OHD level) and its potential role. Although conflicting, the vitamin D studies suggest a more complicated association than a linear dose response in all individuals, with some studies indicating different associations based on host characteristics (e.g. concominant eczema, genetic polymorphisms, country of birth). Most studies have not fully examined the myriad effects of sunlight but have instead focused on a single maternal, neonatal or childhood 25OHD level. SUMMARY: Many studies have linked sunlight with the development of food allergy but whether this is directly related to vitamin D status or a myriad of other sunlight-derived, seasonal and/or geographic factors remains uncertain. More studies are needed to investigate the role of sunlight and vitamin D status in food allergy because of their potential for primary prevention and disease modification.

Early treatment of food-induced anaphylaxis with epinephrine is associated with a lower risk of hospitalization.

BACKGROUND: Food-induced anaphylaxis (FIA) is potentially life threatening. Prompt administration of epinephrine is universally recommended by current treatment guidelines. OBJECTIVE: To identify factors associated with early epinephrine treatment for FIA and to specifically examine the association between early epinephrine treatment and hospitalization. METHODS: A chart review study conducted at Hasbro Children's Hospital/Rhode Island Hospital. By using the International Classification of Diseases, Ninth Revision codes, we identified all patients who presented to the emergency department with FIA between January 1, 2004, and December 31, 2009. Early epinephrine treatment was defined as receipt of epinephrine before arrival to the emergency department. The independent association between early epinephrine treatment and hospitalization was assessed using logistic regression. RESULTS: Among the 384 emergency department visits for FIA identified during the study period, 234 patients received epinephrine (61%). Among this subset, most (164 [70%]) received early epinephrine treatment, whereas a smaller number of patients (70 [30%]) first received epinephrine in the emergency department (late treatment). Patients who received early epinephrine treatment were older (7.4 vs 4.3 years; P = .008), were more likely to have a known food allergy (66% vs 34%; P < .001), and were more likely to own an epinephrine autoinjector (80% vs 23%; P < .001). Patients treated early were less likely to be hospitalized (17% vs 43%; P < .001). After adjusting for age, sex, and race, the patients who received early epinephrine treatment remained at significantly decreased risk of hospitalization compared with those who received late epinephrine treatment (odds ratio 0.25 [95% CI, 0.12-0.49]). CONCLUSIONS: In this population, early treatment of FIA with epinephrine was associated with significantly lower risk of hospitalization. Accordingly, this study supports the benefit of prompt administration of epinephrine for the treatment of FIA.

Risk factors for severe anaphylaxis in patients receiving anaphylaxis treatment in US emergency departments and hospitals.

BACKGROUND: Although reported risk factors for severe anaphylaxis include older age, presence of comorbid medical conditions, and concomitant medications, previous studies have used varying definitions for anaphylaxis and heterogeneous methodology. OBJECTIVE: To describe risk factors for severe anaphylaxis among US patients treated in emergency departments (EDs) or hospitals for anaphylaxis. METHODS: Individuals with an ED visit/hospitalization for anaphylaxis were identified from 2 MarketScan Research Databases using an expanded International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code algorithm. Eligibility for the current study required continuous medical and prescription coverage for at least 1 year before and after the index date. Severe anaphylaxis was defined as a reaction requiring hospital admission. RESULTS: Among 11,972 individuals, 2,622 (22%) had severe anaphylaxis. Unadjusted analysis showed that severe anaphylaxis was associated with older age and higher comorbidity burden. These patients were also less likely to have filled an epinephrine autoinjector (EAI) prescription or visited an allergist/immunologist, but more likely to have had an ED visit/hospitalization (any cause). On multivariable analysis, filling an EAI prescription (odds ratio [OR], 0.64; 95% CI, 0.53-0.78) or visiting an allergist/immunologist (OR, 0.78; 95% CI, 0.63-0.95) before the index event was associated with a lower risk of severe anaphylaxis, while any previous ED visit (OR, 1.18; 95% CI, 1.07-1.30) or hospitalization (OR, 1.55; 95% CI, 1.36-1.75) was associated with a higher risk of severe anaphylaxis. CONCLUSIONS: In this large cohort with an ED visit or hospitalization for anaphylaxis, 22% had severe anaphylaxis. Pre-index preventive anaphylaxis care (ie, EAI prescription fill and allergist/immunologist visit) was associated with a significantly lower risk, supporting the benefits of preventive anaphylaxis care in real-world practice.

Favorable trends in the frequency of U.S. emergency department visits for food allergy, 2001-2009.

Several studies suggest an increase in both the prevalence of food allergy and in the frequency of emergency department (ED) visits for food-related allergic reactions, including anaphylaxis. This study evaluates time trends in the frequency of ED visits for food allergy, with a focus on possible differences by age. Data from two multicenter ED-based studies were used to identify the proportion of patients assigned to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes with actual food-related acute allergic reaction and the proportion of these patients with food-induced anaphylaxis. We multiplied these proportions against counts from nationally representative data (2001-2009) to estimate the number of U.S. ED visits for each ICD-9-CM code with likely food allergy. Over the 9-year study period, there were ∼1,892,000 ED visits for food allergy. The number of ED visits for food allergy did not significantly change among children aged <18 years (77,000 visits in 2001 versus 92,000 visits in 2009; p = 0.85), but among adults aged ≥18 years, there was a decline (147,000 visits versus 97,000 visits; p = 0.046). Looking across all ED visits (any cause), the proportion of ED visits for food allergy was stable for children (0.29% versus 0.28%; p = 0.22) but decreased for adults (0.18% versus 0.09%; p = 0.01). The number of U.S. ED visits for food-related acute allergic reactions is significantly higher than prior reports. These results also suggest that the frequency of ED visits for food allergy was stable or decreased from 2001 to 2009, despite reports suggesting an ongoing rise in the prevalence of food allergy.

Longitudinal study of 954 patients with stinging insect anaphylaxis.

BACKGROUND: Stinging insect anaphylaxis (SIA) is a common cause of anaphylaxis and is potentially life-threatening. OBJECTIVES: To examine US patients with an emergency department (ED) visit or hospitalization for SIA to evaluate postdischarge follow-up care. METHODS: We identified all patients with an ED visit or hospitalization for SIA during 2002-2008 in the MarketScan Database using International Classification of Diseases, Ninth Revision, Clinical Modification codes (index date was the initial ED visit or hospitalization). Patients were required to have continuous full insurance coverage for 1 year or more before and after index. We examined patient factors during the preindex period, characteristics of the index event, and outcomes during the postindex period. Multivariable logistic regression was used to identify independent predictors of receiving preventive anaphylaxis care. RESULTS: We identified 954 patients with an ED visit or hospitalization for SIA (mean [SD] age, 46 [19] years; 41% female). A total of 85% of patients were discharged directly from the ED. For those hospitalized, the mean hospital stay was 1 day, and 50% spent time in the intensive care unit. Cardiorespiratory failure occurred in 27% of those hospitalized. During the postindex period, 69% filled 1 or more epinephrine autoinjector prescription, but only 14% had 1 or more allergist/immunologist visit. Independent factors associated with receiving preventive anaphylaxis care during the postindex period were higher household income, no ED visit (for any reason) in the preindex period, and no cardiorespiratory arrest or failure during the index event. CONCLUSION: Although two-thirds of patients filled a prescription for an epinephrine autoinjector after an ED visit or hospitalization for SIA, only 14% of patients received follow-up care by an allergist/immunologist. This missed opportunity to provide venom immunotherapy, an essentially curative therapy, unnecessarily places patients at risk for recurrent anaphylaxis.

An update on self-injectable epinephrine.

PURPOSE OF REVIEW: Epinephrine is an important life-saving treatment in patients with anaphylaxis. However, despite the guidelines recommending the use of epinephrine in the management of all patients with anaphylaxis, many patients are either not prescribed epinephrine auto-injectors (EAIs) or remain hesitant to use them. RECENT FINDINGS: In this review, we examine our current knowledge base regarding EAIs, including issues related to dosing, medication availability and new modes of administration. Our findings suggest that all patients at risk for anaphylaxis should always carry two epinephrine doses. Once an EAI is prescribed, the patient should receive appropriate education on when and how to use it and it should be administered without delay. Current EAI devices have been redesigned to address limitations and decrease unintentional injury. SUMMARY: Epinephrine remains the cornerstone of anaphylaxis treatment and EAIs are critical because of their ability to rapidly deliver this potentially life-saving medication outside of a medical setting. Continued efforts are needed to establish evidence-based parameters for delivery of this medication and to optimize education of healthcare providers and patients on the use of EAIs.