Therapeutic approach of anaphylaxis.

PURPOSE OF REVIEW: Anaphylaxis is a recognized cause of death in all ages, which requires prompt recognition and treatment. We here propose to review the current and new pharmacological treatment of anaphylaxis in the view of the new knowledge in the field that can support the quality practice and empower allergists and health professionals with new tools that can be used to treat symptoms and prevent anaphylaxis. RECENT FINDINGS: The recent description of phenotypes provides new insight and understanding into the mechanisms and causes of anaphylaxis through a better understanding of endotypes and application of precision medicine. Several biologic therapies and new devices are emerging as potential preventive treatment for anaphylaxis. SUMMARY: Adrenaline (epinephrine) is still the first-line treatment for any type of anaphylaxis and is recognized as the only medication documented to prevent hospitalizations, hypoxic sequelae and fatalities. ß2-adrenergic agonists and glucagon remains as the second-line treatment of anaphylaxis, meanwhile glucocorticoids and antihistamines should be used only as third-line treatment. Their administration should never delay adrenaline injection in anaphylaxis. More intuitive adrenaline autoinjectors design and features are required as well as a worldwide availability of adrenaline autoinjectors. Biological drugs, such as omalizumab, have been used as therapeutic adjuvants as a preventive treatment of anaphylaxis, but cost-effectiveness should be considered individually. Understanding the specifications of underlying mechanisms can potentially support improvements in the patients' allergological work-up and open the opportunity of developments of potential new drugs, such as biological agents. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among healthcare providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality.

Estimation of Health and Economic Benefits of Commercial Peanut Immunotherapy Products: A Cost-effectiveness Analysis.

Importance: Commercial epicutaneous peanut immunotherapy (EPIT) and peanut oral immunotherapy (POIT) may offer significant quality-of-life improvements for patients with peanut allergy, but the cost-effectiveness of commercial peanut immunotherapies is uncharacterized. Objective: To evaluate critical inputs associated with the cost-effectiveness of EPIT and POIT from a societal perspective. Design, Setting, and Participants: Economic evaluation in which microsimulations with Markov modeling were performed evaluating virtual children aged 4 years over an 80-year time horizon. The base-case costs included a caregiver-reported willingness to pay of $3839 annually for safe and effective food allergy treatment. Estimates of predictive biomarkers or oral challenges were incorporated after the first year of therapy with additional analyses of immunotherapy risk reduction of anaphylaxis and probability of sustained unresponsiveness (SU) to peanut after 4 years. Exposures: Children received EPIT, POIT, or no immunotherapy treatment (n = 10 000 per treatment strategy). Main Outcomes and Measures: Rates of therapy-associated adverse reactions and quality-of-life improvements associated with changes in eliciting or tolerated peanut doses were modeled along with quality-adjusted life-years (QALYs), anaphylaxis, therapy-associated anaphylaxis, and fatalities. Results: In the base-case analysis without SU to peanut, the EPIT strategy cost less than POIT (mean [SD] cost, $154 662 [$46 716] vs $163 524 [$56 800]) and had fewer total episodes of anaphylaxis (mean [SD], 1.33 [1.55] vs 3.83 [5.02] episodes) and fewer episodes of therapy-associated anaphylaxis (mean [SD], 0.62 [1.30] vs 3.10 [4.94] episodes) but had lower QALY accumulation (mean [SD], 26.932 [2.241] vs 26.945 [2.320] QALYs). The incremental cost-effectiveness ratio was $216 061 for EPIT and $255 431 for POIT. Models were sensitive to therapy cost, SU rates, health state utility, and risk reduction of anaphylaxis. With health state utility sensitivity analyses, the ceiling value-based cost (willingness-to-pay threshold $100 000/QALY) was between $1568 and $6568 for EPIT and between $1235 and $5235 for POIT. If high rates of SU to peanut can be achieved in longer-term models, EPIT and POIT could produce savings in terms of both cost and QALY. Conclusions and Relevance: In this simulated analysis, findings showed that EPIT and POIT may be cost-effective under some assumptions. Further research is needed to understand the degree of health state utility improvement associated with each therapy, degree of protection against anaphylaxis, and rates of SU.

Biomarkers in Human Anaphylaxis: A Critical Appraisal of Current Evidence and Perspectives.

Anaphylaxis is a type I hypersensitivity reaction that is potentially fatal if not promptly treated. It is a clinical diagnosis, although measurement of serial serum total mast cell tryptase (MCT) is gold standard and may help differentiate anaphylaxis from its mimics. The performance characteristics of MCT assays in anaphylaxis has been variable in previous studies, due to multiple factors including differences in the definition of anaphylaxis, methods of MCT interpretation, clinical setting of anaphylaxis, causative agents, and timing of blood sample. An international consensus equation for MCT to interpret mast cell activation has been proposed and recently validated in the context of peri-operative anaphylaxis during general anesthesia. There has been an interest in the detection of newer biomarkers in anaphylaxis including platelet activation factor (PAF), chymase, carboxypeptidase A3, dipeptidyl peptidase I (DPPI), basogranulin, and CCL-2. The key determinants of an ideal biomarker in anaphylaxis are half-life, sample handling and processing requirements, and cost. There may be a role for metabolomics and systems biology in the exploration of novel biomarkers in anaphylaxis. Future studies applying these approaches might provide greater insight into factors determining severity, clinical risk stratification, identification of mast cell disorders and improving our understanding of this relatively complex acute immunological condition. Post mortem MCT evaluation is used in Forensic Medicine during autopsy for cases involving sudden death or suspected anaphylaxis. Interpretation of post mortem MCT is challenging since there is limited published evidence and the test is confounded by multiple variables largely linked to putrefaction and site of sampling. Thus, there is no international consensus on a reference range. In this state of the art review, we will focus on the practical challenges in the laboratory diagnosis of anaphylaxis and critically appraise (a) performance characteristics of MCT in anaphylaxis in different clinical scenarios (b) the role for novel biomarkers and (c) post mortem MCT and its role in fatal anaphylaxis.

An economic evaluation of immediate vs non-immediate activation of emergency medical services after epinephrine use for peanut-induced anaphylaxis.

BACKGROUND: Layperson food allergy management plans commonly stipulate that if epinephrine is used to immediately call 911 and seek care in the nearest medical facility for observation. OBJECTIVE: To evaluate the cost-effectiveness of this strategy, vs a watchful waiting approach before activating emergency medical services (EMS). METHODS: We performed a cost-effectiveness analysis using Markov modeling simulated over a 20-year horizon comparing activating EMS immediately after epinephrine use for allergic reactions to peanut vs a "wait and see" approach in which EMS was only activated if symptoms of the reaction did not promptly resolve after treatment. The base-case model assumed a 10-fold increased fatality risk with delayed EMS activation. RESULTS: The fatality risk associated with early EMS use was minimal, with a per-patient fatality rate over a 20-year horizon of 1.2 × 10-6, vs 1.9 × 10-6 for a wait and see approach. The incremental cost per life-year saved was $142,943,447 for early EMS vs wait and see, with the cost per death prevented reaching $1,349,335,651 as the simulation concluded. Cost of early EMS activation rose to $321,625,534 per life-year saved ($3,035,454,848 per death prevented) if a 5-fold increase in fatality risk was assumed, and was $12,997,173 per life-year saved ($122,689,936 per death prevented) if a 100-fold increase in fatality risk was assumed. CONCLUSION: Medical observation of a treated and promptly resolved peanut allergic reaction has minimal benefit and excessive costs. Immediately activating EMS after using epinephrine for a peanut allergic reaction in this context is not cost-effective.

Analysis of Value-Based Costs of Undesignated School Stock Epinephrine Policies for Peanut Anaphylaxis.

Importance: Children experiencing anaphylaxis at school may lack access to a personal epinephrine device, prompting recent legislation permitting undesignated (eg, non-student specific) stock epinephrine autoinjector units at school. However, epinephrine device costs vary, and the cost-effectiveness of undesignated school stock epinephrine is uncharacterized to date. Objective: To define value-based strategies for undesignated school stock epinephrine programs. Design, Setting, and Participants: Markov simulations of the Chicago Public Schools system were used over extended time horizons to model 2 school stock epinephrine autoinjector policies to provide access for at-risk students. The dates of the data used in the analysis were September 2017 to June 2018 (the 2017-2018 school year). Main Outcomes and Measures: This study compared the following 3 strategies: no school undesignated epinephrine supply, school undesignated supplemental epinephrine supply (supplemental model), and school undesignated universal epinephrine supply (universal model). The base-case model assumed a 10-fold reduced fatality risk with having undesignated stock epinephrine units available vs not having undesignated stock epinephrine units available. Costs of school stock epinephrine units available for acquisition by schools were evaluated from a societal perspective. Quality-adjusted life-years (QALYs) and total epinephrine acquisition expenses were calculated. Results: Based on Markov simulations of the Chicago Public Schools system (371 382 students), the cost was $107 816 (95% CI, $107 382-$108 250) for no school undesignated epinephrine supply compared with $108 160 (95% CI, $107 725-$108 595) for the supplemental model and $100 397 (95% CI, $99 979-$100 815) for the universal model. Undesignated stock epinephrine improved outcomes, with 26.869 (95% CI, 26.841-26.897) QALYs accrued as the model concluded compared with 26.867 (95% CI, 26.839-26.896) QALYs for the strategy without undesignated stock epinephrine. When comparing supplemental model stock epinephrine to the strategy without undesignated devices, the incremental cost-effectiveness ratio was high at $268 811 per QALY in the base-case simulation. However, the cost of the supplemental model fell below $100 000 per QALY when the annual undesignated epinephrine acquisition costs did not exceed $338 per school (compared with stock epinephrine unavailability). The universal model dominated all others and was associated with significant cost savings ($7419 per student at risk who would otherwise be prescribed an individual school epinephrine supply). Conclusions and Relevance: Undesignated school stock epinephrine is cost-effective at device acquisition costs not exceeding $338 per school per year, although a universal model vs a supplemental model is associated with superior health and economic outcomes.

Economic evaluation of epinephrine auto-injectors for peanut allergy.

BACKGROUND: Three commercial epinephrine auto-injectors were available in the United States in the summer of 2016: EpiPen, Adrenaclick, and epinephrine injection, USP auto-injector. OBJECTIVE: To describe the variation in pharmacy costs among epinephrine auto-injector devices in New England and evaluate the additional expense associated with incremental auto-injector costs. METHODS: Decision analysis software was used to evaluate costs of the most and least expensive epinephrine auto-injector devices for children with peanut allergy. To evaluate regional variation in epinephrine auto-injector costs, a random sample of New England national and corporate pharmacies was compared with a convenience sample of pharmacies from 10 Canadian provinces. RESULTS: Assuming prescriptions written for 2 double epinephrine packs each year (home and school), the mean costs of food allergy over the 20-year model horizon totaled $58,667 (95% confidence interval [CI] $57,745-$59,588) when EpiPen was prescribed and $45,588 (95% CI $44,873-$46,304) when epinephrine injection, USP auto-injector was prescribed. No effectiveness differences were evident between groups, with 17.19 (95% CI 17.11-17.27) quality-adjusted life years accruing for each subject. The incremental cost per episode of anaphylaxis treated with epinephrine over the model horizon was $12,576 for EpiPen vs epinephrine injection, USP auto-injector. EpiPen costs were lowest at Canadian pharmacies ($96, 95% CI $85-$107). There was price consistency between corporate and independent pharmacies throughout New England by device brand, with the epinephrine injection, USP auto-injector being the most affordable device. CONCLUSION: Cost differences among epinephrine auto-injectors were significant. More expensive auto-injector brands did not appear to provide incremental benefit.

An Economic Analysis of a Peanut Oral Immunotherapy Study in Children.

BACKGROUND: Peanut oral immunotherapy (POIT) decreases the probability of accidental recurrent systemic reactions but reactions from the therapy itself are frequent. OBJECTIVE: The purpose of this economic analysis was to characterize the potential cost-effectiveness of POIT. METHODS: Cohort simulations were used to evaluate the effect of POIT for children with peanut allergy. A POIT with probiotic was used in the base-case simulation and long-term survival was modeled using age-adjusted mortality together with the risk of food allergy-associated mortality. RESULTS: The incremental POIT cost-effectiveness ratio was $2142 per quality-adjusted life-year. A mean number of 12.3 (95% CI, 12.0-12.5) and 2.0 (95% CI, 1.9-2.1) allergic reactions occurred in the POIT and avoidance groups over 20 years of simulation, with 2.3 (95% CI, 2.2-2.3) episodes of anaphylaxis treated with intramuscular epinephrine per subject in the POIT group and 1.1 (95% CI, 1.0-1.2) episodes per subject in the avoidance group. In sensitivity analyses, POIT was associated with lower rates of anaphylaxis than strict avoidance when the annual rate of accidental allergic reactions in the peanut avoidance group exceeded 25%, the annual rate of anaphylaxis in the POIT group dropped below 6%, or the probability of sustained unresponsiveness after 4 years of POIT was 68% or greater. CONCLUSIONS: POIT may be cost-effective in a long-term economic model. However, treated patients may experience a greater rate of peanut-associated allergic reactions and anaphylaxis. The analysis was sensitive to rates of accidental allergic reactions, therapy-associated adverse events, and likelihood of therapy-induced tolerance.

Evaluating the Cost and Utility of Mandating Schools to Stock Epinephrine Auto-injectors.

BACKGROUND: The Michigan Legislature mandated that all public schools stock epinephrine auto-injectors (EAIs). A minimal amount is known regarding the incremental value of EAIs in schools. Our primary objective was to describe the frequency of administration of epinephrine for EMS patients with acute allergic reactions in public schools. Our secondary objective was to estimate the cost of mandating public schools to stock EAIs. METHODS: We performed a retrospective cohort study of EMS cases with an impression of allergic reaction and who received epinephrine recorded in the 2014 Michigan EMS Information System (MI-EMSIS). We abstracted patient demographics, incident location by address to identify public schools, source of epinephrine given, and suspected allergen if known. We calculated advanced life support (ALS) response times to assess temporal impact of school EAIs in communities with ALS systems. We estimated the unsubsidized annual procurement cost of this mandate for Michigan public schools (N = 4,039), using range of costs for the required 2 EAIs (adult and pediatric) as estimated by the legislature ($140/each) and recently reported costs for commercial sources ($1,200). Training costs were not included. Descriptive statistics are reported. RESULTS: During this period, there were 1,550,009 EMS cases in the state with 631 receiving non-cardiac arrest epinephrine for presumed anaphylaxis, of which 23 cases were in public schools. Reported allergens were most often food 12 (51.2%), insect stings 4(22.2%) or unknown 7(30.4%). Among these patients, the source for epinephrine used was from the student, 7 (30.4%), EMS 7 (30.4%), school 7(30.4%), and unknown 2(8.7%). A majority (21, 91.3%) of the public school cases occurred in communities with ALS systems and ALS response was relatively rapid (median response 6 minutes, 90 percentile, 13 minutes). The unsubsidized annual cost of Michigan public schools to stock EAIs ranges from $565,460 to $4,846,800. CONCLUSION: In this study, few public school patients received epinephrine for anaphylaxis and the vast majority occurred in communities with rapid ALS response. The direct annual supply cost of the school EAI mandate is substantial.

Prevention of Anaphylaxis: The Role of the Epinephrine Auto-Injector.

Anaphylaxis is a life-threatening condition, with at-risk individuals remaining at chronic high risk of recurrence. Anaphylaxis is frequently underrecognized and undertreated by healthcare providers. The first-line pharmacologic intervention for anaphylaxis is epinephrine, and guidelines uniformly agree that its prompt administration is vital to prevent progression, improve patient outcomes, and reduce hospitalizations and fatalities. Healthcare costs potentially associated with failure to provide epinephrine (hospitalizations and emergency department visits) generally exceed those of its provision. At-risk patients are prescribed epinephrine auto-injectors to facilitate timely administration in the event of an anaphylactic episode. Despite guideline recommendations that patients carry 2 auto-injectors at all times, a significant proportion of patients fail to do so, with cost of medicine cited as one reason for this lack of adherence. With the increase of high-deductible healthcare plans, patient adherence to recommendations may be further affected by increased cost sharing. The recognition and classification of epinephrine as a preventive medicine by both the US Preventive Services Task Force and insurers could increase patient access, improve outcomes, and save lives.

Anaphylaxis in the young adult population.

It is critical that clinicians treating young adults understand the presentation and management of anaphylaxis. The most common trigger for anaphylaxis in this population is food. The prevalence of food allergy is growing, with 8% of US children and adolescents affected. All patients at risk for anaphylaxis should be prescribed epinephrine autoinjectors, as epinephrine is the only life-saving medication for a severe anaphylactic reaction. The presentation of anaphylaxis can involve multiple organ systems (eg, mucocutaneous, respiratory, cardiovascular, gastrointestinal) and, as such, patient education is needed to assist in prompt recognition. Appropriate training of patients and caregivers about how to identify anaphylaxis and what to do in an emergency is critical. Training of school and college staff also is essential, as 1 in 4 first-time reactions occurs outside the home. Additional counseling for adolescents at risk for anaphylactic reactions should address increased risk-taking behavior, decreased adult supervision, dating, and the transition of disease management from an adult to the patient.

Anaphylaxis: a payor's perspective on epinephrine autoinjectors.

The scope of expenditures due to anaphylaxis likely is underestimated by health care payors because anaphylaxis is underdiagnosed and, when reported, most costs of anaphylaxis borne by payors relate to direct medical expenses. Direct costs of anaphylaxis have been estimated at $1.2 billion per year, with direct expenditures of $294 million for epinephrine, and indirect costs of $609 million. More accurate diagnostic coding will allow payors to improve their understanding of the full impact of anaphylaxis on health care plans, employers, patients, and their families. Similarly, more accurate diagnosis and treatment of anaphylaxis should have a direct effect on overall cost savings achieved in this disease state. This includes savings in both direct costs, such as emergency department visits, and indirect costs, such as lost productivity of patients and caregivers. Educating medical personnel on treatment guidelines regarding the specific use of appropriate epinephrine autoinjectors will contribute to cost savings. Even though the cost of autoinjectors has been increasing, evidence indicates that the cost of improper response to, and treatment of, anaphylaxis outweighs that increase. At this time, there are several branded epinephrine autoinjectors and one generic equivalent for one of these branded products available on the US market; the branded autoinjectors are not considered equivalents for substitution. Barriers to coverage and access, such as managed care organization tier classification, medication copay, and socioeconomic status of specific patients, need to be examined more closely and addressed. Education in the proper use of epinephrine autoinjectors, including regular checking of medication expiration dates, is critical for proper management of anaphylaxis and minimizing the costs of anaphylactic events. Managed care organizations can play a role in educational initiatives.

Proceedings of the AMCP Integrated Care Summit: population health and quality improvement in anaphylaxis.

BACKGROUND: Anaphylaxis is a serious allergic reaction, often caused by food allergies, insect venom, medications, latex, or exercise. The condition is rapid in onset and may cause death. Because of the potential risk of death, it is critical to recognize anaphylaxis quickly and be prepared to treat it appropriately. OBJECTIVES: To review the current trends and challenges related to anaphylaxis management, treatment, and prevention and explore strategies for how to improve access and awareness for patients who are at high risk for anaphylaxis. METHODS: Fifteen stakeholders gathered on May 22, 2013, in Alexandria, Virginia, for a meeting to discuss population health and quality improvement in anaphylaxis convened by the Academy of Managed Care Pharmacy.Summit participants included managed care leaders, nurses, physicians, and organizations that advocate for consumers. SUMMARY: Data on the clinical and financial impact of anaphylaxis are limited and are impacted by under diagnoses, underreporting, and miscoding of anaphylaxis. There is a significant need to increase awareness of the symptoms of anaphylaxis and ensure that patients at risk have access to available treatments. Additional education and training for both patients and health care professionals are needed to recognize the signs and symptoms of anaphylaxis and ensure the appropriate use of epinephrine auto injectors. Managed care companies have a need to better understand how to design and improve health benefits to support patients with anaphylaxis. CONCLUSIONS: Summit participants determined that there are opportunities to improve care for patients with anaphylaxis. The availability of epinephrine auto-injectors is not and should not be highly controlled, and the education and training of patients and health care professionals on the appropriate use of these devices are priorities. Attendees discussed numerous strategies that can be implemented by providers, health plans,and hospitals to improve patient care in this disease state.