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.

Changing the history of anaphylaxis mortality statistics through the World Health Organization's International Classification of Diseases-11.

We review the history of the classification and coding changes for anaphylaxis and provide current and perspective information in the field. In 2012, an analysis of Brazilian data demonstrated undernotification of anaphylaxis-related deaths because of the difficulties of coding using the International Classification of Diseases, 10th Revision. This work triggered strategic international actions supported by the Joint Allergy Academies and the International Classification of Diseases World Health Organization (WHO) leadership to update the classification of allergic disorders for the International Classification of Diseases, 11th Revision (ICD-11), which resulted in construction of the pioneer "Allergic and hypersensitivity conditions" chapter. The usability of the new framework has been tested by evaluating the same data published in 2012 from the ICD-11 perspective. Coding accuracy was much improved, reaching 95% for definite anaphylaxis. As the results were provided to the WHO Mortality Reference Group, coding rules have been changed, allowing anaphylaxis to be recorded as an underlying cause of death in official mortality statistics. The mandatory use of ICD-11 from January 2022 for documenting cause of death could have 2 immediate consequences: (1) the reported number of anaphylaxis-related deaths might increase because of more appropriate coding and (2) the cross-sectional and longitudinal mortality data generated might ultimately lead to a better understanding of anaphylaxis epidemiology and improved health policies directed at reducing anaphylaxis-related mortality.

Definitions and pathophysiology of vasoplegic shock.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition.

Evaluating automated approaches to anaphylaxis case classification using unstructured data from the FDA Sentinel System.

INTRODUCTION: In May 2008, the Food and Drug Administration launched the Sentinel Initiative, a multi-year program for the establishment of a national electronic monitoring system for medical product safety that led, in 2016, to the launch of the full Sentinel System. Under the Mini-Sentinel pilot, several algorithms for identifying health outcomes of interest, including one for anaphylaxis, were developed and evaluated using data available from the Sentinel common data model. PURPOSE: To evaluate whether features extracted from unstructured narrative data using natural language processing (NLP) could be used to classify anaphylaxis cases. METHODS: Using previously developed methods, we extracted features from unstructured narrative data using NLP and applied rule-based and similarity-based algorithms to identify anaphylaxis among 62 potential cases previously classified by human experts as anaphylaxis (N = 33), not anaphylaxis (N = 27), and unknown (N = 2). RESULTS: The rule-based and similarity-based approaches demonstrated almost equal performance (recall 100% vs 100%, precision 60.3% vs 57.4%, F-measure: 0.753 vs 0.729). Reasons for misclassification included the inability of the algorithms to make the same clinical judgments as human experts about the timing, severity, or presence of alternative explanations; and the identification of terms consistent with anaphylaxis but present in conditions other than anaphylaxis. CONCLUSIONS: Although precision needs to be improved before these algorithms could be used without human review, we demonstrated that applying rule-based and similarity-based algorithms to unstructured narrative information from clinical records can be used for classification of anaphylaxis in the Sentinel System. Further development and assessment of these methods in the Sentinel System are warranted.

Allergic reactions following contrast material administration: nomenclature, classification, and mechanisms.

In forensic pathology routine, fatal cases of contrast agent exposure can be occasionally encountered. In such situations, beyond the difficulties inherent in establishing the cause of death due to nonspecific or absent autopsy and histology findings as well as limited laboratory investigations, pathologists may face other problems in formulating exhaustive, complete reports, and conclusions that are scientifically accurate. Indeed, terminology concerning adverse drug reactions and allergy nomenclature is confusing. Some terms, still utilized in forensic and radiological reports, are outdated and should be avoided. Additionally, not all forensic pathologists master contrast material classification and pathogenesis of contrast agent reactions. We present a review of the literature covering allergic reactions to contrast material exposure in order to update used terminology, explain the pathophysiology, and list currently available laboratory investigations for diagnosis in the forensic setting.

Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis.

IgG-mediated anaphylaxis occurs in mice and may contribute to human reactions to infused drugs. To distinguish IgE- from putative IgG-mediated human anaphylaxis, we developed blood markers for murine anaphylaxis and evaluated their human relevance. Both IgG- and IgE-mediated anaphylaxis were characterized by decreased basophil and monocyte percentages and an increased neutrophil percentage in mouse blood. IgE- but not IgG-mediated murine anaphylaxis was accompanied by large increases in IL-4 secretion, plasma soluble IL-4 receptor-α (IL-4Rα) concentration, and T-cell membrane IL-4Rα expression. T-cell IL-4Rα expression also increased when mice that express human Fcε receptor Iα were sensitized with IgG-depleted serum from a peanut-allergic individual and challenged with peanut extract. Increased T-cell IL-4Rα expression is likely to also be a marker for human IgE-mediated anaphylaxis, because IgE-activated human basophils secrete IL-4, and IL-4 increases human T-cell IL-4Rα expression in vitro. Murine IgG- but not IgE-mediated anaphylaxis was characterized by decreased neutrophil Fcγ receptor III (FcγRIII) expression that was observed even when the antigen dose was insufficient to induce shock. Human neutrophils cultured with IgG immune complexes also lost FcγRIII. These observations suggest that decreased blood neutrophil FcγRIII expression without increased IL-4Rα expression can be used to determine whether and when IgG-mediated anaphylaxis occurs in man.

Undernotification of anaphylaxis deaths in Brazil due to difficult coding under the ICD-10.

BACKGROUND: Undernotification is well recognized as a key challenge to the study of anaphylaxis mortality, but it is seldom mentioned that one of its reasons is the difficult coding of the condition under the tenth revision of the international classification of diseases (ICD-10), given that there are no anaphylaxis-specific ICD-10, which are considered valid for coding underlying causes-of-death, and that official mortality statistics consider exclusively the underlying and disregard the contributing causes-of-death data recorded on death certificates. Brazilian mortality data were used as a case study to call attention to the inadequacy of the ICD-10 for the measurement of anaphylaxis deaths. METHODS: Underlying and contributing causes-of-death data were used to estimate the rates of anaphylaxis deaths in the country over the years 2008-2010. RESULTS: Of 498 anaphylaxis deaths were found, of which 75% were classified as 'definite' and 25% as 'possible anaphylaxis deaths'. The average national rate for these years was 0.87 per million per year. None of these deaths would have been found had we exclusively considered information from the underlying cause-of-death field. CONCLUSION/RECOMMENDATIONS: The study of anaphylaxis mortality using secondary data requires the use of information derived from the underlying as well as from the contributing causes-of-death fields. Coding definitions should be standardized with a view of enabling trend analyses and international comparisons. The ICD-11 revision is a unique opportunity to improve the coding system so as to facilitate epidemiological studies of anaphylaxis mortality. Educational interventions targeted at improving the quality of death certificate completion are urgently needed.

Anaphylaxis: Emergency Department Treatment.

Anaphylaxis is a potentially life-threatening, multisystem allergic reaction that can cause airway, breathing, or circulatory compromise. Intramuscular epinephrine is the immediate treatment of all patients. Intravenous epinephrine should be used in patients in shock, either as a bolus or infusion, along with fluid resuscitation. Airway obstruction must be recognized, and early intubation may be necessary. For shock that is refractory to epinephrine, additional vasopressors may be needed. Disposition depends on patient presentation and response to treatment. Mandatory observation periods are not necessary, because biphasic reactions are difficult to predict and may occur outside of typical observation periods.

Classification of anaphylaxis and utility of the EAACI Taskforce position paper on anaphylaxis in children.

Correct management and classification of anaphylaxis is mandatory. Records of emergency department (ED) visits to any of the three pediatric hospitals in Stockholm, because of reactions to foods during 2007, were identified. A retrospective analysis of clinical ED records of 371 children with 381 unique occasions of reactions to foods was performed. Symptoms/signs of reactions to foods recorded for classification of anaphylaxis were related to those presented in the EAACI Taskforce position paper on Anaphylaxis in Children (Allergy 2007; 62: 857). Forty-six different symptoms/signs of reactions to foods were retrieved. Several severe signs or symptoms from the respiratory tract and signs indicating reduced brain perfusion were not described in detail in the EAACI paper, hampering correct classification of anaphylaxis including grading of severity in our material. After modification of the EAACI classification including such signs and symptoms, we were able to classify 128 (35%) children with anaphylaxis. Seventy children (19%) did not fulfill our modified EAACI's criteria for anaphylaxis. They had been given adrenaline before or at arrival to hospital, possibly preventing anaphylaxis. Another 173 (47%) children/adolescents had neither been given adrenalin, nor fulfilled the criteria for anaphylaxis. Classification of food-induced anaphylaxis and severity grading should be built on signs and symptoms to facilitate diagnosis. The existing EAACI tool is helpful, but for Swedish children it is not quite applicable, in particular because of the lack of description of some respiratory, neurological or possible cardiovascular signs and symptoms.

Allergic reactions during anesthesia at a large United States referral center.

BACKGROUND: The types of agents implicated to trigger intraoperative anaphylactic reactions vary among reports, and there are no recent series from the United States. In this retrospective study, we examined perioperative anaphylactic reactions that occurred at a major tertiary referral academic center. METHODS: To characterize perioperative allergens associated with anaphylactic reactions, we reviewed the Mayo Clinic Division of Allergic Diseases skin test database between 1992 to 2010. The records of all patients who were tested for perioperative and anesthetic medications were reviewed. Charts that included a detailed history obtained by an allergist, skin test results, and tryptase measurements when available were reviewed and categorized. RESULTS: Thirty-eight patients were found to have an anaphylactic reaction during anesthesia, of which 18 were immunoglobulin (Ig)E-mediated anaphylactic reactions (likely causative agent identified by skin test), 6 were non-IgE-mediated anaphylactic reactions (elevated tryptase levels and negative skin test), and 14 were probable non-IgE-mediated anaphylactic reactions (tryptase levels normal or not obtained and negative skin test). Of the IgE-mediated anaphylactic reactions, antibiotics were the most prevalent likely causative agent (50%) whereas neuromuscular blocking drugs were implicated as a likely causative agent in 11% of reactions. CONCLUSION: Antibiotics were the most common likely causative agent associated with IgE-mediated anaphylactic reactions; however, for 52.6% of reactions, a causative agent could not be determined, suggesting a non-IgE-mediated anaphylactic reaction. The undiagnosed allergic reactions place patients at risk of a subsequent reexposure to the same allergen, or lead to unnecessary avoidance of needed medications.

[Adverse events following vaccination].

It introduced the case definition by the Brighton classification applied internationally and widely for the anaphylaxis following immunization.

[Hymenoptera venom allergy: new diagnostic tools and management]. / Allergie aux venins d'hyménopteres: nouveautés diagnostiques et prise en charge.

Anaphylactic reactions to hymenoptera venoms are common and, in our latitudes, mainly concern wasps and bees. Recently, molecular biology techniques have contributed to identifying and to sequencing the major allergens of insect venoms and led to the production of recombinant allergens. Assays for specific IgE directed against these recombinant allergens have recently been made available in clinical practice. They provide considerable assistance in identifying the insect responsible for an anaphylactic reaction, in particular when standard tests are positive for both wasp and bee. This article focuses on these new laboratory tests and also reviews the management of patients experiencing an anaphylactic reaction after hymenoptera sting.

Identification of Inpatient Allergic Drug Reactions Using ICD-9-CM Codes.

BACKGROUND: The study of allergic drug reactions has been limited because of challenges in identifying and confirming cases. OBJECTIVE: To determine the utility of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying inpatient allergic drug reactions and to compare findings with previous data in the emergency department. METHODS: By reviewing medical records of inpatients with ICD-9-CM codes and E codes suggestive of allergic drug reactions at a large urban academic medical center, we determined codes that yielded the most drug allergy cases and identified culprit drugs. RESULTS: In 2005 and 2010, 3337 and 5282 possible allergic drug reactions during hospitalization were identified and 1367 were reviewed. Allergic drug reactions were found in 409 (30.1%) of the reviewed charts, with 172 (29.7%) in 2005 and 237 (30.5%) in 2010. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0), allergic urticaria (708), angioneurotic edema (995.1), and anaphylaxis (995.0). Antibiotics were the most common cause (44.4%); however, multiple drug classes were often identified as likely culprit drugs. CONCLUSION: Specific ICD-9-CM codes can identify patients with allergic drug reactions, with antibiotics accounting for almost half of true reactions. Most patients with codes 693.0, 995.1, 708, and 995.0 had allergic drug reactions, with 693.0 as the highest yield code. An aggregate of multiple specific codes consistently identifies a cohort of patients with confirmed allergic drug reactions.

IgE-Mediated Food Allergy.

Food allergies are defined as adverse immune responses to food proteins that result in typical clinical symptoms involving the dermatologic, respiratory, gastrointestinal, cardiovascular, and/or neurologic systems. IgE-mediated food-allergic disease differs from non-IgE-mediated disease because the pathophysiology results from activation of the immune system, causing a T helper 2 response which results in IgE binding to Fcε receptors on effector cells like mast cells and basophils. The activation of these cells causes release of histamine and other preformed mediators, and rapid symptom onset, in contrast with non-IgE-mediated food allergy which is more delayed in onset. The diagnosis of IgE-mediated food allergy requires a history of classic clinical symptoms and evidence of food-specific IgE by either skin-prick or serum-specific IgE testing. Symptoms of IgE-mediated food allergies range from mild to severe. The severity of symptoms is not predicted by the level of specific IgE or skin test wheal size, but the likelihood of symptom onset is directly related. Diagnosis is excluded when a patient can ingest the suspected food without clinical symptoms and may require an in-office oral food challenge if testing for food-specific IgE by serum or skin testing is negative or low. Anaphylaxis is the most severe form of the clinical manifestation of IgE-mediated food allergy, and injectable epinephrine is the first-line treatment. Management of food allergies requires strict avoidance measures, counseling of the family about constant vigilance, and prompt treatment of allergic reactions with emergency medications. Guidelines have changed recently to include early introduction of peanuts at 4-6 months of life. Early introduction is recommended to prevent the development of peanut allergy. Future treatments for IgE-mediated food allergy evaluated in clinical trials include epicutaneous, sublingual, and oral immunotherapy.

Anaphylaxis following quadrivalent human papillomavirus vaccination.

BACKGROUND: In 2007, Australia implemented the National human papillomavirus (HPV) Vaccination Program, which provides quadrivalent HPV vaccine free to all women aged 12-26 years. Following notification of 7 presumptive cases of anaphylaxis in the state of New South Wales, Australia, we verified cases and compared the incidence of anaphylaxis following HPV vaccination to other vaccines in comparable settings. METHODS: We contacted all patients with suspected anaphylaxis and obtained detailed histories from telephone interviews and a review of medical records. A multidisciplinary team determined whether each suspected case met the standardized Brighton definition. Some participants also received skin-prick allergy testing for common antigens and components of the HPV vaccine. RESULTS: Of 12 suspected cases, 8 were classified as anaphylaxis. Of these, 4 participants had negative skin-prick test results for intradermal Gardasil. From the 269 680 HPV vaccine doses administered in schools, 7 cases of anaphylaxis were identified, which represents an incidence rate of 2.6 per 100 000 doses (95% CI 1.0-5.3 per 100 000). In comparison, the rate of identified anaphylaxis was 0.1 per 100 000 doses (95% CI 0.003-0.7) for conjugated meningococcal C vaccination in a 2003 school-based program. INTERPRETATION: Based on the number of confirmed cases, the estimated rate of anaphylaxis following quadrivalent HPV vaccine was significantly higher than identified in comparable school-based delivery of other vaccines. However, overall rates were very low and managed appropriately with no serious sequelae.

Development and validation of an algorithm to identify drug-induced anaphylaxis in the Beijing Pharmacovigilance Database.

Background Pharmacovigilance databases are utilized to identify serious adverse drug events (ADEs). In China, very few studies have evaluated the validity of using pharmacovigilance databases to identify drug-induced anaphylaxis (DIA). Objective We aimed to develop and validate an algorithm to identify DIA using the Beijing Pharmacovigilance Database (BPD). Setting ADEs from the BPD mainly spontaneously reported from 94 hospitals in Beijing, China. Method Using the diagnoses, we developed an algorithm to identify potential DIAs from the BPD between January 2004 and December 2014. A sample of 500 patients was randomly selected for chart abstraction. Two physician adjudicators assessed whether DIA occurred using the published clinical criteria as the gold standard. Main outcome measure Positive predictive values (PPVs) and 95% confidence intervals of the algorithm and algorithm criteria components were calculated. Results 500 patients (53.2% female; the mean age 48.2 years) with potential DIA were selected using the algorithm. 444 were adjudicated as having anaphylaxis by physicians. The PPV of the overall algorithm was 88.8% (95% CI 86.0-91.6%). PPV for the algorithm only using specific diagnoses of "anaphylactic shock", "anaphylactic reaction", and "anaphylactoid reaction [severe]" was 89.6% (95% CI 86.6-92.4%); this partial algorithm identified 387 (87.2%) DIAs. The diagnosis that identified the most DIAs (83.8%) was "anaphylactic shock", with a PPV of 91.6% (95% CI 88.9-94.3%). Conclusion The overall algorithm identified a greater number of DIAs than the algorithm that only used specific diagnoses; however, its PPV was slightly lower. We were able to identify DIAs with the algorithm we developed.