Anaphylaxis mortality in the perioperative setting: Epidemiology, elicitors, risk factors and knowledge gaps.

Perioperative anaphylaxis (PA) is a severe condition that can be fatal, but data on PA mortality are scarce. The aim of this article is to review the epidemiology, elicitors and risk factors for PA mortality and identify knowledge gaps and areas for improvement regarding the management of severe PA. PA affects about 100 cases per million procedures. Mortality is rare, estimated at 3 to 5 cases per million procedures, but the PA mortality rate is higher than for other anaphylaxis aetiologies, at 1.4% to 4.8%. However, the data are incomplete. Published data mention neuromuscular blocking agents and antibiotics, mainly penicillin and cefazolin, as the main causes of fatal PA. Reported risk factors for fatal PA vary in different countries. Most frequently occurring comorbidities are obesity, male gender, cardiovascular diseases and ongoing treatment with beta-blockers. However, there are no clues about how these factors interact and the impact of individual risk factors. The pathophysiology of fatal PA is still not completely known. Genetic factors such as deficiency in PAF-acetyl hydrolase and hereditary alpha-tryptasemia, have been reported as modulators of severe anaphylaxis and possible targets for specific treatments. Our review underlines unmet needs in the field of fatal PA. Although we confirmed the need for timely administration of an adequate dose of adrenaline and the proper infusion of fluids, there is no evidence-based data on the proper dose of intravenous titrated adrenaline and which clinical manifestations would flag the need for fluid therapy. There are no large clinical studies supporting the administration of alternative vasopressors, such as glucagon and methylene blue. Further research on pathophysiological mechanisms of PA and its severity may address these issues and help clinicians to define new therapeutic approaches.

Management of Refractory Anaphylaxis: An Overview of Current Guidelines.

In this review, we compare different refractory anaphylaxis (RA) management guidelines focusing on cardiovascular involvement and best practice recommendations, discuss postulated pathogenic mechanisms underlining RA and highlight knowledge gaps and research priorities. There is a paucity of data supporting existing management guidelines. Therapeutic recommendations include the need for the timely administration of appropriate doses of aggressive fluid resuscitation and intravenous (IV) adrenaline in RA. The preferred second-line vasopressor (noradrenaline, vasopressin, metaraminol and dopamine) is unknown. Most guidelines recommend IV glucagon for patients on beta-blockers, despite a lack of evidence. The use of methylene blue or extracorporeal life support (ECLS) is also suggested as rescue therapy. Despite recent advances in understanding the pathogenesis of anaphylaxis, the factors that lead to a lack of response to the initial adrenaline and thus RA are unclear. Genetic factors, such as deficiency in platelet activating factor-acetyl hydrolase or hereditary alpha-tryptasaemia, mastocytosis may modulate reaction severity or response to treatment. Further research into the underlying pathophysiology of RA may help define potential new therapeutic approaches and reduce the morbidity and mortality of anaphylaxis.

Changing patterns in the epidemiology of drug allergy.

Drug allergy (DA) remains a complex and unaddressed problem worldwide that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. Underdiagnosis and overdiagnosis are common and due to the lack of standardized definitions and biomarkers. The true burden of DA is unknown, and recent efforts in data gathering through electronic medical records are starting to provide emerging patterns around the world. Ten percent of the general population engaged in health care claim to have a DA, and the most common label is penicillin allergy. Up to 20% of emergency room visits for anaphylaxis are due to DA and 15%-20% of hospitalized patients report DA. It is estimated that DA will increase based on the availability and use of new and targeted antibiotics, vaccines, chemotherapies, biologicals, and small molecules, which are aimed at improving patient's options and quality of life. Global and regional variations in the prevalence of diseases such as human immunodeficiency virus and mycobacterial diseases, and the drugs used to treat these infections have an impact on DA. The aim of this review is to provide an update on the global impact of DA by presenting emerging data on drug epidemiology in adult and pediatric populations.

Optimization of the allergen classification of the International Classification Of Diseases, 11th Revision (ICD-11).

BACKGROUND: Accurate diagnosis of triggers or causative allergens is essential for appropriate risk assessment, providing correct advice to patients with allergy and their caregivers and personalized treatment. However, allergens have never been represented in the World Health Organization International Classification of Diseases (ICD). OBJECTIVE: In this article, we present the process of selection of allergens to better fit the ICD, 11th Revision (ICD-11) structure and the outcomes of this process. METHODS: The Logical Observation Identifiers Names and Codes database, containing 1444 allergens, was used as the basis for the selection process. Two independent experts were responsible for the first selection of the allergens according to specific technical criteria. The second step of the selection process was based on real-life relevance of the allergens according to the frequency of requests regarding each of them. RESULTS: We selected 1109 allergens (76.8%) from all 1444 present in the Logical Observation Identifiers Names and Codes database, with considerable agreement between experts (Cohen κ = 8.6). After assessment of real-life data, 297 additional relevant allergens worldwide were selected and grouped as plants (36.4%), drugs (32.6%), animal proteins (21%), mold and other microorganisms (1.5%), occupational allergens (0.4%), and miscellaneous allergens (0.5%). CONCLUSION: The stepwise approach allowed us to select the most relevant allergens in practice, which is the first step to building a classification of allergens for the WHO ICD-11. Aligned with the achievement in the construction of the pioneer section addressed to the allergic and hypersensitivity conditions in the ICD-11, the introduction of a classification for allergens can be considered timely and much needed in clinical practice.

Association between air pollution levels and drug sales for asthma and allergy in 63 million people in metropolitan France.

INTRODUCTION: Air pollution is known to have an impact on respiratory health. However, the assessment of this relationship is far from complete and is rarely extended to the country level. We used drug sales data, both Over-The-Counter (OTC) and prescription drugs, to assess exhaustively the impact of air pollution on asthma and allergy at the national level in France. METHODS: The WHO Anatomical Therapeutic Chemical (ATC) classification system was used to describe the distribution of sales of drugs of class R03 (Drugs for obstructive airways diseases, overall for asthma) and R06 (Antihistamines for systemic use). We performed a Quasi-Poisson regression model with a generalized additive model (GAM) to estimate the relationship (Relative Risks and 95% Confidence Interval) between drug sales and air pollutants, that is Particulate Matter with a diameter less than 2.5 micrometers (PM2.5) and less than 10 micrometers (PM10) and Nitrogen dioxide (NO2), as assessed using the high-resolution CHIMERE dispersion model. We designed unadjusted and adjusted single-pollutant models as well as two-pollutant models. RESULTS: PM2.5, PM10, and NO2 were significantly and positively associated with sales of R03 and R06 class drugs, after adjustment for potential confounders. Results were confirmed in the two-pollutant model for PM10 and NO2 but not for PM2.5. CONCLUSIONS: Our study confirms the presence of an association between major air pollutants and the sales of drugs against asthma and allergies. Further studies on larger databases and over several years are necessary to confirm and better understand these results.

Anaphylaxis in Brazil between 2011 and 2019.

BACKGROUND: There is a lack of population-based studies of anaphylaxis from low- and middle-income countries. This hampers public health planning and investments and may influence availability of adrenaline auto-injectors. OBJECTIVE: We conducted the first national population-based study of anaphylaxis hospitalization in Brazil. METHODS: Descriptive study using routinely reported data to the Brazilian Hospital Information System for the years 2011-2019. Information available is coded based on the International Classification of Diseases (ICD)-10 and covers main cause of hospitalization (primary cause) and any conditions contributing to it (secondary cause). RESULTS: Over 9 years, we identified 5716 admissions due to anaphylaxis for all causes. The average hospitalization rate related to anaphylaxis was 0.71/100,000 population per year, with a 2.4% (95% CI 1.9%, 2.9%) increase per annum over the study period. Admissions were more frequent among females (52.8%), except for cases due to insect sting. Most admissions occurred in adulthood, from 30 to 59 years (36.3%) but 13.8% in preschool children (0-4 years). There were more young children admitted for food-related anaphylaxis, and more adults admitted for drug/iatrogenic-related anaphylaxis. There were 334 cases (5.8% of admissions) of fatal anaphylaxis over the study period, with increased case fatality rate over time. CONCLUSIONS AND CLINICAL RELEVANCE: This is the first study of anaphylaxis hospital admissions using nation-wide data from a low- or middle-income country. Hospital admissions and fatalities from anaphylaxis in Brazil appear to be increasing.

Allergic and hypersensitivity conditions in non-specialist care: Flow diagrams to support clinical practice.

Most patients presenting with allergies are first seen by primary care health professionals. The perceived knowledge gaps and educational needs were recently assessed in response to which the LOGOGRAM Task Force was established with the remit of constructing pragmatic flow diagrams for common allergic conditions in line with an earlier EAACI proposal to develop simplified pathways for the diagnosis and management of allergic diseases in primary care. To address the lack of accessible and pragmatic guidance, we designed flow diagrams for five major clinical allergy conditions: asthma, anaphylaxis, food allergy, drug allergy, and urticaria. Existing established allergy guidelines were collected and iteratively distilled to produce five pragmatic and accessible tools to aid diagnosis and management of these common allergic problems. Ultimately, they should now be validated prospectively in primary care settings.

Food allergy in the World Health Organization's International Classification of Diseases (ICD)-11.

There are increasing global data regarding the prevalence of food allergy and food-induced anaphylaxis. However, knowledge in morbidity and mortality epidemiological data is still not optimal, and international comparable standards remain poorly accessed. This information could in turn support better clinical practice and possibly prevent future severe reactions and avoidable fatalities. The International Classification of Diseases (ICD) is the standard diagnostic tool used for epidemiology, health management, and clinical purposes supported by the World Health Organization (WHO). It is also used to determine health care payment and reimbursement of providers and health care services in hospitals. Thanks to the academic and technical efforts under the ALLERGY in ICD-11 initiative the pioneer "Allergy and hypersensitivity conditions" section has been built under the "Disorders of the Immune System" chapter of the ICD-11. The "Food hypersensitivity" (FH) subsection is classified under the "Complex allergic or hypersensitivity conditions" section and "Food-induced anaphylaxis" is under the "Anaphylaxis" section. In order to inform the development of strategies to reduce preventable FHs/food allergies, the burden of disease in different healthcare settings and patient populations and their common etiologies need to be understood. Besides, greater specificity regarding clinical conditions and services delivered will provide payers, policy makers, and providers with better information to make major refinements to countries payment and reimbursement systems, including the design and implementation of pay-for-performance program.The new classification addressed to FHs will enable the collection of more accurate epidemiological data to support quality management of patients with FHs/food allergies, and better facilitate health care planning and decision-making and public health measures to prevent and reduce their morbidity and mortality. The improved logic and standardized definitions through the ICD-11 (and other WHO classifications) will also facilitate international comparisons of quality care and the sharing of best practice globally.

Allergy in the World Health Organization's International Classification of Diseases (ICD)-11.

The International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes, and health management. The change in the hierarchy in ICD-11 permitted the construction of the pioneer section addressed to allergic and hypersensitivity conditions (A/H), which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology, and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019, and the implementation is ongoing worldwide. The Montpellier World Health Organization (WHO) Collaborating Centre on Classification Scientific Support was designated in 2018 and is responsible for supporting the WHO through representing A/H in the international classifications and quality care of patients from the public health perspective.

Food-induced anaphylaxis morbidity: Emergency department and hospitalization data support preventive strategies.

BACKGROUND: Anaphylaxis is a recognized public health issue. There is no doubt that food-induced anaphylaxis (FIA) has tremendous impact on the quality of life of patients and their families and increases direct and indirect costs. FIA is associated with increasing rates of emergency department admissions and hospitalizations and implies the risk of death. Morbidity epidemiological data are a key to tailor public health actions to this non-communicable disease. The aim of this article was to review published morbidity epidemiological data relating to FIA and potential risk factors, in order to provide evidence-based recommendations to reduce the risk of severe adverse outcomes. METHODS: We identified published studies available in PUBMED/MEDLINE (1966-2020), EMBASE (1980-2020) and CINAHL (1982-2020). The systematic review was carried out using MeSH terms related to FIA ED admissions and hospitalizations. RESULTS: A total of 25 articles were selected, 80% published in the last 5 years. After critical analysis of methodological and clinical characteristics reported in the data selected, we were able to propose preventive strategies. CONCLUSION: Anaphylaxis is a recognized public health issue. FIA is associated with increasing rates of ED admissions and hospitalizations and imply in risk of death. More than reviewing and critically interpreting the key patterns related to FIA morbidity published data, we proposed strategies in order to promote quality care of patients suffering from FIA. Our World Health Organization Collaborative Center is deeply involved in this process, and we believe that the proposed strategies will inform future healthcare policies on anaphylaxis. The long-term objective would be to improve clinical care and quality of life of patients and their families, and develop risk-stratified, cost-effective preventive measures.

Food-induced anaphylaxis in infancy compared to preschool age: A retrospective analysis.

OBJECTIVE: Little is known regarding food anaphylaxis in infancy. We aimed to describe specificities of food anaphylaxis in infants (≤12 months) as compared to preschool children (1-6 years). METHODS: We conducted a retrospective study of all food anaphylaxis cases recorded by the Allergy Vigilance Network from 2002 to 2018, in preschool children focusing on infants. RESULTS: Of 1951 food anaphylaxis reactions, 61 (3%) occurred in infants and 386 (20%) in preschool children. Two infants had two anaphylaxis reactions; thus, we analyzed data among 59 infants (male: 51%; mean age: 6 months [SD: 2.9]); 31% had a history of atopic dermatitis, 11% of previous food allergy. The main food allergens were cow's milk (59%), hen's egg (20%), wheat (7%) and peanut (3%) in infants as compared with peanut (27%) and cashew (23%) in preschool children. Anaphylaxis occurred in 28/61 (46%) cases at the first cow's milk intake after breastfeeding discontinuation. Clinical manifestations were mainly mucocutaneous (79%), gastrointestinal (49%), respiratory (48%) and cardiovascular (21%); 25% of infants received adrenaline. Hives, hypotension and neurologic symptoms were more likely to be reported in infants than in preschool children (P = .02; P = .004; P = .002, respectively). Antihistamines and corticosteroids were more often prescribed in preschool children than in infants (P = .005; P = .025, respectively). CONCLUSION: Our study found that in infants presenting with their first food allergy, in a setting with a high rate of infant formula use, the most predominant trigger was cow's milk. As compared to older preschool children, hives, hypotonia and hypotension were more likely to be reported in infants. We believe that this represents a distinct food anaphylaxis phenotype that can further support developing the clinical anaphylaxis criteria in infants.

The EAACI-AAAAI-WAO Junior Members' joint survey: A worldwide snapshot of Allergy and Clinical Immunology specialty.

BACKGROUND: Education and training in Allergy and Clinical Immunology (A/I) are characterized by a great variability worldwide. However, objective and worldwide data regarding this topic are lacking. METHODS: To investigate personal information, education, and involvement in scientific societies of juniors engaged in A/I field, a questionnaire was developed by representatives from the JMs' boards of the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma, and Immunology (AAAAI), and the World Allergy Organization (WAO). RESULTS: A total of 543 questionnaires were collected from 76 regions of all continents. The geographic distribution of responders was as follows: Africa-Middle East 3.0%, Asia-Pacific 21.4%, Europe 48.2%, Latin America 12.1%, and North America 15.3%. 59.0% of responders declared that A/I is recognized as a separate specialty in their country, Europe mostly accounting for that proportion. Primary interest in the field represents the main motivation for choosing A/I specialty. Concerning involvement in scientific societies, 41.1% of responders ever attended an EAACI Congress, 20.6% an AAAAI Congress, and 20.4% a WAO Congress. According to 40.3% of responders, scientific societies do not provide enough opportunities for young members, and 96.4% believes in a more intensive cooperation between the A/I Societies. CONCLUSIONS: The survey provides the first worldwide perspective about A/I specialty. It represents the first ever example of a structured collaboration between the junior members (JMs) of the three main A/I Societies. The findings suggest the need for harmonization, at least in terms of training and formation in the field of A/I worldwide.

Global implementation of the world health organization's International Classification of Diseases (ICD)-11: The allergic and hypersensitivity conditions model.

The International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes and health management. Since its first edition, the ICD has maintained a framework distributing conditions according to topography, with the result that some complex conditions, such as allergies and hypersensitivity disorders (A/H) including anaphylaxis, have been poorly represented. The change in hierarchy in ICD-11 permitted the construction of the pioneer section addressed to A/H, which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019, and the implementation is ongoing worldwide. We here present the outcomes from an online survey undertaken to reach out the allergy community worldwide in order to peer review the terminology, classification and definitions of A/H introduced into ICD-11 and to support their global implementation. Data are presented here for 406 respondents from 74 countries. All of the subsections of the new A/H section of the ICD-11 had been considered with good accuracy by the majority of respondents. We believe that, in addition to help during the implementation phase, all the comments provided will help to improve the A/H classification and to increase awareness by different disciplines of what actions are needed to ensure more accurate epidemiological data and better clinical management of A/H patients.

Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper.

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

Anaphylaxis in children.

Anaphylaxis in children is a potential acute life-threatening systemic hypersensitivity reaction. Anaphylaxis fatality rate is estimated to be 0.65% to 2%. Food is the main anaphylaxis trigger in children, notably cow's milk, peanuts, and tree nuts. Mucocutaneous manifestations are observed in more than 90% of cases, but it is not essential for diagnosis. Deaths are rather secondary to the laryngeal edema, observed in 40%-50% of cases. Personal history of asthma, allergy to particular foods such as peanuts and tree nuts, and adolescence are known risk factors for anaphylaxis and more severe reactions. Epinephrine (adrenaline) is the medication of choice for the first-aid treatment of anaphylaxis. However, adrenaline auto-injectors (AAIs) are commercially available in only 32% of world countries. There are still considerable unmet needs in the field of anaphylaxis in children. Therefore, the Montpellier WHO Collaborating Centre aims to start the global action plan applied to anaphylaxis.

Controversies in drug allergy: Testing for delayed reactions.

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

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.