Primary, secondary and tertiary prevention of food allergy: current practices and future directions / Prevención primaria, secundaria y terciaria de la alergia alimentaria: prácticas actuales y direcciones futuras

The incidence of food allergies has risen around the globe, and experts have been exploring methods of preventing such allergies in young children to ease the burden of disease and reduce the morbidity and mortality caused by anaphylaxis to food allergens. Such preventative measures can be categorised as primary, secondary and tertiary prevention, which are discussed in detail in this review. Primary prevention is defined as the prevention of becoming sensitised towards specific allergens. The evidence suggests that avoiding common allergenic foods during pregnancy and breastfeeding is not protective against food allergies, and guidelines recommend weaning from 4 to 6 months of age, with recent studies supporting the early introduction of peanuts at 4 months to prevent peanut allergy. Secondary prevention targets patients who are already sensitised and aims to halt the progression of sensitisation, with evidence for high rates of success and safety in trials of early introduction to milk and peanuts using oral immunotherapy in sensitised infants. Tertiary allergy prevention focuses on reducing the risk of a patient having anaphylaxis, with oral immunotherapy being the most common method of promoting tolerance in allergic children. Several studies have demonstrated successful reintroduction for milk, egg and peanut; however, no such guidelines are recommended for other foods. Finally, dietary advancement therapy in the form of milk and egg ladders has been employed as a method of primary, secondary and tertiary prevention of allergies, particularly in Ireland, the UK and Canada.(AU)

Epidemiology of suspected life-threatening perioperative anaphylaxis: a cross-sectional multicentre study in China.

BACKGROUND: Perioperative anaphylaxis is relatively rare but can be life-threatening. The incidence in China is unknown and may differ from other global geographic regions. This study was therefore designed to understand the incidence of perioperative anaphylaxis in China. METHODS: We enrolled 112 tertiary care hospitals from seven distinct geographic areas in mainland China. We collected information about Ring and Messmer III and IV reactions from September 2018 to August 2019. A collaborative educational learning network was used to reduce diagnostic errors. Information about patient characteristics, clinical features, treatment, and clinical outcomes were recorded and analysed. RESULTS: A total of 447 cases of 5 078 118 surgical procedures met inclusion criteria. The incidence of suspected perioperative anaphylaxis throughout China was one in 11 360 anaesthetics (95% confidence interval [CI], with a range of 1:12 521 to 1:10 397). The incidence in South China was higher (one in 6050; 95% CI, from 1:8013 to 1:4859) than in Northeast China (one in 19 262; 95% CI, from 1:33 088 to 1:13 585) (P<0.01) with an increasing trend from the north to the south. The most common clinical manifestations were hypotension (91.1%) and tachycardia (65.3%). The majority of patients (83.4%) were given epinephrine. A total of 27 patients (6.0%) required cardiopulmonary resuscitation. Ultimately, nine patients died (2.0%). CONCLUSIONS: This nationwide survey showed an incidence of perioperative anaphylaxis of one in 11 360, but this varied significantly by region. The underlying reason for this pattern remains unknown and could be attributable to environmental or genetic influences, which requires further investigation. CLINICAL REGISTRY NUMBER: ChiCTR1900025956.

Incidence of Fatal Anaphylaxis A Systematic Review of Observational Studies

Background: Fatal anaphylaxis is very rare, with an incidence ranging from 0.5 to 1 deaths per million person-years. Objective: Based on a systematic review, we aimed to explain differences in the reported incidence of fatal anaphylaxis based on the methodological and demographic factors addressed in the various studies. Methods: We searched PubMed/MEDLINE, EMBASE, and the Web of Science for relevant retrospective and prospective cohort studies and registry studies that had assessed the anaphylaxis mortality rate for the population of a country or for an administrative region. The research strategy was based on combining the term “anaphylaxis” with “death”, “study design”, and “main outcomes” (incidence). Results: A total of 46 studies met the study criteria and included 16,541 deaths. The range of the anaphylaxis mortality rate for all causes of anaphylaxis was 0.002-2.51 deaths per million person-years. Fatal anaphylaxis due to food (range 0.002-0.29) was rarer than deaths due to drugs (range 0.004-0.56) or Hymenoptera venom (range 0.02-0.61). The frequency of deaths due to anaphylaxis by drugs increased during the study period (IRR per year, 1.02; 95%CI, 1.00-1.04). We detected considerable heterogeneity in almost all of the meta-analyses carried out. Conclusion: The incidence of fatal anaphylaxis is very low and differs according to the various subgroups analyzed. The studies were very heterogeneous. Fatal anaphylaxis due to food seems to be less common than fatal anaphylaxis due to drugs or Hymenoptera venom (AU)

Antecedentes: La muerte por anafilaxia es un evento muy excepcional, con una incidencia que varía de 0,5 a 1 muerte por millón de personas/año. Objetivo: Usando las técnicas de una revisión sistemática, nuestro objetivo ha sido explicar las diferencias en la incidencia informada de la muerte por anafilaxia atendiendo a diversos factores metodológicos y demográficos empleados en los diversos estudios de la revisión. Métodos: Se realizaron búsquedas en PubMed/MEDLINE, EMBASE y Web of Science, con el fin de obtener estudios de cohortes y registros prospectivos y retrospectivos relevantes que hubieran evaluado la tasa de muerte por anafilaxia en la población de un país o una región administrativa. La estrategia de investigación se basó en combinar “anafilaxia” con “muerte”, “diseño del estudio” y “resultados principales” (incidencia). Resultados: Un total de 46 estudios cumplieron con los criterios del estudio. Los estudios incluyeron 16.541 muertes. El rango de la tasa de mortalidad por anafilaxia para todas las causas de anafilaxia fue de 0,002 a 2,51 muertes por millón de personas/año. La anafilaxia mortal debida a los alimentos (rango 0,002-0,29) fue más rara que las muertes debidas a medicamentos (rango 0,004-0,56) o veneno de himenópteros (rango 0,02-0,61). La frecuencia de muertes por anafilaxia por fármacos aumentó durante el período de estudio (IRR por año, 1,02; IC del 95%: 1,00-1,04). Se detectó una heterogeneidad considerable en casi todos los metaanálisis realizados. Conclusión: La incidencia de anafilaxia mortal es muy baja y difiere según los distintos subgrupos analizados. Los estudios fueron muy heterogéneos. La muerte por anafilaxia debida a alimentos parece ser menos común que la anafilaxia mortal debida a fármacos o por veneno de himenópteros (AU)

Postmortem investigation of fatalities following vaccination with COVID-19 vaccines.

Thorough postmortem investigations of fatalities following vaccination with coronavirus disease 2019 (COVID-19) vaccines are of great social significance. From 11.03.2021 to 09.06.2021, postmortem investigations of 18 deceased persons who recently received a vaccination against COVID-19 were performed. Vaxzevria was vaccinated in nine, Comirnaty in five, Spikevax in three, and Janssen in one person. In all cases, full autopsies, histopathological examinations, and virological analyses for the severe acute respiratory syndrome coronavirus 2 were carried out. Depending on the case, additional laboratory tests (anaphylaxis diagnostics, VITT [vaccine-induced immune thrombotic thrombocytopenia] diagnostics, glucose metabolism diagnostics) and neuropathological examinations were conducted. In 13 deceased, the cause of death was attributed to preexisting diseases while postmortem investigations did not indicate a causal relationship to the vaccination. In one case after vaccination with Comirnaty, myocarditis was found to be the cause of death. A causal relationship to vaccination was considered possible, but could not be proven beyond doubt. VITT was found in three deceased persons following vaccination with Vaxzevria and one deceased following vaccination with Janssen. Of those four cases with VITT, only one was diagnosed before death. The synopsis of the anamnestic data, the autopsy results, laboratory diagnostic examinations, and histopathological and neuropathological examinations revealed that VITT was the very likely cause of death in only two of the four cases. In the other two cases, no neuropathological correlate of VITT explaining death was found, while possible causes of death emerged that were not necessarily attributable to VITT. The results of our study demonstrate the necessity of postmortem investigations on all fatalities following vaccination with COVID-19 vaccines. In order to identify a possible causal relationship between vaccination and death, in most cases an autopsy and histopathological examinations have to be combined with additional investigations, such as laboratory tests and neuropathological examinations.

Comparative study between conventional and new methods in defining the cause of death from anaphylactic shock.

ABSTRACT: Anaphylaxis is defined as a rapid systemic reaction that develops in individuals previously exposed to specific allergens. The new exposure causes systemic cellular degranulation, which in turn leads to cardiovascular and respiratory changes that are fatal if not treated immediately. One of the main problems of this scenario in the forensic field is the determination of a correct post-mortem diagnosis. Traditional methods, such as histopathological examination of the respiratory tract and the use of specific antibodies used in immunohistochemistry, are sensitive but not always specific and therefore do not guarantee a high degree of probability in the diagnosis of anaphylaxis. For this reason, a new and promising research frontier in this field of forensic pathology could be represented by the application of miRNAs as biomarkers, as has been done in other areas of medicine.

Naturally occurring hypothermia promotes survival in severe anaphylaxis.

Although hypothermia has received substantial attention as an indicator of severity in anaphylaxis, it has been neglected from the perspective of whether it could act as a disease-modifying factor in this condition. Here, the impact of naturally occurring (spontaneous) hypothermia on anaphylaxis was evaluated in a murine model of ovalbumin (OVA)-induced allergy. Nonextreme changes in the ambient temperature (Ta) were used to modulate the magnitude of spontaneous hypothermia. At a Ta of 24°C, challenge with OVA intraperitoneally or intravenously resulted in a rapid, transient fall in body core temperature, which reached its nadir 4-6°C below baseline in 30 min. This hypothermic response was largely attenuated when the mice were kept at a Ta of 34°C. The Ta-dependent attenuation of hypothermia resulted in a survival rate of only 30%, as opposed to survival of 100% in the condition that favored the development of hypothermia. The protective effect of hypothermia did not involve changes in the rate of mast cell degranulation, as assessed by the concentration of mast cell protease-1 in bodily fluids. On the other hand, hypothermia improved oxygenation of the brain and kidneys, as indicated by higher NAD+/NADH ratios. Therefore, it is plausible to propose that naturally occurring hypothermia makes organs more resistant to the anaphylactic insult.

Incidence and risk factors for near-fatal and fatal outcomes after perioperative and periprocedural anaphylaxis in the USA, 2005-2014.

BACKGROUND: The incidence of fatal and near-fatal outcomes after perioperative anaphylaxis is unknown in the USA. Previously identified risk factors of neuromuscular-blocker-induced fatal perioperative anaphylaxis include male sex, obesity, and use of beta blockers. We examined the incidence of fatal and near-fatal outcomes after perioperative anaphylaxis in the USA and the underlying risk factors using a large national database. METHODS: Using the Nationwide Inpatient Sample from 2005 to 2014, we identified cases of fatal and near-fatal perioperative anaphylaxis, defined as perioperative anaphylaxis cases complicated by respiratory or cardiac arrest, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS: Amongst 5223 perioperative anaphylaxis cases, the proportion of near-fatal or fatal cases attributable to perioperative anaphylaxis was 7.0% (95% confidence interval [CI]: 6.2-7.7), with near-fatal perioperative anaphylaxis cases accounting for 5.0% (95% CI: 4.4-5.6%) and fatal cases accounting for 2.0% (95% CI: 1.5-2.5%) of cases overall. Thus, the incidence of fatal or near-fatal perioperative anaphylaxis is 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal perioperative anaphylaxis include age (≥65 yr); undergoing a cardiac procedure; and comorbid conditions of weight loss, non-metastatic solid tumours, metastatic cancer, paralysis, coagulopathy, renal failure, congestive heart failure, fluid and electrolyte disorder, and neurological disorders. Individuals with near-fatal or fatal perioperative anaphylaxis reactions had increased lengths of stay and hospital costs compared with controls. CONCLUSIONS: The incidence of fatal or near-fatal perioperative anaphylaxis in the USA was 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal outcomes include older age, cardiac procedures, and specific comorbidities.

Fatal Anaphylaxis: Epidemiology and Risk Factors.

PURPOSE OF REVIEW: To provide clinicians with an understanding of risk factors associated with fatal anaphylaxis, and to promote individualized management plans with patients based upon key aspects of their clinical history. RECENT FINDINGS: While anaphylaxis can affect a significant percentage of the general population, death from anaphylaxis remains a rare outcome. The presence of asthma and peanut or tree nut allergy is associated with higher risk for severe or fatal anaphylaxis from foods. Specific triggers (medications, venom), underlying comorbid conditions, age, and use of some medications can also impact risk and warrant different counseling and management strategies. Anaphylaxis is a rapidly progressive systemic reaction with multiple different causes and encompasses a wide degree of severity in clinical presentation and risk for future episodes. Individualized management, discussion of risk, and shared decision making should occur with each patient and in consideration of their personal risk factors.

Bovine ß-lactoglobulin-induced passive systemic anaphylaxis model using humanized NOG hIL-3/hGM-CSF transgenic mice.

Food allergy is a common disease caused by intake of allergen-containing foods, such as milk, eggs, peanuts and wheat. Systemic anaphylaxis is a severe hypersensitive allergic reaction resulting from degranulation of mast cells or basophils after cross-linking of surface high-affinity IgE receptors (Fcε-RI) with allergen-specific IgE and allergens. In this study, we developed a novel human mast cell/basophil-engrafted mouse model that recapitulates systemic anaphylaxis triggered by ß-lactoglobulin (BLG), a major allergen found in cow's milk. Human CD34+ hematopoietic stem cells were transferred into NOG (non-Tg) or NOG hIL-3/hGM-CSF transgenic (Tg) mice. After 14-16 weeks, bovine BLG-specific human IgE was intravenously injected into humanized mice, followed by intravenous or oral bovine BLG exposure 1 day later. Body temperature in Tg, but not in non-Tg, mice gradually decreased within 10 min, and 80% of Tg mice died within 1 h by intravenous BLG exposure. Serum histamine levels and anaphylaxis scores in Tg mice were markedly increased compared to non-Tg mice. Furthermore, these allergic symptoms were significantly inhibited by epinephrine treatment of the Tg mice. Therefore, the current NOG hIL-3/hGM-CSF Tg mouse model may be useful for development of novel anaphylaxis drugs for treatment of food allergies and for safety assessment of low-allergenicity extensively hydrolyzed cow's milk whey protein-based infant formulas.

Biologic Agents for the Treatment of Anaphylaxis.

Several biologic therapies and new devices are emerging as potential preventive treatment of anaphylaxis. However, adrenaline (epinephrine) is still the first-line treatment of any type of anaphylaxis. Biologic drugs, such as omalizumab, although not US Food and Drug Administration approved for anaphylaxis, have been used as therapeutic adjuvants in the preventive treatment of anaphylaxis, but cost-effectiveness should be considered individually.

Epidemiology and outcome of patients admitted to intensive care after anaphylaxis in France: a retrospective multicentre study.

BACKGROUND: Few data are available on patients who have experienced anaphylaxis and were admitted to ICUs. The purpose of this observational study was to describe the epidemiology and management of these patients. METHODS: This was a multicentre retrospective study carried out in 23 French ICUs between 2012 and 2017. All patients who suffered anaphylaxis and were transferred to an ICU were included. Data were collected using an electronic database after approval by an ethics committee. RESULTS: A total of 339 patients were included, and 17 (5%) died secondary to anaphylaxis. The main triggers were drugs (77%), contrast media (11%), and food (7%). Epinephrine was administered before ICU admission in 88% of patients with Grade III anaphylaxis and 100% of patients with Grade IV anaphylaxis. Most patients with Grades III and IV anaphylaxes did not receive the recommended dose of i.v. fluid of 30 ml kg-1 within the first 4 h of ICU admission. The time to epinephrine administration was not statistically different between survivors and non-survivors, but non-survivors received a higher dose of epinephrine (median: 5 [3-10] vs 3 [2-7] mg; P<0.0001), which suggests that some forms of anaphylactic shock may be resistant to epinephrine. In multivariate analysis, only lactate concentration at ICU admission was a predictor of death (odds ratio: 1.47 [1.15-1.88]; P=0.002). CONCLUSIONS: Lactate concentration at ICU admission appeared to be the most reliable criterion for assessing prognosis. Epinephrine is widely used during anaphylaxis, but the volume of fluid resuscitation was consistently lower than recommended. CLINICAL TRIAL REGISTRATION: NCT04290507.

Pregnancy and Hymenoptera venom allergy.

PURPOSE OF REVIEW: To evaluate the indication to perform venom immunotherapy (VIT) during pregnancy considering the risks of adverse events during the build-up phase or the maintenance phase and analyzing specific articles and guidelines on VIT. RECENT FINDINGS: Only few studies treat this argument and literature only counts one recent study on the topic, whereas recent guidelines state the behavior to keep in pregnancy. SUMMARY: Hymenoptera venom allergy (HVA) affects about 7.5% of the European population. VIT is the only effective disease-modifying treatment for patients presenting anaphylactic reactions. VIT counts several mechanisms of action, with the increase of IgG1 and IgG4 and a cytokine impairment inducing a Th2-Th1 shift. Pregnancy is a health condition where a Th2 profile is required to prevent fetal rejection, so VIT could be a problem for the fetus when started during pregnancy.

Anaphylaxis in an emergency department: a retrospective 10-year study in a tertiary hospital.

Summary: Background. Anaphylaxis is a potentially fatal medical emergency. The frequency of hospital admissions for anaphylaxis seems to be increasing in the recent decades. Objective. Characterize the patients admitted for anaphylaxis to the adult emergency department (ED) of a tertiary care hospital over a 10-year period, discriminating aetiologies, clinical features and therapy administered. Methods. Retrospective, descriptive and inferential study, evaluating age, sex, Manchester triage system, suspected allergen, site of allergen exposure, comorbidities, cofactors, clinical findings and symptoms, treatment and management. Patients admitted between January 2007 and December 2016 were included. Results. Forty-three patients were enrolled: 23 males, mean age 54.3 ± 16.2 years, n = 22 had history of allergic disease. Two patients were triaged as non-urgent. The most frequently suspected causes of anaphylaxis were: drugs (33%, n = 14), Hymenoptera venoms (23%, n = 10), foods (21%, n = 9) and iodinated contrast products (12%, n = 5). Adrenaline was used in 88% of the episodes (n = 38), 55% of which (n = 21) intramuscularly. Mortality was registered in one case. At discharge, adrenaline auto-injector was prescribed in 7% (n = 3) of the patients, and Allergy and Clinical Immunology consultation (ACIC) was requested in 65% of the episodes (n = 28). Statistically significant associations (p minor 0.05) were established: a, anaphylaxis to drugs associated with a low intramuscular adrenaline use and with frequent oxygen therapy; b, anaphylaxis to food associated with intramuscular adrenaline administration; c, anaphylaxis to Hymenoptera venom associated with male sex; and d, anaphylaxis to iodinated contrasts associated with referral to ACIC and with shock. All obese patients developed shock. Conclusions. Anaphylaxis is a life-threatening condition that requires early recognition. Although most patients received adrenaline, administration was not always performed by the recommended route and only a few patients were prescribed adrenaline auto-injector.

Antimicrobial anaphylaxis: the changing face of severe antimicrobial allergy.

OBJECTIVES: The epidemiology, clinical characteristics and outcomes of antimicrobial-associated anaphylaxis remain ill-defined. We sought to examine antimicrobial anaphylaxis with regard to: (i) the frequency of implicated antimicrobials; (ii) attributable mortality; and (iii) referral for definitive allergy assessment. METHODS: This was conducted through a national retrospective multicentre cohort study at five Australian tertiary hospitals (January 2010 to December 2015). Cases of antimicrobial anaphylaxis were identified from ICD-10 coding and adverse drug reaction committee databases. RESULTS: There were 293 participants meeting the case definition of antimicrobial anaphylaxis and 310 antimicrobial anaphylaxis episodes. Of 336 implicated antimicrobials, aminopenicillins (62/336, 18.5%) and aminocephalosporins (57/336, 17%) were implicated most frequently. ICU admission occurred in 43/310 (13.9%) episodes; however, attributable mortality was low (3/310, 1%). The rate of anaphylaxis to IV antibiotics was 3.5 (95% CI=2.9-4.3) per 100 000 DDDs and the rate of hospital-acquired anaphylaxis was 1.9 (95% CI=2.1-3.3) per 100 000 occupied bed-days. We observed overall low rates of hospital discharge documentation (222/310, 71.6%) and follow-up by specialist allergy services (73/310, 23.5%), which may compromise medication safety and antimicrobial prescribing in future. CONCLUSIONS: This study demonstrated that a high proportion of severe immediate hypersensitivity reactions presenting or acquired in Australian hospitals are secondary to aminopenicillins and aminocephalosporins. Overall rates of hospital-acquired anaphylaxis, predominantly secondary to cephalosporins, are low, and also associated with low inpatient mortality.

Anaphylaxis.

Anaphylaxis is a sudden onset, immediate reaction that implies a risk of death. Think of a "rule of 2s" for anaphylaxis, which implies that reactions usually begin within 2 minutes to 2 hours after injection, infusion, ingestion, contact, or inhalation. Fatalities can be from asphyxiation from laryngeal or oropharyngeal swelling, collapse from hypotensive shock, cardiac arrest, or acute severe bronchoconstriction that causes respiratory failure and arrest. When there is activation of mast cells and basophils in anaphylaxis, chemical mediators are detectable. The preformed mediators from mast cells include histamine, tryptase, carboxypeptidase A, and proteoglycans (heparin, chondroitin sulfates). Newly synthesized mediators include prostaglandin D2, leukotriene D4, and platelet activating factor. Crucial actions of the mediators include an abrupt increase in vascular permeability, vascular smooth muscle relaxation, and bronchial smooth muscle contraction. Anaphylaxis can be classified into immunologic, nonimmunologic, or idiopathic based on the associated mechanism. For example, immunologic causes of anaphylaxis are those mediated by immunoglobulin E (IgE) antibodies acting through the FcεR I (foods, insect venom, 32 ß-lactam antibiotics), whereas non-IgE immunologic anaphylaxis is mediated without the presence of anti-allergen IgE antibodies or via FcεRI activation (radiographic contrast material). Nonimmunologic anaphylaxis involves mast cell mediator release such as occurs with exercise or with cold temperature exposure, or from medications such as opioids or vancomycin. Idiopathic anaphylaxis involves mast cell activation (acutely elevated urine histamine or serum tryptase) and activated lymphocytes. Because anaphylaxis is a medical emergency, the drug of choice is epinephrine, not H1 antihistamines or H2 receptor antagonists.