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Epidemiology of life-threatening and lethal anaphylaxis: a review.

Severe anaphylaxis is a systemic reaction affecting two or more organs or systems and is due to the release of active mediators from mast cells and basophils. A four-grade classification routinely places 'severe' anaphylaxis in grades 3 and 4 (death could be graded as grade 5). Studies are underway to determine the prevalence of severe and lethal anaphylaxis in different populations and the relative frequencies of food, drug, latex and Hymenoptera anaphylaxis. These studies will also analyse the risk arising from the lack of preventive measures applied in schools (personalized management protocols) and from the insufficient use of self-injected adrenalin. Allergy-related conditions may account for 0.2-1% of emergency consultations. Severe anaphylaxis affects 1-3 per 10 000 people, but for the United States and Australia figures are even higher. It is estimated to cause death in 0.65-2% of patients, i.e. 1-3 per million people. An increased prevalence has been revealed by monitoring hospitalized populations by reference to the international classification of disease (ICD) codes. The relative frequency of aetiological factors of allergy (food, drugs, insects and latex) varies in different studies. Food, drug and Hymenoptera allergies are potentially lethal. The risk of food-mediated anaphylaxis can be assessed from the number of personalized management protocols in French schools: 0.065%. Another means of assessment may be the rate of adrenalin prescriptions. However, an overestimation of the anaphylaxis risk may result from this method (0.95% of Canadian children). Data from the literature leads to several possibilities. First, a definition of severe anaphylaxis should be agreed. Secondly, prospective, multicentre enquiries, using ICD codes, should be implemented. Moreover, the high number of anaphylaxis cases for which the aetiology is not identified, and the variation in aetiology in the published series, indicate that a closer cooperation between emergency specialists and allergists is essential.

Anaphylaxis↗

Acute systemic anaphylaxis in the calf.

1. Acute systemic anaphylaxis in calves was characterized by marked systemic hypotension; hypertension in the pulmonary arteries and abdominal vena cava, and transient apnoea. Calves responded with a second reaction to antigen, but a third anaphylactic response could not be evoked.2. Suppression of systemic anaphylaxis could not be effected with mepyramine, whereas methysergide or diethylcarbamazine each suppressed anaphylaxis by 50%. Disodium cromoglycate alone did not inhibit anaphylaxis: however, when disodium cromoglycate was combined with diethylcarbamazine almost total suppression (85%) was achieved. Sodium meclofenamate also was a powerful inhibitor of anaphylaxis (80%). It is tentatively suggested that slow reacting substance (SRS-A) may be an important mediator of bovine anaphylaxis.3. Bilateral vagotomy did not modify the circulatory responses to injected histamine, 5-hydroxytryptamine (5-HT) or antigen, whereas the effects of these agents on ventilation (apnoea) were abolished by vagotomy.4. Plasma histamine concentration was increased during anaphylaxis, whereas plasma 5-HT was not. Whole blood histamine concentration fell sharply and remained depressed during 20 min of anaphylactic shock. Reduced whole blood histamine levels probably reflect the severe leucopoenia in the calves.5. Histamine concentrations in six tissues taken from calves subjected to anaphylaxis were not different from those in control calves; mast cells were of similar numbers to controls, but showed some swelling, granular spilling and metachromasia.6. Histamine, 5-HT, bradykinin and antigen caused increased pulmonary artery perfusion pressure and ventilation resistance in isolated lungs from sensitized calves. However, there was no difference in histamine and 5-HT concentration in perfusates obtained during antigen infusion of sensitized and control lungs.7. Systemic anaphylaxis of calves may result from the interaction of histamine, 5-HT and SRS-A. The present data implicate (by indirect measurement) SRS-A as an important mediator of anaphylaxis in this species.

Anaphylaxis↗

Paediatric emergency department anaphylaxis: different patterns from adults.

BACKGROUND AND AIMS: Data on acute paediatric anaphylaxis presentations to the emergency department (ED) are limited. All allergic presentations to one Australian paediatric ED were studied to determine epidemiological, clinical, and outcome data. METHODS: Retrospective, case based study of patients under 16 years attending one metropolitan, paediatric teaching hospital ED in Australia over three years. The medical records of patients presenting with generalised allergic reactions and anaphylaxis satisfying relevant ICD-9-CM diagnostic codes were studied. The incidence, age, sex ratio, co-morbidities, likely aetiology, clinical features, management, and disposal were determined. RESULTS: A total of 526 children with generalised allergic reactions, and 57 with anaphylaxis were included in the study. This represented incidences of 9.3:1000 ED presentations for generalised allergic reactions and 1:1000 for anaphylaxis. There were no fatalities. In anaphylaxis cases, a cause was recognised in 68.4%. Cutaneous features were present in 82.5%. A past history of asthma was reported in 36.8%. Adrenaline was used in 39.3% of severe anaphylaxis cases. The ED alone definitively cared for 97.8% of all patients. Follow up was inadequate in cases of anaphylaxis. CONCLUSIONS: This is the first reported incidence figure for paediatric anaphylaxis ED presentations in Australia, and is less than that reported in adults in the same local population. However, the incidence of generalised allergic reactions of 9.3:1000 was greater than in the adults. Virtually all paediatric allergic cases may be managed in the ED alone, provided that the importance of specialist follow up, particularly for severe anaphylaxis, is recognised.

Adolescent↗

A pediatric case of anaphylaxis caused by matsutake mushroom (Tricholoma matsutake) ingestion.

BACKGROUND: Anaphylaxis is one of the severest forms of allergic diseases. Some kinds of mushroom are known as causative allergens in food anaphylaxis. Matsutake mushroom (Tricholoma matsutake) is a typical edible mushroom available in autumn in Japan. We encountered an 8-year-old Japanese girl who developed anaphylaxis after ingesting matsutake mushrooms. METHODS: We studied the case in detail, by measuring specific IgE antibodies and conducting skin tests, to confirm the diagnosis. We also detected seven cytokines and chemical mediators in the blood in order to study the pathophysiology of the anaphylaxis. RESULTS: We diagnosed anaphylaxis caused by ingestion of matsutake mushrooms based on the following. A skin prick test showed a positive reaction to matsutake mushroom, and specific IgE antibody for matsutake mushroom extract was detected in the patient's serum by fluorometric ELISA. Blood levels of chemical mediators including histamine, ECP, tryptase and cytokines such as IL-6, IL-5 and IL-10 but not IFN-gamma also increased significantly during the allergic episode. CONCLUSIONS: We demonstrated that chemical mediators including histamine, tryptase and ECP as well as several cytokines were involved significantly during the episode of anaphylaxis. In addition, eosinophils as well as mast cells played significant roles in the anaphylaxis. Furthermore, CD4+CD25+ T regulatory cells that released IL-10 were likely activated during the anaphylaxis. Matsutake mushroom should be considered as a causative allergen in food anaphylaxis.

Adrenergic Agonists↗

Anaphylaxis, killer allergy: long-term management in the community.

Traditionally, physicians are trained to diagnose and treat anaphylaxis as an acute emergency in a health care setting. In addition to this crucial and time-honored role, we should be cognizant of our wider responsibility to (1) provide a risk assessment for individuals with anaphylaxis, (2) prevent future anaphylaxis episodes by developing long-term personalized risk reduction strategies for affected individuals, and (3) emphasize anaphylaxis education. Risk assessment should include verification of the trigger factor or factors for the anaphylaxis episode by obtaining a comprehensive history and performing relevant investigations, including allergen skin tests and measurement of allergen-specific IgE in serum. In addition, the potential effect of comorbidities and concurrently administered medications on the recognition and emergency treatment of subsequent episodes should be determined. Risk reduction strategies should be personalized to include information about avoidance of specific triggers and initiation of relevant specific preventive treatment (eg, venom immunotherapy). At-risk individuals should be coached in the use of self-injectable epinephrine and equipped with an anaphylaxis emergency action plan and with accurate medical identification. Anaphylaxis education should be provided for these individuals, their families and caregivers, health care professionals, and the general public. Further development of an optimal diagnostic test for anaphylaxis and of tests and algorithms to predict future risk and prevent fatality are urgently needed.

Anaphylaxis↗

Assessment of patients who have experienced anaphylaxis: a 3-year survey.

DESIGN: A quality-control retrospective review of medical records was conducted for cases of anaphylaxis encountered at Mayo Clinic Rochester during a 3 1/2-year period. PATIENTS: For inclusion in the study, all patients had to manifest general symptoms of mediator release such as generalized pruritus, urticaria, angioedema, and flushing. Of the 179 patients with anaphylaxis (mean age, 36 years), 66% were female, 49% had atopy, and 37% had a previous history of immediate reactions to allergens. Of these study patients, 11 were receiving medications capable of exacerbating anaphylaxis (beta-blockers in 7 of them). RESULTS: Consultation with an allergist was obtained in 142 cases, and a probable diagnosis was made after review of the medical records. Causes of anaphylaxis included foods in 59 patients, idiopathic in 34, Hymenoptera in 25, medications in 23, and exercise in 12; false-positive diagnoses were recorded in 18. Allergy prick tests were done in 104 patients, 71 of whom had positive results; allergen-specific IgE tests were done in 44 patients, 23 of whom had positive results. In 19 patients, only allergen-specific IgE testing was done, and results were positive in 12. Normal test results included C1 esterase inhibitor in 33 patients, metabisulfite challenge in 15, and dye or preservative challenge in 10. Food skin tests were graded on a relative value scale and revealed 15 highly allergic, 24 moderately allergic, and 39 weakly allergic food groups. CONCLUSION: A standard protocol should be used for assessment of patients with anaphylaxis, and fresh food extracts should be used for prick skin testing. A national incidence study of anaphylaxis is needed. The public and school personnel should be educated about food anaphylaxis, and emergency treatment for anaphylaxis should be readily available for patients.

Adolescent↗

A fatality from idiopathic anaphylaxis.

BACKGROUND: Idiopathic anaphylaxis by definition is a form of anaphylaxis where no identifiable stimulus can be found. In our series of over 350 patients with idiopathic anaphylaxis there have been no reported deaths. OBJECTIVE: To report the clinical course of the first fatality in our series from idiopathic anaphylaxis. METHODS: A patient was evaluated for idiopathic anaphylaxis and started on our previously published protocol of corticosteroids, sympathomimetics, and antihistamines. RESULTS: Despite following our protocol--which has been effective in decreasing the number of emergency room visits, hospitalizations, and intensive care unit admissions--controlling the disease, and placing a high percentage of patients into remission, the patient with idiopathic anaphylaxis died unexpectedly after experiencing symptoms similar to previous episodes of idiopathic anaphylaxis. CONCLUSION: This is the first reported fatality from idiopathic anaphylaxis in our extensive series.

Adult↗

Idiopathic anaphylaxis in children.

BACKGROUND: Idiopathic anaphylaxis is a disease where no identifiable antigen or disease initiates an anaphylactoid reaction. Unlike classic IgE antibody-mediated anaphylaxis, severe idiopathic anaphylaxis is treatable with corticosteroids. To date, only 22 pediatric cases from one referral center have been reported. OBJECTIVE: To describe the characteristics of children with idiopathic anaphylaxis METHODS: A retrospective review of medical records for children presenting to the pediatric allergy clinic with the diagnosis of idiopathic anaphylaxis was performed. RESULTS: The review identified eight children with idiopathic anaphylaxis. All eight patients had a cutaneous finding of either urticaria, angioedema, or generalized flushing. Six of the eight patients were noted to have wheezing or angioedema of the airway causing respiratory difficulties. Diarrhea was noted among six patients. Many of the children clearly had life threatening events. Response to appropriate therapy was generally good. CONCLUSIONS: Pediatric idiopathic anaphylaxis can present at any age. It may be that many pediatric cases are assumed to be anaphylaxis due to some unknown antigen, and the correct diagnosis is never appreciated. It is important to recognize this disease in children so that it may be appropriately treated, because its specific therapeutic regimen has been shown to prevent the potentially fatal consequences of this disease.

Adolescent↗

Exercise-induced anaphylaxis: useful screening of food sensitization.

BACKGROUND AND OBJECTIVES: Exercise-induced anaphylaxis is a well-defined entity as described by Sheffer and Austen. Exercise-induced anaphylaxis can be associated with ingestion of a specific food. We report our experience with a series of cases of exercise-induced anaphylaxis in which anaphylaxis was considered to be associated with food allergy. METHODS: We observed 19 patients in whom severe systemic signs of anaphylaxis occurred during or immediately after exercise, while the severity of reactions excluded challenge testing. The causal relationship with various foods was systematically investigated in all cases, even in the absence of any history of allergy. RESULTS: Sensitization to wheat flour was demonstrated in 12 patients, to peanut in seven, and to tree nuts in six cases with skin tests and/or RAST. Sensitivity to various other foods was found less often. Further, avoidance of specific foods according to results of skin tests and RAST was systematically observed during the five hours prior to exercise and no symptom occurred, suggesting a role of specific food intake in the pathogenesis of exercise-induced anaphylaxis. With such elimination diets, most of these young patients were able to engage in regular vigorous exercises (more than twice a week in some cases) without any clinical manifestation with a median followup of 2 years. In two patients, however, recurrence of exercise-induced anaphylaxis was subsequently explained by concomitant ingestion of other foods such as rice and peanut. Additional avoidance of these foods before exercise was then effective in 14 cases (median follow up: 2 years). CONCLUSIONS: Investigations to detect food sensitization, in particular to wheat, peanut and/or tree nuts, and specific avoidance of these foods five hours before exercise appear essential in cases of exercise-induced anaphylaxis.

Adolescent↗

First aid anaphylaxis management in children who were prescribed an epinephrine autoinjector device (EpiPen).

BACKGROUND: Epinephrine for first aid use by parents and other caregivers and in the form of an autoinjector device (EpiPen, Center Laboratories) is often prescribed for children who have had previous anaphylactic reactions. It is not known whether the EpiPen device is used appropriately during subsequent reactions and whether its use is able to prevent the complications of anaphylaxis. OBJECTIVE: Our purpose was to determine parental knowledge and practice concerning first aid anaphylaxis management, the frequency of recurrent generalized allergic reactions, the first aid measures taken, and the subsequent outcome of these reactions. METHODS: A retrospective survey was performed with a telephone questionnaire of all children with a history of anaphylaxis who attended a specialist allergy service and were prescribed an EpiPen autoinjector device. RESULTS: Recurrent generalized allergic reactions occurred with a frequency of 0.98 episodes per patient per year and were more common in those with food compared with insect venom anaphylaxis. The EpiPen device was only used in 29% of recurrent anaphylactic reactions. Parental knowledge was deficient in recognition of the symptoms of anaphylaxis and use of the EpiPen device, and adequate first aid measures were not in place for the majority of children attending school. Those children in whom the EpiPen device was used were less likely to be given epinephrine in hospital and to require subsequent hospital admission. CONCLUSION: The EpiPen autoinjector device is infrequently used in children with recurrent episodes of anaphylaxis; the reasons for this require further research. It is likely that parents and other caregivers will require continuing education and support in first aid anaphylaxis management. When the EpiPen device is used appropriately, it appears to reduce subsequent morbidity from anaphylaxis.

Adolescent↗

Incidence of anaphylaxis with circulatory symptoms: a study over a 3-year period comprising 940,000 inhabitants of the Swiss Canton Bern.

BACKGROUND: Diagnosis of anaphylaxis is clinically based and usually straightforward. However, data on the epidemiology of anaphylaxis, particularly the most profound and life-threatening form such as anaphylactic shock are limited and thought to be under-reported. OBJECTIVE: The primary aim of this study was to investigate the incidence and the causes of severe anaphylaxis with circulatory signs in the Canton Bern, which comprises about 940 000 inhabitants or approximately one-seventh of the population of Switzerland. METHODS: During a 3-year period, 1 January 1996 to 31 December 1998, all medical records (7739 documents) from the two allergy clinics of the Canton Bern have been reviewed. In addition, all seven board-certified specialists of the Foederatio Medicorum Helveticorum (FMH) in Allergology and Clinical Immunology of this Canton as well as all 17 hospitals with emergency units of this area have been contacted for cases with an anaphylactic event not referred to the allergy clinics. RESULTS: Overall, 226 individuals, 106 females (47%) with a mean age of 41 years (range, 5-74 years) and 120 males (53%) with a mean age of 38 years (8 months-83 years) were diagnosed as having presented generalized, life-threatening anaphylaxis with circulatory symptoms. Altogether, these patients experienced 246 episodes of severe systemic reactions. In addition, death due to anaphylaxis occurred in three subjects. The annual incidence of anaphylaxis per 100 000 inhabitants per year ranged between 7.9 and 9.6 cases. Hymenoptera stings (58.8%), drugs (18.1%), and foods (10.1%) were the most commonly identified culprits for anaphylaxis. In 5.3% of all anaphylactic events, the cause could not be identified. CONCLUSION: The incidence rate of severe life-threatening anaphylaxis with circulatory signs in the Canton Bern, Switzerland, with 7.9-9.6 per 100 000 inhabitants per year is comparable to the findings of other epidemiological investigations. In most events, a causal agent or allergen could be identified by a careful allergological examination.

Adolescent↗

Passive paw anaphylaxis in the rat. Optimum conditions for use in studies on immediate hypersensitivity.

The difficulties involved in quantitating passive cutaneous anaphylaxis led us to examine the rat paw as a site for passive anaphylaxis and to define optimum conditions for passive paw anaphylaxis. Generation of homocytotropic antibodies in a number of different rat strains revealed that female Brown Norway rats were excellent producers of high titre antisera after only a single injection of antigen and Bordetella pertussis. Injection of ratpaws with diluted antisera followed by short (1-2 h) or long (72 h or more) sensitization periods showed that maximum paw swelling occurred 15 min after antigen challenge. Retention of tissue sensitizing capacity in the paw for greater than 35 days but loss of this capacity following heating of antiserum at 56 degrees C, indicated that the rat homocytotropic antibodies involved in passive paw anaphylaxis belong to the IgE class. Experiments using mepyramine, methysergide and diethylcarbamazine showed that 5-hydroxytryptamine is the most important mediator of passive paw anaphylaxis after both a short (2 h) and a long (72 h) sensitization procedure. Passive paw anaphylaxis in the rat is at least as easy to perform as passive cutaneous anaphylaxis, results can be obtained more rapidly and accurate measurement of paw thickness is not difficult. The procedure is a viable alternative to passive cutaneous anaphylaxis and may offer advantages over the latter method especially in the search for, and rapid assessment of, anti-allergic compounds.

Animals↗

IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking.

Although it has long been hypothesized that allergen immunotherapy inhibits allergy, in part, by inducing production of IgG Abs that intercept allergens before they can cross-link mast cell Fc epsilonRI-associated IgE, this blocking Ab hypothesis has never been tested in vivo. In addition, evidence that IgG-allergen interactions can induce anaphylaxis by activating macrophages through Fc gammaRIII suggested that IgG Ab might not be able to inhibit IgE-mediated anaphylaxis without inducing anaphylaxis through this alternative pathway. We have studied active and passive immunization models in mice to approach these issues and to determine whether any inhibition of anaphylaxis observed was a direct effect of allergen neutralization by IgG Ab or an indirect effect of cross-linking of Fc epsilonRI to the inhibitory IgG receptor Fc gammaRIIb. We demonstrate that IgG Ab produced during the course of an immune response or administered passively can completely suppress IgE-mediated anaphylaxis; that these IgG blocking Abs inhibit IgE-mediated anaphylaxis without inducing Fc gammaRIII-mediated anaphylaxis only when IgG Ab concentration is high and challenge allergen dose is low; that allergen epitope density correlates inversely with the allergen dose required to induce both IgE- and Fc gammaRIII-mediated anaphylaxis; and that both allergen interception and Fc gammaRIIb-dependent inhibition contribute to in vivo blocking Ab activity.

Anaphylaxis↗

Preventing and managing drug-induced anaphylaxis.

Drug-induced anaphylaxis and anaphylactoid reactions have increased in frequency with more widespread use of pharmaceutical agents. Anaphylaxis is a systemic, severe immediate hypersensitivity reaction caused by immunoglobulin (Ig) E-mediated immunological release of mediators of mast cells and basophils. An anaphylactoid reaction is an event similar to anaphylaxis but is not mediated by IgE. The incidence of anaphylactic or anaphylactoid reactions differs amongst classes of medications. Antibacterials are the most usual offenders, and penicillins are the most studied. Other compounds commonly causing reactions include non-steroidal anti-inflammatory drugs, anaesthetics, muscle relaxants, latex and radiocontrast media. Prevention, if possible, is the purpose of detailed patient history taking and physical examination. Simple strategies can be employed to decrease the risk of anaphylaxis. These include consideration of the route of drug administration, identification of patients with known causes of anaphylaxis, and the knowledge that certain medications cross react and are contraindicated in those with known history of anaphylaxis. Tests are available, and include IgE-specific skin tests and radioallergosorbent tests. Penicillins are the only compounds whose antigenic determinants are well documented, it is therefore difficult to determine the negative predictive value of other compounds tested. Oral challenge remains an alternative, though entails risk. Desensitisation procedures, as well as gradual dose escalation protocols, are available and can be implemented based on patient history and diagnostic testing. The management of anaphylaxis is based on control of the airway, breathing and circulation. Treatment consists of epinephrine (adrenaline) and supportive measures. Rapid diagnosis and intervention are important in these life-threatening reactions. After stabilisation, all individuals with a documented history of anaphylaxis require a Medic-Alert bracelet or necklace, and an identification card for their wallet or purse.

Adverse Drug Reaction Reporting Systems↗

Current review of anaphylaxis and its relationship to asthma.

Anaphylaxis is the most dramatic of hypersensitivity reactions with a two-fold relationship with asthma, in the immediate and late phases and drugs and immunotherapy may be triggers. There are many causes of anaphylaxis, with IgE-mediated reactions, especially those to some foods very common. Drug reactions are next most common, especially to beta-lactam antibiotics, sulphonamides, Dilantin and aspirin. Exercise-induced anaphylaxis is well documented and may be exacerbated by food. Careful examination of the etiology of anaphylaxis is essential. Anaphylaxis may occur during immunotherapy and skin testing and every physician who uses these techniques must have available for immediate use appropriate remedial measures. In a study of 25 patients three distinct clinical patterns were seen, uniphasic, biphasic and protected degree of anaphylaxis. Latex is now known to be responsible for immediate anaphylaxis, as well as Type IV and is found in a variety of clinical situations, including surgery. The world-wide AIDS epidemic has caused much greater use of latex with a concomitant rise in risk of anaphylaxis.

Adrenergic beta-Antagonists↗

Idiopathic anaphylaxis: long-term follow-up, cost, and outlook.

To determine the efficacy of oral corticosteroids, antihistamines, and sympathomimetics in treating patients with idiopathic anaphylaxis, the charts of 225 patients diagnosed with idiopathic anaphylaxis from 1971 to 1990 treated at a single center were reviewed. Sixty-one patients (34 females and 27 males) were available for long-term follow-up. Ages ranged from 10 to 68 years with an average of 39 years. Patients with frequent episodes were treated with a protocol of oral corticosteroids, antihistamines, and sympathomimetics. Patients with infrequent episodes were treated for acute episodes only. The number of emergency room visits, hospitalizations, intensive care unit admissions, and length of time in remission were recorded. Sixty-five percent of patients with infrequent episodes and 91% of patients with frequent episodes of idiopathic anaphylaxis went into remission. Significant decreases in emergency room visits occurred for the idiopathic anaphylaxis-generalized-frequent group (P < 0.016), the idiopathic-anaphylaxis-generalized-infrequent group (P < 0.0001), and the idiopathic anaphylaxis-angioedema-infrequent group (P < 0.039). Significant decreases in the number of hospitalizations (P < 0.022) and intensive care unit admissions (P < 0.009) occurred for the idiopathic anaphylaxis-generalized-infrequent and frequent groups, respectively. Overall, an estimated $184 740 was saved with the treatment program, for 546 patient-years. Idiopathic anaphylaxis can be controlled and remission induced in most patients. An estimated $11 million per year can be saved for patients in the USA on the basis of the estimated prevalence in this country.

Adolescent↗

Idiopathic anaphylaxis.

Anaphylaxis represents the maximal variant of an immediate-type allergic reaction involving the whole organism with manifestations in different organ systems. IgE-mediated mast cell and basophil activation is the major pathomechanism; however, immune complex and pseudo-allergic reactions also may lead to the same symptomatology. The most common elicitors are drugs, additives, occupational substances, animal venoms, aeroallergens, and contact urticariogens but also physical factors (cold, heat, ultraviolet light, exercise). When no eliciting factors can be detected, the term "idiopathic anaphylaxis" is used. The diagnosis of idiopathic anaphylaxis is, therefore, a diagnosis of exclusion and may be made only after careful allergy history taking and diagnosis involving in vitro tests. Possible mechanisms underlying the pathophysiology of idiopathic anaphylaxis include undetected diseases (eg, mastocytosis occulta), concomitant anaphylaxis-enhancing medication (b-blockers), secretion of histamine-releasing factor from T lymphocytes, autoantibodies against IgE or IgE receptors, and angiotensin II deficiency. One of the many differential diagnoses of anaphylaxis may have been overlooked. The treatment of idiopathic anaphylaxis follows the rules of antianaphylactic therapy.

Anaphylaxis↗

Preventing peptide-induced anaphylaxis: addition of C-terminal amino acids to produce a neutral isoelectric point.

BACKGROUND: Progress in peptide immunotherapy for the treatment of autoimmune diseases has been hampered by reports of anaphylactic reactions in both mice and human subjects. Fatal anaphylaxis in nonobese diabetic (NOD) mice has been described after repeated subcutaneous insulin peptide B:9-23 immunizations. On the basis of observations that rapid systemic delivery of peptide to a sensitized mouse (eg, intravenous delivery) increases the anaphylactic response, it was hypothesized that slowing down the absorption of the peptide would prevent anaphylaxis. OBJECTIVES: We sought to prevent anaphylaxis from B:9-23 peptide by altering the isoelectric point (pI) to neutral, thereby decreasing solubility and rate of absorption after subcutaneous injection. METHODS: B:9-23 peptide was modified by the addition of 2 arginine (RR) amino acids to the C-terminus to create B:9-23RR, thereby increasing the pI from 5.4 to 7.0. Both native and modified B:9-23 peptide were tested for the ability to induce anaphylaxis in a NOD mouse model of self-peptide anaphylaxis. RESULTS: This modification resulted in a peptide vaccine with decreased solubility when administered subcutaneously at a neutral pH. B:9-23RR significantly protected NOD mice from peptide-induced anaphylaxis compared with B:9-23 peptide. Furthermore, B:9-23RR peptide retains its ability to induce insulin autoantibodies and prevent diabetes in NOD mice. CONCLUSION: The modification of the pI of a peptide vaccine might be a generalizable method to prevent anaphylaxis without changing the immunologic properties.

Amino Acid Sequence↗