Systemic Anaphylactic Reactions Research Articles

Toxicology of protein allergenicity: prediction and characterization.

The ability of exogenous proteins to cause respiratory and gastrointestinal allergy, and sometimes systemic anaphylactic reactions, is well known. What is not clear however, are the properties that confer on proteins the ability to induce allergic sensitization. With an expansion in the use of enzymes for industrial applications and consumer products, and a substantial and growing investment in the development of transgenic crop plants that express novel proteins introduced from other sources, the issue of protein allergenicity has assumed considerable toxicological significance. There is a need now for methods that will allow the accurate identification and characterization of potential protein allergens and for estimation of relative potency as a first step towards risk assessment. To address some of these issues, and to review progress that has been made in the toxicological investigation of respiratory and gastrointestinal allergy induced by proteins, a workshop, entitled the Toxicology of Protein Allergenicity: Prediction and Characterization, was convened at the 37th Annual Conference of the Society of Toxicology in Seattle, Washington (1998). The subject of protein allergenicity is considered here in the context of presentations made at that workshop.

MAGNOLIAE FLOS INHIBITS MAST CELL-DEPENDENT IMMEDIATE-TYPE ALLERGIC REACTIONS

The mast cell plays a pivotal role in initiating allergic response by secreting intracytoplasmic granular mediators such as histamine. Magnoliae flos has been used for the treatment of allergic disease in Korea. However, its effect in experimental models remains unknown. The present report describes an inhibitory effect of Magnoliae flos on mast cell-mediated immediate-type allergic reactions. Topical application of compound 48/80 can induce an ear swelling response in normal (WBB6F1-+/+) mice but not in the congenic mast cell-deficient WBB6F1-W/Wvmice. Magnoliae flos inhibited concentration-dependently mast cell-dependent ear swelling response induced by compound 48/80 by topical application. Magnoliae flos inhibited concentration-dependently passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) IgE in rats by topical application. Magnoliae flos also inhibited concentration-dependently the histamine release from the rat peritoneal mast cells by compound 48/80 or anti-DNP IgE. Moreover, Magnoliae flos had a significant inhibitory effect on compound 48/80-induced systemic anaphylactic reaction. These results indicate that Magnoliae flos inhibits immediate-type allergic reactions by inhibition of mast cell degranulationin vivoandin vitro.

Shini-san inhibits mast cell-dependent immediate-type allergic reactions.

Shini-San has been used for treatment of allergic disease in Korea. However, its effect in experimental models remains unknown. The mast cell plays a pivotal role in initiating allergic response by secreting intracytoplasmic granular mediators such as histamine. The present report describes an inhibitory effect of Shini-San on mast cell-mediated immediate-type allergic reactions. Topical application of compound 48/80 can induce an ear swelling response in normal (WBB6F1(-)+/+) mice but not in congenic mast cell-deficient WBB6F1-W/WV mice. Shini-San inhibited concentration-dependent mast cell-dependent ear swelling response induced by compound 48/80 in normal mice. Shini-San inhibited concentration-dependent passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) immunoglobulin E (IgE) in rats by topical application. Shini-San also inhibited in concentration-dependent fashion the histamine release from the rat peritoneal mast cells by compound 48/80 or anti-DNP IgE. Moreover, Shini-San had a significant inhibitory effect on compound 48/80-induced systemic anaphylactic reaction. These results indicate that Shini-San inhibits immediate type allergic reactions by inhibition of mast cell degranulation in vivo and in vitro.

Effect of Kumhwang-San on Anaphylactic Reaction in a Murine Model

We investigated the effect of Kumhwang-San on anaphylactic reaction. Kumhwang-San dose-dependently inhibited mast cell-mediated systemic anaphylactic reaction induced by compound 48/80. Kumhwang-San significantly inhibited plasma histamine levels induced by compound 48/80. Kumhwang-San dose-dependently inhibited histamine release from the rat peritoneal mast cells activated by compound 48/80 or substance P. The level of cAMP in rat peritoneal mast cells, when Kumhwang-San was added, transiently and significantly increased about 3-fold compared with that of basal cells. These results suggest that Kumhwang-San will be beneficial in the treatment of anaphylactic reaction.This study was supported by Non-directed research fund, Korea Research Foundation, 1996–1998 and Partially by Wonkwang University in 1998

Delineation of PLA2 epitopes using short or long overlapping synthetic peptides: interest for specific immunotherapy.

Venom immunotherapy is definitely indicated in severe systemic anaphylactic reactions to bee stings, but is not devoided of risks of anaphylaxis. Safer methods of immunotherapy need to be developed. To delineate phospholipase A2 T-cell epitopes using short 15mer vs long 40-60mer overlapping peptides, and to approach the potential interest of a venom immunotherapy based on the use of long peptides (1-60, 51-99, 90-134) mapping the whole phospholipase A2 molecule vs a restricted number of immunodominant epitopes. Proliferation of a CD8+ T cell depleted peripheral blood mononuclear cell fraction and short-term T-cell lines from unselected bee venom hypersensitive patients in response to phospholipase A2 synthetic peptides. Whereas T-cell proliferation to 15mer overlapping peptides was weak, T-cell response to long overlapping peptides was in contrast vigorous in all patients, mostly directed to C-terminal peptide 90-134. Our results did not support the concept of rare dominant T-cell epitopes, and disclosed T-cell responses to multiple epitopes in several patients. No significant IgE-binding to long overlapping peptides was detected except in one patient against peptide 90-134. 15mer peptides might not be sensitive enough to fully delineate all potential T-cell epitopes scattered along the allergen. Since they do not bind IgE in vitro or only weakly, and taking into account a T-cell response frequently directed to multiple epitopes, long overlapping peptides may represent ideal tools for immunotherapy.

Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy.

The clinical relevance of gastrointestinal food allergy in adults is largely unknown because the mechanisms are poorly understood and the diagnosis is difficult to confirm. To improve the diagnostic means for confirming intestinal food allergy on an objective basis, a new colonoscopic allergen provocation (COLAP) test was developed. The COLAP test was performed in 70 adult patients with abdominal symptoms suspected to be related to food allergy, and in five healthy volunteers. During the COLAP test, the caecal mucosa was challenged endoscopically with three food antigen extracts, a buffer control, and a positive control (histamine). The mucosal weal and flare reaction was registered semiquantitatively 20 minutes after challenge, and tissue biopsy specimens were examined for mast cell and eosinophil activation. No severe systemic anaphylactic reactions were found in response to intestinal challenge. The COLAP test was positive to at least one food antigen in 54 of 70 patients (77%), whereas no reaction in response to antigen was found in healthy volunteers. Antigen induced weal and flare reactions were correlated with intestinal mast cell and eosinophil activation, as well as with patients' history of adverse reactions to food, but not with serum concentrations of total or specific IgE or skin test results. The COLAP test may be a useful diagnostic measure in patients with suspected intestinal food allergy and may provide a new tool for the study of underlying mechanisms.

Anaphylaxis after ingestion of wheat flour contaminated with mites

Background: Anaphylaxis after ingestion of flours contaminated with mites has been recently reported. Objective: The study was designed to determine whether flour-induced reactions in the absence of food sensitivity may result from mite contamination. Methods: Patients with systemic reactions after ingestion of foods containing wheat flour and without food sensitivities were included in a prospective study. The flours were examined microscopically, and major Dermatophagoides allergens were quantified by monoclonal antibody techniques. Skin prick tests and IgE determinations to mites and flours were performed. Single-blind, placebo-controlled oral challenges were also performed. Results: Sixteen patients were included in our protocol. They showed respiratory allergies to dust mites (100%) and intolerance to acetylsalicylic acid (87%). Microscopic examination of four flours implicated in allergic reactions revealed a high degree of mite contamination: Dermatophagoides farinae in one case and Thyreophagus entomophagus in three cases. Our patients' skin test and specific IgE responses to the flours implicated in the reactions were positive. A high level of Der 2 was found in the flour infested by D. farinae. Three of six food challenges with contaminated flours resulted in systemic reactions. Good tolerance to control flours was shown in our patients. Conclusion: Ingestion of foods contaminated with mites may induce systemic anaphylactic reactions in patients with respiratory allergy to mites. (J Allergy Clin Immunol 1997;99:308-13.)

Systemic Anaphylaxis to a Hidden Cross Reactive Food in a Surgical Resident With Latex Hypersensitivity

Background Health-care professionals are at an increased risk for severe latex hypersensitive reactions. Hidden cross-reactive foods can trigger systemic anaphylaxis. It is well recognized that latex-allergic individuals may also be allergic to certain foods due to crossreactive antigens. Objective: We describe a case of a 30-year-old surgical resident who developed a systemic anaphylactic reaction after ingesting snack crackers kept in close proximity to a bowl of guacamole. Results: The patient, who was highly sensitive to latex, was cautioned to avoid cross-reactive foods and to carry epipen and diphenhydramine with him at all times. Progressive anaphylaxis developed in spite of self-administration of epinephrine and prior counseling to avoid latex products, bananas, walnuts, avocados, and chestnuts. Conclusion: This case illustrates the severity of cross-reactive immunoglobulin E mediated food hypersensitivity in health-care workers who are strongly allergic to latex protein.

Risk management in allergen immunotherapy

The major risk of allergen immunotherapy is the development of systemic anaphylactic reactions. The reported frequency of systemic reactions after allergen immunotherapy varies from <1% in patients receiving conventional immunotherapy to >36% in patients receiving rush immunotherapy. Fatal and systemic reactions to allergen immunotherapy have similar characteristics. The onset of both types of reaction occurs <30 minutes after injection in approximately 70% of patients. The most common risk factors for fatal and systemic reactions to allergen immunotherapy include a history of asthma, increasing allergen dose, high allergen sensitivity, previous systemic reaction, and injection during an active allergen season. On the basis of findings from several studies, precautions during allergen immunotherapy have been recommended. In addition, several interventions, including premedication with antihistamines or corticosteroids, measurement of peak flow before injection, and access to an antihistamine or injectable epinephrine after an allergen injection, have been suggested as measures to prevent reactions to and improve the safety of allergen immunotherapy. However, additional studies are necessary before these regimens are implemented routinely in allergen immunotherapy protocols. (J Allergy Clin Immunol 1996;98:S330-4)

Protective effects of Yangambin — a naturally occurring platelet-activating factor (PAF) receptor antagonist — on anaphylactic shock in rats

The purpose of this study was to investigate the ability of yangambin to inhibit cardiovascular collapse and to reduce the mortality due to systemic anaphylaxis induced by antigen challenge in actively sensitized rats. The i.v. injection of the antigen (ovalbumin, 250 or 500 μg/kg), induced a systemic anaphylactic reaction mainly characterized by sudden and marked arterial hypotension and high mortality rates. Yangambin, a PAF receptor antagonist isolated from the Brazilian plant Ocotea duckei Vattimo (Lauraceae), as well as the reference PAF receptor antagonist SR 27417, significantly prevented and partially reversed the circulatory collapse elicited by antigen challenge. Moreover, yangambin and SR 27417, when administered 5 min before re-exposure of the animals to the antigen, markedly improved the survival rate at 120 min. These results confirm that PAF plays an important role in the pathophysiology of anaphylactic shock and show that yangambin presents good therapeutic potential in the treatment of the cardiovascular alterations observed during immediate hypersensitivity reactions.

IgE antibodies to Hymenoptera venoms in the serum are common in the general population and are related to indications of atopy

Determination of Hymenoptera venom (HV)-specific serum IgE antibodies is a useful diagnostic method in patients with systemic anaphylactic reaction (SAR) to Hymenoptera stings. In a general population cohort, we determined the prevalence of SAR and HV-specific IgE antibodies and assessed parameters associated with the latter. A total of 277 voluntarily participating inhabitants of rural Bavaria (Germany) (232 adults, mean age 38.0 years; 45 children, mean age 8.4 years) were investigated for a history of atopic disease or SAR to insect stings; in 258 of these, total IgE and specific IgE antibodies to HV (Apis mellifera, Vespula vulgaris/germanica) and four common aeroallergens (birch pollen, grass pollen, house-dust mite, and cat dander) in the serum were determined. Nine (3.3%) subjects reported SAR to insect stings. In 27.1% of the sera, specific IgE antibodies to HV were found, to bee venom in 24.8%, and to wasp venom in 8.5% (P < 0.0001). Of those exhibiting HV-specific IgE, 7.1% reported SAR to insect stings. A personal history of atopic disease (hay fever, asthma, or atopic eczema) was present in 16.7%, specific IgE to common aeroallergens was found in 32.6%, and total IgE > 100 kU/l was found in 22.5%. Specific serum IgE to HV was significantly associated with male sex (female vs. male, OR = 0.47; CI 0.25-0.86), young age (children vs. adults, OR = 2.80; CI 1.25-6.28), a history of SAR to insect stings (OR = 4.16; CI 1.15-15.03), total sIgE > 100 kU/l (OR = 3.88; CI 1.98-7.60), and specific IgE antibodies to three of the four aeroallergens (grass pollen, OR = 7.24 CI 3.66-14.38; birch pollen, OR = 3.67 CI 1.54-8.81; and house-dust mite, OR = 4.61 CI 2.08-10.32). It is concluded that immunologic sensitization to HV is common in the general population and is associated with atopy-related humoral IgE hyperresponsiveness.

Anaphylactic reaction to local administration of rifamycin SV

Background and objective: Systemic reactions during anesthesia are commonly attributed to muscle relaxants, hypnotics, macromolecular solutions, latex, or parenteral antibiotics. After exclusion of these different components as causes, we were interested in the potential implication of rifamycin in the systemic reaction, which occurred during anesthesia, and in the immunologic mechanism by which it can trigger this reaction. Methods: We report four cases of systemic reactions occurring after local administration of rifamycin. Three patients needed orthopedic surgery, and the fourth needed a urethrotomy. Severe systemic reactions occurred in all four patients when the surgeon washed the incision area with a rifamycin solution. All patients correctly responded to appropriate treatment and recovered. Skin tests were performed 2 months after the incident with the drugs used during anesthesia, latex, and rifamycin. To assess the relationship with a possible IgE-mediated mechanism, two in vitro tests were concomitantly performed to evaluate the cell reactivity to rifamycin: (1) determination of histamine release from peripheral basophils and (2) platelet cytotoxicity test, which explored the presence on platelets of specific IgE antibodies bound to the low-affinity receptor for IgE. Results: Skin tests were performed with different drugs used during surgery, and results were only positive for rifamycin in the four cases, accompanied in two cases by a systemic reaction. Histamine release from basophils was positive in three of four patients. The platelet cytotoxicity test results were positive in all four cases. Conclusion: It appears that rifamycin, used locally during surgery, is apt to trigger severe systemic anaphylactic reactions, which are linked to an IgE-related process. This situation is worth pointing out, especially in patients who undergo repeated orthopedic operations during which, at least in Europe, rifamycin is commonly used for the prevention of local sepsis. (J A LLERGY C LIN I MMUNOL 1995;95:1-7.)

Anaphylaxis to methotrexate: A possible IgE-mediated mechanism

Anaphylaxis to methotrexate: A possible IgE-mediated mechanism

Biphasic systemic anaphylaxis: An inpatient and outpatient study

We attempted to ascertain the incidence of systemic biphasic anaphylactic reactions in both outpatients and inpatients. Madigan Army Medical Center is a large teaching facility. The Allergy Clinic staff sees approximately 20,000 patients per year, and an average of 27,000 allergy immunotherapy injections are administered each year. During the years 1988 to 1991 we collected data from a total of 35 patients who had experienced, during the 30-minute waiting period in the clinic, symptoms and signs consistent with anaphylaxis. A total of 44 anaphylactic reactions were noted, with only two (5%) involving a biphasic systemic pattern. All patients were observed and treated within the clinic until symptoms and signs had resolved. None of the patients were treated with or were presently using glucocorticosteroids during the time of their reactions. Of the reactions noted, 25 (57%) involved only cutaneous manifestations of anaphylaxis, three (7%) involved the laryngeal/upper airway area, eight (18%) involved bronchospasm alone, three (7%) involved the rhinoconjunctivae, and five (11%) involved more than one site or type. None of the patients experienced any symptoms or signs of cardiovascular compromise or collapse after allergy extract injections. During the years 1986 to 1992 a total of 59 patients were admitted to the medical ward or intensive care unit with the diagnosis of systemic anaphylaxis. Of 59 patients, four (7%) experienced a recurrent (biphasic) anaphylactic reaction without reexposure to the initial inciting agent. The remaining 55 patients (93%) did not experience any further systemic anaphylaxis after initial hospital admission and treatment. Two of the patients with biphasic anaphylaxis were first seen with hypotension and generalized urticaria. Of the remaining two patients, one had lip and tongue angioedema, and the other had urticaria only. The biphasic reaction involved antibiotics in two cases and food (shrimp) in the remaining two cases. Forty-two male patients and 17 female patients were included in the study. The age range of male patients was 6 months to 77 years and that of the female patients was 10 to 81 years. There were no deaths in this study. Of the causes for anaphylactic episodes 20 (34%) were drug- or medication-related, 12 (20%) were idiopathic, 13 (22%) were related to food, six (10%) were secondary to exercise, two (3%) were related to vaccine administration and three (3%) were secondary to Hymenoptera stings. The four remaining episodes were secondary to contrast dye administration, allergen skin test extract administration, horse serum administration, and allergen extract injection. We conclude that the incidence of biphasic anaphylactic events is lower than that reported in previously published studies. (J A LLERGY C LIN I MMUNOL 1994;93:977-85.)

Systemic reactions to immunotherapy.

Systemic anaphylactic reactions occur in a small percentage of patients receiving allergen immunotherapy. A 1 year study was performed in a large health maintenance organization to determine the incidence of systemic reactions (SR) to allergen immunotherapy. We measured the number of SR that occurred during a 12 months period. A SR data sheet was completed for each reaction, documenting the time of onset, symptoms, treatment, history of asthma or previous reaction, and concentration and type of extract. Twenty-seven thousand eight hundred six injection visits resulted in 143 SR (0.51%). Forty-five percent of the patients (pts) with SR had a history of prior SR, 50% had a history of asthma, and 36% developed reactions in season. Seventy-two percent of SR started within 30 minutes, although 8% appeared after 2 hours. Fifty-seven percent of SR occurred at concentrations of 1,000-10,000 PNU/cc, 25% at 10-100 PNU/cc, and 17% when both concentrations were given at the same visit. Eighty-three percent of SR were judged to be mild, nonlife threatening reactions, requiring no treatment or antihistamine therapy only. Seventeen percent were judged to be more severe, requiring treatment with epinephrine, with or without other agents. SR are a small but definite risk of immunotherapy. Most SR are mild, but some may be life threatening. The majority of reactions occur within 30 minutes, but significant reactions may occur after 2 hours. A large percentage of SR occurred in patients with a history of asthma, previous SR, or both.

Naturally occurring systemic anaphylactic and anaphylactoid reactions in four groups of pigs injected with commercially available bacterins.

Naturally occurring systemic anaphylactic and anaphylactoid reactions in four groups of pigs injected with commercially available bacterins.

High-level expression in Escherichia coli and rapid purification of enzymatically active honey bee venom phospholipase A 2

Bee venom phospholipase A 2 (BV-PLA2) is a hydrolytic enzyme that specifically cleaves the sn-2 acyl bond of phospholipids at the lipid/water interface. The same enzyme is also believed to be responsible for some systemic anaphylactic reactions in bee venom sensitized individuals. To study the structure/function relationships of this enzyme and to define the molecular determinants responsible for its allergenic potential, a synthetic gene encoding the mature form of BV-PLA2 was expressed in Escherichia coli. This enzyme was produced as a fusion protein with a 6xHis-tag on its amino-terminus yielding 40–50 mg of fusion protein per 1 of culture after metal ion affinity chromatography. A kallikrein protease recognition site was engineered between the 6xHis-tag and the amino-terminus of the enzyme allowing isolation of the protein with its correct N-terminus. Recombinant affinity purified BV-PLA2 was refolded, purified to homogeneity, and cleaved with kallikrein, resulting in a final yield of 8–9 mg of active enzyme per 1 of culture. The enzymatic and immunological properties of the recombinant BV-PLA2 are identical to enzyme isolated from bee venom indicating a native-like folding of the protein.

Allergy treatment with a peptide vaccine

An antiserum, obtained by immunising rabbits with a human peptide-protein conjugate, was shown to inhibit histamine release from rat mast cells both in vitro and in vivo. Immunisation of sensitised rats with the same peptide reduced IgE antibody formation and serum histamine concentration, and abolished systemic anaphylactic reactions in response to allergen challenge. This peptide may form the basis of a vaccine in a new approach to the immunotherapy of atopic disease.

Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis.

Tryptase, a neutral protease of human mast cells, is a potentially important indicator of mast cell involvement in various clinical conditions. The current study examined the time course of appearance and disappearance of tryptase in the circulation after an anaphylactic event and the stability of both endogenous and exogenous tryptase in terms of freeze-thawing and temperature. The peak level of tryptase after an experimentally induced systemic anaphylactic reaction occurred 1-2 h after the initiating bee sting in each of three subjects, in contrast to histamine levels which peaked at 5-10 min. In some cases elevated levels of tryptase may not be detected during the initial 15-30 min. Tryptase levels then declined under apparent first order kinetics with a t1/2 of approximately 2h. Similar disappearance kinetics were observed for two subjects presenting in the emergency room with immediate type reactions, one with severe asthma after indomethacin ingestion, the other with systemic anaphylaxis after a bee sting. Histamine levels declined rapidly and were back to baseline by 15-60 min. Measured levels of tryptase in serum or plasma were not diminished by up to four freeze-thaw cycles. Incubation of serum samples taken from subjects with elevated levels of tryptase at 22 and 37 degrees C indicated that greater than 50% of endogenous tryptase was still detected after 4 d. Purified tryptase added to serum or plasma and incubated as above was less stable: approximately 50% of exogenous tryptase in serum and approximately 15% in plasma was detected after 2d of incubation. Therefore, optimally samples should be stored frozen, but even those stored at room temperature for up to 4 d should be satisfactory. The best time to obtain samples for tryptase determinations is 1-2 h after the precipitating event, but depending on the magnitude of the initial response elevated levels of tryptase may be present in the circulation for several hours.

Anaphylactic reactions affecting the human heart

We have investigated a large number of patients, most of whom suffered from severe systemic anaphylactic or anaphylactoid reactions during the induction of anaesthesia; the term 'anaphylactoid' was restricted to patients who had no history of prior exposure. Cardiac dysrhythmia (including severe bradydysrhythmia), which was documented by electrocardiography, was one of the principal manifestations, and in one case there was evidence of myocardial ischemia as well.