International Consensus on drug allergy.

When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug-specific antibodies or T cells. DHRs may be allergic or nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life-threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under-reporting) and overdiagnosis (due to an overuse of the term 'allergy') are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more-expensive or less-effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class-induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs.

Clinical, pathologic, and toxicologic findings in asthma deaths in Cook County, Illinois.

To identify factors contributing to asthma mortality and improve our understanding of airway pathology in fatal asthma, we studied 44 cases of fatal asthma using records of one pathologist in the Office of the Medical Examiner. Records included death certificates, autopsies, toxicology, accounts by family and friends of the terminal episode, medical history of the deceased, police and paramedic reports, and hospital charts. Additionally, we interviewed by telephone surviving family and friends. Six (17%) of 35 patients were using inhaled corticosteroids at time of death. Of the nine patients who had seen a physician within 2 weeks of death, two were using corticosteroids. Toxicology was positive in 16 (38%) of 42 cases. Of the 20 patients with sudden-onset asthma (prodrome of increasing symptoms < 1 hour before death), 9 (45%) had positive toxicology. Patients with both sudden-onset and slow-onset asthma (prodrome > 3 hours before death) had airway mucosal or submucosal eosinophilic or neutrophilic infiltrates or both, as well as airways with and without mucus plugging. These findings indicate that asthma deaths are confounded by substance abuse and lack of anti-inflammatory therapy, and there is a heterogeneity in histological findings in sudden-onset and slow-onset asthma.

T cell proliferation and cytokine secretion to T cell epitopes of Asp f 2 in ABPA patients.

The pathogenesis of allergic bronchopulmonary aspergillosis (ABPA) involves specific cytokines secreted by lymphocytes in response to Aspergillus fumigatus (Af) allergens. To gain information about the lymphoproliferative response and cytokine production against a major Af allergen, Asp f 2, we studied Asp-f-2-specific T cell clones (TCCs) from ABPA patients. TCCs were stimulated with rAsp f 2, its deletion mutants, and synthetic peptides to identify the T cell epitope(s) and to understand cytokine production. PBMCs from four of five ABPA patients showed proliferation in response to Asp f 2. Three TCCs from one patient showed higher IL-5 secretion compared to IL-4 and IFN-gamma. Two TCCs from the second patient showed a mixed Th1/Th2 response, as evidenced by production of IL-4, IL-5, and IFN-gamma. An epitope from the N-terminal region of Asp f 2 induced only IL-5 secretion. High IL-5 secretion might explain the marked eosinophilia observed in ABPA patients.

Cloning and expression of Aspergillus fumigatus allergen Asp f 16 mediating both humoral and cell-mediated immunity in allergic bronchopulmonary aspergillosis (ABPA).

BACKGROUND: Aspergillus fumigatus, a ubiquitous fungus, is responsible for a number of lung disorders in atopic and non-atopic individuals. Standardized, pure, and relevant allergens are desirable for reliable immunodiagnosis of the disease and to understand the structural and functional properties of these allergens and the role they play in causing ABPA. OBJECTIVE: Molecular cloning and characterization of a relevant allergen from A. fumigatus cDNA library. MATERIALS AND METHODS: A cDNA library was constructed from 96 h old mycelium of A. fumigatus using lambda ZAP expression vector. A novel gene encoding an A. fumigatus allergen was identified by screening the library with sera from ABPA patients. The gene was cloned and the allergen over-expressed in Escherichia coli. This recombinant allergen, Asp f 16, was evaluated in ELISA and Western blots using sera from patients and normal subjects and peripheral blood mononuclear cells (PBMC) for antigen-induced stimulation. RESULTS: Seventy percent of the patients with ABPA demonstrated high levels of serum IgE antibodies to Asp f 16, a 43-kDa protein, whereas patients with allergic asthma, Aspergillus skin test-positive asthmatics without clinical evidence of ABPA, and normal controls failed to show Asp f 16-specific IgE binding by ELISA. The deduced amino acid sequences of Asp f 16 showed extensive sequence homology to 30.6-kDa Asp f 9 at the N-terminal region of the protein. PBMC from the majority of patients with ABPA exhibited significant proliferation with the recombinant Asp f 16 allergen. CONCLUSION: Specific humoral and cell-mediated immune responses of Af-sensitized patients against Asp f 16 suggest its usefulness in the immunodiagnosis of hypersensitivity diseases due to Af and understanding the pathophysiology of ABPA.

Immunologic studies in presumed amniotic fluid embolism.

OBJECTIVE: To evaluate the potential role of immunologic mechanisms that involve mast cell degranulation (anaphylaxis) or complement activation in the mechanism of amniotic fluid embolism. METHODS: This study was a case series of nine women with presumed amniotic fluid embolism and a control group of 22 women who had normal labor. Women were from community and tertiary referral hospitals in Japan and the United States. Main outcome measures were maternal peripartum complement levels (C3 and C4), serum levels of tryptase, urinary histamine concentrations, and serum levels of a fetal antigen (sialyl Tn). RESULTS: Serum tryptase and urinary histamine measurements were negative in women with amniotic fluid embolism; seven of nine had elevated levels of fetal antigen. All eight who had serum available for testing had abnormally low levels of complement. Mean C3 level of 44.0 mg/dL and C4 level of 10.7 mg/dL were significantly lower than corresponding postpartum control values of 117.3 mg/dL and 29.4 mg/dL (P =.018 for C3, P =.012 for C4). Postpartum C3 and C4 levels decreased by 8% and 5%, respectively, compared with intrapartum values (P =.003 for C3, P =.021 for C4) but were still within normal range. CONCLUSION: Serologic findings suggest a role for complement activation in the mechanism of amniotic fluid embolism. Laboratory data from this series did not implicate mast cell degranulation (anaphylaxis) in the pathophysiology of the disease.

Bee pollen-induced anaphylactic reaction in an unknowingly sensitized subject.

BACKGROUND: The food supplement bee pollen has been previously found to cause anaphylactic reactions. It has been proposed as useful for "everything from bronchitis to hemorrhoids." OBJECTIVE: This study describes an atopic patient who experienced a non-life-threatening anaphylactic reaction upon her initial ingestion of bee pollen. Microscopic examination of the pollen sample and ELISA inhibition assays were performed. RESULTS: The patient had a 7 mm/28 mm wheal/erythema reaction to bee pollen at 1 mg/mL concentration. Bee pollen caused 52% inhibition of IgE binding to short ragweed and 55% to ryegrass. Microscopic analysis revealed ragweed, Alternaria, Cladosporium, honeysuckle (Lonicera sp), privet shrub (Ligustrum sp), and vetch (Vicia sativa). CONCLUSIONS: An unknowingly sensitized atopic patient experienced an anaphylactic reaction after ingestion of a small quantity of bee pollen that contained pollens and fungi. Previously administered allergen immunotherapy that had reduced rhinitis symptoms did not prevent this allergic reaction.

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate.

BACKGROUND: The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. OBJECTIVE: We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. METHODS: In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo. RESULTS: Of 130 subjects in protocol A, 50 (38. 5%) responded to MSG only, 17 (13.1%) responded to placebo only (P <. 05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D. CONCLUSION: The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting.

The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance.

BACKGROUND: The development of antimicrobial guidelines is one way in which institutions attempt to control emerging resistance, but the real challenge falls on promoting and ensuring adherence to these guidelines. Investigating reasons for the prescribing of alternative antimicrobial agents outside of these guidelines is crucial for modifying practices that may adversely impact institutional antimicrobial goals. METHODS: Retrospective cross-referencing of computerized pharmacy printouts and concurrent manual medical record review. RESULTS: Approximately 25% (470/1893) of the patients requiring antimicrobial therapy reported an allergy to at least 1 antimicrobial agent. The most commonly reported antimicrobial allergy was penicillin (295/1893 [15.6%]). Eighty-five patients (18.1%) reported having an allergy to 2 or more antimicrobial agents. Only 4% (27/601) of the reported antimicrobial allergies contained documentation as to the nature of the specific allergic reactions, while a manual medical record review revealed that 32% (23/73) of the antimicrobial allergies contained documentation of the specific allergic reaction. Ninety-eight (39. 7%) of 247 patients reporting an allergy only to penicillin and/or cephalosporin received vancomycin in comparison with 247 (17.4%) of 1423 patients without any antimicrobial allergies (P<.001). Similarly, 53 (21.5%) of 247 patients with reported penicillin and/or cephalosporin allergies received levofloxacin compared with 114 (8.0%) of 1423 patients without any antimicrobial allergy (P<. 001). CONCLUSION: The incidence of penicillin allergy at our institution exceeds population averages. This finding, in combination with limited documentation of drug allergies, appears to lead to the prescribing of alternative antimicrobial agents that do not fit into institutional antimicrobial guidelines and, in some instances, may put the patient at risk for infection and/or colonization with resistant organisms. Use of these alternative agents may adversely impact the ability to manage emerging antimicrobial resistance.

Selected recombinant Aspergillus fumigatus allergens bind specifically to IgE in ABPA.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease resulting from exposure to Aspergillus fumigatus allergens. Patients with ABPA show elevated Aspergillus-specific serum IgE, a major criterion used in the diagnosis of the disease. Crude culture filtrate and mycelial antigens have been used widely to demonstrate IgE antibody to Aspergillus in the sera of patients. While these antigens have been useful in the diagnosis of ABPA, occasionally they present inconsistency in their reactivity and lack of specificity. Although in recent years, a number of purified A. fumigatus allergens have been produced by molecular cloning, no attempt was made to evaluate them systematically. OBJECTIVE: To evaluate the recombinant proteins from A. fumigatus for their IgE antibody binding, we studied sera from ABPA patients and controls by antigen specific enzyme linked immunosorbent assay (ELISA). METHODS: Recombinant Aspergillus allergens Asp f 1, f 2, f 3, f 4, and f 6 were studied for their specific binding to IgE in the sera of ABPA patients, A. fumigatus skin prick test positive asthmatics, and normal controls from the USA and Switzerland. The sera were blinded and studied by ELISA in two different laboratories. RESULTS: All the recombinant allergens showed IgE antibody binding with sera from patients with ABPA, whereas only fewer asthmatics and normal sera showed significant binding. The three selected recombinant allergens together reacted with all the ABPA patients studied. CONCLUSIONS: The results demonstrate that Asp f 2, f 4, and f 6 can be used in the serodiagnosis of ABPA, while IgE antibody binding to Asp f 1 and f 3 was not specific.

Corticosteroid therapy in an additional 13 cases of Stevens-Johnson syndrome: a total series of 67 cases.

Stevens-Johnson syndrome (SJS) is a severe cutaneous eruption that can be a life-threatening emergency. Previously, we have reported our favorable experience in treating 54 patients with SJS with systemic corticosteroids. We continued our prospective analysis of consecutive patients with SJS treated with corticosteroids. Possible etiologic factors and clinical outcomes of the patients are described. All 13 patients improved with initiation of systemic corticosteroid therapy. There was no mortality or permanent sequelae attributable to SJS. Drugs were the offending agents in all 13 cases. There was one death unrelated to SJS. In conclusion, prompt treatment with systemic corticosteroids reduces morbidity and improves outcome of SJS patients. This analysis extends our series to 67 consecutive patients with SJS who were treated with corticosteroids and had a favorable outcome.

Antibody binding of deletion mutants of Asp f 2, the major Aspergillus fumigatus allergen.

Asp f 2, a 268 amino acid major allergen from Aspergillus fumigatus (Af) demonstrated nine linear IgE binding regions. It is not known whether any of these linear epitopes are also conformatory epitopes. Hence, we constructed deletion mutants of Asp f 2 devoid of one or more epitopes, and the IgE binding of these proteins with sera from patients with ABPA was compared with the full-length Asp f 2 expressed in E. coli and Pichia. The Pichia expressed protein reacted weakly with IgE, but strongly with IgG of ABPA sera compared to E. coli expressed Asp f 2. Weak IgE binding only was seen when the C-terminal or N-terminal was deleted, while depletion of both ends negated all reactivity. The monoclonal antibody IL-B8 and IgE and IgG of ABPA sera bound significantly to the Asp f 2 E-4 fragment indicating that the major B-cell epitope is located at the N-terminal end of Asp f 2.

Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study.

Monosodium glutamate (MSG) has a long history of use in foods as a flavor enhancer. In the United States, the Food and Drug Administration has classified MSG as generally recognized as safe (GRAS). Nevertheless, there is an ongoing debate exists concerning whether MSG causes any of the alleged reactions. A complex of symptoms after ingestion of a Chinese meal was first described in 1968. MSG was suggested to trigger these symptoms, which were referred to collectively as Chinese Restaurant Syndrome. Numerous reports, most of them anecdotal, were published after the original observation. Since then, clinical studies have been performed by many groups, with varying degrees of rigor in experimental design ranging from uncontrolled open challenges to double-blind, placebo controlled (DBPC) studies. Challenges in subjects who reported adverse reactions to MSG have included relatively few subjects and have failed to show significant reactions to MSG. Results of surveys and of clinical challenges with MSG in the general population reveal no evidence of untoward effects. We recently conducted a multicenter DBPC challenge study in 130 subjects (the largest to date) to analyze the response of subjects who report symptoms from ingesting MSG. The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, the frequency of the responses was low and the responses reported were inconsistent and were not reproducible. The responses were not observed when MSG was given with food.

Molecular characterization of aspergillus fumigatus allergens.

Aspergillus fumigatus (Af) is ubiquitous saprophytic fungus associated with a broad spectrum of diseases in humans. These diseases range from benign colonization of the lung to life threatening diseases such as allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis. Af is the etiologic agent identified in most of the Aspergillus related human diseases and is therefore of particular clinical importance. Af induced obstructive airway diseases may be due to transient exposure to fungal spores resulting in a T helper 2 response. The IgE mediated inflammatory reaction could be due to colonization of bronchial airway epithelium by Af. Early and precise diagnosis of Aspergillus induced respiratory allergy is essential for preventing irreversible lung damages. The major problems in the diagnosis of A. fumigatus induced diseases are due to the lack of standardized and well characterized fungal extracts. The advent of molecular cloning technology and the development of phage surface display technology for cloning genes have facilitated the isolation of more relevant recombinant allergens. Using these techniques, a panel of different Af allergens having distinct IgE binding with various groups of Af sensitized patients have been cloned and characterized. These allergens can be categorized functionally as secreted and cytoplasmic proteins. The distinct IgE binding property of these purified and well characterized recombinant Af allergens may be useful for the differential diagnosis of Af related pulmonary complications.

Sensitization to Aspergillus species in the congenital neutrophil disorders chronic granulomatous disease and hyper-IgE syndrome.

BACKGROUND: Hyper-IgE syndrome (HIE) and chronic granulomatous disease (CGD) are congenital immunodeficiency diseases with increased susceptibility to bacterial and fungal infections. Both carry significant morbidity and mortality rates because of invasive infections by Aspergillus species. We encountered 2 patients, one with HIE and one with CGD, in whom detection of sensitization to Aspergillus species preceded the diagnosis of immunodeficiency. With high-dose systemic corticosteroids for allergic bronchopulmonary aspergillosis (ABPA), an inflammatory disorder caused by sensitization to Aspergillus species, pulmonary abscesses developed in the patient with HIE, and the patient with CGD succumbed to an overwhelming Aspergillus species-induced pneumonia. OBJECTIVE: We sought to assess the prevalence of sensitization to Aspergillus fumigatus and the presence of diagnostic criteria for ABPA in patients with CGD and HIE. METHODS: We measured A fumigatus-specific serum IgE, IgG, and precipitating antibodies as indicators for A fumigatus sensitization in the sera of 18 patients with neutrophil disorders (7 with HIE and 11 with CGD). Hospital records were reviewed for the presence of other diagnostic criteria for ABPA (asthma, elevated total serum IgE concentration, and radiographic abnormalities). RESULTS: Twelve (67%) of 18 patients were sensitized to A fumigatus, as evidenced by precipitating A fumigatus-specific antibodies. Six (33%) of 18 patients had serologic evidence of ABPA. Five of those 6 patients had radiologic abnormalities consistent with a diagnosis of ABPA. One patient with HIE also had asthma, thus fulfilling minimal essential criteria for concurrent ABPA. CONCLUSIONS: Patients with HIE syndrome and CGD have a high incidence of sensitization to Aspergillus species. A clinical picture indistinguishable from ABPA may coexist or emerge in patients with CGD or HIE and create a major management dilemma because systemic corticosteroids may accelerate tissue damage and invasive fungal infections. It is important to distinguish individuals with congenital neutrophil disorders from uncomplicated classic ABPA.

Changing patterns in academic allergy-immunology.

In evaluation of the current Allergy-Immunology (AI) Program of the Department of Medicine at Northwestern University Medical School and in planning for the future, it appeared that our assessment of changes in the AI program since its inception might be of value to other AI academic programs. Further, we might receive suggestions from other academic AI programs, and we request such advice.