The different HIV-1 reading frames were cloned and expressed in Escherichia coli. Selected clones... more The different HIV-1 reading frames were cloned and expressed in Escherichia coli. Selected clones were evaluated applying a variety of human sera from all stages of HIV infection. The N-terminal portion of the transmembrane protein (gp41) was found to be particularly suited for the sensitive detection of HIV-specific antibodies at a very early stage. A DNA fragment which codes for the corresponding part of the HIV-2 transmembrane protein was synthesized and was expressed in E. coli in the same way. Both recombinant antigens and the main core antigen p24 were purified to homogeneity and were used for development of the Anti-HIV-1/-2 ELISA biotest. This screening test was found to give excellent specificity and sensitivity results. (orig.)SIGLEAvailable from TIB Hannover: D.Dt.F.QN1(8,20) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman
To investigate the role of T cells in drug allergy, we stimulated PBMC from penicillin-allergic p... more To investigate the role of T cells in drug allergy, we stimulated PBMC from penicillin-allergic patients with reactive penicillin G itself or penicillin G coupled with human serum albumin (BPO-HSA). T cell clones specific for penicillin G or BPO-HSA were established and their phenotype and reactivity to both forms of the beta-lactam were analyzed. T cell clones stimulated by penicillin G were CD4 and CD8 positive, whereas BPO-HSA stimulated the growth of CD4+ T cells. The penicillin G-specific clones were HLA class I or class II restricted and processing was not required as fixed APC could still present penicillin G. In contrast, BPO-HSA has to undergo processing to stimulate BPO-HSA-specific T cell clones. In addition to classical APC, activated MHC class II expressing T cells could also restimulate the penicillin G-specific clones, indicating that various cell types might serve as APC. Penicillin G and BPO-HSA-specific T cell clones produced a heterogeneous cytokine pattern as mos...
Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized ... more Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized by skin involvement, eosinophilia, and systemic symptoms. These reactions have an immune etiology; however, the role of T cells is not well defined. The aim of this study was to characterize the specificity, phenotype, and cytokine profile of CBZ-specific T cells derived from hypersensitive individuals. Proliferation of blood lymphocytes was measured using the lymphocyte transformation test. CBZ-specific T cell clones were generated by serial dilution and characterized in terms of their cluster of differentiation and T cell receptor V phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [ 3 H]thymidine incorporation, 51 Cr release, and enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were used to study the involvement of antigen-presenting cells. The specificity of the drug T cell receptor interaction was studied using CBZ metab-olites and other structurally related compounds. Lymphocytes from hypersensitive patients (stimulation index: 32.1 Ϯ 24.2 [10 g ml Ϫ1 ]) but not control patients (stimulation index: 1.2 Ϯ 0.4 [10 g ml Ϫ1 ]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4ϩ or CD4ϩ/ CD8ϩ, expressed the ␣ T cell receptor, secreted IFN-␥, and were cytotoxic. T-cell recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched antigen-presenting cells. The T cell receptor of certain clones could accommodate some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants or structural analogs. These studies characterize drug-specific T cells in CBZ-hypersensitive patients that are phenotypically different from T cells involved in other serious cutaneous adverse drug reactions. Administration of carbamazepine (CBZ), which is commonly administered for the treatment of epilepsy, causes hypersensitivity reactions characterized by skin involvement and systemic manifestations such as hepatitis and eosinophilia (Leeder, 1998). Reactions vary in severity and may cause death. The frequency of CBZ hypersensitivity is between 1 in 1000 and 1 in 10,000 new exposures to the drug (Vitorrio and Mulglia, 1995; Tennis and Stern, 1997). Taken from clinical manifestations, CBZ hypersensitivity reactions are believed to have an immune etiology. In accordance with this, a sensitization period of 3 to 4 weeks is required for the initial development of clinical symptoms, whereas rechallenge results in the recurrence of symptoms much sooner than with primary exposure (Leeder, 1998). The mechanism by which CBZ induces a hypersensitivity reaction is unclear. Although CBZ undergoes bioactivation to toxic arene oxide and quinone metabolites (Madden et al., 1996; Ju and Uetrecht, 1999), definite evidence linking this to immunogenicity is lacking (Park et al., 1998). The generation and characterization of drug-specific T cell lines and clones from drug-allergic patients with severe skin reactions has recently led to the classification of cutaneous eruptions in terms of their cellular and molecular pathophysiology (Pichler et al., 2002) (Fig. 1). Skin-infiltrating CD4ϩ T cells, which secrete IL-5, perforin, and granzyme, are characteristic of maculopapular exanthemas (
Virus infections and T cell-mediated drug hypersensitivity reactions (DHR) can influence each oth... more Virus infections and T cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i) : drugs tend to bind to proteins and may even bind to immune receptors. In the absence of viral infections, this low affine binding may be insufficient to elicit T cell activation. During a viral in...
Background Long-term sequelae are frequent and often disabling after epidermal necrolysis (Steven... more Background Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. Objectives We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. Methods Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method.
Background: Omalizumab has been shown to be effective in treating chronic spontaneous urticaria (... more Background: Omalizumab has been shown to be effective in treating chronic spontaneous urticaria (CSU). The reduction of FcεRI receptor density on the surface of basophils and mast cells is thought to play a major role in its effectiveness. We conducted a double-blind, randomized, placebo-controlled trial to investigate the mode of action of omalizumab in patients with antihistamine-resistant CSU. Methods: Thirty patients were randomized in a 2:1 ratio to receive either 300 mg omalizumab or placebo. Four monthly applications of omalizumab/placebo were followed up with a visit 2 months after the last injection. The primary endpoint was the FcεRI receptor density change on basophils. Results: Omalizumab led to a significant reduction of FcεRI receptor density on basophils as soon as 1 week after the first injection: baseline omalizumab vs. placebo group, 80.31 ± 47.18x10³ vs. 78.29 ± 45.09x10³ receptors/basophil ± SD; 1 week, 72.89 ± 47.79x10³ vs. 27.83 ± 20.87x10³, p=0.001. This effect continued during the treatment phase and persisted for 2 months after the last injection: 93.81 ± 56.50x10³ vs. 21.09 ± 15.23x10³, p=0.002. Values for basophil "releasability" and the basophil activation test (CU-BAT) of patient serum using donor basophils were unchanged despite treatment: CU-BAT, CD63 10.75% (7.35) in the placebo group vs. 8.35% (15.20) in the omalizumab group, p=0.778. Conclusion: We demonstrated a rapid reduction of FcεRI receptor density on basophils following treatment with omalizumab. Because CU-BAT using well-characterized, omalizumab-naïve donor basophils did not change during the treatment phase, autoreactive serum factors seem to remain unaltered. This points towards a cellular effect of omalizumab on basophils. To predict the omalizumab response time and to monitor disease, FcεRI density and CU-BAT might be promising cellular-based assays.
The development of T- or B-membrane determinants on human foetal lymphoid cells was studied by th... more The development of T- or B-membrane determinants on human foetal lymphoid cells was studied by the direct immunofluorescence technique, using a tetramethyl rhodamine isothiocyanate (TRITC) labelled horse antihuman T-cell conjugate (ATC) for the detection of T lymphocytes and a fluorescein isothiocyanate (FITC) labelled goat antihuman Fab conjugate for the demonstration of Ig-bearing B lymphocytes. Human foetal lymphocytes were also tested for spontaneous rosette formation with sheep red blood cells (SRBC). Cell suspensions of liver, spleen, thymus, bone marrow and blood of twenty-five human foetuses of 5·5–26 weeks of gestational age have been investigated. ATC-positive lymphoid cells were first seen in the liver at 5·5 weeks; E rosette-forming cells (ERFC) and Ig-bearing lymphoid cells were first found at 9 weeks. ERFC were also present in the thymus at 9 weeks. By 12 weeks, fluorescent B and T lymphocytes were found in bone marrow and spleen. ERFC were also found in bone marrow at...
Antibiotics are used extensively in the treatment of various infections. Consequently, they can b... more Antibiotics are used extensively in the treatment of various infections. Consequently, they can be considered among the most important agents involved in adverse reactions to drugs, including both allergic and non-allergic drug hypersensitivity [J Allergy Clin Immunol 113:832-836, 2004]. Most studies published to date deal mainly with reactions to the beta-lactam group, and information on hypersensitivity to each of the other antimicrobial agents is scarce. The present document has been produced by the Special Committee on Drug Allergy of the World Allergy Organization to present the most relevant information on the incidence, clinical manifestations, diagnosis, possible mechanisms, and management of hypersensitivity reactions to non beta-lactam antimicrobials for use by practitioners worldwide.
Allergist/clinical immunologist maintenance of certification and training program reaccreditation... more Allergist/clinical immunologist maintenance of certification and training program reaccreditation are mandatory in some countries. The World Allergy Organization conducted surveys in 2009 and 2011 to assess where such programs were available and to promote the establishment of such programs on a global level. This was done with the presumption that after such an "inventory," World Allergy Organization could offer guidance to its Member Societies on the promotion of such programs to assure the highest standards of practice in the field of allergy and clinical immunology. This review draws on the experience of countries where successful programs are in place and makes recommendations for those wishing to implement such programs for the specialty.
To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among memb... more To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO). Methods: A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009. Results: Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%. Conclusions: Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.
Background: Fungal spores are universal components in the air and established as important causes... more Background: Fungal spores are universal components in the air and established as important causes of respiratory allergies. Whereas fungi imperfecti are accepted sources of allergic asthma and rhinitis, the significance of basidiomycetes as respiratory allergens is not established. Objectives: The aims of the present study were to investigate the rate of sensitization in subjects referred to an allergy clinic to 3 basidiomycetes commonly found in Europe. We demonstrate the clinical relevance of basidiomycete sensitization by active anterior rhinomanometry and identified basidiomycete allergens by immunoblotting. Methods and Results: Consecutive outpatient clinic attendees (n = 1207, >12 years of age) were given the skin prick test with a panel of common inhalant allergens and extracts of Boletus, Coprinus, and Pleurotus. To evaluate a cause-and-effect relation between basidiomycete allergens and respiratory allergies, 12 Pleurotus pulmonalis spore-sensitized subjects with respiratory symptoms and 6 control subjects were challenged by anterior rhinomanometry. SDS-PAGE immunoblots were used to identify basidiomycete-specific IgE antibodies in sera from subjects with positive skin prick test results. Of 1207 subjects tested, 48 (4%) reacted to at least 1 of the basidiomycete extracts. Whereas all of the 12 subjects with Pleurotus pulmonalis-positive skin test results showed a significant decrease in nasal air flow (mean 73%), none of the control subjects reacted. Immunoblots revealed several different IgE-binding proteins in Pleurotus and Coprinus extracts. Conclusions: Our results demonstrate that sensitization to basidiomycetes in subjects with respiratory allergies is frequent. Furthermore, Pleurotus pulmonalis spore extracts can definitely induce respiratory allergy in sensitized subjects. Immunoblot assays disclosed different IgE-reactive bands indicating the existence of basidiomycete allergens.
To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among memb... more To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO). Methods: A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009. Results: Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%. Conclusions: Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.
When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DH... more 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.
The different HIV-1 reading frames were cloned and expressed in Escherichia coli. Selected clones... more The different HIV-1 reading frames were cloned and expressed in Escherichia coli. Selected clones were evaluated applying a variety of human sera from all stages of HIV infection. The N-terminal portion of the transmembrane protein (gp41) was found to be particularly suited for the sensitive detection of HIV-specific antibodies at a very early stage. A DNA fragment which codes for the corresponding part of the HIV-2 transmembrane protein was synthesized and was expressed in E. coli in the same way. Both recombinant antigens and the main core antigen p24 were purified to homogeneity and were used for development of the Anti-HIV-1/-2 ELISA biotest. This screening test was found to give excellent specificity and sensitivity results. (orig.)SIGLEAvailable from TIB Hannover: D.Dt.F.QN1(8,20) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman
To investigate the role of T cells in drug allergy, we stimulated PBMC from penicillin-allergic p... more To investigate the role of T cells in drug allergy, we stimulated PBMC from penicillin-allergic patients with reactive penicillin G itself or penicillin G coupled with human serum albumin (BPO-HSA). T cell clones specific for penicillin G or BPO-HSA were established and their phenotype and reactivity to both forms of the beta-lactam were analyzed. T cell clones stimulated by penicillin G were CD4 and CD8 positive, whereas BPO-HSA stimulated the growth of CD4+ T cells. The penicillin G-specific clones were HLA class I or class II restricted and processing was not required as fixed APC could still present penicillin G. In contrast, BPO-HSA has to undergo processing to stimulate BPO-HSA-specific T cell clones. In addition to classical APC, activated MHC class II expressing T cells could also restimulate the penicillin G-specific clones, indicating that various cell types might serve as APC. Penicillin G and BPO-HSA-specific T cell clones produced a heterogeneous cytokine pattern as mos...
Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized ... more Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized by skin involvement, eosinophilia, and systemic symptoms. These reactions have an immune etiology; however, the role of T cells is not well defined. The aim of this study was to characterize the specificity, phenotype, and cytokine profile of CBZ-specific T cells derived from hypersensitive individuals. Proliferation of blood lymphocytes was measured using the lymphocyte transformation test. CBZ-specific T cell clones were generated by serial dilution and characterized in terms of their cluster of differentiation and T cell receptor V phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [ 3 H]thymidine incorporation, 51 Cr release, and enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were used to study the involvement of antigen-presenting cells. The specificity of the drug T cell receptor interaction was studied using CBZ metab-olites and other structurally related compounds. Lymphocytes from hypersensitive patients (stimulation index: 32.1 Ϯ 24.2 [10 g ml Ϫ1 ]) but not control patients (stimulation index: 1.2 Ϯ 0.4 [10 g ml Ϫ1 ]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4ϩ or CD4ϩ/ CD8ϩ, expressed the ␣ T cell receptor, secreted IFN-␥, and were cytotoxic. T-cell recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched antigen-presenting cells. The T cell receptor of certain clones could accommodate some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants or structural analogs. These studies characterize drug-specific T cells in CBZ-hypersensitive patients that are phenotypically different from T cells involved in other serious cutaneous adverse drug reactions. Administration of carbamazepine (CBZ), which is commonly administered for the treatment of epilepsy, causes hypersensitivity reactions characterized by skin involvement and systemic manifestations such as hepatitis and eosinophilia (Leeder, 1998). Reactions vary in severity and may cause death. The frequency of CBZ hypersensitivity is between 1 in 1000 and 1 in 10,000 new exposures to the drug (Vitorrio and Mulglia, 1995; Tennis and Stern, 1997). Taken from clinical manifestations, CBZ hypersensitivity reactions are believed to have an immune etiology. In accordance with this, a sensitization period of 3 to 4 weeks is required for the initial development of clinical symptoms, whereas rechallenge results in the recurrence of symptoms much sooner than with primary exposure (Leeder, 1998). The mechanism by which CBZ induces a hypersensitivity reaction is unclear. Although CBZ undergoes bioactivation to toxic arene oxide and quinone metabolites (Madden et al., 1996; Ju and Uetrecht, 1999), definite evidence linking this to immunogenicity is lacking (Park et al., 1998). The generation and characterization of drug-specific T cell lines and clones from drug-allergic patients with severe skin reactions has recently led to the classification of cutaneous eruptions in terms of their cellular and molecular pathophysiology (Pichler et al., 2002) (Fig. 1). Skin-infiltrating CD4ϩ T cells, which secrete IL-5, perforin, and granzyme, are characteristic of maculopapular exanthemas (
Virus infections and T cell-mediated drug hypersensitivity reactions (DHR) can influence each oth... more Virus infections and T cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i) : drugs tend to bind to proteins and may even bind to immune receptors. In the absence of viral infections, this low affine binding may be insufficient to elicit T cell activation. During a viral in...
Background Long-term sequelae are frequent and often disabling after epidermal necrolysis (Steven... more Background Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. Objectives We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. Methods Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method.
Background: Omalizumab has been shown to be effective in treating chronic spontaneous urticaria (... more Background: Omalizumab has been shown to be effective in treating chronic spontaneous urticaria (CSU). The reduction of FcεRI receptor density on the surface of basophils and mast cells is thought to play a major role in its effectiveness. We conducted a double-blind, randomized, placebo-controlled trial to investigate the mode of action of omalizumab in patients with antihistamine-resistant CSU. Methods: Thirty patients were randomized in a 2:1 ratio to receive either 300 mg omalizumab or placebo. Four monthly applications of omalizumab/placebo were followed up with a visit 2 months after the last injection. The primary endpoint was the FcεRI receptor density change on basophils. Results: Omalizumab led to a significant reduction of FcεRI receptor density on basophils as soon as 1 week after the first injection: baseline omalizumab vs. placebo group, 80.31 ± 47.18x10³ vs. 78.29 ± 45.09x10³ receptors/basophil ± SD; 1 week, 72.89 ± 47.79x10³ vs. 27.83 ± 20.87x10³, p=0.001. This effect continued during the treatment phase and persisted for 2 months after the last injection: 93.81 ± 56.50x10³ vs. 21.09 ± 15.23x10³, p=0.002. Values for basophil "releasability" and the basophil activation test (CU-BAT) of patient serum using donor basophils were unchanged despite treatment: CU-BAT, CD63 10.75% (7.35) in the placebo group vs. 8.35% (15.20) in the omalizumab group, p=0.778. Conclusion: We demonstrated a rapid reduction of FcεRI receptor density on basophils following treatment with omalizumab. Because CU-BAT using well-characterized, omalizumab-naïve donor basophils did not change during the treatment phase, autoreactive serum factors seem to remain unaltered. This points towards a cellular effect of omalizumab on basophils. To predict the omalizumab response time and to monitor disease, FcεRI density and CU-BAT might be promising cellular-based assays.
The development of T- or B-membrane determinants on human foetal lymphoid cells was studied by th... more The development of T- or B-membrane determinants on human foetal lymphoid cells was studied by the direct immunofluorescence technique, using a tetramethyl rhodamine isothiocyanate (TRITC) labelled horse antihuman T-cell conjugate (ATC) for the detection of T lymphocytes and a fluorescein isothiocyanate (FITC) labelled goat antihuman Fab conjugate for the demonstration of Ig-bearing B lymphocytes. Human foetal lymphocytes were also tested for spontaneous rosette formation with sheep red blood cells (SRBC). Cell suspensions of liver, spleen, thymus, bone marrow and blood of twenty-five human foetuses of 5·5–26 weeks of gestational age have been investigated. ATC-positive lymphoid cells were first seen in the liver at 5·5 weeks; E rosette-forming cells (ERFC) and Ig-bearing lymphoid cells were first found at 9 weeks. ERFC were also present in the thymus at 9 weeks. By 12 weeks, fluorescent B and T lymphocytes were found in bone marrow and spleen. ERFC were also found in bone marrow at...
Antibiotics are used extensively in the treatment of various infections. Consequently, they can b... more Antibiotics are used extensively in the treatment of various infections. Consequently, they can be considered among the most important agents involved in adverse reactions to drugs, including both allergic and non-allergic drug hypersensitivity [J Allergy Clin Immunol 113:832-836, 2004]. Most studies published to date deal mainly with reactions to the beta-lactam group, and information on hypersensitivity to each of the other antimicrobial agents is scarce. The present document has been produced by the Special Committee on Drug Allergy of the World Allergy Organization to present the most relevant information on the incidence, clinical manifestations, diagnosis, possible mechanisms, and management of hypersensitivity reactions to non beta-lactam antimicrobials for use by practitioners worldwide.
Allergist/clinical immunologist maintenance of certification and training program reaccreditation... more Allergist/clinical immunologist maintenance of certification and training program reaccreditation are mandatory in some countries. The World Allergy Organization conducted surveys in 2009 and 2011 to assess where such programs were available and to promote the establishment of such programs on a global level. This was done with the presumption that after such an "inventory," World Allergy Organization could offer guidance to its Member Societies on the promotion of such programs to assure the highest standards of practice in the field of allergy and clinical immunology. This review draws on the experience of countries where successful programs are in place and makes recommendations for those wishing to implement such programs for the specialty.
To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among memb... more To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO). Methods: A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009. Results: Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%. Conclusions: Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.
Background: Fungal spores are universal components in the air and established as important causes... more Background: Fungal spores are universal components in the air and established as important causes of respiratory allergies. Whereas fungi imperfecti are accepted sources of allergic asthma and rhinitis, the significance of basidiomycetes as respiratory allergens is not established. Objectives: The aims of the present study were to investigate the rate of sensitization in subjects referred to an allergy clinic to 3 basidiomycetes commonly found in Europe. We demonstrate the clinical relevance of basidiomycete sensitization by active anterior rhinomanometry and identified basidiomycete allergens by immunoblotting. Methods and Results: Consecutive outpatient clinic attendees (n = 1207, >12 years of age) were given the skin prick test with a panel of common inhalant allergens and extracts of Boletus, Coprinus, and Pleurotus. To evaluate a cause-and-effect relation between basidiomycete allergens and respiratory allergies, 12 Pleurotus pulmonalis spore-sensitized subjects with respiratory symptoms and 6 control subjects were challenged by anterior rhinomanometry. SDS-PAGE immunoblots were used to identify basidiomycete-specific IgE antibodies in sera from subjects with positive skin prick test results. Of 1207 subjects tested, 48 (4%) reacted to at least 1 of the basidiomycete extracts. Whereas all of the 12 subjects with Pleurotus pulmonalis-positive skin test results showed a significant decrease in nasal air flow (mean 73%), none of the control subjects reacted. Immunoblots revealed several different IgE-binding proteins in Pleurotus and Coprinus extracts. Conclusions: Our results demonstrate that sensitization to basidiomycetes in subjects with respiratory allergies is frequent. Furthermore, Pleurotus pulmonalis spore extracts can definitely induce respiratory allergy in sensitized subjects. Immunoblot assays disclosed different IgE-reactive bands indicating the existence of basidiomycete allergens.
To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among memb... more To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO). Methods: A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009. Results: Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%. Conclusions: Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.
When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DH... more 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.
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Papers by W. Pichler