Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers.

BACKGROUND: We investigated potential for hypersensitivity reactions after repeated sugammadex administration and explored the mechanism of hypersensitivity. METHODS: In this double-blind, placebo-controlled study (NCT00988065), 448 healthy volunteers were randomised to one of three arms to receive three repeat i.v. administrations of either sugammadex 4 mg kg-1, 16 mg kg-1, or placebo. Primary endpoint was percentage of subjects with hypersensitivity (assessed by an independent adjudication committee). Secondary endpoint of anaphylaxis was classified per Sampson and Brighton criteria. Exploratory endpoints included skin testing, serum tryptase, anti-sugammadex antibodies [immunoglobulin (Ig) E/IgG], and other immunologic parameters. RESULTS: Hypersensitivity was adjudicated for 1/148 (0.7%), 7/150 (4.7%), and 0/150 (0.0%) subjects after sugammadex 4 mg kg-1, 16 mg kg-1, and placebo, respectively. After sugammadex 16 mg kg-1, one subject met Sampson criterion 1 and Brighton level 1 (highest certainty) anaphylaxis criteria; two met Brighton level 2 criteria. After database lock it was determined that certain protocol deviations could have introduced bias in the reporting of hypersensitivity signs/symptoms in a subject subset. Objective laboratory investigations indicated that potential underlying hypersensitivity mechanisms were unlikely to have been activated; the results suggest that most of the observed hypersensitivity reactions were unlikely IgE/IgG-mediated. CONCLUSION: Dose-dependent hypersensitivity or anaphylaxis reactions to sugammadex were observed when administered without prior neuromuscular blocking agent. Laboratory investigations do not suggest prevalent allergen-specific IgE/IgG-mediated immunologic hypersensitivity. Because it could not be fully excluded that estimates of hypersensitivity/anaphylaxis incidence were unbiased, an additional study was conducted to characterise the potential for hypersensitivity reactions and is described in a companion report. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00988065; Protocol number P06042.

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

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.

Functional changes of dendritic cells in hypersensivity reactions to amoxicillin.

A better understanding of dendritic cell (DC) involvement in responses to haptenic drugs is needed, because it represents a possible approach to the development of an in vitro test, which could identify patients prone to drug allergies. There are two main DC subsets: plasmacytoid DC (pDC) and myeloid DC (mDC). ß-lactams form hapten-carrier conjugates and may provide a suitable model to study DC behavior in drug allergy reactions. It has been demonstrated that drugs interact differently with DC in drug allergic and non-allergic patients, but there are no studies regarding these subsets. Our aim was to assess the functional changes of mDC and pDC harvested from an amoxicillin-hypersensitive 32-year-old woman who experienced a severe maculopapular exanthema as reflected in interleukin-6 (IL-6) production after stimulation with this drug and penicillin. We also aim to demonstrate, for the first time, the feasibility of this method for dendritic cell isolation followed by in vitro stimulation for studies of drug allergy physiopathology. DC were harvested using a double Percoll density gradient, which generates a basophil-depleted cell (BDC) suspension. Further, pDC were isolated by blood DC antigen 4-positive magnetic selection and gravity filtration through magnetized columns. After stimulation with amoxicillin, penicillin and positive and negative controls, IL-6 production was measured by ELISA. A positive dose-response curve for IL-6 after stimulation with amoxicillin and penicillin was observed for pDC, but not for mDC or BDC suspension. These preliminary results demonstrate the feasibility of this methodology to expand the knowledge of the effect of dendritic cell activation by drug allergens.

Effect of in vitro aspirin stimulation on basophils in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Basophil activation has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). However, a comprehensive analysis of basophil responses to aspirin in terms of mediator release, cytokine secretion and increased expression of surface activation markers has not been performed. OBJECTIVE: To study the in vitro effects of aspirin on the concurrent release of histamine, leukotriene C4 (LTC4) and IL-4 from human basophils and to also evaluate changes in surface activation markers (CD63, CD69 and CD203c) expressed by these cells. METHODS: Basophil-enriched cell suspensions from 10 patients with AERD and 10 healthy volunteers were incubated with lysine-aspirin for up to 3 h. Cells were analysed for expression of CD63, CD69 and CD203c using flow cytometry. Cell-free supernatants were evaluated for histamine, and LTC4 release and for IL-4 secretion. RESULTS: Aspirin-induced expression of CD63, CD69 and CD203c yielded 30%, 80% and 70% sensitivity, respectively, but with poor specificity. There was no significant difference in LTC4 synthesis between groups. None of the patients with AERD (or controls) released IL-4 in response to aspirin. A higher dose of 5 mg/mL aspirin-mediated non-specific effects on basophils. CONCLUSION: Basophil responses to in vitro aspirin challenge are poor indicators of clinical sensitivity. Aspirin activates some basophils by means of mechanisms that differ from the classical IgE-mediated pathway. Our study also shows that the use of 27 mm of aspirin (5 mg/mL) by previous investigators causes non-specific basophil activation, thereby eliminating its usefulness in a cell-based diagnostic test for AERD. Evaluation of in vitro basophil activation has low clinical value in identifying aspirin-induced respiratory reactions.

Repeated latex aeroallergen challenges employing a hooded exposure chamber: safety and reproducibility.

BACKGROUND: Bronchial, nasal, and conjunctival challenges are useful for clarifying discordant clinical history (Hx) and skin and/or serologic tests and in assessing semiquantitative changes in biologic sensitivity over time. The objective of this study was to determine the safety and reproducibility of repeated latex-allergen challenges with a hooded exposure chamber (HEC). METHODS: The HEC system comprises a powered forced-air respirator with a fitted face shield and hood that uses glove-derived latex-allergen associated cornstarch particles (LAC) to expose simultaneously the conjunctiva, nose, and lungs. Serial control and incremental LAC challenges are conducted until an endpoint based on upper and/or lower respiratory tract symptoms and peak expiratory flow rates is reached. Six latex-allergic (Hx and puncture skin test [PST]- and 5/6 radioallergosorbent test [RAST]-positive) subjects were challenged on three separate occasions at least 2 weeks apart. Serial latex PST midpoints and serum anti-latex IgE by RAST were monitored at each visit and at a fourth follow-up visit. RESULTS: All subjects responded to LAC, but not to air or control cornstarch administered as controls. All responses were confined to mild symptoms of allergic rhinoconjunctivitis and/or asthma that either resolved spontaneously or were reversed with inhaled albuterol. No subject experienced a systemic or delayed reaction. There were no significant changes in the endpoint LAC doses over the three challenge visits (P>0.2). The mean coefficient of variation for log2 endpoints within-subjects was 17.3+/-17.2% (SD). The serum latex-specific IgE was not significantly boosted by the three challenges (P>0.2). The concentration of latex extract necessary to produce an 8-mm wheal by PST was not significantly changed during the study (P>0.1), indicating that latex sensitivity was not affected by the repeated LAC exposures. CONCLUSIONS: The results of this study indicate that repeated HEC latex-allergen challenges are both reproducible and safe, and do not increase latex sensitivity.

Natural rubber pharmaceutical vial closures release latex allergens that produce skin reactions.

BACKGROUND: The release of allergenic proteins from natural rubber vial closures (stoppers) into aqueous pharmaceuticals may induce allergic reactions in individuals with latex allergy (LA) receiving medications from such vials. OBJECTIVE: The goal of this study was to determine whether solutions stored in vials containing natural rubber closures release allergenic proteins detectable by skin testing of subjects with LA. METHODS: Five pharmaceutical vial closures (2 natural rubber and 3 synthetic) were coded, inserted onto vials containing phenol-saline-human serum albumin, and stored in an inverted position before use. Twelve volunteers with and 11 volunteers without LA underwent skin testing with solutions from each of the 5 vials, either those not punctured (0P) or those punctured 40 times with a 21-gauge needle 12 to 24 hours before testing (40P). RESULTS: All intradermal skin test responses in the group without LA were negative. Two and 5 of the 12 subjects with LA had positive intradermal skin reactions to 0P and 40P solutions, respectively, from vials containing rubber closures. Two subjects with LA had inexplicable, positive, nonreproducible intradermal skin test reactions to solutions from vials containing bromobutyl but not vials with isoprene synthetic closures. In vitro inhibition analysis detected 6 to 7 AU/g latex allergen in extracts of cut natural rubber containing closures but not in extracts of synthetic closures. CONCLUSION: Natural rubber vial closures released allergenic latex proteins into the tested solutions in direct contact during storage in sufficient quantities to elicit positive intradermal skin reactions in some individuals with LA. These data support a recommendation to eliminate natural rubber from closures of pharmaceutical vials.

House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program.

BACKGROUND: Children with asthma have a high prevalence of environmental allergies, especially to indoor allergens. The relationships of exposure to indoor allergens (dust mites, cat, dog, cockroach, and molds) and other host factors to allergy sensitization have not been evaluated simultaneously in a large cohort. OBJECTIVES: We studied 1041 children aged 5 to 12 years with mild-to-moderate asthma to determine risk factors associated with having positive allergy skin test responses to indoor allergens. Also, we described, compared, and contrasted 6 allergens in the home environments of these children from 8 North American cities. METHODS: Data were used from baseline visits of the Childhood Asthma Management Program. Patients' sensitivities to house dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus), cats, dogs, cockroaches, and molds were examined for relationships to demographic variables, home dust allergen exposures, number of other positive allergy skin test responses, total serum IgE levels, and smoking in the home. RESULTS: San Diego (78.5%) and Toronto (59.3%) had the topmost percentages of homes with moderate-to-high house dust mite levels. Boston (21.5%), St Louis (16.3%), and Baltimore (13.4%) had the highest percentages of homes with detectable levels of cockroach allergen. For house dust mites, the higher the level of allergen exposure, the more likely patients were to have positive allergy skin test responses, with relative odds of 9.0 (95% confidence interval, 5.4-15.1) for those exposed to high mite levels (>10.0 microg/g dust) relative to those unexposed. Even exposure to low levels of mite allergen (0.020-2.0 microg/g) was found to be a significant risk factor for sensitization. For cockroach allergen, those with detectable home exposure were more likely to have positive skin test responses (relative odds, 2.2; 95% confidence interval, 1.3-3.8) than those with undetectable exposure. In contrast, levels of exposure to cat, dog, and mold allergens were not related to sensitization rates. For cat allergen, this may reflect lower rates of cat ownership among highly sensitized subjects. Furthermore, the number of allergy skin test responses that were positive, excluding the test for the outcome of interest for each model, and total serum IgE levels were strong independent predictors of sensitization. CONCLUSIONS: Levels of exposure determined by house dust analysis are important determinants of sensitization for dust mite and cockroach allergen. This relationship was not demonstrable for cat, dog, or mold allergens, possibly because of confounding factors. For all allergens studied, the degree of atopy, determined by the total number of positive skin test responses or by total serum IgE levels, is an important contributing risk factor for sensitization.

A hooded exposure chamber method for semiquantitative latex aeroallergen challenge.

BACKGROUND: Allergen challenges are useful in adjudicating discordant clinical histories and skin test responses, serologic test responses, or both, as well as in determining the degree of allergic reactivity. Latex allergen challenges have been developed but have limitations that reduce their usefulness. OBJECTIVE: We sought to develop a novel hooded exposure chamber (HEC) system to allow safe, sensitive, and semiquantitative evaluation of respiratory latex allergy. METHODS: The HEC system uses an impinger to produce a particle cloud of cornstarch isolated from powdered latex gloves. The particles are air driven into a face shield and hood to simultaneously challenge the subject's conjunctiva, nose, and lungs during 3 minutes of normal tidal breathing. A cloud of respirable latex allergen-associated cornstarch particles (LACs) is consistently produced in the HEC during challenges. Twenty-three subjects with latex allergy (history and positive skin test response, positive serologic test response, or both) and 3 atopic control subjects not allergic to latex (history and negative skin test response, negative serologic test response, or both) were sequentially exposed to air, control cornstarch, and then progressive 2-fold increments of LACs in a single-masked fashion. A positive challenge result was defined as (1) a peak expiratory flow rate decline of 15% or greater from baseline; (2) a peak expiratory flow rate decline of 10% or greater and an increase of either the rhinoconjunctivitis or chest symptom score scale of 3 or more points from baseline; or (3) an increase of either the rhinoconjunctivitis or chest symptom score scale of 6 or more points from baseline. RESULTS: Twenty-two of the 23 subjects with latex allergy reached threshold criteria for a positive challenge at LAC titers of 1:8 or greater, giving a sensitivity of 0.96. Challenge endpoints were moderately corrected with skin test sensitivity (r (s) = -0.55, P =.01) but not with RAST reactivity. None of the 3 control subjects responded to LACs at the 1:8 dilution. No patient or control subject responded to the air or control cornstarch control exposures. All responses were confined to mild symptoms of allergic rhinoconjunctivitis, asthma, or both that either resolved spontaneously or were easily reversed with inhaled albuterol. No subject experienced a systemic or late-phase reaction. CONCLUSION: The HEC procedure is a safe, sensitive, and specific method for masked semiquantitative latex aeroallergen challenges that mimic occupational latex exposure to powdered latex gloves.

Recent advances in the diagnosis of drug allergy.

The diagnosis of immunologic drug reactions is based primarily on a detailed clinical history and historical data on relative immunogenicity of the culprit drugs. Except for a few standardized skin tests, most of the other methods for diagnosing drug allergy have unproven diagnostic or predictive clinical utility. Many tests for drug-specific immune responses are suggestive if positive, but have unknown negative predictive values. The present review addresses the most recent published literature regarding the diagnosis of drug allergy. Recent advances in the use of the lymphocyte transformation test, and delayed intradermal skin tests and patch tests for the diagnosis of delayed cutaneous reactions to penicillins suggest that these tests may have clinical utility, although confirmatory reports are still missing. For the diagnosis of acute vaccine reactions, gelatin-specific IgE as measured by radioallergosorbent test has now been shown to be reliably associated with allergic reactions to gelatin-containing vaccines.

Diagnosis of natural rubber latex allergy: multicenter latex skin testing efficacy study. Multicenter Latex Skin Testing Study Task Force.

BACKGROUND: No characterized diagnostic natural rubber latex skin testing material is licensed for use in the United States. OBJECTIVE: We have conducted a multicenter clinical skin testing study to document the safety and diagnostic sensitivity and specificity of a candidate Hevea brasiliensis nonammoniated latex (NAL) extract. These data are intended to support the licensing of this reagent for the diagnosis of latex allergy in high-risk populations. METHODS: Three hundred twenty-four subjects (304 adults and 20 children) were classified by their clinical history as having latex allergy (LA group, 124 adults and 10 children) or having no latex allergy (NLA group, 180 adults and 10 children). All subjects provided blood samples and then received sequential puncture skin tests (PSTs) at 1, 100, or 1000 microg/mL protein with a bifurcated needle and NAL (Greer Laboratories) from Malaysian Hevea brasiliensis (clone 600) sap. A 2-stage glove provocation test was used to clarify latex allergy status of individuals with positive history/negative PST result and negative history/positive PST result mismatches. RESULTS: Twenty-four subjects (15%) originally designated as having LA on the basis of their initial clinical history were reclassified to the NLA group on the basis of a negative glove provocation test result. Of the 134 subjects with LA, 54 (40%) were highly sensitive to latex, with a positive PST result at 1 microg/mL NAL. The Greer NAL reagent produced a positive PST rate (sensitivity) of 95% and 99% in subjects with LA at 100 microg/mL and 1 mg/mL, respectively. The negative PST rate (specificity) in 190 subjects with a negative history with the NAL extract at 100 microg/mL and 1 mg/mL, was 100% and 96%, respectively. Immediately after the PST, mild systemic reactions (mainly pruritus) were recorded in 16.1 % of the adults in the LA group and 4.4% of the adults in the NLA group. No reactions required treatment with epinephrine. Only mild delayed reactions were observed in 9.6% (LA group) and 2.8% (NLA group) of subjects 24 to 48 hours after PST. Mean wheal and erythema diameters measured in the 10 children in the LA group with spina bifida at 100 microg/mL and 1 mg/mL were similar to those observed in the adults in the LA group, suggesting that children are not at increased risk for systemic reactions compared with adults. CONCLUSIONS: A suggestive clinical history is necessary but not sufficient for a definitive diagnosis of IgE-dependent latex allergy. These data support the safety and diagnostic efficacy of the Greer NAL, skin test reagent at 100 micro/mL and 1 mg/mL for confirmatory PSTs.

Repeated aerosol exposure to small doses of allergen. A model for chronic allergic asthma.

To improve our understanding of the pathophysiology of chronic allergic asthma, we mimicked natural allergen exposure by giving tiny doses of dust-mite extract (equivalent to estimated daily exposure in a typical bedroom) in three weekly sessions for 4 wk. Nine mild asthmatic adults who were highly sensitive to dust-mite allergen participated in the study. Serial assessments of bronchial reactivity by methacholine challenge, pulmonary function, symptoms, and bronchodilator requirements were obtained. Seven of nine subjects had a twofold or more (median: 6, range: 2.7 to 25) reduction (p = 0.008) in PC20, after which saline inhalations were substituted for dust-mite extract. Bronchial reactivity returned to normal within 2 to 3 wk after cessation of dust-mite inhalations in all but one subject. Predosing FEV1 dropped 10% over 4 wk of provocation (p = 0.001) and 7 of 9 returned to prestudy level within 2 wk after dosing was stopped. Late-phase responses were seen in 6 of 9 subjects. We conclude that repeated aerosol exposure to dust-mite allergen in doses comparable to natural bedroom exposure is sufficient to adversely affect pulmonary function and bronchial hyperractivity in sensitized individuals. These changes are rapidly reversible. This low-dose provocational strategy provides an attractive model for the experimental study of allergic asthma. Arshad SH, Hamilton RG, Adkinson NF, Jr. Repeated aerosol exposure to small doses of allergen: a model for chronic allergic asthma.

Ragweed-specific antibodies in bronchoalveolar lavage fluids and serum before and after segmental lung challenge: IgE and IgA associated with eosinophil degranulation.

BACKGROUND: Migration of eosinophils and release of eosinophil degranulation products into bronchoalveolar lavage fluid is a consistent finding in studies of late responses to allergen challenge in the lung. However, the mechanism of eosinophil activation and release of eosinophil products in vivo is unclear. OBJECTIVE: We investigated the hypothesis that antigen-specific IgG, IgA, secretory IgA, or IgE is responsible for the eosinophil activation observed in the late-phase pulmonary reaction. METHODS: Ragweed-specific IgE, IgA, secretory IgA, and IgG were measured by monoclonal antibody-based immunoassays in bronchoalveolar lavage (BAL) fluid and in serum from 19 asthmatic subjects allergic to ragweed and six healthy nonallergic control subjects before and 20 hours after segmental lung challenge with ragweed extract. Eosinophil cationic protein (ECP) was also measured in BAL fluid as a marker of eosinophil activation. RESULTS: Most allergic asthmatic subjects had detectable levels of ragweed-specific IgE, IgA, and IgG in their serum and BAL fluid, whereas normal subjects had ragweed-specific IgA with no ragweed-specific IgE and little ragweed-specific IgG. IgA was the dominant ragweed-specific antibody isotype in BAL fluids. Ragweed-specific sIgA (r[s] = 0.52, p = 0.02) and IgA (r[s] = 0.50, p = 0.03) in BAL fluid after segmental lung challenge were significantly correlated with ECP. Ragweed-specific IgE and IgA in serum also correlated with ECP (r[s] = 0.74, p < 0.001 and r[s] = 0.48, p = 0.04, respectively). CONCLUSIONS: The correlation of allergen-specific IgA and IgE antibody levels with ECP as a marker of eosinophil degranulation suggests an important role for IgE antibodies in allergic pulmonary inflammation and a potential role for antigen-specific IgA in eosinophil degranulation in the lung after antigen challenge.

Nasal provocation with allergen induces a secondary serum IgE antibody response.

The study of the IgE response to seasonal antigen exposure is limited by its occurrence once a year and by the variability of patient exposure to pollens. To overcome these problems, we investigated whether nasal challenge with antigen causes an increase in serum anti-ragweed IgE levels. We challenged individuals with ragweed allergy intranasally with nanogram quantities of ragweed antigen extract and measured their serum anti-ragweed IgE levels before and at weekly intervals after challenge. In a series of studies we found that there was a reproducible rise in antigen-specific serum IgE levels beginning the first week after challenge that plateaued at about 180% of baseline levels during the fourth week and remained elevated for 8 weeks. Not all individuals showed this response. The magnitude of the allergen-specific IgE response to nasal challenge appeared to be greater than the response to seasonal exposure. Treatment with intranasal beclomethasone before challenge did not affect the response. The results demonstrate a human in vivo model for the study of the antigen-specific secondary IgE response to allergen.