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TABLE OF CONTENTS I. Preface S1 II. Glossary S2 III. Classification of Recommendations and Evidence Category S3 IV. Executive Summary S3 V. Collation of Summary Statements S5 VI. Algorithm and Annotations S7 VII. Clinical Background S9 VIII. Pathophysiology of CD S9 IX. Susceptibility and Genetics of CD S10 X. Clinical Diagnosis of ACD S11 XI. Patch Tests S13 XII. Differential Diagnosis of CD S17 XIII. Special Exposures Associated With CD S17 XIV. ACD in Children S24 XV. Management and Prognosis of ACD S24 XVI. Appendix S27 XVII. Acknowledgments S30 XVIII. References S30

TABLE OF CONTENTS I. Preface S1 II. Glossary S2 III. Executive Summary S3 IV. Summary Statements S6 V. Classification of Major Food Allergens and Clinical Implications S11 VI. Mucosal Immune Responses Induced by Foods S12 VII. The Clinical Spectrum of Food Allergy S15 VIII. Algorithm and Annotations S18 IX. Prevalence and Epidemiology S21 X. Natural History of Food Allergy S22 XI. Risk Factors and Prevention of Food Allergy S23 XII. Cross-reactivity of Food Allergens S24 XIII. Adverse Reactions to Food Additives S30 XIV. Genetically Modified Foods S32 XV. Diagnosis of Food Allergy S33 XVI. Food-Dependent Exercise-Induced Anaphylaxis S39 XVII. Differential Diagnosis of Adverse Reactions to Foods S40 XVIII. General Management of Food Allergy S44 XIX. Management in Special Settings and Circumstances S45 XX. Future Directions S47 XXI. Appendix: Suggested Oral Challenge Methods S48 XXII. Acknowledgments S49 XXIII. References S50

The second Jack Pepys Workshop on Occupational Asthma was held in Toronto, Canada, in May 2004. The present report summarises key questions and research needs as identified by the international participants. The audiotapes from the workshop discussions were summarised by the organising chairs of the Symposium and the resulting document was circulated for input from all invited workshop participants. In total, 100 key questions and research needs were identified. Identified needs included: provision of different definitions depending on the use of data; explanations for differences in frequency studies; and better characterisation of genetic and environmental determinants of occupational asthma. The role of irritants and the pathogenesis of various forms of work-related asthma need further research, and there are also questions and research needs for diagnosis, prevention and understanding of persistence and airway remodelling. In conclusion, although advances have been made in the understanding of occupational asthma and other work-related asthma, further key issues remain that need addressing.

Background Herbal products are widely used by consumers as alternatives to prescription drugs in treating symptoms of allergic rhinitis. However, there have been few placebo-controlled clinical trials that have examined the efficacy or safety of these products. Although grapeseed extract (GSE) is an herbal that is marketed for treating allergic rhinitis, its efficacy is unproven. Objective The aim of this study was to compare the efficacy and safety of GSE with placebo in the treatment of seasonal allergic rhinitis (SAR). Methods This was a randomized, double-blind, placebo-controlled study of GSE 100 mg, twice daily, versus placebo. Patients with SAR and skin prick test sensitivity to ragweed were randomized to 8 weeks of active treatment or placebo which was begun before the ragweed pollen season. Outcomes included: daily symptom diary scores recorded by patients, rhinitis quality of life scores at baseline and after 4 and 8 weeks of treatment; and requirements for rescue chlorpheniramine. Safety was monitored with routine laboratory studies. Results Over 8 weeks of treatment, no significant differences were observed between active and placebo groups in rhinitis quality of life assessments, symptom diary scores, or requirements for rescue antihistamine. No significant laboratory abnormalities were detected. Conclusions This study did not show trends supporting the efficacy of GSE in the treatment of SAR.

Although health risks to pesticides containing Bacillus thuringiensis (Bt) have been minimal, the potential allergenicity of these organisms has not been evaluated. Therefore, a health survey was conducted in farm workers before and after exposure to Bt pesticides. Farm workers who picked vegetables that required Bt pesticide spraying were evaluated before the initial spraying operation (n = 48) and 1 and 4 months after (n = 32 and 20, respectively). Two groups of low- (n = 44) and medium- (n = 34) exposure workers not directly exposed to Bt spraying were also assessed. The investigation included questionnaires, nasal/mouth lavages, ventilatory function assessment, and skin tests to indigenous aeroallergens and to a variety of Bt spore and vegetative preparations. To authenticate exposure to the organism present in the commercial preparation, isolates from lavage specimens were tested for Bt genes by DNA-DNA hybridization. Humoral immunoglobulin G (IgG) and immunoglobulin E (IgE) antibody responses to spore and vegetative Bt extracts were assayed. There was no evidence of occupationally related respiratory symptoms. Positive skin-prick tests to several spore extracts were seen chiefly in exposed workers. In particular, there was a significant (p < 0.05) increase in the number of positive skin tests to spore extracts 1 and 4 months after exposure to Bt spray. The number of positive skin test responses was also significantly higher in high (p < 0.05) than in low- or medium-exposure workers. The majority of nasal lavage cultures from exposed workers was positive for the commercial Bt organism, as demonstrated by specific molecular genetic probes. Specific IgE antibodies were present in more high-exposure workers (p < 0.05) than in the low and medium groups. Specific IgG antibodies occurred more in the high (p < 0.05) than in the low-exposure group. Specific IgG and IgE antibodies to vegetative organisms were present in all groups of workers. Exposure to Bt sprays may lead to allergic skin sensitization and induction of IgE and IgG antibodies, or both. Images Figure 1 Figure 2 Figure 3

BACKGROUND Localized vaginal inflammation after contact with seminal plasma has been previously described but without a clear understanding of the underlying immunopathogenesis. The purpose of this report is to describe three women who presented with localized postcoital vaginal reactions that were successfully treated with rapid immunotherapy using human seminal plasma proteins. CASES One atopic and two nonatopic women with histories of immediate onset of localized postcoital vaginal symptoms and immediate skin test reactions to human seminal plasma were treated with rapid immunotherapy using their spouse's purified seminal plasma protein fractions. One of the women had decreased cutaneous reactivity post-therapy and detectable circulating specific immunoglobulin (Ig) G and IgE antibodies to her spouse's fractionated seminal plasma proteins. Increased IgG, IgE, and IgA antibodies were found in these patients' sera to whole seminal plasma of a normal male control and to fractionated proteins of different men, indicating that one or more homologous seminal plasma proteins may be responsible for these reactions. Their localized vaginal symptoms resolved completely after rapid immunotherapy treatment. Two of the women have remained symptom-free, whereas the third woman had recurrent localized vaginal symptoms after failing to maintain frequent sexual intercourse after treatment. CONCLUSIONS Rapid immunotherapy immediately alleviated vaginal reactions to seminal plasma in all patients. These cases indicate that the pathogenesis of some localized vaginal inflammatory reactions may involve IgE-mediated or other immune responses to human seminal plasma proteins.

Diisocyanate chemicals are leading causes of occupational asthma (OA).We conducted a cross-sectional study of 243 workers exposed to diphenylmethane diisocyanate (MDI) in a urethane mold plant that had been designed to minimize MDI exposure (levels were maintained below 0.005 ppm and were continuously monitored). All participants were screened by questionnaire and tests for serum antibodies to MDI-human serum albumin (HSA). On the basis of questionnaire responses, diagnoses were derived that included OA; non-OA; work-related and non-work-related rhinitis; and lower respiratory irritant responses. Serial peak expiratory flow rate studies were performed for 2 weeks in 43 workers with and in 23 workers without lower respiratory symptoms.Results of serial peak expiratory flow rate studies were abnormal in 3 (33%) of 9 workers with OA, in 2 (50%) of 4 with non-OA, and in 2 (9%) of 23 case control subjects. A significant association was found between peak flow rate variability and a questionnaire asthma diagnosis (chi 2 p0.002). Physicians confirmed three cases of OA, one of which occurred in a control worker who was free of symptoms. In all three cases asthma symptoms remitted after the worker left the workplace. Serum specific IgE and IgG levels were elevated in 2 of 243 workers, one of whom was prick test positive to MDI-HSA and had had cutaneous anaphylaxis after MDI exposure.On the basis of these cases, specific work activities associated with exposure to MDI were identified and corrective measures were instituted. Strict control and monitoring of ambient MDI exposure was associated with a low prevalence of specific sensitization to MDI and a lower than expected prevalence of OA.

We recently demonstrated morphine-6-hemisuccinate-human serum albumin conjugate (M-6-HS-HSA)-specific IgG in serum from ethic narcotics-manufacturing workers. In this article, we present results of epicutaneous tests to opiate compounds and lung-function studies in these same workers. Thirty-nine workers, exposed to opiates, were evaluated for possible work-related changes in lung function and were administered a questionnaire concerning opiate exposure and health history in February 1988. In December 1988, 33 employees with occupational exposure to opiates, six other workers (New Jersey referent) employed at the same factory with minimal exposure to opiate compounds, and 17 nonexposed individuals from Cincinnati, Ohio, were subjected to epicutaneous threshold testing with a panel of six opiate compounds and nine common aeroallergens. In opiate-exposed workers, significantly lower epicutaneous threshold concentrations were detected (compared to New Jersey referent and Cincinnati control subjects) for dihydrocodeine (p less than 0.01), hydrocodone (p less than 0.05), codeine (p less than 0.01), and morphine (p less than 0.05). Significant associates existed among epicutaneous threshold concentrations between the agents tested; that is, individuals with a positive morphine skin test would generally have a positive codeine skin test, etc. Atopic status (positive cutaneous test results to two or more of nine common aeroallergens) was not significantly associated (p greater than 0.05) with positive opiate skin sensitivity. Although the mean cross-shift decrements in FEV1 for all workers were nonsignificant, five opiate-exposed individuals demonstrated cross-shift decrements in FEV1 of greater than 10%. Daily maximum-minus-minimum changes in workweek PEFR (PEFRmax-min) were significantly reduced for Monday through Thursday (p less than 0.05) compared to PEFRmax-min changes during a nonwork, nonexposure 3-day weekend. Ten exposed workers demonstrated daily PEFRmax-min changes of greater than 20%, suggesting acute airway obstruction. Increased cutaneous reactivity to opiate compounds among opiate-exposed workers may reflect development of pharmacologic hyperresponsiveness to opiate compounds.

The discovery of food aversion learning several decades ago attracted widespread interest because it is a highly adaptive, powerful type of learning with features which make it unusual and robust when compared to other learning paradigms. It was also of interest because it had both practical and theoretical ramifications. It has relevance to human problems in that it is likely to contribute to food choice and appetite problems, especially in certain clinical situations. In recent years it has been recognized that the robustness of this learning makes it an excellent model for neurobiologists interested in understanding neural mechanisms of plasticity. This chapter provides a broad overview of these aspects of taste aversion learning and points to areas where questions remain and additional research is needed.

An investigation of a platinum refinery operation consisted of an administered questionnaire, spirometry, skin prick testing with platinum salts and common aeroallergens, serum total IgE, radioallergosorbent test for platinum salts, and measurement of nonspecific airway hyperresponsiveness by cold air challenge testing. Among 136 employees examined, there were 107 current and 29 medically terminated workers; 23 (17 percent) subjects had a positive platinum salts prick skin test and 19 (14 percent) displayed a positive cold air challenge. RAST binding for platinum salts IgE antibodies showed a high level of agreement with platinum skin prick test results. A proportion (63 percent) of the population (74 current and 12 terminated workers) underwent repeat platinum skin testing one year later. Among current workers, there was conversion of the platinum skin test from negative to a positive test in five employees, with three conversions occurring in workers who showed only a positive cold air challenge test the year before. Platinum skin sensitivity, asthma symptoms, and nonspecific airway hyperresponsiveness persisted for years after termination of exposure in some medically terminated workers presumably because of a delay in removal from work of employees who became sensitized to platinum salts. It is suggested that proper surveillance for occupational asthma involves the use of several testing procedures. Prompt removal from work of individuals found to become sensitized to platinum salts is important in this industry.

Background: Increased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE. Objective: We hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms. Methods: Two hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period. Results: Adverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE–dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (≤24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months. Conclusions: Because rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases. (J Allergy Clin Immunol 1997;100:110-21.)

The density and species prevalence of dust mites were determined at various times over a 5-year-period in 252 homes of dust mite sensitive people with asthma who lived in eight geographic areas of the United States (Cincinnati, Ohio; New Orleans, La.; Memphis, Tenn.; Galveston, Texas; Greenville, N.C.; Delray Beach, Fla.; San Diego and Los Angeles, Calif.). The most common dust mites found in the homes were Dermatophagoides farinae (DF), D. pteronyssinus (DP), Euroglyphus maynei (EM), and Blomia tropicalis. All homes in all locations contained Dermatophagoides spp. mites, but few homes were populated exclusively by either DF or DP alone. Most homes (81.7%) were coinhabitated by both DF and DP. In coinhabited homes one species was predominant and usually made up at least 75% of the total mite population. Prevalence of the dominant or only species present varied between homes within a geographic area. EM occurred in significant numbers in 35.7% of homes in New Orleans, Memphis, Galveston, Delray Beach, and San Diego. Blomia tropicalis occurred in these same cities but in low densities. For all dust samples, only 13 homes of the 252 sampled had 100 or fewer mites/gm dust, which is considered to be the threshold for sensitivity. Most homes had average mite densities of 500 or more mites/gm dust. The results of the present study suggest a significant and widespread occurrence of both DF and DP. Therefore extracts of both mite species should be considered for diagnostic tests and immunotherapy. Significant levels of EM were present in some areas. Thus sensitivity to EM should be considered in these areas.

According to the International Narcotics Control Board, over 45,000 kg of morphine and 54,000 kg of codeine were ethically manufactured in 1986 at three facilities in the United States. Little information exists about possible adverse health effects associated with workplace exposure to opiate compounds in this industry. Because there are no specific federal standards for workplace exposure to narcotic dusts, exposure-control defaults to the nuisance dust standard (10 mg/m3, as an 8 hr time-weighted average). Narcotics manufacturing workers were evaluated for anti-morphine IgG before and 10 mo. after the implementation of an improved respiratory protection program (RPP). Significantly elevated IgG levels were measured before the improved RPP (P less than 0.005). After the improved RPP, a significant reduction was observed (P less than 0.001), suggesting that specific antibody levels could be used as biomarkers of exposure. Inhibition studies showed that the antibodies were specifically directed against morphine with some cross reactivity with morphine derivatives. Preliminary results are also shown which indicate that similar anti-morphine antibodies are present in the sera of intravenous heroin abusers. Elevated levels (P less than 0.05) of anti-morphine antibodies were detected in sera from heroin abusers, providing evidence that similar antibodies may be produced from non-occupational exposure to opiates. These finding have potentially far-reaching implications for addiction research and drug testing.

Rationale Churg-Strauss Syndrome (CSS) consists of necrotizing vasculitis of small to medium sized arteries, necrotizing extravascular granulomas, and prominent tissue eosinophilia. CSS classically begins with a prolonged period of allergic rhinitis, nasal polyposis, and asthma. This is followed by the development of peripheral blood eosinophilia and eosinophilic tissue infiltrates, with culmination in a systemic vasculitic phase. Many published series investigating CSS exclude patients without asthma. Clinicians may overlook the diagnosis of CSS in patients who lack asthma. Methods We report the case of a 57-year-old male in whom CSS was diagnosed in the absence of asthma or bronchial hyperresponsiveness. Results The patient had a nine-month history of progressive lower extremity weakness and pain accompanied by a peripheral eosinophilia (absolute eosinophil count approximately 5500 cells per microliter). Past medical history was significant for interstitial lung disease of unknown etiology, with a restrictive pattern on pulmonary function testing. A methacholine challenge test was negative. Definitive diagnosis of CSS was made with muscle and nerve biopsies, which demonstrated necrotizing vasculitis of medium-sized arteries, predominately lymphocytic extravascular granulomas with few eosinophils, and eosinophil-rich endomysial inflammatory infiltrate with evidence of eosinophil degranulation. The combination of clinical and laboratory features in this case meets four of the six 1990 ACR diagnostic criteria for CSS, confirming the diagnosis with greater than 99% specificity. Conclusions Churg-Strauss Syndrome does occur in the absence of asthma. Clinicians should not exclude the possibility of this diagnosis in patients lacking asthma.

Six extracts were prepared from Alternaria tenuis isolates ATCC 6663, ATCC 16086 and DAOM (Agriculture Canada) 183905 grown separately on two synthetic media, revised tobacco and Czapek’s, and their biochemical and immunological properties were examined. High-performance liquid chromatography revealed considerable variations in UV absorbance and carbohydrate profiles among extracts from the different isolates. These differences were less marked among samples of the same isolate cultured on different media. Enzyme screening showed that all extracts contained large amounts of phosphatases and glucosidases and moderate quantities of esterases. Only the α-galactosidase activity showed any correlation with allergenic activity. No significant variation was observed in isoelectric focusing patterns. Extensive antigenic cross-reactivity even between the different isolates was found in precipitin studies. In mouse IgE passive cutaneous anaphylaxis tests, all extracts gave reactions of similar intensity. In direct RAST and RAST inhibition assays, ATCC 16086 grown on revised tobacco medium was found to be the most potent and approached the activity of an extract from a commercial material (B-I). DAOM 183905 grown on either medium was next in potency while ATCC 6663 samples were the least potent. The results indicate that it is possible to obtain extracts of high allergenic potency for standardization purposes from growth of selected A. tenuis isolates on a chemically defined medium.

Leukocyte migration inhibitory factor assay was employed as an in vitro diagnostic aid in nickel dermatitis, the second most common contact dermatitis in North America. 15 patch test-positive and 5 patch test-negative patients, all giving a past history suggestive of nickel dermatitis, were investigated. Significant inhibition of leukocyte migration in both groups of patients was obtained only with nickel sulfate-albumin conjugate and not with unconjugated nickel sulfate. Specificity of this system was tested by utilizing an unrelated metallic albumin complex, and no inhibition was found. When patch testing is equivocal or contraindicated, this in vitro technique may be a practical alternative.

Abundance of the house dust mites, Dermatophagoides farinae and D. pteronyssinus, in various sites in the homes of dust-sensitive patients was sequentially monitored at approximately 3 wk intervals for 2 yr, and mite density was correlated with indoor physical and climatic factors. Significantly higher mite levels occurred on the most heavily used fabric-upholstered furniture and carpeted floor areas of the living/family room and bedrooms. Mattresses were not found to be the major foci for mites. No significant positive correlation was noted between mite abundance and frequency or thoroughness of cleaning, amount of dust, and age of furnishings or dwelling. Significantly higher mite levels occurred on carpeted floors than on noncarpeted floors. Successive vacuuming did not significantly reduce mite abundance. Mite density exhibited a seasonal fluctuation, with highest density occurring in the humid summer months and the lowest density during the dryer, late heating season. Live mites were more abundant than dead mites during the period when total abundance was high. In homes inhabited by both species, D. farinae was the dominant species, except in one home that had a significantly higher relative humidity.

The efficacy and safety of astemizole (AST), a new long-acting H1 antagonist with minimal sedative or anticholinergic side effects, were studied in an 8-week double-blind trial of 51 patients with chronic idiopathic urticaria. Patients with chronic idiopathic urticaria were randomized to AST-treated (10 mg every day) or placebo-treated groups. Patients were followed at weekly intervals and evaluated for pruritus, erythema, extent of wheals, frequency of urticarial episodes, and total control of urticaria. Only three of 27 AST-treated patients stopped the double-blind phase before 8 weeks because of inadequate response as compared to 11 of 24 placebo-treated subjects (p = 0.027). On the last evaluable visit of the double-blind phase of the study, 85% of the AST-treated patients reported an excellent or good response compared to 30% of the placebo-treated group (p = 0.0001). AST-treated patients also reported significant improvement compared to placebo-treated patients in pruritus (p = 0.0001), erythema (p = 0.0001), and extent of wheals (p = 0.003). Mild sedative effects were observed in only two of 27 patients receiving AST. It was concluded that AST is a potent and safe drug for symptomatic control of chronic idiopathic urticaria.

Comparison of intracutaneous skin tests and RAST in 2 groups of patients, one consisting of 16 individuals having multiple allergies to pollen, mold and animal dander and the other of 10 patients allergic to mold only, revealed that skin tests were more sensitive than RAST. Skin reactions of 3+ to 4+ were frequently associated with negative RAST results. This was observed more so in mold-allergic patients. In a few cases (6%) RAST showed 2+ reactions while the skin tests were negative. Leukocytes from allergic individuals who had positive skin tests and negative RAST released a significant amount of histamine upon challenge with specific allergen as well as antihuman IgG4, suggesting that this immunoglobulin is a functional component of some immediate hypersensitivity reactions.

House dust mite density in 5 homes with high mite numbers exhibited a seasonal fluctuation, with peak density occurring during the humid summer months and lowest density during the drier late winter heating season. We hypothesize that house dust mite populations survive dry winter months in homes as desiccation-resistant pharate tritonymphs. This life stage provides the major source of breeding mites for population growth in the spring.

Abnormalities of second-wave platelet aggregation were demonstrated in 17 of 33 asthmatic patients in whom drug and diet intake were controlled in the hospital. Mean abnormal responses were significantly greater after epinephrine- (p less than 0.001), adenosine diphosphate-(less than 0.001), collagen- (p = 0.01), and thrombin- (p less than 0.001) induced platelet aggregation in patients with immunologically mediated asthma and serum IgE levels greater than 250 U/ml as compared to patients without immunologic factors and/or normal controls. Mean pollen-specific radioallergosorbent (RAST) binding was also significantly higher in patients with abnormal aggregation as compared to normal platelet responders (p = 0.02). Release of serotonin generally reflected abnormal aggregation patterns in asthmatic patients. Platelet factor 4 release was significantly decreased in the same groups of patients. These results suggest that the allergic state may affect platelet membrane responsiveness to multiple aggregating agents.

House dust mite materials containing D. farinae and their emanations were isolated from laboratory cultures by an ethanol suspension method, and an extract was prepared. The protein nitrogen content of this extract was 250 μg PN/ml. Allergenic potency of the extract was determined by scratch and intracutaneous skin testing. The extract showed good discrimination in patient sensitivity when tested with commercial house dust extracts.

Acid anhydride compounds cause IgE-mediated respiratory sensitization in the workplace. In this study reaginic responses in four workers sensitized to phthalic anhydride (PA), hexahydrophthalic (HHPA), or himic anhydride (HA) were determined by direct RAST by use of PA-human serum albumin (HSA), HPPA-HSA, and HA-HSA methylcellulose disc substrates. RAST inhibition of binding to anhydride-HSA substrates was done with various concentrations of sodium salts, lysine, and HSA conjugates of PA, HHPA, HA, and trimellitic anhydride (TMA) in order to characterize cross-reactivity and specificity of humoral responses in these workers. Molar concentrations of anhydride bound to lysine and HSA carriers were assayed by protein hydrolysis followed by gas Chromatographic analysis. Significant direct RAST binding against PA-HSA, HHPA-HSA, and HA-HSA was found in all four workers. PA-HSA-IgE binding in one PA-sensitive worker (no. 1) was inhibited significantly by PA-HSA alone and not by sodium PA or PA lysine. In contrast, another PA-sensitized worker (no. 2) exhibited 50% inhibition of PA-HSA binding by PA-HSA (1 × 10 −9 M), PA-lysine (7 × 10 −8 M), and NaPA (1 × 10 −7 M); no inhibition of PA-HSA by heterologous HHPA-, HA-, or TMA-inhibitory reagents was found in either of the PA workers. RAST binding to HHPA-HSA in the HHPA-sensitive worker was inhibited by HHPA-HSA alone. In the HA-sensitive worker, 50% inhibition of HA-HSA substrate was accomplished by HA-HSA (5 × 10 −11 M), HA-lysine (5 × 10 −9 M), NaHA (8 × 10 −9 M), and also 2 log 10 concentrations less of respective HHPA but not with PA-inhibiting reagents. In this study, acid anhydride-induced reaginic responses were heterogeneous and differed between individuals. Hapten-specific new antigenic determinants were demonstrated in some workers (PA no. 2 and HA), whereas new antigenic determinants with relatively less hapten specificity were present in others (PA no. 1 and HHPA), Haptenic cross-reactivity between HA, PA, and HHPA allergenic determinants in the HA-sensitive worker was also demonstrated.

The biochemical and immunological characteristics of a series of commercial samples of Alternaria tenuis were examined, including samples from two different companies. There was a considerable variation in the biochemical parameters such as the gel filtration profile on Sephadex G-100, isoelectric focussing pattern and immunodiffusion precipitin band pattern. The content and proportion of two high molecular weight polysaccharides, one a galactomannan and the other a glucan, also varied greatly. In contrast, the allergenic properties of the samples were more consistent. In rat IgE passive cutaneous anaphylaxis tests, extensive cross-reactivity was observed among batches from the same company, but this cross-reactivity was weaker when batches from the two companies were compared. In direct radioallergosorbent tests (RAST) the samples showed similar reactivities, but RAST inhibition tests showed a 40-fold range in activity between samples from one company and 55-fold between batches from the two sources. It was found that the proportions of the major A. tenuis allergen and a related hypoallergenic antigen in the samples were relatively constant, hence RAST inhibition can be used as a measure of allergenic potency despite the presence of this cross-reacting antigen. The lack of correlation between allergenic and biochemical properties of the various samples suggests that a simple biochemical test is unlikely to be a satisfactory replacement for the RAST inhibition assay in standardizing A. tenuis extracts.

Asthma can be induced or exacerbated at work by several means. Four work-related disorders, characterized by airflow obstruction and airway hyperresponsivene ss, have been described. These include: occupational asthma, byssinosis, the reactive airways dysfunction syndrome, and variable airflow obstruction caused by irritant substances. This committee has elected to focus only on the topic of occupational asthma, which is defined as asthma that is either induced or exacerbated by exposure to a specific (as opposed to an irritant) agent found at work. The Committee has decided to exclude discussion of other causes of asthmatic exacerbations at work, which does not mean that these conditions are not important. It may also, as discussed in other sections of this report, be quite difficult to distinguish an irritant effect from a specific bronchospastic response. A preexisting history of asthma before exposure to the offending agent does not preclude the diagnosis of occupational asthma.

The allergenic potencies of samples of two commercial Alternaria tenuis extracts stored under various conditions were compared at 3 months intervals over a period of 1 year. Aliquots of the extracts at 5.12 mg/ml were maintained in: (a) saline; (b) 50% glycerol-saline mixture; (c) 0.4% phenol-saline; (d) 0.4% phenol-saline containing 0.03% human serum albumin, and (e) samples were also kept in lyophilized form. The samples were stored at ––20, 4, 24, 37 and 56°C. Their potency was measured by radioallergosorbent inhibition assay and by mouse IgE passive cutaneous anaphylaxis (PCA) tests. The lyophilized extracts fully maintained their activity at all temperatures for 12 months. Aqueous extracts with or without preservatives also maintained their potency if stored at ––20,4 and 24°C, but showed a significant loss of PCA activity at 56°C, after 3 months. A deleterious effect of phenol was observed in one of the extracts stored at ––20°C for 3 months, by PCA tests. The use of preservatives to retain potency over a period of 12 months is therefore unnecessary and may be deleterious. The results indicate that, while storage of A. tenuis in a lyophilized form is best at all temperatures, aqueous extracts are also remarkedly stable when stored at ––20, 4 and 24°C, over a 12-month period.

Crossed immunoelectrophoresis (CIE) and crossed radioimmunoelectrophoresis (CRIE) were used to characterize antigens (Ags) and allergens derived from Dermatophagoides farinae (DF) culture media-free mite body and mite fecal matter extracts. CIE of DF body and DF feces extracts revealed the presence of 35 and 20 Ags, respectively. CRIE experiments demonstrated IgE binding by 14 and seven DF body and DF feces Ags, respectively, when CIE gels were incubated with reference sera from clinically mite-sensitive patients. Binding of specific IgE to the various Ags in the two extracts varied significantly both in frequency and in strength from patient to patient and within the same patient's serum. Sera from some patients demonstrated IgE binding predilection for specific DF body Ags, whereas other sera exhibited greater binding preference for DF feces Ags. Homologous, heterologous, and intermediate gel CIE and CRIE clearly demonstrated that DF bodies and DF feces share some common Ags or epitopes, but the two different extracts also were quantitatively different. Some Ags and allergens originate from mite body material and are not present in mite feces. These results indicate that only extracts containing high concentrations of both body and fecal allergens should be used in clinical testing and therapy.

Nine adult male Cynomolgus monkeys (Macaca fascicularis) were exposed for 10 min to 2.55 +/- 0.03 ppm formaldehyde (HCHO; mean +/- standard error of the mean, SEM) generated from formalin with a newly developed HCHO challenge system. The generation system was capable of producing highly stable HCHO vapor concentrations with fluctuations of HCHO concentrations of less than +/- 5%. The experimental design included pre-exposure methacholine challenge to determine if responses to HCHO were associated with pre-existing bronchial hyperreactivity. Significant changes in average pulmonary flow resistance (RL) were observed (compared to control RL values) at 2 (p less than 0.01), 5 (p less than 0.01), and 10 min (p less than 0.005) post-HCHO challenge. Pre-challenge RL values (mean +/- SEM) were 11.3 +/- 1.4 cm H2O.l/s, while at 2, 5, and 10 min after HCHO challenge, values were 16.1 +/- 2.1, 16.9 +/- 2.8 and 20.0 +/- 3.4 cm H2O.l/s, respectively. Methacholine challenge data suggest that reactions to HCHO tend to be greater in monkeys hyperreactive to methacholine, but the relationship does not reach statistical significance in this small series of animals. These data indicate that significant pulmonary function deficits occur immediately after challenge with 2.55 ppm HCHO vapor in monkeys.

Crossed immunoelectrophoresis (CIE) and crossed radioimmunoelectrophoresis (CRIE) demonstrated that extracts of both bodies and feces of Dermatophagoides pteronyssinus (DP) contained multiple antigens and allergens. DP feces extract contained significantly fewer antigens than did DP body extract. Five DP body antigens and at least 4 DP feces antigens were allergens and bound specific IgE in the 2 mite-sensitive reference sera tested. Several antigens in each extract were potent allergens. Heterologous CIE demonstrated some cross antigenicity between body and fecal extracts, but many of the antigens present in DP bodies were not present in DP feces. All cross-reacting DP body and DP feces antigens were weak allergens for the 2 test sera, based on the long autoradiographic time required for visualization compared to the relatively short exposure time required to visualize IgE binding with the homologous CRIE system. Binding of specific IgE in mite-allergic patient sera to the many antigens varied significantly both in frequency and in strength between and within patients. The results of the study are particularly significant because extracts produced from well-defined, media-free mite body and relatively pure mite feces were used. Inconsistencies in the reported number and potency of mite antigens and allergens are due to the use of poorly defined mite extracts of widely varying quality. Use of highly concentrated, well-defined, natural mite material is important for determining the origin and significance of specific mite allergens.

Heterologous crossed immunoelectrophoresis (CIE) analysis demonstrated that Dermatophagoides pteronyssinus body and D. farinae body extracts contained up to 21 cross-reacting antigens (Ags). Incubation of CIE gels with two mite-sensitive individual sera and a serum pool of mite-sensitive patients indicated that up to nine cross-reacting Ags bound mite-specific IgE on crossed radioimmunoelectrophoresis and were common allergens. Likewise, heterologous CIE analysis of D. pteronyssinus feces and D. farinae feces extracts demonstrated approximately 13 cross-reacting Ags. Up to eight of these cross-reacting fecal Ags bound mite feces-specific human IgE. Additional cross antigenicity and allergenicity was evident between body extract of one species and feces extract of the other species. The amount of specific IgE binding to cross-reacting Ags in interspecific extracts varied both between and within individual sera. Different cross-reacting Ags contained potent allergens, and these varied from patient to patient. Also of major significance was the fact that body and fecal extracts of each species contained Ags and allergens that were unique and species specific.

Ten individuals developed an asthma-like illness after a single exposure to high levels of an irritating vapor, fume, or smoke. In most instances, the high level exposure was the result of an accident occurring in the workplace or a situation where there was poor ventilation and limited air exchange in the area. In all cases, symptoms developed within a few hours and often minutes after exposure. We have designated the illness as reactive airway dysfunction syndrome (RADS) because a consistent physiologic accompaniment was airways hyperreactivity. When tested, all subjects showed positive methacholine challenge tests. No documented preexisting respiratory illness was identified nor did subjects relate past respiratory complaints. In two subjects, atopy was documented, but in all others, no evidence of allergy was identified. In the majority of the cases, there was persistence of respiratory symptoms and continuation of airways hyperreactivity for more than one year and often several years after the incident. The incriminated etiologic agent varied, but all shared a common characteristic of being irritant in nature. In two cases, bronchial biopsy specimens were available, and an airways inflammatory response was noted. This investigation suggests acute high level, uncontrolled irritant exposures may cause an asthma-like syndrome in some individuals which is different from typical occupational asthma. It can lead to long-term sequelae and chronic airways disease. Nonimmunologic mechanisms seem operative in the pathogenesis of this syndrome.

Chemicals of the isocyanate family are required for the production of a variety of commercial products, including insulation materials, automobile upholstery, furniture, and surface coatings. They are highly reactive with other chemicals containing hydrogen atoms. Early reports of medical toxicity appeared 25 yr ago and have been confirmed on a worldwide basis. Adverse respiratory symptoms have been the chief concern, and a wide spectrum of work-related lung diseases has been described. Although some of these reactions were undoubtedly due to primary irritation, the majority presented with airways obstructive abnormalities clearly identified as classic asthma. The possibility of an underlying hypersensitivity mechanism was suggested by the insidious onset of symptoms, a latency period of weeks to months, peripheral and tissue eosinophilia, and the elicitation of symptoms after exposure to very small subtoxic levels of these chemicals. Some cases consistent with the unique clinical features of hypersensitivity pneumonitis have also been recognized. Early animal experimental studies had suggested that immunologic factors were important etiologic components of these syndromes. However, when several independent groups of investigators could not confirm these preliminary results, the pathogenesis of these diseases soon became a highly controversial subject. Current experimental and clinical approaches have therefore been redirected to encompass the role of nonimmunologic mechanisms in the pathogenesis of adverse isocyanate reactions. Collectively, these recent investigations suggest that both immunologic and nonimmunologic mechanisms appear to be operative as causes of isocyanate-induced asthma. There is in vitro evidence both for and against possible specific pharmacologic effects of diisocyanate compounds. Parallel bronchoprovocation studies comparing the activities of diisocyanates, methacholine, and histamine suggest that diisocyanates may act either as direct pharmacologic agonists or as inducers of nonspecific bronchial reactivity. Recent evidence of immunoreactivity to both monofunctional and bifunctional isocyanates in several animal models and sensitized workers has also mandated a reassessment of immunologic factors. Hapten-specific, IgE-mediated antibody responses have been observed in both animal and human investigations. However, only a small subset of sensitized workers developed specific IgE antibodies to p-tolyl monoisocyanate and/or hexyl monoisocyanate. Both IgE and precipitating antibodies have been reported in several cases of workers sensitized to methylene diphenyl diisocyanate. Some toluene diisocyanate-sensitive patients also exhibit other types of immunologic responses, including antigen-induced lymphocyte transformation and synthesis of a leukocyte inhibitory factor. Detailed immunologic investigations have not yet been carried out in most of the suspected cases of hypersensitivity pneumonitis. Other possible nonimmunologic sequelae of isocyanate reactions include chronic bronchitis, recurrent pneumonia, pulmonary edema, and pulmonary emphysema. However, the question of chronic pulmonary disability associated with these diseases is poorly understood and requires further long-term investigation. Despite the brisk controversy that still exists about the pathogenesis of isocyanate-induced pulmonary diseases, new data derived from animal models and clinical investigation of sensitized workers suggest that application of several innovative approaches could result in early detection and treatment of clinical reactions. These are considered in the context of pre-employment screening, serial monitoring in the workplace, and postemployment surveillance.

Efects of staphylococcal enterotoxin A (SEA) on the mouse homocytotropic antibody (HCA) system were studied. Groups of BDF mice received 10 µg SEA either orally or intraperitoneally at 0, 24, 48 h before or after immunization with 100 µg ovalbumin in 1 mg A1(OH)3 gel. Primary and secondary HCA responses were determined by 48-hour passive cutaneous anaphylactic reactions in genetically hairless mice. It was found that effects of SEA on HCA responses were dependent on the time and route of SEA administration. In general, early administration (48 h before immunization) of SEA showed suppression, while later administration (either 24 h before or after immunization) of SEA demonstrated enhancement. A further delay of SEA administration (48 h after immunization) exerted suppressive effects except when it was given intraperitoneally in the anamnestic HCA experiments. The mouse HCA system proved to be a suitable in vivo correlate of in vitro plaque-forming cell responses modulated by SEA.