Martha A. Shaughnessy

Prepolymers of hexamethylene diisocyanate as a cause of occupational asthma

BACKGROUND Occupational asthma (OA) caused by products that contain hexamethylene diisocyanate (HDI) has been ascribed to the highly volatile monomer of HDI. Most two-component paints are now made up primarily of nonvolatile prepolymers of HDI (30% to 60%) with only trace amounts (< 0.1%) of the monomer. The respective role of the two chemical forms of HDI in causing OA has never been investigated. METHODS Twenty workers who were consecutively referred for possible OA that resulted from exposure to spray paints underwent inhalation challenges on separate days with pure HDI monomer and the commercial formulation of HDI prepolymers to which they had been exposed at work. RESULTS Specific inhalation challenges elicited a positive asthmatic reaction in 10 of the 20 subjects. Among these subjects, four had positive bronchial reactions (two early, one late, and one dual) to both the monomer and the prepolymers. Four other subjects had asthmatic reactions (two early, one late, and one dual) after exposure to the prepolymers but not after exposure to the monomer. The discordance in bronchial response elicited by the monomer and the prepolymers could not be due to differences in the level of baseline nonspecific bronchial reactivity or in HDI concentrations during the tests. One subject showed an atypical progressive reaction after exposure to the monomer but not after exposure to the prepolymer. In this case, the discordant response could be explained by differences in HDI concentration. CONCLUSION These observations show that, although they are nonvolatile, the prepolymers of HDI can induce OA and that asthmatic reactions as a result of exposure to prepolymers but not the monomer is not a rare occurrence.

Review of Alleged Reaction to Monosodium Glutamate and Outcome of a Multicenter Double-Blind Placebo-Controlled Study

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

A double-blind, placebo-controlled trial of polymerized whole ragweed for immunotherapy of ragweed allergy

Immunotherapy with polymerized ragweed (PRW) has been demonstrated to be safe and effective when compared with monomeric ragweed or untreated controls. To further establish the efficacy of PRW, a trial was conducted comparing PRW, placebo, and no treatment in ragweed-sensitive individuals. In a double-blind manner, 21 patients were treated before the 1981 ragweed season with 15 weekly injections of PRW totaling about 50,000 PNU and 1200 microgram antigen E, while 19 patients were treated with 15 weekly injections of a caramelized glucose and histamine placebo. An additional control group received no injections. Blood was drawn for IgE against ragweed antigen E (IgE-a-AgE) and for blocking antibody against AgE before treatment, after treatment (before season), and after season. In the untreated patients, blood was drawn before season and after season. Daily symptom score sheets were completed by patients each day of the ragweed season. Blocking antibody rose more than 40-fold with treatment (p = 0.0001) in the PRW group but was unchanged in the placebo group with treatment. IgE-a-AgE rose with PRW therapy. Clinical efficacy of PRW was again confirmed in this study. Symptom score mean in the PRW group was statistically lower than the mean in the placebo group (p = 0.022) and in the untreated group (p = 0.018). There were no systemic reactions and only minor local reactions during treatment. In summary, PRW is an improved form of immunotherapy.

A double-blind histamine placebo—controlled trial of polymerized whole grass for immunotherapy of grass allergy

Twenty-six patients were recruited for a study of the safety and efficacy of immunotherapy with IPG. They were randomly assigned to two groups based on skin test titrations to grass allergens. One group was treated in a double-blind fashion before the 1982 grass season with 12 weekly injections totaling approximately 48,000 PNU, and the other group was treated with 12 weekly injections of caramelized glucose histamine placebo. Daily symptom and medication score sheets were completed by all patients each day of the grass season. Blocking antibody rose ninefold in the IPG group (p less than 0.007) but was unchanged in the placebo group. There was no significant change in IgE against rye grass group I in either the IPG or the placebo group. Symptom-score mean in the IPG group was 217 +/- 71 (S.E.M.), statistically lower (p less than 0.02) than the mean in the placebo group 496 +/- 117 (S.E.M.). There were no systemic reactions and only minor local reactions. There was no change in routine laboratory tests in either group. Although two prior studies with grass allergen immunotherapy reported efficacy, these studies did not use symptom-score analysis. This is the first double-blind, histamine placebo-controlled study of grass immunotherapy that demonstrates efficacy by symptom-score index evaluation. IPG is a safe, clinically effective, and potentially cost-effective therapy for grass pollinosis.

Persistence of efficacy after a brief course of polymerized ragweed allergen: A controlled study☆

Immunotherapy with PRW has been demonstrated to be safe and effective. To determine whether the efficacy would remain in successive ragweed seasons without further therapy, a trial was conducted comparing PRW to histamine placebo therapy in patients that had received courses of PRW previously. Those patients were also compared to previously untreated ragweed-sensitive patients. In a double-blind fashion, 21 previously treated patients were treated before the 1982 ragweed season with four injections of PRW therapy, whereas 21 previously treated patients were treated with four injections of placebo therapy. An additional control group of 21 previously untreated ragweed-sensitive patients received no injections. Daily symptom and medication score sheets were completed by patients each day of the ragweed season. Blocking antibody rose elevenfold with treatment (p less than 0.0001) in the PRW group. There was a statistically significant difference in symptom score mean between untreated patients (1007 +/- 174) and previously treated patients whether they received supplemental injections (554 +/- 180) (p less than 0.01) or whether they did not (650 +/- 168) (p less than 0.03). In summary the efficacy of 15 injections of PRW immunotherapy persists at least several years without need for supplemental immunotherapy.

Clinical and immunologic evaluation of 37 workers exposed to gaseous formaldehyde

Thirty-seven workers exposed to formaldehyde (F) were evaluated to determine whether any of their respiratory or ocular symptoms were mediated by an immunologic response to F. Because there has never been a case of defined immunologically mediated respiratory or ocular disease as a result of exposure to gaseous F, we used clinical and immunologic criteria developed for immunologic respiratory diseases that result from inhalational exposure to trimellitic anhydride. A clinical assessment included review of a medical summary of history, physical examination, chest x-ray films, and pulmonary function studies. Serologic assessment was made with an ELISA for IgE and IgG to F human serum albumin. The final evaluation for immunologically mediated disease was based on both the clinical and serologic assessments. None of the workers had IgE or IgG antibody to F-human serum albumin or an immunologically mediated respiratory or ocular disease caused by F; however, some of the workers appeared to experience irritant symptoms caused by workplace exposure to F or other irritant chemicals.

A double-blind placebo-controlled trial of polymerized whole grass administered in an accelerated dosage schedule for immunotherapy of grass pollinosis☆

Forty-four patients were entered into a study of the efficacy and safety of individually polymerized grass (IPG) immunotherapy with an accelerated dosage schedule. Patients were paired on the basis of cutaneous end point titrations to timothy, orchard, and Bermuda grass-pollen extracts. In a double-blind manner, one patient in each pair was treated in nine weekly visits with 13 injections that totaled 24,000 PNU of each grass to which the patient had cutaneous reactivity. The other patient in each pair received caramelized glucose histamine placebo. Symptom and medication score sheets were completed by 33 patients each day of the grass season. Blocking antibody rose significantly in the IPG-treated group but was unchanged in the placebo-treated group. By Wilcoxon paired signed-rank test, the symptom medication scores in the IPG-treated group were significantly lower than those in the placebo-treated group. There were no systemic reactions and no clinically significant changes in routine laboratory tests in either group. In summation, this study demonstrates the safety, immunogenicity, and efficacy of IPG therapy in an accelerated dosage schedule for treatment of grass pollinosis.

Prospective immunologic and clinical study of a population exposed to hexamethylene diisocyanate

We have prospectively evaluated 150 workers exposed to hexamethylene diisocyanate (HDI) and its trimer (THDI) during an 18-month period. The evaluation consisted of periodic serum antibody studies and a questionnaire that was designed to attempt to identify symptoms compatible with work-related syndromes of allergic rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, asthma, or irritant reactions. The study population was divided into seven groups on the basis of job classification. The groups differed in exposure levels but were similar in terms of age, sex, smoking history, and duration of work with isocyanates. IgE and IgG against HDI and THDI conjugated to human serum albumin (HSA) (HDI-HSA and THDI-HSA) were determined by ELISA. There were no instances of immunologically induced disease among the 21% of workers in this sample with antibody; however, there is insufficient evidence at this time to make judgments about the relationship between antibody and clinical disease. The antibody was generally low-level IgG that may be a sensitive indicator to detect exposure to certain reactive chemicals. The level of antibody was not different among job classes or between smokers and nonsmokers. Moreover, there was no correlation between antibody level and exposure duration in these workers whose exposure levels are all well below National Institute for Occupational Safety and Health recommendations. Further evaluation will extend these observations.

Lymphocyte subsets and activation markers in patients with acute episodes of idiopathic anaphylaxis

BACKGROUND Idiopathic anaphylaxis (IA), a type of anaphylaxis in which no external allergen can be identified, is a corticosteroid-responsive disease, that suggests that it may have an immunologic pathogenesis. OBJECTIVE The objective of this study is to compare patients with acute episodes of IA with normals, patients with chronic idiopathic urticaria, and patients with IA in remission relative to lymphocyte subsets and activation markers. METHODS This is a prospective cohort study of 38 adults: 5 normals, 4 idiopathic urticaria, 11 IA patients in remission, 9 IA patients with acute attacks who had not yet received prednisone, and 9 IA patients who had received prednisone. The main outcome measures were lymphocyte subset and activation markers determined by two and three color flow cytometry (CD2, CD3, CD4, CD5, CD8, CD16, CD19, CD23, CD25, CD56, and HLA-DR). RESULTS Comparing patients with acute IA with those in remission, the only significant difference was that the acute IA patients had a significantly higher percentage of CD3+HLA-DR+ cells. Normals had a significantly lower percentage of CD3+ HLA-DR+ cells than all other groups. Patients with acute IA on prednisone as well as IA patients in remission had a significantly higher percentage of CD 19+ CD23+ cells than normals. CONCLUSIONS These results suggest that there are more activated T cells in patients with acute episodes of IA than in patients in remission. Perhaps, these activated T cells have a role in the pathogenesis of IA.

Characterization of an antigen in acute anaphylactic dialysis reactions: ethylene oxide-altered human serum albumin.

Anaphylactic reactions to dialysis have been associated with antibody to human serum albumin (HSA) that has been reacted with ethylene oxide (ETO). ETO, an agent used to sterilize dialyzers, is a potent alkylator of proteins. We have studied the antigenic characteristics of ETO-HSA. By use of immunoelectrophoresis we have demonstrated differences in electrophoretic mobility between HSA and ETO-HSA. By gel chromatography we have observed an apparent increase in the molecular weight of ETO-HSA as compared to HSA. Antigenic activity of ETO-HSA as determined by the technique of Lidd and Farr is found in all molecular weight fractions. Cutaneous reactivity to ETO-HSA can be transferred to subhuman primates. That reactivity is lost if the sera are heated to 56 degrees C for 4 hours. Antibody activity to ETO-HSA cannot be inhibited by ETO-glycine or HSA but can partially be inhibited by ETO-polylysine or ETO-ovalbumin. This suggests that antibody is directed against a new antigenic determinant on the ETO-protein moiety, probably an ETO-amino acid determinant like lysine.