Immunoglobulin E-mediated asthma and hypersensitivity pneumonitis with precipitating anti-hapten antibodies due to diphenylmethane diisocyanate (MDI) exposure

Two workers are presented who were exposed to diphenylmethane diisocyanate (MDI) while coating pipes with a polyurethane foam. After a latent period of exposure, worker A developed immediate-onset asthma and worker B developed a clinical picture of hypersensitivity pneumonitis for which he was hospitalized. The antibody response of these workers to a conjugate of MDI with human serum albumin (MDI-HSA) was measured by gel precipitation, total antibody binding of 125I MDI-HSA, and specific IgG and IgE antibody by polystyrene-tube radioimmunoassay (PTRAI). Worker B had precipitating antibody to MDI-HSA by double immunodiffusion in gel. Both workers had high levels of IgG antibody specific for MDI-HSA which had some cross-reactivity with a conjugate or toluene diisocyanate and HSA. Total serum antibody binding of 125I MDI-HSA was 15 microgram/ml in worker A and 900 microgram/ml in worker B. Both workers had serum IgE antibody specific for MDI-HSA as measured by two PTRIA techniques. These results indicate that a marked immunologic response to MDI is possible in exposed workers and that hypersensitivity pneumonitis can occur subsequent to the inhalation of a low-molecular-weight chemical in the industrail setting.     

Refractory period to aspirin in a patient with aspirin-induced asthma

Oral aspirin challenge was used to detect unrecognized aspirin intolerance in a select group of 50 asthmatic patients who denied aspirin intolerance. A double-blind protocol was used to furtner study those patients who reacted to initial graded aspirin challenge. In one patient the use of a double-blind protocol led to the serendipitous discovery of a 72-hr refractory period to the adverse effects of aspirin, after initial ingestion of aspirin resulted in respiratory and systemic symptoms.     

Comparison of the radioallergosorbent test and a quantitative solid-phase radioimmunoassay for the detection of ragweed-specific immunoglobulin E antibody in patients undergoing immunotherapy

Commercially available radioallergosorbent test (RAST) was compared with a quantitative solid-phase polystyrene tube radioimmunoassay (PTRIA) for the detection of ragweed-specific IgE antibody in sera of patients undergoing ragweed immunotherapy. Both assays showed good replication over a wide range of IgE antibody activity. The RAST was limited in the ability to discriminate between sera with high levels of specific IgE antibody. In addition, RAST gave falsely low values of IgE antibody activity in the presence of high levels of blocking antibody.     

Polymerized whole ragweed: An improved method of immunotherapy

A single-blind study compared the effectiveness of glutaraldehyde-treated polymerized ragweed with nonpolymerized monomeric ragweed. These studies are an extension of those previously reported for polymerized AgE using a readily available ragweed preparation containing all ragweed antigens. Nineteen ragweed-sensitive patients were randomized into 2 groups; 10 received the polymerized form and 9 received the monomeric form. Four parameters were followed: serum-specific IgE against antigen E, total blocking antibody against antigen E, local and systemic reactions to injection therapy, and symptom score indices. Pretreatment levels of antigen E-specific IgE and blocking antibody activity were similar in both groups. After a total of 15,000 protein nitrogen units (PNU) had been given, blocking antibody activity in the monomer group rose from a mean of 173 ng AgE bound per ml to a mean of 2,813. The rise in blocking antibody activity in the polymer group was from a mean of 181 ng AgE bound per ml to 1,574. At 15,000 PNU, blocking antibody activity levels were not statistically different in the 2 groups. After 1 year of treatment, no consistent decrease in postseasonal specific IgE rise could be shown in either group. Forty times less erythema and 15 times less induration were found with polymerized ragweed. There were 7 systemic reactions with the monomer and none with the polymer. Both groups experienced symptomatic improvement with treatment.     

Effect of deep inspiration on airway conductance in subjects with allergic rhinitis and allergic asthma

We measured specific airway conductance ($\text{Gaw}\text{Vtg}$) in a body plethysmograph before and after a deep inspiratory maneuver in 8 subjects with allergic rhinitis and 8 subjects with allergic asthma. In hay fever subjects deep inspiration had no effect on $\text{Gaw}\text{Vtg}$ if it was performed in the control state; however, when methacholine-induced bronchoconstriction was present, deep inspiration transiently increased $\text{Gaw}\text{Vtg}$. In asthmatic subjects deep inspiration was followed by a transient fall in baseline $\text{Gaw}\text{Vtg}$ in the control state; however, when bronchoconstriction was present, deep inspiration was followed by small and variable changes in $\text{Gaw}\text{Vtg}$ in 7 subjects and marked improvement in $\text{Gaw}\text{Vtg}$ in 1 subject. In asthmatic subjects the bronchoconstrictor response to deep inspiration performed in the control state is thought to be due to reflex changes in bronchomotor tone mediated by cholinergic (vagal) nerve pathways. Like asthmatic subjects, hay fever subjects also possess cholinergic-mediated airway hyperreactivity compared with normals. Our results indicate that, in spite of their increased airway reactivity, hay fever subjects respond more like normal subjects than like asthmatic subjects after a deep inspiratory maneuver.     

The qualitative evaluation of airway responses to immunologic and pharmacologic stimuli in rhesus monkeys.

This report describes the current status of a colony of rhesus monkeys composed of a group of animals with consistent asthmatic responses to Ascaris antigen challenge, a variable group and a negative group. The cumulative experience with the consistent group of 5 animals totals 144 months of observation with 86 positive respiratory responses to 86 aerosol challenges. Further studies compare rhesus airway responses to Ascaris antigen, anti-IgE, histamine, prostaglandin (PG)F2alpha, carbocholine, and physostigmine. We report that two abnormalities of pulmonary function which occur as a result of aerosol challenge, an increase in breathing frequency (f) and pulmonary resistance (PR), differ in degree of abnormality and time of onset following challenge with different agonists. These results indicate that the f and PR changes in response to these agonists are controlled by different physiologic mechanisms in rhesus monkeys. We suggest that the f changes may occur as a result of reflex afferent vagal stimulation and PR changes as a result of direct effect on smooth muscle receptors. The effect of histamine and PGF2alpha on the airway of rhesus monkeys more closely simulates the airway response to immunologic stimuli than does the effect of cholinergic type agonists.     

Quantitation of IgE antibody specific for ragweed and grass allergens: Binding of radiolabeled allergens by solid-phase bound IgE

IgE antibody specific for multiple allergens extracted from grass and ragweed pollens was measured by radioimmunoassay. The assay depends on the interaction between IgE antibody bound to a polystyrene solid phase, ¹²⁵I-labeled grass allergens (GA), and ragweed allergens (RW). The binding of ¹²⁵I RW by serum IgE antibody from 37 allergic patients ranged from 0.2 ng to 75 ng RW protein (P) bound per ml. This binding of ¹²⁵I RW by patient's IgE was paralleled by their IgE binding of ¹²⁵I antigen E (AgE), a purified allergen from ragweed pollen (r = 0.90, p < 0.001). Inhibition of patient's IgE binding of ¹²⁵I RW by highly purified AgE ranged from 25% to 85% indicating individual differences in patient's IgE response to inhaled ragweed pollen. The binding of ¹²⁵I GA by serum IgE antibody from 7 grass-sensitive patients ranged from 0.6 ng GA P bound per ml to 15 ng. This assay should be useful in the study of IgE responses to environmental agents containing multiple allergens and has the advantage that other antibody classes cannot interfere with the interaction between IgE antibody and labeled allergens.     

Methacholine and physostigmine airway reactivity in asthmatic and nonasthmatic subjects

Inhalation challenges using methacholine and physostigmine were performed in 3 human asthmatic and 3 nonallergic normal subjects. Plethysmographic measurements of specific airways conductance ($\text{Gaw}\text{Vtg}$) were used to monitor the response. The dose required to produce a 17% fall in $\text{Gaw}\text{Vtg}$ was significantly lower in asthmatic subjects than in normal subjects for both physostigmine (p < 0.0125) and methacholine (p < 0.05). Moreover, in all subjects the relative airway sensitivity to methacholine correlated with the relative airway sensitivity to physostigmine. Both methacholine and physostigmine are cholinergic agents. Whereas methacholine acts directly at the end organ cholinergic receptor, physostigmine acts by increasing release and decreasing destruction of endogenous acetycholine at the vagal distal innervation. This suggests that the cholinergic airway hyperreactivity characteristic of asthma is a manifestation of end organ hypersensitivity.     

The relationship of airborne trimellitic anhydride concentrations to trimellitic anhydride-induced symptoms and immune responses

Eighteen workers exposed to trimellitic anhydride (TMA) powder were evaluated in 1979. Twelve of these workers were available for longitudinal study until 1982. Annual clinical evaluations and serum radioimmunoassays for total antibody binding and specific IgE binding to 125I-TM-HSA were performed. In 1979, five workers had antibody against TM-HSA. Of these, three workers were diagnosed with the late respiratory systemic syndrome (LRSS) and one worker with TMA-induced allergic rhinitis. The LRSS workers had significantly elevated total antibody binding of 125I-TM-HSA and the worker with rhinitis had significantly elevated specific IgE binding of 125I-TM-HSA per milliliter of serum. Although TMA handling was intermittent throughout the year, average airborne dust concentrations from 1974 to 1978 at job stations of the two heaviest TMA-exposed occupations, operator and assistant operator, were 2.1 and 0.82 mg/m3, respectively. After local exhaust ventilation had been improved, average airborne dust concentrations of TMA at the two latter job stations fell to levels of 0.03 and 0.01 mg/m3, respectively, in 1982. The decrease in TMA exposure coincided with a gradual fall in total antibody binding of 125I-TM-HSA per milliliter in 1982 and symptomatic improvement in the three individuals with the LRSS. The continuous low-level exposure of the worker with TMA rhinitis was sufficient to elicit a rise in specific IgE against TM-HSA from 1.1 ng of 125I-TM-HSA bound per milliliter in 1979 to 2.12 in 1982.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polymerized whole ragweed: A two-year follow-up of patients treated with an improved method of immunotherapy

We have previously reported, in a 1-yr study, the effectiveness of polymerized ragweed (PRW) as an improved method of immunotherapy for patients suffering from ragweed hay fever. In that study, treatment with PRW was found to be superior to treatment with monomer ragweed extract (MRW) because of the reduced allergenicity of the PRW. The current study is a 2-yr follow-up of nine patients treated with PRW and nine patients treated with MRW. After 1 yr of immunotherapy, both MRW- and PRW-treated patients received 9,000 protein nitrogen units (PNU) and after a second year of maintenance therapy both groups received a cumulative dose of 15,000 PNU. Serum blocking antibody against ragweed antigen E (AgE) was measured periodically during the study. After 1 yr of immunotherapy, blocking antibody in the PRW- and MRW-treated groups was similar with respective means of 1,300 and 1,500 ng AgE bound per milliliter of serum. At the end of 2 yr of therapy, these serum AgE binding activities rose to 2,700 and 4,100, respectively. No significant local or systemic reactions occurred in the PRW-treated group during the year of maintenance therapy. However, large local reactions prevented three of the nine patients treated with MRW from achieving a monthly maintenance schedule. A significant decrease in rhinitis symptoms was noted in both treated groups as compared with the season before immunotherapy and also to a group of patients untreated with immunotherapy during the 1978 ragweed season.     

Acute laryngeal hemorrhage with laryngeal obstruction initially confused with penicillin anaphylaxis

A case of acute laryngeal obstruction was considered to be penicillin anaphylaxis because the onset followed penicillin administration. The laryngeal obstruction was found to be the result of laryngeal hemorrhage in a patient on chronic anticoagulant therapy. The hemorrhagic lesions appeared to be induced by coughing due to bronchitis for which the penicillin was given.     

Further studies on the safety of polymerized antigens for immunotherapy

Six patients receiving immunotherapy with standard aqueous extracts for the treatment of atopic disease were selected from the patient population of Northwestern University Allergy Clinics for continued immunotherapy with polymerized antigens. These six patients could not tolerate quantities of conventional aqueous extracts considered maintenance doses because of immediate-type local or systemic allergic reactions or both to immunotherapy. These six patients were treated with separate preparations of polymerized ragweed (PRW) and polymerized grass (PG), and each of the six patients was rapidly advanced to previously unobtainable maintenance doses of PRW and PG without local or systemic reactions. Treatment with other aeroallergen standard extracts was continued to maintenance dosage without further systemic reactions. In patients highly sensitive to ragweed and grass aqueous extracts, the substitution of these extracts with PRW and PG allows these patients to receive therapeutic immunotherapy injections with decreased risk of immediate-type local and systemic reactions.     

An agent that releases basophil and mast cell histamine but blocks cyclooxygenase and lipoxygenase metabolism of arachidonic acid inhibits immunoglobulin E-mediated asthma in rhesus monkeys

An inhibitor of the lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism, BW755C, was evaluated with the rhesus monkey model of IgE-mediated asthma. BW755C was found to release histamine from human and rhesus peripheral blood leukocytes and rhesus bronchial lavage cells. BW755C did not induce a rhesus airway response but inhibited antigen-induced airway changes in pulmonary resistance and dynamic compliance. The results demonstrated that a lipoxygenase and cyclooxygenase inhibitor that is a histamine releaser may inhibit some pulmonary function abnormalities of an IgE-mediated response and suggested that histamine has a minor role as a stimulator of airway reaction in this model. This was supported by studies showing failure of the histamine H1 blocker pyrilamine maleate to inhibit the antigen-induced airway response. Although BW755C has been shown to be a lipoxygenase and cyclooxygenase inhibitor, it is not established that the inhibiting action of this agent on an antigen-induced airway response is due to an effect on arachidonate metabolism in the lung.     

A study of the effect of slow-reacting substances of anaphylaxis on the rhesus monkey airway

Slow-reacting substance of anaphylaxis (SRS-A) generated from rat peritoneal mast cells was aerosolized to the airways of a group of rhesus monkeys with established airway responses to ascaris antigen. A selective effect of SRS-A on pulmonary resistance and a lesser but significant effect on compliance was observed which differed from antigen, histamine, carbocholine, or prostaglandin (PG) F2alpha responses. The airway recovery from the PR change is slower than that from histamine and simulated PGF2alpha and some antigen experiments. The cutaneous reactions in rhesus monkeys due to SRS-A could be blocked in a dose response pattern by FPL55712 which did not affect histamine responses in rhesus skin.     

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.