Albert L. Sheffer

Standardization of bronchial inhalation challenge procedures

A group of investigators interested in the standardization of inhalation challenge techniques was selected by the program directors of the Asthma and Allergic Disease Centers (AADC). This effort has been assisted by the National Institute of Allergic and Infectious Diseases of the National Institutes of Health. At the last meeting of the panel on February 15, 19’75, criteria for procedures and materials used were suggested in order to standardize bronchial inhalation challenges as they pertain to allergic disease.

Generation of Antigen-Specific Suppressor Cells during Allergy Desensitization

We used a suppressor-cell assay to study a possible mechanism of allergy desensitization. Before specific immunotherapy, blood mononuclear cells from 20 patients with ragweed hayfever failed to exhibit suppressor activity in vitro after stimulation by ragweed antigen E. However, when the 10 patients with allergic rhinitis had been desensitized by injections of ragweed extract, their mononuclear cells specifically suppressed a ragweed proliferative response six and 12 months after desensitization was begun (31 per cent and 48 per cent suppression, respectively). Suppressor mononuclear cells were not detected in 10 control subjects of in 10 patients with ragweed hayfever who were not desensitized. When mononuclear cells taken from treated patients were passed over columns containing insolubilized histamine, antigen-specific suppressor cells that could be activated by ragweed antigen were depleted. These results indicate that antigen-specific suppressor cells, probably bearing histamine receptors, are generated during desensitization to allergy and may be partly responsible for the efficacy of this therapy.

Ecallantide for the Treatment of Acute Attacks in Hereditary Angioedema

BACKGROUND Hereditary angioedema is a rare genetic disorder characterized by acute, intermittent, and potentially life-threatening attacks of edema of the skin and mucosa. We evaluated ecallantide, a newly developed recombinant plasma kallikrein inhibitor, for the treatment of acute attacks of angioedema. METHODS In this double-blind, placebo-controlled trial, patients with hereditary angioedema presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo. Two measures of patient-reported outcomes were used to assess the response: treatment outcome scores, which range from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and the change from baseline in the mean symptom complex severity score, which range from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after). The primary end point was the treatment outcome score 4 hours after study-drug administration. Secondary end points included the change from baseline in the mean symptom complex severity score at 4 hours and the time to significant improvement. RESULTS A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; P=0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P=0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P=0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events. CONCLUSIONS Four hours after administration of ecallantide or placebo for acute attacks of angioedema in patients with hereditary angioedema, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. (Funded by Dyax; ClinicalTrials.gov number, NCT00262080.)

Tranexamic Acid Therapy in Hereditary Angioneurotic Edema

HEREDITARY angioneurotic edema results from an inborn error in the biosynthesis of a serum alpha-2 globulin that inhibits the enzymatic activity of the first component of complement and is thus des...

The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study.

BACKGROUND Exercise-induced anaphylaxis (EIA) is a unique physical allergy that is triggered by exertion, the clinical spectrum and modifying factors of which have been previously studied. At the time of initial description, it was postulated that other factors contributed to this disorder. OBJECTIVE We sought to determine the clinical course and potential modifying factors in EIA. METHODS In 1993, we conducted a cross-sectional analysis of 671 individuals with exercise-associated symptoms for more than a decade using a validated 75-item questionnaire. Subjects met criteria for EIA if they had anaphylactic symptoms, including hypotension or upper airway obstruction, urticaria, or angioedema with physical exertion but without a passive increase in core body temperature. RESULTS Of 365 (54%) questionnaire respondents, 279 (87%) met criteria for EIA (199 females and 80 males). At the time of study entry, subjects with EIA (mean age, 37.5 years; range, 13 to 77 years) had an average of 10.6 years of symptoms, which were most frequently triggered by aerobic activities such as jogging or brisk walking (78% and 42%, respectively). On average, subjects reported that the frequency of attacks had decreased (47% of subjects) or stabilized (46% of subjects) since onset. One hundred (41%) subjects reported being completely free of attacks in the past year. Subjects reduced their attacks by avoiding exercise during extremely hot or cold weather (44%), avoiding ingestion of certain foods before exercise (37%), and restricting exercise during their allergy season (36%) or humid weather (33%). The most common pharmacologic agents used to manage symptoms were H1 antagonists (56%) and/or epinephrine (31%). However, 28% used no treatment at all. CONCLUSION EIA is an episodic condition in which the frequency of attacks tends to stabilize or decrease over time. Improvement appears to result from individual modification of exercise and avoidance of known environmental and ingestible precipitants.

Acquired C1-Inhibitor Deficiency Associated with Antiidiotypic Antibody to Monoclonal Immunoglobulins

The syndrome of acquired angioedema and C1-inhibitor deficiency is associated with B-cell lymphoproliferative disease. It is characterized by accelerated consumption of C1q and C1 inhibitor in vivo and by low levels of serum C2 and C4. Four patients with B-cell malignant diseases (IgA myeloma, macroglobulinemia, chronic lymphocytic leukemia, and B-cell lymphoma, respectively) and acquired C1-inhibitor deficiency were found to have circulating antiidiotypic antibodies to the monoclonal immunoglobulin expressed on the surface of their B cells (three patients) or in the cytoplasm of their bone-marrow cells (one patient). Two of the four patients had circulating M components, and their antiidiotypic antibodies reacted with the M components. In three patients studied the percentage of B cells bearing C1q was 18, 24, and 35 per cent, as compared with 2.3 +/- 1.7 per cent (mean +/- S.D.) in six normal controls. These results suggest that an interaction between the idiotype of monoclonal immunoglobulins and antiidiotypic antibodies causes increased consumption of C1q and C1 inhibitor in patients with acquired angioedema and C1-inhibitor deficiency. We propose that the subsequent activation of the early components of complement leads to increased vascular permeability and to angioedema and that these patients have a disease caused by antiidiotypic antibodies.

Exercise-induced anaphylaxis: a distinct form of physical allergy

Seven individuals with exercise-induced anaphylaxis under natural circumstances, characterized by the appearance of pruritic cutaneous erythema and urticaria and associated vascular collapse and/or upper respiratory tract symptoms and signs of angioedema, were subjected to a controlled period of exercise in a laboratory. Experimental challenge consisted of running in an occlusive suit on a treadmill of moving grade with maintenance or acceleration of speed for 5 to 17 min. Cutaneous pruritus and erythema without urticaria developed in four of the subjects and progressed to angioedema in two of them; the other three subjects were unaffected. Repeat challenge of three of the abnormal responders elicited a clinical response similar to that of the previous exercise challenge. In those subjects with a clinical response to exercise challenge, mean change from baseline levels of histamine to peak levels was 7.0 +/- 3.0 ng/ml (mean +/- SEM), whereas in the group without clinical symptoms the mean change from baseline was an increase of 0.6 +/- 1.6 ng/ml (mean +/- SEM). The abnormal elevations in serum histamine during the seven exercise-induced symptomatic episodes returned to normal in about 20 min while clinical signs were also subsiding. There were no changes in pulmonary function. Exercise-induced anaphylaxis is clinically separable from cholinergic urticaria and represents a distinct form of physical allergy.

Exercise-induced anaphylaxis: A serious form of physical allergy associated with mast cell degranulation

Exercise-induced anaphylaxis (EIA) is a unique and an increasingly recognized syndrome consisting of premonitory symptoms and signs of generalized body warmth, pruritus, and erythema, which progresses on continued exertion to confluent urticaria, laryngeal edema with stridor or hoarseness, and gastrointestinal colic and frequently culminates in vascular collapse. Previous studies of five individuals with this condition have demonstrated significant elevations of serum histamine concurrent with the early clinical manifestations after experimental exercise. To assess relevant morphologic alterations in the skin of these patients, cutaneous mast cells were examined by light and transmission electron microscopy before and during the initial erythema elicited by exertion. The marked alterations observed in mast cells immediately after exercise consisted of (1) loss of electron density and internal substructure of granules, (2) fusion of granule membranes with those of adjacent granules and with mast cell membranes creating conduits to the extracellular space, and (3) an apparent decrease in the number of intact granules per cell. Biopsy specimens obtained before exercise from patients with EIA and from two normal individuals who served as control subjects were identical, and the control subjects had normal mast cell morphology after exercise. Serum histamine levels were significantly elevated in patients with EIA after exercise at the time of biopsy, whereas control subjects had normal levels. These observations provide evidence that EIA is a distinct form of physical allergy associated with mast cell degranulation similar in morphology to that of human pulmonary mast cell IgE-Fc-dependent activation secretion. Characterization of this disorder is important because its prevalence may be underestimated, and its clinical consequences, which may include some morbidity, are not fully known.

Detection of Hereditary Angioneurotic Edema by Demonstration of a Reduction in the Second Component of Human Complement

ACUTE circumscribed subepithelial edema of the skin was recognized as a distinct clinical entity by Milton1 and by Quincke,2 and shortly thereafter was termed angioneurotic edema by Strubing.3 In 1...

Cromolyn sodium in the management of systemic mastocytosis

A multicenter, double-blind, placebo-controlled trial of the efficacy of oral cromolyn sodium (200 mg orally four times per day) was conducted in 11 patients with systemic mastocytosis who had been maintained with the drug on an individualized compassionate-need basis. Efficacy was measured by physician assessment of overall disease severity based on history and physical examination at specified intervals and by the average daily patient symptom diary scores for each of three mastocytosis-related symptoms that had previously appeared to be alleviated by the use of this drug. Efficacy variables were compared for a 4-week baseline period, during which patients received open-labeled cromolyn sodium, and at 4-week intervals during a 16-week period of random assignment to cromolyn sodium or placebo. Overall disease severity and symptoms recorded in patient diaries were graded on a scale of 0 (absent) to 5 (incapacitating). The average physician assessment of disease severity and symptom scores of the patients in the placebo-treated group increased significantly during the randomization phase relative to patients in the cromolyn sodium-treated group, reflecting an exacerbation of symptoms with drug withdrawal (p less than 0.05 and less than 0.028, respectively). When the symptom scores were analyzed separately for gastrointestinal manifestations of disease (diarrhea, abdominal pain, nausea, and vomiting), cromolyn sodium treatment was significantly beneficial relative to placebo (p less than 0.02), whereas the benefit for nongastrointestinal manifestations did not reach statistical significance.