Michael J. Reid

Survey of fatalities from skin testing and immunotherapy 1985–1989

BACKGROUND The Committee on Allergen Standardization of the American Academy of Allergy and Immunology (AAAI) began a study of fatalities associated with skin testing and immunotherapy in an effort to identify risk factors and to ascertain whether any additional precautions are required to prevent and treat serious reactions. METHODS Questionnaire data was obtained from members of the AAAI and the American College of Allergy and Immunology, regarding 17 fatalities associated with immunotherapy for the years 1985 to 1989. In this period, no fatalities were reported with skin testing. The mean age of patients who died was 36.0 years (range: 10 to 77 years), and 69% were female. Of the patients who died, 76% had asthma, and most were reported to have had factors associated with severity (i.e., lability, required steroids, and/or prior hospitalizations). The only patient who had rhinitis alone had cardiovascular disease and was receiving a beta-blocker. High sensitivity by skin test or RAST was reported by 71%, and 36% reported prior systemic reactions. Sixty-five percent of the patients were undergoing build-up therapy. Fatalities involved use of allergen doses between 1:1 million to 1:10 wt/vol. Other factors associated with fatalities were: changing to a new vial of extract, 5; dosing error or inappropriate dose adjustment, 5; allergen season, 5; symptomatic before injection, 4; not waiting after injection, 2; and home injection, 1. Onset of anaphylaxis occurred within 20 minutes in eleven patients, within 20 to 30 minutes in one, and after more than 30 minutes in one. In eleven cases the cause of death was associated with respiratory compromise. These data reinforce the need for special precautions in treating high-risk patients with asthma. The annual fatality rate from administration of allergenic extracts in the United States remains very low: 1 fatality per 2 million doses, but additional educational efforts to further reduce the fatality rate are needed.

Allergic Bipolaris sinusitis: Clinical and immunopathologic characteristics

Allergic Aspergillus sinusitis was first reported in 1983. We present the first three cases of allergic fungal sinusitis caused by the black fungus Bipolaris spicifera. The patients were young, atopic, and immunocompetent. All three patients demonstrated pansinusitis with nasal polyps and underwent multiple surgical procedures. Pathologic features included a characteristic mucoid exudate containing eosinophils, Charcot-Leyden crystals, and fungal hyphae. In two cases there was bony erosion revealed by computed tomography scan but no histologic evidence of direct fungal invasion into the mucosa or bony trabeculae. Immunologic features, including total eosinophil count, total serum IgE, immediate and late-phase skin response to B. spicifera, serum precipitins, and specific IgE and IgG to B. spicifera, are described. B. spicifera is a previously unrecognized cause of allergic fungal sinusitis that may be an underdiagnosed disorder. This diagnosis should be considered in atopic patients with nasal polyps and pansinusitis unresponsive to conventional medical therapy. Diagnostic criteria include characteristic histologic allergic mucin, culture identification of fungus, positive immediate cutaneous reactivity to fungal extract, positive serum precipitins, and elevated specific IgE and IgG antibodies.

Suppression of the late cutaneous response by immunotherapy

In a prospective, double-blind, placebo-controlled study, we examined the effect of mountain cedar (MC) immunotherapy on the MC-induced late cutaneous response (LCR). Fourteen MC-sensitive patients were intradermally skin tested before and after immunotherapy with MC extract. We measured the size of the wheal at 15 minutes and the area of tissue swelling at 6 hours. Patients were matched by the size of the LCR and started receiving either MC immunotherapy or placebo immunotherapy. MC-specific immunoglobulins (MC sIgG, MC sIgG1, MC sIgG4, and MC sIgE) were measured by ELISA. Symptom-medication scores (SMSs) were recorded on a daily basis during the MC season and tabulated at the end of the study. Comparison of the 14 paired patients revealed no significant differences between MC-treated and placebo-treated groups in preimmunotherapy MC sIgG1 and SIgG4. However, when MC immunotherapy was compared to placebo immunotherapy, patients receiving MC immunotherapy developed significantly higher MC sIgG1 (p less than 0.04) and MC sIgG4 (p less than 0.01) after immunotherapy. Patients receiving MC immunotherapy also demonstrated significantly greater suppression of the LCR after immunotherapy (p less than 0.005) with the postimmunotherapy LCR correlating significantly with both MC sIgG4 (rs = 0.715; p = 0.008) and cumulative dose of MC received (rs = 0.808; p = 0.004). MC sIgE was similar in both groups after immunotherapy. The reduction in SMSs in the MC-treated group did not reach significance, nor was there a correlation of SMSs with MC sIgE, sIgG, sIgG1, or sIgG4.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA-DR4-associated nonresponsiveness to mountain-cedar allergen

We did human lymphocyte antigen (HLA)-DR and DQ typing on 37 subjects with mountain-cedar (MC) pollinosis as defined by history and a positive skin test. Of these 37 subjects, 31 were subdivided into 18 subjects with a single positive skin test (SPST) and 13 subjects with multiple positive skin tests (MPSTs). We also typed 51 subjects without MC sensitivity or atopy as defined by history and negative skin tests to a battery of aeroallergens. We also typed 116 subjects in whom MC sensitivity had not been determined. Total IgE, Mc-specific immunoglobulin E (sIgE), and MC-sIgE binding bands by immunoblot were also determined on the subjects with SPSTs and MPSTs. No significant differences were found between the subjects with SPSTs and MPSTs for HLA type, total IgE, MC sIgE, or bands bound by MC sIgE by immunoblot. There was a strong negative relationship between HLA-DR4 and subjects with MC pollinosis; chi-square, 14.857; p = 0.0096; and odds ratio, 0.139. These findings suggest that there is no difference in genetic immunoregulation between subjects with SPSTs and MPSTs but that the presence of the DR4 gene product is associated with a decreased risk of an IgE response to MC and protection from MC pollenosis.

The relationships between late cutaneous responses and specific antibody responses with outcome of immunotherapy for seasonal allergic rhinitis

Mountain cedar (MC) (Juniperus ashei) causes a significant and isolated seasonal allergic rhinitis in south-central Texas during the winter months. Retrospective studies have indicated that patients segregate into two categories based on skin test reactions: single positive skin test to MC only and multiple positive skin tests. These two populations differed in age, personal and family history of atopy, levels of both IgE and total MC-specific IgE (sIgE), and symptomatology. It has been speculated that the subjects with only a single positive skin test may actually be nonatopic and develop an IgE response to MC because of some peculiarity of the antigen. In a prospective, randomized, controlled trial, we tested the efficacy of immunotherapy (IT) with MC extract in 51 subjects, 12 single positive skin tests and 39 multiple positive skin tests, to determine if these differences indeed exist and if IT is equally effective in both groups. We failed to demonstrate significant differences in age, sex, MC sIgE, total IgE, initial immediate cutaneous response, initial late cutaneous response, or personal or family history of atopy. IT was equally effective in both groups of subjects with no significant differences noted in response to MC sIgE, MC sIgG1, MC sIgG4, or with suppression of the late cutaneous response. In addition, we found that suppression of the late cutaneous response correlated significantly with cumulative dose of MC extract, postseasonal level of MC sIgG1 and MC sIgG4, and improvement of symptomatology. Suppression of the late cutaneous response may be a clinically useful parameter to follow in monitoring patients during IT. Caution is advised because this procedure may result in systemic reactions.

Isotypic and antigenic restriction of the blocking antibody response to ryegrass pollen: Correlation of rye group I antigen-specific IgG1 with clinical response

To investigate the role of blocking antibodies in allergen immunotherapy (IT), we analyzed IgE, IgG, and IgG subclass 1 to 4 antibody responses to ryegrass group I antigen (RGGI) in a prospective double-blind, heterologous allergen, allergen-controlled trial of grass-pollen IT in 18 adults with seasonal rhinitis and asthma. Serum was assayed preseasonally before starting IT and again in midseason at time of documented highest natural exposure. Antibodies were measured by ELISA, and immunogenic specificities of ryegrass extract were examined by Western immunoblots. Nine subjects receiving grass-pollen IT and nine control subjects had similar clinical and immunologic status before IT. RGGI-specific IgE antibodies (sIgE) did not change from pretreatment levels in actively treated subjects but increased in control subjects (p less than 0.002). RGGI sIgG increased approximately thirteen-fold with active IT versus threefold during natural seasonal exposure (p less than 0.0005). The IgG-blocking response to RGGI was restricted to IgG1 and IgG4. Ten nonatopic subjects had similar RGGI sIgG1 but lower or undetectable sIgE and sIgG4 than the 18 atopic study subjects. Active IT dramatically increased RGGI sIgG4 (p less than 0.001) and to a lesser extent RGGI sIgG1 (p less than 0.01). Immunoblots demonstrated eight IgE-binding ryegrass-polypeptide allergens, with RGGI ubiquitous, and 11 IgG-binding polypeptides, including all eight allergens. A negative correlation between seasonal rhinitis symptom-medication scores and RGGI sIgG1 levels was found (r = -0.62, p less than 0.01), but no other immunologic parameters assayed were related to clinical improvement. Although RGGI sIgG4 predominates in the blocking response and is a useful marker of effective IT, early beneficial biologic effects may involve IgG1 antibodies.

The relationship of serum IgA concentration to human immunodeficiency virus (HIV) infection: a cross-sectional study of HIV-seropositive individuals detected by screening in the United States Air Force

Serum immunoglobulins were measured in 107 patients with human immunodeficiency virus seropositivity. Each patient was categorized by the Walter Reed staging classification and serum concentrations of immunoglobulins were compared with patient staging. Serum IgM concentrations were normal in all but nine patients. Serum IgG concentrations were elevated in 74 of 107 patients, with no significant differences noted between different stages of disease severity. Serum IgA concentrations were elevated in 38 of 107 patients, with a significant relationship noted between increasing staging category and increasing serum IgA concentration (p = 0.0001). Serum IgA concentrations in patients with human immunodeficiency virus seropositivity may be a useful marker of immunologic progression of disease.

Mountain cedar pollinosis: can it occur in non-atopics?

In 1984 Ramirez postulated the existance of two subgroups of patients with Mountain Cedar (MC) pollinosis. One subgroup had a single positive skin test (SPST) to MC only, lacked other atopic diseases, and required prolonged MC exposure to develop the disease. The second subgroup had multiple positive skin tests (MPST) in addition to MC, had other atopic diseases, and developed clinical symptoms after a shorter period of MC exposure. To validate these findings, and to explore the clinical and immunologic differences between these two subgroups, 13 SPST and nine MPST patients underwent immunotherapy with MC pollen extract. Six SPST and ten non-allergic controls did not receive immunotherapy. MC specific IgE (sIgE), MC sIgG, and MC sIgG subclasses were measured by ELISA pre and intra season. Symptom Medication Score (SMS) were measured during the MC season. SPST patients had a significantly lower baseline sIgE than MPST patients, 2.1 IU/ml versus 22.3 IU/ml, p = 0.023, and were also older than MPST patients, 52.4 versus 32.2 years, p less than 0.001. Baseline MC sIgG and MC sIgG subclass antibody levels were similar in both patient groups. SMS were lower in treated SPST patients compared to treated MPST patients, p less than 0.01, but in vitro responses to immunotherapy were not significantly different between the two groups. MC sIgE, MC sIgG, MC sIgG1 and MC sIgG4 rose in both treated groups. MC sIgG1 (but not MC sIgG4) rose during the MC season in both non-immunotherapy groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoassay technique for specific immunoglobulin E

Using monoclonal mouse anti-human IgE antibodies, the microtiter solid phase radioimmunoassay (MSPRIA) and the enzyme-linked immunoabsorbent assay (EILSA) were modified to quantitatively measure honeybee venom (HBV) and perennial rye grass (PRG) specific immunoglobulin E (sIgE). By using a novel dilution, serial transfer and cummulative counting technique, the inhibiting and interfering effects of specific immunoglobulin G (sIgG) in the assay of (sIgE) can be reduced and the quantitative determination of (sIgE) accomplished with precision and reliability.

High-titer IgE antibody specific for pollen allergens in northern California is associated with both wheezing and total serum IgE

Summary In an area with high exposure, grass pollen specific IgE can contribute to total IgE. This allergen specific characteristic is relevant to understanding relationships between the immune response and clinical allergic disease.