Richard P. Stankus

Cigarette smoke-sensitive asthma: Challenge studies☆

The effects of exposure to environmental tobacco smoke on pulmonary function were assessed in 21 subjects with asthma who claimed respiratory complaints (cough, shortness of breath, and chest tightness) on previous exposure to cigarette smoke. Exposure to mechanically produced tobacco smoke was performed in a static inhalation chamber for two-hour intervals at two distinct smoke levels (as measured by carbon monoxide, nicotine, and particulate levels). Seven of the 21 smoke-challenged subjects experienced a significant (greater than 20%) decline in FEV1 during passive exposure to tobacco smoke. One of these seven subjects was nonatopic, whereas a second subject had a negative response to methacholine challenge. The smoke-challenge responses were reproducible in all seven reactive subjects. Increasing concentrations of tobacco smoke failed to elicit pulmonary changes in previously challenged, unreactive or smoke-tolerant subjects. There was no association between a positive smoke challenge and the presence of serum IgE antibodies and/or a positive immediate wheal-and-flare skin test to a tobacco leaf extract. Collectively, these studies document a significant decline in pulmonary function in a substantial percentage (33%) of a population of smoke-sensitive subjects with asthma exposed to environmental tobacco smoke. The data also dissociate this effect from tobacco-leaf hypersensitivity.

Passive cigarette smoke—challenge studies: Increase in bronchial hyperreactivity

Degree and duration of bronchial hyperreactivity (BHR) after environmental tobacco smoke (ETS) inhalation was assessed in 31 smoke-sensitive subjects with asthma who exhibited lower airway symptoms on ETS exposure (group I) and 39 smoke-sensitive subjects without asthma who manifested only upper airway symptoms on cigarette-smoke exposure (group II). Subjects were challenged with ETS for 4 hours in a static-test chamber. The atmosphere was continuously monitored for airborne particulate levels (800 cpm), total suspended particulates (1266 +/- 283 micrograms/m3), and airborne nicotine levels (226 +/- 49 micrograms/m2). Methacholine challenges were performed before and serially after cigarette-smoke exposure, and the provocative dose causing a 20% fall in FEV1 was determined. Five of the 31 smoke-sensitive subjects with asthma and none of the smoke-sensitive subjects without asthma reacted to cigarette-smoke challenge (greater than or equal to 20% fall from baseline FEV1). Thirty-two percent (10/31) of the subjects with asthma demonstrated increased BHR at 6 hours, 29% (9/31) at 24 hours, and 13% (4/31) up to day 14 after ETS challenge. Of the subjects without asthma, 18% (7/39) demonstrated increased BHR at 6 hours, 10% (4/39) at 24 hours, and 8% (3/39) at 3 weeks. These studies demonstrated an increase in BHR after cigarette-smoke challenge in a number of study subjects (although they were clinically asymptomatic) and suggest that prolonged subclinical airway inflammation can occur in the absence of demonstrable change in airway caliber on exposure to ETS.

Immune complexes and autoantibodies in silicosis

Serum specimens from 53 patients with silicosis were examined for the presence of antinuclear antibodies (ANA), rheumatoid factor (RF), immunoglobulins, and immune complexes. These humoral immunologic parameters were compared with radiographic changes and pulmonary function studies. A significant percentage of patients had an increased prevalence of ANA, RF, and immunoglobulin elevation (IgG, IgA). Immune complexes determined by the Raji-cell assay were detected in 31% of the patients. However, there was no significant correlation between any humoral immunologic abnormality and radiographic changes or declines in pulmonary function tests. These findings suggest that humoral immunologic abnormalities are not directly responsible for the lung changes in silicosis and cannot be used as guides to predict severity or progression of disease.

Antigenic/allergenic characterization of American and German cockroach extracts

Cockroach allergens have been implicated as clinically significant sensitizing agents in the induction/exacerbation of urban asthma. In the present study, approximately 50% of atopic, predominantly inner-city residents had immediate wheal-and-flare cutaneous reactivity to a commercial American cockroach whole body extract. Crude whole body extracts were prepared in our laboratory from both American (Periplaneta americana) and German (Blatella germanica) cockroach species. Crossed immunoelectrophoresis of American cockroach whole body extract (AWBE) and German cockroach whole body extract (GWBE) detected a total of 50 and 56 precipitin peaks, respectively, when extracts were reacted with hyperimmunized rabbit antisera. Crossed radioimmunoelectrophoresis identified at least five electrophoretically distinct allergens each in AWBE and GWBE. Cockroach whole body extracts produced two major protein peaks when extracts were fractionated on Sephadex G-75. RAST-inhibition studies demonstrated allergens in both peak 1 and the immediate trailing fractions of the column. Direct RAST and end point prick skin testing confirmed the presence of significant/important allergens in column fraction 2 of AWBE. Skin testing and RAST analysis suggested the occurrence of shared and species-specific allergens between AWBE and GWBE. Collectively, these studies confirm the important sensitizing potential of cockroach allergens, characterize their number and size distribution by crossed radioimmunoelectrophoresis and column chromatography, support the occurrence of significant allergens in column fraction 2, and suggest the occurrence of both species-specific and shared interspecies allergens.

Comparison of cockroach allergenic activity in whole body and fecal extracts

Previous studies have established cockroach allergens as important sensitizing agents in the induction/exacerbation of urban asthma. The present investigation compared saline extracts of American cockroach (Periplaneta americana) whole bodies and feces and German cockroach (Blattella germanica) whole bodies and feces as important sources of allergens. All extracts were tested before or after gel filtration on Sephadex G-75 columns (fraction 2) as previously described. Skin test studies of 69 subjects with asthma with extracts of American or German cockroaches demonstrated a significant correlation of reactivity to whole body and fecal extracts for both species. Direct RASTs of 13 sera from cockroach skin test-positive subjects were generally greater to both German whole body extracts (GWBEs) and German fecal extracts (GFEs) as compared to American whole body and fecal extracts. There was a good correlation of RAST reactivity to GWBE with GFE. RAST inhibition demonstrated that GFE contained most of the allergenic activity present in GWBE. These studies demonstrate the allergenic similarities of cockroach whole body and fecal extracts and suggest that cockroach feces are an important sensitizing agent in atopic asthma.

In vitro effect of asbestos fibers on polymorphonuclear leukocyte function.

Incubation of chrysotile and amphibole asbestos fibers with normal human peripheral blood polymorphonuclear leukocytes (PMN) resulted in a significant stimulation of PMN metabolic activity and generation of toxic oxygen by-products as measured by chemiluminescence (CL). Although all asbestos fibers tested were cytotoxic to PMN, cytotoxicity and CL varied disproportionately with fiber type. Anthophyllite asbestos produced the greatest PMN cytotoxicity. It also depressed PMN phagocytosis of latex beads the most and induced the greatest PMN CL response of the fiber types examined. We postulate that asbestos-induced release of toxic oxygen by-products from PMN which have infiltrated into the pulmonary alveoli may contribute to disease pathogenesis in asbestosis.

Asthmatic responses to passive cigarette smoke: Persistence of reactivity and effect of medications

The present study assessed the persistence of cigarette-smoke reactivity and the effects of drug pretreatment on bronchial responsiveness to environmental tobacco smoke (ETS). Two groups of subjects were chosen for the study. Group I consisted of 15 atopic smoke-sensitive subjects with asthma, six of whom were defined reactors and nine nonreactors to ETS challenge. Group II consisted of 15 atopic subjects without asthma and with documented upper respiratory tract symptoms on exposure to ETS. All subjects were challenged for 2 to 6 hours with mechanically generated ETS in a static inhalation chamber. Five/six subjects in group I, who were previously demonstrated as reactors 24 months earlier, remained reactive within 1 to 2 hours of continuous ETS exposure. Pretreatment with albuterol, cromolyn, and a combination of albuterol and cromolyn 30 minutes before ETS exposure significantly diminished airway reactivity to ETS. All nine previous nonreactors in group I remained nonreactive despite rechallenge with ETS for up to 6 hours. Group II subjects challenged under identical conditions did not reveal a significant decline in FEV1 on challenge with ETS. These studies demonstrate the persistence of ETS reactivity during a 2-year period. Although cromolyn sodium and/or albuterol can protect against reactivity, mechanisms of ETS-induced airway reactivity remain unknown.

Identification and characterization of important cockroach allergens.

Allergens extracted from American and German cockroach species have been identified as significant sensitizing agents in the induction/exacerbation of asthma. In the present study, gel-filtration fractions of saline extracts of American cockroach (Periplaneta americana) whole bodies (AWBE fraction 2) and German cockroach (Blattella germanica) whole bodies (GWBE fraction 2) were used to identify and characterize important cockroach allergens by immunoprinting. In addition, allergens from AWBE and GWBE fractions 2 were additionally fractionated by chromatofocusing on polybuffer exchanger. Immunoprinting studies demonstrated several important acidic allergens in cockroach whole body extracts. All but one allergen had an acid isoelectric point (pH 2.80 to 5.20). Two allergens, one that focused at pH 3.50 and another allergen (or group of isoallergens) that focused between pH 4.15 to 4.55 were reactive with most sera obtained from cockroach-sensitive subjects. Chromatofocusing and subsequent skin test and RAST studies of AWBE and GWBE confirmed the presence of significant cockroach allergens with isoelectric points within the zone of pH 3.75 to 4.50. RAST-inhibition studies demonstrated the similarity of these allergens between AWBE and GWBE. Collectively, these observations identify the presence of several acidic cockroach allergens presumably shared between AWBE and GWBE.

Humoral immunologic abnormalities in workers exposed to asbestos cement dust

Serum specimens from 144 workers exposed to asbestos cement dust were examined for the presence of ANA, RF, immunoglobulins, and IC. These immunologic findings were compared with chest radiographic changes. A high percentage of workers had polyclonal hypergammaglobulinemia, and there was a statistically significant association between elevated levels of IgG and IgM and radiographic classification. Although a significant number of workers had an increased prevalence of ANA and elevated levels of IC, there was no correlation between these parameters and chest radiographs. These findings support B cell hyperactivity in workers exposed to asbestos and suggest that autoantibody production and IC are not directly involved in disease pathogenesis.

Immunology of Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (extrinsic allergic alveolitis) represents a spectrum of granulomatous, interstitial, and alveolar-filling lung disorders of which farmers lung is a classic example. A major source of offending antigens in these diseases are thermophilic actinomycetes growing in moldy vegetable matter especially Micropolyspora faeni, and members of the Thermoactinomyces genus. Acutely, hypersensitivity pneumonitis presents as cough, dyspnea and fever, with crepitant rales, leucocytosis, diffuse interstitial and alveolar pulmonary infiltrates and a restrictive-type pulmonary functional deficit. Symptoms usually begin 4 to 6 hr after exposure to large quantities of causative organic dust. Chronically, these diseases may present with the gradual onset of cough, dyspnea on exertion, fatigue, anorexia, and weight loss which may progress to pulmonary fibrosis or severe pulmonary insufficiency. While early ideas on the pathogenesis of hypersensitivity pneumonitis support the role of Type III immune complex hypersensitivity, more recent evidence attests to the important and integral role of Type IV or delayed-type hypersensitivity. It is the purpose of this review, therefore, to describe those immune mechanisms relevant to the pathogenesis of hypersensitivity pneumonitis and stress the importance of local pulmonary immune responsiveness.