Emil J. Bardana

Effects of phenytoin on man's immunity: Evaluation of changes in serum immunoglobulins, complement, and antinuclear antibody

To determine the effects of phenytoin on serum immunoglobulins, complement, and antinuclear antibody conversion, a prospective, five-year longitudinal study was undertaken in 118 patients. Three major diagnostic groups were evaluated: 27 patients with idiopathic epilepsy, 50 with secondary epilepsy, and 41 with neuropathic syndromes without epilepsy. In addition, 83 normal volunteers were studied in a similar manner. Evaluations were performed prior to administration of phenytoin and at six-month intervals thereafter. Prior to treatment, patients with idiopathic epilepsy had a higher than expected incidence (13.5 percent, p less than 0.01) of low serum IgA (less than 61 mg/dl). Patients with secondary epilepsy and neuropathic disorders without epilepsy had a greater than expected incidence (9.2 percent, p less than 0.01; and 12 percent, p less than 0.01, respectively) of high serum IgA (greater than 417 mg/dl). Phenytoin treatment was associated with further decreases in serum IgA in patients with idiopathic epilepsy (p = 0.063) and secondary epilepsy (p = 0.008). Total serum IgE concentrations also decreased significantly in all patient categories during treatment with phenytoin. Minor decreases in serum IgG and IgM were noted, but serum IgD and complement remained unaffected. Antinuclear antibodies were observed with essentially the same frequency (10 percent) before and after phenytoin therapy.

Reactive airways dysfunction syndrome (RADS): guidelines for diagnosis and treatment and insight into likely prognosis

Reactive airways dysfunction syndrome (RADS) is defined as the sudden onset of asthma following a high level exposure to a corrosive gas, vapor, or fume. This variant of occupational asthma continues to generate controversy regarding the criteria for its diagnosis. There is also some disagreement as to the likely prognosis with this disorder. Currently, the diagnosis requires the assumption of normal premorbid pulmonary physiology and absence of bronchial hyperreactivity. Criteria for the diagnosis of RADS are discussed with a proposal for both major and minor criteria to increase the confidence of an accurate diagnosis. The pathology of RADS involves a primarily lymphocytic inflammatory response with some evidence of subepithelial thickening and fibrosis. Most patients with this condition who survive the short-term exposure to a toxicant recover completely without significant clinical or physiologic sequelae. The issue of low-level RADs remains controversial and problematic as a tenable diagnosis, and will require further careful investigation to evaluate the premise that chronic, low-level toxicants are capable of leading to such a condition. More likely, most of the cases which have been reported represent preexisting asthma and/or expressions of an atopic predisposition.

The prognostic and therapeutic implications of DNA:Anti-DNA immune complexes in systemic lupus erythematosus (SLE)

Serum samples serially obtained from 50 patients with systemic lupus erythematosus (SLE) were studied for antibody to deoxyribonucleic acid (DNA) and circulating DNA:anti-DNA complexes during the active and inactive phases of their disease. The patients were divided into four categories: Group I: six patients without clinical evidence of central nervous system (CNS) or renal involvement. Group II: three patients with CNS lupus. Group III: nine patients with normal urinalyses and glomerular filtration rates, but morphologic evidence of glomerular disease. Group IV: 32 patients with overt lupus nephritis. Elevated anti-DNA levels were observed in 16 of 18 patients (88 per cent) in groups I, II and III during active disease. This persisted in 14 (77 per cent) during remission. DNA:anti-DNA complexes were demonstrated in four of 18 (22 per cent) during active disease and disappeared in all but one patient with progressive disease. In 30 of the 32 patients (94 per cent) in group IV, DNA binding was increased during active disease; this persisted in 21 (70 per cent) despite remission. Complexes were observed in 25 of the patients in group IV (78 per cent) with active disease. In six of these patients, complexes have persisted; two have died, one has progressed to renal failure and the remaining three patients continue to manifest active disease. This study suggests that measurement of DNA:anti-DNA complexes provides a valuable additional index of disease activity and prognosis in SLE.

Partial lipodystrophy, C3 nephritic factor and clinically inapparent mesangiocapillary glomerulonephritis

A case of partial lipodystrophy with C3 nephritic factor was found to be associated with mesangiocapillary glomerulonephritis although all clinical parameters of renal function were normal. Diagnosis of mesangiocapillary glomerulonephritis required renal biopsy. Nephriti factor obtained from this patient was immunochemically related to nephritic factor isolated from the serum of patients with typical mesangiocapillary glomerulonephritis without partial lipodystrophy.

Diet-Induced Systemic Lupus Erythematosus (SLE) in Primates

Ten adult, female cynomolgus macaques were randomly assigned to two equal groups: (1) semipurified diet (SPD); and (2) SPD with 45% ground alfalfa seed (AS). Both groups were studied at monthly intervals after 5 mo on their respective diets. Control animals had a mean hematocrit (Hct) of 43 +/- 2%, negative antiglobulin (AG), antinuclear antibody (ANA) and LE cell tests. Mean values for C3 and C4 were 309 +/- 47 mg/dl and 35 +/- 7 mg/dl, respectively. Mean serum binding to radiolabeled double stranded deoxyribonucleic acid (dsDNA) was 1.9 +/- 0.2%. Three of five animals fed AS developed signs of an SLE-like illness characterized by AG-positive anemia (lowest Hct 30%), positive ANA (highest titer greater than 1:15, 360; rim pattern) and elevated anti-dsDNA binding (highest 96%) with variable degrees of hypocomplementemia. One animal had granular deposition of immunoglobulin and complement at the dermal-epidermal junction of clinically normal skin the presence of immune complex-induced glomerulonephritis.

10. Occupational asthma

A diversity of airborne dusts, gases, fumes, and vapors can induce dose-related respiratory symptoms in individuals exposed in the workplace. These agents can cause annoyance reactions, irritational effects, sensitization, or the induction of corrosive changes in the respiratory tract, depending on their composition, concentration, and duration of exposure. The prevalence of occupational asthma (OA) ranges from 9% to 15% of the asthmatic population. Factors that might influence the development of OA include the work environment, climatic conditions, genetic proclivities, tobacco and recreational drug use, respiratory infection, bronchial hyperresponsiveness, and endotoxin exposure. Pathogenetically, new-onset OA can be allergic or nonallergic in origin. The allergic variants are usually caused by high-molecular-weight allergens, such as grain dust and animal or fish protein. Selected low-molecular-weight agents are also capable of inducing allergic OA. Symptoms ensue after a latent period of months to years. Nonallergic OA can be precipitated by a brief high-level exposure to a potent irritant. Symptoms occur immediately or within a few hours of the exposure. Once the diagnosis of allergic OA is established, the worker should be removed from further exposure in the workplace. In nonallergic OA the worker can return to work if the exposure was clearly a nonrecurring event. If the diagnosis is made in a timely fashion, most workers experience improvement. Prevention is the best therapeutic intervention.

Indoor pollution and its impact on respiratory health.

LEARNING OBJECTIVES This overview discusses the respiratory complications of indoor air pollution, emphasizing the most common pollutants that individuals are likely to encounter outside the workplace. DATA SOURCES Data were obtained from a review of the recent literature. STUDY SELECTION The expert opinion of the author was used to select and synthesize relevant data on this multifaceted subject. RESULTS There have been a number of studies documenting an association between exposure to indoor allergens and development of both sensitization and asthma in children. In addition to classic allergens, chemical indoor air pollution may also exert an adverse effect on both the upper and lower respiratory tract by a variety of nonimmunologic, irritative mechanisms. CONCLUSIONS Our understanding of the adverse effects of indoor air pollution on health and comfort has broadened in recent years. It has supplied a credible framework for developing and implementing a variety of control strategies.

Seasonal Variation in Bronchial Hyperreactivity (BHR) in Allergic Patients

As summarized in Table 1, the literature consistently supports the hypothesis that allergic asthmatic patients have seasonal BHR changes that parallel allergen exposure. These seasonal changes appear to be preventable by treatment with corticosteroids (systemic, inhaled, or nasal), disodium cromoglycate, and immunotherapy. Studies have almost exclusively focused on pollens, though similar limited data exist for dust mites. Though the dust mite is a perennial allergen, mite levels are well known to fluctuate with seasonal temperature and humidity trends (44-46), and therefore, seasonal BHR variation in mite-sensitive asthmatic patients is not surprising. Allergenic mold species have not been studied in this regard. In allergic rhinitis patients, the data are less consistent (see Table 2). However, the studies that failed to identify a seasonal BHR difference were either small or had other design limitations. The seasonal changes identified by the larger analyses were similar to those identified for asthmatic patients. Thus, although confirmatory studies would be helpful, it seems likely that in the absence of clinical asthma, allergic rhinitis patients with baseline BHR have allergen-related seasonal changes in BHR. The BHR effects of seasonal changes in air pollution and viral URIs are not known, since they have not yet been directly studied. However, interesting recent reports have identified possible synergistic effects of air pollution exposure on BHR and allergic responses. Similarly, the availability of new viral identification techniques has resulted in the discovery that viral infection may be more prevalent during clinical asthma exacerbation than previously realized. Therefore, air pollution and viral infections may well influence BHR seasonally, and (along with allergens) may contribute to seasonal asthma morbidity and mortality peaks. The mechanism(s) underlying seasonal BHR changes is (are) not known. One plausible possibility with regard to allergen-driven BHR changes involves a type I hypersensitivity late-phase reaction. Characterized by recruitment of eosinophils, lymphocytes, and other cells that are central components of allergic inflammation and are not normally found in the lower airways, this reversible inflammatory process could in turn act, presumably via chemical mediators, on the airway smooth muscle. This may cause bronchoconstriction, but may also increase responsiveness to bronchoconstrictive stimuli independent of bronchoconstriction. This explanation for seasonal BHR changes is supported by findings of blood eosinophil (31,47) and BAL eosinophilic cationic protein (31) level changes that parallel BHR. Prevention of seasonal BHR changes using anti-inflammatory medications (32,33,35) also supports this hypothesis (30) however, and the complex potential interactions between infectious agents and air pollutants on seasonal BHR changes have yet to be studied directly. Therefore, although BHR indeed may predictably vary season to season in allergic individuals, additional investigation is needed to better characterize the reasons for this phenomenon. Further insight in this area may help address the reasons why there are often seasonal epidemics in asthma morbidity and mortality.

Azathioprine in steroid-insensitive nephropathy

Twenty patients with steroid-insensitive glomerulonephritis were treated with azathioprine and prednisone in sustained low dosages. Serial parameters were measured to (1) assess functional response; (2) define any relationship between improvement in renal function and changes in the immune apparatus; (3) define criteria for patient selection; and (4) identify useful parameters to gauge therapeutic progress. Three patients had a complete remission, ten a partial remission, three slight improvement, and four continued to show deterioration despite treatment. Only one patient had septic complications. Functional response did not correlate with the degree of humoral or cellular immunosuppression. Azathioprine initially depressed immunoglobulin G (IgG) levels but after six months of therapy the levels of all immunoglobulins exceeded baseline values by nearly 50 per cent. Cellular immunity was never suppressed completely. Immunosuppression of humoral autoantibodies did not correlate with functional response. Renal histology, hyperalpha 2 -globulinemia and hypocomplementemia were the most reliable parameters in judging selection and probability of response in a patient with lupus glomerulonephritis. With other forms of glomerulonephritis, histopathologic criteria are not as well established and less useful. Hypocomplementemia and hyperalpha 2 -globulinemia, in the face of steroid unresponsiveness, were considered to be indications for antimetabolite therapy.

Indoor air quality and health: Does fungal contamination play a significant role?

Fungal contamination in buildings can vary greatly, and their presence in a dwelling does not necessarily constitute exposure. Measurement of mold spores and fragments varies depending on the methodology and instruments used. Meaningful comparison of data is rarely possible. The presence of a specific immune response to a fungal antigen only connotes that exposure to one or more related species has occurred, but not that there is a symptomatic clinical state. The response of individuals to indoor bioaerosols is complex and depends on age, gender, state of health, genetic makeup, and degree and time of bioaerosol exposure. In general, mold contamination in buildings is associated with incursion of water or moisture, which should be remedied as efficiently as possible. When disease occurs, it more likely is related to transient annoyance or irritational reactions. Allergic symptoms may be related to mold proliferation in the home environment. Because molds are encountered both indoors and outdoors, it is difficult to determine where the sensitivity initially arose and if the response is solely provoked by either an indoor or outdoor source. As an indoor allergen, mold is considered to be an infrequent participant in the induction of allergic disease when compared with housedust mites, animal dander, and cockroach allergens. Infection in healthy individuals is rare and usually is caused by an outdoor source. Building-related disease caused by mycotoxicosis has not been proved in the medical literature.