Ketoconazole treatment of nonprimary coccidioidomycosis. Evaluation of 60 patients during three years of study.

Sixty patients with coccidioidomycosis were treated with ketoconazole rather than with another antifungal agent, and their responses were evaluated in relation to the predominant site of involvement. For the three main groups, improvement occurred in 12 of 19 patients with chronic pulmonary infections, in 20 of 23 with soft tissue lesions and in six of 11 with skeletal involvement. Infections in soft tissues improved most rapidly (average of 34 days) and often with 200 mg per day, whereas pulmonary and skeletal infections improved more slowly (63 and 165 days, respectively), usually requiring 400 mg per day. Of 12 patients with response in whom therapy has been discontinued, seven have had relapses. Recurrence was apparent usually within the first month and after six months or less of treatment. Patients in remission had received ketoconazole for six to 17 months. Untoward drug effects included abdominal complaints (23 percent) and gynecomastia (8 percent). Therapy was discontinued in only three patients for side effects. Our findings support the use of ketoconazole in the treatment of certain forms of chronic coccidioidal infections.

Clinical usefulness of lymphocyte transformation in patients with coccidioidomycosis.

The development of an appropriate host defense in coccidioidomycosis is predicated on the presence of a positive delayed skin test reaction to coccidioidin. In severe and/or disseminated disease, coccidioidin reactions are routinely negative. By employing serial in vitro spherulin-induced lymphocyte blast transformation (LT) studies in a group of eight severely-ill coccidioidomycosis patients, prognostic clinical data were provided which could not have been obtained from their skin test status alone. Four of the eight demonstrated positive LT responses early in the course of their disease, quickly converted their skin tests to positive, and were cured of their disease. Two patients had negative LT responses until their skin test converted after several months of therapy. The final two have continued to demonstrate negative LT values despite several years of therapy and have experienced exacerbations of their disease when treatment was discontinued. The use of LT data in such patients can be very helpful in guiding therapeutic decisions in this difficult clinical problem.

A longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking, allergen skin-test reactivity, and serum IgE.

Chronic cough and/or phlegm, wheeze in the absence of colds, and rhinitis attributed to allergies are three of the most common respiratory symptoms encountered in community populations. In this study, we have determined the prevalence of these complaints in a random population sample (n = 1,109) using standardized questionnaires at two points in time, eight years apart. Cross-sectional prevalence and changes in symptom occurrence have been correlated with smoking status, allergen skin test reactivity, and total serum IgE levels. Our objective was to determine the individual and combined influence of these three variables on symptom prevalence. Initially, 19.2 percent of the population admitted to wheeze, 17.9 percent to cough, and 44.1 percent to allergic rhinitis. Cough and wheeze prevalence changed little over the eight-year period, while rhinitis increased 11 percent by the second survey. The occurrence of chronic cough was strongly correlated with smoking, and was not further influenced by either allergen skin reactivity or IgE level. Conversely, rhinitis prevalence was related to skin test reactivity with no additional association with smoking or IgE level. The occurrence of wheeze in the absence of colds was associated with both smoking and allergen skin reactivity. Among smokers, the prevalence was over 30 percent and was similar in both skin test positive (STP) and skin test negative (STN) individuals. However, on both surveys, STP ex-smokers and nonsmokers had significantly more wheeze than those who were STN. While the prevalence of wheeze in STN nonsmokers was low (6.8 percent), an IgE-wheeze relationship was also suggested on the second survey. In addition to these cross-sectional symptom relationships, changes in either smoking status or allergen skin reactivity during the study period were associated with changes in the prevalence of each symptom.

The maternal immune response in coccidioidomycosis. Is pregnancy a risk factor for serious infection?

Seven subjects with prior coccidioidal disease and three with active Coccidioides immitis infection during their first trimester were studied during pregnancy and postpartum to determine their general and antigen-specific cell-mediated immune status. All ten were white and carried their pregnancies to term without incident. Decreases in total lymphocytes and T-helper and T-suppressor subsets were noted during the third trimester, presumably secondary to an increase in plasma volume. Lymphocyte responses to the mitogens phytohemagglutinin, concanavalin A, and pokeweed were mildly decreased late in pregnancy, with significant intrasubject and intersubject variation. Responses to tetanus antigen were consistently and significantly lower as pregnancy progressed, rising above first trimester levels by 12 weeks postpartum. A similar pattern of response was noted with spherulin antigen for the seven subjects with previously demonstrated coccidioidal immunity. The three subjects with active coccidioidomycosis either failed to mount a significant spherulin immune response or demonstrated an early response that fell as pregnancy progressed. This antigen-specific immune suppression continued for up to 16 months postpartum despite the fact that there was no clinical evidence of coccidioidal activity beyond the first trimester. Thus, while all three completed pregnancy without complication, the data suggest that significantly increased maternal risk may be present when active coccidioidomycosis and pregnancy occur together. This risk may be greatest among darker-skinned individuals who become infected during the latter half of pregnancy.

The absence of a relationship between serum precipitins and pulmonary disease in a community.

To study the role of serum precipitins in respiratory illness in a community, sera obtained from 3,047 residents of Tucson, Ariz., were tested for the presence of precipitating antibody to a battery of antigens. Positive reactions were obtained in 54 subjects (1.8 percent), a lower incidence than has been reported previously. The majority of these subjects were older than 54 years of age, an age distribution significantly older than the entire sample (P less than 0.01). Pulmonary function among the subjects with positive precipitin reactions was not significantly different from that of the asymptomatic nonsmokers of the entire sample. None of the subjects who were lifelong residents of Arizona had serum precipitins to any of the thermophilic actinomycetes antigens which were used in the testing. These antigens have been found in association with extrinsic allergic alveolitis, most frequently among patients living in the north central United States and were derived from strains of Micropolyspora faeni, Thermoactinomycetes candidus and vulgaris. Each subject with precipitins to one or more of the tested antigens was matched by age, sex, and socioeconomic class with two subjects from the sample who had negative precipitin reactions. The groups did not differ in their prevalence of respiratory symptoms or abnormalities of pulmonary function. We conclude that the presence of precipitating serum antibodies among subjects in a community is not indicative of the presence of immunologic pulmonary disease but merely reflects previous exposure to the tested antigen. In addition, individuals whose sera contain precipitating antibody appear to have no increased tendency to develop other types of pulmonary disease.

Detection of fungi and other pathogens in immunocompromised patients by bronchoalveolar lavage in an area endemic for coccidioidomycosis.

Bronchoalveolar lavage (BAL) was performed in 51 adult immunocompromised patients (30 acquired immunodeficiency syndrome [AIDS] and 21 non-AIDS) as part of an extensive diagnostic evaluation for diffuse pulmonary infiltrates. Because multiple episodes occurred in several patients, a total of 60 BALs were performed. A diagnosis of fungal pneumonia was eventually made in 12 patients (24 percent). The organism was identified in BALs from seven of the 12, including five of seven cases of cocciodoidomycosis, one of two cases of aspergillosis, and one of three cases of cryptococcosis. Among the AIDS patients, only one case of coccidioidomycosis was diagnosed, whereas six such diagnoses were made from the 25 BALs performed on the 21 non-AIDS patients. This suggests that coccidioidomycosis is not as frequent an infection in AIDS patients in this endemic area as has been suggested previously. Candida-like organisms were identified in 23 BALs, but in no case were they clinically pathogenic. Their presence correlated with oral candidiasis (p = 0.01). Twenty-seven of 29 episodes related to Pneumocystis carinii were identified by Papanicolaou-stained cytocentrifuged BAL preparations, all but two of which were in AIDS patients. In addition, BALs detected six episodes of bacterial pneumonia and three of five cases of radiation pneumonitis. Overall, the diagnostic sensitivity of BAL was 52 of 60 or 87 percent. While examination of induced sputum for the presence of Pneumocystis may eliminate the need for bronchoscopy in some AIDS patients, BAL remains an excellent diagnostic procedure in the immunocompromised patient without AIDS.

The epidemiology of asthma.

Significant strides have been made in recent years in the epidemiologic study of obstructive lung diseases including asthma. Community population samples are being evaluated prospectively and followed up longitudinally to document the appearance of morbidity and clinical diagnoses. Also, a variety of environmental, physiologic, and immunologic variables are being collected on a serial basis to correlate changes with the appearance (or disappearance) of recognizable disease. Unfortunately, until the semantics and diagnostic labeling of airway abnormalities becomes more precise, especially in the older population, the incidence and prevalence of disease will lack the precision it should have.

Characteristics of asthma among elderly adults in a sample of the general population.

This article describes the characteristics and course of asthma among subjects who were older than 65 years at the time of enrollment in a longitudinal study of a general population sample. It was present in 3.8 percent of men and 7.1 percent of women. An additional 4.1 percent of men reported having "asthma," but they also had seen a physician for "emphysema" and had smoked significantly; their "asthma" diagnosis is regarded as highly questionable. They did not show the elevated rate of allergy skin test reactivity of high serum IgE levels that were characteristic of other asthmatics. Many of the elderly asthmatics (mean age, 72 years) had severe disease with marked ventilatory impairment. There was a close relationship between the severity of wheezing complaints and impairment of the FEV1. Of the 46 patients, 48 percent reported an onset before age 40 years. There was no relationship between severity and age of onset or duration of disease. A second diagnosis of "chronic bronchitis" was reported by 46 percent of the asthmatics, but this did not delineate a distinctive group with late-onset, smoking-related disease. Death rates in the asthmatics tended to be higher than in nonasthmatics (odds ratio, 1.9; CI, 0.998 to 3.70, after stratifying by sex). Over a mean follow-up of 7.44 years, most symptoms as well as the FEV1 remained relatively stable. Chronic productive cough did tend to remit (p less than 0.01), but this was noted in the nonasthmatics as well. We estimate that no more than 19 percent of the asthmatics went into complete remission during follow-up. Most of these had mild initial symptoms; there were no remissions in subjects with severe disease at the time of entry. We concluded that asthma in the elderly is not a rare disease and may be associated with severe symptoms and chronic airways obstruction. If severe, it rarely goes into complete remission but tends to remain a severe, disabling disorder.

Interactions of smoking and immunologic factors in relation to airways obstruction.

The relationships of smoking, allergy skin test reactivity, and serum IgE to ventilatory function have been analyzed in 1,182 subjects from a general population sample. The study group consisted of subjects aged 35 or more who deny previous lung surgery, old tuberculosis, or a current diagnosis of heart disease in the absence of chronic bronchitis or emphysema. Impairment of the forced expiratory volume in one second (FEV1) shows a definite relationship to total serum IgE. However, this relationship is significant only for a low FEV1 which is accompanied by symptoms suggesting asthmatic or a chronic bronchitis type disease. Allergy skin test reactivity to a battery of common aeroallergens shows no overall relationship to FEV1. However, after accounting for total serum IgE, positive allergy skin tests tend to be associated with high rather than low FEV1 values. The findings suggest that some type of IgE which is not specific for aeroallergens but which is associated with smoking, may be important in the pathogenesis of the "chronic asthmatic bronchitis" syndrome.

Kinetics of theophylline; variability and effect of arterial pH in chronic obstructive lung disease.

The pharmacokinetic behavior of theophylline was determined in 12 patients during an acute exacerbation of their chronic obstructive pulmonary disease. A 5.6 mg/kg loading dose of aminophylilne was administered, followed three hours later by a 0.9 mg/kg/hr continuous infusion. The loading dose increased the serum theophylline level an average of only 5.77 microgram/ml. After the loading dose, only five patients had levels greater than 10 microgram/ml. Mean initial drug clearance was 0.77 L/kg/hr, half-life 9.1 hr, and apparent volume of drug distribution .887 L/kg. Wide inter- and intrapatient pharmacokinetic variability was observed. The variability of drug distribution was inversely correlated with the arterial pH. These patients with chronic obstructive pulmonary disease appeared to require more theophylline when acidemic than when alkalemic to achieve similar serum theophylline concentrations.

Efficacy of salmeterol xinafoate in the treatment of COPD.

STUDY OBJECTIVES: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. DESIGN: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. SETTING: Multiple sites at clinics and university medical centers throughout the United States. PATIENTS: Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. INTERVENTIONS: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. RESULTS: Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. CONCLUSIONS: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.

Evaluation of methodologic variables of the in vitro lymphocyte transformation assay.

Optimum methodologic variables for assessing cellular immunity by in vitro lymphocyte transformation (LT) were determined using spherulin and coccidioidin antigens. This study was conducted in an area endemic for coccidioidomycosis and included healthy, coccidioidomycosis skin test positive (STP) and negative (STN) subjects, and patients with mild, acute disease. The authors examined the relationship between coccidioidin (1:100) and spherulin (low dose) skin test reactivity and lymphocyte transformation (LT) responses to the same antigens. Counts per minute (CPM) and stimulation index (SI) as methods of expressing tritiated thymidine uptake were compared. The LT assays were set up in duplicate test systems using autologous and homologous plasma. Both antigens differentiated between STP and STN groups (P less than or equal to 0.001-0.004), but values obtained with spherulin-induced LT were greater than those using coccidioidin (P less than 0.001). Values in CPM and SI were greater in the spherulin-induced LT assay using autologous compared with AB plasma. Specifically, for detecting cellular immunity to coccidioidomycosis, the combination of spherulin-induced LT using autologous plasma and expressing the results in CPM gave the best discrimination between STP and STN subjects. Based on epidemiologic data, the latter method also appeared more sensitive than the skin test in detecting cellular immunity to coccidioidomycosis. In general, these data illustrate the variable effectiveness of different antigens for inducing LT responses and further show how different plasma sources affect the LT response. Finally, these data suggest that lymphocyte blast transformation results expressed as CPM may give more consistent values and better discrimination between immune and nonimmune subjects than results expressed as stimulation indices.

The epidemiology of asthma.

As noted earlier, the clinician and the epidemiologist are in many respects in similar positions in terms of our current understanding of asthma. Through the efforts of the pharmaceutical industry the practitioner has a much wider range of therapeutic tools available to manage reversible airways disease. B-agonists are more specific, have a longer duration of action, minimizing the potential for abuse and coincident toxicity. Theophylline preparations are long-acting and therapeutic drug levels can be accurately assessed. Inhaled corticosteroids provide the opportunity to reduce the negative side aspects of hormonal therapy. Unfortunately, with all these tools, the morbidity and mortality of asthma have not been decreased. In fact, it may be that the disease is a greater worldwide health problem than it was a generation ago. Similarly, epidemiologic research has provided us with increasingly meaningful information, not only of the prevalence of the disease, but with recent longitudinal studies, the factors which impact upon disease remission and relapse. Whether we separate the wheezing syndromes into separate categories of wheezy bronchitis, asthmatic bronchitis, and asthma is probably less important than our understanding of a disease entity which is characterized by bronchial hyper-reactivity in response to a variety of stimuli. The most encouraging aspects of recent epidemiologic research have been the selection of representative populations, using standardized methods, from which significant conclusions can be drawn. At the least, these studies have confirmed and extended our knowledge of a disease that we still do not fully understand. Woolcock et al.[56], and others, have included inhalation challenge testing into their epidemiologic protocols in an attempt to add physiologic assessments to the more traditional symptom complexes. Unfortunately, even this addition has not solved the problem of an asthma diagnosis in the older adult population whose irreversible airways obstructive disease is a confounding variable. Even in younger subjects, as reported by Townley et al.[14], a gradation of responses to methacholine inhalation in atopic subjects, may make the identification of asthmatics more difficult than initially thought. The fact that ex-asthmatics appear to retain their hyper-responsiveness, however, could make inhalation challenge a valuable tool in longitudinal epidemiologic research. What can epidemiologic studies contribute in the future?.(ABSTRACT TRUNCATED AT 400 WORDS)

The natural history of asthma.

Our understanding of the natural history of asthma is improving through the establishment of a more precise definition of asthma linked with information from large-scale longitudinal studies. Risk factors for the development of childhood asthma including sex, atopic status, genetic and familial factors, respiratory infections, and outdoor and indoor pollution are now more clearly understood. New information on the relation of viral wheezing episodes in infancy to later childhood asthma is evolving. We now know that children who start wheezing early in life and continue to wheeze at age 6 years are more likely to have a maternal history of asthma, elevated serum IgE levels, and normal lung function in the first year of life. However, at age 6 years they have both elevated serum IgE levels and diminished lung function. Approximately 50% of adults who report having had childhood asthma no longer have symptoms. Airway responsiveness in childhood tends to predict airway responsiveness in adulthood and to be greater in asthmatics with persistent symptoms. Studies of the natural history of asthma support the hypothesis that early therapeutic intervention in mild disease may lead to an improved clinical outcome. Adults exposed to specific occupational environments are at additional risk for the development of asthma. As we learn more about the natural history of asthma, we will have a better understanding of the effect of early diagnosis, environmental control, and therapy on the outcome of the disease.

Student decision-making and performance in a flexible-time curriculum.

Three consecutive classes (213 students) entering the University of Arizona College of Medicine under a flexible-time three-year curriculum were provided the option of extending their program by a year or more. Of the 30 percent who availed themselves of this option, a majority did so because they desired a better personal or academic "life-style" rather than for specific academic reasons. Most continued to pursue medical interests during the free time which became available to them. Through none of the usual admission data was it possible to predict which students would choose to extend their program. At the time of graduation students completing the curriculum in three years achieved scores on the Part II examination of the National Board of Medical Examiners comparable with those earned by students who extended for a four-year program. Nonacademic factors may be of greater importance than academic factors in student acceptance of accelerated curricula.

The prevalence of cellular immunity to coccidioidomycosis in a highly endemic area.

Intradermal skin test reactivity to spherulin and coccidioidin and in vitro spherulin-induced lymphocyte transformation were used to assess cellular immunity in healthy subjects and patients with acute, self-limited coccidioidomycosis (cocci). The objectives of this study were to evaluate the relative sensitivities of the two assays in assessing cellular immunity to cocci, especially in long-term residents of an endemic area (Tucson) and, based on data from both assays, determine the prevalence of detectable cellular immunity to cocci in this highly endemic area. The lymphocyte transformation assay appeared to be more sensitive than the skin test in assessing long-term immune status, and the prevalence of detectable immunity to cocci in this highly endemic area was only 75% in long-term residents. This is much lower than previous prevalence estimates (90%) in other endemic areas. The absence of a demonstrable cell-mediated immunity may indicate either no prior antigen exposure (infection) or previous remote exposure with a diminished immune response (no reexposure to boost immunity). A possible explanation for the lower prevalence of immunity to cocci in this endemic area may relate to the increased urbanization of the Southwest in the past several years. Therefore, the clinical suspicion of acute cocci should not be restricted to recent arrivals to endemic areas.

Reversibility of severe bleomycin-induced pneumonitis.

The use of bleomycin sulfate as an antineoplastic agent has been limited by its substantial pulmonary toxic effects. The exact incidence and prognosis of bleomycin-pneumonitis is unresolved. Although bleomycin pulmonary toxicity is thought to be dose-related, recent reports have emphasized severe reactions at low doses. Furthermore, severe pulmonary toxicity has been suggested to be progressive, irreversible, and ultimately, fatal. We report clinical, roentgenographic, and pathophysiologic recovery after severe, bleomycin-induced pneumonitis.

Distribution of IgE in a community population sample: correlations with age, sex, and allergen skin test reactivity.

The distribution of total serum IgE determined by the paper radioimmunosorbent test (PRIST) is examined in a large random stratified community population. Prior to logarithmic conversion the distribution of this immunoglobulin is not normal, with almost 40% of values below 20 IU/ml. A normal distribution occurs following such conversion, with a geometric mean value of 32.1 IU/ml. Both age and sex, in addition to atopic status, relate to IgE level. In both sexes highest levels occur among 6- to 14-year-olds, and males have higher levels than females at any given age. Women over age 75 yr have the lowest levels (geometric mean 9.2 IU/ml). Subjects with positive skin test results have several times the concentration of IgE as their nonatopic counterparts.