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BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

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BACKGROUND: Allergic bronchopulmonary aspergillosis is a hypersensitivity disorder that can progress from an acute phase to chronic disease. The main treatment is systemic corticosteroids, but data from uncontrolled studies suggest that itraconazole, an orally administered antifungal agent, may be an effective adjunctive therapy. METHODS: We conducted a randomized, double-blind trial of treatment with either 200 mg of itraconazole twice daily or placebo for 16 weeks in patients who met immunologic and pulmonary-function criteria for corticosteroid-dependent allergic bronchopulmonary aspergillosis. A response was defined as a reduction of at least 50 percent in the corticosteroid dose, a decrease of at least 25 percent in the serum IgE concentration, and one of the following: an improvement of at least 25 percent in exercise tolerance or pulmonary-function tests or resolution or absence of pulmonary infiltrates. In a second, open-label part of the trial, all the patients received 200 mg of itraconazole per day for 16 weeks. RESULTS: There were responses in 13 of 28 patients in the itraconazole group (46 percent), as compared with 5 of 27 patients in the placebo group (19 percent, P=0.04). The rate of adverse events was similar in the two groups. In the subsequent open-label phase, 12 of the 33 patients who had not had a response during the double-blind phase (36 percent) had responses, and none of the patients who had a response in the double-blind phase of the trial had a relapse. CONCLUSIONS: For patients with corticosteroid-dependent allergic bronchopulmonary aspergillosis, the addition of itraconazole can lead to improvement in the condition without added toxicity.

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BACKGROUND: Long-acting beta(2)-sympathomimetic agonists such as salmeterol have been proved safe and effective for the treatment of asthma. However, controversy still exists as to the appropriateness of scheduled long-term therapy with these agents. OBJECTIVE: This study assessed the degree of bronchodilation provided by treatment with salmeterol for a period of 52 weeks and evaluated bronchial hyperresponsiveness to methacholine during and after the treatment period. METHODS: Three hundred fifty-two patients with mild to moderate asthma were assessed by 12-hour serial spirometry and serial methacholine challenge tests. RESULTS: The mean area under the FEV(1) curve above baseline over 12 hours after drug at day 1 was significantly greater with salmeterol powder compared with placebo (5.06 liter hours vs 0.77 L/h) and did not change significantly over 1 year. The mean increase in the log(2) of the provocative cumulative methacholine dose producing a 20% decrease in FEV(1) (PD(20)FEV(1)) during treatment was significantly higher in the salmeterol-treated patients than in the placebo group (1.02 doubling doses vs 0.43 doubling doses at week 4, 1.06 doubling doses vs 0.41 doubling doses at week 24). At week 52 the increase from baseline in log(2)PD(20)FEV(1) was not significantly different between salmeterol and placebo (1.08 vs 0.69 doubling doses). Seven days after treatment the log(2)PD(20)FEV(1) was -0.60 doubling doses lower than baseline for salmeterol compared with 0.10 doubling doses for placebo (P =.031). Long-term salmeterol use was not associated with a deleterious effect on asthma control during and after treatment. CONCLUSION: This study demonstrates that the bronchodilator properties of salmeterol are sustained over 52 weeks and that bronchial hyperresponsiveness to methacholine is decreased to a modest degree during treatment. Clinically significant increases in hyperresponsiveness did not develop after discontinuation of salmeterol treatment.

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Hypersensitivity pneumonitis (HP) as a sentinel event implies a remediable exposure and an exposed cohort that require evaluation. A patient with HP convincingly related to her building led to a questionnaire survey in follow-up. Building coworkers demonstrated substantially higher symptom rates than did controls in five other buildings, although no further cases of disease were identified. It is likely that moisture sources in the building included an oversized cooling system and below-grade moisture, but the building met all applicable regulations and standards. Screening investigations for disease are not mandated by law and are often not conducted, in part because cost coverage is unclear. The absence of regulatory or professional standards that adequately address moisture in the built environment forces occupational health professionals to rely on disease documentation strategies to justify intervention.

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The efficacy, persistence of bronchodilator action, and safety of the quaternary ammonium anticholinergic agent, ipratropium bromide (500 microgram), and placebo were compared when each was added in solution form to the beta-adrenergic agonist solution, metaproterenol sulfate (15 mg), and administered three times daily for 12 weeks to a total of 213 patients with chronic obstructive pulmonary disease (COPD). Subjects had a mean forced expiratory volume in 1 second (FEV1) of approximately 1 liter (37% of predicted) and were permitted to use nonanticholinergic therapy for COPD throughout the trial. The study was a randomized, double-blind, 85-day, parallel-group, eight-center study. On a 3 test days, 1, 43, and 85, mean peak responses for FEV1 and forced vital capacity and mean area under the curve were significantly higher for the iprathropium bromide-metaproterenol combination than for metaproterenol only. Duration of action was also significantly longer for the combination therapy than for the beta-agonist alone on test days 1 and 43. Neither treatment regimen produced an demonstrable effect on daily morning peak expiratory flow rates, reported respiratory symptoms, or quality of life. Both treatment regimens were similarly well tolerated with a comparable frequency of adverse events. These results suggest that the combination of iprathropium bromide and metaproterenol inhalation solutions offers a potential therapeutic advantage to patients with symptomatic COPD over nebulized metaproterenol alone without the risk of increased side effects.

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We speculated that changes in endogenous prostaglandin synthesis might be responsible for the syndrome of premenstrual asthma (worsening of asthma in relation to menstruation). To test our hypothesis, we compared the effects of sodium meclofenamate, a prostaglandin synthesis inhibitor, and placebo on premenstrual asthma in a 4-month, double-blind, crossover study of 17 women with asthma. Day-by-day evaluation revealed that peak expiratory flow reached a nadir during menstruation on both meclofenamate and placebo therapy and varied inversely with menstrual symptoms and asthma symptoms. Meclofenamate therapy resulted in significant improvement in peak expiratory flow during the early premenstrual period but had no treatment effect on the exacerbation of asthma during the late premenstrual period and early menstruation. The overall improvement in pulmonary function caused by meclofenamate therapy was correlated with the treatment effect on menstrual symptoms. Meclofenamate caused a small, nonsignificant decrease in use of theophylline and oral beta-agonist agents, whereas corticosteroid use increased slightly but not significantly. This study demonstrates the temporal relationship between menstrual symptoms and asthma. The study also demonstrates that inhibition of prostaglandin synthesis does not prevent exacerbation of asthma in relation to menstruation.

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In order to evaluate whether adverse reactions to a nonsteroidal antiinflammatory agent (NSAIA) were related to variations in prostaglandin levels during the menstrual cycle, we measured 13-14-diOH-15-keto-prostaglandin F2 alpha in serum and the effect on airways of a single dose of 100 mg oral meclofenamate and 1.5 mg inhaled metaproterenol during the early (follicular phase) and late (luteal phase) menstrual cycle. Among 24 women with premenstrual asthma (PMA), four women with regular asthma (REA), and four healthy women, the 13-14-diOH-15-keto-PGF2 alpha averaged 140.9 +/- 68.4 pg/0.1 ml during the follicular phase but only 14.4 +/- 2.2 pg/0.1 ml during the luteal phase (p less than 0.0001). Acute asthma reactions to the meclofenamate occurred during the follicular phase in six women with PMA but were never observed during the luteal phase (p = 0.016). These reactions occurred preferentially in patients on corticosteroids (p = 0.004). Conversely, one patient with PMA had 18% improvement in FEV1 with meclofenamate during the luteal phase. A placebo-controlled, double-blind evaluation of the healthy women and the women with REA revealed a trend toward improvement in FEV1 during the luteal phase (0.15 less than p less than 0.10) but no change during the follicular phase. The effect of metaproterenol did not vary with the menstrual cycle, and there was no interaction between the effects of meclofenamate and those of metaproterenol. It appears that meclofenamate causes adverse effects on pulmonary function in asthmatic women primarily during the follicular phase of the menstrual cycle. This effect is associated with corticosteroid treatment and may be related to monthly variation in serum 13-14-diOH-15-keto-PGF2 alpha.

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After observing three cases of severe recurrent exacerbations of asthma in relation to menstruation, we conducted a survey among women with asthma inquiring about the relationship of asthma symptoms to the menstrual cycle. Of 57 women with asthma, 19 (33%) had significant worsening (p = 0.006) of total pulmonary symptom scores during either the premenstrual period, the menstrual period, or both with maximum increase in dyspnea, wheezing, and chest tightness during the premenstrual period (p = 0.002). The other 38 (66%) women noted no such changes in their asthma. Logistic regression analysis comparing women with and without worsening of their asthma around menstruation revealed that the former group reported significantly more severe wheezing in general (p less than 0.05) and also more severe pulmonary symptoms during the premenstrual period (p less than 0.05). Of the women whose asthma was affected by menses, 13 (68%) had been hospitalized for asthma but only 10 (26%) of the women who were unaffected (p = 0.002). Both dysmenorrhea scores and premenstrual syndrome scores correlated significantly with baseline pulmonary symptom scores in the premenstrual asthma group. It appears that asthma morbidity is affected by the menstrual cycle in a subgroup of women with asthma.

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Multiple criteria for obstruction and reversibility are being used at present to define patient populations for bronchodilator studies. In order to establish whether the use of different criteria would result in variation in results, we evaluated 4 criteria for obstruction and found that the outcome of a bronchodilator trial, mean response, will depend on the definition of obstruction used. The obstruction criteria evaluated were: (1) FEV less than lower 95% confidence limit (CL) of predicted, (2) FEV1/FVC% less than lower 95% CL, (3) FEV1 between 500 and 1,500 ml, and (4) FEV1 less than 60% of predicted. Patients selected by criterion (1) had 8.9% FEV1 response, whereas those selected by criterion (3) had 14% FEV1 response. This difference resulted mostly from the difference in the degree of obstruction among the groups as well as the effect of regression to the mean compounded by calculating the results as percent of baseline. Also, it appears the use of obstruction criteria based on the absolute value of the FEV1 or on predicted FEV1 may create an age and height bias for bronchodilator response, this being of minimal clinical importance, though. Finally, we found that the conventional reversibility criterion: 15% improvement of the initial FEV1, could be misleading. This criterion could not be used to define disease, and when it was applied to a patient population it resulted in the selection of the most obstructed subjects, which is a contradiction of the very definition of reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)

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The carotid bodies of four infants who died of sudden infant death syndrome (SIDS) were compared, using electron microscopic techniques, with the carotid bodies of various control subjects. In the SIDS patients, there was a marked reduction or absence of the dense cytoplasmic granules of the carotid chemorecptor cells, as well as a reduction in cell number and size. These ultrastructural abnormalities may be pathophysiologically related to SIDS. A defect in this respiratory control organ could block normal stimulation of respiration during the periods of hypoxia that occur during episodes of sleep apnea in infancy. Further studies by electron microscopy are required to confirm degranulation of the carotid body as a pathognomonic sign of SIDS. Screening of high-risk infants should be directed at studying the carotid body and its mediated responses to hypoxia.

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The leukotactic function of patients with sarcoidosis was studied. A defect was found in 19 of the 20 patients tested and was due to moderately elevated serum levels of the chemotactic factor inactivator. The chemotactic factor inactivator levels were not as high as those previously reported in patients with Hodgkin's disease or cirrhosis of the liver. The effect of the inactivator was irreversible and was directed toward all three of the chemotactic factors tested. The physicochemical characteristics of chemotactic factor inactivator in serum from sarcoid patients resembled in most respects the features of chemotactic factor inactivator in normal serum. As expected, the generation of chemotactic activity in some sarcoid serums by zymosan was impaired. The results of this study may relate to some of the reported defects in expression of immunity in sarcoid patients.

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