One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal.A total of 117 adults with asthma were entered into a multicentre, randomised, parallel groupeffectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils f2%; symptoms and spirometry were used to identify clinical control, exacerbations and other treatments. Patients were blind to sputum cell counts in both strategies and physicians were blind in the CS, thus removing bias. First, the minimum treatment to maintain control was identified in 107 patients (Phase 1) and then this treatment was continued (Phase 2) for the remaining of the 2 yrs. The primary outcomes were the relative risk reduction for the occurrence of the first exacerbation in Phase 2 and the length of time without exacerbation. The current authors also examined the type and severity of exacerbations and the cumulative dose of inhaled steroid needed.The duration and number of exacerbations in Phase 1 were similar in both groups. In Phase 2 there were a 126 exacerbations of which 79 occurred in the CS (62.7%) and 47 (37.3%) in the SS groups. The majority of the 126 exacerbations (101; 80.1%) were mild. The majority of the 102 exacerbations, where sputum examination was performed before any treatment (n570), were noneosinophilic. In the SS patients, the time to the first exacerbation was longer (by 213 days) especially in those considered to need treatment with a long acting b 2 -agonist (by 490 days), the relative risk ratio was lower (by 49%), and the number of exacerbations needing prednisone was reduced (5 versus 15). This benefit was seen mainly in patients needing treatment with inhaled steroid in a daily dose equivalent to fluticasone .250 mg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups.Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations.

The major respiratory complications of obesity include a heightened demand for ventilation, elevated work of breathing, respiratory muscle inefficiency and diminished respiratory compliance. The decreased functional residual capacity and expiratory reserve volume, with a high closing volume to functional residual capacity ratio of obesity, are associated with the closure of peripheral lung units, ventilation to perfusion ratio abnormalities and hypoxemia, especially in the supine position. Conventional respiratory function tests are only mildly affected by obesity except in extreme cases. The major circulatory complications are increased total and pulmonary blood volume, high cardiac output and elevated left ventricular end-diastolic pressure. Patients with obesity commonly develop hypoventilation and sleep apnea syndromes with attenuated hypoxic and hypercapnic ventilatory responsiveness. The final result is hypoxemia, pulmonary hypertension and progressively worsening disability. Obese patients have increased dyspnea and decreased exercise capacity, which are vital to quality of life. Decreased muscle, increased joint pain and skin friction are important determinants of decreased exercise capacity, in addition to the cardiopulmonary effects of obesity. The effects of obesity on mortality in heart failure and chronic obstructive pulmonary disease have not been definitively resolved. Whether obesity contributes to asthma and airway hyper-responsiveness is uncertain. Weight reduction and physical activity are effective means of reversing the respiratory complications of obesity.

A reliable predictor of benefit from corticosteroid treatment in patients with chronic airflow limitation is needed. In a single-blind, sequential crossover trial of placebo and prednisone (30 mg/day) treatment, with each given for 2 wk, we investigated whether an increased proportion of sputum eosinophils (>= 3%) predicts a beneficial effect of prednisone in smokers with severe obstructive bronchitis. Patients were seen before and after each treatment. Clinical measurements were made blind to the laboratory findings and vice-versa. Eighteen of 20 patients completed the study. Eight had sputum eosinophilia and similar clinical and physiologic characteristics to those of 10 patients without a finding of sputum eosinophilia. Only in patients with sputum eosinophilia did prednisone, as compared with placebo, produce a statistically significant and clinically important mean effect on effort dyspnea of 0.8 (95% confidence interval [CI]: 0.3 to 1.2), p = 0.008, and in quality of life of 1.96 (95% CI: 0.5 to 3.3), p = 0.01, associated with a small improvement in FEV1 of 0.11 L (95% CI: - 0.04 to 0.23 L), p = 0.05. In these patients, prednisone also produced a significant decline in the median sputum eosinophil percentage, from 9.7% to 0.5% (p = 0.002), eosinophil cationic protein (ECP), from 6, 000 microgram/L to 1,140 microgram/L (p < 0.001), and fibrinogen, from 25. 3 mg/L to 5.4 mg/L (p < 0.001). These findings indicate that in smokers with severe airflow limitation, sputum eosinophilia predicts a beneficial effect of prednisone treatment. Improvement in FEV1, after prednisone treatment in this population, is small, and may not be appreciated in clinical practice.

Induced sputum cell counts provide a relatively noninvasive method to evaluate the presence, type, and degree of inflammation in the airways of the lungs. Their interpretation requires a knowledge of normal values from a healthy population. The objective was to examine the total and differential cell counts in induced sputum from a sample of healthy adults. A total of 118 healthy nonsmoking adults were studied. None had asthma or airflow obstruction (negative history, FEV(1) >/= 80% predicted, ratio of FEV(1) to vital capacity [FEV(1)/VC] >/= 80%, methacholine PC(20) >/= 16 mg/ml). Forty-six were atopic. Sputum induction produced an adequate sample in 96 subjects [53 males, mean age (range) 36 (18 to 60) yr]. The expectorate was processed within 2 h; sputum was selected, treated with dithiothreitol, filtered, and examined in a hemocytometer for total cell count and viability and on Wright-stained cytospins for a differential cell count. The mean, median (90th percentile) total cell count was 4.1, 2.4 (9.7) x 10(6) cells/g and cell viability was 69.6, 72.0 (89.7)%. The proportions of eosinophils were 0.4, 0.0 (1.1)%, neutrophils 37.5, 36.7 (64.0)%, macrophages 58.8, 60.8 (86.1)%, lymphocytes 1.0, 0.5 (2.6)%, metachromatic cells 0.0, 0.0 (0.04)%, and bronchial epithelial cells 1.6, 0.3 (4.4)%, respectively. Female gender and atopy were associated with a significant elevation of eosinophils; mean difference between male/female was 0.3% (p = 0.043) and between atopic/nonatopic 0.4% (p = 0.024). This study has identified reference values for total and differential cell counts in induced sputum of healthy adults.

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Allergen-induced late airway responses are associated with increased numbers of airway eosinophils and basophils. The purpose of this study was to compare and contrast the effects of inhaled cysteinyl leukotrienes LTD(4) and LTE(4), which are released during allergen- induced airway responses, and allergen, on airway inflammatory cells. Fifteen subjects with atopic, mild asthma inhaled diluent, LTD(4), LTE(4), and allergen. Spirometry was performed for 7 h, and sputum inflammatory cells were measured before, 7 h, and 24 h after challenges. The maximum early percent fall in FEV(1) was 23.6 +/- 1.4%, 21.6 +/- 2.3%, 29.3 +/- 2.4%, and 4.0 +/- 1.1% after LTD(4), LTE(4), allergen, and diluent, respectively. Only inhaled LTE(4) and allergen significantly increased sputum eosinophils at 7 h and 24 h, and sputum basophils at 7 h. Six additional subjects underwent airway biopsies 4 h after inhalation. There were significantly more eosinophils in the lamina propria after inhalation of LTE(4) compared with LTD(4) and diluent (p < 0.05). These results suggest cysteinyl leukotrienes play a role in eosinophil migration into the airways in allergic asthma, and for the same degree of bronchoconstriction, inhaled LTE(4) causes more tissue and airway eosinophilia than LTD(4).

Cysteinyl leukotrienes promote airway smooth muscle (ASM) contraction and proliferation. Little is known about their role in ASM migration. We investigated this using cultured human ASMs (between the second and fifth passages) obtained from the large airways of resected nonasthmatic lung. Platelet-derived growth factor-BB (1 ng/ml) promoted significant (3.5-fold) ASM migration of myocytes across collagen-coated 8- micro m polycarbonate membranes in Transwell culture plates. Leukotriene E(4) (10(-7), 10(-8), 10(-9) M) did not demonstrate a chemotactic effect; it did promote chemokinesis. Priming by leukotriene E(4) (10(-7) M) significantly augmented the directional migratory response to platelet-derived growth factor (1.5-fold, p < 0.05). This was blocked by montelukast (10(-6) M), demonstrating the effect to be mediated by the cysteinyl leukotriene receptor. The "priming effect" was also partially attenuated by prostaglandin E(2) (10(-7) M). Whereas both the chemokinetic and the chemotactic "primed" responses were equally attenuated by a p38 mitogen-activated protein kinase inhibitor (SB203580, 25 micro M) and by a Rho-kinase inhibitor (Y27632, 10 micro M), the chemotactic response showed greater inhibition than chemokinesis by a phosphatidylinositol-3 kinase inhibitor (LY294002, 50 micro M). These experiments suggest that cysteinyl leukotrienes play an augmentary role in human ASM migration. The phosphatidylinositol-3 kinase pathway is a key signaling mechanism in the chemotactic migration of ASM cells in response to cysteinyl leukotrienes.

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