Effects of combined treatment with glycopyrrolate and albuterol in acute exacerbation of asthma

STUDY OBJECTIVE: Recent reports suggest that glycopyrrolate is as effective as metaproterenol in the treatment of acute bronchospasm. The purpose of this study was to investigate whether the addition of a single aerosolized dose of glycopyrrolate to an albuterol regimen results in a greater improvement in pulmonary function than treatment with an albuterol regimen alone in patients with acute asthma. DESIGN: Prospective, randomized, double-blinded, controlled study. All patients received a total of three aerosol treatments and 60 mg solumedrol IV push. Patients were randomized to receive 2 mg aerosolized glycopyrrolate (combination therapy) or aerosolized placebo (control) in addition to their first 2.5 mg albuterol aerosol treatment. Both groups received 2.5 mg aerosolized albuterol alone for the next two treatments. SETTING: An urban teaching hospital emergency department. PARTICIPANTS: One hundred twenty-five patients with acute exacerbation of asthma were entered into the study. MAIN RESULTS: There was no difference in pretreatment forced expiratory volume (one second) (FEV1) between the control group and the glycopyrrolate group. Asthmatic patients receiving combination therapy had less of a change in FEV1 (52%) than did control patients (82%, P < .05). CONCLUSION: The combination of glycopyrrolate and albuterol does not appear to be beneficial over albuterol alone in treating patients with acute exacerbation of asthma.     

Cytologic evaluation of bronchoalveolar lavage fluid from horses with recurrent airway obstruction after aerosol and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively

OBJECTIVE: To determine cytologic changes in horses with recurrent airway obstruction (heaves) after administration of aerosolized beclomethasone dipropionate and dexamethasone parenterally. ANIMALS: 6 horses with inducible and reversible heaves. PROCEDURE: Episodes of heaves were induced by exposure to moldy hay and straw for 7 days. Horses were assigned to treatment groups (aerosolized beclomethasone, parenterally administered dexamethasone, aerosolized propellant), and pulmonary inflammation was evaluated by serial cytologic examination of bronchoalveolar lavage (BAL) fluid samples obtained on days 0, 7, 10, 14, and 21. Total and differential cell counting and phenotypic analysis of lymphocyte subpopulations in BAL fluid were performed. RESULTS: 7 days of natural challenge induced neutrophilic inflammation. Neutrophil counts in BAL fluid were reduced in beclomethasone- and dexamethasone-treated horses on days 10 and 14 but rebounded to pretreatment values on day 21. The proportion of proinflammatory lymphocyte subpopulations (CD4+ and B+) and MHC class-II antigen expression were increased on days 14 and 21 in propellant-treated horses, compared with beclomethasone- and dexamethasone-treated horses. CONCLUSIONS: Aerosolized beclomethasone attenuated neutrophilic pulmonary inflammation and prevented alteration in lymphocyte subpopulations in horses with heaves. Results were similar to the response associated with parenterally administered dexamethasone. Short-term administration of aerosolized beclomethasone without minimizing environmental allergen exposure is not expected to provide prolonged anti-inflammatory benefit for horses with heaves.     

Costing methods in the Canadian literature on the economic evaluation of health care. A survey and assessment

Administration of interleukin 2 (IL-2) has been associated with potent in vitro antitumor effects. However, systemic in vivo toxicity has been problematic. Because local delivery and liposomal formulations of IL-2 may improve the therapeutic index, we used dogs to evaluate and compare immunological activation of inhaled free IL-2 and IL-2 liposomes. Twelve normal dogs were treated with nebulized IL-2 formulations and controls for 2 to 7 weeks. Cellular immune activation of peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) effector leukocytes against tumor cell lines, changes in effector leukocyte populations, and toxicity were monitored. No toxicity was seen with either aerosolized free IL-2 or IL-2 liposomes. Free IL-2 given at 0.5 x 10(6) Biologic Response Modifier Program (BRMP) units twice daily to dogs resulted in increased peripheral blood mononuclear cell activation compared with saline control-treated dogs. IL-2 liposomes given at 0.5 x 10(6) BRMP units twice daily to dogs resulted in significantly increased BAL effector activation compared with IL-2 liposomes given at 1.0 x 10(6) BRMP units once daily (P = 0.018) and empty liposome controls (P = 0.016). The BAL leukocyte cell count was increased significantly after inhalation of IL-2 liposomes versus inhalation of free IL-2 (P = 0.011). BAL effector populations included a greater proportion and total number of lymphocytes and eosinophils after treatment with IL-2 liposomes. Nontoxic activation of pulmonary immune effectors for the treatment of cancer in the lung may be possible using nebulized IL-2 liposomes.     

Successful myoblast transplantation in primates depends on appropriate cell delivery and induction of regeneration in the host muscle

In a double-blind, cross-over study, we examined the effect of inhaled budesonide (800 microgram twice daily via Turbohaler) on lung function and various markers of airway inflammation including airway responsiveness to methacholine (PC20), exhaled nitric oxide (NO), eosinophils in induced sputum, bronchoalveolar lavage (BAL), and airway biopsies from 14 patients with mild asthma needing beta2- agonist therapy only. After inhaled steroids, there was a significant increase in FEV1 and PC20, and reduction in exhaled NO. Eosinophils in induced sputum and airway biopsy sections were also significantly decreased, although BAL eosinophil counts remained unchanged. At baseline, significant correlations were observed between exhaled NO and PC20 methacholine (r = 0.64, p < 0.05), exhaled NO and peak expiratory flow rate (PEFR) variability (r = 0. 65, p < 0.05), sputum eosinophils and FEV1 (r = -0.63, p = 0.05), and sputum eosinophils and log PC20 methacholine (r = -0.67, p < 0. 05). After treatment with inhaled steroids, there was a significant correlation between eosinophils in biopsy sections, and BAL, with log PC20 methacholine. It is likely that these parameters represent different aspects of the inflammatory process, which are all inhibited by inhaled steroids.     

Respiratory symptoms, lung function tests, airway responsiveness, and bronchoalveolar lymphocyte subsets in B-chronic lymphocytic leukemia

A respiratory questionnaire was completed and spirometry, tests for lung volumes, diffusion capacity for CO, and methacholine bronchial challenge were performed in 24 outpatients with B-chronic lymphocytic leukemia (B-CLL), aged 44-79, presenting in different stages of their disease. In 10 patients, bronchoalveolar lavage (BAL) fluid was also obtained. Ten of twenty-four patients had symptoms consistent with chronic bronchitis, unrelated both to smoking history and to the clinical stage. Abnormal values (< 2 SD) were found in 4 patients for total lung capacity (TLC), in 9 for vital capacity (VC), 8 for forced expiratory volume in 1 sec (FEV1), 11 for MEF50, 15 for MEF25 and in 7 for diffusing capacity for carbon monoxide. Seven of nineteen patients had PD20FEV1 at less than 1,600 micrograms of methacholine chloride. There was a significantly negative correlation between white blood cell count and VC (r = 0.41, P < 0.05). A positive correlation was found between PD20FEV1 and FEV1/VC (r = 0.61, P < 0.01). The mean and SEM for BAL cells/ml was 463 (71.8) x 10(3). No leukemic cells but a marked increase in T lymphocytes (32.5 +/- 7.8%) were found in BAL fluid. There were significantly negative correlations between the number of BAL CD3+ T lymphocytes and PD20FEV1 (r = 0.61, P < 0.05), and between the number of BAL CD8+ T lymphocytes and PD20FEV1 (r = 0.84, P < 0.01). In conclusion, patients with B-CLL have a high prevalence of respiratory symptoms, small airway dysfunction and CD8 "alveolitis" related to airway responsiveness; despite the well-known lung interstitial lymphocyte infiltration in B-CLL, leukemic cells are not found in BAL fluid.     

Leucocyte kinesis in blood, bronchoalveoli and nasal cavities during late asthmatic responses in guinea-pigs

Recently, we reported a reproducible model of asthma in guinea-pigs in vivo, which developed a late asthmatic response (LAR) as well as an early response. In this study, time-related changes in the occurrence of the LAR and leucocyte kinesis were assessed. Furthermore, the state of the activation of eosinophils that migrated into the lower airways was characterized in vitro. Guinea-pigs were alternately sensitized/challenged by inhalation with aerosolized ovalbumin adsorbed on aluminium hydroxide and ovalbumin alone, once every 2 weeks. At defined times before and after the fifth challenge, airway resistance was measured, blood was drawn and bronchoalveolar lavage (BAL) and nasal cavity lavage (NCL) were performed. Superoxide anion (.O2-) production of eosinophils was measured with cytochrome c. Occurrence of LAR and considerable increases in circulating eosinophils coincided with each other 5-7 h after the challenge. After 7 h, eosinophil infiltrations into bronchoalveolar spaces were observed. The capacity of eosinophils from the sensitized animals to produce .O2- was higher than those from the non-sensitized ones, when eosinophils were stimulated by platelet-activating factor. Although an increased number of eosinophils in the NCL fluid was observed, it was much less than that in the BAL fluid. Thus, it has been concluded that eosinophilia in the blood and the lung may participate in the occurrence of the late asthmatic response, which is thought to be preferentially evoked in the lower airways in guinea-pigs in vivo.     

Effect of sputum induction on arterial oxygen saturation and spirometry in HIV-infected patients

We wanted to study the effect of sputum induction on forced expiratory volume in one second (FEV1) and on oxygen saturation in normal controls, asymptomatic human immunodeficiency virus (HIV)-seropositive individuals, and HIV-seropositive patients under investigation for suspected Pneumocystis carinii pneumonia (PCP). Over a five month period, sputum induction with ultrasonically nebulized 3% saline was performed on 110 HIV-seropositive patients with suspected PCP, 10 asymptomatic HIV-seropositive patients, and 15 normal controls. Oxygen saturation (peak, trough and change in oxygen saturation (delta O2)) was measured throughout the procedure using pulse oximetry, and these results compared with the chest radiograph and the final pulmonary diagnosis. In addition, the effect of sputum induction on FEV1 was measured in the 15 control subjects and 10 asymptomatic HIV-seropositive patients. Compared with bronchoalveolar lavage, sputum induction had a diagnostic sensitivity for PCP of 76%. Chest radiography was 79% sensitive, and had specificity of 83%. Patients with PCP had lower peak and trough oxygen saturation values compared with the non-PCP group (mean peak 95 vs 97%; mean trough 88 vs 91%), and greater falls in O2 saturation during the procedure (mean delta O2 7.6 vs 5.5%). One subject desaturated to 76%, requiring supplemental oxygen. Sputum induction caused significant but temporary falls in FEV1 both in control and HIV-seropositive groups (mean maximum fall in FEV1 10.4 vs 12.5%). We conclude that although sputum induction causes significant falls in oxygen saturation and FEV1, it remains sensitive and safe, and provides a useful alternative to bronchoscopy for the diagnosis of PCP.     

Local expansion of allergen-specific CD30+Th2-type gamma delta T cells in bronchial asthma

BACKGROUND: T lymphocytes infiltrating airways during the allergic immune response play a fundamental role in recruiting other specialized cells, such as eosinophils, by secreting interleukin 5 (IL-5), and promoting local and systemic IgE synthesis by producing IL-4. Whether these presumed allergen-specific T cells are of mucosal or systemic origin is still a matter of conjecture. MATERIALS AND METHODS: Immunophenotype, IL-4 production, and in vitro proliferative response to specific or unrelated allergens were analyzed in the bronchoalveolar lavage (BAL) fluid lymphocyte suspensions obtained from untreated patients with allergic asthma. Healthy subjects and patients affected by pulmonary sarcoidosis, a granulomatous lung disease characterized by infiltrating Th1 CD4+ lymphocytes, served as controls. RESULTS: The proportions of gamma delta T lymphocytes, mostly CD4+ or CD4- (-)CD8-, was higher in asthmatic subjects than in controls (p < 0.05). Most BAL gamma delta CD4+ lymphocytes of asthmatic patients displayed the T cell receptor (TCR)-gamma delta V delta 1 chain. While CD30 antigen coexpression on the surface of BAL alpha beta(+) T lymphocytes was low (ranging from 5 to 12%), about half of pulmonary gamma delta T cells coexpressed it. These cells produced IL-4 and negligible amounts of interferon-gamma (IFN gamma), and proliferated in vitro in response to purified specific but not unrelated allergens. In contrast, control or sarcoidosis gamma delta T cells never displayed the CD30 surface molecule or produced significant quantities of IL-4. CONCLUSIONS: These findings not only confirm our previous hypothesis that the allergen-specific Th2-type lymphocytes found in the lungs of asthmatic patients are gamma delta T cells belonging to airway mucosal immunocytes, but also strongly support the notion that asthma is a local rather than a systemic disease.     

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer

BACKGROUND: Interleukin-2 (IL-2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level. METHODS: To test feasibility, antitumor activity, pulmonary and systemic immunologic effects, and pulmonary function changes of continuous-infusion recombinant IL-2 given to patients with non-small cell lung cancer, eleven subjects with Stage III-IV disease were treated in a standard pulmonary medicine unit with a dose of 18 million IU/m2/day from day 1 to day 13 with 1-day rest on day 7. A second induction course was given after a 3-week rest. In patients with nonprogressive disease, four maintenance courses of 6 days' duration at the same dose were planned. Immunologic tests, including lymphocyte phenotype analysis and assays for the detection of tumor necrosis factor (TNF) and of anti-IL-2 antibodies, were performed before and after treatment in serum and bronchoalveolar lavage fluid (BAL). Cardiopulmonary function tests, including spirometry, arterial blood gas analysis, diffusion capacity, and echocardiography, were obtained before, during, and after treatment. RESULTS: Twenty-one cycles (15 induction courses plus 6 maintenance courses) were administered. No patient was able to complete the six planned courses, and only 3 patients entered the maintenance phase. Reasons for discontinuation included progressive disease in five cases, toxicity in three cases, and patient request in three cases. The most common side effects were fever, hypotension, oliguria, and elevated serum creatinine and liver enzyme levels. No patient required intubation or intensive care. No objective response was seen, and the median survival time was 10 months. Lymphocytosis and eosinophilia were observed in all patients. Surface marker analysis revealed a statistically significant increase in the percentage of CD3+, CD4+, CD25+ and DR+ cells in peripheral blood. Lymphoid cells derived from BAL disclosed an increased natural killer activity after IL-2 treatment, and TNF was increased in BAL fluid. Pulmonary function tests evidenced an increased alveolar-arterial difference for oxygen allied with a decrease of forced expiratory volume in 1 second, forced vital capacity, and carbon monoxide transfer coefficient consistent with a significant, albeit not clinically relevant, interstitial lung defect. CONCLUSION: Continuous-infusion IL-2 is feasible in patients with advanced lung cancer even outside an intensive care unit, but overall compliance is poor. Although clinical pulmonary toxicity is negligible, small but statistically significant alterations of the pulmonary function are evident. In addition, this regimen produces a significant activation of the immune system at the pulmonary level.     

Airway response of children with primary ciliary dyskinesia to exercise and beta2-agonist challenge

In primary ciliary dyskinesia (PCD), chest physiotherapy for airway clearance is essential. Exercise and inhaled beta2-agonists can produce bronchodilation thereby augmenting physiotherapy. However, both can also cause bronchoconstriction, and the effects of these stimuli in PCD are not known. In a preliminary study, the mean coefficients of variation for forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) in children with PCD were determined. They were 5.4%, 4.4% and 8.4%, respectively. Twelve children with PCD and 12 normal children performed pulmonary functions under resting conditions; during and after a validated treadmill exercise test; and before and 15 min after 200 microg of inhaled salbutamol. At baseline, FEV1, FVC, forced mid-expiratory flow (FEF25-75%) and PEFR were significantly reduced in the PCD group compared with the control group. Exercise produced a significant increase in PEFR in the PCD group. There was no significant difference between the groups in response to salbutamol. Within the PCD group, exercise produced a significantly greater increase in PEFR than beta2-agonist therapy. In conclusion, in children with primary ciliary dyskinesia there is evidence of obstructive pulmonary disease. In these children, exercise is a more potent stimulus for bronchodilation than by inhaled beta2-agonists. Enhancement of airway clearance may best be achieved by encouraging patients to exercise before physiotherapy rather than by inhaling beta2-agonists, but the effects of each should be assessed for each individual before instigating treatment.     

Relationship between lung inflammation, changes in lung function and severity of exposure in victims of the Bhopal tragedy

The world's worst chemical industrial disaster, which occurred at Bhopal on 2-3 December, 1984, resulted in considerable respiratory morbidity in the exposed population. Therefore, a study was planned to evaluate the relationship between lower respiratory tract inflammation, lung function and severity of exposure. Sixty patients exposed to methyl isocyanate and presenting with respiratory symptoms were studied using bronchoalveolar lavage (BAL) 1-7 yrs after the accident. Pulmonary function tests included forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). An index of severity of exposure was derived retrospectively on the basis of the acute symptoms in the victims themselves or the occurrence of death among their family members. Total lung inflammatory cells (p < 0.01) and absolute numbers of macrophages (p = 0.01) and lymphocytes (p < 0.05) increased as severity of exposure increased. FEV1/FVC % (p = 0.05) was also significantly lower as severity of exposure increased. Moderately exposed subjects had significantly lower FEV1/FVC % (p < 0.05) compared to those mildly exposed. In nonsmokers, BAL neutrophils, both percentage and absolute numbers, showed significant negative correlations with FEV1 % predicted (rs = -0.350, p < 0.05; and rs = -0.374, p < 0.01, respectively). Neutrophil percentage was negatively correlated with FEV1/FVC % (rs = -0.378; p < 0.01). Absolute lymphocytes had significant negative correlations with FVC % pred (rs = -0.318; p < 0.05). Macrophages had significant positive correlations with FVC % pred (rs = 0.322; p < 0.05) and FEV1 % pred (rs = 0.433; p < 0.01). Radiographic abnormalities (International Labour Organization (ILO) classification) were associated with decline in FEV1 % pred (p < 0.05). This study suggests that pulmonary function abnormalities occur in gas-exposed subjects as a consequence of an abnormal accumulation of lung inflammatory cells (lymphocytes and neutrophils), and that the intensity of lung inflammation and reduction in pulmonary function are greater in severely exposed subjects. As it has been observed that decline in pulmonary function is associated with radiographic abnormalities, there is a suggestion that injury following toxic gas exposure can lead to irreversible lung damage.     

Nonbronchoscopic bronchoalveolar lavage in mechanically ventilated infants: technique, efficacy, and applications

Bronchoalveolar lavage with the fiberoptic bronchoscope is commonly used for the diagnosis of pulmonary infections in mechanically ventilated adults and children. However, its use for intubated infants is precluded because the small artificial airway does not permit the passage of the bronchoscope. We have developed a technique for nonbronchoscopic bronchoalveolar lavage, performed via a sterile, disposable feeding tube. We have used this technique in 15 infants with diffuse interstitial disease and/or atelectasis, while they were intubated and mechanically ventilated. The volume of the lavage effluent averaged 70.3% of the volume instilled. Specific diagnosis on the basis of the cytologic evaluation and/or culture of the lavage fluid was possible in 9 (60%) patients. Two patients with atelectasis showed radiographic evidence of improvement following the procedure. There were no complications. We conclude that nonbronchoscopic bronchoalveolar lavage is well tolerated, and clinically useful in small, mechanically ventilated infants with respiratory failure due to diffuse pulmonary disease. This technique provides a lower risk alternative to more invasive, and costly procedures.     

Differential effects of nasal continuous positive airway pressure on reversible or fixed upper and lower airway obstruction

Our study was to assess whether there were differential effects of nasal continuous positive airway pressure (nCPAP) on different kinds of obstruction in either upper or lower airways in patients with chronic obstructive pulmonary disease (COPD). nCPAP (6 cmH2O for ten minutes) was applied to 7 patients with reversible extrathoracic upper airway obstruction (RUAO) and 3 patients with fixed extrathoracic upper airway obstruction (FUAO). Eighteen stable asthmatics, receiving methacholine challenge to induce a more than 20% reduction in FEV1, were randomly investigated for the effect of nCPAP or sham pressure on reversible lower airway obstruction. Nine stable COPD patients were enrolled to study the effect on irreversible lower airway obstruction. Maximal expiratory and inspiratory flow volume curves and dyspnoea scores were obtained before and after immediate withdrawal of nCPAP. In the RUAO group, nCPAP significantly improved stridor and dyspnoea scores, decreased the ratio of FEF50/FIF50 from 2.05 +/- 0.25 to 1.42 +/- 0.16, and increased peak inspiratory flow (PIF) as well as forced inspiratory vital capacity by 26 +/- 8% and 9 +/- 4%, respectively. In expiratory phase, there was no significant change in pulmonary functions. In asthmatics, nCPAP significantly reversed methacholine-induced bronchoconstriction increasing forced vital capacity by 10 +/- 3%, FEV1 by 15 +/- 4% and PIF by 32 +/- 11%. nCPAP significantly increased the response to bronchodilators. The improvement in airflow rate persisted for at least 5 min after nCPAP withdrawal and was highly correlated with the response to bronchodilators. There was no significant effect of nCPAP on airflow rate in COPD patients. Subjective dyspnoea score changes paralleled the pulmonary function improvement. We conclude that there are differential effects of nCPAP on airflow rates in patients with different nature of airway obstruction. Patients with airway obstruction caused by structural changes may not benefit from the use of nCPAP in improving airflow rates.     

Induction of pulmonary allergic responses by antigen-specific Th2 cells

The development of pulmonary allergic responses was examined in mice following pulmonary transfer of Ag (conalbumin)-specific Th2 cells. The levels of serum-specific IgE, cellular infiltrates, airway mucus goblet cells, and airway responsiveness were analyzed and compared with those in Ag-sensitized and -challenged mice. Pulmonary transfer of the conalbumin-specific Th2 clone (D10) induced, in an Ag-specific manner, high levels of the Th2 cytokines IL-4 and IL-5 in the bronchoalveolar lavage fluids and mucosal eosinophils, concomitant with an increase in airway responsiveness. The D10 cell-induced responses were seen in the absence of serum specific IgE. In the presence of Ag, the transferred D10 cells not only remained in the lungs, but also increased in number 72 h post-cell transfer. Although significantly higher levels of IL-4 and IL-5 in the bronchoalveolar lavage fluids were found in D10-transferred mice, the levels of pulmonary eosinophilia, mucus goblet cells, and airway responsiveness were significantly lower than those in Ag-sensitized and -challenged mice. These results demonstrate that although Ag-specific activation of Th2 cells at mucosal sites is able to mediate the recruitment of eosinophils and the subsequent induction of airway hyper-responsiveness, the more severe pulmonary allergic responses were observed only in mice sensitized and challenged with Ag.     

Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice

The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1(+) T cells (NKT cells), and gamma/delta T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1(+) cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3(+) T cell infiltration as well as increased levels of interleukin (IL)-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. Moreover, systemic allergen-specific immunoglobulin (Ig)E and IgG2a levels and the number of IL-4 and interferon gamma-producing splenic cells were diminished in mice depleted of NK1.1(+) cells before the priming regime. Depletion of NK1.1(+) cells during the challenge period only did not influence pulmonary eosinophilic inflammation. CD1d1 mutant mice, deficient in NKT cells but with normal NK cells, developed lung tissue eosinophilia and allergen-specific IgE levels not different from those observed in wild-type mice. Mice deficient in gamma/delta T cells showed a mild attenuation of lung tissue eosinophilia in this model. Taken together, these findings suggest a critical role of NK cells, but not of NKT cells, for the development of allergen-induced airway inflammation, and that this effect of NK cells is exerted during the immunization. If translatable to humans, these data suggest that NK cells may be critically important for deciding whether allergic eosinophilic airway disease will develop. These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.     

Dose-related reversal of acute lung rejection by aerosolized cyclosporine

This study evaluated the effectiveness of aerosolized cyclosporine as rescue therapy for refractory acute rejection in lung-transplant patients that is unresponsive to conventional therapy. Over 2 yr, nine allograft recipients with histologic evidence of persistent acute rejection and worsening pulmonary function were enrolled. Twenty-two patients with similar degrees of unremitting rejection served as historical controls. Aerosolization of cyclosporin A (300 mg in 4.8 ml propylene glycol) using an AeroTech II jet nebulizer was instituted daily for 12 consecutive days followed by a maintenance regimen of 3 d/wk. Cyclosporine and tacrolimus blood and plasma levels were maintained within therapeutic ranges throughout this trial. Efficacy was assessed by histologic grade of rejection, interleukin-6 (IL-6) mRNA expression by graft bronchoalveolar lavage cells, and pulmonary function testing before and during cyclosporine therapy. In seven patients, results were correlated to deposition of cyclosporine aerosol in the allograft(s) as measured by radioisotopic techniques. At a mean of 37 d after initiation of aerosolized cyclosporine, graft histology improved in eight of the nine patients. Cellular IL-6 mRNA expression decreased significantly in seven patients (mean IL-6/actin +/- SD, 40.96 +/- 118 versus 0.33 +/- 0.57 [p = 0.038]). Pulmonary function (FEV1), which had decreased posttransplant (over a mean of 347 d of observation) from a best value of 1.98 +/- 0.8 L to 1.59 +/- 0.6 L (p = 0.0077), improved over time (152 d) to a posttransplant value of 1.90 +/- 0.8 (p = 0.025). In the control subjects, FEV1 inexorably declined over a comparable period of observation (best posttransplant value 2.36 +/- 0.86 to 1.32 +/- 0.53, p < 0.0001). There was a strong correlation between cyclosporine deposition in the allograft and improvement in FEV1 (r = 0.900, p < 0.01). Fewer cycles of pulsed corticosteroids (1.4 +/- 0.9 versus 0.2 +/- 0.4, p = 0.011) and anti-thymocyte globulin 0.8 +/- 0.4 versus 0, p = 0.018) and reduced doses of oral prednisone (10.8 +/- 3.1 versus 6.1 +/- 4.2 mg/d, p = 0.026) were observed during treatment with aerosolized cyclosporine. Episodes of pneumonia also were reduced significantly during aerosol therapy (2.6 versus 0.95 episodes/100 d, p = 0.029). Nephrotoxicity and hepatotoxicity did not occur, and no patients withdrew from the study. Aerosolized cyclosporine appears to be safe and effective therapy for refractory acute rejection, but confirmation by a larger, randomized trial is necessary. The correlation observed between deposition of cyclosporine aerosol and physiologic improvement of lung function suggests that there is a dose-response relationship between the concentration of cyclosporine in the allograft and immunologic tolerance.     

Should sperm donors be paid? A survey of the attitudes of the general public

Human immunodeficiency virus (HIV) infection has been associated with a wide spectrum of pulmonary disease. We report three HIV-seropositive patients with rapidly worsening airway obstruction associated with bronchiectasis. All subjects (age range 33-39 yrs) were cigarette smokers. Two had previously used intravenous drugs. The CD4 lymphocyte count ranged 40-250 cells x mm(-3). All individuals had complained of increasing dyspnoea for 3-6 months. Within 1 yr, they all developed severe airway obstruction with a decrease in both forced expiratory volume in one second (FEV1) and ratio of FEV1 to forced vital capacity (FEV1/FVC) to less than 60% of predicted value, and a decrease in mean forced expiratory flow at 25-75% of the forced vital capacity (FEF25-75) to less than 35% of predicted value. Computed tomography of the chest disclosed bilateral dilated and thickened bronchi. No classical causes of genetic or acquired bronchiectasis were identified in our patients. Recurrent bacterial bronchitis occurred in the follow-up period of the three patients. In conclusion, unusually rapid airway obstruction associated with bronchiectasis should be added to the wide spectrum of respiratory complications of human immunodeficiency virus infection.     

Two patients with idiopathic pulmonary fibrosis and monoclonal gammopathy

A 67-year-old man and a 70-year-old man were admitted to our hospital because of dyspnea and dry coughing. Chest X-ray films showed bilateral reticulonodular shadows in the middle and lower lung fields. Specimens were obtained by open lung biopsies and the findings were compatible with those of usual interstitial pneumonia. Immunoelectrophoresis revealed monoclonal gammopathy in both patients. The levels of interleukin 6 in bronchoalveolar lavage fluid were high. In these two patients, idiopathic pulmonary fibrosis was associated with multiple myeloma and monoclonal gammopathy, and the levels of interleukin-6 in bronchoalveolar lavage fluid were high. These findings may help to elucidate the pathogenesis and development of idiopathic pulmonary fibrosis.     

Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs

OBJECTIVE: To assess the effects of the lazaroid, tirilazad mesylate, a potent lipid peroxidation inhibitor, in an animal model of Pseudomonas sepsis. DESIGN: Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment. SETTING: University animal laboratory. SUBJECTS: Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO2 of 0.4. INTERVENTIONS: Sepsis was induced by infusing Pseudomonas aeruginosa at 1 x 10(6) colony-forming units/kg/min over 120 mins. The tirilazad mesylate-treated group received a 5-mg/kg bolus 30 mins before, and a 3-mg/kg bolus 3 hrs after, the onset of sepsis. Hemodynamics, PaO2, and neutrophil counts were measured for 6 hrs. Thiobarbituric acid reactive material (TBARM) in tissue (lung, liver, and intestine), lung wet/dry weight ratio, lung myeloperoxidase activity, plasma tumor necrosis factor (TNF)-alpha concentrations, protein content, and percent neutrophils in bronchoalveolar lavage fluid were evaluated at the time the animals were killed (6 hrs). MEASUREMENTS AND MAIN RESULTS: Sepsis induced significant systemic hypotension, pulmonary hypertension, hypoxemia, and neutropenia. Sepsis also significantly increased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, plasma TNF-alpha concentrations, and bronchoalveolar lavage neutrophil percentage. Treatment with tirilazad mesylate significantly attenuated hypoxemia and decreased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, bronchoalveolar lavage protein, and bronchoalveolar lavage neutrophil percentage, but did not affect sepsis-induced hemodynamics, including systemic hypotension and pulmonary hypertension, plasma TNF-alpha concentrations, or neutropenia. CONCLUSIONS: Pretreatment with the tirilazad mesylate did not change P. aeruginosa sepsis-induced hemodynamic consequences. However, tirilazad mesylate attenuated sepsis-induced acute lung injury.     

Bronchodilator response to salbutamol after spontaneous recovery from nonspecific bronchial provocation tests in asthma

Assessment of airway responsiveness by bronchoprovocation and bronchodilatation tests is important in the diagnostic work-up protocol of bronchial asthma and it would be convenient to undertake both tests on the same occasion. However, it is not known whether this can be done accurately. Therefore, this study evaluated the effect of a prior bronchial provocation test on the bronchodilator response to salbutamol after spontaneous recovery of the forced expiratory volume in one second (FEV1) in a group of asthmatic subjects. On two separate occasions at the same time of day, concentration-response studies with inhaled histamine or methacholine, or a sham challenge with normal saline were carried out in a blinded, randomized manner. Changes in airway calibre were followed as FEV1 and agonist responsiveness expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). After either spontaneous recovery or a fixed-duration wait of 45 min (when appropriate), the subjects received 2x100 microg of salbutamol from a metered dose inhaler with a spacer. The bronchodilator response to salbutamol was expressed as a percentage of initial FEV1 (deltaFEV1% init). Bronchial challenge with both agonists failed to alter significantly the airway response to salbutamol, with the deltaFEV1% init mean value (range) being 16.9% (9.0-31.9) and 17.5% (11.6-31.2) on the sham and histamine/methacholine challenge day respectively. It was shown that the degree of bronchodilatation achieved after salbutamol 200 microg is not affected by prior bronchoprovocation testing when enough time is allowed for the airways to recover spontaneously to baseline forced expiratory volume in one second. Thus evaluation of airway responsiveness by both bronchial provocation tests and bronchodilator testing can be assessed reliably within a few hours in asthmatic patients.