Pulmonary function in an international sample of HIV-positive, treatment-naïve adults with CD4 counts > 500 cells/µL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: The aim of the study was to describe the prevalence and correlates of chronic obstructive pulmonary disease (COPD) in a multicentre international cohort of persons living with HIV (PLWH). METHODS: We performed a cross-sectional analysis of adult PLWH, naïve to HIV treatment, with baseline CD4 cell count > 500 cells/µL enrolled in the Pulmonary Substudy of the Strategic Timing of AntiRetroviral Treatment (START) trial. We collected standardized, quality-controlled spirometry. COPD was defined as forced expiratory volume in 1 s:forced vital capacity (FEV1 :FVC) ratio less than the lower limit of normal. RESULTS: Among 1026 participants from 80 sites and 20 countries, the median age was 36 [interquartile range (IQR) 30, 44] years, 29% were female, and the median time since HIV diagnosis was 1.2 (IQR 0.4, 3.5) years. Baseline median CD4 cell count was 648 (IQR 583, 767) cells/µL, median viral load was 4.2 (IQR 3.5, 4.7) log10 HIV-1 RNA copies/mL, and 10% had a viral load ≤ 400 copies/mL despite lack of HIV treatment. Current/former/never smokers comprised 28%/11%/61% of the cohort, respectively. COPD was present in 6.8% of participants, and varied by age, smoking status and region. Forty-eight per cent of those with COPD reported lifelong nonsmoking. In multivariable regression, age and pack-years of smoking had the strongest associations with FEV1 :FVC ratio (P < 0.0001). There was a significant effect of region on FEV1 :FVC ratio (P = 0.010). CONCLUSIONS: Our data suggest that, among PLWH who were naïve to HIV treatment and had CD4 cell counts > 500 cells/µL, smoking and age were important factors related to COPD. Smoking cessation should remain a high global priority for clinical care and research in PLWH.

Vitamin D status and longitudinal lung function decline in the Lung Health Study.

Low blood vitamin D levels have been postulated to be a risk factor for worse lung function, based largely on cross-sectional data. We sought to use longitudinal data to test the hypothesis that baseline plasma 25-hydroxyvitamin D (25(OH)D) is lower in subjects with more rapid lung function decline, compared to those with slow lung function decline. We conducted a nested, matched case-control study in the Lung Health Study 3 cohort. Cases and controls were continuous smokers with rapid and slow lung function decline, respectively, over ~6 yrs of follow-up. We compared baseline 25(OH)D levels between cases and controls, matching date of phlebotomy and clinical centre. Among 196 subjects, despite rapid and slow decliners experiencing strikingly and significantly different rates of decline of forced expiratory volume in 1 s (-152 versus -0.3 mL·yr⁻¹; p < 0.001), there was no significant difference in baseline 25(OH)D levels (25.0 versus 25.9 ng·mL⁻¹; p = 0.54). There was a high prevalence of vitamin D insufficiency (35%) and deficiency (31%); only 4% had a normal 25(OH)D level in the winter. Although vitamin D insufficiency and deficiency are common among continuous smokers with established mild-to-moderate chronic obstructive pulmonary disease, baseline 25(OH)D levels are not predictive of subsequent lung function decline.

Premature discontinuation of patients: a potential bias in COPD clinical trials.

Premature discontinuation from clinical trials may bias results against effective therapies. In the present study mortality rates were retrospectively reviewed in a 6-month, randomised, placebo-controlled trial in which tiotropium 18 mug daily was shown to decrease chronic obstructive pulmonary disease exacerbations. Patients participated for 6 months even if trial medication was prematurely discontinued. Exposure-adjusted incidence rates (IRs) were calculated for randomisation-end trial, randomisation-end trial drug (0-ED) and end trial drug-end trial (ED-ET). Of 1,829 patients (forced expiratory volume in one second 1.04 L (36% predicted), mean age 68 yrs, 99% male), 16% tiotropium and 27% placebo patients prematurely stopped trial medication. The number of fatal events for the entire cohort was: 62 all cause, including 16 cardiac and 16 lower respiratory. IRs for fatal events per 100 patient-yrs were higher in the discontinued period: 1.9 (0-ED) versus 23.0 (ED-ET) in the tiotropium group and 1.8 versus 19.0 in the placebo group. Respective IRs for fatal cardiac events were 0.7 versus 2.8 (tiotropium) and 0.5 versus 6.2 (placebo); for fatal lower respiratory events were 0.7 versus 2.8 (tiotropium) and 0.8 versus 5.4 (placebo). Rate ratios (tiotropium/placebo) for fatal events were lower in the discontinued period: 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory. Higher incidence rates of fatal events occurred following premature discontinuation of study medication. Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials.

Role of corticosteroids in acute exacerbations of chronic obstructive pulmonary disease.

Systemic corticosteroid therapy for patients with exacerbations of chronic obstructive pulmonary disease has become increasingly commonplace over the past two decades. This practice was controversial because a number of small clinical trials provided inconclusive evidence about efficacy. Experience from recent trials indicates that systemic cortico-steroids are modestly effective in this setting. Systemic corticosteroids administered to hospitalized patients reduces the absolute treatment rate by about 10%, increases the forced expiratory volume in 1 second (FEV(1)) by about 100 mL, and shortens the hospital stay by 1 to 2 days. Treatment should not extend longer than 2 weeks. The optimal starting dose is not known. Hyperglycemia and possibly an increased rate of secondary infections are expected complications of treatment.

Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial.

The benefits of chronic systemic corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are not well established. To determine whether chronic corticosteroid treatment can be safely withdrawn in "steroid-dependent""COPD patients, we performed a double-blind, placebo-controlled study of 38 patients with steroid-dependent COPD. Patients were randomly assigned to receive their usual maintenance prednisone dose for 6 mo (continuous group) or to be withdrawn from prednisone at a rate of 5 mg per week (demand group). The number of COPD exacerbations per patient (primary outcome) was 2.5 +/- 2.7 (mean +/- SD) in the continuous group and 2.7 +/- 2.5 in the demand group (p = 0.60, 95% confidence interval for the difference: -1.1 to 1.7). Spirometric results, dyspnea, and health-related quality of life did not differ significantly in the two groups. The average daily corticosteroid dose was 10.7 +/- 5.2 mg in the continuous group and 6.3 +/- 6.4 mg in the demand group (p = 0.003). Weight decreased in the demand group by 4.8 +/- 2.0 kg, compared with an increase in the continuous group of 0.5 +/- 3.5 kg (p = 0.007). Discontinuation of chronic systemic corticosteroid treatment in steroid-dependent COPD patients did not cause a significant increase in COPD exacerbations, but did reduce total systemic corticosteroid use and body weight. Larger studies may be warranted to establish the relative risks and benefits of chronic corticosteroid treatment of patients with COPD.

Relation of FEV(1) to clinical outcomes during exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group.

FEV(1) is an objective measure of airflow obstruction used in clinical practice and in therapeutic trials. The precise relationship of FEV(1) to clinical outcomes is generally uncertain. As part of a randomized trial to assess systemic corticosteroid efficacy, we obtained serial FEV(1) measurements in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD). Over the first 14 Study Days at least one FEV(1) value was obtained in 261 subjects. Sixty-four of these subjects experienced treatment failure, defined as death, intubation, readmission for COPD, or intensification of drug therapy, by Study Day 30. After adjustment, both FEV(1) at entry into the study (odds ratio [OR] for a 100-ml increase, 0.87; 95% confidence interval [CI], 0.79 to 0.96) and change in FEV(1) over the first two Study Days (OR for a 100 ml increase, 0.80; 95% CI, 0.69 to 0.92) predicted treatment failure. We identified no baseline characteristic that was significantly related to FEV(1) at entry into the study. Assignment to the systemic corticosteroid treatment arm was associated with a significantly larger FEV(1) at Study Day two (p = 0.01). We conclude that FEV(1) measurements at admission and over the first several days of hospitalization are highly predictive of clinical outcomes during exacerbations of COPD.

Corticosteroids in chronic obstructive pulmonary disease. Clinical benefits and risks.

The use of systemic and inhaled corticosteroids for COPD has increased appreciably over the past 20 years. Clearer indications for corticosteroid therapy in COPD are beginning to emerge as the results from large clinical trials become available. Systemic corticosteroids are only modestly effective for acute COPD exacerbations, increase the risk for hyperglycemia, and should be given for no more than 2 weeks. The efficacy of long-term systemic corticosteroid therapy has not been adequately evaluated in this patient population. If longer term use of systemic steroids in COPD should be found to be useful, this conclusion would have to be weighed against the risk for serious adverse effects. High doses of inhaled corticosteroids cause a small sustained increase of the FEV1 in patients with mild and moderately severe COPD, but they do not slow the rate of FEV1 decline. Based on analyses of secondary outcome, inhaled corticosteroids may improve the respiratory symptoms and decrease the number and severity of COPD exacerbations in patients with more advanced disease. Low doses of inhaled corticosteroids appear to be safe, but there is growing awareness that higher doses may not be so benign.

Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group.

BACKGROUND AND METHODS: Although their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy. RESULTS: Of 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002). CONCLUSIONS: Treatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication.

Steroid-induced osteoporosis. Are your asthmatic patients at risk?

Asthmatic patients who rely on long-term, high-dose corticosteroid therapy are at increased risk for osteoporosis. The use of low-dose inhaled corticosteroids may be safe enough not to require special assessment of bone loss or preventive measures. However, evidence is lacking on the risks of long-term use of higher doses. Regardless of dose, all patients given long-term systemic corticosteroids should be carefully examined and, if necessary, treated for bone loss.

Systemic corticosteroids for chronic obstructive pulmonary disease: benefits and risks.

Systemic corticosteroids have become an increasingly common therapy for patients with stable and unstable chronic obstructive pulmonary disease (COPD), despite uncertain clinical efficacy and known adverse effects. A recently completed, large clinical trial has confirmed that systemic corticosteroids hasten recovery from exacerbations of COPD. Maximum benefits occur with only 2 weeks of therapy. The appropriate role of systemic corticosteroids in stable COPD has not been adequately defined. Prolonged therapy with systemic corticosteroids confers a large risk for developing osteoporotic fractures. Measures for reducing this risk are described.

Serum carcinoembryonic antigen as an adjunct to preoperative staging of lung cancer.

OBJECTIVE: To determine whether measurement of preoperative serum carcinoembryonic antigen concentrations adds useful prognostic data to current preoperative staging of lung cancer by computed tomography, bronchoscopy, and mediastinoscopy. METHODS: A prospective cohort study of 130 consecutive patients was evaluated for suspected lung cancer from July 1991 through December 1992 at a university-affiliated Veterans Affairs Medical Center. Serum concentrations of carcinoembryonic antigen were measured before diagnosis, staging, or resection of cancer. RESULTS: Malignant disease was diagnosed by bronchoscopy, needle biopsy, mediastinoscopy, or resection in 111 of 130 patients. In the 50 patients undergoing resection with curative intent, multivariate analysis indicated that carcinoembryonic antigen was a significant predictor of survival independent of patient age, pathologic stage, histologic type, and tumor size (P=.0357). CONCLUSIONS: Elevated preoperative serum concentrations of carcinoembryonic antigen predict a poor prognosis for lung cancer independent of other conventional staging parameters and have an adjunctive role in the staging of lung cancer.

Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations (SCCOPE): rationale and design of an equivalence trial. Veterans Administration Cooperative Trials SCCOPE Study Group.

The Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations Trial (SCCOPE) was a randomized, double-blind, placebo-controlled, multicenter trial sponsored by the U.S. Department of Veterans Affairs Cooperative Studies Program. Its principal purpose was to determine whether withholding systemic corticosteroids in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD) who were treated with other usual therapy resulted in a clinically significant increase in the rate of treatment failure. Because placebo was compared to a standard therapy, the study was designed as an equivalence trial. If corticosteroids proved effective, the study would also determine whether a short course was as effective as a long one. SCCOPE was to enroll up to 1100 subjects from more than 20 Veterans Administration Medical Centers over 3 years. Patients were screened shortly after hospital admission for acute exacerbation of COPD. Principal criteria for eligibility were age of 50 years or older, smoking history of 30 pack-years or more, clinical diagnosis of COPD as opposed to asthma, nonuse of systemic corticosteroids in the previous 30 days, and forced expiratory volume in 1 sec (FEV1) of 1500 ml or less. Eligible subjects were randomized to one of three treatment arms: (1) short course (2 weeks) of systemic corticosteroids, (2) long course (8 weeks) of systemic corticosteroids, or (3) placebo. We standardized most other aspects of care. We followed patients for 6 months. The primary endpoint of the study was treatment failure, defined as death, intubation with mechanical ventilation, hospital readmission for COPD, or intensification of pharmacologic therapy. Secondary endpoints included length of hospital stay, changes in FEV1, and changes in dyspnea score. We also evaluated possible adverse effects from systemic corticosteroids.

Do molecular markers predict survival in non-small-cell lung cancer?

Patients with non-small-cell lung cancer (NSCLC) survive for variable lengths of time, even when adjustment is made for pathological stage. Numerous reports suggest that biological markers predict survival in patients undergoing surgery for NSCLC with curative intent, but many of these claims are unconfirmed or conflicting. We postulated that the use of multiple putative markers might provide greater power in predicting survival. We studied 101 consecutive patients with NSCLC who underwent exploratory thoracotomy and who were followed for at least 2 yr. We assessed mutations in the p53 tumor suppressor gene (exons 5-8) and the K-ras oncogene (codons 12 and 13) by polymerase chain reaction amplification and single strand conformation polymorphism of the product. We identified 19 K-ras mutations (all adenocarcinomas except for two) and 40 p53 mutations among the 101 cases. We also evaluated p53 protein, bcl-2 protein, c-erbB-1 protein, c-erbB-2 protein, and MIA-15-5 antigen by standard immunocytochemical techniques, and we found that all of these antigens were variably expressed. As expected, we found a strong inverse association between surgical tumor stage and survival. Of the molecular markers studied, only MIA-15-5 antigen expression correlated strongly with survival by univariate analysis (p = 0.001) and it remained a significant predictor by multivariate analysis (p = 0.01). However, in this study, overexpression of MIA-15-5 antigen predicted an improved survival, whereas the original report showed a worse prognosis (N. Engl. J. Med. 1992;327:14). We conclude the multiple cell markers are not clinically useful in predicting survival among patients undergoing surgery for NSCLC. Differences between our results and prior reports may be due to chance, to true population differences, or to other factors.

Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.

Osteoporosis is a major complication of long-term corticosteroid administration, but the magnitude of the effect in patients with chronic obstructive pulmonary disease (COPD) is not well defined. In a cross-sectional study, we evaluated the association between steroid use and vertebral fractures in 312 men, 50 yr of age or older, with COPD. Subjects were evaluated according to their corticosteroid use: Never Steroid Users (NSU) (n = 117), Inhaled Steroid Users (ISU) (n = 70), and Systemic Steroid Users (SSU) (n = 125). The prevalence of one or more vertebral fractures was 48.7% in the NSU group, 57.1% in the ISU group, and 63.3% in the SSU group. Compared with NSU, SSU were two times as likely to have one or more vertebral fractures: age-adjusted odds ratio (OR) = 1.80; 95% CI, 1.08 to 3.07. This relationship was primarily due to a strong association between continuous systemic steroid use and vertebral fractures: age-adjusted OR = 2.36; 95% CI, 1.26 to 4.38. In addition, fractures in SSU were more likely to be multiple and more severe. A weaker relationship existed between inhaled steroid use and vertebral fractures: age-adjusted OR = 1.35; 95% CI, 0.77 to 2.56 compared with NSU. These data indicate that vertebral fractures are common in older men with COPD; the likelihood of these fractures is greatest in those men using continuous systemic steroids.

Adverse effects of corticosteroid therapy for COPD. A critical review.

Inhaled and systemic corticosteroids are commonly prescribed for the treatment of COPD. Despite their frequent use, there is insufficient evidence regarding efficacy of steroid therapy in COPD. While awaiting the results of more definitive prospective trials, the clinician must evaluate whether the benefits of such therapy outweigh the potential for adverse events. This is particularly pertinent in the population of patients with COPD who generally are older, less active, and have significant tobacco use histories, all of which may place them at greater risk for adverse effects. In this review, we examine the current scientific evidence supporting the many purported adverse systemic effects associated with the use of corticosteroids in the treatment of COPD.

Rb and p16INK4a expression in resected non-small cell lung tumors.

Inactivation of the cyclin-dependent kinase inhibitor p16INK4a (CDKN2/MTS1) is documented in a wide variety of cancer cell lines and tumors. We have shown that loss of p16INK4a protein expression is a common event in early stage non-small cell lung cancer (NSCLC), correlates with a significantly worse survival, and is more common in higher stage disease. One hundred NSCLC tumors from patients undergoing definitive thoracotomies at a single institution were examined for p16INK4a and retinoblastoma protein (pRB) expression. Abnormal pRB staining was identified in 15% of the tumors, whereas 51% possessed aberrant p16INK4a protein expression. Tumors with aberrant expression of p16INK4a by immunohistochemistry were associated with a significantly worse survival (P=0.04). Additionally, the inverse correlation of pRB and p16INK4a expression previously noted in lung cancer cell lines and tumors was confirmed in this large cohort of patients, with 65% of the tumors demonstrating inverse expression of pRB and p16INK4a (p=0.00019). A statistically significant increase in aberrant p16INK4a expression, as well as inverse expression of p16INK4a and pRB, was seen with increasing pathological stage of disease. These findings establish the prognostic significance (of the absence of p16INK4, in resected NSCLC and confirm the critical importance of disrupting the pathway of cyclin-dependent kinase-mediated phosphorylation of pRB in the molecular oncogenesis and progression of NSCLC.

Lung cancer surgery. A critical review of the evidence.

Surgery is generally considered to be the treatment of choice for anatomically localized non-small-cell lung cancer, but its effectiveness remains unproven. Observational studies have been of limited value because the criteria by which patients are selected for surgery create substantial differences between patients who undergo surgery and those who do not. One small randomized trial of surgery vs radiotherapy was inconclusive, but several large trials of lung cancer screening have provided indirect evidence against a benefit from surgery. Two ongoing randomized trials, one on extensive vs limited resection and the other on the effect of surgery in more extensive disease, may provide further insight into the effectiveness of surgery in the treatment of localized non-small-cell lung cancer. Development of a large randomized trial to directly assess the effectiveness of surgery in the treatment of localized non-small-cell lung cancer has been precluded by ethical concerns, but may need to be reconsidered if indicated by the findings of the two ongoing studies.

Pneumolysin activates phospholipase A in pulmonary artery endothelial cells.

Pneumolysin has been identified as a virulence factor in Streptococcus pneumoniae disease. In addition to producing tissue injury through its cytolytic effect, pneumolysin might injure tissues indirectly by eliciting an inflammatory response. We demonstrate for the first time that pneumolysin is a rapid and potent activator of cellular phospholipase A in bovine pulmonary artery endothelial cells. In contrast to other toxin-activated phospholipases, pneumolysin-stimulated phospholipase A showed no substrate specificity among major cellular membrane phospholipids. Phospholipase A activation required the formation of functional transmembrane pores by pneumolysin rather than membrane lipid perturbation. Pneumolysin stimulation of phospholipase A was calcium dependent; however, pneumolysin did not appear to function simply as a calcium ionophore. Pneumolysin was capable of stimulating purified bee and snake venom phospholipase A2s against a phospholipid substrate isolated from endothelial cells. Thus, pneumolysin stimulates cellular phospholipase A and the resulting products might further injure tissues by direct cytolytic effect or by evoking inflammatory responses.