Uso crónico de teofilina y mortalidad en la enfermedad pulmonar obstructiva crónica: un metaanálisis / Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis

Antecedentes: Se ha demostrado que la teofilina mejora la función respiratoria y la oxigenación en pacientes con enfermedad pulmonar obstructiva crónica (EPOC). Sin embargo, no está suficientemente evaluado el impacto de la teofilina sobre la mortalidad de los pacientes con EPOC. Método: Dos investigadores buscaron de forma independiente artículos elegibles en 4 bases de datos. Los artículos seleccionados para el presente metaanálisis debían ser artículos de investigación originales que proporcionaran el cociente de riesgos instantáneos (HR) de la mortalidad por cualquier causa en pacientes con EPOC tratados con teofilina. Se permitió incluir tanto ensayos controlados aleatorizados como estudios observacionales. Después de confirmar que la heterogeneidad no era significativa (I2<50%), para estimar el cociente de riesgos instantáneos del metaanálisis se empleó un modelo fijo con un método de varianza inversa genérica. Resultados: Se seleccionaron 364 artículos potencialmente elegibles. De los 364 artículos, 259 fueron excluidos basándose en el título y el resumen, y 99 fueron excluidos después de considerar sus textos completos. Finalmente, nuestro análisis incluyó 6 estudios observacionales y ningún ensayo controlado aleatorizado. Un estudio estaba realizado con 2 cohortes. El número de pacientes en cada cohorte varió de 47 a 46.403. La heterogeneidad (I2 = 42%, p = 0,11) y el sesgo de publicación (r = 0,21, p = 0,662 en la prueba de Begg) no fueron significativos. El metaanálisis del modelo fijo arrojó un cociente de riesgos instantáneos combinado de mortalidad por cualquier causa con teofilina de 1,07 (intervalo de confianza del 95%: 1,2-1,13, p = 0,003). Conclusión: El presente metaanálisis de 7 cohortes observacionales sugiere que la teofilina aumenta ligeramente la mortalidad por cualquier causa de los pacientes con EPOC

Background: Theophylline has been shown to improve respiratory function and oxygenation in patients with chronic obstruction pulmonary disease (COPD). However, the impact of theophylline on mortality in COPD patients has not been not sufficiently evaluated. Method: Two investigators independently searched for eligible articles in 4 databases. The eligibility criterion for this meta-analysis was an original research article that provided a hazard ratio for theophylline for all-cause mortality of COPD patients. Both randomized controlled trials and observational studies were accepted. After we confirmed no substantial heterogeneity (I2 < 50%), the fixed-model method with generic inverse variance was used for meta-analysis to estimate the pooled hazard ratio. Results: We screened 364 potentially eligible articles. Of the 364 articles, 259 were excluded on the basis of title and abstract, and 99 were excluded after examination of the full text. Our final analysis included 6 observational studies and no randomized controlled trials. One study reported 2 cohorts. The number of patients in each cohort ranged from 47 to 46,403. Heterogeneity (I2 = 42%, P = .11) and publication bias (Begg's test r = 0.21, P = .662) were not substantial. Fixed-model meta-analysis yielded a pooled hazard ratio for theophylline for all-cause death of 1.07 (95% confidence interval: 1.02-1.13, P = .003). Conclusion: This meta-analysis of 7 observational cohorts suggests that theophylline slightly increases all-cause death in COPD patients

Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis. / Uso crónico de teofilina y mortalidad en la enfermedad pulmonar obstructiva crónica: un metaanálisis.

BACKGROUND: Theophylline has been shown to improve respiratory function and oxygenation in patients with chronic obstruction pulmonary disease (COPD). However, the impact of theophylline on mortality in COPD patients has not been not sufficiently evaluated. METHOD: Two investigators independently searched for eligible articles in 4 databases. The eligibility criterion for this meta-analysis was an original research article that provided a hazard ratio for theophylline for all-cause mortality of COPD patients. Both randomized controlled trials and observational studies were accepted. After we confirmed no substantial heterogeneity (I(2)<50%), the fixed-model method with generic inverse variance was used for meta-analysis to estimate the pooled hazard ratio. RESULTS: We screened 364 potentially eligible articles. Of the 364 articles, 259 were excluded on the basis of title and abstract, and 99 were excluded after examination of the full text. Our final analysis included 6 observational studies and no randomized controlled trials. One study reported 2 cohorts. The number of patients in each cohort ranged from 47 to 46,403. Heterogeneity (I(2)=42%, P=.11) and publication bias (Begg's test r=0.21, P=.662) were not substantial. Fixed-model meta-analysis yielded a pooled hazard ratio for theophylline for all-cause death of 1.07 (95% confidence interval: 1.02-1.13, P=.003). CONCLUSION: This meta-analysis of 7 observational cohorts suggests that theophylline slightly increases all-cause death in COPD patients.

Topotecan for Relapsed Small-cell Lung Cancer: Systematic Review and Meta-Analysis of 1347 Patients.

Topotecan is the most reliable chemotherapy regimen for relapsed small-cell lung carcinoma (SCLC). The efficacy and adverse effects of topotecan as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for 6-month over-all survival (OS) rate, 1-year OS rate, objective responses, and/or adverse effects of single agent topotecan as a second line chemotherapy for SCLC, written in English language as a full article. Any topotecan regimen were allowed. Binary data were meta-analyzed with the random-model generic inverse variance method. We included 14 articles consisted of 1347 patients. Pooled values were estimated as follows. Six-month OS rate: 37% (95% CI: 28-46%). One-year OS rate: 9% (95% CI: 5-13%). Response rate: 5% (95% CI: 1-8%). Six-month OS rate: 57% (95% CI: 50-64%). One-year OS rate: 27% (95% CI: 22-32%). Response rate: 17% (95% CI: 11-23%). Grade III/IV neutropenia 69% (95% CI: 58-80%). Grade III/IV thrombopenia 41% (95% CI: 34-48%). Grade III/IV anemia 24% (95% CI: 17-30%). Non-hematorogical events were rare. Chemotherapy-related death 2% (95% CI: 1-3%). In conclusion, Topotecan provided a possibly promising outcome for sensitive-relapse SCLC and poor outcome for refractory relapse SCLC. Adverse events were mainly hematological.

Impact of Corticosteroids on Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: The impact of corticosteroids on acute respiratory distress syndrome (ARDS) mortality remains controversial following the publication of numerous trials, observational studies and meta-analyses. An updated meta-analysis is warranted, as a few original studies on this topic have been published since the last meta-analysis. METHODS: We searched for eligible articles using four databases. In particular, we included full-length original articles providing sufficient data for evaluating the impact of corticosteroid treatment on adult ARDS mortality in the form of odds ratios. A fixed model with the confidence interval method was used. An assessment of publication bias and sensitivity analyses were also conducted. RESULTS: We included 11 of 185 articles. The pooled odds ratio for corticosteroids with respect to all-cause mortality involving 949 patients was 0.77 [95% confidence interval (CI): 0.58-1.03, p=0.079] with strong heterogeneity(I2=70%, p<0.001). The results of the sensitivity analysis, Begg-Kendall test (τ=0.53, p=0.024)and funnel plot consistently suggested the existence of strong publication bias. After six potentially unpublished cohorts were filled using Duval's trim and fill method, the pooled odds ratio shifted to 1.11 (95% CI0.86-1.44, p=0.427). In addition, the sensitivity analyses suggested that corticosteroid treatment has a different impact on mortality depending on the comorbidities and trigger events. CONCLUSION: We were unable to confirm, based on the data of published studies, the favorable impact of corticosteroid therapy on mortality in overall ARDS cases. Published articles exhibit strong publication bias,and previous meta-analyses may be affected by this publication bias. Further research focusing on pathophysiology- or trigger event-specific ARDS is anticipated.

Long-acting muscarinic antagonist + long-acting beta agonist versus long-acting beta agonist + inhaled corticosteroid for COPD: A systematic review and meta-analysis.

Some trials have been conducted to compare long-acting muscarinic antagonist (LAMA) + long-acting beta agonist (LABA) versus LABA + inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), but no meta-analysis were reported. Two investigators independently searched for eligible articles using the PubMed, Web of Science and Cochrane databases. Articles in authors' reference files were also regarded as candidates. The eligibility criteria for the current meta-analysis were original trials written in English comparing the impact of LAMA + LABA and LABA + ICS for COPD patients. A pooled value for the continuous value was calculated using the genetic inverse variance method for mean difference. Incidence of events was evaluated using the odds ratio (OR). Minimal clinically important difference were 50 mL for forced expiratory volume in 1 s (FEV1 ), four points for St George Respiratory Questionnaire (SGRQ) and one point for transition dyspnoea index (TDI). We included seven randomized controlled trials and one cross-over trial with follow-up period of 6-26 weeks. Compared with LABA + ICS, LAMA + LABA led to significantly greater improvements of trough FEV1 by 71 (95% CI: 48-95) mL, TDI by 0.38 points (95% CI: 0.17-0.58), less exacerbations with an OR of 0.77 (95% CI: 0.62-0.96) and less pneumonia with an OR of 0.28 (95% CI: 0.12-0.68). Frequencies of any adverse event, serious adverse event, adverse event leading to discontinuation, all-cause death and change of total score of SGRQ were not different in both arms. LAMA + LABA might be a better option for treating COPD than LABA + ICS.

Vitamin D binding protein genotype variants and risk of chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND AND OBJECTIVE: Genetic susceptibility for development of chronic obstructive pulmonary disease (COPD) is under intensive investigation. Among the three alleles of vitamin D binding protein, or group-specific (GC) components, some have suggested that having GC-1F and GC-2 alleles was associated with a risk of COPD. Although previous studies have shown considerable variance, no meta-analysis has been conducted. METHODS: Through four databases, two independent investigators searched for case-control studies providing sufficient data to calculate odds ratios by the vitamin D binding protein allele variant and genotype variant for a case of COPD. Studies whose control did not satisfy the Hardy-Weinberg equilibrium (Chi-square P ≥ 0.05) were excluded. We used a fixed-model to estimate the pooled odds ratio at both allele and genotype level. RESULTS: Of 141 candidate studies, six were included. We analysed 1712 subjects, consisting of 466 Asians, 1246 Caucasians, 531 COPD cases and 1181 non-COPD controls. The prevalence of each allele among the 1181 controls was as follows: GC-1F 14.0%, GC-1S 53.8% and GC-2 31.9%. When compared to GC-1S, the GC-1F allele and GC-2 allele were associated with COPD risk with pooled odds ratios of 1.44 (95% CI 1.14-1.83, P = 0.002) and 0.83 (95% CI 0.69-0.996, P = 0.045), respectively. When compared to the 1S-1S genotype, the 1F-1F genotype was a risk factor of COPD with pooled odds ratio of 2.64 (95% CI 1.29-5.39, P = 0.008). CONCLUSION: The GC-1F allele of the vitamin D binding protein was a risk for COPD in recessive mode.

Minimum clinically important difference in diffusing capacity of the lungs for carbon monoxide among patients with severe and very severe chronic obstructive pulmonary disease.

BACKGROUND: The minimum clinically important difference (MCID) for diffusing capacity of the lungs for carbon monoxide (DLCO) has not yet been solidly established. METHODS: We used the dataset of surgical cohort of National Emphysema Treatment Trial. Briefly, severe and very severe chronic obstructive pulmonary disease (COPD) patients who were candidate for volume reduction surgery and who could provide sufficient data at 12-month follow-up were included. We used two anchor methods using 6-minute walk distance (6MWD. MCID = 40 m) and forced expiratory volume in 1 sec (FEV1. MCID = 100 ml) as anchors, and two distribution methods. We proposed MCID with a median of estimated values. We estimated MCID for DLCO in raw value and % change from the baseline independently. RESULTS: The surgical cohort included 356 patients, whose average age was 66.6 ± 5.5 years, and the average % predicted FEV1 was 27.8 ± 7.3%. The estimated MCID for DLCO in raw value and % change from the baseline were as follows: anchor method (average, 6MWD) 1.2 ml/min/mmHg, 17%; anchor method (average, FEV1) 0.7 ml/min/mmHg, 11%; anchor method (receiver operating characteristic, 6MWD) 1.1 ml/min/mmHg, 10%; anchor method (receiver operating characteristic, FEV1) 1.2 ml/min/mmHg, 3%; distribution method (0.3 units of standard deviation), 0.9 ml/min/mmHg, 11%; distribution method (standard error of measurement), 1.1 ml/min/mmHg. The median of these values was 1.1 ml/min/mmHg and 11%. CONCLUSION: We estimated the group-level MCID for DLCO for patients with severe and very severe COPD patients as 1.1 ml/min/mmHg and 11% of baseline DLCO.

Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies.

BACKGROUND: Recent observational studies have suggested that use of statins reduces mortality in patients suffering from chronic obstructive pulmonary disease. However, no meta-analysis has reported the pooled hazard ratio of statins to all-cause mortality. METHODS: We searched for eligible articles using five databases. We included randomized controlled trials and cohort studies written in English using original data reporting the hazard ratio of statins to all-cause, cardiovascular-related, cancer-related, or respiratory-related mortality. A fixed model with the confidence interval method was used. Publication bias was evaluated by funnel plot and Begg's test, and was corrected using Duval's trim and fill method. Sensitivity analyses were also conducted. RESULTS: We included 10 out of 128 articles. The pooled hazard ratio of statins to all-cause mortality involving 16269 patients was 0.81 (95% CI: 0.75-0.86, P < 0.001) with moderate heterogeneity (I2 = 52%, P = 0.032). The sensitivity analysis and funnel plot suggested the existence of publication bias. After three possibly unpublished cohorts were imputed, the pooled hazard ratio of 0.83 (95% CI: 0.78-0.88, P < 0.001) still suggested a favorable prognosis in statin-treated patients. The pooled hazard ratio of statins to cardiovascular-related, cancer-related, and respiratory-related mortality were 0.52 (95% CI: 0.27-1.01, P = 0.052), 0.57 (95% CI: 0.32-1.01, P = 0.056), and 0.55 (95% CI: 0.43-0.78, P < 0.001), respectively, although these results were not conclusive as we could not find a sufficient number of original studies dealing with those forms of mortality. CONCLUSIONS: The use of statins for patients suffering from chronic obstructive pulmonary disease may reduce all-cause mortality. This conclusion should be re-evaluated by a registered large-scale randomized controlled trial.

Three cases of mesalazine-induced pneumonitis with eosinophilia.

Oral mesalazine, or 5-aminosalicylate, is one of the first-choice medications for the treatment of ulcerative colitis and is commonly used for both induction and maintenance therapy. In a 6-month period, we treated three cases of mesalazine-induced pneumonitis. In all three cases, computed tomography images revealed upper lobe dominant bilateral peripherally localized consolidations. Such images are commonly observed in patients with cryptogenic organizing pneumonia or chronic eosinophilic pneumonia. Computed tomography images for mesalazine-induced pneumonitis have been rarely reported in the literature.

Evidence suggesting that oral corticosteroids increase mortality in stable chronic obstructive pulmonary disease.

BACKGROUND: Oral corticosteroids were used to control stable chronic obstructive pulmonary disease (COPD) decades ago. However, recent guidelines do not recommend long-term oral corticosteroids (LTOC) use for stable COPD patients, partly because it causes side-effects such as respiratory muscle deterioration and immunosuppression. Nonetheless, the impact of LTOC on life prognosis for stable COPD patients has not been clarified. METHODS: We used the data of patients randomized to non-surgery treatment in the National Emphysema Treatment Trial. Severe and very severe stable COPD patients who were eligible for volume reduction surgery were recruited at 17 clinical centers in the United States and randomized during 1998-2002. Patients were followed-up for at least five years. Hazard ratios for death by LTOC were estimated by three models using Cox proportional hazard analysis and propensity score matching. RESULTS: The pre-matching cohort comprised 444 patients (prescription of LTOC: 23.0%. Age: 66.6 ± 5.4 year old. Female: 35.6%. Percent predicted forced expiratory volume in one second: 27.0 ± 7.1%. Mortality during follow-up: 67.1%). Hazard ratio using a multiple-variable Cox model in the pre-matching cohort was 1.54 (P = 0.001). Propensity score matching was conducted with 26 parameters (C-statics: 0.73). The propensity-matched cohort comprised of 65 LTOC(+) cases and 195 LTOC(-) cases (prescription of LTOC: 25.0%. Age: 66.5 ± 5.3 year old. Female: 35.4%. Percent predicted forced expiratory volume in one second: 26.1 ± 6.8%. Mortality during follow-up: 71.3%). No parameters differed between cohorts. The hazard ratio using a single-variable Cox model in the propensity-score-matched cohort was 1.50 (P = 0.013). The hazard ratio using a multiple-variable Cox model in the propensity-score-matched cohort was 1.73 (P = 0.001). CONCLUSIONS: LTOC may increase the mortality of stable severe and very severe COPD patients.

Sensitivity and specificity of the Streptococcus pneumoniae urinary antigen test for unconcentrated urine from adult patients with pneumonia: a meta-analysis.

Studies on the sensitivity and specificity of the Binax Now Streptococcus pneumonia urinary antigen test (index test) show considerable variance of results. Those written in English provided sufficient original data to evaluate the sensitivity and specificity of the index test using unconcentrated urine to identify S. pneumoniae infection in adults with pneumonia. Reference tests were conducted with at least one culture and/or smear. We estimated sensitivity and two specificities. One was the specificity evaluated using only patients with pneumonia of identified other aetiologies ('specificity (other)'). The other was the specificity evaluated based on both patients with pneumonia of unknown aetiology and those with pneumonia of other aetiologies ('specificity (unknown and other)') using a fixed model for meta-analysis. We found 10 articles involving 2315 patients. The analysis of 10 studies involving 399 patients yielded a pooled sensitivity of 0.75 (95% confidence interval: 0.71-0.79) without heterogeneity or publication bias. The analysis of six studies involving 258 patients yielded a pooled specificity (other) of 0.95 (95% confidence interval: 0.92-0.98) without no heterogeneity or publication bias. We attempted to conduct a meta-analysis with the 10 studies involving 1916 patients to estimate specificity (unknown and other), but it remained unclear due to moderate heterogeneity and possible publication bias. In our meta-analysis, sensitivity of the index test was moderate and specificity (other) was high; however, the specificity (unknown and other) remained unclear.

The presence of pretreatment cavitations and the bacterial load on smears predict tuberculosis infectivity negative conversion judged on sputum smear or culture.

OBJECTIVE: There are no rules to predict the time to infectivity negative conversion based on sputum smear conversion or culture conversion during chemotherapy in smear-positive tuberculosis patients. We aimed to develop and validate rules of sputum smear grades and cavitations in the lungs due to tuberculosis. METHODS: This study was a retrospective cohort study that consisted of development (n=158, 64 ± 19 years of age) and validation (n=214, 63 ± 20 years of age) steps in different cohorts. We developed a rule with pretreatment smear grades and the existence of cavitations in the lungs due to tuberculosis as independent variables and the duration to infectivity negative conversion as the dependent variable in a Cox hazard model. The smear grade indicating the pretreatment bacterial load was classified into four grades according to the Japanese guidelines. The presence of cavitations was assessed on X-ray. Infectivity conversion was defined according to the criteria of the Japanese Ministry of Health, Labour and Welfare: a patient is currently receiving proper treatment and shows clinical improvement and sputum smears and cultures in any combination are consecutively negative three times. RESULTS: We developed an "Infectivity Conversion Score" classifying each patient with a smear grade of I though IV and assessing the existence of cavitations in the lungs due to tuberculosis. The median time to infectivity conversion in the validation cohort was 13, 22, 35 and 50 days for Infectivity Conversion Scores I through IV, respectively (p<0.001). CONCLUSION: We developed and validated Infectivity Conversion Scores.