313 pubs · 26,873 cites · h-index 76
BACKGROUND: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM. METHODS: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.
Methicillin Resistant Staphylococcus aureus (MRSA) cause pneumonia and empyema thoraces. TLR9 activation provides protection against bacterial infections and Heme oxygenase-1 (HO-1) is known to enhance host innate immunity against bacterial infections. However, it is still unclear whether HO-1 regulates TLR-9 expression in the pleura and modulates the host innate defenses during MRSA empyema. In order to determine if HO-1 regulates host innate immune functions via modulating TLR expression, in MRSA empyema, HO-1+/+ and HO-1-/- mouse pleural mesothelial cells (PMCs) were infected with MRSA (1:10, MOI) in the presence or absence of Cobalt Protoporphyrin (CoPP) and Zinc Protoporphyrin (ZnPP) or CORM-2 (a Carbon monoxide donor) and the expression of mTLR9 and mBD14 was assessed by RT-PCR. In vivo, HO-1+/+ and HO-1-/- mice were inoculated with MRSA (5x106 CFU) intra-pleurally and host bacterial load was measured by CFU, and TLR9 expression in the pleura was determined by histochemical-immunostaining. We noticed MRSA inducing differential expression of TLR9 in HO-1+/+ and HO-1 -/- PMCs. In MRSA infected HO-1+/+ PMCs, TLR1, TLR4, and TLR9 expression was several fold higher than MRSA infected HO-1-/- PMCs. Particularly TLR9 expression was very low in MRSA infected HO-1-/- PMCs both in vivo and in vitro. Bacterial clearance was significantly higher in HO-1+/+ PMCs than compared to HO-1-/- PMCs in vitro, and blocking TLR9 activation diminished MRSA clearance significantly. In addition, HO-1-/- mice were unable to clear the MRSA bacterial load in vivo. MRSA induced TLR9 and mBD14 expression was significantly high in HO-1+/+ PMCs and it was dependent on HO-1 activity. Our findings suggest that HO-1 by modulating TLR9 expression in PMCs promotes pleural innate immunity in MRSA empyema.
Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.
BACKGROUND: The 6-minute walk test distance (6MWD) has been shown to be a valid and responsive outcome measure in patients with idiopathic pulmonary fibrosis (IPF). The analyses were based, however, on a single phase 3 trial and require validation in an independent cohort. OBJECTIVE: To confirm the performance characteristics and estimates of minimal clinically important difference (MCID) of 6MWD in an independent cohort of patients with IPF. METHODS: Patients randomized to placebo in the phase 3 CAPACITY trials who had a baseline 6MWD measurement were included in these analyses. The 6MWD and other functional parameters (lung function, dyspnea, and health-related quality of life) were measured at baseline and 24-week intervals. Validity and responsiveness were examined using Spearman correlation coefficients. The MCID was estimated using distribution- and anchor-based methods. RESULTS: The analysis comprised 338 patients. Baseline 6MWD was significantly correlated with lung function measures, patient-reported outcomes, and quality-of-life measures (validity). Compared with baseline 6MWD, change in 6MWD (responsiveness) showed stronger correlations with change in lung function parameters and quality-of-life measures. Dyspnea measured by the University of California San Diego Shortness of Breath Questionnaire showed the strongest correlations with 6MWD (baseline: coefficient -0.35; 48-week change: coefficient -0.37; both p < 0.001). The distribution-based analyses of MCID using standard error of measurement yielded an MCID of 37 m, and distribution-based analyses by effect size resulted in 29.2 m. The MCID by anchor-based analysis using criterion referencing (health events of hospitalization or death) was 21.7 m. CONCLUSIONS: The 6MWD is a valid and responsive clinical endpoint, which provides objective and clinically meaningful information regarding functional status and near-term prognosis. These results confirm previous findings in an independent cohort of patients with IPF.
Yellow nail syndrome (YNS) can be associated with a pleural effusion (PE) but the characteristics of these patients are not well defined. We performed a systematic review across four electronic databases for studies reporting clinical findings, PE characteristics, and most effective treatment of YNS. Case descriptions and retrospective studies were included, unrestricted by year of publication. We reviewed 112 studies (150 patients), spanning a period of nearly 50 years. The male/female ratio was 1.2/1. The median age was 60 years (range: 0-88). Seventy-eight percent were between 41-80 years old. All cases had lymphoedema and 85.6% had yellow nails. PEs were bilateral in 68.3%. The appearance of the fluid was serous in 75.3%, milky in 22.3% and purulent in 3.5%. The PE was an exudate in 94.7% with lymphocytic predominance in 96% with a low count of nucleated cells. In 61 of 66 (92.4%) of patients, pleural fluid protein values were >3 g/dL, and typically higher than pleural fluid LDH. Pleurodesis and decortication/pleurectomy were effective in 81.8% and 88.9% of cases, respectively, in the treatment of symptomatic PEs. The development of YNS and PE occurs between the fifth to eighth decade of life and is associated with lymphoedema. The PE is usually bilateral and behaves as a lymphocyte-predominant exudate. The most effective treatments appear to be pleurodesis and decortication/pleurectomy.
Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).
BACKGROUND AND OBJECTIVE: Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. METHODS: All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. RESULTS: A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week-7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. CONCLUSIONS: This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated.
Rationale FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials. Objectives To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF. Methods The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design. Measurements and Main Results A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients. Conclusions The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.
6-min walk distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with idiopathic pulmonary fibrosis (IPF); however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF. A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon γ-1b (n=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD. Baseline 6MWD <250 m was associated with a two-fold increase in the risk of mortality (hazard ratio 2.12, 95% CI 1.15-3.92) and a 24-week decline in 6MWD >50 m was associated with a nearly three-fold increase in mortality risk (hazard ratio 2.73; 95% CI 1.60-4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic 0.80 (95% CI 0.76-0.85) versus 0.75 (0.71-0.79)). Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model.
May support TPE diagnosis via high-specificity pleural fluid criteria; leaves open prospective validation before clinical use.
Although a pleural effusion (PE) is a common condition in clinical practice (with a prevalence of slightly >400 patients/100,000), a definitive diagnosis is not established in approximately 20% of cases. In the classic publications, thoracentesis provided a definitive or presumptive diagnosis in 73% of cases, although it is estimated that today this percentage could reach 95%. An undiagnosed PE is defined as one that remains of unknown origin after performing complete pleural fluid analysis (nucleated cell counts with differential diagnosis, biochemistry, culture, cytology, and flow cytometry). The aim of this paper is to review the difficulties that may be encountered when attempting to establish the cause of a PE. The reason for this diagnostic dilemma may be an atypical clinical or radiologic presentation or false-positive or false-negative results. Furthermore, the limited frequency of some PEs is often not considered when determining the differential diagnosis.
Virtually, every pulmonary disease and most non-pulmonary diseases may be associated with a pleural effusion. The presence of a pleural effusion allows the clinician to 'diagnose' or narrow the differential diagnosis and aetiology of the fluid collection. However, pleural fluid analysis (PFA) in isolation rarely provides a definitive diagnosis. This review discusses the rationale for evaluating patients with a pleural effusion. If the clinician obtains a detailed history, performs a comprehensive physical examination, reviews pertinent blood tests, and evaluates the chest imaging findings prior to thoracentesis, there should be a high likelihood of establishing a firm clinical diagnosis based on the appropriate PFA. This manuscript reviews the clinical presentation, chest imaging findings, duration and natural course of specific pleural effusions to help narrow the range of pre-thoracentesis diagnoses. A diagnosis of transudative effusion confirms an imbalance in hydrostatic and oncotic pressures, normal pleura and a limited differential diagnosis, which is typically apparent from the clinical presentation. Exudates are the result of infections, malignancies, inflammation, impaired lymphatic drainage or the effects of drugs, and pose a greater diagnostic challenge. The differential diagnosis for a pleural exudate can be narrowed if LDH levels exceed 1000 IU/L, the proportion of lymphocytes is ≥80%, pleural fluid pH is <7.30 or there is pleural eosinophilia of >10%.
Clinical trial analysis reveals measurement reliability and clinical significance of forced vital capacity in idiopathic pulmonary fibrosis, indicating subtle declines carry mortality risk.
Numerous intrapleural therapies have been adopted to treat a vast array of pleural diseases. The first intrapleural therapies proposed focused on the use of fibrinolytics and DNase to promote fluid drainage in empyema. Numerous case series and five randomized controlled trials have been published to determine the outcomes of fibrinolytics in empyema treatment. In the largest randomized trial, the use of streptokinase had no reduction in mortality, decortication rates or hospital days compared with placebo in the treatment of empyema. Criticism over study design and patient selection may have potentially affected the outcomes in this study. The development of dyspnoea is common in the setting of malignant pleural effusions. Pleural fluid evacuation followed by pleurodesis is often attempted. Numerous sclerosing agents have been studied, with talc emerging as the most effective agent. Small particle size of talc should be avoided because of increased systemic absorption potentiating toxicity, such as acute lung injury. Over the past several years, the use of chronic indwelling pleural catheters have emerged as the preferred modality in the treating a symptomatic malignant pleural effusion. For patients with malignant-related lung entrapment, pleurodesis often fails due to the presence of visceral pleural restriction; however, chronic indwelling pleural catheters are effective in palliation of dyspnoea. Finally, the use of staphylococcal superantigens has been proposed as a therapeutic model for the treatment of non-small lung cancer. Intrapleural instillation of staphylococcal superantigens increased median survival by 5 months in patients with non-small cell lung cancer with a malignant pleural effusion.
Rationale Several predictors of mortality in patients with idiopathic pulmonary fibrosis have been described; however, there is a need for a practical and accurate method of quantifying the prognosis of individual patients. Objectives Develop a practical mortality risk scoring system for patients with idiopathic pulmonary fibrosis. Methods We used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with idiopathic pulmonary fibrosis. From the comprehensive model, an abbreviated clinical model comprised of only those predictors that are readily and reliably ascertained by clinicians was derived. Beta coefficients for each predictor were then used to develop a practical mortality risk scoring system. Measurements and Main Results Independent predictors of mortality included age, respiratory hospitalization, percent predicted FVC, 24-week change in FVC, percent predicted carbon monoxide diffusing capacity, 24-week change in percent predicted carbon monoxide diffusing capacity, and 24-week change in health-related quality of life. An abbreviated clinical model comprising only four predictors (age, respiratory hospitalization, percent predicted FVC, and 24-wk change in FVC), and the corresponding risk scoring system produced estimates of 1-year mortality risk consistent with observed data (9.9% vs. 9.7%; C statistic = 0.75; 95% confidence interval, 0.71–0.79). Conclusions The prognosis for patients with idiopathic pulmonary fibrosis may be accurately determined using four readily ascertainable predictors. Our simplified scoring system may be a valuable tool for determining prognosis and guiding clinical management. Additional research is needed to validate the applicability and accuracy of the scoring system.
Rationale The 6-minute-walk test (6MWT) is a practical and clinically meaningful measure of exercise tolerance with favorable performance characteristics in various cardiac and pulmonary diseases. Performance characteristics in patients with idiopathic pulmonary fibrosis (IPF) have not been systematically evaluated. Objectives To assess the reliability, validity, and responsiveness of the 6MWT and estimate the minimal clinically important difference (MCID) in patients with IPF. Methods The study population included all subjects completing a 6MWT in a clinical trial evaluating interferon gamma-1b (n = 822). Six-minute walk distance (6MWD) and other parameters were measured at baseline and at 24-week intervals using a standardized protocol. Parametric and distribution-independent correlation coefficients were used to assess the strength of the relationships between 6MWD and measures of pulmonary function, dyspnea, and health-related quality of life. Both distribution-based and anchor-based methods were used to estimate the MCID. Measurements and Main Results Comparison of two proximal measures of 6MWD (mean interval, 24 d) demonstrated good reliability (coefficient = 0.83; P < 0.001). 6MWD was weakly correlated with measures of physiologic function and health-related quality of life; however, values were consistently and significantly lower for patients with the poorest functional status, suggesting good construct validity. Importantly, change in 6MWD was highly predictive of mortality; a 24-week decline of greater than 50 m was associated with a fourfold increase in risk of death at 1 year (hazard ratio, 4.27; 95% confidence interval, 2.57– 7.10; P < 0.001). The estimated MCID was 24–45 m. Conclusions The 6MWT is a reliable, valid, and responsive measure of disease status and a valid endpoint for clinical trials in IPF.
RATIONALE: Arformoterol, a single isomer long-acting beta(2)-agonist, was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD. METHODS: The pulmonary function efficacy of nebulized arformoterol (15 micro g BID, 25 micro g BID, 50 micro g QD) and salmeterol MDI (42 micro g BID) versus placebo was assessed in 1456 subjects (mean FEV(1) 1.2L, mean predicted 41%). Data were pooled from 2 identical, 12-week, double-blind, randomized trials. The percent change in trough FEV(1), percent change in FEV(1) average AUC((0 - 12 hrs)) and peak percent change FEV(1) from predose were analyzed. RESULTS: Improvement in trough FEV(1) averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo (mean differences from placebo [95% CI] arformoterol-15 micro g BID: 11.4% [8.4, 14.3]; 25 micro g BID: 15.4% [12.2, 18.6]; 50 micro g QD: 10.9% [7.9, 13.9]); salmeterol: (11.6% [8.8, 14.4]). Greater improvements versus placebo occurred after the first dose (mean differences between arformoterol and placebo for trough FEV(1): 13-19%; FEV(1) AUC((0 - 12 hrs)): 19-24%; peak percent change: 20-25%) and at week 12 (trough FEV(1): 10-13%; FEV(1) AUC((0 - 12 hrs)): 6-13%; peak percent change: 7-14%); all 95% CIs excluded zero. Increases in FEV(1) AUC((0 - 12 hrs)) and peak percent change were greater for arformoterol than for salmeterol (95% CIs excluded zero). After 12 weeks, 78-87% of arformoterol subjects had > or = 10% increases in FEV(1) from pre-dose (56% salmeterol, 44% placebo); the median time to response was 3-13 minutes (142 minutes salmeterol). CONCLUSIONS: In these trials, COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks.
The development of pleural fibrosis follows severe pleural space inflammation which is typically associated with an exudative pleural effusion. The response of the mesothelial cell to injury and its ability, along with the basement membrane, to maintain its integrity, is vital in determining whether there is normal healing or pleural fibrosis. The formation of a fibrinous intrapleural matrix is critical to the development of pleural fibrosis. This matrix is the result of disordered fibrin turnover, whereby fibrin formation is up-regulated and fibrin dissolution is down-regulated. Cytokines, such as TGF-beta and TNF-alpha, facilitate the fibrin matrix formation. A complete understanding of the pathogenesis of pleural fibrosis and why abnormal pleural space remodeling occurs in some and not in others, remains unknown. Clinically significant pleural fibrosis requires involvement of the visceral pleura. Isolated parietal pleural fibrosis, as with asbestos pleural plaques, does not cause restriction or respiratory impairment. The causes of visceral pleural fibrosis include asbestos-associated diffuse pleural thickening, coronary bypass graft surgery, pleural infection (including tuberculous pleurisy), drug-induced pleuritis, rheumatoid pleurisy, uraemic pleurisy, and haemothorax. Systemic and intrapleural corticosteroids administered during the initial presentation of rheumatoid pleurisy in small series may decrease the incidence of pleural fibrosis. Several randomised control trials using corticosteroids in tuberculous pleurisy have not shown efficacy in reducing residual pleural fibrosis. Decortication is effective in treating symptomatic patients regardless of the cause of pleural fibrosis as long as chronicity has been documented and significant underlying parenchymal disease has been excluded.
The case of a 49-year-old alcoholic man with obtundation is presented. The patient was presumptively diagnosed with methanol intoxication due to the presence of metabolic acidosis with high anion and osmolar gaps. Laboratory testing revealed toxic levels of propylene glycol instead. An exercise in estimating the concentration of toxic alcohols and glycols is given, and the literature on poisoning with this unusual but commonly encountered intoxicant is briefly reviewed.
An 81-year-old man was referred for evaluation of a chronic transudative pleural effusion that required 8 therapeutic thoracenteses over 11 months for relief of dyspnea. Extensive lumbar disk surgery had been performed 2 years prior to his onset of dyspnea. The diagnosis of duro-pleural fistula was confirmed by finding the presence of beta2-transferrin in the pleural fluid. The 'water-like' pleural fluid had a total protein of <1 gm/dl, an LDH of 92 IU/l, a glucose of 101 mg/dl, and pH of 7.55. beta2-Transferrin has a sensitivity approaching 100% and a specificity of 95% in identifying CSF leaks from head trauma. To our knowledge, this is the first report of beta2-transferrin in pleural fluid from a duro-pleural fistula.