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Background Despite Food and Drug Administration approval of 2 new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Preclinical and clinical data support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was the first study designed to evaluate the safety of a single infusion of bone marrow–derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis. Methods Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3 cohorts and dosed with a single IV infusion of 20, 100, or 200 × 10 6 human bone marrow–derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary end point was the incidence (at week 4 postinfusion) of treatment-emergent serious adverse events, defined as the composite of death, nonfatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter. Secondary efficacy end points were exploratory and measured disease progression. Results No treatment-emergent serious adverse events were reported. Two nontreatment-related deaths occurred because of progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide. Conclusions Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild-moderate IPF. Trial Registry ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.

Background Sirolimus (SIR) has been shown to stabilize the lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, there is no long-term data on the prophylactic use of SIR in lung transplant recipients. This retrospective study examines the effects of SIR in the prevention of BOS. Methods From 1999 to 2009, 24 lung transplant recipients whose maintenance immunosuppression regimen consisted of tacrolimus (Tac), mycophenolate mofetil (MMF) or azathioprine (AZA), and prednisone (Pred), were switched to Tac, SIR, and Pred at 1 year after transplantation. From these 24 patients, 5 developed side effects that necessitated the cessation of SIR within 1 year, while 19 patients tolerated long-term use of SIR. The clinical outcomes of these 19 patients (SIR group) were compared with 22 lung transplant recipients whose immunosupression regimen consisted of Tac, MMF or AZA, and Pred from the time of transplant (MMF group). Survival rates and freedom from BOS were calculated by the Kaplan-Meier method. Results The SIR group had a lower incidence of BOS and viral infection ( p = 0.05), and higher survival rates ( p = 0.004). The SIR group had lower levels of Tac and received less Pred. The incidences of acute rejection, carcinoma, hypertension, and diabetes were similar between both groups. Conclusions Results from this study suggest that conversion to SIR 1 year after lung transplantation improves survival and decreases the development of BOS. Randomized studies with higher number of patients are needed to determine the prophylactic efficacy of sirolimus in preventing the development of BOS.

Background This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer. Methods Current guidelines and medical literature applicable to this issue were identified by computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee. Results The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV 1 . If diffuse parenchymal lung disease is evident on radiographic studies or if there is dyspnea on exertion that is clinically out of proportion to the FEV 1 , the diffusing capacity of the lung for carbon monoxide (D lco ) should also be measured. In patients with either an FEV 1 or D lco 1 or D lco o 2 max) should be performed to further define the perioperative risk of surgery; a V˙ o 2 max of o 2 max of o 2 max of 1 of > 20% predicted, and a D lco of > 20% predicted. Conclusions A careful preoperative physiologic assessment will be useful to identify those patients who are at increased risk with standard lung cancer resection and to enable an informed decision by the patient about the appropriate therapeutic approach to treating their lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment for this disease.

Introduction Estimating the clinical probability of mediastinal metastasis in patients with non-small cell lung cancer (NSCLC) can facilitate the selection and interpretation of staging tests. Purpose We sought to identify independent clinical predictors of mediastinal metastasis and to develop a prediction rule to estimate the pretest probability of nodal metastasis in patients with NSCLC. Methods We used data from a randomized controlled trial of selective versus routine mediastinoscopy to develop a clinical prediction model. Results Five hundred sixty-six patients were included, with a mean age of 65 ± 9 years; 31% had positive lymph nodes. Independent predictors of positive nodes included adenocarcinoma or large cell histology (OR 2.6, 95% confidence interval [CI] = 1.8–3.9), apparent metastatic disease on chest radiography (OR 2.4, 95% CI=1.2–4.7), central location of the primary tumor (OR 2.1, 95% CI=1.4–3.3), symptoms from the primary tumor (OR 1.6, 95% CI=1.1–2.4), tumor diameter ≥3.6 cm (OR 1.5, 95% CI=1.0–2.3), and age less than 65 years (OR 1.5, 95% CI=1.0–2.2). Model accuracy and calibration were good, with an area under the receiver operating characteristic curve of 0.70 (95% CI=0.66–0.75) and good agreement between observed and predicted probabilities of mediastinal metastasis. Conclusions Our prediction rule can be used to estimate the pretest probability of mediastinal metastasis in patients with NSCLC. Such estimates can facilitate clinical decision making when selecting and interpreting the results of noninvasive and invasive staging tests.

Study objectives: Patients with pulmonary arterial hypertension (PAH) often present with dyspnea and severe functional limitations, but their health-related quality of life (HRQOL) has not been studied extensively. This study describes HRQOL in a cohort of patients with PAH. Design: Cross-sectional study. Setting: A tertiary care, university hospital-based, pulmonary hypertension (PH) clinic. Participants: We studied HRQOL in 53 patients with PAH (mean age, 47 years; median duration of disease, 559 days). Eighty-three percent were women, 53% received epoprostenol, and 72% reported moderate-to-severe functional limitations with a New York Heart Association class 3 or 4 at enrollment. Measurements and results: We examined HRQOL by administering the Nottingham Health Profile, Congestive Heart Failure Questionnaire, and Hospital Anxiety and Depression Scale. We used the Visual Analog Scale and standard gamble (SG) techniques to measure preferences for current health (utilities). Compared with population norms, participants reported moderate-to-severe impairment in multiple domains of HRQOL, including physical mobility, emotional reaction, pain, energy, sleep, and social isolation. Mean SG utilities were 0.71, suggesting that, on average, participants were willing to accept a 29% risk of death in order to be cured of PH. Conclusions: PAH is a devastating condition that affects predominately young women in the prime of their life. Understanding HRQOL and preferences are important in the care and management of these patients. Compared with population norms, patients with PAH have substantial functional and emotional limitations that adversely affect their HRQOL.

Sepsis is a common cause of morbidity and death in critically ill patients, and blood culture samples are often drawn in an effort to identify a responsible pathogen. Blood culture results are usually negative, however, and even when positive are sometimes difficult to interpret. Distinguishing between true bacteremia and a false-positive blood culture result is important, but complicated by a variety of factors in the ICU. False-positive culture results are costly because they often prompt more diagnostic testing and more antibiotic prescriptions, and increase hospital length of stay. A number of factors influence the yield of blood cultures in critically ill patients, including the use of antibiotics, the volume of blood drawn, the frequency with which culture samples are drawn, and the site from which the culture samples are taken. Skin preparation techniques, handling of the cultures in the microbiology laboratory, and the type of blood culture system employed also influence blood culture yield. Attempts to identify predictors of true bacteremia in critically ill patients have been disappointing. In this review, we discuss factors that influence blood culture yield in critically ill patients, suggest ways to improve yield, and discuss true bacteremia vs false-positive blood culture results. We also discuss the costs and consequences of false-positive blood culture results, and list noninfectious causes of fever in the ICU.

Anthrax, a disease of great historical interest, is once again making headlines as an agent of biological warfare. Bacillus anthracis, a rod-shaped, spore-forming bacterium, primarily infects herbivores. Humans can acquire anthrax by agricultural or industrial exposure to infected animals or animal products. More recently, the potential for intentional release of anthrax spores in the environment has caused much concern. The common clinical manifestations of anthrax are cutaneous disease, pulmonary disease from inhalation of anthrax spores, and GI disease. The course of inhalational anthrax is dramatic, from the insidious onset of nonspecific influenza-like symptoms to severe dyspnea, hypotension, and hemorrhage within days of exposure. A rapid decline, culminating in septic shock, respiratory distress, and death within 24 h is not uncommon. The high mortality seen in inhalational anthrax is in part due to delays in diagnosis. Classic findings on the chest radiograph include widening of the mediastinum as well as pleural effusions. Pneumonia is less common; key pathologic manifestations include severe hemorrhagic mediastinitis, diffuse hemorrhagic lymphadenitis, and edema. Diagnosis requires a high index of suspicion. Treatment involves supportive care in an intensive care facility and high doses of penicillin. Resistance to third-generation cephalosporins has been noted. Vaccines are currently available and have been shown to be effective against aerosolized exposure in animal studies.