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OBJECTIVES:. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH. DESIGN:. Observational pilot study. SETTING:. Single-center tertiary academic ICU. PATIENTS:. Nine adults (≥ 18 yr) who fulfilled at least five of the eight HLH-2004 criteria. INTERVENTION:. Triplet regimen combining: 1) ruxolitinib, 2) polyvalent human IV immunoglobulins (IVIG) at a dose of 1 g/kg bodyweight for 5 days, and 3) high-dose corticosteroids (CSs, dexamethasone 10 mg/m² body surface area, or methylprednisolone equivalent) with subsequent tapering according to the HLH-2004 protocol. MEASUREMENT AND MAIN RESULTS:. Nine patients (median age: 42 yr [25th-75th percentile: 32–54]; male: n = 6 males, median H-score: 299 [255–304]) were treated with the triplet regimen. The median Sequential Organ Failure Assessment score at HLH diagnosis was 9 (median; 25th–75th percentile: 7–12), indicating multiple-organ dysfunction in all patients. Within 10 days a significant decrease of the inflammatory parameters soluble interleukin-2 receptor and ferritin as well as a stabilization of the blood count could be shown. All patients were alive at ICU discharge (100% ICU survival), 1 patient died after ICU discharge because of traumatic intracerebral hemorrhage that might be related to HLH or treatment, corresponding to an overall survival of 86% in a 6 months follow-up period. CONCLUSION:. In this small case series, a triplet regimen of ruxolitinib in combination with IVIG and CS was highly effective and save for treating critically ill adults with sHLH.

Purpose: We evaluated the efficacy and safety of roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, for chemotherapy-induced anemia (CIA) in patients with nonmyeloid malignancies receiving multicycle treatments of chemotherapy., Patients and Methods: In this open-label, noninferiority phase III study conducted at 44 sites in China, 159 participants age ≥18 years with CIA nonmyeloid malignancy and CIA were randomly assigned (1:1) to oral roxadustat or subcutaneous recombinant human erythropoietin-α (rHuEPO-α) three times a week for 12 weeks. Roxadustat starting dosages were 100, 120, and 150 mg three times a week for participants weighing 40-<50, 50-60, and >60 kg, respectively. rHuEPO-α starting dosage for all participants was 150 IU/kg three times a week. Both roxadustat and rHuEPO-α dosages could be modified. The primary end point was least-squares mean (LSM) change in hemoglobin (Hb) concentration from baseline to the concentration averaged over weeks 9-13., Results: Of the 159 participants randomly assigned, 140 were included in the per-protocol set (roxadustat, n = 78; rHuEPO-α, n = 62). The LSM (95% two-sided CI) change from baseline to weeks 9-13 in Hb concentration was 17.1 (13.58 to 20.71) g/L with roxadustat and 15.4 (11.34 to 19.50) g/L with rHuEPO-α (mean difference [95% CI], 1.7 [-3.39 to 6.84]). The lower bound of the one-sided 97.5% CI for the treatment difference (‒3.4 g/L) was greater than the predefined noninferiority margin of ‒6.6 g/L, establishing noninferiority. Noninferiority was supported by five of six key secondary end points. Rates of adverse events were generally comparable between treatments and consistent with previous findings., Conclusion: Roxadustat was noninferior to rHuEPO-α in treating CIA in participants with nonmyeloid malignancies receiving multicycle treatments of myelosuppressive chemotherapy. The oral formulation of roxadustat may potentially increase compliance.

Background: Quality improvement initiatives improve health care delivery but may be resource intensive and disrupt clinical care. An embedded heart failure order set (HFOS) within a computerized physician order-entry system may mitigate these concerns. Methods: An HFOS, based on proven interventions, was implemented within an existing computerized physician order-entry system in all adult acute-care hospitals in a single Canadian metropolitan city and interrogated between January 1, 2013 and December 31, 2015. The composite of repeat hospitalization or death within 30 days of hospital discharge and hospital length of stay were reported. Results: In total, 8969 patients were included with mean age 75.6 ± 13.5 years; 4673 (52.1%) were male. The HFOS was used in 731 (8.2%) patients. After analysis of 724 pairs of propensity-score matched cohorts, patients with HFOS use experienced a lower median length of stay (8.6 vs 9.4 days, P = 0.016) and a trend toward lower composite repeat hospitalization or death (14.5% vs 17.7%, P = 0.115, hazard ratio 0.79 (0.60–1.05). Patients with HFOS use were more likely to undergo a test for left ventricular ejection fraction (88.6% vs 76.7%, P < 0.001, and to be referred to a heart failure clinic (48.5% vs 6.3%), with similar rates of discharge prescription of beta-blockers (88.7% vs 86.3) and angiotensin-converting enzyme inhibitors (87.4% vs 89.0%). Conclusions: Use of a designated HFOS within a computerized physician order-entry system is associated with shorter hospital length of stay without increase in deaths or readmissions. These findings should be confirmed in a prospective controlled trial. Résumé: Contexte: Les initiatives visant à l'amélioration de la qualité favorisent la prestation des soins de santé, mais elles peuvent nécessiter beaucoup de ressources et perturber les soins cliniques. Un ensemble d’ordonnances relatives à l’insuffisance cardiaque (HFOS pour heart failure order set) intégré dans un système informatisé de saisie des ordonnances des médecins pourrait atténuer ces préoccupations. Méthodes: Un HFOS, basé sur des interventions éprouvées, a été mis en place au sein d’un système informatisé de saisie d’ordonnances médicales existant dans tous les hôpitaux de soins actifs pour adultes d'une même métropole canadienne et a été interrogé entre le 1er janvier 2013 et le 31 décembre 2015. Les données combinées de réadmission ou de décès pour les 30 jours suivant la sortie de l'hôpital et la durée du séjour à l'hôpital ont été répertoriées. Résultats: Au total, 8 969 patients ont été inclus avec un âge moyen de 75,6 ± 13,5 ans ; 4 673 (52,1 %) étaient des hommes. Le HFOS a été utilisé pour 731 (8,2 %) patients. Après analyse de 724 paires de cohortes appariées par score de propension, les patients associés à l’usage du HFOS ont connu une durée médiane de séjour hospitalier plus faible (8,6 contre 9,4 jours, p = 0.016) et une tendance combinée de réadmission ou de décès plus faible (14,5 % contre 17,7 %, p = 0,115, rapport de risque 0,79 (0,60-1,05). Les patients associés à l’usage du HFOS étaient plus susceptibles de subir un examen pour mesurer leur fraction d'éjection ventriculaire gauche (88,6 % contre 76,7 %, p < 0,001, et d'être orientés vers une clinique d'insuffisance cardiaque (48,5 % contre 6,3 %), avec des taux similaires de prescription à la sortie de bêta-bloquants (88,7 % contre 86,3 %) et d'inhibiteurs de l'enzyme de conversion de l'angiotensine (87,4 % contre 89,0 %). Conclusions: L'utilisation d'un HFOS particulier dans un système informatisé de saisie d’ordonnances médicales est associée à une réduction de la durée du séjour hospitalier sans augmentation des décès ou des réadmissions. Ces résultats devraient être confirmés dans le cadre d'un essai comparatif prospectif.

Because the morbidity and mortality from adult asthma have been increasing, the identification of modifiable environmental exposures that exacerbate asthma has become a priority. Limited evidence suggests that exposure to environmental tobacco smoke (ETS) may adversely affect adults with asthma. To study the effects of ETS better, we developed a survey instrument to measure ETS exposure in a cohort of adults with asthma living in northern California, where public indoor smoking is limited. To validate this survey instrument, we used a passive badge monitor that measures actual exposure to ambient nicotine, a direct and specific measure of ETS. In this validation study, we recruited 50 subjects from an ongoing longitudinal asthma cohort study who had a positive screening question for ETS exposure or potential exposure. Each subject wore a passive nicotine badge monitor for 7 days. After the personal monitoring period, we readministered the ETS exposure survey instrument. Based on the survey, self-reported total ETS exposure duration ranged from 0 to 70 hr during the previous 7 days. Based on the upper-range boundary, bars or nightclubs (55 hr) and the home (50 hr) were the sites associated with greatest maximal self-reported exposure. As measured by the personal nicotine badge monitors, the overall median 7-day nicotine concentration was 0.03 microg/m(3) (25th-75th interquartile range 0-3.69 microg/m(3)). Measured nicotine concentrations were highest among persons who reported home exposure (median 0.61 microg/m(3)), followed by work exposure (0.03 microg/m(3)), other (outdoor) exposure (0.025 microg/m(3)), and no exposure (0 microg/m(3); p = 0.03). The Spearman rank correlation coefficient between self-reported ETS exposure duration and directly measured personal nicotine concentration during the same 7-day period was 0.47, supporting the survey's validity (p = 0.0006). Compared to persons with no measured exposure, lower-level [odds ratio (OR) 1.9; 95% confidence interval (CI), 0.4-8.8] and higher-level ETS exposures (OR 6.8; 95% CI, 1.4-32.3) were associated with increased risk of respiratory symptoms. A brief, validated survey instrument can be used to assess ETS exposure among adults with asthma, even with low levels of exposure. This instrument could be a valuable tool for studying the effect of ETS exposure on adult asthma health outcomes.

BackgroundThe morbidity and mortality from asthma have markedly increased since the late 1970s. The hospitalization rate, an important marker of asthma severity, remains substantial.MethodsIn adults with health care access, we prospectively studied 242 with asthma, aged 18-50 years, recruited from a random sample of allergy and pulmonary physician practices in Northern California to identify risk factors for subsequent hospitalization.ResultsThirty-nine subjects (16%) reported hospitalization for asthma during the 18-month follow-up period. On controlling for asthma severity in multiple logistic regression analysis, non-white race (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.8) and lower income (OR, 1.1 per $10,000 decrement; 95% CI, 0.9-1.3) were associated with a higher risk of asthma hospitalization. The severity-of-asthma score (OR, 3.4 per 5 points; 95%, CI 1.7-6.8) and recent asthma hospitalization (OR, 8.3; 95%, CI, 2.1-33.4) were also related to higher risk, after adjusting for demographic characteristics. Reliance on emergency department services for urgent asthma care was also associated with a greater likelihood of hospitalization (OR, 3.2; 95% CI, 1.0-9.8). In multivariate analysis not controlling for asthma severity, low income was even more strongly related to hospitalization (OR, 1.2 per $10,000 decrement; 95% CI, 1.02-1.4).ConclusionIn adult asthmatics with access to health care, non-white race, low income, and greater asthma severity were associated with a higher risk of hospitalization. Targeted interventions applied to high-risk asthma patients may reduce asthma morbidity and mortality.

Summary:. In recent years, there has been a growing emphasis placed on reducing length of hospital stay and health costs associated with breast surgery. Adequate pain control is an essential component of enhanced recovery after surgery. Postoperative pain management strategies include use of narcotic analgesia, non-narcotic analgesia, and local anesthetics. However, these forms of pain control have relatively brief durations of action and multiple-associated side effects. Intraoperative regional blocks have been effectively utilized in other areas of surgery but have been understudied in breast surgery. The aim of this article was to review various intraoperative techniques for regional anesthesia and local pain control in breast surgery and to highlight areas of future technique development.

Background: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases., Methods: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging., Results: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was -4.2 (0.7) (95% CI -5.5, -2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation., Conclusions: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results.

Cigarette smoking increases the risk of acute respiratory distress syndrome (ARDS; Calfee CS, Matthay MA, Eisner MD, Benowitz N, Call M, Pittet J-F, Cohen MJ. Am J Respir Crit Care Med 183: 1660-1665, 2011; Calfee CS, Matthay MA, Kangelaris KN, Siew ED, Janz DR, Bernard GR, May AK, Jacob P, Havel C, Benowitz NL, Ware LB. Crit Care Med 43: 1790-1797, 2015; Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirschler N, Sanchez Rosen R, Matthay MA, TRALI Study Group. Blood 119: 1757-1767, 2012) and causes emphysema. However, it is not known why some individuals develop disease, whereas others do not. We found that smoke-exposed AKR mice were more susceptible to lipopolysaccharides (LPS)-induced acute lung injury (ALI) than C57BL/6 mice (Sakhatskyy P, Wang Z, Borgas D, Lomas-Neira J, Chen Y, Ayala A, Rounds S, Lu Q. Am J Physiol Lung Cell Mol Physiol 312: L56-L67, 2017); thus, we investigated strain-dependent lung transcriptomic responses to cigarette smoke (CS). Eight-week-old male AKR and C57BL/6 mice were exposed to 3 wk of room air (RA) or cigarette smoke (CS) for 6 h/day, 4 days/wk, followed by intratracheal instillation of LPS or normal saline (NS) and microarray analysis of lung homogenate gene expression. Other groups of AKR and C57 mice were exposed to RA or CS for 6 wk, followed by evaluation of static lung compliance and tissue elastance, morphometric evaluation for emphysema, or microarray analysis of lung gene expression. Transcriptomic analyses of lung homogenates show distinct strain-dependent lung transcriptional responses to CS and LPS, with AKR mice having larger numbers of genes affected than similarly treated C57 mice, congruent with strain differences in physiologic and inflammatory parameters previously observed in LPSinduced ALI after CS priming. These results suggest that genetic differences may underlie differing susceptibility of smokers to ARDS and emphysema. Strain-based differences in gene transcription contribute to CS and LPS-induced lung injury. There may be a genetic basis for smoking-related lung injury. Clinicians should consider cigarette smoke exposure as a risk factor for ALI and ARDS. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS)., Objectives: Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI., Methods: The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination., Results: This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs)., Conclusion: However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, in-silico approaches, and drug repurposing., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Rationale: Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation., Objectives: To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value., Methods: The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value., Results: From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person-years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm., Conclusions: A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non-IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF.

Background: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies., Objective: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS., Methods: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events., Results: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non-omalizumab group (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non-omalizumab-treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non-omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91)., Conclusion: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non-omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Second-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD., Methods: Among the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity., Results: Of the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George's Respiratory Questionnaire score (SGRQ, β 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (β 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (β 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, β 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes., Conclusion: Individuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS., Trial Registration Number: NCT01969344 (clinicaltrials.gov)., Competing Interests: DPT has provided consulting services for AstraZeneca, Sunovion, Mylan, Novartis, Glenmark, Theravance, has been a speaker for AstraZeneca, Sunovion, and Boehringer-Ingelheim, and has received research grants from Boehringer-Ingelheim, Sunovion, and GlaxoSmithKlline. The remainder of the authors report no significant interests to disclose., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, and diffuse alveolar damage (DAD) is considered its histological hallmark. Sepsis is one of the most common aetiology of ARDS with the highest case-fatality rate. Identifying ARDS patients and differentiate them from other causes of acute respiratory failure remains a challenge. To address this, many studies have focused on identifying biomarkers that can help assess lung epithelial injury. However, there is scarce information available regarding the tissue expression of these markers. Evaluating the expression of elafin, RAGE, and SP-D in lung tissue offers a potential bridge between serological markers and the underlying histopathological changes. Therefore, we hypothesize that the expression of epithelial injury markers varies between sepsis and ARDS as well as according to its severity., Methods: We compared the post-mortem lung tissue expression of the epithelial injury markers RAGE, SP-D, and elafin of patients that died of sepsis, ARDS, and controls that died from non-pulmonary causes. Lung tissue was collected during routine autopsy and protein expression was assessed by immunohistochemistry. We also assessed the lung injury by a semi-quantitative analysis., Results: We observed that all features of DAD were milder in septic group compared to ARDS group. Elafin tissue expression was increased and SP-D was decreased in the sepsis and ARDS groups. Severe ARDS expressed higher levels of elafin and RAGE, and they were negatively correlated with PaO 2 /FiO 2 ratio, and positively correlated with bronchopneumonia percentage and hyaline membrane score. RAGE tissue expression was negatively correlated with mechanical ventilation duration in both ARDS and septic groups. In septic patients, elafin was positively correlated with ICU admission length, SP-D was positively correlated with serum lactate and RAGE was correlated with C-reactive protein., Conclusions: Lung tissue expression of elafin and RAGE, but not SP-D, is associated with ARDS severity, but does not discriminate sepsis patients from ARDS patients., (© 2024. The Author(s).)

Background: Inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy.Objective: To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy.Design: Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575).Setting: 193 investigational sites in the United States and 4 sites in Canada.Patients: 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers.Intervention: Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks.Measurements: The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events.Results: During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively.Limitations: The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup.Conclusion: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy.Primary Funding Source: Genentech and Novartis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.Objectives: To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.Methods: Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.Measurements and Main Results: APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.Conclusions: APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity. [ABSTRACT FROM AUTHOR]

Objective: Patients with trauma-associated acute lung injury have better outcomes than patients with other clinical risks for lung injury, but the mechanisms behind these improved outcomes are unclear. We sought to compare the clinical and biological features of patients with trauma-associated lung injury with those of patients with other risks for lung injury and to determine whether the improved outcomes of trauma patients reflect their baseline health status or less severe lung injury, or both.Design, Setting, and Patients: Analysis of clinical and biological data from 1,451 patients enrolled in two large randomized, controlled trials of ventilator management in acute lung injury.Measurements and Main Results: Compared with patients with other clinical risks for lung injury, trauma patients were younger and generally less acutely and chronically ill. Even after adjusting for these baseline differences, trauma patients had significantly lower plasma levels of intercellular adhesion molecule-1, von Willebrand factor antigen, surfactant protein-D, and soluble tumor necrosis factor receptor-1, which are biomarkers of lung epithelial and endothelial injury previously found to be prognostic in acute lung injury. In contrast, markers of acute inflammation, except for interleukin-6, and disordered coagulation were similar in trauma and nontrauma patients. Trauma-associated lung injury patients had a significantly lower odds of death at 90 days, even after adjusting for baseline clinical factors including age, gender, ethnicity, comorbidities, and severity of illness (odds ratio, 0.44; 95% confidence interval, 0.24-0.82; p = .01).Conclusions: Patients with trauma-associated lung injury are less acutely and chronically ill than other lung injury patients; however, these baseline clinical differences do not adequately explain their improved outcomes. Instead, the better outcomes of the trauma population may be explained, in part, by less severe lung epithelial and endothelial injury. [ABSTRACT FROM AUTHOR]

Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI).Objectives: We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower VT would reduce urine NO as a result of less stretch injury.Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg VT ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr).Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure-free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg VT group (p = 0.04).Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg VT strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Airways Questionnaire 20 (AQ20) is a concise measure of health-related quality of life (HRQL) in obstructive airway disease; however, its original format may underestimate impairment due to the complete cessation of certain activities. METHODS: We revised seven items of the original AQ20 (revised AQ20 [AQ20-R]), adding response options for inability to perform certain activities. We assessed the performance of the AQ20-R among 352 adults with various airway conditions identified through a random telephone sample. Concurrent validity of the AQ20-R was assessed relative to the Short Form-12 (SF-12) physical component summary (PCS), FEV(1), and medication use. Predictive validity was assessed relative to health-care utilization among 278 subjects studied longitudinally. RESULTS: Twenty-one of 352 subjects were unable to perform at least one activity. These subjects demonstrated higher AQ20-R scores (p < 0.001) indicating worse HRQL. Mean (+/- SD) AQ20-R scores differed significantly (p < 0.001) among subjects with COPD (8.9 +/- 5.2), asthma (6.7 +/- 5.0), and chronic bronchitis (4.7 +/- 4.2). At baseline, the AQ20-R correlated with the SF-12 PCS (r = - 0.55, p < 0.001) and FEV(1) (r = - 0.43, p < 0.001), and was associated with the use of respiratory-specific therapies (p

OBJECTIVE: We sought to study the combined effects of multiple home indoor environmental exposures in adult asthma and rhinitis. METHODS: We studied 226 adults with asthma and rhinitis by structured interviews and home assessments. Environmental factors included dust allergen, endotoxin and glucan concentrations, and indoor air quality (IAQ) variables. Outcomes included forced expiratory volume in 1 second (FEV1) percent predicted, Severity of Asthma Score (SAS), Short-Form (SF)-12 Physical Component Scale (PCS), and asthma Quality of Life (QOL) score. RESULTS: House dust-associated exposures together with limited IAQ variables were related to FEV1 % predicted (R = 0.24; P = 0.0001) and SAS (R = 0.18; P = 0.007). IAQ and limited dust variables were associated with SF-12 PCS (R = 0.15; P = 0.02), but not QOL (R = 0.13; P = 0.16). CONCLUSIONS: The home environment is strongly linked to lung function, health status, and disease severity in adult asthma and rhinitis. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of mechanical ventilation with a tidal volume of 6 mL/kg compared with 12 mL/kg predicted body weight on hemodynamics, vasopressor use, fluid balance, diuretics, sedation, and neuromuscular blockade within 48 hrs in patients with acute lung injury and acute respiratory distress syndrome.Design: Retrospective analysis of a previously conducted randomized, clinical trial.Setting: Two adult intensive care units at a tertiary university medical center and a large county hospital.Patients: One hundred eleven patients who were enrolled in the National Institutes of Health ARDS Network trial at the University of California, San Francisco.Interventions: None.Measurements and Main Results: Compared with 12 mL/kg predicted body weight, treatment with a tidal volume of 6 mL/kg predicted body weight had no adverse effects on hemodynamics. There were also no differences in the need for supportive therapies, including vasopressors, intravenous fluids, or diuretics. In addition, there were no differences in body weight, urine output, and fluid balance. Finally, there was no difference in the need for sedation or neuromuscular blockade between the two tidal volume protocols.Conclusions: When compared with ventilation with 12 mL/kg predicted body weight, patients treated with the lung-protective 6 mL/kg predicted body weight tidal volume protocol had no difference in their supportive care requirements. Therefore, concerns regarding potential adverse effects of this protocol should not preclude its use in patients with acute lung injury or the acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association between interleukin-6, interleukin-8, and interleukin-10 and clinical outcomes including mortality in patients with acute lung injury and to determine whether lower tidal volume ventilation was associated with a decrease in plasma cytokines in patients with acute lung injury.Design: Multiple-center, randomized trial.Setting: Intensive care units in ten university centers.Patients: The study included 861 patients enrolled in the National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for acute lung injury.Interventions: Patients were randomized to a 6 mL/kg or a 12 mL/kg tidal volume strategy that has been previously described.Measurements and Main Results: Baseline plasma levels of interleukin-6, interleukin-8, and interleukin-10 were each associated with an increased risk of death in both logistic regression analyses controlling for ventilator group (odds ratio 1.63 per log-10 increment, 95% confidence interval 1.33-1.98; odds ratio 2.33 per log-10 increment, 95% confidence interval 1.79-3.03; odds ratio 2.02 per log-10 increment, 95% confidence interval 1.47-2.76, respectively) and multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, platelet count, and vasopressor use (odds ratio 1.63 per log-10 increment, 95% confidence interval 0.93-1.49; odds ratio 1.73 per log-10 increment, 95% confidence interval 1.29-2.34; odds ratio 1.23 per log-10 increment, 95% confidence interval 0.86-1.76, respectively). Interleukin-6 and interleukin-8 levels were also associated with a significant decrease in ventilator free and organ failure free days. Patients with sepsis had the highest cytokine levels and the greatest risk of death per cytokine elevation. By day 3, the 6 mL/kg strategy was associated with a greater decrease in interleukin-6 and interleukin-8 levels. There was a 26% reduction in interleukin-6 (95% confidence interval, 12-37%) and a 12% reduction in interleukin-8 (95% confidence interval, 1-23%) in the 6 mL/kg group compared with the 12 mL/kg group.Conclusions: In patients with acute lung injury, plasma interleukin-6 and interleukin-8 levels are associated with morbidity and mortality. The severity of inflammation varies with clinical risk factor, suggesting that clinical risk factor should be considered when both developing and testing therapeutic interventions. Low tidal volume ventilation is associated with a more rapid attenuation of the inflammatory response. [ABSTRACT FROM AUTHOR]

Systemic endothelial activation and injury are important causes of multiorgan system failure. We hypothesized that plasma levels of von Willebrand factor (VWF), a marker of endothelial activation and injury, would be associated with clinical outcomes in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In 559 patients with ALI/ARDS enrolled in the National Heart, Lung, and Blood Institute ARDS Network trial of two VT strategies, plasma VWF levels were measured at randomization (mean 350 +/- 265% of normal control plasma) and Day 3 (344 +/- 207%). Baseline VWF levels were similar in patients with and without sepsis, and were significantly higher in nonsurvivors (435 +/- 333%) versus survivors (306 +/- 209%) even when controlling for severity of illness, sepsis, and ventilator strategy (increased odds ratio of death of 1.6 per SD size increase in VWF; 95% confidence interval, 1.4-2.1). Higher VWF levels were also significantly associated with fewer organ failure-free days. Ventilator strategy had no effect on VWF levels. In conclusion, the degree of endothelial activation and injury is strongly associated with outcomes in ALI/ARDS, regardless of the presence or absence of sepsis, and is not modulated by a protective ventilatory strategy. To improve outcomes further, new treatment strategies targeted at the endothelium should be investigated. [ABSTRACT FROM AUTHOR]

Background: Asthma and rhinosinusitis are common medical conditions among adults. Alternative treatments could have important impacts on health status among those individuals with these conditions, but specific prevalence data for these treatments are limited.Objective: To estimate the prevalence of specific alternative treatment modalities, including herbal agents, ingestion of caffeinated beverages, homeopathy, acupuncture, and massage therapies.Design: Random population telephone sample.Setting: Northern California.Participants: Three hundred adults aged 18 to 50 years with self-report of a physician diagnosis of asthma (n = 125) or rhinosinusitis without concomitant asthma (n = 175).Measurements: Structured telephone interviews covering demographics and clinical variables, including the following alternative treatments used in the previous 12 months: herbal agents; caffeine-containing products; homeopathy; acupuncture; aromatherapy; reflexology; and massage.Results: Any alternative practice was reported by 127 subjects (42%; 95% confidence interval [CI], 36 to 48%). Of these, 33 subjects (26%; 95% CI, 21 to 31%) were not current prescription medication users. Herbal use was reported by 72 subjects (24%), caffeine treatment by 54 subjects (18%), and other alternative treatments by 66 subjects (22%). Taking into account demographic variables, subjects with asthma were more likely than those with rhinitis alone to report caffeine self-treatment for their condition (odds ratio, 2.5; 95% CI, 1.4 to 4.8%), but herbal use and other alternative treatments did not differ significantly by condition group.Conclusion: Alternative treatments are frequent among adults with asthma or rhinosinusitis and should be taken into account by health-care providers and public health and policy analysts. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: To examine the association between exposure to environmental tobacco smoke (ETS) and demographic, lifestyle, occupational characteristics and self reported health conditions. DESIGN: Cross sectional study, using data from multiphasic health checkups between 1979 and 1985. SETTING: Large health plan in Northern California, USA. PARTICIPANTS: 16 524 men aged 15-89 years and 26 197 women aged 15-105 years who never smoked. RESULTS: Sixty eight per cent of men and 64 per cent of women reported any current ETS exposure (at home, in small spaces other than home or in large indoor areas). The exposure time from all three sources of ETS exposure correlated negatively with age. Men and women reporting high level ETS exposure were more likely to be black and never married or separated/divorced, to have no college or partial college education, to consume three alcoholic drink/day or more and to report exposure to several occupational hazards. Consistent independent relations across sexes were found between any current exposure to ETS and a positive history of hay fever/asthma (odds ratio (OR)=1.22 in men, 1.14 in women), hearing loss (OR=1.30 in men, 1.27 in women), severe headache (OR=1.22 in men, 1.17 in women), and cold/flu symptoms (OR=1.52 in men, 1.57 in women). Any current ETS exposure was also associated with chronic cough (OR=1.22) in men and with heart disease (OR=1.10) in women. Self reported stroke was inversely associated with any current ETS exposure in men (OR=0.27). No associations were noted for cancer or tumour and for migraine. CONCLUSION: ETS exposure correlated with several personal characteristics potentially associated with adverse health outcomes. Although the study design precluded causal inference, ETS exposure was associated with several self reported acute and chronic medical conditions. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Because they experience respiratory symptoms, adults with asthma might be expected to avoid cigarette smoking. However, previous studies have not adequately addressed whether adults with asthma have a lower prevalence of smoking than the general population. The authors sought to determine whether adult asthmatics are less likely to smoke cigarettes than members of the general population. METHODS: The authors used data from a random sample of 2,902 California adults ages 18 years or older,with oversampling of African Americans, Asian/Pacific Islanders, adults with disabilities, and adults aged 45 to 70 years. Sampling weights were used in all analyses. In this cross-sectional study, 217 participants (7.5%) reported a physician diagnosis of asthma. RESULTS: The prevalence of 'ever smoking' was similar among adults with asthma (48.3%) and those without asthma (43.0%) (risk difference 5.3%; 95% CI -1.6%, 12.2%). There was also no difference in the prevalence of 'current smoking' among adults with asthma (20.2%) compared with the non-asthmatic subjects (18.8%) (risk difference 1.4%; 95% CI -4.2%, 6.9%). After controlling for age, gender, race, and education, there was no evidence that adults with asthma were less likely to ever smoke. Although the confidence intervals did not exclude 'no association,' asthma was actually associated with an increased risk of ever smoking (OR 1.3; 95% CI 1.0, 1.8). There was also no association between asthma and the risk of current smoking after controlling for covariates (OR 1.1; 95% CI 0.8, 1.6). Moreover, there were no differences in 'age of smoking initiation,' 'duration of smoking,' or 'intensity of smoking' after adjusting for demographic characteristics. Redefining the referent group to exclude respondents with other chronic lung diseases did not appreciably change study conclusions. CONCLUSION: Adults with asthma do not appear to selectively avoid cigarette smoking. Specific smoking prevention and cessation efforts should be targeted to adults with asthma. [ABSTRACT FROM AUTHOR]

A 44-year-old man presented to the accident and emergency department with chest pain and shortness of breath. Admission ECG revealed ischaemic changes. He had markedly elevated troponin T and a severely impaired left ventricular ejection fraction with regional motion wall abnormalities. He was initially treated in intensive care for acute myocardial infarction. When his renal function improved, an angiogram was performed, which showed unobstructed coronary arteries. He was later found to have a phaeochromocytoma. This case illustrates a rare diagnosis presenting with common symptoms that could easily have been missed. On admission to hospital, patients can easily be labelled with a diagnosis and put on a treatment pathway, such as acute coronary syndrome. It is important for clinicians to keep an open mind and be prepared to review the diagnosis if the history does not fit., (2015 BMJ Publishing Group Ltd.)