Docosatetraenoyl LPA is elevated in exhaled breath condensate in idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective medical therapies. Recent research has focused on identifying the biological processes essential to the development and progression of fibrosis, and on the mediators driving these processes. Lysophosphatidic acid (LPA), a biologically active lysophospholipid, is one such mediator. LPA has been found to be elevated in bronchoalveolar lavage (BAL) fluid of IPF patients, and through interaction with its cell surface receptors, it has been shown to drive multiple biological processes implicated in the development of IPF. Accordingly, the first clinical trial of an LPA receptor antagonist in IPF has recently been initiated. In addition to being a therapeutic target, LPA also has potential to be a biomarker for IPF. There is increasing interest in exhaled breath condensate (EBC) analysis as a non-invasive method for biomarker detection in lung diseases, but to what extent LPA is present in EBC is not known. Methods: In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess for the presence of LPA in the EBC and plasma from 11 IPF subjects and 11 controls. Results: A total of 9 different LPA species were detectable in EBC. Of these, docosatetraenoyl (22:4) LPA was significantly elevated in the EBC of IPF subjects when compared to controls (9.18 pM vs. 0.34 pM; p = 0.001). A total of 13 different LPA species were detectable in the plasma, but in contrast to the EBC, there were no statistically significant differences in plasma LPA species between IPF subjects and controls. Conclusions: These results demonstrate that multiple LPA species are detectable in EBC, and that 22:4 LPA levels are elevated in the EBC of IPF patients. Further research is needed to determine the significance of this elevation of 22:4 LPA in IPF EBC, as well as its potential to serve as a biomarker for disease severity and/or progression

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases

BACKGROUND Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD

Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis.

PurposeProne positioning for ARDS has been performed for decades without definitive evidence of clinical benefit. A recent multicenter trial demonstrated for the first time significantly reduced mortality with prone positioning. This meta-analysis was performed to integrate these findings with existing literature and test whether differences in tidal volume explain conflicting results among randomized trials.MethodsStudies were identified using MEDLINE, EMBASE, Cochrane Register of Controlled Trials, LILACS, and citation review. Included were randomized trials evaluating the effect on mortality of prone versus supine positioning during conventional ventilation for ARDS. The primary outcome was risk ratio of death at 60 days meta-analyzed using random effects models. Analysis stratified by high (>8 ml/kg predicted body weight) or low (≤ 8 ml/kg PBW) mean baseline tidal volume was planned a priori.ResultsSeven trials were identified including 2,119 patients, of whom 1,088 received prone positioning. Overall, prone positioning was not significantly associated with the risk ratio of death (RR 0.83; 95% CI 0.68-1.02; p = 0.073; I (2) = 64%). When stratified by high or low tidal volume, prone positioning was associated with a significant decrease in RR of death only among studies with low baseline tidal volume (RR 0.66; 95% CI 0.50-0.86; p = 0.002; I (2) = 25%). Stratification by tidal volume explained over half the between-study heterogeneity observed in the unstratified analysis.ConclusionsProne positioning is associated with significantly reduced mortality from ARDS in the low tidal volume era. Substantial heterogeneity across studies can be explained by differences in tidal volume

Air leak during CPAP titration as a risk factor for central apnea.

ObjectivesEmergence of central sleep apnea has been described in the setting of continuous positive airway pressure (CPAP) initiation. The underlying mechanism is unclear; however, we postulate that air leak washing out anatomical dead space is a contributing factor.DesignData were obtained from 310 patients with obstructive sleep apnea (OSA) who underwent either split-night or full-night CPAP titration during January to July of 2009. The majority (n = 245) underwent titration with a nasal mask. Average total leak and maximum total leak were measured at therapeutic CPAP level. Unintentional leak was calculated by subtracting manufacturer-defined intentional leak from maximum leak.ResultsSUBJECTS WERE DIVIDED INTO TWO GROUPS: central apnea index (CAI) during titration < 5/hour and ≥ 5/hour. The groups were similar in terms of gender, age, BMI, and AHI. The CAI < 5 group had a median average leak of 45.5 L/min (IQR 20.8 L/min) versus 51.0 L/min (IQR 21.0 L/min) with CAI ≥ 5 (p = 0.056). Maximum leak was 59.5 L/min (IQR 27.0 L/min) with CAI < 5 and 75.0 L/min (IQR 27.8 L/min) with CAI ≥ 5 (p = 0.003). In the subset of subjects titrated using a nasal mask, median average leak was 42.0 L/min (IQR 17.0) in the CAI < 5 group and 50.0 L/min (IQR 16.8) in the CAI ≥ 5 group (p = 0.001). In the CAI < 5 group, median maximum leak was 57.0 L/min (IQR 23.0) versus 74.5 L/min (IQR 24.3) in the CAI ≥ 5 group (p < 0.001).ConclusionsLeak during CPAP titration is associated with the development of acute central apnea; these data may have mechanistic and therapeutic implications for complex apnea.CommentaryA commentary on this article appears in this issue on page 1193