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Dupilumab efficacy and safety in children aged 6–11 years with uncontrolled, moderate-to-severe asthma were shown in the VOYAGE study—a 52-week, multinational, multicentre, phase 3 randomised, double-blind, placebo-controlled trial. We aimed to evaluate the long-term safety and efficacy of dupilumab in children with moderate-to-severe asthma who previously participated in the VOYAGE study.

Study objectives: There are no studies focused on skeletal status in patients with diffuse parenchymal lung disease (DPLD). We hypothesized that patients with DPLD referred for lung transplantation would have [...]

Dupilumab, a biological therapy that blocks the shared receptor component for interleukins-4/13, reduced exacerbations and improved lung function in children with uncontrolled moderate-to-severe type 2 asthma independent of most baseline patient and asthma characteristics.

In phase 3 VOYAGE (NCT02948959), dupilumab showed clinical efficacy with an acceptable safety profile in children aged 6 to 11 years with uncontrolled moderate to severe type 2 asthma (blood eosinophils ≥150 cells/μL or FeNO ≥20 ppb).

BackgroundIdentifying subtypes of acute respiratory failure survivors may facilitate patient selection for post-intensive care unit (ICU) follow-up clinics and trials.MethodsWe conducted a single-centre prospective cohort study of 185 acute respiratory failure survivors, aged [Formula]65 years. We applied latent class modelling to identify frailty subtypes using frailty phenotype and cognitive impairment measurements made during the week before hospital discharge. We used Fine-Gray competing risks survival regression to test associations between frailty subtypes and recovery, defined as returning to a basic Activities of Daily Living disability count less than or equal to the pre-hospitalisation count within 6 months. We characterised subtypes by pre-ICU frailty (Clinical Frailty Scale score [Formula]5), the post-ICU frailty phenotype, and serum inflammatory cytokines, hormones and exosome proteomics during the week before hospital discharge.ResultsWe identified five frailty subtypes. The recovery rate decreased 49% across each subtype independent of age, sex, pre-existing disability, comorbidity and Acute Physiology and Chronic Health Evaluation II score (recovery rate ratio: 0.51, 95% CI 0.41 to 0.63). Post-ICU frailty phenotype prevalence increased across subtypes, but pre-ICU frailty prevalence did not. In the subtype with the slowest recovery, all had cognitive impairment. The three subtypes with the slowest recovery had higher interleukin-6 levels (p=0.03) and a higher prevalence of [Formula]2 deficiencies in insulin growth factor-1, dehydroepiandrostersone-sulfate, or free-testosterone (p=0.02). Exosome proteomics revealed impaired innate immunity in subtypes with slower recovery.ConclusionsFrailty subtypes varied by prehospitalisation frailty and cognitive impairment at hospital discharge. Subtypes with the slowest recovery were similarly characterised by greater systemic inflammation and more anabolic hormone deficiencies at hospital discharge.

Adipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults.

At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD.

CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI −20 to −8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI −21 to −10). CT imaging may improve candidate risk stratification.

Connective tissue growth factor (CTGF) is a secreted glycoprotein that has a central role in the process of fibrosis. This study was designed to assess the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a fully recombinant human monoclonal antibody against CTGF, in idiopathic pulmonary fibrosis. The aim was to establish whether pamrevlumab could slow, stop, or reverse progression of idiopathic pulmonary fibrosis.

Frailty is a state of decreased physiologic reserve associated with poor outcomes before and after lung transplantation. Obesity, particularly central obesity characterized by excess proinflammatory visceral adipose tissue (VAT), is associated with incident frailty in middle-aged and older adults. The association between VAT and frailty in advanced lung disease, however, is unknown. In two, nonoverlapping multicenter cohorts of adults listed for lung transplantation, we measured VAT area on bioelectrical impedance assay (BIA) in one cohort and cross-sectional VAT and subcutaneous adipose tissue (SAT) areas on abdominal computed tomography (CT) in the other. We identified a nonlinear relationship between greater VAT by BIA and frailty. In fully adjusted piecewise regression models, every 20 cm2increase in VAT area was associated with 50% increased odds of frailty in subjects with high VAT (95% CI 1.2-1.9, P< .001), and 10% decreased odds of frailty (95% CI 0.7-1.04, P= .12) in subjects with low VAT. Compared to frail subjects with low VAT, those with high VAT were more likely to have low grip strength and less likely to have weight loss, suggesting that mechanisms of frailty may differ by VAT. Further investigation of mechanisms linking VAT and frailty may identify new targets for prevention and treatment.

Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF.

In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test.

Solid organ transplantation disrupts virus-host relationships, potentially resulting in viral transfer from donor to recipient, reactivation of latent viruses, and new viral infections. Viral transfer, colonization, and reactivation are typically monitored using assays for specific viruses, leaving the behavior of full viral populations (the “virome”) understudied. Here we sought to investigate the temporal behavior of viruses from donor lungs and transplant recipients comprehensively. We interrogated the bronchoalveolar lavage and blood viromes during the peritransplant period and 6-16 months posttransplant in 13 donor-recipient pairs using shotgun metagenomic sequencing. Anelloviridae, ubiquitous human commensal viruses, were the most abundant human viruses identified. Herpesviruses, parvoviruses, polyomaviruses, and bacteriophages were also detected. Anelloviridae populations were complex, with some donor organs and hosts harboring multiple contemporaneous lineages. We identified transfer of Anelloviridae lineages from donor organ to recipient serum in 4 of 7 cases that could be queried, and immigration of lineages from recipient serum into the allograft in 6 of 10 such cases. Thus, metagenomic analyses revealed that viral populations move between graft and host in both directions, showing that organ transplantation involves implantation of both the allograft and commensal viral communities.

Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown.

Type 2 inflammation is common in children with asthma. Dupilumab, a human antibody, blocks the signaling of interleukin -4 and -13, key and central drivers of type 2 inflammation. In the LIBERTY ASTHMA VOYAGE (NCT02948959) study, dupilumab reduced severe asthma exacerbations and improved lung function in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma.

David J Lederer, MD(*) and Ivor S Douglas, MD. Department of Medicine, New York Presbyterian Hospital, New York City, NY and Department of Pulmonary, Allergy, and Critical Care New York [...]

In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB(n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score–adjusted Cox models. We calculated postestimation marginalized standardized risks for 1‐year mortality by frailty status using multivariate logistic regression. SPPBfrailty was associated with an increased risk of both 1‐ and 4‐year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6‐36.0 and aHR3.8; 95%CI: 1.8‐8.0, respectively). Each 1‐point worsening in SPPBwas associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08‐1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%‐21%). In secondary analyses, FFPfrailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1‐13.2) but not over longer follow‐up. Preoperative frailty is associated with an increased risk of death after lung transplantation. In this multicenter prospective cohort study, preoperative physical frailty is independently associated with a substantially higher risk of mortality after lung transplantation.

We aimed to examine short- and long-term mortality in a mixed population of patients with interstitial lung disease (ILD) with acute respiratory failure, and to identify those at lower vs higher risk of in-hospital death.

Despite the importance of pretransplantation outcomes, 1‐year posttransplantation survival is typically considered the primary metric of lung transplant center performance in the United States. We designed a novel lung transplant center performance metric that incorporates both pre‐ and posttransplantation survival time. We performed an ecologic study of 12 187 lung transplant candidates listed at 56 U.S. lung transplant centers between 2006 and 2012. We calculated an “intention‐to‐treat” survival (ITTS) metric as the percentage of waiting list candidates surviving at least 1 year after transplantation. The median center‐level 1‐year posttransplantation survival rate was 84.1%, and the median center‐level ITTSwas 66.9% (mean absolute difference 19.6%, 95% limits of agreement 4.3 to 35.1%). All but 10 centers had ITTSvalues that were significantly lower than 1‐year posttransplantation survival rates. Observed ITTSwas significantly lower than expected ITTSfor 7 centers. These data show that one third of lung transplant candidates do not survive 1 year after transplantation, and that 12% of centers have lower than expected ITTS. An “intention‐to‐treat” survival metric may provide a more realistic expectation of patient outcomes at transplant centers and may be of value to transplant centers and policymakers. Incorporation of pretransplant survival time into a novel lung transplant center performance metric provides a realistic expectation of patient outcomes that may be of value to transplant centers and policymakers. Van Berkel provides words of caution in his editorial on page 11.

Preclinical studies have demonstrated that low-dose carbon monoxide (CO) can abrogate experimental lung fibrosis. To test the therapeutic role of inhaled CO, we designed a clinical study in patients with idiopathic pulmonary fibrosis (IPF).

PURPOSE: The National Emphysema Treatment Trial (NETT) found that lung volume reduction surgery (LVRS) improves survival, exercise capacity, and quality-of-life in a subset of patients with severe emphysema. We report [...]

In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks.

Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF.

The 52-week, phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients aged above or equal to 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo.

Uncontrolled asthma in growing children can impair lung growth that may lead to adverse complications in later life. Dupilumab, a human monoclonal antibody, blocks the shared receptor for IL-4 and IL-13, key drivers of type 2 inflammation.

Heterogenous frailty pathobiology might explain the inconsistent associations observed between frailty and lung transplant outcomes. Subphenotype analysis could refine frailty measurement. In a three-center pilot cohort study, we measured frailty by the Short Physical Performance Battery, body composition, and serum biomarkers reflecting causes of frailty. We applied latent class modeling these baseline data. We tested class construct validity with disability, waitlist delisting/death, and early post-operative complications. Among 422 lung transplant candidates, 2 class model fit best (p=0.01). Compared to Subphenotype 1 (n=333), Subphenotype 2 (n=89) was characterized by systemic and innate inflammation (higher IL-6, CRP, PTX3, TNF-R1, IL-1RA); mitochondrial stress (higher GDF-15,FGF-21); sarcopenia; malnutrition; lower hemoglobin and walk distance. Subphenotype 2 had worse disability and higher risk of waitlist delisting or death (HR 4.0; 95%CI: 1.8–9.1). Of the cohort, , 257 underwent transplant (Subphenotype 1: 196; Subphenotype 2: 61). Subphenotype 2 had higher need for take-back to the operating room (48% vs 28%, p=0.005) and longer post-transplant hospital LOS (21 days [IQR: 14, 33] vs 18 [14, 28]; p=0.04). Subphenotype 2 trended towards fewer ventilator free days, needing more post-operative ECMO and dialysis, and higher need for discharge to rehabilitation facilities (p ≤0.20). In this early phase study, we identified biological frailty subphenotypes in lung transplant candidates. A hyperinflammatory, sarcopenic subphenotype appears to be associated with worse clinical outcomes.

Muscle mitochondrial dysfunction is implicated in intensive care unit-acquired weakness, but there is no serum biomarker of muscle mitochondrial function for critical illness survivors. Higher serum growth differentiation factor-15 (GDF-15) is a biomarker of inherited mitochondrial myopathy disease and is associated with mortality in several age-related diseases. Among 142 older (age [Formula]65 years) survivors of acute respiratory failure, we found that higher serum GDF-15 measured during the week prior to hospital discharge was cross-sectionally associated with weaker diaphragm, limb and hand-grip strength, and longitudinally associated with lower rates of functional recovery over 6 months, independent of age, sex, pre-existing disability, comorbidity, frailty, Acute Physiology and Chronic Health Evaluation II scores and concurrent interleukin-6 levels.

To determine whether total sleep time (TST) and specific sleep stage duration are associated with bodily pain perception and whether sex, age, or subjective sleepiness modifies this relationship.

FoxPro provides us with wonderful tools and commands for presenting data. One of those features, the ability to cross tabulate fields, is a powerful reporting capability. Here's how cross tabulation […]

Emphysema on CT is associated with accelerated lung function decline in heavy smokers and patients with COPD; however, in the general population, it is not known whether greater emphysema-like lung on CT is associated with incident COPD. We used data from 2045 adult participants without initial prebronchodilator airflow limitation, classified by FEV1/FVC<0.70, in the Multi-Ethnic Study of Atherosclerosis. Emphysema-like lung on baseline cardiac CT, defined as per cent low attenuation areas<—950HU>upper limit of normal, was associated with increased odds of incident airflow limitation at 5-year follow-up on both prebronchodilator (adjusted OR 2.62, 95% CI 1.47 to 4.67) and postbronchodilator (adjusted OR 4.38, 95% CI 1.63 to 11.74) spirometry, independent of smoking history. These results support investigation into whether emphysema-like lung could be informative for COPD risk stratification.

FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF.

We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between −600 and −250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45–84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.

Many patients with severe asthma require chronic corticosteroids to maintain asthma control.

There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and patterns of resolution.

Serum albumin concentration has been recognized as a marker of nutrition, severity of inflammation, and hepatic function in patients with various chronic diseases. The purpose of this study was to investigate the impact of pretransplant serum albumin concentration on post-transplant outcome in heart transplant recipients.

Although 1.4 million elderly Americans survive hospitalization involving intensive care annually, many are at risk for early mortality following discharge. No models that predict the likelihood of death after discharge exist explicitly for this population. Therefore, we derived and externally validated a 6-month postdischarge mortality prediction model for elderly ICU survivors.

Abstract The pulmonary vasculature is an important site of renin-angiotensin metabolism. While angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (collectively AIABs) have a role in left ventricular (LV) disease, the impact of AIABs on right ventricular (RV) function is unknown. AIAB use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were obtained via cardiac magnetic resonance imaging. The relationship between AIAB use and RV measures was assessed using multivariable linear regression, stratified by race/ethnicity, and adjusted for multiple covariates. AIAB use was associated with lower RV mass (−0.7 g, 95% confidence interval [CI] −1.3 to −0.1, P=0.03) in African Americans (N=1012) after adjustment for multiple covariates including LV mass. Among Caucasians (N=1591), AIAB use was associated with larger RV end-diastolic volume (3.7 mL, 95% CI 0.7–6.8, P=0.02) after adjustment for LV volume. No significant associations were seen between AIAB use and other RV measures or in Hispanic or Chinese American participants. AIAB use was associated with RV morphology in a race-specific and LV-independent manner, suggesting the renin-angiotensin system may play a unique role in RV structure and function. The use of AIABs in those with RV dysfunction warrants further study.

Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (RPA) and compliance (CPA) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load.

Serum levels of surfactant protein D (SP-D) have been suggested as reflecting epithelial damage in acute lung injury, COPD, and idiopathic pulmonary fibrosis (IPF). However, little is known about SP-D levels in the setting of lung transplantation.

Idiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF.

The tuberculin skin test (TST) has a low specificity in the setting of bacille Calmette-Guérin (BCG) vaccination. Interferon-γ release assays (IGRAs) appear to be more specific but have not been validated in this population under routine clinical conditions. We sought to validate the routine clinical use of the T-SPOT.TBtest (Oxford Immunotec; Oxford, UK), an IGRA, in a predominantly foreign-born population with a high rate of BCG vaccination.

Lung transplantation is currently limited by the number of suitable donor organs. Many lung-transplant programs use lungs that do not meet the formal criteria for acceptability; however, the immediate and long-term consequences of this approach remain unclear.

As seen in this CME online activity (available at http://courses.elseviercme.com/694), idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrotic lung disease of unknown cause that is associated with substantial health-care utilization and high rates of mortality. The clinical symptoms of IPF are nonspecific and overlap with many pulmonary and cardiac diseases making differential diagnosis challenging. The American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines strongly recommend a multidisciplinary approach to the diagnosis of interstitial lung diseases; however, there are several limitations to the feasibility of this approach in clinical practice. Although early diagnosis is relevant to any chronic, progressive, and irreversible disorder, it is crucially important that effective treatments for IPF are prescribed without delay. A window of opportunity may exist during which time treatment can have optimal outcomes. Evidence on the clinical management of IPF is rapidly evolving, and key updates were made to the most recent ATS/ERS/JRS/ALAT guidelines. The widely used combination of prednisone, azathioprine, and N-acetylcysteine has now been associated with increased risk of hospitalization and death compared with placebo in patients with IPF. These treatments and others for IPF have been mostly supportive, but recently pirfenidone and nintedanib have demonstrated efficacy in reducing functional decline and disease progression in IPF. A pooled analysis of three phase 3 studies of pirfenidone found a significant 48% reduction in all-cause mortality, and a pooled analysis of a phase 2 and two phase 3 studies of nintedanib found a significant 43% reduction in on-treatment mortality. As patient exposure to these two new drugs increases, data continue to emerge on how and when to use these medications and on how to manage their side effects. Finally, several medications targeting the fibrotic pathobiology of IPF are currently in development. Given the limited treatment options for IPF, enrollment in a clinical trial may be the best chance to delay or prevent progression of IPF. This CME-certified expert video roundtable from CHESTreviews the ATS/ERS/JRS/ALAT guidelines with a specific focus on accurate and timely diagnosis of IPF and the latest data on the treatment of IPF.