Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not ...known.
We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.
A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval CI, 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).
Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).
Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of ...high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings.
A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would
) identify patients with the currently accepted conceptual framework for ARDS,
) facilitate rapid ARDS diagnosis for clinical care and research,
) be applicable in resource-limited settings,
) be useful for testing specific therapies, and
) be practical for communication to patients and caregivers.
The committee made four main recommendations:
) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min;
) use Pa
:Fi
⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry Sp
:Fi
⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia;
) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and
) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices.
We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States.
To systematically review literature on the accuracy of screening questionnaires and office-based ...screening pulmonary function testing and the efficacy and harms of treatment of screen-detected COPD.
MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant English-language studies published through January 2015.
Two reviewers independently screened abstracts and studies. The search yielded 13,141 unique citations; 465 full-text articles were reviewed, and 33 studies met the inclusion criteria.
Two reviewers rated the quality of each study using USPSTF criteria.
Diagnostic accuracy (sensitivity, specificity, positive predictive value PPV, and negative predictive value NPV; treatment efficacy (COPD exacerbations, all-cause mortality, quality of life, and dyspnea); and treatment harms.
All screening questionnaires were based on symptoms as well as risk factors such as age and smoking history. The COPD Diagnostic Questionnaire was the most extensively studied (5 studies, n = 3048), with moderate overall performance for COPD detection: area under the receiver operating characteristic curve (AUC), 0.65 to 0.72; sensitivity, 80% to 93%; and specificity, 24% to 49%, at a threshold of greater than 16.5. Positive predictive value and NPV ranged from 17% to 45% and 76% to 98%, respectively. For pulmonary function-based screening tools, FEV1/FEV6 was the best studied (3 studies, n = 1587), with AUC ranging from 0.84 to 0.85. Sensitivity ranged from 51% to 80%. Specificity (range, 90%-95%) and PPV (range, 63%-75%) appeared better than questionnaires. There was not strong evidence to support that screening and supplying smokers with spirometry results improves smoking cessation rates. Treatment trials were unavailable for screen-detected patients. Trials that reported outcomes in patients with mild to moderate COPD included 2 trials of long-acting β-agonists (LABAs) (n = 3174), 1 RCT of LABAs and inhaled corticosteroids (ICS) (n = 1097), 5 RCTs of the long-acting muscarinic antagonist tiotropium (n = 4592), and 6 RCTs of ICS (n = 3983). They suggested no benefit in all-cause mortality, but a decrease in annual rates of exacerbations with pharmacologic treatments. Few trials reported harms for any individual drug class. Adverse effects were generally mild (eg, dry mouth and cough).
There was no direct evidence available to determine the benefits and harms of screening asymptomatic adults for COPD using questionnaires or office-based screening pulmonary function testing or to determine the benefits of treatment in screen-detected populations. Indirect evidence suggests that the COPD Diagnostic Questionnaire has moderate overall performance for COPD detection. Among patients with mild to moderate COPD, the benefit of pharmacotherapy for reducing exacerbations was modest.
Less invasive, nonsurgical approaches are needed to treat severe emphysema.
To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.
In this ...multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).
The primary efficacy outcome was the difference in mean FEV
from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV
responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (
= 113) or control (
= 59). Mean FEV
showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.
In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).
A pneumococcal conjugate vaccine (PCV) specifically focused on serotypes associated with adult residual disease burden is urgently needed. We aimed to assess V116, an investigational 21-valent PCV, ...that contains pneumococcal polysaccharides (PnPs), which account for 74–94% of invasive pneumococcal disease in adults aged 65 years or older.
We did a phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, non-inferiority and superiority trial. The phase 1 study was done at two clinical sites in the USA, and the phase 2 study was done in 18 clinical sites in the USA. Eligible participants were healthy adults with or without chronic medical conditions assessed as stable, aged 18–49 years in the phase 1 trial and aged 50 years or older in the phase 2 trial. Participants were excluded if they had a history of invasive pneumococcal disease or other culture-positive pneumococcal disease within the past 3 years, known hypersensitivity to a vaccine component, known or suspected impairment of immunological function, were pregnant or were breastfeeding, or had previously received any pneumococcal vaccine. Participants had to abstain from sexual activity or use protocol approved contraception. All participants were centrally randomly assigned to a vaccine group using an interactive response technology system. Participants and investigators were masked to group assignment. In phase 1, participants were randomly assigned (1:1:1) to receive a single dose of V116-1 (2 μg per pneumococcal polysaccharide PnP per 0·5 mL) or V116-2 (4 μg per PnP per 1·0 mL) or the 23-valent unconjugated PnP vaccine, PPSV23 (25 μg per PnP per 0·5 mL). In phase 2, participants were randomly assigned (1:1) to receive one dose of V116 (4 μg per PnP per 1·0 mL) or PPSV23 (25 μg per PnP per 0·5 mL), stratified by age. Safety analyses included all randomly assigned participants who received study vaccine; immunogenicity analyses were per protocol. For both phases, the primary safety outcome was the proportion of participants with solicited injection-site adverse events and solicited systemic adverse events up to day 5 after vaccination and the proportion of participants with vaccine-related serious adverse events to 6 months after vaccination. In phase 2, primary immunogenicity outcomes were to test non-inferiority of V116 compared with PPSV23 as measured by serotype-specific opsonophagocytic antibody geometric mean titres (OPA-GMT) ratios for the serotypes common to the two vaccines at 30 days after vaccination (using a 0·33 margin) and to test superiority of V116 compared with PPSV23 as measured by serotype-specific OPA-GMT ratios for the serotypes unique to V116 at 30 days after vaccination (using a 1·0 margin). This trial is registered with Clinicaltrials.gov, NCT04168190.
Between Dec 6 and 26, 2019, 92 volunteers were screened and 90 (98%) enrolled for phase 1 (59 66% women; 31 34% men); 30 participants were assigned to each group and received study vaccine. 30 (100%) participants in the V116-1 group, 29 (97%) in the V116-2 group, and 30 (100%) participants in the PPSV23 group were included in the per-protocol immunogenicity evaluation. From Sept 23, 2020, to Jan 12, 2021, 527 volunteers were screened, and 510 (97%) participants were enrolled in the phase 2 trial. 508 participants (>99%; 254 100% of 254 participants randomly assigned to the V116 group and 254 99% of 256 randomly assigned to PPSV23 group) received study vaccine (281 55% women; 227 45% men). 252 (99%) of 254 of participants in the V116 group and 254 (99%) of 256 participants in the PPSV23 group were included in the primary immunogenicity analyses. There were no vaccine-related serious adverse events or vaccine-related deaths in either study phase. In both phases, the most common solicited injection site adverse event was injection site pain (phase 1 22 73% participants in V116-1 group, 23 77% participants in V116-2 group, and 17 57% participants in the PPSV23 group; phase 2 118 46% of 254 participants in the V116 group and 96 38% of 254 in the PPSV23 group. The most common solicited systemic adverse events in phase 1 was fatigue (eight 27% participants in the V116-1 group, eight 27% participants in the V116-2 group, and five 17% participants in PPSV23 group) and myalgia (eight 27% participants in the V116-1 group, nine (30%) participants in the V116-2 group, and four (13%) participants in the PPSV23 group. In phase 2, the most frequently reported solicited systemic adverse event was fatigue (49 19% participants in V116 group, and 31 12% participants in PPSV23 group). In both phases, most of the solicited adverse events in all vaccine groups were mild and of short duration (≤3 days). V116 met non-inferiority criteria compared with PPSV23 for the 12 shared serotypes and met superiority criteria compared to PPSV23 for the nine unique serotypes.
V116 was well tolerated with a safety profile generally similar to PPSV23; consistent with licensed pneumococcal conjugate vaccines. Functional OPA antibodies were induced to all V116 vaccine serotypes. The vaccine was non-inferior to PPSV23 for the 12 serotypes common to both vaccines and superior to PPSV23 for the nine unique serotypes in V116. Our findings support the development of V116 for prevention of pneumococcal disease in adults.
Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA.
Great differences in end-of-life practices in treating the critically ill around the world warrant agreement regarding the major ethical principles. This analysis determines the extent of worldwide ...consensus for end-of-life practices, delineates where there is and is not consensus, and analyzes reasons for lack of consensus. Critical care societies worldwide were invited to participate. Country coordinators were identified and draft statements were developed for major end-of-life issues and translated into six languages. Multidisciplinary responses using a web-based survey assessed agreement or disagreement with definitions and statements linked to anonymous demographic information. Consensus was prospectively defined as >80% agreement. Definitions and statements not obtaining consensus were revised based on comments of respondents, and then translated and redistributed. Of the initial 1,283 responses from 32 countries, consensus was found for 66 (81%) of the 81 definitions and statements; 26 (32%) had >90% agreement. With 83 additional responses to the original questionnaire (1,366 total) and 604 responses to the revised statements, consensus could be obtained for another 11 of the 15 statements. Consensus was obtained for informed consent, withholding and withdrawing life-sustaining treatment, legal requirements, intensive care unit therapies, cardiopulmonary resuscitation, shared decision making, medical and nursing consensus, brain death, and palliative care. Consensus was obtained for 77 of 81 (95%) statements. Worldwide consensus could be developed for the majority of definitions and statements about end-of-life practices. Statements achieving consensus provide standards of practice for end-of-life care; statements without consensus identify important areas for future research.
COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and ...sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations.
In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion.
The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the patient with COPD.
This guideline is unique because it provides an up-to-date, rigorous, evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.
Background: This consensus statement was developed based on the understanding that patients with advanced lung or heart disease are not
being treated consistently and effectively for relief of ...dyspnea.
Methods: A panel of experts was convened. After a literature review, the panel developed 23 statements covering five domains that
were considered relevant to the topic condition. Endorsement of these statements was assessed by levels of agreement or disagreement
on a five-point Likert scale using two rounds of the Delphi method.
Results: The panel defined the topic condition as âdyspnea that persists at rest or with minimal activity and is distressful despite
optimal therapy of advanced lung or heart disease.â The five domains were: measurement of patient-reported dyspnea, oxygen
therapy, other therapies, opioid medications, and ethical issues. In the second round of the Delphi method, 34 of 56 individuals
(61%) responded, and agreement of at least 70% was achieved for 20 of the 23 statements.
Conclusions: For patients with advanced lung or heart disease, we suggest that: health-care professionals are ethically obligated to treat
dyspnea, patients should be asked to rate the intensity of their breathlessness as part of a comprehensive care plan, opioids
should be dosed and titrated for relief of dyspnea in the individual patient, both the patient and clinician should reassess
whether specific treatments are serving the goal of palliating dyspnea without causing adverse effects, and it is important
for clinicians to communicate about palliative and end-of-life care with their patients.
The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has ...not been fully determined. In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥30 L/min. This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials.
The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients. This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population. Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations.
A total of 1460 (207608/207609) and 3282 (KPNW) patients were included. There was considerable overlap between spirometric PIF distributions for both populations. Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥50 L/min, estimated as equivalent to ELLIPTA PIFR ≥30 L/min. In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF.
Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥30 L/min through the ELLIPTA DPI. Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities.
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