Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial.

PURPOSE: Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or "ready for discharge" (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days. RESULTS: Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or "ready for discharge" was 14 (95% CI 12-15) days with tocilizumab plus remdesivir and 14 (95% CI 11-16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78-1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28. CONCLUSIONS: Tocilizumab plus remdesivir did not shorten time to hospital discharge or "ready for discharge" to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.

A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER).

BACKGROUND: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. OBJECTIVE: To report safety and efficacy results from enrolled participants with available data from CLAVIER. METHODS: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling. RESULTS: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. CONCLUSIONS & CLINICAL RELEVANCE: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling. CLINICAL TRIAL REGISTRATION: NCT02099656.

Hospital characteristics associated with timeliness of care in veterans with lung cancer.

RATIONALE: Timeliness is one of six important dimensions of health care quality recognized by the Institute of Medicine. OBJECTIVES: To evaluate timeliness of lung cancer care and identify institutional characteristics associated with timely care within the Veterans Affairs (VA) health care system. METHODS: We used data from a VA nation-wide retrospective chart review and an independent audit of VA cancer programs to examine the association between time to first treatment and potentially explanatory institutional characteristics (e.g., volume of lung cancer patients) for 2,372 veterans diagnosed with lung cancer between 1 January 2002 and 1 September 2005 at 127 VA medical centers. We developed linear mixed effects models to control for clustering of patients within hospitals and we stratified analyses by stage. MEASUREMENTS AND MAIN RESULTS: Median time to treatment varied widely between (23 to 182 d) and within facilities. Median time to treatment was 90 days in patients with stage I or II cancer and 52 days in those with more advanced disease (P < 0.0001). Factors associated with shorter times to treatment included a nonacademic setting and the existence of a specialized diagnostic clinic (in patients with limited-stage disease), performing a patient flow analysis (in patients with advanced disease), and leadership beliefs about providing timely care (in both groups). However, institutional characteristics explained less than 1% of the observed variation in treatment times. CONCLUSIONS: Time to lung cancer treatment in U.S. veterans is highly variable. The numerous institutional characteristics we examined explained relatively little of this variability, suggesting that patient, clinician, and/or unmeasured institutional characteristics may be more important determinants of timely care.

Timeliness of care in veterans with non-small cell lung cancer.

BACKGROUND: Timeliness is an important dimension of quality of care for patients with lung cancer. METHODS: We reviewed the records of consecutive patients in whom non-small cell lung cancer (NSCLC) had been diagnosed between January 1, 2002, and December 31, 2003, at the Veterans Affairs Palo Alto Health Care System. We used multivariable statistical methods to identify independent predictors of timely care and examined the effect of timeliness on survival. RESULTS: We identified 129 veterans with NSCLC (mean age, 67 years; 98% men; 83% white), most of whom had adenocarcinoma (51%) or squamous cell carcinoma (30%). A minority of patients (18%) presented with a solitary pulmonary nodule (SPN). The median time from the initial suspicion of cancer to treatment was 84 days (interquartile range, 38 to 153 days). Independent predictors of treatment within 84 days included hospitalization within 7 days (odds ratio [OR], 8.2; 95% confidence interval [CI], 2.9 to 23), tumor size of > 3.0 cm (OR, 4.8; 95% CI, 1.8 to 12.4), the presence of additional chest radiographic abnormalities (OR, 3.0; 95% CI, 1.1 to 8.5), and the presence of one or more symptoms suggesting metastasis (OR, 2.6; 95% CI, 1.1 to 6.2). More timely care was not associated with better survival time (adjusted hazard ratio, 1.6; 95% CI, 1.3 to 1.9). However, in patients with SPNs, there was a trend toward better survival time when the time to treatment was < 84 days. CONCLUSIONS: The time to treatment for patients with NSCLC was often longer than recommended. Patients with larger tumors, symptoms, and other chest radiographic abnormalities receive more timely care. In patients with malignant SPNs, survival may be better when treatment is initiated promptly.

Surgical and interventional therapies for pulmonary arterial hypertension.

Surgical and interventional therapies for pulmonary arterial hypertension (PAH) in appropriately selected patients have the potential to dramatically improve or, in some cases, cure PAH. These include atrial septostomy, a palliative procedure or bridge to transplantation in patients with refractory right heart failure, pulmonary thromboendarterectomy for pulmonary hypertension associated with chronic thromboembolic disease, and closure of congenital systemic-pulmonary shunts in patients with PAH but without significant pulmonary vascular disease. Lung transplantation should be considered for patients with all forms of PAH who demonstrate advanced or progressive disease.