The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. OBJECTIVE To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (PaO 2 /FIO 2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. INTERVENTIONS Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. MAIN OUTCOME AND MEASURES The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a PaO 2 /FIO 2 ratio less than 150 mm Hg, whichever came first. RESULTS A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and PaO 2 /FIO 2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

BACKGROUND:Patients with congestive heart failure or COPD may share an increased response in minute ventilation (V E ) to carbon dioxide output (V CO 2 ) during exercise. The goal of this study was to ascertain whether the V E /V CO 2 slope and V E /V CO 2 intercept can discriminate between subjects with congestive heart failure and those with COPD at equal peak oxygen uptake (V O 2 ). METHODS: We studied 46 subjects with congestive heart failure (mean age 61 ؎ 9 y) and 46 subjects with COPD (mean age 64 ؎ 8 y) who performed a cardiopulmonary exercise test. RESULTS: The V E /V CO 2 slope was significantly higher in subjects with congestive heart failure compared with those with COPD (39.5 ؎ 9.5 vs 31.8 ؎ 7.4, P < .01) at peak V O 2 < 16 mL/kg/min, but not > 16 mL/kg/min (28.3 ؎ 5.3 vs 28.9 ؎ 6.6). The V E /V CO 2 intercept was significantly higher in both subgroups of subjects with COPD compared with the corresponding values in the subjects with congestive heart failure (3.60 ؎ 1.7 vs ؊0.16 ؎ 1.7 L/min, P < .01; 3.63 ؎ 2.7 vs 0.87 ؎ 1.5 L/min, P < .01). According to receiver operating characteristic curve analysis, when all subjects with peak V O 2 < 16 mL/kg/min were considered, subjects with COPD had a higher likelihood to have the V E /V CO 2 intercept > 2.14 L/min (0.92 sensitivity, 0.96 specificity). Regardless of peak V O 2 , the end-tidal pressure of CO 2 (P ETCO 2 ) at peak exercise was not different in subjects with congestive heart failure (P ‫؍‬ .42) and was significantly higher in subjects with COPD (P < .01) compared with the corresponding unloaded P ETCO 2 . CONCLUSIONS: The ventilatory response to V CO 2 during exercise was significantly different between subjects with congestive heart failure and those with COPD in terms of the V E /V CO 2 slope with moderate-to-severe reduction in exercise capacity and in terms of the V E /V CO 2 intercept regardless of exercise capacity.

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BackgroundObese patients (OB) with COPD may better tolerate exercise as compared to normal weight (NW) COPD patients, even if the reason for this is not yet fully understood. We investigated the interactions between obesity, lung hyperinflation, fat-free mass (FFM) and exercise capacity in COPD.MethodsForty-four patients (16 females; age 65 ± 8 yrs) were assessed by resting lung function and body composition and exercised on a cycle-ergometer to exhaustion.ResultsTwenty-two OB and 22 NW patients did not differ in age, gender and airflow obstruction degree, but in FFM (p < 0.05). OB had significantly higher values in inspiratory capacity/total lung capacity ratio (IC/TLC) at rest (p < 0.01), but not at peak of exercise and showed significantly higher values in peak workload (p < 0.05) and in peak oxygen uptake (VO2), when expressed as absolute value (p < 0.05), but not when corrected by FFM. OB compared to NW experienced lower leg fatigue (p < 0.05), but similar dyspnea on exertion. In all patients, the regression equation by stepwise multiple regression analysis for peak workload and VO2, as dependent variables included both FFM and IC/TLC at rest, as independent variables (r2 = 0.43 and 0.37, respectively).ConclusionsOB with COPD, as compared to NW patients matched for age, gender and airflow obstruction, had greater FFM and less resting lung hyperinflation and showed greater maximal exercise capacity. Pulmonary and non-pulmonary factors may explain the preservation of exercise tolerance in patients with COPD associated with obesity.

Despite being a hallmark and an independent prognostic factor in several cardiopulmonary diseases, ventilatory efficiency—i.e., minute ventilation/carbon dioxide output relationship (V̇e/V̇co2)—has never been systematically explored in cystic fibrosis (CF). To provide a comprehensive frame of reference regarding measures of ventilatory efficiency in CF adults with normal to moderately impaired lung function and to confirm the hypothesis that V̇e/V̇co2 is a sensitive marker of early lung disease. CF patients were divided into three groups, according to their spirometry: normal (G1), mild impairment (G2), and moderate impairment (G3) in lung function. All participants underwent incremental cardiopulmonary exercise testing on a cycle ergometer. Lowest V̇e/V̇co2 ratio (nadir) and the slope and the intercept of the linear region of the V̇e/V̇co2 relationship were contrasted in a two-center retrospective analysis, involving 72 CF patients and 36 healthy controls (HC). Compared with HC, CF patients had significantly higher V̇e/V̇co2 nadir, slope, and intercept ( P < 0.001, P < 0.001, and P = 0.049, respectively). Subgroup analysis revealed significant differences in nadir ( P = 0.001) and slope ( P = 0.012) values even between HC and G1. Dynamic hyperinflation related negatively with slope ( P = 0.045) and positively with intercept ( P = 0.001), while no impact on nadir was observed. Ventilatory inefficiency is a clear feature of adults with CF, even among patients with normal spirometry. V̇e/V̇co2 nadir seems to be the most reliable metric to describe ventilatory efficiency in CF adults. Further prospective studies are needed to clarify whether V̇e/V̇co2 could represent a useful marker in the evaluation of early lung disease in CF. NEW & NOTEWORTHY This is the first study to investigate ventilatory efficiency in a cohort of adult cystic fibrosis (CF) patients with nonsevere lung disease. The finding of impaired ventilatory efficiency in patients with normal lung function confirms the higher sensitivity of exercise testing in detecting early lung disease compared with spirometry. Dynamic hyperinflation plays a significant role in determining the behavior of V̇e/V̇co2 slope and intercept values with increasing lung function impairment. Apparently free from interference from mechanical constraints, V̇e/V̇co2 nadir seems the most reliable parameter to evaluate ventilatory efficiency in CF adults.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by genetic mutations in CF transmembrane conductance regulator protein. Several reports have indicated the presence of specific fatty acid alterations in CF patients, most notably decreased levels of plasmatic and tissue docosahexaenoic acid (DHA), the precursor of specialized pro-resolving mediators. We hypothesized that DHA supplementation could restore the production of DHA-derived products and possibly contribute to a better control of the chronic pulmonary inflammation observed in CF subjects. Sputum samples from 15 CF and 10 chronic obstructive pulmonary disease (COPD) subjects were collected and analyzed by LC/MS/MS, and blood fatty acid were profiled by gas chromatography upon lipid extraction and transmethylation. Interestingly, CF subjects showed increased concentrations of leukotriene B 4 (LTB 4 ), prostaglandin E 2 (PGE 2 ), and 15-hydroxyeicosatetraenoic acid (15-HETE), when compared with COPD patients, whereas the concentrations of DHA metabolites did not differ between the two groups. After DHA supplementation, not only DHA/arachidonic acid (AA) ratio and highly unsaturated fatty acid index were significantly increased in the subjects completing the study ( p < 0.05) but also a reduction in LTB 4 and 15-HETE was observed, together with a tendency for a decrease in PGE 2, and an increase in 17-hydroxy-docosahexaenoic acid (17OH-DHA) levels. At the end of the washout period, LTB 4 , PGE 2 , 15-HETE, and 17OH-DHA showed a trend to return to baseline values. In addition, 15-HETE/17OH-DHA ratio in the same sample significantly decreased after DHA supplementation ( p < 0.01) when compared with baseline. In conclusion, our results show here that in CF patients, an impairment in fatty acid metabolism, characterized by increased AA-derived metabolites and decreased DHA-derived metabolites, could be partially corrected by DHA supplementation.

BACKGROUND:In patients with COPD, we investigated the effect of the fat-free mass (FFM) on maximal exercise capacity and the relationship with changes in operational lung volumes during exercise. METHODS: In a cross-sectional study 57 patients (16 females; age 65 ؎ 8 y) were consecutively assessed by resting lung function, symptom-limited cardiopulmonary exercise test, and body composition by means of bioelectrical impedance analysis to measure the FFM index (FFMI; in kilograms per square meter). RESULTS: Patients were categorized as depleted (n ‫؍‬ 14) or nondepleted (n ‫؍‬ 43) according to FFMI. No significant difference in gender, age, and resting lung function was found between depleted and nondepleted patients. When compared with nondepleted COPD patients, the depleted COPD patients had a significantly lower O 2 uptake at the peak of exercise and at anaerobic threshold as well as at peak oxygen pulse, oxygen uptake efficiency slope (OUES), and heart rate recovery (HRR) (P < .05 for all comparisons), but similar inspiratory capacity/total lung capacity at the peak of exercise. Moreover, they also reported significantly higher leg fatigue (P < .05), but not dyspnea on exertion. In all patients, significant correlations (P < .01) were found between FFMI and peak oxygen pulse, OUES, HRR, and leg fatigue. CONCLUSIONS: This study shows that FFM depletion plays a part in the reduction of exercise capacity in COPD patients, regardless of dynamic hyperinflation, and is strictly associated with poor cardiovascular response to exercise and to leg fatigue, but not with dyspnea.