CCL18, CHI3L1, ANG2, IL-6 systemic levels are associated with the extent of lung damage and radiomic features in SARS-CoV-2 infection.

OBJECTIVE AND DESIGN: We aimed to identify cytokines whose concentrations are related to lung damage, radiomic features, and clinical outcomes in COVID-19 patients. MATERIAL OR SUBJECTS: Two hundred twenty-six patients with SARS-CoV-2 infection and chest computed tomography (CT) images were enrolled. METHODS: CCL18, CHI3L1/YKL-40, GAL3, ANG2, IP-10, IL-10, TNFα, IL-6, soluble gp130, soluble IL-6R were quantified in plasma samples using Luminex assays. The Mann-Whitney U test, the Kruskal-Wallis test, correlation and regression analyses were performed. Mediation analyses were used to investigate the possible causal relationships between cytokines, lung damage, and outcomes. AVIEW lung cancer screening software, pyradiomics, and XGBoost classifier were used for radiomic feature analyses. RESULTS: CCL18, CHI3L1, and ANG2 systemic levels mainly reflected the extent of lung injury. Increased levels of every cytokine, but particularly of IL-6, were associated with the three outcomes: hospitalization, mechanical ventilation, and death. Soluble IL-6R showed a slight protective effect on death. The effect of age on COVID-19 outcomes was partially mediated by cytokine levels, while CT scores considerably mediated the effect of cytokine levels on outcomes. Radiomic-feature-based models confirmed the association between lung imaging characteristics and CCL18 and CHI3L1. CONCLUSION: Data suggest a causal link between cytokines (risk factor), lung damage (mediator), and COVID-19 outcomes.

Acute-phase reactants during tocilizumab therapy for severe COVID-19 pneumonia.

OBJECTIVES: To identify predictors of clinical improvement and intubation/death in tocilizumab-treated severe COVID19, focusing on IL6 and CRP longitudinal monitoring. METHODS: 173 consecutive patients with severe COVID-19 pneumonia receiving tocilizumab in Reggio Emilia province Hospitals between 11 March and 3 June 2020 were enrolled in a prospective cohort study. Clinical improvement was defined as status improvement on a six-category ordinal scale or discharge from the hospital, whichever came first. A composite outcome of intubation/death was also evaluated. CRP and IL-6 levels were determined before TCZ administration (T0) and after 3 (T3), and 7 (T7) days. RESULTS: At multivariate analysis T0 and T3 CRP levels were negatively associated with clinical improvement (OR 0.13, CI 0.03-0.55 and OR 0.11, CI 0.0-0.46) (p=0.006 and p=0.003) and positively associated with intubation/death (OR 17.66, CI 2.47-126.14 and OR 5.34, CI: 1.49-19.12) (p=0.01 and p=0.004). No significant associations with IL-6 values were observed. General linear model analyses for repeated measures showed significantly different trends for CRP from day 3 to day 7 between patients who improved and those who did not, and between patients who were intubated or died and those who were not (p<0.0001 for both). ROC analysis identified a baseline CRP level of 15.8 mg/dl as the best cut-off to predict intubation/death (AUC = 0.711, sensitivity = 0.67, specificity = 0.71). CONCLUSIONS: CRP serial measurements in the first week of TCZ therapy are useful in identifying patients developing poor outcomes.

The value of high-resolution computed tomography (HRCT) to determine exercise ventilatory inefficiency and dynamic hyperinflation in adult patients with cystic fibrosis.

INTRODUCTION: In Cystic Fibrosis (CF), exercise ventilatory inefficiency and dynamic hyperinflation (DH) cause exercise limitation and induce poor exercise tolerance. High-resolution computed tomography (HRCT) of the lung can detect pulmonary abnormalities in CF patients. We aimed to identify the determinants of exercise ventilatory inefficiency and DH using HRCT-derived metrics. METHODS: Fifty-two adult CF patients were prospectively enrolled; all participants underwent cardio-pulmonary exercise test (CPET) and HRCT. Radiological impairment was evaluated by the Brody II scoring system. Slope and intercept of the minute ventilation/CO2 production (V'E/V'CO2) regression line and the ratio of inspiratory capacity/total lung capacity (IC/TLC) at rest and at peak of exercise were measured. RESULTS: Four groups of patients were identified based on the combination of ventilatory efficiency (Vef) or inefficiency (Vin) and the presence/absence of DH. Compared to other groups, CF adults with Vin and DH had worse functional status and higher total (T), bronchiectasis (B) and air trapping (AT) scores at HRCT. Significant correlations were found between V'E/V'CO2 intercept and V'E/V'CO2 slope (ρ - 0.455, p = 0.001) and between V'E/V'CO2 intercept and Δ inspiratory capacity (IC) (ρ - 0.334, p = 0.015). Regression analysis identified AT score (cut-off 7.9, odds ratio-OR 3.50) as the only independent predictor of Vin and T (cut-off 53.6, OR 4.98), B (cut-off 16.1, OR 4.88), airways wall thickening (AWT) (cut-off 13, OR 3.41), and mucous plugging (MP) scores (cut-off 11.7, OR 4.18) as significant predictors of DH. CONCLUSION: In adult CF cohort, values of HRCT metrics are determinants of Vin (AT) and DH (T, B, AWT, MP).

Maximal exercise in obese patients with COPD: the role of fat free mass.

BACKGROUND: Obese 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. METHODS: Forty-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. RESULTS: Twenty-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 (r(2) = 0.43 and 0.37, respectively). CONCLUSIONS: OB 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.

Predictive factors of clinical outcomes in patients with COVID-19 treated with tocilizumab: A monocentric retrospective analysis.

OBJECTIVE: The aim of this retrospective observational study is to analyse clinical, serological and radiological predictors of outcome in patients with COVID-19 pneumonia treated with tocilizumab, providing clinical guidance to its use in real-life. METHOD: This is a retrospective, monocentric observational cohort study. All consecutive patients hospitalized between February the 11th and April 14th 2020 for severe COVID-19 pneumonia at Reggio Emilia AUSL and treated with tocilizumab were enrolled. The patient's clinical status was recorded every day using the WHO ordinal scale for clinical improvement. Response to treatment was defined as an improvement of one point (from the status at the beginning of tocilizumab treatment) during the follow-up on this scale. Bivariate association of main patients' characteristics with outcomes was explored by descriptive statistics and Fisher or Kruskal Wallis tests (respectively for qualitative or quantitative variables). Each clinically significant predictor was checked by a loglikelihood ratio test (in univariate logistic models for each of the considered outcomes) against the null model. RESULTS: A total of 173 patients were included. Only hypertension, the use of angiotensin-converting enzyme inhibitors, PaO2/FiO2, respiratory rate and C-reactive protein were selected for the multivariate analysis. In the multivariable model, none of them was significantly associated with response. CONCLUSIONS: Evaluating a large number of clinical variables, our study did not find new predictors of outcome in COVID19 patients treated with tocilizumab. Further studies are needed to investigate the use of tocilizumab in COVID-19 and to better identify clinical phenotypes which could benefit from this treatment.

Inflammatory burden and persistent CT lung abnormalities in COVID-19 patients.

Inflammatory burden is associated with COVID-19 severity and outcomes. Residual computed tomography (CT) lung abnormalities have been reported after COVID-19. The aim was to evaluate the association between inflammatory burden during COVID-19 and residual lung CT abnormalities collected on follow-up CT scans performed 2-3 and 6-7 months after COVID-19, in severe COVID-19 pneumonia survivors. C-reactive protein (CRP) curves describing inflammatory burden during the clinical course were built, and CRP peaks, velocities of increase, and integrals were calculated. Other putative determinants were age, sex, mechanical ventilation, lowest PaO2/FiO2 ratio, D-dimer peak, and length of hospital stay (LOS). Of the 259 included patients (median age 65 years; 30.5% females), 202 (78%) and 100 (38.6%) had residual, predominantly non-fibrotic, abnormalities at 2-3 and 6-7 months, respectively. In age- and sex-adjusted models, best CRP predictors for residual abnormalities were CRP peak (odds ratio [OR] for one standard deviation [SD] increase = 1.79; 95% confidence interval [CI] = 1.23-2.62) at 2-3 months and CRP integral (OR for one SD increase = 2.24; 95%CI = 1.53-3.28) at 6-7 months. Hence, inflammation is associated with short- and medium-term lung damage in COVID-19. Other severity measures, including mechanical ventilation and LOS, but not D-dimer, were mediators of the relationship between CRP and residual abnormalities.

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: 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 (Pao2/Fio2) 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 Pao2/Fio2 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 Pao2/Fio2 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. Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.

Arachidonic Acid and Docosahexaenoic Acid Metabolites in the Airways of Adults With Cystic Fibrosis: Effect of Docosahexaenoic Acid Supplementation.

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 B4 (LTB4), prostaglandin E2 (PGE2), 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 LTB4 and 15-HETE was observed, together with a tendency for a decrease in PGE2, and an increase in 17-hydroxy-docosahexaenoic acid (17OH-DHA) levels. At the end of the washout period, LTB4, PGE2, 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.

Reduced exercise ventilatory efficiency in adults with cystic fibrosis and normal to moderately impaired lung function.

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.

Heart rate recovery is associated with ventilatory constraints and excess ventilation during exercise in patients with chronic obstructive pulmonary disease.

Background Heart rate recovery delay is a marker of cardiac autonomic dysfunction. In chronic obstructive pulmonary disease patients, the ventilatory response to exercise during incremental cardiopulmonary exercise test may add information about dynamic hyperinflation by low values of inspiratory capacity/total lung capacity ratio (at peak) and excess ventilation by the slope of minute ventilation to carbon dioxide output ratio (VE/VCO2 slope). We aimed to assess if the ventilatory response to exercise might be a determinant for heart rate recovery delay. Design An observational, prospective study. Methods Anthropometric characteristics, lung function and cardiopulmonary exercise test data were recorded in chronic obstructive pulmonary disease outpatients. A cut-off of heart rate recovery of 12 or more beats was used to define heart rate recovery delay. Results Of 254 patients enrolled, 156 (61%) showed heart rate recovery delay. As compared to patients with normal heart rate recovery, patients with delay were older, with a worse lung function and with lower values of peak oxygen uptake, maximal workload, oxygen pulse at rest and at peak, and inspiratory capacity/total lung capacity at peak. Conversely, VE/VCO2 slope and dyspnoea and leg fatigue perception at peak were higher in patients with heart rate recovery delay. In the multivariate regression model adjusted for age, sex, fat-free mass, heart rate at rest and use of ß-blockers, we found that inspiratory capacity/total lung capacity at peak (<0.25) (odds ratio 2.61; P = 0.007) and VE/VCO2 slope (>32) (odds ratio 2.26; P = 0.018) predict the risk of heart rate recovery delay. Conclusions In chronic obstructive pulmonary disease outpatients, heart rate recovery is associated with dynamic hyperinflation and excess ventilation during exercise.

Excess ventilation and ventilatory constraints during exercise in patients with chronic obstructive pulmonary disease.

We assessed the relationship between minute ventilation/carbon dioxide output (VE/VCO2) and ventilatory constraints during an incremental cardiopulmonary exercise testing (CPET) in patients with chronic obstructive pulmonary disease (COPD). Slope and intercept of the VE/VCO2 linear relationship, the ratios of inspiratory capacity/total lung capacity (IC/TLC) and of tidal volume (VT) over vital capacity (VTpeak/VC) and IC (VTpeak/IC) and over forced expiratory volume at 1st second (VTpeak/FEV1) at peak of exercise were measured in 52 COPD patients during a CPET. The difference peak-rest in end-tidal pressure of CO2 (PETCO2) was also measured. VE/VCO2 intercept showed a negative correlation with IC/TLC peak (p<0.01) and a positive one with VTpeak/FEV1 (p<0.01) and with PETCO2 peak-rest (p<0.01). VE/VCO2 slope was negatively related to VTpeak/VC, VTpeak/IC and VTpeak/FEV1 (all correlations p<0.05) and to PETCO2 peak-rest (p<0.01). In COPD, VE/VCO2 slope and intercept provide complementary information on the ventilatory limitation to exercise, as assessed by changes in the end-expiratory lung volume and in tidal volume excursion.

Fat-free mass depletion is associated with poor exercise capacity irrespective of dynamic hyperinflation in COPD patients.

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 O2 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.

Pulmonary arterial hypertension in childhood: an unsual presentation with fibrosing mediastinitis.

Acquired stenosis of normally connected pulmonary veins is a rare condition in children, usually associated with mediastinal processes. It may present later with a less specific clinical picture, symptoms and signs mimicking chronic lung disease. Fibrosing mediastinitis is a rarer disorder of unknown etiology, although several suspected causes such as granulomatous diseases, characterized by fibrous tissue proliferation within the mediastinum, leading to respiratory and cardiac failure by bronchial obstruction or pulmonary hypertension.

Ventilatory response to carbon dioxide output in subjects with congestive heart failure and in patients with COPD with comparable exercise capacity.

BACKGROUND: Patients with congestive heart failure or COPD may share an increased response in minute ventilation (V̇E) to carbon dioxide output (V̇CO2 ) during exercise. The goal of this study was to ascertain whether the V̇E/V̇CO2 slope and V̇E/V̇CO2 intercept can discriminate between subjects with congestive heart failure and those with COPD at equal peak oxygen uptake (V̇O2 ). 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 V̇E/V̇CO2 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 V̇O2 < 16 mL/kg/min, but not ≥ 16 mL/kg/min (28.3 ± 5.3 vs 28.9 ± 6.6). The V̇E/V̇CO2 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 V̇O2 < 16 mL/kg/min were considered, subjects with COPD had a higher likelihood to have the V̇E/V̇CO2 intercept > 2.14 L/min (0.92 sensitivity, 0.96 specificity). Regardless of peak V̇O2 , the end-tidal pressure of CO2 (PETCO2 ) 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 PETCO2 . CONCLUSIONS: The ventilatory response to V̇CO2 during exercise was significantly different between subjects with congestive heart failure and those with COPD in terms of the V̇E/V̇CO2 slope with moderate-to-severe reduction in exercise capacity and in terms of the V̇E/V̇CO2 intercept regardless of exercise capacity.