JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

The relationship between cardiac injury, inflammation and coagulation in predicting COVID-19 outcome.

High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of inflammatory response/coagulation abnormalities and hsTnT in Coronavirus Disease 2019 (COVID-19). We then explored the relevance of these pathways in defining mortality and complications risk and the potential effects of the treatments to attenuate such risk. In this single-center, prospective, observational study we enrolled 266 consecutive patients hospitalized for SARS-CoV-2 pneumonia. Primary endpoint was in-hospital COVID-19 mortality. hsTnT, even after adjustment for confounders, was associated with mortality. D-dimer and CRP presented stronger associations with hsTnT than PaO2. Changes of hsTnT, D-dimer and CRP were related; but only D-dimer was associated with mortality. Moreover, low molecular weight heparin showed attenuation of the mortality in the whole population, particularly in subjects with higher hsTnT. D-dimer possessed a strong relationship with hsTnT and mortality. Anticoagulation treatment showed greater benefits with regard to mortality. These findings suggest a major role of SARS-CoV-2 coagulopathy in hsTnT elevation and its related mortality in COVID-19. A better understanding of the mechanisms related to COVID-19 might pave the way to therapy tailoring in these high-risk individuals.

Role of Low-Molecular-Weight Heparin in Hospitalized Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia: A Prospective Observational Study.

BACKGROUND: This study was conducted to evaluate the impact of low-molecular-weight heparin (LMWH) on the outcome of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: This is a prospective observational study including consecutive patients with laboratory-confirmed SARS-CoV-2 pneumonia admitted to the University Hospital of Pisa (March 4-April 30, 2020). Demographic, clinical, and outcome data were collected. The primary endpoint was 30-day mortality. The secondary endpoint was a composite of death or severe acute respiratory distress syndrome (ARDS). Low-molecular-weight heparin, hydroxychloroquine, doxycycline, macrolides, antiretrovirals, remdesivir, baricitinib, tocilizumab, and steroids were evaluated as treatment exposures of interest. First, a Cox regression analysis, in which treatments were introduced as time-dependent variables, was performed to evaluate the association of exposures and outcomes. Then, a time-dependent propensity score (PS) was calculated and a PS matching was performed for each treatment variable. RESULTS: Among 315 patients with SARS-CoV-2 pneumonia, 70 (22.2%) died during hospital stay. The composite endpoint was achieved by 114 (36.2%) patients. Overall, 244 (77.5%) patients received LMWH, 238 (75.5%) received hydroxychloroquine, 201 (63.8%) received proteases inhibitors, 150 (47.6%) received doxycycline, 141 (44.8%) received steroids, 42 (13.3%) received macrolides, 40 (12.7%) received baricitinib, 13 (4.1%) received tocilizumab, and 13 (4.1%) received remdesivir. At multivariate analysis, LMWH was associated with a reduced risk of 30-day mortality (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21-0.6; P < .001) and composite endpoint (HR, 0.61; 95% CI, 0.39-0.95; P = .029). The PS-matched cohort of 55 couples confirmed the same results for both primary and secondary endpoint. CONCLUSIONS: This study suggests that LMWH might reduce the risk of in-hospital mortality and severe ARDS in coronavirus disease 2019. Randomized controlled trials are warranted to confirm these preliminary findings.

Role of low-molecular weight heparin in hospitalized patients with SARS-CoV-2 pneumonia: a prospective observational study

Objectives To evaluate the impact of low molecular weight heparin (LMWH) on the outcome of patients with SARS-CoV-2 pneumonia. Methods Prospective observational study including consecutive patients with laboratory confirmed SARS-CoV-2 pneumonia admitted to the University Hospital of Pisa (4th March-30th April 2020). Demographic, clinical, and outcome data were collected. The primary endpoint was 30-day mortality. The secondary endpoint was a composite of death or severe ARDS. LMWH, hydroxychloroquine, doxycycline, macrolides, antiretrovirals, remdesivir, baricitinib, tocilizumab, and steroids were evaluated as treatment exposures of interest. First, a Cox-regression analysis, in which treatments were introduced as time-dependent variables, was performed to evaluate the association of exposures and outcomes. Then, a time-dependent Propensity-score (PS) was calculated and a PS-matching performed for each treatment variable. Results Among 315 patients with SARS-CoV-2 pneumonia, 70 (22.2%) died during hospital stay. The composite endpoint was achieved by 114 (36.2%) patients. Overall, 244 (77.5%) patients received LMWH, 238 (75.5%) hydroxychloroquine, 201 (63.8%) proteases inhibitors, 150 (47.6%) doxycycline, 141 (44.8%) steroids, 42 (13.3%) macrolides, 40 (12.7%) baricitinib, 13 (4.1%) tocilizumab, and 13 (4.1%) remdesivir. At multivariate analysis, LMWH was associated with a reduced risk of 30-day mortality (HR 0.36 [95% CI 0.21-0.6], p<0.001) and composite endpoint (HR 0.61 [95% CI 0.39-0.95], p=0.029). The PS-matched cohort of 55 couples confirmed the same results for both primary and secondary endpoint. Conclusions This study suggests that LMWH might reduce the risk of in-hospital mortality and severe ARDS in Covid-19. Randomized controlled trials are warranted to confirm these preliminary findings.

Obesity prolongs the hospital stay in patients affected by COVID-19, and may impact on SARS-COV-2 shedding.

INTRODUCTION: On the last three months the new SARS-COV-2 coronavirus has created a pandemic, rapidly spreading all around the world. The aim of the study is to investigate whether obesity impacts on COVID-19 morbidity. METHODS: One hundred consecutive patients with COVID-19 pneumonia admitted in our Medical Unit were evaluated. Anthropometric parameters and past medical history were registered. Nasopharyngeal swab samples and biochemical analysis were obtained at admission and during hospital stay. RESULTS: Patients with (OB, 29) and without obesity (N-OB, 71) were similar in age, gender and comorbidities, with the exception of hypertension that was more frequent in OB group. At admission, inflammatory markers were higher in OB than N-OB group. OB group showed a worse pulmonary clinical picture, with lower PaO2 (57 ± 15 vs. 68 ± 14 mmHg, p = 0.042), and SaO2 (88 ± 6 vs. 92 ± 5%, p = 0.049) at admission consequently requiring higher volumes of oxygen (Fi02: 38 ± 15 vs. 29 ± 19%, p = 0.047) and a longer period to achieve oxygen weaning (10 ± 6 vs. 15 ± 7 days, p = 0.03). OB group also had positive swabs for longer time (19 ± 8 vs. 13 ± 7, days, p = 0.002), and required longer hospital stay (21 ± 8 vs. 13 ± 8, days, p = 0.0008). Partial least square regression analysis showed that BMI, age and CRP at admission were related to longer length of hospital stay, and time for negative swab. On the contrary, in this cohort, obesity did not predict higher mortality. CONCLUSIONS: Subjects with obesity affected by COVID-19 require longer hospitalization, more intensive and longer oxygen treatment, and they may have longer SARS-COV-2 shedding.