Compassionate use of ruxolitinib in patients with SARS-Cov-2 infection not on mechanical ventilation: Short-term effects on inflammation and ventilation.

Ruxolitinib is an anti-inflammatory drug that inhibits the Janus kinase-signal transducer (JAK-STAT) pathway on the surface of immune cells. The potential targeting of this pathway using JAK inhibitors is a promising approach in patients affected by coronavirus disease 2019 (COVID-19). Ruxolitinib was provided as a compassionate use in patients consecutively admitted to our institution for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. Inclusion criteria were oxygen saturation less than or equal to 92%, signs of interstitial pneumonia, and no need of mechanical ventilation. Patients received 5 mg b.i.d. of ruxolitinib for 15 days, data were collected at baseline and on days 4, 7, and 15 during treatment. Two main targets were identified, C-reactive protein (CRP) and PaO2 /FiO2 ratio. In the 31 patients who received ruxolitinib, symptoms improved (dyspnea scale) on day 7 in 25 of 31 patients (80.6%); CRP decreased progressively from baseline (79.1 ± 73.4 mg/dl) to day 15 (18.6 ± 33.2, p = 0.022). In parallel with CRP, PO2/FiO2 ratio increased progressively during the 3 steps from 183 ± 95 to 361 ± 144 mmHg (p < 0.001). In those patients with a reduction of polymerase chain reaction less than or equal to 80%, delta increase of the PO2/FiO2 ratio was significantly more pronounced (129 ± 118 vs. 45 ± 35 mmHg, p = 0.02). No adverse side effects were recorded during treatment. In patients hospitalized for COVID-19, compassionate-use of ruxolitinib determined a significant reduction of biomarkers of inflammation, which was associated with a more effective ventilation and reduced need for oxygen support. Data on ruxolitinib reinforces the hypothesis that targeting the hyperinflammation state, may be of prognostic benefit in patients with SARS-CoV-2 infection. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Some evidence suggest that patients affected by coronavirus disease 2019 (COVID-19) present an exuberant inflammatory response represented by a massive production of type I interferons and different pro-inflammatory cytokines. Nonetheless, as for the present, there are no proven therapeutic agents for COVID-19, in particular anti-inflammatory and antiviral, with a significant and reproducible positive clinical response. WHAT QUESTION DID THIS STUDY ADDRESS? Targeted therapeutic management of pro-inflammatory pathways appears to be a promising strategy against COVID-19, and ruxolitinib, due to its established broad and fast anti-inflammatory effect, appears to be a promising candidate worthy of focused investigations in this field. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Ruxolitinib rapidly reduces the systemic inflammation, which accompanies the disease, thereby improving respiratory function and the need of oxygen support. This effect may contribute to avoid progression of the disease and the use of invasive ventilation. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Data on ruxolitinib contributes the reinforcement of the hypothesis that it is crucial to counteract the early hyperinflammation state, particularly of the lungs, induced by COVID-19 infection.

Neutrophil gelatinase-associated lipocalin predicts worsening of renal function in acute heart failure: methodological and clinical issues.

BACKGROUND: Worsening of renal function (WRF) in acute heart failure (AHF) strongly predicts adverse clinical outcome. Plasma neutrophil gelatinase-associated lipocalin (NGAL) has been proposed as an earlier biomarker of tubular damage, but important methodological issues remain unsolved, particularly in AHF. METHODS AND RESULTS: In 30 consecutive patients admitted for AHF, 108 serum NGAL (Alere system) measurements were performed at entry and in the first days of recovery, and reproducibility within the same blood samples was very high (r = 0.98). NGAL at entry was related to kidney function [r = 0.51 vs. creatinine (Cr) and r = -0.49 vs. estimated glomerular filtration rate (eGFR), both P < 0.001], and weakly with hemoglobin (r = -0.36, P < 0.05) and C-reactive protein (CRP) (r = 0.26, P < 0.05). During hospitalization, WRF occurred in 26.7% of the patients. Baseline NGAL was only slightly higher in patients who developed WRF as compared to those who did not (151 ±â€Š90 vs. 119 ±â€Š75 ng/ml, NS), but it increased significantly in the following days, always preceding WRF occurrence (max. previous 24 h, average 95%, range 25-200%). The area under the Receiver Operating Characteristic (ROC) curve (AUC-ROC) was 0.69 for pathological NGAL at entry and 0.91 for delta NGAL changes during the first days. CONCLUSIONS: In patients with AHF, serum NGAL measurement is highly reproducible and at entry it is related to baseline Cr and eGFR, but does not predict WRF during subsequent hospitalization. On the contrary, serial measurements of NGAL in the first days of hospitalization can accurately predict WRF.

Exercise-induced increase in baroreflex sensitivity predicts improved prognosis after myocardial infarction.

BACKGROUND: Despite the rational expectation for a survival benefit produced by exercise training among post-myocardial infarction (MI) patients, direct evidence remains elusive. Clinically, changes in autonomic balance toward lower vagal activity have consistently been associated with increased mortality risk; conversely, among both control and post-MI dogs, exercise training improved vagal reflexes and prevented sudden death. Accordingly, we tested the hypothesis that exercise training, if accompanied by a shift toward increased vagal activity of an autonomic marker such as baroreflex sensitivity (BRS), could reduce mortality in post-MI patients. METHODS AND RESULTS: Ninety-five consecutive male patients surviving a first uncomplicated MI were randomly assigned to a 4-week endurance training period or to no training. Age (51+/-8 versus 52+/-8 years), site of MI (anterior 41% versus 43%), left ventricular ejection fraction (52+/-13 versus 51+/-14%), and BRS (7.9+/-5.4 versus 7.9+/-3.4 ms/mm Hg) did not differ between the two groups. After 4 weeks, BRS improved by 26% (P=0.04) in trained patients, whereas it did not change in nontrained patients. During a 10-year follow-up, cardiac mortality among the 16 trained patients who had an exercise-induced increase in BRS >or = 3 ms/mm Hg (responders) was strikingly lower compared with that of the trained patients without such a BRS increase (nonresponders) and that of the nontrained patients (0 of 16 versus 18 of 79 [23%], P=0.04). Cardiac mortality was also lower among responders irrespective of training (4% versus 24%, P=0.04). CONCLUSIONS: Post-MI exercise training can favorably modify long-term survival, provided that it is associated with a clear shift of the autonomic balance toward an increase in vagal activity.