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

ABSTRACT: 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.

SUBMITTER: Mortara A

PROVIDER: S-EPMC8212747 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction and aim:Studies regarding asynchrony in patients in the cardiac postoperative period are still only a few. The main objective of our study was to compare asynchronies incidence and its index (AI) in 3 different modes of ventilation (volume-controlled ventilation [VCV], pressure-controlled ventilation [PCV] and pressure-support ventilation [PSV]) after ICU admission for postoperative care. Methods:A prospective parallel randomised trialin the setting of a non-profitable hospital in Brazil. The participants were patients scheduled for cardiac surgery. Patients were randomly allocated to VCV or PCV modes of ventilation and later both groups were transitioned to PSV mode. Results:All data were recorded for 5 minutes in each of the three different phases: T1) in assisted breath, T2) initial spontaneous breath and T3) final spontaneous breath, a marking point prior to extubation. Asynchronies were detected and counted by visual inspection method by two independent investigators. Reliability, inter-rater agreement of asynchronies, asynchronies incidence, total and specific asynchrony indexes (AIt and AIspecific) and odds of AI ?10% weighted by total asynchrony were analysed. A total of 17 patients randomly allocated to the VCV (n=9) or PCV (n=8) group completed the study. High inter-rated agreement for AIt (ICC 0.978; IC95%, 0,963-0.987) and good reliability (r=0.945; p<0.001) were found. Eighty-two % of patients presented asynchronies, although only 7% of their total breathing cycles were asynchronous. Early cycling and double triggering had the highest rates of asynchrony with no difference between groups. The highest odds of AI ?10% were observed in VCV regardless the phase: OR 2.79 (1.36-5.73) in T1 vs T2, p=0.005; OR 2.61 (1.27-5.37) in T1 vs T3, p=0.009 and OR 4.99 (2.37-10.37) in T2 vs T3, p<0.001. Conclusions:There was a high incidence of breathing asynchrony in postoperative cardiac patients, especially when initially ventilated in VCV. VCV group had a higher chance of AI ?10% and this chance remained high in the following PSV phases.

Project description:BackgroundStandard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features.MethodsIn this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only.ResultsAfter an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time.DiscussionOur preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.

Project description:BackgroundMechanical ventilation is strongly associated with cognitive decline after critical illness. This finding is particularly evident among older individuals who have pre-existing cognitive impairment, most commonly characterized by varying degrees of cerebral amyloid-β accumulation, neuroinflammation, and blood-brain barrier dysfunction. We sought to test the hypothesis that short-term mechanical ventilation contributes to the neuropathology of cognitive impairment by (i) increasing cerebral amyloid-β accumulation in mice with pre-existing Alzheimer's disease pathology, (ii) increasing neurologic and systemic inflammation in wild-type mice and mice with pre-existing Alzheimer's disease pathology, and (iii) increasing hippocampal blood-brain barrier permeability in wild-type mice and mice with pre-existing Alzheimer's disease pathology.MethodsWe subjected double transgenic Alzheimer's disease (APP/PSEN1) and wild-type mice to mechanical ventilation for 4 h and compared to non-mechanically ventilated Alzheimer's disease model and wild-type mice. Cerebral soluble/insoluble amyloid-β1-40/amyloid-β1-42 and neurological and systemic markers of inflammation were quantified. Hippocampal blood-brain barrier permeability was quantified using a novel methodology that enabled assessment of small and large molecule permeability across the blood-brain barrier.ResultsMechanical ventilation resulted in (i) a significant increase in cerebral soluble amyloid-β1-40 (p = 0.007) and (ii) significant increases in neuroinflammatory cytokines in both wild-type and Alzheimer's disease mice which, in most cases, were not reflected in the plasma. There were (i) direct correlations between polymorphonuclear cells in the bronchoalveolar fluid and cerebral soluble amyloid-β1-40 (p = 0.0033), and several Alzheimer's disease-relevant neuroinflammatory biomarkers including cerebral TNF-α and IL-6; (iii) significant decreases in blood-brain barrier permeability in mechanically ventilated Alzheimer's disease mice and a trend towards increased blood-brain barrier permeability in mechanically ventilated wild-type mice.ConclusionsThese results provide the first evidence that short-term mechanical ventilation independently promotes the neuropathology of Alzheimer's disease in subjects with and without pre-existing cerebral Alzheimer's disease pathology. Future studies are needed to further clarify the specific mechanisms by which this occurs and to develop neuroprotective mechanical ventilation strategies that mitigate the risk of cognitive decline after critical illness.

Project description:BackgroundThe oral, selective SMN2-splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients ≥ 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1-4 SMN2 gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy.Patients and methodsPatients with SMA1/2, aged ≥ 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs).ResultsBetween March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving ≥ 1 risdiplam dose, respectively. The median (range) age was 10.5 (3-52) years in the SMA1 cohort, and 26.5 (3-60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naïve. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients.ConclusionsWe present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam.

Project description:BackgroundThe probability of weaning and of long-term survival of chronically mechanically ventilated cancer patients is unknown, with incomplete information available to guide therapeutic decisions. We sought to determine the probability of weaning and overall survival of cancer patients requiring long-term mechanical ventilation in a specialized weaning unit.MethodsA single-institution retrospective review of patients requiring mechanical ventilation outside of a critical care setting from 2008 to 2012 and from January 1 to December 31, 2018, was performed. Demographic and clinical data were recorded, including cancer specifics, comorbidities, treatments, and outcomes. Overall survival was determined using the Kaplan-Meier approach. Time to weaning was analyzed using the cumulative incidence function, with death considered a competing risk. Prognostic factors were evaluated for use in prospective evaluations of weaning protocols.ResultsBetween 2008 and 2012, 122 patients required mechanical ventilation outside of a critical care setting with weaning as a goal of care. The cumulative incidence of weaning after discharge from the intensive care unit was 42% at 21 days, 49% at 30 days, 58% at 60 days, 61% at 90 days, and 61% at 120 days. The median survival was 0.16 years (95% CI, 0.12 to 0.33) for those not weaned and 1.05 years (95% CI, 0.60 to 1.34) for those weaned. Overall survival at 1 year and 2 years was 52 and 32% among those weaned and 16 and 9% among those not weaned. During 2018, 36 patients at our institution required mechanical ventilation outside of a critical care setting, with weaning as a goal of care. Overall, with a median follow-up of 140 days (range, 0-425 days; average, 141 days), 25% of patients requiring long-term mechanical ventilation (9 of 36) are alive.ConclusionsCancer patients can be weaned from long-term mechanical ventilation, even after prolonged periods of support. Implementation of a resource-intensive weaning program did not improve rates of successful weaning. No clear time on mechanical ventilation could be identified beyond which weaning was unprecedented. Short-term overall survival for these patients is poor.

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

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