Benefits of early aggressive immunomodulatory therapy (tocilizumab and methylprednisolone) in COVID-19: Single center cohort study of 685 patients.

INTRODUCTION: A growing evidence suggests that immune dysregulation and thrombotic phenomena are key features in the pathophysiology of COVID-19. Apart from antivirals and respiratory support, anticoagulants, corticoids and immunomodulators are increasingly being prescribed, especially for more severe cases. We describe the clinical outcome of a large cohort of patients preferentially treated with glucocorticoids and interleukin inhibitors. METHODS: Single center and retrospective case series. Adult patients admitted with COVID-19 related respiratory insufficiency were included. Patients who died within 2 days after admission and those testing positive but asymptomatic were excluded. We defined two study periods: from March 3rd to March 31 st, 2020 (beginning of epidemic until peak of incidence) and April 1 st to May 7 th, 2020 (second half of epidemic). The majority of patients received respiratory support, combinations of antimicrobials, anticoagulants, corticoids and interleukin inhibitors. Antivirals were preferentially given in the first period. The clinical outcome (death and ventilator dependency) of both periods was compared. RESULTS: From March 3 rd to May 7 th, 685 patients were included for analysis (58.4% males, mean age 68.9 years). Patients in the first period (n â€‹= â€‹408) were younger (66.6 vs 71.1 years, p â€‹= â€‹0.003), presented lower mean P a O 2/F i O2 ratio at admission (256.5 vs 270.4 â€‹mm Hg,p â€‹= â€‹0.0563), higher ferritin (1520 vs 1221 â€‹ng/ml, p â€‹= â€‹0.01), higher IL-6 (679 vs 194 â€‹pg/ml, p â€‹< â€‹0.0001) and similar D-dimer levels (3.59 vs 3.39 â€‹µg/mL, p â€‹= â€‹0.65) compared to the second period (n â€‹= â€‹277). Lopinavir/ritonavir and interferon were preferentially given in the first period (23.8% and 32% vs 1.8% and 11.9%, p â€‹< â€‹0.0001). Use of corticoids (88.2% vs 87.4%, p â€‹= â€‹0,74) and tocilizumab (26.29 vs 20.22% p â€‹= â€‹0.06) were similarly administered in both periods. Patients in the second period needed less mechanical ventilation (4.9% vs 16.9%, p â€‹< â€‹0.0001), fewer ICU admission (6.1% vs 20.1%,p â€‹< â€‹0.0001) and showed similar mortality (17.7% vs 15.4%, p â€‹= â€‹0.43). Infectious and thrombotic complications were comparable in both periods (both around 8%, with no statistical difference). Patients treated with tocilizumab (n â€‹= â€‹163) had lower mortality rate compared to those untreated under the same indication (7.9% vs 24.2%, p â€‹< â€‹0.0001). CONCLUSIONS: In this large retrospective COVID-19 in-hospital cohort, lopinavir/ritonavir and interferon showed no significant impact on survival. Extensive use of corticosteroids and tocilizumab resulted in good overall outcome and showed acceptable complication rates.

High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients.

OBJECTIVE: Severely ill COVID-19 patients may end in acute respiratory distress syndrome (ARDS) and multi-organ failure. Some of them develop a systemic hyperinflammatory state produced by the massive release of inflammatory agents, known as cytokine storm syndrome (CSS). Inhibition of IL-1 by Anakinra (ANK) is a potential life-saving therapy for severe CSS cases. We propose a rationale for the use of subcutaneous ANK and review our initial experience in a small cohort of severe COVID-19 CSS patients. METHODS: Retrospective cohort study of COVID-19 patients developing ARDS (PaO2/FiO2 <300) and exhibiting signs of hyperinflammation (ferritin >1000 ng/mL and/or d-dimers > 1.5 µg/mL, plus IL-6 < 40 mg/mL) that received ANK. For comparison, a propensity score matched historical cohort of patients treated with IL-6 inhibitor Tocilizumab (TCZ) was used. Patients had previously received combinations of azithromycin, hydroxy-chloroquine, and methyl-prednisolone. Laboratory findings, respiratory function and adverse effects were monitored. Resolution of ARDS within the first 7 days of treatment was considered a favorable outcome. RESULTS: Subcutaneous ANK (100 mg every 6 h) was given to 9 COVID-19 ARDS CSS patients (77.8% males). Median age was 62 years (range, 42 to 87). A TCZ cohort of 18 patients was selected by propensity score matching and treated with intravenous single dose of 600 mg for patients weighing >75 Kg, or 400 mg if < 75 Kg. Prior to treatment, median PaO2/FiO2 ratio of the ANK and TCZ cohorts were 193 and 249, respectively (p = 0.131). After 7 days of treatment, PaO2/FiO2 ratio improved in both groups to 279 (104-335) and 331 (140-476, p = 0.099) respectively. On day 7, there was significant reduction of ferritin (p = 0.046), CRP (p = 0.043), and IL-6 (p = 0.043) levels in the ANK cohort but only of CRP (p = 0.001) in the TCZ group. Favorable outcome was achieved in 55.6% and 88.9% of the ANK and TCZ cohorts, respectively (p = 0.281). Two patients that failed to respond to TCZ improved after ANK treatment. Aminotransferase levels significantly increased between day 1 and day 7 (p = 0.004) in the TCZ group. Mortality was the same in both groups (11%). There were not any opportunistic infection in the groups nor other adverse effects attributable to treatment. CONCLUSION: Overall, 55.6% of COVID-19 ARDS CSS patients treated with ANK exhibited favorable outcome, not inferior to a TCZ treated matched cohort. ANK may be a potential alternative to TCZ for patients with elevated aminotransferases, and may be useful in non-responders to TCZ.

Necrosis cutánea secundaria a terlipresina, un raro pero grave efecto secundario. Reporte de un caso y revisión de la literatura / Cutaneous necrosis secondary to terlipressin therapy. A rare but serious side effect. Case report and literature review

La terlipresina es un análogo de la vasopresina, utilizado tanto en el tratamiento de la hemorragia por varices esofágicas como en el síndrome hepatorrenal. En general es un fármaco seguro, con efectos secundarios leves. Sin embargo, en ocasiones pueden ocurrir complicaciones isquémicas potencialmente graves, como la necrosis cutánea, que es necesario reconocer de forma precoz para realizar la retirada inmediata del fármaco. Presentamos el caso de una paciente que presentó necrosis cutánea extensa secundaria a la administración de terlipresina, y realizamos una revisión de los casos publicados, describiendo sus características, posibles factores de riesgo, localización de las lesiones, dosis recibida, forma de administración y posibles tratamientos (AU)

Terlipressin is a vasopressin analogue used in esophageal variceal bleeding and hepatorenal syndrome management. It is a safe drug with mild secondary effects. However, potentially serious ischemic complications may occur, such as cutaneous necrosis. It is useful to recognize these events early, in order to withdraw terlipressin and introduce other adjuvant drugs if needed. We report a detailed case of cutaneous necrosis secondary to terlipressin administration and present a case review of patients, describing their characteristics, risk factors, lesion locations, doses, methods of administration and possible treatments (AU)

Cutaneous necrosis secondary to terlipressin therapy. A rare but serious side effect. Case report and literature review.

Terlipressin is a vasopressin analogue used in esophageal variceal bleeding and hepatorenal syndrome management. It is a safe drug with mild secondary effects. However, potentially serious ischemic complications may occur, such as cutaneous necrosis. It is useful to recognize these events early, in order to withdraw terlipressin and introduce other adjuvant drugs if needed. We report a detailed case of cutaneous necrosis secondary to terlipressin administration and present a case review of patients, describing their characteristics, risk factors, lesion locations, doses, methods of administration and possible treatments.

TRAF-mediated modulation of NF-kB AND JNK activation by TNFR2.

Tumor Necrosis Factor Receptor 2 (TNFR2) activates transcription factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). Most of the biological activities triggered by TNFR2 depend on the recruitment of TNF Receptor-Associated Factor 2 (TRAF2) to the intracellular region of the receptor. The intracellular region of TNFR2 contains five highly conserved amino acid sequences, three of which appear implicated in receptor signaling. In this work we have studied the interaction of TNFR2 with TRAF proteins as well as the functional consequences of this interaction. We show that TRAF1, TRAF2 and TRAF3 bind to the receptor through two different binding sites located at conserved modules IV and V of its intracellular region, respectively. We also show that TRAF1 and TRAF3 have opposite effects to TRAF2 on NF-κB and JNK activation by TNFR2. Moreover, we show that TNFR2 is able to induce JNK activation in a TRAF2-independent fashion. This new receptor activity relies on a sequence located in the conserved module III. This region is also responsible for the ability of TNFR2 to induce TRAF2 degradation, thus emphasizing the role of conserved module III (amino acids 338-379) on receptor signaling and regulation. We show that only TNFR2 can induce TRAF2 degradation while TRAF1 or TRAF3 is not subjected to this regulatory mechanism and that TRAF1, but not TRAF3, is able to inhibit TRAF2 degradation.

A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1.

Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity.