Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study).

Background: Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. Methods: In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings: Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths. Interpretation: The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results. Funding: This study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.

Clinical Dilemma of Diabetic Ketoacidosis and COVID-19 Infection

The COVID-19 Pneumonia with diabetic ketoacidosis is a dreadful health condition. Diabetic ketoacidosis is one of the severe metabolic complications and it can be precipitated by infection. We presented a case of 48 years female with no known comorbidities who presented with COVID-19 symptoms and with Diabetic Ketoacidosis. The case presented with elevated inflammatory markers, high anion gap metabolic acidosis with type I respiratory failure. During admission, the oxygen saturation had marked drop, later her improvement was steady followed by gradual tapering of the oxygenation. Marked improvement was noticed in the subsequent follow-up. COVID-19 infection can be precipitated by preexisting diabetes or newly diagnosed diabetes and the severity of COVID-19 infection is more pronounced in patients with diabetes mellitus, thus should be managed timely and accordingly. The scarce studies among the COVID-19 cases with diabetic ketoacidosis reflect the need for further studies for the availability of a wider range of information. Copyright © 2021, Kathmandu University. All rights reserved.

Comparison of the efficacy of equivalent doses of dexamethasone, methylprednisolone, and hydrocortisone for treatment of COVID-19-related acute respiratory distress syndrome: a prospective three-arm randomized clinical trial.

BACKGROUND: This prospective controlled clinical trial aimed to compare the efficacy of methylprednisolone, dexamethasone, and hydrocortisone at equivalent doses in patients with severe COVID-19. METHODS: In total, 106 patients with mild to moderate COVID-19-related acute respiratory distress syndrome (ARDS) were randomized to receive either dexamethasone (6 mg once a day), methylprednisolone (16 mg twice a day), or hydrocortisone (50 mg thrice a day) for up to 10 days. All participants received a standard of care for COVID-19. The primary and secondary efficacy outcomes included all-cause 28-day mortality, clinical status on day 28 assessed using the World Health Organization (WHO) eight-category ordinal clinical scale, number of patients requiring mechanical ventilation and intensive care unit (ICU) care, number of ventilator-free days, length of hospital and ICU stay, change in PaO2:FiO2 ratios during the first 5 days after treatment, and incidence of serious adverse events. P-values below 0.008 based on Bonferroni's multiple-testing correction method were considered statistically significant. RESULTS: According to the obtained results, there was a trend toward more favorable clinical outcomes in terms of needing mechanical ventilation and ICU care, number of ventilator-free days, change in PaO2:FiO2 ratios during the first 5 days after treatment, clinical status score at day 28, length of ICU and hospital stay, and overall 28-day mortality in patients receiving dexamethasone compared to those receiving methylprednisolone or hydrocortisone; however, likely due to the study's small sample size, the difference between groups reached a significant level only in the case of clinical status score on day 28 (p-value = 0.003). There was no significant difference in the incidence of serious adverse events between the study groups. CONCLUSION: Based on the results, severe cases of COVID-19 treated with dexamethasone might have a better clinical status at 28-day follow-up compared to methylprednisolone and hydrocortisone at an equivalent dose. Larger multicenter trials are required to confirm our findings.

Clinical Dilemma of Diabetic Ketoacidosis and COVID-19 Infection

The COVID-19 Pneumonia with diabetic ketoacidosis is a dreadful health condition. Diabetic ketoacidosis is one of the severe metabolic complications and it can be precipitated by infection. We presented a case of 48 years female with no known comorbidities who presented with COVID-19 symptoms and with Diabetic Ketoacidosis. The case presented with elevated inflammatory markers, high anion gap metabolic acidosis with type I respiratory failure. During admission, the oxygen saturation had marked drop, later her improvement was steady followed by gradual tapering of the oxygenation. Marked improvement was noticed in the subsequent follow-up. COVID-19 infection can be precipitated by preexisting diabetes or newly diagnosed diabetes and the severity of COVID-19 infection is more pronounced in patients with diabetes mellitus, thus should be managed timely and accordingly. The scarce studies among the COVID-19 cases with diabetic ketoacidosis reflect the need for further studies for the availability of a wider range of information. © 2021, Kathmandu University. All rights reserved.

Case Report: Potential Role of Corticosteroids in the Management of Post-COVID-19 Pneumonia.

Certain patients who recover from severe pneumonia due to coronavirus disease 2019 (COVID-19) remain symptomatic in the post-infectious period, either clinically, radiologically, or respiratory. The post-COVID-19 period is characterized by clinical symptoms of varying duration from one subject to another and does not seem to depend on the severity of initial pneumonia. The persisting inflammatory and/or immune reactions in the post-COVID-19 period may play a role in the development of pulmonary lesions. Here, we report the case of a 61-year-old man with severe COVID-19 pneumonia, complicated by acute respiratory distress syndrome and pulmonary embolism, which required the patient's admission to the intensive care unit and high-flow oxygen therapy. The patient was hospitalized for 23 days for the management of his severe COVID-19 pneumonia. Afterwards, he was discharged home following a negative SARS-CoV-2 PCR test. The post-COVID-19 period was characterized by a complex respiratory symptomatology associating cough, resting dyspnea, and exertional dyspnea requiring oxygen therapy for several weeks. Surprisingly, the follow-up chest CT scan performed 4 weeks after discharge revealed bilateral interstitial lung lesions. After ruling out pulmonary superinfection, the patient was treated with oral corticosteroid for 3 months at a digressive dose. In our case, the use of corticosteroid therapy in the post-COVID19 phase had improved the outcome of the lung disease. These benefits are characterized by a rapid symptomatic improvement, accelerated repair of pulmonary images, rapid oxygen withdrawal, and rapid return to daily activities.

Intravenous methylprednisolone with or without tocilizumab in patients with severe COVID-19 pneumonia requiring oxygen support: A prospective comparison.

BACKGROUND: Cytokine storm is a marker of severity and severe mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia. Immunomodulatory treatments may reduce morbidity and mortality. OBJECTIVES: To determine whether a 7-day course of methylprednisolone (MP) administered with and without tocilizumab improves outcomes in patients with severe COVID-19 (SARS-CoV-2) pneumonia requiring oxygen therapy, relative to historical controls. STUDY DESIGN AND METHOD: In this randomized controlled study, patients hospitalized with severe COVID-19 at Rashid Hospital, Dubai, in June 2020 were randomized 1:1 to receive intravenous MP (40 mg twice daily for 7 days) with or without a single dose of intravenous tocilizumab (400 mg). While data from the control arm, consisting of patients administered usual care, were obtained through retrospective review of their electronic medical records. The patients in the three arms were matched by disease severity and inclusion and exclusion criteria. The primary outcomes were day 45 all-cause mortality after randomization, rate of admission to the intensive care unit (ICU), length of ICU stay, days on ventilators, and length of hospital stay. RESULTS: In total, 76 patients were recruited, including 23 treated with MP, 26 with MP plus tocilizumab, and 27 historical controls. The rates of admission to the ICU and invasive mechanical ventilation were lowest in patients treated with MP alone, with the rates in this group being significantly lower than the rates in the control group (p = 0.04). Time on a ventilator was lowest in the MP group (1.09 ± 3.68 days) and highest in the control group (7.93 ± 14.86 days). The number of days in the ICU was significantly lower in the MP group than in the control and MP plus tocilizumab groups (p = 0.043). One patient (4.3%) in the MP group and five (18.5%) in the control arm died within 45 days. Survival was highest in patients treated with MP alone, with the addition of tocilizumab not improving survival or any of the other outcomes significantly. INTERPRETATION/CONCLUSION: In patients with severe COVID-19 pneumonia on oxygen support, administration of MP daily for 7 days had reduced mortality at 45 days and was associated with significantly lower ICU admission and ventilation rates compared with usual. Adding tocilizumab to MP did not improve any of the studied outcomes significantly.

Impact of high dose of baricitinib in severe COVID-19 pneumonia: a prospective cohort study in Bangladesh.

PURPOSE: Hyperinflammation in severe COVID-19 infection increases the risk of respiratory failure and one of the cogent reasons of mortality associated with COVID-19. Baricitinib, a janus kinases inhibitor, can potentially suppress inflammatory cascades in severe COVID-19 pneumonia. METHODS: The objective of this study was to compare the clinical outcomes of high dose of baricitinib with its usual dose in patients with severe COVID-19 pneumonia. This prospective cohort study was conducted on 238 adult patients with severe COVID-19 pneumonia. Eight milligram and 4 mg of baricitinib was given orally to 122 patients in the high dose (HD) group and 116 patients the usual dose (UD) group, respectively daily for 14 days, and clinical outcomes were compared among the groups. RESULTS: Blood oxygen saturation level was stabilized (≥94% on room air) earlier in the HD group compared to the UD group [5 (IQR: 4-5)/8 (IQR: 6-9), P < 0.05]. Patients in the HD group required intensive care unit (ICU) and intubation supports more in the UD group than that in patients of the HD group [17.2%/9%, P < 0.05; 11.2%/4.1%, P > 0.05; N = 116/122, respectively]. The 30-day mortality and 60-day rehospitalization rate were higher in the UD group than the HD group [6%/3.3%, P < 0.01; 11.9%/7.6%, P > 0.05; N = 116/122, respectively]. CONCLUSION: The daily high dose of baricitinib in severe COVID-19 results in early stabilization of the respiratory functions, declined requirements of critical care supports, reduced rehospitalization with mortality rate compared to its daily usual dose.

Cerebral Venous Thrombosis in Acute Lymphoblastic Leukemia with Severe COVID-19: a Case Report.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought an unprecedented upheaval in our health-care systems. Amongst the many challenges posed by the disease, increased risk of thromboembolism has presented a distinct new front for increased mortality and morbidity. While there are multiple documented evidences for the same, the exact mechanism, knowledge of groups at-risk, and mitigation strategies are evolving. We present a case of a young individual who was diagnosed with acute lymphoblastic leukemia (ALL), was started on appropriate chemotherapy, and subsequently developed severe COVID-19 pneumonia. He was treated for COVID-19 pneumonia and recovered from the illness. However, his recovery from COVID-19 was further complicated by cortical venous sinus thrombosis (CVT). Contrast enhanced magnetic resonance imaging (CEMRI) brain and magnetic resonance venography (MRV) revealed the diagnosis of CVT with hemorrhagic parenchymal changes. He was managed with therapeutic anticoagulation and cerebral decongestants and was subsequently shifted to oral anticoagulant therapy. While the case was managed at a tertiary care setting, it opened up the question of identifying the high-risk groups and to formulate guidelines for extended thromboprophylaxis in these patients.

Radiomics analysis of chest CT to predict the overall survival for the severe patients of COVID-19 pneumonia.

Personalized assessment and treatment of severe patients with COVID-19 pneumonia have greatly affected the prognosis and survival of these patients. This study aimed to develop the radiomics models as the potential biomarkers to estimate the overall survival (OS) for the COVID-19 severe patients. A total of 74 COVID-19 severe patients were enrolled in this study, and 30 of them died during the follow-up period. First, the clinical risk factors of the patients were analyzed. Then, two radiomics signatures were constructed based on two segmented volumes of interest of whole lung area and lesion area. Two combination models were built depend on whether the clinic risk factors were used and/or whether two radiomics signatures were combined. Kaplan-Meier analysis were performed for validating two radiomics signatures and C-index was used to evaluated the predictive performance of all radiomics signatures and combination models. Finally, a radiomics nomogram combining radiomics signatures with clinical risk factors was developed for predicting personalized OS, and then assessed with respect to the calibration curve. Three clinical risk factors were found, included age, malignancy and highest temperature that influence OS. Both two radiomics signatures could effectively stratify the risk of OS in COVID-19 severe patients. The predictive performance of the combination model with two radiomics signatures was better than that only one radiomics signature was used, and became better when three clinical risk factors were interpolated. Calibration curves showed good agreement in both 15 d survival and 30 d survival between the estimation with the constructed nomogram and actual observation. Both two constructed radiomics signatures can act as the potential biomarkers for risk stratification of OS in COVID-19 severe patients. The radiomics+clinical nomogram generated might serve as a potential tool to guide personalized treatment and care for these patients.

Corticosteroid treatment in severe COVID-19 pneumonia: two cases and literature review.

Coronavirus disease 2019 (COVID-19) pneumonia, firstly reported in Wuhan, Hubei province, China, has rapidly spread around the world with high mortality rate among critically ill patients. The use of corticosteroids in COVID-19 remains a major controversy. Available evidences are inconclusive. According to WHO guidance, corticosteroids are not recommended to be used unless for another reason. Chinese Thoracic Society (CTS) proposes an expert consensus statement that suggests taking a prudent attitude of corticosteroid usage. In our clinical practice, we do not use corticosteroids routinely; only low-to-moderate doses of corticosteroids were given to several severely ill patients prudently. In this paper, we will present two confirmed severe COVID-19 cases admitted to isolation wards in Optical Valley Campus of Tongji hospital, Tongji Medical College, Huazhong University of Science and Technology. We will discuss questions related to corticosteroids usages.