Epidemiology, clinical presentation and management of COVID-19 associated Mucormycosis: A single center experience from Pune, Western India. (preprint)

BackgroundThe second COVID-19 wave in India, triggered by the Delta variant,has been associated with an unprecedented increase in cases of COVID-19 associated Mucormycosis(CAM), mainly Rhino-orbito-cerebral mucormycosis(ROCM).The primary reason appears to be an unusual alignment of multiple risk factors in patients like prevalence of hypoxia, uncontrolled diabetes mellitus, indiscriminate use of steroids, high iron levels and immune dysfunction. MethodsThis retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, Western India between 1st April 2020 and 1st August 2021 to identify patients admitted with CAM. The primary endpoint was incidence of all cause mortality due to CAM. Secondary outcomes studied were need for mechanical ventilation and intensive care unit(ICU) admission. Baseline and time dependent risk factors significantly associated with death due to CAM were identified by Relative risk estimation. Results59 patients were diagnosed with Mucormycosis at NHRC (58 ROCM, 1 Renal (disseminated) mucormycosis). Median age of the cohort was 52(IQR: 41,61) years and it included 20.3% females. Median duration from first positive COVID-19 RT PCR test to diagnosis of Mucormycosis was 17(IQR: 12,22) days. 90% patients were diabetic with 30% being newly diagnosed at the time of COVID-19 admission and 89% having uncontrolled sugar level (HbA1c > 7%). All patients were prescribed steroids during treatment for COVID-19. 56% patients were prescribed steroids for non-hypoxemic, mild COVID (irrational steroid therapy) while in 9%, steroids were indicated but were prescribed in inappropriately high dose. Majority of the patients were treated with a combination of surgical debridement(94%), intravenous Amphotericin B(91%) and concomitant oral Posoconazole therapy(95.4%). 74.6% patients were discharged after clinical and radiologic recovery while 25.4% (15 patients) died. On Relative risk analysis, CT severity score during COVID-19 admission [≥]18 (p=0.017), presence of orbital symptoms(p=0.002), presence of diabetic ketoacidosis(p=0.011) and cerebral involvement by Mucor(p=0.0004) were associated with increased risk of death. Duration of Amphotericin B therapy of [≥] 21 days was associated with statistically significant reduction in mortality(p=0.002). ConclusionsCAM is an uncommon, rapidly progressive, angioinvasive, opportunistic fungal infection which is fatal if left untreated. Combination of surgical debridement and antifungal therapy leads to clinical and radiologic improvement in majority of cases.

Seven Days Treatment With the Angiotensin II Type 2 Receptor Agonist C21 in Hospitalized COVID-19 Patients: A Placebo-Controlled Randomized Phase 2 Trial (preprint)

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomized phase 2 trial to evaluate efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. Findings: 106 patients were randomised (51 C21, 55 placebo). There was no significant group difference in CRP (primary endpoint). In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (p=0.057). A post hoc analysis showed that at day 14, the proportion of patients still requiring supplemental oxygen was reduced by 90% in the C21 group compared to placebo (p=0.003). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, there was a marked reduction of requirement for oxygen at day 14. Funding: Vicore Pharma AB and LifeArc.Clinical Trial Registration Details: The study protocol is available online at ClinicalTrials.gov, NCT04452435.Funding Information: Vicore Pharma AB and LifeArc.Declaration of Interests: Dr. Tornling reports personal fees from Vicore Pharma and Vicore Pharma shares. Dr. Batta reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stock options; in addition, Dr. Batta has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Porter has nothing to disclose. Dr. Williams has nothing to disclose. Dr. Bengtsson reports consultancy fees from Vicore Pharma. Dr. Parmar reports grants from Vicore Pharma, during the conduct of the study. Dr. Kashiva reports grants from Vicore Pharma, during the conduct of the study. Dr. Hallberg reports personal fees from Vicore Pharma. Anne Katrine Cohrt reports personal fees from Vicore Pharma and Vicore Pharma stock options. Kate Westergaard reports personal fees from Vicore Pharma. Dr. Dalsgaard reports a grant from LifeArc Medical Research Charity, during the conduct of the study; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Dalsgaard has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Raud reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Raud has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending.Ethics Approval Statement: The protocol, patient information, patient consent form and other documents, as required, were approved by properly constituted IECs and by the national regulatory authorities.

Combination therapy of Tocilizumab and steroid for management of COVID-19 associated cytokine release syndrome: A single center experience from Pune, Western India (preprint)

Background: Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednisolone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for the treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroids in COVID-19 associated CRS. Methods: This retrospective cohort study was conducted at a tertiary level private hospital in Pune, India between 2nd April and 2nd November 2020. All patients administered TCZ and steroids for treatment of CRS were included. The primary endpoint was the incidence of all-cause mortality. Secondary outcomes studied were the need for mechanical ventilation and incidence of infectious complications. Baseline and time-dependent risk factors significantly associated with death were identified by Relative risk estimation. Results: Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. Median age of the cohort was 57 (IQR: 46.5, 66) years. Almost 72 % patients had preexisting co-morbidities. Median time to TCZ administration since onset of symptoms was 9 days (IQR: 7, 11). 63% patients needed intensive care unit (ICU) admission. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Infectious complications like hospital acquired pneumonia, bloodstream bacterial and fungal infections were observed in 2.13 %, 2.13 % and 0.06 % patients respectively. Age [≥] 60 years (p=0.014), presence of co-morbidities like hypertension (p = 0.011), IL-6 [≥] 100 pg/ml (p = 0.002), D-dimer [≥] 1000 ng/ml (p < 0.0001), CT severity index [≥] 18 (p < 0.0001) and systemic complications like lung fibrosis (p = 0.019), cardiac arrhythmia (p < 0.0001), hypotension (p < 0.0001) and encephalopathy (p < 0.0001) were associated with increased risk of death. Conclusions: Combination therapy of TCZ and Steroids is likely to be safe and effective in the management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled clinical trials.

The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial (preprint)

BackgroundAlthough several therapies have been evaluated for treatment of COVID-19, the morbidity and mortality in COVID-19 are still significant, and the need for safe and effective drugs remains high even after launch of vaccine programs. MethodsWe conducted a double-blind, randomized, placebo-controlled trial with the novel oral angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients with C-reactive protein 50-150 mg/L but not needing mechanical ventilation. Patients were randomly assigned to oral C21 (100 mg twice daily) or placebo for 7 days in addition to standard of care, including glucocorticoids and remdesivir. Results106 patients underwent randomization (51 in the C21 group and 55 in the placebo group). At day 14 after start of treatment, the proportion of patients still requiring supplemental oxygen was significantly reduced by 90% in the C21 group compared to the placebo group (p=0.003). Moreover, fewer patients required mechanical ventilation (one C21 patient and four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one and three deaths in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. ConclusionsAs studied in hospitalized COVID-19 patients, C21 on top of standard of care led to a clinically beneficial improvement in respiratory function compared to placebo, paving the way for a pivotal randomised controlled trial. This study is registered at ClinicalTrials.gov with identifier NCT04452435.