Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial.

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients. Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization. Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39-1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360-842] vs. 870 mg [IQR 364-1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00-17.5] vs. 18.5 days [3.00-53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05-2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC. Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19. Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis.

BACKGROUND: A higher incidence of thrombotic events, mainly pulmonary embolism (PE), has been reported in hospitalized patients with COVID-19. The main objective was to assess clinical and laboratory differences in hospitalized COVID-19 patients according to occurrence of PE. METHODS: This retrospective study included all consecutive patients hospitalized with COVID-19 who underwent a computed tomography (CT) angiography for PE clinical suspicion. Clinical data and median blood test results distributed into weekly periods from COVID-19 symptoms onset, were compared between PE and non-PE patients. RESULTS: Ninety-two patients were included, 29 (32%) had PE. PE patients were younger (63.9 (SD 13.7) vs 69.9 (SD 12.5) years). Clinical symptoms and COVID-19 CT features were similar in both groups. PE was diagnosed after a mean of 20.0 (SD 8.6) days from the onset of COVID-19 symptoms. Corticosteroid boluses were more frequently used in PE patients (62% vs. 43%). No patients met ISTH DIC criteria. Any parameter was statistically significant or clinically relevant except for D-Dimer when comparing both groups. Median values [IQR] of D-dimer in PE vs non-PE patients were: week 2 (2010.7 [770.1-11208.9] vs 626.0 [374.0-2382.2]; p = 0.004); week 3 (3893.1 [1388.2-6694.0] vs 1184.4 [461.8-2447.8]; p = 0.003); and week 4 (2736.3 [1202.1-8514.1] vs 1129.1 [542.5-2834.6]; p = 0.01). Median fold-increase of D-dimer between week 1 and 2 differed between groups (6.64 [3.02-23.05] vs 1.57 [0.64-2.71], p = 0.003); ROC curve AUC was 0.879 (p = 0.003) with a sensitivity and specificity for PE of 86% and 80%, respectively. CONCLUSIONS: Among hospitalized COVID-19 patients, D-dimer levels are higher at weeks 2, 3 and 4 after COVID-19 symptom onset in patients who develop PE. This difference is more pronounced when the fold increase between weeks 1 and 2 is compared.

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registry including adult patients with HHT. A 27-item survey that captured clinical data of admitted HHT patients for COVID-19 was distributed to all RiHHTa investigators from June 8th to June 24th 2020. Only one out of 1177 HHT patients was admitted for COVID-19 pneumonia. She is a 74 years-old woman with a pathogenic variant in ACVRL1 gene. Her clinical course did not involve mechanical ventilation or worsening epistaxis, and she was successfully discharged after two weeks. The endothelial damage and the consequent angiogenic process in COVID-19 patients deserve further investigation.

Beneficial effect of corticosteroids in preventing mortality in patients receiving tocilizumab to treat severe COVID-19 illness.

OBJECTIVES: To assess the characteristics and risk factors for mortality in patients with severe coronavirus disease-2019 (COVID-19) treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). METHODS: From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. RESULTS: A total of 1,092 patients with COVID-19 were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186 patients, 155 (83.3 %) patients were receiving noninvasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (±4.3) and 4.3 days (±3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p < 0.001), chronic heart failure (HR = 4.4, p = 0.003), and chronic liver disease (HR = 4.69, p = 0.004). The use of CS, in combination with TCZ, was identified as a protective factor against mortality (HR = 0.26, p < 0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up. CONCLUSIONS: In patients with severe COVID-19 receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed a beneficial effect in preventing in-hospital mortality.