Mycobiome analyses of critically ill COVID-19 patients suggests antifungal prophylaxis may be protective against A. fumigatus-associated mortality (preprint)

Rationale: Covid-associated pulmonary aspergillosis (CAPA) is a life-threatening complication in patients with severe COVID -19. Previously, acute respiratory distress syndrome in patients with COVID-19 has been associated with lung fungal dysbiosis, evidenced by reduced microbial diversity and Candida colonisation. Increased fungal burden in the lungs of critically ill COVID-19 patients is linked to prolonged mechanical ventilation and increased mortality. However, specific mycobiome signatures associated with severe COVID-19 in the context of survival and antifungal drug prophylaxis have not yet been determined and such knowledge could have an important impact on treatment. Objectives: To understand the composition of the respiratory mycobiome in critically ill COVID -19 patients with and without CAPA, the impact of antifungal use and its role in patient outcome. Methods: We performed a multi-national study of 39 COVID-19 patients in intensive care units (ICU) with and without CAPA. Respiratory mycobiome was profiled using ITS1 sequencing and Aspergillus fumigatus burden was further validated using qPCR. Fungal communities were investigated using alpha diversity, beta diversity, taxa prevalence and taxa abundances. Measurements and Main Results: Respiratory mycobiomes were dominated by Candida and Aspergillus. There was no significant association with corticosteroid use or CAPA diagnosis and respiratory fungal communities. Increased A. fumigatus burden was associated with mortality. The use of antifungals at ICU admission was associated with an absence of A. fumigatus. Conclusions: Our findings suggest that systemic antifungal treatment at ICU admission may be protective against A. fumigatus-associated mortality in CAPA.

Intermediate monocytes expansion and homing markers expression in COVID-19 patients associate with kidney dysfunction (preprint)

Patients with severe SARS-CoV-2 infection have an overwhelming inflammatory response characterized by remarkable organs monocyte infiltration. We performed an immunophenotypic analysis on circulating monocytes in 19 COVID-19 patients in comparison with 11 naïve HIV-1 patients and 10 healthy subjects. Reduced frequency of classical monocytes and increased frequency of intermediate monocytes characterized COVID-19 patients with respect to both HIV naïve patients and healthy subjects. Intensity of C-C motif chemokine receptor 2 (CCR2) monocyte expression highly correlated with parameters of kidney dysfunction. Our data indicate that highly activated monocytes of COVID-19 patients may be pathogenically associated to the development of renal disease.

Neurological Complications and Noninvasive Multimodal Neuromonitoring in Critically ill COVID-19 Patients (preprint)

Background: The incidence and clinical presentation of neurological manifestations of coronavirus disease 2019 (COVID-19) remain unclear. No data regarding the use of neuromonitoring tools in this group of patients are available. Methods: This is a retrospective study of prospectively collected data. The primary aim was to assess the incidence and type of neurological complications in critically ill COVID-19 patients and their effect on survival, as well as on hospital and intensive care unit (ICU) length-of-stay. The secondary aim was to describe cerebral hemodynamic changes detected by noninvasive neuromonitoring modalities such as transcranial doppler (TCD), optic nerve sheath diameter (ONSD), and pupillometry. Results: Ninety-four patients with COVID-19 receiving mechanical ventilation and admitted to an ICU from February 28 to June 30, 2020, were included in this study. Fifty-three patients underwent noninvasive neuromonitoring. Neurological complications were detected in 47/94 patients (50%), with delirium as the most common manifestation. Patients with neurological complications, compared to those without, had longer hospital (36.8±25.1 vs. 19.4±16.9 days, p <0.001) and ICU (31.5±22.6 vs. 11.5±10.1 days, p <0.001) stay. The duration of mechanical ventilation was independently associated with risk of developing neurological complications (OR 1.100, 95%CI 1.046-1.175, p=0.001). Patients with increased intracranial pressure (ICP) measured by ONSD (19% of the overall population) had longer ICU stays. Conclusions: In conclusion, neurological complications are common in critically ill patients with COVID-19 receiving invasive mechanical ventilation and are associated with prolonged ICU length-of-stay. Multimodal noninvasive neuromonitoring systems are useful tools for early detection of cerebrovascular changes in COVID-19. Registration number: 163/2020

Tocilizumab and steroid treatment in patients with severe Covid-19 pneumonia. (preprint)

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome. MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW). ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n=29, 22.3%), methylprednisolone (n=45, 34.6%), or both (n=56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW 0.48, 95%CI, 0.23-0.99; p=0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW 0.41, 95%CI: 0.19-0.89, p=0.025. ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.