Myocarditis mortality with and without COVID-19: insights from a national registry.

BACKGROUND: Myocarditis in context of a SARS-CoV-2 infection is vividly discussed in the literature. Real-world data however are sparse, and relevance of the myocarditis diagnosis to outcome in coronavirus disease (COVID-19) is unclear. PATIENTS AND METHODS: Retrospective analysis of 75,304 patients hospitalized in Germany with myocarditis between 2007 and 2020 is reported by DESTATIS. Patients hospitalized between 01/2016 and 12/2019 served as reference cohort for the COVID-19 patients hospitalized in 2020. RESULTS: A total of 75,304 patients were hospitalized between 2007 and 2020 (age 42.5 years, 30.1% female, hospital mortality 2.4%). In the reference cohort, 24,474 patients (age 42.8 years, 29.5% female, hospital mortality 2.2%) were registered. In 2020, annual myocarditis hospitalizations dropped by 19.6% compared to reference (4921 vs. 6119 annual hospitalization), of which 443/4921 (9.0%) were connected to COVID-19. In 2020, hospital mortality of myocarditis in non-COVID-19 patients increased significantly compared to reference (2.9% vs. 2.2%, p = 0.008, OR 1.31, 95% CI 1.08-1.60). In COVID-19 myocarditis, hospital mortality was even higher compared to reference (13.5% vs. 2.2%, p < 0.001, OR 6.93, 95% CI 5.18-9.18). CONCLUSION: The burden of patients with myocarditis and COVID-19 in 2020 was low. Hospital mortality was more than sixfold higher in patients with myocarditis and COVID-19 compared to those with myocarditis but without COVID-19.

[ECMO support during the first two waves of the corona pandemic-a survey of high case volume centers in Germany]. / ECMO-Unterstützung während der ersten 2 Wellen der Coronapandemie ­ eine Umfrage an Zentren mit hohen Fallzahlen in Deutschland.

BACKGROUND: At the onset of the coronavirus pandemic, concerns were raised about sufficiency of available intensive care resources. In many places, routine interventions were postponed and criteria for the allocation of scarce resources were formulated. In Germany, some hospitals were at times seriously burdened during the course of the pandemic. Intensive care units in particular experienced a shortage of resources, which may have led to a restriction of services and a stricter indication setting for resource-intensive measures such as extracorporeal membrane oxygenation (ECMO). The aim of this work is to provide an overview of how these pressures were managed at large ECMO centers in Germany. METHODS: One representative of each major ECMO referral center in Germany was invited to participate in an online survey in spring 2021. RESULTS: Of 34 invitations that were sent out, the survey was answered by 23 participants. In all centers, routine procedures were postponed during the pandemic. Half of the centers increased the number of beds on which ECMO procedures could be offered. Nevertheless, in one-third of the centers, the start of at least one ECMO support was delayed because of a feared resource shortage. In 17% of centers, at least one patient was denied ECMO that he or she would have most likely received under prepandemic conditions. CONCLUSION: The results of this online survey indicate that the experienced pressures and resource constraints led some centers to be cautious about ECMO indications.

SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA-vaccinated individuals.

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.

Extracorporeal membrane oxygenation during the first three waves of the coronavirus disease 2019 pandemic: A retrospective single-center registry study.

BACKGROUND: Despite increasing knowledge about the optimal treatment for patients with severe COVID-19, data from different cohorts suggested that survival of patients treated with ECMO seemed to decline over the course of the pandemic. METHODS: In this non-interventional retrospective single-center registry study we analyzed all consecutive patients tested positive for SARS-CoV-2 infection and supported with VV ECMO in our center during the first three waves of the pandemic. From March 2020 through June 2021, 59 patients have been included. RESULTS: Overall 90-day survival was 32%. Besides changes in drug treatment for COVID-19 and a lower PaO2 /FiO2 ratio before ECMO initiation during the third wave, all other patient baseline characteristics were similar during the three waves. Survival rate was highest during the first wave and lowest during the third wave, yet this difference was not statistically significant. CONCLUSIONS: VV ECMO has shown to be a feasible and safe support option for patients with severe respiratory failure due to COVID-19. The results from this single-center study confirm findings from other cohorts showing declining survival rates of patients treated with VV ECMO during the COVID-19 pandemic, however, the specific reasons for this finding remain unclear.

Case Report: Lymphohistiocytic Myocarditis With Severe Cardiogenic Shock Requiring Mechanical Cardiocirculatory Support in Multisystem Inflammatory Syndrome Following SARS-CoV-2 Infection.

Multisystem Inflammatory Syndrome (MIS) is a novel hyperinflammatory syndrome associated with SARS-CoV-2 infection. It predominantly affects children (MIS-C) a few weeks after a usually asymptomatic SARS-CoV-2 infection and is only rarely seen in adults above 21 years (MIS-A). Only scarce data on histological findings in both pediatric and adult patients has been published so far. An 18-year-old male patient was admitted to hospital in a febrile state, which progressed to severe cardiogenic shock and multi-organ failure requiring extracorporeal life support. Myocardial biopsy revealed small vessel-associated immune cell infiltrates. Diagnosis of MIS-C was made after ruling out all potential differential diagnosis. Use of immunosuppressive treatment with steroids, interleukin-1 blockade and high-dose intravenous immunoglobulins resulted in the patient's full recovery. Multisystem Inflammatory Syndrome (MIS) is a new differential diagnosis of cardiac dysfunction in pediatric and adult patients. The lack of myocardial necrosis differentiates the disease from other viral myocarditis and offers an explanation for the fast response to immunomodulatory therapy and the favorable prognosis. The preceding SARS-CoV-2 infection might only have been mildly symptomatic or even asymptomatic.

Delirium in Critically Ill Patients with and without COVID-19-A Retrospective Analysis.

BACKGROUND: Delirium complicating the course of Intensive care unit (ICU) therapy is a known driver of morbidity and mortality. It has been speculated that infection with the neurotrophic SARS-CoV-2 might promote delirium. METHODS: Retrospective registry analysis including all patients treated at least 48 h on a medical intensive care unit. The primary endpoint was development of delirium as diagnosed by Nursing Delirium screening scale ≥2. Results were confirmed by propensity score matching. RESULTS: 542 patients were included. The primary endpoint was reached in 352/542 (64.9%) patients, without significant differences between COVID-19 patients and non-COVID-19 patients (51.4% and 65.9%, respectively, p = 0.07) and correlated with prolonged ICU stay in both groups. In a subgroup of patients with ICU stay >10 days delirium was significantly lower in COVID-19 patients (p ≤ 0.01). After adjustment for confounders, COVID-19 correlated independently with less ICU delirium (p ≤ 0.01). In the propensity score matched cohort, patients with COVID-19 had significantly lower delirium incidence compared to the matched control patients (p ≤ 0.01). CONCLUSION: Delirium is frequent in critically ill patients with and without COVID-19 treated at an intensive care unit. Data suggests that COVID-19 itself is not a driver of delirium per se.

Influence of immunosuppression in patients with severe acute respiratory distress syndrome on veno-venous extracorporeal membrane oxygenation therapy.

Prognosis of patients suffering from acute respiratory distress syndrome (ARDS) is poor. This is especially true for immunosuppressed patients. It is controverisal whether these patients should receive veno-venous extracorporeal membrane oxygenation (VV ECMO) while evidence on this topic is sparse. We report retrospective data of a single-center registry of patients with severe ARDS requiring ECMO support between October 2010 and June 2019. Patients were analyzed by their status of immunosuppression. ECMO weaning success and hospital survival were analyzed before and after propensity score matching (PSM). Moreover, ventilator free days (VFD) were compared. A total of 288 patients were analyzed (age 55 years, 67% male), 88 (31%) presented with immunosuppression. Survival rates were lower in immunosuppressed patients (27% vs. 53%, P < .001 and 27% vs. 48% after PSM, P = .006). VFD (60 days) were lower for patients with immunosuppression (11.9 vs. 22.4, P < .001), and immunosuppression was an independent predictor for mortality in multivariate analysis. Hospital survival was 20%, 14%, 35%, and 46% for patients with oncological malignancies, solid organ transplantation, autoimmune diseases, and HIV, respectively. In this analysis immunosuppression was an independent predictor for mortality. However, there were major differences in the weaning and survival rates between the etiologies of immunosuppression which should be considered in decision making.

Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial.

BACKGROUND: We sought to clarify the benefit of cytokine adsorption in patients with COVID-19 supported with venovenous extracorporeal membrane oxygenation (ECMO). METHODS: We did a single-centre, open-label, randomised, controlled trial to investigate cytokine adsorption in adult patients with severe COVID-19 pneumonia requiring ECMO. Patients with COVID-19 selected for ECMO at the Freiburg University Medical Center (Freiburg, Germany) were randomly assigned (1:1) to receive cytokine adsorption using the CytoSorb device or not. Randomisation was computer-generated, allocation was concealed by opaque, sequentially numbered sealed envelopes. The CytoSorb device was incorporated into the ECMO circuit before connection to the patient circuit, replaced every 24 h, and removed after 72 h. The primary endpoint was serum interleukin-6 (IL-6) concentration 72 h after initiation of ECMO analysed by intention to treat. Secondary endpoints included 30-day survival. The trial is registered with ClinicalTrials.gov (NCT04324528) and the German Clinical Trials Register (DRKS00021300) and is closed. FINDINGS: From March 29, 2020, to Dec 29, 2020, of 34 patients assessed for eligibility, 17 (50%) were treated with cytokine adsorption and 17 (50%) without. Median IL-6 decreased from 357·0 pg/mL to 98·6 pg/mL in patients randomly assigned to cytokine adsorption and from 289·0 pg/mL to 112·0 pg/mL in the control group after 72 h. One patient in each group died before 72 h. Adjusted mean log IL-6 concentrations after 72 h were 0·30 higher in the cytokine adsorption group (95% CI -0·70 to 1·30, p=0·54). Survival after 30 days was three (18%) of 17 with cytokine adsorption and 13 (76%) of 17 without cytokine adsorption (p=0·0016). INTERPRETATION: Early initiation of cytokine adsorption in patients with severe COVID-19 and venovenous ECMO did not reduce serum IL-6 and had a negative effect on survival. Cytokine adsorption should not be used during the first days of ECMO support in COVID-19. FUNDING: None.

Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients.

Subpleural consolidations have been found in lung ultrasound in patients with COVID-19, possibly deriving from pulmonary embolism (PE). The diagnostic utility of impact of lung ultrasound in critical-ill patients with COVID-19 for PE diagnostics however is unclear. We retrospectively evaluated all SARS-CoV2-associated ARDS patients admitted to our ICU between March 8th and May 31th 2020. They were enrolled in this study, when a lung ultrasound and a computed tomography pulmonary angiography (CTPA) were documented. In addition, wells score was calculated to estimate the probability of PE. The CTPA was used as the gold standard for the detection of PE. Twenty out of 25 patients met the inclusion criteria. In 12/20 patients (60%) (sub-) segmental PE were detected by CT-angiography. Lung ultrasound found subpleural consolidations in 90% of patients. PE-typical large supleural consolidations with a size ≥ 1 cm were detectable in 65% of patients and were significant more frequent in patients with PE compared to those without (p = 0.035). Large consolidations predicted PE with a sensitivity of 77% and a specificity of 71%. The Wells score was significantly higher in patients with PE compared to those without (2.7 ± 0.8 and 1.7 ± 0.5, respectively, p = 0.042) and predicted PE with an AUC of 0.81. When combining the two modalities, comparing patients with considered/probable PE using LUS plus a Wells score ≥ 2 to patients with possible/unlikely PE in LUS plus a Wells score < 2, PE could be predicted with a sensitivity of 100% and a specificity of 80%. Large consolidations detected in lung ultrasound were found frequently in COVID-19 ARDS patients with pulmonary embolism. In combination with a Wells score > 2, this might indicate a high-risk for PE in COVID-19.

Conservative management of COVID-19 associated hypoxaemia.

This correspondence argues that data presented previously cannot justify a novel approach for treating hypoxic patients with severe #COVID19 https://bit.ly/3dLaPlk.

Mobile ECMO retrieval of patients during the COVID-19 pandemic.

ECMO support is particularly resource-intensive and should be provided in highly specialized centers. Occasionally, ECMO needs to be initiated in non-ECMO centers by mobile ECMO retrieval teams. Subsequently, patients must be transferred on ECMO to the ECMO center. We report single-center data from out-of-center initiations of ECMO during the COVID-19 pandemic. From March 2020 through February 2021, nine patients were connected to ECMO before transfer to our center. Median travel distance (IQR) from the referring hospital to our center was 66 km (20-92), median land travel time (IQR) was 51 minutes (26-92). Personal protective equipment was available for all team members and used throughout the missions. No infections of team members with SARS-CoV-2 occurred. Three patients survived until hospital discharge. Median duration of ECMO (IQR) was 18 days (2-78) in survivors and 19 days (9-42) in non-survivors, respectively. Out-of-center initiation of ECMO during the COVID-19 pandemic was feasible and safe for patients and staff.

Hemoadsorption eliminates remdesivir from the circulation: Implications for the treatment of COVID-19.

Both antiviral treatment with remdesivir and hemoadsorption using a CytoSorb® adsorption device are applied in the treatment of severe COVID-19. The CytoSorb® adsorber consists of porous polymer beads that adsorb a broad range of molecules, including cytokines but also several therapeutic drugs. In this study, we evaluated whether remdesivir and its main active metabolite GS-441524 would be adsorbed by CytoSorb® . Serum containing remdesivir or GS-441524 was circulated in a custom-made system containing a CytoSorb® device. Concentrations of remdesivir and GS-441524 before and after the adsorber were analyzed by liquid chromatography-tandem mass spectrometry. Measurements of remdesivir in the outgoing tube after the adsorber indicated almost complete removal of remdesivir by the device. In the reservoir, concentration of remdesivir showed an exponential decay and was not longer detectable after 60 mins. GS-441524 showed a similar exponential decay but, unlike remdesivir, it reached an adsorption-desorption equilibrium at ~48 µg/L. Remdesivir and its main active metabolite GS-441524 are rapidly eliminated from the perfusate by the CytoSorb® adsorber device in vitro. This should be considered in patients for whom both therapies are indicated, and simultaneous application should be avoided. In general, plasma levels of therapeutic drugs should be closely monitored under concurrent CytoSorb® therapy.

Intensive Care Resources and 60-Day Survival of Critically-Ill COVID-19 Patients.

BACKGROUND: Germany reported sufficient intensive care unit (ICU) resources throughout the first wave of coronavirus disease 2019 (COVID-19). The treatment of critically ill COVID-19 patients without rationing may improve the outcome. We therefore analyzed ICU resources allocated to COVID-19 patients with respiratory failure and their outcomes. METHODS: Retrospectively, we enrolled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR)-positive patients with respiratory failure from 03/08/2020 to 04/08/2020 and followed until 05/28/2020 in the university hospital of Freiburg, Germany. RESULTS: In the defined interval, 34 COVID-19 patients were admitted to the ICU with median age of 67±13 (31-86) years. Six of 34 (17.6%) were female. All patients suffered from moderate or severe acute respiratory distress syndrome (ARDS), 91.2% of the patients were intubated and 23.5% required extracorporeal membrane oxygenation (ECMO). Proning was performed in 67.6%, renal replacement therapy (RRT) was required in 35.3%. Ninety-six percent required more than 20 nursing hours per day. Mean ICU stay was 21±19 (1-81) days. Sixty-day survival of critically ill COVID-19 patients was 50.0% (17/34). Causes of death were multi-organ failure (52.9%), refractory ARDS (17.6%) and intracerebral hemorrhage (17.6%). CONCLUSIONS: Treatment of critically ill COVID-19 patients is protracted and resource-intense. In a context without resources shortage, 50% of COVID-19 with respiratory failure survived up to 60 days.

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation-A Retrospective International Multicenter Study.

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. METHODS: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V­V ECMO (PRESERVE) Score, and 30-day survival. RESULTS: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic-AUROC) ranged between 0.548 and 0.605. CONCLUSIONS: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V­V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO.

Intracerebral Hemorrhage in COVID-19 Patients with Pulmonary Failure: A Propensity Score-Matched Registry Study.

BACKGROUND: Hypercoagulability in Coronavirus Disease 2019 (COVID-19) causes deep vein thrombosis and pulmonary embolism necessitating systemic anticoagulation. Case reports of intracerebral hemorrhages in ventilated COVID-19 patients warrant precaution. It is unclear, however, if COVID-19 patients with acute respiratory distress syndrome (ARDS) with or without veno-venous extracorporeal membrane oxygenation therapy (VV-ECMO) have more intracerebral hemorrhages (ICH) compared to other ARDS patients. METHODS: We conducted a retrospective observational single-center study enrolling all patients with ARDS from 01/2018 to 05/2020. PCR-positive SARS-CoV-2 patients with ARDS were allocated to the COVID-19 group. Propensity score matching was performed for age, VV-ECMO, and bleeding risk. RESULTS: A total of 163 patients with moderate or severe ARDS were identified, 47 (28.8%) in the COVID-19 group, and 116 (71.2%) in the non-COVID-19 group. In 63/163 cases (38.7%), VV-ECMO therapy was required. The ICU survival was 52.8%. COVID-19 patients were older, more often male, and exhibited a lower SOFA score, but the groups showed similar rates of VV-ECMO therapy. Treatments with antiplatelet agents (p = 0.043) and therapeutic anticoagulation (p = 0.028) were significantly more frequent in the COVID-19 patients. ICH was detected in 22 patients (13.5%) with no statistical difference between the groups (11.2 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.21). Propensity score matching confirmed similar rates of ICH in both groups (12.8 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.57), thus leveling out possible confounders. CONCLUSIONS: Intracerebral hemorrhage was detected in every tenth patient with ARDS. Despite statistically higher rates of antiplatelet therapy and therapeutic anticoagulation in COVID-19 patients, we found a similar rate of ICH in patients with ARDS due to COVID-19 compared to other causes of ARDS.