Impact of Invasive Pulmonary Aspergillosis in Critically Ill Surgical Patients with or without Solid Organ Transplantation.

BACKGROUND: Critically ill patients, especially those who have undergone solid organ transplantation (SOT), are at risk of invasive pulmonary aspergillosis (IPA). The outcome relevance of adequately treated putative IPA (pIPA) is a matter of debate. The aim of this study is to assess the outcome relevance of pIPA in a cohort of critically ill patients with and without SOT. METHODS: Data from 121 surgical critically ill patients with pIPA (n = 30) or non-pIPA (n = 91) were included. Cox regression analysis was used to identify risk factors for mortality and unfavourable outcomes after 28 and 90 days. RESULTS: Mortality rates at 28 days were similar across the whole cohort of patients (pIPA: 31% vs. non-pIPA: 27%) and did not differ in the subgroup of patients after SOT (pIPA: 17% vs. non-pIPA: 22%). A higher Sequential Organ Failure Assessment (SOFA) score and evidence of bacteraemia were identified as risk factors for mortality and unfavourable outcome, whereas pIPA itself was not identified as an independent predictor for poor outcomes. CONCLUSIONS: Adequately treated pIPA did not increase the risk of death or an unfavourable outcome in this mixed cohort of critically ill patients with or without SOT, whereas higher disease severity and bacteraemia negatively affected the outcome.

Early Treatment with Monoclonal Antibodies or Convalescent Plasma Reduces Mortality in Non-Vaccinated COVID-19 High-Risk Patients.

Vulnerable patients such as immunosuppressed or elderly patients are at high risk for a severe course of COVID-19 upon SARS-CoV-2 infection. Immunotherapy with SARS-CoV-2 specific monoclonal antibodies (mAb) or convalescent plasma represents a considerable treatment option to protect these patients from a severe or lethal course of infection. However, monoclonal antibodies are not always available or less effective against emerging SARS-CoV-2 variants. Convalescent plasma is more commonly available and may represent a good treatment alternative in low-income countries. We retrospectively evaluated outcomes in individuals treated with mAbs or convalescent plasma and compared the 30-day overall survival with a patient cohort that received supportive care due to a lack of SARS-CoV-2 specific therapies between March 2020 and April 2021. Our data demonstrate that mAb treatment is highly effective in preventing severe courses of SARS-CoV-2 infection. All patients treated with mAb survived. Treatment with convalescent plasma improved overall survival to 82% compared with 61% in patients without SARS-CoV-2 targeted therapy. Our data indicate that early convalescent plasma treatment may be an option to improve the overall survival of high-risk COVID-19 patients. This is especially true when other antiviral drugs are not available or their efficacy is significantly reduced, which may be the case with emerging SARS-CoV-2 variants.

Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming

Rationale Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis;however, its function in the host response to viral infections during sepsis remains elusive. Objectives To investigate the role of IL-3 during viral pneumonia in sepsis. Methods We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.

Identification of two early blood biomarkers ACHE and CLEC12A for improved risk stratification of critically ill COVID-19 patients.

In order to identify biomarkers for earlier prediction of COVID-19 outcome, we collected blood samples from patients with fatal outcomes (non-survivors) and with positive clinical outcomes (survivors) at ICU admission and after seven days. COVID-19 survivors and non-survivors showed significantly different transcript levels for 93 genes in whole blood already at ICU admission as revealed by RNA-Seq. These differences became even more pronounced at day 7, resulting in 290 differentially expressed genes. Many identified genes play a role in the differentiation of hematopoietic cells. For validation, we designed an RT-qPCR assay for C-type lectin domain family 12 member A (CLEC12A) and acetylcholinesterase (ACHE), two transcripts that showed highest potential to discriminate between survivors and non-survivors at both time points. Using our combined RT-qPCR assay we examined 33 samples to accurately predict patient survival with an AUROC curve of 0.931 (95% CI = 0.814-1.000) already at ICU admission. CLEC12A and ACHE showed improved prediction of patient outcomes compared to standard clinical biomarkers including CRP and PCT in combination (AUROC = 0.403, 95% CI = 0.108-0.697) or SOFA score (AUROC = 0.701 95% CI = 0.451-0.951) at day 0. Therefore, analyzing CLEC12A and ACHE gene expression from blood may provide a promising approach for early risk stratification of severely ill COVID-19 patients.

Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming.

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive. Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis. Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.

Upregulation of miRNA-200c during Disease Progression in COVID-19 Patients.

The COVID-19 pandemic has caused more than 6 million deaths worldwide since its first outbreak in December 2019 and continues to be a major health problem. Several studies have established that the infection by SARS-CoV-2 can be categorized in a viremic, acute and recovery or severe phase. Hyperinflammation during the acute pneumonia phase is a major cause of severe disease progression and death. Treatment of COVID-19 with directly acting antivirals is limited within a narrow window of time between first clinical symptoms and the hyperinflammatory response. Therefore, early initiation of treatment is crucial to assure optimal health care for patients. Molecular diagnostic biomarkers represent a potent tool to predict the course of disease and thus to assess the optimal treatment regimen and time point. Here, we investigated miRNA-200c as a potential marker for the prediction of the severity of COVID-19 to preventively initiate and personalize therapeutic interventions in the future. We found that miRNA-200c correlates with the severity of disease. With retrospective analysis, however, there is no correlation with prognosis at the time of hospitalization. Our study provides the basis for further evaluation of miRNA-200c as a predictive biomarker for the progress of COVID-19.

Patients with SARS-CoV-2-Induced Viral Sepsis Simultaneously Show Immune Activation, Impaired Immune Function and a Procoagulatory Disease State.

BACKGROUND: It is widely accepted that SARS-CoV-2 causes a dysregulation of immune and coagulation processes. In severely affected patients, viral sepsis may result in life endangering multiple organ dysfunction. Furthermore, most therapies for COVID-19 patients target either the immune system or coagulation processes. As the exact mechanism causing SARS-CoV-2-induced morbidity and mortality was unknown, we started an in-depth analysis of immunologic and coagulation processes. METHODS: 127 COVID-19 patients were treated at the University Hospital Essen, Germany, between May 2020 and February 2022. Patients were divided according to their maximum COVID-19 WHO ordinal severity score (WHO 0-10) into hospitalized patients with a non-severe course of disease (WHO 4-5, n = 52) and those with a severe course of disease (WHO 6-10, n = 75). Non-infected individuals served as healthy controls (WHO 0, n = 42). Blood was analyzed with respect to cell numbers, clotting factors, as well as pro- and anti-inflammatory mediators in plasma. As functional parameters, phagocytosis and inflammatory responses to LPS and antigen-specific stimulation were determined in monocytes, granulocytes, and T cells using flow cytometry. FINDINGS: In the present study, immune and coagulation systems were analyzed simultaneously. Interestingly, many severe COVID-19 patients showed an upregulation of pro-inflammatory mediators and at the same time clear signs of immunosuppression. Furthermore, severe COVID-19 patients not only exhibited a disturbed immune system, but in addition showed a pronounced pro-coagulation phenotype with impaired fibrinolysis. Therefore, our study adds another puzzle piece to the already complex picture of COVID-19 pathology implying that therapies in COVID-19 must be individualized. CONCLUSION: Despite years of research, COVID-19 has not been understood completely and still no therapies exist, fitting all requirements and phases of COVID-19 disease. This observation is highly reminiscent to sepsis. Research in sepsis has been going on for decades, while the disease is still not completely understood and therapies fitting all patients are lacking as well. In both septic and COVID-19 patients, immune activation can be accompanied by immune paralysis, complicating therapeutic intervention. Accordingly, therapies that lower immune activation may cause detrimental effects in patients, who are immune paralyzed by viral infections or sepsis. We therefore suggest individualizing therapies and to broaden the spectrum of immunological parameters analyzed before therapy. Only if the immune status of a patient is understood, can a therapeutic intervention be successful.

[Pathophysiology of sepsis]. / Pathophysiologie der Sepsis.

Up to now, sepsis is one of the most threatening diseases and its therapy remains challenging. Sepsis is currently defined as a severely dysregulated immune response to an infection resulting in organ dysfunction. The pathophysiology is mainly driven by exogenous PAMPs ("pathogen-associated molecular patterns") and endogenous DAMPs ("damage-associated molecular patterns"), which can activate PRRs ("pattern recognition receptors") on different cell types (mainly immune cells), leading to the initiation of manifold downstream pathways and a perpetuation of patients' immune response. Sepsis is neither an exclusive pro- nor an anti-inflammatory disease: both processes take place in parallel, resulting in an individual immunologic disease state depending on the severity of each component at different time points. Septic shock is a complex disorder of the macro- and microcirculation, provoking a severe lack of oxygenation further aggravating sepsis defining organ dysfunctions. An in-depth knowledge of the heterogeneity and the time-dependency of the septic immunopathology will be essential for the design of future sepsis trials and therapy planning in patients with sepsis. The big aim is to achieve a more individualized treatment strategy in patients suffering from sepsis or septic shock.

Effect of Dexamethasone on the Incidence and Outcome of COVID-19 Associated Pulmonary Aspergillosis (CAPA) in Critically Ill Patients during First- and Second Pandemic Wave-A Single Center Experience.

Superinfections with Aspergillus spp. in patients with Coronavirus disease 2019 (CAPA: COVID-19-associated pulmonary aspergillosis) are increasing. Dexamethasone has shown beneficial effects in critically ill COVID-19 patients. Whether dexamethasone increases the risk of CAPA has not been studied exclusively. Moreover, this retrospective study aimed to identify risk factors for a worse outcome in critically ill COVID-19 patients. Data from 231 critically ill COVID-19 patients with or without dexamethasone treatment from March 2020 and March 2021 were retrospectively analysed. Only 4/169 (6.5%) in the DEXA-group and 13/62 (7.7%) in the Non-DEXA group were diagnosed with probable CAPA (p = 0.749). Accordingly, dexamethasone was not identified as a risk factor for CAPA. Moreover, CAPA was not identified as an independent risk factor for death in multivariable analysis (p = 0.361). In contrast, elevated disease severity (as assessed by Sequential Organ Failure Assessment [SOFA]-score) and the need for organ support (kidney replacement therapy and extracorporeal membrane oxygenation [ECMO]) were significantly associated with a worse outcome. Therefore, COVID-19 treatment with dexamethasone did not increase the risk for CAPA. Moreover, adequately treated CAPA did not represent an independent risk factor for mortality. Accordingly, CAPA might reflect patients' severe disease state instead of directly influencing outcome.

The Distinctive Activation of Toll-Like Receptor 4 in Human Samples with Sepsis.

Clinical success of Toll-Like receptor-4 (TLR-4) antagonists in sepsis therapy has thus far been lacking. As inhibition of a receptor can only be useful if the receptor is active, stratification of patients with active TLR-4 would be desirable. Our aim was to establish an assay to quantify phosphorylated TLR-4 using the proximity ligation assay (PLA). HEK293 TLR4/MD2/CD14 as well as THP-1 cells were stimulated with LPS and the activation of TLR-4 was measured using the PLA. Furthermore, peripheral blood mononuclear cells (PBMCs) from 25 sepsis patients were used to show the feasibility of this assay in clinical material. Activation of TLR-4 in these samples was compared to the PBMCs of 11 healthy individuals. We could show a transient activation of TLR-4 in both cell lines. Five min after the LPS stimulation, the signal increased 6.7-fold in the HEK293 cells and 4.3-fold in the THP-1 cells. The assay also worked well in the PBMCs of septic patients. Phosphorylation of TLR-4 at study inclusion was 2.9 times higher in septic patients compared to healthy volunteers. To conclude, we established a diagnostic assay that is able to quantify the phosphorylation of TLR-4 in cell culture and in clinical samples of sepsis patients. This makes large-scale stratification of sepsis patients for their TLR-4 activation status possible.

Biomarkers extracted by fully automated body composition analysis from chest CT correlate with SARS-CoV-2 outcome severity.

The complex process of manual biomarker extraction from body composition analysis (BCA) has far restricted the analysis of SARS-CoV-2 outcomes to small patient cohorts and a limited number of tissue types. We investigate the association of two BCA-based biomarkers with the development of severe SARS-CoV-2 infections for 918 patients (354 female, 564 male) regarding disease severity and mortality (186 deceased). Multiple tissues, such as muscle, bone, or adipose tissue are used and acquired with a deep-learning-based, fully-automated BCA from computed tomography images of the chest. The BCA features and markers were univariately analyzed with a Shapiro-Wilk and two-sided Mann-Whitney-U test. In a multivariate approach, obtained markers were adjusted by a defined set of laboratory parameters promoted by other studies. Subsequently, the relationship between the markers and two endpoints, namely severity and mortality, was investigated with regard to statistical significance. The univariate approach showed that the muscle volume was significant for female (pseverity ≤ 0.001, pmortality ≤ 0.0001) and male patients (pseverity = 0.018, pmortality ≤ 0.0001) regarding the severity and mortality endpoints. For male patients, the intra- and intermuscular adipose tissue (IMAT) (p ≤ 0.0001), epicardial adipose tissue (EAT) (p ≤ 0.001) and pericardial adipose tissue (PAT) (p ≤ 0.0001) were significant regarding the severity outcome. With the mortality outcome, muscle (p ≤ 0.0001), IMAT (p ≤ 0.001), EAT (p = 0.011) and PAT (p = 0.003) remained significant. For female patients, bone (p ≤ 0.001), IMAT (p = 0.032) and PAT (p = 0.047) were significant in univariate analyses regarding the severity and bone (p = 0.005) regarding the mortality. Furthermore, the defined sarcopenia marker (p ≤ 0.0001, for female and male) was significant for both endpoints. The cardiac marker was significant for severity (pfemale = 0.014, pmale ≤ 0.0001) and for mortality (pfemale ≤ 0.0001, pmale ≤ 0.0001) endpoint for both genders. The multivariate logistic regression showed that the sarcopenia marker was significant (pseverity = 0.006, pmortality = 0.002) for both endpoints (ORseverity = 0.42, 95% CIseverity: 0.23-0.78, ORmortality = 0.34, 95% CImortality: 0.17-0.67). The cardiac marker showed significance (p = 0.018) only for the severity endpoint (OR = 1.42, 95% CI 1.06-1.90). The association between BCA-based sarcopenia and cardiac biomarkers and disease severity and mortality suggests that these biomarkers can contribute to the risk stratification of SARS-CoV-2 patients. Patients with a higher cardiac marker and a lower sarcopenia marker are at risk for a severe course or death. Whether those biomarkers hold similar importance for other pneumonia-related diseases requires further investigation.

Critically Ill COVID-19 Patients Show Reduced Point of Care-Measured Butyrylcholinesterase Activity-A Prospective, Monocentric Observational Study.

A biomarker for risk stratification and disease severity assessment in SARS-CoV-2 infections has not yet been established. Point of care testing (POCT) of butyrylcholinesterase (BChE) enables early detection of systemic inflammatory responses and correlates with disease severity in sepsis and burns. In acute care or resource-limited settings, POCT facilitates rapid clinical decision making, a particularly beneficial aspect in the management of pandemic situations. In this prospective observational study, POCT-measured BChE activity was assessed in 52 critically ill COVID-19 patients within 24 h of ICU admission and on the third and seventh day after ICU admission. Forty (77%) of these patients required venovenous extracorporeal membrane oxygenation (vvECMO). In critically ill COVID-19 patients, BChE activity is significantly decreased compared with healthy subjects, but also compared with other inflammatory conditions such as sepsis, burns, or trauma. POCT BChE activity reflects the severity of organ dysfunction and allows prediction of 28-day mortality in critically ill COVID-19 patients. Implementing early POCT BChE measurement could facilitate risk stratification and support admission and transfer decisions in resource-limited settings.

Anesthetic Management during Robotic-Assisted Minimal Invasive Thymectomy Using the Da Vinci System: A Single Center Experience.

BACKGROUND: Robotic-assisted surgery is gaining more adaption in different surgical specialties. The number of patients undergoing robotic-assisted thymectomy is continuously increasing. Such procedures are accompanied by new challenges for anesthesiologists. We are presenting our primary anesthesiologic experience in such patients. METHODS: This is a retrospective single center study, evaluating 28 patients who presented with thymoma or myasthenia gravis (MG) and undergone minimal invasive robotic-assisted thoracic thymectomy between 01/2020-01/2022. We present our fast-track anesthesia management as a component of the enhanced recovery program and its primary results. RESULTS: Mean patient's age was 46.8 ± 18.1 years, and the mean height was 173.1 ± 9.3 cm. Two-thirds of patients were female (n = 18, 64.3%). The preoperative mean forced expiratory volume in the first second (FEV1) was 3.8 ± 0.7 L, forced vital capacity (FVC) was 4.7 ± 1.1 L, and the FEV1/FVC ratio was 80.4 ± 5.3%. After the creation of capnomediastinum, central venous pressure and airway pressure have been significantly increased from the baseline values (16.5 ± 4.9 mmHg versus 13.4 ± 5.1 mmHg, p < 0.001 and 23.4 ± 4.4 cmH2O versus 19.3 ± 3.9 cmH2O, p < 0.001, respectively). Most patients (n = 21, 75%) developed transient arrhythmias episodes with hypotension. All patients were extubated at the end of surgery and discharged awake to the recovery room. The first 16 (57.1%) patients were admitted to the intensive care unit and the last 12 patients were only observed in intermediate care. Postoperatively, one patient developed atelectasis and was treated with non-invasive ventilation therapy. Pneumonia or reintubation was not observed. Finally, no significant difference was observed between MG and thymoma patients regarding analgesics consumption or incidence of complications. CONCLUSIONS: Robotic-assisted surgery is a rapidly growing technology with increased adoption in different specialties. Fast-track anesthesia is an important factor in an enhanced recovery program and the anesthetist should be familiar with challenges in this kind of operation to achieve optimal results. So far, our anesthetic management of patients undergoing robotic-assisted thymectomy reports safe and feasible procedures.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Differential Regulation of CD45 Expression on Granulocytes, Lymphocytes, and Monocytes in COVID-19.

CD45 is a transmembrane glycoprotein and protein tyrosine phosphatase expressed on the surface of all nucleated hematopoietic cells. While there is increasing evidence demonstrating the involvement of CD45 in immune system regulation, no information on CD45 expression in inflammation and sepsis is currently available. Therefore, we determined the CD45 surface expression on granulocytes, lymphocytes, and monocytes in patients with COVID-19 and healthy volunteers in both absence and presence of lipopolysaccharide (LPS). Following approval by the local ethics committee, whole blood samples were obtained from patients with COVID-19 infection on day 1 of hospital admission and healthy volunteers. Samples were incubated in absence and presence of LPS and CD45 was measured in granulocytes, lymphocytes, and monocytes using flow cytometry. In comparison with healthy individuals, COVID-19 patients showed an increased CD45 expression on the surface of granulocytes (+35%, p < 0.02) and lymphocytes (+39%, p < 0.0001), but a reduced CD45 expression on monocytes (-35%, p < 0.0001). LPS incubation of whole blood from healthy individuals increased the CD45 expression on granulocytes (+430%, p < 0.0001), lymphocytes (+32%, p = 0.0012), and monocytes (+36%, p = 0.0005), respectively. LPS incubation of whole blood samples from COVID-19 patients increased the CD45 expression on granulocytes and monocytes, and decreased the CD45 expression on lymphocytes. In conclusion, CD45 expression on leucocytes is altered: (1) in COVID-19 patients, and (2) in in vitro endotoxemia in a complex cell-specific way, thus representing a new immunoregulatory mechanism.

[Treatment of sepsis-induced coagulopathy : Results of a Germany-wide survey in intensive care units]. / Therapie der sepsisinduzierten Koagulopathie : Ergebnisse einer deutschlandweiten Umfrage auf Intensivstationen.

BACKGROUND: In the context of sepsis and septic shock, coagulopathy often occurs due to the close relationship between coagulation and inflammation. Sepsis-induced coagulopathy (SIC) is the most severe and potentially fatal form. Anticoagulants used in prophylactic or therapeutic doses are discussed to potentially exert beneficial effects in patients with sepsis and/or SIC; however, due to the lack of evidence recent guidelines are limited to recommendations for drug prophylaxis of venous thromboembolism (VTE), while treatment of SIC has not been addressed. METHODS: In order to determine the status quo of VTE prophylaxis as well as treatment of SIC in German intensive care units (ICU), we conducted a Germany-wide online survey among heads of ICUs from October 2019 to May 2020. In April 2020, the survey was supplemented by an additional block of questions on VTE prophylaxis and SIC treatment in coronavirus disease 2019 (COVID-19) patients. RESULTS: A total of 67 senior doctors took part in the survey. The majority (n = 50; 74.6%) of the responses were from ICU under the direction of an anesthesiologist and/or a department of anesthesiology. Most of the participants worked either at a university hospital (n = 31; 47.8%) or an academic teaching hospital (n = 27; 40.3%). The survey results show a pronounced heterogeneity in clinical practice with respect to the prophylaxis of VTE as well as SIC treatment. In an exemplary case of pneumogenic sepsis, low molecular weight heparins (LMWH) were by far the most frequently mentioned group of medications (n = 51; 76.1% of the responding ITS). In the majority of cases (n = 43; 64.2%), anti-FXa activity is not monitored with the use of LMWH in prophylaxis doses. Unfractionated heparin (UFH) was listed as a strategy for VTE prophylaxis in 37.3% of the responses (n = 25). In an exemplary case of abdominal sepsis 54.5% of the participants (n = 36; multiple answers possible) stated the use of UFH or LMWH and UFH with dosage controlled by PTT is used on two participating ICUs. The anti-FXa activity under prophylactic anticoagulation with LMWH is monitored in 7 participating clinics (10.6%) in abdominal sepsis. Systematic screening for sepsis-associated coagulation disorders does not take place in most hospitals and patterns in the use of anticoagulants show significant variability between ICUs. In the case of COVID-19 patients, it is particularly noticeable that in three quarters of the participating ICUs the practice of drug-based VTE prophylaxis and SIC treatment does not differ from that of non-COVID-19 patients. CONCLUSION: The heterogeneity of answers collected in the survey suggests that a systematic approach to this topic via clinical trials is urgently needed to underline individualized patient care with the necessary evidence.

Long-Term SARS-CoV-2 Specific Immunity Is Affected by the Severity of Initial COVID-19 and Patient Age.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the greatest medical challenge. Although crucial to the future management of the pandemic, the factors affecting the persistence of long-term SARS-CoV-2 immunity are not well understood. Therefore, we determined the extent of important correlates of SARS-CoV-2 specific protection in 200 unvaccinated convalescents after COVID-19. To investigate the effective memory response against the virus, SARS-CoV-2 specific T cell and humoral immunity (including virus-neutralizing antibodies) was determined over a period of one to eleven months. SARS-CoV-2 specific immune responses were present in 90% of individual patients. Notably, immunosuppressed patients did not have long-term SARS-CoV-2 specific T cell immunity. In our cohort, the severity of the initial illness influenced SARS-CoV-2 specific T cell immune responses and patients' humoral immune responses to Spike (S) protein over the long-term, whereas the patients' age influenced Membrane (M) protein-specific T cell responses. Thus, our study not only demonstrated the long-term persistence of SARS-CoV-2 specific immunity, it also determined COVID-19 severity and patient age as significant factors affecting long-term immunity.

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

BACKGROUND: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. METHODS: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. RESULTS: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. CONCLUSIONS: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.

COVID-19 Co-infection with Legionella pneumophila in 2 Tertiary-Care Hospitals, Germany.

We describe screening results for detection of co-infections with Legionella pneumophila in patients infected with severe acute respiratory syndrome coronavirus 2. In total, 93 patients were tested; 1 was positive (1.1%) for L. pneumophila serogroup 1. Co-infections with L. pneumophila occur in coronavirus disease patients and should not be missed.