Impact of Vaccination Status on Outcome of Patients With COVID-19 and Acute Ischemic Stroke Undergoing Mechanical Thrombectomy.

BACKGROUND: Data on impact of COVID-19 vaccination and outcomes of patients with COVID-19 and acute ischemic stroke undergoing mechanical thrombectomy are scarce. Addressing this subject, we report our multicenter experience. METHODS AND RESULTS: This was a retrospective analysis of patients with COVID-19 and known vaccination status treated with mechanical thrombectomy for acute ischemic stroke at 20 tertiary care centers between January 2020 and January 2023. Baseline demographics, angiographic outcome, and clinical outcome evaluated by the modified Rankin Scale score at discharge were noted. A multivariate analysis was conducted to test whether these variables were associated with an unfavorable outcome, defined as modified Rankin Scale score >3. A total of 137 patients with acute ischemic stroke (48 vaccinated and 89 unvaccinated) with acute or subsided COVID-19 infection who underwent mechanical thrombectomy attributable to vessel occlusion were included in the study. Angiographic outcomes between vaccinated and unvaccinated patients were similar (modified Thrombolysis in Cerebral Infarction ≥2b: 85.4% in vaccinated patients versus 86.5% in unvaccinated patients; P=0.859). The rate of functional independence (modified Rankin Scale score, ≤2) was 23.3% in the vaccinated group and 20.9% in the unvaccinated group (P=0.763). The mortality rate was 30% in both groups. In the multivariable analysis, vaccination status was not a significant predictor for an unfavorable outcome (P=0.957). However, acute COVID-19 infection remained significant (odds ratio, 1.197 [95% CI, 1.007-1.417]; P=0.041). CONCLUSIONS: Our study demonstrated no impact of COVID-19 vaccination on angiographic or clinical outcome of COVID-19-positive patients with acute ischemic stroke undergoing mechanical thrombectomy, whereas worsening attributable to COVID-19 was confirmed.

Hypercalcemia as a rare manifestation of immune reconstitution inflammatory syndrome (IRIS) in a person living with Human Immunodeficiency Virus (HIV) with disseminated nontuberculous mycobacteriosis.

INTRODUCTION: Granulomatosis due to immune reconstitution inflammatory syndrome (IRIS) and disseminated Mycobacterium avium-intracellulare (M. avium) infection may trigger hypercalcemia. Here, we report a rare case of hypercalcemia and acute kidney damage related to IRIS in a person living with Human Immunodeficiency Virus (HIV). CASE PRESENTATION: A 39-year-old male person living with HIV presented with muscle weakness and unwanted weight loss of 8 kg within the last 2 weeks. Laboratory findings included serum hypercalcemia of 3.27 mmol/mL associated with elevated calcitriol and acute kidney damage. Since the first diagnosis of HIV and concomitant disseminated M. avium infection, the patient received antiretroviral therapy (ART), rifabutin, clarithromycin, and ethambutol. 18Fluoro-D-glucose positron emission computed tomography (18FDG-PET/CT) showed progressive multilocular lymphadenopathy. Biopsy specimen from the duodenum as well as retroperitoneal and mediastinal lymph nodes revealed granulomatous inflammation consistent with IRIS. Treatment with forced diuresis, bisphosphonates, and calcitonin normalized serum calcium and kidney function recovered. CONCLUSION: Hypercalcemia due to IRIS is a rare differential diagnosis in persons living with HIV and may lead to acute kidney damage, despite sufficient ART and antimycobacterial treatment.

The Association of HIV-Specific Risk Factors with Cardiovascular Events in Addition to Traditional Risk Factors in People Living with HIV.

Traditional cardiovascular risk scores underestimate the incidence of cardiovascular diseases (CVD) in people living with HIV (PLH). This study compared the effect of HIV-specific cardiovascular risk factors (CRF) with traditional CRF at baseline for their association with incident CVD in PLH. The ongoing, prospective HIV HEART Aging (HIVH) study assesses CVD in PLH in the German Ruhr Area since 2004. PLH from the HIVH study with at least 5 years of follow-up were examined with the help of Cox proportional hazards models using inverse probability-of-censoring weights. The models were adjusted for age and sex. The obtained hazard ratios (HR) and 95% confidence limits (CL) assessed the strength of the associations between CRF and CVD. One thousand two hundred forty-three individuals (male 1,040, female 203; mean age of 43 ± 10 years) with 116 incident CVD events were analyzed. After adjusting for the traditional CRF, the HIV-specific CRF "a history of AIDS" and "higher age at diagnosis of HIV infection" (per 10 years) were associated with an increased CVD risk (HR 1.55, 95% CL: 1.05-2.28 and HR 1.55, 95% CL: 1.09-1.22, respectively). Higher CD4/CD8 ratio (per standard deviation), longer cumulative duration of antiretroviral therapies, and longer duration of HIV infection (per 10 years) showed indications for a decreased CVD risk (HR 0.75, 95% CL: 0.58-0.97, HR 0.71, 95% CL: 0.41-1.23, and HR 0.63, 95% CL: 0.44-0.90, respectively). Out of the traditional CRF, current smoking showed the strongest impact on CVD risk (HR 3.12, 95% CL: 2.06-4.74). In conclusion, HIV-specific factors, such as history of AIDS and CD4/CD8 ratio, were independently associated with an increased cardiovascular risk. Traditional CRF maintained a major effect on CVD. Clinical Trials Number (NCT04330287).

Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC).

BACKGROUND: A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems, and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce. METHODS: In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests, and physical examination were obtained from all patients. SARS-CoV-2 reactive T-cell response was analyzed via multiparametric flow cytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay. RESULTS: The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache, and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells. CONCLUSIONS: Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

Macrophage migration inhibitory factor receptor CD74 expression is associated with expansion and differentiation of effector T cells in COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused millions of COVID-19 cases and deaths worldwide. Severity of pulmonary pathologies and poor prognosis were reported to be associated with the activation non-virus-specific bystander T cells. In addition, high concentrations of the macrophage migration inhibitory factor (MIF) were found in serum of COVID-19 patients. We hypothesized that these two pathogenic factors might be related and analyzed the expression of receptors for MIF on T cells in COVID-19. T cells from PBMCs of hospitalized patients with mild and severe COVID-19 were characterized. A significantly higher proportion of CD4+ and CD8+ T cells from COVID-19 patients expressed CD74 on the cell surface compared to healthy controls. To induce intracellular signaling upon MIF binding, CD74 forms complexes with CD44, CXCR2, or CXCR4. The vast majority of CD74+ T cells expressed CD44, whereas expression of CXCR2 and CXCR4 was low in controls but increased upon SARS-CoV-2 infection. Hence, T cells in COVID-19 patients express receptors that render them responsive to MIF. A detailed analysis of CD74+ T cell populations revealed that most of them had a central memory phenotype early in infection, while cells with an effector and effector memory phenotype arose later during infection. Furthermore, CD74+ T cells produced more cytotoxic molecules and proliferation markers. Our data provide new insights into the MIF receptor and co-receptor repertoire of bystander T cells in COVID-19 and uncovers a novel and potentially druggable aspect of the immunological footprint of SARS-CoV-2.

Fading SARS-CoV-2 humoral VOC cross-reactivity and sustained cellular immunity in convalescent children and adolescents.

Cross-reactive cellular and humoral immunity can substantially contribute to antiviral defense against SARS-CoV-2 variants of concern (VOC). While the adult SARS-CoV-2 cellular and humoral immunity and its cross-recognition potential against VOC is broadly analyzed, similar data regarding the pediatric population are missing. In this study, we perform an analysis of the humoral and cellular SARS-CoV-2 response immune of 32 convalescent COVID-19 children (children), 27 convalescent vaccinated adults(C + V+) and 7 unvaccinated convalescent adults (C + V-). Similarly to adults, a significant reduction of cross-reactive neutralizing capacity against delta and omicron VOC was observed 6 months after SARS-CoV-2 infection. While SAR-CoV-2 neutralizing capacity was comparable among children and C + V- against all VOC, children demonstrated as expected an inferior humoral response when compared to C + V+. Nevertheless, children generated SARS-CoV-2 reactive T cells with broad cross-recognition potential. When compared to V + C+, children presented even comparable frequencies of WT-reactive CD4 + and CD8 + T cells with high avidity and functionality. Taking into consideration the limitations of study - unknown disease onset for 53% of the asymptomatic pediatric subjects, serological detection of SARS-CoV-2 infection-, our results suggest that following SARS-CoV-2 infection children generate a humoral SARS-CoV-2 response with neutralizing potential comparable to unvaccinated COVID-19 convalescent adults as well a sustained SARS-CoV-2 cellular response cross-reactive to VOC.

Immune responses in COVID-19 patients during breakthrough infection with SARS-CoV-2 variants Delta, Omicron-BA.1 and Omicron-BA.5.

Background: Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are increasingly observed in vaccinated individuals. Immune responses towards SARS-CoV-2 variants, particularly Omicron-BA.5, are poorly understood. We investigated the humoral and cellular immune responses of hospitalized COVID-19 patients during Delta and Omicron infection waves. Methods: The corresponding SARS-CoV-2 variant of the respective patients were identified by whole genome sequencing. Humoral immune responses were analyzed by ELISA and a cell culture-based neutralization assay against SARS-CoV-2 D614G isolate (wildtype), Alpha, Delta (AY.43) and Omicron (BA.1 and BA.5). Cellular immunity was evaluated with an IFN-γ ELISpot assay. Results: On a cellular level, patients showed a minor IFN-γ response after stimulating PBMCs with mutated regions of SARS-CoV-2 variants. Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced. Double-vaccinated patients with Delta breakthrough infection showed a significantly increased neutralizing antibody response against Delta compared to double-vaccinated uninfected controls (median complete neutralization titer (NT100) 640 versus 80, p<0.05). Omicron-BA.1 infection increased neutralization titers against BA.1 in double-vaccinated patients (median NT100 of 160 in patients versus 20 in controls, p=0.07) and patients that received booster vaccination (median NT100 of 50 in patients versus 20 in controls, p=0.68). For boosted patients with BA.5 breakthrough infection, we found no enhancing effect on humoral immunity against SARS-CoV-2 variants. Conclusion: Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced in SARS-CoV-2 breakthrough infections. Delta and Omicron-BA.1 but not Omicron-BA.5 infections boosted the humoral immunity in double-vaccinated patients and patients with booster vaccination. Despite BA.5 breakthrough infection, those patients may still be vulnerable for reinfections with BA.5 or other newly emerging variants of concern.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

PURPOSE: We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. METHODS: Case report and detailed description of the clinical course of diagnosis and treatment. CASE: The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. CONCLUSION: We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19.

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed. We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls. In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Peripheral HLA-G/ILT-2 immune checkpoint axis in acute and convalescent COVID-19 patients.

The immunosuppressive non-classical human leukocyte antigen-G (HLA-G) can elicits pro-viral activities by down-modulating immune responses. We analysed soluble forms of HLA-G, IL-6 and IL-10 as well as on immune effector cell expression of HLA-G and its cognate ILT-2 receptor in peripheral blood obtained from hospitalised and convalescent COVID-19 patients. Compared with convalescents (N = 202), circulating soluble HLA-G levels (total and vesicular-bound molecules) were significantly increased in hospitalised patients (N = 93) irrespective of the disease severity. During COVID-19, IL-6 and IL-10 levels were also elevated. Regarding the immune checkpoint expression of HLA-G/ILT-2 on peripheral immune effector cells, the frequencies of membrane-bound HLA-G on CD3+ and CD14+ cells were almost identical in patients during and post COVID-19, while the frequency of ILT-2 receptor on CD3+ and CD14+ cells was increased during acute infection. A multi-parametric correlation analysis of soluble HLA-G forms with IL-6, IL-10, activation markers CD25 and CD154, HLA-G, and ILT-2 expression on immune cells revealed a strong positive correlation of soluble HLA-G forms with membrane-bound HLA-G molecules on CD3+/CD14+ cells only in convalescents. During COVID-19, only vesicular-bound HLA-G were positively correlated with the activation marker CD25 on T cells. Thus, our data suggest that the elevated levels of soluble HLA-G in COVID-19 are due to increased expression in organ tissues other than circulating immune effector cells. The concomitant increased expression of soluble HLA-G and ILT-2 receptor frequencies supports the concept that the immune checkpoint HLA-G/ILT-2 plays a role in the immune-pathogenesis of COVID-19.

Changes in body mass index, weight, and waist-to-hip ratio over five years in HIV-positive individuals in the HIV Heart Aging Study compared to the general population.

PURPOSE: Overweight and obesity have increased in people living with HIV (PLH). Our study evaluated weight, body-mass-index (BMI), and waist-to-hip ratio (WHR) change over 5 years of follow-up in PLH compared to the general population. METHODS: HIV-positive participants in the HIV Heart Aging (HIVH) study were matched 1:2 by age and sex with HIV-negative controls of the population-based Heinz Nixdorf Recall (HNR) study. Both studies were recruited in the German Ruhr area. The association between HIV and weight, BMI, and WHR changes was examined using linear regression. Regression models were adjusted for parameters potentially affecting weight gain. RESULTS: The matched HIVH and HNR participants (N = 585 and N = 1170, respectively; 14.7% females) had a mean age of 55 years at baseline. Despite the lower baseline weight (- 6 kg, 95% CI - 7.46 to - 4.59), the linear regression showed greater absolute and relative weight and BMI increases after 5 years in HIVH compared to HNR. Adjusting the linear regression models for smoking amplified that HIVH had a higher absolute and relative weight difference of 0.7 kg or ~ 1% compared to HNR after 5 years (95% Cl 0.1 to 1.3 and 0.2 to 1.6, respectively). Adjusting for HDL, LDL, systolic blood pressure, and diabetes mellitus did not affect the results. CONCLUSIONS: PLH had lower weight than the general population at baseline and after 5 years, but experienced greater increases in body weight after 5 years. WHR change after 5 years was lower in PLH compared to the general population, despite a higher WHR at baseline.

COVID-19 associated acute transplant failure after AB0-incompatible living donor kidney transplantation - a case report.

INTRODUCTION: Immunosuppressive therapy is associated with an increased risk of severe courses of SARS-CoV-2 infection, with frequently delayed viral clearance. We report a case of an acute kidney transplant failure in persistent SARS-CoV-2 infection in a patient with absolute B-cell depletion after administration of rituximab for AB0-incompatible living donor kidney transplantation. CASE PRESENTATION: A 34-year-old unvaccinated patient is diagnosed with SARS-CoV-2 infection four months after kidney transplantation. With only mild symptoms and an estimated glomerular filtration rate (eGFR) of 44 ml/min/1.73 m2, therapy with molnupiravir was initially given. Within the next eight weeks, transplant biopsies were performed for acute graft failure. These showed acute T-cell rejection with severe acute tubular epithelial damage with only mild interstitial fibrosis and tubular atrophy (BANFF cat. 4 IB), and borderline rejection (BANFF cat. 3). A therapy with prednisolone and intravenous immunoglobulins was performed twice. With unchanged graft failure, the third biopsy also formally showed BANFF cat. 4 IB. However, fluorescence in situ hybridization detected SARS-CoV-2 viruses in large portions of the distal tubules. After nine weeks of persistent COVID-19 disease neither anti-SARS-CoV-2 IgG nor a SARS-CoV-2-specific cellular immune response could be detected, leading to the administration of sotrovimab and remdesivir. Among them, SARS-CoV-2 clearance, detection of IgG, and improvement of graft function were achieved. CONCLUSION: Lack of viral clearance can lead to complications of SARS-CoV-2 infection with atypical manifestations. In kidney transplant patients, before initiating therapy, the differential diagnoses of "rejection" and "virus infection" should be weighed against each other in an interdisciplinary team of nephrologists, infectious diseases specialists and pathologists.

SARS-CoV-2 infection in chronic kidney disease patients with pre-existing dialysis: description across different pandemic intervals and effect on disease course (mortality).

PURPOSE: Patients suffering from chronic kidney disease (CKD) are in general at high risk for severe coronavirus disease (COVID-19) but dialysis-dependency (CKD5D) is poorly understood. We aimed to describe CKD5D patients in the different intervals of the pandemic and to evaluate pre-existing dialysis dependency as a potential risk factor for mortality. METHODS: In this multicentre cohort study, data from German study sites of the Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) were used. We multiply imputed missing data, performed subsequent analyses in each of the imputed data sets and pooled the results. Cases (CKD5D) and controls (CKD not requiring dialysis) were matched 1:1 by propensity-scoring. Effects on fatal outcome were calculated by multivariable logistic regression. RESULTS: The cohort consisted of 207 patients suffering from CKD5D and 964 potential controls. Multivariable regression of the whole cohort identified age (> 85 years adjusted odds ratio (aOR) 7.34, 95% CI 2.45-21.99), chronic heart failure (aOR 1.67, 95% CI 1.25-2.23), coronary artery disease (aOR 1.41, 95% CI 1.05-1.89) and active oncological disease (aOR 1.73, 95% CI 1.07-2.80) as risk factors for fatal outcome. Dialysis-dependency was not associated with a fatal outcome-neither in this analysis (aOR 1.08, 95% CI 0.75-1.54) nor in the conditional multivariable regression after matching (aOR 1.34, 95% CI 0.70-2.59). CONCLUSIONS: In the present multicentre German cohort, dialysis dependency is not linked to fatal outcome in SARS-CoV-2-infected CKD patients. However, the mortality rate of 26% demonstrates that CKD patients are an extreme vulnerable population, irrespective of pre-existing dialysis-dependency.

Cerebral Taenia crassiceps larvae infection in a 71-year-old immunocompetent male.

We report a rare case of a cerebral infection with Taenia crassiceps tapeworm larvae in an immunocompetent 71-year-old German male. Initially, an intracerebral malignoma was suspected after the patient experienced stroke-like symptoms. After surgery, helminth larvae, later identified as T. crassiceps, were detected. Identification on the species level was possible by specific PCR and sequencing. After complete surgical removal, the patient was treated with albendazole and dexamethasone for two weeks. No residual symptoms were reported up to date.

Superior humoral immunity in vaccinated SARS-CoV-2 convalescence as compared to SARS-COV-2 infection or vaccination.

Emerging variants of concern (VOC) raise obstacles in shaping vaccination strategies and ending the pandemic. Vaccinated SARS-CoV-2 convalescence shapes the current immune dynamics. We analyzed the SARS-CoV-2 VOC-specific cellular and humoral response of 57 adults: 42 convalescent mRNA vaccinated patients (C+V+), 8 uninfected mRNA vaccinated (C-V+) and 7 unvaccinated convalescent individuals (C+V-). While C+V+ demonstrated a superior humoral SARS-CoV-2 response against all analyzed VOC (alpha, delta, omicron) compared to C-V+ and C+V-, SARS-CoV-2 reactive CD4+ and CD8+ T cells, which can cross-recognize the alpha, delta and omicron VOC after infection and/or vaccination were observed in all there groups without significant differences between the groups. We observed a preserved cross-reactive C+V+ and C-V+ T cell memory. An inferior humoral response but preserved cross-reactive T cell memory in C+V- compared to C+V+ was observed, as well as an inferior humoral response but preserved cross-reactive T cell memory in C+V- compared to C-V+. Adaptive immunity generated after SARS-CoV-2 infection and vaccination leads to superior humoral immune response against VOC compared to isolated infection or vaccination. Despite the apparent loss of neutralization potential caused by viral evolution, a preserved SARS-CoV-2 reactive T cell response with a robust potential for cross-recognition of the alpha, delta and omicron VOC was detected in all studied cohorts. Our results may have implications on current vaccination strategies.

Evaluation of a new COVID-19 triage algorithm in the emergency department including combined antigen and PCR-testing: A case-control study.

The coronavirus disease 2019 (COVID-19) pandemic is a major challenge for global healthcare systems. Early and safe triage in the emergency department (ED) is crucial for proper therapy. However, differential diagnosis remains challenging. Rapid antigen testing (RAT) may help to improve early triage and patient safety. We performed a retrospective study of 234 consecutive patients with suspected COVID-19 who presented to our ED in November 2020. All underwent SARS-CoV-2-nasopharyngeal swab testing using both RAT and reverse transcription polymerase chain reaction (RT-PCR). The inpatient treatment was established according to an empirically developed triage algorithm. The accuracy of the suggested algorithm was analyzed based on the rate of outpatients returning within 7 days and inpatients staying for less than 48 hours. COVID-19 inpatients and outpatients were compared for symptoms, vital signs, and C-reactive protein levels. Of the 221 included patients with suspected COVID-19 infection, the diagnosis could be confirmed in 120 patients (54.3%) by a positive RT-PCR result, whereas only 72% of those had a positive antigen test. Of the 56 COVID-19 outpatients, three returned within 7 days with the need for hospital treatment due to clinical deterioration. Among the 64 COVID-19 inpatients, 4 were discharged within 48 hours, whereas 60 stayed longer (mean duration 10.2 days). The suggested triage algorithm was safe and efficient in the first 234 consecutive patients. RAT can confirm a diagnosis in 72% of PCR proven COVID-19 patients and allows early cohort isolation as an important way to save hospital capacity.

A Multipathogen Bile Sample-based PCR Assay Can Guide Empirical Antimicrobial Strategies in Cholestatic Liver Diseases.

Background and objectives: Polymerase chain reaction (PCR) techniques provide rapid detection of pathogens. This pilot study evaluated the diagnostic utility and clinical impact of multiplex real-time PCR (mRT-PCR, SeptiFast) vs. conventional microbial culture (CMC) in bile samples of patients with chronic cholestatic liver diseases (cCLDs), endoscopic retrograde cholangio-pancreatography (ERCP), and peri-interventional-antimicrobial-prophylaxis (pAP). Methods: We prospectively collected bile samples from 26 patients for microbiological analysis by CMC and mRT-PCR. Concordance of the results of both methods was determined by Krippendorff's alpha (α) for inter-rater reliability and the Jaccard index of similarity. Results: mRT-PCRbile and CMCbile results were concordant for only Candida albicans (α=0.8406; Jaccard index=0.8181). mRT-PCRbile detected pathogens in 8/8 cases (100%), CMCbile in 7/8 (87.5%), and CMCblood in 5/8 (62.5%) with clinical signs of infection. mRT-PCRbile, CMCbile, and CMCblood had identical detection results in 3/8 (37.5%) with clinical signs of infection (two Klebsiella spp. and one Enterococcus faecium). The total pathogen count was significantly higher with mRT-PCRbile than with CMCbile (62 vs. 31; χ2=30.031, p<0.001). However, pathogens detected by mRT-PCRbile were more often susceptible to pAP according to the patient infection/colonization history (PI/CH) and surveillance data for antibiotic resistance in our clinic (DARC). Pathogens identified by mRT-PCRbile and resistant to pAP by PI/CH and DARC were likely to be clinically relevant. Conclusions: mRT-PCR in conjunction with CMCs for bile analysis increased diagnostic sensitivity and may benefit infection management in patients with cholestatic diseases. Implementation of mRT-PCR in a bile sample-based diagnostic routine can support more rapid and targeted use of antimicrobial agents in cCLD-patients undergoing ERCP and reduce the rate/length of unnecessary administration of broad-spectrum antibiotics.

A Multicentre, Prospective, and Retrospective Registry to Characterize the Use, Effectiveness, and Safety of Dalbavancin in German Clinical Practice.

The antibiotic dalbavancin is approved for intravenous treatment of adults with acute bacterial skin and skin structure infections. This study aimed to observe the use, effectiveness, and safety of dalbavancin in clinical practice in Germany. It was a multicentre, prospective, and retrospective registry and consecutively enrolled patients treated with dalbavancin. Each patient was observed from the first to the last dose of dalbavancin, with a 30-day follow-up. Patient inclusion was planned for 2 years, but was terminated early due to low recruitment. All analyses were descriptive. Between November 2018 and December 2019, nine patients were enrolled. Only three patients were treated for the approved indication. Outcome was assessed by the physicians as 'success' in five (55.6%) patients, 'failure' in one (11.1%) patient, and non-evaluable in three (33.3%) patients. Although the success rate of dalbavancin was lower than reported previously, this may be due to the severity of underlying infections and patients' high Charlson Comorbidity Index. None of the two reported adverse events were considered related to dalbavancin. These findings were in line with real-world data for dalbavancin from other countries, supporting the drug's positive benefit-risk profile and suggesting frequent off-label use in German routine practice.

The Fungal Gut Microbiome Exhibits Reduced Diversity and Increased Relative Abundance of Ascomycota in Severe COVID-19 Illness and Distinct Interconnected Communities in SARS-CoV-2 Positive Patients.

Clinical and experimental studies indicate that the bacterial and fungal gut microbiota modulates immune responses in distant organs including the lungs. Immune dysregulation is associated with severe SARS-CoV-2 infection, and several groups have observed gut bacterial dysbiosis in SARS-CoV-2 infected patients, while the fungal gut microbiota remains poorly defined in these patients. We analyzed the fungal gut microbiome from rectal swabs taken prior to anti-infective treatment in 30 SARS-CoV-2 positive (21 non-severe COVID-19 and 9 developing severe/critical COVID-19 patients) and 23 SARS-CoV-2 negative patients by ITS2-sequencing. Pronounced but distinct interconnected fungal communities distinguished SARS-CoV-2 positive and negative patients. Fungal gut microbiota in severe/critical COVID-19 illness was characterized by a reduced diversity, richness and evenness and by an increase of the relative abundance of the Ascomycota phylum compared with non-severe COVID-19 illness. A dominance of a single fungal species with a relative abundance of >75% was a frequent feature in severe/critical COVID-19. The dominating fungal species were highly variable between patients even within the groups. Several fungal taxa were depleted in patients with severe/critical COVID-19.The distinct compositional changes of the fungal gut microbiome in SARS-CoV-2 infection, especially in severe COVID-19 illness, illuminate the necessity of a broader approach to investigate whether the differences in the fungal gut microbiome are consequences of SARS-CoV-2 infection or a predisposing factor for critical illness.