Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine.

SARS-CoV-2 spike mRNA vaccines1-3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4-6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.

Epidemiological trends and susceptibility patterns of bloodstream infections caused by Enterococcus spp. in six German university hospitals: a prospectively evaluated multicentre cohort study from 2016 to 2020 of the R-Net study group.

PURPOSE: To analyse recent epidemiological trends of bloodstream infections (BSI) caused by Enterococcus spp. In adult patients admitted to tertiary care centres in Germany. METHODS: Epidemiological data from the multicentre R-NET study was analysed. Patients presenting with E. faecium or E. faecalis in blood cultures in six German tertiary care university hospitals between October 2016 and June 2020 were prospectively evaluated. In vancomycin-resistant enterococci (VRE), the presence of vanA/vanB was confirmed via molecular methods. RESULTS: In the 4-year study period, 3001 patients with BSI due to Enterococcus spp. were identified. E. faecium was detected in 1830 patients (61%) and E. faecalis in 1229 patients (41%). Most BSI occurred in (sub-) specialties of internal medicine. The pooled incidence density of enterococcal BSI increased significantly (4.0-4.5 cases per 10,000 patient days), which was primarily driven by VRE BSI (0.5 to 1.0 cases per 10,000 patient days). In 2020, the proportion of VRE BSI was > 12% in all study sites (range, 12.8-32.2%). Molecular detection of resistance in 363 VRE isolates showed a predominance of the vanB gene (77.1%). CONCLUSION: This large multicentre study highlights an increase of BSI due to E. faecium, which was primarily driven by VRE. The high rates of hospital- and ICU-acquired VRE BSI point towards an important role of prior antibiotic exposure and invasive procedures as risk factors. Due to limited treatment options and high mortality rates of VRE BSI, the increasing incidence of VRE BSI is of major concern.

Antimicrobial resistance is not increasing in subsequent cases of ischaemic foot infections, a single-centre cohort from 2012 to 2021.

Patients with chronic limb-threatening ischaemia (CLTI) are at risk of foot infections, which is associated with an increase in amputation rates. The use of antibiotics may lead to a higher incidence of antimicrobial resistance (AMR) in subsequent episodes of ischaemic foot infections (IFI). This retrospective single-centre cohort study included 130 patients with IFI undergoing endovascular revascularisation. Staphylococcus aureus and Pseudomonas aeruginosa were the two most common pathogens, accounting for 20.5% and 10.8% of cases, respectively. The prevalence of antimicrobial resistance (AMR) and multi-drug resistance did not significantly increase between episodes (10.2% vs. 13.4%, p = 0.42). In 59% of subsequent episodes, the identified pathogens were unrelated to the previous episode. However, the partial concordance of identified pathogens significantly increased to 66.7% when S. aureus was identified (p = 0.027). Subsequent episodes of IFI in the same patient are likely to differ in causative pathogens. However, in the case of S. aureus, the risk of reinfection, particularly with S. aureus, is increased. Multi-drug resistance does not appear to change between IFI episodes. Therefore, recommendations for empirical antimicrobial therapy should be based on local pathogen and resistance statistics without the need to broaden the spectrum of antibiotics in subsequent episodes.

Imported Toxigenic Corynebacterium Diphtheriae in Refugees with Polymicrobial Skin Infections, Germany, 2022.

During August-December 2022, toxigenic Corynebacterium diphtheriae was isolated from 25 refugees with skin infections and 2 refugees with asymptomatic throat colonization at a refugee reception center in Germany. None had systemic toxin-mediated illness. Of erosive/ulcerative skin infections, 96% were polymicrobial. Erosive/ulcerative wounds in refugees should undergo testing to rule out cutaneous diphtheria.

Anti-platelet factor 4 antibodies causing VITT do not cross-react with SARS-CoV-2 spike protein.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.

Already current practice? A snapshot survey on doxycycline use for prevention of sexually transmitted infections in parts of the German MSM community.

PURPOSE: Recent studies point toward a potential benefit of doxycycline use for post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP) to prevent sexually transmitted infections (STIs). Although prescribing doxycycline in a prophylactic intention is not generally recommended yet, we noticed an increasing number of inquiries from individuals within the LGBTQ community for doxycycline prescriptions. METHODS: We conducted an anonymous online survey to evaluate the current extent of doxycycline use for PEP or PrEP within the LGBTQ community using REDCap electronic data capture tools. Participants gained access to the online survey through a QR code on posters in the premises of our STI outpatient department and at LGBTQ community-related events in the south-western region of Germany. Additional access was provided by a direct link shared on social media profiles for men having sex with men (MSM), transgender, and queers. RESULTS: 96 of 99 responses were eligible for analysis. Twenty-two participants (23%) indicated to have already used doxycycline for PEP and six participants (6%) used doxycycline for PrEP. The majority of participants used pills left over from previous doxycycline treatment. Forty percent of indicated modes of access were without a regular prescription, e.g., by provision from acquaintances (with or without healthcare profession) or by ordering online. CONCLUSION: Our study shows that the concept of doxycycline use for prevention of STIs is already well known and applied in the LGBTQ community. Further analysis, especially modeling studies, are needed to evaluate strategies aiming to reduce doxycycline intake (PEP/PrEP versus repeated targeted therapies) and improve sexual health outcomes within the community.

Efficacy of a novel patient-focused intervention aimed at increasing adherence to guideline-based preventive measures in asplenic patients: the PrePSS trial.

PURPOSE: To determine whether a novel intervention improves the adherence to guideline-based preventive measures in asplenic patients at risk of post-splenectomy sepsis (PSS). METHODS: We used a prospective controlled, two-armed historical control group design to compare a novel, health action process approach (HAPA)-based telephonic intervention involving both patients and their general practitioners to usual care. Eligible patients were identified in cooperation with the insurance provider AOK Baden-Wuerttemberg, Germany. Patients with anatomic asplenia (n = 106) were prospectively enrolled and compared to a historical control group (n = 113). Comparisons were done using a propensity-score-based overlap-weighting model. Adherence to preventive measures was quantified by the study-specific 'Preventing PSS score' (PrePSS score) which includes pneumococcal and meningococcal vaccination status, the availability of a stand-by antibiotic and a medical alert card. RESULTS: At six months after the intervention, we estimated an effect of 3.96 (95% CI 3.68-4.24) points on the PrePSS score scale (range 0-10) with mean PrePSS scores of 3.73 and 7.70 in control and intervention group, respectively. Substantial improvement was seen in all subcategories of the PrePSS score with the highest absolute gains in the availability of stand-by antibiotics. We graded the degree of participation by the general practitioner (no contact, short contact, full intervention) and noted that the observed effect was only marginally influenced by the degree of physician participation. CONCLUSIONS: Patients who had received the intervention exhibited a significantly higher adherence to guideline-based preventive measures compared to the control group. These data suggest that widespread adoption of this pragmatic intervention may improve management of asplenic patients. Health insurance provider-initiated identification of at-risk patients combined with a patient-focused intervention may serve as a blueprint for a wide range of other preventive efforts leading to patient empowerment and ultimately to better adherence to standards of care.

Long-term follow-up after introduction of a systematic sexually transmitted infection screening program for men having sex with men living with HIV in a primary care setting: uptake, STI incidence, and risk factors for infection and reinfection.

PURPOSE: Annual screening for asymptomatic infections with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) is recommended by international guidelines in people living with HIV but uptake in routine care remains poor. This study analyzed the effects of the implementation of a CT/NG screening program in a primary HIV treatment center. METHODS: In this single-center cohort study, we included men having sex with men (MSM) living with HIV during the study period from January 2016 to December 2019. From January 2018 on, annual sexual health counseling including CT/NG screening was proactively offered to all MSM presenting at the center. CT/NG screening rates, test positivity rates and case detection rates in the years 2018 and 2019 were compared to those in the years 2016 and 2017. RESULTS: A total of 234 patients were enrolled in the study contributing to 798.7 patient years (py) during the four-year study period. Screening rates increased from 3.1% and 3.9% in 2016 and 2017 to 51.1% in 2018 and decrease to 35.4% in 2019. Over the study period, 19.7% (46/234) had at least one positive CT/NG result. After the intervention, case detection per 100 py increased for CT (2016: 2.6, 2017: 3.7, 2018: 7.7, 2019: 7.1) and NG (2016: 3.2, 2017: 3.1, 2018: 5.3, 2019: 7.6). The number needed to test was 8.9 for CT and 10.4 for NG. CONCLUSION: Regular CT/NG screening is feasible in a primary care setting, leads to an increase in case detection and may contribute to decrease transmission and complications of CT/NG. TRIAL REGISTRATION: The trial is registered in ClinicalTrials.gov (NCT02149004).

Clinical phenotype and outcome of persistent SARS-CoV-2 replication in immunocompromised hosts: a retrospective observational study in the Omicron era.

PURPOSE: This study aims to describe clinical, virological and radiological characteristics as well as treatment strategies and outcomes of immunocompromised patients with persistent SARS-CoV-2 replication. METHODS: We performed a retrospective cohort study of immunocompromised patients at the University Medical Center Freiburg between 01/2022 and 05/2023. Patients with substantial immunosuppression and persistent SARS-CoV-2 detection (Ct-value < 30 after 14 days) were included. RESULTS: 36 patients in our cohort reported mainly fever, dyspnoea or continuous cough. Viral load was significantly higher in concurrent samples taken from the lower respiratory tract (Ct-value = 26) than from the upper respiratory tract (Ct-value = 34). Time of detectable viral RNA after start of antiviral treatment was shorter in patients receiving two antivirals (median 15 days vs. 31 days with one antiviral agent). Short-course antiviral therapy (≤ 5 days) was less efficient in reduction of symptoms and viral load than prolonged therapy > 10 days. In 30% (8/27) of patients with repeated CT scans, we found the emergence of chronic pulmonary changes, which were more frequently in patients with B cell depletion (37%, 7/19) compared to patients with organ transplantation (12%, 2/17). CONCLUSION: Ongoing SARS-CoV-2 replication in the lower respiratory tract is a relevant differential diagnosis in patients with severe immunosuppression and continuous cough, fever or dyspnoea even if nasopharyngeal swabs test negative for SARS-CoV-2. Especially in B cell-depleted patients, this may lead to inflammatory or fibrotic-like pulmonary changes, which are partially reversible after inhibition of viral replication. Antiviral therapy seems to be most effective in combination and over a prolonged period of time of > 10 days. TRIAL REGISTRATION NUMBER: DRKS 00027299.

Covid-19 triage in the emergency department 2.0: how analytics and AI transform a human-made algorithm for the prediction of clinical pathways.

The Covid-19 pandemic has pushed many hospitals to their capacity limits. Therefore, a triage of patients has been discussed controversially primarily through an ethical perspective. The term triage contains many aspects such as urgency of treatment, severity of the disease and pre-existing conditions, access to critical care, or the classification of patients regarding subsequent clinical pathways starting from the emergency department. The determination of the pathways is important not only for patient care, but also for capacity planning in hospitals. We examine the performance of a human-made triage algorithm for clinical pathways which is considered a guideline for emergency departments in Germany based on a large multicenter dataset with over 4,000 European Covid-19 patients from the LEOSS registry. We find an accuracy of 28 percent and approximately 15 percent sensitivity for the ward class. The results serve as a benchmark for our extensions including an additional category of palliative care as a new label, analytics, AI, XAI, and interactive techniques. We find significant potential of analytics and AI in Covid-19 triage regarding accuracy, sensitivity, and other performance metrics whilst our interactive human-AI algorithm shows superior performance with approximately 73 percent accuracy and up to 76 percent sensitivity. The results are independent of the data preparation process regarding the imputation of missing values or grouping of comorbidities. In addition, we find that the consideration of an additional label palliative care does not improve the results.

Ethical and coordinative challenges in setting up a national cohort study during the COVID-19 pandemic in Germany.

With the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), global researchers were confronted with major challenges. The German National Pandemic Cohort Network (NAPKON) was launched in fall 2020 to effectively leverage resources and bundle research activities in the fight against the coronavirus disease 2019 (COVID-19) pandemic. We analyzed the setup phase of NAPKON as an example for multicenter studies in Germany, highlighting challenges and optimization potential in connecting 59 university and nonuniversity study sites. We examined the ethics application process of 121 ethics submissions considering durations, annotations, and outcomes. Study site activation and recruitment processes were investigated and related to the incidence of SARS-CoV-2 infections. For all initial ethics applications, the median time to a positive ethics vote was less than two weeks and 30 of these study sites (65%) joined NAPKON within less than three weeks each. Electronic instead of postal ethics submission (9.5 days (Q1: 5.75, Q3: 17) vs. 14 days (Q1: 11, Q3: 26), p value = 0.01) and adoption of the primary ethics vote significantly accelerated the ethics application process. Each study center enrolled a median of 37 patients during the 14-month observation period, with large differences depending on the health sector. We found a positive correlation between recruitment performance and COVID-19 incidence as well as hospitalization incidence. Our analysis highlighted the challenges and opportunities of the federated system in Germany. Digital ethics application tools, adoption of a primary ethics vote and standardized formal requirements lead to harmonized and thus faster study initiation processes during a pandemic.

Early and Rapid Identification of COVID-19 Patients with Neutralizing Type I Interferon Auto-antibodies.

PURPOSE: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions. METHODS: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome. RESULTS: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE. CONCLUSION: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.

Prediction of COVID-19 deterioration in high-risk patients at diagnosis: an early warning score for advanced COVID-19 developed by machine learning.

PURPOSE: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization. METHODS: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16). RESULTS: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface. CONCLUSION: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.

Complement system component dysregulation is a distinctive feature of COVID-19 disease: a prospective and comparative analysis of patients admitted to the emergency department for suspected COVID-19 disease.

The complement system (CS) plays a pivotal role in Coronavirus disease 2019 (COVID-19) pathophysiology. The objective of this study was to provide a comparative, prospective data analysis of CS components in an all-comers cohort and COVID-19 patients. Patients with suspected COVID-19 infection admitted to the Emergency department were grouped for definite diagnosis of COVID-19 and no COVID-19 accordingly. Clinical presentation, routine laboratory and von Willebrand factor (vWF) antigen as well as CS components 3, 4 and activated 5 (C5a) were assessed. Also, total complement activity via the classical pathway (CH50) was determined. Levels of calprotectin in serum were measured using an automated quantitative lateral flow assay. We included 80 patients in this prospective trial. Of those 19 (23.7%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 had higher levels of CS components 5a and 4 (54.79 [24.14-88.79] ng/ml vs. 35 [23.15-46.1] ng/ml; p = 0.0433 and 0.3772 [± 0.1056] g/L vs. 0.286 [0.2375-0.3748] g/L; p = 0.0168). COVID-19 patients had significantly higher levels of vWF antigen when compared to the control group (288.3 [± 80.26] % vs. 212 [151-320] %; p = 0.0469). There was a significant correlation between CS C3 and 5a with vWF antigen (rs = 0.5957 [p = 0.0131] and rs = 0.5015 [p = 0.042]) in COVID-19 patients. There was no difference in calprotectin plasma levels (4.786 [± 2.397] µg/ml vs. 4.233 [± 2.142] µg/ml; p = 0.4175) between both groups. This prospective data from a single centre all-comers cohort accentuates altered levels of CS components as a distinct feature of COVID-19 disease. Deregulation of CS component 3 and C5a are associated with increased vWF antigen possibly linking vascular damage to alternative CS activation in COVID-19.

[Complaints and clinical findings six months after COVID-19: outpatient follow-up at the University Medical Center Freiburg]. / Persistierende Beschwerden 6 Monate nach COVID-19 ­ Erfahrungen aus der COVID-19-Nachsorgeambulanz des Universitätsklinikums Freiburg.

BACKGROUND: Increasing evidence suggests that some patients suffer from persistent symptoms for months after recovery from acute COVID-19. However, the clinical phenotype and its pathogenesis remain unclear. We here present data on complaints and results of a diagnostic workup of patients presenting to the post-COVID clinic at the University Medical Center Freiburg. METHODS: Retrospective data analysis of persistently symptomatic patients presenting to our clinic at least 6 months after onset of acute COVID-19. All patients were assessed by a doctor and routine laboratory analysis was carried out. Quality of life was assessed using SF-36 questionnaire. In case of specific persisting symptoms, further organ-specific diagnostic evaluation was performed, and patients were referred to respective departments/specialists. FINDINGS: 132 Patients (58 male, 74 female; mean age 53.8 years) presented to our clinic at least 6 months after COVID-19. 79 (60 %) had been treated as outpatients and 53 (40 %) as inpatients. Most common complaints were persistent fatigue (82 %) and dyspnea on exertion (61 %). Further common complaints were impairments of concentration (54 %), insomnia (43 %), and impairments of smell or taste (35 %). Quality of life was reduced in all sections of the SF-36 questionnaire, yielding a reduced working capacity. Significant pathological findings in laboratory, echocardiographic and radiological work-up were rare. Impairments in lung function tests were more common in previously hospitalized patients. CONCLUSION: Patients presenting 6 months after onset of acute COVID-19 suffer from a diverse spectrum of symptoms with impaired quality of life, also referred to as Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Further research is needed to determine the frequency of these post-COVID syndromes and their pathogenesis, natural course and treatment options. Evaluation and management should be multi-disciplinary.

Serum Protein Profiling Reveals a Specific Upregulation of the Immunomodulatory Protein Progranulin in Coronavirus Disease 2019.

BACKGROUND: Severe courses of coronavirus disease 2019 (COVID-19) are associated with elevated levels of interleukin 6 (IL-6). However, there is a growing body of evidence pointing to a broad and more complex disorder of proinflammatory and antiviral responses with disturbed interferon signaling in COVID-19. METHODS: In this prospective, single-center registry, we included severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients and patients with similar symptoms and severity of disease but negative for SARS-CoV-2 admitted to the emergency department and compared their serum protein expression profiles. RESULTS: IL-6 abundance was similar in SARS-CoV-2-positive patients (n = 24) compared with SARS-CoV-2-negative controls (n = 61). In contrast, we observed a specific upregulation of the immunomodulatory protein progranulin (GRN). High GRN abundance was associated with adverse outcomes and increased expression of IL-6 in COVID-19. CONCLUSIONS: The data from this registry reveal that GRN is specifically upregulated in SARS-CoV-2-positive patients while IL-6 may serve as marker for disease severity. The potential of GRN as a biomarker and a possible impact of increased GRN expression on interferon signaling, virus elimination, and virus-induced lung tissue damage in COVID-19 should be further explored.

Impact of Immunosuppressive Agents on Clinical Manifestations and Outcome of Staphylococcus aureus Bloodstream Infection: A Propensity Score-Matched Analysis in 2 Large, Prospectively Evaluated Cohorts.

BACKGROUND: Staphylococcus aureus bloodstream infection (SAB) is a common, life-threatening infection. The impact of immunosuppressive agents on the outcome of patients with SAB is incompletely understood. METHODS: Data from 2 large prospective, international, multicenter cohort studies (Invasive Staphylococcus aureus Infections Cohort [INSTINCT] and International Staphylococcus aureus Collaboration [ISAC]) between 2006 and 2015 were analyzed. Patients receiving immunosuppressive agents were identified and a 1:1 propensity score-matched analysis was performed to adjust for baseline characteristics of patients. Overall survival and time to SAB-related late complications (SAB relapse, infective endocarditis, osteomyelitis, or other deep-seated manifestations) were analyzed by Cox regression and competing risk analyses, respectively. This approach was then repeated for specific immunosuppressive agents (corticosteroid monotherapy and immunosuppressive agents other than steroids [IMOTS]). RESULTS: Of 3188 analyzed patients, 309 were receiving immunosuppressive treatment according to our definitions and were matched to 309 nonimmunosuppressed patients. After propensity score matching, baseline characteristics were well balanced. In the Cox regression analysis, we observed no significant difference in survival between the 2 groups (death during follow-up: 105/309 [33.9%] immunosuppressed vs 94/309 [30.4%] nonimmunosuppressed; hazard ratio [HR], 1.20 [95% confidence interval {CI}, .84-1.71]). Competing risk analysis showed a cause-specific HR of 1.81 (95% CI, .85-3.87) for SAB-related late complications in patients receiving immunosuppressive agents. The cause-specific HR was higher in patients taking IMOTS (3.69 [95% CI, 1.41-9.68]). CONCLUSIONS: Immunosuppressive agents were not associated with an overall higher mortality. The risk for SAB-related late complications in patients receiving specific immunosuppressive agents such as IMOTS warrants further investigations.

Development and validation of a simplified risk score for the prediction of critical COVID-19 illness in newly diagnosed patients.

Scores to identify patients at high risk of progression of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may become instrumental for clinical decision-making and patient management. We used patient data from the multicentre Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) and applied variable selection to develop a simplified scoring system to identify patients at increased risk of critical illness or death. A total of 1946 patients who tested positive for SARS-CoV-2 were included in the initial analysis and assigned to derivation and validation cohorts (n = 1297 and n = 649, respectively). Stability selection from over 100 baseline predictors for the combined endpoint of progression to the critical phase or COVID-19-related death enabled the development of a simplified score consisting of five predictors: C-reactive protein (CRP), age, clinical disease phase (uncomplicated vs. complicated), serum urea, and D-dimer (abbreviated as CAPS-D score). This score yielded an area under the curve (AUC) of 0.81 (95% confidence interval [CI]: 0.77-0.85) in the validation cohort for predicting the combined endpoint within 7 days of diagnosis and 0.81 (95% CI: 0.77-0.85) during full follow-up. We used an additional prospective cohort of 682 patients, diagnosed largely after the "first wave" of the pandemic to validate the predictive accuracy of the score and observed similar results (AUC for the event within 7 days: 0.83 [95% CI: 0.78-0.87]; for full follow-up: 0.82 [95% CI: 0.78-0.86]). An easily applicable score to calculate the risk of COVID-19 progression to critical illness or death was thus established and validated.

Neurological symptoms and complications in predominantly hospitalized COVID-19 patients: Results of the European multinational Lean European Open Survey on SARS-Infected Patients (LEOSS).

BACKGROUND AND PURPOSE: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. METHODS: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. RESULTS: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20-1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07-1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. CONCLUSION: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.

Enterococcus faecalis bloodstream infection: does infectious disease specialist consultation make a difference?

PURPOSE: To evaluate the relationship between mortality or relapse of bloodstream infection (BSI) due to Enterococcus faecalis and infectious diseases specialist consultation (IDC) and other factors potentially associated with outcomes. METHODS: In a tertiary-care center, consecutive adult patients with E. faecalis BSI between January 1, 2016 and January 31, 2019, were prospectively followed. The management of E. faecalis BSI was evaluated in terms of adherence to evidence-based quality-of-care indicators (QCIs). IDC and other factors potentially associated with 90-day-mortality or relapse of E. faecalis BSI were analyzed by multivariate logistic regression. RESULTS: A total of 151 patients with a median age of 68 years were studied. IDC was performed in 38% of patients with E. faecalis BSI. 30 cases of endocarditis (20%) were diagnosed. All-cause in-hospital mortality was 23%, 90-day mortality was 37%, and 90-day relapsing E. faecalis BSI was 8%. IDC was significantly associated with better adherence to 5 QCIs. Factors significantly associated with 90-day mortality or relapsing EfB in multivariate analysis were severe sepsis or septic shock at onset (HR 4.32, CI 2.36e7.88) and deep-seated focus of infection (superficial focus HR 0.33, CI 0.14e0.76). CONCLUSION: Enterococcus faecalis bacteremia is associated with a high mortality. IDC contributed to improved diagnostic and therapeutic management.