Cytokine levels associated with favorable clinical outcome in the CAPSID randomized trial of convalescent plasma in patients with severe COVID-19.

Objectives: To determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP). Methods: Patients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models. Results: The majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models. Conclusion: This analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.

Surgical Procedure Time and Mortality in Patients with Infective Endocarditis Caused by Staphylococcus aureus or Streptococcus Species.

Staphylococcus aureus (SA) and Streptococcus species (SS) show different clinical manifestations in infective endocarditis (IE), but the impact on the complexity of surgical treatment remains unclear. All patients with surgically treated IE due to SA or SS between July 2013 and December 2016 were extracted from a prospectively collected, single-center registry. Data on patient characteristics, surgical procedures, and postprocedural outcomes were collected. SA-IE was more common with prosthetic valves (26.3% vs. 7.3%, p = 0.04), cardiac devices (14.3% vs. 0%, p = 0.03), previous cardiac surgery (28.6% vs. 9.8%, p = 0.03), intravenous drug abuse (14.3% vs. 0%, p = 0.03), and embolic events (57.1% vs. 26.8%, p = 0.007). Preoperative CRP was significantly higher in SA-IE (median 96.1 mg/L vs. 42.4 mg/L, p = 0.002). Otherwise, SS-IE affected more cusps/leaflets (mean 2.4 vs. 1.8, p = 0.03) and led to more valve dysfunction (83.8% vs. 54.3%, p = 0.007). Surgery times did not differ between the groups, though patients with SA spent more time in the intensive care unit (median 7 vs. 4.5 days, p = 0.04). Hospital mortality did not differ, but patients with SA-IE had unfavorable long-term survival (p = 0.001). Future studies need to be larger and focus on the mechanism behind the reduced long-term survival to mitigate the deleterious effect of SA in surgically treated patients with IE.

Outcome of kidney transplantations from ≥65-year-old deceased donors with acute kidney injury.

Kidney transplantation (KT) from donors with acute kidney injury (AKI) has been associated with delayed graft function (DGF) but similar graft survival compared with KT from donors without AKI. Kidneys from ≥65-year-old donors with comorbidities are more susceptible to cold ischemia time (CIT) and DGF and it is unknown whether such elderly kidneys with AKI can also be transplanted with satisfactory outcomes. All KTs from ≥65-year-old donors performed at our center from 1999 to 2019 (n = 233) were retrospectively analyzed and short- as well as long-term outcomes were compared for KTs from donors with (n = 64) and without AKI (n = 169). There were no significant differences regarding the frequency of DGF as well as the estimated glomerular filtration rate (eGFR) 1 and 3 years post-transplant between the no-AKI and the AKI group (DGF: no-AKI 30.2% vs. AKI 40.6%, P = .17; eGFR at 1-year: 31.9 ml/min/1.73 m2 vs. 35.5 ml/min/1.73 m2 , P = .32; at 3-years: 33.8 ml/min/1.73 m2 vs. 40.9 ml/min/1.73 m2 , P = .18; respectively). Death-censored graft survival and patient survival were also not significantly different. Multivariable Cox regression analysis did not identify AKI as a significant risk factor for graft loss or death. Following careful donor and recipient selection, kidneys from ≥65-year-old AKI donors may potentially be transplanted with satisfactory outcomes.

Improving Emergency Department Patient-Physician Conversation Through an Artificial Intelligence Symptom-Taking Tool: Mixed Methods Pilot Observational Study.

BACKGROUND: Establishing rapport and empathy between patients and their health care provider is important but challenging in the context of a busy and crowded emergency department (ED). OBJECTIVE: We explore the hypotheses that rapport building, documentation, and time efficiency might be improved in the ED by providing patients a digital tool that uses Bayesian reasoning-based techniques to gather relevant symptoms and history for handover to clinicians. METHODS: A 2-phase pilot evaluation was carried out in the ED of a German tertiary referral and major trauma hospital that treats an average of 120 patients daily. Phase 1 observations guided iterative improvement of the digital tool, which was then further evaluated in phase 2. All patients who were willing and able to provide consent were invited to participate, excluding those with severe injury or illness requiring immediate treatment, with traumatic injury, incapable of completing a health assessment, and aged <18 years. Over an 18-day period with 1699 patients presenting to the ED, 815 (47.96%) were eligible based on triage level. With available recruitment staff, 135 were approached, of whom 81 (60%) were included in the study. In a mixed methods evaluation, patients entered information into the tool, accessed by clinicians through a dashboard. All users completed evaluation Likert-scale questionnaires rating the tool's performance. The feasibility of a larger trial was evaluated through rates of recruitment and questionnaire completion. RESULTS: Respondents strongly endorsed the tool for facilitating conversation (61/81, 75% of patients, 57/78, 73% of physician ratings, and 10/10, 100% of nurse ratings). Most nurses judged the tool as potentially time saving, whereas most physicians only agreed for a subset of medical specialties (eg, surgery). Patients reported high usability and understood the tool's questions. The tool was recommended by most patients (63/81, 78%), in 53% (41/77) of physician ratings, and in 76% (61/80) of nurse ratings. Questionnaire completion rates were 100% (81/81) by patients and 96% (78/81 enrolled patients) by physicians. CONCLUSIONS: This pilot confirmed that a larger study in the setting would be feasible. The tool has clear potential to improve patient-health care provider interaction and could also contribute to ED efficiency savings. Future research and development will extend the range of patients for whom the history-taking tool has clinical utility. TRIAL REGISTRATION: German Clinical Trials Register DRKS00024115; https://drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024115.

Impact of the explanting surgeon's impression of donor arteriosclerosis on outcome of kidney transplantations from donors aged ≥65 years.

PURPOSE: Careful donor selection is important for kidney transplantations (KT) from suboptimal donors aged ≥65 years. Several tools such as histopathological assessment of preimplant biopsies have been shown to predict allograft survival and can be applied for selection. Whether the explanting surgeon's appraisal is associated with outcomes of KTs from suboptimal donors is unknown. METHODS: We compared outcomes of KTs from ≥65-year-old deceased donors performed at our centre between 1999 and 2018 for which grading of macroscopic 'donor arteriosclerosis' (n=104) and 'organ quality' (n=208) as judged by the explanting surgeon and documented on the Eurotransplant kidney organ report was available. RESULTS: No association was observed between degree of macroscopic donor arteriosclerosis and death-censored graft survival in univariable or multivariable regression analyses. Compared to KTs from donors with no/mild arteriosclerosis, KTs from donors with moderate/severe arteriosclerosis were associated with a significantly impaired allograft function 3 months, 1 year and 3 years after transplantation (e.g. at 3 years: 176.8 µmol/l vs 137.0 µmol/l, P=0.003). Following multivariable regression analysis, these differences remained significant at 3 months and 3 years after KT. No association was observed between degree of macroscopic arteriosclerosis and mortality or primary non-function as well as no consistent association with delayed graft function and histological arteriosclerosis. Assessment of 'organ quality' was not associated with outcomes. CONCLUSION: Our data suggest that the explanting surgeon's assessment of donor arteriosclerosis is associated with allograft function. Larger studies and better standardization of kidney inspection after explantation are required to further explore the impact of surgeon's appraisal in KT.

Providing care in isolation while awaiting SARS-CoV-2 test results: Considering differential diagnoses and avoiding anchoring bias.

ABSTRACT: Isolation of confirmed or suspected coronavirus disease 2019 (COVID-19) cases is essential but, as symptoms of COVID-19 are non-specific and test results not immediately available, case identification at admission remains challenging. To inform optimization of triage algorithms, patient flow and patient care, we analyzed characteristics of patients admitted to an isolation ward, both severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) positive patients and patients in which initial suspicion was not confirmed after appropriate testing.Data from patients with confirmed or suspected COVID-19 treated in an isolation unit were analyzed retrospectively. Symptoms, comorbidities and clinical findings were analyzed descriptively and associations between patient characteristics and final SARS-CoV-2 status were assessed using univariate regression.Eighty three patients (49 SARS-CoV-2 negative and 34 positive) were included in the final analysis. Of initially suspected COVID-19 cases, 59% proved to be SARS-CoV-2-negative. These patients had more comorbidities (Charlson Comorbidity Index median 5(interquartile range [IQR] 2.5, 7) vs 2.7(IQR 1, 4)), and higher proportion of active malignancy than patients with confirmed COVID-19 (47% vs 15%; P = .004), while immunosuppression was frequent in both patient groups (20% vs 21%; P = .984). Of SARS-CoV-2 negative patients, 31% were diagnosed with non-infectious diseases.A high proportion of patients (59%) triaged to the isolation unit were tested negative for SARS-CoV-2. Of these, many suffered from active malignancy (47%) and were immunosuppressed (20%). Non-infectious diseases were diagnosed in 31%, highlighting the need for appropriate patient flow, timely expert medical care including evaluation for differential diagnostics while providing isolation and ruling out of COVID-19 in these patients with complex underlying diseases.

Predictors of COVID-19 in an outpatient fever clinic.

BACKGROUND: The objective of this study was to identify clinical risk factors for COVID-19 in a German outpatient fever clinic that allow distinction of SARS-CoV-2 infected patients from other patients with flu-like symptoms. METHODS: This is a retrospective, single-centre cohort study. Patients were included visiting the fever clinic from 4th of April 2020 to 15th of May 2020. Symptoms, comorbidities, and socio-demographic factors were recorded in a standardized fashion. Multivariate logistic regression was used to identify risk factors of COVID-19, on the bases of those a model discrimination was assessed using area under the receiver operation curves (AUROC). RESULTS: The final analysis included 930 patients, of which 74 (8%) had COVID-19. Anosmia (OR 10.71; CI 6.07-18.9) and ageusia (OR 9.3; CI 5.36-16.12) were strongly associated with COVID-19. High-risk exposure (OR 12.20; CI 6.80-21.90), especially in the same household (OR 4.14; CI 1.28-13.33), was also correlated; the more household members, especially with flu-like symptoms, the higher the risk of COVID-19. Working in an essential workplace was also associated with COVID-19 (OR 2.35; CI 1.40-3.96), whereas smoking was inversely correlated (OR 0.19; CI 0.08-0.44). A model that considered risk factors like anosmia, ageusia, concomitant of symptomatic household members and smoking well discriminated COVID-19 patients from other patients with flu-like symptoms (AUROC 0.84). CONCLUSIONS: We report a set of four readily available clinical parameters that allow the identification of high-risk individuals of COVID-19. Our study will not replace molecular testing but will help guide containment efforts while waiting for test results.

Contrast-Enhanced Ultrasound for the Detection of Abdominal Complications in Infective Endocarditis: First Experience From a Prospective Cohort.

Embolic events are associated with increased mortality in patients with infective endocarditis (IE). The goal of this study was to gain experience with the application of contrast-enhanced ultrasound (CEUS) in IE to detect abdominal complications. CEUS was performed in 40 patients from a prospective register of IE. CEUS was able to detect abdominal embolic events or metastatic infection in 12 patients (30%). Most commonly seen were splenic infarctions (n = 10), followed by renal infarction (n = 2), liver abscess (n = 1) and mycotic aneurysm (n = 1). Six out of 14 lesions were only detected by CEUS and not by conventional ultrasound. Abdominal complications revealed by CEUS were associated with a detectable valve vegetation (p = 0.04) and larger vegetation size (p = 0.01). In three patients, a non-IE related abdominal lesion (two hepatocellular carcinomas, one psoas hematoma) was detected. CEUS is a feasible diagnostic method in detection of abdominal complications of IE.

Vocal Fold Paralysis is a Common Complication in Esophageal Cancer Patients with Esophagorespiratory Fistula.

BACKGROUND AND AIMS: The development of an esophagorespiratory fistula (ERF) in patients with esophageal cancer (EC) is associated with poor prognosis. We observed a high rate of vocal fold paralysis (VFP) in patients with ERF. Data on prevalence and complications of VFP in ERF are lacking. The present study investigated the incidence of VFP in patients with malignant ERF and examined possible risk factors and the impact on survival. METHODS: We performed a retrospective case-control study of 46 institutional cases of EC patients with ERF in a time period of eleven years. Patients were matched to 92 randomly selected controls (EC patients without ERF) in a 1:2 fashion for tumor localization and histology. Demographics, clinical characteristics, recurrence, treatment modalities as well as survival were analyzed. RESULTS: Esophageal cancer patients with ERF developed more often VFP than EC patients without ERF (59% vs. 21%; p=0.02; odds ratio (OR) 4.9). Esophageal cancer patients with ERF had a more pronounced weight loss (7.1 vs. 11.5 kg; P = 0.008), as well as higher rates of esophageal (p=<0.001; OR 22.9) and tracheal stenting (p=<0.001; OR 76.8). Proximal tumor growth (p=0.004; OR 7.9), fistula formation to the trachea (p=<0.001; OR 17.2) and recurrent disease (p=0.04, OR 4.7) was associated with VFP development in EC patients with ERF. Vocal fold paralysis in ERF did not adversely affect five-year survival. CONCLUSIONS: Vocal fold paralysis is a common complication in more than half of the patients with ERF in EC. It is associated with proximal tumor growth, fistula formation to the trachea and disease recurrence, but does not influence survival.

Risk Factors for the Development of Esophagorespiratory Fistula in Esophageal Cancer.

BACKGROUND AND AIMS: The development of esophagorespiratory fistula (ERF) in esophageal cancer (EC) is a devastating complication, leading to poor survival rates and low quality of life. Goal of this study was to identify risk factors leading to fistula formation in esophageal cancer. METHODS: We identified 47 patients with malignant ERF formation in EC in a period of 10 years. Clinical characteristics were compared by univariable analysis to 47 randomly selected patients with EC, but without ERF. A case-control study was conducted for patients with squamous cell carcinoma (SCC) and ERF matching in a 1:2 fashion for primary tumor localization. RESULTS: Identifiable risk factors in EC patients were histology of SCC (P-value < 0.001), former or current smoking status (P = 0.002) and primary tumor localization in the proximal esophagus (P < 0.001). The "hot spot" for ERF formation was tumor growth 20-25cm distal to dental arch. An additional risk factor in SCC patients was age. Patients with ERF formation in SCC were younger than patients without ERF (median 63 vs. 67 years, P = 0.02). No difference in the rate of fistula formation was seen between esophagectomy and definitive chemoradiation, but the latter developed ERF earlier in the course of the disease (237 vs. 596.5 days, P = 0.01). CONCLUSION: Patients with proximal SCC of the esophagus and a smoking history, as well as young patients with SCC should be closely monitored for ERF formation.

Overt Increase of Oxidative Stress and DNA Damage in Murine and Human Colitis and Colitis-Associated Neoplasia.

Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated-cancer (CAC); however, the underlying processes of disease progression are not completely understood. Here, the molecular processes of inflammation-driven colon carcinogenesis were investigated using IL10-deficient mice (IL10 KO). IL10 KO mice were euthanized after development of colitis and dysplasia. IHC was performed for markers of colitis-induced DNA damage (CIDD): oxidative DNA lesions (8-oxoG), double-strand breaks (DSB; γH2AX). and DSB repair. MSI, LOH (Trp53, Apc), and global methylation (CIMP) were assessed on microdissected tissue. Comet assay for DNA damage, immunofluorescence, and immunoblotting were performed on intestinal organoids from wild-type (WT) and IL10 KO mice. Sequential biopsies and surgical specimens from IBD and CAC patients were used for IHC analysis. Severity of inflammation correlated with number of dysplasia. 8-oxoG and γH2AX-positive cells were significantly increased in inflamed and dysplastic areas along with activation of DSB repair. The amount of positively stained cells strongly correlated with degree of inflammation (8-oxoG: R = 0.923; γH2AX: R = 0.858). Neither CIMP, MSI nor LOH was observed. Enhanced DSBs in IL10 KO organoids were confirmed by comet assay and increased expression of γH2AX. Human clinical specimens exhibited significantly higher γH2AX and 8-oxoG in IBD, dysplasia, and CAC compared with normal mucosa. These data indicate that inflammation-driven colon carcinogenesis in IL10 KO mice and IBD patients is associated with oxidative DNA damage and overt presence of DSB. Mol Cancer Res; 16(4); 634-42. ©2018 AACR.

IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis.

The mucosal immune response in the setting of intestinal inflammation contributes to colorectal cancer. IL10 signaling has a central role in gut homeostasis and is impaired in inflammatory bowel disease (IBD). Out of two IL10 receptor subunits, IL10R1 and IL10R2, the latter is shared among the IL10 family of cytokines and activates STAT signaling. STAT3 is oncogenic in colorectal cancer; however, knowledge about IL10 signaling upstream of STAT3 in colorectal cancer is lacking. Here, expression of IL10 signaling genes was examined in matched pairs from normal and tumor tissue from colorectal cancer patients showing overexpression (mRNA, protein) of IL10R2 and STAT3 but not IL10R1. IL10R2 overexpression was related to microsatellite stability. Transient overexpression of IL10R2 in HT29 cells increased proliferation upon ligand activation (IL10 and IL22). IL22, and not IL10, phosphorylated STAT3 along with increased phosphorylation of AKT and ERK. A significantly higher expression of IL22R1 and IL10R2 was also confirmed in a separate cohort of colorectal cancer samples. IL22 expression was elevated in gut mucosa from patients with IBD and colitis-associated cancer, which also exhibited increased expression of IL22R1 but not its coreceptor IL10R2. Overall, these data indicate that overexpression of IL10R2 and STAT3 contributes to colorectal carcinogenesis in microsatellite-stable tumors through IL22/STAT3 signaling.