Beyond muscles: Investigating immunoregulatory myokines in acute resistance exercise - A systematic review and meta-analysis.

Myokines, released from the muscle, enable communication between the working muscles and other tissues. Their release during physical exercise is assumed to depend on immune-hormonal-metabolic interactions concerning mode (endurance or resistance exercise), duration, and intensity. This meta-analysis aims to examine the acute changes of circulating myokines inducing immunoregulatory effects caused by a bout of resistance exercise and to consider potential moderators of the results. Based on this selection strategy, a systematic literature search was conducted for resistance exercise intervention studies measuring interleukin (IL-) 6, IL-10, IL-1ra, tumor necrosis factor (TNF-) α, IL-15, IL-7, transforming growth factor (TGF-) ß1, and fractalkines (FKN) before and immediately after resistance exercise in healthy individuals. Random-effects meta-analysis was performed for each myokine. We identified a moderate positive effect of resistance exercise for IL-6 and IL-1ra. Regarding IL-15 and TNF-α, small to moderate effects were found. For IL-10, no significant effect was observed. Due to no data, meta-analyses for IL-7, TGF-ß1, and FKN could not be performed. No moderators (training status, type of exercise, risk of bias, age, sex, time of day, exercise volume, exercise intensity, exercise dose) of the results were detected for all tested myokines. Taken together, this systematic review and meta-analysis showed immediate positive effects of an acute resistance exercise session on IL-6, IL-1ra, TNF-α, and IL-15 levels.

Efficient formation and maintenance of humoral and CD4 T-cell immunity targeting the viral capsid in acute-resolving hepatitis E infection.

BACKGROUND & AIMS: CD4 T cells shape the neutralizing antibody (nAb) response and facilitate viral clearance in various infections. Knowledge of their phenotype, specificity and dynamics in hepatitis E virus (HEV) infection is limited. HEV is enterically transmitted as a naked virus (nHEV) but acquires a host-derived quasi-envelope (eHEV) when budding from cells. While nHEV is composed of the open reading frame (ORF)-2-derived capsid, eHEV particles also contain ORF3-derived proteins. We aimed to longitudinally characterize the HEV-specific CD4 T cells targeting ORF1, 2 and 3 and antibodies against nHEV or eHEV in immunocompetent individuals with acute and resolved HEV infection. METHODS: HEV-specific CD4 T cells were analyzed by intracellular cytokine staining after stimulation with in silico-predicted ORF1- and ORF2-derived epitopes and overlapping peptides spanning the ORF3 region. Ex vivo multiparametric characterization of capsid-specific CD4 T cells was performed using customized MHC class II tetramers. Total and neutralizing antibodies targeting nHEV or eHEV particles were determined. RESULTS: HEV-specific CD4 T-cell frequencies and antibody titers are highest in individuals with acute infection and decline in a time-dependent process with an antigen hierarchy. HEV-specific CD4 T cells strongly target the ORF2-derived capsid and ORF3-specific CD4 T cells are hardly detectable. NAbs targeting nHEV are found in high titers while eHEV particles are less efficiently neutralized. Capsid-specific CD4 T cells undergo memory formation and stepwise contraction, accompanied by dynamic phenotypical and transcriptional changes over time. CONCLUSION: The viral capsid is the main target of HEV-specific CD4 T cells and antibodies in acute-resolving infection, correlating with efficient neutralization of nHEV. Capsid-specific immunity rapidly emerges followed by a stepwise contraction several years after infection. IMPACT AND IMPLICATIONS: The interplay of CD4 T cells and neutralizing antibody responses is critical in the host defense against viral infections, yet little is known about their characteristics in hepatitis E virus (HEV) infection. We conducted a longitudinal study of immunocompetent individuals with acute and resolved HEV infection to understand the characteristics of HEV-specific CD4 T cells and neutralizing antibodies targeting different viral proteins and particles. We found that HEV-specific CD4 T cells mainly target capsid-derived epitopes. This correlates with efficient neutralization of naked virions while quasi-enveloped particles are less susceptible to neutralization. As individuals with pre-existing liver disease and immunocompromised individuals are at risk for fulminant or chronic courses of HEV infection, these individuals might benefit from the development of vaccination strategies which require a detailed knowledge of the composition and longevity of HEV-specific CD4 T-cell and antibody immunity.

Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection.

BACKGROUND & AIMS: Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs). METHODS: PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide LPS, and IFN or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP. RESULTS: E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced LPS-mediated tumor necrosis factor production without toll-like receptor 4 tolerance induction. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1ß upon bacterial infection. Proteomic screen in mouse macrophages revealed progranulin as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin-D in a type-I IFN and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP. CONCLUSIONS: Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP. IMPACT AND IMPLICATIONS: Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment.

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients. To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3 T-MRI scans and signature inflammatory markers in n = 120 participants comprising healthy never-infected controls (n = 30), healthy COVID-19 survivors (n = 29), and subgroups of long-COVID patients with (n = 26) and without (n = 35) cognitive impairment according to screening with Montreal Cognitive Assessment. Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry. We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p < 0.05, FWE-corrected). Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNγ, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment. We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

[Post-COVID patients with persistent chemosensory symptoms are rare in the general population]. / Post-COVID-Patienten mit persistierenden chemosensorischen Symptomen sind in der Bevölkerung selten.

OBJECTIVE: The prevalence of long-/post-COVID-associated chemosensory symptoms is reported in the literature to be significantly higher than clinical reality reflects. METHODS: 1. N= 4062 adults acutely infected with SARS-CoV-2 and their symptoms transmitted by the Jena health office to the Robert Koch Institute between March 2020 and September 2021 were evaluated. 2. Part of the same cohort (N = 909 of 4062) answered an extensive questionnaire at least 3 months after the start of the infection, including existing chemosensory post-COVID-associated complaints. 3. Fourteen post-COVID Jena patients with chemosensory symptoms who had become acutely infected during the same period were diagnosed, treated and advised in our ENT specialist outpatient clinic. RESULTS: The prevalence of chemosensory symptoms at the onset of infection was 19% (600/3187). About every second written respondent of the formerly acutely infected (441/890) remembered chemosensory symptoms during their COVID-19 infection. Of these, around 38% (167/441) complained of persistent chemosensory post-COVID symptoms after an average of 14.5 months. Only 2.3% (14/600) of the previously acutely infected patients with chemosensory symptoms sought medical help in a special consultation. Quantitative chemosensory damage could only be objectified in half, i.e. 1.2% (7/600) of the total cohort. CONCLUSIONS: Despite a high prevalence of subjective chemosensory symptoms in acutely and formerly SARS-CoV-2 infected people, there is only a low need for specialized treatment, so that, unlike other post-COVID-associated complaints, the healthcare system as a whole appears to be less significantly burdened.

Influence of NOD2 risk variants on hepatic encephalopathy and association with inflammation, bacterial translocation and immune activation.

BACKGROUND: Nucleotide-binding oligomerization domain containing 2 (NOD2) risk variants lead to impaired mucosal barrier function, increased bacterial translocation (BT), and systemic inflammation. AIM: To evaluate the association between the presence of NOD2 risk variants, BT, inflammation, and hepatic encephalopathy (HE). PATIENTS AND METHODS: This prospective multicenter study included patients with cirrhosis and testing for NOD2 risk variants (p.R702W, p.G908R, c.3020insC, N289S, and c.-958T>C). Patients were evaluated for covert (C) and overt (O) HE. Markers of systemic inflammation (leukocytes, CRP, IL-6, LBP) and immune activation (soluble CD14) as well as bacterial endotoxin (hTRL4 activation) were determined in serum. RESULTS: Overall, 172 patients (70% men; median age 60 [IQR 54-66] years; MELD 12 [IQR 9-16]; 72% ascites) were included, of whom 53 (31%) carried a NOD2 risk variant. In this cohort, 11% presented with OHE and 27% and CHE. Presence and severity of HE and surrogates of inflammation, BT, and immune activation did not differ between patients with and without a NOD2 risk variant, also not after adjustment for MELD. HE was associated with increased ammonia and systemic inflammation, as indicated by elevated CRP (w/o HE: 7.2 [2.7-16.7]; with HE 12.6 [4.5-29.7] mg/dL; p < 0.001) and elevated soluble CD14 (w/o HE 2592 [2275-3033]; with HE 2755 [2410-3456] ng/mL; p = 0.025). CONCLUSIONS: The presence of NOD2 risk variants in patients with cirrhosis is not associated with HE and has no marked impact on inflammation, BT, or immune activation. In contrast, the presence of HE was linked to ammonia, the acute phase response, and myeloid cell activation.

Visualizing exertional dyspnea in a post-COVID patient using electrical impedance tomography.

PURPOSE AND METHOD: Many post-COVID patients suffer from dyspnea on exertion. To visualize exercise-induced dyspnea, a post-COVID patient and a healthy volunteer underwent an exercise test on a treadmill under stress relevant to everyday life monitored by electrical impedance tomography (EIT). RESULTS: The lung-healthy volunteer showed an even ventilation distribution throughout the assessment, a large ventilated area, and a butterfly-like lung shape with a convex lung rim. The post-COVID patient showed clear differences in the ventilated area compared to the control subject. During exercise, a constantly changing picture of differently ventilated areas is shown. However, especially the anterior regions were under-ventilated and larger areas were partially absent from ventilation. Overall, uncoordinated breathing and an uneven distribution of ventilation dominated the findings. CONCLUSION: EIT is suitable for visualizing disturbed ventilation of the lungs, both at rest and under stress. The potential as a diagnostic tool in dyspnea assessment should be investigated.

Mobile primary healthcare for post-COVID patients in rural areas: a proof-of-concept study.

INTRODUCTION: Post-COVID syndrome is increasingly recognized as a new clinical entity after SARS-CoV-2 infection. Patients living in rural areas may have to travel long with subjectively great effort to be examined using all necessary interdisciplinary tools. This problem could be addressed with mobile outpatient clinics. METHODS: In this prospective observational study, we investigated physical fitness, fatigue, depression, cognitive dysfunction, and dyspnea in patients with post-COVID syndrome in a mobile interdisciplinary post-COVID outpatient clinic. Upon referral from their primary care physician, patients were offered an appointment at a mobile post-COVID outpatient clinic close to their home. RESULTS: We studied 125 patients (female, n = 79; 63.2%) in our mobile unit. All patients reported symptoms lasting for more than 12 weeks after acute infection. 88.3% and 64.1% of patients reported significant impairment in physical and mental quality of life. Patients reported a median of three symptoms. The most frequently reported symptoms were fatigue (86.4%), cognitive dysfunction (85.6%), and dyspnea (37.6%). 56.0% of patients performed at < 2.5th percentile at the 1 min sit-to-stand test compared to age- and sex-matched healthy controls, and 25 patients (20.0%) exhibited a drop in oxygen saturation. A questionnaire given to each patient regarding the mobile unit revealed a very high level of patient satisfaction. CONCLUSION: There is an increasing need for high-quality and locally available care for patients with post-COVID syndrome. A mobile post-COVID outpatient clinic is a new concept that may be particularly suitable for use in rural regions. Patients' satisfaction following visits in such units is very high.

Post-COVID-19 condition is not only a question of persistent symptoms: structured screening including health-related quality of life reveals two separate clusters of post-COVID.

PURPOSE: Some patients experience long-term sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, despite a present post-COVID condition, defined as "any symptom lasting longer than 12 weeks," only a subset of patients search for medical help and therapy. METHOD: We invited all adults with a positive real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 between March 2020 and September 2021 (n = 4091) in the city of Jena to answer a standardized questionnaire including demographic information, the course of the acute infection and current health status. K-means-clustering of quality of life (QoL) was used to explore post-COVID subgroups. RESULTS: A total of 909 participants at a median interval of 367 (IQR 291/403) days after acute infection were included in the analysis. Of those, 643 (70.7%) complained of having experienced persistent symptoms at the time of the survey. Cluster analysis based on QoL revealed two subgroups of people with persistent post-COVID symptoms. Whereas 189/643 participants (29.4%) showed markedly diminished QoL, normal QoL was detected in 454/643 individuals (70.6%). CONCLUSION: Despite persistent symptoms being reported by nearly three quarters of participants, only one-third of these described a significant reduction in QoL (cluster 1), whereas the other two-thirds reported a near-normal QoL (cluster 2), thus indicating a differentiation between "post-COVID disease" and "post-COVID condition". The prevalence of clinically relevant post-COVID disease was at least 20.7%. Health policies should focus on this subset.

Quality of life and ability to work of patients with Post-COVID syndrome in relation to the number of existing symptoms and the duration since infection up to 12 months: a cross-sectional study.

PURPOSE: Following SARS-CoV-2 virus infection, patients may suffer from long-lasting symptoms regardless of disease severity. Preliminary results show limitations in health-related quality of life (HRQoL). The aim of this study is to show a possible change depending on the duration since infection and the accumulation of symptoms. Additionally, other possible influencing factors will be analyzed. METHODS: The study population consisted of patients (18-65 years) presenting to the Post-COVID outpatient clinic of the University Hospital Jena, Germany, between March and October 2021. The HRQoL was assessed by the use of the RehabNeQ and the SF-36. Data analysis was descriptive with frequencies, means, and/or percentages. In addition, a univariate analysis of variance was performed to show the dependence of physical and psychological HRQoL on specific factors. This was finally tested for significance at an alpha level of 5%. RESULTS: Data from 318 patients were analyzed, most of whom had 3-6 months of infection (56%) and 5-10 symptoms persisted (60.4%). Both mental (MCS) and physical sum score (PCS) of HRQoL were significantly lower than those of the German normal population (p < .001). The number of remaining symptoms (MCS p = .0034, PCS p = .000) as well as the perceived ability to work (MCS p = .007, PCS p = .000) influenced the HRQoL. CONCLUSION: The HRQoL of patients with Post-COVID-syndrome is still reduced months after infection and so is their occupational performance. In particular, the number of symptoms could have an influence on this deficit, which would need to be further investigated. Further research is needed to detect other factors influencing HRQoL and to implement appropriate therapeutic interventions.

[Outpatient Long/Post-COVID Care: Barriers and Desires of Affected Persons to Medical Care]. / Ambulante Long/Post-COVID-Versorgung: Analyse möglicher Barrieren und Wünsche von Betroffenen an die ärztliche Betreuung.

INTRODUCTION: Persistent and new-onset symptoms after SARS-CoV-2 infection (so-called Long/Post-COVID syndrome) represent a major challenge for our healthcare system. However, there have been limited data on primary outpatient care and care planning, complicating patient flow management and ultimately patient care. Assessing the care reality of patients with Long/Post-COVID-symptoms, as well as their difficulties and desires in receiving medical care, is a necessary first step toward improving outpatient care. METHODS: The JenUP study (Jena study on the population-based incidence of Post-COVID complaints) is a questionnaire-based survey of all adults in the city of Jena who were registered with RT-PCR-confirmed SARS-CoV-2 infection between March 2020 and September 2021. Part of this study focused on the medical care of the affected persons as well as subjective difficulties of the patients in the context of treatment. RESULTS: A total of 1,008 of the 4,209 individuals responded to the questionnaire; 922 (91,5%) experienced at least one Long/Post-COVID-associated symptom. 85,6% of these individuals (790/922) also provided detailed information about contacts with health care facilities. Three out of four persons (590/790) consulted their general practitioner/family doctor in connection with their complaints and 155/790 (19,6%) specialists in addition (most frequently mentioned were specialists in internal medicine - 7,1% (55/790)). Difficulties in obtaining a subjectively required therapy were mentioned by 22,6% (162/718). The main reasons were the patient's apparent feeling of "not being sick enough" (69/162) and a lack of a specialist consultant (65/162). 27% (247/919) of all subjects with Long/Post-COVID complaints expressed a desire for a specific consultant. CONCLUSION: Primary care physicians represent a central element of outpatient care for Long/Post-COVID patients. In addition, nationwide structures for interdisciplinary care should be established according to the national S1 guideline. Analysis of wishes for medical care and perceived barriers to accessing it represent a first step in improving outpatient care for Long/Post-COVID patients.

Comparison of fatigue, cognitive dysfunction and psychological disorders in post-COVID patients and patients after sepsis: is there a specific constellation?

BACKGROUND: Sequelae of COVID-19 can be severe and longlasting. We compared frequencies of fatigue, depression and cognitive dysfunction in survivors of SARS-CoV-2-infection and sepsis. METHODS: We performed a prospective cohort study of 355 symptomatic post-COVID patients who visited our out-patient clinic for post-COVID-19 care. We compared them with 272 symptomatic patients from the Mid-German Sepsis Cohort, which investigates the long-term courses of sepsis survivors. Possible predictors for frequent clinical findings (fatigue, signs of depression, cognitive dysfunction) in post-COVID were investigated with multivariable logistic regression. RESULTS: Median age of the post-COVID patients was 51 years (range 17-86), 60.0% were female, and 31.8% required hospitalization during acute COVID-19. In the post-COVID patients (median follow-up time: 163 days) and the post-sepsis patients (180 days), fatigue was found in 93.2% and 67.8%, signs of depression were found in 81.3% and 10.9%, and cognitive dysfunction was found in 23.5% and 21.3%, respectively. In post-COVID, we did not observe an association between fatigue or depression and the severity of acute COVID-19. In contrast, cognitive dysfunction was associated with hospitalization (out-patient versus in-patient) and more frequent in post-COVID patients treated on an ICU compared to the MSC patients. CONCLUSION: In post-COVID patients, fatigue and signs of depression are more common than in sepsis survivors, independent from the acute SARS-CoV-2-infection. In contrast, cognitive dysfunction is associated with hospitalization. Despite the differences in frequencies, owing to the similarity of post-COVID and post-sepsis sequelae, this knowledge may help in implementing follow-up approaches after SARS-CoV-2 infection.

Recurrent Upper Gastrointestinal Bleeding from Isolated Gastric Varices as Primary Symptom of Myelofibrosis: A Case Report on Combining Interventional and Pharmacologic Treatment Options.

Portal hypertension leads to pronounced venous collateralization and development of varices. Besides manifest liver cirrhosis, primarily left-sided portal hypertension is causal for the development of gastric varices. We present a case of a 36-year-old female patient with splenomegaly, underlying primary myelofibrosis, and detection of somatic Janus-kinase-2 driver-mutation JAK2V617F. Following first upper gastrointestinal bleeding, isolated gastric varices could be detected as a result of underlying left-sided portal hypertension. Within a few months, repeated life-threatening bleedings with transfusion requirements and frequent hospitalizations occurred. Despite multiple injections of cyanoacrylates, the proven therapy of choice, varices could not be stabilized. Combination of targeted JAK-inhibitor therapy in conjunction with the use of EUS-guided application of coils with subsequent cyanoacrylate injection resulted in acute and long-term bleeding control.

Real-World Effectiveness of Piperacillin/Tazobactam with and without Linezolid for Spontaneous Bacterial Peritonitis.

BACKGROUND: Guidelines recommend empirical therapy with piperacillin/tazobactam (TZP) for spontaneous bacterial peritonitis (SBP) with low risk of multidrug-resistant organisms. Whether coverage of beta-lactam-resistant Gram-positive bacteria, such as ampicillin-resistant Enterococcus faecium, provides clinical benefit in such situations is unknown. METHODS: In this observational study, we investigated the real-world effectiveness of empirical therapy with TZP monotherapy versus TZP plus linezolid (LZD) combination therapy in patients with SBP from two centers. Treatment failure, defined as the need to escalate antibiotic therapy due to in vitro resistance, lack of neutrophil decrease in ascitic fluid, or clinical decision, and 30-day survival were retrospectively assessed. RESULTS: In the first cohort, 100 SBP episodes were empirically treated with TZP + LZD combination therapy (n = 50) or TZP monotherapy (n = 50). Treatment failure was recorded in 48% with TZP monotherapy compared with 16% with TZP + LZD combination therapy (p = 0.001), and this difference persisted after stratification for community-acquired versus hospital-acquired SBP. Although treatment failure after TZP therapy was associated with lower 30-day survival (56% vs. 82%; p = 0.04), 30-day survival with empirical TZP + LZD combination therapy was not different from empirical TZP monotherapy (Kaplan-Meier estimates 74% vs. 69%; p = 0.87). TZP concentrations in ascitic fluid were >32 mg/L in 94% samples after continuous administration. In a second cohort of 41 patients empirically treated with TZP, treatment failure was observed in 37%, which was also higher than in episodes treated with TZP + LZD in cohort 1 (p = 0.03). CONCLUSION: In this retrospective analysis, empirical TZP + LZD combination therapy for SBP was associated with fewer treatment failures without impact on short-term survival.

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol.

The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov).

[Inflammatory bowel disease during the COVID-19 pandemic: manifestations and management]. / Chronisch-entzündliche Darmerkrankungen in der COVID-Pandemie: Manifestationen und Management.

The COVID-19 pandemic is significantly affecting the lives of patients with inflammatory bowel disease (IBD). Those affected and their relatives have numerous questions about the risk of the disease, the course of a possible SARS-CoV-2 infection or the influence of CED-specific therapy on these. Many IBD patients also have additional questions about the safety and effectiveness of a vaccination against SARS-CoV-2. The aim of this review is to summarize the latest findings on COVID-19 and IBD, but also to discuss vaccine response (humoral/cellular), the influence of ongoing therapy on the vaccine response as well as the frequency of side effects and the importance of booster immunizations and to create an evidence-based basis for discussion with patients.

SARS-CoV-2 vaccination does not induce relapses of patients with inflammatory bowel disease.

BACKGROUND: Vaccination against SARS-CoV-2 is a promising strategy to protect immunocompromised IBD patients from a severe course of COVID-19. As these patients were excluded from initial clinical vaccination trials, patients frequently express concerns regarding the safety of these vaccines, especially whether vaccination might trigger IBD flares ("hit-and-run-hypothesis"). METHODS: In order to assess the risk of an IBD flare after vaccination against SARS-CoV-2, an anonymous survey was performed at five German IBD centers and one patient organization (Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung (DCCV) e.V.) in August and October 2021. RESULTS: The questionnaire was answered by 914 patients, 781 of whom reported a previous vaccination against SARS-CoV-2 (85.4%). Vaccination against SARS-CoV-2 was not associated with an increased risk of IBD flares (p=0.319) or unscheduled visits to the IBD physician (p=0.848). Furthermore, typical symptoms of an IBD flare including abdominal pain, increases in stool frequency, or rectal bleeding were not influenced by the vaccination. CONCLUSION: Vaccination against SARS-CoV-2 is safe in IBD patients. These results may help to reduce fears regarding the vaccination in IBD patients. Our results can help to reduce fears in IBD patients regarding the SARS-CoV-2 vaccine. A close communication between patients and physicians before and after the vaccination may be beneficial.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 µg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Peritoneal Level of CD206 Associates With Mortality and an Inflammatory Macrophage Phenotype in Patients With Decompensated Cirrhosis and Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: Peritoneal macrophages (PMs) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PMs and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). METHODS: We isolated PMs from ascites samples of 66 patients with decompensated cirrhosis (19 with SBP) and analyzed them by flow cytometry, quantitative real-time polymerase chain reaction, functional analysis, and RNA microarrays. We used ascites samples of a separate cohort of 111 patients with decompensated cirrhosis (67 with SBP) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor by enzyme-linked immunosorbent assay (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease but without cirrhosis were included as controls. RESULTS: We used surface levels of CD206 to identify subsets of large PMs (LPM) and small PMs (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPMs vs SPMs from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPMs vs SPMs, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPMs had an inflammatory phenotype, were less susceptible to tolerance induction, and released more tumor necrosis factor than SPMs. LPMs from patients with cirrhosis produced more inflammatory cytokines than LPMs from controls. Activation of PMs by Toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPMs and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPMs in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (>0.53 mg/L) were less likely to survive for 90 days than those with lower levels. CONCLUSIONS: Surface level of CD206 can be used to identify mature, resident, inflammatory PMs in patients with cirrhosis. Soluble CD206 is released from activated LPMs and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.