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

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

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

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

Electrochemiluminescence in paired signal electrode (ECLipse) enables modular and scalable biosensing.

Electrochemiluminescence (ECL) has an inherently low background and enables precise chemical reactions through electrical control. Here, we report an advanced ECL system, termed ECLipse (ECL in paired signal electrode). We physically separated ECL generation from target detection: These two processes were carried out in isolated chambers and coupled through an electrode. The strategy allowed us to minimize cross-chemical reactions, design electrodes for high ECL signals, and integrate multiple sensors in a chip. As a proof of concept, we implemented an eight-plex ECLipse and applied it to detect host factors in human plasma. ECLipse achieved higher signal-to-noise ratio than conventional ECL assays and was >7000-fold more sensitive than enzyme-linked immunosorbent assay. In a pilot clinical study, we could detect septic conditions by measuring host factors [i.e., interleukin-3 (IL-3), IL-6, and procalcitonin (PCT)]. ECLipse assay further revealed distinct IL-3 and IL-6 patterns in patients with severe acute respiratory syndrome coronavirus 2 infection.

Induction of a cytokine storm involves suppression of the Osteopontin-dependent TH1 response.

Cytokine release syndromes represent a severe turn in certain disease states, which may be caused by several infections, including those with the virus SARS-CoV-2. This inefficient, even harmful, immune response has been associated with a broad release of chemokines. Although a cellular (type I) immune reaction is efficacious against viral infections, we noted a type I deficit in the cytokine patterns produced by cytokine storms of all reported etiologies. Agents including lipopolysaccharide (LPS, bacterial), anti-CD3 (antibody) and a version of the prominent SARS-CoV-2 viral surface molecule, Spike Glycoprotein, were individually sufficient to induce IL-6 and multiple chemokines in mice. They failed to upregulate the TH1 inducer cytokine Osteopontin, and the pathophysiologic triggers actually suppressed the PMA-induced Osteopontin secretion from monocytic cells. Osteopontin administration partially reversed the chemokine elevation, more effectively so in a mouse strain with TH1 bias. Corroboration was obtained from the inverse correlation in the levels of IL-6 and Osteopontin in plasma samples from acute COVID-19 patients. We hypothesize that the inhibition of Osteopontin by SARS-CoV-2 Spike Glycoprotein or LPS represents an immune evasion mechanism employed by the pathogens of origin. The ensuing dysfunctional inflammatory response promotes a vicious cycle of amplification, resulting in a cytokine storm.

Complex systems analysis informs on the spread of COVID-19

The non-linear progression of new infection numbers in a pandemic poses challenges to the evaluation of its management. The tools of complex systems research may aid in attaining information that would be difficult to extract with other means.To study the COVID-19 pandemic, we utilize the reported new cases per day for the globe, nine countries and six US states through October 2020. Fourier and univariate wavelet analyses inform on periodicity and extent of change.Evaluating time-lagged data sets of various lag lengths, we find that the autocorrelation function, average mutual information and box counting dimension represent good quantitative readouts for the progression of new infections. Bivariate wavelet analysis and return plots give indications of containment vs. exacerbation. Homogeneity or heterogeneity in the population response, uptick vs. suppression, and worsening or improving trends are discernible, in part by plotting various time lags in three dimensions.The analysis of epidemic or pandemic progression with the techniques available for observed (noisy) complex data can extract important characteristics and aid decision making in the public health response.

[Economic impact of the COVID-19 pandemic in general and visceral surgery : A comparison of performance and revenue data from two departments of hospitals with different levels of referral]. / Ökonomische Auswirkung der COVID-19-Pandemie in der Allgemein- und Viszeralchirurgie : Ein Vergleich von Leistungs- und Erlösdaten zweier Kliniken aus Krankenhäusern unterschiedlicher Versorgungsstufen.

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, German hospitals were required to limit the capacity for elective surgery to prevent the healthcare system from general overload. In March 2020, the German government passed the COVID-19 Hospital Relief Act that guaranteed compensation payments for these limitations. In this study the regional impact of this intervention were analyzed. MATERIAL AND METHODS: The performance data and revenue figures for the departments of general and visceral surgery of the University Hospital of Erlangen (UKER) and the District Hospital St. Anna Höchstadt/Aisch (KKH) during the period from 1 April to 30 June 2019 were compared with the respective period in 2020. RESULTS: There was a significant decrease in bed occupancy rates and case numbers of inpatient treatment. The latter declined by 20.06% in the UKER and 60.76% in the KKH. Nononcological elective surgery was reduced by 33.04% in the UKER and 60.87% in the KKH. The number of emergency procedures remained unchanged in the UKER, while they decreased by 51.58% in the KKH. The revenues from diagnosis-related groups (DRG) decreased by 22.12% (UKER) and 54% (KKH), respectively. After taking compensation payments and savings from variable material costs into account, the UKER recorded a loss of -3.87%, while there was a positive revenue effect of 6.5% in the KKH. DISCUSSION: The nonselective restriction of elective surgery had a significant impact on patient care and revenue figures at both locations. With respect to the increase of intensive care capacities, such untargeted measures do not appear to be efficient. In addition, the fixed rate of compensation payments led to an unbalanced distribution of the financial aid between the two departments.

An overview of proteomic methods for the study of 'cytokine storms'.

Introduction: The cytokine storm is a form of excessive systemic inflammatory reaction triggered by a myriad of factors that may lead to multi-organ failure, and finally to death. The cytokine storm can occur in a number of infectious and noninfectious diseases including COVID-19, sepsis, ebola, avian influenza, and graft versus host disease, or during the severe inflammatory response syndrome.Area covered: This review mainly focuses on the most common and well-known methods of protein studies (PAGE, SDS-PAGE, and high- performance liquid chromatography). It also discusses other modern technologies in proteomics like mass spectrometry, soft ionization techniques, cytometric bead assays, and the next generation of microarrays that have been used to get an in-depth understanding of the pathomechanisms involved during the cytokine storm.Expert opinion: Overactivation of leukocytes drives the production and secretion of inflammatory cytokines fueling the cytokine storm. These events lead to a systemic hyper-inflammation, circulatory collapse and shock, and finally to multiorgan failure. Therefore, monitoring the patient's systemic cytokine levels with proteomic technologies that are redundant, economical, and require minimal sample volume for real-time assessment might help in a better clinical evaluation and management of critically ill patients.

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.

Oncological colorectal surgery during the COVID-19pandemic-a national survey.

PURPOSE: The aim of this study was to clarify the surgical supply situation of oncological colorectal patients in Germany during limitations of the OR caseload due to the COVID-19 pandemic. METHODS: Between 11th and 19th April 2020, all members of a consortium of German colorectal cancer centers were invited to participate in a web-based survey on the current status of surgical care situation of colorectal cancer patients in Germany. RESULTS: A total of 112 colorectal surgeons of 101 German hospitals participated in the survey. Eighty-seven percent of the participating hospitals had to reduce their total surgical caseload and 34% their surgical volume for oncological colorectal patients during COVID-19 pandemic. Restrictions of the surgical caseload were independent of the size of the hospital and the number of cases of COVID-19 in the federal state of the hospital. Sixteen percent of colorectal surgeons consider surgical limitations to be not justified and 78% to be justified only if the care of oncological patients is ensured. Ninety-five percent of the colorectal surgeons interviewed stated that all oncological colorectal patients with an indication for surgery should be operated in time, despite the current reservations for COVID-19 patients. For the majority of the respondents (63% and 51%, respectively), an extended waiting time for surgery of up to 2 weeks was acceptable for non-metastatic and metastatic patients, respectively. CONCLUSION: In Germany, there is a temporarily relevant reduction of surgical volume in oncological colorectal patients. Most colorectal surgeons stated that oncological colorectal surgery should not be compromised despite the measures taken during the COVID-19 pandemic.