Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease.

Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with predisposition to severe Coronavirus Disease 2019 (COVID-19). Here, we screened for such autoantibodies in 103 critically ill COVID-19 patients in a tertiary intensive care unit (ICU) in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFNα or anti-IFNα/anti-IFNω IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFNα IgG. Strikingly, all patients with plasma anti-IFNα IgG also had anti-IFNα IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically ill COVID-19 cohort appeared to predict herpesvirus disease (caused by herpes simplex viruses types 1 and 2 (HSV-1/-2) and/or cytomegalovirus (CMV)), which has been linked to worse clinical outcomes. Indeed, all 7 tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesviruses, and analysis revealed that these patients were more likely to experience CMV than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for age, gender, and systemic steroid treatment (odds ratio (OR) 7.28, 95% confidence interval (CI) 1.14 to 46.31, p = 0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates the likelihood of latent herpesvirus reactivations in critically ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04410263.

Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19.

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients.

Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success.

Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistance. Even antibiotic-susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations, and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic pH, abscess environment, and antibiotic exposure promoted persister formation in vitro and in vivo. Multiomics analysis identified molecular changes in S. aureus in response to acid stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters, including down-regulation of virulence and cell division and up-regulation of ribosomal proteins, nucleotide-, and amino acid-metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP levels and accumulation of insoluble proteins involved in transcription, translation, and energy production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype, including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted antipersister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult to treat.

Impact of sex and gender on post-COVID-19 syndrome, Switzerland, 2020.

BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown.AimWe assessed the impact of sex and gender on PASC in a Swiss population.MethodOur multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030).ConclusionSpecific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident.

The Angiopoietin-2/Angiopoietin-1 ratio increases early in burn patients and predicts mortality.

BACKGROUND: Angiopoietin-2 (Angpt-2) is involved in the pathogenesis of the capillary leak syndrome in sepsis and has been shown to be associated with worse outcomes in diverse critical illnesses. It is however unclear whether Angpt-2 plays a similar role in severely burned patients during the early phase characterized by massive capillary leakage. Our aim was to analyze the Angiopoietin-2/Angiopoietin-1 ratio (Angpt-2/Angpt-1 ratio) over the first two days in critically ill burn patients and examine its association with survival and further clinical parameters. METHODS: Adult burn patients with a total burn surface area (TBSA) ≥ 20% treated in the burn intensive care unit (ICU) of the University Hospital of Zurich, Switzerland, were included. Serum samples were collected prospectively and serum Angpt-1 and Angpt-2 were measured by enzyme-linked immunosorbent assay (ELISA) over the first two days after burn insult and stratified according to survival status, TBSA and the abbreviated burn severity index (ABSI). Due to hemodilution in the initial resuscitation phase, the Angpt-2/Angpt-1 ratio was normalized to albumin. RESULTS: Fifty-six patients were included with a median age of 51.5 years. Overall mortality was 14.3% (8/56 patients). The total amount of infused crystalloids was 12́902 ml (IQR 9́362-16́770 ml) at 24 h and 18́461 ml (IQR 13́024-23́766 ml) at 48 h. The amount of substituted albumin was 20 g (IQR 10-50 g) at 24 h and 50 g (IQR 20-60 g) at 48 h. The albumin-corrected Angpt-2/Angpt-1 ratios increased over the first 48 h after the burn insult (d0: 0.5 pg*l/ml*g [IQR 0.24 - 0.80 pg*l/ml*g]; d1: 0.83 pg*l/ml*g [IQR 0.29 - 1.98 pg*l/ml*g]; d2: 1.76 pg*l/ml*g [IQR 0.70 - 3.23 pg*l/ml*g]; p < 0.001) and were significantly higher in eventual ICU non-survivors (p = 0.005), in patients with a higher TBSA (p = 0.001) and in patients with a higher ABSI (p = 0.001). CONCLUSIONS: In analogy to the pathological host response in sepsis, the Angpt-2/Angpt-1 ratio steadily increases in the first two days in critically ill burn patients, suggesting a putative involvement in the pathogenesis of capillary leakage in burns. A higher Angpt-2/Angpt-1 ratio is associated with mortality, total burn surface area and burn scores.

Intracranial Hemorrhages on Extracorporeal Membrane Oxygenation: Differences Between COVID-19 and Other Viral Acute Respiratory Distress Syndrome.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage. DESIGN: Multicenter, retrospective analysis between January 2010 and May 2021. SETTING: Three tertiary care ECMO centers in Germany and Switzerland. PATIENTS: Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%. CONCLUSIONS: This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies.

The importance of intravenous immunoglobulin treatment in critically ill patients with necrotizing soft tissue infection: a retrospective cohort study.

BACKGROUND: Necrotizing soft-tissue infections are infections with high mortality. The use of immunoglobulins within a combination therapy including broad-spectrum antibiotics has been debated. We assessed potential benefits of immunoglobulins and hypothesized that they were associated with a treatment benefit in a high-resource setting. METHODS: Patients with necrotizing soft-tissue infection hospitalized in the tertiary intensive care unit of the University Hospital of Zurich, Switzerland, between 2008 and 2020 were included retrospectively. The association between immunoglobulin administration and in-hospital survival, intensive care unit length of stay, the incidences of acute renal failure, acute respiratory distress syndrome and septic shock were analyzed. RESULTS: After adjustment for confounders, no difference for in-hospital survival (hazard ratio 2.20, 95% confidence interval [CI] 0.24-20.20, p = 0.5), intensive care unit length of stay (subhazard ratio [SHR] 0.90, CI 0.41-1.98, p = 0.8) and the development of acute respiratory distress syndrome (SHR 1.2, CI 0.36-4.03, p = 0.77) was observed in patients with or without immunoglobulin treatment. The Simplified Acute Physiology Score II, the risk of developing acute renal failure (SHR 2.86, CI 1.33-6.15, p = 0.01) and septic shock (SHR 1.86, CI 1.02-3.40, p = 0.04) was higher in patients treated with immunoglobulins, possibly reflecting a higher disease severity beyond measured confounders. CONCLUSIONS: No clear evidence for a benefit of immunoglobulins in our cohort with consistent antibiotic use was found. Patients receiving immunoglobulins appeared more severely ill. Complementary to high treatment standards and appropriate antibiotics including beta lactams and protein synthesis inhibitors, immunoglobulins should be administered on a case-to-case basis, at least while more evidence from larger randomized controlled trials is missing.

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome.

BACKGROUND: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels. METHODS: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels. RESULTS: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01). CONCLUSIONS: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Microcirculatory alterations in critically ill COVID-19 patients analyzed using artificial intelligence.

BACKGROUND: The sublingual microcirculation presumably exhibits disease-specific changes in function and morphology. Algorithm-based quantification of functional microcirculatory hemodynamic variables in handheld vital microscopy (HVM) has recently allowed identification of hemodynamic alterations in the microcirculation associated with COVID-19. In the present study we hypothesized that supervised deep machine learning could be used to identify previously unknown microcirculatory alterations, and combination with algorithmically quantified functional variables increases the model's performance to differentiate critically ill COVID-19 patients from healthy volunteers. METHODS: Four international, multi-central cohorts of critically ill COVID-19 patients and healthy volunteers (n = 59/n = 40) were used for neuronal network training and internal validation, alongside quantification of functional microcirculatory hemodynamic variables. Independent verification of the models was performed in a second cohort (n = 25/n = 33). RESULTS: Six thousand ninety-two image sequences in 157 individuals were included. Bootstrapped internal validation yielded AUROC(CI) for detection of COVID-19 status of 0.75 (0.69-0.79), 0.74 (0.69-0.79) and 0.84 (0.80-0.89) for the algorithm-based, deep learning-based and combined models. Individual model performance in external validation was 0.73 (0.71-0.76) and 0.61 (0.58-0.63). Combined neuronal network and algorithm-based identification yielded the highest externally validated AUROC of 0.75 (0.73-0.78) (P < 0.0001 versus internal validation and individual models). CONCLUSIONS: We successfully trained a deep learning-based model to differentiate critically ill COVID-19 patients from heathy volunteers in sublingual HVM image sequences. Internally validated, deep learning was superior to the algorithmic approach. However, combining the deep learning method with an algorithm-based approach to quantify the functional state of the microcirculation markedly increased the sensitivity and specificity as compared to either approach alone, and enabled successful external validation of the identification of the presence of microcirculatory alterations associated with COVID-19 status.

Closed-Loop Versus Conventional Mechanical Ventilation in COVID-19 ARDS.

BACKGROUND: Lung-protective ventilation is key in bridging patients suffering from COVID-19 acute respiratory distress syndrome (ARDS) to recovery. However, resource and personnel limitations during pandemics complicate the implementation of lung-protective protocols. Automated ventilation modes may prove decisive in these settings enabling higher degrees of lung-protective ventilation than conventional modes. METHOD: Prospective study at a Swiss university hospital. Critically ill, mechanically ventilated COVID-19 ARDS patients were allocated, by study-blinded coordinating staff, to either closed-loop or conventional mechanical ventilation, based on mechanical ventilator availability. Primary outcome was the overall achieved percentage of lung-protective ventilation in closed-loop versus conventional mechanical ventilation, assessed minute-by-minute, during the initial 7 days and overall mechanical ventilation time. Lung-protective ventilation was defined as the combined target of tidal volume <8 ml per kg of ideal body weight, dynamic driving pressure <15 cmH2O, peak pressure <30 cmH2O, peripheral oxygen saturation ≥88% and dynamic mechanical power <17 J/min. RESULTS: Forty COVID-19 ARDS patients, accounting for 1,048,630 minutes (728 days) of cumulative mechanical ventilation, allocated to either closed-loop (n = 23) or conventional ventilation (n = 17), presenting with a median paO2/ FiO2 ratio of 92 [72-147] mmHg and a static compliance of 18 [11-25] ml/cmH2O, were mechanically ventilated for 11 [4-25] days and had a 28-day mortality rate of 20%. During the initial 7 days of mechanical ventilation, patients in the closed-loop group were ventilated lung-protectively for 65% of the time versus 38% in the conventional group (Odds Ratio, 1.79; 95% CI, 1.76-1.82; P < 0.001) and for 45% versus 33% of overall mechanical ventilation time (Odds Ratio, 1.22; 95% CI, 1.21-1.23; P < 0.001). CONCLUSION: Among critically ill, mechanically ventilated COVID-19 ARDS patients during an early highpoint of the pandemic, mechanical ventilation using a closed-loop mode was associated with a higher degree of lung-protective ventilation than was conventional mechanical ventilation.

Use of eye tracking in analyzing distribution of visual attention among critical care nurses in daily professional life: an observational study.

Patient safety is a priority in healthcare, yet it is unclear how sources of errors should best be analyzed. Eye tracking is a tool used to monitor gaze patterns in medicine. The aim of this study was to analyze the distribution of visual attention among critical care nurses performing non-simulated, routine patient care on invasively ventilated patients in an ICU. ICU nurses were tracked bedside in daily practice. Eight specific areas of interest were pre-defined (respirator, drug preparation, medication, patient data management system, patient, monitor, communication and equipment/perfusors). Main independent variable and primary outcome was dwell time, secondary outcomes were hit ratio, revisits, fixation count and average fixation time on areas of interest in a targeted tracking-time of 60 min. 28 ICU nurses were analyzed and the average tracking time was 65.5 min. Dwell time was significantly higher for the respirator (12.7% of total dwell time), patient data management system (23.7% of total dwell time) and patient (33.4% of total dwell time) compared to the other areas of interest. A similar distribution was observed for fixation count (respirator 13.3%, patient data management system 25.8% and patient 31.3%). Average fixation time and revisits of the respirator were markedly elevated. Apart from the respirator, average fixation time was highest for the patient data management system, communication and equipment/perfusors. Eye tracking is helpful to analyze the distribution of visual attention of critical care nurses. It demonstrates that the respirator, the patient data management system and the patient form cornerstones in the treatment of critically ill patients. This offers insights into complex work patterns in critical care and the possibility of improving work flows, avoiding human error and maximizing patient safety.

Human Streptococcal Necrotizing Fasciitis Histopathology Mirrored in a Murine Model.

Streptococcal necrotizing fasciitis (NF) causes high morbidity and mortality despite state-of-the-art therapy. Low incidence and rapid disease progression, necessitating immediate initiation of therapy, have proven challenging aspects for setting up prospective randomized trials. This has resulted in little therapeutic progress over the past decade. The validation of reliable murine NF models to study both pathogenesis and optimized therapeutic regimens of streptococcal NF are thus essential. In this study, we characterized a murine NF model and compared the pathology with an in-depth tissue analysis of streptococcal NF in patients. We found that the streptococcal murine NF model closely reflected all histologic characteristics encountered in human streptococcal NF. This murine NF model helps understanding of human NF pathology better in a time-dependent manner and will allow studying novel therapeutic options in the future.

Correction to: protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.

[This corrects the article DOI: 10.1186/s12959-019-0194-8.].

Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.

Inflammatory diseases have become increasingly prevalent with industrialization. To address this, numerous anti-inflammatory agents and molecular targets have been considered in clinical trials. Among molecular targets, protease-activated receptors (PARs) are abundantly recognized for their roles in the development of chronic inflammatory diseases. In particular, several inflammatory effects are directly mediated by the sensing of proteolytic activity by PARs. PARs belong to the seven transmembrane domain G protein-coupled receptor family, but are unique in their lack of physiologically soluble ligands. In contrast with classical receptors, PARs are activated by N-terminal proteolytic cleavage. Upon removal of specific N-terminal peptides, the resulting N-termini serve as tethered activation ligands that interact with the extracellular loop 2 domain and initiate receptor signaling. In the classical pathway, activated receptors mediate signaling by recruiting G proteins. However, activation of PARs alternatively lead to the transactivation of and signaling through receptors such as co-localized PARs, ion channels, and toll-like receptors. In this review we consider PARs and their modulators as potential therapeutic agents, and summarize the current understanding of PAR functions from clinical and in vitro studies of PAR-related inflammation.

Immunoglobulin Attenuates Streptokinase-Mediated Virulence in Streptococcus dysgalactiae Subspecies equisimilis Necrotizing Fasciitis.

Background: Necrotizing fasciitis (NF) retains a very high mortality rate despite prompt and adequate antibiotic treatment and surgical debridement. Necrotizing fasciitis has recently been associated with Streptococcus dysgalactiae subspecies equisimilis (SDSE). Methods: We investigated the causes of a very severe clinical manifestation of SDSE-NF by assessing both host and pathogen factors. Results: We found a lack of streptokinase-function blocking antibodies in the patient resulting in increased streptokinase-mediated fibrinolysis and bacterial spread. At the same time, the clinical SDSE isolate produced very high levels of streptokinase. Exogenous immunoglobulin Gs (ex-IgGs) efficiently blocked streptokinase-mediated fibrinolysis in vitro, indicating a protective role against the action of streptokinase. In vivo, SDSE infection severity was also attenuated by ex-IgGs in a NF mouse model. Conclusions: These findings illustrate for the first time that the lack of specific antibodies against streptococcal virulence factors, such as streptokinase, may contribute to NF disease severity. This can be counteracted by ex-IgGs.

Pulmonary hypertension is not a risk factor for grade 3 primary graft dysfunction after lung transplantation.

Grade 3 primary graft dysfunction (PGD3) represents the most important risk factor for patient mortality during the first year after lung transplantation (LTX). We investigated whether pretransplant pulmonary hypertension (PH) is a risk factor for the development of PGD3. This retrospective, single-center cohort study included 96 candidates undergoing right heart catheterization (RHC) prior to being listed for LTX between March 2000 and October 2015. Based on their mean pulmonary artery pressure (mPAP) levels, the patients were classified into 3 groups: (1) <25 mm Hg, (2) 25-34 mm Hg and (3) ≥35 mm Hg. Forty-seven patients were classified in group 1, 31 in group 2, and 18 in group 3. Fifteen recipients (16%, 95%-CI 8-23) developed PGD3. In the univariate analysis, the diagnosis of interstitial lung disease (ILD) compared to COPD (OR: 7.06, P = .005), blood transfusion >1000 mL during surgery (OR: 5.25, P = .005), the need for intra-operative cardio-pulmonary bypass (CPB) or extra-corporeal membrane oxygenation (ECMO) (OR: 4, P = .027), mPAP (OR 1.06, P = .007) and serum high density lipoprotein-cholesterol (HDL-C) (OR 0.09, P = .005) were associated with PGD3. In the multivariable logistic regression analysis, only HDL-C (OR 0.10, P = .016) was associated with PGD3 based on our single-center cohort data analysis.

Low Level of Vegetative State After Traumatic Brain Injury in a Swiss Academic Hospital.

BACKGROUND: No standards exist regarding decision making for comatose patients, especially concerning life-saving treatments. The aim of this retrospective, single-center study was to analyze outcomes and the decision-making process at the end of life (EOL) in patients with traumatic brain injury (TBI) in a Swiss academic tertiary care hospital. METHODS: Consecutive admissions to the surgical intensive care unit (ICU) with stays of at least 48 hours between January 1, 2012 and June 30, 2015 in patients with moderate to severe TBI and with fatality within 6 months after trauma were included. Descriptive statistics were used. RESULTS: Of 994 ICU admissions with TBI in the study period, 182 had an initial Glasgow Coma Scale <13 and a length of stay in the ICU >48 hours. For 174 of them, a 6-month outcome assessment based on the Glasgow Outcome Scale (GOS) was available: 43.1% (36.0%-50.5%) had favorable outcomes (GOS 4 or 5), 28.7% (22.5%-35.9%) a severe disability (GOS 3), 0.6% (0%-3.2%) a vegetative state (GOS 2), and 27.6% (21.5%-34.7%) died (GOS 1). Among the GOS 1 individuals, 45 patients had a complete dataset (73% men; median age, 67 years; interquartile range, 43-79 years). Life-prolonging therapies were limited in 95.6% (85.2%-99.2%) of the cases after interdisciplinary prognostication and involvement of the surrogate decision maker (SDM) to respect the patient's documented or presumed will. In 97.7% (87.9%-99.9%) of the cases, a next of kin was the SDM and was involved in the EOL decision and process in 100% (96.3%-100.0%) of the cases. Written advance directives (ADs) were available for 14.0% (6.6%-27.3%) of the patients, and 34.9% (22.4%-49.8%) of the patients had shared their EOL will with relatives before trauma. In the other cases, each patient's presumed will was acknowledged after a meeting with the SDM and was binding for the EOL decision. CONCLUSIONS: At our institution, the majority of deaths after TBI follow a decision to limit life-prolonging therapies. The frequency of patients in vegetative state 6 months after TBI is lower than expected; this could be due to the high prevalence of limitation of life-prolonging therapies. EOL decision making follows a standardized process, based on patients' will documented in the ADs or on preferences assumed by the SDM. The prevalence of ADs was low and should be encouraged.

Effect of diagnosis related groups implementation on the intensive care unit of a Swiss tertiary hospital: a cohort study.

BACKGROUND: In 2013 the Swiss Diagnosis Related Groups ((Swiss)-DRG) was implemented in Intensive Care Units (ICU). Its impact on hospitalizations has not yet been examined. We compared the number of ICU admissions, according to clinical severity and referring institution, and screened whether implementation of Swiss-DRG affected admission policy, ICU length-of-stay (ICU-LOS) or ICU mortality. METHODS: Retrospective, single centre, cohort study conducted at the University Hospital Zurich, Switzerland between January 2009 and end of September 2013. Demographic and clinical data was retrieved from a quality assurance database. RESULTS: Admissions (n = 17,231) before the introduction of Swiss-DRG were used to model expected admissions after DRG, and then compared to the observed admissions. Forecasting matched observations in patients with a high clinical severity admitted from internal units and external hospitals (admitted / predicted: 709 / 703, [95% Confidence Interval (CI), 658-748] and 302 / 332, [95% CI, 269-365] respectively). In patients with low severity of disease, in-house admissions became more frequent than expected and external admission were less frequent (admitted / predicted: 1972 / 1910, [95% CI, 1898-1940] and 436 / 518, [95% CI, 482-554] respectively). Various mechanisms related to Swiss-DRG may have led to these changes. DRG could not be linked to significant changes in regard to ICU-LOS and ICU mortality. CONCLUSIONS: DRG introduction had not affected ICU admissions policy, except for an increase of in-house patients with a low clinical severity of disease. DRG had neither affected ICU mortality nor ICU-LOS.

Clindamycin Affects Group A Streptococcus Virulence Factors and Improves Clinical Outcome.

Group A Streptococcus (GAS) has acquired an arsenal of virulence factors, promoting life-threatening invasive infections such as necrotizing fasciitis. Current therapeutic regimens for necrotizing fasciitis include surgical debridement and treatment with cell wall-active antibiotics. Addition of clindamycin (CLI) is recommended, although clinical evidence is lacking. Reflecting the current clinical dilemma, an observational study showed that only 63% of the patients with severe invasive GAS infection received CLI. This work thus aimed to address whether CLI improves necrotizing fasciitis outcome by modulating virulence factors of CLI-susceptible and CLI-resistant GAS in vitro and in vivo. Treatment with CLI reduced extracellular DNase Sda1 and streptolysin O (SLO) activity in vivo, whereas subinhibitory CLI concentrations induced expression and activity of SLO, DNase, and Streptococcus pyogenes cell envelope protease in vitro. Our in vivo results suggest that CLI should be administered as soon as possible to patients with necrotizing fasciitis, while our in vitro studies emphasize that a high dosage of CLI is essential.

Interferon α-Enhanced Clearance of Group A Streptococcus Despite Neutropenia.

BACKGROUND: Neutrophils and monocytes are crucial for controlling bacterial infections. More-frequent bacterial infections are accordingly encountered in neutropenic patients undergoing chemotherapy. This is not the case for pegylated interferon α (IFN-α)-induced neutropenia. We hypothesized that IFN-α induces a compensatory innate antibacterial state that prevents bacterial infections despite the neutropenia. METHODS: To investigate whether patients with hepatitis C virus infection treated with IFN-α killed group A Streptococcus (GAS) better than before initiating therapy, whole blood was used to perform ex vivo GAS killing assays before, during, and after IFN-α therapy. RESULTS: We found that IFN-α therapy enhanced GAS killing in whole blood ex vivo despite the decreased neutrophil and monocyte numbers during IFN-α therapy. IFN-α also boosted neutrophil- and monocyte-mediated GAS killing in vitro. Underlying mechanisms included increased production of the antibacterial properdin, a regulator of the complement activation, as well as reactive oxygen species. CONCLUSIONS: These findings help to explain the rather discrepant facts of neutropenia but preserved antibacterial immune defenses in patients treated with IFN-α.