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Clinical & Experimental Immunology, Accepted Article.

Abstract In patients who develop sepsis, whether due to primary, secondary or metastatic lesions, the skin is frequently affected. However, there are unresolved aspects regarding the general clinical manifestations in the skin or the prognosis and/or therapeutic implications. The main challenge in the approach to sepsis is its early diagnosis and management. In this review, we address the sepsis–skin relationship and the potential impact of early dermatological intervention on the septic patient through ten basic questions. We found little evidence of the participation of the dermatologist in sepsis alert programs. There are early skin changes that may alert clinicians on a possible sepsis, such as skin mottling or variations in acral skin temperature. In addition, the skin is an accessible and highly cost-effective tissue for etiological studies of some forms of sepsis (e.g., meningococcal purpura) and its involvement defines the prognosis of certain patients (e.g., infective endocarditis).

Objectives: We investigated the prevalence of pre- and postsepsis depression and examined the association between diagnosis of pre- and postsepsis depression and 5-year all-cause mortality among survivors of sepsis. Design: A population-based cohort study. Setting: Data were obtained from the National Health Insurance Service database in South Korea. Patients: Sepsis survivors were defined as those who were admitted with a main diagnosis of sepsis or septic shock and had survived for over 365 days. Measurements and Main Results: Sepsis survivors who were diagnosed with depression before sepsis were defined as the presepsis depression group, whereas those who had no history of depression but were newly diagnosed with depression within 1 year of diagnosis of sepsis were defined as the postsepsis depression group. All other participants comprised the control group. A total of 45,826 sepsis survivors were included in the final analysis. Among the survivors, 1,105 (2.4%) were in the postsepsis depression group, whereas 9,626 (21.0%) were in the presepsis depression group. The 5-year all-cause mortality rate in the pre- and postsepsis depression group was 44.1% and 46.2%, whereas that in the control group was 30.4%. Multivariable Cox regression modeling revealed that the risk of 5-year all-cause mortality rate in the postsepsis depression group was 1.29-fold (hazard ratio = 1.29; 95% CI = 1.18–1.41; p < 0.001) higher than that of the control group, whereas the presepsis depression group was not significantly associated with 5-year all-cause mortality (p = 0.509). Conclusions: Among sepsis survivors in South Korea, 2.4%% were newly diagnosed with depression within 1 year after their sepsis diagnosis. In addition, postsepsis depression was independently associated with higher 5-year all-cause mortality among sepsis survivors. Our results suggest that patients with a history of sepsis and associated depression may be a high-risk group that interventions may be directed toward. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: songoficu@outlook.kr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Sepsis is a life-threatening condition and is one of the leading causes of death in the United States. The burden of sepsis-related mortality in the United States in recent years is not well characterized. We sought to describe sepsis-related mortality rates and mortality trends in the United States from 2005 to 2018. Design: Retrospective population-based study. Setting: We used the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website. Patients: Decedents with sepsis-related deaths were identified using previously validated International Classification of Diseases codes. Interventions: None. MEASUREMENTS AND Main Results: From 2005 to 2018, 6.7% of decedents had a diagnosis of sepsis. The overall sepsis-related mortality rates remained stable in both males (57 deaths per 100,000) and females (45.1 deaths per 100,000) during this period. Compared with Whites, the sepsis-related mortality rates were higher in Blacks (rate ratio = 1.78), Native Americans (rate ratio = 1.43), and Hispanics (rate ratio = 1.04) and were lower in Asians (rate ratio = 0.73). Sepsis-related mortality rates declined in Blacks, Hispanics, and Asians but increased in Whites and Native Americans. The majority of sepsis-related deaths occurred in the hospital. The percentage of deaths in the nursing home decreased, whereas deaths occurring at home and hospice increased. Conclusions: From 2005 to 2018, the overall sepsis-related mortality rates were stable, but there were significant racial and gender disparities in mortality trends. Further research is needed to evaluate the genetic and environmental contributors to these differences. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: njeganathan@llu.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Recent sepsis studies have defined patients as “infected” using a combination of culture and antibiotic orders rather than billing data. However, the accuracy of these definitions is unclear. We aimed to compare the accuracy of different established criteria for identifying infected patients using detailed chart review. Design: Retrospective observational study. Setting: Six hospitals from three health systems in Illinois. Patients: Adult admissions with blood culture or antibiotic orders, or Angus International Classification of Diseases infection codes and death were eligible for study inclusion as potentially infected patients. Nine-hundred to 1,000 of these admissions were randomly selected from each health system for chart review, and a proportional number of patients who did not meet chart review eligibility criteria were also included and deemed not infected. Interventions: None. Measurements and Main Results: The accuracy of published billing code criteria by Angus et al and electronic health record criteria by Rhee et al and Seymour et al (Sepsis-3) was determined using the manual chart review results as the gold standard. A total of 5,215 patients were included, with 2,874 encounters analyzed via chart review and a proportional 2,341 added who did not meet chart review eligibility criteria. In the study cohort, 27.5% of admissions had at least one infection. This was most similar to the percentage of admissions with blood culture orders (26.8%), Angus infection criteria (28.7%), and the Sepsis-3 criteria (30.4%). Sepsis-3 criteria was the most sensitive (81%), followed by Angus (77%) and Rhee (52%), while Rhee (97%) and Angus (90%) were more specific than the Sepsis-3 criteria (89%). Results were similar for patients with organ dysfunction during their admission. Conclusions: Published criteria have a wide range of accuracy for identifying infected patients, with the Sepsis-3 criteria being the most sensitive and Rhee criteria being the most specific. These findings have important implications for studies investigating the burden of sepsis on a local and national level. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Churpek and Edelson received funding from National Institute of General Medical Sciences R01 GM123193; disclosed a patent pending (ARCD. P0535US. P2) for risk stratification algorithms for hospitalized patients and have received research support from EarlySense (Tel Aviv, Israel). Drs. Churpek, Winslow, Shah, and Afshar received support for article research from the National Institutes of Health. Dr. Afshar also received support from a K23 from National Institute on Alcohol Abuse and Alcoholism K23 AA024503. Dr. Edelson received support for article research from the American Heart Association (Dallas, TX) and Laerdal Medical (Stavanger, Norway), and she received research support from Philips Healthcare (Andover, MA). She disclosed ownership interest in Quant HC (Chicago, IL), which is developing products for risk stratification of hospitalized patients; she is president/co-founder and shareholder of AgileMD with licensing agreements with Philips Healthcare and EarlySense; and she is the chair for the American Heart Association Get with The Guidelines adult research task force. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mchurpek@medicine.wisc.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Haloperidol is commonly administered in the ICU to reduce the burden of delirium and its related symptoms despite no clear evidence showing haloperidol helps to resolve delirium or improve survival. We evaluated the association between haloperidol, when used to treat incident ICU delirium and its symptoms, and mortality. Design: Post hoc cohort analysis of a randomized, double-blind, placebo-controlled, delirium prevention trial. Setting: Fourteen Dutch ICUs between July 2013 and December 2016. Patients: One-thousand four-hundred ninety-five critically ill adults free from delirium at ICU admission having an expected ICU stay greater than or equal to 2 days. Interventions: Patients received preventive haloperidol or placebo for up to 28 days until delirium occurrence, death, or ICU discharge. If delirium occurred, treatment with open-label IV haloperidol 2 mg tid (up to 5 mg tid per delirium symptoms) was administered at clinician discretion. Measurements and Main Results: Patients were evaluated tid for delirium and coma for 28 days. Time-varying Cox hazards models were constructed for 28-day and 90-day mortality, controlling for study-arm, delirium and coma days, age, Acute Physiology and Chronic Health Evaluation-II score, sepsis, mechanical ventilation, and ICU length of stay. Among the 1,495 patients, 542 (36%) developed delirium within 28 days (median [interquartile range] with delirium 4 d [2–7 d]). A total of 477 of 542 (88%) received treatment haloperidol (2.1 mg [1.0–3.8 mg] daily) for 6 days (3–11 d). Each milligram of treatment haloperidol administered daily was associated with decreased mortality at 28 days (hazard ratio, 0.93; 95% CI, 0.91–0.95) and 90 days (hazard ratio, 0.97; 95% CI, 0.96–0.98). Treatment haloperidol administered later in the ICU course was less protective of death. Results were stable by prevention study-arm, predelirium haloperidol exposure, and haloperidol treatment protocol adherence. Conclusions: Treatment of incident delirium and its symptoms with haloperidol may be associated with a dose-dependent improvement in survival. Future randomized trials need to confirm these results. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by ZonMw program Goed Gebruik Geneesmiddelen (dossier number 836031004). ZonMw had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr. Duprey’s efforts are supported by the National Institute of Aging 1F31AG066460-01. Drs. Duprey, Devlin, Briesacher, and Saczynski received support for article research from the National Institutes of Health. Dr. Duprey disclosed off-label product use of haloperidol for delirium. Dr. van den Boogaard’s institution received funding and support for research from ZonMw. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this aticle, E-mail: j.devlin@neu.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

The updated national Dutch Working Party on Antibiotic Policy (SWAB) guideline for antibacterial therapy of adult patients with sepsis recommends against the addition of an aminoglycoside to a beta-lactam agent for patients with sepsis or septic shock unless local distribution of pathogens associated with sepsis and their antimicrobial susceptibilities justify its additional use. [1] However, this data is generally not readily available and adjunctive gentamicin is often given. From an antimicrobial stewardship perspective, we evaluated our local sepsis protocol by assessing the potential benefit and risk of gentamicin adjunctive to cefuroxime by studying blood culture results and incidence of acute kidney injury (AKI).

To the Editor—In their article “Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2–Related Encephalitis,” Pilotto and colleagues reported on the incidence of encephalitis in a multicenter cohort of coronavirus disease 2019 (COVID-19) patients [1]. The reported incidence of 50 per 100 000 may be overestimated. Their definition of encephalitis corresponds to the designation of “possible encephalitis” as proposed by Venkatesan et al in their 2013 consensus article [2]. The diagnosis of probable encephalitis requires presentation with altered mental status (AMS) and at least 3 minor criteria relating to cerebrospinal fluid (CSF) pleocytosis, magnetic resonance imaging (MRI) changes, electroencephalogram changes, new-onset seizures, or focal neurologic deficits [2]. The diagnosis of confirmed encephalitis further requires pathological confirmation or laboratory evidence of a causative organism or highly clinically relevant neuronal autoantibody. The definition used by Pilotto et al (AMS and 2 minor criteria) allows for overestimation of encephalitis. In fact, 8 of their 25 patients (32%) had unremarkable brain MRI and CSF. The diagnosis of encephalitis in those 8 patients was based solely on the clinical picture, which makes the diagnosis questionable at best. Generalized seizures and AMS can occur in the setting of viral sepsis or metabolic derangements associated with COVID-19 infection [3]. They should not be utilized as evidence of encephalitis in this setting. In addition, aphasia and dysarthria are difficult to ascertain in the setting of AMS and should not be considered as focal deficits in altered patients. The fact that nearly half the patients were not tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) in the CSF or for neuronal autoantibodies adds to the limitations of this study by allowing significant misclassification of infectious versus parainfectious versus autoimmune etiologies. The authors concluded that most cases of COVID-19–related encephalitis were parainfectious in nature, secondary to the associated cytokine storm. This claim cannot be made if half the patients were not tested for SARS-CoV-2 PCR in the CSF nor for neuronal autoantibodies in both the serum and CSF. Moreover, the authors did not report on cancer screening in their cohort, possibly missing patients with an incidental paraneoplastic etiology, a major cause of encephalitis [4]. With modern epidemiological data suggesting that autoimmune encephalitis may be as common as viral encephalitis [5], scientific reports addressing encephalitis related to COVID-19 (or any cause) should adhere to certain reporting standards to avoid etiological misclassification. At a minimum, all patients should be tested for common microbiological pathogens of encephalitis as well as clinically relevant neuronal autoantibodies [6]. Patients without evidence of direct CNS infection should undergo cancer screening to rule out paraneoplastic etiologies. Administering unnecessary immunomodulating therapies to encephalopathic patients with COVID-19 can have negative effects, especially in cases complicated by secondary bacterial infections. In addition, overestimating the incidence of COVID-19–related encephalitis may result in missing important alternative causes of encephalitis (eg, cancer or antibody mediated) if full encephalitis workup is not pursued in each case.

AbstractA successful Staphylococcus aureus vaccine remains elusive, and one controversy in the field is whether humans generate a protective adaptive immune response to infection. We developed a bacterial challenge murine assay that directly assesses the protective capacity of adoptively transferred human serum samples. We first validated the model by showing that postpneumococcal vaccine serum samples from humans induced effective clearance of Streptococcus pneumoniae in mice. We then found that human serum samples adoptively transferred from children with invasive S. aureus infections exhibited protection from disease in a murine model, with some samples conferring near complete protection. These findings demonstrate that human serum samples are capable of conferring a protective adaptive response generated by humans during invasive staphylococcal disease, allowing for the study of protective factors in a murine model. Identification of the protective factors present in the most efficacious serum samples would be of high interest as potential staphylococcal vaccine candidates or passive therapeutics.

To the Editor—We read with interest the article by Honda et al [1] highlighting the critical shortages of cefazolin in Japan. While it is commendable that the Ministry of Health, Labor, and Welfare of Japan issued a list suggesting potential substitute drugs for surgical prophylaxis and for specific infections, we find the lists are quite similar and thus disconcerting. As is evident in their report, the use of third-generation cephalosporins—cefotaxime and ceftriaxone, both “watch” group antibiotics—increased by more than 60-fold following cefazolin shortages [2]. Given that gram-positive cocci continue to be the predominant pathogens in most surgical site infections, routine use of broad-spectrum agents for surgical prophylaxis promotes the selection of multidrug-resistant species as well as limits the choice of effective agents in case the patients develop severe sepsis. Moreover, several studies including pharmacokinetic-pharmacodynamic analysis have demonstrated superior activity of cefazolin against methicillin-susceptible Staphylococcus aureus (MSSA) when compared with ceftriaxone [3–6]. This could be ascribed to the latter’s concentration-dependent significant protein binding (>90%), resulting in relatively low serum-free drug concentrations that are responsible for its antimicrobial activity [4, 7]. Even vancomycin is less effective than cefazolin for surgical prophylaxis against MSSA, hence the recommendation of using it in combination with cefazolin when there is a risk of both MSSA and methicillin-resistant S. aureus surgical site infections [8].

sepsishematopoietic cell transplantSIRSqSOFANEWS…

AbstractBackgroundSepsis disproportionately affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit end-points in patients with suspected infections (SIs) are used in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate 3 criteria among allogeneic HCT recipients with SIs.MethodsWe evaluated Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) in relation to short-term mortality among recipients transplanted between September 2010 and July 2017. We used cut-points of ≥ 2 for qSOFA/SIRS and ≥ 7 for NEWS and restricted to first SI per hospital encounter during patients’ first 100 days posttransplant.ResultsOf the 880 recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of an SI. In relation to 10-day mortality, SIRS was the most sensitive (91.3% [95% confidence interval {CI}, 72.0%–98.9%]) but least specific (35.0% [95% CI, 32.6%–37.5%]), whereas qSOFA was the most specific (90.5% [95% CI, 88.9%–91.9%]) but least sensitive (47.8% [95% CI, 26.8%–69.4%]). NEWS was moderately sensitive (78.3% [95% CI, 56.3%–92.5%]) and specific (70.2% [95% CI, 67.8%–72.4%]).ConclusionsNEWS outperformed qSOFA and SIRS, but each criterion had low to moderate predictive accuracy, and the magnitude of the known limitations of qSOFA and SIRS was at least as large as in the general population. Our data suggest that population-specific criteria are needed for immunocompromised patients.

Accumulating evidence shows that nervous system governs host immune responses; however, how -aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3–ASC–caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

by Lisa Mellhammar, Louise Thelaus, Sixten Elén, Jane Fisher, Adam Linder Background and aims Neutrophil-derived heparin binding protein (HBP; also known as azurocidin or CAP-37) is a key player in bacterial sepsis and a promising biomarker in severe infections.The aims of this study were to assess whether HBP is involved in the pathophysiology of COVID-19 and, if so, whether it can be used to predict severe disease preferably using a point-of-care test. Methods This was a prospective convenience sample study of biomarkers in patients admitted to Skåne University hospital in Sweden with a confirmed COVID-19 diagnosis. Plasma samples and clinical data were collected within 72h after admission, during hospital stay and at discharge. Plasma HBP concentrations samples were measured both with enzyme-linked immunosorbent assay (ELISA) and with a novel dry immunofluorescence analyzer (Joinstar) point-of-care test. Results Thirty-five COVID-19 patients were enrolled in the study. Twenty-nine patients had blood samples taken within 72h after admission. We compared the highest HBP value taken within 72h after admission in patients who eventually developed organ dysfunction (n = 23) compared to those who did not (n = 6), and found that HBP was significantly elevated in those who developed organ dysfunction (25.0 ng/mL (interquartile range (IQR) 16.6–48.5) vs 10.6 ng/mL (IQR 4.8–21.7 ng/mL), p = 0.03). Point-of-care test measurements correlated well with ELISA measurements (R = 0.83). HBP measured by the POC device predicted development of COVID-induced organ dysfunction with an AUC of 0.88 (95% confidence interval (CI) 0.70–1.0). Conclusions HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.

Serotype M28 isolates of the group A Streptococcus (GAS; Streptococcus pyogenes) are non-randomly associated with cases of puerperal sepsis, a potentially life-threatening infection that can occur in women following childbirth. Previously, we discovered that the 36.3 kb RD2 pathogenicity island, which is present in serotype M28 isolates but lacking from most other isolates, promotes the ability of M28 GAS to colonize the female reproductive tract. Here, we performed a gain-of-function study in which we introduced RD2 into representative serotype M1, M49, and M59 isolates and assessed the phenotypic consequences of RD2 acquisition. All RD2-containing derivatives colonized a higher percentage of mice, and at higher colony-forming-unit levels, than did the parental isolates in a mouse vaginal colonization model. However, for two additional phenotypes, survival in heparinized whole human blood and adherence to two human vaginal epithelial cell lines, there were serotype-specific differences to RD2-acquisition. Using transcriptomic comparisons, we identified that such differences may be a consequence of RD2 altering the abundance of transcripts from select core genome genes along serotype-specific lines. Our study is the first that interrogates RD2 function in GAS serotypes other than M28 isolates, shedding light on variability in the phenotypic consequences of RD2 acquisition, and informing on why this mobile genetic element is not ubiquitous in the GAS population.

Abstract Background Blood stream infection (BSI) and sepsis are serious clinical conditions and identification of the disease-causing pathogen is important for patient management. The RISE (Rapid Identification of SEpsis) study was carried out to collect a cohort allowing high-quality studies on different aspects of BSI and sepsis. The aim of this study was to identify patients at high risk for BSI who might benefit most from new, faster, etiological testing using neutrophil to lymphocyte count ratio (NLCR) and Shapiro score. Methods Adult patients (≥ 18 years) presenting at the emergency department (ED) with suspected BSI were prospectively included between 2014 and 2016 at Örebro University Hospital. Besides extra blood sampling, all study patients were treated according to ED routines. Electronic patient charts were retrospectively reviewed. A modified Shapiro score (MSS) and NLCR were extracted and compiled. Continuous score variables were analysed with area under receiver operator characteristics curves (AUC) to evaluate the ability of BSI prediction. Results The final cohort consisted of 484 patients where 84 (17%) had positive blood culture judged clinically significant. At optimal cut-offs, MSS (≥3 points) and NLCR (> 12) showed equal ability to predict BSI in the whole cohort (AUC 0.71/0.74; sensitivity 69%/67%; specificity 64%/68% respectively) and in a subgroup of 155 patients fulfilling Sepsis-3 criteria (AUC 0.71/0.66; sensitivity 81%/65%; specificity 46%/57% respectively). In BSI cases only predicted by NLCR> 12 the abundance of Gram-negative to Gram-positive pathogens (n = 13 to n = 4) differed significantly from those only predicted by MSS ≥3 p (n = 7 to n = 12 respectively) (p < 0.05). Conclusions MSS and NLCR predicted BSI in the RISE cohort with similar cut-offs as shown in previous studies. Combining the MSS and NLCR did not increase the predictive performance. Differences in BSI prediction between MSS and NLCR regarding etiology need further evaluation.

Abstract Background The primary objective of our study was to examine predictors for readmission in a prospective cohort of sepsis patients admitted to an emergency department (ED) and identified by the new Sepsis-3 criteria. Method A single-center observational population-based cohort study among all adult (≥18 years) patients with sepsis admitted to the emergency department of Slagelse Hospital during 1.10.2017–31.03.2018. Sepsis was defined as an increase in the sequential organ failure assessment (SOFA) score of ≥2. The primary outcome was 90-day readmission. We followed patients from the date of discharge from the index admission until the end of the follow-up period or until the time of readmission to hospital, emigration or death, whichever came first. We used competing-risks regression to estimate adjusted subhazard ratios (aSHRs) with 95% confidence intervals (CI) for covariates in the regression models. Results A total of 2110 patients were admitted with infections, whereas 714 (33.8%) suffered sepsis. A total of 52 patients had died during admission and were excluded leaving 662 patients (44.1% female) with a median age of 74.8 (interquartile range: 66.0–84.2) years for further analysis. A total of 237 (35,8%; 95% CI 32.1–39.6) patients were readmitted within 90 days, and 54(8.2%) had died after discharge without being readmitted. We found that a history of malignant disease (aSHR 1,61; 1.16–2.23), if previously admitted with sepsis within 1 year before the index admission (aSHR; 1.41; 1.08–1.84), and treatment with diuretics (aSHR 1.51; 1.17–1.94) were independent predictors for readmission. aSHR (1.49, 1.13–1.96) for diuretic treatment was almost unchanged after exclusion of patients with heart failure, while aSHR (1.47, 0.96–2.25) for malignant disease was slightly attenuated after exclusion of patients with metastatic tumors. Conclusions More than one third of patients admitted with sepsis, and discharged alive, were readmitted within 90 days. A history of malignant disease, if previously admitted with sepsis, and diuretic treatment were independent predictors for 90-day readmission.

Objective To provide a general overview of the reported current surgical capacity and delivery in order to advance current knowledge and suggest targets for further development and research within the region of sub-Saharan Africa. Design Scoping review. Setting District hospitals in sub-Saharan Africa. Data sources PubMed and Ovid EMBASE from January 2000 to December 2019. Study selection Studies were included if they contained information about types of surgical procedures performed, number of operations per year, types of anaesthesia delivered, cadres of surgical/anaesthesia providers and/or patients’ outcomes. Results The 52 articles included in analysis provided information about 16 countries. District hospitals were a group of diverse institutions ranging from 21 to 371 beds. The three most frequently reported procedures were caesarean section, laparotomy and hernia repair, but a wide range of orthopaedics, plastic surgery and neurosurgery procedures were also mentioned. The number of operations performed per year per district hospital ranged from 239 to 5233. The most mentioned anaesthesia providers were non-physician clinicians trained in anaesthesia. They deliver mainly general and spinal anaesthesia. Depending on countries, articles referred to different surgical care providers: specialist surgeons, medical officers and non-physician clinicians. 15 articles reported perioperative complications among which surgical site infection was the most frequent. Fifteen articles reported perioperative deaths of which the leading causes were sepsis, haemorrhage and anaesthesia complications. Conclusion District hospitals play a significant role in sub-Saharan Africa, providing both emergency and elective surgeries. Most procedures are done under general or spinal anaesthesia, often administered by non-physician clinicians. Depending on countries, surgical care may be provided by medical officers, specialist surgeons and/or non-physician clinicians. Research on safety, quality and volume of surgical and anaesthesia care in this setting is scarce, and more attention to these questions is required.

Abstract Background Escherichia coli (E. coli) is one of the important causative pathogens of neonatal invasive infection. The epidemiological and clinical profile of invasive E. coli infection in Chinese newborns is not well characterized. Methods Ninety-four infants with invasive E. coli infection were categorized into E. coli early onset disease (EOD) group (onset ≤72 h after birth) (n = 46) and E. coli late onset disease (LOD) group (onset > 72 h) (n = 48). We compared and analyzed the clinical characteristics and drug sensitivity profile of early-onset and late-onset E. coli invasive infection in neonates. Results The incidence of E. coli-EOD and E.coli-LOD was 0.45/1000 live births (LBs) and 0.47/1000 LBs, respectively. The incidence of gestational diabetes mellitus, perinatal fever, urinary tract infection, chorioamnionitis, and positive E. coli culture among mothers in the E. coli-EOD group were significantly higher than that in E. coli-LOD group. The incidence of premature birth, low-birth-weight, nosocomial infection, and hospitalization time were significantly higher in the E. coli-LOD group. The main disease in E. coli-EOD group was pneumonia (main clinical manifestation: dyspnea). The main disease in E. coli-LOD group was sepsis (main clinical manifestation: fever). The sensitivity rates of E. coli strains to ampicillin and piperacillin were low (25.00–28.79%); sensitivity to cephalosporins was also low except ceftazidime (lowest sensitivity rate: 57.14%). Sensitivity to compound preparations containing β-lactamase inhibitors was high, even for extended spectrum β-lactamase-positive strains (nearly 100%). Conclusion E. coli is an important cause of invasive infection of newborns in Xiamen, China. E. coli-EOD was largely attributable to perinatal factors, while E. coli-LOD was largely related to nosocomial infection. Compound preparations containing β-lactamase inhibitor or carbapenem antibiotics should be preferred for neonatal invasive infection by E. coli.

Background: Accelerate Pheno system and BacT/ALERT VIRTUO may improve bacteremia management. This study evaluated the impact of both devices on outcomes in patients with sepsis and concurrent gram-negative bacteremia. Methods: This quasi-experimental study included a retrospective pre-implementation and a prospective post-implementation group. Patients ≥18 years old with gram-negative bacteremia were included. Patients with neutropenia, pregnancy, were transferred from an outside hospital with active bloodstream infection, or polymicrobial bacteremia were excluded. Blood culture incubation in the BacT/ALERT 3D and microdilution antimicrobial susceptibility testing from culture plate growth was used prior to implementation of BacT/ALERT VIRTUO and Accelerate Pheno. MALDI-TOF identification directly from blood culture was used pre- and post-implementation. Time to gram-stain, identification, susceptibility reporting, initiation of narrow spectrum gram-negative therapy at 72 hours, 30-day inpatient mortality, sepsis resolution, and hospital length of stay were evaluated. Results: 116 patients were included (63 pre-implementation, 53 post-implementation). Median time to gram-stain and susceptibility results were significantly shorter post-implementation (P < 0.001). The post-implementation group had an improved hazard for narrow spectrum gram-negative therapy at 72 hours (HR [95% CI] = 2.685 [1.348 – 5.349]), reduced hazard for 30-day inpatient mortality (aHR: 0.150 [0.026 – 0.846]) and improved sepsis resolution (77.8% vs. 92.5%, P = 0.030). Hospital length of stay was unchanged between groups. Conclusion: The implementation of BacT/Alert VIRTUO and the Accelerate Pheno system improved microbiology laboratory processes, antibiotic utilization processes and clinical outcomes. These data support the use of rapid diagnostics in sepsis with concurrent gram-negative bacteremia.

Immune paralysis is a protracted state of immune suppression following the early/acute inflammatory phase of sepsis. CD11b+Gr-1+ cells induced during sepsis are heterogeneous myeloid-derived cells (MDCs). This study investigated the contribution of MDCs to immune paralysis. Treatment of mice with zymosan (ZM) induced a marked increase in the total number of splenocytes with an increase in the ratio of Gr-1hi cells and a decease in the ratio of T cells on day 7, eventually returning to levels similar to those of control mice on day 21. T cell activation and IFN- expression by CD8+ T cells were clearly impaired in ZM-treated mice on day 21 (d21-ZM mice). Gr-1hi cells showed a CD11b+Ly6Ghi polymorphonuclear phenotype. Injection of lipopolysaccharide (LPS) into d21-ZM mice impaired IL-6 production in serum, accompanied by accumulation of CD11b+Gr-1hi cells in the peripheral blood. Transfer of Gr-1hi cells from d21-ZM mice into intact mice impaired IL-6 production, but similar transfer of Gr-1hi cells from PD-1/PD-L1-deficient d21-ZM mice showed no such suppressive effect. Conversely, either depletion of Gr-1hi cells by treatment with anti-Gr-1 monoclonal antibody (mAb) or neutralization of the PD-1/PD-L1 pathway by anti-PD-1 and anti-PD-L1 mAbs during the induction phase of sepsis ameliorated ZM-induced immune suppression. Our results suggest that the PD-1/PD-L1-mediated generation of Gr-1hi cells in the early phase of sepsis is required for late-phase of immune paralysis.