Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis

INTRODUCTION: A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. METHODS: Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry. RESULTS: Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01). CONCLUSIONS: In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality

Uncertainty analysis of chest X-ray lung height measurements and size matching for lung transplantation

Background: Errors in measuring chest X-ray (CXR) lung heights could contribute to the occurrence of size-mismatched lung transplant procedures. Methods: We first used Bland-Altman analysis for repeated measures to evaluate contributors to measurement error of chest X-ray lung height. We then applied error propagation theory to assess the impact of measurement error on size matching for lung transplantation. Results: A total 387 chest X-rays from twenty-five donors and twenty-five recipients were measured by two raters. Individual standard deviation for lung height differences were independent of age, sex, donor Conclusions: Individual chest X-ray lung heights are imprecise for the purpose of size matching in lung transplantation. Averaging chest X-rays lung heights reduced uncertainty

A pragmatic machine learning model to predict carbapenem resistance

Infection caused by carbapenem-resistant (CR) organisms is a rising problem in the United States. While the risk factors for antibiotic resistance are well known, there remains a large need for the early identification of antibiotic-resistant infections. Using machine learning (ML), we sought to develop a prediction model for carbapenem resistance. All patients \u3e18 years of age admitted to a tertiary-care academic medical center between 1 January 2012 and 10 October 2017 with ≥1 bacterial culture were eligible for inclusion. All demographic, medication, vital sign, procedure, laboratory, and culture/sensitivity data were extracted from the electronic health record. Organisms were considered CR if a single isolate was reported as intermediate or resistant. Patients with CR and non-CR organisms were temporally matched to maintain the positive/negative case ratio. Extreme gradient boosting was used for model development. In total, 68,472 patients met inclusion criteria, with 1,088 patients identified as having CR organisms. Sixty-seven features were used for predictive modeling. The most important features were number of prior antibiotic days, recent central venous catheter placement, and inpatient surgery. After model training, the area under the receiver operating characteristic curve was 0.846. The sensitivity of the model was 30%, with a positive predictive value (PPV) of 30% and a negative predictive value of 99%. Using readily available clinical data, we were able to create a ML model capable of predicting CR infections at the time of culture collection with a high PPV

Effectiveness of sequential intravenous-to-oral antibiotic switch therapy in hospitalized patients with gram-positive infection: the SEQUENCE cohort study.

Switching from intravenous to oral antibiotic therapy may improve inpatient management and reduce hospital stays and the complications of intravenous treatment. We aimed to assess the effectiveness of intravenous-to-oral antibiotic switch therapy and an early discharge algorithm in hospitalized patients with gram-positive infection. We performed a prospective cohort study with a retrospective comparison cohort, recruited from eight tertiary, acute-care Spanish referral hospitals. All patients included had culture-confirmed methicillin-resistant gram-positive infection, or methicillin-susceptible gram-positive infection and beta-lactam allergy and had received intravenous treatment with glycopeptides, lipopeptides, or linezolid. The study comprised two cohorts: the prospective cohort to assess the effectiveness of a sequential intravenous-to-oral antibiotic switch algorithm and early discharge, and a retrospective cohort in which the algorithm had not been applied, used as the comparator. A total of 247 evaluable patients were included; 115 in the prospective and 132 in the retrospective cohort. Forty-five retrospective patients (34 %) were not changed to oral antibiotics, and 87 (66 %) were changed to oral antibiotics without following the proposed algorithm. The duration of hospitalization was significantly shorter in the prospective cohort compared to the retrospective group that did not switch to oral drugs (16.7 ± 18.7 vs 23 ± 13.4 days, P  < 0.001). No differences were observed regarding the incidence of catheter-related bacteraemia (4.4 % vs 2.6 %, P = 0.621). Our results suggest that an intravenous-to-oral antibiotic switch strategy is effective for reducing the length of hospital stay in selected hospitalized patients with gram-positive infection.This study was supported by an unrestricted educational grant from Pfizer S.L.U and by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, co-financed by the European Development Regional Fund “A way to achieve Europe” and the Spanish Network for Research in Infectious Diseases (REIPI RD12/0015). Drs D. Rodrıguez-Pardo, C. Pigrau, L. Sorli, and B. Almirante belong to the REIPI network