The innate immune response to HSV-1: glycoprotein mediated activation of dendritic cells

Herpes Simplex Virus (HSV) – 1 also known as Human Herpes Virus (HHV) – 1 is a common infectious agent of humans which can cause a wide variety of clinical outcomes, ranging from mild mucocutaneous lesions to long term morbidity and possible mortality. Viral entry into cells requires the co-ordinated action of at least four HSV-1 envelope glycoproteins: gB, gD and the heterodimer gHgL. Dendritic cells (DC) are the most potent antigen presenting cells and are likely to encounter the virus early after entry into the host. HSV-1 readily infects DC leading to a series of both morphological and functional changes, and yet the pathway induced by HSV-1 that leads to DC maturation has not been elucidated. This thesis aims to understand the role of the viral entry glycoproteins in the activation of DC and the consequent initiation of an immune response. Defining this role has important implications not only in understanding immunopathogenesis, but also in the study of HSV-1 as an immunotherapeutic vector, and in the design of an efficient HSV-1 vaccine. Monocyte-derived DCs (MDDC) were found to recognise and respond to the complex of four essential viral glycoproteins, independent of other viral proteins or nucleic acids. MDDC recognition of these four glycoproteins leads to the upregulation of a maturation phenotype and the production of type I interferon (IFN) as well as the induction of a strongly polarised TH1, IFN-γ dominated allogeneic T cell response. In contrast, monocyte-derived Langerhans cells (MDLC), display only partial maturation phenotype and do not produce type I IFN. Plasmacytoid DC (pDC) induce a strong type I IFN response to a viral infection, but not to the viral surface glycoproteins. In the context of natural HSV-1 infection, these results suggest a model in which at the site of HSV-1 infection, different DC sub-populations respond differently to a viral infection and to glycoproteins expressed on the surface of infected cells in order to provide an effective immune response

Biosimilars and cancer treatment of older patients

AbstractBiosimilar monoclonal antibodies are being developed globally to meet clinical demand in oncology and potentially provide greater access to biologic therapies for patients with cancer, including older patients. In this supplement, we present an overview of the development, approval requirements, and characteristics of biosimilar monoclonal antibodies that may help practicing oncologists and other healthcare providers to acquire familiarity with this new group of therapeutic biologic agents. Furthermore, we review and discuss some of the challenges and potential strategies for the management of older patients with cancer, who represent an increasing population in many countries

Risk for Clostridium difficile infection after allogeneic hematopoietic cell transplant remains elevated in the postengraftment period

BACKGROUND: Clostridium difficile infection (CDI) is a frequent cause of diarrhea among allogeneic hematopoietic cell transplant (HCT) recipients. It is unknown whether risk factors for CDI vary by time posttransplant. METHODS: We performed a 3-year prospective cohort study of CDI in allogeneic HCT recipients. Participants were enrolled during their transplant hospitalizations. Clinical assessments were performed weekly during hospitalizations and for 12 weeks posttransplant, and monthly for 30 months thereafter. Data were collected through patient interviews and chart review, and included CDI diagnosis, demographics, transplant characteristics, medications, infections, and outcomes. CDI cases were included if they occurred within 1 year of HCT and were stratified by time from transplant. Multivariable logistic regression was used to determine risk factors for CDI. RESULTS: One hundred eighty-seven allogeneic HCT recipients were enrolled, including 63 (34%) patients who developed CDI. 38 (60%) CDI cases occurred during the preengraftment period (days 0-30 post-HCT) and 25 (40%) postengraftment (day >30). Lack of any preexisting comorbid disease was significantly associated with lower risk of CDI preengraftment (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.9). Relapsed underlying disease (OR, 6.7; 95% CI, 1.3-33.1), receipt of any high-risk antimicrobials (OR, 11.8; 95% CI, 2.9-47.8), and graft-versus-host disease (OR, 7.8; 95% CI, 2.0-30.2) were significant independent risk factors for CDI postengraftment. CONCLUSIONS: A large portion of CDI cases occurred during the postengraftment period in allogeneic HCT recipients, suggesting that surveillance for CDI should continue beyond the transplant hospitalization and preengraftment period. Patients with continued high underlying severity of illness were at increased risk of CDI postengraftment

An evaluation of food as a potential source for clostridium difficile acquisition in hospitalized patients

OBJECTIVETo determine whetherClostridium difficileis present in the food of hospitalized patients and to estimate the risk of subsequent colonization associated withC. difficilein food.METHODSThis was a prospective cohort study of inpatients at a university-affiliated tertiary care center, May 9, 2011–July 12, 2012. Enrolled patients submitted a portion of food from each meal. Patient stool specimens and/or rectal swabs were collected at enrollment, every 3 days thereafter, and at discharge, and were cultured forC. difficile. Clinical data were reviewed for evidence of infection due toC. difficile.A stochastic, discrete event model was developed to predict exposure toC. difficilefrom food, and the estimated number of new colonization events from food exposures per 1,000 admissions was determined.RESULTSA total of 149 patients were enrolled and 910 food specimens were obtained. Two food specimens from 2 patients were positive forC. difficile(0.2% of food samples; 1.3% of patients). Neither of the 2 patients was colonized at baseline withC. difficile. Discharge colonization status was available for 1 of the 2 patients and was negative. Neither was diagnosed withC. difficileinfection while hospitalized or during the year before or after study enrollment. Stochastic modeling indicated contaminated hospital food would be responsible for less than 1 newly colonized patient per 1,000 hospital admissions.CONCLUSIONSThe recovery ofC. difficilefrom the food of hospitalized patients was rare. Modeling suggests hospital food is unlikely to be a source ofC. difficileacquisition.Infect Control Hosp Epidemiol2016;1401–1407</jats:sec

ICD-9 Codes and Surveillance for Clostridium difficile–associated Disease

We conducted a retrospective cohort study to compare Clostridium difficile–associated disease rates determined by C. difficile–toxin assays and International Classification of Diseases, 9th Revision (ICD-9) codes. The correlation between toxin assay results and ICD-9 codes was good (κ = 0.72, p<0.01). The sensitivity of the ICD-9 codes was 78% and the specificity was 99.7%

Assessment of healthcare worker protocol deviations and self-contamination during personal protective equipment donning and doffing

OBJECTIVETo evaluate healthcare worker (HCW) risk of self-contamination when donning and doffing personal protective equipment (PPE) using fluorescence and MS2 bacteriophage.DESIGNProspective pilot study.SETTINGTertiary-care hospital.PARTICIPANTSA total of 36 HCWs were included in this study: 18 donned/doffed contact precaution (CP) PPE and 18 donned/doffed Ebola virus disease (EVD) PPE.INTERVENTIONSHCWs donned PPE according to standard protocols. Fluorescent liquid and MS2 bacteriophage were applied to HCWs. HCWs then doffed their PPE. After doffing, HCWs were scanned for fluorescence and swabbed for MS2. MS2 detection was performed using reverse transcriptase PCR. The donning and doffing processes were videotaped, and protocol deviations were recorded.RESULTSOverall, 27% of EVD PPE HCWs and 50% of CP PPE HCWs made ≥1 protocol deviation while donning, and 100% of EVD PPE HCWs and 67% of CP PPE HCWs made ≥1 protocol deviation while doffing (P=.02). The median number of doffing protocol deviations among EVD PPE HCWs was 4, versus 1 among CP PPE HCWs. Also, 15 EVD PPE protocol deviations were committed by doffing assistants and/or trained observers. Fluorescence was detected on 8 EVD PPE HCWs (44%) and 5 CP PPE HCWs (28%), most commonly on hands. MS2 was recovered from 2 EVD PPE HCWs (11%) and 3 CP PPE HCWs (17%).CONCLUSIONSProtocol deviations were common during both EVD and CP PPE doffing, and some deviations during EVD PPE doffing were committed by the HCW doffing assistant and/or the trained observer. Self-contamination was common. PPE donning/doffing are complex and deserve additional study.Infect Control Hosp Epidemiol 2017;38:1077–1083</jats:sec