David C. Lye

Effects of Early Oseltamivir Therapy on Viral Shedding in 2009 Pandemic Influenza A (H1N1) Virus Infection

BACKGROUND Pandemic influenza (H1N1) 2009 is susceptible to oseltamivir. There are few reports on its clinical and virologic response to oseltamivir. METHODS During the pandemic containment response in Singapore, all patients with positive polymerase chain reaction (PCR) results for pandemic influenza (H1N1) 2009 were hospitalized, given oseltamivir for 5 days, and discharged when daily PCR results for combined nasal and throat swab samples became negative. Six patients had concurrent positive viral culture and PCR results. RESULTS The median age of the first 70 consecutive patients was 26 years (interquartile range, 21-38 years); 60% were men, and 29% had comorbidity. The mean time (+/-SD) from illness onset to hospital admission was 3+/-2 days. Influenza-like illness was noted in 63% of patients. Fever occurred in 91%, cough in 88%, sore throat in 66%, and rhinorrhea in 53% of patients. The mean duration (+/-SD) of viral shedding from illness onset was day 6+/-2 days. Viral shedding persisted beyond 7 days in 37% of patients. Clinical features and viral shedding were similar between those with and without comorbidity, except the former had more cough and lower oxygen saturation. Patients receiving oseltamivir on days 1 to 3 of illness had significantly shorter viral shedding duration, compared with those treated from day 4 onwards (P < .05). The mean durations (+/-SD) of positive PCR and viral culture results were 5+/-8 and 4+/-18 days, respectively, for 6 patients with concurrent positive viral culture and PCR results. CONCLUSIONS Prolonged viral shedding was noted in young immunocompetent adults with mild pandemic influenza (H1N1) 2009 despite receipt of oseltamivir. When prescribed during the first 3 days of illness, oseltamivir shortened the duration of viral shedding.

Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy

OBJECTIVES Continuous vancomycin infusion is increasingly used for outpatient management of infections, but the relationship between vancomycin and nephrotoxicity is controversial. We investigated the risk factors associated with nephrotoxicity in this setting. METHODS A retrospective cohort study of patients receiving continuous vancomycin infusion as outpatient parenteral antibiotic therapy (OPAT) was performed. The likelihood of developing nephrotoxicity (> or =50% increase in serum creatinine from baseline) was evaluated in relation to demographic variables, underlying co-morbidities, infectious disease diagnoses, concomitant drug exposures and vancomycin concentration. Logistic regression was used to determine the association of various variables. Classification and regression tree analysis was used to determine the most significant breakpoint for continuous variables. RESULTS We examined 102 adult patients between January 2004 and June 2007. The mean +/- SD age, baseline serum creatinine and steady-state vancomycin concentration were 48.2 +/- 17.6 years, 78.0 +/- 32.5 micromol/L and 15.5 +/- 10.8 mg/L, respectively. The majority of the patients (66.7%) were treated for bone and joint infection. The cumulative incidence of nephrotoxicity was 15.7%. Nephrotoxicity was found to be associated with hypertension [odds ratio (OR) 5.302 (95% confidence interval (CI) 1.159-24.246), P = 0.031], exposure to aminoglycosides [OR 6.594 (95% CI 1.026-42.385), P = 0.047], loop diuretics [OR 8.123 (95% CI 1.449-45.528), P = 0.017], and steady-state vancomycin concentration > or =28 mg/L [OR 21.236 (95% CI 2.687-167.857), P = 0.004]. CONCLUSIONS We have identified independent risk factors for nephrotoxicity in patients receiving continuous infusion vancomycin in OPAT. A serum steady-state vancomycin concentration > or =28 mg/L markedly increases the risk.

Differential Targeting of Viral Components by CD4+ versus CD8+ T Lymphocytes in Dengue Virus Infection

ABSTRACT Dengue virus (DENV) is the principal arthropod-borne viral pathogen afflicting human populations. While repertoires of antibodies to DENV have been linked to protection or enhanced infection, the role of T lymphocytes in these processes remains poorly defined. This study provides a comprehensive overview of CD4+ and CD8+ T cell epitope reactivities against the DENV 2 proteome in adult patients experiencing secondary DENV infection. Dengue virus-specific T cell responses directed against an overlapping 15mer peptide library spanning the DENV 2 proteome were analyzed ex vivo by enzyme-linked immunosorbent spot assay, and recognition of individual peptides was further characterized in specific T cell lines. Thirty novel T cell epitopes were identified, 9 of which are CD4+ and 21 are CD8+ T cell epitopes. We observe that whereas CD8+ T cell epitopes preferentially target nonstructural proteins (NS3 and NS5), CD4+ epitopes are skewed toward recognition of viral components that are also targeted by B lymphocytes (envelope, capsid, and NS1). Consistently, a large proportion of dengue virus-specific CD4+ T cells have phenotypic characteristics of circulating follicular helper T cells (CXCR5 expression and production of interleukin-21 or gamma interferon), suggesting that they are interacting with B cells in vivo. This study shows that during a dengue virus infection, the protein targets of human CD4+ and CD8+ T cells are largely distinct, thus highlighting key differences in the immunodominance of DENV proteins for these two cell types. This has important implications for our understanding of how the two arms of the human adaptive immune system are differentially targeted and employed as part of our response to DENV infection.

Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial

BACKGROUND Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever. METHODS To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969. FINDINGS We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups. INTERPRETATION Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue. FUNDING STOP Dengue Translational Clinical Research.

Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study

BackgroundDengue re-emerges in Singapore despite decades of effective vector control; the infection predominantly afflicts adults. Severe dengue not fulfilling dengue hemorrhagic fever (DHF) criteria according to World Health Organization (WHO) 1997 guideline was increasingly reported. A new WHO 2009 guideline emphasized warning signs and a wider range of severe dengue manifestations. We aim to evaluate the utility of these two guidelines in confirmed adult dengue fatalities.MethodsWe conducted a multi-center retrospective chart review of all confirmed adult dengue deaths in Singapore from 1 January 2004 to 31 December 2008.ResultsOf 28 adult dengue deaths, median age was 59 years. Male gender comprised 67.9% and co-morbidities existed in 75%. From illness onset, patients presented for admission at a median of 4 days and death occurred at a median of 12 days. Intensive care admission was required in 71.4%. Probable dengue was diagnosed in 32.1% by WHO 1997 criteria and 78.6% by WHO 2009. The earliest warning sign was persistent vomiting at a median of 1.5 days. Hematocrit change ≥20% concurrent with platelet count <20 × 10^9/L was associated with the shortest interval to death at a median of 3 days. Only 35.7% of death cases fulfilled DHF criteria by WHO 1997 versus severe dengue in 100.0% by WHO 2009 criteria. Deaths were due to shock and organ failure. Acute renal impairment occurred in 71.4%, impaired consciousness 57.1% and severe hepatitis 53.6%.ConclusionsIn our adult fatal dengue cohort, WHO 2009 criteria had higher sensitivity in diagnosing probable dengue and severe dengue compared with WHO 1997. As warning signs, persistent vomiting occurred early and hematocrit change ≥20% concurrent with platelet count <20 × 10^9/L preceded death most closely.

Economic Impact of Dengue Illness and the Cost-Effectiveness of Future Vaccination Programs in Singapore

Background Dengue illness causes 50–100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact of dengue in higher resourced countries or the cost-effectiveness of potential dengue vaccines in such settings. Methods and Findings We estimate the direct and indirect costs of dengue from hospitalized and ambulatory cases in Singapore. We consider inter alia the impacts of dengue on the economy using the human-capital and the friction cost methods. Disease burden was estimated using disability-adjusted life years (DALYs) and the cost-effectiveness of a potential vaccine program was evaluated. The average economic impact of dengue illness in Singapore from 2000 to 2009 in constant 2010 US

Diabetes with hypertension as risk factors for adult dengue hemorrhagic fever in a predominantly dengue serotype 2 epidemic: a case control study.

ranged between

Simple clinical and laboratory predictors of chikungunya versus dengue infections in adults

0.85 billion and

Lack of Efficacy of Prophylactic Platelet Transfusion for Severe Thrombocytopenia in Adults with Acute Uncomplicated Dengue Infection

1.15 billion, of which control costs constitute 42%–59%. Using empirically derived disability weights, we estimated an annual average disease burden of 9–14 DALYs per 100 000 habitants, making it comparable to diseases such as hepatitis B or syphilis. The proportion of symptomatic dengue cases detected by the national surveillance system was estimated to be low, and to decrease with age. Under population projections by the United Nations, the price per dose threshold for which vaccines stop being more cost-effective than the current vector control program ranged from

The impact of multidrug resistance in healthcare-associated and nosocomial Gram-negative bacteraemia on mortality and length of stay: cohort study

50 for mass vaccination requiring 3 doses and only conferring 10 years of immunity to