Markers of prolonged hospitalisation in severe dengue.

BACKGROUND: Dengue is one of the most common diseases in the tropics and subtropics. Whilst mortality is a rare event when adequate supportive care can be provided, a large number of patients get hospitalised with dengue every year that places a heavy burden on local health systems. A better understanding of the support required at the time of hospitalisation is therefore of critical importance for healthcare planning, especially when resources are limited during major outbreaks. METHODS: Here we performed a retrospective analysis of clinical data from over 1500 individuals hospitalised with dengue in Vietnam between 2017 and 2019. Using a broad panel of potential biomarkers, we sought to evaluate robust predictors of prolonged hospitalisation periods. RESULTS: Our analyses revealed a lead-time bias, whereby early admission to hospital correlates with longer hospital stays - irrespective of disease severity. Importantly, taking into account the symptom duration prior to hospitalisation significantly affects observed associations between hospitalisation length and previously reported risk markers of prolonged stays, which themselves showed marked inter-annual variations. Once corrected for symptom duration, age, temperature at admission and elevated neutrophil-to-lymphocyte ratio were found predictive of longer hospitalisation periods. CONCLUSION: This study demonstrates that the time since dengue symptom onset is one of the most significant predictors for the length of hospital stays, independent of the assigned severity score. Pre-hospital symptom durations need to be accounted for to evaluate clinically relevant biomarkers of dengue hospitalisation trajectories.

Aetiologies and clinical presentation of central nervous system infections in Vietnamese patients: a prospective study.

Knowledge of the clinical presentation of central nervous system (CNS) infections and the causative pathogens is crucial for appropriate diagnosis and rapid initiation of appropriate treatment to prevent severe neurological sequelae. The aim of this study is to understand the aetiology of CNS infections based on the clinical presentation of Vietnamese patients. A prospective hospital-based cohort study was conducted between May 2014 and May 2017. We screened 137 patients with clinically suspected CNS infection for fungal, bacterial and viral pathogens using their cerebrospinal fluid (CSF) and blood cultures. In addition, DNA or RNA extracted from CSF samples were subjected to nucleic acid testing (NAT) with a selective panel of bacterial, viral and fungal pathogens. At least one pathogen could be detected in 41% (n = 56) of the patients. The main pathogens causing CNS infections were Streptococcus suis (n = 16; 12%) and Neisseria meningitidis (n = 9; 7%), followed by Herpes simplex virus 1/2 (n = 4; 3%) and Klebsiella pneumoniae (n = 4; 3%). Other pathogens were only identified in a few cases. Patients with bacterial CNS infections were significantly older, had a worse outcome, a lower Glasgow Coma Scale (GCS), a higher rate of speech impairment and neck stiffness than patients with viral or tuberculous CNS infections. In northern Vietnam, adults are mostly affected by bacterial CNS infections, which have a severe clinical course and worse outcomes compared to viral or tuberculous CNS infections. Clinicians should be aware of the regional occurrence of pathogens to initiate rapid and appropriate diagnosis and treatment.

Predominance of HBV Genotype B and HDV Genotype 1 in Vietnamese Patients with Chronic Hepatitis.

Hepatitis delta virus (HDV) coinfection will additionally aggravate the hepatitis B virus (HBV) burden in the coming decades, with an increase in HBV-related liver diseases. Between 2018 and 2019, a total of 205 HBV patients clinically characterized as chronic hepatitis B (CHB; n = 115), liver cirrhosis (LC; n = 21), and hepatocellular carcinoma (HCC; n = 69) were recruited. HBV surface antigen (HBsAg), antibodies against surface antigens (anti-HBs), and core antigens (anti-HBc) were determined by ELISA. The presence of hepatitis B viral DNA and hepatitis delta RNA was determined. Distinct HBV and HDV genotypes were phylogenetically reconstructed and vaccine escape mutations in the "a" determinant region of HBV were elucidated. All HBV patients were HbsAg positive, with 99% (n = 204) and 7% (n = 15) of them being positive for anti-HBc and anti-HBs, respectively. Anti-HBs positivity was higher among HCC (15%; n = 9) compared to CHB patients. The HBV-B genotype was predominant (65%; n = 134), followed by HBV-C (31%; n = 64), HBV-D, and HBV-G (3%; n = 7). HCC was observed frequently among young individuals with HBV-C genotypes. A low frequency (2%; n = 4) of vaccine escape mutations was observed. HBV-HDV coinfection was observed in 16% (n = 33) of patients with the predominant occurrence of the HDV-1 genotype. A significant association of genotypes with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme levels was observed in HBV monoinfections. The prevalence of the HDV-1 genotype is high in Vietnam. No correlation was observed between HDV-HBV coinfections and disease progression when compared to HBV monoinfections.

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers.

High rates of artemisinin-based combination therapy (ACT) failures in the treatment of Plasmodium falciparum malaria in Southeast Asia have led to triple-drug strategies to extend the useful life of ACTs. In this study, we determined whether methylene blue [MB; 3,7-bis(dimethylamino)phenothiazin-5-ium chloride hydrate] alters the pharmacokinetics of artesunate-amodiaquine (ASAQ) and enhances the ex vivo antimalarial activity of ASAQ. In an open-label, randomized crossover design, a single oral dose of ASAQ (200 mg AS/540 mg AQ) alone or with MB (325 mg) was administered to 15 healthy Vietnamese volunteers. Serial blood samples were collected up to 28 days after dosing. Pharmacokinetic properties of the drugs were determined by noncompartmental analysis. After drug administration, plasma samples from seven participants were assessed for ex vivo antimalarial activity against the artemisinin-sensitive MRA1239 and the artemisinin-resistant MRA1240 P. falciparum lines, in vitro MB significantly increased the mean area under the curve of the active metabolite of AS, dihydroartemisinin (1,246 ± 473 versus 917 ± 405 ng·h/ml, P = 0.009) but did not alter the pharmacokinetics of AQ, AS, or desethylamodiaquine. Comparing the antimalarial activities of the plasma samples from the participants collected up to 48 h after ASAQ plus MB (ASAQ+MB) and ASAQ dosing against the MRA1239 and MRA1240 lines, MB significantly enhanced the blood schizontocidal activity of ASAQ by 2.0-fold and 1.9-fold, respectively. The ring-stage survival assay also confirmed that MB enhanced the ex vivo antimalarial activity of ASAQ against MRA1240 by 2.9-fold to 3.8-fold, suggesting that the triple-drug combination has the potential to treat artemisinin-resistant malaria and for malaria elimination. (This study has been registered in the Australian New Zealand Clinical Trials Registry [https://anzctr.org.au/] under registration number ACTRN12612001298808.).

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate-Amodiaquine and Artemisinin-Piperaquine in Healthy Volunteers for Preselection Malaria Therapy.

The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin-piperaquine [ARN-PPQ] [Artequick®] and artesunate-amodiaquine [ARS-AQ] [Coarsucam™]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs. The area under the concentration-time curve (AUC0-∞) was 3.6-fold higher for dihydroartemisinin (active metabolite of ARS) than that for ARN, whereas the AUC0-∞ of desethylamodiaquine (active metabolite of AQ) was 2.0-fold lower than that of PPQ. Based on the 50% inhibitory dilution values of the volunteers' plasma samples collected from 0.25 to 3 hours after the last dose, the ex vivo activity of ARS-AQ was 2.9- to 16.2-fold more potent than that of ARN-PPQ against the drug-sensitive D6 Plasmodium falciparum line. In addition, at 1.5, 4.0, and 24 hours after the last dose, the ex vivo activity of ARS-AQ was 20.8-, 3.5-, and 8.5-fold more potent than that of ARN-PPQ against the ARN-sensitive MRA1239 line. By contrast, at 1.5 hours, the ex vivo activity of ARS-AQ was 5.4-fold more active than that of ARN-PPQ but had similar activities at 4 and 24 hours against the ARN-resistant MRA1240 line. The PK-PD data suggest that ARS-AQ possesses superior antimalarial activity than that of ARN-PPQ and would be the preferred ACT for further in vivo efficacy testing in multidrug-resistant falciparum malaria areas.

Pharmacokinetics and ex vivo antimalarial activity of artesunate-azithromycin in healthy volunteers.

In 18 male healthy subjects, artesunate (200 mg)-azithromycin (1,500 mg) daily for 3 days was found to be well tolerated, with only mild gastrointestinal disturbances reported. The pharmacokinetic properties of artesunate-azithromycin given in combination are comparable to those of the drugs given alone. Artesunate and its major active metabolite, dihydroartemisinin, are responsible for most of the ex vivo antimalarial activity, with a delayed contribution by azithromycin.