Phylodynamics of foot-and-mouth disease virus O/PanAsia in Vietnam 2010-2014

© 2017 The Author(s). Foot-and-mouth disease virus (FMDV) is endemic in Vietnam, a country that plays an important role in livestock trade within Southeast Asia. The large populations of FMDV-susceptible species in Vietnam are important components of food production and of the national livelihood. In this study, we investigated the phylogeny of FMDV O/PanAsia in Vietnam, reconstructing the virus' ancestral host species (pig, cattle or buffalo), clinical stage (subclinical carrier or clinically affected) and geographical location. Phylogenetic divergence time estimation and character state reconstruction analyses suggest that movement of viruses between species differ. While inferred transmissions from cattle to buffalo and pigs and from pigs to cattle are well supported, transmission from buffalo to other species, and from pigs to buffalo may be less frequent. Geographical movements of FMDV O/PanAsia virus appears to occur in all directions within the country, with the South Central Coast and the Northeast regions playing a more important role in FMDV O/PanAsia spread. Genetic selection of variants with changes at specific sites within FMDV VP1 coding region was different depending on host groups analyzed. The overall ratio of non-synonymous to synonymous nucleotide changes was greater in pigs compared to cattle and buffalo, whereas a higher number of individual amino acid sites under positive selection were detected in persistently infected, subclinical animals compared to viruses collected from clinically diseased animals. These results provide novel insights to understand FMDV evolution and its association with viral spread within endemic countries. These findings may support animal health organizations in their endeavor to design animal disease control strategies in response to outbreaks

Unexpected combination of acute croup and myocarditis: Case report

BACKGROUND: Lower vaccination coverage among foreign-born children is of concern because they live in households and communities characterized by more intense exposure to infectious diseases. Because of their higher prevalence rates, there is an increasing occurrence of infectious diseases imported into developed countries. This case report emphasizes the emerging necessity for new clinicians and pathologists of having competence with old infectious disease pathology. CASE PRESENTATION: A three and a half year old girl, who presented with croup history of 5 days and has been in severe respiratory distress, was admitted to the Pediatric Intensive Care Unit in shock and acute respiratory failure. The patient was immediately intubated, and a grayish nonadherent membrane extending through the glottis down into the larynx was apparent during the procedure. Echocardiographic findings, which were consistent with acute myocarditis, confirmed poor left ventricular contractility despite escalating high doses of inotropes. Autopsy showed numerous strains of toxigenic corynobacterium diphtheriae, which also grew on the Loeffler cultures of membranes received during the intubation. CONCLUSION: It is critical that new generations of clinicians and bio-pathologists not only be trained in the subspecialty of infectious disease pathology, but that they also be willing participants in the diagnosis and investigation of infectious diseases

Site-specific substitution (Q172R) in the VP1 protein of FMDV isolates collected from asymptomatic carrier ruminants in Vietnam

The epidemiological significance of asymptomatic persistent foot-and-mouth disease virus (FMDV) infection in carrier animals, specifically its ability to seed new clinical outbreaks, is undetermined, and consistent viral determinants of FMDV persistence have not been identified. We analyzed 114 FMDV O/ME-SA/PanAsia VP1 sequences from naturally infected animals in Vietnam, of which 31 were obtained from persistently infected carrier animals. A site-specific substitution was identified at VP1 residue 172 where arginine was present in all 31 of the carrier-associated viruses, whereas outbreak viruses typically contained glutamine. Additionally, we characterized multiple viruses from a single persistently infected animal that were collected over the course of eight months and at multiple distinct anatomic sites (larynx, dorsal soft palate and dorsal nasopharynx). This work sheds new light on naturally occurring viral mutations within the host and provides a basis for understanding the viral evolution and persistence mechanisms of FMDV

Novel Recombinant Foot-and-Mouth Disease Virus Circulating in Vietnam.

We report the genome sequences of 12 recombinant foot-and-mouth disease virus isolates from Vietnam. The recombinant strain has a capsid region from an A/Sea-97 strain and a nonstructural segment from an O/ME-SA/PanAsia strain. The isolates were obtained from two outbreak samples collected in June 2017 and 10 subclinical samples collected between 2017 and 2019

A traditional evolutionary history of foot-and-mouth disease viruses in Southeast Asia challenged by analyses of non-structural protein coding sequences

© 2018 The Author(s). Recombination of rapidly evolving RNA-viruses provides an important mechanism for diversification, spread, and emergence of new variants with enhanced fitness. Foot-and-mouth disease virus (FMDV) causes an important transboundary disease of livestock that is endemic to most countries in Asia and Africa. Maintenance and spread of FMDV are driven by periods of dominance of specific viral lineages. Current understanding of the molecular epidemiology of FMDV lineages is generally based on the phylogenetic relationship of the capsid-encoding genes, with less attention to the process of recombination and evolution of non-structural proteins. In this study, the putative recombination breakpoints of FMDVs endemic to Southeast Asia were determined using full-open reading frame sequences. Subsequently, the lineages' divergence times of recombination-free genome regions were estimated. These analyses revealed a close relationship between two of the earliest endemic viral lineages that appear unrelated when only considering the phylogeny of their capsid proteins. Contrastingly, one lineage, named O/CATHAY, known for having a particular host predilection (pigs) has evolved independently. Additionally, intra-lineage recombination occurred at different breakpoints compared to the inter-lineage process. These results provide new insights about FMDV recombination patterns and the evolutionary interdependence of FMDV serotypes and lineages

Orally formulated artemisinin in healthy fasting Vietnamese male subjects: a randomized, four-sequence, open-label, pharmacokinetic crossover study.

BACKGROUND: Artemisinin derivatives are used in antimalarial drug combination therapy. Artemisinin and piperaquine have recently been proven to be prospective candidates for combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. OBJECTIVE: The goal of this study was to evaluate the relative bioavailability and to characterize the pharmacokinetic properties of a new micronized powder formulation of artemisinin against the previous standard Vietnamese formulation when administered as a single oral dose or in combination with piperaquine. METHODS: This was a single-center, randomized, 4-sequence, open-label, crossover study conducted in 15 healthy male Vietnamese volunteers under fasting conditions with a washout period of 3 weeks between study visits. A single oral dose of 160 or 500 mg of artemisinin was administered alone or in combination with piperaquine. Potential adverse events were monitored daily by the clinician and by using laboratory test results. Frequent blood samples were drawn for 12 hours after dose. Artemisinin was quantified in plasma using LC-MS/MS. Pharmacokinetic parameters were computed from the plasma concentration-time profiles using a noncompartmental analysis method. RESULTS: Pharmacokinetic parameters T(max), C(max), AUC(0-∞), V(d)/F, CL/F, and t(1/2) (mean [SD]) for the new formulation of artemisinin were 1.83 (0.88) hours, 178 (97) ng/mL, 504 (210) h × ng/mL, 1270 (780) L, 401 (260) L/h, and 2.21 (0.29) hours, respectively. The mean percentage of the test/reference formulation ratio for the logarithmically transformed values of C(max), AUC(0-last,) and AUC(0-∞) were 121% (90% CI, 92.5-158), 122% (90% CI, 101-148), and 120% (90% CI, 98.0-146), respectively. CONCLUSIONS: This single-dose study found that the dose-normalized C(max), AUC(0-last), and AUC(0-∞) mean geometric differences between the test and reference formulations were relatively small (<40%) and will probably not have a clinical impact in the treatment of malaria infections

Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis

Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30 % mortality and 50 % of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen.We performed a prospective observational study of 100 consecutively treated children (≤15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled non-compartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or &gt; 4 years of age.Results: Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with −14 %, −22 % and −16 % for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children.Conclusions: There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.</p

Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study

Background: Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. Methods: A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. Results: The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33%) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6%. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19–10.13, p=0.02), decreased consciousness (HR 22.9, 95CI 3.01-174.3, p<0.001), focal neurological deficits (HR 15.7, 95CI 1.67-2075, p= 0.01), Blantyre Coma Score (HR 3.75, 95CI 0.99-14.2, p<0.001) and CSF protein, lactate and glucose levels. Neck stiffness, MRC grade (children aged >5years) and hydrocephalus were also associated with the combined endpoint of death or disability. Conclusions: Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes

Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis.

BACKGROUND: The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses. RESULTS: A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). CONCLUSIONS: Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration. ISRCTN63659091