Emerging Enterovirus A71 Subgenogroup B5 Causing Severe Hand, Foot, and Mouth Disease, Vietnam, 2023.

We report on a 2023 outbreak of severe hand, foot, and mouth disease in southern Vietnam caused by an emerging lineage of enterovirus A71 subgenogroup B5. Affected children were significantly older than those reported during previous outbreaks. The virus should be closely monitored to assess its potential for global dispersal.

Spatiotemporal Evolution of SARS-CoV-2 Alpha and Delta Variants during Large Nationwide Outbreak of COVID-19, Vietnam, 2021.

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions.

Neisseria gonorrhoeae FC428 Subclone, Vietnam, 2019-2020.

Among 114 clinical Neisseria gonorrhoeae isolates collected in Vietnam during 2019-2020, we detected 15 of subclone sequence type 13871 of the FC428 clonal complex. Fourteen sequence type 13871 isolates with mosaic penA allele 60.001 were ceftriaxone or cefixime nonsusceptible, and 3/14 were azithromycin nonsusceptible. Emergence of this subclone threatens treatment effectiveness.

Optimizing antibiotic use in Indonesia: A systematic review and evidence synthesis to inform opportunities for intervention.

Background: A major driver of antimicrobial resistance (AMR) and poor clinical outcomes is suboptimal antibiotic use, although data are lacking in low-resource settings. We reviewed studies on systemic antibiotic use (WHO ATC/DDD category J01) for human health in Indonesia, and synthesized available evidence to identify opportunities for intervention. Methods: We systematically searched five international and national databases for eligible peer-reviewed articles, in English and Indonesian, published between 1 January 2000 and 1 June 2021 including: (1) antibiotic consumption; (2) prescribing appropriateness; (3) antimicrobial stewardship (AMS); (4) consumers' and providers' perceptions. Two independent reviewers included studies and extracted data. Study-level data were summarized using random-effects model meta-analysis for consumption and prescribing appropriateness, effect direction analysis for antimicrobial stewardship (AMS) interventions, and qualitative synthesis for perception surveys. (PROSPERO: CRD42019134641). Findings: Of 9323 search hits, we included 100 reports on antibiotic consumption (20), prescribing appropriateness (49), AMS interventions (13), and/or perception (25) (8 categorized in >1 domain). The pooled estimate of overall antibiotic consumption was 134.8 DDD per 100 bed-days (95%CI 82.5-187.0) for inpatients and 121.1 DDD per 1000 inhabitants per day (10.4-231.8) for outpatients. Ceftriaxone, levofloxacin, and ampicillin were the most consumed antibiotics in inpatients, and amoxicillin, ciprofloxacin, and cefadroxil in outpatients. Pooled estimates for overall appropriate prescribing (according to Gyssens method) were 33.5% (18.1-53.4) in hospitals and 49.4% (23.7-75.4) in primary care. Pooled estimates for appropriate prescribing (according to reference guidelines) were, in hospitals, 99.7% (97.4-100) for indication, 84.9% (38.5-98.0) for drug choice, and 6.1% (0.2-63.2) for overall appropriateness, and, in primary care, 98.9% (60.9-100) for indication, 82.6% (50.5-95.7) for drug choice and 10.5% (0.8-62.6) for overall appropriateness. Studies to date evaluating bundled AMS interventions, although sparse and heterogeneous, suggested favourable effects on antibiotic consumption, prescribing appropriateness, guideline compliance, and patient outcomes. Key themes identified in perception surveys were lack of community antibiotic knowledge, and common non-prescription antibiotic self-medication. Interpretation: Context-specific intervention strategies are urgently needed to improve appropriate antibiotic use in Indonesian hospitals and communities, with critical evidence gaps concerning the private and informal healthcare sectors. Funding: Wellcome Africa Asia Programme Vietnam.

Novel Mutation of SARS-CoV-2, Vietnam, July 2020.

A cluster of severe acute respiratory syndrome coronavirus 2 infections in Danang, Vietnam, began July 25, 2020, and resulted in 551 confirmed cases and 35 deaths as of February 2021. We analyzed 26 sequences from this cluster and identified a novel shared mutation in nonstructural protein 9, suggesting a single introduction into Vietnam.

Superspreading Event of SARS-CoV-2 Infection at a Bar, Ho Chi Minh City, Vietnam.

We report a superspreading event of severe acute respiratory syndrome coronavirus 2 infection initiated at a bar in Vietnam with evidence of symptomatic and asymptomatic transmission, based on ministry of health reports, patient interviews, and whole-genome sequence analysis. Crowds in enclosed indoor settings with poor ventilation may be considered at high risk for transmission.

Molecular strategy for the direct detection and identification of human enteroviruses in clinical specimens associated with hand, foot and mouth disease.

BACKGROUND: Diseases caused by human enteroviruses (EVs) are a major global public health problem. Thus, the effective diagnosis of all human EVs infections and the monitoring of epidemiological and ecological dynamic changes are urgently needed. METHODS: Based on two comprehensive virological surveillance systems of hand, foot and mouth disease (HFMD), real-time PCR and nested RT-PCR (RT-snPCR) methods based on the enteroviral VP1, VP4-VP2 and VP4 regions were designed to directly detect all human EVs serotypes in clinical specimens. RESULTS: The results showed that the proposed serotyping strategy exhibit very high diagnostic efficiency (Study 1: 99.9%; Study 2: 89.5%), and the variance between the study was due to inclusion of the specific Coxsackie virus A6 (CVA6) real-time RT-PCR and VP4 RT-snPCR in Study 1 but not Study 2. Furthermore, only throat swabs were collected and analyzed in Study 2, whereas in Study 1, if a specific EV serotype was not identified in the primary stool sample, other sample types (rectal swab and throat swab) were further tested where available. During the study period from 2013 to 2018, CVA6 became one of the main HFMD causative agents, whereas the level of enterovirus A71 (EV-A71) declined in 2017. CONCLUSION: The findings of this study demonstrate the appropriate application of PCR methods and the combination of biological sample types that are useful for etiological studies and propose a molecular strategy for the direct detection of human EVs in clinical specimens associated with HFMD.

Viral Factors Associated With the High Mortality Related to Human Infections With Clade 2.1 Influenza A/H5N1 Virus in Indonesia.

BACKGROUND: Since their emergence in Indonesia in 2005, 200 human infections with clade 2.1 highly pathogenic avian influenza A/H5N1 virus have been reported, associated with exceptionally high mortality (84%) compared to regions affected by other genetic clades of this virus. To provide potential clues towards understanding this high mortality, detailed clinical virological analyses were performed in specimens from 180 H5N1 patients, representing 90% of all Indonesian patients and 20% of reported H5N1-infected patients globally. METHODS: H5N1 RNA was quantified in available upper- and lower-respiratory tract specimens as well as fecal and blood samples from 180 patients with confirmed infection between 2005 and 2017. Mutations in the neuraminidase and M2 genes that confer resistance to oseltamivir and adamantanes were assessed. Fatal and nonfatal cases were compared. RESULTS: High viral RNA loads in nasal and pharyngeal specimens were associated with fatal outcome. Mortality increased over time during the study period, which correlated with increasing viral RNA loads on admission. Furthermore, the prevalence of amantadine resistance-conferring M2 mutations increased over time, and viral loads were higher in patients infected with viruses that harbored these mutations. Compared to observations from other regions, viral RNA was detected more frequently in feces (80%) and particularly in blood (85%), and antiviral responses to oseltamivir appeared less pronounced. CONCLUSIONS: These observations confirm the association of viral load with outcome of human H5N1 infections and suggest potential differences in virulence and antiviral responses to oseltamivir that may explain the exceptionally high mortality related to clade 2.1 H5N1 infections in Indonesia.

Plans for Nationwide Serosurveillance Network in Vietnam.

In recent years, serosurveillance has gained momentum as a way of determining disease transmission and immunity in populations, particularly with respect to vaccine-preventable diseases. At the end of 2017, the Oxford University Clinical Research Unit and the National Institute of Hygiene and Epidemiology held a meeting in Vietnam with national policy makers, researchers, and international experts to discuss current seroepidemiologic projects in Vietnam and future needs and plans for nationwide serosurveillance. This report summarizes the meeting and the plans that were discussed to set up nationwide serosurveillance in Vietnam.

Enterovirus A71 Phenotypes Causing Hand, Foot and Mouth Disease, Vietnam.

We investigated enterovirus A71-associated hand, foot and mouth disease in Vietnam and found that, after replacing subgenogroup C4 in 2013, B5 remained the leading cause of this disease. In contrast with previous observations, this switch did not result in an explosive outbreak, and B5 evolution was driven by negative selection.

Clinical Manifestations and Molecular Diagnosis of Scrub Typhus and Murine Typhus, Vietnam, 2015-2017.

Rickettsioses are endemic to Vietnam; however, only a limited number of clinical studies have been performed on these vectorborne bacteria. We conducted a prospective hospital-based study at 2 national referral hospitals in Hanoi to describe the clinical characteristics of scrub typhus and murine typhus in northern Vietnam and to assess the diagnostic applicability of quantitative real-time PCR assays to diagnose rickettsial diseases. We enrolled 302 patients with acute undifferentiated fever and clinically suspected rickettsiosis during March 2015-March 2017. We used a standardized case report form to collect clinical information and laboratory results at the time of admission and during treatment. We confirmed scrub typhus in 103 (34.1%) patients and murine typhus in 12 (3.3%) patients. These results highlight the need for increased emphasis on training for healthcare providers for earlier recognition, prevention, and treatment of rickettsial diseases in Vietnam.

Detection and Characterization of Human Pegivirus 2, Vietnam.

We report human pegivirus 2 (HPgV-2) infection in Vietnam. We detected HPgV-2 in some patients with hepatitis C virus/HIV co-infection but not in patients with HIV or hepatitis A, B, or C virus infection, nor in healthy controls. HPgV-2 strains in Vietnam are phylogenetically related to global strains.

Epidemic dynamics, interactions and predictability of enteroviruses associated with hand, foot and mouth disease in Japan.

Outbreaks of hand, foot and mouth disease have been documented in Japan since 1963. This disease is primarily caused by the two closely related serotypes of Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Here, we analyse Japanese virologic and syndromic surveillance time-series data from 1982 to 2015. As in some other countries in the Asia Pacific region, EV-A71 in Japan has a 3 year cyclical component, whereas CV-A16 is predominantly annual. We observe empirical signatures of an inhibitory interaction between the serotypes; virologic lines of evidence suggest they may indeed interact immunologically. We fit the time series to mechanistic epidemiological models: as a first-order effect, we find the data consistent with single-serotype susceptible-infected-recovered dynamics. We then extend the modelling to incorporate an inhibitory interaction between serotypes. Our results suggest the existence of a transient cross-protection and possible asymmetry in its strength such that CV-A16 serves as a stronger forcing on EV-A71. Allowing for asymmetry yields accurate out-of-sample predictions and the directionality of this effect is consistent with the virologic literature. Confirmation of these hypothesized interactions would have important implications for understanding enterovirus epidemiology and informing vaccine development. Our results highlight the general implication that even subtle interactions could have qualitative impacts on epidemic dynamics and predictability.

Outcomes following severe hand foot and mouth disease: A systematic review and meta-analysis.

BACKGROUND: Hand, foot and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) is associated with acute neurological disease in children. This study aimed to estimate the burden of long-term sequelae and death following severe HFMD. METHODS: This systematic review and meta-analysis pooled all reports from English and Chinese databases including MEDLINE and Wangfang on outbreaks of clinically diagnosed HFMD and/or laboratory-confirmed EV-A71 with at least 7 days' follow-up published between 1st January 1966 and 19th October 2015. Two independent reviewers assessed the literature. We used a random effects meta-analysis to estimate cumulative incidence of neurological sequelae or death. Studies were assessed for methodological and reporting quality. PROSPERO registration number: 10.15124/CRD42015021981. FINDINGS: 43 studies were included in the review, and 599 children from 9 studies were included in the primary analysis. Estimated cumulative incidence of death or neurological sequelae at maximum follow up was 19.8% (95% CI:10.2%, 31.3%). Heterogeneity (Iˆ2) was 88.57%, partly accounted for by year of data collection and reporting quality of studies. Incidence by acute disease severity was 0.00% (0.00, 0.00) for grade IIa; 17.0% (7.9, 28.2) for grade IIb/III; 81.6% (65.1, 94.5) for grade IV (p = 0.00) disease. CONCLUSIONS: HFMD with neurological involvement is associated with a substantial burden of long-term neurological sequelae. Grade of acute disease severity was a strong predictor of outcome. Strengths of this study include its bilingual approach and clinical applicability. Future prospective and interventional studies must use rigorous methodology to assess long-term outcomes in survivors. FUNDING: There was no specific funding for this study. See below for researcher funding.

Emerging Coxsackievirus A6 Causing Hand, Foot and Mouth Disease, Vietnam.

Hand, foot and mouth disease (HFMD) is a major public health issue in Asia and has global pandemic potential. Coxsackievirus A6 (CV-A6) was detected in 514/2,230 (23%) of HFMD patients admitted to 3 major hospitals in southern Vietnam during 2011-2015. Of these patients, 93 (18%) had severe HFMD. Phylogenetic analysis of 98 genome sequences revealed they belonged to cluster A and had been circulating in Vietnam for 2 years before emergence. CV-A6 movement among localities within Vietnam occurred frequently, whereas viral movement across international borders appeared rare. Skyline plots identified fluctuations in the relative genetic diversity of CV-A6 corresponding to large CV-A6-associated HFMD outbreaks worldwide. These data show that CV-A6 is an emerging pathogen and emphasize the necessity of active surveillance and understanding the mechanisms that shape the pathogen evolution and emergence, which is essential for development and implementation of intervention strategies.

Workshop on use of intravenous immunoglobulin in hand, foot and mouth disease in Southeast Asia.

The South East Asia Infectious Disease Clinical Research Network convened subject matter experts at a workshop to make consensus recommendations for study design of a clinical trial for use of intravenous immunoglobulin (IVIg) in severe hand, foot and mouth disease (HFMD). HFMD is a highly contagious emerging infection among children in the region, a small proportion of whom develop neurologic and cardiopulmonary complications with high case-fatality rates. The use of IVIg for treatment of severe disease is widespread and a part of local, national, and international guidelines, but no clinical evidence warrants the use of this drug, which is expensive and has potentially serious side effects. During a 2-day workshop in March 2014, a group of HFMD experts reviewed the current evidence related to use of IVIg in HFMD and discussed potential study design, feasibility, inclusion and exclusion criteria, sample size, primary and secondary endpoints, and subsidiary studies for a randomized, placebo-controlled trial.

Subclinical avian influenza A(H5N1) virus infection in human, Vietnam.

Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern Vietnam.

Valacyclovir for herpes simplex encephalitis.

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.