[Show abstract][Hide abstract] ABSTRACT: Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance , and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC 1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC 1/2 and risk of recrudes-cence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC 1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28–63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC 1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC 1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC 1/2 by 8.1 % (95 % CI 3.2–12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC 1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC 1/2 (HR = 2.91, 95 % CI 1.95–4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44–3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC 1/2 since 2007. Conclusions: Several factors affect PC 1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC 1/2 data. Studies with frequent parasite count measurements to characterize PC 1/2 should be encouraged. In western Cambodia, where PC 1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.
[Show abstract][Hide abstract] ABSTRACT: Acinetobacter baumannii has become one of the major infection threats in intensive care units (ICUs) globally. Since 2008 A. baumannii has been the leading cause of ventilator associated pneumonia (VAP) in our ICU at an infectious disease hospital in southern Vietnam. The emergence of this pathogen is associated with the persistence of a clone resistant to carbapenems. Antimicrobial combinations may be a strategy to treat infections caused by these multidrug-resistant A. baumannii. We assessed potential antimicrobial combinations against local carbapenem resistant A. baumannii by measuring in vitro interaction of colistin with four locally recommended antimicrobials. We performed antimicrobial susceptibility testing and MLVA genotyping on all 74 A. baumannii isolated from quantitative tracheal aspirates from patients with VAP over an eighteen-month period. These 74 isolates could be subdivided into 21 main clusters by MLVA and >80% were resistant to carbapenems. We selected 56 representative isolates for in vitro combination synergy testing. Synergy was observed in 4 (7%), 7 (13%), 5 (21%) and 38 (68%) isolates with combinations of colistin with ceftazidime, ceftriaxone, imipenem and meropenem, respectively. More carbapenem-resistant A. baumannii isolates (36/43; 84%) exhibited synergistic activity with a combination of colistin and meropenem than carbapenem susceptible isolates A. baumannii isolates (2/13; 15%) (p=0.023; Fisher's exact test). The results suggest that a combination of colistin and meropenem should be considered when treating carbapenem-resistant A. baumannii infections in Vietnam, and we advocate clinical trials investigating combination therapy for VAP.
Journal of Medical Microbiology 07/2015; DOI:10.1099/jmm.0.000137 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Enterovirus A71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD) and is particularly prevalent in parts of Southeast Asia, affecting thousands of children and infants each year. Revealing the evolutionary and epidemiological dynamics of EV-A71 through time and space is central to understanding its outbreak potential. We generated the full genome sequences of 200 EV-A71 strains sampled from various locations in Viet Nam between 2011 and 2013 and used these sequence data to determine the evolutionary history and phylodynamics of EV-A71 in Viet Nam, providing estimates of the effective reproduction number (Re) of the infection through time. In addition, we described the phylogeography of EV-A71 throughout Southeast Asia, documenting patterns of viral gene flow. Accordingly, our analysis reveals that a rapid genogroup switch from C4 to B5 likely took place during 2012 in Viet Nam. We show that the Re of subgenogroup C4 decreased during the time frame of sampling, whereas that of B5 increased and remained >1 at the end of 2013, corresponding to a rise in B5 prevalence. Our study reveals that the subgenogroup B5 virus that emerged into Viet Nam is closely related to variants that were responsible for large epidemics in Malaysia and Taiwan and therefore extends our knowledge regarding its associated area of endemicity. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia.
Journal of Virology 06/2015; 89(17):JVI.00706-15. DOI:10.1128/JVI.00706-15 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Influenza constitutes a leading cause of morbidity and mortality worldwide. There is limited information about the etiology of infection presenting clinically as influenza in hospitalized adults and children in Southeast Asia. Such data are important for future management of respiratory infections.
To describe the etiology of infection presenting clinically as influenza in those hospitalized in Southeast Asia METHODS: Respiratory specimens archived from July 2008 to June 2009 from patients hospitalised with suspected influenza from (Indonesia, Thailand and Vietnam were tested for respiratory viruses and atypical bacteria by polymerase chain reaction.
A total of 1222 patients' samples were tested. 776/1222 (63.5%) patients were under the age of 5. Viruses detected included rhinoviruses in 229/1222 patients (18.7%), bocaviruses in 200/1222 (16.4%), respiratory syncytial viruses in 144 (11.8%), parainfluenzaviruses in 140 (11.5%; PIV1: 32; PIV2: 12; PIV3: 71;PIV4: 25), adenovirus in 102 (8.4%), influenza viruses in 93 (7.6%; influenza A: 77; influenza B: 16), coronaviruses in 23 (1.8%; OC43: 14; E229: 9). Bacterial pathogens were: Mycoplasma pneumoniae (n=33, 2.7%), Chlamydophila psittaci (n=2), C. pneumoniae (n=1), Bordetella pertussis (n=1), and Legionella pneumophila (n=2). Overall in-hospital case fatality rate was 29/1222 (2.4%).
Respiratory viruses were the most commonly detected pathogens in patients hospitalized with a clinical suspicion of influenza. Rhinovirus was the most frequently detected virus, and M. pneumoniae the most common atypical bacterium. The low number of detected influenza viruses demonstrate a low benefit for empirical oseltamivir therapy, unless during an influenza outbreak. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Influenza and Other Respiratory Viruses 05/2015; DOI:10.1111/irv.12326 · 2.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined.
Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course.
On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 10(9)/L) and 328 (50.7%) had a platelet count <50 × 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 10(9)/L versus 50 (34 to 78) × 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study.
Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management.
BMC Medicine 04/2015; 13(1):97. DOI:10.1186/s12916-015-0324-5 · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adjunctive dexamethasone saves lives in the treatment of tuberculous meningitis but this response is influenced by the patient's LTA4H genotype. Despite less certain benefit, adjunctive dexamethasone is also frequently used in the treatment of pyogenic bacterial meningitis, but the influence of LTA4H genotype on outcomes has not been previously investigated. We genotyped the LTA4H promoter region SNP (rs17525495) in 390 bacterial meningitis patients and 751 population controls. rs17525495 was associated with susceptibility to bacteriologically confirmed bacterial meningitis (P = 0.01, OR 1.27 95% confidence interval [CI] 1.05-1.54) but did not influence clinical presentation, disease severity or survival following dexamethasone treatment.
PLoS ONE 03/2015; 10(3):e0118789. DOI:10.1371/journal.pone.0118789 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple transcontinental waves of drug resistance in Plasmodium falciparum have originated in Southeast Asia before spreading westward, first into the rest of Asia and then to sub-Saharan Africa. In vitro studies have suggested that hypermutator P. falciparum parasites may exist in Southeast Asia and that an increased rate of acquisition of new mutations in these parasites may explain the repeated emergence of drug resistance in Southeast Asia. This study is the first to test the hypermutator hypothesis using field isolates. Using genome-wide SNP data from human P. falciparum infections in Southeast Asia and West Africa and a test for relative rate differences we found no evidence of increased relative substitution rates in P. falciparum isolates from Southeast Asia. Instead, we found significantly increased substitution rates in Mali and Bangladesh populations relative to those in populations from Southeast Asia. Additionally we found no association between increased relative substitution rates and parasite clearance following treatment with artemisinin derivatives.
[Show abstract][Hide abstract] ABSTRACT: Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.
[Show abstract][Hide abstract] ABSTRACT: Background: Cryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa. Method: A double-blind placebo-controlled trial with parallel arms in which patients are randomised to receive either dexamethasone or placebo, in addition to local standard of care. The study recruits patients in both Asia and Africa to ensure the relevance of its results to the populations in which the disease burden is highest. The 10-week mortality risk in the control group is expected to be between 30% and 50%, depending on location, and the target hazard ratio of 0.7 corresponds to absolute risk reductions in mortality from 30% to 22%, or from 50% to 38%. Assuming an overall 10-week mortality of at least 30% in our study population, recruitment of 824 patients will be sufficient to observe the expected number of deaths. Allowing for some loss to follow-up, the total sample size for this study is 880 patients. To generate robust evidence across both continents, we aim to recruit roughly similar numbers of patients from each continent. The primary end point is 10-week mortality. Ethical approval has been obtained from Oxford University's Tropical Research Ethics Committee (OxTREC), and as locally mandated at each site. Trial registration: International Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012.
[Show abstract][Hide abstract] ABSTRACT: Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C(1). We conducted a genome-wide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10(-10)), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.
[Show abstract][Hide abstract] ABSTRACT: Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 x 10-4 with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.
[Show abstract][Hide abstract] ABSTRACT: Background:
The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia.
P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently.
The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas.
K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.
The Journal of Infectious Diseases 09/2014; 211(5). DOI:10.1093/infdis/jiu491 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Central nervous system (CNS) infections are important diseases in both children and adults worldwide. The spectrum of infections is broad, encompassing bacterial/aseptic meningitis and encephalitis. Viruses are regarded as the most common causes of encephalitis and aseptic meningitis. Better understanding of the viral causes of the diseases is of public health importance, in order to better inform immunization policy, and may influence clinical management.
Study was conducted at the Hospital for Tropical Diseases in Ho Chi Minh City, a primary, secondary, and tertiary referral hospital for all southern provinces of Vietnam. Between December 1996 and May 2008, patients with CNS infections of presumed viral origin were enrolled. Laboratory diagnostics consisted of molecular and serological tests targeted at 14 meningitis/encephalitis-associated viruses.
Of 291 enrolled patients, fatal outcome and neurological sequelae were recorded in 10% (28/291) and 27% (78/291), respectively. Mortality was especially high (9/19, 47%) amongst those with confirmed herpes simplex encephalitis which is attributed to the limited availability of intravenous acyclovir/valacyclovir. Japanese encephalitis virus, dengue virus, herpes simplex virus, and enteroviruses were the most common viruses detected, responsible for 36 (12%), 19 (6.5%), 19 (6.5%) and 8 (2.7%) respectively, followed by rubella virus (6, 2%), varicella zoster virus (5, 1.7%), mumps virus (2, 0.7%), cytomegalovirus (1, 0.3%), and rabies virus (1, 0.3%).
Viral infections of the CNS in adults in Vietnam are associated with high morbidity and mortality. Despite extensive laboratory testing, 68% of the patients remain undiagnosed. Together with our previous reports, the data confirm that Japanese encephalitis virus, dengue virus, herpes simplex virus, and enteroviruses are the leading identified causes of CNS viral infections in Vietnam, suggest that the majority of morbidity/mortality amongst patients with a confirmed/probable diagnosis is preventable by adequate vaccination/treatment, and are therefore of public health significance.
[Show abstract][Hide abstract] ABSTRACT: Background:
Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.
Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.
The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.
Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
New England Journal of Medicine 07/2014; 371(5):411-23. DOI:10.1056/NEJMoa1314981 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Streptococcus suis, a bacterium that affects pigs, is a neglected pathogen that causes systemic disease in humans. We conducted a systematic review and meta-analysis to summarize global estimates of the epidemiology, clinical characteristics, and outcomes of this zoonosis. We searched main literature databases for all studies through December 2012 using the search term "streptococcus suis." The prevalence of S. suis infection is highest in Asia; the primary risk factors are occupational exposure and eating of contaminated food. The pooled proportions of case-patients with pig-related occupations and history of eating high-risk food were 38.1% and 37.3%, respectively. The main clinical syndrome was meningitis (pooled rate 68.0%), followed by sepsis, arthritis, endocarditis, and endophthalmitis. The pooled case-fatality rate was 12.8%. Sequelae included hearing loss (39.1%) and vestibular dysfunction (22.7%). Our analysis identified gaps in the literature, particularly in assessing risk factors and sequelae of this infection.
[Show abstract][Hide abstract] ABSTRACT: Streptococcus suis, a pig bacterium, is an emerging but neglected zoonotic disease in humans. We conducted a systematic review and meta-analysis to summarize the global estimates on the epidemiology, clinical characteristics and outcomes of this important zoonosis. Main literature databases were searched for all studies by December 2012 using the search term “streptococcus suis”. Two reviewers independently reviewed and extracted the data. S. suis infection burden is mainly in Asia with occupational exposure and eating possibly contaminated dishes as prime risk factors. The pooled proportion of cases with a pig-related occupation and history of eating high-risk dishes was 38.1% and 37.3%, respectively. The main clinical syndrome was meningitis (pooled rate 0.68), followed by sepsis, endocarditis, and arthritis. The pooled death rate was 0.13. Sequelae included hearing loss (0.39) and vestibular dysfunction (0.23). This analysis identified gaps in the current literature, particularly in assessing risk factors and sequelae of this infection.
[Show abstract][Hide abstract] ABSTRACT: The dihydropteroate synthase (dhps) genes of 44 P. malariae strains from four Asian countries were isolated. Only a limited number of polymorphisms were observed. Comparison with homologous mutations in other Plasmodium species showed that these polymorphisms are unlikely to be associated with sulfadoxine resistance.
PLoS ONE 04/2014; 9(4):e93942. DOI:10.1371/journal.pone.0093942 · 3.23 Impact Factor