register interest

Professor Peter Horby

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health
Keywords: Public health, influenza, emerging infections, epidemiology, antibiotic resistance, Ebola and outbreak research
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Predicted geographic spread of swine-origin influenza A (H1N1) in Vietnam.  Medians from 1000 model simulations.

Predicted geographic spread of swine-origin influenza A (H1N1) in Vietnam. Medians from 1000 model ...

Training on taking swabs for a household-based influenza transmission study.

Training on taking swabs for a household-based influenza transmission study.

Peter Horby is Professor of Emerging Infectious Diseases and Global Health.  He is the former, and founding, Director of the Oxford University Clinical Research Unit in Hanoi, Vietnam. The unit was established in early 2006 and conducts research on infectious diseases which crosses the disciplines of basic science, medical science and public health.

Peter returned to Oxford in 2014 and established the Epidemic disease Research Group Oxford (ERGO). ERGO is engaged in an international program of clinical and epidemiological research to prepare for and respond to emerging infections that may develop into epidemics or pandemics. ERGO is involved in a number of international projects including the European Commission funded PREPARE project, and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The group is conducting research on a range of epidemic diseases including Ebola virus disease, bird flu (H5N1 and H7N9), MERS-CoV, and Enterovirus 71. ERGO currently comprises a team of eight people under the leadership of Professor Peter Horby and is funded by the Wellcome Trust, the Medical Research Council, and the European Commission.

There are no collaborations listed for this principal investigator.

Nguyen DN, Mai LEQ, Bryant JE, Hang NLEK, Hoa LENM, Nadjm B, Thai PQ, Duong TN, Anh DD, Horby P et al. 2016. Epidemiology and etiology of influenza-like-illness in households in Vietnam; it's not all about the kids! J Clin Virol, 82 pp. 126-132. | Show Abstract | Read more

BACKGROUND: Household studies provide opportunities to understand influenza-like-illness (ILI) transmission, but data from (sub)tropical developing countries are scarce. OBJECTIVE: To determine the viral etiology and epidemiology of ILI in households. STUDY DESIGN: ILI was detected by active case finding amongst a cohort of 263 northern Vietnam households between 2008 and 2013. Health workers collected nose and throat swabs for virus detection by multiplex real-time RT-PCR. RESULTS: ILI was detected at least once in 219 (23.7%) of 945 household members. 271 (62.3%) of 435 nose/throat swabs were positive for at least one of the 15 viruses tested. Six viruses predominated amongst positive swabs: Rhinovirus (28%), Influenza virus (17%), Coronavirus (8%), Enterovirus (5%), Respiratory syncytial virus (3%), Metapneumovirus virus (2.5%) and Parainfluenza virus 3 (1.8%). There was no clear seasonality, but 78% of episodes occurred in Winter/Spring for Influenza compared to 32% for Rhinovirus. Participants, on average, suffered 0.49 ILI, and 0.29 virus-positive ILI episodes, with no significant effects of gender, age, or household size. In contrast to US and Australian community studies, the frequency of ILI decreased as the number of household members aged below 5 years increased (p=0.006). CONCLUSION: The findings indicate the need for tailored ILI control strategies, and for better understanding of how local childcare practices and seasonality may influence transmission and the role of children.

Koh WM, Bogich T, Siegel K, Jin J, Chong EY, Tan CY, Chen MI, Horby P, Cook AR. 2016. The Epidemiology of Hand, Foot and Mouth Disease in Asia: A Systematic Review and Analysis. Pediatr Infect Dis J, 35 (10), pp. e285-e300. | Show Abstract | Read more

CONTEXT: Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). OBJECTIVE: This study reports a systematic review of the epidemiology of HFMD in Asia. DATA SOURCES: PubMed, Web of Science and Google Scholar were searched up to December 2014. STUDY SELECTION: Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. DATA EXTRACTION: Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. RESULTS: HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. LIMITATIONS: Diversity of study designs complicates attempts to identify features of HFMD epidemiology. CONCLUSIONS: Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps.

Lai S, Qin Y, Cowling BJ, Ren X, Wardrop NA, Gilbert M, Tsang TK, Wu P, Feng L, Jiang H et al. 2016. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data. Lancet Infect Dis, 16 (7), pp. e108-e118. | Show Abstract | Read more

Avian influenza A H5N1 viruses have caused many, typically severe, human infections since the first human case was reported in 1997. However, no comprehensive epidemiological analysis of global human cases of H5N1 from 1997 to 2015 exists. Moreover, few studies have examined in detail the changing epidemiology of human H5N1 cases in Egypt, especially given the outbreaks since November, 2014, which have the highest number of cases ever reported worldwide in a similar period. Data on individual patients were collated from different sources using a systematic approach to describe the global epidemiology of 907 human H5N1 cases between May, 1997, and April, 2015. The number of affected countries rose between 2003 and 2008, with expansion from east and southeast Asia, then to west Asia and Africa. Most cases (67·2%) occurred from December to March, and the overall case-fatality risk was 483 (53·5%) of 903 cases which varied across geographical regions. Although the incidence in Egypt has increased dramatically since November, 2014, compared with the cases beforehand, there were no significant differences in the fatality risk, history of exposure to poultry, history of patient contact, and time from onset to hospital admission in the recent cases.

Hoa LENM, Mai LEQ, Bryant JE, Thai PQ, Hang NLEK, Yen NT, Duong TN, Thoang DD, Horby P, Werheim HF, Fox A. 2016. Association between Hemagglutinin Stem-Reactive Antibodies and Influenza A/H1N1 Virus Infection during the 2009 Pandemic. J Virol, 90 (14), pp. 6549-6556. | Show Abstract | Read more

UNLABELLED: The discovery of influenza virus broadly neutralizing (BrN) antibodies prompted efforts to develop universal vaccines. Influenza virus stem-reactive (SR) broadly neutralizing antibodies have been detected by screening antibody phage display libraries. However, studies of SR BrN antibodies in human serum, and their association with natural infection, are limited. To address this, pre- and postpandemic sera from a prospective community cohort study in Vietnam were assessed for antibodies that inhibit SR BrN monoclonal antibody (MAb) (C179) binding to H1N1 pandemic 2009 virus (H1N1pdm09). Of 270 households, 33 with at least one confirmed H1N1pdm09 illness or at least two seroconverters were included. The included households comprised 71 infected and 41 noninfected participants. Sera were tested as 2-fold dilutions between 1:5 and 1:40. Fifty percent C179 inhibition (IC50) titers did not exceed 10, although both IC50 titers and percent C179 inhibition by sera diluted 1:5 or 1:10 correlated with hemagglutination inhibition (HI) and microneutralization (MN) titers (all P < 0.001). Thirteen (12%) participants had detectable prepandemic IC50 titers, but only one reached a titer of 10. This proportion increased to 44% after the pandemic, when 39 participants had a titer of 10, and 67% of infected compared to 44% of noninfected had detectable IC50 titers (P < 0.001). The low levels of SR antibodies in prepandemic sera were not associated with subsequent H1N1pdm09 infection (P = 0.241), and the higher levels induced by H1N1pdm09 infection returned to prepandemic levels within 2 years. The findings indicate that natural infection induces only low titers of SR antibodies that are not sustained. IMPORTANCE: Universal influenza vaccines could have substantial health and economic benefits. The focus of universal vaccine research has been to induce antibodies that prevent infection by diverse influenza virus strains. These so-called broadly neutralizing antibodies are readily detected in mice and ferrets after infection with a series of distinct influenza virus strains. The 2009 H1N1 pandemic provided an opportunity to investigate whether infection with a novel strain induced broadly neutralizing antibodies in humans. We found that broadly neutralizing antibodies were induced, but levels were low and poorly maintained. This could represent an obstacle for universal vaccine development and warrants further investigation.

Hope-Gill B, Idriss B, Massaquoi T, Horby P. 2016. Teaching research methodology within an Ebola virus outbreak. Med Educ, 50 (5), pp. 584-585. | Read more

Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK et al. 2016. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial. PLoS Med, 13 (4), pp. e1001997. | Show Abstract | Read more

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Whitehead J, Olliaro P, Lang T, Horby P. 2016. Trial design for evaluating novel treatments during an outbreak of an infectious disease. Clin Trials, 13 (1), pp. 31-38. | Show Abstract | Read more

Tragically, the outbreak of Ebola that started in West Africa in 2014 has been far more extensive and damaging than any previous outbreaks. The duration of the outbreak has, for the first time, allowed the clinical evaluation of Ebola treatments. This article discusses the designs used for two such clinical trials which have recruited patients in Liberia and Sierra Leone. General principles are outlined for trial designs intended to be deployed quickly, adapt flexibly and provide results soon enough to influence the course of the current epidemic rather than just providing evidence for use should Ebola break out again. Lessons are drawn for the conduct of clinical research in future outbreaks of infectious diseases, where the sequence of events may or may not be similar to the West African Ebola epidemic.

van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, Horby PW, Raoul H, Magassouba N, Antierens A et al. 2016. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med, 374 (1), pp. 33-42. | Show Abstract | Read more

BACKGROUND: In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS: In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS: A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS: The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Le Viet T, Choisy M, Bryant JE, Vu Trong D, Pham Quang T, Horby P, Nguyen Tran H, Tran Thi Kieu H, Nguyen Vu T, Nguyen Van K et al. 2015. A dengue outbreak on a floating village at Cat Ba Island in Vietnam. BMC Public Health, 15 (1), pp. 940. | Show Abstract | Read more

BACKGROUND: A dengue outbreak in an ecotourism destination spot in Vietnam, from September to November 2013, impacted a floating village of fishermen on the coastal island of Cat Ba. The outbreak raises questions about how tourism may impact disease spread in rural areas. METHODS: Epidemiological data were obtained from the Hai Phong Preventive Medical Center (PMC), including case histories and residential location from all notified dengue cases from this outbreak. All household addresses were geo-located. Knox test, a spatio-temporal analysis that enables inference dengue clustering constrained by space and time, was performed on the geocoded locations. From the plasma available from two patients, positive for Dengue serotype 3 virus (DENV3), the Envelope (E) gene was sequenced, and their genetic relationships compared to other E sequences in the region. RESULTS: Of 192 dengue cases, the odds ratio of contracting dengue infections for people living in the floating villages compared to those living on the island was 4.9 (95 % CI: 3.6-6.7). The space-time analyses on 111 geocoded dengue residences found the risk of dengue infection to be the highest within 4 days and a radius of 20 m of a given case. Of the total of ten detected clusters with an excess risk greater than 2, the cluster with the highest number of cases was in the floating village area (24 patients for a total duration of 31 days). Phylogenetic analysis revealed a high homology of the two DENV3 strains (genotype III) from Cat Ba with DENV3 viruses circulating in Hanoi in the same year (99.1 %). CONCLUSIONS: Our study showed that dengue transmission is unlikely to be sustained on Cat Ba Island and that the 2013 epidemic likely originated through introduction of viruses from the mainland, potentially Hanoi. These findings suggest that prevention efforts should be focused on mainland rather than on the island.

Qin Y, Horby PW, Tsang TK, Chen E, Gao L, Ou J, Nguyen TH, Duong TN, Gasimov V, Feng L et al. 2015. Differences in the Epidemiology of Human Cases of Avian Influenza A(H7N9) and A(H5N1) Viruses Infection. Clin Infect Dis, 61 (4), pp. 563-571. | Show Abstract | Read more

BACKGROUND: The pandemic potential of avian influenza viruses A(H5N1) and A(H7N9) remains an unresolved but critically important question. METHODS: We compared the characteristics of sporadic and clustered cases of human H5N1 and H7N9 infection, estimated the relative risk of infection in blood-related contacts, and the reproduction number (R). RESULTS: We assembled and analyzed data on 720 H5N1 cases and 460 H7N9 cases up to 2 November 2014. The severity and average age of sporadic/index cases of H7N9 was greater than secondary cases (71% requiring intensive care unit admission vs 33%, P = .007; median age 59 years vs 31, P < .001). We observed no significant differences in the age and severity between sporadic/index and secondary H5N1 cases. The upper limit of the 95% confidence interval (CI) for R was 0.12 for H5N1 and 0.27 for H7N9. A higher proportion of H5N1 infections occurred in clusters (20%) compared to H7N9 (8%). The relative risk of infection in blood-related contacts of cases compared to unrelated contacts was 8.96 for H5N1 (95% CI, 1.30, 61.86) and 0.80 for H7N9 (95% CI, .32, 1.97). CONCLUSIONS: The results are consistent with an ascertainment bias towards severe and older cases for sporadic H7N9 but not for H5N1. The lack of evidence for ascertainment bias in sporadic H5N1 cases, the more pronounced clustering of cases, and the higher risk of infection in blood-related contacts, support the hypothesis that susceptibility to H5N1 may be limited and familial. This analysis suggests the potential pandemic risk may be greater for H7N9 than H5N1.

Taylor WR, Fox A, Pham KT, Le HN, Tran NT, Tran GV, Nguyen BT, Nguyen MV, Nguyen LT, Yacoub S et al. 2015. Dengue in adults admitted to a referral hospital in Hanoi, Vietnam. Am J Trop Med Hyg, 92 (6), pp. 1141-1149. | Show Abstract | Read more

Knowledge of adult dengue virus (DENV) infection from Hanoi, Vietnam, is limited. In 2008, we prospectively studied 143 (77 male) confirmed (nonstructural 1 antigen enzyme-linked immunosorbent assay [ELISA], DENV polymerase chain reaction, paired serology) adult dengue patients of median age 23.5 (range 16-72) years. They were admitted to the National Hospital for Tropical Diseases, Hanoi, on median illness day (D) 5 (range 1-8). By D8, 141 (98.6%) were afebrile. Platelet counts and hematocrit (median, interquartile range [IQR]) nadired and peaked on D5 and D4, respectively: 40,000/μL (10,000-109,000/μL), 43.4% (34.9-49.7%). Four (2.8%) patients had severe dengue: 1) D10 shock (N = 1) and 2) aspartate aminotransferase (AST) ≥ 1,000 IU/L (N = 3, D5 and D7). Of 143 patients, 118 (82.5%) had ≥ 1 warning sign (World Health Organization [WHO] 2009 criteria): mucosal bleeding 66/143 (46.1%), soft tissue edema 54/143 (37.7%), and ultrasound detected plasma leakage (pleural effusions/ascites) 30/129 (23.25%). 138 (96.5%) patients received intravenous (IV) fluids: 3 L (IQR: 0.5-8.5 L). Most patients had non-severe dengue with warning signs. High rates of edema and plasma leakage may be explained partly by liberal use of IV fluids. Studies are needed on optimizing fluid management in non-severe adult dengue.

Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med, 12 (4), pp. e1001815. | Show Abstract | Read more

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Huong VT, Thanh LV, Phu VD, Trinh DT, Inui K, Tung N, Oanh NT, Trung NV, Hoa NT, Bryant JE et al. 2016. Temporal and spatial association of Streptococcus suis infection in humans and porcine reproductive and respiratory syndrome outbreaks in pigs in northern Vietnam. Epidemiol Infect, 144 (1), pp. 35-44. | Show Abstract | Read more

Porcine reproductive and respiratory syndrome (PRRS) outbreaks in pigs are associated with increased susceptibility of pigs to secondary bacterial infections, including Streptococcus suis - an important zoonotic pathogen causing bacterial meningitis in humans. This case-control study examined the association between human S. suis infection and PRRS outbreaks in pigs in northern Vietnam. We included 90 S. suis case-patients and 183 non-S. suis sepsis controls from a referral hospital in Hanoi in 2010, a period of major PRRS epizootics in Vietnam. PRRS exposure was determined using data from the National Centre of Veterinary Diagnosis. By univariate analysis, significantly more S. suis patients were reported residing in or adjacent to a PRRS district compared to controls [odds ratio (OR) 2·82, 95% confidence interval (CI) 1·35-5·89 and OR 3·15, 95% CI 1·62-6·15, respectively]. Only residency in adjacent districts remained significantly associated with risk of S. suis infection after adjusting for sex, occupation, and eating practices. SaTScan analysis showed a possible cluster of S. suis infection in humans around PRRS confirmed locations during the March-August period. The findings indicate an epidemiological association between PRRS in pigs and S. suis infections in humans. Effective strategies to strengthen control of PRRS in pigs may help reduce transmission of S. suis infection to humans.

Yazdanpanah Y, Horby P, van Griensven J, Mentre F, Nguyen VK, Malvy JM, Dunning J, Sissoko D, Delfraissy JF, Levy Y. 2015. Drug assessment in the Ebola virus disease epidemic in west Africa. Lancet Infect Dis, 15 (11), pp. 1258. | Read more

Horby PW, Endzt H, Muyembe-Tamfum JJ, van Griensven J, Gevao S, Goossens H, Malvy D, Haba NY, Yazdanpanah Y, Olliaro P et al. 2015. Ebola: Europe-Africa research collaborations. Lancet Infect Dis, 15 (11), pp. 1258-1259. | Read more

Hoa LN, Bryant JE, Choisy M, Nguyet LA, Bao NT, Trang NH, Chuc NT, Toan TK, Saito T, Takemae N et al. 2015. Population susceptibility to a variant swine-origin influenza virus A(H3N2) in Vietnam, 2011-2012. Epidemiol Infect, 143 (14), pp. 2959-2964. | Show Abstract | Read more

A reassortant swine-origin A(H3N2) virus (A/swine/BinhDuong/03-9/2010) was detected through swine surveillance programmes in southern Vietnam in 2010. This virus contains haemagglutinin and neuraminidase genes from a human A(H3N2) virus circulating around 2004-2006, and the internal genes from triple-reassortant swine influenza A viruses (IAVs). To assess population susceptibility to this virus we measured haemagglutination inhibiting (HI) titres to A/swine/BinhDuong/03-9/2010 and to seasonal A/Perth/16/2009 for 947 sera collected from urban and rural Vietnamese people during 2011-2012. Seroprevalence (HI ⩾ 40) was high and similar for both viruses, with 62·6% [95% confidence interval (CI) 59·4-65·7] against A/Perth/16/2009 and 54·6% (95% CI 51·4-57·8%) against A/swine/BinhDuong/03-9/2010, and no significant differences between urban and rural participants. Children aged <5 years lacked antibodies to the swine origin H3 virus despite high seroprevalence for A/Perth/16/2009. These results reveal vulnerability to infection to this contemporary swine IAV in children aged <5 years; however, cross-reactive immunity in adults would likely limit epidemic emergence potential.

Thai PQ, Choisy M, Duong TN, Thiem VD, Yen NT, Hien NT, Weiss DJ, Boni MF, Horby P. 2015. Seasonality of absolute humidity explains seasonality of influenza-like illness in Vietnam. Epidemics, 13 pp. 65-73. | Show Abstract | Read more

BACKGROUND: Experimental and ecological studies have shown the role of climatic factors in driving the epidemiology of influenza. In particular, low absolute humidity (AH) has been shown to increase influenza virus transmissibility and has been identified to explain the onset of epidemics in temperate regions. Here, we aim to study the potential climatic drivers of influenza-like illness (ILI) epidemiology in Vietnam, a tropical country characterized by a high diversity of climates. We specifically focus on quantifying and explaining the seasonality of ILI. METHODS: We used 18 years (1993-2010) of monthly ILI notifications aggregated by province (52) and monthly climatic variables (minimum, mean, maximum temperatures, absolute and relative humidities, rainfall and hours of sunshine) from 67 weather stations across Vietnam. Seasonalities were quantified from global wavelet spectra, using the value of the power at the period of 1 year as a measure of the intensity of seasonality. The 7 climatic time series were characterized by 534 summary statistics which were entered into a regression tree to identify factors associated with the seasonality of AH. Results were extrapolated to the global scale using simulated climatic times series from the NCEP/NCAR project. RESULTS: The intensity of ILI seasonality in Vietnam is best explained by the intensity of AH seasonality. We find that ILI seasonality is weak in provinces experiencing weak seasonal fluctuations in AH (annual power <17.6), whereas ILI seasonality is strongest in provinces with pronounced AH seasonality (power >17.6). In Vietnam, AH and ILI are positively correlated. CONCLUSIONS: Our results identify a role for AH in driving the epidemiology of ILI in a tropical setting. However, in contrast to temperate regions, high rather than low AH is associated with increased ILI activity. Fluctuation in AH may be the climate factor that underlies and unifies the seasonality of ILI in both temperate and tropical regions. Alternatively, the mechanism of action of AH on disease transmission may be different in cold-dry versus hot-humid settings.

Heymann DL, Chen L, Takemi K, Fidler DP, Tappero JW, Thomas MJ, Kenyon TA, Frieden TR, Yach D, Nishtar S et al. 2015. Global health security: the wider lessons from the west African Ebola virus disease epidemic. Lancet, 385 (9980), pp. 1884-1901. | Show Abstract | Read more

The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security--its definition, meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.

Ding H, Chen Y, Yu Z, Horby PW, Wang F, Hu J, Yang X, Mao H, Qin S, Chai C et al. 2014. A family cluster of three confirmed cases infected with avian influenza A (H7N9) virus in Zhejiang Province of China. BMC Infect Dis, 14 (1), pp. 698. | Show Abstract | Read more

BACKGROUND: A total of 453 laboratory-confirmed cases infected with avian influenza A (H7N9) virus (including 175 deaths) have been reported till October 2,2014, of which 30.68% (139/453) of the cases were identified from Zhejiang Province. We describe the largest reported cluster of virologically confirmed H7N9 cases, comprised by a fatal Index case and two mild secondary cases. METHODS: A retrospective investigation was conducted in January of 2014. Three confirmed cases, their close contacts, and relevant environments samples were tested by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), viral culture, and sequencing. Serum samples were tested by haemagglutination inhibition (HI) assay. RESULTS: The Index case, a 49-year-old farmer with type II diabetes, who lived with his daughter (Case 2, aged 24) and wife (Case 3, aged 43) and his son-in-law (H7N9 negative). The Index case and Case 3 worked daily in a live bird market. Onset of illness in Index case occurred in January 13, 2014 and subsequently, he died of multi-organ failure on January 20. Case 2 presented with mild symptoms on January 20 following frequent unprotected bed-side care of the Index case between January 14 to 19, and exposed to live bird market on January 17. Case 3 became unwell on January 23 after providing bedside care to the Index case on January 17 to 18, and following the contact with Case 2 during January 21 to 22 at the funeral of the Index case. The two secondary cases were discharged on February 2 and 5 separately after early treatment with antiviral medication. Four virus strains were isolated and genome analyses showed 99.6 ~100% genetic homology, with two amino mutations (V192I in NS and V280A in NP). 42% (11/26) of environmental samples collected in January were H7N9 positive. Twenty-five close contacts remained well and were negative for H7N9 infection by RT-PCR and HI assay. CONCLUSIONS: In the present study, the Index case was infected from a live bird market while the two secondary cases were infected by the Index case during unprotected exposure. This family cluster is, therefore, compatible with non-sustained person-to-person transmission of avian influenza A/H7N9.

Nguyen DN, Nguyen TV, Dao TT, Nguyen LT, Horby P, Nguyen KV, Wertheim HF. 2014. One year experience using mycobacterial blood cultures to diagnose tuberculosis in patients with prolonged fever in Vietnam. J Infect Dev Ctries, 8 (12), pp. 1620-1624. | Show Abstract | Read more

INTRODUCTION: To evaluate the use of mycobacterial blood cultures (MBC) in diagnosing tuberculosis (TB) in patients with prolonged fever admitted to a Vietnamese referral hospital. RESULTS: MBCs from 94 patients (66% male; median age 33 years; 75% HIV positive) were evaluated: 14 were mycobacterium positive (all HIV positive), and MBC was the only positive specimen in 9 cases (41%). Three positive cases were identified as Mycobacterium avium and the remaining M. tuberculosis (one case could not be identified). CONCLUSION: MBC can be a valuable additional method to diagnose TB, particularly in immunosuppressed HIV patients when sputum cannot be collected.

Fonville JM, Wilks SH, James SL, Fox A, Ventresca M, Aban M, Xue L, Jones TC, Le NM, Pham QT et al. 2014. Antibody landscapes after influenza virus infection or vaccination. Science, 346 (6212), pp. 996-1000. | Show Abstract | Read more

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.

Huong VT, Hoa NT, Horby P, Bryant JE, Van Kinh N, Toan TK, Wertheim HF. 2014. Raw pig blood consumption and potential risk for Streptococcus suis infection, Vietnam. Emerg Infect Dis, 20 (11), pp. 1895-1898. | Show Abstract | Read more

We assessed consumption of raw pig blood, which is a risk factor for Streptococcus suis infection in Vietnam, by using a mix-method design. Factors associated with consumption included rural residency, age, sex, occupation, income, and marital status. We identified risk groups and practices and perceptions that should be targeted by communication programs.

Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy JF, Heymann D, Horby P, Kaleebu P, Tamfum JJ et al. 2014. Randomised controlled trials for Ebola: practical and ethical issues. Lancet, 384 (9952), pp. 1423-1424. | Read more

Fox A, Mai LEQ, Thanh LET, Wolbers M, Le Khanh Hang N, Thai PQ, Thi Thu Yen N, Minh Hoa LEN, Bryant JE, Duong TN et al. 2015. Hemagglutination inhibiting antibodies and protection against seasonal and pandemic influenza infection. J Infect, 70 (2), pp. 187-196. | Show Abstract | Read more

OBJECTIVES: Hemagglutination inhibiting (HI) antibodies correlate with influenza vaccine protection but their association with protection induced by natural infection has received less attention and was studied here. METHODS: 940 people from 270 unvaccinated households participated in active ILI surveillance spanning 3 influenza seasons. At least 494 provided paired blood samples spanning each season. Influenza infection was confirmed by RT-PCR on nose/throat swabs or serum HI assay conversion. RESULTS: Pre-season homologous HI titer was associated with a significantly reduced risk of infection for H3N2 (OR 0.61, 95%CI 0.44-0.84) and B (0.65, 95%CI 0.54-0.80) strains, but not H1N1 strains, whether re-circulated (OR 0.90, 95%CI 0.71-1.15), new seasonal (OR 0.86, 95%CI 0.54-1.36) or pandemic H1N1-2009 (OR 0.77, 95%CI 0.40-1.49). The risk of seasonal and pandemic H1N1 decreased with increasing age (both p < 0.0001), and the risk of pandemic H1N1 decreased with prior seasonal H1N1 (OR 0.23, 95%CI 0.08-0.62) without inducing measurable A/California/04/2009-like titers. CONCLUSIONS: While H1N1 immunity was apparent with increasing age and prior infection, the effect of pre-season HI titer was at best small, and weak for H1N1 compared to H3N2 and B. Antibodies targeting non-HI epitopes may have been more important mediators of infection-neutralizing immunity for H1N1 compared to other subtypes in this setting.

Pigott DM, Golding N, Mylne A, Huang Z, Henry AJ, Weiss DJ, Brady OJ, Kraemer MU, Smith DL, Moyes CL et al. 2014. Mapping the zoonotic niche of Ebola virus disease in Africa. Elife, 3 pp. e04395. | Show Abstract | Read more

Ebola virus disease (EVD) is a complex zoonosis that is highly virulent in humans. The largest recorded outbreak of EVD is ongoing in West Africa, outside of its previously reported and predicted niche. We assembled location data on all recorded zoonotic transmission to humans and Ebola virus infection in bats and primates (1976-2014). Using species distribution models, these occurrence data were paired with environmental covariates to predict a zoonotic transmission niche covering 22 countries across Central and West Africa. Vegetation, elevation, temperature, evapotranspiration, and suspected reservoir bat distributions define this relationship. At-risk areas are inhabited by 22 million people; however, the rarity of human outbreaks emphasises the very low probability of transmission to humans. Increasing population sizes and international connectivity by air since the first detection of EVD in 1976 suggest that the dynamics of human-to-human secondary transmission in contemporary outbreaks will be very different to those of the past.

Van Nguyen K, Zhang T, Thi Vu BN, Dao TT, Tran TK, Thi Nguyen DN, Thi Tran HK, Thi Nguyen CK, Fox A, Horby P, Wertheim H. 2014. Staphylococcus aureus nasopharyngeal carriage in rural and urban northern Vietnam. Trans R Soc Trop Med Hyg, 108 (12), pp. 783-790. | Show Abstract | Read more

BACKGROUND: Staphylococcus aureus is a common human pathogen that can colonise the respiratory tract and cause infection. Here we investigate the risk factors associated with nasopharyngeal carriage of S. aureus (including methicillin-resistant S. aureus [MRSA]) in Vietnam. METHODS: Between February and June 2012, nasal and pharyngeal swabs for S. aureus culture, and demographic and socioeconomic data were taken from 1016 participants in urban and rural northern Vietnam, who were randomly selected from pre-specified age strata. RESULTS: Overall S. aureus prevalence was 303/1016 (29.8%; adjusted for age: 33.8%). Carriage in the main cohort was found to be associated with younger age (≤5 years [OR 3.13, CI 1.62-6.03]; 6-12 [OR 6.87, CI 3.95-11.94]; 13-19 [OR 6.47, CI 3.56-11.74]; 20-29 [OR 4.73, CI 2.40-9.31]; 30-59 [OR 1.74, CI 1.04-2.92); with ≥60 as reference), living in an urban area (OR 1.36, CI 1.01-1.83) and antibiotics use (OR 0.69, CI 0.49-0.96). MRSA was detected in 80/1016 (7.9%). Being aged ≤5 years (OR 4.84, CI 1.47-15.97); 6-12 (OR 10.21, CI 3.54-29.50); 20-29 (OR 4.01, CI 1.09-14.77) and wealth (>3/5 wealth index, OR 1.63 CI 1.01-2.62) were significant risk factors for MRSA carriage. CONCLUSIONS: Nasopharyngeal carriage of S. aureus is present in one-third of the Vietnamese population, and is more prevalent among children. Pharyngeal carriage is more common than nasal carriage. Risk factors for S. aureus (including MRSA) carriage are identified in the community.

Balasingam S, Horby P, Wilder-Smith A. 2014. The potential for a controlled human infection platform in Singapore. Singapore Med J, 55 (9), pp. 456-461. | Show Abstract | Read more

For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies.

Zhang W, Wan J, Qian K, Liu X, Xiao Z, Sun J, Zeng Z, Wang Q, Zhang J, Jiang G et al. 2014. Clinical characteristics of human infection with a novel avian-origin influenza A(H10N8) virus. Chin Med J (Engl), 127 (18), pp. 3238-3242. | Show Abstract | Read more

BACKGROUND: Novel influenza A viruses of avian-origin may be the precursors of pandemic strains. This descriptive study aims to introduce a novel avian-origin influenza A (H10N8) virus which can infect humans and cause severe diseases. METHODS: Collecting clinical data of three cases of human infection with a novel reassortment avian influenza A (H10N8) virus in Nanchang, Jiangxi Province, China. RESULTS: Three cases of human infection with a new reassortment avian influenza A(H10N8) virus were described, of which two were fatal cases, and one was severe case. These cases presented with severe pneumonia that progressed to acute respiratory distress syndrome (ARDS) and intractable respiratory failure. CONCLUSION: This novel reassortment avian influenza A (H10N8) virus in China resulted in fatal human infections, and should be added to concerns in clinical practice.

Cauchemez S, Ferguson NM, Fox A, Mai LEQ, Thanh LET, Thai PQ, Thoang DD, Duong TN, Minh Hoa LEN, Tran Hien N, Horby P. 2014. Determinants of influenza transmission in South East Asia: insights from a household cohort study in Vietnam. PLoS Pathog, 10 (8), pp. e1004310. | Show Abstract | Read more

To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza in the community or in the household. Here, we analyse a large household cohort study conducted in 2007-2010 in Vietnam using innovative statistical methods to ascertain in an integrative framework the relative contribution of variables that influence the transmission of seasonal (H1N1, H3N2, B) and pandemic H1N1pdm09 influenza. Influenza infection was diagnosed by haemagglutination-inhibition (HI) antibody assay of paired serum samples. We used a Bayesian data augmentation Markov chain Monte Carlo strategy based on digraphs to reconstruct unobserved chains of transmission in households and estimate transmission parameters. The probability of transmission from an infected individual to another household member was 8% (95% CI, 6%, 10%) on average, and varied with pre-season titers, age and household size. Within households of size 3, the probability of transmission from an infected member to a child with low pre-season HI antibody titers was 27% (95% CI 21%-35%). High pre-season HI titers were protective against infection, with a reduction in the hazard of infection of 59% (95% CI, 44%-71%) and 87% (95% CI, 70%-96%) for intermediate (1∶20-1∶40) and high (≥1∶80) HI titers, respectively. Even after correcting for pre-season HI titers, adults had half the infection risk of children. Twenty six percent (95% CI: 21%, 30%) of infections may be attributed to household transmission. Our results highlight the importance of integrated analysis by influenza sub-type, age and pre-season HI titers in order to infer influenza transmission risks in and outside of the household.

Thanh TH, Ngoc SD, Viet NN, Van HN, Horby P, Cobelens FG, Wertheim HF. 2014. A household survey on screening practices of household contacts of smear positive tuberculosis patients in Vietnam. BMC Public Health, 14 (1), pp. 713. | Show Abstract | Read more

BACKGROUND: Close contacts of tuberculosis (TB) patients are at increased risk of developing tuberculosis. Although passive contact screening guidelines are incorporated in the national TB control program, currently it is unknown how frequent close contacts are screened for TB in Vietnam. This study assesses current contact screening practices in Vietnam and determines the proportion of household contacts screened of newly registered TB patients. METHOD: Survey of household contacts of smear-positive TB patients (index patients) registered for treatment in 2008 in three Vietnamese cities. Households were interviewed in 2010 about screening for TB since treatment registration date of the index patient. RESULTS: We interviewed 4,118 household contacts of 1,091 identified index cases. Contact screening mainly relied on self-referral by household contacts. Of the 4,118 household contacts, 474 (11.5%) self-referred for TB screening, while this screening proportion was only 5.5% among contacts under 5 years old (16/293). Sputum examinations were performed in 374 (78.9%) of the screened contacts. Contact screening identified 27 cases of pulmonary TB (0.7%; or 656 cases/100,000 contacts), of which 20 were detected by sputum smear. CONCLUSIONS: The low proportion of household TB contacts screened for TB illustrates the limitations of passive contact screening as currently practiced in Vietnam. Children under 5 years of age are particularly neglected with this approach. Active contact screening with fixed follow-up times of close contacts of newly diagnosed TB patients should be considered in Vietnam, particularly in case of young children and drug-resistant TB.

Huong VT, Ha N, Huy NT, Horby P, Nghia HD, Thiem VD, Zhu X, Hoa NT, Hien TT, Zamora J et al. 2014. Epidemiology, clinical manifestations, and outcomes of Streptococcus suis infection in humans. Emerg Infect Dis, 20 (7), pp. 1105-1114. | Show Abstract | Read more

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.

Horby PW. 2014. Community studies of influenza: new knowledge, new questions. Lancet Respir Med, 2 (6), pp. 430-431. | Read more

Horby P. 2014. Systematic review and meta-analysis: For some groups traditionally considered to be 'high risk', the evidence of an increased risk of severe influenza-associated illness is poor quality Evidence-Based Medicine, 19 (3), pp. 110. | Read more

Thai PQ, Mai LEQ, Welkers MR, Hang NLEK, Thanh LET, Dung VT, Yen NT, Duong TN, Hoa LENM, Thoang DD et al. 2014. Pandemic H1N1 virus transmission and shedding dynamics in index case households of a prospective Vietnamese cohort. J Infect, 68 (6), pp. 581-590. | Show Abstract | Read more

OBJECTIVES: Influenza household transmission studies are required to guide prevention strategies but most passively recruit index cases that seek healthcare. We investigated A(H1N1)pdm09 transmission in a household-based cohort during 2009. METHODS: Health-workers visited 270 households weekly, and collected swabs from influenza-like-illness cases. If A(H1N1)pdm09 was RT-PCR-confirmed, all household members had symptoms assessed and swabs collected daily for 10-15 days. Viral RNA was quantified and sequenced and serology performed on pre-pandemic sera. RESULTS: Index cases were detected in 20 households containing 81 people. 98.5% lacked A(H1N1)pdm09 neutralizing antibodies in pre-pandemic sera. Eleven (18.6%, 95% CI 10.7-30.4%) of 59 contacts were infected. Virus genetic diversity within households was negligible and less than between households. Index and secondary cases were distributed between mothers, daughters and sons, and had similar virus-RNA shedding and symptom dynamics. Fathers were rarely infected. Five secondary cases (45%) had no apparent symptoms and three shed virus before symptoms. Secondary infection was associated with index case wet cough (OR 1.56, 95% CI 1.22-1.99). CONCLUSIONS: In this cohort of A(H1N1)pdm09 susceptible persons, virus sequencing was capable of discriminating household from community transmission. Household transmission involved mothers and children but rarely fathers. Asymptomatic or pre-symptomatic shedding was common.

Peto L, Nadjm B, Horby P, Ngan TT, van Doorn R, Van Kinh N, Wertheim HF. 2014. The bacterial aetiology of adult community-acquired pneumonia in Asia: a systematic review. Trans R Soc Trop Med Hyg, 108 (6), pp. 326-337. | Show Abstract | Read more

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of adult mortality in Asia. Appropriate empirical treatment depends on knowledge of the pathogens commonly responsible. However, assessing the aetiological significance of identified organisms is often difficult, particularly with sputum isolates that might represent contamination with oropharyngeal flora. METHODS: A systematic review of all adult CAP aetiology studies from Asia, excluding the Middle East, published in English between 1 January 1990 and 1 March 2012 was conducted. Forty-eight studies reporting on 10 423 patients were included, representing data from China, India, Indonesia, Japan, Malaysia, The Philippines, Singapore, South Korea, Taiwan, Thailand and Vietnam. Data from large parts of Asia were unavailable and there was substantial heterogeneity in methodology. RESULTS: As in western studies, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella spp. and Haemophilus influenzae were all significant pathogens. However, compared with western studies, S. pneumoniae was of less relative importance. Gram-negative bacilli and Mycobacterium tuberculosis were more important, and in northeast Thailand Burkholderia pseudomallei was a major pathogen. CONCLUSION: These data have major implications for diagnostic strategies and empirical treatment. Narrow-spectrum antibiotics targeting S. pneumoniae may be inappropriate in many Asian settings, and agents active against TB may lead to partial response and delayed TB diagnosis.

Fox A, Whitehead S, Anders KL, Hoa LENM, Mai LEQ, Thai PQ, Yen NT, Duong TN, Thoang DD, Farrar J et al. 2014. Investigation of dengue and Japanese encephalitis virus transmission in Hanam, Viet Nam. Am J Trop Med Hyg, 90 (5), pp. 892-896. | Show Abstract | Read more

This study investigated whether a large dengue epidemic that struck Hanoi in 2009 also affected a nearby semirural area. Seroconversion (dengue virus-reactive immunoglobulin G enzyme-linked immunosorbent assay) was high during 2009 compared with 2008, but neutralization assays showed that it was caused by both dengue virus and Japanese encephalitis virus infections. The findings highlight the importance of continued Japanese encephalitis virus vaccination and dengue surveillance.

Nga DOTT, Chuc NT, Hoa NP, Hoa NQ, Nguyen NT, Loan HT, Toan TK, Phuc HD, Horby P, Van Yen N et al. 2014. Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study. BMC Pharmacol Toxicol, 15 (1), pp. 6. | Show Abstract | Read more

BACKGROUND: The irrational overuse of antibiotics should be minimized as it drives the development of antibiotic resistance, but changing these practices is challenging. A better understanding is needed of practices and economic incentives for antibiotic dispensing in order to design effective interventions to reduce inappropriate antibiotic use. Here we report on both quantitative and qualitative aspects of antibiotic sales in private pharmacies in northern Vietnam. METHOD: A cross-sectional study was conducted in which all drug sales were observed and recorded for three consecutive days at thirty private pharmacies, 15 urban and 15 rural, in the Hanoi region in 2010. The proportion of antibiotics to total drug sales was assessed and the revenue was calculated for rural and urban settings. Pharmacists and drug sellers were interviewed by a semi-structured questionnaire and in-depth interviews to understand the incentive structure of antibiotic dispensing. RESULTS: In total 2953 drug sale transactions (2083 urban and 870 rural) were observed. Antibiotics contributed 24% and 18% to the total revenue of pharmacies in urban and rural, respectively. Most antibiotics were sold without a prescription: 88% in urban and 91% in rural pharmacies. The most frequent reported reason for buying antibiotics was cough in the urban setting (32%) and fever in the rural area (22%). Consumers commonly requested antibiotics without having a prescription: 50% in urban and 28% in rural area. The qualitative data revealed that drug sellers and customer's knowledge of antibiotics and antibiotic resistance were low, particularly in rural area. CONCLUSION: Over the counter sales of antibiotic without a prescription remains a major problem in Vietnam. Suggested areas of improvement are enforcement of regulations and pricing policies and educational programs to increase the knowledge of drug sellers as well as to increase community awareness to reduce demand-side pressure for drug sellers to dispense antibiotics inappropriately.

Wang C, Yu H, Horby PW, Cao B, Wu P, Yang S, Gao H, Li H, Tsang TK, Liao Q et al. 2014. Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1. Clin Infect Dis, 58 (8), pp. 1095-1103. | Show Abstract | Read more

BACKGROUND: Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections. METHODS: We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population. RESULTS: The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24-17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154). CONCLUSIONS: The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity.

de Jong MD, Reusken C, Horby P, Koopmans M, Bonten M, Chiche J, Giaquinto C, Welte T, Leus F, Schotsman J, Goossens H. 2014. Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August-September 2014 Euro surveillance : bulletin Européen sur les maladies transmissibles = European communicable disease bulletin, 19 (48), pp. 20980. | Show Abstract

In response to the Ebola virus disease (EVD) outbreak in West Africa, the World Health Organization has advised all nations to prepare for the detection, investigation and management of confirmed and suspected EVD cases in order to prevent further spread through international travel. To gain insights into the state of preparedness of European hospitals, an electronic survey was circulated in August–September 2014 to 984 medical professionals representing 736 hospitals in 40 countries. The survey addressed the willingness and capacity to admit patients with suspected EVD as well as specific preparedness activities in response to the current Ebola crisis. Evaluable responses were received from representatives of 254 (32%) hospitals in 38 countries, mostly tertiary care centres, of which 46% indicated that they would admit patients with suspected EVD. Patient transfer agreements were in place for the majority of hospitals that would not admit patients. Compared with non-admitting hospitals, admitting hospitals were more frequently engaged in various preparedness activities and more often contained basic infrastructural characteristics such as admission rooms and laboratories considered important for infection control, but some gaps and concerns were also identified. The results of this survey help to provide direction towards further preparedness activities and prioritisation thereof.

de Jong MD, Reusken C, Horby P, Koopmans M, Bonten M, Chiche J, Giaquinto C, Welte T, Leus F, Schotsman J et al. 2014. Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August-September 2014. Euro Surveill, 19 (48), pp. 20980. | Show Abstract

In response to the Ebola virus disease (EVD) outbreak in West Africa, the World Health Organization has advised all nations to prepare for the detection, investigation and management of confirmed and suspected EVD cases in order to prevent further spread through international travel. To gain insights into the state of preparedness of European hospitals, an electronic survey was circulated in August–September 2014 to 984 medical professionals representing 736 hospitals in 40 countries. The survey addressed the willingness and capacity to admit patients with suspected EVD as well as specific preparedness activities in response to the current Ebola crisis. Evaluable responses were received from representatives of 254 (32%) hospitals in 38 countries, mostly tertiary care centres, of which 46% indicated that they would admit patients with suspected EVD. Patient transfer agreements were in place for the majority of hospitals that would not admit patients. Compared with non-admitting hospitals, admitting hospitals were more frequently engaged in various preparedness activities and more often contained basic infrastructural characteristics such as admission rooms and laboratories considered important for infection control, but some gaps and concerns were also identified. The results of this survey help to provide direction towards further preparedness activities and prioritisation thereof.

Dao TT, Liebenthal D, Tran TK, Ngoc Thi Vu B, Ngoc Thi Nguyen D, Thi Tran HK, Thi Nguyen CK, Thi Vu HL, Fox A, Horby P et al. 2014. Klebsiella pneumoniae oropharyngeal carriage in rural and urban Vietnam and the effect of alcohol consumption. PLoS One, 9 (3), pp. e91999. | Show Abstract | Read more

INTRODUCTION: Community acquired K. pneumoniae pneumonia is still common in Asia and is reportedly associated with alcohol use. Oropharyngeal carriage of K. pneumoniae could potentially play a role in the pathogenesis of K. pneumoniae pneumonia. However, little is known regarding K. pneumoniae oropharyngeal carriage rates and risk factors. This population-based cross-sectional study explores the association of a variety of demographic and socioeconomic factors, as well as alcohol consumption with oropharyngeal carriage of K. pneumoniae in Vietnam. METHODS AND FINDINGS: 1029 subjects were selected randomly from age, sex, and urban and rural strata. An additional 613 adult men from a rural environment were recruited and analyzed separately to determine the effects of alcohol consumption. Demographic, socioeconomic, and oropharyngeal carriage data was acquired for each subject. The overall carriage rate of K. pneumoniae was 14.1% (145/1029, 95% CI 12.0%-16.2%). By stepwise logistic regression, K. pneumoniae carriage was found to be independently associated with age (OR 1.03, 95% CI 1.02-1.04), smoking (OR 1.9, 95% CI 1.3-2.9), rural living location (OR 1.6, 95% CI 1.1-2.4), and level of weekly alcohol consumption (OR 1.7, 95% CI 1.04-2.8). CONCLUSION: Moderate to heavy weekly alcohol consumption, old age, smoking, and living in a rural location are all found to be associated with an increased risk of K. pneumoniae carriage in Vietnamese communities. Whether K. pneumoniae carriage is a risk factor for pneumonia needs to be elucidated.

Horby PW. 2014. Community studies of influenza: new knowledge, new questions The Lancet Respiratory Medicine, 2 (6), pp. 430-431. | Read more

Dunning JW, Merson L, Rohde GG, Gao Z, Semple MG, Tran D, Gordon A, Olliaro PL, Khoo SH, Bruzzone R et al. 2014. Open source clinical science for emerging infections. Lancet Infect Dis, 14 (1), pp. 8-9. | Read more

Horby P. 2014. For some groups traditionally considered to be 'high risk', the evidence of an increased risk of severe influenza-associated illness is poor quality. Evid Based Med, 19 (3), pp. 110. | Read more

Nguyen KV, Thi Do NT, Chandna A, Nguyen TV, Pham CV, Doan PM, Nguyen AQ, Thi Nguyen CK, Larsson M, Escalante S et al. 2013. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. BMC Public Health, 13 (1), pp. 1158. | Show Abstract | Read more

BACKGROUND: Antimicrobial resistance is a major contemporary public health threat. Strategies to contain antimicrobial resistance have been comprehensively set forth, however in developing countries where the need for effective antimicrobials is greatest implementation has proved problematic. A better understanding of patterns and determinants of antibiotic use and resistance in emerging economies may permit more appropriately targeted interventions.Viet Nam, with a large population, high burden of infectious disease and relatively unrestricted access to medication, is an excellent case study of the difficulties faced by emerging economies in controlling antimicrobial resistance. METHODS: Our working group conducted a situation analysis of the current patterns and determinants of antibiotic use and resistance in Viet Nam. International publications and local reports published between 1-1-1990 and 31-8-2012 were reviewed. All stakeholders analyzed the findings at a policy workshop and feasible recommendations were suggested to improve antibiotic use in Viet Nam.Here we report the results of our situation analysis focusing on: the healthcare system, drug regulation and supply; antibiotic resistance and infection control; and agricultural antibiotic use. RESULTS: Market reforms have improved healthcare access in Viet Nam and contributed to better health outcomes. However, increased accessibility has been accompanied by injudicious antibiotic use in hospitals and the community, with predictable escalation in bacterial resistance. Prescribing practices are poor and self-medication is common - often being the most affordable way to access healthcare. Many policies exist to regulate antibiotic use but enforcement is insufficient or lacking.Pneumococcal penicillin-resistance rates are the highest in Asia and carbapenem-resistant bacteria (notably NDM-1) have recently emerged. Hospital acquired infections, predominantly with multi-drug resistant Gram-negative organisms, place additional strain on limited resources. Widespread agricultural antibiotic use further propagates antimicrobial resistance. CONCLUSIONS: Future legislation regarding antibiotic access must alter incentives for purchasers and providers and ensure effective enforcement. The Ministry of Health recently initiated a national action plan and approved a multicenter health improvement project to strengthen national capacity for antimicrobial stewardship in Viet Nam. This analysis provided important input to these initiatives. Our methodologies and findings may be of use to others across the world tackling the growing threat of antibiotic resistance.

Le MQ, Lam HM, Cuong VD, Lam TT, Halpin RA, Wentworth DE, Hien NT, Thanh LET, Phuong HV, Horby P, Boni MF. 2013. Migration and persistence of human influenza A viruses, Vietnam, 2001-2008. Emerg Infect Dis, 19 (11), pp. 1756-1765. | Show Abstract | Read more

Understanding global influenza migration and persistence is crucial for vaccine strain selection. Using 240 new human influenza A virus whole genomes collected in Vietnam during 2001-2008, we looked for persistence patterns and migratory connections between Vietnam and other countries. We found that viruses in Vietnam migrate to and from China, Hong Kong, Taiwan, Cambodia, Japan, South Korea, and the United States. We attempted to reduce geographic bias by generating phylogenies subsampled at the year and country levels. However, migration events in these phylogenies were still driven by the presence or absence of sequence data, indicating that an epidemiologic study design that controls for prevalence is required for robust migration analysis. With whole-genome data, most migration events are not detectable from the phylogeny of the hemagglutinin segment alone, although general migratory relationships between Vietnam and other countries are visible in the hemagglutinin phylogeny. It is possible that virus lineages in Vietnam persisted for >1 year.

Le MQ, Horby P, Fox A, Nguyen HT, Le Nguyen HK, Hoang PM, Nguyen KC, de Jong MD, Jeeninga RE, Rogier van Doorn H et al. 2013. Subclinical avian influenza A(H5N1) virus infection in human, Vietnam. Emerg Infect Dis, 19 (10), pp. 1674-1677. | Show Abstract | Read more

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.

Van Kerkhove MD, Hirve S, Koukounari A, Mounts AW, H1N1pdm serology working group. 2013. Estimating age-specific cumulative incidence for the 2009 influenza pandemic: a meta-analysis of A(H1N1)pdm09 serological studies from 19 countries. Influenza Other Respir Viruses, 7 (5), pp. 872-886. | Show Abstract | Read more

BACKGROUND: The global impact of the 2009 influenza A(H1N1) pandemic (H1N1pdm) is not well understood. OBJECTIVES: We estimate overall and age-specific prevalence of cross-reactive antibodies to H1N1pdm virus and rates of H1N1pdm infection during the first year of the pandemic using data from published and unpublished H1N1pdm seroepidemiological studies. METHODS: Primary aggregate H1N1pdm serologic data from each study were stratified in standardized age groups and evaluated based on when sera were collected in relation to national or subnational peak H1N1pdm activity. Seropositivity was assessed using well-described and standardized hemagglutination inhibition (HI titers ≥ 32 or ≥ 40) and microneutralization (MN ≥ 40) laboratory assays. The prevalence of cross-reactive antibodies to the H1N1pdm virus was estimated for studies using sera collected prior to the start of the pandemic (between 2004 and April 2009); H1N1pdm cumulative incidence was estimated for studies in which collected both pre- and post-pandemic sera; and H1N1pdm seropositivity was calculated from studies with post-pandemic sera only (collected between December 2009-June 2010). RESULTS: Data from 27 published/unpublished studies from 19 countries/administrative regions - Australia, Canada, China, Finland, France, Germany, Hong Kong SAR, India, Iran, Italy, Japan, Netherlands, New Zealand, Norway, Reunion Island, Singapore, United Kingdom, United States, and Vietnam - were eligible for inclusion. The overall age-standardized pre-pandemic prevalence of cross-reactive antibodies was 5% (95%CI 3-7%) and varied significantly by age with the highest rates among persons ≥ 65 years old (14% 95%CI 8-24%). Overall age-standardized H1N1pdm cumulative incidence was 24% (95%CI 20-27%) and varied significantly by age with the highest in children 5-19 (47% 95%CI 39-55%) and 0-4 years old (36% 95%CI 30-43%). CONCLUSIONS: Our results offer unique insight into the global impact of the H1N1 pandemic and highlight the need for standardization of seroepidemiological studies and for their inclusion in pre-pandemic preparedness plans. Our results taken together with recent global pandemic respiratory-associated mortality estimates suggest that the case fatality ratio of the pandemic virus was approximately 0.02%.

South East Asia Infectious Disease Clinical Research Network. 2013. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ, 346 (may30 2), pp. f3039. | Show Abstract | Read more

OBJECTIVE: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. DESIGN: Double blind randomised trial. SETTING: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. PARTICIPANTS: Patients aged ≥ 1 year admitted to hospital with confirmed severe influenza. INTERVENTIONS: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). MAIN OUTCOME MEASURE: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. RESULTS: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found. CONCLUSIONS: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. REGISTRATION: Clinical Trials NCT00298233.

Alexander N, Fox A, Lien VTK, Dong T, Lee LY-H, Hang NLK, Mai LQ, Horby P. 2013. Defining ELISpot cut-offs from unreplicated test and control wells JOURNAL OF IMMUNOLOGICAL METHODS, 392 (1-2), pp. 57-62. | Show Abstract | Read more

In the absence of replication of wells, empirical criteria for enzyme-linked immunospot (ELISpot) positivity use fixed differences or ratios between spot forming units (SFU) counts between test and control. We propose an alternative approach which first identifies the optimally variance-stabilizing transformation of the SFU counts, based on the Bland-Altman plot of the test and control wells. The second step is to derive a positivity threshold from the difference in between-plate distribution functions of the transformed test and control SFU counts. This method is illustrated using 1309 assay results from a cohort study of influenza in Vietnam in which some, but not all, of the peptide pools have clear tendencies for SFU counts to be higher in test than control wells. © 2013 Elsevier B.V.

Horby PW, Pfeiffer D, Oshitani H. 2013. Prospects for emerging infections in East and southeast Asia 10 years after severe acute respiratory syndrome. Emerg Infect Dis, 19 (6), pp. 853-860. | Show Abstract | Read more

It is 10 years since severe acute respiratory syndrome (SARS) emerged, and East and Southeast Asia retain a reputation as a hot spot of emerging infectious diseases. The region is certainly a hot spot of socioeconomic and environmental change, and although some changes (e.g., urbanization and agricultural intensification) may reduce the probability of emerging infectious diseases, the effect of any individual emergence event may be increased by the greater concentration and connectivity of livestock, persons, and products. The region is now better able to detect and respond to emerging infectious diseases than it was a decade ago, but the tools and methods to produce sufficiently refined assessments of the risks of disease emergence are still lacking. Given the continued scale and pace of change in East and Southeast Asia, it is vital that capabilities for predicting, identifying, and controlling biologic threats do not stagnate as the memory of SARS fades.

Liverani M, Waage J, Barnett T, Pfeiffer DU, Rushton J, Rudge JW, Loevinsohn ME, Scoones I, Smith RD, Cooper BS et al. 2013. Understanding and managing zoonotic risk in the new livestock industries. Environ Health Perspect, 121 (8), pp. 873-877. | Show Abstract | Read more

BACKGROUND: In many parts of the world, livestock production is undergoing a process of rapid intensification. The health implications of this development are uncertain. Intensification creates cheaper products, allowing more people to access animal-based foods. However, some practices associated with intensification may contribute to zoonotic disease emergence and spread: for example, the sustained use of antibiotics, concentration of animals in confined units, and long distances and frequent movement of livestock. OBJECTIVES: Here we present the diverse range of ecological, biological, and socioeconomic factors likely to enhance or reduce zoonotic risk, and identify ways in which a comprehensive risk analysis may be conducted by using an interdisciplinary approach. We also offer a conceptual framework to guide systematic research on this problem. DISCUSSION: We recommend that interdisciplinary work on zoonotic risk should take into account the complexity of risk environments, rather than limiting studies to simple linear causal relations between risk drivers and disease emergence and/or spread. In addition, interdisciplinary integration is needed at different levels of analysis, from the study of risk environments to the identification of policy options for risk management. CONCLUSION: Given rapid changes in livestock production systems and their potential health implications at the local and global level, the problem we analyze here is of great importance for environmental health and development. Although we offer a systematic interdisciplinary approach to understand and address these implications, we recognize that further research is needed to clarify methodological and practical questions arising from the integration of the natural and social sciences.

Horby P. 2013. H7N9 is a virus worth worrying about. Nature, 496 (7446), pp. 399. | Read more

Tran ST, Renschler JP, Le HT, Dang HT, Dao TM, Pham AN, Nguyen LT, Van Nguyen H, Thi Thu Nguyen T, Ngoc Le S et al. 2013. Correction: Diagnostic Accuracy of Microscopic Observation Drug Susceptibility (MODS) Assay for Pediatric Tuberculosis in Hanoi, Vietnam. PLoS One, 8 (9), | Show Abstract | Read more

[This corrects the article on p. e72100 in vol. 8.].

Murhekar M, Arima Y, Horby P, Vandemaele KA, Vong S, Zijian F, Lee CK, Li A, World Health Organization Regional Office for the Western Pacific Event Management Team. 2013. Avian influenza A(H7N9) and the closure of live bird markets. Western Pac Surveill Response J, 4 (2), pp. 4-7. | Read more

Tran ST, Renschler JP, Le HT, Dang HT, Dao TM, Pham AN, Nguyen LT, Van Nguyen H, Thi Thu Nguyen T, Ngoc Le S et al. 2013. Diagnostic accuracy of microscopic Observation Drug Susceptibility (MODS) assay for pediatric tuberculosis in Hanoi, Vietnam. PLoS One, 8 (9), pp. e72100. | Show Abstract | Read more

INTRODUCTION: Microscopic [corrected] Observation Drug Susceptibility (MODS) has been shown to be an effective and rapid technique for early diagnosis of tuberculosis (TB). Thus far only a limited number of studies evaluating MODS have been performed in children and in extra-pulmonary tuberculosis. This study aims to assess relative accuracy and time to positive culture of MODS for TB diagnosis in children admitted to a general pediatric hospital in Vietnam. METHODS/PRINCIPAL FINDINGS: Specimens from children with suspected TB were tested by smear, MODS and Lowenstein-Jensen agar (LJ). 1129 samples from 705 children were analyzed, including sputum (n=59), gastric aspirate (n=775), CSF (n=148), pleural fluid (n=33), BAL (n=41), tracheal fluid (n=45), other (n=28). 113 TB cases were defined based on the "clinical diagnosis" (confirmed and probable groups) as the reference standard, in which 26% (n=30) were diagnosed as extra-pulmonary TB. Analysis by patient shows that the overall sensitivity and specificity of smear, LJ and MODS against "clinical diagnosis" was 8.8% and 100%, 38.9% and 100%, 46% and 99.5% respectively with MODS significantly more sensitive than LJ culture (P=0.02). When analyzed by sample type, the sensitivity of MODS was significantly higher than LJ for gastric aspirates (P=0.004). The time to detection was also significantly shorter for MODS than LJ (7 days versus 32 days, P<0.001). CONCLUSION: MODS [corrected] is a sensitive and rapid culture technique for detecting TB in children. As MODS culture can be performed at a BSL2 facility and is inexpensive, it can therefore be recommended as a routine test for children with symptoms suggestive of TB in resource-limited settings.

Horby P, Nguyen NY, Dunstan SJ, Baillie JK. 2013. An updated systematic review of the role of host genetics in susceptibility to influenza. Influenza Other Respir Viruses, 7 Suppl 2 (SUPPL.2), pp. 37-41. | Show Abstract | Read more

The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted in June 2011 to summarise the evidence on the role of host genetics in susceptibility to influenza, and this report updates that previously published review. Animal studies suggest that genetic control of susceptibility to severe influenza in mice is complex and not controlled by a single locus, but there is encouraging evidence that some of the host genetic determinants of susceptibility to severe disease may be common across influenza subtypes. Although a number of studies on genetic susceptibility to influenza in humans have been published recently, all are underpowered and unreplicated, so do not provide robust statistical evidence of an association between the identified genetic loci and susceptibility. One study does however present convincing functional evidence for an important role for IFITM3 in susceptibility to severe influenza in mice, and some evidence that this may also be important in human A/H1N1/pdm2009 infection.

Fox A, Hung TM, Wertheim H, Hoa LENM, Vincent A, Lang B, Waters P, Ha NH, Trung NV, Farrar J et al. 2013. Acute measles encephalitis in partially vaccinated adults. PLoS One, 8 (8), pp. e71671. | Show Abstract | Read more

BACKGROUND: The pathogenesis of acute measles encephalitis (AME) is poorly understood. Treatment with immune-modulators is based on theories that post-infectious autoimmune responses cause demyelination. The clinical course and immunological parameters of AME were examined during an outbreak in Vietnam. METHODS AND FINDINGS: Fifteen measles IgM-positive patients with confusion or Glasgow Coma Scale (GCS) score below 13, and thirteen with uncomplicated measles were enrolled from 2008-2010. Standardized clinical exams were performed and blood collected for lymphocyte and measles- and auto-antibody analysis. The median age of AME patients was 21 years, similar to controls. Eleven reported receiving measles vaccination when aged one year. Confusion developed a median of 4 days after rash. Six patients had GCS <8 and four required mechanical ventilation. CSF showed pleocytosis (64%) and proteinorrhachia (71%) but measles virus RNA was not detected. MRI revealed bilateral lesions in the cerebellum and brain stem in some patients. Most received dexamethasone +/- IVIG within 4 days of admission but symptoms persisted for ≥3 weeks in five. The concentration of voltage gated calcium channel-complex-reactive antibodies was 900 pM in one patient, and declined to 609 pM ∼ 3 months later. Measles-reactive IgG antibody avidity was high in AME patients born after vaccine coverage exceeded 50% (∼ 25 years earlier). AME patients had low CD4 (218/µl, p = 0.029) and CD8 (200/µl, p = 0.012) T-cell counts compared to controls. CONCLUSION: Young adults presenting with AME in Vietnam reported a history of one prior measles immunization, and those aged <25 years had high measles-reactive IgG avidity indicative of prior vaccination. This suggests that one-dose measles immunization is not sufficient to prevent AME in young adults and reinforces the importance of maintaining high coverage with a two-dose measles immunization schedule. Treatment with corticosteroids and IVIG is common practice, and should be assessed in randomized clinical trials.

Dieu Ngan TT, Thomas S, Larsson M, Horby P, Diep NN, Dat VQ, Trung NV, Ha NH, Rogier van Doorn H, Van Kinh N, Wertheim HFL. 2013. First report of human psittacosis in Vietnam Journal of Infection, 66 (5), pp. 461-464. | Read more

Cauchemez S, Horby P, Fox A, Mai LEQ, Thanh LET, Thai PQ, Hoa LENM, Hien NT, Ferguson NM. 2012. Influenza infection rates, measurement errors and the interpretation of paired serology. PLoS Pathog, 8 (12), pp. e1003061. | Show Abstract | Read more

Serological studies are the gold standard method to estimate influenza infection attack rates (ARs) in human populations. In a common protocol, blood samples are collected before and after the epidemic in a cohort of individuals; and a rise in haemagglutination-inhibition (HI) antibody titers during the epidemic is considered as a marker of infection. Because of inherent measurement errors, a 2-fold rise is usually considered as insufficient evidence for infection and seroconversion is therefore typically defined as a 4-fold rise or more. Here, we revisit this widely accepted 70-year old criterion. We develop a Markov chain Monte Carlo data augmentation model to quantify measurement errors and reconstruct the distribution of latent true serological status in a Vietnamese 3-year serological cohort, in which replicate measurements were available. We estimate that the 1-sided probability of a 2-fold error is 9.3% (95% Credible Interval, CI: 3.3%, 17.6%) when antibody titer is below 10 but is 20.2% (95% CI: 15.9%, 24.0%) otherwise. After correction for measurement errors, we find that the proportion of individuals with 2-fold rises in antibody titers was too large to be explained by measurement errors alone. Estimates of ARs vary greatly depending on whether those individuals are included in the definition of the infected population. A simulation study shows that our method is unbiased. The 4-fold rise case definition is relevant when aiming at a specific diagnostic for individual cases, but the justification is less obvious when the objective is to estimate ARs. In particular, it may lead to large underestimates of ARs. Determining which biological phenomenon contributes most to 2-fold rises in antibody titers is essential to assess bias with the traditional case definition and offer improved estimates of influenza ARs.

Hai LET, Bich VT, Ngai LEK, Diep NT, Phuc PH, Hung VP, Taylor WR, Horby P, Liem NT, Wertheim HF. 2012. Fatal respiratory infections associated with rhinovirus outbreak, Vietnam. Emerg Infect Dis, 18 (11), pp. 1886-1888. | Show Abstract | Read more

During an outbreak of severe acute respiratory infections in 2 orphanages, Vietnam, 7/12 hospitalized children died. All hospitalized children and 26/43 children from outbreak orphanages tested positive for rhinovirus versus 9/40 control children (p = 0.0005). Outbreak rhinoviruses formed a distinct genetic cluster. Human rhinovirus is an underappreciated cause of severe pneumonia in vulnerable groups.

Tran TK, Eriksson B, Nguyen CT, Horby P, Bondjers G, Petzold M. 2012. DodaLab: an urban health and demographic surveillance site, the first three years in Hanoi, Vietnam. Scand J Public Health, 40 (8), pp. 765-772. | Show Abstract | Read more

RATIONALE: Health and demographic surveillance sites (HDSSs) are important sources for health planning and policy in many low and middle income countries. Almost all HDSSs are in rural settings. The article aims to present the experiences and some concrete results for the first three years of operation of an urban HDSS in Hanoi, Vietnam, and discuss advantages and disadvantages of conducting health studies in HDSSs. DESIGN, POPULATION AND SAMPLE SIZE: The DodaLab urban HDSS was established in 2007 in three communes at different economic levels in Dong Da district, Hanoi, Vietnam. Demographic, social and economic information about 10,000 households and their 37,000 persons was obtained through household interviews. Quarterly follow-up was initiated to provide information about vital events, birth, death and migration. A new household survey was undertaken in 2009. The existing rural HDSS FilaBavi, started in 1999, with 12,000 households and 52,000 persons, was used as the blueprint. CONCLUSIONS: It was possible to establish and run an urban HDSS with experiences from the rural site. The urban and rural contexts are different and demographically, economically and socially complex, but the use of HDSSs can facilitate research beyond very simplified models for comparisons. General statements about external validity of results from the HDSS cannot be made. This issue has to be considered specifically in every situation as an integral part of the research so that the results can be made useful outside the researched HDSS and in performing relevant comparisons.

Wertheim HF, Ngoc DM, Wolbers M, Binh TT, Hải NT, Loan NQ, Tú PT, Sjodin A, Romanoff L, Li Z et al. 2012. Studying the effectiveness of activated carbon R95 respirators in reducing the inhalation of combustion by-products in Hanoi, Vietnam: a demonstration study. Environ Health, 11 (1), pp. 72. | Show Abstract | Read more

BACKGROUND: Urban air pollution is an increasing health problem, particularly in Asia, where the combustion of fossil fuels has increased rapidly as a result of industrialization and socio-economic development. The adverse health impacts of urban air pollution are well established, but less is known about effective intervention strategies. In this demonstration study we set out to establish methods to assess whether wearing an R95 activated carbon respirator could reduce intake of polycyclic aromatic hydrocarbons (PAH) in street workers in Hanoi, Vietnam. METHODS: In this demonstration study we performed a cross-over study in which non-smoking participants that worked at least 4 hours per day on the street in Hanoi were randomly allocated to specific respirator wearing sequences for a duration of 2 weeks. Urines were collected after each period, i.e., twice per week, at the end of the working day to measure hydroxy PAHs (OH-PAH) using gas chromatography/high resolution mass spectrometry. The primary endpoint was the urinary concentration of 1-hydroxypyrene (1-OHP). RESULTS: Forty-four participants (54.5% male, median age 40 years) were enrolled with the majority being motorbike taxi drivers (38.6%) or street vendors (34.1%). The baseline creatinine corrected urinary level for 1-OHP was much higher than other international comparisons: 1020 ng/g creatinine (IQR: 604-1551). Wearing a R95 mask had no significant effect on 1-OHP levels: estimated multiplicative effect 1.0 (95% CI: 0.92-1.09) or other OH-PAHs, except 1-hydroxynaphthalene (1-OHN): 0.86 (95% CI: 0.11-0.96). CONCLUSIONS: High levels of urine OH-PAHs were found in Hanoi street workers. No effect was seen on urine OH-PAH levels by wearing R95 particulate respirators in an area of high urban air pollution, except for 1-OHN. A lack of effect may be de to gaseous phase PAHs that were not filtered efficiently by the respirator. The high levels of urinary OH-PAHs found, urges for effective interventions. TRIAL REGISTRATION: ISRCTN74390617 (date of assignation: 04/08/2009).

Gething PW, Elyazar IR, Moyes CL, Smith DL, Battle KE, Guerra CA, Patil AP, Tatem AJ, Howes RE, Myers MF et al. 2012. A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis, 6 (9), pp. e1814. | Show Abstract | Read more

BACKGROUND: Current understanding of the spatial epidemiology and geographical distribution of Plasmodium vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination. Here we present the first systematic effort to map the global endemicity of this hitherto neglected parasite. METHODOLOGY AND FINDINGS: We first updated to the year 2010 our earlier estimate of the geographical limits of P. vivax transmission. Within areas of stable transmission, an assembly of 9,970 geopositioned P. vivax parasite rate (PvPR) surveys collected from 1985 to 2010 were used with a spatiotemporal Bayesian model-based geostatistical approach to estimate endemicity age-standardised to the 1-99 year age range (PvPR(1-99)) within every 5×5 km resolution grid square. The model incorporated data on Duffy negative phenotype frequency to suppress endemicity predictions, particularly in Africa. Endemicity was predicted within a relatively narrow range throughout the endemic world, with the point estimate rarely exceeding 7% PvPR(1-99). The Americas contributed 22% of the global area at risk of P. vivax transmission, but high endemic areas were generally sparsely populated and the region contributed only 6% of the 2.5 billion people at risk (PAR) globally. In Africa, Duffy negativity meant stable transmission was constrained to Madagascar and parts of the Horn, contributing 3.5% of global PAR. Central Asia was home to 82% of global PAR with important high endemic areas coinciding with dense populations particularly in India and Myanmar. South East Asia contained areas of the highest endemicity in Indonesia and Papua New Guinea and contributed 9% of global PAR. CONCLUSIONS AND SIGNIFICANCE: This detailed depiction of spatially varying endemicity is intended to contribute to a much-needed paradigm shift towards geographically stratified and evidence-based planning for P. vivax control and elimination.

Larsson M, Nguyen LH, Wertheim HF, Dao TT, Taylor W, Horby P, Nguyen TV, Nguyen MH, Le T, Nguyen KV. 2012. Clinical characteristics and outcome of Penicillium marneffei infection among HIV-infected patients in northern Vietnam. AIDS Res Ther, 9 (1), pp. 24. | Show Abstract | Read more

OBJECTIVE: This study reports the clinical characteristics and outcome of HIV-associated Penicilliummarneffei infection in northern Vietnam. METHODS: We conducted a retrospective chart review of all patients with laboratory confirmed Penicilliummarneffei infection admitted to the National Hospital for Tropical Diseases in Hanoi, Vietnam, between July 2006 and September 2009. RESULTS: 127 patients with P. marneffei infection were identified. All were HIV-infected; median CD4+ T-cell count was 24 cells/μl (IQR:12-48); 76% were men. Common clinical features were fever (92.9%), skin lesions (82.6%), hepatomegaly (61.4%), lymphadenopathy (40.2%), weight loss (59.1%) and cough (49.6%). Concurrent opportunistic infections were present in 22.0%; half of those had tuberculosis. Initial treatment regimens were: itraconazole or ketoconazole capsule (77.2%), amphotericin B (20.5%), and fluconazole (1.6%). In-hospital mortality was 12.6% and showed no significant difference in patients treated with itraconazole (or ketoconazole) and amphotericin B (p = 0.43). Dyspnea, ascites, and increased LDH level were independent predictors of mortality. No seasonality was observed. CONCLUSION: The clinical features, treatments and outcomes of HIV-associated P. marneffei infection in northern Vietnam are similar to those reported in other endemic regions. Dyspnea was an important predictor of mortality. More patients were treated with itraconazole than amphotericin B and no significant difference in treatment outcome was observed. It would be of clinical value to compare the efficacy of oral itraconazole and amphotericin B in a clinical trial.

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Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P et al. 2012. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: A modelling study The Lancet Infectious Diseases, 12 (9), pp. 687-695. | Show Abstract | Read more

Background: 18 500 laboratory-confirmed deaths caused by the 2009 pandemic influenza A H1N1 were reported worldwide for the period April, 2009, to August, 2010. This number is likely to be only a fraction of the true number of the deaths associated with 2009 pandemic influenza A H1N1. We aimed to estimate the global number of deaths during the first 12 months of virus circulation in each country. Methods: We calculated crude respiratory mortality rates associated with the 2009 pandemic influenza A H1N1 strain by age (0-17 years, 18-64 years, and >64 years) using the cumulative (12 months) virus-associated symptomatic attack rates from 12 countries and symptomatic case fatality ratios (sCFR) from five high-income countries. To adjust crude mortality rates for differences between countries in risk of death from influenza, we developed a respiratory mortality multiplier equal to the ratio of the median lower respiratory tract infection mortality rate in each WHO region mortality stratum to the median in countries with very low mortality. We calculated cardiovascular disease mortality rates associated with 2009 pandemic influenza A H1N1 infection with the ratio of excess deaths from cardiovascular and respiratory diseases during the pandemic in five countries and multiplied these values by the crude respiratory disease mortality rate associated with the virus. Respiratory and cardiovascular mortality rates associated with 2009 pandemic influenza A H1N1 were multiplied by age to calculate the number of associated deaths. Findings: We estimate that globally there were 201 200 respiratory deaths (range 105 700-395 600) with an additional 83 300 cardiovascular deaths (46 000-179 900) associated with 2009 pandemic influenza A H1N1. 80% of the respiratory and cardiovascular deaths were in people younger than 65 years and 51% occurred in southeast Asia and Africa. Interpretation: Our estimate of respiratory and cardiovascular mortality associated with the 2009 pandemic influenza A H1N1 was 15 times higher than reported laboratory-confirmed deaths. Although no estimates of sCFRs were available from Africa and southeast Asia, a disproportionate number of estimated pandemic deaths might have occurred in these regions. Therefore, efforts to prevent influenza need to effectively target these regions in future pandemics. Funding: None. © 2012 Elsevier Ltd.

Taylor WR, Nguyen K, Nguyen D, Nguyen H, Horby P, Nguyen HL, Lien T, Tran G, Tran N, Nguyen HM et al. 2012. The spectrum of central nervous system infections in an adult referral hospital in Hanoi, Vietnam. PLoS One, 7 (8), pp. e42099. | Show Abstract | Read more

OBJECTIVES: To determine prospectively the causative pathogens of central nervous system (CNS) infections in patients admitted to a tertiary referral hospital in Hanoi, Vietnam. METHODS: From May 2007 to December 2008, cerebrospinal fluid (CSF) samples from 352 adults with suspected meningitis or encephalitis underwent routine testing, staining (Gram, Ziehl-Nielsen, India ink), bacterial culture and polymerase chain reaction targeting Neisseria meningitidis, Streptococcus pneumoniae, S. suis, Haemophilus influenzae type b, Herpes simplex virus (HSV), Varicella Zoster virus (VZV), enterovirus, and 16S ribosomal RNA. Blood cultures and clinically indicated radiology were also performed. Patients were classified as having confirmed or suspected bacterial (BM), tuberculous (TBM), cryptococcal (CRM), eosinophilic (EOM) meningitis, aseptic encephalitis/meningitis (AEM), neurocysticercosis and others. RESULTS: 352 (male: 66%) patients were recruited: median age 34 years (range 13-85). 95/352 (27.3%) diagnoses were laboratory confirmed and one by cranial radiology: BM (n = 62), TBM (n = 9), AEM (n = 19), CRM (n = 5), and neurocysticercosis (n = 1, cranial radiology). S. suis predominated as the cause of BM [48/62 (77.4%)]; Listeria monocytogenese (n = 1), S. pasteurianus (n = 1) and N. meningitidis (n = 2) were infrequent. AEM viruses were: HSV (n = 12), VZV (n = 5) and enterovirus (n = 2). 5 patients had EOM. Of 262/352 (74.4%) patients with full clinical data, 209 (79.8%) were hospital referrals and 186 (71%) had been on antimicrobials. 21 (8%) patients died: TBM (15.2%), AEM (10%), and BM (2.8%). CONCLUSIONS: Most infections lacked microbiological confirmation. S. suis was the most common cause of BM in this setting. Improved diagnostics are needed for meningoencephalitic syndromes to inform treatment and prevention strategies.

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Horby P, Mai LQ, Fox A, Thai PQ, Thi Thu Yen N, Thanh LT, Le Khanh Hang N, Duong TN, Thoang DD, Farrar J et al. 2012. The epidemiology of interpandemic and pandemic influenza in Vietnam, 2007-2010 American Journal of Epidemiology, 175 (10), pp. 1062-1074. | Show Abstract | Read more

Prospective community-based studies have provided fundamental insights into the epidemiology of influenza in temperate regions, but few comparable studies have been undertaken in the tropics. The authors conducted prospective influenza surveillance and intermittent seroprevalence surveys in a household-based cohort in Vietnam between December 2007 and April 2010, resulting in 1,793 person-seasons of influenza surveillance. Age-and sex-standardized estimates of the risk of acquiring any influenza infection per season in persons 5 years of age or older were 21.1% (95% confidence interval: 17.4, 24.7) in season 1, 26.4% (95% confidence interval: 22.6, 30.2) in season 2, and 17.0% (95% confidence interval: 13.6, 20.4) in season 3. Some individuals experienced multiple episodes of infection with different influenza types/subtypes in the same season (n = 27) or reinfection with the same subtype in different seasons (n = 22). The highest risk of influenza infection was in persons 5-9 years old, in whom the risk of influenza infection per season was 41.8%. Although the highest infection risk was in school-aged children, there were important heterogeneities in the age of infection by subtype and season. These heterogeneities could influence the impact of school closure and childhood vaccination on influenza transmission in tropical areas, such as Vietnam. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Horby P, Nguyen NY, Dunstan SJ, Baillie JK. 2012. The role of host genetics in susceptibility to influenza: a systematic review. PLoS One, 7 (3), pp. e33180. | Show Abstract | Read more

BACKGROUND: The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380). METHODS AND FINDINGS: PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven. CONCLUSION: The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.

Fox A, Le NM, Horby P, van Doorn HR, Nguyen VT, Nguyen HH, Nguyen TC, Vu DP, Nguyen MH, Diep NT et al. 2012. Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses. PLoS One, 7 (2), pp. e31535. | Show Abstract | Read more

BACKGROUND: It is unclear why the severity of influenza varies in healthy adults or why the burden of severe influenza shifts to young adults when pandemic strains emerge. One possibility is that cross-protective T cell responses wane in this age group in the absence of recent infection. We therefore compared the acute cellular immune response in previously healthy adults with severe versus mild pandemic H1N1 infection. METHODS AND PRINCIPAL FINDINGS: 49 previously healthy adults admitted to the National Hospital of Tropical Diseases, Viet Nam with RT-PCR-confirmed 2009 H1N1 infection were prospectively enrolled. 39 recovered quickly whereas 10 developed severe symptoms requiring supplemental oxygen and prolonged hospitalization. Peripheral blood lymphocyte subset counts and activation (HLADR, CD38) and differentiation (CD27, CD28) marker expression were determined on days 0, 2, 5, 10, 14 and 28 by flow cytometry. NK, CD4 and CD8 lymphopenia developed in 100%, 90% and 60% of severe cases versus 13% (p<0.001), 28%, (p = 0.001) and 18% (p = 0.014) of mild cases. CD4 and NK counts normalized following recovery. B cell counts were not significantly associated with severity. CD8 activation peaked 6-8 days after mild influenza onset, when 13% (6-22%) were HLADR+CD38+, and was accompanied by a significant loss of resting/CD27+CD28+ cells without accumulation of CD27+CD28- or CD27-CD28- cells. In severe influenza CD8 activation peaked more than 9 days post-onset, and/or was excessive (30-90% HLADR+CD38+) in association with accumulation of CD27+CD28- cells and maintenance of CD8 counts. CONCLUSION: Severe influenza is associated with transient T and NK cell deficiency. CD8 phenotype changes during mild influenza are consistent with a rapidly resolving memory response whereas in severe influenza activation is either delayed or excessive, and partially differentiated cells accumulate within blood indicating that recruitment of effector cells to the lung could be impaired.

Powell TJ, Fox A, Peng Y, Quynh Mai LET, Lien VT, Hang NL, Wang L, Lee LY, Simmons CP, McMichael AJ et al. 2012. Identification of H5N1-specific T-cell responses in a high-risk cohort in vietnam indicates the existence of potential asymptomatic infections. J Infect Dis, 205 (1), pp. 20-27. | Show Abstract | Read more

BACKGROUND: Most reported human H5N1 viral infections have been severe and were detected after hospital admission. A case ascertainment bias may therefore exist, with mild cases or asymptomatic infections going undetected. We sought evidence of mild or asymptomatic H5N1 infection by examining H5N1-specific T-cell and antibody responses in a high-risk cohort in Vietnam. METHODS: Peripheral blood mononuclear cells were tested using interferon-γ enzyme-linked immunospot T assays measuring the response to peptides of influenza H5, H3, and H1 hemagglutinin (HA), N1 and N2 neuraminidase, and the internal proteins of H3N2. Horse erythrocyte hemagglutination inhibition assay was performed to detect antibodies against H5N1. RESULTS: Twenty-four of 747 individuals demonstrated H5-specific T-cell responses but little or no cross-reactivity with H3 or H1 HA peptides. H5N1 peptide-specific T-cell lines that did not cross-react with H1 or H3 influenza virus HA peptides were generated. Four individuals also had antibodies against H5N1. CONCLUSIONS: This is the first report of ex vivo H5 HA-specific T-cell responses in a healthy but H5N1-exposed population. Our results indicate that the presence of H5N1-specific T cells could be an additional diagnostic tool for asymptomatic H5N1 infection.

Khurana S, Sasono P, Fox A, Nguyen VK, Le QM, Pham QT, Nguyen TH, Nguyen TL, Horby P, Golding H. 2011. H5N1-SeroDetect EIA and rapid test: a novel differential diagnostic assay for serodiagnosis of H5N1 infections and surveillance. J Virol, 85 (23), pp. 12455-12463. | Show Abstract | Read more

Continuing evolution of highly pathogenic (HP) H5N1 influenza viruses in wild birds with transmission to domestic poultry and humans poses a pandemic threat. There is an urgent need for a simple and rapid serological diagnostic assay which can differentiate between antibodies to seasonal and H5N1 strains and that could provide surveillance tools not dependent on virus isolation and nucleic acid technologies. Here we describe the establishment of H5N1 SeroDetect enzyme-linked immunosorbent assay (ELISA) and rapid test assays based on three peptides in HA2 (488-516), PB1-F2 (2-75), and M2e (2-24) that are highly conserved within H5N1 strains. These peptides were identified by antibody repertoire analyses of H5N1 influenza survivors in Vietnam using whole-genome-fragment phage display libraries (GFPDLs). To date, both platforms have demonstrated high levels of sensitivity and specificity in detecting H5N1 infections (clade 1 and clade 2.3.4) in Vietnamese patients as early as 7 days and up to several years postinfection. H5N1 virus-uninfected individuals in Vietnam and the United States, including subjects vaccinated with seasonal influenza vaccines or with confirmed seasonal virus infections, did not react in the H5N1-SeroDetect assays. Moreover, sera from individuals vaccinated with H5N1 subunit vaccine with moderate anti-H5N1 neutralizing antibody titers did not react positively in the H5N1-SeroDetect ELISA or rapid test assays. The simple H5N1-SeroDetect ELISA and rapid tests could provide an important tool for large-scale surveillance for potential exposure to HP H5N1 strains in both humans and birds.

Cuong HQ, Hien NT, Duong TN, Phong TV, Cam NN, Farrar J, Nam VS, Thai KT, Horby P. 2011. Quantifying the emergence of dengue in Hanoi, Vietnam: 1998-2009. PLoS Negl Trop Dis, 5 (9), pp. e1322. | Show Abstract | Read more

BACKGROUND: An estimated 2.4 billion people live in areas at risk of dengue transmission, therefore the factors determining the establishment of endemic dengue in areas where transmission suitability is marginal is of considerable importance. Hanoi, Vietnam is such an area, and following a large dengue outbreak in 2009, we set out to determine if dengue is emerging in Hanoi. METHODS AND PRINCIPAL FINDINGS: We undertook a temporal and spatial analysis of 25,983 dengue cases notified in Hanoi between 1998 and 2009. Age standardized incidence rates, standardized age of infection, and Standardized Morbidity Ratios (SMR) were calculated. A quasi-Poisson regression model was used to determine if dengue incidence was increasing over time. Wavelet analysis was used to explore the periodicity of dengue transmission and the association with climate variables. After excluding the two major outbreak years of 1998 and 2009 and correcting for changes in population age structure, we identified a significant annual increase in the incidence of dengue cases over the period 1999-2008 (incidence rate ratio  =  1.38, 95% confidence interval  =  1.20-1.58, p value  =  0.002). The age of notified dengue cases in Hanoi is high, with a median age of 23 years (mean 26.3 years). After adjusting for changes in population age structure, there was no statistically significant change in the median or mean age of dengue cases over the period studied. Districts in the central, highly urban, area of Hanoi have the highest incidence of dengue (SMR>3). CONCLUSIONS: Hanoi is a low dengue transmission setting where dengue incidence has been increasing year on year since 1999. This trend needs to be confirmed with serological surveys, followed by studies to determine the underlying drivers of this emergence. Such studies can provide insights into the biological, demographic, and environmental changes associated with vulnerability to the establishment of endemic dengue.

Fox A, Le NM, Simmons CP, Wolbers M, Wertheim HF, Pham TK, Tran TH, Trinh TM, Nguyen TL, Nguyen VT et al. 2011. Immunological and viral determinants of dengue severity in hospitalized adults in Ha Noi, Viet Nam. PLoS Negl Trop Dis, 5 (3), pp. e967. | Show Abstract | Read more

BACKGROUND: The relationships between the infecting dengue serotype, primary and secondary infection, viremia and dengue severity remain unclear. This cross-sectional study examined these interactions in adult patients hospitalized with dengue in Ha Noi. METHODS AND FINDINGS: 158 patients were enrolled between September 16 and November 11, 2008. Quantitative RT-PCR, serology and NS1 detection were used to confirm dengue infection, determine the serotype and plasma viral RNA concentration, and categorize infections as primary or secondary. 130 (82%) were laboratory confirmed. Serology was consistent with primary and secondary infection in 34% and 61%, respectively. The infecting serotype was DENV-1 in 42 (32%), DENV-2 in 39 (30%) and unknown in 49 (38%). Secondary infection was more common in DENV-2 infections (79%) compared to DENV-1 (36%, p<0.001). The proportion that developed dengue haemorrhagic fever (DHF) was 32% for secondary infection compared to 18% for primary infection (p = 0.14), and 26% for DENV-1 compared to 28% for DENV-2. The time until NS1 and plasma viral RNA were undetectable was shorter for DENV-2 compared to DENV-1 (p≤0.001) and plasma viral RNA concentration on day 5 was higher for DENV-1 (p = 0.03). Plasma viral RNA concentration was higher in secondary infection on day 5 of illness (p = 0.046). We didn't find an association between plasma viral RNA concentration and clinical severity. CONCLUSION: Dengue is emerging as a major public health problem in Ha Noi. DENV-1 and DENV-2 were the prevalent serotypes with similar numbers and clinical presentation. Secondary infection may be more common amongst DENV-2 than DENV-1 infections because DENV-2 infections resulted in lower plasma viral RNA concentrations and viral RNA concentrations were higher in secondary infection. The drivers of dengue emergence in northern Viet Nam need to be elucidated and public health measures instituted.

Horby P, Pham QT, Hens N, Nguyen TT, Le QM, Dang DT, Nguyen ML, Nguyen TH, Alexander N, Edmunds WJ et al. 2011. Social contact patterns in Vietnam and implications for the control of infectious diseases. PLoS One, 6 (2), pp. e16965. | Show Abstract | Read more

BACKGROUND: The spread of infectious diseases from person to person is determined by the frequency and nature of contacts between infected and susceptible members of the population. Although there is a long history of using mathematical models to understand these transmission dynamics, there are still remarkably little empirical data on contact behaviors with which to parameterize these models. Even starker is the almost complete absence of data from developing countries. We sought to address this knowledge gap by conducting a household based social contact diary in rural Vietnam. METHODS AND FINDINGS: A diary based survey of social contact patterns was conducted in a household-structured community cohort in North Vietnam in 2007. We used generalized estimating equations to model the number of contacts while taking into account the household sampling design, and used weighting to balance the household size and age distribution towards the Vietnamese population. We recorded 6675 contacts from 865 participants in 264 different households and found that mixing patterns were assortative by age but were more homogenous than observed in a recent European study. We also observed that physical contacts were more concentrated in the home setting in Vietnam than in Europe but the overall level of physical contact was lower. A model of individual versus household vaccination strategies revealed no difference between strategies in the impact on R(0). CONCLUSIONS AND SIGNIFICANCE: This work is the first to estimate contact patterns relevant to the spread of infections transmitted from person to person by non-sexual routes in a developing country setting. The results show interesting similarities and differences from European data and demonstrate the importance of context specific data.

Bui HM, Clements AC, Nguyen QT, Nguyen MH, Le XH, Hay SI, Tran TH, Wertheim HF, Snow RW, Horby P. 2011. Social and environmental determinants of malaria in space and time in Viet Nam. Int J Parasitol, 41 (1), pp. 109-116. | Show Abstract | Read more

The malaria burden in Viet Nam has been in decline in recent decades, but localised areas of high transmission remain. We used spatiotemporal analytical tools to determine the social and environmental drivers of malaria risk and to identify residual high-risk areas where control and surveillance resources can be targeted. Counts of reported Plasmodium falciparum and Plasmodium vivax malaria cases by month (January 2007-December 2008) and by district were assembled. Zero-inflated Poisson regression models were developed in a bayesian framework. Models had the percentage of the district's population living below the poverty line, percent of the district covered by forest, median elevation, median long-term average precipitation, and minimum temperature included as fixed effects, and terms for temporal trend and residual district-level spatial autocorrelation. Strong temporal and spatial heterogeneity in counts of malaria cases was apparent. Poverty and forest cover were significantly associated with an increased count of malaria cases but the magnitude and direction of associations between climate and malaria varied by socio-ecological zone. There was a declining trend in counts of malaria cases during the study period. After accounting for the social and environmental fixed effects, substantial spatial heterogeneity was still evident. Unmeasured factors which may contribute to this residual variation include malaria control activities, population migration and accessibility to health care. Forest-related activities and factors encompassed by poverty indicators are major drivers of malaria incidence in Viet Nam.

Horby P. 2010. Why are so few people infected with influenza A (H5N1) despite a large exposed population? The role of host genetics INFLUENZA AND OTHER RESPIRATORY VIRUSES, 4 pp. 40-40.

Horby P, Sudoyo H, Viprakasit V, Fox A, Thai PQ, Yu H, Davila S, Hibberd M, Dunstan SJ, Monteerarat Y et al. 2010. What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1? Epidemiol Infect, 138 (11), pp. 1550-1558. | Show Abstract | Read more

The apparent family clustering of avian influenza A/H5N1 has led several groups to postulate the existence of a host genetic influence on susceptibility to A/H5N1, yet the role of host factors on the risk of A/H5N1 disease has received remarkably little attention compared to the efforts focused on viral factors. We examined the epidemiological patterns of human A/H5N1 cases, their possible explanations, and the plausibility of a host genetic effect on susceptibility to A/H5N1 infection. The preponderance of familial clustering of cases and the relative lack of non-familial clusters, the occurrence of related cases separated by time and place, and the paucity of cases in some highly exposed groups such as poultry cullers, are consistent with a host genetic effect. Animal models support the biological plausibility of genetic susceptibility to A/H5N1. Although the evidence is circumstantial, host genetic factors are a parsimonious explanation for the unusual epidemiology of human A/H5N1 cases and warrant further investigation.

Wertheim HF, Horby P, Viet TL, Tanh TNT, Woodall J. 2010. The making of a world atlas of infectious diseases INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 14 pp. E282-E283. | Read more

Le QM, Wertheim HF, Tran ND, van Doorn HR, Nguyen TH, Horby P, Vietnam H1N1 Investigation Team. 2010. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med, 362 (1), pp. 86-87. | Read more

Fox A, Horby P, Ha NH, Hoa LENM, Lam NT, Simmons C, Farrar J, Van Kinh N, Wertheim H. 2010. Influenza A H5N1 and HIV co-infection: case report. BMC Infect Dis, 10 (1), pp. 167. | Show Abstract | Read more

BACKGROUND: The role of adaptive immunity in severe influenza is poorly understood. The occurrence of influenza A/H5N1 in a patient with HIV provided a rare opportunity to investigate this. CASE PRESENTATION: A 30-year-old male was admitted on day 4 of influenza-like-illness with tachycardia, tachypnea, hypoxemia and bilateral pulmonary infiltrates. Influenza A/H5N1 and HIV tests were positive and the patient was treated with Oseltamivir and broad-spectrum antibiotics. Initially his condition improved coinciding with virus clearance by day 6. He clinically deteriorated as of day 10 with fever recrudescence and increasing neutrophil counts and died on day 16. His admission CD4 count was 100/microl and decreased until virus was cleared. CD8 T cells shifted to a CD27+CD28- phenotype. Plasma chemokine and cytokine levels were similar to those found previously in fatal H5N1. CONCLUSIONS: The course of H5N1 infection was not notably different from other cases. Virus was cleared despite profound CD4 T cell depletion and aberrant CD8 T cell activation but this may have increased susceptibility to a fatal secondary infection.

Taylor WR, Burhan E, Wertheim H, Soepandi PZ, Horby P, Fox A, Benamore R, de Simone L, Hien TT, Chappuis F. 2010. Avian influenza--a review for doctors in travel medicine. Travel Med Infect Dis, 8 (1), pp. 1-12. | Show Abstract | Read more

First identified in humans in Hong Kong, influenza A/H5N1, known commonly as avian influenza, has caused human disease in 15 countries around the world. Although the current number of confirmed patients is tiny compared to seasonal and the recently emerged H1N1 'swine' influenza, H5N1 remains a candidate for the next highly pathogenic influenza pandemic. Currently, H5N1 has very limited ability to spread from person-to-person but this may change because of mutation or reassortment with other influenza viruses leading to an influenza pandemic with high mortality. If this occurs travellers are likely to be affected and travel medicine doctors will need to consider avian influenza in returning febrile travellers. The early clinical features may be dismissed easily as 'the flu' resulting in delayed treatment. Treatment options are limited. Oral oseltamivir alone has been the most commonly used drug but mortality remains substantial, up to 80% in Indonesia. Intravenous peramivir has been filed for registration and IV zanamivir is being developed. This review will focus on the epidemiological and clinical features of influenza A/H5N1 avian influenza and will highlight aspects relevant to travel medicine doctors.

Horby P, Wertheim H, Ha NH, Trung NV, Trinh DT, Taylor W, Ha NM, Lien TT, Farrar J, Van Kinh N. 2010. Stimulating the development of national Streptococcus suis guidelines in Viet Nam through a strategic research partnership. Bull World Health Organ, 88 (6), pp. 458-461. | Show Abstract | Read more

PROBLEM: Streptococcus suis is a common cause of adult bacterial meningitis in Viet Nam, and possibly other parts of Asia, yet this disabling infection has been largely neglected. Prevention, diagnosis and treatment are relatively straightforward and affordable but, in early 2007, no national diagnostic, case management or prevention guidelines existed in Viet Nam. APPROACH: Enhanced detection of S. suis infections was established in 2007 as part of a collaborative research programme between the National Hospital for Tropical Diseases, a key national hospital with very close links to the Ministry of Health, and a research group affiliated with Oxford University based in Viet Nam. The results were reported directly to policy-makers at the Ministry of Health. LOCAL SETTING: Viet Nam is a low-income country with a health-care system that has seen considerable improvements and increased autonomy. However, parts of the system remain fairly centralized the Ministry of Health. RELEVANT CHANGES: Following the improved detection and reporting of S. suis cases, the Ministry of Health issued guidance to all hospitals in Viet Nam on the clinical and laboratory diagnosis, treatment and prevention of S. suis. A public health laboratory diagnostic service was established at the National Institute of Hygiene and Epidemiology and training courses were conducted for clinicians and microbiologists. Ministry of Health guidance on surveillance and control of communicable diseases was updated to include a section on S. suis. LESSONS LEARNT: Research collaborations can efficiently inform and influence national responses if they are well positioned to reach policy-makers.

Taylor WR, Tran GV, Nguyen TQ, Dang DV, Nguyen VK, Nguyen CT, Nguyen LT, Luong CQ, Scott T, Dang TC et al. 2009. Acute febrile myalgia in Vietnam due to trichinellosis following the consumption of raw pork. Clin Infect Dis, 49 (7), pp. e79-e83. | Show Abstract | Read more

Trichinellosis outbreaks occur occasionally in Vietnam following the consumption of undercooked pork. Diagnosing trichinella can be problematic because fever and myalgia are nonspecific, and diagnosis may be delayed. We describe 5 Vietnamese patients in whom trichinellosis was diagnosed after several weeks of illness.

Liem NT, Tung CV, Hien ND, Hien TT, Chau NQ, Long HT, Hien NT, Mai LEQ, Taylor WR, Wertheim H et al. 2009. Clinical features of human influenza A (H5N1) infection in Vietnam: 2004-2006. Clin Infect Dis, 48 (12), pp. 1639-1646. | Show Abstract | Read more

BACKGROUND: The first cases of avian influenza A (H5N1) in humans in Vietnam were detected in early 2004, and Vietnam has reported the second highest number of cases globally. METHODS: We obtained retrospective clinical data through review of medical records for laboratory confirmed cases of influenza A (H5N1) infection diagnosed in Vietnam from January 2004 through December 2006. Standard data was abstracted regarding clinical and laboratory features, treatment, and outcome. RESULTS: Data were obtained for 67 (72%) of 93 cases diagnosed in Vietnam over the study period. Patients presented to the hospital after a median duration of illness of 6 days with fever (75%), cough (89%), and dyspnea (81%). Diarrhea and mucosal bleeding at presentation were more common in fatal than in nonfatal cases. Common findings were bilateral pulmonary infiltrates on chest radiograph (72%), lymphopenia (73%), and increased serum transaminase levels (aspartate aminotransferase, 69%; alanine aminotransferase, 61%). Twenty-six patients died (case fatality rate, 39%; 95% confidence interval, 27%-51%) and the most reliable predictor of a fatal outcome was the presence of both neutropenia and raised alanine aminotransferase level at admission, which correctly predicted 91% of deaths and 82% of survivals. The risk of death was higher among persons aged < or =16 years, compared with older persons (P < .001), and the risk of death was higher among patients who did not receive oseltamivir treatment (P = .048). The benefit of oseltamivir treatment remained after controlling for potential confounding by 1 measure of severity (odds ratio, 0.15; 95% confidence interval, 0.026-0.893; P = .034). CONCLUSION: In cases of infection with Influenza A (H5N1), the presence of both neutropenia and raised serum transaminase levels predicts a poor outcome. Oseltamivir treatment shows benefit, but treatment with corticosteroids is associated with an increased risk of death.

Wertheim HF, Nguyen TQ, Nguyen KA, de Jong MD, Taylor WR, Le TV, Nguyen HH, Nguyen HT, Farrar J, Horby P, Nguyen HD. 2009. Furious rabies after an atypical exposure. PLoS Med, 6 (3), pp. e44. | Read more

Wertheim HF, Nguyen HN, Taylor W, Lien TT, Ngo HT, Nguyen TQ, Nguyen BN, Nguyen HH, Nguyen HM, Nguyen CT et al. 2009. Streptococcus suis, an important cause of adult bacterial meningitis in northern Vietnam. PLoS One, 4 (6), pp. e5973. | Show Abstract | Read more

BACKGROUND: Streptococcus suis can cause severe systemic infection in adults exposed to infected pigs or after consumption of undercooked pig products. S. suis is often misdiagnosed, due to lack of awareness and improper testing. Here we report the first fifty cases diagnosed with S. suis infection in northern Viet Nam. METHODOLOGY/PRINCIPAL FINDINGS: In 2007, diagnostics for S. suis were set up at a national hospital in Hanoi. That year there were 43 S. suis positive cerebrospinal fluid samples, of which S. suis could be cultured in 32 cases and 11 cases were only positive by PCR. Seven patients were blood culture positive for S. suis but CSF culture and PCR negative; making a total of 50 patients with laboratory confirmed S. suis infection in 2007. The number of S. suis cases peaked during the warmer months. CONCLUSIONS/SIGNIFICANCE: S. suis was commonly diagnosed as a cause of bacterial meningitis in adults in northern Viet Nam. In countries where there is intense and widespread exposure of humans to pigs, S. suis can be an important human pathogen.

Boni MF, Manh BH, Thai PQ, Farrar J, Hien TT, Hien NT, Van Kinh N, Horby P. 2009. Modelling the progression of pandemic influenza A (H1N1) in Vietnam and the opportunities for reassortment with other influenza viruses. BMC Med, 7 (1), pp. 43. | Show Abstract | Read more

BACKGROUND: A novel variant of influenza A (H1N1) is causing a pandemic and, although the illness is usually mild, there are concerns that its virulence could change through reassortment with other influenza viruses. This is of greater concern in parts of Southeast Asia, where the population density is high, influenza is less seasonal, human-animal contact is common and avian influenza is still endemic. METHODS: We developed an age- and spatially-structured mathematical model in order to estimate the potential impact of pandemic H1N1 in Vietnam and the opportunities for reassortment with animal influenza viruses. The model tracks human infection among domestic animal owners and non-owners and also estimates the numbers of animals may be exposed to infected humans. RESULTS: In the absence of effective interventions, the model predicts that the introduction of pandemic H1N1 will result in an epidemic that spreads to half of Vietnam's provinces within 57 days (interquartile range (IQR): 45-86.5) and peaks 81 days after introduction (IQR: 62.5-121 days). For the current published range of the 2009 H1N1 influenza's basic reproductive number (1.2-3.1), we estimate a median of 410,000 cases among swine owners (IQR: 220,000-670,000) with 460,000 exposed swine (IQR: 260,000-740,000), 350,000 cases among chicken owners (IQR: 170,000-630,000) with 3.7 million exposed chickens (IQR: 1.9 M-6.4 M), and 51,000 cases among duck owners (IQR: 24,000 - 96,000), with 1.2 million exposed ducks (IQR: 0.6 M-2.1 M). The median number of overall human infections in Vietnam for this range of the basic reproductive number is 6.4 million (IQR: 4.4 M-8.0 M). CONCLUSION: It is likely that, in the absence of effective interventions, the introduction of a novel H1N1 into a densely populated country such as Vietnam will result in a widespread epidemic. A large epidemic in a country with intense human-animal interaction and continued co-circulation of other seasonal and avian viruses would provide substantial opportunities for H1N1 to acquire new genes.

Wertheim HF, Farrar J, Horby P. 2009. Online video sharing and patients' privacy. BMJ, 339 pp. b3991. | Read more

Phan PH, Wertheim H, Luong ST, Ngo BT, Pham HV, Nguyen TT, Le HT, Taylor W, Horby P, Liem NT. 2008. Fatal Lower Respiratory Tract Infections with Rhinovirus A in Infants in Vietnam INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 12 pp. E81-E81. | Read more

Nguyen TH, Farrar J, Horby P. 2008. Person-to-person transmission of influenza A (H5N1). Lancet, 371 (9622), pp. 1392-1394. | Read more

Taylor WR, Thinh BN, Anh GT, Horby P, Wertheim H, Lindegardh N, de Jong MD, Stepniewska K, Hanh TT, Hien ND et al. 2008. Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. PLoS One, 3 (10), pp. e3410. | Show Abstract | Read more

In the absence of a parenteral drug, oral oseltamivir is currently recommended by the WHO for treating H5N1 influenza. Whether oseltamivir absorption is adequate in severe influenza is unknown. We measured the steady state, plasma concentrations of nasogastrically administered oseltamivir 150 mg bid and its active metabolite, oseltamivir carboxylate (OC), in three, mechanically ventilated patients with severe H5N1 (male, 30 yrs; pregnant female, 22 yrs) and severe H3N2 (female, 76 yrs). Treatments were started 6, 7 and 8 days after illness onset, respectively. Both females were sampled while on continuous venovenous haemofiltration. Admission and follow up specimens (trachea, nose, throat, rectum, blood) were tested for RNA viral load by reverse transcriptase PCR. In vitro virus susceptibility to OC was measured by a neuraminidase inhibition assay. Admission creatinine clearances were 66 (male, H5N1), 82 (female, H5N1) and 6 (H3N2) ml/min. Corresponding AUC(0-12) values (5932, 10,951 and 34,670 ng.h/ml) and trough OC concentrations (376, 575 and 2730 ng/ml) were higher than previously reported in healthy volunteers; the latter exceeded 545 to 3956 fold the H5N1 IC(50) (0.69 ng/ml) isolated from the H5N1 infected female. Two patients with follow-up respiratory specimens cleared their viruses after 5 (H5N1 male) and 5 (H3N2 female) days of oseltamivir. Both female patients died of respiratory failure; the male survived. 150 mg bid of oseltamivir was well absorbed and converted extensively to OC. Virus was cleared in two patients but two patients died, suggesting viral efficacy but poor clinical efficacy.

Le MT, Wertheim HF, Nguyen HD, Taylor W, Hoang PV, Vuong CD, Nguyen HL, Nguyen HH, Nguyen TQ, Nguyen TV et al. 2008. Influenza A H5N1 clade 2.3.4 virus with a different antiviral susceptibility profile replaced clade 1 virus in humans in northern Vietnam. PLoS One, 3 (10), pp. e3339. | Show Abstract | Read more

BACKGROUND: Prior to 2007, highly pathogenic avian influenza (HPAI) H5N1 viruses isolated from poultry and humans in Vietnam were consistently reported to be clade 1 viruses, susceptible to oseltamivir but resistant to amantadine. Here we describe the re-emergence of human HPAI H5N1 virus infections in Vietnam in 2007 and the characteristics of the isolated viruses. METHODS AND FINDINGS: Respiratory specimens from patients suspected to be infected with avian influenza in 2007 were screened by influenza and H5 subtype specific polymerase chain reaction. Isolated H5N1 strains were further characterized by genome sequencing and drug susceptibility testing. Eleven poultry outbreak isolates from 2007 were included in the sequence analysis. Eight patients, all of them from northern Vietnam, were diagnosed with H5N1 in 2007 and five of them died. Phylogenetic analysis of H5N1 viruses isolated from humans and poultry in 2007 showed that clade 2.3.4 H5N1 viruses replaced clade 1 viruses in northern Vietnam. Four human H5N1 strains had eight-fold reduced in-vitro susceptibility to oseltamivir as compared to clade 1 viruses. In two poultry isolates the I117V mutation was found in the neuraminidase gene, which is associated with reduced susceptibility to oseltamivir. No mutations in the M2 gene conferring amantadine resistance were found. CONCLUSION: In 2007, H5N1 clade 2.3.4 viruses replaced clade 1 viruses in northern Vietnam and were susceptible to amantadine but showed reduced susceptibility to oseltamivir. Combination antiviral therapy with oseltamivir and amantadine for human cases in Vietnam is recommended.

Horby P. 2007. Determining risk factors for infection with influenza A (H5N1) - Response EMERGING INFECTIOUS DISEASES, 13 (6), pp. 956-956.

Tuan PA, Horby P, Dinh PN, Mai LT, Zambon M, Shah J, Huy VQ, Bloom S, Gopal R, Comer J et al. 2007. SARS transmission in Vietnam outside of the health-care setting. Epidemiol Infect, 135 (3), pp. 392-401. | Show Abstract | Read more

To evaluate the risk of transmission of SARS coronavirus outside of the health-care setting, close household and community contacts of laboratory-confirmed SARS cases were identified and followed up for clinical and laboratory evidence of SARS infection. Individual- and household-level risk factors for transmission were investigated. Nine persons with serological evidence of SARS infection were identified amongst 212 close contacts of 45 laboratory-confirmed SARS cases (secondary attack rate 4.2%, 95% CI 1.5-7). In this cohort, the average number of secondary infections caused by a single infectious case was 0.2. Two community contacts with laboratory evidence of SARS coronavirus infection had mild or sub-clinical infection, representing 3% (2/65) of Vietnamese SARS cases. There was no evidence of transmission of infection before symptom onset. Physically caring for a symptomatic laboratory-confirmed SARS case was the only independent risk factor for SARS transmission (OR 5.78, 95% CI 1.23-24.24).

Horby P. 2007. The global war on terrorism. Clin Infect Dis, 44 (1), pp. 151. | Read more

Roberton SI, Bell DJ, Smith GJ, Nicholls JM, Chan KH, Nguyen DT, Tran PQ, Streicher U, Poon LL, Chen H et al. 2006. Avian influenza H5N1 in viverrids: implications for wildlife health and conservation. Proc Biol Sci, 273 (1595), pp. 1729-1732. | Show Abstract | Read more

The Asian countries chronically infected with avian influenza A H5N1 are 'global hotspots' for biodiversity conservation in terms of species diversity, endemism and levels of threat. Since 2003, avian influenza A H5N1 viruses have naturally infected and killed a range of wild bird species, four felid species and a mustelid. Here, we report fatal disseminated H5N1 infection in a globally threatened viverrid, the Owston's civet, in Vietnam, highlighting the risk that avian influenza H5N1 poses to mammalian and avian biodiversity across its expanding geographic range.

Reynolds MG, Anh BH, Thu VH, Montgomery JM, Bausch DG, Shah JJ, Maloney S, Leitmeyer KC, Huy VQ, Horby P et al. 2006. Factors associated with nosocomial SARS-CoV transmission among healthcare workers in Hanoi, Vietnam, 2003. BMC Public Health, 6 (1), pp. 207. | Show Abstract | Read more

BACKGROUND: In March of 2003, an outbreak of Severe Acute Respiratory Syndrome (SARS) occurred in Northern Vietnam. This outbreak began when a traveler arriving from Hong Kong sought medical care at a small hospital (Hospital A) in Hanoi, initiating a serious and substantial transmission event within the hospital, and subsequent limited spread within the community. METHODS: We surveyed Hospital A personnel for exposure to the index patient and for symptoms of disease during the outbreak. Additionally, serum specimens were collected and assayed for antibody to SARS-associated coronavirus (SARS-CoV) antibody and job-specific attack rates were calculated. A nested case-control analysis was performed to assess risk factors for acquiring SARS-CoV infection. RESULTS: One hundred and fifty-three of 193 (79.3%) clinical and non-clinical staff consented to participate. Excluding job categories with < 3 workers, the highest SARS attack rates occurred among nurses who worked in the outpatient and inpatient general wards (57.1, 47.4%, respectively). Nurses assigned to the operating room/intensive care unit, experienced the lowest attack rates (7.1%) among all clinical staff. Serologic evidence of SARS-CoV infection was detected in 4 individuals, including 2 non-clinical workers, who had not previously been identified as SARS cases; none reported having had fever or cough. Entering the index patient's room and having seen (viewed) the patient were the behaviors associated with highest risk for infection by univariate analysis (odds ratios 20.0, 14.0; 95% confidence intervals 4.1-97.1, 3.6-55.3, respectively). CONCLUSION: This study highlights job categories and activities associated with increased risk for SARS-CoV infection and demonstrates that a broad diversity of hospital workers may be vulnerable during an outbreak. These findings may help guide recommendations for the protection of vulnerable occupational groups and may have implications for other respiratory infections such as influenza.

World Health Organization Writing Group, Bell D, Nicoll A, Fukuda K, Horby P, Monto A, Hayden F, Wylks C, Sanders L, Van Tam J. 2006. Non-pharmaceutical interventions for pandemic influenza, international measures. Emerg Infect Dis, 12 (1), pp. 81-87. | Show Abstract | Read more

Since global availability of vaccine and antiviral agents against influenza caused by novel human subtypes is insufficient, the World Health Organization (WHO) recommends non-pharmaceutical public health interventions to contain infection, delay spread, and reduce the impact of pandemic disease. Virus transmission characteristics will not be completely known in advance, but difficulties in influenza control typically include peak infectivity early in illness, a short interval between cases, and to a lesser extent, transmission from persons with incubating or asymptomatic infection. Screening and quarantining entering travelers at international borders did not substantially delay virus introduction in past pandemics, except in some island countries, and will likely be even less effective in the modern era. Instead, WHO recommends providing information to international travelers and possibly screening travelers departing countries with transmissible human infection. The principal focus of interventions against pandemic influenza spread should be at national and community levels rather than international borders.

World Health Organization Writing Group, Bell D, Nicoll A, Fukuda K, Horby P, Monto A, Hayden F, Wylks C, Sanders L, van Tam J. 2006. Non-pharmaceutical interventions for pandemic influenza, national and community measures. Emerg Infect Dis, 12 (1), pp. 88-94. | Show Abstract | Read more

The World Health Organization's recommended pandemic influenza interventions, based on limited data, vary by transmission pattern, pandemic phase, and illness severity and extent. In the pandemic alert period, recommendations include isolation of patients and quarantine of contacts, accompanied by antiviral therapy. During the pandemic period, the focus shifts to delaying spread and reducing effects through population-based measures. Ill persons should remain home when they first become symptomatic, but forced isolation and quarantine are ineffective and impractical. If the pandemic is severe, social distancing measures such as school closures should be considered. Nonessential domestic travel to affected areas should be deferred. Hand and respiratory hygiene should be routine; mask use should be based on setting and risk, and contaminated household surfaces should be disinfected. Additional research and field assessments during pandemics are essential to update recommendations. Legal authority and procedures for implementing interventions should be understood in advance and should respect cultural differences and human rights.

Dinh PN, Long HT, Tien NT, Hien NT, Mai LETQ, Phong LEH, Tuan LEV, Van Tan H, Nguyen NB, Van Tu P et al. 2006. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerg Infect Dis, 12 (12), pp. 1841-1847. | Show Abstract | Read more

To evaluate risk factors for human infection with influenza A subtype H5N1, we performed a matched case-control study in Vietnam. We enrolled 28 case-patients who had laboratory-confirmed H5N1 infection during 2004 and 106 age-, sex-, and location-matched control-respondents. Data were analyzed by matched-pair analysis and multivariate conditional logistic regression. Factors that were independently associated with H5N1 infection were preparing sick or dead poultry for consumption < or =7 days before illness onset (matched odds ratio [OR] 8.99, 95% confidence interval [CI] 0.98-81.99, p = 0.05), having sick or dead poultry in the household < or =7 days before illness onset (matched OR 4.94, 95% CI 1.21-20.20, p = 0.03), and lack of an indoor water source (matched OR 6.46, 95% CI 1.20-34.81, p = 0.03). Factors not significantly associated with infection were raising healthy poultry, preparing healthy poultry for consumption, and exposure to persons with an acute respiratory illness.

Horby P, Macintyre CR, McIntyre PB, Gilbert GL, Staff M, Hanlon M, Heron LG, Cagney M, Bennett C. 2005. A boarding school outbreak of pertussis in adolescents: value of laboratory diagnostic methods. Epidemiol Infect, 133 (2), pp. 229-236. | Show Abstract | Read more

Culture for Bordetella pertussis (B. pertussis) is the traditional gold standard for laboratory diagnosis of pertussis but is insensitive, especially later in the course of illness and in vaccinated persons. Interpretation of serology is limited by the lack of an appropriate reference standard. An outbreak of pertussis in a crowded boarding-school dormitory allowed evaluation of laboratory correlates of infection. Questionnaires, serum samples and throat swabs were collected from members of the exposed group. Serum samples from unexposed controls of a similar age group were used for comparison. B. pertussis PCR was performed on throat swabs, and sera were tested for IgA antibodies against whole-cell (WC) B. pertussis antigen and IgG antibodies to pertussis toxin (PT). The Centers for Disease Control and Prevention definition for pertussis was used to define clinical cases. We evaluated the use of a previously published cut-off for PT IgG of 125 EIA units (EU)/ml. Completed questionnaires were obtained from 115 students, of whom 85 (74%) reported coughing symptoms, including 32 (28%) who met the clinical case definition for pertussis. B. pertussis was detected by PCR in 17 (15%) and WC IgA in 22 (19%) students; neither correlated with symptoms, but dormitory of residence strongly predicted PCR status. The mean PT IgG geometric mean concentration, in this situation of high pertussis exposure, correlated with severity of symptoms and was significantly higher in both symptomatic and asymptomatic children exposed during the outbreak (P < 0.001) than in control children. A cut-off for PT IgG of 125 EU/ml was too high in an outbreak situation to be sensitive enough to identify pertussis cases. A case of pertussis in a crowded boarding-school dormitory resulted rapidly in an outbreak. Serology and PCR were useful in identifying the outbreak and commencing disease control measures. The use of serology has mostly been evaluated in community serosurveys, where it is not possible to determine if immunity reflects vaccination, asymptomatic disease or symptomatic disease. This outbreak gave us the opportunity to evaluate the value of serology and PCR in the presence of confirmed exposure to pertussis.

Liem NT, Lim W, World Health Organization International Avian Influenza Investigation Team, Vietnam. 2005. Lack of H5N1 avian influenza transmission to hospital employees, Hanoi, 2004. Emerg Infect Dis, 11 (2), pp. 210-215. | Show Abstract | Read more

To establish whether human-to-human transmission of influenza A H5N1 occurred in the healthcare setting in Vietnam, we conducted a cross-sectional seroprevalence survey among hospital employees exposed to 4 confirmed and 1 probable H5N1 case-patients or their clinical specimens. Eighty-three (95.4%) of 87 eligible employees completed a questionnaire and provided a serum sample, which was tested for antibodies to influenza A H5N1. Ninety-five percent reported exposure to > or = 1 H5N1 case-patients; 59 (72.0%) reported symptoms, and 2 (2.4%) fulfilled the definition for a possible H5N1 secondary case-patient. No study participants had detectable antibodies to influenza A H5N1. The data suggest that the H5N1 viruses responsible for human cases in Vietnam in January 2004 are not readily transmitted from person to person. However, influenza viruses are genetically variable, and transmissibility is difficult to predict. Therefore, persons providing care for H5N1 patients should continue to take measures to protect themselves.

Horby PW, Williams A, Burgess MA, Wang H. 2005. Prevalence and determinants of influenza vaccination in Australians aged 40 years and over--a national survey. Aust N Z J Public Health, 29 (1), pp. 35-37. | Show Abstract | Read more

OBJECTIVES: To determine influenza vaccination coverage in 2001 in Australian adults aged > or = 40 years, assess awareness of and attitudes to influenza vaccine, factors associated with vaccination, and estimate uptake of free vaccine provided to those aged > or = 65 years. METHODS: National computer-assisted telephone interview (CATI) survey in October/November 2001. RESULTS: Interviews were completed with 5,266 people aged > or = 65 and 2,415 aged 40-64 years. Thirty per cent of selected households participated. Overall, 67% of respondents believed that the vaccine was somewhat to very effective in preventing influenza. Seventy-eight per cent of those aged > or = 65 years reported influenza vaccination; 89% had received it free. Independent predictors of vaccination were: belief that influenza vaccine is effective in preventing influenza (OR=13.5, 95% CI 10.6-17.2); and the presence of chronic disease (OR=1.6, 95% CI 1.3-2.0). Overall, 24% of those aged 40-64 years were vaccinated; only 34% of those who met any of the criteria for vaccination (medical risk factor, at-risk occupation, or being Aboriginal or Torres Strait Islander) reported vaccination. CONCLUSIONS: Influenza vaccine coverage was high in those aged > or = 65 years, but coverage of those at-risk aged 40-64 years remained suboptimal. Immunisation against influenza was influenced more by beliefs about the vaccine's effectiveness and existing medical risk factors, rather than socio-demographic factors such as gender and income.

Hethcote HW, Horby P, McIntyre P. 2004. Using computer simulations to compare pertussis vaccination strategies in Australia. Vaccine, 22 (17-18), pp. 2181-2191. | Show Abstract | Read more

High levels of notified pertussis in adolescents and adults, persisting severe disease (hospitalization and deaths) in infants despite high childhood immunization coverage, together with the availability of adult-formulated pertussis vaccines, have made alternate strategies for vaccine control of pertussis an important issue in Australia. An age-structured computer simulation model was used to compare the likely effects of adopting different vaccination strategies in Australia on pertussis transmission by age group over a 50 year time period. Epidemiological parameters and vaccination coverage in Australia were estimated from previous pertussis modeling studies and existing data. In the simulations, replacing the pertussis booster at 18 months with a booster dose for adolescents at an age between 12 and 17 years, assuming 80% coverage, led to decreases in pertussis cases of 30% in children of ages 0-23 months (who have the highest complication rates) and of 25% in adolescents, but an increase of 15% in cases in 2-4-year-old children. The simulations did not suggest any shift of pertussis cases into the adult child-bearing years. Varying parameter values in the simulations in a series of sensitivity analyses showed the model predictions to be robust over a plausible range. The results of these simulations suggest that the recent change in the Australian pertussis vaccination schedule, replacing the 18 month dose with a pertussis booster in 15-17-year-old adolescents, is very likely to reduce overall pertussis incidence in Australia without increasing the cost of the current vaccine program.

Tran TH, Nguyen TL, Nguyen TD, Luong TS, Pham PM, Nguyen VV, Pham TS, Vo CD, Le TQ, Ngo TT et al. 2004. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med, 350 (12), pp. 1179-1188. | Show Abstract | Read more

BACKGROUND: Recent outbreaks of avian influenza A (H5N1) in poultry throughout Asia have had major economic and health repercussions. Human infections with this virus were identified in Vietnam in January 2004. METHODS: We report the clinical features and preliminary epidemiologic findings among 10 patients with confirmed cases of avian influenza A (H5N1) who presented to hospitals in Ho Chi Minh City and Hanoi, Vietnam, in December 2003 and January 2004. RESULTS: In all 10 cases, the diagnosis of influenza A (H5N1) was confirmed by means of viral culture or reverse transcriptase-polymerase chain reaction with primers specific for H5 and N1. None of the 10 patients (mean age, 13.7 years) had preexisting medical conditions. Nine of them had a clear history of direct contact with poultry (median time before onset of illness, three days). All patients presented with fever (temperature, 38.5 to 40.0 degrees C), respiratory symptoms, and clinically significant lymphopenia (median lymphocyte count, 700 per cubic millimeter). The median platelet count was 75,500 per cubic millimeter. Seven patients had diarrhea. In all patients, there were marked abnormalities on chest radiography. There was no definitive evidence of human-to-human transmission. Eight patients died, one patient has recovered, and one is recovering. CONCLUSIONS: Influenza A (H5N1) infection, characterized by fever, respiratory symptoms, and lymphopenia, carries a high risk of death. Although in all 10 cases the infection appears to have been acquired directly from infected poultry, the potential exists for genetic reassortment with human influenzaviruses and the evolution of human-to-human transmission. Containment of influenza A (H5N1) in poultry throughout Asia is therefore urgently required.

Le DH, Bloom SA, Nguyen QH, Maloney SA, Le QM, Leitmeyer KC, Bach HA, Reynolds MG, Montgomery JM, Comer JA et al. 2004. Lack of SARS transmission among public hospital workers, Vietnam. Emerg Infect Dis, 10 (2), pp. 265-268. | Show Abstract | Read more

The severe acute respiratory syndrome (SARS) outbreak in Vietnam was amplified by nosocomial spread within hospital A, but no transmission was reported in hospital B, the second of two designated SARS hospitals. Our study documents lack of SARS-associated coronavirus transmission to hospital B workers, despite variable infection control measures and the use of personal protective equipment.

Chow JY, Anderson SR, Delpech V, Leese J, Horby P, Sedgwick JE, Rooney CI, Nicoll A, Watson JM. 2003. SARS: UK public health response--past, present and future. Commun Dis Public Health, 6 (3), pp. 209-215. | Show Abstract

The emergence of severe acute respiratory syndrome (SARS) in China, the occurrence of epidemics of SARS in China and a number of Southeast Asian countries, and its spread to countries elsewhere, have presented major challenges to public health systems throughout the world. Although very few true cases of SARS were detected in the United Kingdom, the public health response to the threat of SARS was considerable. The main components of this response were the early detection, isolation and reporting of cases, and the provision of comprehensive information to health professionals, cases, their contacts and the public. The development of the response to SARS raised a number of more general issues relevant to future infectious epidemic threats. Although the World Health Organisation has now declared SARS 'contained', the possibility of re-emergence is ever present. All countries will need to be vigilant and plan their response to the possibility of a renewed SARS epidemic.

Horby P, Gilmour R, Wang H, McIntyre P. 2003. Progress towards eliminating Hib in Australia: an evaluation of Haemophilus influenzae type b prevention in Australia, 1 July 1993 to 30 June 2000. Commun Dis Intell Q Rep, 27 (3), pp. 324-341. | Show Abstract

The status of Haemophilus influenzae (Hib) disease and its prevention by vaccination was reviewed for the period 1997 to 2000. This forms the background to a change in national vaccine policy, from the use of two Hib vaccines to the use of PRP-OMP only throughout Australia from May 2000. Notifications of Hib in the 7-year period between 1993 and 2000 declined by 87 per cent among children 0-4 years of age; adjustment for likely under-reporting increase this to a 95 per cent reduction. Among age groups not included in the immunisation program, there was also a substantial decline in notified cases. Overall, a minimum 430 cases and 13 deaths were prevented by Hib immunisation annually in Australia. Enhanced Hib surveillance recorded 532 cases over seven years, with 353 in unvaccinated persons, 74 fulfilling criteria for true vaccine failure and 75 partially immunised. Of unvaccinated cases, 60 and 182 were eligible for routine and catch-up immunisation respectively. Although the overall incidence for 0-4 years of age declined from 15 to 1.2 cases per 100,000 population, the proportion of cases under six months of age increased from 11 per cent to 23 per cent. Overall vaccine effectiveness, estimated using data from the last five years of the program, was 83 per cent (95% CI 71-91%), increasing to 90 per cent (95% CI 83-94%) when adjusted for under-reporting to the Australian Childhood Immunisation Register. Among Aboriginal and Torres Strait Islander people, the incidence of invasive Hib disease fell from 4.6 cases per 100,000 population to 0.7 cases per 100,000 population but the proportion of cases now occurring among Aboriginal or Torres Strait Islander people increased significantly, from 7 to 15 per cent. The Hib immunisation program in Australia has been highly successful. Nevertheless, experience in Australia and elsewhere indicates that continued careful monitoring of Hib disease, with high quality laboratory surveillance, remains important.

Horby PW, O'Brien SJ, Adak GK, Graham C, Hawker JI, Hunter P, Lane C, Lawson AJ, Mitchell RT, Reacher MH et al. 2003. A national outbreak of multi-resistant Salmonella enterica serovar Typhimurium definitive phage type (DT) 104 associated with consumption of lettuce. Epidemiol Infect, 130 (2), pp. 169-178. | Show Abstract | Read more

Between 1 August and 15 September 2000, 361 cases of Salmonella enterica serotype Typhimurium definitive phage type (DT) 104, resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides, spectinomycin and tetracycline (R-type ACSSuSpT), were identified in England and Wales residents. Molecular typing of 258 isolates of S. Typhimurium DT104 R-type ACSSuSpT showed that, although isolates were indistinguishable by pulsed-field gel electrophoresis, 67% (174/258) were characterized by a particular plasmid profile. A statistically significant association between illness and consumption of lettuce away from home was demonstrated (OR = 7.28; 95% CI=2.25-23.57; P=0.0006) in an unmatched case-control study. Environmental investigations revealed that a number of food outlets implicated in the outbreak had common suppliers of salad vegetables. No implicated foods were available for microbiological testing. An environmental audit of three farms that might have supplied salad vegetables to the implicated outlets did not reveal any unsafe agricultural practices. The complexity of the food supply chain and the lack of identifying markers on salad stuffs made tracking salad vegetables back to their origin extremely difficult in most instances. This has implications for public health since food hazard warnings and product withdrawal are contingent on accurate identification of the suspect product.

Horby P. 2002. Variant Creutzfeldt-Jakob disease: an unfolding epidemic of misfolded proteins. J Paediatr Child Health, 38 (6), pp. 539-542. | Show Abstract | Read more

Variant Creutzfeldt-Jakob disease (vCJD) is an emerging infectious disease believed to be the human manifestation of bovine spongiform encephalopathy (BSE). Variant CJD belongs to a family of human and animal diseases called transmissible spongiform encephalopathies (TSE). The pathogenesis of TSE is not fully understood, but a modified form of a normal cellular protein plays a central role. Current measures to control vCJD aim to prevent transmission of the infectious agent from animals to humans through food or pharmaceutical products and to prevent transmission from person to person via medical interventions. The anticipated development of preclinical diagnostic tests and treatments for vCJD will create new control options and difficult choices.

Gillespie IA, O'Brien SJ, Frost JA, Adak GK, Horby P, Swan AV, Painter MJ, Neal KR, Campylobacter Sentinel Surveillance Scheme Collaborators. 2002. A case-case comparison of Campylobacter coli and Campylobacter jejuni infection: a tool for generating hypotheses. Emerg Infect Dis, 8 (9), pp. 937-942. | Show Abstract | Read more

Preventing campylobacteriosis depends on a thorough understanding of its epidemiology. We used case-case analysis to compare cases of Campylobacter coli infection with cases of C. jejuni infection, to generate hypotheses for infection from standardized, population-based sentinel surveillance information in England and Wales. Persons with C. coli infection were more likely to have drunk bottled water than were those with C. jejuni infection and, in general, were more likely to have eaten pâté. Important differences in exposures were identified for these two Campylobacter species. Exposures that are a risk for infection for both comparison groups might not be identified or might be underestimated by case-case analysis. Similarly, the magnitude or direction of population risk cannot be assessed accurately. Nevertheless, our findings suggest that case-control studies should be conducted at the species level.

McIntyre P, Gidding H, Gilmour R, Lawrence G, Hull B, Horby P, Wang H, Andrews R, Burgess M, National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases. 2002. Vaccine preventable diseases and vaccination coverage in Australia, 1999 to 2000. Commun Dis Intell Q Rep, Suppl pp. i-111.

Horby P. 2002. Rendering beef safe. Clin Infect Dis, 34 (1), pp. 129. | Read more

Horby P, Rushdy A, Graham C, O'Mahony M, PHLS Overview of Communicable Diseases Committee. 2001. PHLS overview of communicable diseases 1999. Commun Dis Public Health, 4 (1), pp. 8-17. | Show Abstract

Every other year since 1995 the Public Health Laboratory Service has undertaken a consultation exercise to identify communicable diseases of high public health priority. The purpose of identifying disease priorities is to guide rational and transparent service planning and resource allocation. Also, the process aims to ensure a customer sensitive service. This paper presents the results of the priority setting exercise undertaken in 1999. A postal questionnaire was sent to 1130 key professionals involved in communicable disease control in the United Kingdom. Respondents were asked to assess the relative priority of 61 communicable diseases and to identify priority areas of work associated with these diseases. Five criteria were used to assess relative priority. The five criteria were; present burden of ill-health, social and economic impact, potential threat to health, health gain opportunity and public concern and confidence. For each disease, respondents were asked to score the importance of each criterion. Forty six percent of participants (518/1130) returned completed questionnaires. There was no significant difference in response rate by professional group. Based on the scores assigned to each of the five criteria, the relative priority of 61 communicable diseases has been established. The top ten diseases in descending order of priority are, HIV/AIDS, meningococcal diseases, Chlamydia trachomatis, influenza, tuberculosis, E. coli O157, Methicillin resistant Staphylococcus aureus, salmonellosis, transmissible spongiform encephalopathies and Helicobacter pylori. The opinion of a large number of health care professionals has been used to establish a priority rank for a wide range of communicable diseases. This work provides planners and policy makers with a synthesis of current professional opinion that can be used as a foundation for making decisions on service developments.

Horby P, Murray V, Cummins A, Mackway-Jones K, Euripidou R. 2000. The capability of accident and emergency departments to safely decontaminate victims of chemical incidents. J Accid Emerg Med, 17 (5), pp. 344-347. | Show Abstract | Read more

OBJECTIVES: To evaluate the capability of accident and emergency (A&E) departments in six health regions of England to safely decontaminate casualties exposed to hazardous chemicals. METHODS: In January 1999 a postal questionnaire was sent to the clinical director of all A&E departments in Trent, North and South Thames, South and West, North West and, Anglia and Oxford Health Regions. The questionnaire inquired about characteristics of the department, decontamination facilities and equipment, and staff training. Nonresponders were sent a second questionnaire and contacted by telephone if they failed to respond to the second mailing. RESULTS: 308 of 326 departments identified (94%) returned a questionnaire. There was no significant difference in response rate by region (p = 0.99). Analysis was restricted to 154 major departments seeing more than 20000 new attendances per year. Of these 154 departments, 109 (71%) had a written chemical incident plan but only 55 (36%) maintained a list of nearby industrial chemical sites. Fifty nine departments (38%) stated that members of staff had received training in the management of chemically contaminated casualties in the preceding year. Eighteen departments (12%) possessed the level of personal protective equipment (PPE) recommended for decontamination by the Ambulance Services Association. Ninety six departments (62%) had a designated decontamination room but only seven (7%) of them incorporated all the features generally considered necessary for safe decontamination. Forty one units (27%) had the capability to decontaminate casualties outside of the department either with warm water from a shower attachment or with a mobile decontamination unit. Thirty six departments (23%) had neither a decontamination room nor the ability to decontaminate casualties outside the department. Only 16 units (10%) had both adequate PPE and either a decontamination room or the capability to decontaminate outside the department. CONCLUSIONS: This study has identified deficiencies in the current NHS capability to respond to chemical incidents. To resolve this, nationally recognised standards for decontamination facilities, equipment and training should be formulated, agreed and implemented.

Dyke T, Flew S, Bramwell S, Murray F, Horby P. 1993. Haemophilia A in the highlands: the investigation and management of two families in Tari. P N G Med J, 36 (1), pp. 22-28. | Show Abstract

A 12-year-old boy from Tari in the Southern Highlands of Papua New Guinea presented with prolonged bleeding from a minor injury to the lip. He had a history of profuse bleeding and joint swelling following minor trauma. He has two younger brothers with a similar history. It was demonstrated that they had a coagulation profile compatible with factor VIII deficiency and a family tree suggestive of haemophilia A. A further case was investigated some months later. Despite the neighbouring places of residence of the two families no familial connection could be established by involved discussions between family members. This was confirmed by reviewing the data held on the demographic surveillance system of the Tari Unit of the Papua New Guinea Institute of Medical Research. These families are considered against a background of the diagnosis and management of this condition in a rural part of Papua New Guinea. The long-term support of these patients and other similarly affected individuals presents difficult clinical and ethical problems for rural health services.

Dunning J, Kennedy SB, Antierens A, Whitehead J, Ciglenecki I, Carson G, Kanapathipillai R, Castle L, Howell-Jones R, Pardinaz-Solis R et al. 2016. Experimental Treatment of Ebola Virus Disease with Brincidofovir. PLoS One, 11 (9), pp. e0162199. | Show Abstract | Read more

BACKGROUND: The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. METHODS AND FINDINGS: In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. CONCLUSIONS: Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000939962.

Horby PW, Laurie KL, Cowling BJ, Engelhardt OG, Sturm-Ramirez K, Sanchez JL, Katz JM, Uyeki TM, Wood J, Van Kerkhove MD. 2016. CONSISE statement on the reporting of Seroepidemiologic Studies for influenza (ROSES-I statement): An extension of the STROBE statement Influenza and other Respiratory Viruses, | Show Abstract | Read more

© 2016 John Wiley & Sons Ltd.Background: Population-based serologic studies are a vital tool for understanding the epidemiology of influenza and other respiratory viruses, including the early assessment of the transmissibility and severity of the 2009 influenza pandemic, and Middle East respiratory syndrome coronavirus. However, interpretation of the results of serologic studies has been hampered by the diversity of approaches and the lack of standardized methods and reporting. Objective: The objective of the CONSISE ROSES-I statement was to improve the quality and transparency of reporting of influenza seroepidemiologic studies and facilitate the assessment of the validity and generalizability of published results. Methods: The ROSES-I statement was developed as an expert consensus of the CONSISE epidemiology and laboratory working groups. The recommendations are presented in the familiar format of a reporting guideline. Because seroepidemiologic studies are a specific type of observational epidemiology study, the ROSES-I statement is built upon the STROBE guidelines. As such, the ROSES-I statement should be seen as an extension of the STROBE guidelines. Results: The ROSES-I statement presents 42 items that can be used as a checklist of the information that should be included in the results of published seroepidemiologic studies, and which can also serve as a guide to the items that need to be considered during study design and implementation. Conclusions: We hope that the ROSES-I statement will contribute to improving the quality of reporting of seroepidemiologic studies.

Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK et al. 2016. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial. PLoS Med, 13 (4), pp. e1001997. | Show Abstract | Read more

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, Horby PW, Raoul H, Magassouba N, Antierens A et al. 2016. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med, 374 (1), pp. 33-42. | Show Abstract | Read more

BACKGROUND: In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS: In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS: A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS: The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med, 12 (4), pp. e1001815. | Show Abstract | Read more

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Fonville JM, Wilks SH, James SL, Fox A, Ventresca M, Aban M, Xue L, Jones TC, Le NM, Pham QT et al. 2014. Antibody landscapes after influenza virus infection or vaccination. Science, 346 (6212), pp. 996-1000. | Show Abstract | Read more

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.

Cauchemez S, Ferguson NM, Fox A, Mai LEQ, Thanh LET, Thai PQ, Thoang DD, Duong TN, Minh Hoa LEN, Tran Hien N, Horby P. 2014. Determinants of influenza transmission in South East Asia: insights from a household cohort study in Vietnam. PLoS Pathog, 10 (8), pp. e1004310. | Show Abstract | Read more

To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza in the community or in the household. Here, we analyse a large household cohort study conducted in 2007-2010 in Vietnam using innovative statistical methods to ascertain in an integrative framework the relative contribution of variables that influence the transmission of seasonal (H1N1, H3N2, B) and pandemic H1N1pdm09 influenza. Influenza infection was diagnosed by haemagglutination-inhibition (HI) antibody assay of paired serum samples. We used a Bayesian data augmentation Markov chain Monte Carlo strategy based on digraphs to reconstruct unobserved chains of transmission in households and estimate transmission parameters. The probability of transmission from an infected individual to another household member was 8% (95% CI, 6%, 10%) on average, and varied with pre-season titers, age and household size. Within households of size 3, the probability of transmission from an infected member to a child with low pre-season HI antibody titers was 27% (95% CI 21%-35%). High pre-season HI titers were protective against infection, with a reduction in the hazard of infection of 59% (95% CI, 44%-71%) and 87% (95% CI, 70%-96%) for intermediate (1∶20-1∶40) and high (≥1∶80) HI titers, respectively. Even after correcting for pre-season HI titers, adults had half the infection risk of children. Twenty six percent (95% CI: 21%, 30%) of infections may be attributed to household transmission. Our results highlight the importance of integrated analysis by influenza sub-type, age and pre-season HI titers in order to infer influenza transmission risks in and outside of the household.

Cauchemez S, Horby P, Fox A, Mai LEQ, Thanh LET, Thai PQ, Hoa LENM, Hien NT, Ferguson NM. 2012. Influenza infection rates, measurement errors and the interpretation of paired serology. PLoS Pathog, 8 (12), pp. e1003061. | Show Abstract | Read more

Serological studies are the gold standard method to estimate influenza infection attack rates (ARs) in human populations. In a common protocol, blood samples are collected before and after the epidemic in a cohort of individuals; and a rise in haemagglutination-inhibition (HI) antibody titers during the epidemic is considered as a marker of infection. Because of inherent measurement errors, a 2-fold rise is usually considered as insufficient evidence for infection and seroconversion is therefore typically defined as a 4-fold rise or more. Here, we revisit this widely accepted 70-year old criterion. We develop a Markov chain Monte Carlo data augmentation model to quantify measurement errors and reconstruct the distribution of latent true serological status in a Vietnamese 3-year serological cohort, in which replicate measurements were available. We estimate that the 1-sided probability of a 2-fold error is 9.3% (95% Credible Interval, CI: 3.3%, 17.6%) when antibody titer is below 10 but is 20.2% (95% CI: 15.9%, 24.0%) otherwise. After correction for measurement errors, we find that the proportion of individuals with 2-fold rises in antibody titers was too large to be explained by measurement errors alone. Estimates of ARs vary greatly depending on whether those individuals are included in the definition of the infected population. A simulation study shows that our method is unbiased. The 4-fold rise case definition is relevant when aiming at a specific diagnostic for individual cases, but the justification is less obvious when the objective is to estimate ARs. In particular, it may lead to large underestimates of ARs. Determining which biological phenomenon contributes most to 2-fold rises in antibody titers is essential to assess bias with the traditional case definition and offer improved estimates of influenza ARs.

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Horby P, Mai LQ, Fox A, Thai PQ, Thi Thu Yen N, Thanh LT, Le Khanh Hang N, Duong TN, Thoang DD, Farrar J et al. 2012. The epidemiology of interpandemic and pandemic influenza in Vietnam, 2007-2010 American Journal of Epidemiology, 175 (10), pp. 1062-1074. | Show Abstract | Read more

Prospective community-based studies have provided fundamental insights into the epidemiology of influenza in temperate regions, but few comparable studies have been undertaken in the tropics. The authors conducted prospective influenza surveillance and intermittent seroprevalence surveys in a household-based cohort in Vietnam between December 2007 and April 2010, resulting in 1,793 person-seasons of influenza surveillance. Age-and sex-standardized estimates of the risk of acquiring any influenza infection per season in persons 5 years of age or older were 21.1% (95% confidence interval: 17.4, 24.7) in season 1, 26.4% (95% confidence interval: 22.6, 30.2) in season 2, and 17.0% (95% confidence interval: 13.6, 20.4) in season 3. Some individuals experienced multiple episodes of infection with different influenza types/subtypes in the same season (n = 27) or reinfection with the same subtype in different seasons (n = 22). The highest risk of influenza infection was in persons 5-9 years old, in whom the risk of influenza infection per season was 41.8%. Although the highest infection risk was in school-aged children, there were important heterogeneities in the age of infection by subtype and season. These heterogeneities could influence the impact of school closure and childhood vaccination on influenza transmission in tropical areas, such as Vietnam. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Cuong HQ, Hien NT, Duong TN, Phong TV, Cam NN, Farrar J, Nam VS, Thai KT, Horby P. 2011. Quantifying the emergence of dengue in Hanoi, Vietnam: 1998-2009. PLoS Negl Trop Dis, 5 (9), pp. e1322. | Show Abstract | Read more

BACKGROUND: An estimated 2.4 billion people live in areas at risk of dengue transmission, therefore the factors determining the establishment of endemic dengue in areas where transmission suitability is marginal is of considerable importance. Hanoi, Vietnam is such an area, and following a large dengue outbreak in 2009, we set out to determine if dengue is emerging in Hanoi. METHODS AND PRINCIPAL FINDINGS: We undertook a temporal and spatial analysis of 25,983 dengue cases notified in Hanoi between 1998 and 2009. Age standardized incidence rates, standardized age of infection, and Standardized Morbidity Ratios (SMR) were calculated. A quasi-Poisson regression model was used to determine if dengue incidence was increasing over time. Wavelet analysis was used to explore the periodicity of dengue transmission and the association with climate variables. After excluding the two major outbreak years of 1998 and 2009 and correcting for changes in population age structure, we identified a significant annual increase in the incidence of dengue cases over the period 1999-2008 (incidence rate ratio  =  1.38, 95% confidence interval  =  1.20-1.58, p value  =  0.002). The age of notified dengue cases in Hanoi is high, with a median age of 23 years (mean 26.3 years). After adjusting for changes in population age structure, there was no statistically significant change in the median or mean age of dengue cases over the period studied. Districts in the central, highly urban, area of Hanoi have the highest incidence of dengue (SMR>3). CONCLUSIONS: Hanoi is a low dengue transmission setting where dengue incidence has been increasing year on year since 1999. This trend needs to be confirmed with serological surveys, followed by studies to determine the underlying drivers of this emergence. Such studies can provide insights into the biological, demographic, and environmental changes associated with vulnerability to the establishment of endemic dengue.

Horby P, Sudoyo H, Viprakasit V, Fox A, Thai PQ, Yu H, Davila S, Hibberd M, Dunstan SJ, Monteerarat Y et al. 2010. What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1? Epidemiol Infect, 138 (11), pp. 1550-1558. | Show Abstract | Read more

The apparent family clustering of avian influenza A/H5N1 has led several groups to postulate the existence of a host genetic influence on susceptibility to A/H5N1, yet the role of host factors on the risk of A/H5N1 disease has received remarkably little attention compared to the efforts focused on viral factors. We examined the epidemiological patterns of human A/H5N1 cases, their possible explanations, and the plausibility of a host genetic effect on susceptibility to A/H5N1 infection. The preponderance of familial clustering of cases and the relative lack of non-familial clusters, the occurrence of related cases separated by time and place, and the paucity of cases in some highly exposed groups such as poultry cullers, are consistent with a host genetic effect. Animal models support the biological plausibility of genetic susceptibility to A/H5N1. Although the evidence is circumstantial, host genetic factors are a parsimonious explanation for the unusual epidemiology of human A/H5N1 cases and warrant further investigation.

Le QM, Wertheim HF, Tran ND, van Doorn HR, Nguyen TH, Horby P, Vietnam H1N1 Investigation Team. 2010. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med, 362 (1), pp. 86-87. | Read more

Liem NT, Tung CV, Hien ND, Hien TT, Chau NQ, Long HT, Hien NT, Mai LEQ, Taylor WR, Wertheim H et al. 2009. Clinical features of human influenza A (H5N1) infection in Vietnam: 2004-2006. Clin Infect Dis, 48 (12), pp. 1639-1646. | Show Abstract | Read more

BACKGROUND: The first cases of avian influenza A (H5N1) in humans in Vietnam were detected in early 2004, and Vietnam has reported the second highest number of cases globally. METHODS: We obtained retrospective clinical data through review of medical records for laboratory confirmed cases of influenza A (H5N1) infection diagnosed in Vietnam from January 2004 through December 2006. Standard data was abstracted regarding clinical and laboratory features, treatment, and outcome. RESULTS: Data were obtained for 67 (72%) of 93 cases diagnosed in Vietnam over the study period. Patients presented to the hospital after a median duration of illness of 6 days with fever (75%), cough (89%), and dyspnea (81%). Diarrhea and mucosal bleeding at presentation were more common in fatal than in nonfatal cases. Common findings were bilateral pulmonary infiltrates on chest radiograph (72%), lymphopenia (73%), and increased serum transaminase levels (aspartate aminotransferase, 69%; alanine aminotransferase, 61%). Twenty-six patients died (case fatality rate, 39%; 95% confidence interval, 27%-51%) and the most reliable predictor of a fatal outcome was the presence of both neutropenia and raised alanine aminotransferase level at admission, which correctly predicted 91% of deaths and 82% of survivals. The risk of death was higher among persons aged < or =16 years, compared with older persons (P < .001), and the risk of death was higher among patients who did not receive oseltamivir treatment (P = .048). The benefit of oseltamivir treatment remained after controlling for potential confounding by 1 measure of severity (odds ratio, 0.15; 95% confidence interval, 0.026-0.893; P = .034). CONCLUSION: In cases of infection with Influenza A (H5N1), the presence of both neutropenia and raised serum transaminase levels predicts a poor outcome. Oseltamivir treatment shows benefit, but treatment with corticosteroids is associated with an increased risk of death.

Wertheim HF, Nguyen HN, Taylor W, Lien TT, Ngo HT, Nguyen TQ, Nguyen BN, Nguyen HH, Nguyen HM, Nguyen CT et al. 2009. Streptococcus suis, an important cause of adult bacterial meningitis in northern Vietnam. PLoS One, 4 (6), pp. e5973. | Show Abstract | Read more

BACKGROUND: Streptococcus suis can cause severe systemic infection in adults exposed to infected pigs or after consumption of undercooked pig products. S. suis is often misdiagnosed, due to lack of awareness and improper testing. Here we report the first fifty cases diagnosed with S. suis infection in northern Viet Nam. METHODOLOGY/PRINCIPAL FINDINGS: In 2007, diagnostics for S. suis were set up at a national hospital in Hanoi. That year there were 43 S. suis positive cerebrospinal fluid samples, of which S. suis could be cultured in 32 cases and 11 cases were only positive by PCR. Seven patients were blood culture positive for S. suis but CSF culture and PCR negative; making a total of 50 patients with laboratory confirmed S. suis infection in 2007. The number of S. suis cases peaked during the warmer months. CONCLUSIONS/SIGNIFICANCE: S. suis was commonly diagnosed as a cause of bacterial meningitis in adults in northern Viet Nam. In countries where there is intense and widespread exposure of humans to pigs, S. suis can be an important human pathogen.

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