Publications by authors named "Annette Fox"

59 Publications

Impact of prior vaccination on antibody response and influenza-like illness among Australian healthcare workers after influenza vaccination in 2016.

Vaccine 2021 May 10. Epub 2021 May 10.

WHO Collaborating Centre for Reference and Research on Influenza, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Fielding School of Public Health, University of California, Los Angeles, USA; Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. Electronic address:

Background: Epidemiological studies suggest that influenza vaccine effectiveness decreases with repeated administration. We examined antibody responses to influenza vaccination among healthcare workers (HCWs) by prior vaccination history and determined the incidence of influenza infection.

Methods: HCWs were vaccinated with the 2016 Southern Hemisphere quadrivalent influenza vaccine. Serum samples were collected pre-vaccination, 21-28 days and 7 months post-vaccination. Influenza antibody titres were measured at each time-point using the haemagglutination inhibition (HI) assay. Immunogenicity was compared by prior vaccination history.

Results: A total of 157 HCWs completed the study. The majority were frequently vaccinated, with only 5 reporting no prior vaccinations since 2011. Rises in titres for all vaccine strains among vaccine-naïve HCWs were significantly greater than rises observed for HCWs who received between 1 and 5 prior vaccinations (p < 0.001, respectively). Post-vaccination GMTs against influenza A but not B strains decreased as the number of prior vaccinations increased from 1 to 5. There was a significant decline in GMTs post-season for both B lineages. Sixty five (41%) HCWs reported at least one influenza-like illness episode, with 6 (4%) identified as influenza positive.

Conclusions: Varying serological responses to influenza vaccination were observed among HCWs by prior vaccination history, with vaccine-naïve HCWs demonstrating greater post-vaccination responses against A(H3N2).
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http://dx.doi.org/10.1016/j.vaccine.2021.04.036DOI Listing
May 2021

Influenza A(H1N1)pdm09 but not A(H3N2) virus infection induces durable sero-protection: results from the Ha Nam Cohort.

J Infect Dis 2020 Jun 2. Epub 2020 Jun 2.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Hanoi, Viet Nam.

Background: The extent to which influenza recurrence depends upon waning immunity from prior-infection is undefined. We used antibody titres of Ha-Nam cohort participants to estimate protection curves and decay trajectories.

Methods: 270 households participated in influenza-like-illness surveillance and provided blood at intervals spanning RTPCR-confirmed transmission. Sera were tested in haemagglutination inhibition assay. Infection was defined as RTPCR+ influenza-like-illness and/or seroconversion. Median protective titres were estimated using scaled-logistic-regression to model pre-transmission titre against infection status in that season, limiting analysis to households with infection(s). Titres were modelled against month since infection using mixed-effects linear regression to estimate decay and when titres fell below protection-thresholds.

Results: 295 and 314 participants were infected with H1N1pdm09-like and A/Perth/16/09-like (H3N2Pe09) viruses, respectively between December 2008-2012. The proportion of householders not-infected (protected) rose more steeply with titre for H1N1pdm09 than for H3N2Pe09, and estimated 50% protection titres were 19.6 and 37.3, respectively. Post-infection titres started higher against H3N2Pe09 but decayed more steeply than against H1N1pdm09. Sero-protection was estimated to be sustained against H1N1pdm09 but to wane by 8-months for H3N2Pe09.

Conclusions: Estimates indicate that infection induces durable sero-protection against H1N1pdm09 but not H3N2Pe09, which could in part account for the younger age of A(H1N1) versus A(H3N2) cases.
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http://dx.doi.org/10.1093/infdis/jiaa293DOI Listing
June 2020

Distinguishing naive- from memory-derived human B cells during acute responses.

Clin Transl Immunology 2019 13;8(11):e01090. Epub 2019 Nov 13.

WHO Collaborating Centre for Reference and Research on Influenza VIDRL at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia.

Objectives: A fundamental question in influenza research is whether antibody titre decline upon successive exposure to variant strains is consequent to recall of cross-reactive memory B cells that competitively inhibit naive B-cell responses. In connection, it is not clear whether naive and memory B cells remain phenotypically distinct acutely after activation such that they may be distinguished .

Methods: Here, we first compared the capacity of anti-Ig and Toll-like-receptor (TLR) 7/8 and TLR9 agonists (R848 and CpG) to augment human B-cell differentiation induced by IL-21 and sCD40L. The conditions that induced optimal differentiation were then used to compare the post-activation phenotype of sort-purified naive and memory B-cell subsets by FACS and antibody-secreting cell (ASC) ELISPOT.

Results: Sort-purified naive and memory B cells underwent robust plasmablast and ASC formation when stimulated with R848, but not CpG, and co-cultured with monocytes. This coincided with increased IL-1β and IL-6 production when B cells were co-cultured with monocytes and stimulated with R848, but not CpG. Naive B cells underwent equivalent ASC generation, but exhibited less class-switch and modulation of CD27, CD38 and CD20 expression than memory B cells after stimulation with R848 and monocytes for 6 days.

Conclusion: Stimulation with R848, IL-21 and sCD40L in the presence of monocytes induces robust differentiation and ASC generation from both naive and memory B-cells. However, naive and memory B cells retain key phenotypic differences after activation that may facilitate discrimination and better characterisation of acute responses to variant antigens.
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http://dx.doi.org/10.1002/cti2.1090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851823PMC
November 2019

Neuraminidase escape attempts.

Nat Microbiol 2019 12;4(12):2031-2032

WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1038/s41564-019-0615-2DOI Listing
December 2019

Recalling the Future: Immunological Memory Toward Unpredictable Influenza Viruses.

Front Immunol 2019 2;10:1400. Epub 2019 Jul 2.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4 T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against "drifted" (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 "swine" flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8 T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such "memory" cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8 CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 "Spanish flu," which killed more than 50 million people worldwide.
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http://dx.doi.org/10.3389/fimmu.2019.01400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614380PMC
July 2020

Limited Phenotypic and Functional Plasticity of Influenza Virus-Specific Memory CD8 T Cells during Activation in an Alternative Cytokine Environment.

J Immunol 2018 12 26;201(11):3282-3293. Epub 2018 Oct 26.

Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia

Naive CD8 T cells show phenotypic, functional, and epigenetic plasticity, enabling differentiation into distinct cellular states. However, whether memory CD8 T cells demonstrate similar flexibility upon recall is poorly understood. We investigated the potential of influenza A virus (IAV)-specific memory CD8 T cells from mice to alter their phenotype and function in response to reactivation in the presence of IL-4 and anti-IFN-γ Ab (type 2 conditions). Compared with naive CD8 T cells, only a small proportion of IAV-specific memory T cells exhibited phenotypic and functional plasticity after clonal activation under type 2 conditions. The potential for modulation of cell-surface phenotype (CD8α expression) was associated with specific epigenetic changes at the locus, was greater in central memory T cells than effector memory T cells, and was observed in endogenous memory cells of two TCR specificities. Using a novel technique for intracellular cytokine staining of small clonal populations, we showed that IAV-specific memory CD8 T cells reactivated under type 2 conditions displayed robust IFN-γ expression and, unlike naive CD8 T cells activated under type 2 conditions, produced little IL-4 protein. Secondary activation of memory cells under type 2 conditions increased GATA-3 levels with minimal change in T-bet levels. These data suggest that a small population of memory cells, especially central memory T cells, exhibits plasticity; however, most IAV-specific memory CD8 T cells resist reprogramming upon reactivation and retain the functional state established during priming.
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http://dx.doi.org/10.4049/jimmunol.1701672DOI Listing
December 2018

Extending the Breadth of Influenza Vaccines: Status and Prospects for a Universal Vaccine.

Drugs 2018 Sep;78(13):1297-1308

WHO Collaborating Centre for Reference and Research on Influenza, and the Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, VIC, Australia.

Despite the widespread use of seasonal influenza vaccines, there is urgent need for a universal influenza vaccine to provide broad, long-term protection. A number of factors underpin this urgency, including threats posed by zoonotic and pandemic influenza A viruses, suboptimal effectiveness of seasonal influenza vaccines, and concerns surrounding the effects of annual vaccination. In this article, we discuss approaches that are being investigated to increase influenza vaccine breadth, which are near-term, readily achievable approaches to increase the range of strains recognized within a subtype, or longer-term more challenging approaches to produce a truly universal influenza vaccine. Adjuvanted and neuraminidase-optimized vaccines are emerging as the most feasible and promising approaches to extend protection to cover a broader range of strains within a subtype. The goal of developing a universal vaccine has also been advanced with the design of immunogenic influenza HA-stem constructs that induce broadly neutralizing antibodies. However, these constructs are not yet sufficiently immunogenic to induce lasting universal immunity in humans. Advances in understanding how T cells mediate protection, and how viruses are packaged, have facilitated the rationale design and delivery of replication-incompetent virus vaccines that induce broad protection mediated by lung-resident memory T cells. While the lack of clear mechanistic correlates of protection, other than haemagglutination-inhibiting antibodies, remains an impediment to further advancing novel influenza vaccines, the pressing need for such a vaccine is supporting development of highly innovative and effective strategies.
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http://dx.doi.org/10.1007/s40265-018-0958-7DOI Listing
September 2018

Age-Related Decline in Primary CD8 T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8 T Cells.

Cell Rep 2018 06;23(12):3512-3524

Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Department of Microbiology and Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia. Electronic address:

Age-associated decreases in primary CD8 T cell responses occur, in part, due to direct effects on naive CD8 T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated "virtual memory" (T) cells, but their contribution to age-related functional decline is unclear. Here, we show that T cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (T cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged T cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population.
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http://dx.doi.org/10.1016/j.celrep.2018.05.057DOI Listing
June 2018

Exposure of Human CD8 T Cells to Type-2 Cytokines Impairs Division and Differentiation and Induces Limited Polarization.

Front Immunol 2018 28;9:1141. Epub 2018 May 28.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

Effector CD8 T cells generally produce type-1 cytokines and mediators of the perforin/granzyme cytolytic pathway, yet type-2-polarized CD8 cells (Tc2) are detected in type-2 (T2) cytokine-driven diseases such as asthma. It is unclear whether T2 cytokine exposure during activation is sufficient to polarize human CD8 T cells. To address this question, a protocol was developed for high-efficiency activation of human CD8 T cells in which purified single cells or populations were stimulated with plate-bound anti-CD3 and anti-CD11a mAb for up to 8 days in T2 polarizing or neutral conditions, before functional analysis. Activation of CD8 naïve T cells (T) in T2 compared with neutral conditions decreased the size of single-cell clones, although early division kinetics were equivalent, indicating an effect on overall division number. Activation of T in T2 conditions followed by brief anti-CD3 mAb restimulation favored expression of T2 cytokines, GATA3 and , and lowered expression of type-1 cytokines, , Gzmb, T-BET, and . However, IL-4 was only weakly expressed, and PMA and ionomycin restimulation favored IFN-γ over IL-4 expression. Activation of T in T2 compared with neutral conditions prevented downregulation of costimulatory (CD27, CD28) and lymph-node homing receptors (CCR7) and CD95 acquisition, which typically occur during differentiation into effector phenotypes. CD3 was rapidly and substantially induced after activation in neutral, but not T2 conditions, potentially contributing to greater division and differentiation in neutral conditions. CD8 central memory T cells (T) were less able to enter division upon reactivation in T2 compared with neutral conditions, and were more refractory to modulating IFN-γ and IL-4 production than CD8 T In summary, while activation of T in T2 conditions can generate T2 cytokine-biased cells, IL-4 expression is weak, T2 bias is lost upon strong restimulation, differentiation, and division are arrested, and reactivation of T is reduced in T2 conditions. Taken together, this suggests that exposure to T2 cytokines during activation may not be sufficient to generate and retain human Tc2 cells.
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http://dx.doi.org/10.3389/fimmu.2018.01141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985406PMC
July 2019

Infants Harness the Germline against RSV.

Immunity 2018 02;48(2):190-192

WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.

In this issue of Immunity, Goodwin et al. (2018) offer hope for an RSV vaccine for young infants by demonstrating that RSV infection in very young infants induces neutralizing antibodies that are close to the germline and have unusual epitope specificity.
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http://dx.doi.org/10.1016/j.immuni.2018.02.005DOI Listing
February 2018

Circulating T cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity.

Sci Transl Med 2018 02;10(428)

Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.

Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (T) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5CXCR3 antibody-secreting B cell population, CD21CD27 memory B cells, and CD21CD27 B cells. Activation of circulating T cells correlated with the development of both CD21 and CD21 memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8, mucosal-associated invariant T, γδ T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21CD27) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating T cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.
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http://dx.doi.org/10.1126/scitranslmed.aan8405DOI Listing
February 2018

Strongyloides stercoralis seroprevalence in Vietnam.

Epidemiol Infect 2017 11 17;145(15):3214-3218. Epub 2017 Oct 17.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme,Hanoi,Vietnam.

Strongyloidiasis is a neglected tropical disease caused by the roundworm Strongyloides stercoralis affecting 30-100 million people worldwide. Many Southeast-Asian countries report a high prevalence of S. stercoralis infection, but there are little data from Vietnam. Here, we evaluated the seroprevalence of S. stercoralis related to geography, sex and age in Vietnam through serological testing of anonymized sera. Sera (n = 1710, 1340 adults and 270 children) from an anonymized age-stratified serum bank from four regions in Vietnam between 2012 and 2013 were tested using a commercial Strongyloides ratti immunoglobulin G ELISA. Seroreactivity was found in 29·1% (390/1340) of adults and 5·5% (15/270) of children. Male adults were more frequently seroreactive than females (33·3% vs. 24·9%, P = 0·001). The rural central highlands had the highest seroprevalence (42·4% of adults). Seroreactivity in the other regions was 29·9% (Hue) and 26·0% and 18·2% in the large urban centres of Hanoi and Ho Chi Minh City, respectively. We conclude that seroprevalence of S. stercoralis was high in the Vietnamese adult population, especially in rural areas.
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http://dx.doi.org/10.1017/S0950268817002333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116469PMC
November 2017

Seroprevalence of Scrub Typhus, Typhus, and Spotted Fever Among Rural and Urban Populations of Northern Vietnam.

Am J Trop Med Hyg 2017 May;96(5):1084-1087

Center for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.

AbstractRickettsial infections are recognized as important causes of fever throughout southeast Asia. Herein, we determined the seroprevalence to rickettsioses within rural and urban populations of northern Vietnam. Prevalence of individuals with evidence of prior rickettsial infections (IgG positive) was surprisingly low, with 9.14% (83/908) testing positive to the three major rickettsial serogroups thought to circulate in the region. Prevalence of typhus group rickettsiae (TG)-specific antibodies (6.5%, 58/908) was significantly greater than scrub typhus group orientiae (STG)- or spotted fever group rickettsiae (SFG)-specific antibodies ( < 0.05). The majority of TG seropositives were observed among urban rather than rural residents ( < 0.05). In contrast, overall antibody prevalence to STG and SFG were both very low (1.1%, 10/908 for STG; 1.7%, 15/908 for SFG), with no significant differences between rural and urban residents. These results provide data on baseline population characteristics that may help inform development of serological testing criteria in future clinical studies.
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http://dx.doi.org/10.4269/ajtmh.16-0399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417199PMC
May 2017

Epidemiology and etiology of influenza-like-illness in households in Vietnam; it's not all about the kids!

J Clin Virol 2016 09 26;82:126-132. Epub 2016 Jul 26.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Vietnam; The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, Parkville, Victoria, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jcv.2016.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994428PMC
September 2016

Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study.

J Infect Dis 2016 Sep 26;214(5):697-706. Epub 2016 May 26.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Hanoi Nuffield Department of Medicine, University of Oxford, United Kingdom.

Background: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown.

Methods: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points.

Results: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated.

Conclusions: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1.
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http://dx.doi.org/10.1093/infdis/jiw220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978369PMC
September 2016

Association between Hemagglutinin Stem-Reactive Antibodies and Influenza A/H1N1 Virus Infection during the 2009 Pandemic.

J Virol 2016 07 24;90(14):6549-6556. Epub 2016 Jun 24.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Hanoi, Vietnam

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.
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http://dx.doi.org/10.1128/JVI.00093-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936154PMC
July 2016

Population structure of colonizing and invasive strains in northern Vietnam.

J Med Microbiol 2016 Apr 12;65(4):298-305. Epub 2016 Jan 12.

Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands.

is an important global health problem worldwide. There is still scarce information on the population structure of strains in Asia, where the majority of the world population lives. This study characterized the diversity of strains in northern Vietnam through multilocus sequence typing (MLST). Eighty-five carriage isolates from the community and 77 invasive isolates from the clinical setting were selected and tested for meticillin resistance and the presence of Panton-Valentine leukocidin (PVL). MLST was performed on these isolates, of which CC59 (25.4 %), CC188 (17.3 %) and CC45 (16.7 %) were the predominant clonal complexes (CCs). CC59 carriage isolates had significantly lower rates of meticillin-resistant (MRSA) than their corresponding clinical group isolates (32 vs 83 %). There were no significant differences in rates of MRSA between carriage isolates and clinical isolates of CC45 and CC188. CC59 carriage isolates were significantly lower in rates of PVL than CC59 clinical isolates (32 vs 83 %), but the converse was shown in CC45 isolates (14 vs 0 %, respectively). This study revealed vast differences in the molecular epidemiology and population structure of in community and clinical settings in Vietnam. Nevertheless, the data underline the spread of virulent and/or resistant strains (MRSA and/or PVL) in the community, suggesting the necessity for further surveillance to determine the mechanism of transmission of these strains (i.e. MRSA/PVL) outside clinical settings.
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http://dx.doi.org/10.1099/jmm.0.000220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819339PMC
April 2016

Biomonitoring of polycyclic aromatic hydrocarbons exposure in small groups of residents in Brisbane, Australia and Hanoi, Vietnam, and those travelling between the two cities.

Chemosphere 2015 Nov 14;139:358-64. Epub 2015 Jul 14.

The University of Queensland, The National Research Centre for Environmental Toxicology (Entox), Australia.

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse health outcomes. Concentrations of urinary PAH metabolites (OH-PAHs) provide an integrated measure of human exposure to PAHs but measurement of urinary OH-PAHs has not been done in Australia and rarely in Vietnam, where air pollution is of concern. In this study, we assessed exposure to PAHs in 16 participants living in Brisbane, Australia and Hanoi, Vietnam, with 4 participants travelling between the two cities during the monitoring period. A total of 312 first morning urine samples were collected over 10weeks and were analysed for nine OH-PAHs. Concentrations of the urinary OH-PAHs were 2-10 times higher in participants from Hanoi than those from Brisbane. For example, the median concentrations of 1-hydroxypyrene were 292pg/mL in Hanoi, compared to 64pg/mL in Brisbane. For participants travelling from Brisbane to Hanoi and back, differences in exposure to PAHs in these two cities resulted in corresponding changes of urinary OH-PAH concentrations, demonstrating that the more polluted environment in Hanoi was likely the source for higher PAH exposure there.
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http://dx.doi.org/10.1016/j.chemosphere.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596407PMC
November 2015

Dengue in adults admitted to a referral hospital in Hanoi, Vietnam.

Am J Trop Med Hyg 2015 Jun 27;92(6):1141-1149. Epub 2015 Apr 27.

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.
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http://dx.doi.org/10.4269/ajtmh.14-0472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458817PMC
June 2015

Patient-based transcriptome-wide analysis identify interferon and ubiquination pathways as potential predictors of influenza A disease severity.

PLoS One 2014 3;9(11):e111640. Epub 2014 Nov 3.

Genome Institute of Singapore, Singapore, Singapore.

Background: The influenza A virus is an RNA virus that is responsible for seasonal epidemics worldwide with up to five million cases of severe illness and 500,000 deaths annually according to the World Health Organization estimates. The factors associated with severe diseases are not well defined, but more severe disease is more often seen among persons aged >65 years, infants, pregnant women, and individuals of any age with underlying health conditions.

Methodology/principal Findings: Using gene expression microarrays, the transcriptomic profiles of influenza-infected patients with severe (N = 11), moderate (N = 40) and mild (N = 83) symptoms were compared with the febrile patients of unknown etiology (N = 73). We found that influenza-infected patients, regardless of their clinical outcomes, had a stronger induction of antiviral and cytokine responses and a stronger attenuation of NK and T cell responses in comparison with those with unknown etiology. More importantly, we found that both interferon and ubiquitination signaling were strongly attenuated in patients with the most severe outcomes in comparison with those with moderate and mild outcomes, suggesting the protective roles of these pathways in disease pathogenesis.

Conclusion/significances: The attenuation of interferon and ubiquitination pathways may associate with the clinical outcomes of influenza patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111640PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218794PMC
August 2015

Hemagglutination inhibiting antibodies and protection against seasonal and pandemic influenza infection.

J Infect 2015 Feb 16;70(2):187-96. Epub 2014 Sep 16.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Viet Nam; Center for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1016/j.jinf.2014.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309889PMC
February 2015

Staphylococcus aureus nasopharyngeal carriage in rural and urban northern Vietnam.

Trans R Soc Trop Med Hyg 2014 Dec 3;108(12):783-90. Epub 2014 Sep 3.

Oxford University Clinical Research Unit, Hanoi, Vietnam Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK

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.
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http://dx.doi.org/10.1093/trstmh/tru132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235569PMC
December 2014

Determinants of influenza transmission in South East Asia: insights from a household cohort study in Vietnam.

PLoS Pathog 2014 Aug 21;10(8):e1004310. Epub 2014 Aug 21.

Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programme, Hanoi, Vietnam.

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.
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http://dx.doi.org/10.1371/journal.ppat.1004310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140851PMC
August 2014

Klebsiella pneumoniae oropharyngeal carriage in rural and urban Vietnam and the effect of alcohol consumption.

PLoS One 2014 25;9(3):e91999. Epub 2014 Mar 25.

Oxford University Clinical Research Unit, Hanoi, Viet Nam; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091999PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965401PMC
January 2015

Investigation of dengue and Japanese encephalitis virus transmission in Hanam, Viet Nam.

Am J Trop Med Hyg 2014 May 10;90(5):892-896. Epub 2014 Mar 10.

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.
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http://dx.doi.org/10.4269/ajtmh.13-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015583PMC
May 2014

Pandemic H1N1 virus transmission and shedding dynamics in index case households of a prospective Vietnamese cohort.

J Infect 2014 Jun 1;68(6):581-90. Epub 2014 Feb 1.

Oxford University Clinical Research Unit and Wellcome Trust Major Overseas Programme, Viet Nam; Center for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Department of Microbiology and Immunology, University of Melbourne, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jinf.2014.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031397PMC
June 2014

Dengue virus in sub-tropical northern and central Viet Nam: population immunity and climate shape patterns of viral invasion and maintenance.

PLoS Negl Trop Dis 2013 5;7(12):e2581. Epub 2013 Dec 5.

Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom ; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

Dengue virus transmission occurs in both epidemic and endemic cycles across tropical and sub-tropical regions of the world. Incidence is particularly high in much of Southeast Asia, where hyperendemic transmission plagues both urban and rural populations. However, endemicity has not been established in some areas with climates that may not support year-round viral transmission. An understanding of how dengue viruses (DENV) enter these environments and whether the viruses persist in inapparent local transmission cycles is central to understanding how dengue emerges in areas at the margins of endemic transmission. Dengue is highly endemic in tropical southern Vietnam, while increasingly large seasonal epidemics have occurred in northern Viet Nam over the last decade. We have investigated the spread of DENV-1 throughout Vietnam to determine the routes by which the virus enters northern and central regions of the country. Phylogeographic analysis of 1,765 envelope (E) gene sequences from Southeast Asia revealed frequent movement of DENV between neighboring human populations and strong local clustering of viral lineages. Long-distance migration of DENV between human population centers also occurred regularly and on short time-scales, indicating human-mediated viral invasion into northern Vietnam. Human populations in southern Vietnam were found to be the primary source of DENV circulating throughout the country, while central and northern Vietnam acted as sink populations, likely due to reduced connectedness to other populations in the case of the central regions and to the influence of temperature variability on DENV replication and vector survival and competence in the north. Finally, phylogeographic analyses suggested that viral movement follows a gravity model and indicates that population immunity and physical and economic connections between populations may play important roles in shaping patterns of DENV transmission.
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http://dx.doi.org/10.1371/journal.pntd.0002581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854975PMC
July 2014

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

Emerg Infect Dis 2013 Oct;19(10):1674-7

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.
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http://dx.doi.org/10.3201/eid1910.130730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810763PMC
October 2013

Diagnostic accuracy of microscopic Observation Drug Susceptibility (MODS) assay for pediatric tuberculosis in Hanoi, Vietnam.

PLoS One 2013 4;8(9):e72100. Epub 2013 Sep 4.

National Hospital of Pediatrics, Hanoi, Vietnam ; Oxford University Clinical Research Unit, Hanoi, Vietnam.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072100PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762843PMC
April 2014

Acute measles encephalitis in partially vaccinated adults.

PLoS One 2013 13;8(8):e71671. Epub 2013 Aug 13.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City and Ha Noi, Viet Nam.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071671PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742472PMC
May 2014