@Oxford Publications 2012

RTS,S Clinical Trials Partnership, Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BGNO, Kabwende AL, Adegnika AA, Mordmüller B, Issifou S et al. 2012. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med, 367 (24), pp. 2284-2295. | Citations: 352 (Scopus) | Show Abstract | Read more

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

Cauchemez S, Horby P, Fox A, Mai LQ, Thanh LT, Thai PQ, Hoa LNM, Hien NT, Ferguson NM. 2012. Influenza infection rates, measurement errors and the interpretation of paired serology. PLoS Pathog, 8 (12), pp. e1003061. | Citations: 32 (Scopus) | 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 LT, Bich VTN, Ngai LK, Diep NTN, Phuc PH, Hung VP, Taylor WR, Horby P, Liem NT, Wertheim HFL. 2012. Fatal respiratory infections associated with rhinovirus outbreak, Vietnam. Emerg Infect Dis, 18 (11), pp. 1886-1888. | Citations: 15 (Scopus) | 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.

Talisuna AO, Karema C, Ogutu B, Juma E, Logedi J, Nyandigisi A, Mulenga M, Mbacham WF, Roper C, Guerin PJ et al. 2012. Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems. Lancet Infect Dis, 12 (11), pp. 888-896. | Citations: 36 (Scopus) | Show Abstract | Read more

Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and has been detected in western Thailand. The situation is ominously reminiscent of the emergence of resistance to chloroquine and to sulfadoxine-pyrimethamine several decades ago. Artemisinin resistance is a major threat to global public health, with the most severe potential effects in sub-Saharan Africa, where the disease burden is highest and systems for monitoring and containment of resistance are inadequate. The mechanisms that underlie artemisinin resistance are not fully understood. The main phenotypic trait associated with resistance is a substantial delay in parasite clearance, so far reported in southeast Asia but not in Africa. One of the pillars of the WHO global plan for artemisinin resistance containment is to increase monitoring and surveillance. In this Personal View, we propose strategies that should be adopted by malaria-endemic countries in Africa: resource mobilisation to reactivate regional surveillance networks, establishment of baseline parasite clearance profiles to serve as benchmarks to track emerging artemisinin resistance, improved data sharing to allow pooled analyses to identify rare events, modelling of risk factors for drug resistance, and development and validation of new approaches to monitor resistance.

Tran TK, Eriksson B, Nguyen CTK, 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. | Citations: 12 (Scopus) | 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.

Hien TT, Thuy-Nhien NT, Phu NH, Boni MF, Thanh NV, Nha-Ca NT, Thai LH, Thai CQ, Toi PV, Thuan PD et al. 2012. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J, 11 (1), pp. 355. | Citations: 63 (Scopus) | Show Abstract | Read more

BACKGROUND: By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. METHODS: From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. RESULTS: 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). CONCLUSIONS: This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam. TRIAL REGISTRATION: NTC01165372.

Nair M, Ariana P, Webster P. 2012. What influences the decision to undergo institutional delivery by skilled birth attendants? A cohort study in rural Andhra Pradesh, India. Rural Remote Health, 12 (4), pp. 2311. | Citations: 15 (Scopus) | Show Abstract

INTRODUCTION: Despite continuing efforts to promote skilled institutional delivery, eight women die every hour in India due to causes related to pregnancy and child birth. The objectives of this study were to assess the prevalence and the determinants of institutional delivery by skilled birth attendants in a rural population in Andhra Pradesh, India. METHODS: This cross-sectional study used data from 'Young Lives', a longitudinal study on childhood poverty, and the study population was a cohort of 1419 rural, economically deprived women (from the Young Lives study) in Andhra Pradesh, India. The data are from round-1 of Young Lives younger cohort recruited in 2002 and followed until 2015. The participation rate of households was 99.5%. RESULTS: Prevalence of skilled institutional delivery was 36.8%. Women's education (odds ratio [OR] for secondary education 2.06; 95% confidence interval [95%CI] 1.33-3.19), desire to be pregnant (OR 1.89; 95% CI 1.12-3.22) and adequate prenatal care (OR 1.69; 95% CI 1.30-2.21) were found to be the positive determinants of skilled institutional delivery. High birth order (OR for second birth 0.44; 95% CI 0.32-0.60, OR for third birth 0.47; 95% CI 0.30-0.72 and OR for ≥fourth 0.47; 95% CI 0.27-0.81), schedule caste/schedule tribe social background (OR 0.70; 95% CI 0.53-0.93) and poor economic status of the household (OR for the poorest households 0.67; 95% CI 0.46-0.99) were negatively associated with skilled institutional delivery. CONCLUSIONS: Despite existence of supporting schemes, the utilisation of skilled institutional delivery services was low in the study population. Educated women and women with adequate prenatal care who have a desired pregnancy were more likely to utilise health institutions and skilled delivery care. There is a need for integrated approaches through maternal health, family planning and education programs, and a focus on uneducated, poor women belonging to disadvantaged social groups.

Wertheim HFL, Ngoc DM, Wolbers M, Binh TT, Hải NTT, 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. | Citations: 6 (Scopus) | 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 IRF, 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. | Citations: 279 (Scopus) | 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.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection (vol 42, pg 535, 2012) INTERNATIONAL JOURNAL FOR PARASITOLOGY, 42 (10), pp. 961-961. | Read more

Thomas S, Thomson G, Dowall S, Bruce C, Cook N, Easterbrook L, O'Donoghue L, Summers S, Ajazaj L, Hewson R et al. 2012. Review of Crimean Congo hemorrhagic fever infection in Kosova in 2008 and 2009: prolonged viremias and virus detected in urine by PCR. Vector Borne Zoonotic Dis, 12 (9), pp. 800-804. | Show Abstract | Read more

Crimean-Congo hemorrhagic fever (CCHF) is a virus transmitted predominantly by ticks. However, contact with infected body fluids or tissues can result in animal-to-human or human-to-human transmission. Numbers of CCHF cases appear to be increasing, especially in Europe. We reviewed cases admitted to a tertiary referral unit in Kosova with suspected CCHF in 2008 and 2009, and looked at a smaller number of specimens which were sent to the Health Protection Agency, Porton Down, U.K., in further detail. The clinical features of cases admitted with suspected CCHF infection were assessed in more detail, and these are the focus of this article. Between 2008 and 2009, the numbers of patients admitted for suspected CCHF infection increased. Of the samples received in Porton Down, CCHF virus was detected in urine samples, and these patients were found to have prolonged viremia. The detection of CCHF in urine, as well as the prolonged viremias seen, are important for clinicians to know, as they may have public health implications with regard to the risk of infection, as well as provide insights into the biology and pathophysiology of infection. Further studies are required regarding the pathogenesis of this virus.

Thomson G, Glaser V. 2012. Gail Thomson, M.D. Health Protection Agency (HPA), Porton, United Kingdom. Vector Borne Zoonotic Dis, 12 (9), pp. 715-717. | Read more

Tarning J, Kloprogge F, Piola P, Dhorda M, Muwanga S, Turyakira E, Nuengchamnong N, Nosten F, Day NPJ, White NJ et al. 2012. Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda. Malar J, 11 (1), pp. 293. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. METHODS: Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. RESULTS: The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. CONCLUSION: The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

Larsson M, Nguyen LHT, Wertheim HF, Dao TT, Taylor W, Horby P, Nguyen TV, Nguyen MHT, 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. | Citations: 18 (Scopus) | 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.

Chan J-A, Howell KB, Reiling L, Ataide R, Mackintosh CL, Fowkes FJI, Petter M, Chesson JM, Langer C, Warimwe GM et al. 2012. Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity. J Clin Invest, 122 (9), pp. 3227-3238. | Citations: 77 (Scopus) | Show Abstract | Read more

Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

Gharbi M, Pillai DR, Lau R, Hubert V, Khairnar K, Existe A, Kendjo E, Dahlström S, Guérin PJ, Le Bras J, French National Reference Center for Imported Malaria Study. 2012. Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake. Emerg Infect Dis, 18 (8), pp. 1346-1349. | Citations: 14 (Scopus) | Show Abstract | Read more

We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance.

Read RC, Carson G. 2012. Using the NIHR Comprehensive Clinical Research Network for infectious diseases and microbiology research. J Infect, 65 (2), pp. 99-101. | Read more

Manske M, Miotto O, Campino S, Auburn S, Almagro-Garcia J, Maslen G, O'Brien J, Djimde A, Doumbo O, Zongo I et al. 2012. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature, 487 (7407), pp. 375-379. | Citations: 196 (Web of Science Lite) | Show Abstract | Read more

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

Maltezou HC, Fusco FM, Schilling S, De Iaco G, Gottschalk R, Brodt H-R, Bannister B, Brouqui P, Thomson G, Puro V et al. 2012. Infection control practices in facilities for highly infectious diseases across Europe. J Hosp Infect, 81 (3), pp. 184-191. | Show Abstract | Read more

BACKGROUND: The management of patients with highly infectious diseases (HIDs) is a challenge for healthcare provision requiring a high level of care without compromising the safety of other patients and healthcare workers. AIM: To study the infection control practice in isolation facilities participating in the European Network for Highly Infectious Diseases (EuroNHID) project. METHODS: A survey was conducted during 2009 of 48 isolation facilities caring for patients with HIDs in 16 European countries. Checklists and standard evaluation forms were used to collect and interpret data on hand hygiene, routine hygiene and disinfection, and waste management. FINDINGS: Forty percent of HIDs had no non-hand-operated sinks or alcohol-based antiseptic distributors, while 27% did not have procedures for routine hygiene, final disinfection, or safe discarding of non-disposable objects or equipment. There was considerable variation in the management of waste and in the training of housekeeping personnel. EuroNHID has developed recommendations for hand hygiene, disinfection, routine hygiene, and waste management. CONCLUSIONS: Most aspects of hand hygiene, routine hygiene and disinfection, and waste management were considered at least partially adequate in the majority of European isolation facilities dedicated for the care of patients with HIDs. But considerable variability was observed, with management of waste and training of housekeeping personnel being generally less satisfactory.

Molyneux S, Mulupi S, Mbaabu L, Marsh V. 2012. Benefits and payments for research participants: experiences and views from a research centre on the Kenyan coast. BMC Med Ethics, 13 (1), pp. 13. | Citations: 33 (Scopus) | Show Abstract | Read more

BACKGROUND: There is general consensus internationally that unfair distribution of the benefits of research is exploitative and should be avoided or reduced. However, what constitutes fair benefits, and the exact nature of the benefits and their mode of provision can be strongly contested. Empirical studies have the potential to contribute viewpoints and experiences to debates and guidelines, but few have been conducted. We conducted a study to support the development of guidelines on benefits and payments for studies conducted by the KEMRI-Wellcome Trust programme in Kilifi, Kenya. METHODS: Following an initial broad based survey of cash, health services and other items being offered during research by all programme studies (n = 38 studies), interviews were held with research managers (n = 9), and with research staff involved in 8 purposively selected case studies (n = 30 interviewees). Interviews explored how these 'benefits' were selected and communicated, experiences with their administration, and recommendations for future guidelines. Data fed into a consultative workshop attended by 48 research staff and health managers, which was facilitated by an external ethicist. FINDINGS: The most commonly provided benefits were medical care (for example free care, and strengthened quality of care), and lunch or snacks. Most cash given to participants was reimbursement of transport costs (for example to meet appointments or facilitate use of services when unexpectedly sick), but these payments were often described by research participants as benefits. Challenges included: tensions within households and communities resulting from lack of clarity and agreement on who is eligible for benefits; suspicion regarding motivation for their provision; and confusion caused by differences between studies in types and levels of benefits. CONCLUSIONS: Research staff differed in their views on how benefits should be approached. Echoing elements of international benefit sharing and ancillary care debates, some research staff saw research as based on goodwill and partnership, and aimed to avoid costs to participants and a commercial relationship; while others sought to maximise participant benefits given the relative wealth of the institution and the multiple community needs. An emerging middle position was to strengthen collateral or indirect medical benefits to communities through collaborations with the Ministry of Health to support sustainability.

Barasa EW, Ayieko P, Cleary S, English M. 2012. Out-of-pocket costs for paediatric admissions in district hospitals in Kenya. Trop Med Int Health, 17 (8), pp. 958-961. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To describe out-of-pocket costs of inpatient care for children under 5 years of age in district hospitals in Kenya. METHODS: A total of 256 caretakers of admitted children were interviewed in 2-week surveys conducted in eight hospitals in four provinces in Kenya. Caretakers were asked to report care seeking behaviour and expenditure related to accessing inpatient care. Family socio-economic status was assessed through reported expenditure in the previous month. RESULTS: Seventy eight percent of caretakers were required to pay user charges to access inpatient care for children. User charges (mean, US$ 8.1; 95% CI, 6.4-9.7) were 59% of total out-of-pocket costs, while transport costs (mean, US$ 4.9; 95% CI, 3.9-6.0) and medicine costs (mean, US$ 0.7; 95% CI, 0.5-1.0) were 36% and 5%, respectively. The mean total out-of-pocket cost per paediatric admission was US$ 14.1 (95% CI, 11.9-16.2). Out-of-pocket expenditures on health were catastrophic for 25.4% (95% CI, 18.4-33.3) of caretakers interviewed. Out-of-pocket expenditures were regressive, with a greater burden being experienced by households with lower socio-economic status. CONCLUSION: Despite a policy of user fee exemption for children under 5 years of age in Kenya, our findings show that high unofficial user fees are still charged in district hospitals. Financing mechanisms that will offer financial risk protection to children seeking care need to be developed to remove barriers to child survival.

Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, Yan H, Huang X, Angus B, Kuldanek K et al. 2012. Antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ T-cell decline in HIV-1 infection. J Infect Dis, 206 (4), pp. 552-561. | Citations: 52 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Rare human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain control of viremia without therapy show potent CD8+ T-cell-mediated suppression of viral replication in vitro. Whether this is a determinant of the rate of disease progression in viremic individuals is unknown. METHODS: We measured CD8+ T-cell-mediated inhibition of a heterologous HIV-1 isolate in 50 HIV-1-seropositive adults with diverse progression rates. Linear mixed models were used to determine whether CD8+ T-cell function could explain variation in the rate of CD4+ T-cell decline. RESULTS: There was a significant interaction between CD8+ T-cell antiviral activity in vitro and the rate of CD4+ T-cell decline in chronically infected individuals (P < .0001). In a second prospective analysis of recently infected subjects followed for up to 3 years, CD8+ T-cell antiviral activity strongly predicted subsequent CD4+ T-cell decline (P < .0001) and explained up to 73% of the interindividual variation in the CD4+ T-cell slope. In addition, it was inversely associated with viral load set point (r = -0.68 and P = .002). CONCLUSIONS: The antiviral inhibitory capacity of CD8+ T cells is highly predictive of CD4+ T-cell loss in early HIV-1 infection. It has potential as a benchmark of effective immunity in vaccine evaluation.

Lang T, Siribaddana S. 2012. Clinical trials have gone global: is this a good thing? PLoS Med, 9 (6), pp. e1001228. | Citations: 40 (Scopus) | Read more

Lang T. 2012. Using digital technology to support and enhance clinical trials in resource-limited settings TROPICAL MEDICINE & INTERNATIONAL HEALTH, 17 pp. 49-49.

Barasa EW, Ayieko P, Cleary S, English M. 2012. A multifaceted intervention to improve the quality of care of children in district hospitals in Kenya: a cost-effectiveness analysis. PLoS Med, 9 (6), pp. e1001238. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: To improve care for children in district hospitals in Kenya, a multifaceted approach employing guidelines, training, supervision, feedback, and facilitation was developed, for brevity called the Emergency Triage and Treatment Plus (ETAT+) strategy. We assessed the cost effectiveness of the ETAT+ strategy, in Kenyan hospitals. Further, we estimate the costs of scaling up the intervention to Kenya nationally and potential cost effectiveness at scale. METHODS AND FINDINGS: Our cost-effectiveness analysis from the provider's perspective used data from a previously reported cluster randomized trial comparing the full ETAT+ strategy (n = 4 hospitals) with a partial intervention (n = 4 hospitals). Effectiveness was measured using 14 process measures that capture improvements in quality of care; their average was used as a summary measure of quality. Economic costs of the development and implementation of the intervention were determined (2009 US$). Incremental cost-effectiveness ratios were defined as the incremental cost per percentage improvement in (average) quality of care. Probabilistic sensitivity analysis was used to assess uncertainty. The cost per child admission was US$50.74 (95% CI 49.26-67.06) in intervention hospitals compared to US$31.1 (95% CI 30.67-47.18) in control hospitals. Each percentage improvement in average quality of care cost an additional US$0.79 (95% CI 0.19-2.31) per admitted child. The estimated annual cost of nationally scaling up the full intervention was US$3.6 million, approximately 0.6% of the annual child health budget in Kenya. A "what-if" analysis assuming conservative reductions in mortality suggests the incremental cost per disability adjusted life year (DALY) averted by scaling up would vary between US$39.8 and US$398.3. CONCLUSION: Improving quality of care at scale nationally with the full ETAT+ strategy may be affordable for low income countries such as Kenya. Resultant plausible reductions in hospital mortality suggest the intervention could be cost-effective when compared to incremental cost-effectiveness ratios of other priority child health interventions.

Waddington C, Darton T, Jones C, Haworth K, Peters A, Kerridge S, Crook D, Lockhart S, Farrar J, Dougan G et al. 2012. Variations in attack rate in a single-blind, dose escalation challenge study of Salmonella Typhi in healthy adult volunteers INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E244-E244. | Read more

Jones C, Waddington C, Darton T, Bowman J, Farrar J, Dougan G, Levine M, Lockhart S, Sztein M, Crook D et al. 2012. Quantification of antibody secreting cell responses in a human challenge model of Salmonella Typhi infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E224-E224. | Read more

Darton T, Jones C, Waddington C, Dougan G, Sztein M, Levine M, Angus B, Farrar J, Lockhart S, Crook D et al. 2012. Demonstration of primary and asymptomatic DNAaemia in participants challenged with Salmonella Typhi (Quailes strain) during the development of a human model of typhoid infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E215-E215. | Citations: 1 (Web of Science Lite) | Read more

Puro V, Fusco FM, Schilling S, Thomson G, De Iaco G, Brouqui P, Maltezou HC, Bannister B, Gottschalk R, Brodt H-R et al. 2012. Biosecurity measures in 48 isolation facilities managing highly infectious diseases. Biosecur Bioterror, 10 (2), pp. 208-214. | Show Abstract | Read more

Biosecurity measures are traditionally applied to laboratories, but they may also be usefully applied in highly specialized clinical settings, such as the isolation facilities for the management of patients with highly infectious diseases (eg, viral hemorrhagic fevers, SARS, smallpox, potentially severe pandemic flu, and MDR- and XDR-tuberculosis). In 2009 the European Network for Highly Infectious Diseases conducted a survey in 48 isolation facilities in 16 European countries to determine biosecurity measures for access control to the facility. Security personnel are present in 39 facilities (81%). In 35 facilities (73%), entrance to the isolation area is restricted; control methods include electronic keys, a PIN system, closed-circuit TV, and guards at the doors. In 25 facilities (52%), identification and registration of all staff entering and exiting the isolation area are required. Access control is used in most surveyed centers, but specific lacks exist in some facilities. Further data are needed to assess other biosecurity aspects, such as the security measures during the transportation of potentially contaminated materials and measures to address the risk of an "insider attack."

Espié E, Lima A, Atua B, Dhorda M, Flévaud L, Sompwe EM, Palma Urrutia PP, Guerin PJ. 2012. Efficacy of fixed-dose combination artesunate-amodiaquine versus artemether-lumefantrine for uncomplicated childhood Plasmodium falciparum malaria in Democratic Republic of Congo: a randomized non-inferiority trial. Malar J, 11 (1), pp. 174. | Citations: 19 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In 2005, the Democratic Republic of Congo (DRC) adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment. In order to compare the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL), a randomized, non-inferiority open-label trial was conducted in Katanga. METHODS: Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed. RESULTS: Between April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference -0.7%, one sided 95% CI -3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated. CONCLUSION: Both ASAQ and AL are highly effective and currently adequate as the first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces. TRIAL REGISTRATION: The protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.

Ndungu FM, Olotu A, Mwacharo J, Nyonda M, Apfeld J, Mramba LK, Fegan GW, Bejon P, Marsh K. 2012. Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children. Proc Natl Acad Sci U S A, 109 (21), pp. 8247-8252. | Citations: 42 (Scopus) | Show Abstract | Read more

Humans respond to foreign antigen by generating plasma Abs and memory B cells (MBCs). The Ab response then declines, sometimes to below the limit of detection. In contrast, MBCs are generally thought to be long-lived. We tested and compared Plasmodium falciparum (Pf)-specific Ab and MBC responses in two populations of children: (i) previously exposed children who had documented Pf infections several years ago, but minimal exposure since then; and (ii) persistently exposed children living in a separate but nearby endemic area. We found that although Pf-specific plasma Abs were lower in previously exposed children compared with persistently exposed children, their cognate MBCs were maintained at similar frequencies. We conclude that serological analysis by itself would greatly underestimate the true memory of Pf-specific Ab responses in previously exposed children living in areas where Pf transmission has been reduced or eliminated.

Muehlenbachs A, Nabasumba C, McGready R, Turyakira E, Tumwebaze B, Dhorda M, Nyehangane D, Nalusaji A, Nosten F, Guerin PJ, Piola P. 2012. Artemether-lumefantrine to treat malaria in pregnancy is associated with reduced placental haemozoin deposition compared to quinine in a randomized controlled trial. Malar J, 11 (1), pp. 150. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance. METHODS: Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data. RESULTS: Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria. CONCLUSIONS: Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy. TRIAL REGISTRATION: REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508.

Abdulla S, Alonso P, Binka F, Graves P, Greenwood B, Leke R, Malik E, Marsh K, Meek S, Mendis K et al. 2012. Inaugural meeting of the malaria policy advisory committee to the WHO: conclusions and recommendations MALARIA JOURNAL, 11 (1), pp. 137-137. | Read more

Scott JAG, Bauni E, Moisi JC, Ojal J, Gatakaa H, Nyundo C, Molyneux CS, Kombe F, Tsofa B, Marsh K et al. 2012. Profile: The Kilifi Health and Demographic Surveillance System (KHDSS). Int J Epidemiol, 41 (3), pp. 650-657. | Citations: 87 (Scopus) | Show Abstract | Read more

The Kilifi Health and Demographic Surveillance System (KHDSS), located on the Indian Ocean coast of Kenya, was established in 2000 as a record of births, pregnancies, migration events and deaths and is maintained by 4-monthly household visits. The study area was selected to capture the majority of patients admitted to Kilifi District Hospital. The KHDSS has 260 000 residents and the hospital admits 4400 paediatric patients and 3400 adult patients per year. At the hospital, morbidity events are linked in real time by a computer search of the population register. Linked surveillance was extended to KHDSS vaccine clinics in 2008. KHDSS data have been used to define the incidence of hospital presentation with childhood infectious diseases (e.g. rotavirus diarrhoea, pneumococcal disease), to test the association between genetic risk factors (e.g. thalassaemia and sickle cell disease) and infectious diseases, to define the community prevalence of chronic diseases (e.g. epilepsy), to evaluate access to health care and to calculate the operational effectiveness of major public health interventions (e.g. conjugate Haemophilus influenzae type b vaccine). Rapport with residents is maintained through an active programme of community engagement. A system of collaborative engagement exists for sharing data on survival, morbidity, socio-economic status and vaccine coverage.

Warimwe GM, Fegan G, Musyoki JN, Newton CRJC, Opiyo M, Githinji G, Andisi C, Menza F, Kitsao B, Marsh K, Bull PC. 2012. Prognostic indicators of life-threatening malaria are associated with distinct parasite variant antigen profiles. Sci Transl Med, 4 (129), pp. 129ra45. | Citations: 41 (Scopus) | Show Abstract | Read more

PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called "group A" in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the var genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A-like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population.

Holloway C, Ntusi N, Suttie J, Mahmod M, Clutton G, Hancock G, Wainwright E, Angus B, Asaad M, Beak P et al. 2012. Comprehensive Cardiac Magnetic Resonance Reveals HIV is Associated with High Burden of Myocardial Disease HIV MEDICINE, 13 pp. 3-3.

Clutterbuck EA, Lazarus R, Yu L-M, Bowman J, Bateman EAL, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. 2012. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J Infect Dis, 205 (9), pp. 1408-1416. | Citations: 125 (Scopus) | Show Abstract | Read more

BACKGROUND: A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults. METHODS: We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved. RESULTS: A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans. CONCLUSIONS: This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP. Clinical Trials Registration. ISRCTN: 78768849.

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: the Ha Nam household cohort study I. Am J Epidemiol, 175 (10), pp. 1062-1074. | Citations: 44 (Web of Science Lite) | 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.

Nga TVT, Parry CM, Le T, Lan NPH, Diep TS, Campbell JI, Hoang NVM, Dung LT, Wain J, Dolecek C et al. 2012. The decline of typhoid and the rise of non-typhoid salmonellae and fungal infections in a changing HIV landscape: bloodstream infection trends over 15 years in southern Vietnam. Trans R Soc Trop Med Hyg, 106 (1), pp. 26-34. | Citations: 36 (Scopus) | Show Abstract | Read more

The etiological spectrum of bloodstream infections is variable between industrialized and developing countries and even within a defined location over time. We investigated trends in bloodstream infections at an infectious disease hospital in Ho Chi Minh City, Vietnam, from 1994-2008. Amongst 66,111 blood cultures performed, a clinically relevant pathogen was isolated in 7645 episodes (positivity rate; 116/1000 cultures). Salmonella Typhi was the predominant pathogen until 2002; however, a considerable annual decline in the proportion of S. Typhi was observed (OR 0.6993, 95% CI [0.6885, 0.7103], p<0.0001). Conversely, there was a significant increase in the proportions of non-typhoidal Salmonella (NTS), Cryptococcus neoformans and Penicillium marneffei, concurrent with increasing HIV prevalence. These data document a substantial longitudinal shift in bloodstream infection etiology in southern Vietnam. We propose such changes are related to increasing economic prosperity and HIV prevalence, and this pattern marks a substantial change in the epidemiology of invasive salmonellosis in Southeast Asia.

Dhorda M, Piola P, Nyehangane D, Tumwebaze B, Nalusaji A, Nabasumba C, Turyakira E, McGready R, Ashley E, Guerin PJ, Snounou G. 2012. Performance of a histidine-rich protein 2 rapid diagnostic test, Paracheck Pf®, for detection of malaria infections in Ugandan pregnant women. Am J Trop Med Hyg, 86 (1), pp. 93-95. | Citations: 17 (Scopus) | Show Abstract | Read more

Improved laboratory diagnosis is critical to reduce the burden of malaria in pregnancy. Peripheral blood smears appear less sensitive than Plasmodium falciparum histidine-rich protein 2-based rapid diagnostic tests (RDTs) for placental malaria infections in studies conducted at delivery. In this study, 81 women in Uganda in the second or third trimester of pregnancy were followed-up until delivery. At each visit, peripheral blood was tested by blood smear, RDT, and nested species-specific polymerase chain reaction (PCR). Sensitivity and specificity of the tests was calculated with PCR, which detected 22 infections of P. falciparum, as the gold standard. The sensitivity and specificity of blood smears were 36.4% (95% confidence interval [CI] = 18.0-59.2%) and 99.6% (95% CI = 97.7-100%), respectively. The corresponding values for RDT were 31.8% (95% CI = 14.7-54.9%) and 100% (95% CI = 98.3-100%). The RDTs could replace blood smears for diagnosis of malaria in pregnancy by virtue of their relative ease of use. Field-based sensitive tests for malaria in pregnancy are urgently needed.

Gitau EN, Tuju J, Stevenson L, Kimani E, Karanja H, Marsh K, Bull PC, Urban BC. 2012. T-cell responses to the DBLα-tag, a short semi-conserved region of the Plasmodium falciparum membrane erythrocyte protein 1. PLoS One, 7 (1), pp. e30095. | Citations: 9 (Scopus) | Show Abstract | Read more

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant surface antigen expressed on mature forms of infected erythrocytes. It is considered an important target of naturally acquired immunity. Despite its extreme sequence heterogeneity, variants of PfEMP1 can be stratified into distinct groups. Group A PfEMP1 have been independently associated with low host immunity and severe disease in several studies and are now of potential interest as vaccine candidates. Although antigen-specific antibodies are considered the main effector mechanism in immunity to malaria, the induction of efficient and long-lasting antibody responses requires CD4+ T-cell help. To date, very little is known about CD4+ T-cell responses to PfEMP1 expressed on clinical isolates. The DBLα-tag is a small region from the DBLα-domain of PfEMP1 that can be amplified with universal primers and is accessible in clinical parasite isolates. We identified the dominant expressed PfEMP1 in 41 individual clinical parasite isolates and expressed the corresponding DBLα-tag as recombinant antigen. Individual DBLα-tags were then used to activate CD4+ T-cells from acute and convalescent blood samples in children who were infected with the respective clinical parasite isolate. Here we show that CD4+ T-cell responses to the homologous DBLα-tag were induced in almost all children during acute malaria and maintained in some for 4 months. Children infected with parasites that dominantly expressed group A-like PfEMP1 were more likely to maintain antigen-specific IFNγ-producing CD4+ T-cells than children infected with parasites dominantly expressing other PfEMP1. These results suggest that group A-like PfEMP1 may induce long-lasting effector memory T-cells that might be able to provide rapid help to variant-specific B cells. Furthermore, a number of children induced CD4+ T-cell responses to heterologous DBLα-tags, suggesting that CD4+ T-cells may recognise shared epitopes between several DBLα-tags.

Weiss GE, Ndungu FM, McKittrick N, Li S, Kimani D, Crompton PD, Marsh K, Pierce SK. 2012. High efficiency human memory B cell assay and its application to studying Plasmodium falciparum-specific memory B cells in natural infections Journal of Immunological Methods, 375 (1-2), pp. 68-74. | Citations: 16 (Scopus) | Show Abstract | Read more

Memory B cells (MBCs) are a key component of long term humoral immunity to many human infectious diseases. Despite their importance, we know little about the generation or maintenance of antigen-(Ag)-specific MBCs in humans in response to infection. A frequently employed method for quantifying Ag-specific MBCs in human peripheral blood (Crotty et al., 2004) relies on the ability of MBCs but not naïve B cells to differentiate into antibody secreting cells (ASCs) in response to polyclonal activators and Toll-like receptor agonists in vitro and the measurement of Ag-specific ASCs by ELISPOT assays. Here we report on studies to optimize the efficiency of this ELISPOT-based assay and to apply this assay to the detection of Plasmodium falciparum (Pf)-specific MBCs in adults living in a malaria endemic area where immunity to Pf is acquired through natural infection. We show that the addition of IL-10 to in vitro cultures of human peripheral blood mononuclear cells increased the efficiency of the assay from 10% to over 90% without increasing the ASC burst size and without any substantial increase in background from naïve B cells or plasma cells (PCs). Using this assay we were able to quantify the frequency of Pf-specific MBCs in peripheral blood of adults living in a malaria endemic area. Thus, this highly efficient assay appears to be well suited to field studies of the generation and maintenance of MBCs where the volumes of blood obtainable are often limiting. © 2011 Elsevier B.V.

Midega JT, Smith DL, Olotu A, Mwangangi JM, Nzovu JG, Wambua J, Nyangweso G, Mbogo CM, Christophides GK, Marsh K, Bejon P. 2012. Wind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya. Nat Commun, 3 pp. 674. | Citations: 34 (Web of Science Lite) | Show Abstract | Read more

Studies of the fine-scale spatial epidemiology of malaria consistently identify malaria hotspots, comprising clusters of homesteads at high transmission intensity. These hotspots sustain transmission, and may be targeted by malaria-control programmes. Here we describe the spatial relationship between the location of Anopheles larval sites and human malaria infection in a cohort study of 642 children, aged 1-10-years-old. Our data suggest that proximity to larval sites predict human malaria infection, when homesteads are upwind of larval sites, but not when homesteads are downwind of larval sites. We conclude that following oviposition, female Anophelines fly upwind in search for human hosts and, thus, malaria transmission may be disrupted by targeting vector larval sites in close proximity, and downwind to malaria hotspots.

Fox A, Le NMH, Horby P, van Doorn HR, Nguyen VT, Nguyen HH, Nguyen TC, Vu DP, Nguyen MH, Diep NTN 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. | Citations: 25 (Scopus) | 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.

Mwai L, Diriye A, Masseno V, Muriithi S, Feltwell T, Musyoki J, Lemieux J, Feller A, Mair GR, Marsh K et al. 2012. Genome wide adaptations of Plasmodium falciparum in response to lumefantrine selective drug pressure. PLoS One, 7 (2), pp. e31623. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

The combination therapy of the Artemisinin-derivative Artemether (ART) with Lumefantrine (LM) (Coartem®) is an important malaria treatment regimen in many endemic countries. Resistance to Artemisinin has already been reported, and it is feared that LM resistance (LMR) could also evolve quickly. Therefore molecular markers which can be used to track Coartem® efficacy are urgently needed. Often, stable resistance arises from initial, unstable phenotypes that can be identified in vitro. Here we have used the Plasmodium falciparum multidrug resistant reference strain V1S to induce LMR in vitro by culturing the parasite under continuous drug pressure for 16 months. The initial IC(50) (inhibitory concentration that kills 50% of the parasite population) was 24 nM. The resulting resistant strain V1S(LM), obtained after culture for an estimated 166 cycles under LM pressure, grew steadily in 378 nM of LM, corresponding to 15 times the IC(50) of the parental strain. However, after two weeks of culturing V1S(LM) in drug-free medium, the IC(50) returned to that of the initial, parental strain V1S. This transient drug tolerance was associated with major changes in gene expression profiles: using the PFSANGER Affymetrix custom array, we identified 184 differentially expressed genes in V1S(LM). Among those are 18 known and putative transporters including the multidrug resistance gene 1 (pfmdr1), the multidrug resistance associated protein and the V-type H+ pumping pyrophosphatase 2 (pfvp2) as well as genes associated with fatty acid metabolism. In addition we detected a clear selective advantage provided by two genomic loci in parasites grown under LM drug pressure, suggesting that all, or some of those genes contribute to development of LM tolerance--they may prove useful as molecular markers to monitor P. falciparum LM susceptibility.

Lairumbi GM, Parker M, Fitzpatrick R, English MC. 2012. Forms of benefit sharing in global health research undertaken in resource poor settings: a qualitative study of stakeholders' views in Kenya. Philos Ethics Humanit Med, 7 (1), pp. 7. | Citations: 24 (Scopus) | Show Abstract | Read more

BACKGROUND: Increase in global health research undertaken in resource poor settings in the last decade though a positive development has raised ethical concerns relating to potential for exploitation. Some of the suggested strategies to address these concerns include calls for providing universal standards of care, reasonable availability of proven interventions and more recently, promoting the overall social value of research especially in clinical research. Promoting the social value of research has been closely associated with providing fair benefits to various stakeholders involved in research. The debate over what constitutes fair benefits; whether those that addresses micro level issues of justice or those focusing on the key determinants of health at the macro level has continued. This debate has however not benefited from empirical work on what stakeholders consider fair benefits. This study explores practical experiences of stakeholders involved in global health research in Kenya, over what benefits are fair within a developing world context. METHODS AND RESULTS: We conducted in-depth interviews with key informants drawn from within the broader health research system in Kenya including researchers from the mainstream health research institutions, networks and universities, teaching hospitals, policy makers, institutional review boards, civil society organisations and community representative groups.The range of benefits articulated by stakeholders addresses both micro and macro level concerns for justice by for instance, seeking to engage with interests of those facilitating research, and the broader systemic issues that make resource poor settings vulnerable to exploitation. We interpret these views to suggest a need for global health research to engage with current crises that face people in these settings as well as the broader systemic issues that produce them. CONCLUSION: Global health research should provide benefits that address both the micro and macro level issues of justice in order to forestall exploitation. Embracing the two is however challenging in terms of how the various competing interests/needs should be balanced ethically, especially in the absence of structures to guide the process. This challenge should point to the need for greater dialogue to facilitate value clarification among stakeholders.

Agweyu A, Opiyo N, English M. 2012. Experience developing national evidence-based clinical guidelines for childhood pneumonia in a low-income setting--making the GRADE? BMC Pediatr, 12 (1), pp. 1. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The development of evidence-based clinical practice guidelines has gained wide acceptance in high-income countries and reputable international organizations. Whereas this approach may be a desirable standard, challenges remain in low-income settings with limited capacity and resources for evidence synthesis and guideline development. We present our experience using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for the recent revision of the Kenyan pediatric clinical guidelines focusing on antibiotic treatment of pneumonia. METHODS: A team of health professionals, many with minimal prior experience conducting systematic reviews, carried out evidence synthesis for structured clinical questions. Summaries were compiled and distributed to a panel of clinicians, academicians and policy-makers to generate recommendations based on best available research evidence and locally-relevant contextual factors. RESULTS: We reviewed six eligible articles on non-severe and 13 on severe/very severe pneumonia. Moderate quality evidence suggesting similar clinical outcomes comparing amoxicillin and cotrimoxazole for non-severe pneumonia received a strong recommendation against adopting amoxicillin. The panel voted strongly against amoxicillin for severe pneumonia over benzyl penicillin despite moderate quality evidence suggesting clinical equivalence between the two and additional factors favoring amoxicillin. Very low quality evidence suggesting ceftriaxone was as effective as the standard benzyl penicillin plus gentamicin for very severe pneumonia received a strong recommendation supporting the standard treatment. CONCLUSIONS: Although this exercise may have fallen short of the rigorous requirements recommended by the developers of GRADE, it was arguably an improvement on previous attempts at guideline development in low-income countries and offers valuable lessons for future similar exercises where resources and locally-generated evidence are scarce.

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. | Citations: 51 (Scopus) | 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.

Lang TA, Gould J, von Seidlein L, Lusingu JP, Mshamu S, Ismael S, Liheluka E, Kamuya D, Mwachiro D, Olotu A et al. 2012. Approaching the community about screening children for a multicentre malaria vaccine trial International Health, 4 (1), pp. 47-54. | Citations: 10 (Scopus) | Show Abstract | Read more

Community sensitisation, as a component of community engagement, plays an important role in strengthening the ethics of community-based trials in developing countries and is fundamental to trial success. However, few researchers have shared their community sensitisation strategies and experiences. We report on our perspective as researchers on the sensitisation activities undertaken for a phase II malaria vaccine trial in Kilifi District (Kenya) and Korogwe District (Tanzania), with the aim of informing and guiding the operational planning of future trials. We report wide variability in recruitment rates within both sites; a variability that occurred against a backdrop of similarity in overall approaches to sensitisation across the two sites but significant differences in community exposure to biomedical research. We present a range of potential factors contributing to these differences in recruitment rates, which we believe are worth considering in future community sensitisation plans. We conclude by arguing for carefully designed social science research around the implementation and impact of community sensitisation activities. © 2011 Royal Society of Tropical Medicine and Hygiene.

Olotu A, Fegan G, Wambua J, Nyangweso G, Ogada E, Drakeley C, Marsh K, Bejon P. 2012. Estimating individual exposure to malaria using local prevalence of malaria infection in the field. PLoS One, 7 (3), pp. e32929. | Citations: 22 (Scopus) | Show Abstract | Read more

BACKGROUND: Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level. METHOD AND FINDINGS: We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1(142) were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1(142) antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66-0.73), 0.71 (95%CI: 0.69-0.73) and 0.82 (95%CI: 0.80-0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1(142) antibody levels provided an AUC of 0.83 (95%CI: 0.79-0.88). CONCLUSION: We have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria.

Snow RW, Amratia P, Kabaria CW, Noor AM, Marsh K. 2012. The changing limits and incidence of malaria in Africa: 1939-2009. Adv Parasitol, 78 pp. 169-262. | Citations: 32 (Web of Science Lite) | Show Abstract | Read more

Understanding the historical, temporal changes of malaria risk following control efforts in Africa provides a unique insight into what has been and might be archived towards a long-term ambition of elimination on the continent. Here, we use archived published and unpublished material combined with biological constraints on transmission accompanied by a narrative on malaria control to document the changing incidence of malaria in Africa since earliest reports pre-second World War. One result is a more informed mapped definition of the changing margins of transmission in 1939, 1959, 1979, 1999 and 2009.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection. Int J Parasitol, 42 (6), pp. 535-548. | Citations: 26 (Web of Science Lite) | Show Abstract | Read more

Malaria is a vector-borne infectious disease caused by infection with eukaryotic pathogens termed Plasmodium. Epidemiological hallmarks of Plasmodium falciparum malaria are continuous re-infections, over which time the human host may experience several clinical malaria episodes, slow acquisition of partial protection against infection, and its partial decay upon migration away from endemic regions. To overcome the exposure-dependence of naturally acquired immunity and rapidly elicit robust long-term protection are ultimate goals of malaria vaccine development. However, cellular and molecular correlates of naturally acquired immunity against either parasite infection or malarial disease remain elusive. Sero-epidemiological studies consistently suggest that acquired immunity is primarily directed against the asexual blood stages. Here, we review available data on the relationship between immune responses against the Anopheles mosquito-transmitted sporozoite and exo-erythrocytic liver stages and the incidence of malaria. We discuss current limitations and research opportunities, including the identification of additional sporozoite antigens and the use of systematic immune profiling and functional studies in longitudinal cohorts to look for pre-erythrocytic signatures of naturally acquired immunity.

Page A-L, Alberti KP, Mondonge V, Rauzier J, Quilici M-L, Guerin PJ. 2012. Evaluation of a rapid test for the diagnosis of cholera in the absence of a gold standard. PLoS One, 7 (5), pp. e37360. | Citations: 21 (Scopus) | Show Abstract | Read more

BACKGROUND: Early detection and confirmation of cholera outbreaks are crucial for rapid implementation of control measures. Because cholera frequently affects regions with limited laboratory resources, rapid diagnostic tests (RDT) designed for field conditions are important to enhance rapid response. Stool culture remains the "gold standard" for cholera diagnosis; however, its lack of sensitivity may lead to underestimation of test specificity. We evaluated the Crystal VC® immunochromatographic test (Span Diagnostics, India) for cholera diagnosis using a modified reference standard that combines culture-dependent and independent assays, or a Bayesian latent class model (LCM) analysis. METHODOLOGY/PRINCIPAL FINDINGS: The study was conducted during a cholera epidemic in 2008, in Lubumbashi, Democratic Republic of Congo. Stools collected from 296 patients were used to perform the RDT on site and sent to Institut Pasteur, Paris, for bacterial culture. In comparison with culture as the gold standard, the RDT showed good sensitivity (92.2%; 95% CI: 86.8%-95.9%) but poor specificity when used by a trained laboratory technician (70.6%; 95% CI: 60.7%-79.2%) or by clinicians with no specific test training (60.4%, 95% CI: 50.2%-70.0%). The specificity of the test performed by the laboratory technician increased to 88.6% (95% CI: 78.7-94.9) when PCR was combined with culture results as the reference standard, and to 85.0% (95% CI: 70.4-99.2), when the Bayesian LCM analysis was used for performance evaluation. In both cases, the sensitivity remained high. CONCLUSION: Using an improved reference standard or appropriate statistical methods for diagnostic test evaluations in the absence of a gold standard, we report better performance of the Crystal VC® RDT than previously published. Our results confirm that this test can be used for early outbreak detection or epidemiological surveillance, key components of efficient global cholera control. Our analysis also highlights the importance of improving evaluations of RDT when no reliable gold standard is available.

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. | Citations: 46 (Scopus) | 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.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection International Journal for Parasitology, 42 (6), pp. 535-548. | Citations: 29 (Scopus) | Show Abstract | Read more

Malaria is a vector-borne infectious disease caused by infection with eukaryotic pathogens termed . Plasmodium. Epidemiological hallmarks of . Plasmodium falciparum malaria are continuous re-infections, over which time the human host may experience several clinical malaria episodes, slow acquisition of partial protection against infection, and its partial decay upon migration away from endemic regions. To overcome the exposure-dependence of naturally acquired immunity and rapidly elicit robust long-term protection are ultimate goals of malaria vaccine development. However, cellular and molecular correlates of naturally acquired immunity against either parasite infection or malarial disease remain elusive. Sero-epidemiological studies consistently suggest that acquired immunity is primarily directed against the asexual blood stages. Here, we review available data on the relationship between immune responses against the . Anopheles mosquito-transmitted sporozoite and exo-erythrocytic liver stages and the incidence of malaria. We discuss current limitations and research opportunities, including the identification of additional sporozoite antigens and the use of systematic immune profiling and functional studies in longitudinal cohorts to look for pre-erythrocytic signatures of naturally acquired immunity. © 2012 Australian Society for Parasitology Inc..

Opiyo N, Shepperd S, Musila N, English M, Fretheim A. 2012. The "Child Health Evidence Week" and GRADE grid may aid transparency in the deliberative process of guideline development. J Clin Epidemiol, 65 (9), pp. 962-969. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To explore the evidence translation process during a 1-week national guideline development workshop ("Child Health Evidence Week") in Kenya. STUDY DESIGN AND SETTING: Nonparticipant observational study of the discussions of a multidisciplinary guideline development panel in Kenya. Discussions were aided by GRADE (Grading of Recommendations Assessment, Development, and Evaluation) grid. RESULTS: Three key thematic categories emerged: 1) "referral to other evidence to support or refute the proposed recommendations;" 2) "assessment of the presented research evidence;" and 3) "assessment of the local applicability of evidence." The types of evidence cited included research evidence and anecdotal evidence based on clinician experiences. Assessment of the research evidence revealed important challenges in the translation of evidence into recommendations, including absence of evidence, low quality or inconclusive evidence, inadequate reporting of key features of the management under consideration, and differences in panelists' interpretation of the research literature. A broad range of factors with potential to affect local applicability of evidence were discussed. CONCLUSION: The process of the "Child Health Evidence Week" combined with the GRADE grid may aid transparency in the deliberative process of guideline development, and provide a mechanism for comprehensive assessment, documentation, and reporting of multiple factors that influence the quality and applicability of guideline recommendations.

Midega JT, Smith DL, Olotu A, Mwangangi JM, Nzovu JG, Wambua J, Nyangweso G, Mbogo CM, Christophides GK, Marsh K, Bejon P. 2012. Wind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya Nature Communications, 3 | Citations: 35 (Scopus) | Show Abstract | Read more

Studies of the fine-scale spatial epidemiology of malaria consistently identify malaria hotspots, comprising clusters of homesteads at high transmission intensity. These hotspots sustain transmission, and may be targeted by malaria-control programmes. Here we describe the spatial relationship between the location of Anopheles larval sites and human malaria infection in a cohort study of 642 children, aged 1-10-years-old. Our data suggest that proximity to larval sites predict human malaria infection, when homesteads are upwind of larval sites, but not when homesteads are downwind of larval sites. We conclude that following oviposition, female Anophelines fly upwind in search for human hosts and, thus, malaria transmission may be disrupted by targeting vector larval sites in close proximity, and downwind to malaria hotspots. © 2012 Macmillan Publishers Limited. All rights reserved.

Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA, Miller MA, Esposito R, Louie TJ, Stoesser NE, Young BC et al. 2012. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis, 55 Suppl 2 (suppl_2), pp. S93-103. | Citations: 106 (Scopus) | Show Abstract | Read more

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

Irimu GW, Gathara D, Zurovac D, Kihara H, Maina C, Mwangi J, Mbori-Ngacha D, Todd J, Greene A, English M. 2012. Performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital: before and after a training intervention. PLoS One, 7 (7), pp. e39964. | Citations: 22 (Scopus) | Show Abstract | Read more

BACKGROUND: Implementation of WHO case management guidelines for serious common childhood illnesses remains a challenge in hospitals in low-income countries. The impact of locally adapted clinical practice guidelines (CPGs) on the quality-of-care of patients in tertiary hospitals has rarely been evaluated. METHODS AND FINDINGS: We conducted, in Kenyatta National Hospital, an uncontrolled before and after study with an attempt to explore intervention dose-effect relationships, as CPGs were disseminated and training was progressively implemented. The emergency triage, assessment and treatment plus admission care (ETAT+) training and locally adapted CPGs targeted common, serious childhood illnesses. We compared performance in the pre-intervention (2005) and post-intervention periods (2009) using quality indicators for three diseases: pneumonia, dehydration and severe malnutrition. The indicators spanned four domains in the continuum of care namely assessment, classification, treatment, and follow-up care in the initial 48 hours of admission. In the pre-intervention period patients' care was largely inconsistent with the guidelines, with nine of the 15 key indicators having performance of below 10%. The intervention produced a marked improvement in guideline adherence with an absolute effect size of over 20% observed in seven of the 15 key indicators; three of which had an effect size of over 50%. However, for all the five indicators that required sustained team effort performance continued to be poor, at less than 10%, in the post-intervention period. Data from the five-year period (2005-09) suggest some dose dependency though the adoption rate of the best-practices varied across diseases and over time. CONCLUSION: Active dissemination of locally adapted clinical guidelines for common serious childhood illnesses can achieve a significant impact on documented clinical practices, particularly for tasks that rely on competence of individual clinicians. However, more attention must be given to broader implementation strategies that also target institutional and organisational aspects of service delivery to further enhance quality-of-care.

Barasa EW, Ayieko P, Cleary S, English M. 2012. Out-of-pocket costs for paediatric admissions in district hospitals in Kenya Tropical Medicine and International Health, 17 (8), pp. 958-961. | Citations: 4 (Scopus) | Show Abstract | Read more

Objective To describe out-of-pocket costs of inpatient care for children under 5years of age in district hospitals in Kenya. Methods A total of 256 caretakers of admitted children were interviewed in 2-week surveys conducted in eight hospitals in four provinces in Kenya. Caretakers were asked to report care seeking behaviour and expenditure related to accessing inpatient care. Family socio-economic status was assessed through reported expenditure in the previous month. Results Seventy eight percent of caretakers were required to pay user charges to access inpatient care for children. User charges (mean, US$ 8.1; 95% CI, 6.4-9.7) were 59% of total out-of-pocket costs, while transport costs (mean, US$ 4.9; 95% CI, 3.9-6.0) and medicine costs (mean, US$ 0.7; 95% CI, 0.5-1.0) were 36% and 5%, respectively. The mean total out-of-pocket cost per paediatric admission was US$ 14.1 (95% CI, 11.9-16.2). Out-of-pocket expenditures on health were catastrophic for 25.4% (95% CI, 18.4-33.3) of caretakers interviewed. Out-of-pocket expenditures were regressive, with a greater burden being experienced by households with lower socio-economic status. Conclusion Despite a policy of user fee exemption for children under 5years of age in Kenya, our findings show that high unofficial user fees are still charged in district hospitals. Financing mechanisms that will offer financial risk protection to children seeking care need to be developed to remove barriers to child survival. © 2012 Blackwell Publishing Ltd.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Erratum to ''Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection" [Int. J. Parasitol. 42 (2012) 535-548] (DOI:10.1016/j.ijpara.2012.03.011) International Journal for Parasitology,

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. | Citations: 17 (Scopus) | 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.

Acestor N, Cooksey R, Newton PN, Ménard D, Guerin PJ, Nakagawa J, Christophel E, González IJ, Bell D. 2012. Mapping the aetiology of non-malarial febrile illness in Southeast Asia through a systematic review--terra incognita impairing treatment policies. PLoS One, 7 (9), pp. e44269. | Citations: 48 (Scopus) | Show Abstract | Read more

BACKGROUND: An increasing use of point of care diagnostic tests that exclude malaria, coupled with a declining malaria burden in many endemic countries, is highlighting the lack of ability of many health systems to manage other causes of febrile disease. A lack of knowledge of distribution of these pathogens, and a lack of screening and point-of-care diagnostics to identify them, prevents effective management of these generally treatable contributors to disease burden. While prospective data collection is vital, an untapped body of knowledge already exists in the published health literature. METHODS: Focusing on the Mekong region of Southeast Asia, published data from 1986 to 2011 was screened to for frequency of isolation of pathogens implicated in aetiology of non-malarial febrile illness. Eligibility criteria included English-language peer-reviewed studies recording major pathogens for which specific management is likely to be warranted. Of 1,252 identified papers, 146 met inclusion criteria and were analyzed and data mapped. RESULTS: Data tended to be clustered around specific areas where research institutions operate, and where resources to conduct studies are greater. The most frequently reported pathogen was dengue virus (n = 70), followed by Orientia tsutsugamushi and Rickettsia species (scrub typhus/murine typhus/spotted fever group n = 58), Leptospira spp. (n = 35), Salmonella enterica serovar Typhi and Paratyphi (enteric fever n = 24), Burkholderia pseudomallei (melioidosis n = 14), and Japanese encephalitis virus (n = 18). Wide tracts with very little published data on aetiology of fever are apparent. DISCUSSION AND CONCLUSIONS: This mapping demonstrates a very heterogeneous distribution of information on the causes of fever in the Mekong countries. Further directed data collection to address gaps in the evidence-base, and expansion to a global database of pathogen distribution, is readily achievable, and would help define wider priorities for research and development to improve syndromic management of fever, prioritize diagnostic development, and guide empirical therapy.

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. | Citations: 426 (Scopus) | 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.

Ariana P. 2012. Challenging Our Understanding of Health: Indigenous Perspectives from the Highlands of Chiapas, Mexico Oxford Development Studies, 40 (3), pp. 405-421. | Citations: 2 (Scopus) | Show Abstract | Read more

In the context of development, considerable attention is paid to population health, usually interpreted according to mortality rates or burden of disease estimates. However, health is more complex than such physical indices can convey. This is particularly evident among many contemporary indigenous communities whose concepts of well-being extend well beyond conventional biomedical measures. Such misalignment of perspectives can have implications for how the health effects of development are determined. To gauge the relevance of alternative perspectives, indigenous notions of health among Highland communities in Chiapas, Mexico are examined. This paper begins with a historical account of health and healing rituals in the region, then describes current beliefs and practices among a set of Highland communities. © 2012 Copyright Oxford Department of International Development.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Erratum to ‘‘Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection” [Int. J. Parasitol. 42 (2012) 535–548] International Journal for Parasitology, 42 (10), pp. 961-961. | Read more

Dongol S, Thompson CN, Clare S, Nga TVT, Duy PT, Karkey A, Arjyal A, Koirala S, Khatri NS, Maskey P et al. 2012. The microbiological and clinical characteristics of invasive salmonella in gallbladders from cholecystectomy patients in kathmandu, Nepal. PLoS One, 7 (10), pp. e47342. | Citations: 25 (Scopus) | Show Abstract | Read more

Gallbladder carriage of invasive Salmonella is considered fundamental in sustaining typhoid fever transmission. Bile and tissue was obtained from 1,377 individuals undergoing cholecystectomy in Kathmandu to investigate the prevalence, characteristics and relevance of invasive Salmonella in the gallbladder in an endemic area. Twenty percent of bile samples contained a Gram-negative organism, with Salmonella Typhi and Salmonella Paratyphi A isolated from 24 and 22 individuals, respectively. Gallbladders that contained Salmonella were more likely to show evidence of acute inflammation with extensive neutrophil infiltrate than those without Salmonella, corresponding with higher neutrophil and lower lymphocyte counts in the blood of Salmonella positive individuals. Antimicrobial resistance in the invasive Salmonella isolates was limited, indicating that gallbladder colonization is unlikely to be driven by antimicrobial resistance. The overall role of invasive Salmonella carriage in the gallbladder is not understood; here we show that 3.5% of individuals undergoing cholecystectomy in this setting have a high concentration of antimicrobial sensitive, invasive Salmonella in their bile. We predict that such individuals will become increasingly important if current transmission mechanisms are disturbed; prospectively identifying these individuals is, therefore, paramount for rapid local and regional elimination.

Ginsburg AS, Van Cleve WC, Thompson MIW, English M. 2012. Oxygen and pulse oximetry in childhood pneumonia: a survey of healthcare providers in resource-limited settings. J Trop Pediatr, 58 (5), pp. 389-393. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

Globally, pneumonia is the leading cause of death in children <5 years of age. Hypoxemia, a frequent complication of pneumonia, is a risk factor for death. To better understand the availability of oxygen and pulse oximetry, barriers to use and provider perceptions and practices regarding their role in childhood pneumonia, we conducted a survey using a convenience sampling strategy targeting clinicians working in resource-limited countries. Most respondents were physicians from public district and provincial hospitals with access to oxygen and pulse oximetry; however, reported therapeutic use for childhood pneumonia was low. Common barriers included insufficient supply, competition for use, lack of policies, guidelines and training and perceived high cost. Despite the frequency of hypoxemia, the inaccuracy of clinical predictors, the poor outcome hypoxemia portends and the effectiveness of pulse oximetry and oxygen in childhood pneumonia, our data indicate that these tools may be underused in resource-limited settings.

Ayieko P, Okiro EA, Edwards T, Nyamai R, English M. 2012. Variations in mortality in children admitted with pneumonia to Kenyan hospitals. PLoS One, 7 (11), pp. e47622. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The existing case fatality estimates of inpatient childhood pneumonia in developing countries are largely from periods preceding routine use of conjugate vaccines for infant immunization and such primary studies rarely explore hospital variations in mortality. We analysed case fatality rates of children admitted to nine Kenyan hospitals with pneumonia during the era of routine infant immunization with Hib conjugate vaccine to determine if significant variations exist between hospitals. METHODS: Pneumonia admissions and outcomes in paediatric wards are described using data collected over two time periods: a one-year period (2007-2008) in nine hospitals, and data from a 9.25-year period (1999-March 2008) in one of the participating hospitals. Hospital case fatality rates for inpatient pneumonia during 2007 to 2008 were modeled using a fixed effect binomial regression model with a logit link. Using an interrupted time series design, data from one hospital were analysed for trends in pneumonia mortality during the period between 1997 and March 2008. RESULTS: Overall, 195 (5.9%) children admitted to all 9 hospitals with pneumonia from March 2007 to March 2008 died in hospital. After adjusting for child's sex, comorbidity, and hospital effect, mortality was significantly associated with child's age (p<0.001) and pneumonia severity (p<0.001). There was evidence of significant variations in mortality between hospitals (LR χ(2) =52.19; p<0.001). Pneumonia mortality remained stable in the periods before (trend -0.03, 95% CI -0.1 to 0.02) and after Hib introduction (trend 0.04, 95% CI -0.04 to 0.11). CONCLUSIONS: There are important variations in hospital-pneumonia case fatality in Kenya and these variations are not attributed to temporal changes. Such variations in mortality are not addressed by existing epidemiological models and need to be considered in allocating resources to improve child health.

Ibison F, Olotu A, Muema DM, Mwacharo J, Ohuma E, Kimani D, Marsh K, Bejon P, Ndungu FM. 2012. Lack of avidity maturation of merozoite antigen-specific antibodies with increasing exposure to Plasmodium falciparum amongst children and adults exposed to endemic malaria in Kenya. PLoS One, 7 (12), pp. e52939. | Citations: 10 (Scopus) | Show Abstract | Read more

BACKGROUND: Although antibodies are critical for immunity to malaria, their functional attributes that determine protection remain unclear. We tested for associations between antibody avidities to Plasmodium falciparum (Pf) antigens and age, asymptomatic parasitaemia, malaria exposure index (a distance weighted local malaria prevalence) and immunity to febrile malaria during 10-months of prospective follow up. METHODS: Cross-sectional antibody levels and avidities to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1(42) (MSP1) and Merozoite Surface Protein 3 (MSP3) were measured by Enzyme Linked Immunosorbent Assay in 275 children, who had experienced at least one episode of clinical malaria by the time of this study, as determined by active weekly surveillance. RESULTS: Antibody levels to AMA1, MSP1 and MSP3 increased with age. Anti-AMA1 and MSP1 antibody avidities were (respectively) positively and negatively associated with age, while anti-MSP3 antibody avidities did not change. Antibody levels to all three antigens were elevated in the presence of asymptomatic parasitaemia, but their associated avidities were not. Unlike antibody levels, antibody avidities to the three-merozoite antigens did not increase with exposure to Pf malaria. There were no consistent prospective associations between antibody avidities and malaria episodes. CONCLUSION: We found no evidence that antibody avidities to Pf-merozoite antigens are associated with either exposure or immunity to malaria.

Paton C, Hansen M, Fernandez-Luque L, Lau AYS. 2012. Self-Tracking, Social Media and Personal Health Records for Patient Empowered Self-Care. Contribution of the IMIA Social Media Working Group. Yearb Med Inform, 7 pp. 16-24. | Citations: 12 (Scopus) | Show Abstract

OBJECTIVES: This paper explores the range of self-tracking devices and social media platforms used by the self-tracking community, and examines the implications of widespread adoption of these tools for scientific progress in health informatics. METHODS: A literature review was performed to investigate the use of social media and self-tracking technologies in the health sector. An environmental scan identified a range of products and services which were used to exemplify three levels of self-tracking: self-experimentation, social sharing of data and patient controlled electronic health records. RESULTS: There appears to be an increase in the use of self-tracking tools, particularly in the health and fitness sector, but also used in the management of chronic diseases. Evidence of efficacy and effectiveness is limited to date, primarily due to the health and fitness focus of current solutions as opposed to their use in disease management. CONCLUSIONS: Several key technologies are converging to produce a trend of increased personal health surveillance and monitoring, social connectedness and sharing, and integration of regional and national health information systems. These trends are enabling new applications of scientific techniques, from personal experimentation to e-epidemiology, as data gathered by individuals are aggregated and shared across increasingly connected healthcare networks. These trends also raise significant new ethical and scientific issues that will need to be addressed, both by health informatics researchers and the communities of self-trackers themselves.

Powell TJ, Fox A, Peng Y, Quynh Mai LT, Lien VTK, Hang NLK, Wang L, Lee LY-H, 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. | Citations: 24 (Scopus) | 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.

Weiss GE, Ndungu FM, McKittrick N, Li S, Kimani D, Crompton PD, Marsh K, Pierce SK. 2012. High efficiency human memory B cell assay and its application to studying Plasmodium falciparum-specific memory B cells in natural infections. J Immunol Methods, 375 (1-2), pp. 68-74. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

Memory B cells (MBCs) are a key component of long term humoral immunity to many human infectious diseases. Despite their importance, we know little about the generation or maintenance of antigen-(Ag)-specific MBCs in humans in response to infection. A frequently employed method for quantifying Ag-specific MBCs in human peripheral blood (Crotty et al., 2004) relies on the ability of MBCs but not naïve B cells to differentiate into antibody secreting cells (ASCs) in response to polyclonal activators and Toll-like receptor agonists in vitro and the measurement of Ag-specific ASCs by ELISPOT assays. Here we report on studies to optimize the efficiency of this ELISPOT-based assay and to apply this assay to the detection of Plasmodium falciparum (Pf)-specific MBCs in adults living in a malaria endemic area where immunity to Pf is acquired through natural infection. We show that the addition of IL-10 to in vitro cultures of human peripheral blood mononuclear cells increased the efficiency of the assay from 10% to over 90% without increasing the ASC burst size and without any substantial increase in background from naïve B cells or plasma cells (PCs). Using this assay we were able to quantify the frequency of Pf-specific MBCs in peripheral blood of adults living in a malaria endemic area. Thus, this highly efficient assay appears to be well suited to field studies of the generation and maintenance of MBCs where the volumes of blood obtainable are often limiting.

Lang TA, Gould J, von Seidlein L, Lusingu JP, Mshamu S, Ismael S, Liheluka E, Kamuya D, Mwachiro D, Olotu A et al. 2012. Approaching the community about screening children for a multicentre malaria vaccine trial. Int Health, 4 (1), pp. 47-54. | Show Abstract | Read more

Community sensitisation, as a component of community engagement, plays an important role in strengthening the ethics of community-based trials in developing countries and is fundamental to trial success. However, few researchers have shared their community sensitisation strategies and experiences. We report on our perspective as researchers on the sensitisation activities undertaken for a phase II malaria vaccine trial in Kilifi District (Kenya) and Korogwe District (Tanzania), with the aim of informing and guiding the operational planning of future trials. We report wide variability in recruitment rates within both sites; a variability that occurred against a backdrop of similarity in overall approaches to sensitisation across the two sites but significant differences in community exposure to biomedical research. We present a range of potential factors contributing to these differences in recruitment rates, which we believe are worth considering in future community sensitisation plans. We conclude by arguing for carefully designed social science research around the implementation and impact of community sensitisation activities.

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