Dr Lorenz Von Seidlein

Research Area: Global Health
Keywords: malaria, treatment, vaccines, prevention, artemisinin, resistance and antimalarial
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Targeted Malaria Elimination

Artemisinin resistance has emerged in Cambodia, eastern Myanmar, southern Lao PDR (Laos) and Vietnam. This severely compromises falciparum malaria control efforts in the region, which depends on the continued efficacy of artemisinin combination therapies (ACT). Artemisinin resistance has the potential to spread throughout the malaria endemic regions of the world. The severity of this threat has been recognized and containment efforts have started or are under development. Addressing the problem involves elimination of falciparum malaria in areas of artemisinin resistance. If parasite populations in these foci are allowed to remain, evolving artemisinin resistance related to continuing drug pressure will spread.

In the last decade, P. falciparum transmission in the Greater Mekong Subregion has decreased substantially. A reversal of the current progress in malaria control would have tragic consequences. We explore the use of presumptive antimalarial treatment with  Dihydroartemisinin-piperaquine (DHA-PIP) of entire village populations. This intervention will target communities with significant levels of subclinical parasite infections and transmission.

DHA-PIP is a highly efficacious and inexpensive ACT, which is well tolerated by all age groups when used to treat uncomplicated multidrug resistant falciparum malaria in South East Asia. Monthly DHA-PIP  treatments have proved highly effective and well tolerated. When used as part of a TME strategy, the addition of a gametocytocidal drug such as primaquine (PQ), will contribute a strong transmission blocking activity by killing gametocytes. PQ, the only currently licensed 8-aminoquinoline, is safe and effective when used at a dose of 0.25 mg base/kg irrespective of G6PD status.

There are no collaborations listed for this principal investigator.

Phyo AP, von Seidlein L. 2017. Challenges to replace ACT as first-line drug. Malar J, 16 (1), pp. 296. | Show Abstract | Read more

The spread of artemisinin and partner drug resistance through Asia requires changes in first-line therapy. The traditional modus has been the replacement of one first-line anti-malarial regimen with another. The number of anti-malarial drug candidates currently in development may have given false confidence in the expectation that resistance to artemisinin-based combination therapy (ACT) can be solved with a switch to the next anti-malarial drug regimen. A number of promising anti-malarial drug regimens did not succeed in becoming first-line drugs due to safety concerns or rapid development of resistance. Currently promising candidates for inclusion in first-line regimens, such as KAE 609, KAF 156, OZ 439, and OZ 277, have already triggered safety concerns or fears that point mutations could render the drugs inefficacious. An additional challenge for a new first-line drug is finding an appropriate partner drug. There is hope that none of the above-mentioned concerns will be substantiated in larger, upcoming trials. Meanwhile, combining already licensed anti-malarials may be a promising stop-gap measure. Practitioners in Vietnam have empirically started to add mefloquine to the current dihydroartemisinin-piperaquine. Practitioners in Africa could do worse than empirically combine already licensed co-artemether and amodiaquine when treatment with ACT no longer clears Plasmodium falciparum. Both combinations are currently undergoing trials.

Grigg MJ, Cox J, William T, Jelip J, Fornace KM, Brock PM, von Seidlein L, Barber BE, Anstey NM, Yeo TW, Drakeley CJ. 2017. Individual-level factors associated with the risk of acquiring human Plasmodium knowlesi malaria in Malaysia: a case-control study. Lancet Planet Health, 1 (3), pp. e97-e104. | Show Abstract | Read more

BACKGROUND: The emergence of human malaria due to the monkey parasite Plasmodium knowlesi threatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reported P knowlesi cases, but the role of individual-level factors is unclear. To address this knowledge gap we assessed human and environmental factors associated with zoonotic knowlesi malaria risk. METHODS: We did this population-based case-control study over a 2 year period in the state of Sabah in Malaysia. We enrolled cases with microscopy-positive, PCR-confirmed malaria who presented to two primary referral hospitals serving the adjacent districts of Kudat and Kota Marudu. We randomly selected three malaria-negative community controls per case, who were matched by village within 2 weeks of case detection. We obtained questionnaire data on demographics, behaviour, and residential malaria risk factors, and we also assessed glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. We used conditional logistic regression models to evaluate exposure risk between P knowlesi cases and controls, and between P knowlesi and human-only Plasmodium spp malaria cases. FINDINGS: From Dec 5, 2012, to Jan 30, 2015, we screened 414 patients and subsequently enrolled 229 cases with P knowlesi malaria mono-infection and 91 cases with other Plasmodium spp infection. We enrolled 953 matched controls, including 683 matched to P knowlesi cases and 270 matched to non-P knowlesi cases. Age 15 years or older (adjusted odds ratio [aOR] 4·16, 95% CI 2·09-8·29, p<0·0001), male gender (4·20, 2·54-6·97, p<0·0001), plantation work (3·50, CI, 1·34-9·15, p=0·011), sleeping outside (3·61, 1·48-8·85, p=0·0049), travel (2·48, 1·45-4·23, p=0·0010), being aware of the presence of monkeys in the past 4 weeks (3·35, 1·91-5·88, p<0·0001), and having open eaves or gaps in walls (2·18, 1·33-3·59, p=0·0021) were independently associated with increased risk of symptomatic P knowlesi infection. Farming occupation (aOR 1·89, 95% CI 1·07-3·35, p=0·028), clearing vegetation (1·89, 1·11-3·22, p=0·020), and having long grass around the house (2·08, 1·25-3·46, p=0·0048) increased risk for P knowlesi infection but not other Plasmodium spp infection. G6PD deficiency seemed to be protective against P knowlesi (aOR 0·20, 95% CI 0·04-0·96, p=0·045), as did residual insecticide spraying of household walls (0·52, 0·31-0·87, p=0·014), with the presence of young sparse forest (0·35, 0·20-0·63, p=00040) and rice paddy around the house (0·16, 0·03-0·78, 0·023) also associated with decreased risk. INTERPRETATION: Adult men working in agricultural areas were at highest risk of knowlesi malaria, although peri-domestic transmission also occurrs. Human behavioural factors associated with P knowlesi transmission could be targeted in future public health interventions. FUNDING: United Kingdom Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council.

Pell C, Tripura R, Nguon C, Cheah P, Davoeung C, Heng C, Dara L, Sareth M, Dondorp A, von Seidlein L, Peto TJ. 2017. Mass anti-malarial administration in western Cambodia: a qualitative study of factors affecting coverage. Malar J, 16 (1), pp. 206. | Show Abstract | Read more

BACKGROUND: Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia. METHODS: Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities. Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo. RESULTS: Malaria was an important health concern and villagers reported a demand for malaria treatment. This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria. Participants generally understood the overall study aim and were familiar with study activities. Comprehension of the study rationale was however limited. After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as "side effects" contributed to a decrease of coverage in round two. Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings. This contributed to a subsequent increase in coverage. CONCLUSION: Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement. Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare.

Abreha T, Hwang J, Thriemer K, Tadesse Y, Girma S, Melaku Z, Assef A, Kassa M, Chatfield MD, Landman KZ et al. 2017. Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial. PLoS Med, 14 (5), pp. e1002299. | Show Abstract | Read more

BACKGROUND: Recent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia. METHODS AND FINDINGS: Patients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42. The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%-10.4%) after CQ treatment and 0% (95% CI 0%-4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%-20.6%) following AL alone and 2.3% (95% CI 0.6%-9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%-28.0%) after CQ, 1.2% (95% CI 0.2%-8.0%) after CQ+PQ, 29.9% (95% CI 21.6%-40.5%) after AL, and 5.9% (95% CI 2.4%-13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0-3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9-9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6-11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms. The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia. CONCLUSIONS: Despite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y. TRIAL REGISTRATION: ClinicalTrials.gov NCT01680406.

Thriemer K, Ley B, Bobogare A, Dysoley L, Alam MS, Pasaribu AP, Sattabongkot J, Jambert E, Domingo GJ, Commons R et al. 2017. Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group. Malar J, 16 (1), pp. 141. | Show Abstract | Read more

The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia-Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by  the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.

Chowdhury FR, Nur Z, Hassan N, von Seidlein L, Dunachie S. 2017. Pandemics, pathogenicity and changing molecular epidemiology of cholera in the era of global warming. Ann Clin Microbiol Antimicrob, 16 (1), pp. 10. | Show Abstract | Read more

BACKGROUND: Vibrio cholerae, a Gram-negative, non-spore forming curved rod is found in diverse aquatic ecosystems around the planet. It is classified according to its major surface antigen into around 206 serogroups, of which O1 and O139 cause epidemic cholera. A recent spatial modelling technique estimated that around 2.86 million cholera cases occur globally every year, and of them approximately 95,000 die. About 1.3 billion people are currently at risk of infection from cholera. Meta-analysis and mathematical modelling have demonstrated that due to global warming the burden of vector-borne diseases like malaria, leishmaniasis, meningococcal meningitis, viral encephalitis, dengue and chikungunya will increase in the coming years in the tropics and beyond. CHOLERA AND CLIMATE: This review offers an overview of the interplay between global warming and the pathogenicity and epidemiology of V. cholerae. Several distinctive features of cholera survival (optimal thriving at 15% salinity, 30 °C water temperature, and pH 8.5) indicate a possible role of climate change in triggering the epidemic process. Genetic exchange (ctxAB, zot, ace, cep, and orfU) between strains and transduction process allows potential emergence of new toxigenic clones. These processes are probably controlled by precise environmental signals such as optimum temperature, sunlight and osmotic conditions. Environmental influences on phytoplankton growth and chitin remineralization will be discussed alongside the interplay of poor sanitary conditions, overcrowding, improper sewage disposal and global warming in promoting the growth and transmission of this deadly disease. CONCLUSION: The development of an effective early warning system based on climate data could help to prevent and control future outbreaks. It may become possible to integrate real-time monitoring of oceanic regions, climate variability and epidemiological and demographic population dynamics to predict cholera outbreaks and support the design of cost-effective public health strategies.

Lu F, Culleton R, Zhang M, Ramaprasad A, von Seidlein L, Zhou H, Zhu G, Tang J, Liu Y, Wang W et al. 2017. Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa. N Engl J Med, 376 (10), pp. 991-993. | Read more

Sahan K, Pell C, Smithuis F, Phyo AK, Maung SM, Indrasuta C, Dondorp AM, White NJ, Day NPJ, von Seidlein L, Cheah PY. 2017. Community engagement and the social context of targeted malaria treatment: a qualitative study in Kayin (Karen) State, Myanmar. Malar J, 16 (1), pp. 75. | Show Abstract | Read more

BACKGROUND: The spread of artemisinin-resistance in Plasmodium falciparum is a threat to current global malaria control initiatives. Targeted malaria treatment (TMT), which combines mass anti-malarial administration with conventional malaria prevention and control measures, has been proposed as a strategy to tackle this problem. The effectiveness of TMT depends on high levels of population coverage and is influenced by accompanying community engagement activities and the local social context. The article explores how these factors influenced attitudes and behaviours towards TMT in Kayin (Karen) State, Myanmar. METHODS: Semi-structured interviews were conducted with villagers from study villages (N = 31) and TMT project staff (N = 14) between March and July 2015. RESULTS: Community engagement consisted of a range of activities to communicate the local malaria situation (including anti-malarial drug resistance and asymptomatic malaria), the aims of the TMT project, and its potential benefits. Community engagement was seen by staff as integral to the TMT project as a whole and not a sub-set of activities. Attitudes towards TMT (including towards community engagement) showed that developing trusting relationships helped foster participation. After initial wariness, staff received hospitality and acceptance among villagers. Offering healthcare alongside TMT proved mutually beneficial for the study and villagers. A handful of more socially-mobile and wealthy community members were reluctant to participate. The challenges of community engagement included time constraints and the isolation of the community with its limited infrastructure and a history of conflict. CONCLUSIONS: Community engagement had to be responsive to the local community even though staff faced time constraints. Understanding the social context of engagement helped TMT to foster respectful and trusting relationships. The complex relationship between the local context and community engagement complicated evaluation of the community strategy. Nonetheless, the project did record high levels of population coverage.

Tripura R, Peto TJ, Veugen CC, Nguon C, Davoeung C, James N, Dhorda M, Maude RJ, Duanguppama J, Patumrat K et al. 2017. Submicroscopic Plasmodium prevalence in relation to malaria incidence in 20 villages in western Cambodia. Malar J, 16 (1), pp. 56. | Show Abstract | Read more

BACKGROUND: Cambodia has seen a marked reduction in the incidence of Plasmodium falciparum over the past decade without a corresponding decline in Plasmodium vivax incidence. It is unknown to what extent local transmission is sustained by a chain of clinical and sub-clinical infections or by continued re-introduction via migration. Using an ultrasensitive molecular technique, 20 villages in western Cambodia were surveyed to detect the low season prevalence of P. falciparum and P. vivax and local treatment records were reviewed. METHODS: During March to May 2015 cross-sectional surveys were conducted in 20 villages in Battambang, western Cambodia. Demographic and epidemiological data and venous blood samples were collected from 50 randomly selected adult volunteers in each village. Blood was tested for Plasmodium infections by rapid diagnostic test (RDT), microscopy and high volume (0.5 ml packed red blood cell) quantitative polymerase chain reaction (uPCR). Positive samples were analysed by nested PCR to determine the Plasmodium species. Malaria case records were collected from the Provincial Health Department and village malaria workers to determine incidence and migration status. RESULTS: Among the 1000 participants, 91 (9.1%) were positive for any Plasmodium infection by uPCR, seven (0.7%) by microscopy, and two (0.2%) by RDT. uPCR P. vivax prevalence was 6.6%, P. falciparum 0.7%, and undetermined Plasmodium species 1.8%. Being male (adjusted OR 2.0; 95% CI 1.2-3.4); being a young adult <30 years (aOR 2.1; 95% CI 1.3-3.4); recent forest travel (aOR 2.8; 95% CI 1.6-4.8); and, a history of malaria (aOR 5.2; 95% CI 2.5-10.7) were independent risk factors for parasitaemia. Of the clinical malaria cases diagnosed by village malaria workers, 43.9% (297/634) and 38.4% (201/523) were among migrants in 2013 and in 2014, respectively. Plasmodium vivax prevalence determined by uPCR significantly correlated with vivax malaria incidences in both 2014 and 2015 (p = 0.001 and 0.002, respectively), whereas no relationship was observed in falciparum malaria (p = 0.36 and p = 0.59, respectively). DISCUSSION: There was heterogeneity in the malaria parasite reservoir between villages, and Plasmodium prevalence correlated with subsequent malaria incidence. The association was attributable chiefly to P. vivax infections, which were nine-fold more prevalent than P. falciparum infections. In the absence of a radical cure with 8-aminoquinolines, P. vivax transmission will continue even as P. falciparum prevalence declines. Migration was associated with over a third of incident cases of clinical malaria. Trial registration clinicaltrials.gov (NCT01872702). Registered 4 June 2013.

Nguyen T-N, Thu PNH, Hung NT, Son DH, Tien NT, Van Dung N, Quang HH, Seidlein LV, Cheah PY, Dondorp AM et al. 2017. Community perceptions of targeted anti-malarial mass drug administrations in two provinces in Vietnam: a quantitative survey. Malar J, 16 (1), pp. 17. | Show Abstract | Read more

BACKGROUND: As part of a targeted malaria elimination project, mass drug administrations (MDAs) were conducted in Vietnam. The impact of MDAs on malaria transmission depends largely on the efficacy of the anti-malarial drug regimen, the malaria epidemiology in the site and the population coverage. To explore why some people participate in MDAs and others do not, a quantitative survey of the villagers' perceptions was undertaken in Vietnam. METHODS: In 2013/2014 MDAs were conducted in a village in Binh Phuoc province and a village in Ninh Thuan province. Within three months of the drug administration, 59 respondents in a village in Binh Phuoc and 79 respondents in a village in Ninh Thuan were randomly selected and interviewed. RESULTS: Comprehension of the purpose of the intervention was of paramount importance for participation in the intervention. Respondents aware that the intervention aims to protect against malaria were significantly more likely to participate than respondents who were unaware of the MDA's purpose. Secondly, how and by whom villagers were informed was critical for participation. There was a strong association between sensitization by an informant such as a member of the local health team with participation in the intervention. CONCLUSIONS: The study suggests several approaches to increase participation in mass drug administration campaigns. Training trustworthy informants to sensitize the study population is critical to maximize village participation in this setting. To achieve high coverage the entire community must understand and agree with the intervention.

von Seidlein L, Kekulé AS, Strickman D. 2017. Novel Vector Control Approaches: The Future for Prevention of Zika Virus Transmission? PLoS Med, 14 (1), pp. e1002219. | Show Abstract | Read more

In a Perspective accompanying Abad-Franch and colleagues, Lorenz von Seidlein, Alexander Kekulé, and Daniel Strickman discuss the importance of developing effective strategies to minimize mosquito-borne transmission of human diseases.

Parker DM, Landier J, von Seidlein L, Dondorp A, White L, Hanboonkunupakarn B, Maude RJ, Nosten FH. 2016. Limitations of malaria reactive case detection in an area of low and unstable transmission on the Myanmar-Thailand border. Malar J, 15 (1), pp. 571. | Show Abstract | Read more

BACKGROUND: Reactive case detection is an approach that has been proposed as a tool for malaria elimination in low-transmission settings. It is an intuitively justified approach based on the concept of space-time clustering of malaria cases. When an index malaria clinical case is detected, it triggers reactive screening and treatment in the index house and neighbouring houses. However, the efficacy of this approach at varying screening radii and malaria prevalence remains ill defined. METHODS: Data were obtained from a detailed demographic and geographic surveillance study in four villages on the Myanmar-Thailand border. Clinical cases were recorded at village malaria clinics and were linked back to patients' residencies. These data were used to simulate the efficacy of reactive case detection for clinical cases using rapid diagnostic tests (RDT). Simulations took clinical cases in a given month and tabulated the number of cases that would have been detected in the following month at varying screening radii around the index houses. Simulations were run independently for both falciparum and vivax malaria. Each simulation of a reactive case detection effort was run in comparison with a strategy using random selection of houses for screening. RESULTS: In approximately half of the screenings for falciparum and 10% for vivax it would have been impossible to detect any malaria cases regardless of the screening strategy because the screening would have occurred during times when there were no cases. When geographically linked cases were present in the simulation, reactive case detection would have only been successful at detecting most malaria cases using larger screening radii (150-m radius and above). At this screening radius and above, reactive case detection does not perform better than random screening of an equal number of houses in the village. Screening within very small radii detects only a very small proportion of cases, but despite this low performance is better than random screening with the same sample size. CONCLUSIONS: The results of these simulations indicate that reactive case detection for clinical cases using RDTs has limited ability in halting transmission in regions of low and unstable transmission. This is linked to high spatial heterogeneity of cases, acquisition of malaria infections outside the village, as well missing asymptomatic infections. When cases are few and sporadic, reactive case detection would result in major time and budgetary losses.

Adhikari B, James N, Newby G, von Seidlein L, White NJ, Day NPJ, Dondorp AM, Pell C, Cheah PY. 2016. Community engagement and population coverage in mass anti-malarial administrations: a systematic literature review. Malar J, 15 (1), pp. 523. | Show Abstract | Read more

BACKGROUND: Mass anti-malarial administration has been proposed as a key component of the malaria elimination strategy in South East Asia. The success of this approach depends on the local malaria epidemiology, nature of the anti-malarial regimen and population coverage. Community engagement is used to promote population coverage but little research has systematically analysed its impact. This systematic review examines population coverage and community engagement in programmes of mass anti-malarial drug administration. METHODS: This review builds on a previous review that identified 3049 articles describing mass anti-malarial administrations published between 1913 and 2011. Further search and application of a set of criteria conducted in the current review resulted in 51 articles that were retained for analysis. These 51 papers described the population coverage and/or community engagement in mass anti-malarial administrations. Population coverage was quantitatively assessed and a thematic analysis was conducted on the community engagement activities. RESULTS: The studies were conducted in 26 countries: in diverse healthcare and social contexts where various anti-malarial regimens under varied study designs were administered. Twenty-eight articles reported only population coverage; 12 described only community engagement activities; and 11 community engagement and population coverage. Average population coverage was 83% but methods of calculating coverage were frequently unclear or inconsistent. Community engagement activities included providing health education and incentives, using community structures (e.g. existing hierarchies or health infrastructure), mobilizing human resources, and collaborating with government at some level (e.g. ministries of health). Community engagement was often a process involving various activities throughout the duration of the intervention. CONCLUSION: The mean population coverage was over 80% but incomplete reporting of calculation methods limits conclusions and comparisons between studies. Various community engagement activities and approaches were described, but many articles contained limited or no details. Other factors relevant to population coverage, such as the social, cultural and study context were scarcely reported. Further research is needed to understand the factors that influence population coverage and adherence in mass anti-malarial administrations and the role community engagement activities and approaches play in satisfactory participation.

von Seidlein L, Knudsen J. 2016. Malaria Epidemiology in Kilifi, Kenya during the 21st Century: What Next? PLoS Med, 13 (6), pp. e1002048. | Show Abstract | Read more

Lorenz von Seidlein and Jakob Knudsen discuss the changes in malaria incidence recorded at a single site in Africa over 25 years, along with future implications for disease prevention.

Phommasone K, Adhikari B, Henriques G, Pongvongsa T, Phongmany P, von Seidlein L, White NJ, Day NPJ, M Dondorp A, Newton PN et al. 2016. Asymptomatic Plasmodium infections in 18 villages of southern Savannakhet Province, Lao PDR (Laos). Malar J, 15 (1), pp. 296. | Show Abstract | Read more

BACKGROUND: A large fraction of Plasmodium infections do not cause clinical signs and symptoms of disease and persist at densities in blood that are not detectable by microscopy or rapid diagnostic tests. These infections may be critical as a transmission reservoir in areas of low malaria endemicity. Understanding the epidemiology of these infections would be helpful for malaria elimination. METHODS: A cross-sectional survey was conducted in Thapangthong and Nong Districts of Savannakhet Province, Lao PDR, to determine the prevalence of parasitaemia. A total of 888 blood samples were collected from afebrile volunteers aged ≥15 years in 18 villages during March and July 2015. Plasmodium infections were diagnosed by rapid diagnostic tests (RDT) and high volume, ultra-sensitive quantitative polymerase chain reaction (uPCR). RESULTS: uPCR detected Plasmodium infections in 175 of 888 samples (20 %). The species distribution was Plasmodium falciparum 3.6 % (32/888), Plasmodium vivax 11.1 % (99/888), mixed infections with P. falciparum and P. vivax 1.6 % (14/888) and Plasmodium of undetermined species 3.4 % (30/888). RDT identified only 2 % (18/888) positive cases. Using uPCR as reference, the sensitivity and specificity of RDTs were 28 and 100 %, respectively, in detecting P. falciparum infections, and 3 and 99 % in detecting asymptomatic P. vivax infections. The K13 kelch propeller domain C580Y mutation, associated with reduced susceptibility to artemisinin derivatives, was found in 75 % (12/18) of P. falciparum isolates from Thapangthong and in 7 % (2/28) from Nong (p < 0.001). In a multivariate analysis, males were more likely to have P. vivax infections [adjusted odds ratio (aOR) 4.76 (95 % CI 2.84-8.00)] while older villagers were at lower risk for parasitaemia [aOR for increasing age 0.98 (95 % CI 0.96-0.99)]. CONCLUSION: There is a high prevalence of asymptomatic Plasmodium infections in southern Savannakhet. Artemisinin-resistant P. falciparum strains form an increasing proportion of the parasite population in Thapangthong District and are already present in the more remote Nong District. This worrying trend has wider implications for Laos and could reverse the gains achieved by the successful control of malaria in Laos and the Greater Mekong Sub-region (GMS). Rapid elimination of P. falciparum has to be a top priority in Laos as well as in the wider GMS.

Peto TJ, Kloprogge SE, Tripura R, Nguon C, Sanann N, Yok S, Heng C, Promnarate C, Chalk J, Song N et al. 2016. History of malaria treatment as a predictor of subsequent subclinical parasitaemia: a cross-sectional survey and malaria case records from three villages in Pailin, western Cambodia. Malar J, 15 (1), pp. 240. | Show Abstract | Read more

BACKGROUND: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub-clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. METHODS: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qPCR. Positive samples were analysed by nested PCR to determine the Plasmodium species. To identify previous episodes of malaria, case records were collected from village malaria workers and local health facilities and linked to study participants. RESULTS: Among 1343 participants, 40/122 (32.8 %) with a history of clinical malaria were parasitaemic during the cross-sectional survey, compared to 172/1221 (14.1 %) without this history (p < 0.001). Among the 212 parasitaemic participants in the survey, 40 (18.9 %) had a history of clinical malaria, compared to 87 out of 1131 (7.7 %) parasite-negative participants; p < 0.001, adjusted OR 3.3 (95 % CI; 2.1-5.1). A history of Plasmodium vivax was associated with sub-clinical P. vivax parasitaemia in the survey (p < 0.001), but this association was not seen with Plasmodium falciparum (p = 0.253); only three participants had both P. falciparum parasites in the survey and a clinical history of P. falciparum. CONCLUSIONS: A clinical episode of vivax malaria was associated with subsequent sub-clinical parasitaemia. Treatment of P. vivax with artemisinin-based combination therapy without primaquine often resulted in recurrent episodes. Targeting individuals with a history of clinical malaria will be insufficient to eliminate the sub-clinical reservoir as they constitute a minority of parasitaemias.

Gosling R, von Seidlein L. 2016. The Future of the RTS,S/AS01 Malaria Vaccine: An Alternative Development Plan. PLoS Med, 13 (4), pp. e1001994. | Show Abstract | Read more

Roly Gosling and Lorenz von Seidlein consider a potential future development plan for the RTS,S/AS01 malaria vaccine.

Von Seidlein L. 2016. Malaria prevention strategies INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 45 pp. 16-16. | Read more

Imwong M, Stepniewska K, Tripura R, Peto TJ, Lwin KM, Vihokhern B, Wongsaen K, von Seidlein L, Dhorda M, Snounou G et al. 2016. Numerical Distributions of Parasite Densities During Asymptomatic Malaria. J Infect Dis, 213 (8), pp. 1322-1329. | Show Abstract | Read more

BACKGROUND: Asymptomatic parasitemia is common even in areas of low seasonal malaria transmission, but the true proportion of the population infected has not been estimated previously because of the limited sensitivity of available detection methods. METHODS: Cross-sectional malaria surveys were conducted in areas of low seasonal transmission along the border between eastern Myanmar and northwestern Thailand and in western Cambodia. DNA was quantitated by an ultrasensitive polymerase chain reaction (uPCR) assay (limit of accurate detection, 22 parasites/mL) to characterize parasite density distributions for Plasmodium falciparum and Plasmodium vivax, and the proportions of undetected infections were imputed. RESULTS: The prevalence of asymptomatic malaria as determined by uPCR was 27.5% (1303 of 4740 people tested). Both P. vivax and P. falciparum density distributions were unimodal and log normal, with modal values well within the quantifiable range. The estimated proportions of all parasitemic individuals identified by uPCR were >70% among individuals infected with P. falciparum and >85% among those infected with P. vivax. Overall, 83% of infections were predicted to be P. vivax infections, 13% were predicted to be P. falciparum infections, and 4% were predicted to be mixed infections. Geometric mean parasite densities were similar; 5601 P. vivax parasites/mL and 5158 P. falciparum parasites/mL. CONCLUSIONS: This uPCR method identified most infected individuals in malaria-endemic areas. Malaria parasitemia persists in humans at levels that optimize the probability of generating transmissible gametocyte densities without causing illness.

Kajeechiwa L, Thwin MM, Shee PW, Yee NL, Elvina E, Peapah P, Kyawt K, Oo PT, PoWah W, Min JR et al. 2016. The acceptability of mass administrations of anti-malarial drugs as part of targeted malaria elimination in villages along the Thai-Myanmar border. Malar J, 15 (1), pp. 494. | Show Abstract | Read more

BACKGROUND: A targeted malaria elimination project, including mass drug administrations (MDA) of dihydroartemisinin/piperaquine plus a single low dose primaquine is underway in villages along the Thailand Myanmar border. The intervention has multiple components but the success of the project will depend on the participation of the entire communities. Quantitative surveys were conducted to study reasons for participation or non-participation in the campaign with the aim to identify factors associated with the acceptance and participation in the mass drug administrations. METHODS: The household heads in four study villages in which MDAs had taken place previously were interviewed between January 2014 and July 2015. RESULTS: 174/378 respondents (46 %) completed three rounds of three drug doses each, 313/378 (83 %) took at least three consecutive doses and 56/378 (15 %) did not participate at all in the MDA. The respondents from the two villages (KNH and TPN) were much more likely to participate in the MDA than respondents from the other two villages (HKT and TOT). The more compliant villages KNH and TPN had both an appearance of cohesive communities with similar demographic and ethnic backgrounds. By contrast the villages with low participation were unique. One village was fragmented following years of armed conflict and many respondents gave little inclination to cooperate with outsiders. The other village with low MDA coverage was characterised by a high percentage of short-term residents with little interest in community interventions. A universal reason for non-participation in the MDA applicable to all villages was an inadequate understanding of the intervention. CONCLUSIONS: It is unlikely that community engagement can unite fragmented communities in participating in an intervention, which benefits the community. Understanding the purpose and the reasons underlying the intervention is an important pre-condition for participation. In the absence of direct benefits and a complete understanding of the indirect benefits trust in the investigators is critical for participation.

Peto TJ, Tripura R, Lee SJ, Althaus T, Dunachie S, Nguon C, Dhorda M, Promnarate C, Chalk J, Imwong M et al. 2016. Association between Subclinical Malaria Infection and Inflammatory Host Response in a Pre-Elimination Setting. PLoS One, 11 (7), pp. e0158656. | Show Abstract | Read more

BACKGROUND: Subclinical infections in endemic areas of Southeast Asia sustain malaria transmission. These asymptomatic infections might sustain immunity against clinical malaria and have been considered benign for the host, but if they are associated with chronic low-grade inflammation this could be harmful. We conducted a case-control study to explore the association between subclinical malaria and C-reactive protein (CRP), an established biomarker of inflammation. METHODS: Blood samples from asymptomatic villagers in Pailin, Western Cambodia were tested for malaria by high-volume ultra-sensitive polymerase chain reaction (uPCR) to determine the Plasmodium species. Plasma CRP concentration was measured in 328 individuals with parasitaemia (cases) and compared with: i) the same individual's value at the first time point when they had no detectable parasites (n = 282); and ii) age- sex- and village-matched controls (n = 328) free of Plasmodium infection. Plasma CRP concentrations were compared against thresholds of 3mg/L and 10mg/L. Subgroup analysis was carried out for cases with P vivax and P falciparum mono-infections. RESULTS: Median plasma CRP level for all samples was 0.59mg/L (interquartile range: 0.24-1.64mg/L). CRP concentrations were higher in parasitaemic individuals compared with same-person-controls (p = 0.050); and matched-controls (p = 0.025). 4.9% of samples had CRP concentrations above 10mg/L and 14.6% were above 3mg/L. Cases were more likely to have plasma CRP concentrations above these thresholds than age/sex matched controls, odds ratio 3.5 (95%CI 1.5-9.8) and 1.8 (95%CI 1.1-2.9), respectively. Amongst cases, parasite density and CRP were positively correlated (p<0.001), an association that remained significant when controlling for age and fever. Individuals with P.vivax mono-infections had the highest plasma CRP concentrations with the greatest association with parasitaemia. DISCUSSION: In this setting persistent malaria infections in asymptomatic individuals were associated with moderately elevated plasma CRP concentrations; chiefly evident in cases with P.vivax mono-infections. As well as interrupting malaria transmission within the community, treatment of asymptomatic malaria infections, in particular radical cure of vivax malaria, may benefit the health of infected individuals.

Espino FE, Bibit J-A, Sornillo JB, Tan A, von Seidlein L, Ley B. 2016. Comparison of Three Screening Test Kits for G6PD Enzyme Deficiency: Implications for Its Use in the Radical Cure of Vivax Malaria in Remote and Resource-Poor Areas in the Philippines. PLoS One, 11 (2), pp. e0148172. | Show Abstract | Read more

OBJECTIVE: We evaluated a battery of Glucose-6-Phosphate Dehydrogenase diagnostic point-of-care tests (PoC) to assess the most suitable product in terms of performance and operational characteristics for remote areas. METHODS: Samples were collected in Puerto Princesa City, Palawan, Philippines and tested for G6PD deficiency with a fluorescent spot test (FST; Procedure 203, Trinity Biotech, Ireland), the semiquantitative WST8/1-methoxy PMS (WST; Dojindo, Japan) and the Carestart G6PD Rapid Diagnostic Test (CSG; AccessBio, USA). Results were compared to spectrophotometry (Procedure 345, Trinity Biotech, Ireland). Sensitivity and specificity were calculated for each test with cut-off activities of 10%, 20%, 30% and 60% of the adjusted male median. RESULTS: The adjusted male median was 270.5 IU/10(12) RBC. FST and WST were tested on 621 capillary blood samples, the CSG was tested on venous and capillary blood on 302 samples. At 30% G6PD activity, sensitivity for the FST was between 87.7% (95%CI: 76.8% to 93.9%) and 96.5% (95%CI: 87.9% to 99.5%) depending on definition of intermediate results; the WST was 84.2% (95%CI: 72.1% to 92.5%); and the CSG was between 68.8% (95%CI: 41.3% to 89.0%) and 93.8% (95%CI: 69.8% to 99.8%) when the test was performed on capillary or venous blood respectively. Sensitivity of FST and CSG (tested with venous blood) were comparable (p>0.05). The analysis of venous blood samples by the CSG yielded significantly higher results than FST and CSG performed on capillary blood (p<0.05). Sensitivity of the CSG varied depending on source of blood used (p<0.05). CONCLUSION: The operational characteristics of the CSG were superior to all other test formats. Performance and operational characteristics of the CSG performed on venous blood suggest the test to be a good alternative to the FST.

Wangchuk S, Drukpa T, Penjor K, Peldon T, Dorjey Y, Dorji K, Chhetri V, Trimarsanto H, To S, Murphy A et al. 2016. Where chloroquine still works: the genetic make-up and susceptibility of Plasmodium vivax to chloroquine plus primaquine in Bhutan. Malar J, 15 (1), pp. 277. | Show Abstract | Read more

BACKGROUND: Bhutan has made substantial progress in reducing malaria incidence. The national guidelines recommend chloroquine (CQ) and primaquine (PQ) for radical cure of uncomplicated Plasmodium vivax, but the local efficacy has not been assessed. The impact of cases imported from India on the genetic make-up of the local vivax populations is currently unknown. METHODS: Patients over 4 years of age with uncomplicated P. vivax mono-infection were enrolled into a clinical efficacy study and molecular survey. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. On day 28 a 14-day regimen of PQ (0.25 mg/kg/day) was commenced under direct observation. After day 42, patients were followed up monthly for a year. The primary and secondary endpoints were risk of treatment failure at day 28 and at 1 year. Parasite genotyping was undertaken at nine tandem repeat markers, and standard population genetic metrics were applied to examine population diversity and structure in infections thought to be acquired inside or outside of Bhutan. RESULTS: A total of 24 patients were enrolled in the clinical study between April 2013 and October 2015. Eight patients (33.3 %) were lost to follow-up in the first 6 months and another eight patients lost between 6 and 12 months. No (0/24) treatment failures occurred by day 28 and no (0/8) parasitaemia was detected following PQ treatment. Some 95.8 % (23/24) of patients were aparasitaemic by day 2. There were no haemolytic or serious events. Genotyping was undertaken on parasites from 12 autochthonous cases and 16 suspected imported cases. Diversity was high (H E 0.87 and 0.90) in both populations. There was no notable differentiation between the autochthonous and imported populations. CONCLUSIONS: CQ and PQ remains effective for radical cure of P. vivax in Bhutan. The genetic analyses indicate that imported infections are sustaining the local vivax population, with concomitant risk of introducing drug-resistant strains.

Tripura R, Peto TJ, Chalk J, Lee SJ, Sirithiranont P, Nguon C, Dhorda M, von Seidlein L, Maude RJ, Day NPJ et al. 2016. Persistent Plasmodium falciparum and Plasmodium vivax infections in a western Cambodian population: implications for prevention, treatment and elimination strategies. Malar J, 15 (1), pp. 181. | Show Abstract | Read more

BACKGROUND: Subclinical Plasmodium parasitaemia is an important reservoir for the transmission and persistence of malaria, particularly in low transmission areas. METHODS: Using ultrasensitive quantitative PCR (uPCR) for the detection of parasitaemia, the entire population of three Cambodian villages in Pailin province were followed for 1 year at three-monthly intervals. A cohort of adult participants found initially to have asymptomatic malaria parasitaemia was followed monthly over the same period. RESULTS: The initial cross sectional survey in June 2013 (M0) of 1447 asymptomatic residents found that 32 (2.2%) had Plasmodium falciparum, 48 (3.3%) had P. vivax, 4 (0.3%) had mixed infections and in 142/1447 (9.8%) malaria was detected but there was insufficient DNA to identify the species (Plasmodium. species). Polymorphisms in the 'K13-propeller' associated with reduced susceptibility to artemisinin derivatives (C580Y) were found in 17/32 (51%) P. falciparum strains. Monthly follow-up without treatment of 24 adult participants with asymptomatic mono or mixed P. falciparum infections found that 3/24 (13%) remained parasitaemic for 2-4 months, whereas the remaining 21/24 (87%) participants had cleared their parasitaemia after 1 month. In contrast, 12/34 (35%) adult participants with P. vivax mono-infection at M0 had malaria parasites (P. vivax or P. sp.) during four or more of the following 11 monthly surveys. CONCLUSIONS: This longitudinal survey in a low transmission setting shows limited duration of P. falciparum carriage, but prolonged carriage of P. vivax infections. Radical treatment of P. vivax infections by 8-aminoquinoline regimens may be required to eliminate all malaria from Cambodia. Trial registration ClinicalTrials.gov NCT01872702.

IMPROV Study Group. 2015. Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens. BMC Infect Dis, 15 (1), pp. 558. | Show Abstract | Read more

BACKGROUND: Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients. DESIGN: This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events. DISCUSSION: This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01814683 . Registered March 18, 2013.

PLOS Medicine Editors, Beck A, Birney E, Graeber M, Tumwine J, Hay P, Ahn HS, Patel A, du Cros P, von Seidlein L et al. 2015. Progress in Medicine: Experts Take Stock. PLoS Med, 12 (12), pp. e1001933. | Show Abstract | Read more

In the year-end editorial, the PLOS Medicine editors ask 11 researchers and clinicians about the most relevant challenges, promising research, and important initiatives in their fields as we head into 2016.

Ley B, Luter N, Espino FE, Devine A, Kalnoky M, Lubell Y, Thriemer K, Baird JK, Poirot E, Conan N et al. 2015. The challenges of introducing routine G6PD testing into radical cure: a workshop report. Malar J, 14 (1), pp. 377. | Show Abstract | Read more

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.

Imwong M, Nguyen TN, Tripura R, Peto TJ, Lee SJ, Lwin KM, Suangkanarat P, Jeeyapant A, Vihokhern B, Wongsaen K et al. 2015. The epidemiology of subclinical malaria infections in South-East Asia: findings from cross-sectional surveys in Thailand-Myanmar border areas, Cambodia, and Vietnam. Malar J, 14 (1), pp. 381. | Show Abstract | Read more

BACKGROUND: The importance of the submicroscopic reservoir of Plasmodium infections for malaria elimination depends on its size, which is generally considered small in low transmission settings. The precise estimation of this reservoir requires more sensitive parasite detection methods. The prevalence of asymptomatic, sub-microscopic malaria was assessed by a sensitive, high blood volume quantitative real-time polymerase chain reaction method in three countries of the Greater Mekong Sub-region. METHODS: Cross-sectional surveys were conducted in three villages in western Cambodia, four villages along the Thailand-Myanmar border and four villages in southwest Vietnam. Malaria parasitaemia was assessed by Plasmodium falciparum/pan malaria rapid diagnostic tests (RDTs), microscopy and a high volume ultra-sensitive real-time polymerase chain reaction (HVUSqPCR: limit of detection 22 parasites/mL). All villagers older than 6 months were invited to participate. RESULTS: A census before the surveys identified 7355 residents in the study villages. Parasite prevalence was 224/5008 (4 %) by RDT, 229/5111 (5 %) by microscopy, and 988/4975 (20 %) when assessed by HVUSqPCR. Of these 164 (3 %) were infected with P. falciparum, 357 (7 %) with Plasmodium vivax, 56 (1 %) with a mixed infection, and 411 (8 %) had parasite densities that were too low for species identification. A history of fever, male sex, and age of 15 years or older were independently associated with parasitaemia in a multivariate regression model stratified by site. CONCLUSION: Light microscopy and RDTs identified only a quarter of all parasitaemic participants. The asymptomatic Plasmodium reservoir is considerable, even in low transmission settings. Novel strategies are needed to eliminate this previously under recognized reservoir of malaria transmission.

Tanner M, Greenwood B, Whitty CJM, Ansah EK, Price RN, Dondorp AM, von Seidlein L, Baird JK, Beeson JG, Fowkes FJI et al. 2015. Malaria eradication and elimination: views on how to translate a vision into reality. BMC Med, 13 (1), pp. 167. | Show Abstract | Read more

Although global efforts in the past decade have halved the number of deaths due to malaria, there are still an estimated 219 million cases of malaria a year, causing more than half a million deaths. In this forum article, we asked experts working in malaria research and control to discuss the ways in which malaria might eventually be eradicated. Their collective views highlight the challenges and opportunities, and explain how multi-factorial and integrated processes could eventually make malaria eradication a reality.

Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. 2015. Global extent of chloroquine-resistant Plasmodium vivax - Authors' reply. Lancet Infect Dis, 15 (6), pp. 630-631. | Read more

Newby G, Hwang J, Koita K, Chen I, Greenwood B, von Seidlein L, Shanks GD, Slutsker L, Kachur SP, Wegbreit J et al. 2015. Review of mass drug administration for malaria and its operational challenges. Am J Trop Med Hyg, 93 (1), pp. 125-134. | Show Abstract | Read more

Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings.

von Seidlein L, Dondorp A. 2015. Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance. Expert Rev Anti Infect Ther, 13 (6), pp. 715-730. | Show Abstract | Read more

The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured.

Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, von Seidlein L, Rajahram GS, Pasay C, McCarthy JS et al. 2016. Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial. Lancet Infect Dis, 16 (2), pp. 180-188. | Show Abstract | Read more

BACKGROUND: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug. INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

Deen J, von Seidlein L, Luquero FJ, Troeger C, Reyburn R, Lopez AL, Debes A, Sack DA. 2016. The scenario approach for countries considering the addition of oral cholera vaccination in cholera preparedness and control plans. Lancet Infect Dis, 16 (1), pp. 125-129. | Show Abstract | Read more

Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists. The supply of licensed, WHO-prequalified cholera vaccines is not sufficient to meet endemic and epidemic needs worldwide and so prioritisation is needed. We have developed a scenario approach to systematically classify situations in which oral cholera vaccination might be useful. Our scenario approach distinguishes between five types of cholera epidemiology based on experiences from around the world and provides evidence that we hope will spur the development of detailed guidelines on how and where oral cholera vaccines could, and should, be most rationally deployed.

White NJ, Ashley EA, Recht J, Delves MJ, Ruecker A, Smithuis FM, Eziefula AC, Bousema T, Drakeley C, Chotivanich K et al. 2014. Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria. Malar J, 13 (1), pp. 483. | Show Abstract | Read more

Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.

Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. 2014. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis, 14 (10), pp. 982-991. | Show Abstract | Read more

BACKGROUND: Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. METHODS: We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. FINDINGS: We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. INTERPRETATION: Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. FUNDING: Wellcome Trust (UK).

Anh DD, Lopez AL, Tran HTM, Cuong NV, Thiem VD, Ali M, Deen JL, von Seidlein L, Sack DA. 2014. Oral cholera vaccine development and use in Vietnam. PLoS Med, 11 (9), pp. e1001712. | Read more

von Seidlein L. 2014. The failure of screening and treating as a malaria elimination strategy. PLoS Med, 11 (1), pp. e1001595. | Read more

Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, Fornace KM, Anstey NM, Yeo TW, Cox J. 2014. Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol. BMJ Open, 4 (8), pp. e006004. | Show Abstract | Read more

INTRODUCTION: Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission. METHODS AND ANALYSIS: A population-based case-control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models. ETHICS: This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Health Research, Australia, and the London School of Hygiene and Tropical Medicine, UK.

Grigg MJ, William T, Dhanaraj P, Menon J, Barber BE, von Seidlein L, Rajahram G, Price RN, Anstey NM, Yeo TW. 2014. A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial). BMJ Open, 4 (8), pp. e006005. | Show Abstract | Read more

INTRODUCTION: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. METHODS AND ANALYSIS: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. ETHICS AND DISSEMINATION: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. TRIAL REGISTRATION NUMBER: NCT01708876.

Riewpaiboon A, Piatti M, Ley B, Deen J, Thriemer K, von Seidlein L, Salehjiddawi M, Busch CJ-L, Schmied WH, Ali SM, The Typhoid Economic Study Group GiDeok Pak Leon R Ochiai Mahesh K Puri Na Yoon Chang Thomas F Wierzba And John D Clemens. 2014. Cost of illness due to typhoid Fever in pemba, zanzibar, East Africa. J Health Popul Nutr, 32 (3), pp. 377-385. | Show Abstract

The aim of this study was to estimate the economic burden of typhoid fever in Pemba, Zanzibar, East Africa. This study was an incidence-based cost-of-illness analysis from a societal perspective. It covered new episodes of blood culture-confirmed typhoid fever in patients presenting at the outpatient or inpatient departments of three district hospitals between May 2010 and December 2010. Cost of illness was the sum of direct costs and costs for productivity loss. Direct costs covered treatment, travel, and meals. Productivity costs were loss of income by patients and caregivers. The analysis included 17 episodes. The mean age of the patients, was 23 years (range=5-65, median=22). Thirty-five percent were inpatients, with a mean of 4.75 days of hospital stay (range=3-7, median=4.50). The mean cost for treatment alone during hospital care was US$ 21.97 at 2010 prices (US$ 1=1,430.50 Tanzanian Shilling─TSH). The average societal cost was US$ 154.47 per typhoid episode. The major expenditure was productivity cost due to lost wages of US$ 128.02 (83%). Our results contribute to the further economic evaluation of typhoid fever vaccination in Zanzibar and other sub-Saharan African countries.

Von Seidlein L, Bejon P. 2013. Malaria vaccines: Past, present and future Archives of Disease in Childhood, 98 (12), pp. 981-985. | Show Abstract | Read more

The currently available malaria control tools have allowed malaria elimination in many regions but there remain many regions where malaria control has made little progress. A safe and protective malaria vaccine would be a huge asset for malaria control. Despite the many challenges, efforts continue to design and evaluate malaria vaccine candidates. These candidates target different stages in the life cycle of Plasmodia. The most advanced vaccine candidates target the pre-erythrocytic stages in the life cycle of the parasite and include RTS, S/AS01, which has progressed through clinical development to the stage that it may be licensed in 2015. Attenuated whole-parasite vaccine candidates are highly protective, but there are challenges to manufacture and to administration. Cellular immunity is targeted by the prime-boost approach. Priming vectors trigger only modest responses but these are focused on the recombinant antigen. Boosting vectors trigger strong but broad non-specific responses. The heterologous sequence produces strong immunological responses to the recombinant antigen. Candidates that target the blood stages of the parasite have to result in an immune response that is more effective than the response to an infection to abort or control the infection of merozoites and hence disease. Finally, the sexual stages of the parasite offer another target for vaccine development, which would prevent the transmission of malaria. Today it seems unlikely that any candidate targeting a single antigen will provide complete protection against an organism of the complexity of Plasmodium. A systematic search for vaccine targets and combinations of antigens may be a more promising approach.

Domingo GJ, Satyagraha AW, Anvikar A, Baird K, Bancone G, Bansil P, Carter N, Cheng Q, Culpepper J, Eziefula C et al. 2013. G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests. Malar J, 12 (1), pp. 391. | Show Abstract | Read more

Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax. Currently available drugs that can completely clear a human of P. vivax (known as "radical cure"), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine. Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses. G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide.Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy. Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patient's G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail. The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure. The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure.

von Seidlein L, Jiddawi M, Grais RF, Luquero F, Lucas M, Deen J. 2013. The value of and challenges for cholera vaccines in Africa. J Infect Dis, 208 Suppl 1 (suppl 1), pp. S8-14. | Show Abstract | Read more

The 21st century saw a shift in the cholera burden from Asia to Africa. The risk factors for cholera outbreaks in Africa are incompletely understood, and the traditional emphasis on providing safe drinking water and improving sanitation and hygiene has proven remarkably insufficient to contain outbreaks. Current killed whole-cell oral cholera vaccines (OCVs) are safe and guarantee a high level of protection for several years. OCVs have been licensed for >20 years, but their potential for preventing and control cholera outbreaks in Africa has not been realized. Although each item in the long list of technical reasons why cholera vaccination campaigns have been deferred is plausible, we believe that the biggest barrier is that populations affected by cholera outbreaks are underprivileged and lack a strong political voice. The evaluation and use of OCVs as a tool for cholera control will require a new, more compassionate, less risk-averse generation of decision makers.

von Seidlein L, Bejon P. 2013. Malaria vaccines: past, present and future. Arch Dis Child, 98 (12), pp. 981-985. | Show Abstract | Read more

The currently available malaria control tools have allowed malaria elimination in many regions but there remain many regions where malaria control has made little progress. A safe and protective malaria vaccine would be a huge asset for malaria control. Despite the many challenges, efforts continue to design and evaluate malaria vaccine candidates. These candidates target different stages in the life cycle of Plasmodia. The most advanced vaccine candidates target the pre-erythrocytic stages in the life cycle of the parasite and include RTS,S/AS01, which has progressed through clinical development to the stage that it may be licensed in 2015. Attenuated whole-parasite vaccine candidates are highly protective, but there are challenges to manufacture and to administration. Cellular immunity is targeted by the prime-boost approach. Priming vectors trigger only modest responses but these are focused on the recombinant antigen. Boosting vectors trigger strong but broad non-specific responses. The heterologous sequence produces strong immunological responses to the recombinant antigen. Candidates that target the blood stages of the parasite have to result in an immune response that is more effective than the response to an infection to abort or control the infection of merozoites and hence disease. Finally, the sexual stages of the parasite offer another target for vaccine development, which would prevent the transmission of malaria. Today it seems unlikely that any candidate targeting a single antigen will provide complete protection against an organism of the complexity of Plasmodium. A systematic search for vaccine targets and combinations of antigens may be a more promising approach.

Thriemer K, Ley B, Ame SS, Deen JL, Pak GD, Chang NY, Hashim R, Schmied WH, Busch CJ-L, Nixon S et al. 2013. Correction: Clinical and Epidemiological Features of Typhoid Fever in Pemba, Zanzibar: Assessment of the Performance of the WHO Case Definitions PLoS ONE, 8 (6), | Read more

Kim J-Y, Ji S-Y, Goo Y-K, Na B-K, Pyo H-J, Lee H-N, Lee J, Kim NH, von Seidlein L, Cheng Q et al. 2013. Comparison of rapid diagnostic tests for the detection of Plasmodium vivax malaria in South Korea. PLoS One, 8 (5), pp. e64353. | Show Abstract | Read more

South Korea is one of many countries with endemic Plasmodium vivax malaria. Here we report the evaluation of four rapid diagnostic tests (RDTs) for diagnosis of this disease. A total of 253 subjects were enrolled in the study. The sensitivities, specificities and agreement frequencies were estimated by comparing the four RDTs against the standard of nested-PCR and microscopic examination. The CareStart(TM) and SD Bioline had higher test sensitivities (99.4 and 98.8%, respectively) compared with the NanoSign and Asan Easy tests (93.0 and 94.7%, respectively). The CareStart(TM) and SD Bioline tests could detect P. vivax in samples with parasite densities <150/μl, which was a slightly better performance than the other two RDTs. The quantitative accuracy of the four RDTs was also estimated by comparing results with P. vivax counts from blood samples. Lower test price would result in increased use of these RDTs in the field. The results of this study contribute valuable information that will aid in the selection of a diagnostic method for the detection of malaria.

Hendriksen ICE, Mtove G, Kent A, Gesase S, Reyburn H, Lemnge MM, Lindegardh N, Day NPJ, von Seidlein L, White NJ et al. 2013. Population pharmacokinetics of intramuscular artesunate in African children with severe malaria: implications for a practical dosing regimen. Clin Pharmacol Ther, 93 (5), pp. 443-450. | Show Abstract | Read more

Parenteral artesunate (ARS) is the drug of choice for the treatment of severe malaria. Pharmacokinetics data on intramuscular ARS are limited with respect to the main treatment group that carries the highest mortality, namely, critically ill children with severe malaria. A population pharmacokinetic study of ARS and dihydroartemisinin (DHA) was conducted from sparse sampling in 70 Tanzanian children of ages 6 months to 11 years. All the children had been admitted with severe falciparum malaria and were treated with intramuscular ARS (2.4 mg/kg at 0, 12, and 24 h). Venous plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling (NONMEM). A one-compartment disposition model accurately described first-dose population pharmacokinetics of ARS and DHA. Body weight significantly affected clearance and apparent volume of distribution (P < 0.001), resulting in lower ARS and DHA exposure levels in smaller children. An adapted dosing regimen including a practical dosing table per weight band is proposed for young children based on the pharmacokinetic model.

Bhattacharya SK, Sur D, Dutta S, Kanungo S, Ochiai RL, Kim DR, Anstey NM, von Seidlein L, Deen J. 2013. Vivax malaria and bacteraemia: a prospective study in Kolkata, India. Malar J, 12 (1), pp. 176. | Show Abstract | Read more

BACKGROUND: Falciparum malaria increases the risk for bacteraemia, whereas the relationship between vivax malaria and bacteraemia is not clear. Data from a prospective fever surveillance study in Kolkata, India were reanalysed for the potential association between Plasmodium vivax malaria and bacteraemia. METHODS: Patients of all ages presenting with fever of three days or more to a project health outpost were invited to participate. A blood film and blood culture was performed on presentation. Treatment and referral were provided according to national guidelines. The case fraction and incidence of malaria, bacteraemia, and co-infection were calculated. RESULTS: 3,371 participants were enrolled during a one-year study period, of whom 93/3,371 (2.8%) had malaria (89/93 [95.7%] Plasmodium vivax) and 256 (7.6%) bacteraemia. There were 154 malaria, 423 bacteraemia and 10 P. vivax-bacteremia coinfection episodes per 100,000/year. Among the malaria-bacteraemia co-infections, all were vivax malaria and 5/6 (83%) bacteria isolated were Gram-negative (one S. Typhi, one S. Paratyphi A, three other Gram-negative). Bacteraemia occurred in 6/89 (6.7% [95%CI: 3.1-13.9%]) of P. vivax cases versus 250/3,278 (7.6% [95% CI: 6.7-8.6%]) without Plasmodium infection (p=0.76). CONCLUSIONS: While an increased risk was not demonstrated, concomitant bacteraemia occurs frequently in vivax malaria in an area with a high background incidence of bacteraemia, and should be considered in cases of vivax malaria with severe manifestations.

Kaljee LM, Pach A, Thriemer K, Ley B, Ali SM, Jiddawi M, Puri M, von Seidlein L, Deen J, Ochiai L et al. 2013. Utilization and accessibility of healthcare on Pemba Island, Tanzania: implications for health outcomes and disease surveillance for typhoid fever. Am J Trop Med Hyg, 88 (1), pp. 144-152. | Show Abstract | Read more

Salmonella enterica serotype Typhi (S. Typhi) was estimated to cause over 200,000 deaths and more than 21 million illnesses worldwide, including over 400,000 illnesses in Africa. The current study was conducted in four villages on Pemba Island, Zanzibar, in 2010. We present data on policy makers', health administrators', and village residents' and leaders' perceptions of typhoid fever, and hypothetical and actual health care use among village residents for typhoid fever. Qualitative data provided descriptions of home-based treatment practices and use of western pharmaceuticals, and actual healthcare use for culture-confirmed typhoid fever. Survey data indicate health facility use was associated with gender, education, residency, and perceptions of severity for symptoms associated with typhoid fever. Data have implications for education of policy makers and health administrators, design and implementation of surveillance studies, and community-based interventions to prevent disease outbreaks, decrease risks of complications, and provide information about disease recognition, diagnosis, and treatment.

von Seidlein L, Auburn S, Espino F, Shanks D, Cheng Q, McCarthy J, Baird K, Moyes C, Howes R, Ménard D et al. 2013. Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report. Malar J, 12 (1), pp. 112. | Show Abstract | Read more

The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here.

Abdullah NR, Barber BE, William T, Norahmad NA, Satsu UR, Muniandy PK, Ismail Z, Grigg MJ, Jelip J, Piera K et al. 2013. Plasmodium vivax population structure and transmission dynamics in Sabah Malaysia. PLoS One, 8 (12), pp. e82553. | Show Abstract | Read more

Despite significant progress in the control of malaria in Malaysia, the complex transmission dynamics of P. vivax continue to challenge national efforts to achieve elimination. To assess the impact of ongoing interventions on P. vivax transmission dynamics in Sabah, we genotyped 9 short tandem repeat markers in a total of 97 isolates (8 recurrences) from across Sabah, with a focus on two districts, Kota Marudu (KM, n = 24) and Kota Kinabalu (KK, n = 21), over a 2 year period. STRUCTURE analysis on the Sabah-wide dataset demonstrated multiple sub-populations. Significant differentiation (F ST  = 0.243) was observed between KM and KK, located just 130 Km apart. Consistent with low endemic transmission, infection complexity was modest in both KM (mean MOI  = 1.38) and KK (mean MOI  = 1.19). However, population diversity remained moderate (H E  = 0.583 in KM and H E  = 0.667 in KK). Temporal trends revealed clonal expansions reflecting epidemic transmission dynamics. The haplotypes of these isolates declined in frequency over time, but persisted at low frequency throughout the study duration. A diverse array of low frequency isolates were detected in both KM and KK, some likely reflecting remnants of previous expansions. In accordance with clonal expansions, high levels of Linkage Disequilibrium (I A (S) >0.5 [P<0.0001] in KK and KM) declined sharply when identical haplotypes were represented once (I A (S)  = 0.07 [P = 0.0076] in KM, and I A (S) = -0.003 [P = 0.606] in KK). All 8 recurrences, likely to be relapses, were homologous to the prior infection. These recurrences may promote the persistence of parasite lineages, sustaining local diversity. In summary, Sabah's shrinking P. vivax population appears to have rendered this low endemic setting vulnerable to epidemic expansions. Migration may play an important role in the introduction of new parasite strains leading to epidemic expansions, with important implications for malaria elimination.

Punjabi NH, Agtini MD, Ochiai RL, Simanjuntak CH, Lesmana M, Subekti D, Oyofo BA, von Seidlein L, Deen J, Shin S et al. 2013. Enteric fever burden in North Jakarta, Indonesia: a prospective, community-based study. J Infect Dev Ctries, 7 (11), pp. 781-787. | Show Abstract | Read more

INTRODUCTION: We undertook a prospective community-based study in North Jakarta, Indonesia, to determine the incidence, clinical characteristics, seasonality, etiologic agent, and antimicrobial susceptibility pattern of enteric fever. METHODOLOGY: Following a census, treatment centre-based surveillance for febrile illness was conducted for two-years. Clinical data and a blood culture were obtained from each patient. RESULTS: In a population of 160,261, we detected 296 laboratory-confirmed enteric fever cases during the surveillance period, of which 221 (75%) were typhoid fever and 75 (25%)  were paratyphoid fever.  The overall incidence of typhoid and paratyphoid cases was 1.4, and 0.5 per thousand populations per year, respectively. Although the incidence of febrile episodes evaluated was highest among children under 5 years of age at 92.6 per thousand persons per year, we found that the burden of typhoid fever was greatest among children between 5 and 20 years of age. Paratyphoid fever occurred most commonly in children and was infrequent in adults. CONCLUSION: Enteric fever is a public health problem in North Jakarta with a substantial proportion due to paratyphoid fever. The results highlight the need for control strategies against enteric fever.

Thriemer K, Ley B, Ame SS, Deen JL, Pak GD, Chang NY, Hashim R, Schmied WH, Busch CJ-L, Nixon S et al. 2012. Clinical and epidemiological features of typhoid fever in Pemba, Zanzibar: assessment of the performance of the WHO case definitions. PLoS One, 7 (12), pp. e51823. | Show Abstract | Read more

BACKGROUND: The gold standard for diagnosis of typhoid fever is blood culture (BC). Because blood culture is often not available in impoverished settings it would be helpful to have alternative diagnostic approaches. We therefore investigated the usefulness of clinical signs, WHO case definition and Widal test for the diagnosis of typhoid fever. METHODOLOGY/PRINCIPAL FINDINGS: Participants with a body temperature ≥37.5°C or a history of fever were enrolled over 17 to 22 months in three hospitals on Pemba Island, Tanzania. Clinical signs and symptoms of participants upon presentation as well as blood and serum for BC and Widal testing were collected. Clinical signs and symptoms of typhoid fever cases were compared to other cases of invasive bacterial diseases and BC negative participants. The relationship of typhoid fever cases with rainfall, temperature, and religious festivals was explored. The performance of the WHO case definitions for suspected and probable typhoid fever and a local cut off titre for the Widal test was assessed. 79 of 2209 participants had invasive bacterial disease. 46 isolates were identified as typhoid fever. Apart from a longer duration of fever prior to admission clinical signs and symptoms were not significantly different among patients with typhoid fever than from other febrile patients. We did not detect any significant seasonal patterns nor correlation with rainfall or festivals. The sensitivity and specificity of the WHO case definition for suspected and probable typhoid fever were 82.6% and 41.3% and 36.3 and 99.7% respectively. Sensitivity and specificity of the Widal test was 47.8% and 99.4 both forfor O-agglutinin and H- agglutinin at a cut-off titre of 1:80. CONCLUSIONS/SIGNIFICANCE: Typhoid fever prevalence rates on Pemba are high and its clinical signs and symptoms are non-specific. The sensitivity of the Widal test is low and the WHO case definition performed better than the Widal test.

Hendriksen ICE, Maiga D, Lemnge MM, Mtove G, Gesase S, Reyburn H, Lindegardh N, Day NPJ, von Seidlein L, Dondorp AM et al. 2013. Population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe Falciparum malaria. Antimicrob Agents Chemother, 57 (2), pp. 775-783. | Show Abstract | Read more

Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.).

Hendriksen ICE, White LJ, Veenemans J, Mtove G, Woodrow C, Amos B, Saiwaew S, Gesase S, Nadjm B, Silamut K et al. 2013. Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration. J Infect Dis, 207 (2), pp. 351-361. | Show Abstract | Read more

BACKGROUND: In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations. METHODS: Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6-60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease. RESULTS: The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%-100%), with a sensitivity of 74% (95% CI, 72%-77%), whereas a concentration of <200 ng/mL denoted severe febrile illness of an alternative diagnosis in >10% (95% CI, 3%-27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles. CONCLUSIONS: The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.

Khatib AM, Ali M, von Seidlein L, Kim DR, Hashim R, Reyburn R, Ley B, Thriemer K, Enwere G, Hutubessy R et al. 2012. Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. Lancet Infect Dis, 12 (11), pp. 837-844. | Show Abstract | Read more

BACKGROUND: Zanzibar, in east Africa, has been severely and repeatedly affected by cholera since 1978. We assessed the effectiveness of oral cholera vaccination in high-risk populations in the archipelago to estimate the indirect (herd) protection conferred by the vaccine and direct vaccine effectiveness. METHODS: We offered two doses of a killed whole-cell B-subunit cholera vaccine to individuals aged 2 years and older in six rural and urban sites. To estimate vaccine direct protection, we compared the incidence of cholera between recipients and non-recipients using generalised estimating equations with the log link function while controlling for potential confounding variables. To estimate indirect effects, we used a geographic information systems approach and assessed the association between neighbourhood-level vaccine coverage and the risk for cholera in the non-vaccinated residents of that neighbourhood, after controlling for potential confounding variables. This study is registered with ClinicalTrials.gov, number NCT00709410. FINDINGS: Of 48,178 individuals eligible to receive the vaccine, 23,921 (50%) received two doses. Between February, 2009, and May, 2010, there was an outbreak of cholera, enabling us to assess vaccine effectiveness. The vaccine conferred 79% (95% CI 47-92) direct protection against cholera in participants who received two doses. Indirect (herd) protection was shown by a decrease in the risk for cholera of non-vaccinated residents within a household's neighbourhood as the vaccine coverage in that neighbourhood increased. INTERPRETATION: Our findings suggest that the oral cholera vaccine offers both direct and indirect (herd) protection in a sub-Saharan African setting. Mass oral cholera immunisation campaigns have the potential to provide not only protection for vaccinated individuals but also for the unvaccinated members of the community and should be strongly considered for wider use. Because this is an internationally-licensed vaccine, we could not undertake a randomised placebo-controlled trial, but the absence of vaccine effectiveness against non-cholera diarrhoea indicates that the noted protection against cholera could not be explained by bias. FUNDING: Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, and the South Korean Government.

Khan MI, Soofi SB, Ochiai RL, Khan MJ, Sahito SM, Habib MA, Puri MK, Von Seidlein L, Park JK, You YA et al. 2012. Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan. J Infect Dev Ctries, 6 (10), pp. 704-714. | Show Abstract | Read more

INTRODUCTION: Enteric fever remains a major public health problem in Asia. Planning appropriate preventive measures such as immunization requires a clear understanding of disease burden. We conducted a community-based surveillance for Salmonella Typhi infection in children in Karachi, Pakistan. METHODOLOGY: A de jure household census was conducted at baseline in the study setting to enumerate all individuals. A health-care facility-based passive surveillance system was used to capture episodes of fever lasting three or more 3 days in children 2 to 16 years old. RESULTS: A total of 7,401 blood samples were collected for microbiological confirmation, out of which 189 S. Typhi and 32 S. Paratyphi A isolates were identified with estimated annual incidences of 451/100,000 (95% CI: 446 - 457) and 76/100,000 (95% CI: 74 - 78) respectively. At the time of presentation, after adjusting for age, there was an association between the duration of fever and temperature at presentation, and being infected with multidrug-resistant S. Typhi. Of 189 isolates 83 were found to be resistant to first-line antimicrobial therapy. There was no statistically significant difference in clinical presentation of blood culture sensitive and resistant S. Typhi isolates. CONCLUSION: Incidence of S. Typhi in children is high in urban squatter settlements of Karachi, Pakistan. Findings from this study identified duration of fever and temperature at the time of presentation as important symptoms associated with blood culture-confirmed typhoid fever. Preventive strategies such as immunization and improvements in water and sanitation conditions should be the focus of typhoid control in urban settlements of Pakistan.

John GK, Douglas NM, von Seidlein L, Nosten F, Baird JK, White NJ, Price RN. 2012. Primaquine radical cure of Plasmodium vivax: a critical review of the literature. Malar J, 11 (1), pp. 280. | Show Abstract | Read more

BACKGROUND: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. METHODS: Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. RESULTS: Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001). CONCLUSIONS: Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.

Ramutton T, Hendriksen ICE, Mwanga-Amumpaire J, Mtove G, Olaosebikan R, Tshefu AK, Onyamboko MA, Karema C, Maitland K, Gomes E et al. 2012. Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria. Malar J, 11 (1), pp. 276. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements. METHODS: Studies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania. RESULTS: There was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration. CONCLUSIONS: These findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.

Hendriksen ICE, Mwanga-Amumpaire J, von Seidlein L, Mtove G, White LJ, Olaosebikan R, Lee SJ, Tshefu AK, Woodrow C, Amos B et al. 2012. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med, 9 (8), pp. e1001297. | Show Abstract | Read more

BACKGROUND: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. METHODS AND FINDINGS: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. CONCLUSIONS: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.

Hendriksen ICE, Ferro J, Montoya P, Chhaganlal KD, Seni A, Gomes E, Silamut K, Lee SJ, Lucas M, Chotivanich K et al. 2012. Diagnosis, clinical presentation, and in-hospital mortality of severe malaria in HIV-coinfected children and adults in Mozambique. Clin Infect Dis, 55 (8), pp. 1144-1153. | Show Abstract | Read more

BACKGROUND: Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria. METHODS: HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status. RESULTS: HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P < .001). In an age- and antimalarial treatment-adjusted logistic regression model, significant, independent predictors for death were renal impairment, acidosis, parasitemia, and plasma PfHRP2 concentration. CONCLUSIONS: Severe malaria in HIV-coinfected patients presents with higher parasite burden, more complications, and comorbidity, and carries a higher case fatality rate. Early identification of HIV coinfection is important for the clinical management of severe malaria.

Hashim R, Khatib AM, Enwere G, Park JK, Reyburn R, Ali M, Chang NY, Kim DR, Ley B, Thriemer K et al. 2012. Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy. PLoS Negl Trop Dis, 6 (7), pp. e1743. | Show Abstract | Read more

INTRODUCTION: Mass vaccinations are a main strategy in the deployment of oral cholera vaccines. Campaigns avoid giving vaccine to pregnant women because of the absence of safety data of the killed whole-cell oral cholera (rBS-WC) vaccine. Balancing this concern is the known higher risk of cholera and of complications of pregnancy should cholera occur in these women, as well as the lack of expected adverse events from a killed oral bacterial vaccine. METHODOLOGY/PRINCIPAL FINDINGS: From January to February 2009, a mass rBS-WC vaccination campaign of persons over two years of age was conducted in an urban and a rural area (population 51,151) in Zanzibar. Pregnant women were advised not to participate in the campaign. More than nine months after the last dose of the vaccine was administered, we visited all women between 15 and 50 years of age living in the study area. The outcome of pregnancies that were inadvertently exposed to at least one oral cholera vaccine dose and those that were not exposed was evaluated. 13,736 (94%) of the target women in the study site were interviewed. 1,151 (79%) of the 1,453 deliveries in 2009 occurred during the period when foetal exposure to the vaccine could have occurred. 955 (83%) out of these 1,151 mothers had not been vaccinated; the remaining 196 (17%) mothers had received at least one dose of the oral cholera vaccine. There were no statistically significant differences in the odds ratios for birth outcomes among the exposed and unexposed pregnancies. CONCLUSIONS/SIGNIFICANCE: We found no statistically significant evidence of a harmful effect of gestational exposure to the rBS-WC vaccine. These findings, along with the absence of a rational basis for expecting a risk from this killed oral bacterial vaccine, are reassuring but the study had insufficient power to detect infrequent events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00709410.

von Seidlein L, Deen JL. 2012. Considerations for oral cholera vaccine use during outbreak after earthquake in Haiti, 2010-2011. Emerg Infect Dis, 18 (7), pp. 1211-1214. | Read more

Deen J, von Seidlein L, Andersen F, Elle N, White NJ, Lubell Y. 2012. Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect Dis, 12 (6), pp. 480-487. | Show Abstract | Read more

Information about community-acquired bacteraemia in developing countries in south and southeast Asia is scarce. We aimed to establish the case fraction of bacteraemia in febrile patients admitted to hospital. We searched four databases and identified studies of south and southeast Asia published between 1990 and 2010 that prospectively assessed patients admitted to hospital and from whom a blood culture was taken. We reviewed 17 eligible studies describing 40,644 patients. Pathogenic organisms were isolated from 3506 patients (9%; range 1-51%); 1784 (12%) of 14,386 adults and 1722 (7%) of 26,258 children. Salmonella enterica serotype Typhi was the most common bacterial pathogen, accounting for 532 of 1798 (30%) isolates in adults and 432 of 1723 (25%) in children. Other commonly isolated organisms in adults were Staphylococcus aureus, Escherichia coli, and other gram-negative organisms, and in children were Streptococcus pneumoniae and Haemophilus influenzae. A substantial case fraction of bacteraemia occurs in patients admitted to hospital with fever in this region. Management could be improved if diagnostic microbiology facilities were more widely available. The prevailing organisms causing bacteraemia and their susceptibility patterns could inform empirical treatment regimens and prevention strategies.

Ley B, Khatib AM, Thriemer K, von Seidlein L, Deen J, Mukhopadyay A, Chang N-Y, Hashim R, Schmied W, Busch CJ-L et al. 2012. Evaluation of a rapid dipstick (Crystal VC) for the diagnosis of cholera in Zanzibar and a comparison with previous studies. PLoS One, 7 (5), pp. e36930. | Show Abstract | Read more

BACKGROUND: The gold standard for the diagnosis of cholera is stool culture, but this requires laboratory facilities and takes at least 24 hours. A rapid diagnostic test (RDT) that can be used by minimally trained staff at treatment centers could potentially improve the reporting and management of cholera outbreaks. METHODS: We evaluated the Crystal VC™ RDT under field conditions in Zanzibar in 2009. Patients presenting to treatment centers with watery diarrhea provided a stool sample for rapid diagnostic testing. Results were compared to stool culture performed in a reference laboratory. We assessed the overall performance of the RDT and evaluated whether previous intake of antibiotics, intravenous fluids, location of testing, and skill level of the technician affected the RDT results. RESULTS: We included stool samples from 624 patients. Compared to culture, the overall sensitivity of the RDT was 93.1% (95%CI: 88.7 to 96.2%), specificity was 49.2% (95%CI: 44.3 to 54.1%), the positive predictive value was 47.0% (95%CI: 42.1 to 52.0%) and the negative predictive value was 93.6% (95%CI: 89.6 to 96.5%). The overall false positivity rate was 50.8% (213/419); fieldworkers frequently misread very faint test lines as positive. CONCLUSION: The observed sensitivity of the Crystal VC RDT evaluated was similar compared to earlier versions, while specificity was poorer. The current version of the RDT could potentially be used as a screening tool in the field. Because of the high proportion of false positive results when field workers test stool specimens, positive results will need to be confirmed with stool culture.

Horowitz A, Hafalla JCR, King E, Lusingu J, Dekker D, Leach A, Moris P, Cohen J, Vekemans J, Villafana T et al. 2012. Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine. J Immunol, 188 (10), pp. 5054-5062. | Show Abstract | Read more

RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum, is undergoing clinical trials. We report an analysis of cellular immune response to component Ags of RTS,S-hepatitis B surface Ag (HBs) and P. falciparum circumsporozoite (CS) protein-among Tanzanian children in a phase IIb RTS,S/AS01(E) trial. RTS,S/AS01 (E) vaccinees make stronger T cell IFN-γ, CD69, and CD25 responses to HBs peptides than do controls, indicating that RTS,S boosts pre-existing HBs responses. T cell CD69 and CD25 responses to CS and CS-specific secreted IL-2 were augmented by RTS,S vaccination. Importantly, more than 50% of peptide-induced IFN-γ(+) lymphocytes were NK cells, and the magnitude of the NK cell CD69 response to HBs peptides correlated with secreted IL-2 concentration. CD69 and CD25 expression and IL-2 secretion may represent sensitive markers of RTS,S-induced, CS-specific T cells. The potential for T cell-derived IL-2 to augment NK cell activation in RTS,S-vaccinated individuals, and the relevance of this for protection, needs to be explored further.

Khan MI, Ochiai RL, Soofi SB, Von-Seidlein L, Khan MJ, Sahito SM, Habib MA, Puri MK, Park JK, You YA et al. 2012. Risk factors associated with typhoid fever in children aged 2-16 years in Karachi, Pakistan. Epidemiol Infect, 140 (4), pp. 665-672. | Show Abstract | Read more

We analysed the data from the control group in a typhoid vaccine trial in Karachi to assess the differences in individual-, household- and cluster-level characteristics for developing typhoid fever. The annual incidence of typhoid in children aged 2-16 years in the control arm of the vaccine trial was 151/100 000 population. After adjustment, the risk of typhoid was lower with increasing age [risk ratio (RR) 0·89, 95% confidence interval (CI) 0·83-0·95], was higher with an increase in population density (RR 1·13, 95% CI 1·05-1·21) and was lower in the households using a safe drinking-water source (RR 0·63, 95% CI 0·41-0·99). Typhoid fever affects younger children living in areas of high population density and lack of access to safe water in Pakistan. A combination of environmental and biological interventions is required to prevent the continued epidemiological and economic impact of typhoid fever in high-risk areas of Pakistan.

von Seidlein L, Olaosebikan R, Hendriksen ICE, Lee SJ, Adedoyin OT, Agbenyega T, Nguah SB, Bojang K, Deen JL, Evans J et al. 2012. Predicting the clinical outcome of severe falciparum malaria in african children: findings from a large randomized trial. Clin Infect Dis, 54 (8), pp. 1080-1090. | Show Abstract | Read more

BACKGROUND: Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. METHODS: African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model. RESULTS: Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models. CONCLUSIONS: Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.

Thriemer K, Ley B, Ame S, von Seidlein L, Pak GD, Chang NY, Hashim R, Schmied WH, Busch CJ-L, Nixon S et al. 2012. The burden of invasive bacterial infections in Pemba, Zanzibar. PLoS One, 7 (2), pp. e30350. | Show Abstract | Read more

BACKGROUND: We conducted a surveillance study to determine the leading causes of bloodstream infection in febrile patients seeking treatment at three district hospitals in Pemba Island, Zanzibar, Tanzania, an area with low malaria transmission. METHODS: All patients above two months of age presenting to hospital with fever were screened, and blood was collected for microbiologic culture and malaria testing. Bacterial sepsis and malaria crude incidence rates were calculated for a one-year period and were adjusted for study participation and diagnostic sensitivity of blood culture. RESULTS: Blood culture was performed on 2,209 patients. Among them, 166 (8%) samples yielded bacterial growth; 87 (4%) were considered as likely contaminants; and 79 (4%) as pathogenic bacteria. The most frequent pathogenic bacteria isolated were Salmonella Typhi (n = 46; 58%), followed by Streptococcus pneumoniae (n = 12; 15%). The crude bacteremia rate was 6/100,000 but when adjusted for potentially missed cases the rate may be as high as 163/100,000. Crude and adjusted rates for S. Typhi infections and malaria were 4 and 110/100,000 and 4 and 47/100,000, respectively. Twenty three (51%), 22 (49%) and 22 (49%) of the S. Typhi isolates were found to be resistant toward ampicillin, chloramphenicol and cotrimoxazole, respectively. Multidrug resistance (MDR) against the three antimicrobials was detected in 42% of the isolates. CONCLUSIONS: In the presence of very low malaria incidence we found high rates of S. Typhi and S. pneumoniae infections on Pemba Island, Zanzibar. Preventive measures such as vaccination could reduce the febrile disease burden.

Thriemer K, Ley B, Ame SM, Puri MK, Hashim R, Chang NY, Salim LA, Ochiai RL, Wierzba TF, Clemens JD et al. 2012. Replacing paper data collection forms with electronic data entry in the field: findings from a study of community-acquired bloodstream infections in Pemba, Zanzibar. BMC Res Notes, 5 (1), pp. 113. | Show Abstract | Read more

BACKGROUND: Entering data on case report forms and subsequently digitizing them in electronic media is the traditional way to maintain a record keeping system in field studies. Direct data entry using an electronic device avoids this two-step process. It is gaining in popularity and has replaced the paper-based data entry system in many studies. We report our experiences with paper- and PDA-based data collection during a fever surveillance study in Pemba Island, Zanzibar, Tanzania. METHODS: Data were collected on a 14-page case report paper form in the first period of the study. The case report paper forms were then replaced with handheld computers (personal digital assistants or PDAs). The PDAs were used for screening and clinical data collection, including a rapid assessment of patient eligibility, real time errors, and inconsistency checking. RESULTS: A comparison of paper-based data collection with PDA data collection showed that direct data entry via PDA was faster and 25% cheaper. Data was more accurate (7% versus 1% erroneous data) and omission did not occur with electronic data collection. Delayed data turnaround times and late error detections in the paper-based system which made error corrections difficult were avoided using electronic data collection. CONCLUSIONS: Electronic data collection offers direct data entry at the initial point of contact. It has numerous advantages and has the potential to replace paper-based data collection in the field. The availability of information and communication technologies for direct data transfer has the potential to improve the conduct of public health research in resource-poor settings.

Eziefula AC, Gosling R, Hwang J, Hsiang MS, Bousema T, von Seidlein L, Drakeley C, Primaquine in Africa Discussion Group. 2012. Rationale for short course primaquine in Africa to interrupt malaria transmission. Malar J, 11 (1), pp. 360. | Show Abstract | Read more

Following the recent successes of malaria control in sub-Saharan Africa, the gametocytocidal drug primaquine needs evaluation as a tool to further reduce the transmission of Plasmodium falciparum malaria. The drug has scarcely been used in Africa because of concerns about its safety in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The evidence base for the use of primaquine as a transmission blocker is limited by a lack of comparable clinical and parasitological endpoints between trials. In March 2012, a group of experts met in London to discuss the existing evidence on the ability of primaquine to block malaria transmission, to define the roadblocks to the use of primaquine in Africa and to develop a roadmap to enable its rapid, safe and effective deployment. The output of this meeting is a strategic plan to optimize trial design to reach desired goals efficiently. The roadmap includes suggestions for a series of phase 1, 2, 3 and 4 studies to address specific hurdles to primaquine's deployment. These include ex-vivo studies on efficacy, primaquine pharmacokinetics and pharmacodynamics and dose escalation studies for safety in high-risk groups. Phase 3 community trials are proposed, along with Phase 4 studies to evaluate safety, particularly in pregnancy, through pharmacovigilance in areas where primaquine is already deployed. In parallel, efforts need to be made to address issues in drug supply and regulation, to map G6PD deficiency and to support the evaluation of alternative gametocytocidal compounds.

Douglas NM, John GK, von Seidlein L, Anstey NM, Price RN. 2012. Chemotherapeutic strategies for reducing transmission of Plasmodium vivax malaria. Adv Parasitol, 80 pp. 271-300. | Show Abstract | Read more

Effective use of anti-malarial drugs is key to reducing the transmission potential of Plasmodium vivax. In patients presenting with symptomatic disease, treatment with potent and relatively slowly eliminated blood schizontocidal regimens administered concurrently with a supervised course of 7 mg/kg primaquine over 7-14 days has potential to exert the greatest transmission-blocking benefit. Given the spread of chloroquine-resistant P. vivax strains, the artemisinin combination therapies dihydroartemisinin + piperaquine and artesunate + mefloquine are currently the most assured means of preventing P. vivax recrudescence. Preliminary evidence suggests that, like chloroquine, these combinations potentiate the hypnozoitocidal effect of primaquine, but further supportive evidence is required. In view of the high rate of P. vivax relapse following falciparum infections in co-endemic regions, there is a strong argument for broadening current radical cure policy to include the administration of hypnozoitocidal doses of primaquine to patients with Plasmodium falciparum malaria. The most important reservoir for P. vivax transmission is likely to be very low-density, asymptomatic infections, the majority of which will arise from liver-stage relapses. Therefore, judicious mass administration of hypnozoitocidal therapy will reduce transmission of P. vivax to a greater extent than strategies focused on treatment of symptomatic patients. An efficacious hypnozoitocidal agent with a short curative treatment course would be particularly useful in mass drug administration campaigns.

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. | 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.

von Seidlein L, Ikonomidis K, Bruun R, Jawara M, Pinder M, Knols BG, Knudsen JB. 2012. Airflow attenuation and bed net utilization: observations from Africa and Asia. Malar J, 11 (1), pp. 200. | Show Abstract | Read more

BACKGROUND/METHODS: Qualitative studies suggest that bed nets affect the thermal comfort of users. To understand and reduce this discomfort the effect of bed nets on temperature, humidity, and airflow was measured in rural homes in Asia and Africa, as well as in an experimental wind tunnel. Two investigators with architectural training selected 60 houses in The Gambia, Tanzania, Philippines, and Thailand. Data-loggers were used to measure indoor temperatures in hourly intervals over a 12 months period. In a subgroup of 20 houses airflow, temperature and humidity were measured at five-minute intervals for one night from 21.00 to 6.00 hrs inside and outside of bed nets using sensors and omni-directional thermo-anemometers. An investigator set up a bed net with a mesh size of 220 holes per inch 2 in each study household and slept under the bed net to simulate a realistic environment. The attenuation of airflow caused by bed nets of different mesh sizes was also measured in an experimental wind tunnel. RESULTS: The highest indoor temperatures (49.0 C) were measured in The Gambia. During the hottest months of the year the mean temperature at night (9 pm) was between 33.1 C (The Gambia) and 26.2 C (Thailand). The bed net attenuated the airflow from a minimum of 27% (Philippines) to a maximum of 71% (The Gambia). Overall the bed nets reduced airflow compared to un-attenuated airflow from 9 to 4 cm sec-1 or 52% (p<0.001). In all sites, no statistically significant difference in temperature or humidity was detected between the inside and outside of the bed net. Wind tunnel experiments with 11 different mesh-sized bed nets showed an overall reduction in airflow of 64% (range 55 - 71%) compared to un-attenuated airflow. As expected, airflow decreased with increasing net mesh size. Nets with a mesh of 136 holes inch-2 reduced airflow by 55% (mean; range 51 - 73%). A denser net (200 holes inch-2) attenuated airflow by 59% (mean; range 56 - 74%). DISCUSSION: Despite concerted efforts to increase the uptake of this intervention in many areas uptake remains poor. Bed nets reduce airflow, but have no influence on temperature and humidity. The discomfort associated with bed nets is likely to be most intolerable during the hottest and most humid period of the year, which frequently coincides with the peak of malaria vector densities and the force of pathogen transmission. CONCLUSIONS: These observations suggest thermal discomfort is a factor limiting bed net use and open a range of architectural possibilities to overcome this limitation.

Mtove G, Amos B, Nadjm B, Hendriksen ICE, Dondorp AM, Mwambuli A, Kim DR, Ochiai RL, Clemens JD, von Seidlein L et al. 2011. Decreasing incidence of severe malaria and community-acquired bacteraemia among hospitalized children in Muheza, north-eastern Tanzania, 2006-2010. Malar J, 10 (1), pp. 320. | Show Abstract | Read more

BACKGROUND: The annual incidence and temporal trend of severe malaria and community-acquired bacteraemia during a four-year period in Muheza, Tanzania was assessed. METHODS: Data on severely ill febrile children aged 2 months to 14 years from three prospective studies conducted at Muheza District Hospital from 2006 to 2010 was pooled and analysed. On admission, each enrolled child had a thin and thick blood film and at least one rapid diagnostic test for falciparum malaria, as well as a blood culture. The annual incidence of bacteraemia and severe malaria among children coming from Muheza was calculated and their temporal trend was assessed. RESULTS: Overall, 1, 898 severe falciparum malaria and 684 bacteraemia cases were included. Of these, 1, 356 (71%) and 482 (71%), respectively, were from the referral population of Muheza. The incidence of falciparum malaria and all-cause bacteraemia in Muheza decreased five-fold and three-fold, respectively, from the first to the fourth year of surveillance (p < 0.0001). During this period, the median ages of children from Muheza admitted with severe malaria increased from 1.7 to 2.5 years (p < 0.0001). The reduction in all-cause bacteraemia was mainly driven by the 11-fold decline in the incidence of non-typhoidal salmonellosis. The annual incidences of Haemophilus influenzae and pneumococcal invasive bacterial infections decreased as well but were much fewer in number. CONCLUSIONS: These results add to the growing evidence of the decline in malaria associated with a decrease in non-typhoidal salmonellosis and possibly other bacteraemias. Malarial prevention and control strategies may provide a greater benefit than the mere reduction of malaria alone.

Price RN, Douglas NM, Anstey NM, von Seidlein L. 2011. Plasmodium vivax treatments: what are we looking for? Curr Opin Infect Dis, 24 (6), pp. 578-585. | Show Abstract | Read more

PURPOSE OF REVIEW: For over 50 years, the treatment of Plasmodium vivax has relied on a combination of chloroquine and primaquine, but this strategy is under threat. Chloroquine efficacy is now compromised across much of the vivax endemic world and there are significant operational difficulties in deploying primaquine. We review the recent advances in P. vivax chemotherapy that may influence the future management of this neglected pathogen. RECENT FINDINGS: New-generation artemisinin combination therapies (ACTs) have shown potent efficacy against the erythrocytic stages of both drug-resistant P. vivax and Plasmodium falciparum. Antimalarial regimens containing slowly eliminated drugs provide a measure of protection against the first, and possibly second, relapse of tropical strains of P. vivax, but reliable radical cure is needed to prevent future relapses. Primaquine is currently the only licensed hypnozoitocidal treatment, but requires long treatment courses and its effectiveness in different endemic settings remains largely unknown. SUMMARY: In regions coendemic for P. vivax and P. falciparum, a unified treatment policy for malaria of any parasitological cause is likely to confer the greatest individual and public health benefit. Optimizing the safety and effectiveness of primaquine through the development of rapid diagnostic tests for glucose-6-phosphate dehydrogenase deficiency and improving drug adherence will be crucial endeavors in the fight against vivax malaria.

Bejon P, Cook J, Bergmann-Leitner E, Olotu A, Lusingu J, Mwacharo J, Vekemans J, Njuguna P, Leach A, Lievens M et al. 2011. Effect of the pre-erythrocytic candidate malaria vaccine RTS,S/AS01E on blood stage immunity in young children. J Infect Dis, 204 (1), pp. 9-18. | Show Abstract | Read more

BACKGROUND: RTS,S/AS01(E) is the lead candidate malaria vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage malaria parasites after natural infection. METHODS: We measured, by enzyme-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-1(42), EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01(E) or a control vaccine. RESULTS:  Antibody concentrations to AMA-1, EBA-175, and MSP-1(42) decreased with age during the first year of life, then increased to 32 months of age. Anti-MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months. Vaccination with RTS,S/AS01(E) resulted in modest reductions in AMA-1, EBA-175, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical malaria. CONCLUSIONS: Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces anti-merozoite antigen antibody concentrations. However, in this study, these antibodies were not correlates of clinical immunity to malaria. Instead, heterogeneous exposure led to confounded, positive associations between increasing antibody concentration and increasing risk of clinical malaria.

Lubell Y, Riewpaiboon A, Dondorp AM, von Seidlein L, Mokuolu OA, Nansumba M, Gesase S, Kent A, Mtove G, Olaosebikan R et al. 2011. Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa. Bull World Health Organ, 89 (7), pp. 504-512. | Show Abstract | Read more

OBJECTIVE: To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. METHODS: The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. FINDINGS: The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. CONCLUSION: Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.

Reyburn R, Kim DR, Emch M, Khatib A, von Seidlein L, Ali M. 2011. Climate variability and the outbreaks of cholera in Zanzibar, East Africa: a time series analysis. Am J Trop Med Hyg, 84 (6), pp. 862-869. | Show Abstract | Read more

Global cholera incidence is increasing, particularly in sub-Saharan Africa. We examined the impact of climate and ocean environmental variability on cholera outbreaks, and developed a forecasting model for outbreaks in Zanzibar. Routine cholera surveillance reports between 1997 and 2006 were correlated with remotely and locally sensed environmental data. A seasonal autoregressive integrated moving average (SARIMA) model determined the impact of climate and environmental variability on cholera. The SARIMA model shows temporal clustering of cholera. A 1°C increase in temperature at 4 months lag resulted in a 2-fold increase of cholera cases, and an increase of 200 mm of rainfall at 2 months lag resulted in a 1.6-fold increase of cholera cases. Temperature and rainfall interaction yielded a significantly positive association (P < 0.04) with cholera at a 1-month lag. These results may be applied to forecast cholera outbreaks, and guide public health resources in controlling cholera in Zanzibar.

Ley B, Thriemer K, Ame SM, Mtove GM, von Seidlein L, Amos B, Hendriksen ICE, Mwambuli A, Shoo A, Kim DR et al. 2011. Assessment and comparative analysis of a rapid diagnostic test (Tubex®) for the diagnosis of typhoid fever among hospitalized children in rural Tanzania. BMC Infect Dis, 11 (1), pp. 147. | Show Abstract | Read more

BACKGROUND: Typhoid fever remains a significant health problem in many developing countries. A rapid test with a performance comparable to that of blood culture would be highly useful. A rapid diagnostic test for typhoid fever, Tubex®, is commercially available that uses particle separation to detect immunoglobulin M directed towards Salmonella Typhi O9 lipopolysaccharide in sera. METHODS: We assessed the sensitivity and specificity of the Tubex test among Tanzanian children hospitalized with febrile illness using blood culture as gold standard. Evaluation was done considering blood culture confirmed S. Typhi with non-typhi salmonella (NTS) and non - salmonella isolates as controls as well as with non-salmonella isolates only. RESULTS: Of 139 samples tested with Tubex, 33 were positive for S. Typhi in blood culture, 49 were culture-confirmed NTS infections, and 57 were other non-salmonella infections. Thirteen hemolyzed samples were excluded. Using all non - S. Typhi isolates as controls, we showed a sensitivity of 79% and a specificity of 89%. When the analysis was repeated excluding NTS from the pool of controls we showed a sensitivity of 79% and a specificity of 97%. There was no significant difference in the test performance using the two different control groups (p > 0.05). CONCLUSION: This first evaluation of the Tubex test in an African setting showed a similar performance to those seen in some Asian settings. Comparison with the earlier results of a Widal test using the same samples showed no significant difference (p > 0.05) for any of the performance indicators, irrespective of the applied control group.

Andersen F, Douglas NM, Bustos D, Galappaththy G, Qi G, Hsiang MS, Kusriastuti R, Mendis K, Taleo G, Whittaker M et al. 2011. Trends in malaria research in 11 Asian Pacific countries: an analysis of peer-reviewed publications over two decades. Malar J, 10 (1), pp. 131. | Show Abstract | Read more

BACKGROUND: Quantitative data are lacking on published malaria research. The purpose of the study is to characterize trends in malaria-related literature from 1990 to 2009 in 11 Asian-Pacific countries that are committed to malaria elimination as a national goal. METHODS: A systematic search was conducted for articles published from January 1990 to December 2009 in PubMed/MEDLINE using terms for malaria and 11 target countries (Bhutan, China, North Korea, Indonesia, Malaysia, Philippines, Solomon Islands, South Korea, Sri Lanka, Thailand and Vanuatu). The references were collated and categorized according to subject, Plasmodium species, and whether they contained original or derivative data. RESULTS: 2,700 articles published between 1990 and 2009 related to malaria in the target countries. The annual output of malaria-related papers increased linearly whereas the overall biomedical output from these countries grew exponentially. The percentage of malaria-related publications was nearly 3% (111/3741) of all biomedical publications in 1992 and decreased to less than 1% (118/12171; p < 0.001) in 2009. Thailand had the highest absolute output of malaria-related papers (n = 1211), followed by China (n = 609) and Indonesia (n = 346). Solomon Islands and Vanuatu had lower absolute numbers of publications, but both countries had the highest number of publications per capita (1.3 and 2.5 papers/1,000 population). The largest percentage of papers concerned the epidemiology and control of malaria (53%) followed by studies of drugs and drug resistance (47%). There was an increase in the proportion of articles relating to epidemiology, entomology, biology, molecular biology, pathophysiology and diagnostics from the first to the second decade, whereas the percentage of papers on drugs, clinical aspects of malaria, immunology, and social sciences decreased. CONCLUSIONS: The proportion of malaria-related publications out of the overall biomedical output from the 11 target Asian-Pacific countries is decreasing. The discovery and evaluation of new, safe and effective drugs and vaccines is paramount. In addition the elimination of malaria will require operational research to implement and scale up interventions.

Hendriksen ICE, Mtove G, Pedro AJ, Gomes E, Silamut K, Lee SJ, Mwambuli A, Gesase S, Reyburn H, Day NPJ et al. 2011. Evaluation of a PfHRP2 and a pLDH-based rapid diagnostic test for the diagnosis of severe malaria in 2 populations of African children. Clin Infect Dis, 52 (9), pp. 1100-1107. | Show Abstract | Read more

BACKGROUND: Rapid diagnostic tests (RDTs) now play an important role in the diagnosis of falciparum malaria in many countries where the disease is endemic. Although these tests have been extensively evaluated in uncomplicated falciparum malaria, reliable data on their performance for diagnosing potentially lethal severe malaria is lacking. METHODS: We compared a Plasmodium falciparum histidine-rich-protein2 (PfHRP₂)-based RDT and a Plasmodium lactate dehydrogenase (pLDH)-based RDT with routine microscopy of a peripheral blood slide and expert microscopy as a reference standard for the diagnosis of severe malaria in 1898 children who presented with severe febrile illness at 2 centers in Mozambique and Tanzania. RESULTS: The overall sensitivity, specificity, positive predictive value, and negative predictive values of the PfHRP₂-based test were 94.0%, 70.9%, 85.4%, and 86.8%, respectively, and for the pLDH-based test, the values were 88.0%, 88.3%, 93.2%, and 80.3%, respectively. At parasite counts < 1000 parasites/μL (n = 173), sensitivity of the pLDH-based test was low (45.7%), compared with that of the PfHRP₂-based test (69.9%). Both RDTs performed better than did the routine slide reading in a clinical laboratory as assessed in 1 of the centers. CONCLUSION: The evaluated PfHRP2-based RDT is an acceptable alternative to routine microscopy for diagnosing severe malaria in African children and performed better than did the evaluated pLDH-based RDT.

Dondorp AM, Fanello CI, von Seidlein L, Day NPJ, White NJ. 2011. Artesunate for severe malaria in African children Reply LANCET, 377 (9772), pp. 1154-1154.

Arvelo W, Blum LS, Nahar N, von Seidlein L, Nahar L, Pack RP, Brooks AW, Pach A, Breiman RF, Luby SP, Ram PK. 2011. Community perceptions of bloody diarrhoea in an urban slum in South Asia: implications for introduction of a Shigella vaccine. Epidemiol Infect, 139 (4), pp. 599-605. | Show Abstract | Read more

Understanding local perceptions of disease causation could help public health officials improve strategies to prevent bloody diarrhoea. A cross-sectional survey was conducted in Dhaka, Bangladesh to elicit community beliefs about the causes of and prevention strategies for bloody diarrhoea. Between March and June 2003, we interviewed 541 randomly selected respondents. Overall, 507 (93%) respondents perceived that a vaccine could prevent bloody diarrhoea. If a vaccine provided lifetime protection, 445 (83%) respondents stated that they would opt to get the vaccine and would pay a median of $0·05 (range U.S.$0·01-0·15) for it, equivalent to <1% of their median weekly income. There was almost universal perception that an effective vaccine to prevent bloody diarrhoea was highly beneficial and acceptable. While respondents valued a vaccine for prevention of bloody diarrhoea, they were only willing to pay minimally for it. Therefore, achieving a high rate of Shigella vaccine coverage may require subsidy of vaccine purchase.

Soofi SB, Habib MA, von Seidlein L, Khan MJ, Muhammad S, Bhutto N, Khan MI, Rasool S, Zafar A, Clemens JD et al. 2011. A comparison of disease caused by Shigella and Campylobacter species: 24 months community based surveillance in 4 slums of Karachi, Pakistan. J Infect Public Health, 4 (1), pp. 12-21. | Show Abstract | Read more

Despite the efforts of the international community diarrheal diseases still pose a major threat to children in children less than five years of age. Bacterial diarrhea has also emerged as a public health concern due to the proliferation of drug resistant species in many parts of the world. There is a paucity of population-based data about the incidence of shigellosis and Campylobacter infections in Pakistan. We report country specific results for Shigella diarrhea that were derived from a multicenter study conducted in six Asian countries. Disease surveillance was conducted over a 24 month period in urban slums of Karachi, Pakistan, a city with a population of 59,584. Cases were detected through passive detection in study treatment centers. Stool specimens or rectal swabs were collected from all consenting patients. Between January 2002 and December 2003 10,540 enteric infection cases were detected. The incidence rate of treated diarrhea in children under 5 was 488/1000/year. In children, 5 years and older, the diarrhea rate was 22/1000/year. 576 (7%) Campylobacter isolates were detected. The pre-dominant Campylobacter species was C. jenuni with an increase of 29/1000 year in children under 5 years. Shigella species were isolated from 394 of 8032 children under 5 years of age. Shigella flexneri was the dominant species (10/1000/year in children under 5 years) followed by Shigella sonnei (3.9/1000/year), Shigella boydii (2.0/1000/year) and Shigella dysenteriae (1.3/1000/year). Shigellosis and Campylobacter infection rates peaked during the second year of life. The incidence rate of shigellosis increased in old age but such a trend was not observed in Campylobacter infections. Of 394 shigellosis patients 123 (31%) presented with dysentery in contrast to only 54 (9%) of 576 patients with Campylobacter infections (p<0.001). Both Campylobacter infections and shigellosis are common in community settings of Pakistan but shigellosis presented more frequently with abdominal pain and dysentery than Campylobacter infections indicating that shigellosis may be a more severe illness than Campylobacter infections. Due to the increased and disease severity, drug resistant shigella have become a significant health problem; moreover it is a disease of poor and impoverished people who do not have the access to standard water and sanitary conditions, health care services or optimal treatment. In the face of these facts it is empirically important to develop a low cost effective vaccine that can protect these populations for a longer duration.

Lubell Y, Staedke SG, Greenwood BM, Kamya MR, Molyneux M, Newton PN, Reyburn H, Snow RW, D'Alessandro U, English M et al. 2011. Likely health outcomes for untreated acute febrile illness in the tropics in decision and economic models; a Delphi survey. PLoS One, 6 (2), pp. e17439. | Show Abstract | Read more

BACKGROUND: Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform. METHODS AND FINDINGS: A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1-5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10-58%) than those from higher transmission areas (median 13%, IQR 7-30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60-73%). However, opinions varied widely for most parameters, and did not converge on resurveying. CONCLUSIONS: This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated.

Reyburn R, Deen JL, Grais RF, Bhattacharya SK, Sur D, Lopez AL, Jiddawi MS, Clemens JD, von Seidlein L. 2011. The case for reactive mass oral cholera vaccinations. PLoS Negl Trop Dis, 5 (1), pp. e952. | Show Abstract | Read more

INTRODUCTION: The outbreak of cholera in Zimbabwe intensified interest in the control and prevention of cholera. While there is agreement that safe water, sanitation, and personal hygiene are ideal for the long term control of cholera, there is controversy about the role of newer approaches such as oral cholera vaccines (OCVs). In October 2009 the Strategic Advisory Group of Experts advised the World Health Organization to consider reactive vaccination campaigns in response to large cholera outbreaks. To evaluate the potential benefit of this pivotal change in WHO policy, we used existing data from cholera outbreaks to simulate the number of cholera cases preventable by reactive mass vaccination. METHODS: Datasets of cholera outbreaks from three sites with varying cholera endemicity--Zimbabwe, Kolkata (India), and Zanzibar (Tanzania)--were analysed to estimate the number of cholera cases preventable under differing response times, vaccine coverage, and vaccine doses. FINDINGS: The large cholera outbreak in Zimbabwe started in mid August 2008 and by July 2009, 98,591 cholera cases had been reported with 4,288 deaths attributed to cholera. If a rapid response had taken place and half of the population had been vaccinated once the first 400 cases had occurred, as many as 34,900 (40%) cholera cases and 1,695 deaths (40%) could have been prevented. In the sites with endemic cholera, Kolkata and Zanzibar, a significant number of cases could have been prevented but the impact would have been less dramatic. A brisk response is required for outbreaks with the majority of cases occurring during the early weeks. Even a delayed response can save a substantial number of cases and deaths in long, drawn-out outbreaks. If circumstances prevent a rapid response there are good reasons to roll out cholera mass vaccination campaigns well into the outbreak. Once a substantial proportion of a population is vaccinated, outbreaks in subsequent years may be reduced if not prevented. A single dose vaccine would be of advantage in short, small outbreaks. CONCLUSIONS: We show that reactive vaccine use can prevent cholera cases and is a rational response to cholera outbreaks in endemic and non-endemic settings. In large and long outbreaks a reactive vaccination with a two-dose vaccine can prevent a substantial proportion of cases. To make mass vaccination campaigns successful, it would be essential to agree when to implement reactive vaccination campaigns and to have a dynamic and determined response team that is familiar with the logistic challenges on standby. Most importantly, the decision makers in donor and recipient countries have to be convinced of the benefit of reactive cholera vaccinations.

Bejon P, Turner L, Lavstsen T, Cham G, Olotu A, Drakeley CJ, Lievens M, Vekemans J, Savarese B, Lusingu J et al. 2011. Serological evidence of discrete spatial clusters of Plasmodium falciparum parasites. PLoS One, 6 (6), pp. e21711. | Show Abstract | Read more

BACKGROUND: Malaria transmission may be considered to be homogenous with well-mixed parasite populations (as in the classic Ross/Macdonald models). Marked fine-scale heterogeneity of transmission has been observed in the field (i.e., over a few kilometres), but there are relatively few data on the degree of mixing. Since the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) is highly polymorphic, the host's serological responses may be used to infer exposure to parasite sub-populations. METHODS AND FINDINGS: We measured the antibody responses to 46 individual PfEMP1 domains at four time points among 450 children in Kenya, and identified distinct spatial clusters of antibody responses to individual domains. 35 domains showed strongly significant sero-clusters at p = 0.001. Individuals within the high transmission hotspot showed the greatest diversity of anti-PfEMP1 responses. Individuals outside the hotspot had a less diverse range of responses, even if as individuals they were at relatively intense exposure. CONCLUSIONS: We infer that antigenically distinct sub-populations of parasites exist on a fine spatial scale in a study area of rural Kenya. Further studies should examine antigenic variation over longer periods of time and in different study areas.

Olotu A, Lusingu J, Leach A, Lievens M, Vekemans J, Msham S, Lang T, Gould J, Dubois M-C, Jongert E et al. 2011. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis, 11 (2), pp. 102-109. | Show Abstract | Read more

BACKGROUND: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. METHODS: Between March, 2007, and October, 2008, we enrolled healthy children aged 5-17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. FINDINGS: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5-54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1-61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12-18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria. INTERPRETATION: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries. FUNDING: PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.

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Mtove G, Amos B, Nadjm B, Hendriksen ICE, Dondorp AM, Mwambuli A, Kim DR, Ochiai RL, Clemens JD, Von Seidlein L et al. 2011. Decreasing incidence of severe malaria and community-acquired bacteraemia among hospitalized children in Muheza, north-eastern Tanzania, 2006-2010 Malaria Journal, 10 | Show Abstract | Read more

Background: The annual incidence and temporal trend of severe malaria and community-acquired bacteraemia during a four-year period in Muheza, Tanzania was assessed. Methods. Data on severely ill febrile children aged 2 months to 14 years from three prospective studies conducted at Muheza District Hospital from 2006 to 2010 was pooled and analysed. On admission, each enrolled child had a thin and thick blood film and at least one rapid diagnostic test for falciparum malaria, as well as a blood culture. The annual incidence of bacteraemia and severe malaria among children coming from Muheza was calculated and their temporal trend was assessed. Results: Overall, 1, 898 severe falciparum malaria and 684 bacteraemia cases were included. Of these, 1, 356 (71%) and 482 (71%), respectively, were from the referral population of Muheza. The incidence of falciparum malaria and all-cause bacteraemia in Muheza decreased five-fold and three-fold, respectively, from the first to the fourth year of surveillance (p < 0.0001). During this period, the median ages of children from Muheza admitted with severe malaria increased from 1.7 to 2.5 years (p < 0.0001). The reduction in all-cause bacteraemia was mainly driven by the 11-fold decline in the incidence of non-typhoidal salmonellosis. The annual incidences of Haemophilus influenzae and pneumococcal invasive bacterial infections decreased as well but were much fewer in number. Conclusions: These results add to the growing evidence of the decline in malaria associated with a decrease in non-typhoidal salmonellosis and possibly other bacteraemias. Malarial prevention and control strategies may provide a greater benefit than the mere reduction of malaria alone. © 2011Mtove et al; licensee BioMed Central Ltd.

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Lubell Y, Riewpaiboon A, Dondorp AM, Von Seidlein L, Mokuolu OA, Nansumba M, Gesase S, Kent A, Mtove G, Olaosebikan R et al. 2011. Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-saharan Africa Bulletin of the World Health Organization, 89 (7), pp. 504-512. | Show Abstract | Read more

Objective To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. Methods The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. Findings The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. Conclusion Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.

Dondorp AM, Fanello CI, von Seidlein L, Day NPJ, White NJ. 2011. Artesunate for severe malaria in African children – Authors' reply The Lancet, 377 (9772), pp. 1154-1154. | Read more

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.

Wang S-M, Ma J-C, Hao Z-Y, Zhang Z-Y, Mason C, Sethabutr O, von Seidlein L, Wang X-Y, Xu Z-Y. 2010. Surveillance of shigellosis by real-time PCR suggests underestimation of shigellosis prevalence by culture-based methods in a population of rural China. J Infect, 61 (6), pp. 471-475. | Show Abstract | Read more

INTRODUCTION: Shigellosis is a leading public health issue in China, especially in Children under 5 years of age. The disease burden of shigellosis is usually underestimated by conventional culture. In this study, real-time PCR was applied to detect Shigella infection in parallel with routine culture, to investigate the true burden of disease caused by Shigella spp. METHODS: Rectal swab specimens of 39 Shigella culture positive and 298 Shigella culture negative patients from a population-based surveillance study were selected randomly. Real-time PCR targeting the invasion plasmid antigen H gene sequence (ipaH) was used to detect DNA sequences characteristic for Shigella spp. RESULTS: ipaH were detected in 174 of 298 (58%) randomly selected Shigella culture negative specimens and in 38 of 39 (97%) Shigella culture positive specimens (p < 0.001). Among 10 variables, culture results was the strongest predictive factor (OR = 15.5; 95% CI: 2.0-119.0), followed by a clinical presentation of diarrhea with fever (OR = 2.8; 95% CI: 1.2-6.2), epidemic season (OR = 2.4; 95% CI: 1.4-4.3), and female gender (OR = 1.8; 95% CI: 1.1-3.0). CONCLUSION: The high detection rate of ipaH in culture negative specimens through use of real-time PCR suggests that earlier estimates of shigellosis burden measured by conventional culture may have underestimated the true disease burden.

Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Olivier A, Benns S, Olomi R, Msham S, Lang T et al. 2010. Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children. PLoS One, 5 (11), pp. e14090. | Show Abstract | Read more

The malaria vaccine candidate, RTS,S/AS01(E), showed promising protective efficacy in a trial of Kenyan and Tanzanian children aged 5 to 17 months. Here we report on the vaccine's safety and tolerability. The experimental design was a Phase 2b, two-centre, double-blind (observer- and participant-blind), randomised (1∶1 ratio) controlled trial. Three doses of study or control (rabies) vaccines were administered intramuscularly at 1 month intervals. Solicited adverse events (AEs) were collected for 7 days after each vaccination. There was surveillance and reporting for unsolicited adverse events for 30 days after each vaccination. Serious adverse events (SAEs) were recorded throughout the study period which lasted for 14 months after dose 1 in Korogwe, Tanzania and an average of 18 months post-dose 1 in Kilifi, Kenya. Blood samples for safety monitoring of haematological, renal and hepatic functions were taken at baseline, 3, 10 and 14 months after dose 1. A total of 894 children received RTS,S/AS01(E) or rabies vaccine between March and August 2007. Overall, children vaccinated with RTS,S/AS01(E) had fewer SAEs (51/447) than children in the control group (88/447). One SAE episode in a RTS,S/AS01(E) recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01(E) group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently reported unsolicited AE. Fever was the most frequently observed solicited AE and was recorded after 11% of RTS,S/AS01(E) doses compared to 31% of doses of rabies vaccine. The candidate vaccine RTS,S/AS01(E) showed an acceptable safety profile in children living in a malaria-endemic area in East Africa. More data on the safety of RTS,S/AS01(E) will become available from the Phase 3 programme.

Dondorp AM, Fanello CI, Hendriksen ICE, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K et al. 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet, 376 (9753), pp. 1647-1657. | Show Abstract | Read more

BACKGROUND: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. METHODS: This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054. FINDINGS: 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects. INTERPRETATION: Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide. FUNDING: The Wellcome Trust.

Kanungo S, Tsuzuki A, Deen JL, Lopez AL, Rajendran K, Manna B, Sur D, Kim DR, Gupta VK, Ochiai RL et al. 2010. Use of verbal autopsy to determine mortality patterns in an urban slum in Kolkata, India. Bull World Health Organ, 88 (9), pp. 667-674. | Show Abstract | Read more

OBJECTIVE: To define mortality patterns in an urban slum in Kolkata, India, in the context of a cholera and typhoid fever project. METHODS: In a well-defined population that was under surveillance for 18 months, we followed a dynamic cohort of 63 788 residents whose households were visited monthly by community health workers to identify deaths. Trained physicians performed verbal autopsies and experienced senior physicians assigned the primary cause of death according to the International classification of diseases, 10th edition. We tabulated causes of death in accordance with Global Burden of Disease 2000 categories and assessed overall and cause-specific mortality rates per age group and gender. FINDINGS: During 87 921 person-years of follow-up, we recorded 544 deaths. This gave an overall mortality rate of 6.2 per 1000 person-years. We assigned a cause to 89% (482/544) of the deaths. The leading causes of death, in descending order, were cardiovascular diseases (especially among adults aged over 40 years), cancer, respiratory ailments and digestive disorders. Most deaths in children under 5 years of age were caused by tuberculosis, respiratory infections and diarrhoeal diseases. CONCLUSION: Although the most common causes of death in children were infectious, non-communicable diseases were predominant among adults. There is a need for continuing interventions against infectious diseases in addition to new and innovative strategies to combat non-infectious conditions.

Dong B-Q, Yang J, Wang X-Y, Gong J, von Seidlein L, Wang M-L, Lin M, Liao H-Z, Ochiai RL, Xu Z-Y et al. 2010. Trends and disease burden of enteric fever in Guangxi province, China, 1994-2004. Bull World Health Organ, 88 (9), pp. 689-696. | Show Abstract | Read more

OBJECTIVE: To determine the burden of enteric fever through trends in morbidity and mortality, bacterial species and antimicrobial resistance in Guangxi, a southern, subtropical, coastal province of China with a disproportionally large burden of enteric fever. METHODS: Data on morbidity and mortality caused by enteric fever between 1994 and 2004 were extracted from the Guangxi Center for Disease Control and Prevention. Laboratory-based surveillance and outbreak investigations were integrated with reports of notifiable infectious diseases to estimate the bacterial species-specific incidence of enteric fever. To adjust for underreporting, survey data were collected from three prefectures that represent the hyper-, moderate- and low-endemic regions of Guangxi province. FINDINGS: In Guangxi province, enteric fever incidence rate varied over the study period, with a peak of 13.5 cases per 100 000 population in 1995 and a low of 6.5 in 2003. The disease occurred most frequently during the summer and autumn months and in the group aged 10-49 years. The incidence of enteric fever varied by region within Guangxi province. During the 11-year period covered by the study, 61 outbreaks of enteric fever were reported, and Salmonella paratyphi A (SPA) became the predominant causative agent in the province. CONCLUSION: Prospective studies may provide a better understanding of the reason for the shifting epidemiology of enteric fever in Guangxi province. Given the emergence of resistance to first- and second-line antimicrobials for the treatment of enteric fever, a bivalent vaccine against both SPA and S. typhi would facilitate for disease control.

Khan MI, Ochiai RL, von Seidlein L, Dong B, Bhattacharya SK, Agtini MD, Bhutta ZA, Do GC, Ali M, Kim DR et al. 2010. Non-typhoidal Salmonella rates in febrile children at sites in five Asian countries. Trop Med Int Health, 15 (8), pp. 960-963. | Show Abstract | Read more

There is increased recognition of non-typhoidal Salmonella (NTS) as a major cause of severe febrile illness in sub-Saharan Africa. However, little is known about community-based incidence of NTS in Asia. In a multicentre, community-based prospective Salmonella surveillance study, we identified a total of six NTS cases: three in Karachi, Pakistan, one in Kolkata, India, and two in North Jakarta, Indonesia. No NTS cases were identified in Hechi, People's Republic of China, and Hue, Viet Nam. Three cases were in children under 3 years, and one case was in a child aged 10 years and one in a child aged 15 years. Only one case was an adult (29 years). The highest incidence of NTS infection was in Karachi (7.2 culture-proven NTS cases per 100,000 person years in age group of 2-15 years). However, in comparison with sub-Saharan Africa, the NTS burden in Asia appears rather limited.

Ali M, Deen JL, Khatib A, Enwere G, von Seidlein L, Reyburn R, Ali SM, Chang NY, Perroud V, Marodon F et al. 2010. Paperless registration during survey enumerations and large oral cholera mass vaccination in Zanzibar, the United Republic of Tanzania. Bull World Health Organ, 88 (7), pp. 556-559. | Show Abstract | Read more

PROBLEM: Field trials require extensive data preparation and complex logistics. The use of personal digital assistants (PDAs) can bypass many of the traditional steps that are necessary in a paper-based data entry system. APPROACH: We programmed, designed and supervised the use of PDAs for a large survey enumeration and mass vaccination campaign. LOCAL SETTING: The project was implemented in Zanzibar in the United Republic of Tanzania. Zanzibar is composed of two main islands, Unguja and Pemba, where outbreaks of cholera have been reported since the 1970s. RELEVANT CHANGES: PDAs allowed us to digitize information at the initial point of contact with the respondents. Immediate response by the system in case of error helped ensure the quality and reliability of the data. PDAs provided quick data summaries that allowed subsequent research activities to be implemented in a timely fashion. LESSONS LEARNT: Portability, immediate recording and linking of information enhanced structure data collection in our study. PDAs could be more useful than paper-based systems for data collection in the field, especially in impoverished settings in developing countries.

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Dondorp AM, Yeung S, White L, Nguon C, Day NPJ, Socheat D, von Seidlein L. 2010. Artemisinin resistance: current status and scenarios for containment (vol 8, pg 272, 2010) NATURE REVIEWS MICROBIOLOGY, 8 (7), pp. 530-530. | Read more

Ley B, Mtove G, Thriemer K, Amos B, von Seidlein L, Hendriksen I, Mwambuli A, Shoo A, Malahiyo R, Ame SM et al. 2010. Evaluation of the Widal tube agglutination test for the diagnosis of typhoid fever among children admitted to a rural hdospital in Tanzania and a comparison with previous studies. BMC Infect Dis, 10 (1), pp. 180. | Show Abstract | Read more

BACKGROUND: The diagnosis of typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi (S. typhi). However, a more rapid, simpler, and cheaper diagnostic method would be very useful especially in developing countries. The Widal test is widely used in Africa but little information exists about its reliability. METHODS: We assessed the performance of the Widal tube agglutination test among febrile hospitalized Tanzanian children. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various anti-TH and -TO titers using culture-confirmed typhoid fever cases as the "true positives" and all other febrile children with blood culture negative for S. typhi as the "true negatives." RESULTS: We found that 16 (1%) of 1,680 children had culture-proven typhoid fever. A single anti-TH titer of 1:80 and higher was the optimal indicator of typhoid fever. This had a sensitivity of 75%, specificity of 98%, NPV of 100%, but PPV was only 26%. We compared our main findings with those from previous studies. CONCLUSION: Among febrile hospitalized Tanzanian children with a low prevalence of typhoid fever, a Widal titer of > or = 1:80 performed well in terms of sensitivity, specificity, and NPV. However a test with improved PPV that is similarly easy to apply and cost-efficient is desirable.

Dondorp AM, Yeung S, White L, Nguon C, Day NPJ, Socheat D, Von Seidlein L. 2010. Erratum: Artemisinin resistance: Current status and scenarios for containment (Nature Reviews Microbiology (2010) 8 (272-280)) Nature Reviews Microbiology, 8 (7), pp. 530.

Dondorp AM, Yeung S, White L, Nguon C, Day NPJ, Socheat D, von Seidlein L. 2010. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol, 8 (4), pp. 272-280. | Show Abstract | Read more

Artemisinin combination therapies are the first-line treatments for uncomplicated Plasmodium falciparum malaria in most malaria-endemic countries. Recently, partial artemisinin-resistant P. falciparum malaria has emerged on the Cambodia-Thailand border. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years, and the availability of substandard artemisinins, have probably been the main driving force in the selection of the resistant phenotype in the region. A multifaceted containment programme has recently been launched, including early diagnosis and appropriate treatment, decreasing drug pressure, optimising vector control, targeting the mobile population, strengthening management and surveillance systems, and operational research. Mathematical modelling can be a useful tool to evaluate possible strategies for containment.

Choi SY, Lee JH, Kim EJ, Lee HR, Jeon Y-S, von Seidlein L, Deen J, Ansaruzzaman M, Lucas GMES, Barreto A et al. 2010. Classical RS1 and environmental RS1 elements in Vibrio cholerae O1 El Tor strains harbouring a tandem repeat of CTX prophage: revisiting Mozambique in 2005. J Med Microbiol, 59 (Pt 3), pp. 302-308. | Show Abstract | Read more

Currently, Vibrio cholerae O1 serogroup biotype El Tor strains producing classical type cholera toxin (altered strains or El Tor variants) are prevalent in Asia and in Mozambique. Mozambican strains collected in 2004 contained a tandem repeat of CTX prophage on the small chromosome and each CTX prophage harboured the classical rstR and classical ctxB. We found that the majority of the strains collected in 2005 in Mozambique contained extra elements on the large chromosome in addition to the tandem repeat of CTX prophage on the small chromosome. New type RS1 elements RS1(cla) and RS1(env), and a CTX(env) with rstR(env) and the classical ctxB were identified on the large chromosome of the Mozambican isolates collected in 2005.

Mtove G, Amos B, von Seidlein L, Hendriksen I, Mwambuli A, Kimera J, Mallahiyo R, Kim DR, Ochiai RL, Clemens JD et al. 2010. Invasive salmonellosis among children admitted to a rural Tanzanian hospital and a comparison with previous studies. PLoS One, 5 (2), pp. e9244. | Show Abstract | Read more

BACKGROUND: The importance of invasive salmonellosis in African children is well recognized but there is inadequate information on these infections. We conducted a fever surveillance study in a Tanzanian rural hospital to estimate the case fraction of invasive salmonellosis among pediatric admissions, examine associations with common co-morbidities and describe its clinical features. We compared our main findings with those from previous studies among children in sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: From 1 March 2008 to 28 Feb 2009, 1,502 children were enrolled into the study. We collected clinical information and blood for point of care tests, culture, and diagnosis of malaria and HIV. We analyzed the clinical features on admission and outcome by laboratory-confirmed diagnosis. Pathogenic bacteria were isolated from the blood of 156 (10%) children, of which 14 (9%) were S. typhi, 45 (29%) were NTS and 97 (62%) were other pathogenic bacteria. Invasive salmonellosis accounted for 59/156 (38%) bacteremic children. Children with typhoid fever were significantly older and presented with a longer duration of fever. NTS infections were significantly associated with prior antimalarial treatment, malarial complications and with a high risk for death. CONCLUSIONS/SIGNIFICANCE: Invasive salmonellosis, particularly NTS infection, is an important cause of febrile disease among hospitalized children in our rural Tanzanian setting. Previous studies showed considerable variation in the case fraction of S. typhi and NTS infections. Certain suggestive clinical features (such as older age and long duration of fever for typhoid whereas concomitant malaria, anemia, jaundice and hypoglycemia for NTS infection) may be used to distinguish invasive salmonellosis from other severe febrile illness.

Cited:

399

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Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K et al. 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial The Lancet, 376 (9753), pp. 1647-1657. | Show Abstract | Read more

Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children ( < 15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054. 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5) patients assigned to artesunate treatment died compared with 297 (10·9) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95 CI 0·63-0·90; relative reduction 22·5, 95 CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5] with artesunate vs 91/1768 [5·1] with quinine; OR 0·69 95 CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3] vs 273/2713 [10·1]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1] vs 208/2713 [7·7]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8] vs 75/2713 [2·8]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects. Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide. The Wellcome Trust. © 2010 Elsevier Ltd.

Zafar A, Hasan R, Nizami SQ, von Seidlein L, Soofi S, Ahsan T, Chandio S, Habib A, Bhutto N, Siddiqui FJ et al. 2009. Frequency of isolation of various subtypes and antimicrobial resistance of Shigella from urban slums of Karachi, Pakistan. Int J Infect Dis, 13 (6), pp. 668-672. | Show Abstract | Read more

OBJECTIVES: Shigellosis remains a major public health problem in developing countries. Antimicrobial resistance has complicated the empirical treatment. Knowledge of serotypes is crucial in vaccine development, as cross-protection between various serotypes is limited. Therefore we conducted a prospective study to determine the frequency of isolation of Shigella serotypes and antimicrobial resistance. METHODS: Stool samples from 8155 individuals, collected through a surveillance study conducted in four slums of Karachi from January 2002 to March 2004, were cultured. RESULTS: Shigella was isolated in 394 (4.8%) of 8155 patients presenting with diarrhea. Two hundred and forty-two (62%) isolates were Shigella flexneri, 72 (18%) were Shigella sonnei, 43 (11%) were Shigella boydii, and 37 (9%) were Shigella dysenteriae. Thirteen S. flexneri serotypes were identified, of which the most frequent were 2a (38), 6 (37), and 1b (25), followed by 2b (23). Only 22 (5.6%) Shigella isolates were found to be pan-susceptible. Large proportions of isolates were resistant to co-trimoxazole (89% S. flexneri, 81% S. dysenteriae, 80% S. sonnei, and 56% S. boydii) and ampicillin (87% S. flexneri, 68% S. dysenteriae, 35% S. boydii, and 4% S. sonnei). CONCLUSIONS: Concurrent circulation of multiple strains with high resistance is worrying and mandates surveillance at the national level to facilitate the control of shigellosis.

Lofgren SM, Morrissey AB, Chevallier CC, Malabeja AI, Edmonds S, Amos B, Sifuna DJ, von Seidlein L, Schimana W, Stevens WS et al. 2009. Evaluation of a dried blood spot HIV-1 RNA program for early infant diagnosis and viral load monitoring at rural and remote healthcare facilities. AIDS, 23 (18), pp. 2459-2466. | Show Abstract | Read more

OBJECTIVE: To assess technical and operational performance of a dried blood spot (DBS)-based HIV-1 RNA service for remote healthcare facilities in a low-income country. DESIGN: A method comparison and operational evaluation of DBS RNA against conventional tests for early infant diagnosis of HIV and HIV RNA quantitation under field conditions in Tanzania. METHODS: DBSs were prepared and plasma was frozen at -80 degrees C. DBSs were mailed and plasma couriered to a central laboratory for testing using the Abbott m2000 system. Infant diagnosis DBSs were also tested for HIV-1 DNA by ROCHE COBAS AmpliPrep/COBAS TaqMan System. Results of DBS RNA were compared with conventional tests; program performance was described. RESULTS: Among 176 infant diagnosis participants, using a threshold of at least 1000 copies/ml, sensitivity and specificity of DBS versus plasma RNA were 1.00 and 0.99, and of DBS RNA versus DBS DNA were 0.97 and 1.00. Among 137 viral load monitoring participants, when plasma and DBS RNA were compared, r value was 0.9709; r value was 0.9675 for at least 5000 copies/ml but was 0.7301 for less than 5000 copies/ml. The highest plasma RNA value at which DBS RNA was not detected was 2084 copies/ml. Median (range) turnaround time from sample collection to result receipt at sites was 23 (4-69) days. The Tanzania mail service successfully transmitted all DBS and results between sites and the central laboratory. CONCLUSION: Under program conditions in Tanzania, DBS provided HIV-1 RNA results comparable to conventional methods to remote healthcare facilities. DBS RNA testing is an alternative to liquid plasma for HIV-1 RNA services in remote areas.

Wang X-Y, Riewpaiboon A, von Seidlein L, Chen X-B, Kilgore PE, Ma J-C, Qi S-X, Zhang Z-Y, Hao Z-Y, Chen J-C, Xu Z-Y. 2009. Potential cost-effectiveness of a rotavirus immunization program in rural China. Clin Infect Dis, 49 (8), pp. 1202-1210. | Show Abstract | Read more

BACKGROUND: To assess the incidence and economic burden of rotavirus diarrhea and the potential cost-effectiveness of a rotavirus immunization program in rural Zhengding County in Hebei Province, China. METHODS: Population-based surveillance was conducted during the peak season for diarrhea among children who were <5 years of age in Zhengding County from 14 October 2004 through 19 January 2005. The cost of illness was measured from the perspectives of both patient and society. A decision-analytic model was applied to the cost-effectiveness analysis using real data derived from surveillance and from a cost-of-illness study. RESULTS: During the surveillance period, 500 episodes of diarrhea were registered. Of these 500 episodes, 125 (25%) occurred in patients who were positive for rotavirus. Of these 125 episodes, 63 (50%) occurred in patients who were hospitalized. The overall incidence rate of rotavirus infection was 61.4 cases per 1000 children per year during the 14-week epidemic season. For a Chinese cohort of 5000 newborns, a universal rotavirus immunization program would prevent 1764 cases of rotavirus diarrhea, averting 882 hospitalizations of patients <or=5 years of age. At 2004 prices, the net savings due to the immunization program would be US$14,112 from a societal perspective and US$34,751 from a patient perspective. CONCLUSION: Rotavirus was a leading cause of severe diarrhea among children <5 years of age and an economic burden for farmers in rural Zhengding County. Rotavirus vaccination should be considered as a potential cost-effective measure against rotavirus infection in China.

Reyburn H, Mtove G, Hendriksen I, von Seidlein L. 2009. Oral quinine for the treatment of uncomplicated malaria. BMJ, 339 (7715), pp. b2066. | Read more

Bejon P, Abdulla S, Lusingu J, Olotu A, Leach A, Lievens M, Tanner M, von Seidlein L. 2009. Response to "Poor control vaccines in two randomised trials of malaria vaccine?". Vaccine, 27 (35), pp. 4745-4746. | Read more

Bhattacharya S, Black R, Bourgeois L, Clemens J, Cravioto A, Deen JL, Dougan G, Glass R, Grais RF, Greco M et al. 2009. Public health. The cholera crisis in Africa. Science (New York, N.Y.), 324 (5929), pp. 885. | Read more

Bhattacharya S, Black R, Bourgeois L, Clemens J, Cravioto A, Deen JL, Dougan G, Glass R, Grais RF, Greco M et al. 2009. Public health. The cholera crisis in Africa. Science, 324 (5929), pp. 885. | Read more

Kernéis S, Guerin PJ, von Seidlein L, Legros D, Grais RF. 2009. A look back at an ongoing problem: Shigella dysenteriae type 1 epidemics in refugee settings in Central Africa (1993-1995) PLoS ONE, 4 (2), | Show Abstract | Read more

Background: Shigella dysenteriae type 1 (Sd1) is a cause of major dysentery outbreaks, particularly among children and displaced populations in tropical countries. Although outbreaks continue, the characteristics of such outbreaks have rarely been documented. Here, we describe the Sd1 outbreaks occurring between 1993 and 1995 in 11 refugee settlements in Rwanda, Tanzania and Democratic Republic of the Congo (DRC). We also explored the links between the different types of the camps and the magnitude of the outbreaks. Methodology/Principal Findings: Number of cases of bloody diarrhea and deaths were collected on a weekly basis in 11 refugee camps, and analyzed retrospectively. Between November 1993 and February 1995, 181,921 cases of bloody diarrhea were reported. Attack rates ranged from 6.3% to 39.1% and case fatality ratios (CFRs) from 1.5% to 9.0% (available for 5 camps). The CFRs were higher in children under age 5. In Tanzania where the response was rapidly deployed, the mean attack rate was lower than in camps in the region of Goma without an immediate response (13.3% versus 32.1% respectively). Conclusions/Significance: This description, and the areas where data is missing, highlight both the importance of collecting data in future epidemics, difficulties in documenting outbreaks occurring in complex emergencies and most importantly, the need to assure that minimal requirements are met. © 2009 Kernéis et al.

Bejon P, Leach A, Von Seidlein L. 2009. The authors reply New England Journal of Medicine, 360 (12), pp. 1253-1254. | Read more

von Seidlein L, Deen JL. 2009. Pre-referral rectal artesunate in severe malaria. Lancet, 373 (9663), pp. 522-523. | Read more

Kernéis S, Guerin PJ, von Seidlein L, Legros D, Grais RF. 2009. A look back at an ongoing problem: Shigella dysenteriae type 1 epidemics in refugee settings in Central Africa (1993-1995). PLoS One, 4 (2), pp. e4494. | Show Abstract | Read more

BACKGROUND: Shigella dysenteriae type 1 (Sd1) is a cause of major dysentery outbreaks, particularly among children and displaced populations in tropical countries. Although outbreaks continue, the characteristics of such outbreaks have rarely been documented. Here, we describe the Sd1 outbreaks occurring between 1993 and 1995 in 11 refugee settlements in Rwanda, Tanzania and Democratic Republic of the Congo (DRC). We also explored the links between the different types of the camps and the magnitude of the outbreaks. METHODOLOGY/PRINCIPAL FINDINGS: Number of cases of bloody diarrhea and deaths were collected on a weekly basis in 11 refugee camps, and analyzed retrospectively. Between November 1993 and February 1995, 181,921 cases of bloody diarrhea were reported. Attack rates ranged from 6.3% to 39.1% and case fatality ratios (CFRs) from 1.5% to 9.0% (available for 5 camps). The CFRs were higher in children under age 5. In Tanzania where the response was rapidly deployed, the mean attack rate was lower than in camps in the region of Goma without an immediate response (13.3% versus 32.1% respectively). CONCLUSIONS/SIGNIFICANCE: This description, and the areas where data is missing, highlight both the importance of collecting data in future epidemics, difficulties in documenting outbreaks occurring in complex emergencies and most importantly, the need to assure that minimal requirements are met.

Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois M-C et al. 2008. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med, 359 (24), pp. 2521-2532. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS: We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS: A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P<0.001) on the basis of Cox regression. Overall, there were 38 episodes of clinical malaria among recipients of RTS,S/AS01E, as compared with 86 episodes among recipients of the rabies vaccine, with an adjusted rate of efficacy against all malarial episodes of 56% (95% CI, 31 to 72; P<0.001). All 894 children were included in the intention-to-treat analysis, which showed an unadjusted efficacy rate of 49% (95% CI, 26 to 65; P<0.001). There were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only due to a difference in the number of admissions directly attributable to malaria. CONCLUSIONS: RTS,S/AS01E shows promise as a candidate malaria vaccine. (ClinicalTrials.gov number, NCT00380393.)

Stepniewska K, Price RN, Sutherland CJ, Drakeley CJ, von Seidlein L, Nosten F, White NJ. 2008. Plasmodium falciparum gametocyte dynamics in areas of different malaria endemicity. Malar J, 7 (1), pp. 249. | Show Abstract | Read more

BACKGROUND: The aim of this study was to identify and compare factors associated with Plasmodium falciparum gametocyte carriage in three regions of differing malaria endemicity. METHODS: Retrospective data from Thailand, The Gambia and Tanzania were used. The data came from large prospective field-based clinical trials, which investigated gametocyte carriage after different anti-malarial drug treatments. RESULTS: Gametocytaemia was detected during the observation period in 12% of patients (931 out of 7548) in Thailand, 34% (683 out of 2020) in The Gambia, and 31% (430 out of 1400) in Tanzania (p < 0.001). Approximately one third (33%, 680/2044) of the patients with gametocytaemia during the observation period, already had patent gametocytaemia at enrolment (day 0 or day 1): 35% (318/931) in Thailand, 37% (250/683) in The Gambia, 26% (112/430) in Tanzania. Maximum gametocytaemia was usually observed on or before the seventh day after starting treatment (93% in Thailand, 70% in Tanzania and 78% in The Gambia). Lowest gametocyte carriage rates were observed following treatment with artemisinin derivatives, while sulphadoxine-pyrimethamine (SP) was associated with significantly greater development of gametocytaemia than other drug treatments (p < 0.001). The duration of gametocyte carriage was shorter in Thailand by 86% and Tanzania by 65% than in The Gambia. Gametocyte carriage was 27% longer among people presenting with anaemia, and was shorter in duration among patients who received artemisinin derivatives, by 27% in Thailand and by 71% in Tanzania and The Gambia. CONCLUSION: This study confirms the independent association of gametocytaemia with anaemia, and the significantly lower prevalence and duration of gametocyte carriage following treatment with an artemisinin derivative. The large differences in gametocyte carriage rates between regions with different levels of malaria transmission suggest that drug interventions to prevent transmission will have different effects in different places.

Dutta S, Deen JL, Sur D, Manna B, Kanungo S, Bhaduri B, Lopez AL, Von Seidlein L, Clemens JD, Bhattacharya SK. 2008. Increased utilization of treatment centre facilities during a dengue fever outbreak in Kolkata, India Dengue Bulletin, 32 pp. 162-166. | Show Abstract

An outbreak of febrile illness occurred in Kolkata (formerly Calcutta), India, which led to an increased utilization of treatment centre facilities during August - September 2005. The etiological agent was confirmed to be dengue by analysing 308 acute-phase clinical specimens for virus-specific IgM antibodies.

Kim DR, Ali M, Thiem VD, Park J-K, von Seidlein L, Clemens J. 2008. Geographic analysis of shigellosis in Vietnam. Health Place, 14 (4), pp. 755-767. | Show Abstract | Read more

Geographic and ecological analysis may provide investigators useful ecological information for the control of shigellosis. This paper provides distribution of individual Shigella species in space, and ecological covariates for shigellosis in Nha Trang, Vietnam. Data on shigellosis in neighborhoods were used to identify ecological covariates. A Bayesian hierarchical model was used to obtain joint posterior distribution of model parameters and to construct smoothed risk maps for shigellosis. Neighborhoods with a high proportion of worshippers of traditional religion, close proximity to hospital, or close proximity to the river had increased risk for shigellosis. The ecological covariates associated with Shigella flexneri differed from the covariates for Shigella sonnei. In contrast the spatial distribution of the two species was similar. The disease maps can help identify high-risk areas of shigellosis that can be targeted for interventions. This approach may be useful for the selection of populations and the analysis of vaccine trials.

Ansaruzzaman M, Chowdhury A, Bhuiyan NA, Sultana M, Safa A, Lucas M, von Seidlein L, Barreto A, Chaignat C-L, Sack DA et al. 2008. Characteristics of a pandemic clone of O3 : K6 and O4 : K68 Vibrio parahaemolyticus isolated in Beira, Mozambique. J Med Microbiol, 57 (Pt 12), pp. 1502-1507. | Show Abstract | Read more

The genetic characteristics of Vibrio parahaemolyticus strains isolated in 2004 and 2005 in Mozambique were assessed in this study to determine whether the pandemic clone of V. parahaemolyticus O3 : K6 and O4 : K68 serotypes has spread to Mozambique. Fifty-eight V. parahaemolyticus strains isolated from hospitalized diarrhoea patients in Beira, Mozambique, were serotyped for O : K antigens and genotyped for toxR, tdh and trh genes. A group-specific PCR, a PCR that detects the presence of ORF8 of the filamentous phage f237, arbitrarily primed PCR, PFGE and multilocus sequence typing were performed to determine the pandemic status of the strains and their ancestry. All strains of serovars O3 : K6 (n=38) and O4 : K68 (n=4) were identified as a pandemic clonal group by these analyses. These strains are closely related to the pandemic reference strains of O3 : K6 and O4 : K68, which emerged in Asia in 1996 and were later found globally. The pandemic serotypes O3 : K6 and O4 : K68 including reference strains grouped into a single cluster indicating emergence from a common ancestor. The O3 : K58 (n=8), O4 : K13 (n=6), O3 : KUT (n=1) and O8 : K41 (n=1) strains showed unique characteristics different from the pandemic clone.

Lusingu JPA, Von Seidlein L. 2008. Challenges in malaria control in sub-Saharan Africa: the vaccine perspective. Tanzan J Health Res, 10 (4), pp. 253-266. | Show Abstract

Malaria is a life-threatening disease of public health importance, especially in sub-Saharan Africa. It is estimated that about 500 million cases of malaria occur annually and among these 1 million die annually. Children below five years and pregnant women are the most vulnerable groups. Several malaria control measures have been applied such as environmental improvements, use of insecticide impregnated nets, residual indoor spraying, early case detection and treatment with effective antimalarial drugs. However, the adaptation of vector and parasite has so far limited the effect of these interventions. The emergence of resistance against drugs and insecticides requires in response a steady stream of new interventions. Up to the beginning of this millennium, most sub-Saharan African countries have been using chloroquine (CQ) as the first-line antimalarial drug, which had to be replaced with sulphadoxine-pyrimethamine (SP) after resistant parasites had rendered CQ ineffective. Currently the first line treatment of malaria consists of combination therapy which includes an artemisinin derivative. The current approach appears robust but history has taught us to be alert and to expect resistance to emerge. There is a pressing need to develop and deploy complimentary strategies. Adding a protective vaccine to the existing control tools for malaria holds great promise yet no malaria vaccine has ever been licensed despite a large number of attempts. The complexity of malaria parasites and the ability of the parasite to suppress and evade immune responses are formidable challenges. Fortunately, there are several promising antimalarial vaccine candidates in the development pipeline. The most promising vaccine candidate is RTSS which is currently tested in various countries in sub-Saharan Africa, including two sites in Tanzania. There is a hope that malaria vaccines could be developed and deployed in malaria endemic communities. This article highlights the challenges of developing and deploying malaria vaccines.

Deen JL, von Seidlein L, Dondorp A. 2008. Therapy of uncomplicated malaria in children: a review of treatment principles, essential drugs and current recommendations. Trop Med Int Health, 13 (9), pp. 1111-1130. | Show Abstract | Read more

Understanding the optimal treatment of uncomplicated malaria in children is challenging because of the availability of new drugs and the shift to combination therapies. This is a review of the guiding principles for the treatment of uncomplicated malaria, the essential anti-malarial drugs for children, and the treatment regimens currently recommended.

Mahalanabis D, Lopez AL, Sur D, Deen J, Manna B, Kanungo S, von Seidlein L, Carbis R, Han SH, Shin SH et al. 2008. A randomized, placebo-controlled trial of the bivalent killed, whole-cell, oral cholera vaccine in adults and children in a cholera endemic area in Kolkata, India. PLoS One, 3 (6), pp. e2323. | Show Abstract | Read more

OBJECTIVES: An effective vaccine against cholera has been used for public health purposes in Vietnam since the 1990s. This vaccine was reformulated to meet WHO requirements. We assessed the safety and immunogenicity of the reformulated bivalent (Vibrio cholerae 01 and 0139) killed whole cell oral vaccine in a cholera endemic area in Kolkata, India. DESIGN: Double-blind, randomized, placebo controlled trial. SETTING: The trial was conducted in the clinical trial ward of the Infectious Diseases Hospital in Kolkata, India. PARTICIPANTS: The participants were 101 healthy adults (males and non-pregnant females) aged 18-40 years and 100 healthy children (males and non-pregnant females) aged 1-17 years. INTERVENTIONS: Participants were randomized to receive either the bivalent killed whole cell oral cholera vaccine or placebo (killed oral Escherichia coli K12). OUTCOME MEASURES: For safety: proportion of subjects with adverse events during the duration of study participation. For immunogenicity: Proportion of subjects who had a > or = 4-fold rise in serum vibriocidal antibody titers 14 days after the second dose of vaccine or placebo. RESULTS: Adverse reactions were observed with similar frequency among vaccine and placebo recipients in both age groups. Among adults 4% of vaccine and 8% of placebo recipients and among children 4% of vaccine and 2% of placebo recipients had at least one adverse event within 28 days of the first dose of the vaccine. Following immunization, 53% of adult and 80% of children vaccinees showed a > or = 4 fold rise in serum V. cholerae O1 vibriocidal antibody titers. A less pronounced response to V. cholerae O139 vibriocidal antibody titers post-immunization was noted among vaccinees. CONCLUSIONS: We found the vaccine to be safe and immunogenic in a cholera-endemic area in India. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119197.

Guh S, Xingbao C, Poulos C, Qi Z, Jianwen C, von Seidlein L, Jichao C, Wang X, Zhanchun X, Nyamete A et al. 2008. Comparison of cost-of-illness with willingness-to-pay estimates to avoid shigellosis: evidence from China. Health Policy Plan, 23 (2), pp. 125-136. | Show Abstract | Read more

Previous studies have shown that cost of illness (COI) measures are lower than the conceptually correct willingness-to-pay (WTP) measure of the economic benefits of disease prevention. We compare COI with stated preference estimates of WTP associated with shigellosis in a rural area of China. COI data were collected through face-to-face interviews at 7 and 14 days after culture-confirmed diagnosis. WTP to avoid an episode similar to the one the respondent just experienced was elicited using a sliding-scale payment card. In contrast to previous studies' findings, average COI estimates (2002 PPP adjusted US dollars 28.2) approximate an upper bound estimate of WTP, rather than a lower bound. One explanation for the similarity between COI and WTP is that preventive expenditures and disutility due to pain and suffering are low for shigellosis. WTP to avoid additional cases in children aged 0-5 years is higher than in adults. Also, average COI (2002 PPP adjusted US dollars 28.4) for children is similar to a lower bound estimate of WTP (2002 PPP adjusted US dollars 16.4) and lies within the WTP range. Because the monetary loss associated with another episode in children is small, caregivers' higher WTP may be attributable to the disutility of illness due to the children's pain and suffering. These findings suggest that for some diseases, COI may approximate more comprehensive measures of economic benefits.

Deen JL, von Seidlein L, Sur D, Agtini M, Lucas MES, Lopez AL, Kim DR, Ali M, Clemens JD. 2008. The high burden of cholera in children: comparison of incidence from endemic areas in Asia and Africa. PLoS Negl Trop Dis, 2 (2), pp. e173. | Show Abstract | Read more

BACKGROUND: Cholera remains an important public health problem. Yet there are few reliable population-based estimates of laboratory-confirmed cholera incidence in endemic areas around the world. METHODS: We established treatment facility-based cholera surveillance in three sites in Jakarta (Indonesia), Kolkata (India), and Beira (Mozambique). The annual incidence of cholera was estimated using the population census as the denominator and the age-specific number of cholera cases among the study cohort as the numerator. FINDINGS: The lowest overall rate was found in Jakarta, where the estimated incidence was 0.5/1000 population/year. The incidence was three times higher in Kolkata (1.6/1000/year) and eight times higher in Beira (4.0/1000/year). In all study sites, the greatest burden was in children under 5 years of age. CONCLUSION: There are considerable differences in cholera incidence across these endemic areas but in all sites, children are the most affected. The study site in Africa had the highest cholera incidence consistent with a growing impression of the large cholera burden in Africa. Burden estimates are useful when considering where and among whom interventions such as vaccination would be most needed.

von Seidlein L, Wang X-Y, Macuamule A, Mondlane C, Puri M, Hendriksen I, Deen JL, Chaignat C-L, Clemens JD, Ansaruzzaman M et al. 2008. Is HIV infection associated with an increased risk for cholera? Findings from a case-control study in Mozambique. Trop Med Int Health, 13 (5), pp. 683-688. | Show Abstract | Read more

OBJECTIVE: As residents of sub-Saharan Africa are at high risk for HIV and cholera, it is biologically plausible that immune suppression caused by HIV infection predisposes to cholera. Our aim was to assess the potential association between both diseases. METHODS: We conducted a case-control study in Beira, Mozambique, a high-risk area for HIV and cholera. Between 1 January 2005 and 30 June 2006, experienced counsellors invited 132 suspected cholera cases and 528 age- and sex-matched controls to an HIV counselling and testing centre. RESULTS: Forty (30%) of the invited cases and 127 (24%) of the invited controls came for HIV testing. No significant differences in demographic and socio-economic baseline characteristics were detected between participants and non-participants. Twenty five of 167 (15%) individuals who underwent testing were found HIV-positive. The probability of a positive HIV-test was highest in participants between 40 and 49 years; 6 of 14 (43%) tested HIV-positive. Nine of 40 (23%) cholera cases were found to be HIV-infected compared with 16 of 127 (13%) controls (adjusted odds ratio 2.6; 95% CI 0.9-7.5; P = 0.08). DISCUSSION: The findings suggest that in a cholera-endemic area, HIV infection is associated with an increased risk for cholera. More research in HIV endemic settings is needed to confirm the findings and to explore the effect of HIV-related immunosuppression on the transmission of cholera.

Gosling RD, Ghani AC, Deen JL, von Seidlein L, Greenwood BM, Chandramohan D. 2008. Can changes in malaria transmission intensity explain prolonged protection and contribute to high protective efficacy of intermittent preventive treatment for malaria in infants? Malar J, 7 (1), pp. 54. | Show Abstract | Read more

BACKGROUND: Intermittent preventive (or presumptive) treatment of infants (IPTi), the administration of a curative anti-malarial dose to infants whether or not they are known to be infected, is being considered as a new strategy for malaria control. Five of the six trials using sulphadoxine-pyrimethamine (SP) for IPTi showed protective efficacies (PEs) against clinical malaria ranging from 20.1 - 33.3% whilst one, the Ifakara study, showed a protective efficacy of 58.6%. MATERIALS AND METHODS: The possible mechanisms that could explain the differences in the reported PE of IPTi were examined by comparing output from a mathematical model to data from the six published IPTi trials. RESULTS: Under stable transmission, the PE of IPTi predicted by the model was comparable with the observed PEs in all but the Ifakara study (ratio of the mean predicted PE to that observed was 1.02, range 0.39 - 1.59). When a reduction in the incidence of infection during the study was included in the model, the predicted PE of IPTi increased and extended into the second year of life, as observed in the Ifakara study. CONCLUSION: A decrease in malaria transmission during the study period may explain part of the difference in observed PEs of IPTi between sites and the extended period of protection into the second year of life observed in the Ifakara study. This finding of continued benefit of interventions in settings of decreasing transmission may explain why rebound of clinical malaria was absent in the large scale trials of insecticide-treated bed nets.

Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya SK, Agtini MD, Bhutta ZA, Canh DG, Ali M, Shin S et al. 2008. A study of typhoid fever in five Asian countries: disease burden and implications for controls. Bull World Health Organ, 86 (4), pp. 260-268. | Show Abstract | Read more

OBJECTIVE: To inform policy-makers about introduction of preventive interventions against typhoid, including vaccination. METHODS: A population-based prospective surveillance design was used. Study sites where typhoid was considered a problem by local authorities were established in China, India, Indonesia, Pakistan and Viet Nam. Standardized clinical, laboratory, and surveillance methods were used to investigate cases of fever of >or= 3 days' duration for a one-year period. A total of 441,435 persons were under surveillance, 159,856 of whom were aged 5-15 years. FINDINGS: A total of 21,874 episodes of fever were detected. Salmonella typhi was isolated from 475 (2%) blood cultures, 57% (273/475) of which were from 5-15 year-olds. The annual typhoid incidence (per 100,000 person years) among this age group varied from 24.2 and 29.3 in sites in Viet Nam and China, respectively, to 180.3 in the site in Indonesia; and to 412.9 and 493.5 in sites in Pakistan and India, respectively. Altogether, 23% (96/413) of isolates were multidrug resistant (chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole). CONCLUSION: The incidence of typhoid varied substantially between sites, being high in India and Pakistan, intermediate in Indonesia, and low in China and Viet Nam. These findings highlight the considerable, but geographically heterogeneous, burden of typhoid fever in endemic areas of Asia, and underscore the importance of evidence on disease burden in making policy decisions about interventions to control this disease.

Chau TT, Campbell JI, Galindo CM, Van Minh Hoang N, Diep TS, Nga TTT, Van Vinh Chau N, Tuan PQ, Page AL, Ochiai RL et al. 2007. Antimicrobial drug resistance of Salmonella enterica serovar typhi in asia and molecular mechanism of reduced susceptibility to the fluoroquinolones. Antimicrob Agents Chemother, 51 (12), pp. 4315-4323. | Show Abstract | Read more

This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the world's typhoid fever cases. These results document the scale of drug resistance across Asia. The Ser83-->Phe substitution in GyrA was the predominant alteration in serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB, parC, or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring a single-amino-acid substitution at codon 83 or 87 of GyrA; this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of serovar Typhi harboring both the single- and double-amino-acid substitutions.

Chen X, Stanton B, Pach A, Nyamete A, Ochiai RL, Kaljee L, Dong B, Sur D, Bhattacharya SK, Santoso SS et al. 2007. Adults' perceived prevalence of enteric fever predicts laboratory-validated incidence of typhoid fever in children. J Health Popul Nutr, 25 (4), pp. 469-478. | Show Abstract

This study was undertaken to develop a model to predict the incidence of typhoid in children based on adults' perception of prevalence of enteric fever in the wider community. Typhoid cases among children, aged 5-15 years, from epidemic regions in five Asian countries were confirmed with a positive Salmonella Typhi culture of the blood sample. Estimates of the prevalence of enteric fever were obtained from random samples of adults in the same study sites. Regression models were used for establishing the prediction equation. The percentages of enteric fever reported by adults and cases of typhoid incidence per 100,000, detected through blood culture were 4.7 and 24.18 for Viet Nam, 3.8 and 29.20 for China, 26.3 and 180.33 for Indonesia, 66.0 and 454.15 for India, and 52.7 and 407.18 for Pakistan respectively. An established prediction equation was: incidence of typhoid (1/100,000= -2.6946 + 7.2296 x reported prevalence of enteric fever (%) (F=31.7, p<0.01; R2=0.992). Using adults' perception of prevalence of disease as the basis for estimating its incidence in children provides a cost-effective behavioural epidemiologic method to facilitate prevention and control of the disease.

Thiem VD, Canh DG, Anh DD, Deen JL, von Seidlein L, Clemens JD, Holmgren J. 2007. Response to "questionable merits of the field trial of an oral killed whole cell cholera vaccine in Vietnam during 1998-2003" Vaccine 2007;25(8):1353-4. Vaccine, 25 (47), pp. 7981-7983. | Read more

von Seidlein L. 2007. Vaccines for cholera control: does herd immunity play a role. PLoS Med, 4 (11), pp. e331. | Read more

Zhou W-Z, Koo H-W, Wang X-Y, Zhang J, Park J-K, Zhu F, Deen J, Acosta CJ, Chen Y, Wang H et al. 2007. Revaccination with locally-produced vi typhoid polysaccharide vaccine among chinese school-aged children: safety and immunogenicity findings. Pediatr Infect Dis J, 26 (11), pp. 1001-1005. | Show Abstract | Read more

OBJECTIVE: To evaluate the safety and immunogenicity of revaccination with locally-produced Vi polysaccharide vaccine 3 years after the first dose in Chinese children aged 9 to 14 years. METHODS: A randomized, placebo-controlled trial was conducted in Suzhou, Jiangsu, China. Six hundred and sixty-seven eligible children who had previously received a primary dose of Vi vaccine were randomly assigned to receive 1 dose of 30 mug Vi vaccine or placebo. In addition, 331 eligible children received 1 dose of Vi polysaccharide vaccine as a primary vaccination. Adverse events were followed for 28 days after vaccination. Serum samples were collected from a subgroup of participants on day 0 and day 28, and Vi antibodies were analyzed using a passive hemagglutination method. RESULTS: Revaccination was found to be safe and immunogenic. No severe adverse events were observed. A significant increase in antibody titers after vaccination was observed among children who had and had not been previously vaccinated. Twenty-eight days after injection, the seropositive rate was 79% in both revaccination and primary injection groups; the geometric mean antibody titer was 1:40 in the primary injection group and 1:29 in the revaccination group (P = 0.24). Although the difference of attained geometric mean titers in follow-up sera was not significantly different in these 2 groups, the fold-rise of these titers from baseline was significantly higher in the primary injection group than in the revaccination group (7.7 versus 3.1, P < 0.001). CONCLUSION: We found that revaccination using the locally produced Vi polysaccharide vaccine among Chinese school-aged children was safe and increased antibody titers. Revaccination can be used to extend the duration of protection provided by Vi polysaccharide vaccine.

Choi SY, Jeon Y-S, Lee JH, Choi B, Moon SH, von Seidlein L, Clemens JD, Dougan G, Wain J, Yu J et al. 2007. Multilocus sequence typing analysis of Shigella flexneri isolates collected in Asian countries. J Med Microbiol, 56 (Pt 11), pp. 1460-1466. | Show Abstract | Read more

The multilocus sequence typing scheme used previously for phylogenetic analysis of Escherichia coli was applied to 107 clinical isolates of Shigella flexneri. DNA sequencing of 3423 bp throughout seven housekeeping genes identified eight new allele types and ten new sequence types among the isolates. S. flexneri serotypes 1-5, X and Y were clustered together in a group containing many allelic variants while serotype 6 formed a distinct group, as previously established.

Ansaruzzaman M, Bhuiyan NA, Safa A, Sultana M, McUamule A, Mondlane C, Wang X-Y, Deen JL, von Seidlein L, Clemens JD et al. 2007. Genetic diversity of El Tor strains of Vibrio cholerae O1 with hybrid traits isolated from Bangladesh and Mozambique. Int J Med Microbiol, 297 (6), pp. 443-449. | Show Abstract | Read more

Vibrio cholerae O1 strains that are hybrids between the classical and El Tor biotypes were isolated during two consecutive years (2004-2005) from diarrheal patients in Mozambique. Similar variants isolated in Bangladesh and recently isolated El Tor strains were analyzed for genetic diversity. Pulsed-field gel electrophoresis (PFGE) analysis using the restriction enzyme NotI, resulted in 18-21 bands showed five closely related PFGE patterns that were distributed similarly in both years (2004-2005) among the 80 strains tested in Mozambique. Overall based on the PFGE patterns the hybrids indicated an El Tor lineage. The restriction patterns of whole-chromosomal DNA grouped the hybrid strains from Mozambique into a separate cluster from Bangladeshi clinical and environmental hybrid strains. A high molecular weight band of 398kb that contain rstR allele of the classical type was detected from all hybrid strains, which was absent in all conventional classical and El Tor strains. This band could be designated as a marker for the hybrid strains. This study suggests that hybrid strains from Mozambique are closely related to each other, different from Bangladeshi hybrid strains that are diverse in nature and all hybrid strains differed markedly from conventional classical and El Tor strains.

Ochiai RL, Acosta CJ, Agtini M, Bhattacharya SK, Bhutta ZA, Do CG, Dong B, Chen X, Stanton B, Kaljee L et al. 2007. The use of typhoid vaccines in Asia: the DOMI experience. Clin Infect Dis, 45 Suppl 1 (Supplement_1), pp. S34-S38. | Show Abstract | Read more

BACKGROUND: Two currently licensed typhoid vaccines have been evaluated in Asia, yet few Asian countries have considered including typhoid vaccines in their vaccination programs. The Diseases of the Most Impoverished (DOMI) Program was initiated to provide evidence to decide on the introduction of typhoid vaccines in Asian countries. METHODS: The centerpiece of the program is a multidisciplinary demonstration project with Vi vaccine in 5 Asian countries. The project includes epidemiologic, economic, sociobehavioral, and policy studies. RESULTS: Policy makers want evidence on which to base their vaccine-related decisions. The DOMI Program has provided updated information on the typhoid fever burden at several Asian sites. Cost-of-illness studies found high costs to governments and individuals. Sociobehavioral studies indicated a positive attitude toward typhoid vaccines. The results of the demonstration projects indicate that mass-immunization campaigns are feasible and acceptable. CONCLUSIONS: The DOMI Program has begun to provide momentum for the evidence-based, rational introduction of typhoid vaccines into the public health programs of several Asian countries.

Lucas MES, Jeuland M, Deen J, Lazaro N, MacMahon M, Nyamete A, Barreto A, von Seidlein L, Cumbane A, Songane FF, Whittington D. 2007. Private demand for cholera vaccines in Beira, Mozambique. Vaccine, 25 (14), pp. 2599-2609. | Show Abstract | Read more

In the summer of 2005, we interviewed 996 randomly selected respondents in Beira, Mozambique concerning their willingness and ability to pay for cholera vaccine for themselves and for other household members. Respondents were told that two doses of the vaccine would be required 2 weeks apart, and that the cholera vaccine would offer excellent protection against infection for the first year following vaccination, and some protection during the second and third year after a person is vaccinated. This research was carried out in order to learn more about private demand for vaccines in a cholera-endemic area. We asked two types of valuation questions: (1) a discrete-price offer for a vaccine that could be purchased for household members and (2) a payment card designed to assess uncertainty in the respondent's demand for a vaccine for self-protection. We estimate average household willingness to pay (WTP) for cholera vaccines in Beira to be 2005 US$ 8.45. This estimate of household WTP represents the perceived private economic benefits to a household--six persons on average--of giving all members free cholera vaccines.

Anh DD, Canh DG, Lopez AL, Thiem VD, Long PT, Son NH, Deen J, von Seidlein L, Carbis R, Han SH et al. 2007. Safety and immunogenicity of a reformulated Vietnamese bivalent killed, whole-cell, oral cholera vaccine in adults. Vaccine, 25 (6), pp. 1149-1155. | Show Abstract | Read more

Vietnam currently produces an orally administered, bivalent (O1 and O139) killed whole-cell vaccine and is the only country in the world with endemic cholera to use an oral cholera vaccine in public health practice. In order to allow international use, the vaccine had to be reformulated to meet World Health Organization (WHO) requirements. We performed a randomized, placebo controlled, safety and immunogenicity studies of this reformulated vaccine among Vietnamese adults. One hundred and forty-four subjects received the two-dose regimen and 143 had two blood samples obtained for analysis. We found that this reformulated oral killed whole-cell cholera vaccine was safe, well tolerated and highly immunogenic.

Wang X-Y, Xu Z-Y, Ma J-C, von Seidlein L, Zhang Y, Hao Z-Y, Han OP, Zhang Y-L, Tian M-Y, Ouyang P-Y et al. 2007. Long-term immunogenicity after single and booster dose of a live attenuated hepatitis A vaccine: results from 8-year follow-up. Vaccine, 25 (3), pp. 446-449. | Show Abstract | Read more

Live, attenuated hepatitis A vaccines are used widely in China but there is uncertainty regarding the persistence of vaccine-induced anti-HAV antibodies after single dose and booster dose administrated at month 12. A large scale clinical trial to evaluate the live, attenuated hepatitis A vaccine was conducted in Hebei province between 1996 and 1999. Five years after the trials, children in single dose and booster dose groups were bled and followed. Seventy two percent (61/85) of children who received a single trial dose had detectable anti-HAV antibodies for 96 months (GMC at 96 months: 89.0 mIU/mL). In the booster group 98% (48/49) children remained anti-HAV positive with GMC of 262.8 mIU/mL at month 96. The reinjection with live attenuated HAV vaccine can elicit a booster effect. Results from single dose group seems not to support the need for booster doses of live attenuated hepatitis A vaccine in immunocompetent individuals regarding the persisting anti-HAV and anamnestic response of a single dose vaccine. Continued monitoring of anti-HAV antibodies is needed for a rational hepatitis A immunization strategy in China.

SonLa Study Group. 2007. Using a fingerprint recognition system in a vaccine trial to avoid misclassification. Bull World Health Organ, 85 (1), pp. 64-67. | Show Abstract | Read more

PROBLEM: The potential for misidentification of trial participants, leading to misclassification, is a threat to the integrity of randomized controlled trials. The correct identification of study subjects in large trials over prolonged periods is of vital importance to those conducting clinical trials. Currently used means of identifying study participants, such as identity cards and records of name, address, name of household head and demographic characteristics, require large numbers of well-trained personnel, and still leave room for uncertainty. APPROACH: We used fingerprint recognition technology for the identification of trial participants. This technology is already widely used in security and commercial contexts but not so far in clinical trials. LOCAL SETTING: A phase 2 cholera vaccine trial in SonLa, Viet Nam. RELEVANT CHANGES: An optical sensor was used to scan fingerprints. The fingerprint template of each participant was used to verify his or her identity during each of eight follow-up visits. LESSONS LEARNED: A system consisting of a laptop computer and sensor is small in size, requires minimal training and on average six seconds for scanning and recognition. All participants' identities were verified in the trial. Fingerprint recognition should become the standard technology for identification of participants in field trials. Fears exist, however, regarding the potential for invasion of privacy. It will therefore be necessary to convince not only trial participants but also investigators that templates of fingerprints stored in databases are less likely to be subject to abuse than currently used information databases.

Agtini MD, Soeharno R, Lesmana M, Punjabi NH, Simanjuntak C, Wangsasaputra F, Nurdin D, Pulungsih SP, Rofiq A, Santoso H et al. 2007. Erratum To: The burden of diarrhoea, shigellosis, and cholera in North Jakarta, Indonesia: findings from 24 months surveillance BMC Infectious Diseases, 7 (1), | Read more

Sur D, Ali M, von Seidlein L, Manna B, Deen JL, Acosta CJ, Clemens JD, Bhattacharya SK. 2007. Comparisons of predictors for typhoid and paratyphoid fever in Kolkata, India. BMC Public Health, 7 (1), pp. 289. | Show Abstract | Read more

BACKGROUND: Exposure of the individual to contaminated food or water correlates closely with the risk for enteric fever. Since public health interventions such as water improvement or vaccination campaigns are implemented for groups of individuals we were interested whether risk factors not only for the individual but for households, neighbourhoods and larger areas can be recognised? METHODS: We conducted a large enteric fever surveillance study and analyzed factors which correlate with enteric fever on an individual level and factors associated with high and low risk areas with enteric fever incidence. Individual level data were linked to a population based geographic information systems. Individual and household level variables were fitted in Generalized Estimating Equations (GEE) with the logit link function to take into account the likelihood that household factors correlated within household members. RESULTS: Over a 12-month period 80 typhoid fever cases and 47 paratyphoid fever cases were detected among 56,946 residents in two bustees (slums) of Kolkata, India. The incidence of paratyphoid fever was lower (0.8/1000/year), and the mean age of paratyphoid patients was older (17.1 years) than for typhoid fever (incidence 1.4/1000/year, mean age 14.7 years). Residents in areas with a high risk for typhoid fever had lower literacy rates and economic status, bigger household size, and resided closer to waterbodies and study treatment centers than residents in low risk areas. CONCLUSION: There was a close correlation between the characteristics detected based on individual cases and characteristics associated with high incidence areas. Because the comparison of risk factors of populations living in high versus low risk areas is statistically very powerful this methodology holds promise to detect risk factors associated with diseases using geographic information systems.

Han KH, Choi SY, Lee JH, Lee H, Shin EH, Agtini MD, von Seidlein L, Ochiai RL, Clemens JD, Wain J et al. 2006. Isolation of Salmonella enterica subspecies enterica serovar Paratyphi B dT+, or Salmonella Java, from Indonesia and alteration of the d-tartrate fermentation phenotype by disrupting the ORF STM 3356. J Med Microbiol, 55 (Pt 12), pp. 1661-1665. | Show Abstract | Read more

Salmonella enterica subspecies enterica serovar Paratyphi B [O1,4,(5),12 : Hb : 1,2] can cause either an enteric fever (paratyphoid fever) or self-limiting gastroenteritis in humans. The d-tartrate non-fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT- (S. Paratyphi B) is the causative agent of paratyphoid fever, and the d-tartrate fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT+ (S. Paratyphi B dT+; formerly called Salmonella Java) causes gastroenteritis. S. Java is currently recognized as an emerging problem worldwide. Twelve dT+ S. Java isolates were collected in Indonesia between 2000 and 2002. One-third of them contained Salmonella genomic island 1 (SGI1), which gives the multidrug-resistant phenotype to the bacteria. In this study, a PCR-based method to detect a single nucleotide difference responsible for the inability to ferment d-tartrate, reported elsewhere, was validated. The d-tartrate fermenting phenotype of S. Java was converted to the non-fermenting phenotype by the disruption of the ORF STM 3356, and the d-tartrate non-fermenting phenotype of the ORF STM 3356-disrupted strain and the dT- reference strain was changed to the dT+ phenotype by complementing ORF STM 3356 in trans. The results show that the dT+ phenotype requires a functional product encoded by STM 3356, and support the use of the PCR-based discrimination method for S. Paratyphi B and S. Java as the standard differentiation method.

von Seidlein L. 2006. Editorial: A small step for WHO, a big step for cholera control. Trop Med Int Health, 11 (12), pp. 1773-1774. | Read more

Ricci KA, Girosi F, Tarr PI, Lim Y-W, Mason C, Miller M, Hughes J, von Seidlein L, Agosti JM, Guerrant RL. 2006. Reducing stunting among children: the potential contribution of diagnostics. Nature, 444 Suppl 1 pp. 29-38. | Read more

Chompook P, Todd J, Wheeler JG, von Seidlein L, Clemens J, Chaicumpa W. 2006. Risk factors for shigellosis in Thailand. Int J Infect Dis, 10 (6), pp. 425-433. | Show Abstract | Read more

OBJECTIVES: To assess the potential risk factors for shigellosis including housefly density. METHODS: A matched case-control study to investigate potential risk factors for shigellosis was conducted in a semi-urban area, Kaengkhoi District, Saraburi Province, central Thailand. Shigella cases were ascertained from a two-year population-based surveillance study detecting diarrhea and shigellosis in the area. The study evaluated a wide range of exposures, which were assessed by odds ratios (OR) adjusted for proxy markers of socioeconomic status: family income, and type of residence, using conditional logistic regression analysis. RESULTS: Hygiene behaviors such as regular hand washing (p<0.05), a clean environment surrounding the household (p<0.001), and the availability of water to flush the toilet (p=0.08) were associated with a reduced risk for shigellosis in the multivariate model. In contrast factors indicating a lower than average socioeconomic status, such as having to rent instead of owning one's housing (p<0.001) and a low family income (p<0.01) were associated with an increased risk for shigellosis. For children, breastfeeding showed a strong protective effect in reducing the risk of shigellosis (p<0.01). Prior to adjustment for environmental factors, fly density in the kitchen area was associated with an increased risk of shigellosis (p<0.01). CONCLUSIONS: We found a correlation between socioeconomic status and the risk for shigellosis. To reduce shigellosis in this setting, we recommend interventions focused on three aspects: improved water supply and sanitation (especially latrines and garbage disposal) including fly control, health education on hand washing, and the promotion of breastfeeding.

Na-Ubol M, Samosornsuk S, Von Seidlein L, Tapchaisri P, Ali M, Clemens JD, Chaicumpa W. 2006. Molecular characteristics of Shigella spp. isolated from patients with diarrhoea in a new industrialized area of Thailand. Epidemiol Infect, 134 (5), pp. 997-1003. | Show Abstract | Read more

In this study, we used plasmid profile analysis, XbaI macrorestriction with pulsed-field gel electrophoresis (PFGE), and PCR of the ipaH gene, to study the molecular characteristics of 183 Shigella spp. isolated during May 2000 to April 2003 from rectal swabs of patients with watery and/or bloody diarrhoea in a new industrialized area of Thailand. Among the 183 isolates, 167 were S. sonnei and 16 were S. flexneri. For plasmid profile analysis, the 183 isolates revealed 16 different plasmid patterns, designated patterns A to P. The sizes of the plasmid bands were: 6, 5.5, 5, 4.5, 4, 3.25, 2.75, 2.5, 2, 1.75, 1.5 and/or 1.25 kb. The frequency of each plasmid band was 4.5 kb (165 isolates), 3.25 kb (161 isolates), 5.5 kb (129 isolates), 1.75 kb (121 isolates), 1.5 kb (35 isolates), 5 kb (21 isolates), 2 kb (16 isolates), 2.75 kb (12 isolates), 1.25 kb (9 isolates), and 6 kb (8 isolates). PFGE analysis revealed 45 different XbaI macrorestricted DNA banding patterns which could be grouped into 11 groups. All the isolates gave PCR amplicons of the ipaH gene. Plasmid profile analysis and PFGE are powerful tools for differentiation of the Shigella spp. This study provides important data on the molecular characteristics of Shigella isolates in Thailand, which could be useful as an epidemiological baseline for identifying relationships with strains that may emerge in the future.

Cavailler P, Lucas M, Perroud V, McChesney M, Ampuero S, Guérin PJ, Legros D, Nierle T, Mahoudeau C, Lab B et al. 2006. Feasibility of a mass vaccination campaign using a two-dose oral cholera vaccine in an urban cholera-endemic setting in Mozambique. Vaccine, 24 (22), pp. 4890-4895. | Show Abstract | Read more

We conducted a study to assess the feasibility and the potential vaccine coverage of a mass vaccination campaign using a two-dose oral cholera vaccine in an urban endemic neighbourhood of Beira, Mozambique. The campaign was conducted from December 2003 to January 2004. Overall 98,152 doses were administered, and vaccine coverage of the target population was 58.6% and 53.6% for the first and second rounds, respectively. The direct cost of the campaign, which excludes the price of the vaccine, amounted to slightly over 90,000 dollars, resulting in the cost per fully vaccinated person of 2.09 dollars, which is relatively high. However, in endemic settings where outbreaks are likely to occur, integrating cholera vaccination into the routine activities of the public health system could reduce such costs.

Khan MI, Ochiai RL, Hamza HB, Sahito SM, Habib MA, Soofi SB, Bhutto NS, Rasool S, Puri MK, Ali M et al. 2006. Lessons and implications from a mass immunization campaign in squatter settlements of Karachi, Pakistan: an experience from a cluster-randomized double-blinded vaccine trial [NCT00125047]. Trials, 7 (1), pp. 17. | Show Abstract | Read more

OBJECTIVE: To determine the safety and logistic feasibility of a mass immunization strategy outside the local immunization program in the pediatric population of urban squatter settlements in Karachi, Pakistan. METHODS: A cluster-randomized double blind preventive trial was launched in August 2003 in 60 geographic clusters covering 21,059 children ages 2 to 16 years. After consent was obtained from parents or guardians, eligible children were immunized parenterally at vaccination posts in each cluster with Vi polysaccharide or hepatitis A vaccine. Safety, logistics, and standards were monitored and documented. RESULTS: The vaccine coverage of the population was 74% and was higher in those under age 10 years. No life-threatening serious adverse events were reported. Adverse events occurred in less than 1% of all vaccine recipients and the main reactions reported were fever and local pain. The proportion of adverse events in Vi polysaccharide and hepatitis A recipients will not be known until the end of the trial when the code is broken. Throughout the vaccination campaign safe injection practices were maintained and the cold chain was not interrupted. Mass vaccination in slums had good acceptance. Because populations in such areas are highly mobile, settlement conditions could affect coverage. Systemic reactions were uncommon and local reactions were mild and transient. Close community involvement was pivotal for information dissemination and immunization coverage. CONCLUSION: This vaccine strategy described together with other information that will soon be available in the area (cost/effectiveness, vaccine delivery costs, etc) will make typhoid fever control become a reality in the near future.

Thiem VD, Deen JL, von Seidlein L, Canh DG, Anh DD, Park J-K, Ali M, Danovaro-Holliday MC, Son ND, Hoa NT et al. 2006. Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam. Vaccine, 24 (20), pp. 4297-4303. | Show Abstract | Read more

We assessed the long-term protection afforded by a killed whole-cell oral cholera vaccine produced in Vietnam. A mass immunization of children and adults with the killed whole-cell oral cholera vaccine was undertaken in half of the communes of Hue, Vietnam, in 1998; the remaining communes were immunized in 2000. No cholera was observed in Hue until 2003, when an outbreak of El Tor cholera made it possible to conduct a case-control study. The overall vaccine effectiveness 3-5 years after vaccination was 50% (9-63%). This low-cost, easily administered vaccine should be considered as a tool for the control of cholera.

Siddiqui FJ, Bhutto NS, von Seidlein L, Khurram I, Rasool S, Ali M, Zafar A, Deen JL, Clemens JD, Nizami Q, Bhutta ZA. 2006. Consecutive outbreaks of Vibrio cholerae O139 and V. cholerae O1 cholera in a fishing village near Karachi, Pakistan. Trans R Soc Trop Med Hyg, 100 (5), pp. 476-482. | Show Abstract | Read more

In July 2002 and June 2003, cholera outbreaks were detected by a diarrhoea surveillance system in a village outside Karachi, Pakistan. Specimens were culture confirmed. The first outbreak was caused by Vibrio cholerae O139 (n = 30) and the second outbreak by V. cholerae O1 (n = 39). Demographic and clinical features of patients were recorded and case-control studies were conducted following each outbreak. Clinical information was obtained for 29 of the 30 patients in the first outbreak, and 2 of the patients in the second outbreak were either out of the area or lost to follow-up, leaving 29 and 37 cases in the analysis for the first and second outbreak, respectively. Eighteen (49%) of the 37 V. cholerae O1 patients were under 2 years of age compared with 6 (21%) of the 29 V. cholerae O139 patients (P = 0.02). Vibrio cholerae O139-infected patients were more likely to be febrile (16/29) than those infected with V. cholerae O1 (2/37; P<0.001). A household contact with cholera was a risk factor in both outbreaks; water source was a risk factor in the first outbreak only. Geographically, cases were clustered during the first outbreak but not during the second. Person-to-person contact and water reservoirs appear to be the main transmission routes for cholera in this setting.

Ali M, Park J-K, von Seidlein L, Acosta CJ, Deen JL, Clemens JD. 2006. Organizational aspects and implementation of data systems in large-scale epidemiological studies in less developed countries. BMC Public Health, 6 (1), pp. 86. | Show Abstract | Read more

BACKGROUND: In the conduct of epidemiological studies in less developed countries, while great emphasis is placed on study design, data collection, and analysis, often little attention is paid to data management. As a consequence, investigators working in these countries frequently face challenges in cleaning, analyzing and interpreting data. In most research settings, the data management team is formed with temporary and unskilled persons. A proper working environment and training or guidance in constructing a reliable database is rarely available. There is little information available that describes data management problems and solutions to those problems. Usually a line or two can be obtained in the methods section of research papers stating that the data are doubly-entered and that outliers and inconsistencies were removed from the data. Such information provides little assurance that the data are reliable. There are several issues in data management that if not properly practiced may create an unreliable database, and outcomes of this database will be spurious. RESULTS: We have outlined the data management practices for epidemiological studies that we have modeled for our research sites in seven Asian countries and one African country. CONCLUSION: Information from this model data management structure may help others construct reliable databases for large-scale epidemiological studies in less developed countries.

Zaidi SSH, Seidlein LV, Nizami SQ, Acosta C, Bhutta ZA. 2006. Health care utilization for diarrhea and fever in 4 urban slums in Karachi. J Coll Physicians Surg Pak, 16 (4), pp. 245-248. | Show Abstract

OBJECTIVE: To estimate the fraction of fever and diarrhea patients making use of private practitioners, self-treatment, hospital care, drug vendors, community health centers and traditional healers. DESIGN: A cross-sectional survey. PLACE AND DURATION OF STUDY: Four slums in and around Karachi during October and November, 2001. PATIENTS AND METHODS: A sample of 1842 households was selected with probability proportional to size of the slum. The household head or a representative was asked regarding the treatment providers for diarrhea and cases of fever persistent for 3 days or more. Only households with an actual case of fever and/or diarrhea were included in the analysis. RESULTS: The study found that more than half of diarrhea and fever cases are seen by private practitioners. Self medication with medicines available in the home or specifically purchased for the disease episode from a drug vendor combined provides 13% to 18% of health care. Only between 11% and 13% of patients are seen by the public sector, hospitals and community health centers. There was no significant difference between the choice of health care provider for diarrhea and fever cases. CONCLUSION: In this survey, the majority of fever and diarrhea patients presented first to private practitioners and not to drug vendors or the public sector. Successful passive surveillance of febrile or diarrheal illness in these communities has to integrate private practitioners.

Lee JH, Han KH, Choi SY, Lucas MES, Mondlane C, Ansaruzzaman M, Nair GB, Sack DA, von Seidlein L, Clemens JD et al. 2006. Multilocus sequence typing (MLST) analysis of Vibrio cholerae O1 El Tor isolates from Mozambique that harbour the classical CTX prophage. J Med Microbiol, 55 (Pt 2), pp. 165-170. | Show Abstract | Read more

Vibrio cholerae O1 isolates belonging to the Ogawa serotype, El Tor biotype, harbouring the classical CTX prophage were first isolated in Mozambique in 2004. Multilocus sequence typing (MLST) analysis using nine genetic loci showed that the Mozambique isolates have the same sequence type (ST) as O1 El Tor N16961, a representative of the current seventh cholera pandemic. Analysis of the CTX prophage in the Mozambique isolates indicated that there is one type of rstR in these isolates: the classical CTX prophage. It was also found that the ctxB-rstR-rstA-rstB-phs-cep fragment was PCR-amplified from these isolates, which indicates the presence of a tandem repeat of the classical CTX prophage in the genome of the Mozambique isolates. The possible origin of these isolates and the presence of the tandem repeat of the classical prophage in them implicate the presence of the classical CTX phage.

Wang X-Y, Ansaruzzaman M, Vaz R, Mondlane C, Lucas MES, von Seidlein L, Deen JL, Ampuero S, Puri M, Park T et al. 2006. Field evaluation of a rapid immunochromatographic dipstick test for the diagnosis of cholera in a high-risk population. BMC Infect Dis, 6 (1), pp. 17. | Show Abstract | Read more

BACKGROUND: Early detection of cholera outbreaks is crucial for the implementation of the most appropriate control strategies. METHODS: The performance of an immunochromatographic dipstick test (Institute Pasteur, Paris, France) specific for Vibrio cholerae O1 was evaluated in a prospective study in Beira, Mozambique, during the 2004 cholera season (January-May). Fecal specimens were collected from 391 patients with acute watery nonbloody diarrhea and tested by dipstick and conventional culture. RESULTS: The overall sensitivity and specificity of the rapid test compared to culture were 95% (95% confidence interval [CI]: 91%-99%) and 89% (95% CI: 86%-93%), respectively. After stratification by type of sample (rectal swab/bulk stool) and severity of diarrhea, the sensitivity ranged between 85% and 98% and specificity between 77% and 97%. CONCLUSION: This one-step dipstick test performed well in the diagnosis of V. cholerae O1 in a setting with seasonal outbreaks where rapid tests are most urgently needed.

Chen X, Stanton B, Wang X, Nyamette A, Pach A, Kaljee L, Pack R, von Seidlein L, Clemens J, Gong Y, Mao R. 2006. Differences in perception of dysentery and enteric fever and willingness to receive vaccines among rural residents in China. Vaccine, 24 (5), pp. 561-571. | Show Abstract | Read more

BACKGROUND: Enteric diseases including dysentery and enteric fever remain significant public health problems in China. While vaccines offer great potential in controlling these diseases, greater understanding of factors influencing acceptance of vaccines is needed to create effective enteric disease control programs in rural China. DESIGN: Cross-sectional quantitative study with randomly sampled households from two sites in China, one experiencing high rates of shigellosis (Zengding) and the other of typhoid/paratyphoid (Lingchuan). METHODS: Sociobehavioral survey data were collected through face-to-face interviews from 501 respondents (56% female) in Zhengding regarding dysentery and 624 in Lingchuan (51% female) regarding enteric fever. Vaccine acceptability was measured by expressed need for vaccination and willingness to pay. Comparative and associative analyses were conducted to assess disease perception, vaccination service satisfaction, likelihood of improvements in water and sanitation, and vaccine acceptability. RESULTS: Nearly all respondents in Lingchuan considered enteric fever to be prevalent in the community, while only one half of the respondents in Zhengding considered dysentery to be problematic (p < 0.01). Nevertheless, more respondents in Zhengding were fearful that a household member would acquire dysentery than were Lingchuan respondents worried that a household member would acquire enteric fever (p < 0.01). Perceived vulnerability of specific subgroups (odds ratios ranging from 1.6 to 8.1), knowing someone who died of the disease (odds ratio reached infinity) and satisfaction with past vaccination services (odds ratios reached infinity) were consistently associated with perceived need for vaccines of target populations of all age groups while the association between perception of sanitary improvement and vaccine need was limited. Perceived need for a vaccine was associated with willingness to pay for the vaccine. CONCLUSIONS: Perceptions of enhanced vulnerability of specific subgroups to a disease and satisfactory experiences with vaccination services may increase the perceived need for a vaccine, leading to increased willingness to pay for vaccine. Vaccines are not perceived as important for the elderly.

Pack R, Wang Y, Singh A, von Seidlein L, Pach A, Kaljee L, Butraporn P, Youlong G, Blum L, Bhutta Z et al. 2006. Willingness to be vaccinated against shigella and other forms of dysentery: a comparison of three regions in Asia. Vaccine, 24 (4), pp. 485-494. | Show Abstract | Read more

We conducted a cross sectional survey of 3163 women and men in six Asian countries to examine willingness for children and adults to be vaccinated against shigellosis and other forms of dysentery. The six sites were clustered into three regions for ease of comparison. The regions are: Northeast Asia (China), Southeast Asia (Thailand, Vietnam, and Indonesia) and South Asia (Bangladesh and Pakistan). We used multiple logistic regression to identify region-specific models for vaccination willingness for both adults and children. A vaccine to protect against dysentery, if available would be very much in demand throughout the three Asian regions for children. For adults, the responses indicate that vaccine uptake by adults will vary. A large proportion of respondents in all regions, specifically in China, do not perceive themselves at risk yet still consider a shigellosis vaccine desirable.

Wang X-Y, Tao F, Xiao D, Lee H, Deen J, Gong J, Zhao Y, Zhou W, Li W, Shen B et al. 2006. Trend and disease burden of bacillary dysentery in China (1991-2000). Bull World Health Organ, 84 (7), pp. 561-568. | Show Abstract | Read more

OBJECTIVE: We aimed to determine the burden of bacillary dysentery in China, its cross-regional variations, trends in morbidity and mortality, the causative bacterial species and antimicrobial resistance patterns. METHODS: We extracted and integrated governmental statistics and relevant medical literature published from 1991 to 2000. Data were also collected from one general hospital each for the six provinces and Jin-an district, Shanghai, representative of six geographical regions and a modern city. FINDINGS: In 2000, 0.8-1.7 million episodes of bacillary dysentery occurred of which 0.5 to 0.7 million were treated at health-care facilities and 0.15-0.20 million patients were hospitalized. The highest morbidity and mortality rates were among the youngest and oldest age groups. Bacillary dysentery peaked during the summer months. The major causative species was Shigella flexneri (86%) and the predominant S. flexneri serotype was 2a (80%). About 74-80% of Shigella isolates remained susceptible to fluorinated quinolones. CONCLUSION: We conclude that while morbidity and mortality due to bacillary dysentery has decreased considerably in China in the past decade due to increasing access to affordable health care and antibiotics, a considerable burden exists among the youngest and oldest age groups and in regions with low economic development. We suggest that while a vaccine would be effective for short- and medium-term control of bacillary dysentery, improved water supply, sanitation, and hygiene are likely to be required for long-term control.

Sur D, von Seidlein L, Manna B, Dutta S, Deb AK, Sarkar BL, Kanungo S, Deen JL, Ali M, Kim DR et al. 2006. The malaria and typhoid fever burden in the slums of Kolkata, India: data from a prospective community-based study. Trans R Soc Trop Med Hyg, 100 (8), pp. 725-733. | Show Abstract | Read more

Recent research has indicated that the malaria burden in Asia may have been vastly underestimated. We conducted a prospective community-based study in an impoverished urban site in Kolkata, India, to estimate the burden of malaria and typhoid fever and to identify risk factors for these diseases. In a population of 60452 people, 3605 fever episodes were detected over a 12-month period. The blood films of 93 febrile patients contained Plasmodium (90 P. vivax, 2 P. falciparum and 1 P. malariae). Blood cultures from 95 patients grew Salmonella enterica serotype Typhi. Malaria patients were found to be significantly older (mean age 29 years) compared with patients with typhoid fever (15 years; P<0.001) but had similar clinical features on presentation. Having a household member with malaria, illiteracy, low household income and living in a structure not built of bricks were associated with an increased risk for malaria. Having a household member with typhoid fever and poor hygiene were associated with typhoid fever. A geographic analysis of the spatial distribution of malaria and typhoid fever cases detected high-risk neighbourhoods for each disease. Focal interventions to minimise human-vector contact and improved personal hygiene and targeted vaccination campaigns could help to prevent malaria and typhoid fever in this site.

Anh DD, Thiem VD, Fischer TK, Canh DG, Minh TT, Tho LH, Van Man N, Luan LT, Kilgore P, von Seidlein L, Glass RI. 2006. The burden of rotavirus diarrhea in Khanh Hoa Province, Vietnam: baseline assessment for a rotavirus vaccine trial. Pediatr Infect Dis J, 25 (1), pp. 37-40. | Show Abstract | Read more

BACKGROUND: In Vietnam, rotavirus is seen as a priority disease because studies have demonstrated that >50% of children hospitalized for treatment of diarrhea have rotavirus as the pathogen. To anticipate the availability of new vaccines, we have examined our field area in Nha Trang, Khanh Hoa Province, Vietnam, as a potential site to conduct a field trial of a future rotavirus vaccine. METHODS: Data from a population census, incidence rates of diarrhea from a previous cholera vaccine trial and hospitalization rates from computerized records collected from the 2 main hospitals in the province were reviewed to estimate the burden of rotavirus-related diarrhea that might be expected during a field trial of a rotavirus vaccine. RESULTS: For a birth cohort of approximately 5000 children, we would expect approximately 2500 clinic visits and 650-850 hospitalizations for treatment of diarrhea, of which approximately 375-425 would be attributable to rotavirus. For the Vietnamese birth cohort of 1,639,000 children, these numbers translate into approximately 820,000 clinic visits, 122,000-140,000 hospitalizations and 2900-5400 deaths annually attributable to rotavirus-related diarrhea. CONCLUSIONS: Vietnam is an early adaptor of new vaccines, has high national coverage rates (>85%) for childhood immunization and receives international donor support for the introduction of new vaccines. We found the epidemiologic features of rotavirus in rural Vietnam to be more similar to those of rotavirus in a developed country than to those of rotavirus in India or Bangladesh.

Dutta S, Sur D, Manna B, Sen B, Deb AK, Deen JL, Wain J, Von Seidlein L, Ochiai L, Clemens JD, Kumar Bhattacharya S. 2006. Evaluation of new-generation serologic tests for the diagnosis of typhoid fever: data from a community-based surveillance in Calcutta, India. Diagn Microbiol Infect Dis, 56 (4), pp. 359-365. | Show Abstract | Read more

Although typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi, rapid and simple diagnostic serologic tests would be useful in developing countries. We examined the performance of Widal test in a community field site and compared it with Typhidot and Tubex tests for diagnosis of typhoid fever. Blood samples were collected from 6697 patients with fever for > or =3 days for microscopy, culture, and serologic testing and from randomly selected 172 consenting healthy individuals to assess the baseline Widal anti-Typhi O lipopolysaccharide antibody (anti-TO) and anti-Typhi H flagellar antibody (anti-TH) titers. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the 3 serologic tests were calculated using culture-confirmed typhoid fever cases as "true positives" and paratyphoid fever and malaria cases as "true negatives". Comparing cutoff values for the Widal test, an anti-TO titer of 1/80 was optimal with 58% sensitivity, 85% specificity, 69% PPV, and 77% NPV. Sensitivity was increased to 67% when the Widal test was done on the 5th day of illness and thereafter. The sensitivity, specificity, PPV, and NPV of Typhidot and Tubex were not better than Widal test. There is a need for more efficient rapid diagnostic test for typhoid fever especially during the acute stage of the disease. Until then, culture remains the method of choice.

Khan MI, Sahito SM, Khan MJ, Wassan SM, Shaikh AW, Maheshwari AK, Acosta CJ, Galindo CM, Ochiai RL, Rasool S et al. 2006. Enhanced disease surveillance through private health care sector cooperation in Karachi, Pakistan: experience from a vaccine trial. Bull World Health Organ, 84 (1), pp. 72-77. | Show Abstract | Read more

INTRODUCTION: In research projects such as vaccine trials, accurate and complete surveillance of all outcomes of interest is critical. In less developed countries where the private sector is the major health-care provider, the private sector must be included in surveillance systems in order to capture all disease of interest. This, however, poses enormous challenges in practice. The process and outcome of recruiting private practice clinics for surveillance in a vaccine trial are described. METHODS: The project started in January 2002 in two urban squatter settlements of Karachi, Pakistan. At the suggestion of private practitioners, a phlebotomy team was formed to provide support for disease surveillance. Children who had a reported history of fever for more than three days were enrolled for a diagnosis. RESULTS: Between May 2003 and April 2004, 5540 children younger than 16 years with fever for three days or more were enrolled in the study. Of the children, 1312 (24%) were seen first by private practitioners; the remainder presented directly to study centres. In total, 5329 blood samples were obtained for microbiology. The annual incidence of Salmonella typhi diagnosed by blood culture was 407 (95% confidence interval (95% CI), 368-448) per 100 000/year and for Salmonella paratyphi A was 198 (95% CI, 171-227) per 100 000/year. Without the contribution of private practitioners, the rates would have been 240 per 100 000/year (95% CI, 211-271) for S. typhi and 114 (95% CI, 94-136) per 100 000/year for S. paratyphi A. CONCLUSION: The private sector plays a major health-care role in Pakistan. Our experience from a surveillance and burden estimation study in Pakistan indicates that this objective is possible to achieve but requires considerable effort and confidence building. Nonetheless, it is essential to include private health care providers when attempting to accurately estimate the burden of disease in such settings.

von Seidlein L, Kim DR, Ali M, Lee H, Wang X, Thiem VD, Canh DG, Chaicumpa W, Agtini MD, Hossain A et al. 2006. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med, 3 (9), pp. e353. | Show Abstract | Read more

BACKGROUND: The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. METHODS AND FINDINGS: Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). CONCLUSIONS: Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.

Tran CT, Dolecek C, Ochiai RLR, Campbell JI, Yang Y, Nguyen HMV, Bhutta ZA, Bhattacharya SK, Vu TD, Agtini M et al. 2005. Investigating the molecular mechanisms of nalidixic acid resistance and reduced susceptibility to fluoroquinolones in Salmonella typhi AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 191-191.

Ochiai RL, Wang X, von Seidlein L, Yang J, Bhutta ZA, Bhattacharya SK, Agtini M, Deen JL, Wain J, Kim DR et al. 2005. Salmonella paratyphi A rates, Asia. Emerg Infect Dis, 11 (11), pp. 1764-1766. | Show Abstract | Read more

Little is known about the causes of enteric fever in Asia. Most cases are believed to be caused by Salmonella enterica serovar Typhi and the remainder by S. Paratyphi A. We compared their incidences by using standardized methods from population-based studies in China, Indonesia, India, and Pakistan.

Agtini MD, Soeharno R, Lesmana M, Punjabi NH, Simanjuntak C, Wangsasaputra F, Nurdin D, Pulungsih SP, Rofiq A, Santoso H et al. 2005. The burden of diarrhoea, shigellosis, and cholera in North Jakarta, Indonesia: findings from 24 months surveillance. BMC Infect Dis, 5 (1), pp. 89. | Show Abstract | Read more

BACKGROUND: In preparation of vaccines trials to estimate protection against shigellosis and cholera we conducted a two-year community-based surveillance study in an impoverished area of North Jakarta which provided updated information on the disease burden in the area. METHODS: We conducted a two-year community-based surveillance study from August 2001 to July 2003 in an impoverished area of North Jakarta to assess the burden of diarrhoea, shigellosis, and cholera. At participating health care providers, a case report form was completed and stool sample collected from cases presenting with diarrhoea. RESULTS: Infants had the highest incidences of diarrhoea (759/1,000/year) and cholera (4/1,000/year). Diarrhea incidence was significantly higher in boys under 5 years (387/1,000/year) than girls under 5 years (309/1,000/year; p < 0.001). Children aged 1 to 2 years had the highest incidence of shigellosis (32/1,000/year). Shigella flexneri was the most common Shigella species isolated and 73% to 95% of these isolates were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol and tetracycline but remain susceptible to nalidixic acid, ciprofloxacin, and ceftriaxone. We found an overall incidence of cholera of 0.5/1,000/year. Cholera was most common in children, with the highest incidence at 4/1,000/year in those less than 1 year of age. Of the 154 V. cholerae O1 isolates, 89 (58%) were of the El Tor Ogawa serotype and 65 (42%) were El Tor Inaba. Thirty-four percent of patients with cholera were intravenously rehydrated and 22% required hospitalization. V. parahaemolyticus infections were detected sporadically but increased from July 2002 onwards. CONCLUSION: Diarrhoea causes a heavy public health burden in Jakarta particularly in young children. The impact of shigellosis is exacerbated by the threat of antimicrobial resistance, whereas that of cholera is aggravated by its severe manifestations.

Chompook P, Samosornsuk S, von Seidlein L, Jitsanguansuk S, Sirima N, Sudjai S, Mangjit P, Kim DR, Wheeler JG, Todd J et al. 2005. Estimating the burden of shigellosis in Thailand: 36-month population-based surveillance study. Bull World Health Organ, 83 (10), pp. 739-746. | Show Abstract

OBJECTIVE: To estimate incidence of shigellosis in the Kaengkhoi district, Saraburi Province, Thailand. METHODS: Population-based surveillance of shigellosis based in treatment centres. The detected rates of treated shigellosis were corrected for the number of cases missed due to the low sensitivity of microbiological culture methods and participants' use of health-care providers not participating in the study. FINDINGS: The overall uncorrected incidence of shigellosis was 0.6/1000 population per year (95% confidence interval (CI) = 0.5-0.8). The unadjusted incidence of treated shigellosis was highest among children less than 5 years old (4/1000 children per year; 95% CI = 3-6) and significantly lower among people aged > 5 years (0.3/1000 population per year; 95% CI = 0.2-0.5; P < 0.001). Adjusting for cases likely to be missed as a result of culture and surveillance methods increased estimates approximately five times. The majority of Shigella isolates (122/146; 84%) were S. sonnei; the rest were S. flexneri. Of the 22 S. flexneri isolates, the three most frequently encountered serotypes were 2a (36%), 1b (23%) and 3b (28%). A total of 90-95% of S. sonnei and S. flexneri isolates were resistant to tetracycline and co-trimoxazole. In contrast to S. sonnei isolates, more than 90% of the S. flexneri isolates were also resistant to ampicillin and chloramphenicol (P < 0.0001). CONCLUSION: Estimates of incidence of Shigella infection in the community are 10-fold to 100-fold greater than those found from routine government surveillance. The high prevalence of Shigella strains resistant to multiple antibiotics adds urgency to the development of a vaccine to protect against shigellosis in this region of Thailand.

Ali M, Canh GD, Clemens JD, Park J-K, von Seidlein L, Minh TT, Thiem DV, Tho HL, Trach DD, Vaccine Safety Datalink Group. 2005. The use of a computerized database to monitor vaccine safety in Viet Nam. Bull World Health Organ, 83 (8), pp. 604-610. | Show Abstract

Health information systems to monitor vaccine safety are used in industrialized countries to detect adverse medical events related to vaccinations or to prove the safety of vaccines. There are no such information systems in the developing world, but they are urgently needed. A large linked database for the monitoring of vaccine-related adverse events has been established in Khanh Hoa province, Viet Nam. Data collected during the first 2 years of surveillance, a period which included a mass measles vaccination campaign, were used to evaluate the system. For this purpose the discharge diagnoses of individuals admitted to polyclinics and hospitals were coded according to the International Classification of Diseases (ICD)-10 guidelines and linked in a dynamic population database with vaccination histories. A case-series analysis was applied to the cohort of children vaccinated during the mass measles vaccination campaign. The study recorded 107,022 immunizations in a catchment area with a population of 357,458 and confirmed vaccine coverage of 87% or higher for completed routine childhood vaccinations. The measles vaccination campaign immunized at least 86% of the targeted children aged 9 months to 10 years. No medical event was detected significantly more frequently during the 14 days after measles vaccination than before it. The experience in Viet Nam confirmed the safety of a measles vaccination campaign and shows that it is feasible to establish health information systems such as a large linked database which can provide reliable data in a developing country for a modest increase in use of resources.

von Seidlein L. 2005. The need for another typhoid fever vaccine. J Infect Dis, 192 (3), pp. 357-359. | Read more

Wang X-Y, Du L, Von Seidlein L, Xu Z-Y, Zhang Y-L, Hao Z-Y, Han O-P, Ma J-C, Lee H-J, Ali M et al. 2005. Occurrence of shigellosis in the young and elderly in rural China: results of a 12-month population-based surveillance study. Am J Trop Med Hyg, 73 (2), pp. 416-422. | Show Abstract

In 2002, population- and treatment center-based surveillance was used to study the disease burden of shigellosis in rural Hebei Province in the People's Republic of China. A total of 10,105 children with diarrhea or dysentery were enrolled. Infants were treated most frequently for diarrhea (1,388/1,000/year) followed by children < or = 5 years old (618/1,000/year). Shigellosis was treated most often in children 3-4 years old (32/1,000/year) and people > 60 years of age (7/1,000/year). Fifty-six percent (184 of 331) Shigella isolates were detected in patients who had non-bloody diarrhea. Shigella flexneri was identified in 93% of 306 isolates. The most common S. flexneri serotypes were 1a (34%), X (33%), and 2a (28%). More than 90% of the Shigella isolates were resistant to cotrimoxazole and nalidixic acid, but remained susceptible to ciprofloxacin, norfloxacin, and gentamicin. Widespread resistance to antibiotics adds urgency to the development and use of vaccines to control shigellosis.

Ali M, Emch M, von Seidlein L, Yunus M, Sack DA, Rao M, Holmgren J, Clemens JD. 2005. Herd immunity conferred by killed oral cholera vaccines in Bangladesh: a reanalysis. Lancet, 366 (9479), pp. 44-49. | Show Abstract | Read more

BACKGROUND: Decisions about the use of killed oral cholera vaccines, which confer moderate levels of direct protection to vaccinees, can depend on whether the vaccines also provide indirect (herd) protection when high levels of vaccine coverage are attained. We reanalysed data from a field trial in Bangladesh to ascertain whether there is evidence of indirect protection from killed oral cholera vaccines. METHODS: We analysed the first year of surveillance data from a placebo-controlled trial of B subunit-killed whole-cell and killed whole-cell-only oral cholera vaccines in children and adult women in Bangladesh. We calculated whether there was an inverse, monotonic trend for the relation between the level of vaccine coverage in a residential cluster and the incidence of cholera in individual vaccine recipients or placebo recipients residing in the cluster after controlling for potential confounding variables. FINDINGS: Vaccine coverage of the targeted population ranged from 4% to 65%. Incidence rates of cholera among placebo recipients were inversely related to levels of vaccine coverage (7.01 cases per 1000 in the lowest quintile of coverage vs 1.47 cases per 1000 in the highest quintile; p<0.0001 for trend). Receipt of vaccine by an individual and the level of vaccine coverage of the individual's cluster were independently related to a reduced risk of cholera. Moreover, after adjustment for the level of vaccine coverage of the cluster, vaccine protective efficacy remained significant (55% [95% CI 41-66], p<0.0001). INTERPRETATION: In addition to providing direct protection to vaccine recipients, killed oral cholera vaccines confer significant herd protection to neighbouring non-vaccinated individuals. Use of these vaccines could have a major effect on the burden of cholera in endemic settings.

Lee H, Kotloff K, Chukaserm P, Samosornsuk S, Chompook P, Deen JL, Von Seidlein L, Clemens JD, Wanpen C. 2005. Shigellosis remains an important problem in children less than 5 years of age in Thailand. Epidemiol Infect, 133 (3), pp. 469-474. | Show Abstract | Read more

This is a review of existing data on the burden of shigellosis in Thailand to determine trends, vulnerable groups, predominant species and serotypes, and antimicrobial resistance patterns. Diarrhoea and dysentery morbidity and mortality data from 1991 to 1999 was collected from the routine surveillance system and demographic data from the government census. International and local literature published between 1988 and 2000 was systematically reviewed. Based on the routine surveillance system, the annual incidence of bacillary dysentery decreased from 1.3 to 0.2/10,000 persons per year. The remaining burden is highest in children <5 years of age at 2.7/10,000 persons per year. In comparison, a prospective study utilizing active surveillance found an incidence in children <5 years of age that was more than 100-fold higher at 640/10,000 persons per year. Despite the decrease in morbidity and mortality based on routinely collected data, shigellosis remains an important problem in children <5 years of age in Thailand.

Ansaruzzaman M, Lucas M, Deen JL, Bhuiyan NA, Wang X-Y, Safa A, Sultana M, Chowdhury A, Nair GB, Sack DA et al. 2005. Pandemic serovars (O3:K6 and O4:K68) of Vibrio parahaemolyticus associated with diarrhea in Mozambique: spread of the pandemic into the African continent. J Clin Microbiol, 43 (6), pp. 2559-2562. | Show Abstract | Read more

Forty-two episodes of Vibrio parahaemolyticus infections were detected in Beira, Mozambique, from January to May 2004. The majority of the isolates (81%) belonged to the pandemic serovars (O3:K6 and O4:K68) of V. parahaemolyticus. The pandemic serovars were positive by group-specific PCR (GS-PCR) and a PCR specific for open reading frame ORF8 (ORF8-PCR), which are molecular markers of the pandemic clone, and were positive for tdh but negative for trh. The remaining 19% of the strains also possessed the tdh gene but were GS-PCR and ORF8-PCR negative and did not belong to the pandemic serovars. Patients with V. parahaemolyticus infection were older (mean age, 27 years) than patients infected by other diarrheal agents (mean age, 21 years). Ten percent of diarrhea patients from whom no V. parahaemolyticus was cultured were severely dehydrated, but none of the V. parahaemolyticus cases were severely dehydrated. This is the first report of the isolation of pandemic strains of V. parahaemolyticus in sub-Saharan Africa and clearly indicates that the pandemic of V. parahaemolyticus has spread into the African continent.

Lucas MES, Deen JL, von Seidlein L, Wang X-Y, Ampuero J, Puri M, Ali M, Ansaruzzaman M, Amos J, Macuamule A et al. 2005. Effectiveness of mass oral cholera vaccination in Beira, Mozambique. N Engl J Med, 352 (8), pp. 757-767. | Show Abstract | Read more

BACKGROUND: New-generation, orally administered cholera vaccines offer the promise of improved control of cholera in sub-Saharan Africa. However, the high prevalence of human immunodeficiency virus (HIV) infection in many cholera-affected African populations has raised doubts about the level of protection possible with vaccination. We evaluated a mass immunization program with recombinant cholera-toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in Beira, Mozambique, a city where the seroprevalence of HIV is 20 to 30 percent. METHODS: From December 2003 to January 2004, we undertook mass immunization of nonpregnant persons at least two years of age, using a two-dose regimen of rBS-WC vaccine in Esturro, Beira (population 21,818). We then assessed vaccine protection in a case-control study during an outbreak of El Tor Ogawa cholera in Beira between January and May 2004. To estimate the level of vaccine protection, antecedent rates of vaccination were compared between persons with culture-confirmed cholera severe enough to have prompted them to seek treatment and age- and sex-matched neighborhood controls without treated diarrhea. RESULTS: We assessed the effectiveness of the vaccine in 43 persons with cholera and 172 controls. Receipt of one or more doses of rBS-WC vaccine was associated with 78 percent protection (95 percent confidence interval, 39 to 92 percent; P=0.004). The vaccine was equally effective in children younger than five years of age and in older persons. A concurrently conducted case-control study designed to detect bias compared persons with treated, noncholeraic diarrhea and controls without diarrhea in the same population and found no protection associated with receipt of the rBS-WC vaccine. CONCLUSIONS: The rBS-WC vaccine was highly effective against clinically significant cholera in an urban sub-Saharan African population with a high prevalence of HIV infection.

Sur D, Deen JL, Manna B, Niyogi SK, Deb AK, Kanungo S, Sarkar BL, Kim DR, Danovaro-Holliday MC, Holliday K et al. 2005. The burden of cholera in the slums of Kolkata, India: data from a prospective, community based study. Arch Dis Child, 90 (11), pp. 1175-1181. | Show Abstract | Read more

AIMS: To conduct a prospective, community based study in an impoverished urban site in Kolkata (formerly Calcutta) in order to measure the burden of cholera, describe its epidemiology, and search for potential risk factors that could be addressed by public health strategies. METHODS: The study population was enumerated at the beginning and end of the study period. Surveillance through five field outposts and two referral hospitals for acute, watery, non-bloody diarrhoea was conducted from 1 May 2003 to 30 April 2004. Data and a stool sample for culture of Vibrio cholerae were collected from each patient. Treatment was provided in accordance with national guidelines. RESULTS: From 62 329 individuals under surveillance, 3284 diarrhoea episodes were detected, of which 3276 (99%) had a stool sample collected and 126 (4%) were culture confirmed cholera. Nineteen (15%) were children less than 2 years of age, 29 (23%) had severe dehydration, and 48 (38%) were hospitalised. Risk factors for cholera included a household member with cholera during the period of surveillance, young age, and lower educational level. CONCLUSIONS: There was a substantial burden of cholera in Kolkata with risk factors not easily amenable to intervention. Young children bear the brunt not only of diarrhoeal diseases in general, but of cholera as well. Mass vaccination could be a potentially useful tool to prevent and control seasonal cholera in this community.

Acosta CJ, Galindo CM, Deen JL, Ochiai RL, Lee HJ, von Seidlein L, Carbis R, Clemens JD. 2004. Vaccines against cholera, typhoid fever and shigellosis for developing countries. Expert Opin Biol Ther, 4 (12), pp. 1939-1951. | Show Abstract | Read more

Enteric diseases, such as cholera, typhoid fever and shigellosis, still produce a significant burden, especially among the poor in countries where these illnesses are endemic. Older-generation, parenteral, whole-cell vaccines against cholera and typhoid fever were abandoned in many countries as public health tools because of problems with insufficient protection and/or inadequate safety profiles. Modern-generation licensed vaccines are available for cholera and typhoid fever, but are not widely used by those in greatest need. A number of experimental candidates exist for all three diseases. Future research should focus on generating the evidence necessary to obtain a consensus on the deployment of existing vaccines against cholera and typhoid fever, and on clinical evaluation of pipeline vaccine candidates against all three diseases.

Deen JL, von Seidlein L, Clemens JD. 2004. Multidisciplinary studies of disease burden in the Diseases of the Most Impoverished Programme. J Health Popul Nutr, 22 (3), pp. 232-239. | Show Abstract

With limited healthcare resources, rational prioritization of healthcare interventions requires knowledge and analysis of disease burden. In the absence of actual disease-burden data from less-developed countries, various types of morbidity and mortality estimates have been made. Besides having questionable reliability, these estimates do not capture the full burden of a disease since they provide only the number of cases and deaths. The modelling methods that include disability are more comprehensive but are difficult to understand, and their reliability is affected by baseline approximations. To provide policy-makers with information needed for rational decision-making, the Diseases of the Most Impoverished (DOMI) Programme of the International Vaccine Institute has used a multidisciplinary approach to describe the burden of disease due to typhoid fever, shigellosis, and cholera. Recognizing the relative advantages and disadvantages of various methodologies, the programme employs passive clinic-based surveillance in defined communities to provide prospective data. The prospective data are complemented with retrospectively-collected information from existing sources, frequently less accurate and complete but readily available for the whole population over extended periods. To create a more complete picture, economic and qualitative studies specific to each disease are incorporated in these prospective studies. The goal is to achieve a more complete and realistic picture by combining the results of these various methodologies, acknowledging the strengths and limitations of each. These projects also build in-country capacity in terms of treatment, diagnosis, epidemiology, and data management.

Samosornsuk S, Jitsanguansuk S, Sirima N, Sudjai S, Tapchaisri P, Chompook P, von Seidlein L, Robertson SE, Ali M, Clemens JD, Chaicumpa W. 2004. Preferences for treatment of diarrhoea and dysentery in Kaengkhoi district, Saraburi province, Thailand. J Health Popul Nutr, 22 (2), pp. 113-118. | Show Abstract

To estimate the proportion of cases missed in a passive surveillance study of diarrhoea and dysentery at health centres and hospitals in Kaengkhoi district, Saraburi province, Thailand, a community-based cluster survey of treatment-seeking behaviours was conducted during 21-23 June 2002. Interviews were conducted at 224 households among a study population of 78,744. The respondents reported where they sought care for diarrhoea and dysentery in children aged less than five years and adults aged over 15 years. Health centres or hospitals were the first treatment choice for 78% of children with dysentery (95% confidence interval [CI] 63-94%), 64% of children with diarrhoea (95% CI 54-74%), 61% of adults with dysentery (95% CI 40-82%), and 35% of adults with diarrhoea (95% CI 17-54%). A high degree of heterogeneity in responses resulted in a relatively large design effect (D=3.9) and poor intra-cluster correlation (rho=0.3). The community survey suggests that passive surveillance estimates of disease incidence will need to be interpreted with caution, since this method will miss nearly a quarter of dysentery cases in children and nearly two-thirds of diarrhoea cases in adults.

Kaljee L, Thiem VD, von Seidlein L, Genberg BL, Canh DG, Tho LH, Minh TT, Thoa LTK, Clemens JD, Trach DD. 2004. Healthcare use for diarrhoea and dysentery in actual and hypothetical cases, Nha Trang, Viet Nam. J Health Popul Nutr, 22 (2), pp. 139-149. | Show Abstract

To better understand healthcare use for diarrhoea and dysentery in Nha Trang, Viet Nam, qualitative interviews with community residents and dysentery case studies were conducted. Findings were supplemented by a quantitative survey which asked respondents which healthcare provider their household members would use for diarrhoea or dysentery. A clear pattern of healthcare-seeking behaviours among 433 respondents emerged. More than half of the respondents self-treated initially. Medication for initial treatment was purchased from a pharmacy or with medication stored at home. Traditional home treatments were also widely used. If no improvement occurred or the symptoms were perceived to be severe, individuals would visit a healthcare facility. Private medical practitioners are playing a steadily increasing role in the Vietnamese healthcare system. Less than a quarter of diarrhoea patients initially used government healthcare providers at commune health centres, polyclinics, and hospitals, which are the only sources of data for routine public-health statistics. Given these healthcare-use patterns, reported rates could significantly underestimate the real disease burden of dysentery and diarrhoea.

Simanjuntak CH, Punjabi NH, Wangsasaputra F, Nurdin D, Pulungsih SP, Rofiq A, Santoso H, Pujarwoto H, Sjahrurachman A, Sudarmono P et al. 2004. Diarrhoea episodes and treatment-seeking behaviour in a slum area of North Jakarta, Indonesia. J Health Popul Nutr, 22 (2), pp. 119-129. | Show Abstract

Visits to household during a census in an impoverished area of north Jakarta were used for exploring the four-week prevalence of diarrhoea, factors associated with episodes of diarrhoea, and the patterns of healthcare use. For 160,261 urban slum-dwellers, information was collected on the socioeconomic status of the household and on diarrhoea episodes of individual household residents in the preceding four weeks. In households with a reported case of diarrhoea, the household head was asked which form of healthcare was used first. In total, 8,074 individuals (5%)--13% of children aged less than five years and 4% of adults--had a diarrhoea episode in the preceding four weeks. The two strongest factors associated with a history of diarrhoea were a diarrhoea episode in another household member in the four weeks preceding the interview (adjusted odds ratio [OR] 11.1; 95% confidence interval [CI] 10.4-11.8) and age less than five years (adjusted OR 3.4; 95% CI 3.2-3.5). Of the 8,074 diarrhoea cases, 1,969 (25%) treated themselves, 1,822 (23%) visited a public-health centre (PHC), 1,462 (18%) visited a private practitioner or a private clinic, 1,318 (16%) presented at a hospital, 753 (9%) bought drugs from a drug vendor, and 750 (9%) used other healthcare providers, such as belian (traditional healers). Children with diarrhoea were most often brought to a PHC, a private clinic, or a hospital for treatment. Compared to children, adults with diarrhoea were more likely to treat themselves. Individuals from households in the lowest-income group were significantly more likely to attend a PHC for treatment of diarrhoea compared to individuals from households in the middle- and higher-income groups.

Kaljee LM, Genberg BL, von Seidlein L, Canh DG, Thoa LTK, Thiem VD, Tho LH, Minh TT, Trach DD. 2004. Acceptability and accessibility of a Shigellosis vaccine in Nha Trang city of Viet Nam. J Health Popul Nutr, 22 (2), pp. 150-158. | Show Abstract

The acceptability and accessibility of a hypothetical Shigella vaccination campaign was explored. A household survey was conducted with 539 randomly-selected residents of six communes in Nha Trang city of Viet Nam. Four categories of acceptability, such as refusers, low acceptors, acceptors, and high acceptors, were established, Refusers were significantly more likely to be elderly women and were less likely to know the purpose of vaccinations. Low acceptors tended to be male, elderly, and live in urban areas. Low acceptors perceived the disease as less serious and themselves as less vulnerable than acceptors and high acceptors. In terms of accessing vaccination, the commune health centre workers and commune leaders were the preferred sources of information and commune health centres the preferred location for vaccination. Direct verbal information from healthcare providers and audio-visual media were preferred to written information. The respondents expressed a desire for knowledge about the side-effects and efficacy of the vaccine. These findings are significant for targeting specific messages about shigellosis and vaccination to different populations and maximizing informed participation in public-health campaigns.

Wang X-Y, von Seidlein L, Robertson SE, Ma J-C, Han C-Q, Zhang Y-L, Lee H, Liu W, Ali M, Clemens JD, Xu Z-Y. 2004. A community-based cluster survey on preferences for treatment of diarrhoea and dysentery in Zhengding county, Hebei province, China. J Health Popul Nutr, 22 (2), pp. 104-112. | Show Abstract

Passive surveillance on the burden of disease due to diarrhoea will underestimate the burden if families use healthcare providers outside the surveillance system. To study this issue, a community-based cluster survey was conducted during October 2001 in the catchment area for a passive surveillance study in Zhengding county, a rural area of northern China. Interviews were conducted at 7 randomly-selected households in each of 39 study villages. The respondents indicated where they sought initial care for cases of diarrhoea or dysentery among children or adults. In the absence of diarrhoea and dysentery cases in the household in the preceding four weeks, the respondents were asked about healthcare use for a hypothetical case. Overall, 80% (95% confidence interval [CI] 67-93%) would chose the village clinic, 11% village pharmacy (95% CI 1-22%), 4% township hospital (95% CI -1-10%), 4% self-treatment (95% CI 1-8%), and 1% county hospital (95% CI 0-2%). Approximately, 84% of patients would seek treatment for diarrhoea and dysentery at centres participating in passive surveillance, suggesting that passive surveillance will provide a relatively accurate assessment of burden of diarrhoea in Zhengding county.

Vu DT, Sethabutr O, Von Seidlein L, Tran VT, Do GC, Bui TC, Le HT, Lee H, Houng H-S, Hale TL et al. 2004. Detection of Shigella by a PCR assay targeting the ipaH gene suggests increased prevalence of shigellosis in Nha Trang, Vietnam. J Clin Microbiol, 42 (5), pp. 2031-2035. | Show Abstract | Read more

Shigella spp. are exquisitely fastidious gram-negative organisms which frequently escape detection by traditional culture methods. To get a more complete understanding of the disease burden caused by Shigella in Nha Trang, Vietnam, real-time PCR was used to detect Shigella DNA. Randomly selected rectal swab specimens from 60 Shigella culture-positive patients and 500 Shigella culture-negative patients detected by population-based surveillance of patients seeking care for diarrhea were processed by real-time PCR. The target of the primer pair is the invasion plasmid antigen H gene sequence (ipaH), carried by all four Shigella species and enteroinvasive Escherichia coli. Shigella spp. could be isolated from the rectal swabs of 547 of 19,206 (3%) patients with diarrhea. IpaH was detected in 55 of 60 (93%) Shigella culture-positive specimens, whereas it was detected in 87 of 245 (36%) culture-negative patients free of dysentery (P < 0.001). The number of PCR cycles required to detect a PCR product was highest for culture-negative, nonbloody diarrheal specimens (mean number of cycles to detection, 36.6) and was lowest for children with culture-positive, bloody diarrheal specimens (mean number of cycles, 25.3) (P < 0.001). The data from real-time PCR amplification indicate that the culture-proven prevalence of Shigella among patients with diarrhea may underestimate the prevalence of Shigella infections. The clinical presentation of shigellosis may be directly related to the bacterial load.

Sur D, Manna B, Deb AK, Deen JL, Danovaro-Holliday MC, von Seidlein L, Clemens JD, Bhattacharya SK. 2004. Factors associated with reported diarrhoea episodes and treatment-seeking in an urban slum of Kolkata, India. J Health Popul Nutr, 22 (2), pp. 130-138. | Show Abstract

In an urban slum in eastern Kolkata, India, reported diarrhoea rates, healthcare-use patterns, and factors associated with reported diarrhoea episodes were studied as a part of a diarrhoea-surveillance project. Data were collected through a structured interview during a census and healthcare-use survey of an urban slum population in Kolkata. Several variables were analyzed, including (a) individual demographics, such as age and educational level, (b) household characteristics, such as number of household members, religious affiliation of the household head, building material, expenditure, water supply and sanitation, and (c) behaviour, such as hand-washing after defecation and healthcare use. Of 57,099 study subjects, 428 (0.7%) reported a diarrhoea episode sometime during the four weeks preceding the interview. The strongest independent factors for reporting a history of diarrhoea were having another household member with diarrhoea (adjusted odds ratio [OR]=3.8; 95% confidence interval [CI] 3.3-4.4) and age less than 60 months (adjusted OR=3.7; 95% CI 3.0-4.7). The first choice of treatment by the 428 subjects was as follows: 151 (35%) had self- or parent-treatment, 150 (35%) consulted a private allopathic practitioner, 70 (16%) went directly to a pharmacy, 29 (7%) visited a hospital, 14 (3%) a homoeopathic practitioner, 2 (0.5%) an ayurvedic practitioner, and 12 (3%) other traditional healers. The choices varied significantly with the age of patients and their religion. The findings increase the understanding of the factors and healthcare-use patterns associated with diarrhoea episodes and may assist in developing public-health messages and infrastructure in Kolkata.

Chowdhury A, Ishibashi M, Thiem VD, Tuyet DTN, Tung TV, Chien BT, Seidlein Lv LV, Canh DG, Clemens J, Trach DD, Nishibuchi M. 2004. Emergence and serovar transition of Vibrio parahaemolyticus pandemic strains isolated during a diarrhea outbreak in Vietnam between 1997 and 1999. Microbiol Immunol, 48 (4), pp. 319-327. | Show Abstract | Read more

We characterized 523 Vibrio parahaemolyticus strains isolated during a survey of diarrhea patients in Khanh Hoa province, Vietnam between 1997 and 1999. Forty-nine percent of the strains were judged to belong to the pandemic strains that emerged around 1996 and spread to many countries. These strains were positive in the GS-PCR assay and carried the tdh gene. The ORF8 of the f237 phage genome, a possible marker of the pandemic clone, was absent in 10% of these strains. Eleven O: K serovars were detected among the pandemic strains and the strains representing all 11 serovars of pandemic strains were shown to be closely related regardless of the ORF8 genotype using arbitrarily primed PCR and pulsed field gel electrophoresis analyses. It was clear that a transition of major serovars occurred among the pandemic strains represented by the emergence of O3: K6 in 1997, O4: K68 in 1998, and O1: K25 in 1998 and 1999.

Ansaruzzaman M, Bhuiyan NA, Nair BG, Sack DA, Lucas M, Deen JL, Ampuero J, Chaignat C-L, Mozambique Cholera vaccine Demonstration Project Coordination Group. 2004. Cholera in Mozambique, variant of Vibrio cholerae. Emerg Infect Dis, 10 (11), pp. 2057-2059. | Read more

Khiem HB, Huan LD, Phuong NTM, Dang DH, Hoang DH, Phuong LT, Sac PK, Chien TM, Tai LA, Dan NT et al. 2003. Mass psychogenic illness following oral cholera immunization in Ca Mau City, Vietnam. Vaccine, 21 (31), pp. 4527-4531. | Show Abstract | Read more

INTRODUCTION: Targeted cholera immunization of high-risk populations in Vietnam is conducted based on routine surveillance data. Following mass immunization of schoolchildren in Ca Mau City using an oral bivalent killed cholera vaccine, adverse reactions were noted. METHODS: Salient data were collected in a systematic fashion including the review of medical records; interview of the school principal, teachers, students, parents and doctors; and review of the storage and handling of the vaccine. FINDINGS: On 18 December 2001, 234 children at a primary school in Ca Mau City received the cholera vaccine. Within 1h of immunization, three children in one of the classrooms complained of trembling, nausea and headache and were brought to the library and soon other children followed. Out of 234, 97 (42%) pupils were affected and brought to the Municipal Health Center or Ca Mau Provincial Hospital. Those who were affected were younger (mean age=9.6 years; 95% CI=9.4-9.7) compared to those who were not affected (mean age=10 years; 95% CI=9.7-10.3; t-test=-2.4; P-value=0.02). The proportion of affected females among those who had received the vaccine (49/114 or 43%) was similar to the proportion in males (48/120 or 40%; RR=1.07; 95% CI=0.79-1.46). The most frequent presenting complaint was cold extremities (60%) followed by headache (27%). All affected children recovered and were discharged in a few hours. None reported any sequelae or relapse. Once the situation was recognized, the cholera immunization campaign was continued. Laboratory tests of vaccine samples from the same batch detected no abnormality or contaminating agent. DISCUSSION: The findings suggest that the children at primary school number 1 suffered from a mass psychogenic illness. This incident was unusual in that a similar number of boys and girls were affected, in contrast to the frequently reported preponderance of female cases. Furthermore the underlying cause was very quickly diagnosed, medical interventions were kept to a minimum, and no relapse was observed. Future vaccination campaigns have to assure that the families are informed in advance.

von Seidlein L, Greenwood BM. 2003. Mass administrations of antimalarial drugs. Trends Parasitol, 19 (10), pp. 452-460. | Show Abstract | Read more

Administration of antimalarial drugs to whole populations has been used as a malaria-control measure for more than 70 years. Drugs have been administered either directly as a full therapeutic course of treatment or indirectly through the fortification of salt. Mass drug administrations (MDAs) were generally unsuccessful in interrupting transmission but, in some cases, had a marked effect on parasite prevalence and on the incidence of clinical malaria. MDAs are likely to encourage the spread of drug-resistant parasites and so have only a limited role in malaria control. They could have a part to play in the management of epidemics and in the control of malaria in areas with a short transmission season. To reduce the risk of spreading drug resistance, MDAs should use more than one drug and, preferably include a drug, such as an artemisinin, which has a gametocidal effect.

Ali M, Canh DG, Clemens JD, Park J-K, von Seidlein L, Thiem VD, Tho LH, Trach DD. 2003. The vaccine data link in Nha Trang, Vietnam: a progress report on the implementation of a database to detect adverse events related to vaccinations. Vaccine, 21 (15), pp. 1681-1686. | Show Abstract | Read more

Real, perceived and unknown adverse events secondary to vaccinations are a source of concern for care providers of children. In the USA large linked databases have provided helpful information regarding the safety of vaccines. Very little prospectively collected data on vaccine safety is available from resource poor countries, but safety concerns may be even more relevant in such settings. Vaccine manufacturers do not have to pass the same rigorous safety standards as vaccine manufacturers in rich countries. Vaccines, which protect against cholera, Japanese encephalitis, rabies or typhoid fever are predominantly used in resource poor, tropical countries and frequently do not undergo vigorous post marketing surveillance. New vaccines specifically suited for resource poor countries are sometimes marketed without the scrutiny of vigilant, independent regulatory authorities. We describe here the design and implementation of a large linked database for a semi-rural province in central Vietnam. The design overcomes several problems inherent in data bases of medical events and vaccinations in developing countries. Assigning a permanent identification (ID) number to each resident avoids the ambiguities of ID numbers based on the address. The distribution and use of medical identification cards with a permanent ID number assists in the unambiguous identification of vaccinees and patients. Medical records of all admissions are coded according to International Classification of Diseases (ICD-10) and transcribed into a computer system. Because these processes are novel the data collected by the study will be validated. Project staff will check records on vaccinations and hospital admissions through household visits at regular intervals. Data describing vaccinations and medical events are linked to the data collected by the project staff in a computer system. Based on the validation of the data we hope to optimize this model. Once we find the model working it is planned export this vaccine data safety link to other settings of similar economic status.

von Seidlein L, Walraven G, Milligan PJ, Alexander N, Manneh F, Deen JL, Coleman R, Jawara M, Lindsay SW, Drakeley C et al. 2003. The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Trans R Soc Trop Med Hyg, 97 (2), pp. 217-225. | Show Abstract | Read more

A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The Gambia between June and December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. Overall 14,017 (85%) individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS). Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept under surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season. During a 20-week surveillance period 637 episodes of malaria were detected. The mean incidence rate was 2.5/100 child-weeks in the placebo villages, and 2.3/100 child-weeks in villages that received SP + AS. The mean rate ratio, adjusted for individual and village-level covariates, was 0.91 (95% CI 0.68-1.22, P = 0.49). During the first 2 months of surveillance, the malaria incidence was lower in treated villages. After 2 months the incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA could be detected. The reason for the absence of an impact on malaria transmission is probably the very high basic reproductive number of malaria, and the persistence of mature gametocytes, which are not affected by AS treatment.

Tuyet DT, Thiem VD, Von Seidlein L, Chowdhury A, Park E, Canh DG, Chien BT, Van Tung T, Naficy A, Rao MR et al. 2002. Clinical, epidemiological, and socioeconomic analysis of an outbreak of Vibrio parahaemolyticus in Khanh Hoa Province, Vietnam. J Infect Dis, 186 (11), pp. 1615-1620. | Show Abstract | Read more

From 1996 onward, a pandemic spread of Vibrio parahaemolyticus infections due to one clone has been reported in several Asian countries. During a population-based study that relied on passive surveillance, 548 cases of V. parahaemolyticus infection were detected between 1997 and 1999 in the Khanh Hoa province of Vietnam. Detection of cases of V. parahaemolyticus infection abruptly stopped in November 1999, although Vibrio species other than V. parahaemolyticus continued to be isolated throughout 2000. Of the infections, 90% occurred in individuals >5 years old; 53% of the patients presented with watery stools, and 6% reported blood in their stools. All patients had recovered by the time of discharge. A surprising risk factor for V. parahaemolyticus infections was high socioeconomic status. Like the interruption of the transmission of V. cholerae infections that had been observed earlier, the transmission of V. parahaemolyticus came to a halt without meteorological changes or changes in water supply and sanitation.

Deen JL, von Seidlein L. 2002. Antimalarial use during pregnancy and its effect on birthweight. Trans R Soc Trop Med Hyg, 96 (5), pp. 573-574. | Read more

von Seidlein L, Clarke S, Alexander N, Manneh F, Doherty T, Pinder M, Walraven G, Greenwood B. 2002. Treatment uptake by individuals infected with Plasmodium falciparum in rural Gambia, West Africa. Bull World Health Organ, 80 (10), pp. 790-796. | Show Abstract

OBJECTIVE: To find out what proportion of Plasmodium falciparum infections are treated in rural Gambia. METHODS: Subjects from four villages in the Gambia were followed over nine months through visits to village health workers. Monthly cross-sectional malaria surveys measured the prevalence of P. falciparum infection. Linked databases were searched for treatment requests. Treated cases were individuals with parasitaemia who requested treatment during narrow or extended periods (14 or 28 days, respectively) before or after a positive blood film was obtained. FINDINGS: Parasite prevalence peaked in November 1998, when 399/653 (61%) individuals had parasitaemia. Parasite prevalence was highest throughout the study in children aged 5-10 years. Although access to treatment was better than in most of sub-Saharan Africa, only 20% of infected individuals sought medical treatment up to 14 days before or after a positive blood film. Within two months of a positive blood film, 199/726 (27%) individuals with parasitaemia requested treatment. Despite easy access to health care, less than half (42%) of those with parasite densities consistent with malaria attacks (5000/ l) requested treatment. High parasite density and infection during October-November were associated with more frequent treatment requests. Self-treatment was infrequent in study villages: in 3/120 (2.5%) households antimalarial drugs had been used in the preceding malaria season. CONCLUSION: Many P. falciparum infections may be untreated because of their subclinical nature. Intermittent presumptive treatment may reduce morbidity and mortality. It is likely that not all untreated infections were asymptomatic. Qualitative research should explore barriers to treatment uptake, to allow educational interventions to be planned.

Deen JL, Walraven GEL, von Seidlein L. 2002. Increased risk for malaria in chronically malnourished children under 5 years of age in rural Gambia. J Trop Pediatr, 48 (2), pp. 78-83. | Show Abstract | Read more

Malaria and malnutrition cause high morbidity and mortality in rural sub-Saharan Africa. To explore the relationship between nutritional status and malaria, a cohort of Gambian children under 5 years of age was followed weekly during one malaria season. Anthropometric measurements were made at the beginning and at the end of the season. A total of 55/107 (51.4 per cent) children with baseline stunting, defined as having a height-for-age z-score below -2 standard deviations, subsequently experienced malaria episodes, compared to 145/380 (38.2 per cent) children who were not stunted (RR = 1.35; 95 per cent CI, 1.08-1.69; p value = 0.01). Neither wasting (weight-for-height z-score below -2 standard deviations) nor undernutrition (weight-for-age z-score below -2 standard deviations) influenced susceptibility to malaria. Adjustment for characteristics of age, sex, and ethnicity did not significantly change the risk ratios. Malaria had no effect on the nutritional status from the beginning to the end of the malaria season. Our findings suggest that chronically malnourished children may be at higher risk for developing malaria episodes.

Targett G, Drakeley C, Jawara M, von Seidlein L, Coleman R, Deen J, Pinder M, Doherty T, Sutherland C, Walraven G, Milligan P. 2001. Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae. J Infect Dis, 183 (8), pp. 1254-1259. | Show Abstract | Read more

Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria.

Deen JL, von Seidlein L, Pinder M, Walraven GE, Greenwood BM. 2001. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Trans R Soc Trop Med Hyg, 95 (4), pp. 424-428. | Show Abstract | Read more

Malaria during pregnancy is associated with an increased risk of severe anaemia and low-birthweight babies. Effective intermittent therapy with pyrimethamine-sulfadoxine (PSD) decreases parasitaemia and severe anaemia and improves birthweight in areas where Plasmodium falciparum is sensitive to this drug. Increasing resistance to PSD is a concern and alternative antimalarial regimens during pregnancy are needed. Artesunate with PSD is a promising antimalarial combination but few data are available on the safety of artemisinins when taken during pregnancy. Outcome of pregnancy was evaluated for 287 women in The Gambia who were exposed in June 1999 to a single dose of the combination artesunate and PSD during a mass drug administration and 172 women who were not exposed. Women who received placebo (40) and those who did not participate in the mass drug administration (132) comprised the non-exposed group. There was no difference in the proportion of abortions, stillbirths, or infant deaths among those exposed or not exposed to the drugs. The mean weight of 18 infants born to mothers who had received artesunate and PSD during the third trimester was 3.10 kg compared to a mean weight of 2.62 kg of the 10 infants of untreated mothers (adjusted P value = 0.05). We found no evidence of a teratogenic or otherwise harmful effect of gestational exposure to artesunate and PSD. Treatment of a self-selected group of pregnant women with PSD and artesunate during pregnancy was associated with a greater birthweight, which may have resulted from clearance of malaria parasites. However, the influence of confounding factors cannot be excluded.

von Seidlein L, Drakeley C, Greenwood B, Walraven G, Targett G. 2001. Risk factors for gametocyte carriage in Gambian children. Am J Trop Med Hyg, 65 (5), pp. 523-527. | Show Abstract | Read more

A widespread reduction in Plasmodium falciparum gametocyte prevalence could reduce malaria transmission. After infection with P. falciparum, a variable proportion of people are found to be gametocytemic. We analyzed risk factors associated with gametocytemia at presentation and 7 days later. We enrolled 1,198 children in 2 antimalarial drug trials between September and December 1998. The children were assigned to 1 of 4 treatment groups: chloroquine only; pyrimethamine-sulfadoxine (PSD) only; PSD combined with 1 dose of artesunate; and PSD combined with 3 doses of artesunate. By the time of enrollment, 200 (17%) of 1,198 children were gametocyte carriers. Three independent risk factors were associated with gametocytemia at enrollment. Children with anemia were more likely to carry gametocytes, whereas children with fever (> 37.4 degrees C) or high parasite densities (> 100,000 parasites/microL) were less frequently gametocyte carriers. Children with at least 2 of the risk factors were 4 times more likely to be gametocytemic than children with < 2 risk factors (odds ratio [OR], 4.4; 95% confidence interval [CI], 2.7-7.1). Seven days after the start of treatment, 355 (37%) of 466 assessable children were found to be gametocyte carriers. Children treated with PSD alone had a significantly higher risk of being gametocytemic by Day 7 compared with children in the other 3 treatment groups. In the subgroup of children who had no detectable gametocytes on enrollment, the effect of treatment with PSD + 3 doses of artesunate was most marked. Nineteen (10%) of 198 children treated with PSD + 3 doses of artesunate became gametocytemic, in contrast to 184 (57%) of 321 children treated with PSD alone (OR, 12.7; 95% CI, 7.3-22.1). Early treatment with highly effective antimalarial therapy has the greatest chance of preventing gametocytemia. The choice of a first-line antimalarial drug for uncomplicated malaria should not only take into consideration the ablation asexual parasitemia but also the suppression of gametocytemia.

von Seidlein L, Jawara M, Coleman R, Doherty T, Walraven G, Targett G. 2001. Parasitaemia and gametocytaemia after treatment with chloroquine, pyrimethamine/sulfadoxine, and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria. Trop Med Int Health, 6 (2), pp. 92-98. | Show Abstract | Read more

As part of a study to assess the infectivity of gametocytes after treatment with four antimalarial regimens, the efficacy of each treatment was also determined. From September to December 1998, 598 children with uncomplicated malaria were treated; 135 received chloroquine (CQ) alone, 276 received pyrimethamine/sulfadoxine (Fansidar, PSD) alone, 113 received PSD with a single dose of artesunate (PSD + 1ART) and 74 received PSD combined with three doses of artesunate (PSD + 3ART). On day 28 19/63 (30.2%; 95% C.I. 19.2% to 43.1%) of children treated with CQ alone, 5/134 (3.7%; 95% C.I. 1.2% to 8.5%) treated with PSD alone, 1/71 (1.4%, 95% C.I. 0.0% to 7.9%) treated with PSD + 1ART and 0/45 (0.0%; 95% C.I. 0.0% to 7.9%) treated with PSD + 3ART were parasitaemic. The proportion of children with gametocytes on day 7 after treatment with CQ alone was 16/89 (18.0%; 95% C.I. 10.6% to 27.6%), 98/174 (56.3%; 95% C.I. 48.6% to 63.8%) after treatment with PSD alone, 8/70 (11.4%; 95% C.I. 5.1% to 21.3%) after treatment with PSD + 1ART and 4/46 (8.7%; 95% C.I., 2.4% to 20.8%) after treatment with PSD + 3ART. CQ thus has a lower efficacy than PSD or either of the PSD and artesunate combinations. Use of PSD alone as an alternative first line treatment results in a very high post-treatment gametocyte prevalence that is likely to enhance transmission. There would be greater and more sustainable benefits from using PSD and artesunate combinations.

Warhurst DC, Adagu IS, Beck HP, Duraisingh MT, Kirby GC, Von Seidlein L, Wright CW. 2001. Mode of action of artemether/lumefantrine (coartem®: The sole, fixed, oral ADDC) and its role in combatting multidrug-resistance Southeast Asian Journal of Tropical Medicine and Public Health, 32 (SUPPL. 1), pp. 4-8.

De Martin S, von Seidlein L, Deen JL, Pinder M, Walraven G, Greenwood B. 2001. Community perceptions of a mass administration of an antimalarial drug combination in The Gambia. Trop Med Int Health, 6 (6), pp. 442-448. | Show Abstract | Read more

To test the hypothesis that widespread treatment with artemisinin derivatives can reduce malaria transmission, a mass drug administration (MDA) campaign was undertaken in an area of The Gambia in 1999. Coverage of 85% of the target population was achieved, but the intervention did not reduce overall malaria transmission. We studied the perceptions, knowledge and attitudes of the community to the MDA campaign. A validated questionnaire was administered to randomly selected MDA participants (n = 90) and MDA refusers (n = 71). Individuals who believed in the importance of the MDA (adjusted OR 58.3%; 95% CI 17.4-195.8) and those who were aware that a high level of participation was needed for the MDA to be successful (adjusted OR 28.1; 95% CI 10.3-75.9) were more likely to participate. Understanding that the purpose of the MDA was to reduce malaria (adjusted OR 13.9; 95% CI 5.5-35.1) and knowledge of the fact that malaria is transmitted by mosquitoes and of the clinical signs of malaria (adjusted OR 3.4; 95% CI 3.1-9.0) were associated with participation. Individuals who discussed the MDA with other villagers (adjusted OR 5.5; 95% CI 2.2-13.5) and those who attended the sensitization meeting (adjusted OR 2.6; 95% CI 1.1-6.0) were also more likely to participate. Women were significantly more likely to participate in the MDA than men (adjusted OR 3.1; 95% CI 1.5-6.2). Individuals who refused to participate were unlikely to plan participation in future MDAs. One of the most difficult challenges in the implementation of a malaria control strategy such as an MDA is to convince villagers to participate and to make them aware that a high level of participation by the community is needed for success. We found that our sensitization meetings could be improved by giving more information on how the MDA works and finding means to generate small group discussions after the meeting.

Von Seidlein L. 2000. Erratum: Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: A double-blind, randomised, controlled trial (The Lancet (2000) Jan 29 (352)) Lancet, 355 (9220), pp. 2080.

Duraisingh MT, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst DC. 2000. The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Mol Biochem Parasitol, 108 (1), pp. 13-23. | Show Abstract | Read more

Although chloroquine-resistance (CQR) in Plasmodium falciparum is increasing and resistance to other blood schizonticidal anti-malarials has been reported, the molecular basis remains unclear. In this study fresh field isolates were obtained from The Gambia, an area of emerging CQR and tested for sensitivity to the anti-malarial drugs mefloquine, halofantrine, artemisinin, dihydroartemisinin, chloroquine and quinine. Sequence polymorphisms in the pfmdr1 gene and size polymorphisms in the cg2 gene were assessed using PCR-based systems. A strong association was observed between the presence of the tyr-86 allele of pfmdr1 and increased sensitivity to mefloquine and halofantrine, as well as the structurally unrelated drugs artemisinin and dihydroartemisinin. A weaker association was found between the presence of tyr-86 and increased resistance to chloroquine and quinine. The cg2 Dd2-like omega repeat size polymorphism was associated with increased resistance to chloroquine and increased sensitivity to mefloquine and halofantrine. An intragenic association was also found between a polymorphism in the polyasparagine linker region of pfmdr1 and the tyr-86 allele, which may be due to genetic hitchhiking, indicative of recent selection by chloroquine. Our data support a hypothesis where the pfmdr1 gene confers a true multidrug resistance phenotype which is lost by mutation.

von Seidlein L, Milligan P, Pinder M, Bojang K, Anyalebechi C, Gosling R, Coleman R, Ude JI, Sadiq A, Duraisingh M et al. 2000. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet, 355 (9201), pp. 352-357. | Show Abstract | Read more

BACKGROUND: Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment. METHODS: We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared. FINDINGS: The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment. INTERPRETATION: The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.

Duraisingh MT, von Seidlein LV, Jepson A, Jones P, Sambou I, Pinder M, Warhurst DC. 2000. Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum. Parasitology, 121 ( Pt 1) (1), pp. 1-7. | Show Abstract | Read more

Chloroquine-resistance in Plasmodium falciparum is associated with polymorphisms in a locus on or near the cg2 gene on chromosome 7, and in the pfmdr1 gene on chromosome 5. In this study we typed P. falciparum DNA from uncomplicated malaria cases in The Gambia in 1990, 1995 and 1996 for size polymorphism in the omega repeat of cg2, for sequence polymorphisms in pfmdr1 at codons 86 and 184, in dhfr at codon 108 and in the msp2 gene. Chloroquine sensitivity tests were conducted in vitro. A significant but incomplete association was found between the presence of the cg2 Dd2-like omega repeat size polymorphism and in vitro resistance, and between the tyr-86 allele of pfmdr1 and in vitro resistance. Furthermore there was strong linkage disequilibrium between the pfmdr1 asn-86 allele and the cg2 not Dd2-like omega repeat allele located on different chromosomes. In contrast, no linkage disequilibrium was found between these alleles and either the dhfr ser-108 allele or the msp2 IC sequence polymorphism. No significant linkage was measured between pfmdr1 asn-86 and phe-184 although these loci are separated only by 296 base pairs. Our results suggest that genetic elements linked to the cg2 and the pfmdr1 genes are important determinants of chloroquine resistance. It can be concluded that the observed linkage disequilibrium is maintained epistatically through selection by chloroquine.

Price RN. 2000. Adding 3 dose artesunate to pyrimethamine sulfadoxine reduced treatment failure in children with acute uncomplicated malaria Evidence-Based Medicine, 5 (6), pp. 176-176. | Read more

Duraisingh MT, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst DC. 1999. Inoculum effect leads to overestimation of in vitro resistance for artemisinin derivatives and standard antimalarials: a Gambian field study. Parasitology, 119 ( Pt 5) (5), pp. 435-440. | Show Abstract | Read more

Artemisinin (QHS) and its derivatives are new antimalarials which are effective against Plasmodium falciparum parasites resistant to chloroquine (CQ). As these drugs are introduced it is imperative that resistance is monitored. In this paper we demonstrate that the inoculum size used in in vitro testing influences the measured in vitro susceptibility to QHS and its derivative dihydroartemisinin (DHA) and to mefloquine (MEF) and CQ over the range of parasitaemias routinely used in testing with the WHO in vitro microtest. An increase in parasitaemia and/or haematocrit was accompanied by a decrease in the measured sensitivity of 2 laboratory lines. In the context of a field study testing in vitro susceptibility of parasite isolates from patients with uncomplicated malaria in Fajara, The Gambia we demonstrate that failure to control for inoculum size significantly overestimates the level of resistance to QHS and DHA as well as MEF, halofantrine (HAL) and quinine (QUIN). When controlling for the inoculum effect, cross-resistance was observed between QHS, MEF and HAL suggesting the presence of a multidrug resistance-like mechanism. These studies underline the importance of inoculum size in in vitro susceptibility testing.

Doherty JF, Sadiq AD, Bayo L, Alloueche A, Olliaro P, Milligan P, von Seidlein L, Pinder M. 1999. A randomized safety and tolerability trial of artesunate plus sulfadoxine--pyrimethamine versus sulfadoxine-pyrimethamine alone for the treatment of uncomplicated malaria in Gambian children. Trans R Soc Trop Med Hyg, 93 (5), pp. 543-546. | Show Abstract | Read more

Artemisinin derivatives, such as artesunate, have a short half-life and very rapid anti-malarial activity. Theoretically, using such agents in conjunction with well-established anti-malarial drugs such as sulfadoxine-pyrimethamine may reduce the rate of drug resistance. Such a combination has not previously been used in Africa. We have conducted a pilot safety trial of artesunate (4 mg/kg for 3 days) given with a single dose of sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine) compared to sulfadoxine-pyrimethamine alone among 40 Gambian children with uncomplicated malaria. Both regimens were safe and well tolerated and there were no adverse experiences attributed to the combination. The addition of artesunate resulted in a higher proportion of afebrile children and children with a negative blood film on Day 2, and a reduction in the proportion of gametocyte carriers, when compared to sulfadoxine-pyrimethamine alone.

von Seidlein L, Plaeger S, Dickover R, Krogstad P, Stiehm ER, Bryson Y. 1998. Primary human immunodeficiency virus type 1 infection during pregnancy associated with transmission of SI/MT-2 cell tropic virus and precipitous loss of CD4 cells in mother and infant. Pediatr Infect Dis J, 17 (6), pp. 528-530. | Read more

Price RN, Nosten F, White NJ, Von Seidlein L, Jaffar S, Greenwood B. 1998. Letters to the editor [1] (multiple letters) American Journal of Tropical Medicine and Hygiene, 59 (4), pp. 503.

von Seidlein L, Bojang K, Jones P, Jaffar S, Pinder M, Obaro S, Doherty T, Haywood M, Snounou G, Gemperli B et al. 1998. A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. Am J Trop Med Hyg, 58 (5), pp. 638-644. | Show Abstract | Read more

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697.

vn Seidlein L, Jaffar S, Greenwood B. 1997. Prolongation of the QTc interval in African children treated for falciparum malaria. Am J Trop Med Hyg, 56 (5), pp. 494-497. | Show Abstract | Read more

Antimalarial drugs can affect the heart and trigger life-threatening arrhythmias. However, little is known about the frequency with which cardiac abnormalities occur during uncomplicated attacks of malaria. Therefore, we have studied the electrocardiograms of 139 Gambian children with uncomplicated falciparum malaria who were treated with co-artemether, pyrimethamine/sulfadoxine, or chloriquine. The QTc intervals were measured on presentation, and four and eight days after treatment. No significant differences in mean QTc or heart rate were found between children in the three treatment groups on days 0, 4, or 8. After adjustment for the type of antimalarial thearapy in an analysis of variance, the mean (SD) QTc intervals on days 0, 4, and 8 were 402 (22.6), 416 (23.1), and 405 (24.3) msec, respectively. The mean QTc on day 4 was significantly longer than the mean QTc on days 0 or 8 (P < 0.01 in both cases). A quadratic line was fitted for QTc against time for each antimalarial therapy. No significant differences were found between the quadratic lines of the three groups. A weak association was found between QTc and the degree of parasitemia (r = 0.17, P = 0.04) and temperature (r = -0.23, P = 0.01) measured on day 0. The QTcs were measured in 18 children who experienced a second episode of malaria. The changes in QTc observed during second episodes were similar to those observed during the first attack. Changes in QTc in five children who developed severe malaria were similar to those found in the remaining children who did not develop severe malaria. This study indicates that the QTc interval changes during the early phase of malaria and this change is independent of the type of antimalarial therapy given.

von Seidlein L, Jaffar S, Pinder M, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, Greenwood B. 1997. Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis, 176 (4), pp. 1113-1116. | Show Abstract | Read more

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

von Seidlein L, Jammeh K, Bailey R, Doherty T. 1997. The utility of using a distended abdomen to predict intestinal parasites in asymptomatic children. J Trop Pediatr, 43 (5), pp. 311-312. | Read more

von Seidlein L, Duraisingh MT, Drakeley CJ, Bailey R, Greenwood BM, Pinder M. 1997. Polymorphism of the Pfmdr1 gene and chloroquine resistance in Plasmodium falciparum in The Gambia. Trans R Soc Trop Med Hyg, 91 (4), pp. 450-453. | Show Abstract | Read more

To assess the level of resistance to chloroquine (CQ) of Plasmodium falciparum in The Gambia in 1995-1996 we measured susceptibility in vivo by quantifying parasitaemia of children with mild malaria on days 4 and 8 after treatment. Pretreatment blood samples were used for susceptibility testing in vitro by the World Health Organization microtest and the prevalence of the tyrosine (tyr)86 allele of the Pfmdr1 gene was assessed by the polymerase chain reaction and restriction fragment length polymorphism analysis. Seven of 42 children (17%) treated with CQ remained parasitaemic on day 4 and required a change of antimalarial treatment. Susceptibility assays in vitro were performed on 50 P. falciparum isolates obtained from eligible children before treatment; 36 (72%) were resistant to CQ (> or = 1.6 mumol/L). The median minimum inhibitory concentration (MIC) of artemether was 3.38 nmol/L (range 0.42-13.51 nmol/L) and the median MIC of dihydroartemisinin was 0.88 nmol/L (range 0.22-14.04 nmol/L). Susceptibility in vitro to CQ and the Pfmdr1 genotype were determined for 31 fresh isolates. The allele was present in 12 of 22 isolates found to be resistant to CQ in vitro, but in none of the 9 isolates which were susceptible (Fisher's exact test, P = 0.005). All P. falciparum isolates with the tyr86 allele were CQ resistant in vitro, but since only half of all resistant isolates contained the allele, additional explanations for CQ resistance are required.

Harpaz R, Von Seidlein L, Averhoff FM, Tormey MP, Sinha SD, Kotsopoulou K, Lambert SB, Robertson BH, Cherry JD, Shapiro CN. 1996. Transmission of hepatitis B virus to multiple patients from a surgeon without evidence of inadequate infection control. N Engl J Med, 334 (9), pp. 549-554. | Show Abstract | Read more

BACKGROUND: Although about 1 percent of surgeons are infected with hepatitis B virus (HBV), transmission from surgeons to patients is thought to be uncommon. In July 1992, a 47-year-old woman became ill with acute hepatitis B after undergoing a thymectomy in which a thoracic-surgery resident who had had acute hepatitis B six months earlier assisted. METHODS: To determine whether the surgeon transmitted HBV to this patient and others, we conducted chart reviews, interviews, and serologic testing of thoracic-surgery patients at the two hospitals where the surgeon worked from July 1991 to July 1992. Hepatitis B surface antigen (HBsAg) subtypes and DNA sequences from the surgeon and from infected patients were determined. RESULTS: Of 144 susceptible patients in whose surgery the infected surgeon participated, 19 had evidence of recent HBV infection (13 percent). One of the hospitals was selected for additional study, and none of the 124 susceptible patients of the other thoracic surgeons at this hospital had evidence of recent HBV infection (relative risk, infinity; 95 percent confidence interval, 4.7 to infinity). No evidence was found for any common source of HBV other than the infected surgeon. The HBsAg subtype and the partial HBV DNA sequences from the surgeon were identical to those in the infected patients. Transmission of the infection was associated with cardiac transplantation (relative risk, 4.9; 95 percent confidence interval, 1.5 to 15.5) but not with other surgical procedures. The surgeon was positive for hepatitis B e antigen and had a high serum HBV DNA concentration (15 ng per milliliter). Our investigations identified no deficiencies in the surgeon's infection-control practices. CONCLUSIONS: In this outbreak there was surgeon-to-patient HBV transmission despite apparent compliance with recommended infection-control practices. We could not identify any specific events that led to transmission.

von Seidlein L, Gillette SG, Bryson Y, Frederick T, Mascola L, Church J, Brunell P, Kovacs A, Deveikis A, Keller M. 1996. Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1. J Pediatr, 128 (1), pp. 52-57. | Show Abstract | Read more

OBJECTIVE: To examine complications and treatment of varicella-zoster virus (VZV) infections in children infected with human immunodeficiency virus type 1 (HIV-1). METHODS: Cases of VZV infection were identified retrospectively by reports to the department of health services and review of medical charts. The CD4+ cell counts were correlated with severity and frequency of VZV episodes. RESULTS: We identified 117 episodes of VZV infection in 73 HIV-1-infected children between Aug. 21, 1986, and Dec. 1, 1993. The most common complications were recurrence and persistence; 38 children (53%) had 69 recurrent episodes of VZV infection. The majority of children (61%) had zoster during the first recurrent episode, and 32% had a disseminated eruption typical of varicella. There was a strong association between an increasing number of episodes of VZV infection and low CD4+ cell count (p = 0.0008). In a subgroup followed for at least 2 years after their primary varicella episode, 10 of 22 children had a recurrence. Persistence of VZV infection was documented in 10 of 73 children, whereas other complications were rare. Thirty-three children (45%) were hospitalized and received acyclovir intravenously. CONCLUSION: Primary, recurrent, and persistent VZV infections are a frequent cause of morbidity and hospitalization for HIV-1-infected children. Studies of improved preventive and therapeutic agents are urgently needed in this population.

Weiss IK, Krogstad PA, Botero C, Von Seidlein L, Nash K. 1995. Fatal Mycobacterium avium meningitis after mis-identification of M tuberculosis. Lancet, 345 (8955), pp. 991-992. | Read more

Dondorp AM, Fanello CI, Hendriksen ICE, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K et al. 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet, 376 (9753), pp. 1647-1657. | Show Abstract | Read more

BACKGROUND: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. METHODS: This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054. FINDINGS: 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects. INTERPRETATION: Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide. FUNDING: The Wellcome Trust.

Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois M-C et al. 2008. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med, 359 (24), pp. 2521-2532. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS: We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS: A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P<0.001) on the basis of Cox regression. Overall, there were 38 episodes of clinical malaria among recipients of RTS,S/AS01E, as compared with 86 episodes among recipients of the rabies vaccine, with an adjusted rate of efficacy against all malarial episodes of 56% (95% CI, 31 to 72; P<0.001). All 894 children were included in the intention-to-treat analysis, which showed an unadjusted efficacy rate of 49% (95% CI, 26 to 65; P<0.001). There were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only due to a difference in the number of admissions directly attributable to malaria. CONCLUSIONS: RTS,S/AS01E shows promise as a candidate malaria vaccine. (ClinicalTrials.gov number, NCT00380393.)

Ali M, Emch M, von Seidlein L, Yunus M, Sack DA, Rao M, Holmgren J, Clemens JD. 2005. Herd immunity conferred by killed oral cholera vaccines in Bangladesh: a reanalysis. Lancet, 366 (9479), pp. 44-49. | Show Abstract | Read more

BACKGROUND: Decisions about the use of killed oral cholera vaccines, which confer moderate levels of direct protection to vaccinees, can depend on whether the vaccines also provide indirect (herd) protection when high levels of vaccine coverage are attained. We reanalysed data from a field trial in Bangladesh to ascertain whether there is evidence of indirect protection from killed oral cholera vaccines. METHODS: We analysed the first year of surveillance data from a placebo-controlled trial of B subunit-killed whole-cell and killed whole-cell-only oral cholera vaccines in children and adult women in Bangladesh. We calculated whether there was an inverse, monotonic trend for the relation between the level of vaccine coverage in a residential cluster and the incidence of cholera in individual vaccine recipients or placebo recipients residing in the cluster after controlling for potential confounding variables. FINDINGS: Vaccine coverage of the targeted population ranged from 4% to 65%. Incidence rates of cholera among placebo recipients were inversely related to levels of vaccine coverage (7.01 cases per 1000 in the lowest quintile of coverage vs 1.47 cases per 1000 in the highest quintile; p<0.0001 for trend). Receipt of vaccine by an individual and the level of vaccine coverage of the individual's cluster were independently related to a reduced risk of cholera. Moreover, after adjustment for the level of vaccine coverage of the cluster, vaccine protective efficacy remained significant (55% [95% CI 41-66], p<0.0001). INTERPRETATION: In addition to providing direct protection to vaccine recipients, killed oral cholera vaccines confer significant herd protection to neighbouring non-vaccinated individuals. Use of these vaccines could have a major effect on the burden of cholera in endemic settings.

Lucas MES, Deen JL, von Seidlein L, Wang X-Y, Ampuero J, Puri M, Ali M, Ansaruzzaman M, Amos J, Macuamule A et al. 2005. Effectiveness of mass oral cholera vaccination in Beira, Mozambique. N Engl J Med, 352 (8), pp. 757-767. | Show Abstract | Read more

BACKGROUND: New-generation, orally administered cholera vaccines offer the promise of improved control of cholera in sub-Saharan Africa. However, the high prevalence of human immunodeficiency virus (HIV) infection in many cholera-affected African populations has raised doubts about the level of protection possible with vaccination. We evaluated a mass immunization program with recombinant cholera-toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in Beira, Mozambique, a city where the seroprevalence of HIV is 20 to 30 percent. METHODS: From December 2003 to January 2004, we undertook mass immunization of nonpregnant persons at least two years of age, using a two-dose regimen of rBS-WC vaccine in Esturro, Beira (population 21,818). We then assessed vaccine protection in a case-control study during an outbreak of El Tor Ogawa cholera in Beira between January and May 2004. To estimate the level of vaccine protection, antecedent rates of vaccination were compared between persons with culture-confirmed cholera severe enough to have prompted them to seek treatment and age- and sex-matched neighborhood controls without treated diarrhea. RESULTS: We assessed the effectiveness of the vaccine in 43 persons with cholera and 172 controls. Receipt of one or more doses of rBS-WC vaccine was associated with 78 percent protection (95 percent confidence interval, 39 to 92 percent; P=0.004). The vaccine was equally effective in children younger than five years of age and in older persons. A concurrently conducted case-control study designed to detect bias compared persons with treated, noncholeraic diarrhea and controls without diarrhea in the same population and found no protection associated with receipt of the rBS-WC vaccine. CONCLUSIONS: The rBS-WC vaccine was highly effective against clinically significant cholera in an urban sub-Saharan African population with a high prevalence of HIV infection.

von Seidlein L, Walraven G, Milligan PJ, Alexander N, Manneh F, Deen JL, Coleman R, Jawara M, Lindsay SW, Drakeley C et al. 2003. The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Trans R Soc Trop Med Hyg, 97 (2), pp. 217-225. | Show Abstract | Read more

A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The Gambia between June and December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. Overall 14,017 (85%) individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS). Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept under surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season. During a 20-week surveillance period 637 episodes of malaria were detected. The mean incidence rate was 2.5/100 child-weeks in the placebo villages, and 2.3/100 child-weeks in villages that received SP + AS. The mean rate ratio, adjusted for individual and village-level covariates, was 0.91 (95% CI 0.68-1.22, P = 0.49). During the first 2 months of surveillance, the malaria incidence was lower in treated villages. After 2 months the incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA could be detected. The reason for the absence of an impact on malaria transmission is probably the very high basic reproductive number of malaria, and the persistence of mature gametocytes, which are not affected by AS treatment.

von Seidlein L, Milligan P, Pinder M, Bojang K, Anyalebechi C, Gosling R, Coleman R, Ude JI, Sadiq A, Duraisingh M et al. 2000. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet, 355 (9201), pp. 352-357. | Show Abstract | Read more

BACKGROUND: Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment. METHODS: We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared. FINDINGS: The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment. INTERPRETATION: The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.

von Seidlein L, Jaffar S, Pinder M, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, Greenwood B. 1997. Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis, 176 (4), pp. 1113-1116. | Show Abstract | Read more

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

Harpaz R, Von Seidlein L, Averhoff FM, Tormey MP, Sinha SD, Kotsopoulou K, Lambert SB, Robertson BH, Cherry JD, Shapiro CN. 1996. Transmission of hepatitis B virus to multiple patients from a surgeon without evidence of inadequate infection control. N Engl J Med, 334 (9), pp. 549-554. | Show Abstract | Read more

BACKGROUND: Although about 1 percent of surgeons are infected with hepatitis B virus (HBV), transmission from surgeons to patients is thought to be uncommon. In July 1992, a 47-year-old woman became ill with acute hepatitis B after undergoing a thymectomy in which a thoracic-surgery resident who had had acute hepatitis B six months earlier assisted. METHODS: To determine whether the surgeon transmitted HBV to this patient and others, we conducted chart reviews, interviews, and serologic testing of thoracic-surgery patients at the two hospitals where the surgeon worked from July 1991 to July 1992. Hepatitis B surface antigen (HBsAg) subtypes and DNA sequences from the surgeon and from infected patients were determined. RESULTS: Of 144 susceptible patients in whose surgery the infected surgeon participated, 19 had evidence of recent HBV infection (13 percent). One of the hospitals was selected for additional study, and none of the 124 susceptible patients of the other thoracic surgeons at this hospital had evidence of recent HBV infection (relative risk, infinity; 95 percent confidence interval, 4.7 to infinity). No evidence was found for any common source of HBV other than the infected surgeon. The HBsAg subtype and the partial HBV DNA sequences from the surgeon were identical to those in the infected patients. Transmission of the infection was associated with cardiac transplantation (relative risk, 4.9; 95 percent confidence interval, 1.5 to 15.5) but not with other surgical procedures. The surgeon was positive for hepatitis B e antigen and had a high serum HBV DNA concentration (15 ng per milliliter). Our investigations identified no deficiencies in the surgeon's infection-control practices. CONCLUSIONS: In this outbreak there was surgeon-to-patient HBV transmission despite apparent compliance with recommended infection-control practices. We could not identify any specific events that led to transmission.

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