Lorenz von Seidlein

Publications (117)718.98 Total impact

• Article: Utilization and Accessibility of Healthcare on Pemba Island, Tanzania: Implications for Health Outcomes and Disease Surveillance for Typhoid Fever.

  Linda M Kaljee, Alfred Pach, Kamala Thriemer, Benedikt Ley, Said M Ali, Mohamed Jiddawi, Mahesh Puri, Lorenz von Seidlein, Jacqueline Deen, Leon Ochiai, Thomas Wierzba, John Clemens
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  ABSTRACT: 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.
  The American journal of tropical medicine and hygiene 12/2012; · 2.59 Impact Factor
• Article: The population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe falciparum malaria.

  Ilse C E Hendriksen, Deogratius Maiga, Martha M Lemnge, George Mtove, Samwel Gesase, Hugh Reyburn, Niklas Lindegardh, P J Day Nicholas, Lorenz von Seidlein, Arjen M Dondorp, Joel Tarning, Nicholas J White
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  ABSTRACT: 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 often not used.A population pharmacokinetic study was conducted in 75 Tanzanian children aged 4 months to 8 years with severe malaria receiving intramuscular quinine; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg. 21 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 (%RSE) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 (6.50%) L/h, 16.7 (6.39%) L and 1.42 (21.5%) h, respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after a standard weight-based dosing; there was 18% less exposure over 24 hours in patients of 5 kg compared with those of 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 of 20 mg salt/kg is recommended, provided no loading dose was administered within 24 hours and no routine dose within 12 hours of admission.
  Antimicrobial Agents and Chemotherapy 11/2012; · 4.84 Impact Factor
• Article: Defining falciparum malaria attributable severe febrile illness in moderate to high transmission settings based on plasma PfHRP2.

  Ilse C E Hendriksen, Lisa J White, Jacobien Veenemans, George Mtove, Charles Woodrow, Ben Amos, Somporn Saiwaew, Samwel Gesase, Behzad Nadjm, Kamolrat Silamut, Sarah Joseph, Kesinee Chotivanich, Nicholas P J Day, Lorenz von Seidlein, Hans Verhoef, Hugh Reyburn, Nicholas J White, Arjen M Dondorp
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  ABSTRACT: Background. In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein-2 is produced by Plasmodium falciparum (PfHRP2), and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria attributable fraction of severe febrile illness using plasma PfHRP2 distributions from parasitemic children with different clinical presentations.Methods. Plasma samples and peripheral blood slides were collected from 1,435 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 RDT-negative controls. PfHRP2 distributions in the different groups were used to model severe malaria attributable disease.Results. Plasma PfHRP2 showed a close correlation with the severity of infection. PfHRP2 concentrations above 1000 ng/ml denoted a malaria attributable fraction of 99% (95%CI 96-100%) with a sensitivity of 74% (95%CI 72-77%), whereas a concentration below 200 ng/mL denoted a proportion of >10% (95%CI 3-27%) of patients with severe febrile illness of an alternative diagnosis. Bacteremia was more common in patients within the lowest and highest PfHRP2 quintiles.Conclusions. Plasma PfHRP2 concentration defines malaria attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate to high transmission setting.
  The Journal of Infectious Diseases 11/2012; · 6.41 Impact Factor
• Article: Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study.

  Ahmed M Khatib, Mohammad Ali, Lorenz von Seidlein, Deok Ryun Kim, Ramadhan Hashim, Rita Reyburn, Benedikt Ley, Kamala Thriemer, Godwin Enwere, Raymond Hutubessy, Maria Teresa Aguado, Marie-Paule Kieny, Anna Lena Lopez, Thomas F Wierzba, Said Mohammed Ali, Abdul A Saleh, Asish K Mukhopadhyay, John Clemens, Mohamed Saleh Jiddawi, Jacqueline Deen
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  ABSTRACT: 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. 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. 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. 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. Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, and the South Korean Government.
  The Lancet Infectious Diseases 09/2012; 12(11):837-44. · 17.39 Impact Factor
• Article: Primaquine radical cure of Plasmodium vivax: a critical review of the literature.

  George K John, Nicholas M Douglas, Lorenz von Seidlein, Francois Nosten, Kevin J Baird, Nicholas J White, Ric N Price
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  ABSTRACT: 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 ([less than or equal to]2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high ([greater than or equal to] 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.
  Malaria Journal 08/2012; 11(1):280. · 3.19 Impact Factor
• Article: Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria.

  Thiranut Ramutton, Ilse Ce Hendriksen, Juliet Mwanga-Amumpaire, George Mtove, Rasaq Olaosebikan, Antoinette K Tshefu, Marie A Onyamboko, Corine Karema, Kathryn Maitland, Ermelinda Gomes, [......], Kamolrat Silamut, Kesinee Chotivanich, Kamoltip Promnares, Caterina I Fanello, Lorenz von Seidlein, Nicholas Pj Day, Nicholas J White, Arjen M Dondorp, Mallika Imwong, Charles J Woodrow
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  ABSTRACT: 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. 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. 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. 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.
  Malaria Journal 08/2012; 11:276. · 3.19 Impact Factor
• Article: Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement.

  Ilse C E Hendriksen, Juliet Mwanga-Amumpaire, Lorenz von Seidlein, George Mtove, Lisa J White, Rasaq Olaosebikan, Sue J Lee, Antoinette K Tshefu, Charles Woodrow, Ben Amos, [......], Wirichada Pan-Ngum, Samwel Gesase, Kamolrat Silamut, Hugh Reyburn, Sarah Joseph, Kesinee Chotivanich, Caterina I Fanello, Nicholas P J Day, Nicholas J White, Arjen M Dondorp
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  ABSTRACT: 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. 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. 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.
  PLoS Medicine 08/2012; 9(8):e1001297. · 16.27 Impact Factor
• Article: Diagnosis, Clinical Presentation, and In-Hospital Mortality of Severe Malaria in HIV-Coinfected Children and Adults in Mozambique.

  Ilse C E Hendriksen, Josefo Ferro, Pablo Montoya, Kajal D Chhaganlal, Amir Seni, Ermelinda Gomes, Kamolrat Silamut, Sue J Lee, Marcelino Lucas, Kesinee Chotivanich, Caterina I Fanello, Nicholas P J Day, Nicholas J White, Lorenz von Seidlein, Arjen M Dondorp
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  ABSTRACT: 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.
  Clinical Infectious Diseases 07/2012; 55(8):1144-53. · 9.15 Impact Factor
• Source

  Available from: Kamala Thriemer

  Article: Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy.

  Ramadhan Hashim, Ahmed M Khatib, Godwin Enwere, Jin Kyung Park, Rita Reyburn, Mohammad Ali, Na Yoon Chang, Deok Ryun Kim, Benedikt Ley, Kamala Thriemer, [......], Raymond Hutubessy, Maria Teresa Aguado, Marie Paule Kieny, David Sack, Stephen Obaro, Attiye J Shaame, Said M Ali, Abdul A Saleh, Lorenz von Seidlein, Mohamed S Jiddawi
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  ABSTRACT: 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. 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. 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. ClinicalTrials.gov NCT00709410.
  PLoS Neglected Tropical Diseases 07/2012; 6(7):e1743. · 4.69 Impact Factor
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  Available from: PubMed Central

  Article: Considerations for oral cholera vaccine use during outbreak after earthquake in Haiti, 2010-2011.

  Lorenz von Seidlein, Jacqueline L Deen
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  ABSTRACT: TO THE EDITOR: We wish to thank Date et al. for their clear discussion of the arguments against the use of oral cholera vaccines (OCVs) in Haiti in 2010-11 (1). The epidemic curve in their article suggests that the control activities had an effect on mortality rates, resulting in a decrease in case-fatality rates to <1%. This finding is a remarkable success not achieved during the recent cholera outbreak in Zimbabwe that affected 98,531 persons, of whom 4,282 (4.3%) died (2). However, the article does not discuss the lack of effect of the control measures in Haiti on the spread of the epidemic. Considering the failure of containment, it would have been interesting to read how the authors judge the recommendation not to vaccinate, with the benefit of hindsight.
  Emerging Infectious Diseases 07/2012; 18(7):1211-4. · 6.79 Impact Factor
• Article: Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review.

  Jacqueline Deen, Lorenz von Seidlein, Finn Andersen, Nelson Elle, Nicholas J White, Yoel Lubell
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  ABSTRACT: 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.
  The Lancet Infectious Diseases 06/2012; 12(6):480-7. · 17.39 Impact Factor
• Article: Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine.

  Amir Horowitz, Julius C R Hafalla, Elizabeth King, John Lusingu, Denise Dekker, Amanda Leach, Philippe Moris, Joe Cohen, Johan Vekemans, Tonya Villafana, Patrick H Corran, Philip Bejon, Chris J Drakeley, Lorenz von Seidlein, Eleanor M Riley
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  ABSTRACT: 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.
  The Journal of Immunology 04/2012; 188(10):5054-62. · 5.79 Impact Factor
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  Available from: Olugbenga A Mokuolu

  Article: Predicting the clinical outcome of severe falciparum malaria in african children: findings from a large randomized trial.

  Lorenz von Seidlein, Rasaq Olaosebikan, Ilse C E Hendriksen, Sue J Lee, Olanrewaju Timothy Adedoyin, Tsiri Agbenyega, Samuel Blay Nguah, Kalifa Bojang, Jacqueline L Deen, Jennifer Evans, [......], Marie A Onyamboko, Hugh Reyburn, Tharisara Sakulthaew, Kamolrat Silamut, Antoinette K Tshefu, Noella Umulisa, Samwel Gesase, Nicholas P J Day, Nicholas J White, Arjen M Dondorp
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  ABSTRACT: 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. 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. 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. 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.
  Clinical Infectious Diseases 03/2012; 54(8):1080-90. · 9.15 Impact Factor
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  Available from: Benedikt Ley

  Article: Replacing paper data collection forms with electronic data entry in the field: findings from a study of community-acquired bloodstream infections in Pemba, Zanzibar.

  Kamala Thriemer, Benedikt Ley, Shaali M Ame, Mahesh K Puri, Ramadhan Hashim, Na Yoon Chang, Luluwa A Salim, R Leon Ochiai, Thomas F Wierzba, John D Clemens, Lorenz von Seidlein, Jaqueline L Deen, Said M Ali, Mohammad Ali
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  ABSTRACT: 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. 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. 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. 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.
  BMC Research Notes 02/2012; 5:113.
• Article: Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan.

  M Imran Khan, Sajid Bashir Soofi, R Leon Ochiai, Mohammad Jawed Khan, Shah Muhammad Sahito, Mohammad Atif Habib, Mahesh K Puri, Lorenz Von Seidlein, Jin Kyung Park, Young Ae You, Mohammad Ali, S Qamarudding Nizami, Camilo J Acosta, Richard Bradley Sack, John D Clemens, Zulfiqar A Bhutta
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  ABSTRACT: 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. 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. 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.
  The Journal of Infection in Developing Countries 01/2012; 6(10):704-14. · 1.19 Impact Factor
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  Available from: Rita Reyburn

  Article: Evaluation of a rapid dipstick (Crystal VC) for the diagnosis of cholera in Zanzibar and a comparison with previous studies.

  Benedikt Ley, Ahmed M Khatib, Kamala Thriemer, Lorenz von Seidlein, Jacqueline Deen, Asish Mukhopadyay, Na-Yoon Chang, Ramadhan Hashim, Wolfgang Schmied, Clara J-L Busch, Rita Reyburn, Thomas Wierzba, John D Clemens, Harald Wilfing, Godwin Enwere, Theresa Aguado, Mohammad S Jiddawi, David Sack, Said M Ali
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  ABSTRACT: 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. 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. 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. 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.
  PLoS ONE 01/2012; 7(5):e36930. · 4.09 Impact Factor
• Article: Risk factors associated with typhoid fever among children 2 – 16 years of age in Karachi, Pakistan

  M. Imran Khan, Rion Leon Ochiai, Sajid Bashir Soofi, Lorenz von Seidlein, Javed Khan, Shah Muhammad Sahito, Mohammad Atif Habib, Mahesh K Puri, YoungAe You, Mohammad Ali, S. Qamaruddin Nizami, Camilo J Acosta, R. Bradley-Sack, John D Clemens, Zulfiqar A Bhutta
  Epidemiology and Infection 01/2012; 140(4):(April):665-72. · 2.84 Impact Factor
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  Available from: Benedikt Ley

  Article: The burden of invasive bacterial infections in Pemba, Zanzibar.

  Kamala Thriemer, Benedikt Ley, Shaali Ame, Lorenz von Seidlein, Gi Deok Pak, Na Yoon Chang, Ramadhan Hashim, Wolfgang Hellmut Schmied, Clara Jana-Lui Busch, Shanette Nixon, Anne Morrissey, Mahesh K Puri, Mohammad Ali, R Leon Ochiai, Thomas Wierzba, Mohammad S Jiddawi, John D Clemens, Said M Ali, Jaqueline L Deen
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  ABSTRACT: 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. 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. 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. 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.
  PLoS ONE 01/2012; 7(2):e30350. · 4.09 Impact Factor
• Article: Chemotherapeutic Strategies for Reducing Transmission of Plasmodium vivax Malaria.

  Nicholas M Douglas, George K John, Lorenz von Seidlein, Nicholas M Anstey, Ric N Price
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  ABSTRACT: 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.
  Advances in Parasitology 01/2012; 80:271-300. · 4.39 Impact Factor
• Article: Clinical and Epidemiological Features of Typhoid Fever in Pemba, Zanzibar: Assessment of the Performance of the WHO Case Definitions.

  Kamala Thriemer, Benedikt B Ley, Shaali S Ame, Jaqueline L Deen, Gi Deok Pak, Na Yoon Chang, Ramadhan Hashim, Wolfgang Hellmut Schmied, Clara Jana-Lui Busch, Shanette Nixon, Anne Morrissey, Mahesh K Puri, R Leon Ochiai, Thomas Wierzba, John D Clemens, Mohammad Ali, Mohammad S Jiddawi, Lorenz von Seidlein, Said M Ali
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  ABSTRACT: 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. 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. 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.
  PLoS ONE 01/2012; 7(12):e51823. · 4.09 Impact Factor