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ABSTRACT: PURPOSE: It is unclear why some children with falciparum malaria develop acute seizures and what determines the phenotype of seizures. We sought to determine if polymorphisms of malaria candidate genes are associated with acute seizures. METHODS: Logistic regression was used to investigate genetic associations with malaria-associated seizures (MAS) and complex MAS (repetitive, prolonged, or focal seizures) in four MalariaGEN African sites, namely: Blantyre, Malawi; Kilifi, Kenya; Kumasi, Ghana; and Muheza, Tanzania. The analysis was repeated for five inheritance models (dominant, heterozygous, recessive, additive, and general) and adjusted for potential confounders and multiple testing. KEY FINDINGS: Complex phenotypes of seizures constituted 71% of all admissions with MAS across the sites. MAS were strongly associated with cluster of differentiation-ligand-rs3092945 in females in Kilifi (p = 0.00068) and interleukin (IL)-17 receptor E-rs708567 in the pooled analysis across the sites (p = 0.00709). Complex MAS were strongly associated with epidermal growth factor module-containing mucin-like hormone receptor (EMR)1-rs373533 in Kumasi (p = 0.00033), but none in the pooled analysis. Focal MAS were strongly associated with IL-20 receptor A-rs1555498 in Muheza (p = 0.00016), but none in the pooled analysis. Prolonged MAS were strongly associated with complement receptor 1-rs17047660 in Kilifi (p = 0.00121) and glucose-6-phosphate dehydrogenase-rs1050828 in females in the pooled analysis (p = 0.00155). Repetitive MAS were strongly associated with EMR1-rs373533 in Kumasi (p = 0.00003) and cystic fibrosis transmembrane conductance receptor-rs17140229 in the pooled analysis (p = 0.00543). MAS with coma/cerebral malaria were strongly associated with EMR1-rs373533 in Kumasi (p = 0.00019) and IL10-rs3024500 in the pooled analysis across the sites (p = 0.00064). SIGNIFICANCE: We have identified a number of genetic associations that may explain the risk of seizures in >2,000 cases admitted to hospitals with MAS across four sites in Africa. These associations differed according to phenotype of seizures and site.
Epilepsia 04/2013; · 3.96 Impact Factor
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Kathryn Maitland,
Elizabeth C George,
Jennifer A Evans,
Sarah Kiguli,
Peter Olupot-Olupot,
Samuel O Akech,
Robert O Opoka,
Charles Engoru,
Richard Nyeko,
George Mtove, [......],
Daniel Semakula,
Ahmed Ddungu,
Vicent Okuuny,
Ronald Wokulira,
Molline Timbwa,
Benedict Otii,
Michael Levin,
Jane Crawley,
Abdel G Babiker,
Diana M Gibb
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ABSTRACT: Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload.
Pre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events.
Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events.
Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids.
ISRCTN69856593.
BMC Medicine 01/2013; 11:68. · 6.03 Impact Factor
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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
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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
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ABSTRACT: The WHO recommendation for parasitological diagnosis of malaria wherever possible is challenged by evidence of poor-quality microscopy in African hospitals but the reasons are not clear.
All 12 of the busier district hospital laboratories from three regions of Tanzania were assessed for quality of the working environment and slide readers read 10 reference slides under exam conditions. Slides that had been routinely read were removed for expert reading.
Of 44 slide readers in the study, 39 (88·6%) correctly read >90% of the reference slides. Of 206 slides that had been routinely read, 33 (16%) were judged to be unreadable, 104 (51%) were readable with difficulty, and 69 (34%) were easily readable. Compared to expert reading of the same slide, the sensitivity of routine slide results of easily readable slides was 85·7% (95% confidence interval: 77·4-94·0), falling to 44·4% (95% confidence interval: 34·5-54·4) for slides that were 'readable with difficulty'.
The commonest cause of inaccurate results was the quality of the slide itself, correction of which is likely to be achievable within existing resources. A minority of slide readers were unable to read slides even under ideal conditions, suggesting the need for a 'slide reading licence' scheme.
Pathogens and global health. 10/2012; 106(6):330-4.
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ABSTRACT: Severe febrile illness is a major cause of adult hospital admission in Africa. Studies of non-malarial fever come largely from children or from high HIV prevalence settings. This prospective study of adult admissions with severe febrile illness in a malaria-endemic area with moderate/low HIV prevalence investigated admission diagnosis as well as final diagnosis based on results of investigations. Severe malaria was the admission diagnosis in 148/198 (74.7%) cases. Plasmodium falciparum was identified in 38/188 (20.2%) admissions and 26/198 (13.1%) were bacteraemic, with 13/25 (52%) prescribed empirical antibiotics. HIV was equally common among those with (16/37; 43.2%) and without P. falciparum (50/138; 36.2%) (p=0.44). In 6/22 (27.3%) deaths, blood cultures were positive for a pathogen, with Streptococcus pneumoniae, Escherichia coli and non-Typhi Salmonella predominating. Chest radiography was suspicious for bacterial/mycobacterial disease in 5/22 additional deaths. Systemic inflammatory response syndrome criteria were more sensitive but less specific than WHO severe malaria criteria for predicting mortality. Malaria is overdiagnosed in adults with severe febrile illness and was not associated with mortality in the absence of co-infection in this high-incidence setting. Adults with severe febrile illness should be tested for malaria and HIV using rapid, sensitive tests. Early antibiotic use should be promoted. Improved diagnostics for invasive bacterial disease are needed.
Transactions of the Royal Society of Tropical Medicine and Hygiene 09/2012; 106(11):688-95. · 2.16 Impact Factor
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ABSTRACT: Excluding HIV infection among infants and young children in resource-poor settings where nucleic acid amplification tests (NAAT) are not routinely available remains a considerable challenge.
To assess the performance of two rapid HIV antibody tests (RT) used alone and in parallel for excluding HIV infection among acutely ill infants and children <18 months in comparison to NAAT in a region where maternal HIV prevalence was approximately 7%.
Infants and children ≥2<18 months admitted to hospital with an acute febrile illness had two rapid antibody tests in parallel, with single and parallel results subsequently compared against NAAT.
HIV prevalence among 1602 enrolled infants was 3.4%. All 1526 infants with 2 negative RT were HIV negative by NAAT. All 46 infants with 2 positive RT were HIV positive by NAAT. The overall specificity of two rapid tests for excluding HIV infection was 99.5%. Sensitivity and specificity were ≥99% and >98%, respectively, across all age brackets ≥2<18 months. Overall sensitivity and specificity for a single RT was 98.2% and 99%, respectively, for Determine, and 85.5% and 99.6%, respectively, for Capillus.
In a setting with a maternal HIV prevalence rate of <10%, a single negative RT had excellent specificity and two negative RT performed in parallel had a perfect negative predictive value for HIV infection among acutely ill patients <18 months of age. In this and similar settings, RT could assist with excluding HIV infection with much lower complexity and cost than NAAT.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 08/2012; 55(3):244-9. · 3.12 Impact Factor
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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
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Laura Anthony,
Andrea Meehan,
Ben Amos,
George Mtove,
Julius Mjema,
Rajabu Malahiyo,
Jiehui Kevin Yin,
Shahin Oftadeh,
Gwendolyn L Gilbert,
Delane Shingadia, Hugh Reyburn,
Jacqueline Deen,
Peter C Richmond,
Robert Booy
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ABSTRACT: Pneumococcal colonization of the nasopharynx is especially common in young children and is a pre-requisite for pneumococcal disease. Those with immunosuppression, such as HIV, are at higher risk of colonization and disease, especially at older ages. Currently, vaccination schedules are only offered to children under 6 months of age, despite the large impact of pneumococcal disease in older unvaccinated children with HIV. We conducted a study to assess the prevalence of, and risk factors for, pneumococcal carriage in HIV-positive children aged <15 years.
We collected a single nasopharyngeal swab from 142 HIV-infected children aged 1-14 years over a 2-month period. To detect carriage of pneumococcus, these samples were cultured and serotyped; PCR was performed on negative samples. We also collected epidemiological data via survey and medical records.
The overall carriage rate was 81% and was at least 76% in those aged 5-14 years. The 7-, 10-, and 13-valent pneumococcal vaccines would cover 37%, 37%, and 49% of children with carriage, respectively. In the multivariate analysis, we identified increase in weight since last visit (p=0.028) and the existence of care-givers who had respiratory symptoms in the past week (p=0.022) as risk factors for carriage. Weight gain was also significantly associated with antiretroviral use (p=0.002).
These data illuminate the little known area of pneumococcal carriage in older HIV-infected children as well as finding novel risk factors for pneumococcal carriage, namely the association with household members who have respiratory symptoms and with an increase in the child's weight prior to swabbing. Weight gain may be due to an increase in health enabling more mobility and increasing the risk of acquiring carriage. The carriage rate observed (81%) is one of the highest recorded. Further research should address whether vaccination can prevent the acquisition of carriage and so protect against disease.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 08/2012; 16(10):e753-7. · 2.17 Impact Factor
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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
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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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Alphaxard Manjurano,
Taane G Clark,
Behzad Nadjm,
George Mtove,
Hannah Wangai,
Nuno Sepulveda,
Susana G Campino,
Caroline Maxwell,
Raimos Olomi,
Kirk R Rockett,
Anna Jeffreys,
Eleanor M Riley, Hugh Reyburn,
Christopher Drakeley
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ABSTRACT: Human genetic background strongly influences susceptibility to malaria infection and progression to severe disease and death. Classical genetic studies identified haemoglobinopathies and erythrocyte-associated polymorphisms, as protective against severe disease. High throughput genotyping by mass spectrometry allows multiple single nucleotide polymorphisms (SNPs) to be examined simultaneously. We compared the prevalence of 65 human SNP's, previously associated with altered risk of malaria, between Tanzanian children with and without severe malaria. Five hundred children, aged 1-10 years, with severe malaria were recruited from those admitted to hospital in Muheza, Tanzania and compared with matched controls. Genotyping was performed by Sequenom MassArray, and conventional PCR was used to detect deletions in the alpha-thalassaemia gene. SNPs in two X-linked genes were associated with altered risk of severe malaria in females but not in males: heterozygosity for one or other of two SNPs in the G6PD gene was associated with protection from all forms of severe disease whilst two SNPs in the gene encoding CD40L were associated with respiratory distress. A SNP in the adenyl cyclase 9 (ADCY9) gene was associated with protection from acidosis whilst a polymorphism in the IL-1α gene (IL1A) was associated with an increased risk of acidosis. SNPs in the genes encoding IL-13 and reticulon-3 (RTN3) were associated with increased risk of cerebral malaria. This study confirms previously known genetic associations with protection from severe malaria (HbS, G6PD). It identifies two X-linked genes associated with altered risk of severe malaria in females, identifies mutations in ADCY9, IL1A and CD40L as being associated with altered risk of severe respiratory distress and acidosis, both of which are characterised by high serum lactate levels, and also identifies novel genetic associations with severe malaria (TRIM5) and cerebral malaria(IL-13 and RTN3). Further studies are required to test the generality of these associations and to understand their functional consequences.
PLoS ONE 01/2012; 7(10):e47463. · 4.09 Impact Factor
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ABSTRACT: In malaria endemic areas, individuals are frequently asymptomatic and may be undetected by conventional microscopy or newer, rapid diagnostic tests. Molecular techniques allow a more accurate assessment of this asymptomatic parasite burden, the extent of which is important for malaria control. This study examines the relative prevalence of sub-microscopic level parasite carriage and clonal complexity of infections (multiplicity of infection) over a range of endemicities in a region of north-eastern Tanzania where altitude is an established proxy of malaria transmission. The PCR prevalence was then compared against other measures of transmission intensity collected in the same area.
This study used 1,121 blood samples collected from a previously conducted cross-sectional malario-metric survey during the short rainy season in 2001 from 13 villages (three at < 600 m, four at 600-1,200 m and six at > 1,200 m in altitude above sea level). Samples were analysed by PCR for carriage of parasites and multiplicity of infection. These data were compared with other measures of transmission intensity collected from the same area.
Parasite prevalence was 34.7% by PCR and 13.6% by microscopy; a 2.5-fold difference in line with other recent observations. This fold difference was relatively consistent at the different altitude bands despite a marked decrease in parasite prevalence with altitude: < 600 m 70.9 vs 28.6, 600-1,200 m 35.5 vs 9.9, > 1,200 m 15.8 vs 5.9. The difference between parasite prevalence by PCR was 3.2 in individuals aged between 15 and 45 years (34.5 vs 10.9) compared with 2.5 in those aged 1-5 (34.0 vs 13.5) though this was not statistically significant. Multiplicity of infection (MOI) ranged from 1.2 to 3.7 and was positively associated with parasite prevalence assessed by both PCR and microscopy. There was no association of MOI and age.Village level PCR parasite prevalence was strongly correlated with altitude, sero-conversion rate and predicted entomological inoculation rate.
Asymptomatic, low density, multi-clone malaria infection was common in this study area. These infections are important as potential contributors to the infectious reservoir of parasites and need to be identified by control programmes especially in this era where malaria elimination is a focus. High throughput standardized PCR approaches are needed to identify individuals who are malaria carriers.
Malaria Journal 12/2011; 10:370. · 3.19 Impact Factor
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ABSTRACT: Lactic acidosis is a consistent predictor of mortality owing to severe infectious disease, but its detection in low-income settings is limited to the clinical sign of "deep breathing" because of the lack of accessible technology for its measurement. We evaluated the use of a point-of-care (POC) diagnostic device for blood lactate measurement to assess the severity of illness in children admitted to a district hospital in Tanzania.
Children between the ages of 2 months and 13 years with a history of fever were enrolled in the study during a period of 1 year. A full clinical history and examination were undertaken, and blood was collected for culture, microscopy, complete blood cell count, and POC measurement of blood lactate and glucose.
The study included 3248 children, of whom 164 (5.0%) died; 45 (27.4%) of these had raised levels of blood lactate (>5 mmol/L) but no deep breathing. Compared with mortality in children with lactate levels of ≤ 3 mmol/L, the unadjusted odds of dying were 1.6 (95% confidence interval [CI].8-3.0), 3.4 (95% CI, 1.5-7.5), and 8.9 (95% CI, 4.7-16.8) in children with blood lactate levels of 3.1-5.0, 5.1-8.0, or >8.0 mmol/L, respectively. The prevalence of raised lactate levels (>5 mmol/L) was greater in children with malaria than in children with nonmalarial febrile illness (P < .001) although the associated mortality was greater in slide-negative children.
POC lactate measurement can contribute to the assessment of children admitted to hospital with febrile illness and can also create an opportunity for more hospitals in resource-poor settings to participate in clinical trials of interventions to reduce mortality associated with hyperlactatemia.
Clinical Infectious Diseases 09/2011; 53(6):548-54. · 9.15 Impact Factor
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Kathryn Maitland,
Sarah Kiguli,
Robert O Opoka,
Charles Engoru,
Peter Olupot-Olupot,
Samuel O Akech,
Richard Nyeko,
George Mtove, Hugh Reyburn,
Trudie Lang,
Bernadette Brent,
Jennifer A Evans,
James K Tibenderana,
Jane Crawley,
Elizabeth C Russell,
Michael Levin,
Abdel G Babiker,
Diana M Gibb
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ABSTRACT: The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established.
We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks.
The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia.
Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.).
New England Journal of Medicine 05/2011; 364(26):2483-95. · 53.30 Impact Factor
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Ilse C E Hendriksen,
George Mtove,
Alínia José Pedro,
Ermelinda Gomes,
Kamolrat Silamut,
Sue J Lee,
Abraham Mwambuli,
Samwel Gesase, Hugh Reyburn,
Nicholas P J Day,
Nicholas J White,
Lorenz von Seidlein,
Arjen M Dondorp
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ABSTRACT: 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.
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.
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.
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.
Clinical Infectious Diseases 05/2011; 52(9):1100-7. · 9.15 Impact Factor
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John A. Crump,
Habib O. Ramadhani,
Anne B. Morrissey,
Levina J. Msuya,
Lan-Yan Yang,
Shein-Chung Chow,
Susan C. Morpeth, Hugh Reyburn,
Boniface N. Njau,
Andrea V. Shaw,
Helmut C. Diefenthal,
John A. Bartlett,
John F. Shao,
Werner Schimana,
Coleen K. Cunningham,
Grace D. Kinabo
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ABSTRACT: Objective To describe the contribution of paediatric HIV and of HIV co-infections to admissions to a hospital in Moshi, Tanzania, using contemporary laboratory methods.Methods During 1 year, we enrolled consecutively admitted patients aged ≥2 months and <13 years with current or recent fever. All patients underwent standardized clinical history taking, a physical examination and HIV antibody testing; standard aerobic blood cultures and malaria film were also done, and hospital outcome was recorded. Early infant HIV diagnosis by HIV-1 RNA PCR was performed on those aged <18 months. HIV-infected patients also received serum cryptococcal antigen testing and had their CD4-positive T-lymphocyte count and percent determined.Results A total of 467 patients were enrolled whose median age was 2 years (range 2 months–13 years); Of those patients, 57.2% were female and 12.2% were HIV-infected. Admission clinical diagnosis of HIV disease was made in 10.7% and of malaria in 60.4%. Of blood cultures, 5.8% grew pathogens; of these 25.9% were Salmonella enterica (including 6 Salmonella Typhi) and 22.2%Streptococcus pneumoniae. Plasmodium falciparum was identified on blood film of 1.3%. HIV infection was associated with S. pneumoniae (odds ratio 25.7, 95% CI 2.8, 234.0) bloodstream infection (BSI), but there was no evidence of an association with Escherichia coli or P. falciparum; Salmonella Typhi BSI occurred only among HIV-uninfected participants. The sensitivity and specificity of an admission clinical diagnosis of malaria were 100% and 40.3%; and for an admission diagnosis of bloodstream infection, they were 9.1% and 86.4%, respectively.Conclusion Streptococcus pneumoniae is a leading cause of bloodstream infection among paediatric admissions in Tanzania and is closely associated with HIV infection. Malaria was over-diagnosed clinically, whereas invasive bacterial disease was underestimated. HIV and HIV co-infections contribute to a substantial proportion of paediatric febrile admissions, underscoring the value of routine HIV testing.Objectifs: Décrire la contribution du VIH pédiatrique et des coinfections VIH à l’admission dans un hôpital à Moshi, en Tanzanie, en utilisant des méthodes contemporaines de laboratoire.Méthodes: Durant une année, nous avons recruté des patients consécutifs âgés de ≥2 mois et moins de 13 ans admis avec de la fièvre actuelle ou récente. Tous les patients ont subi un relevé standard de l’historique clinique, un examen physique et des tests d’anticorps VIH. Des hémocultures standard en aérobie et des frottis pour la malaria ont également été effectués et les résultats d’hôpital ont été enregistrés. Un diagnostic précoce du VIH infantile par la PCR du RNA du VIH-1 a été réalisé chez les moins de 18 mois. Les patients infectés par le VIH ont également subi le test de l’antigène cryptococcique sérique et le pourcentage des lymphocytes T CD4+ a été déterminé (%CD4).Résultats: 467 patients ont été recrutés dont l’âge médian était de 2 ans (intervalle: 2 mois à 13 ans). 57,2%étaient de sexe féminin et 12,2%étaient infectés par le VIH. Un diagnostic clinique provisoire pour la maladie VIH a été effectué chez 10,7% et pour la malaria chez 60,4% d’entre eux. 5,8% des cultures de sang ont révélé des agents pathogènes dont 25,9% de Salmonella enterica (dont 6 Salmonella typhi) et 22,2% de Streptococcus pneumoniae. Le Plasmodium falciparum a été identifié dans 1,3% des frottis sanguins. L’infection par le VIH était associée à l’infection sanguine par S. pneumoniae (odds ratio = 25,7; IC95%: 2,8–234,0), mais il n’y avait aucune preuve d’une association avec Escherichia coli ou P. falciparum. L’infection sanguine par Salmonella typhi a eu lieu seulement chez les participants non infectés par le VIH. La sensibilité et la spécificité d’un diagnostic clinique provisoire de la malaria étaient de 100% et 40,3% et pour un diagnostic à l’admission de l’infection sanguine, de 9,1% et 86,4%, respectivement.Conclusions: Streptococcus pneumoniae est une cause majeure d’infection sanguine dans les admissions pédiatriques en Tanzanie et est étroitement associéà l’infection à VIH. La malaria était sur-diagnostiquée cliniquement, alors que les infections bactériennes invasives étaient sous-estimées. Le VIH et les coinfections VIH contribuent à une proportion importante des admissions fébriles en pédiatrie, ce qui souligne la valeur d’un dépistage en routine du VIH.Objetivos: Describir la contribución del VIH pediátrico y las co-infecciones con VIH en los pacientes admitidos en un hospital de Moshi, Tanzania, utilizando métodos de laboratorio contemporáneos.Métodos: Durante un año se incluyeron de forma consecutiva todos los pacientes con edades entre los ≥2 meses y <13 años, admitidos en el hospital con fiebre o con un episodio reciente de fiebre. A todos los pacientes se les hizo una historia clínica estándar, un examen físico y pruebas de anticuerpos de VIH; también se realizaron hemocultivos aeróbicos estándar y una lámina para malaria y se anotaron los resultados al finalizar la hospitalización. Se realizó un diagnóstico temprano del VIH mediante un PCR del ARN de VIH-1 en aquellos pacientes con <18 meses. A los pacientes infectados con VIH también se les realizó una prueba de antígeno criptocócico en suero y se les determinó el porcentaje de linfocitos T CD4-positivos (CD4%).Resultados: Se incluyeron 467 pacientes con una mediana de edad de 2 años (rango 2 meses-13 años). Un 57.2% eran niñas, y un 12.2% estaban infectadas con VIH. El diagnóstico clínico provisional de la enfermedad por VIH se realizó en un 10.7% y el de malaria en 60.4%. De los hemocultivos, en 5.8% crecieron patógenos; de estos un 25.9% eran Salmonella enterica (incluyendo 6 Salmonella typhi), y 22.2%Streptococcus pneumoniae. Se identificóPlasmodium falciparum en las láminas de 1.3% de los niños. La infección por VIH estaba asociada con infección en sangre (IS) por S. pneumoniae (odds ratio 25.7, 95% IC 2.8, 234.0), pero no había evidencia de una asociación con Escherichia coli o P. falciparum; la IS por Salmonella typhi ocurrió solo entre participantes sin infección por VIH. La sensibilidad y especificidad de un diagnóstico clínico provisional de malaria era del 100% y 40.3%; y por un diagnóstico durante la admisión de infección en sangre eran de 9.1% y 86.4%, respectivamente.Conclusiones: Streptococcus pneumoniae es una causa mayor de infección en sangre entre pacientes pediátricos admitidos en Tanzania y está muy asociado con la infección por VIH. La malaria estaba sobrediagnosticada clínicamente, mientras que la enfermedad bacteriana invasiva estaba subestimada. El VIH y las co-infecciones por VIH contribuyen a una proporción sustancial de admisiones pediátricas febriles, subestimando el valor de la prueba rutinaria para VIH.
Tropical Medicine & International Health 04/2011; 16(7):830 - 837. · 2.80 Impact Factor
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John A Crump,
Habib O Ramadhani,
Anne B Morrissey,
Levina J Msuya,
Lan-Yan Yang,
Shein-Chung Chow,
Susan C Morpeth, Hugh Reyburn,
Boniface N Njau,
Andrea V Shaw,
Helmut C Diefenthal,
John A Bartlett,
John F Shao,
Werner Schimana,
Coleen K Cunningham,
Grace D Kinabo
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[hide abstract]
ABSTRACT: To describe the contribution of paediatric HIV and of HIV co-infections to admissions to a hospital in Moshi, Tanzania, using contemporary laboratory methods.
During 1 year, we enrolled consecutively admitted patients aged ≥2 months and <13 years with current or recent fever. All patients underwent standardized clinical history taking, a physical examination and HIV antibody testing; standard aerobic blood cultures and malaria film were also done, and hospital outcome was recorded. Early infant HIV diagnosis by HIV-1 RNA PCR was performed on those aged <18 months. HIV-infected patients also received serum cryptococcal antigen testing and had their CD4-positive T-lymphocyte count and percent determined.
A total of 467 patients were enrolled whose median age was 2 years (range 2 months-13 years); Of those patients, 57.2% were female and 12.2% were HIV-infected. Admission clinical diagnosis of HIV disease was made in 10.7% and of malaria in 60.4%. Of blood cultures, 5.8% grew pathogens; of these 25.9% were Salmonella enterica (including 6 Salmonella Typhi) and 22.2%Streptococcus pneumoniae. Plasmodium falciparum was identified on blood film of 1.3%. HIV infection was associated with S. pneumoniae (odds ratio 25.7, 95% CI 2.8, 234.0) bloodstream infection (BSI), but there was no evidence of an association with Escherichia coli or P. falciparum; Salmonella Typhi BSI occurred only among HIV-uninfected participants. The sensitivity and specificity of an admission clinical diagnosis of malaria were 100% and 40.3%; and for an admission diagnosis of bloodstream infection, they were 9.1% and 86.4%, respectively.
Streptococcus pneumoniae is a leading cause of bloodstream infection among paediatric admissions in Tanzania and is closely associated with HIV infection. Malaria was over-diagnosed clinically, whereas invasive bacterial disease was underestimated. HIV and HIV co-infections contribute to a substantial proportion of paediatric febrile admissions, underscoring the value of routine HIV testing.
Tropical Medicine & International Health 04/2011; 16(7):830-7. · 2.80 Impact Factor
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John A Crump,
Habib O Ramadhani,
Anne B Morrissey,
Wilbrod Saganda,
Mtumwa S Mwako,
Lan-Yan Yang,
Shein-Chung Chow,
Susan C Morpeth, Hugh Reyburn,
Boniface N Njau,
Andrea V Shaw,
Helmut C Diefenthal,
John F Shao,
John A Bartlett,
Venance P Maro
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ABSTRACT: few studies describe patterns of human immunodeficiency virus (HIV) co-infections in African hospitals in the antiretroviral therapy (ART) era.
we enrolled consecutive admitted patients aged ≥ 13 years with oral temperature of ≥ 38.0°C during 1 year in Moshi, Tanzania. A standardized clinical history and physical examination was done and hospital outcome recorded. HIV antibody testing, aerobic and mycobacterial blood cultures, and malaria film were performed. HIV-infected patients also received serum cryptococcal antigen testing and CD4(+) T lymphocyte count (CD4 cell count).
of 403 patients enrolled, the median age was 38 years (range, 14-96 years), 217 (53.8%) were female, and 157 (39.0%) were HIV-infected. Of HIV-infected patients, the median CD4 cell count was 98 cells/μL (range, 1-1,105 cells/ μL), 20 (12.7%) were receiving ART, and 29 (18.5%) were receiving trimethoprim-sulfamethoxazole prophylaxis. There were 112 (27.7%) patients who had evidence of invasive disease, including 26 (23.2%) with Salmonella serotype Typhi infection, 24 (21.4%) with Streptococcus pneumoniae infection, 17 (15.2%) with Cryptococcus neoformans infection, 12 (10.7%) with Mycobacterium tuberculosis complex infection, 8 (7.1%) with Plasmodium falciparum infection, and 7 (6.3%) with Escherichia coli infection. HIV infection was associated with M. tuberculosis and C. neoformans bloodstream infection but not with E. coli, S. pneumoniae, or P. falciparum infection. HIV infection appeared to be protective against Salmonella. Typhi bloodstream infection (odds ratio, .12; P = .001).
while Salmonella Typhi and S. pneumoniae were the most common causes of invasive infection overall, M. tuberculosis and C. neoformans were the leading causes of bloodstream infection among HIV-infected inpatients in Tanzania in the ART era. We demonstrate a protective effect of HIV against Salmonella. Typhi bloodstream infection in this setting. HIV co-infections continue to account for a large proportion of febrile admissions in Tanzania.
Clinical Infectious Diseases 02/2011; 52(3):341-8. · 9.15 Impact Factor
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ABSTRACT: To compare the performance of the Paracheck™ rapid diagnostic test (RDT) with microscopy for diagnosing malaria in hospitalised children.
Children aged between 2 months and 13 years with fever were enrolled in the study over 1 year. A standard clinical history and examination were recorded and blood drawn for culture, complete blood count, Paracheck™ RDT and double-read blood slide.
Of 3639 children enrolled, 2195 (60.3%) were slide positive. The sensitivity and specificity of Paracheck were 97.5% (95% CI 96.9-98.0) and 65.3% (95% CI 63.8-66.9), respectively. There was an inverse relationship between age-specific prevalence of parasitaemia and Paracheck specificity. In logistic regression model, false-positive Paracheck results were significantly associated with pre-admission use of antimalarial drug (OR 1.44, 95% CI 1.16-1.78), absence of current fever (OR 0.64, 95% CI 0.52-0.79) and non-typhi Salmonella bacteraemia (OR 3.89. 95% CI 2.27-6.63). In spite of high sensitivity, 56/2195 (2.6%) of true infections were Paracheck negative and 8/56 (14.3%) were in patients with >50,000 parasites/μl.
Paracheck had poor specificity in diagnosing malaria in severely ill children; this was likely to be due to HRP2 persistence following recent parasite clearance. The combination of positive Paracheck and negative blood slide results identified a group of children at high risk of non-typhi Salmonella infection. While Paracheck was highly sensitive, some high-density infections were missed. For children with severe febrile illness, at least two reliable negative parasitological test results should be available to justify withholding antimalarial treatment; the optimal choice of these has yet to be identified.
Tropical Medicine & International Health 02/2011; 16(5):545-50. · 2.80 Impact Factor
