[Show abstract][Hide abstract] ABSTRACT: The increasing investment in malaria rapid diagnostic tests (RDTs) to differentiate malarial and non-malarial fevers, and an awareness of the need to improve case management of non-malarial fever, indicates an urgent need for high quality evidence on how best to improve prescribers' practices.
A three-arm stratified cluster-randomised trial was conducted in 36 primary healthcare facilities from September 2010 to March 2012 within two rural districts in northeast Tanzania where malaria transmission has been declining. Interventions were guided by formative mixed-methods research and were introduced in phases. Prescribing staff from all facilities received standard Ministry of Health RDT training. Prescribers from facilities in the health worker (HW) and health worker-patient (HWP) arms further participated in small interactive peer-group training sessions with the HWP additionally receiving clinic posters and patient leaflets. Performance feedback and motivational mobile-phone text messaging (SMS) were added to the HW and HWP arms in later phases. The primary outcome was the proportion of patients with a non-severe, non-malarial illness incorrectly prescribed a (recommended) antimalarial. Secondary outcomes investigated RDT uptake, adherence to results, and antibiotic prescribing.
Standard RDT training reduced pre-trial levels of antimalarial prescribing, which was sustained throughout the trial. Both interventions significantly lowered incorrect prescribing of recommended antimalarials from 8% (749/8,942) in the standard training arm to 2% (250/10,118) in the HW arm (adjusted RD (aRD) 4%; 95% confidence interval (CI) 1% to 6%; P = 0.008) and 2% (184/10,163) in the HWP arm (aRD 4%; 95% CI 1% to 6%; P = 0.005). Small group training and SMS were incrementally effective. There was also a significant reduction in the prescribing of antimalarials to RDT-negatives but no effect on RDT-positives receiving an ACT. Antibiotic prescribing was significantly lower in the HWP arm but had increased in all arms compared with pre-trial levels.
Small group training with SMS was associated with an incremental and sustained improvement in prescriber adherence to RDT results and reducing over-prescribing of antimalarials to close to zero. These interventions may become increasingly important to cope with the wider range of diagnostic and treatment options for patients with acute febrile illness in Africa.
ClinicalTrials.gov (# NCT01292707 ) 29 January 2011.
BMC Medicine 05/2015; 13(1):118. DOI:10.1186/s12916-015-0346-z · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Summary
Background The effi cacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have
been published previously. Herein, we report the fi nal results from the same trial, including the effi cacy of a booster dose.
Methods From March 27, 2009, until Jan 31, 2011, children (age 5–17 months) and young infants (age 6–12 weeks) were
enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at fi rst
vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1,
and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at
month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were
followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection.
Serious adverse events (SAEs) were recorded. Analyses were by modifi ed intention to treat and per protocol. The
coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this fi nal
analysis, we present data for the effi cacy of the booster on the occurrence of malaria. Vaccine effi cacy (VE) against
clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction.
This trial is registered with ClinicalTrials.gov, number NCT00866619.
Findings 8922 children and 6537 young infants were included in the modifi ed intention-to-treat analyses. Children
were followed up for a median of 48 months (IQR 39–50) and young infants for 38 months (34–41) after dose 1. From
month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case defi nition in
children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8–40·5) and 7396 occurred
in the R3C group (28·3%, 23·3–32·9); compared with 171 children who experienced at least one episode of severe
malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%,
13·7 to 46·9) and 169 in the R3C group (1·1%, –23·0 to 20·5). In young infants, compared with 6170 episodes of
clinical malaria that met the primary case defi nition in the C3C group, 4993 episodes occurred in the R3R group (VE
25·9%, 95% CI 19·9–31·5) and 5444 occurred in the R3C group (18·3%, 11·7–24·4); and compared with 116 infants
who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode
of severe malaria in the R3R group (17·3%, 95% CI –9·4 to 37·5) and 104 in the R3C group (10·3%, –17·9 to 31·8).
In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387–2186) in the R3R group and
1363 per 1000 children (995–1797) in the R3C group. The numbers of cases averted per 1000 young infants were
983 (95% CI 592–1337) in the R3R group and 558 (158–926) in the R3C group. The frequency of SAEs overall was
balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the
R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01
booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children.
Interpretation RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3–4 year period in young
infants and children when administered with or without a booster dose. Effi cacy was enhanced by the administration of
a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria
control when used in combination with other eff ective control measures, especially in areas of high transmission.
The Lancet 04/2015; 385:1581. · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological
research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the
few major determinants in severe malaria to be replicated across different African populations and study designs. Within a
case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified
in recent genome-wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4%
of variation in severe malaria risk (HbAS polymorphism, 6.3%; α-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate
dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are
promising targets for the design of future treatment and control interventions.
The Journal of Infectious Diseases 03/2015; 212(7). DOI:10.1093/infdis/jiv192 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Cough or difficult breathing and an increased respiratory rate for their age are the commonest indication for outpatient antibiotic treatment in African children. We aimed to determine if respiratory rate was likely to be transiently raised by a number of contextual factors in a busy clinic leading to inaccurate diagnosis.Methods
Respiratory rates were recorded in children aged 2-59 months presenting with cough or difficulty breathing to one of the two busy outpatient clinics and then repeated at 10-minute intervals over 1 hour in a quiet setting.Results167 children were enrolled with a mean age of 7.1 (SD±2.9) months in infants and 27.6 (SD±12.8) months in children aged 12-59 months. The mean respiratory rate declined from 42.3 and 33.6 breaths per minute (bpm) in the clinic to 39.1 and 32.6 bpm after 10 minutes in a quiet room and to 39.2 and 30.7bpm (p<0.001) after 60 minutes in younger and older children respectively. This resulted in 11/13 (85%) infants and 2/15 (13%) older children being misclassified with non-severe pneumonia. In a random effects linear regression model the variability in respiratory rate within-children (42%) was almost as much as the variability between children (58%). Changing the respiratory rates cut-offs to higher thresholds resulted in a small reduction in the proportion of non-severe pneumonia mis-classifications in infants.Conclusion
Noise and other contextual factors may cause a transient increase in respiratory rate and consequently misclassification of non-severe pneumonia. However, this effect is less pronounced in older children than infants. Respiratory rate is a difficult sign to measure as the variation is large between and within children. More studies of the accuracy and utility of respiratory rate as a proxy for non-severe pneumonia diagnosis in a busy clinic are needed.This article is protected by copyright. All rights reserved.
Tropical Medicine & International Health 02/2015; 20(6). DOI:10.1111/tmi.12492 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Author Summary
Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects red blood cells from oxidative damage. Numerous genetic variants of G6PD, residing in the X chromosome, are found among African populations: mutations causing A- deficiency can lead to serious clinical outcomes (including hemolytic anemia) but also confer protection against severe malaria. Epidemiological studies have used some of the genetic markers that cause A- deficiency to establish who is protected from severe malaria, with differing results. Whether females, with one or two copies of mutant genes, males with one copy, or both genders are protected is uncertain. This uncertainty is due to G6PD and malaria phenotypic complexity and misclassification, and to genetic differences between populations and the limited numbers of genetic markers (usually 2) considered. In this study we analysed more than 30 G6PD genetic markers in 506 Tanzanian children with severe malaria and 477 without malaria. We found that only females with one normal and one mutant copy of the gene (heterozygotes) were protected from severe malaria. Further, we established that the G6PD gene is under evolutionary pressure with the likely mechanism being selection by malaria. Our work demonstrates that studies of severe malaria and G6PD enzymatic function across African populations require, in addition to complete and accurate G6PD phenotypic classification, the identification and analysis of the full repertoire of G6PD genetic markers.
[Show abstract][Hide abstract] ABSTRACT: Background
Perinatal mortality reflects maternal health as well as antenatal, intrapartum and newborn care, and is an important health indicator. This study aimed at classifying causes of perinatal death in order to identify categories of potentially preventable deaths.
We studied a total of 1958 stillbirths and early neonatal deaths above 500 g between July 2000 and October 2010 registered in the Medical Birth Registry and neonatal registry at Kilimanjaro Christian Medical Centre (KCMC) in Northern Tanzania. The deaths were classified according to the Neonatal and Intrauterine deaths Classification according to Etiology (NICE).
Overall perinatal mortality was 57.7/1000 (1958 out of 33 929), of which 1219 (35.9/1000) were stillbirths and 739 (21.8/1000) were early neonatal deaths. Major causes of perinatal mortality were unexplained asphyxia (n=425, 12.5/1000), obstetric complications (n=303, 8.9/1000), maternal disease (n=287, 8.5/1000), unexplained antepartum stillbirths after 37 weeks of gestation (n= 219, 6.5/1000), and unexplained antepartum stillbirths before 37 weeks of gestation (n=184, 5.4/1000). Obstructed/prolonged labour was the leading condition (251/303, 82.8%) among the obstetric complications. Preeclampsia/eclampsia was the leading cause (253/287, 88.2%) among the maternal conditions. When we excluded women who were referred for delivery at KCMC due to medical reasons (19.1% of all births and 36.0% of all deaths), perinatal mortality was reduced to 45.6/1000. This reduction was mainly due to fewer deaths from obstetric complications (from 8.9 to 2.1/1000) and maternal conditions (from 8.5 to 5.5/1000).
The distribution of causes of death in this population suggests a great potential for prevention. Early identification of mothers at risk of pregnancy complications through antenatal care screening, teaching pregnant women to recognize signs of pregnancy complications, timely access to obstetric care, monitoring of labour for fetal distress, and proper newborn resuscitation may reduce some of the categories of deaths.
[Show abstract][Hide abstract] 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 10/2012; 7(10):e47463. DOI:10.1371/journal.pone.0047463 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current decline in under-five mortality shows an increase in share of neonatal deaths. In order to address neonatal mortality and possibly identify areas of prevention and intervention, we studied causes of admission and cause-specific neonatal mortality in a neonatal care unit at Kilimanjaro Christian Medical Centre (KCMC) in Tanzania.
A total of 5033 inborn neonates admitted to a neonatal care unit (NCU) from 2000 to 2010 registered at the KCMC Medical Birth Registry and neonatal registry were studied. Clinical diagnosis, gestational age, birth weight, Apgar score and date at admission and discharge were registered. Cause-specific of neonatal deaths were classified by modified Wigglesworth classification. Statistical analysis was performed in SPSS 18.0.
Leading causes of admission were birth asphyxia (26.8%), prematurity (18.4%), risk of infection (16.9%), neonatal infection (15.4%), and birth weight above 4000 g (10.7%). Overall mortality was 10.7% (536 deaths). Leading single causes of death were birth asphyxia (n = 245, 45.7%), prematurity (n = 188, 35.1%), congenital malformations (n = 49, 9.1%), and infections (n = 46, 8.6%). Babies with birth weight below 2500 g constituted 29% of all admissions and 52.1% of all deaths. Except for congenital malformations, case fatality declined with increasing birth weight. Birth asphyxia was the most frequent cause of death in normal birth weight babies (n = 179/246, 73.1%) and prematurity in low birth weight babies (n = 178/188, 94.7%). The majority of deaths (n = 304, 56.7%) occurred within 24 hours, and 490 (91.4%) within the first week.
Birth asphyxia in normal birth weight babies and prematurity in low birth weight babies each accounted for one third of all deaths in this population. The high number of deaths attributable to birth asphyxia in normal birth weight babies suggests further studies to identify causal mechanisms. Strategies directed towards making obstetric and newborn care timely available with proper antenatal, maternal and newborn care support with regular training on resuscitation skills would improve child survival.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Reduction in neonatal mortality has been slower than anticipated in many low income countries including Tanzania. Adequate neonatal care may contribute to reduced mortality. We studied factors associated with transfer of babies to a neonatal care unit (NCU) in data from a birth registry at Kilimanjaro Christian Medical Centre (KCMC) in Tanzania.
A total of 21 206 singleton live births registered from 2000 to 2008 were included. Multivariable analysis was carried out to study neonatal transfer to NCU by socio-demographic factors, pregnancy complications and measures of the condition of the newborn.
A total of 3190 (15%) newborn singletons were transferred to the NCU. As expected, neonatal transfer was strongly associated with specific conditions of the baby including birth weight above 4000 g (relative risk (RR) = 7.2; 95% confidence interval (CI) 6.5-8.0) or below 1500 g (RR = 3.0; 95% CI: 2.3-4.0), five minutes Apgar score less than 7 (RR = 4.0; 95% CI: 3.4-4.6), and preterm birth before 34 weeks of gestation (RR = 1.8; 95% CI: 1.5-2.1). However, pregnancy- and delivery-related conditions like premature rupture of membrane (RR = 2.3; 95% CI: 1.9-2.7), preeclampsia (RR = 1.3; 95% CI: 1.1-1.5), other vaginal delivery (RR = 2.2; 95% CI: 1.7-2.9) and caesarean section (RR = 1.9; 95% CI: 1.8-2.1) were also significantly associated with transfer. Birth to a first born child was associated with increased likelihood of transfer (relative risk (RR) 1.4; 95% CI: 1.2-1.5), while the likelihood was reduced (RR = 0.5; 95% CI: 0.3-0.9) when the father had no education.
In addition to strong associations between neonatal transfer and classical neonatal risk factors for morbidity and mortality, some pregnancy-related and demographic factors were predictors of neonatal transfer. Overall, transfer was more likely for babies with signs of poor health status or a complicated pregnancy. Except for a possibly reduced use of transfer for babies of non-educated fathers and a high transfer rate for first born babies, there were no signs that transfer was based on non-medical indications.
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 12/2010; 5(11):e14090. DOI:10.1371/journal.pone.0014090 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies.
Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status.
The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-gamma response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-gamma production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status.
The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status.
[Show abstract][Hide abstract] ABSTRACT: Deficiencies in vitamins and mineral elements are important causes of morbidity in developing countries, possibly because they lead to defective immune responses to infection. The aim of the study was to assess the effects of mineral element deficiencies on early innate cytokine responses to Plasmodium falciparum malaria.
Peripheral blood mononuclear cells from 304 Tanzanian children aged 6-72 months were stimulated with P. falciparum-parasitized erythrocytes obtained from in vitro cultures.
The results showed a significant increase by 74% in geometric mean of TNF production in malaria-infected individuals with zinc deficiency (11% to 240%; 95% CI). Iron deficiency anaemia was associated with increased TNF production in infected individuals and overall with increased IL-10 production, while magnesium deficiency induced increased production of IL-10 by 46% (13% to 144%) in uninfected donors. All donors showed a response towards IL-1beta production, drawing special attention for its possible protective role in early innate immune responses to malaria.
In view of these results, the findings show plasticity in cytokine profiles of mononuclear cells reacting to malaria infection under conditions of different micronutrient deficiencies. These findings lay the foundations for future inclusion of a combination of precisely selected set of micronutrients rather than single nutrients as part of malaria vaccine intervention programmes in endemic countries.
[Show abstract][Hide abstract] ABSTRACT: To assess the performance of WHO's "Guidelines for care at the first-referral level in developing countries" in an area of intense malaria transmission and identify bacterial infections in children with and without malaria.
District hospital in Muheza, northeast Tanzania.
Children aged 2 months to 13 years admitted to hospital for febrile illness.
Sensitivity and specificity of WHO guidelines in diagnosing invasive bacterial disease; susceptibility of isolated organisms to recommended antimicrobials.
Over one year, 3639 children were enrolled and 184 (5.1%) died; 2195 (60.3%) were blood slide positive for Plasmodium falciparum, 341 (9.4%) had invasive bacterial disease, and 142 (3.9%) were seropositive for HIV. The prevalence of invasive bacterial disease was lower in slide positive children (100/2195, 4.6%) than in slide negative children (241/1444, 16.7%). Non-typhi Salmonella was the most frequently isolated organism (52/100 (52%) of organisms in slide positive children and 108/241 (45%) in slide negative children). Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P<0.001), and this was true regardless of the presence of P falciparum parasitaemia. The sensitivity and specificity of WHO criteria in identifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative children. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were susceptible to the first recommended antimicrobial agent.
In an area exposed to high transmission of malaria, current WHO guidelines failed to identify almost a third of children with invasive bacterial disease, and more than half of the organisms isolated were not susceptible to currently recommended antimicrobials. Improved diagnosis and treatment of invasive bacterial disease are needed to reduce childhood mortality.
[Show abstract][Hide abstract] ABSTRACT: Abstract
An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies.
Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum -parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status.
The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-γ response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-γ production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status.
The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status.
[Show abstract][Hide abstract] ABSTRACT: In hospital-based studies, alpha(+)-thalassemia has been found to protect against severe, life-threatening falciparum malaria. alpha(+)-Thalassemia does not seem to prevent infection or high parasite densities but rather limits progression to severe disease--in particular, severe malarial anemia. We assessed to what extent alpha(+)-thalassemia influences the association between mild, asymptomatic Plasmodium falciparum infection and hemoglobin concentration.
The study was based on 2 community-based surveys conducted among afebrile children (0.5-8 years old; n=801) in Kenya and Tanzania.
Among children without inflammation (whole-blood C-reactive protein concentration <or=10 mg/L), P. falciparum infection was associated with only small reductions in hemoglobin concentration, and effects were similar across alpha-globin genotypes. By contrast, the reduction in hemoglobin concentration associated with P. falciparum infection accompanied by inflammation was larger and strongly depended on genotype (normal, -21.8 g/L; heterozygous, -16.7 g/L; and homozygous, -4.6 g/L). Relative to children with a normal genotype, this difference in effect was 5.1 g/L (95% confidence interval [CI], -1.0 to 11.1 g/L) for heterozygotes and 17.2 g/L (95% CI, 8.3 to 26.2 g/L) for homozygotes (estimates are adjusted for study site, age, height-for-age z score, and iron deficiency).
alpha(+)-Thalassemia limits the decline in hemoglobin concentration that is associated with afebrile infections, particularly those that are accompanied by inflammation.
The Journal of Infectious Diseases 08/2008; 198(3):401-8. DOI:10.1086/589884 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In Africa antimalarials are often prescribed when malaria is unlikely, a problem that is becoming critical as more expensive antimalarials replace established drugs. However, little is known about what drives the overuse of antimalarials. We conducted this study to explore to what extent current prescribing behaviour in hospitals is driven by patient demand.
Consultations were observed followed by exit interviews with patients or caretakers. Five district hospitals where microscopy was routinely available were selected in areas of low (n = 3) and high (n = 2) malaria transmission in north-eastern Tanzania. All outpatient consultations during the study period were observed (n = 669). Those sent for a malaria blood slide or treated with antimalarials presumptively were interviewed (n = 326). At the end of the study, clinicians were interviewed for their opinions on the use of antimalarials.
Patients were not observed to demand antimalarials from clinicians, but occasionally asked for a malaria slide. Patient satisfaction on exit was similar between those prescribed antimalarials and those not prescribed antimalarials, but more patients or carers expressed satisfaction when the patient had been tested than when not. Clinicians rarely reported perceiving patient demand for antimalarials and asserted that such demand for medication would not affect their prescribing behaviour.
Patient demand was not found to be driving the over-prescription of antimalarials found in the hospitals in our setting. To the contrary, the involvement of patients may provide an opportunity to improve prescribing practice if their expectations for testing and treatment in line with test results can be effectively communicated to clinicians.
Health Policy and Planning 06/2008; 23(3):170-8. DOI:10.1093/heapol/czm046 · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed paediatric care in the 13 public hospitals in the north-east of the United Republic of Tanzania to determine if diagnoses and treatments were consistent with current guidelines for care.
Data were collected over a five-day period in each site where paediatric outpatient consultations were observed, and a record of care was extracted from the case notes of children on the paediatric ward. Additional data were collected from inspection of ward supplies and hospital reports.
Of 1181 outpatient consultations, basic clinical signs were often not checked; e.g. of 895 children with a history of fever, temperature was measured in 57%, and of 657 of children with cough or dyspnoea only 57 (9%) were examined for respiratory rate. Among 509 inpatients weight was recorded in the case notes in 250 (49%), respiratory rate in 54 (11%) and mental state in 47 (9%). Of 206 malaria diagnoses, 123 (60%) were with a negative or absent slide result, and of these 44 (36%) were treated with quinine only. Malnutrition was diagnosed in 1% of children admitted while recalculation of nutritional Z-scores suggested that between 5% and 10% had severe acute malnutrition; appropriate feeds were not present in any of the hospitals. A diagnosis of HIV-AIDS was made in only two cases while approximately 5% children admitted were expected to be infected with HIV in this area.
Clinical assessment of children admitted to paediatric wards is disturbingly poor and associated with missed diagnoses and inappropriate treatments. Improved assessment and records are essential to initiate change, but achieving this will be a challenging task.
Bulletin of the World Health Organisation 03/2008; 86(2):132-9. DOI:10.1590/S0042-96862008000200015 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. In hospital-based studies, ¿+-thalassemia has been found to protect against severe, life-threatening falciparum malaria. ¿+-Thalassemia does not seem to prevent infection or high parasite densities but rather limits progression to severe disease¿in particular, severe malarial anemia. We assessed to what extent ¿+-thalassemia influences the association between mild, asymptomatic Plasmodium falciparum infection and hemoglobin concentration. Methods. The study was based on 2 community-based surveys conducted among afebrile children (0.5¿8 years old; ) in Kenya and Tanzania. Results. Among children without inflammation (whole-blood C-reactive protein concentration 10 mg/L), P. falciparum infection was associated with only small reductions in hemoglobin concentration, and effects were similar across ¿-globin genotypes. By contrast, the reduction in hemoglobin concentration associated with P. falciparum infection accompanied by inflammation was larger and strongly depended on genotype (normal, ¿21.8 g/L; heterozygous, ¿16.7 g/L; and homozygous, ¿4.6 g/L). Relative to children with a normal genotype, this difference in effect was 5.1 g/L (95% confidence interval [CI], ¿1.0 to 11.1 g/L) for heterozygotes and 17.2 g/L (95% CI, 8.3 to 26.2 g/L) for homozygotes (estimates are adjusted for study site, age, height-for-age z score, and iron deficiency). Conclusions. ¿+-Thalassemia limits the decline in hemoglobin concentration that is associated with afebrile infections, particularly those that are accompanied by inflammation.