Low frequency of the TIRAP S180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy.

BACKGROUND: The Toll-like receptors (TLRs) mediate innate immunity to various pathogens. A mutation (S180L) in the TLR downstream signal transducer TIRAP has recently been reported to be common in Europeans and Africans and to roughly half the risks of heterogeneous infectious diseases including malaria, tuberculosis, bacteremia, and invasive pneumococal disease in heterozygous mutation carriers. METHODS: We assessed the TIRAP S180L variant by melting curve and RFLP analysis in 1095 delivering women from malaria-endemic Ghana, as well as in a further 1114 individuals participating in case control studies on sepsis and leprosy in Germany, Turkey and Bangladesh. RESULTS: In Ghana, the TIRAP S180L polymorphism was virtually absent. In contrast, the mutation was observed among 26.6%, 32.9% and 12% of German, Bangladesh and Turkish controls, respectively. No significant association of the heterozygous genotype with sepsis or leprosy was observed. Remarkably, homozygous TIRAP 180L tend to increase the risk of sepsis in the German study (P = 0.04). CONCLUSION: A broad protective effect of TIRAP S180L against infectious diseases per se is not discernible.

Reduced efficacy of intermittent preventive treatment of malaria in malnourished children.

Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], -7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%; P = 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.

Rapid increase in the prevalence of sulfadoxine-pyrimethamine resistance among Plasmodium falciparum isolated from pregnant women in Ghana.

Use of intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) during pregnancy (IPTp-SP) has become policy in much of sub-Saharan Africa but crucially depends on the efficacy of SP. We assessed the frequency of the dhfr triple mutation among Plasmodium falciparum isolates obtained from pregnant Ghanaian women in 1998, 2000, and 2006. The prevalence of the triple mutation, which confers resistance to SP, doubled from 36% to 73% during the study period (P<.001). In 2006, the prevalence was virtually identical among women of early gestation and delivering women with or without a history of IPTp-SP use, indicating that such treatment did not select for mutant parasites. Nevertheless, IPTp-SP may be outdated by drug resistance before it is fully implemented.

Molecular characterization of enteric viral agents from children in northern region of Ghana.

Viral gastrointestinal infections are among the most important causes of childhood morbidity and mortality, especially in non-industrialized countries. The objective of this study was the molecular characterization of rotaviruses, noroviruses, adenoviruses, astroviruses, and enteroviruses obtained from 367 children in the Northern Region of Ghana. One hundred and forty-two rotavirus-positive stool samples were examined. The most frequent type identified was G1P[8] occurring in 80% of the cases. Of 27 norovirus positive samples, 5 isolates belonged to genogroup I and 22 to genogroup II. Adenoviruses were detected in 73 samples; 23.3% of these belonged to genogroup F, 31.5% to D, 17.8% to A, 15.1% to C, and 12.3% to B. Astrovirus typing of 12 positive samples displayed a distribution into four different genotypes: five sequences clustered with AstV-8, four with AstV-2, two with AstV-5, and one with AstV-6. Twenty-three different enterovirus types were identified in 45 positive samples, coxsackievirus A24 being the most frequent pathogen (18%). This first, comprehensive molecular characterization of enteric viruses in northern Ghana provides baseline data for the molecular epidemiology of these pathogens and immunisation strategies. The available rotavirus vaccines cover the predominant G1P[8] type and would reduce substantially disease burden in that area.

pfmdr1 mutations in imported African Plasmodium falciparum isolates.

Amodiaquine/artesunate and artemether/lumefantrine are currently implemented as antimalarial drugs in Africa. In this study, we assessed Plasmodium falciparum pfmdr1 alleles suggesting reduced sensitivity to amodiaquine/artesunate (86Y-184Y-1246Y) and artemether/lumefantrine (184F and 86N-184F-1246D) in 111 African isolates imported to Germany between 1997 and 2005. pfmdr1 86Y-184Y-1246Y occurred less frequently in West African isolates (2.5%) than in East African parasites (45.8%) (P<0.001) and less frequently in infections contracted in countries currently implementing amodiaquine/artesunate (5.7%) compared with countries with an artemether/lumefantrine policy (20.8%) (P=0.03). pfmdr1 184F showed an opposite pattern. pfmdr1 alleles reveal significant differences between West and East Africa, supporting the current implementation of first-line antimalarials.

Mannose-binding lectin variant associated with severe malaria in young African children.

Mannose-binding lectin (MBL) is a serum protein which initiates innate immune responses to microbial pathogens by binding to non-self surface oligosaccharides. MBL deficiency is the most common congenital immunodeficiency of human and has been shown to predispose to infections, particularly in children and immune compromised. In a matched case-control study among 870 Ghanaian children, we examined the influence of six polymorphisms of the MBL2 gene on Plasmodium falciparum infection and severe malaria. A missense mutation resulting in low MBL activity (MBL2*C) was found in 35% of healthy controls, but in 42% of asymptomatically infected children (P=0.01), and in 46% of patients with severe malaria (P=0.007). Heterozygosity for MBL2*C was associated with increased odds of infection (odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.1), severe malaria (OR, 1.7; 95% CI, 1.2-2.4), and of severe anemia in particular (OR, 2.3; 95% CI, 1.4-3.8). The population attributable fraction of severe malaria cases attributable to MBL2*C heterozygosity was 17%. Our results suggest that the MBL pathway of the complement system is a critical determinant of both, susceptibility to P. falciparum infection and manifestation of severe malaria, particularly in young children in whom specific immune responses are weak or absent.

High rate of resistance to locally used antibiotics among enteric bacteria from children in Northern Ghana.

OBJECTIVES: Information on antimicrobial susceptibility of bacterial pathogens is scarce in resource-poor settings. We determined the susceptibility of bacterial enteric pathogens and faecal Escherichia coli isolates obtained from children in urban Tamale, Northern Ghana, to antibiotics widely used in the that area [ampicillin or amoxicillin, trimethoprim/sulfamethoxazole (SXT) and chloramphenicol] and to alternative drugs. METHODS: Five Shigella spp., 6 Salmonella spp. and 318 E. coli were isolated from stool specimens obtained from 367 children with or without acute diarrhoea. Isolates were differentiated using standard laboratory procedures and tested using a breakpoint microbroth dilution method for their susceptibility to 18 antimicrobials and by disc diffusion for their susceptibility to chloramphenicol. RESULTS: Although the salmonellae showed an acceptable resistance pattern, E. coli isolates and the closely related shigellae were highly resistant. About 91% and 81% of E. coli isolates from patients or controls, respectively, were resistant to ampicillin (MICs > or = 8 mg/L), 88% and 76% to trimethoprim/sulfamethoxazole (MICs > or = 80/4 mg/L) and 46% and 41% to chloramphenicol (inhibition zones < or = 12 mm). Resistance to beta-lactam antibiotics or chloramphenicol was observed more frequently among isolates obtained from infants when compared with older children (1-4 years of age). CONCLUSIONS: Enteric bacteria from children in urban Northern Ghana are highly resistant to antibiotics used in that area. Therefore, new antibiotics should be introduced for the treatment of infections caused by these bacteria. Additionally, the establishment of a surveillance of the prevalence of the main bacterial infectious agents and their antimicrobial resistance is desirable.

Decline of placental malaria in southern Ghana after the implementation of intermittent preventive treatment in pregnancy.

BACKGROUND: Intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) has been adopted as policy by many countries in sub-Saharan Africa. However, data on the post-implementation effectiveness of this measure are scarce. METHODS: Clinical and parasitological parameters were assessed among women delivering at a district hospital in rural southern Ghana in the year 2000 when pyrimethamine chemoprophylaxis was recommended (n = 839) and in 2006 (n = 226), approximately one year after the implementation of IPTp-SP. Examinations were performed in an identical manner in 2000 and 2006 including the detection of placental Plasmodium falciparum infection by microscopy, histidine-rich protein 2, and PCR. RESULTS: In 2006, 77% of the women reported to have taken IPTp-SP at least once (26%, twice; 24%, thrice). In 2006 as compared to 2000, placental P. falciparum infection was reduced by 43-57% (P < 0.0001) and maternal anaemia by 33% (P = 0.0009), and median birth weight was 130 g higher (P = 0.02). In 2006, likewise, women who had taken > or = 1 dose of IPTp-SP revealed less infection and anaemia and their children tended to have higher birth weights as compared to women who had not used IPTp-SP. However, placental P. falciparum infection was still observed in 11% (microscopy) to 26% (PCR) of those women who had taken three doses of IPTp-SP. CONCLUSION: In southern Ghana, placental malaria and maternal anaemia have declined substantially and birth weight has increased after the implementation of IPTp-SP. Likely, these effects can further be increased by improving IPTp-SP coverage and adherence. However, the remnant prevalence of infection in women having taken three doses of IPTp-SP suggests that additional antimalarial measures are needed to prevent malaria in pregnancy in this region.

Acute childhood diarrhoea in northern Ghana: epidemiological, clinical and microbiological characteristics.

BACKGROUND: Acute diarrhoea is a major cause of childhood morbidity and mortality in sub-Saharan Africa. Its microbiological causes and clinico-epidemiological aspects were examined during the dry season 2005/6 in Tamale, urban northern Ghana. METHODS: Stool specimens of 243 children with acute diarrhoea and of 124 control children were collected. Patients were clinically examined, and malaria and anaemia were assessed. Rota-, astro-, noro- and adenoviruses were identified by (RT-) PCR assays. Intestinal parasites were diagnosed by microscopy, stool antigen assays and PCR, and bacteria by culturing methods. RESULTS: Watery stools, fever, weakness, and sunken eyes were the most common symptoms in patients (mean age, 10 months). Malaria occurred in 15% and anaemia in 91%; underweight (22%) and wasting (19%) were frequent. Intestinal micro-organisms were isolated from 77% of patients and 53% of controls (P < 0.0001). The most common pathogens in patients were rotavirus (55%), adenovirus (28%) and norovirus (10%); intestinal parasites (5%) and bacteria (5%) were rare. Rotavirus was the only pathogen found significantly more frequently in patients than in controls (odds ratio 7.7; 95%CI, 4.2-14.2), and was associated with young age, fever and watery stools. Patients without an identified cause of diarrhoea more frequently had symptomatic malaria (25%) than those with diagnosed intestinal pathogens (12%, P = 0.02). CONCLUSION: Rotavirus-infection is the predominant cause of acute childhood diarrhoea in urban northern Ghana. The abundance of putative enteropathogens among controls may indicate prolonged excretion or limited pathogenicity. In this population with a high burden of diarrhoeal and other diseases, sanitation, health education, and rotavirus-vaccination can be expected to have substantial impact on childhood morbidity.

Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana.

Morbidity and mortality from malaria remain unacceptably high among young children in sub-Saharan Africa. Intermittent preventive treatment in infancy (IPTi) involves the administration of antimalarials alongside routine vaccinations and might be an option in malaria control. In an area of intense, perennial malaria transmission in northern Ghana, 1,200 children received IPTi with sulfadoxine-pyrimethamine or placebo at approximately 3, 9, and 15 months of age. Children were followed up until 24 months of age to assess morbidity and adverse events. During the intervention period (3 to 18 months of age), IPTi reduced the incidences of malaria and severe anemia by 22.5% (95% confidence interval, 12 to 32%) and 23.6% (95% confidence interval, 4 to 39%), respectively, and reduced hospitalizations and episodes of asymptomatic parasitemia by one-third. Protection was pronounced in the first year of life and not discernible in the second. The malaria-protective effect was largely confined to a period of 1 month after sulfadoxine-pyrimethamine treatments. Following the intervention, protection against asymptomatic parasitemia persisted. In contrast, a significant rebound of severe malaria, predominantly severe malarial anemia, occurred among children having received IPTi. Although the treatment was generally well tolerated, one case of moderately severe skin reaction followed sulfadoxine-pyrimethamine treatment. IPTi reduces malaria and anemia in infants in northern Ghana. Extension of IPTi into the second year of life by administering a dose at 15 months of age provided no substantial benefit beyond a 1-month prophylactic effect. Although this simple intervention offers one of the few available malaria-preventive measures for regions where malaria is endemic, the observed rebound of severe malaria advises caution and requires further investigation.

Field evaluation of a rota- and adenovirus immunochromatographic assay using stool samples from children with acute diarrhea in Ghana.

We evaluated the Rida Quick rotavirus/adenovirus Combi rapid immunochromatographic test (ICT) under field conditions with Ghanaian children with acute diarrhea. Compared to PCR results, sensitivities and specificities were 75% and 95% for rotavirus and 22% and 84% for adenovirus. In resource-poor settings, ICTs may help to overcome difficulties in the diagnosis of rotavirus infection.

Large-scale surveillance of Plasmodium falciparum crt(K76T) in northern Ghana.

Surveillance of Plasmodium falciparum crt(K76T) [Pfcrt(K76T)], a resistance marker of chloroquine and, limitedly, amodiaquine, in >4,000 children in northern Ghana revealed a prevalence of 79%. Pfcrt(K76T) was heterogeneously distributed and associated with chloroquine use, low parasitemia, and the dry season. Widespread chloroquine resistance challenges the regional life span of amodiaquine as a partner drug in artemisinin combination therapy.

High residual chloroquine blood levels in African children with severe malaria seeking healthcare.

Despite widespread resistance, chloroquine remains widely used in West Africa, particularly in home treatment. We examined chloroquine blood levels on admission to a referral hospital with respect to the manifestation of severe malaria in 290 Ghanaian children. Of the patients, 78% exhibited chloroquine concentrations (subtherapeutic, 35%; therapeutic, 37%; supratherapeutic, 6%) and 11% died. Most parasites (78%) carried the pfcrt-T76 chloroquine resistance mutation. High drug concentrations correlated with reduced parasitaemia but also with selection of resistant parasites, lower respiratory and heart rates, increased plasma lactate levels and impaired consciousness. Geometric mean chloroquine concentrations tended to be higher in children who died than in survivors (1.135 vs. 778nmol/l; P=0.09). Supratherapeutic drug levels (>5000nmol/l) were associated with fatal outcome (odds ratio 8.6; 95% CI 1.4-51.7). Residual chloroquine concentrations were found to be abundant in children with severe malaria and to be associated with alterations in the clinical manifestation of the disease and its case fatality. This may result from toxic effects of the drug and/or reflect preceding overtreatment in children with acute life-threatening disease. In areas of intense chloroquine resistance and frequent pre-treatment, additional administration of chloroquine at hospital admission is not only ineffective but may even further endanger patients.

Vaccination against hepatitis B in liver transplant recipients: pilot analysis of cellular immune response shows evidence of HBsAg-specific regulatory T cells.

After liver transplantation for hepatitis-B-related diseases, patients currently receive lifelong treatment with hepatitis B immunoglobulin to prevent endogenous reinfection with hepatitis B virus (HBV). Active immunization with hepatitis B vaccine would be a preferable alternative; however, most attempts to immunize these patients with standard vaccine have failed. A recent study with a new adjuvanted hepatitis B vaccine was exceptionally successful, leading to a high-titered long-lasting antibody response in 80% of all vaccinees. To identify the immunological mechanisms behind these unexpected results, the successfully vaccinated participants were tested for hepatitis B surface antigen (HBsAg)-specific T and B cells, and their cellular responses to revaccination with conventional vaccine were studied. HBsAg-specific CD4(+) T lymphocytes could be detected in 13 of 16 patients after immunization with the new vaccine. Unexpectedly, these T cells produced almost exclusively interleukin (IL)-10 and had a CD4(+)/CD25(+) phenotype. They were functionally active, suppressing cytokine secretion in HBsAg-specific (Th1) cells, thus representing antigen-specific regulatory T cells (T(Reg)). Following a booster dose with conventional vaccine 22-31 months after completion of the initial vaccination series, the T-cell pattern in the revaccinated individuals changed substantially: 7 days after revaccination 9 of 11 individuals showed a switch to a Th1-type immune response with HBsAg-specific T cells secreting IL-2, interferon gamma and tumor necrosis factor alpha as observed in healthy controls. Four weeks after the booster, 4 patients still showed a Th1-type cytokine pattern, whereas in 5 patients only IL-10-secreting cells were detectable. After 1 year, in 3 of 4 revaccinated individuals only IL-10-secreting cells could be found, whereas the specific T cells of the fourth patient still showed a Th1-type of response. HBsAg-specific T(Reg) cells could be demonstrated in HBV-positive liver transplant recipients successfully immunized with a new adjuvanted vaccine. Revaccination led to immediate disappearance of the these cells and the appearance of HBsAg-specific T cells with a Th1-type cytokine profile, which in most cases were replaced by the IL-10-secreting regulatory cells during the following months. The specific induction of T(Reg) cells could contribute to the poor response of liver transplant recipients to conventional vaccine. In conclusion,, for successful vaccination of these patients, a vaccine with a strong inhibitory effect on T(Reg) cells would be desirable.

Field-based evidence for linkage of mutations associated with chloroquine (pfcrt/pfmdr1) and sulfadoxine-pyrimethamine (pfdhfr/pfdhps) resistance and for the fitness cost of multiple mutations in P. falciparum.

Mutations in the Plasmodium falciparum pfcrt gene on chromosome 7 and possibly mutations in pfmdr1 on chromosome 5 have a role in conferring resistance against chloroquine (CQ), as do mutations of pfdhfr on chromosome 4 and pfdhps on chromosome 8 in terms of resistance against sulfadoxine/pyrimethamine (SP). The additive role of multiple mutations in the development of resistance to each drug suggests a non-random occurrence. In this study, parasite isolates were obtained from 50 patients with uncomplicated P. falciparum malaria from rural Eastern Sudan, an endemic setting with minimal overlap of infection. The parasite isolates were genotyped for detection of 12 alleles in CQ and SP resistance genes. Our main findings were: (1) the frequency of mutant alleles, pfcrt K76T, pfmdr1 N86Y, pfdhfr N51I, pfdhfr S108N, pfdhps K540E and pfdhps A581G were; 0.90, 0.86, 0.84, 0.84, 0.80 and 0.20, respectively. (2) No mutations were detected for the pfdhfr loci A16V, C59R and I164L, and for pfdhps loci S436A, A437G and A613S. (3) There was a statistically significant association between the mutations in: (i) the CQ resistance (CQR) genes, pfcrt T76 and pfmdr1 Y86 (P< or =0.001), (ii) the SP resistance (SPR) genes, pfdhfr I51, pfdhfr N108 and pfdhps E540 (P< or =0.001-0.04) and (iii) the CQ "i" and SP "ii" resistance genes (P=0.001) 4. The fitness cost of multiple mutations was revealed by a significantly reduced parasite density of isolates bearing the mutant alleles (P=0.048). However, the significantly higher gametocyte carriage rate among isolates with resistance mutations (P=0.001) is possibly an evolutionary mechanism for survival of mutant parasites.

Markers of sulfadoxine-pyrimethamine-resistant Plasmodium falciparum in placenta and circulation of pregnant women.

Placental sequestration of Plasmodium falciparum in pregnancy may impair the usefulness of molecular markers of sulfadoxine-pyrimethamine resistance. In 300 infected, delivering women, the concordance of PCR-restriction fragment length polymorphism-derived parasite resistance alleles in matched samples from placenta and circulation was 83 to 98%. Sulfadoxine-pyrimethamine resistance typing in peripheral blood is reasonably representative of P. falciparum infecting pregnant women.

Detection and clinical manifestation of placental malaria in southern Ghana.

BACKGROUND: Plasmodium falciparum can be detected by microscopy, histidine-rich-protein-2 (HRP2) capture test or PCR but the respective clinical relevance of the thereby diagnosed infections in pregnant women is not well established. METHODS: In a cross-sectional, year-round study among 839 delivering women in Agogo, Ghana, P. falciparum was screened for in both, peripheral and placental blood samples, and associations with maternal anaemia, low birth weight (LBW) and preterm delivery (PD) were analysed. RESULTS: In peripheral blood, P. falciparum was observed in 19%, 34%, and 53% by microscopy, HRP2 test, and PCR, respectively. For placental samples, these figures were 35%, 41%, and 59%. Irrespective of diagnostic tool, P. falciparum infection increased the risk of anaemia. Positive peripheral blood results of microscopy and PCR were not associated with LBW or PD. In contrast, the HRP2 test performed well in identifying women at increased risk of poor pregnancy outcome, particularly in case of a negative peripheral blood film. Adjusting for age, parity, and antenatal visits, placental HRP2 was the only marker of infection associated with LBW (adjusted odds ratio (aOR), 1.5 (95%CI, 1.0-2.2)) and, at borderline statistical significance, PD (aOR, 1.4 (1.0-2.1)) in addition to anaemia (aOR, 2.3 (1.7-3.2)). Likewise, HRP2 in peripheral blood of seemingly aparasitaemic women was associated with PD (aOR, 1.7 (1.0-2.7)) and anaemia (aOR, 2.1 (1.4-3.2)). CONCLUSION: Peripheral blood film microscopy not only underestimates placental malaria. In this highly endemic setting, it also fails to identify malaria as a cause of foetal impairment. Sub-microscopic infections detected by a HRP2 test in seemingly aparasitaemic women increase the risks of anaemia and PD. These findings indicate that the burden of malaria in pregnancy may be even larger than thought and accentuate the need for effective anti-malarial interventions in pregnancy.

High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia.

BACKGROUND: In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is frequent and intense in some areas. METHODS: In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assessed. RESULTS: P. falciparum and P. vivax were observed in 69% and 31% of the patients, respectively. Pfdhfr triple mutations and pfdhfr/pfdhps quintuple mutations occurred in 87% and 86% of P. falciparum isolates, respectively. Pfcrt T76 was seen in all and pfmdr1 Y86 in 81% of P. falciparum. The P. vivax dhfr core mutations N117 and R58 were present in 94% and 74%, respectively. CONCLUSION: These data point to an extraordinarily high frequency of drug-resistance mutations in both P. falciparum and P. vivax in southern Ethiopia, and strongly support that both SP and CQ are inadequate drugs for this region.

Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy.

Toll-like receptors (TLRs) are involved in recognition of and response to Plasmodium falciparum. In 304 primiparous Ghanaian women, we examined whether common TLR4 and TLR9 polymorphisms influence susceptibility to and manifestation of malaria during pregnancy. The TLR variants did not affect P. falciparum prevalence or parasite density. However, in P. falciparum-infected women, both the TLR4 Asp299Gly and the TLR9 T-1486C polymorphisms increased the risk of low birth weight in term infants 6-fold, and, additionally, TLR4 Asp299Gly increased the risk of maternal anemia 5-fold; preterm delivery was not associated with these TLR variants. These findings suggest that TLR4 and TLR9 play a role in the manifestation of malaria during pregnancy.

Malaria, anemia, and malnutrition in african children--defining intervention priorities.

BACKGROUND: Malaria, anemia, and malnutrition contribute substantially to childhood morbidity in sub-Saharan Africa, but their respective roles and interactions in conferring disease are complex. We aimed to investigate these interactions. METHODS: In 2002, we assessed plasmodial infection, anemia, and nutritional indices in 2 representative surveys comprising >4000 children in northern Ghana. RESULTS: Infection with Plasmodium species was observed in 82% and 75% of children in the rainy and dry season, respectively. The fraction of fever attributable to malaria was 77% in the rainy season and 48% in the dry season and peaked in children of rural residence. Anemia (hemoglobin level, <11 g/dL) was seen in 64% of children and was, in multivariate analysis, associated with young age, season, residence, parasitemia, P. malariae coinfection, and malnutrition (odds ratio [OR], 1.68 [95% confidence interval [CI], 1.38-2.04]). In addition, malnutrition was independently associated with fever (axillary temperature, > or = 37.5 degrees C; OR, 1.59 [95% CI, 1.13-2.23]) and clinical malaria (OR, 1.67 [95% CI, 1.10-2.50]). CONCLUSIONS: Malnutrition is a fundamental factor contributing to malaria-associated morbidity and anemia, even if the latter exhibits multifactorial patterns. Our data demonstrate that malaria-control programs alone may not have the desired impact on childhood morbidity on a large scale without concomitant nutrition programs.