Falciparum Infection In Children Research Articles

Recrudescent Plasmodium falciparum infections in children in an endemic area following artemisinin–based combination treatments: Implications for disease control

Objective To evaluate the features and risk factors associated with recrudescent infections that arose following artemisinin-based combination drug treatment of the primary infections. Methods The clinical features and risk factors associated with subsequent recrudescence of primary Plasmodium falciparum infections were evaluated in 37 of 877 children following artesunate or artemisinin-based combination treatments (ACTs). Recrudescence was determined by polymerase chain reaction. Results Compared to children with sensitive infections, children with recrudescent infections had significantly higher gametocytaemia and proportion with parasitaemia >50 000/μL. Compared with primary infections, recrudescent infections that arose from primary infections were accompanied by significantly fewer symptoms, lower body temperatures and asexual parasitaemias. In age- and gender-matched children with and without recrudescence, declines in parasitaemias following treatment were monoexponential but elimination half-life of parasitaemia was significantly longer in children with recrudescence. In a multiple regression model, at enrolment, 3 factors were independent risk factors for subsequent recrudescence of primary infections: parasitaemia ⩾50 000/μL [adjusted odds ratio (AOR)=2.63, 95% confidence interval ( CI): 1.17-5.90, P=0.018], parasite clearance time ⩾2 days (AOR=2.47, 95% CI: 1.24-4.90, P=0.04) and treatment with artesunate compared with ACTs (AOR=2.35, 95% CI: 1.08-5.12, P=0.03). Conclusions Recrudescent infections following artesunate or ACTs differ significantly from the primary infections from which they arose and have implications for malaria control efforts in Sub-Saharan Africa where ACTs are now first-line treatments.

Platelet Factor 4 Regulation of Monocyte KLF4 in Experimental Cerebral Malaria

Cerebral malaria continues to be a difficult to treat complication of Plasmodium falciparum infection in children. We have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ECM). One of the platelet derived mediators we have identified as particularly important is platelet factor 4/CXCL4. Our prior work demonstrated that PF4−/− mice are protected from ECM, have reduced plasma cytokines, and have reduced T-cell trafficking to the brain. We now show that PF4 drives monocyte cytokine production in a Kruppel like factor 4 (KLF4) dependent manner. Monocyte depleted Plasmodium berghei infected mice have improved survival, and KLF4 is greatly increased in control, but not monocyte depleted mice. PF4−/− mice have less cerebral monocyte trafficking and no change in KLF4 expression. These data indicate that PF4 induction of monocyte KLF4 expression may be an important step in the pathogenesis of ECM.

Nutritional and socio-economic factors associated with Plasmodium falciparum infection in children from Equatorial Guinea: results from a nationally representative survey

BackgroundMalaria has traditionally been a major endemic disease in Equatorial Guinea. Although parasitaemia prevalence on the insular region has been substantially reduced by vector control in the past few years, the prevalence in the mainland remains over 50% in children younger than five years. The aim of this study is to investigate the risk factors for parasitaemia and treatment seeking behaviour for febrile illness at country level, in order to provide evidence that will reinforce the EG National Malaria Control Programme.MethodsThe study was a cross-sectional survey of children 0 to 5 years old, using a multistaged, stratified, cluster-selected sample at the national level. It included a socio-demographic, health and dietary questionnaires, anthropometric measurements, and thick and thin blood smears to determine the Plasmodium infection. A multivariate logistic regression model was used to determine risk factors for parasitaemia, taking into account the cluster design.ResultsThe overall prevalence of parasitemia was 50.9%; it was higher in rural (58.8%) compared to urban areas (44.0%, p = 0.06). Age was positively associated with parasitemia (p < 0.0001). In rural areas, risk factors included longer distance to health facilities (p = 0.01) and a low proportion of households with access to protected water in the community (p = 0.02). Having had an episode of cough in the 15 days prior to the survey was inversely related to parasitemia (p = 0.04). In urban areas, the risk factors were stunting (p = 0.005), not having taken colostrum (p = 0.01), and that someone in the household slept under a bed net (p = 0.002); maternal antimalarial medication intake during pregnancy (p = 0.003) and the household socio-economic status (p = 0.0002) were negatively associated with parasitemia. Only 55% of children with fever were taken outside their homes for care, and treatment seeking behaviour differed substantially between rural and urban populations.ConclusionResults suggest that a national programme to fight malaria in Equatorial Guinea should take into account the differences between rural and urban communities in relation to risk factors for parasitaemia and treatment seeking behaviour, integrate nutrition programmes, incorporate campaigns on the importance of early treatment, and target appropriately for bed nets to reach the under-fives.

Antibody response dynamics to the Plasmodium falciparum conserved vaccine candidate antigen, merozoite surface protein-1 C-terminal 19kD (MSP1-19kD), in Peruvians exposed to hypoendemic malaria transmission

BackgroundIn high-transmission areas, developing immunity to symptomatic Plasmodium falciparum infections requires 2–10 years of uninterrupted exposure. Delayed malaria-immunity has been attributed to difficult-to-develop and then short-lived antibody responses.MethodsIn a study area with <0.5 P. falciparum infections/person/year, antibody responses to the MSP1-19kD antigen were evaluated and associations with P. falciparum infections in children and adults. In months surrounding and during the malaria seasons of 2003–2004, 1,772 participants received ≥6 active visits in one study-year. Community-wide surveys were conducted at the beginning and end of each malaria season, and weekly active visits were completed for randomly-selected individuals each month. There were 79 P. falciparum infections with serum samples collected during and approximately one month before and after infection. Anti-MSP1-19kD IgG levels were measured by ELISA.ResultsThe infection prevalence during February-July was similar in children (0.02–0.12 infections/person/month) and adults (0.03–0.14 infections/person/month) and was negligible in the four-month dry season. In children and adults, the seroprevalence was maintained in the beginning (children = 28.9%, adults = 61.8%) versus ending malaria-season community survey (children = 26.7%, adults = 64.6%). Despite the four-month non-transmission season, the IgG levels in Plasmodium-negative adults were similar to P. falciparum-positive adults. Although children frequently responded upon infection, the transition from a negative/low level before infection to a high level during/after infection was slower in children. Adults and children IgG-positive before infection had reduced symptoms and parasite density.ConclusionIndividuals in low transmission areas can rapidly develop and maintain αMSP1-19kD IgG responses for >4 months, unlike responses reported in high transmission study areas. A greater immune capacity might contribute to the frequent asymptomatic P. falciparum infections in this Peruvian population.

Platelet Factor 4 Mediates Inflammation in Experimental Cerebral Malaria

Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection in children. The pathogenesis of CM involves vascular inflammation, immune stimulation, and obstruction of cerebral capillaries. Platelets have a prominent role in both immune responses and vascular obstruction. We now demonstrate that the platelet-derived chemokine, platelet factor 4 (PF4)/CXCL4, promotes the development of experimental cerebral malaria (ECM). Plasmodium-infected red blood cells (RBCs) activated platelets independently of vascular effects, resulting in increased plasma PF4. PF4 or chemokine receptor CXCR3 null mice had less severe ECM, including decreased T cell recruitment to the brain, and platelet depletion or aspirin treatment reduced the development of ECM. We conclude that Plasmodium-infected RBCs can directly activate platelets, and platelet-derived PF4 then contributes to immune activation and T cell trafficking as part of the pathogenesis of ECM.

Effects of ConcomitantSchistosoma haematobiumInfection on the Serum Cytokine Levels Elicited by AcutePlasmodium falciparumMalaria Infection in Malian Children

Polyparasitism is common in the developing world, and interactions that alter disease severity may occur. We previously demonstrated that infection with Schistosoma hematobium was associated with protection against Plasmodium falciparum infection in children who were 4 to 8 years old. In this study, we determined whether underlying helminth infections affected the cytokine responses to acute falciparum malaria. A total of 338 schistosomiasis-positive [Sch(+)] children who were 4 to 14 years old were matched by age, residence, and sex with 338 schistosomiasis-negative [Sch(-)] children and monitored for a malaria transmission season (25 weeks). Serologic cytokine levels were measured at the time of the first clinical malaria episode and in children who did not contract malaria. Elevated background levels of interleukin-6 (IL-6) (37.1 pg/ml versus 10.9 pg/ml [P = 0.04]), IL-4 (27.7 pg/ml versus 6.9 pg/ml [P = 0.02]), IL-10 (18.2 pg/ml versus 7.2 pg/ml [P < 0.001]), and gamma interferon (18.2 pg/ml versus 4.7 pg/ml [P = 0.006]) were noted in Sch(+) children compared to Sch(-) children without malaria. IL-6 and IL-10 levels were elevated in association with acute malaria, but the levels appeared to be blunted in Sch(+) children compared to Sch(-) children who were 4 to 8 years old (for IL-6, 96.2 pg/ml versus 137.2 pg/ml [P = 0.08]; for IL-10, 195.9 pg/ml versus 282.2 pg/ml [P = 0.06]). The level of IL-10 was similarly lower in Sch(+) children than in Sch(-) children who were 9 to 14 years old (91.2 pg/ml versus 141.2 pg/ml [P = 0.03]). IL-4 levels were inversely correlated with the time until the first malaria infection in both the Sch(+) children (P < 0.001) and the Sch(-) children (P < 0.001) who were 4 to 8 years old. We postulate that the Th2-enriched environment induced by schistosomiasis protects against malaria and alters the cytokine milieu during an actual infection.

Risk of Plasmodium falciparum infection during a malaria epidemic in highland Kenya, 1997

Malaria epidemics in highland areas of East Africa have occurred with increasing frequency since the late 1980s, but the actual risk of Plasmodium falciparum infection in children and adults during these epidemics has not been well characterized. During a malaria epidemic in a highland area of Kenya, risk of infection was assessed in 50 adults (≥18 years old) and 32 children (≤8 years old) after treatment and parasitologic clearance with sulfadoxine-pyrimethamine treatment. Over a 10-week period, 36 of the 82 study participants (43.9%) became infected. The risk of infection was similar in children and adults (hazard ratio for children = 1.21, 95% CI: 0.63–2.33). These findings contrast with the age-related protection from infection reported in areas of stable, intense transmission, and demonstrate that during malaria epidemics, both children and adults in highland areas of Kenya are at high risk of infection.

Complexity and genetic diversity of Plasmodium falciparum infections in young children living in urban areas of Central and West Africa.

A site-based characterization of Plasmodium falciparum infections in children living in two malaria hyperendemic urban areas from West and Central Africa was undertaken. A total of 58 and 46 children with either asymptomatic infections or uncomplicated (symptomatic) malaria were recruited in Gabon and Benin, respectively. Parasite density, hematological factors, the genetic diversity of P. falciparum merozoite surface protein 2 (msp2) and the complexity of infections (mean number of P. falciparum genotypes per infected child) were used for this characterization. Gabonese children with uncomplicated malaria presented a higher mean axillary temperature (39.2 vs 38.6, P=0.004) and a higher geometric mean parasite density (30,538 vs 18,921, P<0.001) associated with a significantly lower hemoglobin level ( P<0.01). A higher degree of msp2 polymorphism and the complexity of P. falciparum infections were also observed in children from Gabon ( P<0.05). With a similar level of malaria transmission in both urban sites, these results suggest an impact of malaria control interventions on the dynamics of concurrent P. falciparum infections.

Epilepsias mioclónicas en la infancia

Malaria is one of the main health problems in the Third World. Plasmodium falciparum infects as many as 300 million people, causing up to three million deaths each year, most of which occur in African children. Cerebral malaria is the most common lethal complication of P. falciparum infection in children and is defined by three criteria: disturbances of consciousness, presence of P. falciparum parasitaemia and absence of other causes of acute encephalopathy. Cerebral malaria is a medical emergency and parenteral quinine is the most recommended treatment because of the frequency of chloroquine-resistant strains. Mortality is as high as 50 per cent and residual disability is present in about 20 per cent of survivors. We want to warm Spaniard neuropaediatricians about the existence of cases of cerebral malaria in our country in order to get a better diagnose and treatment for those children. A retrospective medical scores review of 20 hospitalised children diagnosed of malaria from 1990 to 1998. We selected three cases with neurological signs and we analysed clinical onset, EEG, neuroimaging, and permanent sequels. All patients had acute encephalopathy with fever, obtundation and seizures. They all presented residual disability (mainly hemiparesis). We must know better about cerebral malaria because of an increasing incidence of imported malaria due to emigration from African countries and Spaniard tourism to areas of endemic paludism.

Enhanced efficacy of chloroquine-chlorpheniramine combination in acute uncomplicated falciparum malaria in children

Chlorpheniramine, a histamine H 1 receptor antagonist, reverses chloroquine resistance in Plasmodium falciparum in vitro. However, the clinical significance of this remains unclear. We have evaluated the efficacy of chloroquine and a chloroquine-chlorpheniramine combination in 112 consecutive children with acute symptomatic uncomplicated falciparum malaria. There was no significant difference in the parasite and fever clearance times in the 2 treatment groups. However, the proportion of patients in whom parasitaemia increased 24 h after commencement of treatment was significantly higher in the chloroquine group than in the chloroquine-chlorpheniramine group (28·5% vs. 8·3%,χ 2 = 6·61, P < 0·01). There was also a higher proportion of children with RII and RIII responses to treatment in the chloroquine than in the chloroquine-chlorpheniramine group but the difference was not statistically significant. The cure rate on day 14 was higher in the chloroquine-chlorpheniramine group than in the chloroquine group. Chloroquine and its combination with chlorpheniramine were well tolerated, the only prominent adverse effect being pruritus, with equal incidence in both groups. Chlorpheniramine reversed chloroquine resistance in vitro in a similar manner to verapamil in isolates of P. falciparum obtained from the patients. Failure of a response in vivo to chloroquine correlated with resistance in vitro in patients treated with this drug. In contrast, all but one patient with isolates which were chloroquine resistant in vitro were successfully treated with chloroquine-chlorpheniramine combination. These data suggest the enhanced efficacy of chloroquine-chlorpheniramine combination in treating acute uncomplicated P. falciparum infection in children from an endemic area of Nigeria.

Low-level Plasmodium falciparum transmission and the incidence of severe malaria infections on the Kenyan coast.

The transmission of Plasmodium falciparum was studied in relation to the incidence of severe malaria infections at Sokoke and Kilifi town, Kilifi District, Kenya. Intensive mosquito sampling during a one-year period yielded Anopheles gambiae s.l., An. funestus, and An. coustani. Anopheles gambiae s.l. was the predominant vector, comprising 87.9% and 97.9% of the total anophelines collected in Sokoke and Kilifi town, respectively. The proportion of An. gambiae s.l. with P. falciparum sporozoite infections was 4.1% (20 of 491) in Sokoke and 2.2% (3 of 138) in Kilifi town; no infections were detected in An. funestus or in An. coustani. Entomologic inoculation rates indicated that residents were exposed to only 8.0 infective bites per year in Sokoke and 1.5 in Kilifi town. Transmission was detected during only six months in Sokoke and three months in Kilifi town despite low-level, year-round vector activity. The yearly incidence of severe P. falciparum infections in children, 1-4 years of age was 24.1 per 1,000 in Sokoke and 4.2 per 1,000 in Kilifi town. Monthly patterns of transmission corresponded closely with the incidence of severe infections. At these sites on the coast of Kenya, the spatial and temporal incidence of severe malaria infections is associated with low-level P. falciparum transmission by vector populations.

Comparative efficacy of alternative primary therapies for Plasmodium falciparum infections in Malawi

In Malawi, where high levels of chloroquine resistance were shown using a modified 7-day in vivo test, amodiaquine and pyrimethamine-sulfadoxine were evaluated as alternative initial therapies for Plasmodium falciparum infections in children under 5 years old. Therapy success rates, judged by parasite clearance by day 7 after initiation of therapy, were significantly greater among 39 children treated with amodiaquine at 10mg/kg (90%), 37 receiving amodiaquine at 25 mg/kg (97%), and 34 receiving pyrimethamine-sulfadoxine (100%) at a dose of 25 mg sulfadoxine/kg, than among those treated with chloroquine at a dose of 25 mg/kg (59%) ( P = 0·01). Extension of the follow-up period of those receiving amodiaquine (25mg/kg) and pyrimethamine-sulfadoxine to 21 d revealed a progressively increasing rate of parasite recrudescence in the amodiaquine group (34%), but no recrudescence in the pyrimethamine-sulfadoxine group. These results suggest that, in Malawi, amodiaquine and pyrimethamine-sulfadoxine are superior to chloroquine in producing prompt clearance of P. falciparum parasites among young children, and that pyrimethamine-sulfadoxine alone is superior to the 4-aminoquinolines in sustaining P. falciparum clearance.