Severe malaria in an unstable setting: clinical and laboratory correlates of cerebral malaria and severe malarial anemia and a paradigm for a simplified severity scoring.

An interpretation of historical, clinical, and laboratory data was made to identify the correlates of and the diversity between cerebral malaria (CM) and severe malarial anemia (SMA) in a setting of low, seasonal, and unstable malaria transmission in eastern Sudan. Hemoglobin (Hb), random blood glucose (RBG), and anti-MSP antibodies were measured. Results showed that SMA and CM were significantly different with regard to age, malaria history, fever duration, convulsions, and hepatosplenomegaly. The MSP Ab response was inversely correlated with the number of previous malaria episodes but not with fever duration in the current attack. The spleen size was significantly inversely correlated with Hb level while hepatomegaly was significantly associated with low RBG. Furthermore, two malaria patients presented with neuropsychiatric upset. Finally, the correlates of SMA and CM fit perfectly with an adopted severity numeric scoring.

High frequency of Plasmodium falciparum CICNI/SGEAA and CVIET haplotypes without association with resistance to sulfadoxine/pyrimethamine and chloroquine combination in the Daraweesh area, in Sudan.

Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti-malarial drug resistance. In this study, malaria patients treated with SP alone (60) and SP with CQ (194) had a total treatment failure (TF) of 35.4%, with no difference between the two arms. The polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) method was used to identify polymorphisms in 15 loci in the dhfr, dhps and pfcrt genes in a subset of 168 infections. The results revealed a similar frequency of all single nucleotide polymorphisms (SNPs) in the two arms, except dhps 581G, which was over-represented in infections that failed to respond to SP alone (TF). In all infections, a high frequency of dhfr CICNI haplotype (51I and 108N) was found, but without discrimination between the adequate clinical and parasitological response (ACPR, 75.6%) and TF (82.9%). Similarly, the dhps SGEAA haplotype (437G and 540E) (ACPR, 60.5%; TF, 65.9%) and the combined CICNI/SGEAA haplotype (ACPR, 50%; TF 55%) were not associated with TF. In contrast to other studies in Africa, the triple 51I/59R/108N mutation was rare (0.6%). In addition, the pfcrt CVIET haplotype (93%) was found to be associated with the CICNI/SGEAA haplotype. Finally, these data represent a baseline for SP resistance molecular markers needed before the deployment of SP/artesunate combination therapy in the Sudan.

Determinants of variant surface antigen antibody response in severe Plasmodium falciparum malaria in an area of low and unstable malaria transmission.

The variant surface antigens (VSA) of infected erythrocytes are important pathogenic markers, a set of variants (VSA(SM)), were assumed to be associated with severe malaria (SM), while SM constitutes clinically diverse forms, such as, severe malarial anemia (SMA) and cerebral malaria (CM). This study was conducted in Eastern Sudan, an area of seasonal and unstable malaria transmission. Parasites and plasma were obtained from patients with different clinical grades of malaria, and flow cytometry was used for analysis of VSA antibody (Ab) response. We found that individuals recognized a broader range of isolates had a higher level of VSA Ab against the recognized isolates (correlation coefficient, 0.727, P<0.001). Unexpectedly, at the time of malaria diagnosis, plasma from patients with CM recognized a significantly larger number of isolates than did the plasma from patients with SMA (P<0.001). Parasites obtained from patients with SMA or from children were better recognized than isolates obtained from patients with uncomplicated malaria or from adults, P<0.001, P=0.021, respectively. Taken together, the above findings suggest that the limitations in the VSA immunoglobulin G repertoire were most probably contributing to the pathogenesis of SMA but not to that of CM.

A comparison of the efficacy of artesunate plus sulfadoxine-pyrimethamine with that of sulfadoxine-pyrimethamine alone, in the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan.

In an open, randomized, clinical trial, conducted in New Halfa, eastern Sudan, in September-October 2004, the efficacies and adverse effects of artesunate plus sulfadoxine-pyrimethamine (SP), in the treatment of uncomplicated, Plasmodium falciparum malaria, were compared with those of SP alone. Patients were randomized to receive either artesunate (4 mg/kg. day) on days 0-2 plus SP (25 mg sulfadoxine/kg) on day 0 or the SP alone, and then followed-up for 28 days. Sixty patients completed follow-up. Compared with the 30 given artesunate plus SP (ASP), the 30 given SP alone were much more likely to be febrile (30% v. 3.3%; P=0.006) and parasitaemic (50% v. 6.7%; P<00001) on day 1. By day 3, 16.7% of the patients given SP alone were still febrile and 6.7% of them were still parasitaemic, although all the patients given ASP were then afebrile (P=0.02) and aparasitaemic (P=0.1). Five (16.7%) of the patients treated with SP alone but none of those given ASP appeared to be treatment failures (P<0.05). Parasite genotyping revealed that four of the five apparent treatment failures were true recrudescences but the other represented a re-infection detected on day 28. The true frequencies of cure by day 28 were therefore 100% for ASP and 86.7% for SP alone (P=0.02). Adverse effects of treatment (nausea, itching and giddiness) were observed with similar frequencies in the two treatment arms (10.0% of the patients given ASP v. 13.3% of the patients given SP alone; P>0.05). The frequencies of gametocytaemia during follow-up were, however, much lower in the ASP arm than in the SP-only (0.0% v. 23.3%; P=0.005).Thus, although the problems posed by adverse effects were similar in the two treatment arms, ASP appeared markedly better, in terms of fever- and parasite-clearance times and the prevalence of post-treatment gametocytaemia, than SP alone.

Submicroscopic Plasmodium falciparum infections during pregnancy, in an area of Sudan with a low intensity of malaria transmission.

There are few published studies on the burden of malaria during pregnancy from areas of sub-Saharan Africa where the intensity of malarial transmission is low, and few on submicroscopic malarial infections in pregnant women. The present study was conducted in New Halfa, an area of low-intensity transmission in eastern Sudan, between August 2003 and July 2004. The main aims were to assess the prevalences of submicroscopic and multiple Plasmodium falciparum infections in pregnant women (using the P. falciparum merozoite surface protein-2 as a polymorphic marker in PCR-based assays) and to determine the effects of such infections on anaemia during pregnancy. Of the 142 pregnant women who were recruited, only 17 (11.9%) were found smear-positive for P. falciparum by microscopy. The results of the PCR-based assays revealed, however, that 40 (32%) of the 125 smear-negative women had submicroscopic P. falciparum infections. Blood samples from 32 (80%) of those with submicroscopic infections showed only the FC 27 allele (of merozoite surface protein-2), six (15%) showed only the ICI allele, and two (5%) showed both of these alleles. Although the age, parity, gestational age and haemoglobin concentrations of the women with submicroscopic P. falciparum infections were not significantly different from those of the women who were smear- and PCR-negative, such infections may have a significant impact on materno-foetal health.

Efficacies of mefloquine alone and of artesunate followed by mefloquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan.

In late 2003, the efficacies of mefloquine monotherapy and of an artesunate-mefloquine combination, for the oral treatment of uncomplicated, Plasmodium falciparum malaria, were investigated and compared in New Halfa, in eastern Sudan. Of the patients who completed the 28 days of follow-up, 40 were treated only with single-dose mefloquine (at a dose of 25 mg/kg), and 38 with artesunate (at 4 mg/kg. day) for 3 days followed by single-dose mefloquine (at 15 mg/kg), given on the third day. Compared with those given the combination, the patients given mefloquine alone were more likely to suffer nausea, vomiting and dizziness (25.0% v. 2.6%; P=0.005) and to be found gametocytaemic (12.5% v. 0%; P=0.02) after treatment, and more likely to be found febrile (i.e. with a temperature >37.5 degrees C) on day 2 (25.0% v. 2.6%; P=0.005), although no patients were found febrile on day 3. Six of the patients--three (7.5%) of those given mefloquine only and three (7.9%) of those given the combination (P>0.05)--appeared to be treatment failures. Parasite genotyping indicated, however, that, although five of these six patients had true recrudescences, one (who had been treated with the combination) had been re-infected during the follow-up. The true frequencies of cure were therefore 92.5% after mefloquine alone and 94.7% after the combination (P>0.05). Thus, although the treatments appeared equally effective in clearing parasitaemias, the combination was better at clearing gametocytaemias and was less likely to cause adverse side-effects. It remains unclear why mefloquine given alone was almost 10-fold more likely to trigger adverse effects than treatment with a combination that contained the same drug. This may be a reflection of the different mefloquine doses and, for the patients given the combination, of the use of artesunate before the mefloquine treatment.

Clinical pattern of severe Plasmodium falciparum malaria in Sudan in an area characterized by seasonal and unstable malaria transmission.

A hospital-based study was carried out in Gedarif town, eastern Sudan, an area of markedly unstable malaria transmission. Among the 2488 diagnosed malaria patients, 4.4% fulfilled the WHO criteria for severe malaria, and seven died of cerebral malaria. The predominant complication was severe malarial anemia (45.4%), followed by convulsions (21%), cerebral malaria (16. 4%) and hypotension (11.8%). Severe malaria was recognized in all age groups, but 44.5% of patients were aged 2 to 4 years. The mean ages of patients with severe anemia (5.6 years) and convulsions (5.9 years) were significantly lower than the mean ages of patients with cerebral malaria (14.1 years) or hypotension (35.2 years). Patients with convulsions and cerebral malaria had significantly higher mean parasite count (69972 and 56110 parasites/microL, respectively) than patients with severe anemia (24637 parasites/microL) or hypotension (13667 parasites/microL). The mean blood glucose level was higher in patients with cerebral malaria than in patients with anemia, and higher in patients who died than in patients who survived. In this setting, the clinico-epidemiological pattern of severe malaria varies considerably from that of hyperendemic regions in sub-Saharan Africa, and there is considerable variation between the individual complications of severe malaria.