Red cell selectivity in malaria: a study of multiple-infected erythrocytes.

To characterize red cell susceptibility to invasion in malaria, a selectivity index (SI) was calculated as the ratio of observed number of multiple-infected red cells to that expected from a random process (Poisson distribution). In patients with falciparum malaria (n = 100) SI decreased with increasing parasitaemia (P < 0.001), and correlated inversely with plasma lactate concentrations, chosen prospectively as a measure of disease severity (r = -0.36, P < 0.001). For parasitaemias < 5%, the SI was lower in patients with severe malaria (geometric mean 1.35; 95% confidence interval 1.01-1.80) than in uncomplicated malaria (2.31; 1.89-2.81; P = 0.003), despite similar parasite counts. The geometric mean (range) SI in vivax malaria (n = 20), 7.69 (1.67, 29.75), was significantly greater than that in falciparum malaria at comparable parasitaemias (< or = 2%), 2.44 (0.45, 14.05), P < 0.001, suggesting that about 13% of circulating erythrocytes were susceptible to invasion by Plasmodium vivax. This translates into susceptibility for about 2 weeks after emergence from the bone marrow, if age is the sole determinant of this process. In falciparum malaria selectivity was inversely proportional to severity; lack of selectivity could reflect either a 'favourable' host red cell phenotype, or an indiscriminate parasite population. Both are dangerous for the host.     

The interaction between sickle haemoglobin and the malarial parasite Plasmodium falciparum

The mechanism whereby heterozygous carriers of the sickle cell gene are protected against fatal malarial infections due to Plasmodium falciparum has been examined in a short term in vitro cultivation system. The results have show that both parasite invasion of red cells and parasite growth within red cells containing sickle haemoglobin (Hb-S) is restricted, but only under conditions of low (5%) oxygen tensions. To bring this about, the cells containing Hb-S need not sickle. Furthermore the growth retardation observed in the presence of Hb-S was also found to apply to the mature forms of the parasite. These findings offer a plausible mechanism for the protection of sickle heterozygotes against falciparum malaria.     

Malaria control using permethrin applied to tents of nomadic Afghan refugees in northern Pakistan.

Malaria control among nomadic populations has, in the past, posed serious logistic difficulties. Presented in this article are the results of a pilot study in which permethrin was sprayed on the tents of over 26000 nomadic Afghan refugees in an area of Pakistan where seasonal malaria outbreaks occur. In this area Anopheles culicifacies and A. stephensi are the malaria vectors. Population surveys in the year of the study, before and at the end of the transmission season, showed that the increase in the Plasmodium falciparum prevalence among the Afghan nomads was on average significantly less (increase from 6.4% to 15.3%) than that among the resident Pakistani population (from 3.2% to 45.6%). Surveys at the end of the transmission season among primary schoolchildren the year before and the year of the permethrin trial showed that the P. falciparum prevalence among nomadic children decreased significantly (from 46.9% to 16.3%), whereas an increase was observed among the local Pakistani children. The results show that spraying tents with permethrin was a safe and culturally acceptable intervention for the Afghan refugees and that the findings warrant further investigation.     

Malaria in refugees from Tanzania--King County, Washington, 2007

Recent immigrants and refugees constitute a substantial proportion of malaria cases in the United States, accounting for nearly one in 10 imported malaria cases involving persons with known resident status in 2006. This report describes three cases of Plasmodium falciparum malaria and two cases of Plasmodium ovale malaria that occurred during June 27-October 15, 2007 in King County, Washington. The infections were diagnosed in Burundian refugees who had recently arrived in the United States from two refugee camps in Tanzania. Since 2005, CDC has recommended presumptive malaria treatment with artemisinin-based combination therapy (ACT) (e.g., artemether-lumefantrine) for refugees from sub-Saharan Africa before their departure for the United States (2). Rising levels of resistance to the previous mainstays of treatment, chloroquine and sulfadoxine-pyrimethamine, prompted CDC to make this recommendation. Implementation has been delayed in some countries, including Tanzania, where predeparture administration of presumptive ACT for refugees started in July 2007. The cases in this report highlight the need for health-care providers who care for recently arrived Burundian and other refugee populations to be vigilant for malaria, even among refugees previously treated for the disease.     

Plasmodium malariae in Haitian refugees, Jamaica

Since 1963, reported malaria transmission in Haiti has been restricted to Plasmodium falciparum. However, screening of Haitian refugees in Jamaica in 2004, by microscopic examination, identified P. falciparum, P. vivax, and P. malariae. PCR confirmed the P. malariae and P. falciparum but not P. vivax infections. DNA sequencing and rRNA gene sequences showed transmission of P. malariae. This report confirms that P. malariae is still being transmitted in Haiti.     

A stable, oligosymptomatic malaria focus in Thailand

Blood from most of the 250 residents of a non-migratory farming village in south-eastern Thailand was visually examined for malaria parasites monthly for 2 years. Nearly 97% of the population had at least one (median = 5) patent Plasmodium falciparum infection per year; 72% had one due to P. vivax (median = 1). This contrasted with a slide positivity rate of 17% calculated from 12 months of passive case detection before the study began. Children 1-9 years old had the highest mean monthly prevalence (51%) and highest geometric mean density (10/500 white blood cells) of P. falciparum. Fewer than half the expected number of mixed infections were found but these were more common at high densities of P. falciparum. Individuals over 19 years old comprised 52% of the population but accounted for only 18% of P. vivax and 32% of P. falciparum gametocytaemias. Fever rates were marginally higher in those below 10 years old (8%) but occurred with equal frequency in those with patent infections or negative. The spleen rate (89% stage 1) was 24% in those under 15 years old and 7% in those older. No malaria mortality was seen P. falciparum cases treated for 10 d with quinine+tetracycline (QT) cleared the infection as often as those given one dose of mefloquine+sulfadoxine+pyrimethamine (MSP); both treatments reduced densities in cases not cured. Apparently unsupervised compliance was no better with MSP than with QT. The role played by hyperendemic, cryptic foci in Asian epidemics of malaria may have been underestimated.     

Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies

Insecticide-treated mosquito nets (ITN) provide excellent protection against malaria; however, they have a number of shortcomings that are particularly evident in politically unstable countries or countries at war: not everyone at risk can necessarily afford a net, nets may be difficult to obtain or import, nets may not be suitable for migrants or refugees sleeping under tents or plastic shelter. There is a need to develop cheaper, locally appropriate alternatives for the most impoverished and for victims of complex emergencies. Afghan women, in common with many Muslim peoples of Asia, wear a veil or wrap known as a chaddar to cover the head and upper body. This cloth doubles as a sheet at night, when they are used by both sexes. A randomized controlled trial was undertaken in which 10% of the families of an Afghan refugee camp (population 3950) in north-western Pakistan had their chaddars and top-sheets treated with permethrin insecticide at a dosage of 1 g/m2 while a further 10% had their chaddars treated with placebo formulation. Malaria episodes were recorded by passive case detection at the camp's health centre. From August to November the odds of having a falciparum or vivax malaria episode were reduced by 64% in children aged 0-10 years and by 38% in refugees aged < 20 years in the group using permethrin-treated chaddars and top-sheets. Incidence in refugees over 20 years of age was not significantly reduced. The cost of the permethrin treatment per person protected (US$0.17) was similar to that for treating bednets (and cost only 10-20% of the price of a new bednet). An entomological study simulating real-life conditions indicated that host-seeking mosquitoes were up to 70% less successful at feeding on men sleeping under treated chaddars and some were killed by the insecticide. Permethrin-treated top-sheets and blankets should provide appropriate and effective protection from malaria in complex emergencies. In Islamic and non-Islamic countries in Asia, treated chaddars and top-sheets should offer a satisfactory solution for the most vulnerable who cannot afford treated nets.     

Prevalence and level of antibodies to the circumsporozoite proteins of human malaria parasites, including a variant of Plasmodium vivax, in the population of two epidemiologically distinct areas in the state of Acre, Brazil.

A seroepidemiological study of the prevalence of antibodies against the repeating epitopes of circumsporozoite (CS) proteins of human malaria parasites was conducted in 2 different areas in the state of Acre, Brazil in 1987 and 1990. In 1987 antibodies against the CS protein of the VK 247 variant Plasmodium vivax as well as antibodies against the CS proteins of P. falciparum and the classic P. vivax were found at relatively high rates in the 2 areas, but significant microepidemiological differences were observed. In 1990, when large scale migration in Amazonia had ceased and control measures were applied in the study areas, the malaria endemicity decreased, as determined by the declining prevalence of anti-sporozoite antibodies against all Plasmodium species, and the small number of individuals with positive blood smears. Antibodies against sporozoites of the variant P. vivax did not cross-react with the CS proteins of the classic P. vivax, nor with antibodies against sporozoites of P. falciparum and P. malariae. Sera containing antibodies against the CS protein of P. malariae were found at a very low frequency, and only in 1987. The anti-CS protein antibody response to all Plasmodium species was age-related.     

Evaluation of a new Plasmodium lactate dehydrogenase assay (OptiMAL-IT) for the detection of malaria

The new OptiMAL-IT(R) rapid diagnostic test for malaria was evaluated in 271 patients in Thailand with uncomplicated malaria between June and July 2002. The sensitivity and specificity for the diagnosis of Plasmodium falciparum parasites were 88% and 92%, respectively. For species other than P. falciparum, the sensitivity was 65% and specificity was 99%. The performance of the new test decreased markedly at low levels of parasitaemia.     

Seasonal variation in hyperparasitaemia and gametocyte carriage in patients with Plasmodium falciparum malaria on the Thai-Burmese border

Between January 2000 and December 2002 monthly rainfall was correlated with the proportion of patients with hyperparasitaemic Plasmodium falciparum malaria and with the proportion of patients with P. falciparum gametocytes. During the observation period 6953 cases of P. falciparum malaria were treated at the Shoklo Malaria Research Unit in Maela refugee camp on the Thai-Burmese border. Three hundred and seventy-five of these patients had >/=4% of parasitized red blood cells. Although there were more monthly malaria cases in the rainy season, rainfall was negatively correlated with the proportion of patients with hyperparasitaemia (Spearman's rho = -0.59, P < 0.001 ), and the proportion of gametocyte carriers among P. falciparum cases, (Spearman's rho = -0.39, P = 0.018). After controlling for age and the origin of the patient, the odds ratio for developing hyperparasitaemia during the dry season was 1.6 (95% CI 1.14-2.2; P = 0.006). The adjusted odds ratio for gametocyte carriage during the dry season was 1.3 (95% CI 1.03-1.6; P = 0.02). Migrations, changes in transmission patterns, the haematological burden of cumulative infections, and ultraviolet immunosuppression are discussed as potential explanations for these observations.     

Inhibitory effect of beta zero-thalassaemia/haemoglobin E erythrocytes on Plasmodium falciparum growth in vitro

The growth of Plasmodium falciparum in erythrocytes from individuals with beta zero-thalassaemia or haemoglobin (Hb) E, or both, was assessed in vitro. A significant inhibitory effect on the growth of the parasite was found only with erythrocytes from individuals doubly heterozygous for beta zeros-thalassaemia and HbE. The inhibitory effect was particularly marked with erythrocytes from splenectomized beta zeros-thalassaemia/HbE patients. The protective effect was related to HbF, Hb levels and shape abnormalities of the variant erythrocytes.     

Red cell exchange, erythrocytapheresis, in the treatment of malaria with high parasitaemia in returning travellers

In severe falciparum malaria with high parasitaemia, removal of parasitized erythrocytes is generally considered to be of value as adjunctive therapy in addition to standard chemotherapy. Such removal is commonly achieved by exchange transfusion but this procedure is time-consuming and may be associated with haemodynamic disturbance. Current-generation automated cell-separator hardware and software allows prompt red cell exchange, erythrocytapheresis, in a single continuous-flow isovolaemic procedure. We describe the application of this procedure to 5 cases of severe falciparum malaria in travellers returning to the UK from the tropics. All patients also received quinine and conventional supportive therapy. In all cases, dramatic reduction in parasitaemia was achieved within 2 h with subsequent complete clinical recovery. Erythrocytapheresis has significant advantages over exchange transfusion in terms of speed, efficiency, haemodynamic stability and retention of plasma components such as clotting factors and may thus represent an improvement in adjunctive therapy for severe malaria.     

The treatment of severe falciparum malaria.

In severe falciparum malaria there is a pathophysiological cascade beginning with changes in the parasitized red blood cells which induce intermediate effects, in turn contributing to dysfunction of several organs. A low serum albumin is a common but often unrecognized finding which may contribute to oedema especially in the lung and brain. The only irreversible complication in falciparum malaria is the acute respiratory distress syndrome, manifested by cyanosis and rapid breathing, basically distinct from acute pulmonary oedema caused by therapeutic overhydration. The pathophysiology of falciparum malaria may be complex but the treatment is simple. Drugs, other than antimalarials, are rarely needed. Guidelines for cholorquine or quinine dosage in severe disease are proposed; each drug is given at a dose of 5 to 10 mg/kg in 10 ml/kg of fluid as an intravenous infusion in four hours at a frequency of dosing every 12 to 24 hours. When the disease has been brought under control the treatment should be changed from the intravenous to the oral route.     

Current situation of malaria in Japan and its prevention

Cases of malaria have increased steadily in Japan during the past 20 years, and deaths have been reported. Patients with malaria were all infected in regions where the disease is prevalent (imported malaria). A report from the former West Germany noted a high mortality rate (9.3%) among patients with falciparum malaria. According to the report, the pathological manifestation of the disease and its complications are extremely complex. This report discusses malaria in Japan, especially falciparum malaria, with particular emphasis on the above findings.     

Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria

Approximately one million children die from malaria each year. A recently approved artemisinin-based tablet, Coartem (co-artemether), comprising artemether 120 mg plus lumefantrine 20 mg, given in four doses, provides effective antimalarial treatment for children in many sub-Saharan countries. However, this regimen is considered insufficient for non-immune infants and in areas where multidrug-resistant Plasmodium falciparum predominates. This open-label study assessed the efficacy and safety of co-artemether administered to 310 African children weighing 5-25 kg, with acute, uncomplicated falciparum malaria. Six doses of co-artemether were given over 3 days, with follow-up at 7, 14 and 28 days. Treatment rapidly cleared parasitemia and fever. The overall 28-day cure rate was 86.5%, and 93.9% when corrected by PCR for reinfection. Cure rates at 7 and 14 days exceeded 97.0% (uncorrected) and, on day 28, were similar in infants (5-<10 kg) previously exposed to malaria infection (partially immune: 88.6% uncorrected; 93.3% corrected), and in those who were non-immune (82.5% uncorrected; 95.0% corrected). Adverse events were mostly mild. There was no electrocardiographic evidence of cardiotoxicity. The co-artemether six-dose regimen, treating acute uncomplicated falciparum malaria in African children, achieved rapid parasite clearance and a high cure rate. Treatment was generally safe and well tolerated.     

Malaria in Afghan refugees in Pakistan

Prevalence of malaria in Afghan refugees in Pakistan is higher than in the local population. Malaria control officials in Pakistan hypothesized that Afghan refugees have brought a heavy load of malaria infections with them from Afghanistan, causing a serious setback to the malaria control programme in Pakistan. The purpose of this study was to test this hypothesis, because it is important regarding the selection of appropriate strategy for malaria control. The proposed hypothesis is rejected because of the following evidence against it: (i) a comparison of age-specific parasite rates of malaria in Afghan refugees and a nearby local population at Karachi indicated that Afghan refugees were susceptible to malaria even in later age-groups, while infections in the local population were limited to younger age-groups; (ii) a comparison of epidemiological trends of malaria in Afghan refugees and the local population in the North-West Frontier Province from 1979 to 1986 demonstrated that the rate of increase in the prevalence of malaria over the years was much higher in Afghan refugees than in the local population, a manifestation of low herd immunity in Afghan refugees. The most plausible alternate hypothesis is that Afghan refugees, being more susceptible, were at high risk of malaria infection in Pakistan rather than that they brought a high infection load with them from Afghanistan. Therefore, malaria control in Afghan refugee camps in Pakistan should be primarily based on preventive, rather than curative, measures.     

Control of malaria: a successful experience from Viet Nam

OBJECTIVE: To follow malaria prospectively in an ethnic minority commune in the south of Viet Nam with high malaria transmission and seasonal fluctuation, during malaria control interventions using insecticide-treated bednets (ITBNs) and early diagnosis and treatment (EDT) of symptomatic patients. METHODS: From 1994 onwards the following interventions were used: distribution of ITBNs to all households with biannual reimpregnation; construction of a health post and appointment of staff trained in microscopic diagnosis and treatment of malaria; regular supply of materials and drugs; annual cross-sectional malaria surveys with treatment of all parasitaemic subjects, and a programme of community involvement and health education. Surveys were held yearly at the end of the rainy season. During the surveys, demographic data were updated. Diagnosis and treatment of malaria were free of charge. Plasmodium falciparum infection was treated with artesunate and P. vivax infection with chloroquine plus primaquine. FINDINGS: The baseline survey in 1994 recorded 716 inhabitants. Of the children under 2 years of age, 37% were parasitaemic; 56% of children aged 2-10 years, and 35% of the remaining population were parasitaemic. P. falciparum accounted for 73-79% of these infections. The respective splenomegaly rates for the above-mentioned age groups were 20%, 56%, and 32%. In 1999, the proportion of parasitaemic subjects was 4%, 7% and 1%, respectively, of which P.falciparum contributed 56%. The splenomegaly rate was 0%, 5% and 2%, respectively. CONCLUSIONS: A combination of ITBNs and EDT, provided free of charge, complemented by annual diagnosis and treatment during malaria surveys and community involvement with health education successfully brought malaria under control. This approach could be applied to other regions in the south of Viet Nam and provides a sound basis for further studies in other areas with different epidemiological patterns of malaria.     

Hereditary ovalocytosis and reduced susceptibility to malaria in Papua New Guinea

Ovalocytosis, an hereditary condition in which most erythrocytes are oval in shape, is a polymorphism that occurs in up to 20% or more of the population in Papua New Guinea and Malaysia. Due to the geographical correlation of the trait with endemic malaria, the possibility of a selective advantage in resistance to malaria has been raised. In a study of 202 individuals with greater than or equal to 50% oval red cells matched by age, sex and village of residence with controls having less than or equal to 30% oval cells, ovalocytic subjects had blood films negative for Plasmodium vivax (P = 0.009), for P. falciparum (P = 0.044), and for all species of malaria parasites (P = 0.013), more often than controls. Among individuals parasitaemic at any time there were no clear differences in density of parasitaemia. However, in children 2 to 4 years old, parasite densities of both species were lower in ovalocytic subjects than in controls (0.01 less than P less than 0.025). The differential susceptibility to malaria infection suggested by this study has implications for the evaluation of interventions, including possible future vaccine field trials, in populations where high-frequency ovalocytosis is present.     

A study of the role of immunological factors in the pathogenesis of the anaemia of acute malaria.

Children with acute Plasmodium falciparum malaria and anemia were investigated to see if immunological factors could be implicated in the pathogenesis of their anaemia. Direct Coombs tests using an anti-whole immunoglobulin antiserum were negative in all 12 children tested but two had positive tests with antisera to C3b and C3d. Low plasma levels of C3 and C4 were found but these were not significantly different from values found in a group of children with acute malaria who were not anaemic. Serum levels of immune complexes were normal at the time of their presentation at hospital with anaemia but were elevated one month later. Incubation of group O rhesus-negative red cells in a serum pool obtained from children with acute malaria and anaemia did not cause enhanced haemolysis or reduce their survival time on injection into mice. Splenic uptake of red cells was, however, significantly enhanced. We conclude that the anaemia of acute malaria is due mainly to destruction of red cells by malaria parasites and to enhanced erythrophagocytosis of normal cells.     

Severe malaria

Severe or complicated malaria is defined by infestation by Plasmodium falciparum into all red blood cells, especially those in the brain, causing coma and repeated convulsions; severe anemia (6 g/dl hemoglobin, 20% hematocrit); renal insufficiency (265 mcmol/l creatinine, 400 ml/day diuresis); pulmonary edema; hypoglycemia (2.2 ml/l or 0.4 g/l); shock; diffuse hemorrhaging; massive hemoglobinuria; and blood acidosis. Other possible symptoms of severe malaria are clouded thinking, changes in behavior, and inability to focus. It is most common in people with no immunity to malaria (children aged 4 and travelers in endemic zones). Pregnancy, splenectomy, corticotherapy, or poorly maintained immunity status favor severe anemia in adults. Sources of chloroquine-resistant P. falciparum have existed since 1960. Resistance has since expanded from Southeast Asia and South America to Africa, posing treatment problems. Malaria usually begins with fever (40 or more degrees Celsius), headaches, muscular pain, digestive troubles (e.g., diarrhea, nausea, or vomiting), and abdominal pain. In suspected cases of malaria, a blood sample or a thick blood smear as well as treatment (even in the absence of parasitological proof) needs to be done as soon as possible. Intravenous quinine diluted in a 5-10% glucose solution should be delivered at a rate of 24 mg/kg/day. In the case of severe jaundice, the dose should be cut in half beginning 8 hours after treatment began. If intravenous delivery is impossible, intramuscular delivery should be done. Corticosteroids, anticoagulants, and aspirin are contraindicated. In 2-4 days, oral administration (chloroquine, halofantrine, or mefloquine) is warranted. 20% of malaria-related deaths among patients who receive treatment are due to complications of the central nervous system. Protection against mosquito bites prevents malaria. Chemoprophylaxis in endemic zones should be limited to short trips to malaria zones or to pregnant women.