Clinical case definitions and malaria vaccine efficacy

Reported efficacies from vaccine trials may depend heavily on the clinical case definition used in the trial. The dependence may be particularly striking for diseases such as malaria, in which no single case definition is appropriate. We used logistic regression modeling of the relationship between parasitemia and fever in data sets from Ghanaian children to determine the fraction of fevers attributable to malaria and to model how the choice of a threshold parasitemia in the clinical case definition affects the measured efficacy of malaria vaccines. Calculated clinical attack rates varied 10-fold as a function of the threshold parasitemia. Strikingly, measured vaccine efficacies in reducing clinical malaria depended heavily on the threshold parasitemia, varying between 20% and 80% as the threshold varied between 1 and 5000 parasites/ microL. We suggest that clinical case definitions of malaria that incorporate a threshold parasitemia are arbitrary and do not yield stable estimates of vaccine trial end points.     

HIV, malaria parasites, and acute febrile episodes in Ugandan adults: a case-control study.

BACKGROUND: In sub-Saharan Africa, co-infection with HIV and malaria is probably very common. Although an interaction between the two infections is biologically plausible, it has not been investigated thoroughly. OBJECTIVES: To evaluate the association firstly between co-infection with HIV and malaria parasites and the occurrence of acute fever, and secondly between HIV infection and clinical malaria, defined as the presence of acute fever and malaria parasites. METHODS: A hospital-based case-control study was conducted in Gulu District (northern Uganda), an area endemic for malaria and with a high HIV prevalence. HIV testing and malaria parasite quantification were performed on 167 consecutive adult out-patients with acute fever and no signs or symptoms of localized infection, and on 134 consecutive adult in-patients without fever who were admitted for non-HIV-related trauma or elective surgery. RESULTS: No significant association with acute fever was observed for single infection with either malaria parasites [adjusted odds ratio (AOR), 1.75; 95% confidence interval (CI), 0.73-4.21] or HIV (AOR, 1.01; 95% CI, 0.51-2.03), whereas a significant association was observed for co-infection (AOR, 9.75; 95% CI, 1.19-80.00). An association was found between HIV infection and clinical malaria (AOR, 2.34; 95% CI, 0.89-6.17); the association became statistically significant when the definition of clinical malaria included a cut-off for parasite density (50th percentile; i.e., 586 parasites/microl; AOR, 3.61; 95% CI, 1.04-12.52). CONCLUSIONS: Despite the limited statistical power, the results of our study show an association between HIV infection and clinical malaria; if confirmed, this finding could be important for public health in sub-Saharan Africa.     

Case definitions of clinical malaria under different transmission conditions in Kilifi District, Kenya

BACKGROUND: Clear case definitions of malaria are an essential means of evaluating the effectiveness of present and proposed interventions in malaria. The clinical signs of malaria are nonspecific, and parasitemia accompanied by a fever may not be sufficient to define an episode of clinical malaria in endemic areas. We defined and quantified cases of malaria in people of different age groups from 2 areas with different rates of transmission of malaria. METHODS: A total of 1602 people were followed up weekly for 2 years, and all the cases of fever accompanied by parasitemia were identified. Logistic regression methods were used to derive case definitions of malaria. RESULTS: Two case definitions of malaria were derived: 1 for children 1-14 years old and 1 for infants (<1 year old) and older children and adults (> or =15 years old). We also found a higher number of episodes of clinical malaria per person per year in people from an area of low transmission of malaria, compared with the number of episodes in those from an area of higher transmission (0.84 vs. 0.55 episodes/person/year; incidence rate ratio, 0.66 [95% confidence interval, 0.61-0.72]; P<.001). CONCLUSIONS: Case definitions of malaria are bound to be altered by factors that affect immunity, such as age and transmission. Case definitions may, however, be affected by other immunity-altering factors, such as HIV and vaccination status, and this needs to be borne in mind during vaccine trials.     

Altitude-dependent and -independent variations in Plasmodium falciparum prevalence in northeastern Tanzania

BACKGROUND: Effective malaria control requires information about intensity of transmission across large areas and populations. Estimates based on entomological factors lack precision and are not cost-effective to obtain. We tested altitude and rainfall measurements as correlates of transmission intensity in different ecological settings. METHODS: We conducted 2 cross-sectional surveys of approximately 12,000 people (1-45 years old) in 6 altitude transects (150-1800 m) in the Kilimanjaro and Tanga regions of Tanzania. Data were analyzed for associations with altitude and rainfall estimates by use of appropriate regression models. RESULTS: Plasmodium falciparum prevalence showed a negative relationship with altitude (19% and 21% decrease/100-m altitude increase, respectively, in children in Kilimanjaro and Tanga) and rainfall during the 3 months before the survey (46% decrease/100-mm rainfall increase in children in Kilimanjaro). Mean hemoglobin concentrations increased with altitude (0.05 and 0.09 g/dL/100-m altitude increase, respectively, in children in Kilimanjaro and Tanga) and rainfall (0.17 g/dL/100-mm rainfall increase in children and adults in Kilimanjaro). DISCUSSION: Altitude and rainfall were correlated with parasite prevalence and mean hemoglobin concentration; however, the relationship varied according to ecological setting. Climatological variables alone cannot predict malarial outcomes. Local variations in seasonality of malaria transmission--together with vector species composition, topography, host and parasite genetics, and socioeconomic factors--may influence malaria prevalence.     

What does a single determination of malaria parasite density mean? A longitudinal survey in Mali

Temporal variations of blood parasite density were evaluated in a longitudinal study of young, asymptomatic men in a village with endemic malaria in Mali (West Africa). Our main intention was to challenge the value of a single measure of parasite density for the diagnosis of malaria, and to define the level of endemicity in any given area. Parasitaemia and body temperature were recorded three times a day in the wet season (in 39 subjects on 12 days) and in the dry season (in 41 subjects on 13 days). Two thousand nine hundred and fifty seven blood smears (98.5% of the expected number) were examined for malaria parasites. We often found 100-fold or greater variations in parasite density within a 6-hour period during individual follow-up. All infected subjects had frequent negative smears. Although fever was most likely to occur in subjects with a maximum parasite density exceeding 10000 parasites/mm3 (P = 0.009), there was no clear relationship between the timing of these two events. Examples of individual profiles for parasite density and fever are presented. These variations (probably due to a 'sequestration-release' mechanism, which remains to be elucidated) lead us to expect a substantial impact on measurements of endemicity when only a single sample is taken. In this study, the percentage of infected individuals varied between 28.9% and 57.9% during the dry season and between 27.5% and 70.7% during the wet season. The highest rates were observed at midday, and there were significant differences between days. Thus, high parasite density sometimes associated with fever can no longer be considered as the gold standard in the diagnosis of malaria. Other approaches, such as decision-making processes involving clinical, biological and ecological variables must be developed, especially in highly endemic areas where Plasmodium infection is the rule rather than the exception and the possible causes of fever are numerous.     

Season, fever prevalence and pyrogenic threshold for malaria disease definition in an endemic area of Mali

BACKGROUND: Modelling malaria parasitaemia as function of fever has been proposed as best alternative to estimate the attributable fraction of malaria fever and the sensitivity and specificity of different case definitions of malaria disease. OBJECTIVES: To determine the prevalence of fever and its relation to malaria parasitaemia and to establish a pyrogenic threshold for malaria disease in the area. METHODS: We conducted two cross-sectional surveys in children of 6 months to 9 years of age (2434 during the rainy season of 1993 and 2353 during the dry season of 1994) randomly selected from 21 areas of Bandiagara district, Mali. RESULTS: The relationship between fever and Plasmodium falciparum parasitaemia depends strongly on the season, thus affecting the malaria-attributable fraction of fever cases and the sensitivity and specificity of malaria case definitions. The overall proportion of fever attributable to malaria parasitaemia was 33.6% during the rainy season and 23.3% during the dry season, with the highest proportion occurring among the youngest children. The cut-off value, where the sensitivity curve crosses the specificity curve, was around 3200 pf/microl for all age categories during the rainy season and 200 pf/microl during the dry season. CONCLUSIONS: Malaria remains a main cause of fever in this area of Mali. The pyrogenic threshold of parasitaemia depends strongly on the season, and different cut-off levels of parasitaemia should be used during the two seasons to define malaria cases in this area.     

Long-term asymptomatic carriage of Plasmodium falciparum protects from malaria attacks: a prospective study among Senegalese children.

BACKGROUND: In areas of seasonal malaria transmission, long-term asymptomatic carriage of Plasmodium falciparum throughout the dry season has been primarily studied in terms of the parasites, and the clinical consequences of persistent parasite carriage are unknown. METHODS: A prospective study was conducted in Senegal, from 2001 through 2003 among 1356 children living in areas where malaria is endemic, with seasonal transmission occurring from August through December. Cross-sectional parasitological measurements and detection of active malaria attacks were performed. A malaria attack was defined as an axillary temperature > or =37.5 degrees C, associated with a parasite density >2500 trophozoites/microL. Children harboring P. falciparum in June who did not have clinical signs were defined as asymptomatic carriers. The association of asymptomatic carriage with parasite densities and with the occurrence of malaria attacks during the rainy season were analyzed separately for the years 2002 and 2003, taking into account potential confounding covariates and use of antimalarial drugs. RESULTS: The prevalence of asymptomatic carriage was 32% (332 of 1025 persons) in June 2002 and 23% (208 of 912 persons) in June 2003. Asymptomatic P. falciparum carriers had a significantly higher mean parasite density and a significantly lower probability of developing a malaria attack during the subsequent rainy season than did noncarriers (adjusted odds ratio in 2002, 0.56; P = .01; adjusted odds ratio in 2003, 0.50; P = .01). CONCLUSIONS: These results suggest that in areas of seasonal transmission, asymptomatic carriage of P. falciparum may protect against clinical malaria. Further studies are needed to understand the immune effectors and host susceptibility that could be involved in this phenomenon.     

Parasite density and malaria morbidity in the Pakistani Punjab

The relationship between quantitative Plasmodiumfalciparum or P. vivax parasitemia and clinical illness has not been defined in Pakistan or in other areas where malaria transmission is not highly endemic. Standardized questionnaires were given to and physical examinations and parasitologic tests were performed in 8,941 subjects seen in outpatient clinics in 4 villages for 13 consecutive months in the Punjab region of Pakistan. The results, based on multivariable analysis, showed that a clinical diagnosis of malaria, a history of fever, rigors, headache, myalgia, elevated temperature, and a palpable spleen among children were all strongly associated with the presence and density of P. falciparum or P. vivax malaria in a monotonic dose-response fashion. The malaria attributable fraction of a clinical diagnosis of malaria, and the same symptoms and signs also increased with increasing P. falciparum and, to a lesser extent, P. vivax, parasitemia. Unlike in sub-Saharan Africa, clinical illness due to malaria often occurs in the Punjab among adolescents and adults and in patients with parasite densities less than 1,000/microl. Clinical guidelines based upon parasitemia and symptomatology must be adjusted according to the intensity of transmission and be specific for each geographic area.     

Spatial distribution of Burkitt's lymphoma in Kenya and association with malaria risk

Endemic Burkitt's lymphoma (BL) is the most common paediatric malignancy in equatorial Africa and was originally shown to occur at high-incidence rates in regions where malaria transmission is holoendemic. New ecological models of malaria that are based on both parasite prevalence and disease have been described. In this study, we examined district level data collected from paediatric BL cases in Kenya from 1988 through 1997 and assessed whether the distribution of district level incidence rates could be explained by new ecologic estimates of malaria risk. Chi-square tests and log-linear regression models were used to evaluate these associations. An association with tribe of origin as a factor also was examined. The 10-year average annual incidence rate (IR) for Kenya was 0.61 per 100,000 children. Incidence rates varied by malaria transmission intensity as follows: low malaria risk (BL IR = 0.39), arid/seasonal (0.25), highland (0.66), endemic coast (0.68), and endemic lake (1.23) (chi(2) = 11.32, P = 0.002). In a log-linear model, BL rates were 3.5 times greater in regions with chronic and intense malaria transmission intensity than in regions with no or sporadic malaria transmission (odds ratio = 3.47, 95% confidence interval = 1.30-9.30), regardless of tribe. Although crude tribe-specific incidence rates ranged between 0.0 and 3.26, tribe was not associated with BL after controlling for malaria. These findings support the aetiologic role of intense malaria transmission intensity in BL.     

Relationship between entomological inoculation rate,Plasmodium falciparum prevalence rate,and incidence of malaria attack in rural Gabon

To assess the relationships between variations of Plasmodium falciparum transmission and those of peripheral parasitaemia prevalence or malaria attack incidence rates in regions with limited fluctuations of transmission, we conducted a follow-up in two Gabonese populations. Entomological surveys were carried out from May 1995 to April 1996 in Dienga, and from May 1998 to April 1999 in Benguia. In Dienga, malaria transmission was seasonal, being not detected during two 3-month periods. Mean entomological inoculation rate (EIR) was 0.28 infective bite/person/night. In Benguia, malaria transmission was perennial with seasonal fluctuations, mean EIR being 0.76 infective bite/person/night. In Dienga, 301 schoolchildren were followed from October 1995 to March 1996. Clinical malaria attack was defined as fever associated with >5000 parasites/microl of blood. P. falciparum prevalence varied from 28 to 42%, and monthly malaria attack incidence from 30 to 169 per thousand. In Benguia, the entire population (122 persons) was followed from November 1998 to April 1999. Prevalence varied from 22 to 50%, and monthly malaria attack incidence from 52 to 179 per thousand. In each area, entomological variations were not related to parasite prevalence, but preceded malaria attack incidence with 1- or 2-month time lag, corresponding to the pre-patency period that differs in the two populations, possibly according to differences in immunity related to parasite transmission.     

Relationship between parasite density and fever risk in a community exposed to a low level of malaria transmission in Madagascar highlands

To establish a simple definition of a malaria attack based on blood parasite density and other explanatory covariates, a cohort study was conducted from 1993 to 1996 in the Madagascar highlands undergoing a low seasonal transmission of falciparum malaria. Using logistic regression, the explanatory variables found to be significantly related to the risk of fever are parasite density, age, season, and year. However, and in contrast with other studies, we found no evidence of a clear cutoff in parasite density values consistent with the concept of "pyrogenic threshold" despite a gradual increase of the risk of fever with increasing parasite density. Furthermore, the model evidenced an individual-dependent relationship at a given age. This point was in accordance with the immunological data recorded from the participants. The investigators conclude that the parasite density to distinguish malaria attacks from other causes of fever is not reliable in a context of low falciparum transmission.     

The role of low level Plasmodium falciparum parasitaemia in anaemia among infants living in an area of intense and perennial transmission

Summary Children under one year of age in an area of intense and perennial Plasmodium falciparum transmission were followed up for one year to establish to what extent chronic, low parasitaemia was associated with severe anaemia. There was a significant increase in the prevalence of anaemia (PCV ≥ 25%) with increase in parasite density. PCV levels were related not only to concurrent parasite density but also decreased with densities measured one month previously. At any point in time, the mean PCV level in infants with low parasitaemia (<1000 parasites/μ1) was higher than that of infants with intermediate (1000–9999/μ1) and high parasite densities (≥10 000/μl). After the age of 7 months, infants with low parasite densities tend to recover, probably as a result of developing immunity. At the age of 12 months, they have similar PCV levels to infants with no detectable parasitaemia by microscopy. The maintenance of low parasite density appears crucial to the survival of infants in malaria endemic areas. The findings suggest that interventions which lower parasite densities in areas of intense transmission reduce the development of severe malarial anaemia and thus malaria-related mortality and morbidity in infants.     

Infection with versus Exposure to Taenia solium: What Do Serological Test Results Tell Us?

Taenia solium cysticercosis is an endemic zoonosis in many developing countries. Serological tests are the most appropriate diagnostic tools to understand the transmission dynamics of the parasite, but the performances of these methods in such a setting are not known. A south Ecuadorian human population living in an endemic area was tested using three common serological tests. Because none of them is a gold standard, a Bayesian Latent Class analysis was used to estimate the test characteristics. Two definitions of a case were considered to differentiate between prevalence of current infection and prior exposure to the parasite. Differences between the performances of the same test in function of the definition of a case were observed. This study shows that test results and prior information should be interpreted carefully in a Bayesian analysis framework, particularly when the latter is based on clinical studies.     

Acridine orange fluorescent microscopy and the detection of malaria in populations with low-density parasitemia

Detection of low-density malaria parasites with Giemsa-stained thick smears (G-TS) requires time and experience and becomes impractical with high sample loads. Acridine orange fluorescent microscopy (AO/FM) of capillary centrifuged blood may offer an alternative technique. We compared AO/FM readings with G-TS in 290 specimens from asymptomatic people in Thai villages endemic for malaria. AO/FM specimens were prepared in modified capillary tubes coated with acridine orange (Quantitative Buffy Coat or "QBC tubes") and examined under a fluorescent microscope. Twenty-three (85.2%) of the 27 specimens found positive by G-TS had under 100 parasites/microliters blood (less than 35 parasites/200 microscopic fields). The overall AO/FM sensitivity was 78.9% [range: 66.7% (10/15)-86.7% (13/15)]. For Plasmodium falciparum, regardless of stages, the sensitivities varied from 66.7% (8/12) to 91.7% (11/12). AO/FM performed better for P. falciparum than for Plasmodium vivax and for asexual than for sexual stages of the parasite. However, the species- and stage-specific results must be interpreted with caution because of the small sample sizes and very low parasite densities involved. The test specificity was 96.6% [range: 95.6% (263/275)-97.1% (263/271)]. These levels of accuracy plus the known advantages of AO/FM suggest that the test, supplemented with G-TS to improve species and stage differentiation, is also useful for screening low-density parasitemias.     

Plasmodium gallinaceum preferentially invades vesicular ATPase-expressing cells in Aedes aegypti midgut

Penetration of the mosquito midgut epithelium is obligatory for the further development of Plasmodium parasites. Therefore, blocking the parasite from invading the midgut wall disrupts the transmission of malaria. Despite such a pivotal role in malaria transmission, the cellular and molecular interactions that occur during the invasion are not understood. Here, we demonstrate that the ookinetes of Plasmodium gallinaceum, which is related closely to the human malaria parasite Plasmodium falciparum, selectively invade a cell type in the Aedes aegypti midgut. These cells, unlike the majority of the cells in the midgut, do not stain with a basophilic dye (toluidine blue) and are less osmiophilic. In addition, they contain minimal endoplasmic reticulum, lack secretory granules, and have few microvilli. Instead, these cells are highly vacuolated and express large amounts of vesicular ATPase. The enzyme is associated with the apical plasma membrane, cytoplasmic vesicles, and tubular extensions of the basal membrane of the invaded cells. The high cost of insecticide use in endemic areas and the emergence of drug resistant malaria parasites call for alternative approaches such as modifying the mosquito to block the transmission of malaria. One of the targets for such modification is the parasite receptor on midgut cells. A step toward the identification of this receptor is the realization that malaria parasites invade a special cell type in the mosquito midgut.     

Distinction of recrudescences from new infections by pcr-rflp analysis in a comparative trial of cgp 56 697 and chloroquine in Tanzanian children.

Summary objective To test the efficacy of a new compound drug (CGP 56 697) against acute, uncomplicated falciparum malaria. method Reappearing parasites were analysed by PCR-RFLP within a randomized controlled trial. 130 patients received chloroquine and 130 patients were treated with CGP 56 697. Samples from 96 patients with parasitological failure were tested by PCR-RFLP for MSP2 of Plasmodium falciparum. Seven days after treatment 32 patients of the chloroquine control group with reappearing parasites were tested by PCR and one infection was unequivocally determined as a new infection. After 7 days, in the CGP 56 697 group, 6 samples were tested in which one new infection was identified. Similar observations were made one and three weeks later in both groups. results Although a high multiplicity of infections on admission was observed, there was no significant correlation between multiplicity and either recrudescence or new infection. Patients in both treatment groups with subsequent recrudescent parasites had higher initial mean parasite densities than patients who cleared. Those of the patients with recrudescent parasites who were treated with CGP 56 697 had higher initial parasite densities than those treated with chloroquine. The rate of re-infection increased with time as expected in holoendemic areas and appeared to be higher in chloroquine patients. Generally, CGP 56 697 showed a superior clearance rate, successfully cleared higher parasite densities and suppressed new infections over a longer period of time. conclusion The PCR analysis confirmed that reinfections beyond day 7 are significant in areas highly endemic for malaria and showed the necessity of excluding these when estimating 14 day clearance rates. Provided new infections are excluded, the 28-day clearance rate can also be used to determine the efficacy of antimalarial drugs in highly endemic areas, and adds to our knowledge of drug resistance and dynamics of infections in people living in such areas.     

Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure

The implementation and evaluation of malaria control programs would be greatly facilitated by new tools for the rapid assessment of malaria transmission intensity. Because acquisition and maintenance of antimalarial antibodies depend on exposure to malaria infection, such antibodies might be used as proxy measures of transmission intensity. We have compared the prevalence of IgG antibodies with three Plasmodium falciparum asexual stage antigens in individuals of all ages living at varying altitudes encompassing a range of transmission intensities from hyper- to hypoendemic in northeastern Tanzania, with alternative measures of transmission intensity. The prevalence of antibodies to merozoite surface protein-1(19) was significantly more closely correlated with altitude than either point-prevalence malaria parasitemia or single measures of hemoglobin concentration. Analysis of age-specific seroprevalence rates enabled differentiation of recent (seasonal) changes in transmission intensity from longer-term transmission trends and, using a mathematical model of the annual rate of seroconversion, estimation of the longevity of the antibody response. Thus, serological tools allow us to detect variations in malaria transmission over time. Such tools will be invaluable for monitoring trends in malaria endemicity and the effectiveness of malaria control programs.     

Malaria morbidity among school children living in two areas of contrasting transmission in western Kenya

Research in malaria-endemic areas is usually focused on malaria during early childhood. Less is known about malaria among older school age children. The incidence of clinical attacks of malaria was monitored, using active case detection in primary schools, in two areas of western Kenya that differ in the intensity of transmission. Clinical malaria was more common in schools in the Nandi highlands, with a six-fold higher incidence of malaria attacks during the malaria epidemic in 2002, compared with school children living in a holoendemic area with intense perennial transmission during the same period. The high incidence coupled with the high parasite densities among cases is compatible with a low level of protective immunity in the highlands. The malaria incidence among school children exposed to intense year-round transmission (26 per 100 school children per year) was consistent with reports from other holoendemic areas. Taken together with other published studies, the data suggest that malaria morbidity among school age children increases as transmission intensity decreases. The implications for malaria control are discussed.     

UK malaria treatment guidelines

Malaria is the tropical disease most commonly imported into the UK, with 1500-2000 cases reported each year, and 10-20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, atovaquone plus proguanil (Malarone) or co-artemether (Riamet); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h, since patients can deteriorate suddenly, especially early in the course of treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia. Falciparum malaria in pregnancy is more likely to be severe and complicated: the placenta contains high levels of parasites. Stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered. Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimalarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine-sulfadoxine (Fansidar) may also be an effective substitute. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.     

Relationship between the intensity of exposure to malaria parasites and infection in the Usambara Mountains, Tanzania

The relationship between exposure to Plasmodium falciparum malaria and parasite density and prevalence was studied in six communities along an altitude transect. Prevalence of parasitemia in children decreased by 5% for every 100 meter increase in altitude from 82% in the lowlands at 300 meters to 12% in the highlands at 1,700 meters. This decrease in prevalence corresponded to a 1,000-fold reduction in transmission intensity. The ability to suppress parasite density and prevalence with age increased proportionally with increasing transmission intensity when transmission rates were higher than 0.1 infective bites per year, but developed after 2-3 years of age, regardless of transmission intensity. However, at transmission rates less than 0.1 infective bites per year, prevalence remained similar in all age groups. We propose that both exposure-dependent acquired immunity and age-dependent acquired immunity regulate parasite prevalence and density and suggest that transmission control will not hinder the development of protective anti-parasite immunity.