The epidemiology of malaria in a population surrounding Madang, Papua New Guinea

Malaria is prevalent throughout coastal and lowland Papua New Guinea. Recent changes, including a shift from predominance of Plasmodium vivax to Plasmodium falciparum, appearance of chloroquine-resistant P. falciparum and decreased effectiveness of vector control programs have been observed. Epidemiological features of malaria were studied through four six-month surveys of a population of 16,500 in Madang Province from 1981-1983. Baseline data on parasitology, splenic enlargement, serology, hemoglobin levels, prevalence of 4-aminoquinolines, utilization of mosquito nets and incidence of fever were collected for use in future evaluation of malaria control measures including possible field trials of an antimalarial vaccine. Prevalence of parasitemia (all species, all ages) varied from 35.0% to 42.7% over the four surveys each of which covered a random sample of 25% of the population. The ratio of parasite species was: P. falciparum 70:P. vivax 25:P. malariae 5 in the dry seasons, shifting slightly in favor of P. falciparum during the wet seasons. Intense year-round transmission was indicated by decreasing parasite prevalence and splenic enlargement with age, low density asymptomatic parasitemias and high prevalence of antimalarial antibodies (i.e., greater than 80% of the population over five years of age was ELISA-positive). Levels of endemicity varied geographically, presence of 4-aminoquinolines in urine samples was relatively common (12.7% positive) and chloroquine resistance was widespread (81.6% in vitro, 46.6% in vivo).     

Epidemiology of malaria transmission and development of natural immunity in a malaria-endemic village, San Dulakudar, in Orissa state, India

We describe the epidemiology of malaria in San Dulakudar, a village in Sundargarh District in the state of Orissa in eastern India. Malaria transmission is perennial with Plasmodium falciparum, accounting for greater than 80% of malaria cases. Transmission intensity varies with season with high transmission after the monsoon rains in autumn and winter, low transmission in summer, and intermediate transmission in spring. The anthropophagic mosquito Anopheles fluviatilis was identified as the main vector for malaria transmission. Based on observations of spleen rates and supported by data on malaria parasite prevalence and malaria incidence, San Dulakudar can be classified as a hyperendemic area for P. falciparum malaria. Parasite prevalence and malaria incidence rates decrease with age, suggesting that residents of San Dulakudar develop immunity to malaria. The study demonstrates the presence of regions in the Indian subcontinent such as Sundargarh District where P. falciparum is the primary cause of malaria and where malaria transmission rates are comparable to those found in many parts of Africa.     

Severe malaria in children in areas with low, moderate and high transmission intensity in Uganda

OBJECTIVES: Age and transmission intensity are known to influence the manifestations of severe falciparum malaria in African children. However, it is unclear how specific clinical features such as seizures, impairment of consciousness, or respiratory distress vary with the parasite load and transmission intensity. We examined how the peripheral parasite load varies with transmission intensity and how this influences the symptoms and manifestations of severe malaria in children under 5 years in three areas with different malaria transmission intensity across Uganda. METHODS: We consecutively recruited 617 children with severe malaria presenting to three hospitals in areas with very low (51), moderate (367) and very high (199) transmission intensities and compared the age, admission parasite density and proportions of patients with different manifestations of severe disease. RESULTS: The median age (months) was inversely proportional to transmission intensity and declined with rising transmission (26.4 in very low, 18.0 in moderate and 9.0 under very high transmission). The highest proportion of patients reporting previous malaria admissions came from the area with moderate transmission. The geometric mean parasite density (18,357, 32,508 and 95,433/microl) and the proportion of patients with seizures (13.7%, 36.8% and 45.7%, P < 0.001) from very low, moderate and very high transmission respectively, increased with rising transmission. A linear increase with transmission was also observed in the proportion of those with repeated seizures (9.8%, 13.4% and 30.2%, P < 0.001) or impaired consciousness (7.8%, 12.8% and 18.1%, P = 0.029) but not respiratory distress. The proportion of patients with severe anaemia (19.6%, 24.8% and 37.7%, P = 0.002) mirrored that of patients with seizures. CONCLUSIONS: These findings suggest that heavy Plasmodium falciparum parasitaemia may be important in development of seizures, severe malarial anaemia and impaired consciousness in children under 5 years of age but may not be important in the development of respiratory distress.     

Plasmodium falciparum clinical malaria in Dielmo, a holoendemic area in Senegal: no influence of acquired immunity on initial symptomatology and severity of malaria attacks.

Six hundred eighty-nine Plasmodium falciparum malaria attacks were observed during a three-year period among 226 inhabitants of the village of Dielmo, Senegal, an area of high malaria transmission. Malaria attacks were defined as clinical episodes with fever (body temperature > or = 38.0 degrees C) or reporting of fever or headache or vomiting, associated with a parasite:leukocyte ratio above an age-dependent pyrogenic threshold identified in this population. The symptom frequencies were tested against age, gender, and parasite density using a random-effect logistic regression model and the study of distinguishable clinical presentations was carried out by multi-correspondence analysis. There was little difference between the severity of symptoms during the initial course of attacks in young children and adults, and this severity was not correlated with the duration of the pathologic episode. It was not possible to distinguish objectively different malaria attack types according to the severity of clinical manifestations. In contrast, the duration of fever, symptoms, and parasite clearance were significantly longer among the youngest children than among the oldest children and adults. These findings suggest that of the two components of protective immunity, anti-parasite immunity and anti-toxic immunity, only the first would play a major role as age increases. They suggest also that the initial clinical presentation of malaria attacks is not predictive of the level of protective immunity.     

Plasmodium falciparum malaria in the first year of life in an area of intense and perennial transmission

A longitudinal study of Plasmodium falciparum malaria in infants in Idete village, south‐eastern Tanzania, was conducted over a period of 14 months in order to determine the incidence of P. falciparum infection and clinical malaria in the first year of life. Of 1356 blood slides from cross‐sectional surveys, 52.1% were positive for asexual stages of P. falciparum. There were marked increases in P. falciparum prevalence, parasite densities, overall fever incidence and the incidence of malaria fevers with age for the first 6 months of life. The average attack rate, estimated from a reversible catalytic model, was 0.029 per day with a slight increase with age but there was no initial period of protection against infection in neonates. Estimated average duration of infections was 64 days, with infections in older infants lasting much longer than those contracted during the first 2 months of life.
These results support the hypotheses that the main effect of passively transferred maternal immunity to malaria is in the control of asexual stage parasites, and that the level of clinical immunity depends upon the extent of recent exposure to parasites. Infants as young as 4 months of age are at high risk of clinical attacks. Intervention programmes against malaria in areas of the highest transmission should therefore be designed to include this group.     

Malaria control by chlorproguanil. I. Clinical effects and susceptibility of Plasmodium falciparum in vivo after seven years of monthly chlorproguanil administration to children in a Liberian village

For seven years, chlorproguanil (1.0 to 2.0 mg kg-1) was administered monthly to the children below 15 years of age in a village with holoendemic malaria. Malariometric indices were recorded every six months. Susceptibility in vivo was monitored by the clearance of Plasmodium falciparum parasitaemia after drug intake. Three parasite species were found initially: P. falciparum (52%), P. malariae (8%) and P. ovale (4%). The parasites found during the study were mainly P. falciparum, and parasite rates ranged from 37 to 87% at the different surveys one month after respective drug intake. A fifty-fold decrease of mean parasite density was generally observed seven days after drug intake. Splenomegaly was initially recorded in all two to nine year old children, with a mean size of 2.64 according to Hackett's index. From 18 months onwards as the mean spleen index was 1.15 in the same age group. Chlorproguanil may represent an important alternative drug to groups at risk in malaria control schemes.     

Seasonal patterns of Plasmodium falciparum gametocyte prevalence and density in a rural population of Burkina Faso

Gametocytes are the malaria parasite stages that secure the transmission from the human host to the mosquito. The identification of natural parameters that influence gametocyte carriage can contribute to a better understanding of the dynamics of the sexual stage parasites for transmission reducing strategies. A total of 3400 blood slide readings were done during four cross-sectional surveys (2002-2003) including all age groups to determine the effect of season on Plasmodium falciparum gametocytes in a seasonal malaria transmission area of Burkina Faso. Entomological data were collected to determine the malaria transmission intensity in relation to seasons. Transmission intensity was estimated by monthly EIRs, averaging 28 and 32 infective bites/person/month in the wet seasons of 2002 and 2003, respectively. The EIR in the dry seasons was below one infective bite/person/month. The gametocyte prevalence was significantly higher at the start and peak of the wet season compared to the dry season when corrected for asexual parasite density and age. Gametocyte density significantly increased during the wet season after correction for asexual parasite density and age. In this study, season appears to be an independent parameter that determines gametocyte prevalence and density and should be considered to be included in epidemiological studies on malaria transmission.     

In vitro lymphoproliferative responses to malaria antigens: a prospective study of residents of a holoendemic area with perennial malaria transmission

A longitudinal, prospective study to examine the relationship between the outcome of infection with Plasmodium falciparum parasites and in vitro T-cell proliferative responses to a P. falciparum schizont extract (PfSE) was conducted in a village in south-eastern Gabon, an area where malaria is holoendemic and transmission is intense and perennial. The donor's age was found to have a strong independent influence on all malariometric indices. At the community level, the in vitro lymphoproliferative response to PfSE was bimodal with 30% of the villagers studied showing persistently low responses. The frequency of low or high responders within the study population did not show any consistent relationship with the community parasite rates or the number of either patent parasitaemic episodes or clinical malarial attacks per individual. At the individual donor level, the response was negatively correlated with P. falciparum parasite density in those donors who were parasitaemic at the time of sampling. High in vitro lymphoproliferative responses to PfSE were predictive of resistance to clinical malaria. The PfSE-induced in vitro lymphoproliferative response was dependent on antigen presenting cells, CD4+ T-cells and UCHL-1+cells.     

Characteristics of malaria transmission in Kataragama, Sri Lanka: a focus for immuno-epidemiological studies

Parasitological and entomological parameters of malaria transmission were monitored for 17 months in 3,625 residents in a Plasmodium vivax malaria endemic region in southern Sri Lanka; the study area consisted of 7 contiguous villages where routine national malaria control operations were being conducted. Malaria was monitored in every resident; fever patients were screened and 4 periodical mass blood surveys were conducted. An annual malaria incidence rate of 23.1% was reported during the period: 9.3% was due to P. vivax and 13.8% was due to P. falciparum; there had been a recent epidemic of the latter in this region, whereas the P. falciparum incidence rate in the previous 10 years had been negligible. There was a wide seasonal fluctuation in the malaria incidence, with the peak incidence closely following the monsoon rains. The prevalence of malaria due to both species detected at the 4 mass blood surveys ranged from 0.98% (at low transmission) to 2.35% (at peak transmission periods). Adults and children developed acute clinical manifestations of malaria. Entomological measurements confirmed a low degree of endemicity with estimated inoculation rates of 0.0029 and 0.0109 (infectious bites/man/night) for P. vivax and P. falciparum, respectively. Several anopheline species contributed to the transmission, and the overall man biting rates (MBR) showed a marked seasonal variation. Malaria at Kataragama, typical of endemic areas of Sri Lanka, thus presents characteristics of "unstable" transmission. Malaria was clustered in the population. There was a low clinical tolerance to P. falciparum malaria, to which most had only been at risk, compared to P. vivax, to which most had had a life-long exposure.     

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.     

Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome

Little is known about the changes in white blood cells and platelets in children with falciparum malaria in endemic areas. We measured the white cell count (WCC) and platelets of 230 healthy children from the community, 1369 children admitted to hospital with symptomatic malaria, and 1461 children with other medical conditions. Children with malaria had a higher WCC compared with community controls, and leucocytosis was strongly associated with younger age, deep breathing, severe anaemia, thrombocytopenia and death. The WCC was not associated with a positive blood culture. In children with malaria, high lymphocyte and low monocyte counts were independently associated with mortality. A platelet count of less than 150 x 109/l was found in 56.7% of children with malaria, and was associated with age, prostration and parasite density, but not with bleeding problems or mortality. The mean platelet volume was also higher in children with malaria compared with other medical conditions. This may reflect early release from the bone marrow in response to peripheral platelet destruction. Thus, leucocytosis was associated with both severity and mortality in children with falciparum malaria, irrespective of bacteraemia, whereas thrombocytopenia, although very common, was not associated with adverse outcome.     

Development of immunity against Plasmodium falciparum malaria: clinical and parasitologic immunity cannot be separated

A total of 1622 individuals of all ages living under conditions of continuous malarial transmission in Liberia were enrolled in a cross-sectional study of parasite rates, positive parasite densities, and body temperatures. The age-specific Plasmodium falciparum-positive parasite densities were greatest at ages 0.5-1.0 year, then slowly declined into adulthood. The age-specific mean body temperature at parasite isodensity showed a steady decline even in the oldest age group. The results do not support the hypothesis that adults have higher body temperatures at a given parasite density than do children with the same parasite density. The age-specific P. falciparum parasite density for specific isotemperatures showed that a subgroup of children in the age group 0.5-1.0 year had low temperatures (less than 36.5 degrees C) despite high parasite densities. This indicates that low body temperature should be investigated further as a possible indicator of serious malaria in young children. Parasitologic and clinical immunity develops concomitantly and cannot be separated. The findings do not support the hypothesis that a special "anti-disease" immunity exists independently of parasitologic immunity.     

The impact of age, temperature, and parasite density on treatment outcomes from antimalarial clinical trials in Kampala, Uganda

Antimalarial drug treatment policy in sub-Saharan Africa is generally guided by the results of clinical drug efficacy studies in patients with uncomplicated Plasmodium falciparum malaria. The selection criteria used to enroll these patients often vary and may have a significant impact on treatment outcomes. In Kampala, Uganda, we investigated the impact of age, baseline temperature, and pre-treatment parasite density on estimates of treatment efficacy using a statistical modeling approach in 2,138 patients enrolled in six clinical trials involving seven different treatment regimens. Decreasing age, increasing temperature, and increasing parasite density were all independent predictors of an increased risk of treatment failure across all treatment groups. Compared with an unrestrictive approach to subject selection, enrolling only patients fulfilling selection criteria recommended by the World Health Organization (age < 5 years old, documented fever, and parasite density < 200,000/microL) increased the risk of treatment failure by 25-60% for the different treatment regimens. Caution should be taken when comparing results from drug efficacy studies with different subject selection criteria.     

The risk of malarial infections and disease in Papua New Guinean children

In a treatment re-infection study of 206 Papua New Guinean school children, we examined risk of reinfection and symptomatic malaria caused by different Plasmodium species. Although children acquired a similar number of polymerase chain reaction-detectable Plasmodium falciparum and P. vivax infections in six months of active follow-up (P. falciparum = 5.00, P. vivax = 5.28), they were 21 times more likely to develop symptomatic P. falciparum malaria (1.17/year) than P. vivax malaria (0.06/year). Children greater than nine years of age had a reduced risk of acquiring P. vivax infections of low-to-moderate (>150/microL) density (adjusted hazard rate [AHR] = 0.65 and 0.42), whereas similar reductions in risk with age of P. falciparum infection was only seen for parasitemias > 5,000/microL (AHR = 0.49) and symptomatic episodes (AHR = 0.51). Infection and symptomatic episodes with P. malariae and P. ovale were rare. By nine years of age, children have thus acquired almost complete clinical immunity to P. vivax characterized by a very tight control of parasite density, whereas the acquisition of immunity to symptomatic P. falciparum malaria remained incomplete. These observations suggest that different mechanisms of immunity may be important for protection from these malaria species.     

Dehydroepiandrosterone sulfate levels associated with decreased malaria parasite density and increased hemoglobin concentration in pubertal girls from western Kenya

In areas where Plasmodium falciparum malaria is endemic, parasite density, morbidity, and mortality decrease with increasing age, which supports the view that years of cumulative exposure are necessary for the expression of maximal protective immunity. Developmental changes in the host also have been implicated in the expression of maximal resistance. To further evaluate the contribution of host developmental factors in malaria resistance, we examined the relationship between P. falciparum parasitemia and pubertal development in a cross-sectional sample of 12-18-year-old schoolgirls from an area of intense transmission in western Kenya. Among pubertal girls, dehydroepiandrosterone sulfate (DHEAS) levels were significantly associated with decreased parasite density, even after adjustment for age. DHEAS levels also were related to increased hemoglobin levels, even after accounting for age and other determinants of hemoglobin level. These findings support the hypothesis that host pubertal development, independent of age and, by proxy, cumulative exposure, is necessary for maximal expression of resistance to malarial infection and morbidity, as assessed by hemoglobin level.     

Prevalence of malaria among patients attending public health facilities in Maputo City, Mozambique

We conducted a health facility-based survey to estimate the prevalence of malaria among febrile patients at health facilities (HFs) in Maputo City. Patients answered a questionnaire on malaria risk factors and underwent malaria testing. A malaria case was defined as a positive result for malaria by microscopy in a patient with fever or history of fever in the previous 24 hours. Among 706 patients with complete information, 111 (15.7%) cases were identified: 105 were positive for Plasmodium falciparum only, two for Plasmodium ovale only, and four for both P. falciparum and P. ovale. Fever documented at study enrollment, age ≥ 5 years, rural HF, and travel outside Maputo City were statistically significantly associated with malaria by multivariate analysis. We found a high prevalence of laboratory-confirmed malaria among febrile patients in Maputo City. Further studies are needed to relate these findings with mosquito density to better support malaria prevention and control.     

The effect of altitude on parasite density case definitions for malaria in northeastern Tanzania

OBJECTIVES: Malaria clinical trials need precise endpoints to measure efficacy. In endemic areas where asymptomatic parasitaemia is common, 'fever plus parasitaemia' may not differentiate between malaria cases and non-cases. Case definitions based on parasite cut-off densities may be more appropriate but may vary with age and transmission intensity. This study examines appropriate case definitions from parasitological surveys conducted over a broad range of transmission intensities, using altitude as a proxy for transmission intensity. METHODS: Cross-sectional data collected from 24 villages at different altitudes in an endemic area of northeastern Tanzania were used to calculate malaria-attributable fractions using a modified Poisson regression method. We modelled fever as a function of parasite density and determined the optimum cut-off densities of parasites to cause fever using sensitivity and specificity analyses. RESULTS: The optimum cut-off density varied by altitude in children aged under 5 years: a case definition of 4,000 parasites per mul at altitudes <600 m (high transmission intensity) was most appropriate, compared with 1,000 parasites per mul at altitudes >600 m (low transmission intensity). In children aged over 5 years and adults, there was little variation by altitude and a case definition of any parasites plus fever was the most appropriate. CONCLUSIONS: Locally appropriate case definitions of malaria should be used for research purposes. In our setting, these varied independently with age and transmission intensity.     

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.     

Falciparum malaria and beta-thalassaemia trait in northern Liberia

In a study in northern Liberia of the malaria and beta-thalassaemia hypothesis, the frequencies of beta-thalassaemia and HbS traits were 9.1 and 3.4% in the Mano and 9.5 and 1.7% in the Gio tribal samples. HbC and HbN were present at low frequency. G6PD deficiency was found in 16% of males. An observed increase with age of beta-thalassaemia trait frequencies was consistent with the selection hypothesis. However, we could not entirely exclude that associated iron deficiency influenced the results in the six to 11 month age group. Malaria was holoendemic; Plasmodium falciparum predominated, P. malariae and P. ovale were also identified. Plasmodium falciparum prevalence rates were similar in normal and beta-thalassaemia trait children but parasite densities were consistently lower in the latter. Using the criterion of a falciparum parasite density of 1 x 10(9) 1(-1) or greater to indicate a potentially important infection, the relative risk in beta-thalassaemia traits one to four years old from the cross-sectional study was 0.45 (upper 95% confidence interval 0.79) and 0.41 (0.61) in two to nine year trait carriers from a longitudinal study. Plasmodium falciparum gametocyte rates were lower in beta-thalassaemia trait children (P less than 0.005). The geometric mean titre of P. falciparum antibodies was lower in beta-thalassaemia trait children from the one to four year group (P less than 0.05). Otherwise immunological studies showed little difference between the different Hb types. Parasitological findings were consistent with relative resistance of HbS trait carriers towards P. falciparum infection. We found no evidence for relative resistance of beta-thalassaemia traits towards P. malariae infection nor that G6PD deficient males were more resistant to P. falciparum than those with normal activity. We conclude that the results are consistent with relative resistance of beta-thalassaemia trait carriers to P. falciparum malaria.     

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.