Malarial Endemicity Research Articles

Malarial Antibodies and Endemicity: Does It Affect SARS-CoV-2 Severity and Outcomes?

Background India has a disproportionately lower rateof coronavirus disease 2019 (COVID-19) severe disease and lower death rates with respect to other parts of the world. It has been proposed that malaria-endemic countries such as India are relatively protected against severe COVID-19 disease and deaths. Methods This was a cross-sectional, analytical, observational study conducted from August 2020 to July 2021 at a tertiary care COVID-19-designated center in New Delhi, India. It aimed to study the association between antimalarial antibody levels and COVID-19 disease severity and outcomes. Results One hundred forty-six patients were included in the final analysis. The mean (standard deviation {SD}) age of the study population was 44.6 (17.2) years, and there were 85 (58.2%) males. Sixty-five patients had mild disease, 14 patients had moderatedisease, and 67 patients had severe disease at the time of enrolment in the study. Forty-six patients expired during the hospital stay. For the antimalarial antibody, there was a statistically significant difference between mild and moderate (p=0.018), mild and severe (p=0.016), and mild and combined moderate and severe diseases (p=0.013). However, there was no difference betweenthe patients who survived and those who did not. Conclusion Antimalarial antibody levels may not be associated with the outcomes of COVID-19 during hospital stay. However, this study has provided some insights into the relationship between the severity and outcomes of COVID-19 and the levels of antimalarial antibodies.

Mosquito community composition in Central District, Botswana: insights from a malaria endemic to non-endemic gradient

Spatial distribution of vector mosquitoes plays a critical role in the dynamics of associated diseases’ spread across diverse landscapes. In Botswana, six Districts are implicated as malaria endemic zones, one of which is the Central District comprising both malaria endemic and non-endemic sub-districts. Despite being the biggest in the country, mosquito diversity in this District is under-explored, more so in the malaria non-endemic sub-districts. Here, we thus sampled mosquito adults and larvae from the malaria endemic sub-district of Bobirwa and non-endemic sub-districts of Palapye and Serowe, to determine spatial mosquito abundance and diversity in the District. Overall, all the sub-districts had a representation of key mosquito taxa of medical and economic importance (Aedes, Culex and Anopheles), irrespective of malarial endemicity status. Bobirwa had the highest number of mosquitoes sampled (429) although the greatest species richness (0.8511) was observed from Palapye. Moreover, Palapye also recorded a species from another genus, Culiseta longiareolata, a known natural vector of avian malaria parasites. Given global climate shift projections for the region, there is a need for continuous area-wide surveillance for vector mosquitoes and associated parasites in curbing the risk of emerging and re-emerging infections. While the Anopheles-centric approach to mosquito control is still necessary, a holistic approach, incorporating other vector incriminated mosquito species is warranted, particularly given shifting climates and the presence of invasive disease associated vector mosquito species.

Anopheles salivary antigens as serological biomarkers of vector exposure and malaria transmission: A systematic review with multilevel modelling.

Entomological surveillance for malaria is inherently resource-intensive and produces crude population-level measures of vector exposure which are insensitive in low-transmission settings. Antibodies against Anopheles salivary proteins measured at the individual level may serve as proxy biomarkers for vector exposure and malaria transmission, but their relationship is yet to be quantified. A systematic review of studies measuring antibodies against Anopheles salivary antigens (PROSPERO: CRD42020185449). Multilevel modelling (to account for multiple study-specific observations [level 1], nested within study [level 2], and study nested within country [level 3]) estimated associations between seroprevalence with Anopheles human biting rate (HBR) and malaria transmission measures. From 3981 studies identified in literature searches, 42 studies across 16 countries were included contributing 393 study-specific observations of anti-Anopheles salivary antibodies determined in 42,764 samples. A positive association between HBR (log transformed) and seroprevalence was found; overall a twofold (100% relative) increase in HBR was associated with a 23% increase in odds of seropositivity (OR: 1.23, 95% CI: 1.10-1.37; p<0.001). The association between HBR and Anopheles salivary antibodies was strongest with concordant, rather than discordant, Anopheles species. Seroprevalence was also significantly positively associated with established epidemiological measures of malaria transmission: entomological inoculation rate, Plasmodium spp. prevalence, and malarial endemicity class. Anopheles salivary antibody biomarkers can serve as a proxy measure for HBR and malaria transmission, and could monitor malaria receptivity of a population to sustain malaria transmission. Validation of Anopheles species-specific biomarkers is important given the global heterogeneity in the distribution of Anopheles species. Salivary biomarkers have the potential to transform surveillance by replacing impractical, inaccurate entomological investigations, especially in areas progressing towards malaria elimination. Australian National Health and Medical Research Council, Wellcome Trust.

Desert malaria “Curse of the Thar Desert” – A unique geographical endemicity of malaria and combating it with modern technology

Introduction: This study focuses on the Malaria endemic in the Thar Desert- The most populated desert in the world. Malarial endemicity in a desert environment is a unique and rare geographical presentation, as malaria is usually common in areas where there is rainfall and water stagnation - like ponds, fields, etc. In this study, we want to highlight the unique clinical presentation, lab findings, and reason behind the existence of malaria in the desert. Most importantly we also would like to share our innovative idea to eliminate breeding sites using Quadcopters and drones. Materials and methods: Study type – Prospective observation study, Study duration – October 2020 to December 2020, Sample size-103 cases, Inclusion criteria – all smear-positive Malaria cases, Exclusion criteria – Cases Referred to higher centers because of complications.Tools used for breeding site identification – Quadcopters and Drones with HD cameras. Since the area to be surveyed was vast (&gt;30km), it was very difficult to do a manual survey in the harsh desert climate. The patients’ demographics, Clinical Presentations, and laboratory parameters were collected systematically in a predesigned format and entered into an excel sheet. The finding of our study was compared with the malaria cases from different parts of the country. Results: All malaria was identified as Plasmodium vivax. The mean age group was 36 years (min-21 and max-56). Clinical features- out of 103 cases, 78% of the patients presented with all 4 symptoms of fever, chills, headache, and bodyache.22% presented with atypical isolated symptoms of abdominal pain, vomiting, myalgia, severe joint pain. 77% of patients had mild hepatosplenomegaly, 7 patients presented with hypotension, and 2 were in sepsis. Lab parameters – 88% of the patients had anemia, of which 5% had severe anemia, 40% had leucopenia while 6% had leucocytosis.87%had thrombocytopenia, out of which 56% had a platelet count less than 50,000/ml. 2% had mild AKI, bilirubin levels were elevated in 53%, and 36% had transaminitis. Using technology, the survey of the entire area was done in 1 week and all the breeding sites were eliminated on the same day of identification and a drastic drop in malaria cases was noted. Conclusion: We conclude that desert malarial presentation of Plasmodium vivax is unique in clinical presentation and lab derangements compared to other malarial cases. Usage of technology like quadcopters and drones for breeding site identification played a major role in curtailing cases drastically in a very short period in an effective way.

Unsuspected imported malaria in a case of sudden infant death

Here we describe the case of a 4-mo-old female who died suddenly without any apparent cause that was initially mistaken as a case of sudden infant death syndrome. Histologic observation of brain sections revealed blue-black bodies in erythrocytes of the blood vessels, suggestive of specific stages of the hematic schizogonic cycle. Further examinations revealed hemozoin and hemosiderin deposits in the parenchyma of all organs, leading to the diagnosis of malaria by Plasmodium falciparum (P. falciparum). The death occurred in Italy, the native country of the infant, two weeks after a Christmas holiday spent in Pakistan, the parents’ birthplace, which has a high malarial endemicity. As this case demonstrates, the diagnosis of malaria should always be considered as a differential diagnosis in subjects, including infants, that die unexpectedly after returning from P. falciparum endemic areas. © 2014 Baishideng Publishing Group Inc. All rights reserved.

A Novel ENU-Mutation in Ankyrin-1 Disrupts Malaria Parasite Maturation in Red Blood Cells of Mice

The blood stage of the plasmodium parasite life cycle is responsible for the clinical symptoms of malaria. Epidemiological studies have identified coincidental malarial endemicity and multiple red blood cell (RBC) disorders. Many RBC disorders result from mutations in genes encoding cytoskeletal proteins and these are associated with increased protection against malarial infections. However the mechanisms underpinning these genetic, host responses remain obscure. We have performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen and have identified a novel dominant (haploinsufficient) mutation in the Ank-1 gene (Ank1MRI23420) of mice displaying hereditary spherocytosis (HS). Female mice, heterozygous for the Ank-1 mutation showed increased survival to infection by Plasmodium chabaudi adami DS with a concomitant 30% decrease in parasitemia compared to wild-type, isogenic mice (wt). A comparative in vivo red cell invasion and parasite growth assay showed a RBC-autonomous effect characterised by decreased proportion of infected heterozygous RBCs. Within approximately 6–8 hours post-invasion, TUNEL staining of intraerythrocytic parasites, showed a significant increase in dead parasites in heterozygotes. This was especially notable at the ring and trophozoite stages in the blood of infected heterozygous mutant mice compared to wt (p<0.05). We conclude that increased malaria resistance due to ankyrin-1 deficiency is caused by the intraerythrocytic death of P. chabaudi parasites.

Placental Malarial Infection as a Risk Factor for Hypertensive Disorders During Pregnancy in Africa: A Case-Control Study in an Urban Area of Senegal, West Africa

In tropical countries, malaria and hypertension are common diseases of pregnancy. They have physiopathologic similarities such as placental ischemia, endothelial dysfunction, and production of proinflammatory cytokines. Recent findings suggested their possible link. The authors conducted a case-control study to explore the relation between malaria and hypertension at Guediawaye, a hypoendemic malarial setting in Senegal. Cases were pregnant women admitted to the delivery unit for hypertension. Controls were pregnant women admitted for normal delivery, without any history of hypertension or proteinuria during the present pregnancy. Malarial infection was determined by placental tissue examination. From January to December 2002, 77 cases of gestational hypertension, 113 cases of preeclampsia, 59 cases of eclampsia, and 241 controls were enrolled. Placental malarial infection (PMI) was present in 14 cases (6.3%) and in 15 controls (6.2%). The prevalence of PMI was 4.6% for eclampsia, 4.0% for preeclampsia, and 11.6% for gestational hypertension. In multivariate analysis, PMI appeared to be an independent risk factor for gestational hypertension (adjusted odds ratio = 2.7, 95% confidence interval: 1.0, 7.6). The authors found an association between PMI and nonproteinuric hypertension in women living in a malaria-hypoendemic area. The exact significance of such relation should be clarified in further studies in different settings of malarial endemicity.

High frequencies of short alleles of NOS1 (CA)n polymorphism in β 039 carriers from Corsica Island (France)

In this work we investigated about the presence of a correlation between a (CA)n repeat located in exon 29 of NOS1 gene and the β-thalassemia trait in Corsica Island (France). We genotyped a sample of individuals with β-thalassemia minor ( N = 110) and an ethnically matched control ( N = 113) from Balagna, a region of Corsica Island (France). Results highlighted the high frequencies of allele with 16 and 17 repeats in the thalassemic sample. From these results we suggest, that high frequencies of alleles with 16 and 17 repeats, could be a consequence of past malarial endemicity.

Tropical Malaria Does Not Mean Hot Environments

If global warming progresses, many consider that malaria in presently malaria-endemic areas will become more serious, with increasing development rates of the vector mosquito and malaria parasites. However, the correlation coefficients between the monthly malaria cases and the monthly mean of daily maximum temperature were negative, showing that the number of malaria cases in tropical areas of Africa decreases during the season when temperature was higher than normal. Moreover, an analysis of temperature and development rate using a thermodynamic model showed that the estimated intrinsic optimum temperatures for the development of the malaria parasites, Plasmodium falciparum and P. vivax, in the adult mosquito stage and that of the vector mosquito Anopheles gambiae s.s. were all approximately 23-24 degrees C. Here, the intrinsic optimum temperature is defined in the thermodynamic model as the temperature at which it is assumed that there are no or negligible adverse effects for development. Therefore, this study indicates that the development of malaria parasites in their mosquito hosts and the development of their vector mosquitoes are inhibited at temperatures higher than 23-24 degrees C. If global warming progresses further, the present center of malarial endemicity in sub-Saharan Africa will move to an area with an optimum temperature for both the vector and the parasite, migrating to avoid the hot environment.

Point:Counterpoint: Sickle cell trait should/should not be considered asymptomatic and as a benign condition during physical activity

Sickle cell trait (SCT) is found in ∼8% of African Americans and may be found in up to 40% of West Africans. However, most of them are unaware of their status. This observation suggests that SCT may be asymptomatic and remains a benign condition for daily life activities ([5][1]). Indeed, numerous

Parvovirus B19 Infection Contributes to Severe Anemia in Young Children in Papua New Guinea

Severe anemia (hemoglobin level, <50 g/L) is a major cause of death among young children, and it arises from multiple factors, including malaria and iron deficiency. We sought to determine whether infection with parvovirus B19 (B19), which causes the cessation of erythropoiesis for 3-7 days, might precipitate some cases of severe anemia. Archival blood samples collected in the Wosera District of Papua New Guinea, from 169 children 6 months-5 years old with severe anemia and from 169 control subjects matched for age, sex, and time were tested for B19 immunoglobulin M (IgM) by enzyme immunoassay and for B19 DNA by nested polymerase chain reaction (PCR). A total of 168 separate samples from children in the Wosera District were tested for B19 IgG. A strong association between acute B19 infection (positive by both IgM and PCR) and severe anemia was found (adjusted odds ratio, 5.61 [95% confidence interval, 1.93-16.3]). The prevalence of parvovirus B19 IgG reached >90% in 6-year-olds. B19 infections play a significant role in the etiology of severe anemia in this area of malarial endemicity. Given the high levels of morbidity and mortality associated with severe anemia in such regions, the prevention of B19 infection with a vaccine might be a highly effective public health intervention.

Predicted declines in sickle allele frequency in Jamaica using empirical data

The high frequency of the sickle allele in some parts of Africa is understood to be a consequence of high malarial endemicity. One corollary of this is that the sickle allele frequency should be declining in populations of African ancestry that are no longer exposed to malaria. We have previously shown that there has been no change in sickle allele frequency in malaria-free Jamaica between two large-scale neonatal screening exercises conducted in 1973-1981 and 1995-2003. To evaluate the determinants of, and derive expected values for, sickle allele frequency in Jamaica, local empirical data were used to estimate the parameters of deterministic models of allele frequency decline. We found that although model predictions were broadly consistent with observed values in the 1973-1981 cohort, the predicted change in allele frequency between the two cohorts was larger than the observed, nonsignificant, reduction. Close agreement between predicted and observed values was only achieved by simulating a recent, marked increase in HbSS fitness. Thus, the "unexpected" persistence of the sickle allele in Jamaica may reflect the fact that the actual fitness among SS individuals is higher than that previously realized. If true, our models suggest that without substantial changes in current screening and counseling practice, there will be little "natural" reduction in sickle allele frequency for several hundred years. Better estimates of relative fitness will be helpful in refining these predictions and may aid in assigning health care priorities in Jamaica and the African Diaspora.

Polarisation microscopy increases the sensitivity of hemozoin and Plasmodium detection in the histological assessment of placental malaria

The histological study of the placenta is useful in the diagnosis of malaria during pregnancy. However, the scarcity of parasites and pigment in many malarial infections renders their identification difficult. We have tested the accuracy of standard and polarisation microscopy in the evaluation of 500 placental specimens from an area of high malarial endemicity in Tanzania. Standard microscopy showed a low sensitivity (50.3% for parasites, 40.5% for pigment), due to poor detection rates in cases with scant parasites (12.7% for <1%; 97.8% for >5% parasitised erythrocytes, P<0.001) or minimal pigment deposition (42.4% versus 84.5% when severe, P<0.001). The use of polarisation microscopy significantly increased the sensitivity of detection of pigment to 100% and parasites to 98.1% because of the marked birefringence of hemozoin present in mature stage parasites which accumulate in the placenta. Formalin pigment shares many properties with hemozoin, but the use of neutral buffered formalin prevented the formation of formalin pigment in placentas even after long periods of fixation. In conclusion, polarisation microscopy is a simple tool that markedly increases the sensitivity of the detection of malaria infection in the placenta and has good specificity when used on tissues fixed in neutral formalin. This method can be useful to investigators working in the malaria field.

A Correlative Study of HLA, Sickle Cell Gene and G6PD Deficiency with Splenomegaly and Malaria Incidence Among Bhils and Pawra Tribes from Dhadgon, Dhule, Maharastra

Haldane proposed that the sickle cell gene provides a survival advantage in malarial endemic regions. A high malarial endemicity has also been attributed to a high prevalence of G6PD deficiency in ...

Testing the "malaria hypothesis" for the case of Thailand: a genetic appraisal.

This study provides statistical analyses of allele frequencies for populations of Thailand, with an attempt to trace the roles of differential malarial selection and genetic admixtures on the observed frequency variation of certain red cell genetic abnormalities (the two beta-globin variants--hemoglobin E and beta-thalassemia--and G-6PD deficiency), probably evolving under malarial endemicity. It is found that frequencies of hemoglobin E vary accordingly with those of G-6PD deficiency, and with diverse malarial ecology. The levels of genetic diversity are greater for hemoglobin E and G-6PD deficiency than for most other nonmalarial related genetic markers, suggesting the evolution of these two genetic abnormalities under differential selection. Results of the Mantel's statistical test for correspondence between distance matrices suggest distinctive patterns of allele frequency differentiation between malarial-related and nonmalarial-related genetic loci. Correlations between beta-globin and G-6PD genetic distances, as well as those between both sets of distances and the malarial distances, are statistically significant. On the other hand, a correlation between malarial distances and the genetic distances for nonmalarial-related genetic loci is not significant statistically. A correlation between the beta-globin genetic distances and the genetic distances for nonmalarial-related genetic loci is, however, statistically significant. The latter result could be attributed largely to the clustering of relatively high hemoglobin E frequencies among genetically closely related populations of northeastern Thailand, whose recent homeland was Laos. The consistently low frequencies of beta-thalassemia observed in most studied populations are explained as a result of the replacement of this genetic variant by hemoglobin E, under long-term malarial selection.

Grade of malignancy of cervical cancer in regions of Uganda with varying malarial endemicity.

As in a prior study on malignant lymphomas, 3 and 6 areas of Uganda showing low and high malarial endemicity, respectively, were selected for analysis and the data retrieved from the Kampala Cancer Registry, which in the 1960s and 1970s collected cases of cancer through a widely used free biopsy service from the whole country. Overall incidence rates were derived from 924 cases from the 12-year period 1964-1975. For reasons of economy, grade of tumour was determined only in cases pertaining to the 6-year period 1968-1973. Of 457 cases, 304 could be reviewed histologically. Only the group of squamous cell carcinomas (84.9%, 258 cases) was large enough for subsequent geographic analysis. High incidence rates of CC were found in areas with high malarial endemicity, whereas low incidence rates occurred where malaria was either frequent or rare. A correlate to malarial infection was the proportion of high-grade carcinomas irrespective of the overall incidence of CC. With high prevalence of malaria and high CPRs of 35-74%, the relative share of high-grade cancer amounted to 50-67%. Where malaria was rare with low CPRs of 8-11%, these values were lower and varied only from 25-39% with a similar range of 14%. Geographic agreement between malarial endemicity and the PI of high-grade cancer was high in the 9 study areas and only slightly lower than for BL, for which the association with malaria is beyond doubt. Compared to areas with little malaria, the RR for the incidence of high-grade carcinomas in areas with severe malaria was increased. The value was 2.04 with a 95% confidence interval of 1.37-3.04. Attributable to secondary immunodeficiency, lifelong exposure to malaria may result in excess frequency of high-grade malignant tumours not only in the group of malignant lymphomas but also in CC.

The consequences of reducing transmission of Plasmodium falciparum in Africa

Malaria transmission intensity in Africa varies over several log orders, from less than one infected bite per year to more than one thousand. In this review we examine the consequences in terms of age pattern, clinical spectrum and overall burden of disease and discuss the possible implications for interventions that reduce exposure to infected bites. With very low transmission intensity, all age groups are susceptible to severe malaria. With increasing transmission intensities, older children and adults suffer less severe disease and with high transmission rates the majority of severe cases occur in infants under one year of age. This pattern reflects the increasingly rapid acquisition of immune responses that limit the life-threatening effects of malaria with increasing exposure to the parasite. The clinical spectrum of severe malaria varies with transmission: with high transmission, severe malarial anaemia dominates and cerebral malaria is rare. As one moves towards lower transmission rates, cerebral malaria accounts for an increasingly large proportion of cases. Although the population risk of severe disease falls with age, the risk of death at an individual level may rise with age after an initial fall from very high case fatality rates in children aged under 6 months. Of central interest to malaria control is how the overall amount of disease in childhood varies with transmission. Data from a number of sources suggest that, with low transmission, the amount of malarial disease rises with increasing exposure but that this saturates relatively early. A key issue is whether the same pattern obtains for deaths, both those directly due to malaria and those from all causes. The methodological limitations of ecological comparisons between different areas are discussed before presenting a review of attempts to use this approach in Africa. This suggests that children living in areas of low malarial endemicity have all-cause mortality rates about half of those of children living in areas of moderate to high transmission. Deaths in the first year of life rise linearly with increasing exposure to malaria over a wide range of transmission intensities; by contrast all-cause mortality in children aged 0-4 years appears to saturate at relatively low transmission intensities. These data suggest that interventions that reduce exposure to malaria parasites, such as insecticide-treated bed nets (ITNs), will have the greatest chance of a sustained effect when used in areas where disease burdens are high but the frequency of parasite exposure is low-to-moderate. In conditions of high transmission, initial reductions in mortality may prove difficult to sustain as the reduced level of transmission may still lie on the part of the curve where mortality has saturated. However, at all levels of transmission the overall balance of benefits, including reduced load on families and health services from non-life-threatening malaria, favours the widespread introduction of ITNs in endemic areas of Africa.

Iron and Its Relation to Immunity and Infectious Disease

The continuing unresolved debate over the interaction of iron and infection indicates a need for quantitative review of clinical morbidity outcomes. Iron deficiency is associated with reversible abnormalities of immune function, but it is difficult to demonstrate the severity and relevance of these in observational studies. Iron treatment has been associated with acute exacerbations of infection, in particular, malaria. Oral iron has been associated with increased rates of clinical malaria (5 of 9 studies) and increased morbidity from other infectious disease (4 of 8 studies). In most instances, therapeutic doses of oral iron were used. No studies in malarial regions showed benefits. Knowledge of local prevalence of causes of anemia including iron deficiency, seasonal malarial endemicity, protective hemoglobinopathies and age-specific immunity is essential in planning interventions. A balance must be struck in dose of oral iron and the timing of intervention with respect to age and malaria transmission. Antimalarial intervention is important. No studies of oral iron supplementation clearly show deleterious effects in nonmalarious areas. Milk fortification reduced morbidity due to respiratory disease in two very early studies in nonmalarious regions, but this was not confirmed in three later fortification studies, and better morbidity rates could be achieved by breast-feeding alone. One study in a nonmalarious area of Indonesia showed reduced infectious outcome after oral iron supplementation of anemic schoolchildren. No systematic studies report oral iron supplementation and infectious morbidity in breast-fed infants in nonmalarious regions.

Iron and infection in the tropics: paediatric clinical correlates.

Iron deficiency is prevalent in children worldwide. Programmes of presumptive therapy, mass supplementation and food fortification have been introduced in many countries. The continuing unresolved debate over the interaction of iron and infection in the clinical setting indicates the need for firm guidelines for these practices. Iron overload is associated with increased susceptibility to certain infections, although the exact mechanisms may vary with the main pathology. Iron treatment has been associated with acute exacerbations of infection, in particular malaria. In Papua New Guinea parenteral iron was associated with increased rates of malaria and increased morbidity due to respiratory disease in infants but not in school children. Several subsequent studies in Africa using oral iron showed deleterious effects. In most instances cited, immunity was compromised, and therapeutic doses of oral iron were used. Knowledge of malarial endemicity, immunity with respect to age and the prevalence of haemoglobinopathies is important in planning interventions. A fine balance needs to be struck in the timing and dose of oral iron if informed recommendations are to be made. In parallel with supplementation studies, the effects of iron chelation on infection are being reported increasingly. Such therapy is clearly protective against malaria and some other infections but may predispose to fungal and Yersinia infections.

The IgG-subclass distribution of naturally acquired antibodies to Plasmodium falciparum, in relation to malaria exposure and severity.

A critical role has been proposed for the switch from non-cytophilic IgG2 to cytophilic antibodies of IgG1 and IgG3 subclasses observed in the humoral immune responses to Plasmodium falciparum of some Africans. These Africans have acquired clinically immunity naturally, after several years of exposure to holo-endemic malaria. In the present study, the possibility that life-long exposure to low levels of malarial endemicity may be associated with changes in the IgG-subclass composition of antibodies to P. falciparum was investigated in a native Amazonian community. The subjects were 138 malaria-exposed but non-infected Karitiana Indians. In a separate investigation, the concentrations of IgG-subclass antibodies in acutely ill patients with severe malaria (N = 22) were compared with those in age- and sex-matched controls who had uncomplicated malaria (N = 44). Plasma concentrations of IgG against a detergent-soluble extract of P. falciparum schizonts were measured by quantitative ELISA, using indirect standardization. Among the Karitiana, the concentrations of anti-parasite antibodies of all subclasses increased with age, and there was no correlation between age and the proportion of such antibodies which was cytophilic. The predominance of cytophilic IgG1 and non-cytophilic IgG2 antibodies in all age-groups of the Karitiana provides an example of an intermediate pattern of immune responses to P. falciparum which contrasts with those previously described in both clinically immune and non-immune populations. Although mean concentrations of cytophilic IgG1 against P. falciparum were significantly higher in the controls than in the patients with severe malaria, there were no significant differences in other IgG subclasses. Lack of exposure to malaria in the past was associated with disease severity (odds ratio = 4.75; 95% confidence interval = 1.31-17.42), and may explain, at least partially, the occurrence of defective, low-IgG1 antibody responses to P. falciparum in those subjects who had severe malaria.