When is "malaria" malaria? The different burdens of malaria infection, malaria disease, and malaria-like illnesses.

In this review we discuss the different meanings of the term 'malaria' and urge writers and readers to distinguish accurately between them. The distinction is important in clinical practice, clinical trials, epidemiology, and the evaluation of control programs. Both over- and underdiagnosis of malaria as the cause of a disease episode are inevitable; overdiagnosis is common in high-transmission areas and underdiagnosis is common in areas with little or no transmission. Parasite density thresholds, attributable fractions, and clinical algorithms have played important but only partial roles in strengthening diagnosis. Methods by which malaria infection could be confidently identified as the cause, rather than an irrelevant accompaniment, of an illness, are important targets for research. One such 'signature' is a distinctive retinopathy that occurs in severe malaria and not in clinically similar diseases. Other indicators of a malarial etiology of clinical disease are needed to strengthen clinical and scientific approaches to the control of malaria.

Spatio-Temporal Distribution of Mycobacterium tuberculosis Complex Strains in Ghana.

BACKGROUND: There is a perception that genomic differences in the species/lineages of the nine species making the Mycobacterium tuberculosis complex (MTBC) may affect the efficacy of distinct control tools in certain geographical areas. We therefore analyzed the prevalence and spatial distribution of MTBC species and lineages among isolates from pulmonary TB cases over an 8-year period, 2007-2014. METHODOLOGY: Mycobacterial species isolated by culture from consecutively recruited pulmonary tuberculosis patients presenting at selected district/sub-district health facilities were confirmed as MTBC by IS6110 and rpoß PCR and further assigned lineages and sub lineages by spoligotyping and large sequence polymorphism PCR (RDs 4, 9, 12, 702, 711) assays. Patient characteristics, residency, and risks were obtained with a structured questionnaire. We used SaTScan and ArcMap analyses to identify significantly clustered MTBC lineages within selected districts and spatial display, respectively. RESULTS: Among 2,551 isolates, 2,019 (79.1%), 516 (20.2%) and 16 (0.6%) were identified as M. tuberculosis sensu stricto (MTBss), M. africanum (Maf), 15 M. bovis and 1 M. caprae, respectively. The proportions of MTBss and Maf were fairly constant within the study period. Maf spoligotypes were dominated by Spoligotype International Type (SIT) 331 (25.42%), SIT 326 (15.25%) and SIT 181 (14.12%). We found M. bovis to be significantly higher in Northern Ghana (1.9% of 212) than Southern Ghana (0.5% of 2339) (p = 0.020). Using the purely spatial and space-time analysis, seven significant MTBC lineage clusters (p< 0.05) were identified. Notable among the clusters were Ghana and Cameroon sub-lineages found to be associated with north and south, respectively. CONCLUSION: This study demonstrated that overall, 79.1% of TB in Ghana is caused by MTBss and 20% by M. africanum. Unlike some West African Countries, we did not observe a decline of Maf prevalence in Ghana.

Does apolipoprotein E polymorphism influence susceptibility to malaria?

Outcome of infection varies greatly among people, and in the case of three very different viruses, it is determined by apolipoprotein E (APOE) genotype. APOE might affect outcome of malaria infection also, since apoE protein and the protozoon (like the viruses) share cell entry mediators (heparan sulphate proteoglycans and/or specific apoE receptors). APOE polymorphisms give rise to protein variants that differ in binding strength to these mediators; thus, the extent of competition between apoE and protozoon for cell entry, and hence magnitude of protozoan damage, might depend on apoE isoform. Genotypes of infants infected with malaria were examined. It was found that APOE epsilon 2 homozygotes became infected at an earlier age than those carrying the other genotypes, the difference being statistically significant. Parasite densities, all of which were low, did not differ significantly. This effect, although based on small numbers, suggests that APOE epsilon 2 may be a risk factor for early infection.

Severe anemia in young children after high and low malaria transmission seasons in the Kassena-Nankana district of northern Ghana.

Malaria and anemia accounted for 41% and 18% respectively of hospital deaths in the Kassena-Nankana district of northern Ghana during 1996. We measured hemoglobin (Hb), malaria prevalence, and anthropometric indices of 6--24-month-old infants and young children randomly selected from this community at the end of the high (May-October, n = 347) and low (November-April, n = 286) malaria transmission seasons. High transmission season is characterized by rainfall (the equivalent of 800-900 mm/yr.), while the remaining months receive less than 50 mm/yr. Severe anemia, defined as Hb < 6.0 g/dL, was 22.1% at the end of the high transmission season compared to 1.4% at the end of the low transmission season (Odds Ratio [OR] = 20.1; 95% CI: 7.1-55.3). Parasitemia was 71% and 54.3% at these time points (OR = 2.1; 95% CI: 1.5-2.9). Nutritional anemia appeared to have little impact upon this seasonal difference since anthropometric indices were comparable. Although the relative contributions of other causes of severe anemia were not assessed, repeated malaria infections may be a primary determinant of severe anemia among infants and young children during the high transmission season.

Incidence of symptomatic and asymptomatic Plasmodium falciparum infection following curative therapy in adult residents of northern Ghana.

Adult residents of holoendemic malaria regions in Africa have a naturally acquired immunity (NAI) to malaria that renders them more resistant to new infections, limits parasitemia, and reduces the frequency and severity of illness. Given such attributes, it is not clear how one might evaluate drug or vaccine efficacy in adults without serious confounding. To determine symptomatic and asymptomatic malaria attack rates in adults of northern Ghana, 197 men and women underwent curative therapy for any pre-existing malaria infections at the start of the high transmission (wet) season. They were monitored for first parasitemia and first clinical episode of infection by Plasmodium falciparum over a 20-week period (May-October 1996). The cumulative incidence of primary infection by P. falciparum was 0.98 and incidence density of infection was calculated to be 7.0 cases/person-year. Symptoms were reported by 19.5% of the individuals at the time of first recurrent parasitemia. Incidence of infection, parasite density, and the frequency of symptoms were comparable in males and females. The results suggest that NAI did not provide these adults with significant defense against rapid re-infection and suggest that this population-infection design could serve to demonstrate the efficacy of a drug or vaccine in preventing parasitemia.

Socio-economic risk factors for malaria in a peri-urban area of The Gambia.

Successful control of malaria depends upon a detailed knowledge of its epidemiology, including knowledge of the social and economic factors that influence its prevalence. Little is known about the socio-economic factors that influence the prevalence of malaria in tropical Africa. Therefore, we undertook such a study in over 350 Gambian children with malaria resident in a peri-urban area with seasonal transmission, using the case-control approach. Malaria was associated with poor quality housing and crowding and with travel to rural areas, where the level of malaria transmission is higher than in urban centres. No association was found between the risk of malaria and the overall education level of parents or guardians of study children. However, the knowledge of malaria possessed by mothers of cases of malaria was less than that of controls, suggesting that further education of the study community on the causation of malaria and on ways of preventing it could be of value.

Socio-economic determinants are not major risk factors for severe malaria in Gambian children.

Only a small proportion of subjects infected with Plasmodium falciparum develop severe disease. Why this should be is not fully understood. To investigate the possible importance of socio-economic variables on the severity of malaria in Gambian children we undertook a case-control study of 384 children with severe or mild malaria. Few differences were found between the 2 groups. Children with severe malaria had a longer duration of symptoms when recruited than mild cases but this difference was largely accounted for by the fact the most children with severe disease were recruited at a referral hospital, whilst mild cases were recruited at a primary health care facility nearer their home. There was no difference between groups in the time before mothers sought some form of health care. Mothers of children with severe disease were less ready to take their child to hospital than mothers of mild cases, suggesting that education on the importance of taking a child with features of malaria to a health centre as soon as possible might have some effect on the development of severe disease. However, overall, the results of this study suggested that socio-economic and behavioural factors are not the major determinants for severe malaria in African children.

Anaemia caused by asymptomatic Plasmodium falciparum infection in semi-immune African schoolchildren.

A cohort of 250 Ghanaian schoolchildren aged 5-15 years was followed clinically and parasitologically for 4 months in 1997/98 in order to study the effect of asymptomatic Plasmodium falciparum infections on haematological indices and bone-marrow responses. Of the 250 children 65 met the predefined study criteria. Thus, 14 children were parasite-free throughout (group 1), 44 had P. falciparum in all blood samples collected but no symptoms of malaria (group 2), and 7 had 1 malaria attack during the study period (group 3). At the end of the study the mean haemoglobin (Hb) level in group 1 was 123 g/L, significantly higher than the value of 114 g/L in groups 2 and 3 (P < 0.02, adjusted for age and splenomegaly). The low Hb in group 2 was associated with subnormal plasma iron. Low Hb was associated with elevated erythropoietin (EPO) levels, and there was a positive correlation between EPO and reticulocyte counts. However, the reticulocyte response to EPO was more pronounced in uninfected than in infected children, suggesting a partial interference with erythropoiesis in asymptomatic infections. Children with asymptomatic infections had significantly higher plasma levels of tumour necrosis factor than uninfected children (geometric means 50 ng/L and 27 ng/L, respectively, P < 0.001) and this cytokine may contribute to bone-marrow suppression and disturbed iron metabolism. We suggest that asymptomatic malaria leads to a homeostatic imbalance in which erythrocyte loss due to parasite replication is only partially compensated for by increased erythropoiesis. The consequences of the reduced Hb levels on the development and cognitive abilities of children with asymptomatic infections, and the risk of precipitation of iron deficiency, deserve further study and should be considered in malaria control programmes that aim at reducing morbidity rather than transmission.

Health centre versus home presumptive diagnosis of malaria in southern Ghana: implications for home-based care policy.

A study was conducted in 1997 to compare the accuracy of presumptive diagnosis of malaria in children aged 1-9 years performed by caretakers of the children to that of health centre staff in 2 ecological zones in southern Ghana. Similar symptoms were reported in the children at home and at the health centre. In the home setting, symptoms were reported the same day that they occurred, 77.6% of the children with a report of fever were febrile (axillary temperature > or = 37.5 degrees C) and 64.7% of the reports of malaria were parasitologically confirmed. In the health centre, the median duration of symptoms before a child was seen was 3 days (range 1-14 days), 58.5% of the children with a report of fever were febrile and 62.6% of the clinically diagnosed cases were parasitologically confirmed. In the 2 settings almost all the infections were due to Plasmodium falciparum. Parasite density was 3 times higher in the health centre cases compared to the home-diagnosed cases. Early and appropriate treatment of malaria detected in children by caretakers may prevent complications that arise as a result of persistence of symptoms and attainment of high parasitaemic levels.

Lymphatic filariasis related perceptions and practices on the coast of Ghana: implications for prevention and control.

A qualitative study to investigate lymphatic filariasis related perceptions and practices that may be relevant for the design of appropriate health education and control programmes was conducted in four endemic villages in coastal Ghana. The villagers were aware of the common manifestations of filariasis, such as adenolymphangitis (ADL), lymphoedema, elephantiasis and hydrocele, which were specifically described with local terminology. ADL attacks were identified as the most dreaded health problem in the communities, and elephantiasis and hydrocele also ranked high in importance among reported diseases. Generally the respondents did not accept the mosquito theory of transmission, but they believed in other physical, and in spiritual and hereditary causes. Hydrocele was considered to have no link to the other disease manifestations. The manifestations were most often treated with herbal preparations which were used orally, smeared on affected parts or given as enema. In some cases the affected parts were scarified before herbal preparations were applied. The manifestations affected the work output of its victims and subjected them to hardships such as teasing, unsuitability for marriage, sexual dysfunction and divorce. Although the etiology was seen as different, the local perception of the developmental process of elephantiasis closely paralleled that of the biomedical understanding. It is suggested that this coincidence is used as an entry point for health education, to advance a broader biomedical knowledge on etiology, transmission and treatment options, and thereby to ensure co-operation of the target populations in the control of this complex disease.

Antiplasmodial activity of extracts of Tridax procumbens and Phyllanthus amarus in in vitro Plasmodium falciparum culture systems.

BACKGROUND: Aqueous extracts of Tridax procumbens (TP) (Compositae) and Phyllanthus amarus (PA) (Euphorbiaceae) are used in traditional medicine in Ghana to treat malaria. Previous studies have demonstrated the anti-trypanosoma, anti-bacterial and anti-HIV effects of TP and PA. OBJECTIVE: To assess the antiplasmodial activity of extracts of TP and PA. METHOD: Aqueous extracts of TP and PA were prepared. A portion of each was freeze-dried and the remaining extracted sequentially with ethyl acetate and chloroform. Ethanolic extracts were also prepared. The antiplasmodial activity of the extracts was assessed with the 3H-hypoxanthine assay using chloroquine-resistant (Dd2) Plasmodium falciparum parasites. Chloroquine was used as the reference drug. The modified tetrazolium-based colorimetric assay was also used to evaluate the red blood cell (RBC)-protective/antiplasmodial activities and cytotoxicities of the extracts. RESULTS: Results showed that TP and PA have antiplasmodial activities. The aqueous and ethanolic extracts of PA were the most active, yielding EC50 values of 34.9 µg/ml and 31.2 µg/ml, respectively in the tetrazolium-based assay. The TP and PA produced and IC50 values of 24.8 µg/ml and 11.7 µg/ml, respectively in the hypoxanthine assay. Protection of human RBCs against P. falciparum damage by the extracts highly correlated with their antiplasmodial activities. None of the extracts, within the concentration range (1.9-500 µg/ml) studied produced any overt toxicity to human RBCs. CONCLUSION: The results indicate that both PA and TP have activities against chloroquine-resistant P. falciparum (Dd2) parasites. The antiplasmodial principles extracted into water and ethanol but not chloroform or ethyl acetate.

The in-vitro susceptibilities of Ghanaian Plasmodium falciparum to antimalarial drugs.

In Ghana in 2004 (when choroquine was still the nationally recommended drug for the first-line treatment of malaria), the sensitivities, to chloroquine, amodiaquine, quinine, mefloquine, artesunate and halofantrine, of 60 Plasmodium falciparum isolates from two ecologically distinct areas of the country were assessed in vitro. The aim was to make available, to policy-makers, the field-based evidence needed to review the national strategy for malaria treatment. Drug susceptibilities were explored using the standardized protocol of the Antimalarial Drug Resistance Network. Although 32 of the P. falciparum isolates evaluated (56.1% of the 57 isolates successfully investigated for their susceptibility to choroquine) showed resistance to chloroquine and two showed slightly reduced sensitivity to amodiaquine, all the isolates were sensitive to mefloquine, artesunate, quinine and halofantrine. The median inhibitory concentrations (IC(50)) of chloroquine were positively correlated with those of quinine (r=0.4528; P=0.0008) but not those of any of the other drugs investigated. The IC(50) of amodiaquine and artesunate were also positively correlated (r=0.3703; P=0.0067). These results provide evidence of the presence, in Ghana, of P. falciparum isolates that are highly resistant to chloroquine but generally sensitive to most of the other antimalarial drugs commonly used in the country. Partly in consequence of these observations, the recommended first-line treatment for malaria in Ghana was changed to an amodiaquine-artesunate combination in January 2005.

Antimalarial prescribing practices: a challenge to malaria control in Ghana.

OBJECTIVE: The study was conducted to determine antimalarial prescribing practices among prescribers in 2 of the 6 sentinel sites established to document antimalarial drug efficacy in Ghana in order to provide some explanation underlying chloroquine treatment failures in the country. SUBJECTS AND METHODS: The study was descriptive combining both qualitative and quantitative designs. The qualitative design involved in-depth interviews of general prescribers in the Wassa West and Kassena Nankana districts using an interview guide. The quantitative design involved a review of Outpatient Department prescriptions of 100 patients clinically diagnosed as having malaria within the year 2000 in each of the 7 selected health care facilities. RESULTS: The overall number of drugs prescribed per patient encounter was 4.3 in the Wassa West district and 3.0 in the Kassena Nankana district. The number of drugs per patient encounter was 5.4 and 3.7 in private and government health care facilities, respectively. The commonly prescribed antimalarial drug in all the health care facilities visited was chloroquine. However, only 9.8% of prescriptions in private health care facilities contained correct doses of chloroquine compared to 54% in government health care facilities (p = 0.000). Prescriptions containing chloroquine injections were least likely to have correct doses of chloroquine. CONCLUSION: The findings indicate that although chloroquine remained the first-line drug in the treatment of uncomplicated malaria in the two districts, the level of appropriateness of doses prescribed was generally low. Inappropriate doses of chloroquine prescribed were more prevalent in private than government health care facilities, and among prescriptions containing injections.

Do maternally acquired antibodies protect infants from malaria infection?

Neonates and infants are relatively protected from clinical malaria, but the mechanism of this protection is not well understood. Maternally derived antibodies are commonly believed to provide protection against many infectious diseases, including malaria, for periods of up to 6-9 months but several recent epidemiological studies have produced conflicting results regarding a protective role of passively acquired antimalarial antibodies. In this article, we review the epidemiological evidence for resistance of young infants to malaria, summarize the data on antimalarial antibody levels and specificity and their association with protection from malaria infection or clinical disease, and explore alternative explanations for resistance to malaria in infants.

Malaria-related beliefs and behaviour in southern Ghana: implications for treatment, prevention and control.

A research infrastructure was established in two ecological zones in southern Ghana to study the variables of malaria transmission and provide information to support the country's Malaria Action Plan (MAP) launched in 1992. Residents' beliefs and practices about causes, recognition, treatment and prevention of malaria were explored in two ecological zones in southern Ghana using epidemiological and social research methods. In both communities females constituted more than 80% of caretakers of children 1-9 years and the illiteracy rate was high. Fever and malaria, which are locally called Asra or Atridi, were found to represent the same thing and are used interchangeably. Caretakers were well informed about the major symptoms of malaria, which correspond to the current clinical case definition of malaria. Knowledge about malaria transmission is, however, shrouded in many misconceptions. Though the human dwellings in the study communities conferred no real protection against mosquitoes, bednet usage was low while residents combatted the nuisance of mosquitoes with insecticide sprays, burning of coils and herbs, which they largely considered as temporary measures. Home treatment of malaria combining herbs and over-the-counter drugs and inadequate doses of chloroquine was widespread. There is a need for a strong educational component to be incorporated into the MAP to correct misconceptions about malaria transmission, appropriate treatment and protection of households. Malaria control policies should recognize the role of home treatment and drug shops in the management of malaria and incorporate them into existing control strategies.

Antibody response to 17D yellow fever vaccine in Ghanaian infants.

OBJECTIVES: To assess the seroresponses to yellow fever vaccination at 6 and 9 months of age; assess any possible adverse effects of immunization with the 17D yellow fever vaccine in infants, particularly at 6 months of age. METHODS: Four hundred and twenty infants who had completed BCG, OPV and DPT immunizations were randomized to receive yellow fever immunization at either 6 or 9 months. A single dose of 0.5 ml of the reconstituted vaccine was administered to each infant by subcutaneous injection. To determine the yellow fever antibody levels of the infants, each donated 1 ml whole blood prior to immunization and 3 months post-immunization. Each serum sample was titred on Vero cells against the vaccine virus. FINDINGS: The most common adverse reactions reported were fever, cough, diarrhoea and mild reactions at the inoculation site. The incidences of adverse reactions were not statistically different in both groups. None of the pre-immunization sera in both age groups had detectable yellow fever antibodies. Infants immunized at 6 months recorded seroconversion of 98.6% and those immunized at 9 months recorded 98% seroconversion. The GMT of their antibodies were 158.5 and 129.8, respectively. CONCLUSIONS: The results indicate that seroresponses to yellow fever immunization at 6 and 9 months as determined by seroconversion and GMTs of antibodies are similar. The findings of good seroresponses at 6 months without significant adverse effects would suggest that the 17D yellow fever vaccine could be recommended for use in children at 6 months in outbreak situations or in high risk endemic areas.

Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria.

The relationship between malaria-related outcomes and cytokine production in whole blood cultures associated with cellular immune responses and immunity to Plasmodium falciparum malaria was examined in a study in southern Ghana. Production of malaria-specific interferon (IFN)-gamma was associated with reduced risk of fever and clinical malaria. Protective IFN-gamma responses were induced by live schizonts but not by dead parasites. Production of malaria-specific tumor necrosis factor (TNF)-alpha was associated with reduced risk of fever during follow-up. Baseline levels of TNF-alpha and phytohemagglutinin (PHA)-induced interleukin (IL)-10 were positively associated with hemoglobin concentration. IL-12 production was associated with reduced risk of parasitemia. PHA-induced transforming growth factor-beta production was associated with reduced risk of fever during follow-up. High ratios of proinflammatory to anti-inflammatory cytokines were associated with increased risk of fever and higher hemoglobin concentrations. Thus, absolute levels and ratios of proinflammatory and anti-inflammatory cytokines influence susceptibility to infection, clinical disease, and anemia. These data contradict data from cross-sectional clinical studies and indicate a need for detailed analysis of the relationship between cellular immunity to malaria and resistance to disease.

Comparison of AIK-C measles vaccine in infants at 6 months with Schwarz vaccine at 9 months: a randomized controlled trial in Ghana.

In a randomized controlled trial in a measles endemic area, standard-dose (4.0 log10pfu) AIK-C measles vaccine administered at 6 months of age was compared to standard-dose Schwarz vaccine (3.7log10pfu) given at 9 months. Seroconversion rates at 3 and 6 months after immunization in the two groups were comparable and similar. The geometric mean titres achieved were, however, significantly higher in the Schwarz group (P < 0.05). No immediate serious side-effects were observed with either vaccine. We conclude that standard-dose AIK-C measles vaccine can be recommended for measles immunization in children below 9 months of age, especially in highly endemic and high-risk areas in developing countries.

PIP: The seroresponse of standard-dose heat-stable AIK-C measles vaccine administered to infants at 6 months of age was compared to that of standard-dose Schwarz vaccine administered at 9 months of age in a measles-endemic area in West Africa. The study was conducted in Asamankese, the capital town of Ghana's East Akim District. Infants 24-27 weeks of age who had been attending the Asamankese maternal-child health clinic regularly and had received all the required immunizations were enrolled and randomly assigned to receive the AIK-C (n = 184) or the Schwarz (n = 193) vaccine. No severe adverse reactions were reported during the 10-day follow-up period in either vaccine group. In the AIK-C group, 96.9% of infants who were seronegative at preimmunization and 79.4% of those with preexisting antibodies had seroconverted by 3 months after immunization; at 6 months after immunization, these rates were 97.3% and 100%, respectively. In the Schwarz group, 98.2% of infants seronegative at immunization and 100% of those with preexisting antibodies seroconverted by 3 months after immunization; at 6 months, these rates were 99.1% and 80%, respectively. Although the geometric mean titres achieved were significantly higher in the Schwarz vaccine group, these titres were above the protective level of 200 mIU in the AIK-C group. Administration of measles vaccine at a younger age may be more easily incorporated into current Expanded Program on Immunization schedules.

Entomological risk factors for severe malaria in a peri-urban area of The Gambia.

A study was undertaken of possible entomological risk factors for severe malaria in a peri-urban area of The Gambia. Households of children who had experienced a severe or a mild attack of malaria and of matched controls were visited and their characteristics recorded. Mosquitoes were then collected in the bedrooms of study subjects using both insecticide spray catches and light traps. Mud-walled buildings and bedrooms without ceilings were found more frequently in the households of children who had experienced malaria than in those of controls. Only one difference, which may have arisen by chance, was found between the households of severe and of mild malaria cases; animals were recorded significantly more frequently in the compounds of the severe cases. Mosquito catches reported on two occasions 2 weeks apart showed good reproducibility, indicating that measurements made at the time that a child presented with malaria were likely to reflect those that would have been present at the time that the child was infected. Anopheles gambiae s.l. was found on average more frequently in the bedrooms of children who had experienced malaria than in those of the controls but no difference was found in mosquito numbers between bedrooms of severe or mild cases of malaria. The human blood index and sporozoite rate were similar in mosquitoes caught in households of malaria cases and in those of controls. No evidence was found to support the hypothesis that the level of exposure to malaria-infected mosquitoes is a risk factor for the development of severe malaria.