EHP Library Malaria Bulletin 50 – November 27-December 13, 2002

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Social Sciences and Malaria Control

Afr J of Medicine and Medical Sciences (2001), 30, suppl:

  • Wires, Webs and MIMcom.net. Julia Royal and Elliot Siegol (59-63).
  • Malaria case managment at the community level in Gezira, Sudan. AA Adbel-Hameed (43-46).
  • Household expenditure on malaria case management in Wad-Medani, Sudan.  AA Abdel-Hameed, MNA Abdalla an dAH Alnaury (35-38).
  • Urban malaria treatment behaviour in the context of low levels of malaria transmission in Lagos, Nigeria. WR Brieger et al. (7-15).

Bull World Health Organ  2002;80(10):817-21

A public-private partnership for malaria control: lessons from the Malarone Donation Programme.

Oyediran AB, Ddumba EM, Ochola SA, Lucas AO, Koporc K, Dowdle WR.

Malarone Donation Programme Africa, Nairobi, Kenya.

In 1996, Glaxo Wellcome offered to donate up to a million treatment courses annually of Malarone, a new antimalarial, with a view to reducing the global burden of malaria. The Malarone Donation Programme (MDP) was established the following year. Eight pilot sites were selected in Kenya and Uganda to develop and evaluate an effective, locally sustainable donation strategy that ensured controlled and appropriate use of Malarone. The pilot programme targeted individuals who had acute uncomplicated Plasmodium falciparum malaria that had not responded to first-line treatments with chloroquine or sulfadoxine-pyrimethamine. Of the 161 079 patients clinically diagnosed at the pilot sites as having malaria, 1101 (0.68%) met all the conditions for participation and received directly observed treatment with Malarone. MDP had a positive effect at the pilot sites by improving the diagnosis and management of malaria. However, the provision of Malarone as a second-line drug at the district hospital level was not an efficient and effective use of resources. The number of deaths among children and adults ineligible for MDP at the pilot sites suggested that high priority should be given to meeting the challenges of malaria treatment at the community level. Health Policy 2003 Jan;63(1):17-36

The economic impact of malaria in Africa: a critical review of the evidence.

Chima RI, Goodman CA, Mills A.

Department of Economics, University of Nigeria, Enugu State, Nsukka, Nigeria.

Information on the economic burden of malaria in Africa is needed to target interventions efficiently and equitably, and to justify investment in research and control. A standard method of estimation has been to sum the direct costs of expenditure on prevention and treatment, and the indirect costs of productive labour time lost. This paper discusses the many problems in using such data to reflect the burden to society or the potential benefits from control. Studies have generally focussed on febrile illness, overestimating the burden of uncomplicated malaria, but underestimating the costs of severe illness, other debilitating manifestations, and mortality. Many use weak data to calculate indirect costs, which fail to account for seasonal variations, the difference between the average and marginal product of labour, and the ways households and firms ‘cope’ in response to illness episodes. Perhaps most importantly, the costs of coping mechanisms in response to the risk of disease are excluded, although they may significantly affect productive strategies and economic growth. Future work should be rooted in a sound understanding of the health burden of malaria and the organisation of economic activities, and address the impact on the productive environment, and epidemiological and socio-economic geographical variation. Trop Med Int Health 2002 Dec;7(12):1003-8

Effect of community-wide use of insecticide-treated nets for 3-4 years on malarial morbidity in Tanzania.

Maxwell CA, Msuya E, Sudi M, Njunwa KJ, Carneiro IA, Curtis CF.

London School of Hygiene & Tropical Medicine, London, UK Ubwari Field Station of the Tanzanian National Institute of Medical Research, Muheza, Tanga, Tanzania.

OBJECTIVES: To investigate (1) benefits due to personal protection of individual net users vs. mass killing of mosquitoes within villages as a result of widespread net usage; (2) sustainability over several years of benefits against malarial morbidity of insecticide-treated nets; (3) distribution of the benefits in different age groups of children and (4) whether, as a result of fading immunity, older age groups ‘paid for’ the benefits which they had enjoyed when younger.

METHODS: (1) Tabulation of earlier data to compare personal and community-wide effects against mosquito vectors; (2) two cross-sectional surveys for malaria parasitaemia, malarial fever, anaemia and splenomegaly in children in eight Tanzanian villages, in which there had been community-wide use of bednets which had been annually re-treated with alphacypermethrin for 3-4 years; (3) comparison between children of different age groups and with intact, torn or no nets in these villages and in 4-6 villages without nets. RESULTS: A 90-95% reduction in infective bites outside nets in netted villages and an additional 54-82% reduction of bites among individual net users. Highly significant reductions (by 55-75%) in malarial morbidity for children aged 6 months to 2 years were found in netted villages with, for some outcomes, better results among individuals who themselves had intact treated nets. For older children, benefits were less clear or absent, but there was no sign that the benefits early in life were ‘paid for’ by worse outcomes in the netted villages later in childhood.

CONCLUSIONS: The overall benefits to the community of widespread use of treated nets are sustainable and are not reversed in 3-4 years as a result of fading immunity. It is important to ensure high enough coverage to realize the full potential of the treated net method. By showing an impact on the vector population in the community these results provide a strong argument for organized free provision of net treatment, rather than relying on marketing.

PubMed

Trans R Soc Trop Med Hyg 2002 Sep-Oct;96(5):560-4

Seroprevalence of antibodies to repetitive domains of Plasmodium vivax circumsporozoite protein in United Arab Emirates children.

Abu-Zeid YA, Alwash R, Shaheen HM, Bin-Othman SA, Lukic ML, Amiri KM, Charoenvit Y.

Department of Biology, Faculty of Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. Email: [email protected]

The aim of this study was to determine the exposure of child citizens of the United Arab Emirates (UAE) to Plasmodium vivax, and to elucidate if it was related to place of residence or previous international travel to malaria-endemic areas. Blood samples were collected from 1010 primary schoolchildren resident in 7 out of 9 districts of the UAE during October and November 1999. Plasma samples were tested for antibodies against MAP4 (DGQPAGDR)3P2P30, a multiple antigen peptide containing the repeat amino acid sequences of P. vivax circumsporozoite protein (CSP), conjugated to 2 T-helper epitopes, P2 (QYIKANSKFIGITE) and P30 (FNNFTVSFWLRVPKVSASHLE) from tetanus toxin. For confirmation of P. vivax-specific reactivity, positive samples were further tested against (AGDR)6, a synthetic peptide containing 6 copies of a protective epitope within the CSP, and against a recombinant CSP, designated as NS1(81)V20. Results indicated that 3.3% of the children were seropositive. The seropositivity rates differed significantly in relation to place of residence, whereas travel outside the UAE did not significantly affect the exposure rates to P. vivax. Trans R Soc Trop Med Hyg 2002 Sep-Oct;96(5):551-6

Role of the pfcrt codon 76 mutation as a molecular marker for population-based surveillance of chloroquine (CQ)-resistant Plasmodium falciparum malaria in Ugandan sentinel sites with high CQ resistance.

Talisuna AO, Kyosiimire-Lugemwa J, Langi P, Mutabingwa TK, Watkins W, Van Marck E, Egwang T, D’Alessandro U.

Ministry of Health, P.O. Box 7272, Kampala, Uganda. Email: [email protected]

The mutant genotype at codon 76 of the pfcrt gene (T76) has been proposed as a molecular marker for surveillance of chloroquine (CQ)-resistant Plasmodium falciparum malaria but this proposal has not been validated by population-based surveys. In 1998-99, in 6 Ugandan sentinel sites, the prevalence of P. falciparum infections with the T76 genotype and the level of CQ use were measured by community surveys, and CQ resistance was determined by in-vivo tests on 6-59-month-old children with clinical malaria. The prevalence of T76 was not related to the overall clinical (early and late treatment failure: ETF + LTF; r = 0.14, P = 0.78) or parasitological (RI + RII + RIII; r = 0.17, P = 0.73) CQ resistance. However, the percentage of individuals carrying only infections with the T76 genotype (T76 alone) increased with increasing ETF (r = 0.76, P = 0.07) and type RIII parasitological failure (r = 0.69, P = 0.12). Similarly, the ratio between T76 and K76 (the wild type) prevalences (T76/K76) was strongly and positively correlated with ETF (r = 0.85, P = 0.03) and RIII (r = 0.82, P = 0.04). Moreover, T76 alone (r = 0.90, P = 0.01) as well as T76/K76 (r = 0.90, P = 0.01) significantly increased with increasing community CQ use. T76 alone and T76/K76 can be useful markers to estimate the ETF and RIII prevalence as well as the amount of CQ use in the community. Trans R Soc Trop Med Hyg 2002 Sep-Oct;96(5):499-506

Risk of malaria attacks in Gambian children is greater away from malaria vector breeding sites.

Clarke SE, Bogh C, Brown RC, Walraven GE, Thomas CJ, Lindsay SW.

Danish Bilharziasis Laboratory, Jaegersborg Alle 1D, DK-2920 Charlottenlund, Denmark. Email: [email protected]

The causes of local variation in the prevalence of malaria were investigated in rural Gambia. Cross-sectional prevalence surveys were carried out among 1184 young children (aged 6 months-5 years) in 48 villages, at the end of the transmission season in 1996. Villages were categorized according to distance from the nearest vector breeding sites, and the patterns of malaria transmission, infection and disease compared. Children living in villages within 3 km of breeding sites experienced more infective bites, and higher prevalences of parasitaemia and spleen enlargement than less-exposed children living further away. Clinical illness, in contrast, was more common among infected children who were less exposed. Infected children living 3 km or more from breeding sites were more likely to have high-density parasitaemia (odds ratio [OR] = 1.98), fever (OR = 2.60) and high-density parasitaemia together with fever (OR = 3.17). Clinical attacks did not decline in older children, as seen amongst children who were more exposed. These findings show that significant differences in the risk of infection and clinical attacks can occur over very short distances. The age at which protective immunity is acquired may be delayed in villages where transmission intensity is lower, thus increasing the risk of a clinical attack following infection. Communities with the lowest vector densities may be those at greatest risk of disease. Trans R Soc Trop Med Hyg 2002 Sep-Oct;96(5):481-2

Malaria during a multinational military deployment: the comparative experience of the Italian, British and Australian Armed Forces in East Timor.

Peragallo MS, Croft AM, Kitchener SJ.

Centro Studi e Ricerche di Sanita e Veterinaria dell Esercito, Via S. Stefano Rotondo, 4, 00184 Rome, Italy. Email: [email protected]

Although their efficacy has been shown to be similar in south-east Asia, doxycycline was less effective than mefloquine for malaria chemoprophylaxis in East Timor. Lower adherence, higher incidence of adverse effects and reduced bioavailability of doxycycline may have been possible causes. Mefloquine seems therefore preferable in arduous and prolonged field conditions. Trans R Soc Trop Med Hyg 2002 Sep-Oct;96(5):476-80 Irrigated crop production is associated with less malaria than traditional agricultural practices in Tanzania. Ijumba JN, Shenton FC, Clarke SE, Mosha FW, Lindsay SW. Tropical Pesticides Research Institute, P.O. Box 3024, Arusha, Tanzania. Email: [email protected] There is concern that crop irrigation that results in increased numbers of vector mosquitoes will lead to a rise in malaria in local communities. We evaluated the level of malaria experienced in 3 communities in northern Tanzania with different agricultural practices: rice irrigation, sugar-cane irrigation and traditional maize cultivation. Five cross-sectional surveys were used to measure the prevalence of infection with falciparum malaria in 1-4 years old children in each community over a period of 12 months. Active case detection was also carried out to record clinical episodes of malaria during the study period. Information on antimalarial measures was also recorded. Results from the cross-sectional surveys showed that the overall prevalence of malaria parasites was less near the rice irrigation (12.5%) and sugar-cane (16.9%) schemes than the savannah village (29.4%). There were also significantly fewer clinical episodes of malaria in the rice village (15 cases/1000 child-weeks at risk [cwar]) than either the sugar-cane (36 cases/1000 cwar) or savannah (40 cases/1000 cwar) villages. Overall, rice irrigation was associated with less malaria than alternative agricultural practices, despite the considerable numbers of vectors produced in the paddies. This finding supports other studies that indicate that irrigation in much of sub-Saharan Africa will not lead to increased malaria. Nonetheless, African governments planning irrigation projects need effective policies to encourage local communities to use personal protection measures, such as insecticide-treated bednets, and to ensure that these communities have access to effective antimalarial drugs and efficient health services. Parasitol Res 2002 Dec;89(1):26-33

Parasite-specific immunoglobulin isotypes during lethal and non-lethal murine malaria infections.

Smith EC, Taylor-Robinson AW.

School of Biology, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK.

Production of parasite-specific antibodies is an important component of immunity to blood stage malaria infection, as shown by several previous studies in rodent models. However, no study has addressed the induction of humoral immunity by different parasites in a genetically homogeneous host population. Here, levels of parasite-specific immunoglobulin isotypes were measured during primary infections of Plasmodium chabaudi and of Plasmodium yoelii in inbred NIH mice inoculated with cloned lines of either avirulent or virulent erythrocytic parasites. Non-lethal infections were characterized by early and late significant upregulation of IgG2a and IgG1, respectively. In contrast, for lethal infections, a slower, reduced IgG2a response correlated with a rapidly fatal outcome prior to any significant synthesis of IgG1. It is proposed that the sequential upregulated synthesis of parasite-specific IgG2a (cytophilic) and IgG1 (non-cytophilic) is associated with protective immunity to blood stage malaria infections in mice. This may provide an immunological framework for examining humoral immunity to malaria in humans. Sante 2002 May;12(3):331-335

[Aetiologic factors and clinical features associated with thrombocytopenia in Cameroonese adults: the importance of Plasmodium falciparum malaria] [Article in French]

Mbanya D, Tapko JB, Azowe F, Kaptue L.

Departement d’hematologie, Faculte de medecine et des sciences biomedicales, Universite de Yaounde I, BP 8046, Yaounde, Cameroun.

In order to determine the main aetiologies associated with thrombocytopenia in a hospital setting of Cameroon, 180 adults with platelet counts <100×109/L were examined and screened for a full blood count, thick and thin blood films, basic coagulation tests (activated partial thromboplastine time, a one-stage Quick’s prothrombin time and a bleeding time), an HIV screening test as well as a bone marrow aspirate using standard methods. Other tests were selectively done as dictated by the suspected diagnosis. The major clinical findings among 180 cases included fever >37.5 C (53.9%), splenomegaly (45.6%) and haemorrhage (30.6%). The main laboratory findings were anaemia (defined as haemoglobin (Hb) <11g/dL) in 80.6% of cases and a positive thick blood film (all confirmed to be P. falciparum) in 30.6% of cases. Out of the 18 different aetiologies associated with a low platelet count in the group studied, malaria appears as the unique cause in 22.2% of cases. Petechial bleeding, bruising and epistaxis were the major forms of bleeding involved (69.1%, 27.3%, and 23.6% respectively). However, only 3 cases diagnosed with malaria showed any form of bleeding (mean malaria parasite densities >15,000/muL of blood in each case). No other haemostatic abnormalities were observed. It may be cost-effective for patients with low platelet counts in malarial regions to be systematically screened for malaria parasites. Trends Parasitol 2002 Nov;18(11):510-4

Reducing malaria by mosquito-proofing houses.

Lindsay SW, Emerson PM, Charlwood JD.

School of Biological and Biomedical Sciences, University of Durham, Science Laboratories, South Road, DH1 3LE, Durham, UK.

Sometimes, valuable lessons from history are forgotten, remain unknown, or worse, are ignored. This article reminds us of the pioneering work of Angelo Celli at the end of the 19th century, who demonstrated that people could be protected from malaria by screening their homes against mosquitoes. Since then, public health scientists have continued to show that simple changes in house design have the potential for protecting people against this life-threatening disease. Yet today, this type of intervention remains virtually ignored. The literature reviewed here demonstrates the enormous potential of these methods to reduce malaria, in the hope that it will stimulate scientific debate and further research. Trends Parasitol 2002 Nov;18(11):505-9

Analysis of arthropod bloodmeals using molecular genetic markers.

Mukabana WR, Takken W, Knols BG.

Dept of Zoology, University of Nairobi, PO Box 30197, Nairobi, Kenya.

Little is known about the transmission dynamics of human malaria and other vector-borne diseases, partly because of the limited availability and distribution of appropriate tools for quantifying human-mosquito contact rates. Recent developments in molecular biology have allowed a significant increase in the efficacy and reliability of bloodmeal identification, and DNA-based molecular markers are now being harnessed for typing arthropod bloodmeals. The extent to which these markers have been used for analysis of mosquito bloodmeals and the potential they might have for the future is discussed, and the contributions that the advent of PCR has made are examined here. Trends Parasitol 2002 Nov;18(11):481

Successful model vaccine against malaria.

Clark IA.

School of Biochemistry and Molecular Biology, Australian National University, ACT 0200, Canberra, Australia (No abstract available) Malar J 2002 Nov 15;1(1):15 [epub ahead of print]

Community cooperatives and insecticide-treated materials for malaria control: a new experience in Latin America.

Kroeger A, Avinna A, Ordonnez-Gonzalez J, Escandon C.

Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. Email: [email protected]

BACKGROUND AND OBJECTIVES: Insecticide-treated materials (ITMs) are effective in substantially reducing the burden of malaria and other vector-borne diseases; but how can high coverage rates of ITMs be achieved and maintained? In south Mexico and on the Pacific and Atlantic coasts of Colombia 14 community-based cooperatives offering three different kinds of ITM services (sale of impregnation services; sale of impregnated nets; production of nets and sale of impregnated nets) were formed and supervised by a national health service (IMSS-SOLIDARIDAD, Mexico) and by an academic institution (the Colombian Institute of Tropical Medicine) along with local district health services. The objectives of this research were to analyse the processes and results of this approach and to identify the favourable and limiting factors.

METHODS: The methods used for data collection and analysis were group discussions, individual and semi-structured interviews with users and non-users of ITMs, individual in-depth interviews with cooperative members and supervisors, checks of sales book and observation of impregnation services.

RESULTS: Coverage with unimpregnated nets was above 50% in all study areas. The fastest increase of ITM coverage was achieved through the exclusive sale of impregnation services. Low-cost social marketing techniques were used to increase demand. The large-scale production of nets in two cooperatives was only possible with the aid of an international NGO which ordered impregnated bednets for their target group. A number of favourable and limiting factors relating to the success of ITM cooperatives were identified. Of particular importance for the more successful Mexican cooperatives were: a) support by health services, b) smaller size, c) lesser desire for quick returns and d) lower ITM unit costs.

CONCLUSIONS: ITM community cooperatives supported and supervised by the health services have good potential in the Latin American context for achieving and maintaining high impregnation rates. Arch Inst Pasteur Madagascar 2001;67(1-2):27-30

GIS and malaria in Madagascar [Article in French]

Rakotomanana F, Jeanne I, Duchemin JB, Pietra V, Raharimalala L, Tombo ML, Ariey F.

Institut Pasteur de Madagascar, BP 1274, 101 Antananarivo, Madagascar.

Following the severe malaria outbreak in the central highlands in Madagascar in 1986, a vector control program by use DDT pm 75 house-spraying has been implemented to operate in areas located at altitudes between 1000 and 1500 m. Early treatment with chloroquine has also been incorporated in the control program. To detect areas at particular high risk for malaria outbreak the Geographic Information System (GIS) has been applied and tested. The study has shown that the system can be used in malaria surveillance in order to identify areas in which an intense distribution of Anopheles funestus can be anticipated and, hence, targeted in spraying campaigns. The system may also be used to monitor changes in anti-malarial drug resistance, in addition, to control of other vector-born diseases. Arch Inst Pasteur Madagascar 2001;67(1-2):21-6

Malaria control in Madagascar [Article in French]

Sahondra Harisoa LJ, Pietra V, Tombo ML, Albonico M, Ranaivo LH, De Giorgi F, Razanakolona J, D’Ancona FP, Sabatinelli G, Raveloson A, Modiano D, Rakotondramarina D.

Ministere de la Sante, BP 460, 101 Antananarivo, Madagascar.

The central highlands in Madagascar are characterized by an unstable occurrence of malaria with the risk of sporadic outbreaks. In major parts of the region DDT indoor spraying campaigns have been carried out from 1993 to 1998. This strategy was in 1999 replaced by another anti-vector intervention program targeting residual foci as detected by a surveillance and early warning system. This system is based on monitoring of presumptive malaria cases in the communities by which the number of presumptive cases exceeded a defined warning threshold value per month. The system was in the follow-up period shown to be very sensitive to variation of the coverage of anti-vector interventions: the number of presumptive cases decreased in the villages in which indoor spraying had been carried out and a minor increase was observed in those villages, where indoor spraying has been suspended. An increase of malaria cases was observed in 44 (20.8%) out of 212 study sites in the same period. The increase was in particular predominant in areas at lower attitude at the outer zones of the central highlands. Clin Infect Dis 2002 Dec 15;35(12):1498-504

Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil.

Van Vugt M, Leonardi E, Phaipun L, Slight T, Thway KL, McGready R, Brockman A, Villegas L, Looareesuwan S, White NJ, Nosten F.

Shoklo Malaria Research Unit, Mae Sot, and Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and Academic Medical Centre, Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands.

In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P</=.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria. Clin Infect Dis 2002 Dec 15;35(12):1469-76

Efficacy and safety of dihydroartemisinin-piperaquine (artekin) in Cambodian children and adults with uncomplicated falciparum malaria.

Denis MB, Davis TM, Hewitt S, Incardona S, Nimol K, Fandeur T, Poravuth Y, Lim C, Socheat D.

European Commission, Cambodia Malaria Control Programme, and National Malaria Centre, Phnom Penh, Cambodia.

The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children. Mem Inst Oswaldo Cruz 2002 Oct;97(7):1033-9

In vitro chloroquine resistance modulation study on fresh isolates of Brazilian Plasmodium falciparum: intrinsic antimalarial activity of phenothiazine drugs.

Menezes CM, Kirchgatter K, Di Santi SM, Savalli C, Monteiro FG, Paula GA, Ferreira EI.

Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo, SP, 05508-900, Brasil.

Phenothiazine drugs – fluphenazine, chlorpromazine, methotrimeprazine and trifluoperazine – were evaluated as modulating agents against Brazilian chloroquine-resistant fresh isolates of Plasmodium falciparum. Aiming to simulate therapeutic schedules, chloroquine was employed at the concentration used for sensitive falciparum malaria treatment and anti-psychotic therapeutic concentrations of the phenothiazine drugs were adopted in two-fold serial dilutions. The in vitro microtechnique for drug susceptibility was employed. Unlike earlier reported data, the phenothiazine modulating effect was not observed. However, all the drugs demonstrated intrinsic antiplasmodial activity in concentrations lower than those described in the literature. In addition, IC50 estimates have been shown to be inferior to the usual anti-psychotic therapeutic concentrations. Statistical analysis also suggested an increase in the parasitaemia rate or, even, a predominant antiparasitic effect of phenothiazine over chloroquine when used in combination. Bull World Health Organ 2002;80(10):790-6

Treatment uptake by individuals infected with Plasmodium falciparum in rural Gambia, West Africa.

Von Seidlein L, Clarke S, Alexander N, Manneh F, Doherty T, Pinder M, Walraven G, Greenwood B.

Medical Research Council Laboratories.

OBJECTIVE: To find out what proportion of Plasmodium falciparum infections are treated in rural Gambia. METHODS: Subjects from four villages in the Gambia were followed over nine months through visits to village health workers. Monthly cross-sectional malaria surveys measured the prevalence of P. falciparum infection. Linked databases were searched for treatment requests. Treated cases were individuals with parasitaemia who requested treatment during narrow or extended periods (14 or 28 days, respectively) before or after a positive blood film was obtained.

FINDINGS: Parasite prevalence peaked in November 1998, when 399/653 (61%) individuals had parasitaemia. Parasite prevalence was highest throughout the study in children aged 5-10 years. Although access to treatment was better than in most of sub-Saharan Africa, only 20% of infected individuals sought medical treatment up to 14 days before or after a positive blood film. Within two months of a positive blood film, 199/726 (27%) individuals with parasitaemia requested treatment. Despite easy access to health care, less than half (42%) of those with parasite densities consistent with malaria attacks (5000/ l) requested treatment. High parasite density and infection during October-November were associated with more frequent treatment requests. Self-treatment was infrequent in study villages: in 3/120 (2.5%) households antimalarial drugs had been used in the preceding malaria season.

CONCLUSION: Many P. falciparum infections may be untreated because of their subclinical nature. Intermittent presumptive treatment may reduce morbidity and mortality. It is likely that not all untreated infections were asymptomatic. Qualitative research should explore barriers to treatment uptake, to allow educational interventions to be planned. Science 2002 Dec 6;298(5600):2002-6

A role for the protease falcipain 1 in host cell invasion by the human malaria parasite.

Greenbaum DC, Baruch A, Grainger M, Bozdech Z, Medzihradszky KF, Engel J, DeRisi J, Holder AA, Bogyo M.

Department of Pharmaceutical Chemistry, Veterans Affairs Medical Center, University of California, San Francisco, CA 94143, USA. Email: [email protected]

Cysteine proteases of Plasmodium falciparum are required for survival of the malaria parasite, yet their specific cellular functions remain unclear. We used a chemical proteomic screen with a small-molecule probe to characterize the predominant cysteine proteases throughout the parasite life cycle. Only one protease, falcipain 1, was active during the invasive merozoite stage. Falcipain 1-specific inhibitors, identified by screening of chemical libraries, blocked parasite invasion of host erythrocytes, yet had no effect on normal parasite processes such as hemoglobin degradation. These results demonstrate a specific role for falcipain 1 in host cell invasion and establish a potential new target for antimalarial therapeutics. J Immunol 2002 Dec 15;169(12):6681-5

Cutting Edge: A New Tool to Evaluate Human Pre-Erythrocytic Malaria Vaccines: Rodent Parasites Bearing a Hybrid Plasmodium falciparum Circumsporozoite Protein.

Persson C, Oliveira GA, Sultan AA, Bhanot P, Nussenzweig V, Nardin E.

Michael Heidelberger Division of Immunology, Department of Pathology, and Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10016.

Malaria vaccines containing the Plasmodium falciparum Circumsporozoite protein repeat domain are undergoing human trials. There is no simple method to evaluate the effect of vaccine-induced responses on P. falciparum sporozoite infectivity. Unlike the rodent malaria Plasmodium berghei, P. falciparum sporozoites do not infect common laboratory animals and only develop in vitro in human hepatocyte cultures. We generated a recombinant P. berghei parasite bearing P. falciparum Circumsporozoite protein repeats. These hybrid sporozoites are fully infective in vivo and in vitro. Monoclonal and polyclonal Abs to P. falciparum repeats neutralize hybrid parasite infectivity, and mice immunized with a P. falciparum vaccine are protected against challenge with hybrid sporozoites. Nat Med 2002 Dec 9; [epub ahead of print] Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Maier AG, Duraisingh MT, Reeder JC, Patel SS, Kazura JW, Zimmerman PA, Cowman AF. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria. Proc Natl Acad Sci U S A 2002 Dec 10;99(25):16348-16353

Mosaic organization and heterogeneity in frequency of allelic recombination of the Plasmodium vivax merozoite surface protein-1 locus.

Putaporntip C, Jongwutiwes S, Sakihama N, Ferreira MU, Kho WG, Kaneko A, Kanbara H, Hattori T, Tanabe K.

Laboratory of Biology and Department of Mathematics, Osaka Institute of Technology, Osaka 535-8585, Japan; Department of Protozoology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; Department of Parasitology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Asia; Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, 05508-900, Sao Paulo (SP), Brazil South America; Department of Parasitology and Institute of Malariology, Inje University College of Medicine, Pusan 614-735, South Korea Asia; and Department of International Affairs and Tropical Medicine, Tokyo Women’s Medical University School of Medicine, Tokyo 162-866, Japan.

The organization and allelic recombination of the merozoite surface protein-1 gene of Plasmodium vivax (PvMsp-1), the most widely prevalent human malaria parasite, were evaluated in complete nucleotide sequences of 40 isolates from various geographic areas. Alignment of 31 distinct alleles revealed the mosaic organization of PvMsp-1, consisting of seven interallele conserved blocks flanked by six variable blocks. The variable blocks showed extensive variation in repeats and nonrepeat unique sequences. Numerous recombination sites were distributed throughout PvMsp-1, in both conserved blocks and variable block unique sequences, and the distribution was not uniform. Heterozygosity of PvMsp-1 alleles was higher in Asia (0.953 +/- 0.009) than in Brazil (0.813 +/- 0.047). No identical alleles were shared between Asia and Brazil, whereas all but one variable block nonrepeat sequence found in Brazil occurred in Asia. These observations suggest that P. vivax populations in Asia are ancestral to Brazilian populations, and that PvMsp-1 has heterogeneity in frequency of allelic recombination events. Recurrent origins of new PvMsp-1 alleles by repeated recombination events were supported by a rapid decline in linkage disequilibrium between pairs of synonymous sites with increasing nucleotide distance, with little linkage disequilibrium at a distance of over 3 kb in a P. vivax population from Thailand, evidence for an effectively high recombination rate of the parasite. Meanwhile, highly reduced nucleotide diversity was noted in a region encoding the 19-kDa C-terminal epidermal growth factor-like domain of merozoite surface protein-1, a vaccine candidate. Arch Inst Pasteur Madagascar 2000;66(1-2):32-5

Anopheles gambiae and Anopheles funestus in Madagascar [Article in French]

Rakotondraibe ME, Le Goff G, Rajaonarivelo E, Romi R, Raharimanga R, Rajaonarivelo V, Rabarison P. Service de Lutte contre le Paludisme, Ministere de la Sante de Madagascar, BP 460-101 Antananarivo-Madagascar.

In 1991, Anopheles gambiae and Anopheles funestus, the main malaria vectors in the Highlands of Madagascar, were reported to be fully susceptible to DDT; nevertheless a slight decrease in the susceptibility levels was recorded when compared with previous assays carried out in 1962. From 1993 to 1997, five cycles of indoor residual spraying have been carried out in the Highlands: a total of 1,482,000 kg of 70% wp DDT have been used for the treatment of houses and animal shelters. From 1996 to 1999, adult mosquito susceptibility tests to DDT and to some pyrethroids (lambdacyalothrine, deltamethrine, permethrine and cyfluthrine) have been carried out on samples collected in 20 areas of the Highlands. Bioassays were carried out following the WHO standard method. All tested populations of An. funestus showed a full susceptibility to DDT. An. gambiae showed a widespread decrease in the susceptibility to DDT, particularly marked in the region of the capital city Antananarivo. Both species were susceptible to pyrethroids. Arch Inst Pasteur Madagascar 2000;66(1-2):26-31 Evolution of the chemoresistance of Plasmodium falciparum to chloroquine in Madagascar [Article in French] Raharimalala AL, Randrianarivelojosia M, Randriamanantena A, Ranarivelo LA, Jaureguiberry S, Rason MA, Rakotomalala E, Ariey F. Institut Pasteur de Madagascar, BP 1274, 101 Antananarivo-Madagascar. In order to document the evolution of the chemoresistance of Plasmodium falciparum to chloroquine in Madagascar, a study was carried out in Sainte-Marie island located at 6 km on the eastern border of the country. Symptomatic malaria patients who satisfied criteria for resistance testing, were recruited by a process of passive case detection at two clinics. These patients were enrolled in a sensitivity 14-day in vivo test for uncomplicated P. falciparum malaria attacks. All subjects received a supervised therapeutic regimen of chloroquine (25 mg base/kg over 3 days). Parasitemia and symptoms were monitored for 14 days. 62 (93.9%) out of the 66 enrolled patients completed the 14-day follow-up. A total of 50 of 62 patients (80.6%) presented an adequate clinical response. Early and late treatment failures were observed in 3 (4.8%) and 9 (14.5%) patients respectively. Failure therapeutic treatments treated with sulfadoxine-pyrimethamine were successful. Chloroquine remains effective in the treatment of malaria due to P. falciparum and therefore its choice as a first line drug remains justified. Likewise, guidelines for the use of sulfadoxine-pyrimethamine as second line drug are adequate. In vitro, 4 resistances out of 27 successful tests to chloroquine (14.8%) and 1 resistance out of 25 successful tests to mefloquine (4%) were recorded. No resistance to quinine nor to amodiaquine were noticed. Alternative antimalarial drugs such as quinine, amodiaquine or mefloquine can be used in patients for whom the treatment with chloroquine is not possible. Nevertheless, the level of therapeutic failures to chloroquine detected in this study highlights the need and importance of drug sensitivity test for the development of a rational national antimalarial drug policy. Arch Inst Pasteur Madagascar 2000;66(1-2):23-5

Epidemiological and clinical survey and evaluative aspects of severe malaria in Antananarivo [Article in French]

Raobijaona H, Randrianotahina CH, Razanamparany M.

Hopital general de Befelatanana, Centre Hospitalier Universitaire d’Antananarivo, BP 8394-101 Antananarivo-Madagascar.

The definition of severe malaria is no longer limited to cerebral malaria, but it is as well extended to other clinical forms of the disease. The authors reported the epidemiological and clinical survey and evaluative aspects of severe malaria in Antananarivo. This retrospective study included 48 children less than 15 years old, hospitalized at the paediatric unit Debre of the Centre Hospitalier Universitaire de Befelatanana (Antananarivo) for severe malaria as defined by world Health Organization (WHO) criteria. The hospitalization frequency was 0.87%. Higher frequency was noticed for the children less than 5 years old, the sex-ratio was 1.4/1. The cerebral complications as seen in many African countries were the most frequent clinical form. The death rate was 14.58% and the proportional mortality was 1.07%, 2.1% of the patients had sequel. The improvement of severe malaria prognosis was not only on better equipment in intensive care wards, but also on improved and early diagnosis and management. Arch Inst Pasteur Madagascar 1996;63(1-2):12-5

Results of paludometric and entomological studies carried-out for two years: Ampanihy and Ankilimivory located in the South of Madagascar [Article in French]

Champetier de Ribes G, Rakotoson JD, Ranaivoson G, Rabeson D. Service de Surveillance Epidemiologique, Ministere de la Sante, Direction de la Lutte contreles Maladies Transmissibles (DLMT), BP 460, 101 Antananarivo, Madagascar.

The authors reported the results of paludometric and entomological studies carried-out for two years: 1995-1996 in two localities: Ampanihy and Ankilimivory located in the South of Madagascar. These studies followed a suspect malaria epidemic in Ankilimivory in June and July 1994; the population plasmodic index was of 45%. In April 1995, this data was of 35% in Ampanihy and of 15% in Ankilimivory. Entomological studies carried out in April 1996 allowed to find Anopheles funestus in Ankilimivory and Anopheles gambiae l. s. in the two localities. Both the endemicity of malaria and the role of A. funestus had to be taken into account in the southern part of Madagascar. Until now, rare epidemics in this area were thought to occur only when climatic conditions were favorable, mainly during the rainy season. However, other factors, linked with the development could also facilitate the upset of epidemics, e.g.: irrigation programmes. Trop Med Int Health 2002 Dec;7(12):1042-6

Malaria control: constraints and opportunities.

Kager PA.

Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

The malaria eradication campaign of the 1950s and 1960s achieved elimination of malaria from the industrialized world and drastic reduction of malaria elsewhere, especially Asia. In Africa, eradication was hardly attempted. For various reasons, results could not be maintained. Eradication had to be given up, control became the policy. Since 1992 malaria control is based on four principles: early diagnosis and treatment; selective and sustainable preventive measures, including vector control; detection, containment and prevention of epidemics, and building up of local capacity. Several constraints with the presently available tools are discussed. Major problems are drug resistance and poor performance of the health sector. International awareness of the problem and international co-operation, the financial resources now available and scientific advances offer opportunities for a concerted effort to reduce the burden of malaria. Operational research, field research and implementation and improvement of the peripheral health service will be of paramount importance. Trop Med Int Health 2002 Dec;7(12):1031-41

Increasing antimalarial drug resistance in Uganda and revision of the national drug policy.

Kamya MR, Bakyaita NN, Talisuna AO, Were WM, Staedke SG. Makerere University Medical School, Kampala, Uganda Ministry of Health, Kampala, Uganda Rubaga Hospital, Kampala, Uganda Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, USA.

Chloroquine (CQ) resistance was first documented in Uganda in 1988. Subsequent surveillance of antimalarial drug resistance, conducted by the Ugandan Ministry of Health and several research organizations, suggests that resistance to CQ is now widespread, reaching critical levels in many areas of the country. In June 2000, the Ministry of Health held a National Consensus Meeting to evaluate the available drug efficacy data and review the national antimalarial drug policy. After extensive debate, the combination of CQ + sulfadoxine-pyrimethamine (SP) was chosen to replace CQ as the first-line treatment of uncomplicated malaria as an interim policy. This review evaluates the in vivo drug efficacy studies conducted in Uganda since 1988 and issues confronted in revision of the drug policy. The Ugandan experience illustrates the challenges faced by sub-Saharan African countries confronted with rising CQ resistance but limited data on potential alternative options. The choice of CQ + SP as a provisional policy in the absence of prerequisite efficacy, safety and cost-effectiveness data reflects the urgency of the malaria treatment problem, and growing pressure to adopt combination therapies. Surveillance of CQ + SP treatment efficacy, collection of additional data on alternative regimens and active consensus building among key partners in the malaria community will be necessary to develop a rational long-term antimalarial treatment policy in Uganda. Trop Med Int Health 2002 Dec;7(12):1022-30

Do insecticide-treated bednets have an effect on malaria vectors?

Takken W. Laboratory of Entomology, Wageningen University, Wageningen, The Netherlands.

The use of insecticide-treated bednets (ITNs) has been widely adopted as an important method for malaria control. Few data exist on effects of ITNs on mosquito biology and ecology, other than the development of insecticide resistance against the insecticides used. There is no hard evidence that the insecticide resistance recorded is the result of insecticidal use on bednets or from agricultural use. Resistance against pyrethroids, the preferred class of insecticides for ITN use, has been recorded from countries in Asia, Africa and South America. Resistance is expressed as reduced excito-repellency and mortality of mosquitoes exposed to insecticide-treated materials. In the absence of resistance, however, most studies on ITN effects report a reduced survival of adult mosquitoes as well as mass killing. Other effects are highly variable, and shifts in time of biting, feeding site and blood hosts have occasionally been reported, but not in proportion to the scale of ITN use. In general, a reduced sporozoite rate is recorded in ITN programmes. Because many of the anticipated behavioural effects caused by insecticidal use will be avoided by the use of untreated nets, studies on the efficacy of untreated nets are required. Examples are presented in which untreated nets provided a reasonable degree of protection against malaria. Trop Med Int Health 2002 Dec;7(12):1012-21

The molecular epidemiology of malaria. Greenwood B.

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

This review discusses how the use of molecular genetic techniques such as the polymerase chain reaction are helping in the management and prevention of malaria. infection in owl and squirrel monkeys, whose parasitemia increased by. 22,000 parasites/uL daily during a 14-day interval. After malaria challenge, unprotected animals had significant changes in hematologic values. These changes could not be completely attributed to the increase in the parasite counts. Am J Trop Med Hyg 2002 Oct;67(4):392-5 Molecular epidemiology of malaria in Cameroon. XIV. Plasmodium falciparum chloroquine resistance transporter (PFCRT) gene sequences of isolates before and after chloroquine treatment. Basco LK, Ndounga M, Ngane VF, Soula G. Institut de Recherche pour le Developpement (IRD)-Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la lutte contre les Endemies en Afrique Centrale (OCEAC), B. P. 288, Yaounde, Cameroon. Laboratory studies have strongly suggested that the gene coding for Plasmodium falciparum chloroquine resistance transporter (PFCRT) may play a determinant role in chloroquine resistance. A clinical study in Mali also found evidence for selection of the key PFCRT amino acid substitution, Lys76Thr, in patients who fail to respond to chloroquine treatment. To test the hypothesis that in vivo selection of mutant PFCRT alleles occurs after chloroquine treatment, PFCRT and merozoite surface antigen 2 (msa-2) polymorphisms were compared between 61 pretreatment and posttreatment paired samples from children with either clinical or parasitologic failure. There were six wild-type PFCRT alleles, 44 mutant alleles, and 11 mixed alleles among pretreatment isolates. All posttreatment parasites had mutant PFCRT alleles. Recrudescence accounted for 42 of 61 posttreatment infections, while 19 posttreatment infections were due to new infection (including all isolates with Lys-76 before treatment and Thr-76 after treatment). Seven pretreatment isolates with mixed PFCRT alleles had only Thr-76 on recrudescence, providing a direct evidence for in vivo selection for mutant PFCRT. Although the presence of mutant PFCRT alleles in pretreatment isolates is not predictive of chloroquine treatment failure, our data support the hypothesis that in vivo selection for recrudescent parasites carrying mutant PFCRT alleles occurs. These results may have important implications for the future surveillance of chloroquine resistance by the use of molecular markers. Am J Trop Med Hyg 2002 Oct;67(4):388-91

Molecular epidemiology of malaria in Cameroon. XIII. Analysis of pfcrt mutations and in vitro chloroquine resistance.

Basco LK.

Institut de Recherche pour le Developpement (IRD) and Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la lutte contre les Endemies en Afrique Centrale (OCEAC), B. P. 288, Yaounde, Cameroon.

The key Lys76Thr amino-acid substitution in Plasmodium falciparum chloroquine-resistance transporter (PfCRT) has been shown to be a reliable marker associated with chloroquine-resistant phenotype in reference clones, but few discordant results have been observed in field isolates. To further examine the relationship between in vitro chloroquine response and pfcrt alleles, the entire exon 2 of the pfcrt gene of 157 Cameroonian isolates was sequenced. All isolates were characterized as having either Cys-72, Met-74, Asn-75, and Lys-76 (wild-type alleles), Cys-72, Ile-74, Glu-75, and Thr-76 (mutant alleles), or mixed alleles. The hypothetical threshold 50% inhibitory concentration (IC50) set at 100 nM distinguished between isolates carrying the wild-type alleles and those with mutant alleles in a large majority of cases (135 of 139 isolates with unmixed pfcrt alleles). Isolates presenting discordant results generally had IC50s within an intermediate range. In vitro chloroquine response of isolates with mixed pfcrt alleles was highly variable. Although discordant results between chloroquine-resistant phenotype and pfcrt alleles were not explained by the immediate adjacent codons, the key Lys76Thr codon may prove to be a highly reliable genetic marker for the epidemiologic monitoring of chloroquine resistance by means of molecular techniques. Am J Trop Med Hyg 2002 Oct;67(4):383-7

Molecular epidemiology of malaria in Cameroon. XII. In vitro drug assays and molecular surveillance of chloroquine and proguanil resistance. Basco LK.

Institut de Recherche pour le Developpement (IRD) and Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la lutte contre les Endemies en Afrique Centrale (OCEAC), B. P. 288, Yaounde, Cameroon. Email: [email protected]

Chloroquine-proguanil combination is one of the options for chemoprophylaxis. The rapid evolution of drug resistance status requires a constant upgrade of epidemiologic data. Due to various difficulties in conducting prospective clinical studies on the prophylactic efficacy of the drug combination, especially in highly chloroquine-resistant zones, in vitro drug sensitivity assays and specific molecular markers for chloroquine (Plasmodium falciparum chloroquine-resistance transporter, pfcrt) and cycloguanil (a biologically active metabolite of proguanil; dihydrofolate reductase, dhfr) resistance were evaluated as an alternative approach in this study. Of 116 isolates, 62 (53.4%) were doubly resistant in vitro to chloroquine (IC50 > or = 100 nM) and cycloguanil (IC50 > or = 15 nM). Likewise, 62 of 118 isolates (52.5%) carried both the mutant Thr-76 pfcrt allele and at least one dhfr mutant allele (1 with a single Asn-108 allele, 8 with double Arg-59 and Asn-108 mutations, and 53 with triple Ile-51, Arg-59, and Asn-108 mutations). The in vitro drug response corresponded with the presence or absence of key mutation(s) in the pfcrt and dhfr genes. These results suggest the high proportion of P. falciparum isolates in southern Cameroon that may not respond to chloroquine-proguanil combination. Am J Trop Med Hyg 2002 Oct;67(4):411-4

Plasmodium malariae infection boosts Plasmodium falciparum gametocyte production.

McKenzie FE, Jeffery GM, Collins WE.

Fogarty International Center, National Institutes of Health, Bethesda, Maryland 20892, USA. Email: [email protected]

We analyzed records of malaria therapy patients sequentially or simultaneously inoculated with Plasmodium falciparum and Plasmodium malariae. Gametocyte production was enhanced in P. falciparum by prior or concurrent P. malariae infection but diminished or unaffected in P. malariae by P. falciparum. Conversely, asexual-form production was diminished in P. malariae but unaffected in P. falciparum. Am J Trop Med Hyg 2002 Oct;67(4):400-5 Genetics of drug-resistant Plasmodium falciparum malaria in the Venezuelan state of Bolivar. Contreras CE, Cortese JF, Caraballo A, Plowe CV. Immunology Institute, School of Medicine, Central University, Caracas, Venezuela. Email: [email protected] The state of Bolivar in Venezuela experiences episodic outbreaks of multidrug-resistant Plasmodium falciparum malaria. We obtained P. falciparum-infected blood samples in Bolivar in 1998-2000, and performed molecular assays for mutations conferring resistance to the antifolate combination of sulfadoxine-pyrimethamine (SP) and to chloroquine. All infections carried the dihydrofolate reductase (dhfr) S108A and N51I mutations, and 45% of the infections had the dhfr C50R mutation, which has been implicated in mid-level resistance to SP. Two dihydropteroate synthase (dhps) mutations also involved in SP resistance, A581G and K540E, were detected in 90% and 67% of the samples, respectively. The dhfr 1164L mutation, which confers high-level resistance, was not identified. The P. falciparum chloroquine resistance transporter (pfcrt) K76T mutation, which is critical for chloroquine resistance, was found in 167 of 168 infections. Six dhfr/dhps allelotypes and four pfcrt-resistant alleles were observed. Their interrelationships suggest a semi-clonal propagation of P. falciparum malaria in Bolivar, and an invasion of multi-resistant pathogens from Brazil. Despite national restrictions on the use of SP and chloroquine, genotypic resistance to these therapies remains widespread in Bolivar. Am J Trop Med Hyg 2002 Oct;67(4):396-9

Failure of national guidelines to diagnose uncomplicated malaria in Bangladesh.

Faiz MA, Yunus EB, Rahman MR, Hossain MA, Pang LW, Rahman ME, Bhuiyan SN.

Malaria Research Group, Chittagong Medical College, Chittagong, 4000, Bangladesh.

During the mid 1990s, national guidelines were established in accordance with World Health Organization recommendations for the diagnosis of uncomplicated malaria in Bangladesh. Based on simple clinical and epidemiologic criteria these guidelines were designed to be applied outside of tertiary care centers where microscopy was not feasible. We evaluated the positive predictive value (PPV) of these criteria using microscopic slide examinations as the gold standard in 684 subjects diagnosed and treated for malaria, sampling from eight subdistrict centers. The PPV for malaria was 32% with 19% for falciparum and 14% for Plasmodium vivax. Medical officers assigned to the study also gave their own clinical impression of whether cases could have been malaria. With the additional criteria of a medical officers’ diagnosis, the PPV increased negligibly to 37% with 23% and 14% for falciparum and vivax, respectively. Since the PPV of diagnosis is low and cannot be improved on clinical grounds alone, we recommend the incorporation of laboratory diagnosis. This is especially important as we detect resistance to the first-line therapy chloroquine and require more expensive, potentially more toxic, regimens. Am J Trop Med Hyg 2002 Oct;67(4):378-82

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