GENERAL INTRODUCTION

CHAPTER 1

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Malaria is a systematic disease caused by infection of the red blood cells with intracellular protozoan parasites of the genus Plasmodium. The parasites are inoculated into the human host by a feeding female Anopheles mosquito. The four Plasmodia species that infect humans are P. falciparum, P. vivax, P. ovale, and P. malariae. Among the four species, P. falciparum is the main species that causes severe disease and mortality, and is the most frequently encountered in sub-Saharan Africa. In this thesis, malaria refers to disease caused by P. falciparum unless otherwise stated. Although malaria can be considered the most important infectious disease in the world, over 90% of the burden is borne by populations in sub-Saharan Africa where P. falciparum affects mainly young children and pregnant women. The rest of this dissertation focuses on children. Global estimates indicate that between 300 and 500 million clinical cases of malaria occur annually. In addition, 1.5 2.7 million deaths due to malaria occur every year, mainly in sub-Saharan Africa, and mostly among young children (WHO 1996; SNOW et al., 1999). The number of malaria-related deaths is increasing, and one key factor linked to this, is widespread drug resistance to most of the commonly available antimalarial drugs (TRAPE 1998). The main strategy for the reduction of malaria-related morbidity and mortality in Africa is early diagnosis and institution of prompt, effective treatment (WHO 1993). A major obstacle to this strategy is the development and intensification of antimalarial drug resistance. The severity of malaria infection can vary from mild (uncomplicated) to life threatening (severe malaria). One of the most inevitable manifestations of malaria is anaemiathe reduction of haemoglobin concentration below the normal range for age and sex. World Health Organization (WHO) defines anaemia as haemoglobin concentration below 11.0 g/dL. Malaria-associated anaemia is a major cause of morbidity, admission, and mortality among children in malaria endemic areas of sub-Saharan Africa. Because anaemia presents with non-specific signs and symptoms, the condition is often unrecognized and under-treated (SCHELLENBERG et al., 2003). If left untreated, anaemia is a major risk factor for mortality (MABEZA et al., 1998). Up to three quarters of African children are estimated to be anaemic, mainly from malaria or iron deficiency (DeMAEYER and ADIELS-TEGMAN, 1985). Malaria-related anaemia affects an estimated 1.5 to 6 million African children, causing a case fatality rate of 15% (MURPHY and BREMAN, 2001). In areas of high malaria transmission, young children bear the brunt of malaria and in these settings the commonest presentation of malaria is (severe) anaemia. Malarial anaemia is thought to develop through increased destruction or reduced production of red blood cells or a combination of both processes. However, the predominant pathogenetic mechanism is incompletely understood (ABDALLA et al., 1980). The increasing prevalence of malaria-associated anaemia and mortality in African children is attributed partly to the increase in antimalarial drug resistance (HEDBERG et al., 1993; SLUTSKER et al., 1994; TRAPE et al., 1998; BJORKMAN 2002). WHO defines drug resistance, as the ability of a parasite strain to multiply or to survive in the presence of concentrations of a drug that normally destroys parasites of the same species or prevent their multiplication (WHO, 1963). One of the consequences of

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drug resistance is poor haematological recovery (BLOLAND et al., 1993; VERHOEFF et al., 1997; EKVALL et al., 1998). Failed treatment contributes to malarial anaemia by persistence of parasitaemia, recrudescent infections, and continued bone marrow suppression. Consequently, the incidence of severe anaemia requiring admission and treatment with blood transfusion has increased (GREENBERG et al., 1988; ZUCKER et al., 1996). In some settings 20 to 50 % of paediatric admissions were transfused (GREENBERG et al., 1988; LACKRITZ et al., 1992). Case management of severe malarial anaemia, often includes blood transfusion; a life-saving intervention, whose survival benefit has not been quantified. In sub-Saharan Africa the risk of acquiring human immunodeficiency virus (HIV-1) type 1 infection through blood transfusion is substantial. A number of factors contribute to this high risk of transfusion-associated disease transmission: the high rate of paediatric transfusions, the high HIV seroprevalence in the donor population, the high risk of window-period donations, limits in test sensitivity, lack of antibody testing in some settings, and a high residual risk of contamination in blood supplies despite screening. In a ddition, a high proportion of paediatric transfusions are inappropriately prescribed (McFARLAND et al., 1997; MOORE et al., 2002). Transfusion has become a labour intensive intervention that utilizes a scarce and costly health resource which should be limited to situations where it is likely to improve survival. Malaria control aims to reduce morbidity and prevent complications and death from malaria. Current control strategies focus on vector control (using insecticide treated bed nets), intermittent preventive treatment in pregnancy and case management using combination therapy. In combination therapy, two or more antimalarial drugs with different mechanisms of action are simultaneously administered to improve treatment efficacy and reduce the risk of developing drug resistance (WHITE and OLLIARO, 1996; WHITE 1999). Several antimalarial drug combinations are available but the artemisinin derivatives are the most promising partners in combination therapy (KREMSNER and KRISHNA, 2004). World Health Organization has therefore endorsed the use of artemisinin-based combination therapy (ACT) as the standard care in the treatment of uncomplicated falciparum malaria (WHO 1998). However, the widespread implementation of ACTs is bound to face serious limitations of availability, familiarity and affordability (BLOLAND 2003). In these circumstances, malaria control programs should consider alternatives to ACT, which include non-artemisinin-based combination therapy. Effective antimalarial therapy should lead to better treatment outcomes (cure, survival, haematological recovery and reductions in the prevalence of malaria-associated anaemia). OUTLINE OF THE THESIS The overall objectives of the studies presented in this dissertation were to determine the burden of malarial anaemia in young children, contribute to the development of control strategies and to evaluate the effect of treatment on major outcomes (survival and haematological recovery). Our goal is to extend the understanding of the intercation between malaria, anaemia and antimalarial drug resistance. The thesis is divided into four major chapters: (i) The epidemiology ofmalarial anaemia, (ii) drug

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resistance and combination therapy, (iii) antimalarial drug treatment outcomes, and (iv) transfusion decisions. In this dissertation, we specifically aimed to:

(i) Determine the prevalence and risk factors for malaria-associated anaemia in western Kenya (chapter 2.1).

(ii) Determine the impact of severe malarial anaemia on in-hospital paediatric morbidity and mortality in western Kenya (chapter 2.2).

(iii) Determine the comparative efficacy between artemisinin-based and non-artemisinin-based combination therapy for the treatment of uncomplicated falciparum malaria (chapter 3.1).

(iv) Determine the efficacy of artesunate plus sulfadoxine-pyrimethamine vs. sulfadoxine alone in the treatment of uncomplicated falciparum malaria (chapter 3.2).

(v) Evaluate the impact of continued chloroquine use on case fatality rates following treatment of acute falciparum malaria (chapter 4.1).

(vi) Determine the effect of artesunate plus sulfadoxine-pyrimethamine vs. sulfadoxine-pyrimethamine alone on haematological recovery and anaemia (chapter 4.2).

(vii) Evaluate the circumstances in which routine blood transfusion is beneficial (chapter 5.1).

In view of the findings from chapters two to five, we propose in chapter six that intermittent preventive treatment in the post-discharge period using artemisinin-based combination drugs may be a key intervention to improving the outcomes of severe malarial anaemia in African children. We summarize the results of all the studies in chapter seven. REFERENCES Abdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M, 1980. The anaemia of P.

falciparum malaria. British Journal of Haematology 46, 171-83 Bjorkman, A., 2002. Malaria associated anaemia, drug resistance and antimalarial

combination therapy. International Journal for Parasitology 32, 1637-43 Bloland PB, Lackritz EM, Kazembe PN, Were JBO, Stekettee R, Campbell CC, 1993.

Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa. Journal of Infectious Diseases 167, 932-7

Bloland PB, 2003. A contrarian view of malaria therapy policy in Africa. American Journal of Tropical Medicine and Hygiene 68, 125-6

DeMaeyer E, Adiels-Tegman M, 1985. The prevalence of anaemia in the world. World Health Statistics Quarterly 38, 302-16

Ekvall H, Premji Z., Bjorkman A, 1998. Chloroquine treatment for uncomplicated childhood malaria in an area with drug resistance: early treatment failure aggravates anaemia. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 556-60

Greenberg AE, Nguyen-Dinh P, Mann JM, Kabote N, Colebunders RL, Francis H, Quinn TC, Baudoux P, Lyamba B, Davachi F, Roberts JM, Kabeye N, Curran JW, Campbell CC, 1988. The association between malaria, blood transfusions and HIV seropositivity in a paediatric population in Kinshasa, Zaire. Journal of the American Medical Association 259, 545-549.

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Hedberg K, Shaffer N, Davachi F, Hightower A, Lyamba B, Paluku KM, Nguyen-Dinh P, Breman JG, 1993. Plasmodium falciparum associated anaemia at a large urban hospital in Zaire. American Journal of Tropical Medicine and Hygiene 48, 365-71

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McFarland W, Mvere D, Shandera W, Reingold A, 1997. Epidemiology and prevention of transfusion-associated human immunodeficiency virus transmission in sub-Saharan Africa. Vox Sanguinis 72, 85-92

Moore A, Herrera G, Nyamongo J, Lackritz E, Granade T, Nahlen B, Oloo A, Opondo G, Muga R, Janssen R, 2002. Estimated risk of HIV transmission by blood transfusion in Kenya. Lancet 358, 657-60

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Trape JF, Pison G, Preziosi MP, Enel C, Desgrees du Lou A, Delaunay V, Samb B, Lagarde E, Molez JF, Simondon F, 1998. Impact of chloroquine resistance on malaria mortality. C. R. Acad. Sci. III 321, 689-97

Verhoeff FH, Brabin BJ, Masache P, Kachale B, Kazembe P, Van der Kaay HJ, 1997. Parasitological and haematological responses to treatment of Plasmodium falciparum malaria with sulfadoxine-pyrimethamine in southern Malawi. Annals of Tropical Medicine and Parasitology 91, 133-40

White NJ, Olliaro PL, 1996. Strategies for the prevention of antimalarial drug resistance: rationale for combination therapy for malaria. Parasitology Today 12, 399-401

White NJ, 1999. Antimalarial drug resistance and combination chemotherapy. Philosophical Transactions of the Royal Society of London series B. 354, 739-49

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World Health Organization. Implementation of the Global Malaria Control Strategy. Report of a WHO Study Group on the implementation of the global plan of action

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for malaria control 1993-2000. Technical Report Series no. 839, Geneva: WHO, 1993.

WHO, 1996. Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated falciparum malaria in areas of intense transmission. World Health Organization, Geneva, Switzerland (WHO/MAL/96.1077)

World Health Organization, Malaria Unit. The use of artemisinin and its derivatives as anti-malarial drugs: report of a joint CTD/DMP/TDR informal consultation, Geneva, 10-12 June 1998. [WHO/MAL/98.1086]. Geneva: World Health Organization, 1998.

Zucker JR, Lackritz EM, Ruebush TK, Hightower AW, Adungosi JE, Were JBO, Metchock B, Patrick E, Campbell CC, 1996. Childhood mortality during and after hospitalization in western Kenya: effect of malaria treatment regimens. American Journal of Tropical Medicine and Hygiene 55, 655-60