Malaria, Anaemia and Antimalarial Drug Resistance in African Children Charles O. Obonyo
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Malaria, Anaemia and Antimalarial Drug
Resistance in African Children
Charles O. Obonyo
Malaria, anaemia and antimalarial drug resistance in African children.
Thesis, University of Utrecht, Utrecht, The Netherlands
ISBN-10: 90-393-4348-9
ISBN-13: 978-90-393-4348-7
Copyright © 2006 C. O.Obonyo
Cover design: Juan Felipe Delgado G.
The studies described in this thesis were supported by research grants from
UNDP/World Bank/WHO Special Programme for Research and Training in Tropical
Diseases (TDR), Geneva, Switzerland; Pfizer Global Pharmaceuticals; WHO Africa
Office, Harare, Zimbabwe
Printed by: Gildeprint Drukkerijen, The Netherlands
Malaria, Anaemia and Antimalarial Drug
Resistance in African Children
Malaria, Anemie en Resistente Tegen Antimalaria
Middelen in Afrikaanse Kinderen
(met een samenvattig in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. W.H. Gispen, ingevolge het besluit
van het college voor promoties in het openbaar te verdedigen op dinsdag 19 september 2006 des ochtends te 10.30 uur
door
Charles O. Obonyo Geboren op 17 juni 1965
te South Nyanza District, Kenia
Promotor: Prof. Dr. D.E. Grobbee
Financial support for the printing of this thesis provided by WHO/TDR and Pfizer
Global Pharmaceuticals is acknowledged. I am also grateful for the financial support provided by the Julius Centre towards my travel, accomodation and the thesis defence.
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TABLE OF CONTENTS
Chapter 1 GENERAL INTRODUCTION Chapter 2 EPIDEMIOLOGY OF MALARIAL ANAEMIA 2.1 Prevalence of and risk factors for malaria-associated anaemia 2.2 In-hospital morbidity and mortality due to severe malarial anaemia Chapter 3 DRUG RESISTANCE AND COMBINATION THERAPY 3.1 A meta-analysis of the effect of Amodiaquine plus Sulfadoxine-
Pyrimethamine vs. Artemisinin-based combination therapies for the treatment of uncomplicated falciparum malaria in African children
3.2 A randomized controlled trial of the effect of Artesunate plus Sulfadoxine-Pyrimethamine in the treatment of uncomplicated malaria in children
Chapter 4 ANTIMALARIAL DRUG TREATMENT OUTCOME 4.1 Mortality consequences of continued use of chloroquine in Africa 4.2 Effect of Artesunate plus Sulfadoxine-Pyrimethamine on
haematological recovery Chapter 5 TRANSFUSION DECISIONS 5.1 Blood transfusion for severe malaria-related anaemia in Africa: a
decision analysis Chapter 6 DISCUSSION
Is Intermittent Preventive Therapy in the post-discharge (IPTpd) period the key to improving the outcome of Severe Malarial Anaemia in African children?
Chapter 7 SUMMARY SAMENVATIG (DUTCH SUMMARY) ACKNOWLEDGEMENTS
CURRICULUM VITAE
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PUBLICATIONS AND MANUSCRIPTS BASED ON THE STUDIES DESCRIBED IN THIS THESIS
1. Obonyo CO, Taylor WR, Ogutu BR, Vulule JM, Grobbee DE. Prevalence of and risk factors for malaria-associated anaemia in young Kenyan children. Manuscript (Chapter 2.1)
2. Obonyo CO, Vulule JM, Akhwale W, Grobbee DE. In-hospital morbidity and mortality due to severe malarial anaemia in western Kenya. Manuscript (Chapter 2.2)
3. Obonyo CO, Juma EA., Ogutu BR, Vulule JM, Lau J. Amodiaquine combined with sulfadoxine-pyrimethamine vs. Artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in Africa: a meta-analysis. In press, Trans R Soc Trop Med Hyg (Chapter 3.1)
4. Obonyo CO, Ochieng F, Taylor WRJ, Ochola SA, Mugitu K, Olliaro P, ter Kuile F, Oloo AJ. Artesunate plus Sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomized, double-blind, placebo-controlled trial. Trans R Soc Trop Med Hyg 2003, 97: 585-91 (Chapter 3.2)
5. Zucker JR, Ruebush TK, Obonyo C, Otieno J, Campbell CC. Mortality consequences of the continued use of chloroquine in Africa: experience in Siaya. Am J Trop Med Hyg 2003, 68: 386-90 (Chapter 4.1)
6. Obonyo CO, Taylor WR, Ekvall H, Kaneko A, ter Kuile F, Olliaro P, Bjorkman A, Oloo AJ. Effect of artesunate plus SP on haematological recovery and anaemia in Kenyan children with uncomplicated falciparum malaria. Accepted for publication, Annals of Tropical Medicine and Parasitology (Chapter 4.2)
7. Obonyo CO, Steyerberg EW, Oloo AJ, Habbema JDF. Blood transfusion for severe malaria-related anaemia in Africa: a decision analysis. Am J Trop Med Hyg 1998, 59: 808-12 (Chapter 5.1)
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 anaemia—the 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
Kremsner PG, Krishna S, 2004. Antimalarial combinations. Lancet 364, 285-94. Lackritz EM, Campbell CC, Ruebush TK, Hightower AW, Wakube W, Steketee RW,
Were JBO, 1992. Effect of blood transfusion on survival among children in a Kenyan hospital. Lancet 340, 524-8
Mabeza GF, Biemba G, Brennan AG, Moyo VM, Thuma PE, Gordeuk VR, 1998. The association of pallor with haemoglobin concentrations and mortality in severe malaria. Annals of Tropical Medicine and Parasitology 92, 663-9.
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
Murphy SC & Breman JG, 2001. Gaps in the African childhood malaria burden adding neurological sequelae, anaemia, respiratory distress, hypoglycaemia, and complications of pregnancy. American Journal of Tropical Medicine and Hygiene 64 (Suppl 1), 57-67
Schellenberg D, Armstrong-Schellenberg, JRM, Mushi A, de Savigny D, Mgalula L, Mbuya C, Victoria CG, 2003. The silent burden of anaemia in Tanzanian children: a community-based study. Bulletion of the World Health Organization 81, 581-90
Slutsker L, Taylor TE, Wirima JJ, Steketee RW, 1994. In-hospital morbidity and mortality due to malaria-associated severe anaemia in two areas of Malawi with different patterns of malaria infection. Transations of the Royal Society of Tropical Medicine and Hygiene 88, 548-51
Snow RW, Craig M, Deichmann U, 1999. Estimating mortality and disability due to malaria among Africa’s non-pregnant population. Bulletin of the World Health Organization 77, 624-40
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
World Health Organization. Terminology of malaria and of malaria eradication: report of a drafting committee. Monograph series No. 12. Geneva, 1963.
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
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CHAPTER 2
EPIDEMIOLOGY OF MALARIAL
ANAEMIA IN WESTERN KENYA
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Chapter 2.1
Prevalence of and risk factors for malarial-associated anaemia in
young Kenyan children
Manuscript
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Prevalence of and risk factors for malaria-associated anaemia in
young Kenyan children
Charles O. Obonyo, MSc1, 4; Walter R. Taylor, MD2; Bernhards Ogutu, MD PhD3; John Vulule, PhD1; Diederick E. Grobbee, MD PhD4
Institutional affiliations 1=Centre for Vector Biology and Control Research, Kenya Medical Research Institute, Kisumu, Kenya 2= UNICEF/UNDP/World Bank/Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland 3= Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya 4= Julius Centre for Health Services and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands Corresponding Author: Charles O. Obonyo Centre for Vector Biology and Control Research, Kenya Medical Research Institute, P.O. BOX 1578, Kisumu, Kenya Phone: 254 57 2022924 Cellphone: +254 733837969 Fax: +254 57 2022981 Email: [email protected]
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ABSTRACT Malaria-associated anaemia is a major health problem in settings of intense malaria transmission. Understanding its burden and determinants is essential for designing optimal preventive interventions. We determined the prevalence of and risk factors for malaria-associated anaemia in children under five years of age, from a holoendemic region in western Kenya, who attended the outpatient department of Siaya district hospital for evaluation of fever. Demographic, clinical and parasitological data were recorded. We performed univariate and multivariate analyses to identify the independent risk factors for any anaemia (haemoglobin [Hb] <11g/dL), mild (8.0 – 10.9 g/dL), moderate (Hb 5.0 – 7.9 g/dL) and severe anaemia (Hb < 5.0g/dL). The rates of any, mild, moderate, or severe anaemia in 3586 evaluable children were 80.7% (n=2895), 49.5% (n=1773), 27.9% (n=1000), and 3.4% (n=122), respectively. Malaria infected children numbered 2071 (57.8%). Anaemic children were four times more likely to present with malaria parasitaemia: odds ratio = 4.2 [95% confidence intervals, 3.52 – 5.08]. Anaemia was associated independently with age < 24 months, malaria parasitaemia, splenomegaly, not sleeping under a bednet, fever duration >3 days, malnutrition, and prior treatment with chloroquine or sulfadoxine-pyrimethamine. Malaria, a treatable and preventable infection, was the leading cause of anaemia in infants and young children in this high transmission area. This vulnerable group should be the subject of targeted interventions. Key words: malaria, anaemia, risk factors, paediatric, Kenya
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INTRODUCTION Paediatric anaemia is a major public health problem in malaria-endemic areas of sub-Saharan Africa. Up to 75% of children in sub-Saharan Africa are estimated to be anaemic (haemoglobin <11.0 g/dL), mainly due to malaria and iron deficiency (DeMAEYER &ADIELS-TEGMAN, 1985). The aetiology of anaemia in sub-Saharan Africa is multifactorial, but infection with Plasmodium falciparum is considered the major cause, especially in children below 2 years of age. Other factors contributing to the development of paediatric anaemia include intestinal helminthes (BROOKER et al., 1999; GEISSLER et al., 1998), antimalarial drug resistance (BLOLAND et al., 1993; EKVALL et al., 1998), human immunodeficiency virus (VAN EIJK et al., 2002; OTIENO et al., 2006), haemoglobinopathies (FLEMING & WERBLINSKA, 1982), bacteraemia (GRAHAM et al., 2000), poor nutritional status, and micronutrient deficiencies (VERHOEFF et al., 2002; NUSSENBLATT & SEMBA, 2002). Maternal factors in the antenatal period (e.g., placental malaria, poor nutrition, HIV infection) also predispose African children to the development of anaemia (REDD et al., 1994; VAN EIJK et al., 2002; AYISI et al., 2003). A number of studies have described the risk factors for malaria induced anaemia in Africa and Asia (HEDBERG et al., 1993; REDD et al., 1994; PREMJI et al., 1995; ACHIDI et al., 1996; LUCKNER et al., 1998; CORNET et al., 1998; PRICE et al., 2001; VAN EIJK et al., 2002; KAHIGWA et al., 2002; OWUSU-AGYEI et al., 2002; VERHOEFF et al., 2002; SCHELLENBERG et al., 2003; AKHWALE et al., 2004; DESAI et al., 2005; MULENGA et al., 2005; QUASHIE et al., 2005; OTIENO et al., 2006; ONG’ECHA et al., 2006). Principal factors included the infecting malaria parasite species, intensity of transmission, patient age, host-genetic factors and presence of other concomitant, non-malarial causes of anaemia. The pathogenesis of malarial anaemia is often multifactorial, complex and incompletely understood. Postulated mechanisms fall broadly under haemolysis and dyserythropoiesis. Malaria-associated anaemia may present either as an acute episode or as a chronic process following repeated, often, asymptomatic infection (McGREGOR et al., 1966; PHILLIPS & PASVOL, 1992). Control of malarial anaemia currently depends on rapid diagnosis and treatment of acute malaria, and the use of insecticide treated bed nets (ITNs). Intermittent preventive therapy with iron and an antimalarial is currently the subject of research (EGAN et al., 2005). A clear understanding of the mechanisms and risk factors associated with the development of malarial anaemia is essential for the design of preventive interventions. In this paper we describe the prevalence and characteristics of young anaemic Kenyan children presenting to the outpatient department of a rural district hospital with fever / presumed clinical malaria. MATERIALS AND METHODS Study site This study was conducted between October 1999 and March 2000, during the period of less intense transmission, at Siaya District hospital (SDH) which serves a rural population of approximately 600,000 people in Siaya District, western Kenya. The hospital is located 50 km north-west of Lake Victoria. Malaria transmission is intense
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and perennial (holoendemic) with entomological inoculation rates of between 60-300 infectious bites per person-year (BEIER et al., 1994). Plasmodium falciparum accounts for 90% of the malaria infections (BLOLAND et al., 1999) and the major vector is Anopheles gambiae complex (BEACH et al., 1993). The most common complication of malaria seen at this hospital is anaemia in young children as well as women of childbearing age (LACKRITZ et al., 1992; ZUCKER et al., 1994). The prevalence of childhood malnutrition in the study area is between 20-30% (KWENA et al., 2003). Infant and under 5-mortality rates are 176 and 257 per 1000, respectively (McELROY et al., 2001). At the time of the study, sulfadoxine-pyrimethamine (SP) was the recommended treatment for uncomplicated malaria in Kenya. During the study, the Day 28 parasitological failure rate (adjusted by genotyping to exclude new infections) for SP was 42% (OBONYO et al., 2003) and over 75% for chloroquine (BLOLAND et al., 1993). This study was approved by the National Ethical Review Committee at the Kenya Medical Research Institute (KEMRI), Nairobi, Kenya and also by the WHO Steering Committee for Research Involving Human Subjects. Written informed consent was obtained from all parents or guardians of sick children participating in the study. Study population Parents/guardians of all sick children aged < 5years presenting to the outpatient department of SDH with a history of fever or presumed clinical malaria were interviewed and their children examined by a Clinical Officer. This was undertaken as part of the screening phase of a randomized trial designed to evaluate the efficacy of combination therapy (oral Artesunate plus Sulfadoxine-pyrimethamine [SP]) versus SP alone for treatment of uncomplicated falciparum malaria in children (OBONYO et al., 2003). Information was recorded on demography, symptoms and their duration, perceptions of illness severity, and on treatment-seeking behaviour. The children were clinically examined, including weighing and axillary temperatures. Capillary blood samples were obtained by finger prick and used for estimating haemoglobin and preparing malaria smears. Laboratory investigations Haemoglobin (Hb) concentrations were measured using a portable battery-powered HemoCue® (HemoCue, Anglholm, Sweden) photometer. Giemsa-stained thick and thin blood smears were prepared, read microscopically, and asexual parasites recorded as the number per 200 leucocytes (thick film). Parasite densities were expressed per µL of blood, assuming a total leukocyte count of 8000 cells/µL. Definitions Malaria: Malaria infection was defined as the presence of asexual parasitaemia of any density diagnosed by light microscopy. Clinical malaria was defined as documented temperature > 37.50 C in the presence of malaria parasitaemia. Parasite density was categorized into negative, low (1 – 999 parasites/µL of blood), moderate (1000 – 9999 parasites/µL of blood) or high (≥ 10,000 parasites/µL of blood). Fever was defined as measured temperature of ≥ 37.50 C while, prolonged illness was defined a history of fever lasting more than 3 days.
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Anaemia: Anaemia was defined as a haemoglobin (Hb) < 11.0g/dL, and categorised as mild (Hb 8.0 – 10.9 g/dL), moderate (Hb 5.0 – 7.9 g/dL) or severe (Hb < 5.0 g/dL). Nutritional parameters: Children were classified as underweight if the weight for age z (WAZ) score was below 2 standard deviations, of the growth reference curves developed by the National Centers for Health Statistics (DIBLEY et al., 1987). Malnutrition was also assessed by the method of SHAKIR & MORLEY (1974), which uses the mid-upper arm circumference (MUAC), and classifies nutritional status as normal (MUAC ≥ 13.5cm), mild (MUAC 12.5 –13.4cm) or severe (MUAC<12.5cm). Statistical analysis Data was double entered, checked, and verified for data-entry errors using EPI-Info v 6.04d (Centers for Disease Control, Atlanta, GA, USA). We analysed data using SPSS (v. 12, SPSS Inc., Chicago, IL, USA). Weight-for-age z scores were computed using the EPINUT program in EPI-Info. Categorical data were compared by the chi-square test. Continuous data were compared by student’s t-test and analysis of variance (ANOVA), and assessed using Pearson's correlation coefficient (R). The following were considered in the univariate analysis as potential risk factors for anaemia: sex, age, history of fever, duration of symptoms, reported previous antimalarial treatment, history of sleeping under a bednet, nutritional status, axillary temperature, splenomegaly, positive slide for malaria parasitaemia, and parasite density. Three models were built to identify risk factors for anaemia (Hb < 11.0 g/dL), moderate anaemia (Hb < 8.0 g/dL) and severe anaemia (Hb < 5.0 g/dL). Multivariate analysis was performed using unconditional logistic regression model adjusting for possible confounding variables. A two sided P ≤ 0.05 was considered statistically significant. RESULTS Characteristics of study subjects A total of 3703 children attending the hospital during the study period were evaluated. Twenty-eight (0.8%) children were excluded from further analysis because of missing data. This report is based on data from 3586 (96.8%) children who were between 1 and 59 months of age. Of these, 1756 (49%) were female. The mean (SD) age was 16.5 (13.9) months; the mean body weight (SD) was 9.2 (3.3) kg, while the mean axillary temperature was 37.5 0C (1.2). A total of 1871 (52%) and 3165 (88%) children were below 1 and 3 years of age, respectively. The prevalence of P. falciparum parasitaemia was 2071/3586 (57.8%). Of these, 1868 (90%) children had P. falciparum and the rest had mixed infection consisting of P. malariae (n=29 [1.4%]), P. ovale (n=12 [0.6%]), P. falciparum + P. malariae (n=131 [6.3%]), P. falciparum + P. ovale (n=25 [1.2%]), and P. falciparum + P. malariae + P. ovale (n=6 [0.3%]). Although 3322 (93%) children complained of fever, only 1390 (39%) were febrile at presentation. Splenomegaly was present in 736 (20.5%) children, while, 2250 (62%) had prolonged illness. Overall, 783 (21.8%) children had prior treatment with chloroquine and 578 (16.1%) with SP. The prevalence of underweight children was 17.5%. A total of 1981 (56%) children were classified as well nourished, while 959 (27%) and 618 (17%), respectively, were classified as mildly or severely malnourished. Only 755 (21%) children were reported to be sleeping daily under a bednet. A total of 2895 (80.7%) children were anaemic; of these anaemic children,
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mild anaemia accounted for 61.2% (n=1773), moderate anaemia for 34.54% (n=1000), and severe anaemia for 4.2% (n=122). The mean (SD, range) Hb level for all children was 9.1 (2.3, 2.0 – 21.6) g/dL. The overall mean Hb difference between anaemic versus non-anaemic children was – 3.93 (95% CI – 4.06 to -3.78) g/dL (p<0.0001). Table 1 shows the characteristics of the study subjects. Table 1. Characteristics of children attending Siaya district hospital for evaluation of possible malaria. Hb ≤ 5.0
g/Dl Hb 5.1-7.9 g/dL
Hb 8.0-10.9 g/dL
Hb ≥ 11.0 g/dL
P value
Numbers (%) 122 (3.4) 1000 (27.9) 1773 (49.5) 691 (19.3) Age (months)* 12.2 (10.0) 14.2 (10.8) 17.0 (13.5) 19.3 (18.3) <0.0001 Male:female ratio 51/49 48/52 49/51 50/50 0.884 Body wt (Kg)* 7.6 (2.4) 8.6 (2.6) 9.4 (3.1) 9.6 (4.3) <0.001 History of fever 122 (100%) 963 (96.3%) 1650 (93%) 611 (88.4%) <0.001 Fever duration (days)* 4.3 (2.0) 4.6 (7.8) 4.3 (7.6) 4.0 (7.2) 0.423 Prolonged illness 98 (80.3%) 724 (72.4%) 1075 (60.6%) 353 (51.1%) <0.0001 Temperature (0C)* 37.5 (1.1) 37.6 (1.5) 37.5 (1.1) 37.2 (1.0) <0.001 Febrile (temp>37.50C) 49 (40.2%) 455 (45.5%) 687 (38.7%) 199 (28.8%) <0.0001 Sleep under bednet 15 (12.2%) 162 (16.2%) 377 (21.3%) 201 (29.7%) <0.0001 Prior CQ treatment 39 (32%) 268 (26.8%) 376 (21.2%) 100 (14.5%) <0.001 Prior SP treatment 25 (20.5%) 182 (18.2%) 291 (16.4%) 80 (11.6%) 0.003 Enlarged spleen 58 (45.9%) 339 (34.4%) 311 (17.4% ) 42 (5.5%) <0.0001 Haemoglobin (g/dL)* 4.3 (0.5) 6.8 (0.2) 9.4 (0.2) 12.2 (0.5) <0.0001 Parasitaemic (%) 97 (79.5%) 765 (76.5%) 1005 (56.7%) 207 (30%) <0.0001 Parasite density (µL)* 12884
(1611) 12471 (535) 8293 (348) 3012 (376) <0.0001
High-density parasitaemia
51 (41.8%) 408 (40.8%) 482 (27.2%) 80 (11.6%) <0.0001
Clinical malaria 38 (31.1%) 364 (36.4%) 467 (26.3%) 99 (14.3%) <0.0001 WAZ score <-2 31 (25.4%) 221 (22.1%) 291 (16.5%) 82 (11.9%) <0.0001 MUAC (cm)* 12.9 (1.5) 13.6 (1.5) 13.9 (1.5) 13.9 (1.8) <0.0001 MUAC class
Normal 27 (22.1%) 478 (47.8%) 1074 (61.0%) 402 (58.3%) <0.001 Mild 48 (39.3%) 305 (30.5%) 437 (24.8%) 169 (24.5%) <0.001
Severe 47 (38.5%) 204 (20.4%) 249 (14.1%) 118 (17.1%) <0.001
*Data presented as mean (SD) Risk factors for parasitaemia Compared to aparasitaemic children, significantly higher proportions of parasitaemic children: (i) had a history of fever [2007/2071 (96.9%) vs. 1339/1515 (88.4%), RR 1.10 (1.07 – 1.12)], (ii) were febrile [968/2071 (46.7%) vs. 422/1513 (27.9%),
23
RR=1.68 (1.53 – 1.84)], (iii) had prior treatment with chloroquine [490/1985 (24.7%) vs. 293/1456 (27.9%), RR=1.23 (1.08 – 1.39)], and (iv) enlarged spleens [638/2049 (31.1%) vs. 98/1482 (6.6%), RR= 4.71 (3.85 – 5.76)], (v) were less likely to be sleeping under a bednet [315/2038 (15.5%) vs. 440/1474 (29.9%), RR= 0.52 (0.46 – 0.59)], (v) and less likely to have received SP treatment [278/1985 (14%) vs. 300/1456 (20.6%), RR=0.68 (0.59 – 0.79)]. There was a negative non-significant correlation between parasite density and age (R= - 0.003, P=0.843). The mean falciparum parasite density was higher in children with splenomegaly vs. no splenomegaly (12312 vs. 7735/µL, P<0.001). Risk factors for anaemia Compared to non-anaemic children, anaemic children were significantly younger (15.9 vs. 19.2 months) and lighter (9.1 vs. 9.6 kg). Anaemic children had four times higher odds of parasitaemia: OR=4.23 [95%CI 3.52 to 5.08] and significantly higher mean falciparum parasite density (9871 vs. 3566 /µL, p<0.0001) compared to non-anaemic children. Hb was positively correlated to age (R=0.114, P<0.0001), but negatively correlated to parasite density (R= - 0.222, P<0.0001). In the univariate analysis, the following factors were significantly associated with anaemia: young age, prolonged illness, history of fever, documented fever, malaria parasitaemia, high-density parasitaemia, clinical malaria, splenomegaly, underweight, and recent treatment with ineffective antimalarial drugs. Sleeping under a bednet was protective against anaemia. There was no association between gender and prevalence of anaemia (Table 2). Anaemia, age and malaria parasitaemia The prevalence of any degree of anaemia was strongly age-related (Figure 1). Overall, 2288 of 2895 (79%) anaemic children were <24 months, and 2582 (89%) were below 36 months of age. Age below 24 months was also significantly associated with Hb < 8.0g/dL and severe anaemia. The age-specific prevalence of either anaemia (48.3%) or parasitaemia (44.3%) were highest in infancy defined as age <12 months. There was already a high prevalence of anaemia (71%) in infants < 6 months of age: they represented 563/2895 (19%) of all anaemic and 33/122 (27%) of severely anaemic children. However, the prevalence of any degree of anaemia was highest in those aged 6 to 11 months: 835/958 (87.2%) were anaemic and represented 29% (835/2895) of all anaemic and 30% (37/122) of all severely anaemic children in our sample. Thereafter, both the prevalence of anaemia and parasitaemia decreased with increasing age (Figure 2). Infants < 6 months of age were more likely to present to hospital with severe anaemia than either moderate (relative risk [RR] =1.40; 95% CI 1.02 – 1.93, P = 0.04) or mild (RR=1.42; 95% CI 1.05 – 1.93, P = 0.03) anaemia. There was a significant increase in the prevalence of anaemia with increasing degrees of parasite density (χ2 = 138, P <0.0001). Children with high-density parasitaemia were more likely to present with moderate (41%) or severe (42%) anaemia compared to those with low-density parasitaemia (Figure 3). Low-density parasitaemia were associated with the lowest prevalence of any degree of anaemia.
0
5
10
15
< 6 6 to 11 12 to 17 18 to 23 24 to 29 30 to 35 36 to 41 42 to 47 48 to 53 54 to 59
Age groups (months)
% A
na
em
i
severe anaemia moderate anaemia mild anaemia
20
25
30
35c
child
ren
Figure 1. Age-specific prevalence of anaemia in children evaluated at Siaya district hospital
0
5
10
15
20
25
30
35
40
45
50
<12 12 to 23 24 to 35 36 to 47 48 to 59
Age (months)
Paras
itaem
ia pre
valen
ce (%
)
0
10
20
30
40
50
60
Anae
mia p
revale
nce (
%)
Parasitaemia prevalence Anaemia prevalence
Figure 2. Parasite and anaemia prevalence by age group
24
We found a significantly high prevalence of anaemia in aparasitaemic children: they accounted for 35% of all anaemic children, 21% of severely anaemic children, and had the highest prevalence of mild anaemia (43%). Figure 4 shows how the mean haemoglobin varied with the presence of parasitaemia, frequency of anaemia and age. Aparasitaemic infants <6months of age had the highest mean Hb of 11.0g/dL. Figure 3. Anaemia prevalence by categories of parasite density
0
5
10
15
20
25
30
35
40
45
50
Neg 1 to 999 1000 to 9999 >10000
Parasite density
Anae
mic
prev
alenc
e (%
)
severe anaemia moderate anaemia mild anaemia
Parasitaemic children across all age groups had significantly (F-test = 55.1, P< 0.0001) lower mean haemoglobin concentrations. The overall mean difference in Hb between aparasitaemic and parasitaemic children was 1.64 (range from 0.67 to 2.93) g/dL. The mean haemoglobin did not change significantly between age groups when parasite density was taken into account. Regardless of the presence of parasitaemia, the mean haemoglobin was high in children <6 months of age, falling in children up to 17 months but then increasing steadily in all older age groups. Children > 30 months of age had a significantly higher mean Hb (9.81g/dL) compared to children < 30 months (8.88g/dL, p<0.0001). Figure 5 shows the mean haemoglobin concentrations and anaemia prevalence in children with different levels of parasite density. Compared to parasitaemic children, the highest mean haemoglobin concentration (10g/dL) was in aparasitaemic children. Among children with low, moderate or high parasitaemia, the mean haemoglobin concentrations were 8.9, 8.3 and 8.2g/dL, respectively. The prevalence of anaemia in these groups was 12.9, 19.4 and 32.9% respectively. There was no significant difference in the mean haemoglobin between children with moderate or high parasite densities.
25
Tabl
e 2.
Uni
varia
te ri
sk fa
ctor
s for
any
, mod
erat
e or
seve
re a
naem
ia in
chi
ldre
n at
tend
ing
Siay
a di
stric
t hos
pita
l, w
. Ken
ya
No.
Mea
n H
b[S
D]
Hb
< 11
.0g/
dL
OR
[95%
CI]
P
valu
e H
b <
8.0g
/dL
O
R [9
5%C
I]
P va
lue
Hb<
5.0
g/d
L
OR
[95%
CI]
P
valu
e
Fem
ale
1756
9.
07 [2
.2]
1.04
[0.8
8, 1
.22]
0.
63
1.03
[0.8
9, 1
.19]
0.
64
0.93
[0.6
5, 1
.33]
0.
67
Mal
e
1830
9.
03[2
.2]
1
11
Age
<24
mon
ths
Yes
2760
8.86
[2.3
]1.
75 [1
.46,
2.1
0]<0
.000
12.
34 [1
.93,
2.8
3]<0
.000
12.
82 [1
.54,
5.1
4]<0
.000
1N
o82
6 9.
18[1
.9]
1
11
Age
<36
mon
ths
Yes
3166
8.91
[2.3
]3.
13 [2
.52,
3.8
9]<0
.000
12.
97 [2
.24,
3.9
3]<0
.000
15.
43 [1
.72,
17.
2]0.
001
No
420
10.1
[2.0
]
11
1Pr
olon
ged
illne
ssY
es22
508.
75 [2
.2]
1.67
[1.3
9, 1
.99]
0.00
11.
85 [1
.57,
2.1
8]<0
.000
11.
99 [1
.27,
3.1
3]0.
002
No
1073
9.
43[2
.2]
1
11
His
tory
offe
ver
Yes
3322
8.97
[2.2
]2.
24 [1
.69,
2.9
7]<0
.000
12.
63 [1
.84,
3.7
7]<0
.000
11.
04 [1
.03,
1.0
5]0.
003
No
264
10.1
[2.4
]1
11
Prio
r chl
oroq
uine
trea
tmen
tY
es
783
8.57
[2.1
] 1.
79 [1
.42,
2.2
5]
<0.0
001
1.55
[1.3
1, 1
.83]
<0
.001
1.
69 [1
.14,
2.4
9]
0.00
8 N
o26
58
9.16
[2.3
]
11
1Pr
ior S
P tre
atm
ent
Yes
57
8 8.
70 [2
.1]
1.56
[1.2
1, 2
.0]
0.00
1 1.
25 [1
.04,
1.5
1]
0.01
8 1.
33 [0
.85,
2.0
9]
0.21
N
o28
63
9.09
[2.3
]
11
1Sl
eeps
und
er a
bed
net
Sex
26
Yes
75
5 8.
92 [2
.2]
0.57
[0.4
7, 0
.69]
<0
.000
1 0.
61 [0
.51,
0.7
4]
<0.0
001
0.53
[0.3
1, 0
.91]
0.
02
No
WA
Z<-2
2757
9.
56[2
.3]
1
11
Sple
nom
egal
y Yes
73
6 7.
75 [1
.9]
5.62
[3.9
9, 7
.92]
<0
.000
1 3.
38 [2
.86,
3.9
9]
<0.0
001
3.41
[2.3
6, 4
.91]
<0
.000
1 N
o27
95
9.39
[2.2
]
11
1Fe
brile
Yes
1390
8.69
[2.1
]1.
73 [1
.44,
2.0
7]<0
.000
11.
45 [1
.26,
1.6
8]<0
.000
11.
08 [0
.74,
1.5
6]0.
69N
o21
94
9.28
[2.3
]
11
1Pa
rasi
taem
ia Posi
tive
2071
8.
36 [2
.0]
4.24
[3.5
5, 5
.08]
<0
.000
1 3.
43 [2
.92,
4.0
2]
<0.0
001
2.92
[1.8
7, 4
.56]
<0.0
001
Neg
ativ
e15
11
9.28
[2.2
]
11
1C
linic
alm
alar
iaY
es
968
8.38
[2.3
] 2.
57 [2
.04,
3.2
2]
<0.0
001
1.87
[1.6
1, 2
.18]
<0
.000
1 1.
23 [0
.83,
1.8
2]
0.29
3 N
o26
18
9.29
[2.0
]
11
1H
igh-
dens
ity p
aras
itaem
iaY
es10
218.
18 [1
.9]
3.72
[2.9
1, 4
.75]
<0.0
001
2.35
[2.0
2, 2
.74]
<0.0
001
1.82
[1.2
6, 2
.63]
0.00
1N
o25
29
9.41
[2.3
]
11
1M
UA
Ccl
ass
Nor
mal
1981
9.
28[1
.9]
1
11
Mild
mal
nutri
tion
959
8.77
[2.3
] 1.
19 [0
.98,
1.4
5]
0.08
6 1.
70 [1
.44,
2.0
0]
<0.0
001
3.81
[2.3
6, 6
.15]
<0
.000
1 Se
vere
mal
nutri
tion
618
8.79
[2.9
] 1.
08 [0
.86,
.136
] 0.
515
1.99
[1.6
5, 2
.42]
<0
.000
1 5.
96 [3
.68,
9.6
5]
<0.0
001
Yes
62
5 8.
53 [2
.4]
1.72
[1.3
4, 2
.20]
<0
.000
1 1.
62 [1
.36,
1.9
4]
<0.0
001
1.64
[1.0
8, 2
.49]
0.
019
No
2951
9.
93[2
.2]
1
11
27
0
2
4
6
8
10
12
<6 6 to 11 12 to 17 18 to 23 24 to 29 30 to 35 36 to 41 42 to 47 48 to 53 54 to 59
Age (months)
Mean h
aem
oglo
bin
(g/d
L)
0
5
10
15
20
25
30
35
Anaem
ia p
revale
nce (
%)
Aparasitaemic Parasitaemic Anaemia prevalence
Figure 4. Mean haemoglobin by age group, parasitaemia and anaemia prevalence
14 40
0
2
4
6
8
10
12
Neg 1 to 999 1000 to 9999 >10000
Parasite density
Mea
n H
b (g
/dl)
0
5
10
15
20
25
30
35
Ana
emia
pre
vale
nce
(%)
Figure 5. Mean haemoglobin by parasite density and anaemia prevalence
28
29
Despite the differences in mean haemoglobin concentration, the prevalence of anaemia between children with negative smears and those with high parasitaemia was comparable (34.9% vs. 32.9%, P=0.105). Anaemia and prior antimalarial therapy Children with a history of recent CQ or SP treatment had a significantly lower Hb than children not reporting recent CQ or SP treatment (Table 2). For prior CQ treatment this was significant for those with (8.15 vs. 8.5 g/dL, p <0.001) and without parasitaemia (9.5 vs. 10.1 g/dL, P <0.001); corresponding values for SP were 8.2 vs. 8.4 g/dL (p=0.095) and 9.2 vs. 10.1 g/dL (P <0.0001). CQ but not SP use was associated with: (i) severe anaemia, and (ii) an increased prevalence of parasitaemia. Children reported to have received prior treatment with CQ had an increased odds of fever history (OR=1.64 [1.15 – 2.33]), prolonged illness (OR=1.57 [1.31 – 1.89]), longer mean fever duration (4.1 vs. 3.6 days, P<0.001) and be febrile at assessment (OR=1.20 [1.02 – 1.41]), compared to those without prior CQ treatment. Children with prior SP treatment had an increased odds of prolonged illness (OR=1.83 [1.47 – 2.27]) but similar likelihood of presenting with a history of fever (OR=1.41 [0.94 – 2.09], P=0.09) or being febrile at presentation (OR=1.02 [0.852 – 1.23], P=0.805), compared to those without prior SP treatment. Anaemia and splenomegaly Compared to children without a palpable spleen, children with splenomegaly had a significantly lower mean haemoglobin concentration (Table 2) and an increased odds of anaemia whether they were parasitaemic (OR=4.43 [2.79 – 7.03]) or not (OR= 2.52 [1.46 – 4.35). Splenomegaly was significantly associated with any, moderate or severe anaemia. There was a significantly increased odds of parasitaemia (OR=6.39 [5.09 – 7.99]) or history of fever (OR=2.79 [1.77 – 4.41]) in children with splenomegaly compared to those without a palpable spleen. Anaemia and reported bednet usage Compared to non bed net users, children reportedly sleeping under a bednet had the following significantly lower findings: (i) prevalence of parasitaemia [OR=0.43 (0.37 – 0.51)], (ii) mean parasite density (6663 vs. 9188/µL, P <0.001), (iii) any degree of anaemia, (iv) prevalence of reported fever (OR=0.45 [0.34 – 0.59]), (v) rates of splenomegaly (OR = 0.50 [0.39 – 0.63]), (vi) prevalence of underweight (OR= 0.54 [0.42 – 0.89]) but a significantly higher mean Hb (Table 2). Bednet use was not significantly associated with age or gender. Prevalence of anaemia by nutritional status Malnourished children (WAZ classification) were more likely to present with any, moderate or severe anaemia and to have significantly lower mean haemoglobin concentrations (table 2). Parasitaemia modified the effect of nutrition on haemoglobin levels. The combination of malaria parasitaemia and underweight resulted in significantly lower mean haemoglobin (8.02g/dL) compared to those without parasitaemia (9.40g/dL, P<0.0001).
0
2
4
6
8
10
12
Normal Mild Severe
Nutritional status
Mean
hb (g/
dL)
Parasitaemic Aparasitaemic
Figure 6. Mean haemoglobin by nutritional status A similar trend was observed when malnutrition was assessed by the MUAC classification: parasitaemic malnourished children had significantly lower mean haemoglobin compared well-nourished children. Figure 6 shows the mean haemoglobin concentrations by presence of parasitaemia. The prevalence of moderate or severe anaemia was significantly higher in malnourished, compared to the well-nourished children. Overall model Table 3 shows the overall model from the multivariate logistic regression analysis of the risk factors for anaemia after controlling for sex and parasite density. The following factors were independently associated significantly with anaemia in the multivariate model: age below 36 months, < 24 months (moderate, and severe anaemia only), prolonged illness, malaria parasitaemia, not sleeping under a bednet, splenomegaly, underweight/malnourished (WAZ and MUAC classifications, respectively) and recent treatment with chloroquine or SP. DISCUSSION In this cross-sectional study of Kenyan children under five presenting to the district hospital for evaluation of fever in an area of high malaria transmission, we found a prevalence of 81% for any anaemia and 3% for severe anaemia. Anaemia was significantly associated with young age, malaria parasitaemia, splenomegaly, malnutrition, not sleeping under a bednet, and recent treatment with ineffective antimalarial drugs.
30
31
Anaemia is a common feature of malaria infection. Consistent with previous observations, our study confirms that any degree of anaemia is highly prevalent, but severe malaria-related anaemia is a rare event in the community (GREENWOOD et al., 1991). Similar to findings of community-based studies we found higher prevalence of anaemia in younger children (PREMJI et al., 1995; SCHELLENBERG et al., 2003; DESAI et al., 2005). Infants and young children in our study also had significantly lower mean haemoglobin concentrations, higher parasite densities, and high prevalence of both parasitaemia and anaemia, probably due to a lack of immunity to malaria. Infants < 6 months of age had high mean haemoglobin concentrations and a mean parasite density similar to older children; this may have been due to the passively acquired maternal antibodies. Acquired immunity to malaria limits the density of malaria parasites and severity of anaemia (SNOW et al., 1998). Previous drug treatment using CQ or SP, which are easily purchased from the local shops, was an important risk factor for anaemia. Such children had prolonged illness, were febrile and those previously treated with CQ were more likely to be parasite positive, suggesting that they were probably treatment failures. Interestingly, we also found that CQ but not SP use was a risk factor for severe anaemia. Consistent with persistent parasitaemia following ineffective therapy, children with prior CQ treatment presented to hospital with low-density parasitaemia.Ineffective antimalarial treatment has been shown by previous studies to result in an increased frequency of anaemia and poor haematological recovery (BLOLAND et al., 1993; EKVALL et al., 1998; HEDBERG et al., 1993) as well as increased rates of severe anaemia, paediatric hospitalization, blood transfusion, and case fatality (HEDBERG et al., 1993; BREWSTER & GREENWOOD, 1993; SLUTSKER et al., 1994; ZUCKER et al., 1996; TRAPE et al., 1998; NDYOMUGYENYI & MAGNUSSEN, 2004). Splenomegaly may be a common feature of malaria infection and is used as a crude indicator of the malaria endemicity. Splenomegaly was an independent risk factor for anaemia, consistent with the findings from Zaire, Thailand (HEDBERG et al., 1993; PRICE et al., 2001), and Indonesia (W. Taylor, unpublished data). The spleen has an important pathophysiological role by removing parasitised and non parasitised red blood cells (CHOTIVANICH et al., 2000). One unexpected finding in our study was the high prevalence of anaemia in aparasitaemic children (35%). This is consistent with findings from Tanzania, where up to a third of children admitted with severe anaemia had negative blood smears for malaria parasites (MENENDEZ et al., 2000). Persistently low parasitaemia is a well recognised cause of a chronic anaemia in African children, which responds rapidly to antimalarial treatment (KITUA et al., 1997). In African children, the severity of malarial anaemia is not often proportional to the degree of parasitaemia found at disease presentation but rather may result from the effect of cumulative parasite densities over the past 1 to 3 months (McELROY et al., 2000; EKVALL et al., 2001).
Tabl
e 3.
Mul
tivar
iate
risk
fact
ors f
or a
ny, m
oder
ate
or se
vere
ana
emia
H
b<11
g/dL
O
R [9
5% C
I]
P va
lue
H
b <8
g/dL
O
R [9
5% C
I]
P va
lue
Hb<
5g/d
L
OR
[95%
CI]
P
valu
e
Age
<24
mon
ths
--
----
--
2.83
[2.2
7, 3
.54]
<0
.000
12.
35 [1
.25,
4.4
0]
0.00
8
Age
<36
mon
ths
4.33
[3.3
3, 5
.65]
<0
.000
1 --
----
----
----
----
-3.
17 [0
.97,
1.0
2]
0.05
5
Sple
nom
egal
y 4.
23 [2
.82,
6.3
3]
<0.0
001
2.20
[1.7
7, 2
.75]
<0
.000
1 2.
40 [1
.49,
3.8
7]
<0.0
001
Prol
onge
d ill
ness
1.
51 [1
.22,
1.8
5]
<0.0
001
1.67
[1.3
5, 2
.06]
<0.0
001
2.10
[1.1
6, 3
.82]
0.
014
Para
sita
emia
2.
83 [2
.21,
3.6
3]
<0.0
001
1.89
[1.4
9, 2
.39]
<0.0
001
----
----
Slee
ps u
nder
a
bed
net
0.77
[0.6
1, 0
.97]
0.
029
0.78
[0.6
1, 0
.99]
<0.0
001
----
----
-
Rec
ent S
P
treat
men
t 1.
94 [1
.45,
2.5
9]
<0.0
001
1.45
[1.1
4, 1
.85]
0.
002
----
----
-
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33
Although very low parasitaemia may have been missed by our experienced microscopists, this high proportion suggests that there may be other significant causes of anaemia (e.g. iron deficiency) in Siaya district. The relationship between malaria, nutrition and anaemia is complex and controversial. Some studies have suggested that malnutrition protects children from developing severe consequences of malaria (GENTON et al., 1998), while others have found an association between malnutrition and malaria (DEEN et al., 2002; CAUFIELD et al., 2004). Since both malaria and malnutrition have serious haematological consequences, understanding the interaction between the two should lead to public health action (ERHARDT et al., 2006). Consistent with previous studies, malnourished children in our study, were more likely to be anaemic, and this relationship was significantly modified by the presence of malaria parasites (VERHOEFF et al., 2002; FRIEDMAN et al., 2005). Clearly in this area of drug resistant malaria, strategies are needed that will improve the anaemia status of young children that should, in return, improve their survival. Known beneficial interventions are the use of insecticide treated bed nets, and the use of highly effective antimalarial drugs. The question of iron supplementation is an interesting one. A recent large, placebo controlled trial of 24000 children under five has documented convincingly that the blind supplementation with iron and folic acid of young African children in an area of intense malaria transmission in Zanzibar was detrimental in terms of morbidity but, more importantly, child survival (SAZAWAL et al., 2006). The optimal way to prevent or treat iron deficient children in western Kenya needs careful thought, appropriate community based studies, and sound evidenced-based policies. The high prevalence of anaemia in children with either high-or low-density parasitaemia suggests the need for malaria control interventions that prevent the development of parasitaemia (e.g. bednets), and those that treat and clear chronic, low-density asymptomatic parasitaemia (e.g intermittent preventive treatment). Overall bed net use by children in our study was low (21%). Bed net use in communities residing closer to the hospital has not been evaluated. Consistent use of insecticide-treated bednets is likely to result in a reduction in the prevalence of anaemia with a consequential improvement of mean haemoglobin concentrations, in malaria parasite prevalence and lower parasite densities (TER KUILE et al., 2003). Our study had a few limitations. It was hospital based: therefore, certain rates in this population may be different from those found in the community (Berkson's bias). However, given the very high rate of anaemia, we believe anaemia to be a significant health problem in this community and is likely to be above the internationally recommended threshold (40% in children aged 6 to 24 months) for mass iron supplementation (STOLZFUS et al., 1998). Our study has not provided much clinical data but this is not unexpected in a hospital of limited resources. The measurement of the MCV as a rough indicator of iron deficient anaemia would have been very useful. Never the less, our study reminds clinicians of the magnitudes of anaemia and malaria in children presenting to a rural African hospital. Because malnutrition is a chronic process, we cannot make any causal inferences with our cross-sectional design on the temporal relationship between malaria, anaemia and poor nutritional status. We did
34
not evaluate other causes of anaemia. Community-based studies of parasitic infections have not been performed recently in Siaya, however, it is likely that hookworm and/or schistosomiasis may be important aetiologies. In conclusion, we identified malaria, a treatable and preventable infection, as the leading cause of anaemia in infants and young children in this area of high malaria transmission. Children below 3 years of age should be targeted for preventive interventions aimed at reducing the prevalence of malaria parasitaemia, malnutrition and anaemia. A greater knowledge of the causes of non malaria anaemia in Siaya should also lead to the design and testing of promising interventions. ACKNOWLEDGEMENTS This work was supported by UNICEF/UNDP/World Bank/Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, SWITZERLAND. We thank the Director, Kenya Medical Research Institute (KEMRI) for permission to publish the results of this study. CONFLICT OF INTEREST STATEMENT All authors declare that they have no conflict of interest REFERENCES Abdalla S, Weatherall D, Wickramasinghe S, Hughes M, 1982. The anaemia of P.
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Chapter 2.2
In-hospital morbidity and mortality due to severe malarial anaemia
in Western Kenya
Submitted: American Journal for Tropical Medicine and Hygiene
41
In-hospital morbidity and mortality due to severe malarial anaemia
in Western Kenya
Charles O. Obonyo, MSc 1, 2; John Vulule, PhD1; Willis S. Akhwale, MD PhD3; Diederick E Grobbee, MD PhD2 Institutional affiliation 1=Centre for Vector Biology & Control Research, Kenya Medical Research Institute, Kisumu, Kenya; 2= Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 3=Division of Malaria Control, Kenyan Ministry of Health, Nairobi, Kenya Corresponding author Charles O. Obonyo, Centre for Vector Biology & Control Research, Kenya Medical Research Institute, P.O. BOX 1578, Kisumu 40100, KENYA Phone: 254 57 2022924; Cellphone: 254 733837969; Fax: 254 57 2022981 Email: [email protected]
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ABSTRACT Severe malarial anaemia is a leading cause of paediatric morbidity, hospitalization and mortality in sub-Saharan Africa, and yet the contribution of severe anaemia to malaria-specific mortality is not well documented. We retrospectively reviewed clinical records of 1116 children <5 years of age admitted to Siaya district hospital, western Kenya, to assess the contribution of severe malarial anaemia to overall in-hospital mortality. We recorded information on demographics, malaria smear results, admission haemoglobin, diagnosis, treatment and outcome of hospitalization. Of 1116 admissions, 83% had malaria parasitaemia, 86% were anaemic (Hb<11g/dL) and 21% were severely anaemic. Severe anaemia was associated with parasitaemia in 85% of the admissions. Transfusions were given to 20% of all admissions. Overall, 83 (7.5%) children died, including 12% with severe anaemia. Of the deaths, 66% were malaria-related. Severe anaemia contributed to 53% of malaria-related deaths. Children below 3 years formed 86% of all admissions, 88% of those with severe anaemia, received 89% of transfusions and comprised 89% of the deaths. Transfusion did not result in significantly lower mortality rates. In areas of high malaria transmission, severe anaemia is often associated with parasitaemia and contributes to over half of malaria-related deaths. Children below 3 years are a high-risk group for malaria, anaemia, blood transfusion and mortality. Key words: malaria, anaemia, morbidity, mortality, paediatric, Africa
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INTRODUCTION Severe malarial anaemia (SMA) is a leading cause of paediatric morbidity, hospitalization and mortality in sub-Saharan Africa (LACKRITZ et al., 1992; BREWSTER et al., 1992; ZUCKER et al., 1996; MURPHY and BREMAN, 2001). World Health Organization defines SMA as a haemoglobin level [Hb] below 5.0g/dL in the presence of malaria parasites (WHO, 2000). Efforts to estimate the burden of SMA are limited by paucity of data and variations in case definitions. However, SMA is the major presentation of severe Plasmodium falciparum malaria in areas of high malaria transmission, especially in very young children (GREENWOOD 1997). Between 1.4 and 5.7 million cases of SMA and approximately 1 million deaths occur in African children aged <5 years annually (MURPHY and BREMAN, 2001). Severe anaemia contributes to between 17 and 54% of malaria-attributed mortality in children under five years of age (SLUTSKER et al., 1994; MARSH et al., 1995; BIEMBA et al., 2000). Beginning from the 1980’s, the incidence of SMA has increased in parallel with the increasing prevalence of antimalarial drug resistance (HEDBERG et al., 1993). Two major presentations of SMA occur; an acute episode of clinical disease or a consequence of the slow and insidious process of repeated, often asymptomatic, malaria infections (ABDALLA et al., 1980). Severe anaemia may develop rapidly in the course of a malaria illness especially in the presence of a high parasite density (EKVALL et al., 2001). Case management of SMA is complicated because of diagnostic difficulties in the absence of a supportive diagnostic laboratory, and the difficult decision on the use of blood transfusion. The mortality risk due to SMA is higher than that due to other causes of severe paediatric anaemia (NEWTON et al., 2000) and death often occurs soon after admission (LACKRITZ et al., 1992; BOJANG et al., 1997; ENGLISH et al., 2002). Case fatality rates in children with SMA increases with young age and transmission intensity (SLUTSKER et al., 1994; REYBURN et al., 2005). Treatment of SMA often includes a blood transfusion, which has become an important risk factor for transmission of the human immunodeficiency virus in sub-Saharan Africa (OBONYO et al., 1998). Over 30% of paediatric admissions to district hospitals in Kenya are due to malaria. The cost to the healthcare system of treating a case of severe malaria is substantial (KIRIGIA et al., 1998). To optimize survival, it is necessary that these facilities be adequately equipped with trained staff, drugs, and supplies to deal with the rising burden of SMA. Specifically, the availability and appropriate use of blood transfusion and antimalarial drugs could substantially impact on patient survival (LACKRITZ et al., 1992; LACKRITZ et al., 1993; ZUCKER et al., 1996). As part of a regional survey on the quality of clinical care available for severe paediatric malaria, we assessed the contribution of SMA and the effect of treatment practices to the overall malaria-related mortality in a typical Kenyan district hospital. MATERIALS AND METHODS Study Site The study was undertaken at Siaya district hospital (SDH), located in Siaya district, Nyanza province, western Kenya. The hospital is located in an area of high perennial
44
malaria transmission in the lake region and serves mainly a rural population. SDH is the main public hospital in the district, with a total of 260 beds, including 60 beds in the paediatric unit. Malaria infection in the surrounding rural area is mainly due to P. falciparum and the major complication of malaria in this setting is severe malarial anaemia in young children. The entomological inoculation rate in the surrounding rural area is approximately 60 to 300 infective bites per person-year (BEIER et al., 1994). During the study period, intravenous quinine was the drug of choice for severe malaria, while Sulfadoxine/pyrimethamine [SP] was the recommended first-line therapy for uncomplicated falciparum malaria. The treatment for severe anaemia (any cause) in the hospital is HIV-negative whole blood. During the study period, there was no change in the level of nursing and clinical care. A high prevalence of both chloroquine (BLOLAND et al., 1993) and SP resistance (OBONYO et al., 2003) has been recorded in children with uncomplicated falciparum malaria is this hospital. Data sources This study was part of a larger study evaluating the quality of in-patient care for severe paediatric malaria in western Kenya. In October 2003, we conducted a retrospective review of a random sample of 100 case records per month for children aged between 1 month and 9 years who were admitted to the paediatric inpatient department at SDH with severe malaria between January through December 2002. The children were identified through the admission register of the paediatric department. At this hospital, hospital records contain all information on a patient from admission to discharge or death recorded by nurses, laboratory staff and clinicians. Data collected for the sample of children selected included the following: name, age, sex, inpatient number, date and time of admission and discharge (or death), admission haemoglobin and malaria smear result, diagnosis, treatments received (antimalarial, blood, IV fluids, oxygen) and the outcome of hospitalization (absconded/died/discharged alive). At this hospital, haemoglobin was measured using the HemoCue machine (Angelholm, Sweden). Thick and thin malaria smears were stained using Giemsa and read by experienced microscopists. Parasitaemia was variably quantified using either the scanty to heavy or the plus (+) system. Because of this variability, we used for this analysis, the presence or absence of parasitaemia. Definitions Malaria was defined as the presence of asexual parasitaemia of any non-zero density. Anaemia was defined as haemoglobin (Hb) concentration <11.0g/dL and categorized as severe (Hb level ≤ 5.0g/dL), moderate (Hb 5.1 to 7.9g/dL) and mild (Hb 8.0 to 10.9g/dL) anaemia. Severe malarial anaemia (SMA) was defined as Hb level ≤ 5.0g/dL in the presence of malaria parasitaemia. Malaria-associated mortality was defined as death before discharge of a child admitted with severe anaemia and having parasitaemia.
45
Statistical methods Data was entered, cleaned and validated using EPI Info v. 6.04d (Centers for Disease Control and Prevention, Atlanta, GA) and analyzed using SPSS for windows (version 12.0, SPSS Inc., Chicago, IL). Descriptive statistics were used to compute the frequencies, proportions, means, and confidence intervals. For data not conforming to normal distribution, medians and inter-quartile ranges (IQR) were computed. P values <0.05 were considered statistically significant. We compared the mortality rates between children with Hb ≤ 5.0, vs. Hb > 5.0g/dL and transfused vs not transfused, using relative risk measures, and present the results as the point estimate together with the 95% confidence intervals. When the 95% confidence interval for a relative risk included 1, then the value was considered statistically not significant. RESULTS Characteristics of study population During the study period (January through December 2002), a total of 2432 children were admitted to the paediatric inpatient department. We retrieved a total of 1216 case records (a 50% random sample) for the paediatric admissions during the study period. The rest of this report relates to 1116 (92%) children who were aged below 60 months. Table 1 shows the characteristics of the 1116 children whose records we sampled for this study. There were 592 (53%) male children and the mean age of study population was 16 months. A total of 497 (44.5%) children were aged below one year, 792 (71%) below two years while 960 (86%) were below 3 years. The mean age, body weight, duration of hospitalization and haemoglobin were similar between the male and female children (data not shown). Blood smears were taken for 1062 (95%) of the children and 1032 (92.5%) had a haemoglobin measurement taken at admission. Only 54 (4.8%) and 84 (7.5%) children had no malaria smear or Hb results, respectively. Body weight measurements were taken for 869 (77.9%) children. Malaria was the leading cause of admission (98.4%). The outcome of hospitalization was known for 1104 (99%) of the children. Prevalence of malaria parasitaemia Overall, 876/1062 (82.5%) children with a smear taken on admission had malaria parasitaemia. Figure 1 shows the age-specific parasite prevalence, which was not statistically different between the ages (χ2 for trend = 3.26, p=0.660). The highest parasite prevalence was among those aged 6-11 months (84.4%) and the lowest among those aged 48-59 months (76%). The prevalence of parasitaemia was high throughout the year with significant differences between the months (χ2 for trend=21.8, p=0.026). The peak prevalence was between March and June with smaller peaks between September and January, corresponding to the long and short rains, respectively (Figure 2).
Table 2. Characteristics of 1116 children admitted to Siaya district hospital in the year 2002
N (%) Records reviewed 1116 Male/Female (%) 53/47 Mean Age [±SD] months 16 [13] Mean body weight (Kg) 8.5 (3.1) Mean admission duration [±SD] (days) 3.5 [3.0] No with Malaria smear taken 1062 (95.2%) Proportion parasitaemic 876 (82.5%) No. with Haemoglobin taken 1032 (92.5.%) Mean Hb [SD] 7.2 [2.6] Proportion with severe anaemia 233 (20.9%) No of blood transfusions given 217 (19.4%) Mortality (%) 83 (7.5%) Received an antimalarial drug 1096 (98.2%) Antimalarial drugs prescribed: IV Quinine 903 (82.4%) Oral SP 105 (9.6%) Amodiaquine 29 (2.6%) Tab Quinine 57 (5.2%) Artenam Injection 2 (0.2%) Common diagnoses: Malaria 1099 (98.5%) Pneumonia 324 (29%) Diarrhoea 167 (15%) Severe anaemia 368 (33%)
Malaria-related severe anaemia The haemoglobin measurements ranged from 1.0 to 18.0g/dL with a mean (SD) of 7.1 ± 2.6g/dL. Overall, 960 (86%) of all admissions were anaemic: 233 (20.9%) were severely, 389 (34.9%) were moderately and 338 (30.3%) mildly anaemic. Profound anaemia (Hb ≤ 4.0g/dL) was present in 141/1032 (13.7%) of all admissions. Overall, 206/233 (88.4%) of children with severe anaemia were below 3 years of age. The mean age of severely anaemic children was significantly lower than that of children with Hb>5.0g/dL (14 vs. 17 months, P = 0.003). A total of 191/1067 (18%) had SMA. Of these, 171/191(89.5%), were below 3 years of age. The age-specific prevalence of SMA is shown in figure 1. Children aged 1 to 5 months had the highest SMA prevalence (59/227 [26.0%]) and the lowest prevalence was in those 48 to 59 months of age (5/52 [9.6%]). There was a negative
46
correlation between SMA prevalence and age. The mean age of those with SMA was significantly lower than those without SMA (13.8 vs. 17 months, P=0.002). The mean Hb was significantly lower in parasitaemic compared to aparasitaemic children (7.01 vs. 7.74g/dL, P < 0.001). Severe anaemia was associated with parasitaemia in 191/226 (84.5%) of the admissions. Among children with Hb level between 5.1 to 7.9g/dL, 86.9% were parasitaemic; among those with Hb ≥ 8.0g/dL, 78.4% were parasitaemic. Figure 1. Age-specific prevalence of parasitaemia and Severe Malarial Anaemia in children admitted with severe malaria
70
72
74
76
78
80
82
84
86
1 to 5 6 to 11 12 to 23 24 to 35 36 to 47 48 to 59
Age (months)
Pe
rcen
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issi
on
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ith
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ara
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emia
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25
30
Per
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ith
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A
Parasitaemia SMA
Mortality due to severe malarial anaemia Overall, the outcome of hospitalization was known for 1104 (99%) children. Of these, 12 (1.1%) absconded and 83 (7.5%) are known to have died. Death was significantly associated with a diagnosis of anaemia (RR=1.99, 95%CI 1.32 – 3.01), severe anaemia (RR=2.04, 95%CI 1.32 – 3.16), or diarrhoea (RR=2.40, 95%CI 1.56 – 3.69). There was no difference in the risk of in-hospital mortality among children with or without a diagnosis of malaria (RR=0.44, 95%CI 0.15 – 1.77). Most deaths occurred early during hospitalization: 21/83 (40.4%) of the deaths occurred on the day of admission and 44/83 (53%) had occurred by 24 hours after admission. Children who died were hospitalized for significantly shorter duration compared to those who
47
survived (2.4 ± 2.8 vs. 3.6 ± 3.0 days, p<0.0001). In total, 33/83 (45.8%) and 74/83 (89%) of those who died were aged below 1 and 3 years, respectively. The mean age of the children who died was not significantly different from that of those who survived: 15.2 vs. 16.8 months, F-statistic=1.04, P=0.307. Figure 3 shows the age-specific mortality rates. Infants had the highes risk of dying in-hospital. Thereafter, the risk of in-hospital mortality decreased with increasing age. Figure 2. Prevalence of parasitaemia and transfused children by months
0
10
20
30
40
50
60
70
80
90
100
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Month
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sion
s w
ith
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site
mia
0
5
10
15
20
25
30
35
Per
cent
of a
dmis
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s tr
ansf
used
Parasitaemia Transfusions
At admission, children who died had significantly lower mean Hb compared to those who survived (6.06 ± 2.7 vs. 7.26 ± 2.6g/dL, p < 0.0001). The risk of mortality for severely anaemic children was significantly higher compared to that of children with Hb > 5.0g/dL: 28/233 [12.0%] vs. 49/883 [5.5%], RR=2.17 (95% CI, 1.39 – 3.37). Among severely anaemic children, those who died had significantly lower mean Hb compared to those who survived (3.28 ± 1.1 vs. 3.70 ± 0.9, p=0.027). Of the 83 deaths, 55 (66.3%) were malaria-related. The relative contribution of severe anaemia to malaria-related deaths was 28/55 (52.7%). The case fatality rate for children with SMA in this hospital was 19/83 (22.8%). Compared to weekdays (Monday through Friday), mortality over the weekends and out of working hours (between 5 pm and 7 am) was substantially high: (11/53 [20.8%] vs. 72/1051 [6.9%], RR=3.03 [95%CI, 1.71-5.36], P < 0.0001).
48
Figure 3. Age specific mortality rates of children admitted with malaria in western Kenya, presented as percentages.
45.8
27.7
15.7
6 4.8
05
101520253035404550
<1 1- 2- 3- 4-Age (years)
Mor
talit
y (%
)
Treatment practices Blood transfusions were given to 19.5% (217) of all the admissions. The transfusion rate varied greatly throughout the year with peaks in February and July, corresponding to the period after the short and long rains, respectively (Figure 2). Transfused children were significantly younger than non-transfused children (median age 11 vs. 13 months, p = 0.020). Overall, 193/217(88.9%) of transfusions were given to children below 3 years of age (Fig 4A). At admission, transfused children had significantly lower mean Hb compared to those not transfused (4.3 ± 1.9 vs. 7.9 ± 2.3g/dL, p<0.0001). About 151/217 (70%) of the transfusions were given to children with severe anaemia (Fig 4B). The proportion of severely anaemic children transfused was 151/233 (64.8%). Transfusion prescriptions in this hospital did not always adhere to the guidelines: 51/798 (6.4%) children with Hb > 5.0g/dL were transfused, as were 15/84 (17.9%) others without haemoglobin measurement. Of the 191 children with SMA, 127 (66.5%) were transfused.
49
were transfused died compared to 4/64 (6.3%) that were not transfused (RR=1.94 [95%CI, 0.67, 5.59]).
Overall, the receipt of a transfusion was protective against the risk of mortality: 22/83 (26.5%) died among those transfused compared to 45/83 (54.2%) among those not transfused (RR=0.49, 95%CI 0.32 – 0.74). However, among severely anaemic children, transfusion was associated with an increased risk of mortality [RR=2.08, 95%CI 0.88 – 4.91], although this difference was not statistically significant between those who were transfused compared with those who were not transfused: 23/151 (15.2%) vs. 6/82 (7.3%), P=0.096. Similarly, 15/124 (12.1%) children with SMA who
50
e prescribed for 1062 (98.2%) children, and of these, 870 1.9%) had positive smears for malaria. A total of 174 (16.4%) children with
ine
drug.
ortality compared to those treated with other antimalarial drugs: 70/892 (7.8%) vs rved
this audit of paediatric admissions we found a high perennial prevalence of malaria ich was associated with proportionately high rates of severe anaemia
aemia in very oung children is the commonest presentation of P. falciparum (SNOW et al., 1994;
d th
with
en
f
ion
Antimalarial drugs wer(8negative malaria smears also received an antimalarial drug. Intravenous (IV) quinwas the most commonly prescribed antimalarial received by 903 (81%) of all admissions. A total of 105 (9.9%) children with negative smears also received IV quinine. Only 6 children with positive malaria smears received no antimalarial Overall, children treated with IV quinine had a non-significant increased risk of m10/192 (5.2%), RR=1.51, 95%CI 0.79 – 2.87, P=0.204. A similar effect was obsein children with Hb ≤5g/dL: 26/181 (14.4%) vs 2/44 (4.5%), RR=3.16, 95%CI 0.78 –12.8, P=0.077. Among children with Hb > 5g/dL, administration of IV quinine had no effect on the risk of in-hospital mortality (P=0.97). DISCUSSION Inparasitaemia, whand malaria-related deaths in young children. In this hospital, children below 3 years of age were at high risk of malaria, anaemia, blood transfusion and mortality. Twenty percent of all admissions were transfused and despite the high transfusion rate (65%), proportionately more children with severe anaemia died compared to those without severe anaemia. Paediatric deaths in this setting occurred early during hospitalization and by 24 hours after admission over half of the deaths had occurred. Our study confirms that in areas of high malaria transmission severe anyPREMJI et al., 1995). Malaria transmission in this western Kenya setting is intense and stable throughout the year, and malaria was the leading cause of admission and paediatric mortality. A high proportion of the children were already anaemic at admission: 86% were anaemic and 21% had severe anaemia. Severe anaemia occurrealmost always in very young children below 3 years of age and in association wimalaria parasitaemia. It is not clear whether the high prevalence of severe malarial anaemia was due to resistant parasites that had failed therapy or from an acute on chronic, asymptomatic parasitaemia. The rising prevalence of malaria-associated severe anaemia in areas of high malaria transmission has been attributed to the emergence and intensification of drug resistance (DORWARD et al., 1989; BLOLAND et al., 1993; VERHOEFF et al., 1997; EKVALL et al., 1998; NDYOMUGYENYI & MAGNUSSEN, 2004). Consequently, the frequencywhich blood transfusions are administered has increased (OBONYO et al., 1998) and similarly, malaria-specific mortality has increased (SNOW et al 2001). In Zaire, whdrug-resistant parasites emerged, the requirements for paediatric transfusions increased by 250% (GREENBERG et al., 1988). Other possible explanations for the rising prevalence of severe anaemia may include the changing epidemiology opaediatric human immunodeficiency virus (HIV) type 1. Recent studies in western Kenya have documented high prevalences of severe malarial anaemia in associatwith HIV infection or exposure (VAN EIJK et al., 2003; OTIENO et al., 2006). We
51
ACKRITZ et al., 1992; MARSH et al., 1995; SCHELLENBERG et al., 1999). The
H et r
92;
d
ions were given to 20% of all admissions. Although, in 70% of the cases ansfusion was given to severely anaemic children the mortality rate among severely
e.
en e
: we r
pital discharge cords, which has the advantage that data is readily available at low or no cost and
could not assess the contribution of HIV to the high prevalence of severe anaemia, asinformation about the HIV status of the children in our study was not available. Asymptomatic severe anaemia per se is associated with very low risk of mortality(Lrisk of mortality in a child with SMA increases with the presence of respiratory distress (LACKRITZ et al., 1992; MARSH et al., 1995; BOJANG et al., 1997; ENGLISH et al., 2002), impaired consciousness (MARSH et al., 1995; ENGLISal., 2002) or bacteraemia (ZUCKER et al., 1996; GRAHAM et al., 2000). In oustudy, 23% of children with severe malaria-related anaemia died. This is consistent with previous studies that found rates between 2.3 and 18% (LACKRITZ et al., 19ENGLISH et al., 2002; SCHELLENBERG et al., 1999). Over half of the malaria-related deaths in our study, were due to severe anaemia, consistent with findings from Malawi over a decade ago, that highlighted the significant contribution of severe anaemia to malaria-specific mortality in areas of high transmission (SLUTSKER et al., 1994). Death in severely anaemic children occurred soon after admission. Thishighlights the need for early decision-making regarding the need for a transfusion anthe availability of screened banked blood (LACKRITZ et al., 1993). Previous studies at our study site showed that severely anaemic children have a high risk of in-hospital mortality which extends upto 8 weeks in the post-discharge period (LACKRITZ et al.,1997). It is noteworthy that in our study, children hospitalized over the weekends and outside normal working hours were three times more likely to die compared to those admitted during weekdays and normal office hours. A possible explanation could be the compromised quality of care probably arising from understaffing. Similar findingshave been found at Kilifi district hospital on the Kenyan coast (BERKLEY et al., 2004). Transfustranaemic children who were transfused vs. non-transfused children were comparablThis could be explained by the case mix of the children we sampled which did not distinguish children at high risk of mortality. Indeed, there was a non-significant increase in the risk of mortality among transfused severely anaemic children. We speculate that these children were sicker or were hospitalized too late that the available interventions could not save them. We did not record information on whtransfusions actually occurred in relation to time of admission. This would havhelped to confirm whether there was a benefit in transfusing children early during their hospitalization. Our findings confirm the results of a review that found poorcorrelation between transfusion rates and case fatality rates (BRABIN et al., 2001).Consistent with previous studies not all severely anaemic children were transfuseddid not evaluate the reasons why they were not transfused, but we suspect that similafactors found in the early 1990’s at this hospital may still apply (LACKRITZ et al., 1993). Transfusion is an intervention of undetermined benefit that can transmit HIV, and should be limited to situations where it can improve survival. Our study had several limitations. We reviewed retrospectively hosre
52
d of
t
Our
layed s, hyperparasitaemia, respiratory distress, impaired consciousness,
ciparum
n
s a major cause of admission, which carries igh fatality rate among very young children (less than 3 years) who have malaria
DGEMENTS his study was financially supported by an Operational Research grant from World
Office for Africa. We thank the Director, Kenya
bdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M, 1980. The anaemia of P. aria. British Journal of Haematology 46, 171-83
994. Plasmodium
Be ton children admitted to a rural district hospital on
Bil Medicine and
International Health 5, 9-6
contain routinely collected data, which may be useful for evaluating health servicesand for epidemiological research. However, because multiple health workers collectethe data for different purposes, the quality of the data may be questionable. Because the cross-sectional design, we cannot make causality inferences. We included mainly children with admission haemoglobin measurements, so we may have missed some children with emergency transfusions or deaths that occurred on arrival before diagnostic laboratory investigations were undertaken. There were 84 children withouhaemoglobin measurements, of whom 5 (6%) died and 4 (5%) absconded. We analyzed mortality in the context of routine medical care, therefore we did not control for many factors that could impact on outcome e.g. the use of supportive care. estimates of malaria-specific mortality estimates may be a gross under-estimation, as it is common for children to die at home or before arriving at a health facility. Prognostic factors in a case of severe malaria-associated anaemia include a dediagnosihypoglycaemia and a delayed transfusion (LACKRITZ et al., 1992; MARSH et al., 1995; BOJANG et al., 1997; ENGLISH et al., 2002). Death from severe falmalaria can be prevented by early diagnosis and prompt institution of effective antimalarial treatment. However, the condition is often recognized late, and not all cases present to health facilities. It would be important to educate communities oearly recognition of severe malaria, to strengthen referral systems and to avail pre-referral treatment e.g. rectal artesunate. Our study has identified severe anaemia aa hparasitaemia. ACKNOWLETHealth Organization, RegionalMedical Research Institute for permission to publish these results. REFERENCES A
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56
CHAPTER 3
DRUG RESISTANCE AND COMBINATION
THERAPY
58
Chapter 3.1
Amodiaquine combined with sulfadoxine-pyrimethamine versus
artemisinin-based combinations for the treatment of uncomplicated
falciparum malaria in Africa: A meta-analysis
Accepted for publication: Transactions of the Royal Society of Tropical Medicine and
Hygiene
59
Amodiaquine combined with sulfadoxine/pyrimethamine versus artemisinin-based combinations for the treatment of uncomplicated
falciparum malaria in Africa: a meta-analysis
Charles O. Obonyoa,*, Elizabeth A. Jumaa, Bernhards R. Ogutub, John M. Vululea, Joseph Lauc a Centre for Vector Biology & Control Research, Kenya Medical Research Institute, P.O. Box 1578-40100, Kisumu, Kenya b Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya c Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA 02111, USA Corresponding author Charles O. Obonyo, Centre for Vector Biology & Control Research, Kenya Medical Research Institute, P.O. BOX 1578, Kisumu 40100, KENYA Phone: 254 57 2022924; Cellphone: 254 733837969; Fax: 254 57 2022981 Email: [email protected]
60
ABSTRACT Drug resistance in Plasmodium falciparum is a major obstacle to malaria control. Artemisinin-based combination therapy (ACT) is being advocated to improve treatment efficacy and to delay development of resistance. Here we summarise the available data on the efficacy of amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus ACTs in the treatment of uncomplicated malaria in sub-Saharan Africa. We searched for randomised trials in which patients with uncomplicated malaria treated with AQ+SP were compared with those treated with either amodiaquine plus artesunate (AQ+AS), artesunate plus sulfadoxine/pyrimethamine (AS+SP) or artemether/lumefantrine (AL). Medline, EMBASE, Cochrane Central Register of Controlled Trials and reference lists up to July 2005 were searched. Two reviewers independently extracted the data. The primary outcome measure was treatment failure by Day 28. Outcome measures were combined using a random effects model. Seven randomised trials of 4472 children were included. Trial quality was generally high. Treatment failure of AQ+SP was significantly reduced compared with AS+SP (relative risk (RR) = 0.56, 95% CI 0.42–0.75), but increased compared with AL (RR = 2.80, 95% CI 2.32–3.39). The overall failure rate of AQ+SP was similar compared with AQ+AS (RR = 1.12, 95% CI 0.81–1.54), but there was significant heterogeneity of results across the studies. All the treatment regimens were safe and well tolerated. AQ+SP should be considered in some settings before the full implementation of an ACT. KEYWORDS Malaria; Amodiaquine; Sulfadoxine/pyrimethamine; Artemisinin; Combination therapy; Africa
61
INTRODUCTION Although malaria is a global disease, over 90% of the burden is borne by populations in sub-Saharan Africa where Plasmodium falciparum particularly affects young children and pregnant women (SNOW et al., 2005). At least 300 million clinical cases of malaria occur each year, resulting in more than a million childhood deaths globally. Early diagnosis and prompt effective treatment remains the cornerstone strategy for reduction of malaria-related morbidity and mortality (WHO, 1993). The parasite has developed resistance to most of the standard affordable antimalarial drugs. Drug resistance is a major obstacle to malaria control in sub-Saharan Africa, accounting for most of the current increases in the incidence of malaria-specific morbidity and mortality (TRAPE et al., 1998). Despite the huge malaria problem in sub-Saharan Africa, the resources available to national control programmes are inadequate. Treatment of malaria is in transition: for over 50 years, malaria was treated successfully using chloroquine (CQ). With the emergence of CQ resistance, sulfadoxine/pyrimethamine (SP) replaced CQ in many settings, but unfortunately the effectiveness of SP has decreased in some areas within a few years of its introduction (SIBLEY et al., 2001). Malaria can no longer be treated using a single drug; however, the list of available antimalarials is limited. Moreover, development of new antimalarial drugs has not kept pace with the rate of development of drug resistance. Careful use must therefore be made of the available antimalarial drugs. The incidence of antimalarial drug resistance can be slowed by the use of combination therapy (WHITE & OLLIARO, 1996). In combination therapy, two or more drugs with different modes of action are administered simultaneously to improve treatment efficacy and to extend the useful therapeutic life of the constituent drugs by reducing the rate at which resistance develops (WHITE, 1998). Of the available antimalarial drugs, the artemisinins are the most potent and the WHO specifically advocates the use of artemisinin-based combination therapy (ACT) as the standard policy in the treatment of uncomplicated falciparum malaria (WHO, 1998). ACT results in rapid clinical and parasitological response, may delay the development of resistance and may reduce malaria transmission by killing gametocytes. However, ACTs are relatively expensive, are untested in sub-Saharan Africa, are currently unavailable on a wide scale and have complex dosing regimens compared with single-dose SP (BLOLAND, 2003). By 2004, over 16 countries in sub-Saharan Africa had selected an ACT for first-line therapy, but implementation of the revised policies was delayed by both the cost and the unavailability of ACTs. It is unclear whether ACTs should be used for empirical management of febrile illnesses outside the formal health sector without laboratory confirmation, in the same way that CQ and SP were utilised for several years. Combination regimens including artesunate plus sulfadoxine/pyrimethamine (AS+SP) or amodiaquine plus artesunate (AQ+AS) have demonstrated superior treatment efficacy compared with that of SP or amodiaquine (AQ) monotherapy (ADJUIK et al., 2002, 2004). However, when artemisinin derivatives were combined with a standard drug that was already failing, the efficacy of that combination was greatly compromised (OBONYO et al., 2003).
62
Most malaria control programmes are currently revising their treatment policies to replace the current first-line failing monotherapies with combination therapy, but they may be challenged to afford the effective but more expensive ACTs. In these circumstances, the control programmes may need to consider alternatives to ACT, which include non-artemisinin-based combination therapy (NACT). Potential candidates for NACT include amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) or clindamycin plus quinine. The combination of clindamycin plus quinine is effective, well tolerated and safe, although it is rarely used (LELL & KREMSNER, 2002). There has been renewed interest in AQ+SP (GASASIRA et al., 2003; SCHELLENBERG et al., 2002). The WHO’s Roll Back Malaria programme has recommended that the combination AQ+SP can be used to treat uncomplicated malaria in settings where the efficacy of both component drugs is high. In some studies, AQ+SP was shown to be as effective as or better than ACT in treating uncomplicated malaria (DORSEY et al., 2002; RWAGACONDO et al., 2003). Non-artemisinin-based drug combinations may offer an attractive option during a transition period while securing resources for ACT implementation; in the right setting, the combination may be relatively effective and the drugs are familiar, available and affordable. Changing the malaria treatment policy is a complex, lengthy and expensive process (SHRETTA et al., 2001). Many ministries of health in sub-Saharan Africa may wish to opt for an efficacious ‘interim’ regimen before fully implementing the ACT policy. The ideal ‘transitional’ antimalarial drug combination has not been found (KREMSNER & KRISHNA, 2004). Hence, there is uncertainty regarding the optimal choice of antimalarial drug combinations to use in the interim and, similarly, there are insufficient data to guide the choice of ACT. The background treatment failure rates are likely to determine significantly the timing of a policy change: higher failure rates with monotherapies (CQ, SP and AQ) have been documented in eastern African compared with the western Africa regions. In this systematic review, we summarise the available evidence on the efficacy of one potential transitional regimen (AQ+SP) compared with antimalarial drug combinations containing an artemisinin derivative in the treatment of uncomplicated falciparum malaria in Africa.
MATERIALS AND METHODS 2.1. Criteria for selecting studies All randomised controlled trials conducted in Africa that compared AQ+SP with an ACT in participants with uncomplicated falciparum malaria were included. The ACTs were specified as AQ+AS, AS+SP or artemether/lumefantrine (AL). Articles published both in English and non-English languages were included. The primary outcome measure was prospectively defined as parasitological treatment failure by Day 28 after starting treatment. Treatment failure was considered as the sum of early and late treatment failures, as defined by the WHO (2002). Secondary outcomes were Day 28 measurements of recrudescence, gametocyte carriage, mean change in haemoglobin and the incidence of adverse events. Adverse events were defined as any unfavourable or unintended sign, symptom or diseases temporally associated with the
63
use of a medicinal product, whether or not it was considered as related to the medicinal product. A serious adverse event was defined as a sign, symptom or intercurrent illness that was fatal, life threatening or required admission to hospital. Review papers, studies in pregnant women or participants with signs of severe malaria, studies comparing an ACT with another ACT or with monotherapy with standard antimalarial drugs, economic analyses, pharmacokinetic studies and studies performed outside Africa were excluded. 2.2. Search strategy Using the OVID platform, the following electronic databases were searched according to the Cochrane collaboration’s optimum search strategy for randomised controlled trials (ALDERSON et al., 2004): Medline (1966 to July 2005); EMBASE (1980 to July 2005); and the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (Issue 3, 2005). The search terms used included the following: amodiaquine, sulfadoxine/pyrimethamine, fansidar, artesunate, artemether, benflumetol, co-artemether, lumefantrine and malaria. These terms were combined with the search strategy for retrieving randomised trials (ALDERSON et al., 2004). The corresponding authors of each included trial and experts on this subject were contacted for details of unpublished or ongoing trials. The reference lists of included studies and review articles were searched for additional studies. 2.3. Quality assessment The following aspects of methodological quality from each included trial report were independently assessed by two reviewers, without using a score or being masked: generation of the allocation sequence; adequacy of concealment of the allocation of treatment; degree of blinding; and completeness of follow-up. Generation of the allocation sequence and allocation concealment were classified as adequate, inadequate or unclear (JUNI et al., 2001). Blinding was classified as open, single or double. The proportion of patients lost to follow-up was computed and considered adequate if <10%. The included studies were also assessed regarding whether a sample size was determined using power calculations and whether an intention-to-treat analysis was performed. 2.4. Data extraction Two reviewers independently screened the results of the literature search and selected eligible studies according to pre-set criteria. Differences over inclusion of studies were resolved by discussion. The following information from each trial report was abstracted: date of trial; location of trial; background drug failure rates; study design; inclusion criteria; participants; interventions; and outcomes. The lead authors were contacted to seek additional information if data from the published study reports were insufficient or missing. 2.5. Statistical analysis Data were extracted to allow for an intention-to-treat analysis (the analysis includes all participants in the groups to which they were originally randomised). Information from comparable trials was combined using a random effects model (DerSIMONIAN
64
& LAIRD, 1986). Meta-analyses were performed on the Day 28 parasitological failure rate as well as the failure rate corrected by parasite genotyping. In addition, data were analysed on gametocyte carriage and haemoglobin changes. Estimates of treatment efficacy were compared using the relative risk (RR) for dichotomous data and weighted mean differences (WMD) for continuous data. RR was computed as the proportion of treatment failures (gametocyte carriers) that received AQ+SP divided by those who received an ACT. The pooled point estimates are presented together with the 95% CIs. Heterogeneity between trials was assessed using the I2 statistic, which is derived from Cochran’s Q heterogeneity statistic and describes the percentage of total variation in the effect estimates due to heterogeneity rather than chance (HIGGINS & THOMPSON, 2002). A value >50% was considered substantial heterogeneity. When heterogeneity was detected, explanations were sought using sensitivity analyses. The following factors were pre-specified as possible reasons for heterogeneity: patient age (<5 years and >5 years); treatment dosage; transmission intensity; trial quality; study size; and event rates of treatment failure. Data were analysed using the Cochrane collaboration software (Review Manager 4.2.8; http://www.cochrane.org).
RESULTS 3.1. Characteristics of included studies Sixteen studies were identified comparing AQ+SP with other antimalarial drugs. Nine of these studies were excluded: the comparison group was CQ+SP (three trials) or monotherapy with CQ or SP (five trials), and one study was not a randomised trial. Thus, a total of seven studies met our inclusion criteria: ABACASSAMO et al., 2004 (Study I); DORSEY et al., 2002 (Study II); MOCKENHAUPT et al., 2005 (Study III); MUTABINGWA et al., 2005 (Study IV); RWAGACONDO et al., 2003 (Study V); STAEDKE et al., 2004 (Study VI); and YEKA et al., 2005 (Study VII). None of the seven corresponding authors knew of any other ongoing or unpublished studies. A total of 4472 children were enrolled in these studies. Individually, the trials enrolled between 276 and 1541 children. AQ+SP was compared with AQ+AS in four trials (Studies I, IV, VI, VII), AS+SP in four trials (Studies I, II, III, V) and AL in one trial (Study IV). In two trials (Studies I, IV), AQ+SP was compared with two different artemisinin-based combinations. Table 1 summarises the characteristics of the included studies. One study each was conducted in Rwanda (Study V), Ghana (Study III), Mozambique (Study I) and Tanzania (Study IV), and three were carried out in Uganda (Studies II, VI, VII). The studies were all undertaken between 2001 and 2004 and included children aged between 4 months and 59 months in five studies (Studies I, II, III, IV, V) and between 6 months and 10 years in two studies (Studies VI, VII). The proportion of children lost to follow-up was <10% in all the included trials. In all the trials except one (Study V), the methodological quality was high and the randomisation sequence was computer-generated. Two trials were open (Studies I, IV), three trials were single-blinded (Studies II, V, VII) and two trials were double-blinded (Studies III, VI). The basis for the sample size studied was provided in six of the trials (Studies I, II, III, IV, VI, VII). Table 2 summarises the aspects of methodological quality assessed.
65
In all the included studies, the primary treatment outcome was early or late treatment failure or adequate clinical and parasitological response (Figure 1). Six trials (Studies II, III, IV, V, VI, VII) also presented the treatment failure data as corrected by parasite genotyping to distinguish new from recrudescent infections (Figure 2). All trials reported data on haemoglobin levels during follow-up, but only four trials presented the data as mean change in haemoglobin (± SD) (Studies III, IV, VI, VII). All the trials except Study V reported data on the prevalence of gametocyte carriage at study enrolment and during follow-up (7–14 days after treatment). Figure 3 shows the gametocyte carriage rates during follow-up. Two studies (Studies I, II) did not assess for adverse events (Table 3). The study from Tanzania (Study IV) was an effectiveness trial, whilst the study from Mozambique (Study I) assessed treatment failure at Day 21. The study by Dorsey et al. (Study II) had a follow-up period of 1 year. One study (Study VII) from Uganda was conducted in four geographical areas with different transmission intensities. The authors presented their results according to the different study areas. We have similarly presented the meta-analysis results from this study as four different substudies of the same trial. 3.2. Amodiaquine plus sulfadoxine/pyrimethamine vs. artesunate plus sulfadoxine/pyrimethamine Four trials compared AQ+SP with AS+SP in 1055 children (Studies I, II, III, V). Overall, there was a significant reduction in the risk of treatment failure by Day 28 in children treated with AQ+SP compared with those treated with AS+SP (RR = 0.56, 95% CI 0.42–0.75; I2 = 0%). There was a non-significant reduction in the recrudescence risk following AQ+SP treatment compared with AS+SP (RR = 0.58, 95% CI 0.32–1.04; I2 = 46.3%) in the three trials (Studies II, III, V) that performed genotyping. Compared with AS+SP, treatment with AQ+SP was associated with a significant increase in the risk of gametocyte carriage (RR = 4.03, 95% CI 1.35–12.03; I2 = 48%) in three trials (Studies I, II, III). The mean haemoglobin change at Day 28, reported in only one trial (Study III), was not significantly different between the two regimens (WMD –0.01, 95% CI –0.35 to 0.33). There was no difference in the number (2/280 vs. 2/289) of children who developed serious adverse events between those treated with AQ+SP compared with AS+SP. 3.3. Amodiaquine plus sulfadoxine/pyrimethamine vs. amodiaquine plus artesunate Meta-analysis of four trials (Studies I, IV, VI, VII) involving 2962 children that compared AQ+SP with AQ+AS found no difference in treatment failure (RR = 1.12, 95% CI 0.81–1.54). However, there was significant heterogeneity across the studies (χ2 = 55.79; P < 0.00001; I2 = 89.2%). One of the four studies was a large trial (Study VII) performed in 1537 children between 6 months and ≥5 years of age in four areas with different malaria transmission intensities. Combining the four areas in this study, there was a non-significant reduction in failure risk following AQ+SP compared with AQ+AS (RR = 0.91, 95% CI 0.71–1.17; I2 = 77.5%), but with significant heterogeneity across the four study sites.
Tab
le 1
Cha
ract
eris
tics o
f inc
lude
d tri
als
No.
of p
artic
ipan
ts ra
ndom
ised
a St
udy
Loca
tion
Tran
smis
sion
inte
nsity
AQ
+SP
AQ
+AS
AS+
SPA
L
No.
lost
to
follo
w-u
p B
ackg
roun
d dr
ug fa
ilure
ra
te
Incl
usio
n cr
iteria
Aba
cass
amo
et a
l.,
2004
(S
tudy
I)
Moz
ambi
que
Seas
onal
6461
60—
AQ
+SP
(3),
AS+
AS
(3)
AQ
(25.
9%)c ,
SP (2
1.4%
)c
Age
6–5
9 m
onth
s, te
mpe
ratu
re
>37.
5 °C
, Pf d
ensi
ty 2
000–
100
000 µl
D
orse
y et
al.,
200
2 (S
tudy
II)
Uga
nda
Mes
oend
emic
164b
—19
8b—
0SP
(32%
)c A
ge 6
–59
mon
ths,
tem
pera
ture
≥3
8.0 °C
, Pf d
ensi
ty >
500 µl
M
ocke
nhau
pt e
t al.,
20
05
(Stu
dy II
I)
Gha
naH
yper
ende
mic
148
—14
5—
A
Q+S
P(1
),A
S+A
S (4
) SP
(23%
) A
ge 6
–59
mon
ths,
tem
pera
ture
>3
7.5 °C
, Pf d
ensi
ty 2
000–
200
000 µl
M
utab
ingw
a et
al.,
20
05 (S
tudy
IV)
Tanz
ania
Hol
oend
emic
507
515
—51
9 A
Q+S
P (4
1),
AQ
+AS
(38)
,
AL
(36)
AQ
(42%
)c , A
Q (7
6%)c
Age
4–5
9 m
onth
s, sy
mpt
omat
ic, P
f den
sity
>2
000 µl
R
wag
acon
do e
t al.,
20
03
(Stu
dy V
)
Rw
anda
Se
ason
al
132
—
144
—
0 A
Q (2
3%)
Age
6–5
9 m
onth
s, te
mpe
ratu
re
>37.
5 °C
, Pf d
ensi
ty 1
000–
100
000 µl
St
aedk
e et
al.,
200
4 (S
tudy
VI)
U
gand
aM
esoe
ndem
ic13
913
9—
—
AQ
+SP
(1),
AQ
+AS
(0)
SP (1
4%)c
Age
6 m
onth
s to
10 y
ears
, te
mpe
ratu
re ≥
38.0
°C, P
f de
nsity
500
–200
000
µl
Yek
a et
al.,
200
5 (S
tudy
VII
) U
gand
a Ji
nja
(low
), A
rua
(hig
h),
Toro
ro (h
igh)
, Apa
c (v
ery
high
)
770
767
——
AQ
+SP
(22)
,A
Q+A
S (1
8)
NR
A
ge 6
mon
ths t
o ≥5
yea
rs,
axill
ary
tem
pera
ture
>37
.5
°C, P
f den
sity
200
0–20
0 00
0 µl
66
AQ
: am
odia
quin
e; S
P: su
lfado
xine
/pyr
imet
ham
ine;
AS:
arte
suna
te; A
L: a
rtem
ethe
r/lum
efan
trine
; Pf:
Plas
mod
ium
falc
ipar
um; N
R: n
ot
repo
rted.
a T
he d
osag
es w
ere:
AS,
4 m
g/kg
onc
e da
ily fo
r 3 d
ays;
SP,
1.2
5 m
g/kg
of p
yrim
etha
min
e an
d 25
mg/
kg o
f sul
fado
xine
, giv
en a
s a si
ngle
do
se; A
Q, 3
0 m
g/kg
ove
r 3 d
ays i
n th
ree
trial
s (St
udie
s I, I
II, V
) and
as 2
5 m
g/kg
ove
r 3 d
ays (
i.e. 1
0 m
g/kg
dai
ly fo
r 2 d
ays a
nd 5
mg/
kg o
n th
e th
ird d
ay) i
n fo
ur tr
ials
(Stu
dies
II, I
V, V
I, V
II);
AL
(six
-dos
e re
gim
en o
ver 3
day
s, gi
ven
as o
ne ta
blet
for c
hild
ren
wei
ghin
g 10
–15
kg,
two
tabl
ets f
or th
ose
15–2
5 kg
, thr
ee ta
blet
s for
thos
e 25
–35
kg a
nd fo
ur ta
blet
s for
thos
e >3
5 kg
). b D
enot
es th
e nu
mbe
r of t
reat
men
ts g
iven
rath
er th
an p
atie
nts.
c Den
otes
Day
14
failu
re ra
tes.
67
Figure 1 Parasitological failure rates in randomised trials comparing amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus artemisinin-based combination therapies (ACT). AQ+AS: amodiaquine plus artesunate; SP+AS: sulfadoxine/pyrimethamine plus artesunate; RR: relative risk.
68
69
Table 2 Study features analysed for methodological quality of randomised controlled trials Study Generation of
allocation sequence
Allocation concealment
Blinding Follow-up
Sample size calculation
Intention-to-treat analysis
Dorsey et al., 2002
(Study II)
Adequate Adequate Single Adequate Yes No
Rwagacondo et al., 2003 (Study V)
Not described Unclear Single Adequate No No
Staedke et al., 2004
(Study VI)
Adequate Adequate Double Adequate Yes No
Abaccasamo et al., 2004 (Study I)
Adequate Adequate Open Adequate Yes No
Mutabingwa et al., 2005 (Study IV)
Adequate Adequate Open Adequate Yes Yes
Mockenhaupt et al., 2005 (Study III)
Adequate Adequate Double Adequate Yes No
Yeka et al., 2005
(Study VII)
Adequate Adequate Single Adequate Yes No
Similarly, when stratified by age, treatment with AQ+SP was associated with a non-significant reduction in failure risk in children <5 years (RR = 0.90, 95% CI 0.74–1.10; I2 = 66.5%) and those aged ≥5 years (RR = 0.70, 95% CI 0.31–1.60; I2 =36.8%) compared with AQ+AS. Stratifying by transmission intensity, AQ+SP was associated with a significant reduction in failure risk in the high transmission areas (RR = 0.75, 95% CI 0.65–0.86; I2 = 0%) but a non-significant increase in the two low–moderate transmission sites (RR = 1.15, 95% CI 0.85–1.57; I2 = 50.6%) compared with AQ+AS. In the meta-analysis of three studies (Studies IV, VI, VII) that adjusted the failure risk by genotyping, AQ+SP was associated with a higher risk of recrudescence compared with AQ+AS (RR = 1.70, 95% CI 1.16–2.49; I2 = 54.6%).
70
All the four trials reported on gametocyte carriage during follow-up. Compared with AQ+AS, AQ+SP was associated with a significantly higher risk of gametocyte carriage (RR = 1.33, 95% CI 1.13–1.57; I2 =33.4%). The mean change in haemoglobin by Day 28 reported in two trials (Studies VI, VII) was similar between the two regimens (WMD = 0.02, 95% CI –0.31 to 0.35). The incidence of serious adverse events reported in three trials (Studies IV, VI, VII) was comparable (18/1416 vs. 6/1421) between those treated with AQ+SP compared with AQ+AS, respectively. 3.4. Amodiaquine plus sulfadoxine/pyrimethamine vs. artemether/lumefantrine Only one study of 1026 children compared AQ+SP with AL (Study IV). Compared with AL, treatment with AQ+SP significantly increased the risk of treatment failure (RR = 2.80, 95% CI 2.32–3.39), recrudescence (RR = 11.26, 95% CI 4.54–27.90) and gametocyte carriage (RR = 3.74, 95% CI 2.31–6.03). AQ+SP was associated with a significantly lower weighted mean change in haemoglobin on Day 14 compared with AL (WMD = –0.07, 95% CI –0.09 to –0.05). Serious adverse events were rare (1/507 vs. 1/519).
DISCUSSION In this systematic review and meta-analysis, we summarise the available data from seven randomised trials on the comparative efficacy and safety between AQ+SP and artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in African children. We found that treatment failure risks were significantly reduced following AQ+SP compared with AS+SP but were increased compared with AL, and similar compared with AQ+AS. However, the comparison with AQ+AS should be interpreted with caution because there was significant heterogeneity across the studies. Gametocyte carriage was consistently and significantly reduced in all the treatment arms with an artemisinin-based combination. The incidence of serious adverse events was similar in all the treatment arms, although the numbers were small. With the emergence of resistance to commonly used and affordable antimalarial drugs, control programmes must decide when to change the first-line treatment for uncomplicated malaria and what to change it to. Combination therapy offers great promise for extending the useful therapeutic life and improving the efficacy of available drugs, but the choices are limited. Consequences of not changing from the current monotherapies include increasing costs of treating patients with treatment failures and increased morbidity and mortality. In this review, we compared the efficacy of the WHO-recommended ACTs with that of AQ+SP. All the included trials were generally of high methodological quality. They were done in children and hence should be extrapolated to adults with caution. The treatment outcome evaluated between 14 days and 28 days after therapy essentially documents the risk of late treatment failure and is an indirect measure of recurrent parasitaemia or risk of rescue treatment. Genotyping assisted in differentiating whether these recurrent infections were due to recrudescence or new infections. Recrudescent infections are likely to stimulate the production of gametocytes that accelerate the transmission of drug resistance.
Figure 2 Parasitological failure rates corrected by genotyping in the randomised controlled trials comparing amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus artemisinin-based combination therapies (ACT). AQ+AS: amodiaquine plus artesunate; SP+AS: sulfadoxine/pyrimethamine plus artesunate; RR: relative risk.
71
72
Table 3 Adverse events reported in the included studies Treatment arm Study Adverse events
AQ+SP AQ+AS AS+SP AL
Any 0 – 0 – Rwagacondo et al., 2003 (Study V) Serious 0 – 0 – Any 4 – 3 – Mockenhaupt et al., 2005 (Study III) Serious 2 – 2 – Any 2 1 – 1 Mutabingwa et al., 2005 (Study IV) Serious 1 1 – 1 Any 8 2 – – Staedke et al., 2004 (Study VI) Serious 6 1 – – Any 11 4 – – Yeka et al., 2005 (Study VII) Serious 11 4 – –
AQ: amodiaquine; SP: sulfadoxine/pyrimethamine; AS: artesunate; AL:
artemether/lumefantrine. The assumption that ACTs are always more efficacious than NACTs is not always true. In our review, AS+SP was not as efficacious as AQ+SP, consistent with the findings of a previous meta-analysis that compared 3 days of AS+SP with SP monotherapy (ADJUIK et al., 2004). We speculate that AQ+SP performed better than AS+SP in the included trials because of the post-treatment prophylactic effect of AQ and because of the extensive use of SP in many settings following the emergence of CQ resistance. Because of the rapid elimination of artesunate (AS) from the bloodstream, a 3-day course of AS+SP treatment will essentially be equivalent to SP monotherapy. Currently, only a few settings remain where SP monotherapy is still efficacious. In a meta-analysis of four trials, AQ+SP was as efficacious as AQ+AS, but with significant heterogeneity across the studies. AQ+SP was significantly more efficacious than AQ+AS in high transmission areas. In areas of high malaria transmission, it may be beneficial to use an antimalarial drug with post-treatment prophylactic properties, but this benefit must be weighed against the risk of selecting for resistance, which is common with drugs with a long terminal elimination half-life (HASTINGS et al., 2002). The risk of recrudescence was significantly higher with AQ+SP, but the results were still heterogeneous. It may be argued that evidence from large trials is preferable to meta-analysis of small trials. Our review included a large trial (Study VII) conducted in sites with different malaria transmission intensities. The large trial was associated with significant heterogeneity and, surprisingly, showed a treatment effect similar to that found by a meta-analysis of three smaller trials (Studies I, IV, VI).
Figure 3 Proportion of children with gametocyte carriage in the randomised controlled trials comparing amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus artemisinin-based combination therapies (ACT). AQ+AS: amodiaquine plus artesunate; SP+AS: sulfadoxine/pyrimethamine plus artesunate; RR: relative risk. The transmission intensity explained a large proportion of the heterogeneity in the treatment effect in the large trial, demonstrating the difficulties commonly encountered in interpreting multicentre studies conducted in sites with different transmission intensities. Drug-resistant P. falciparum is thought to spread faster in high transmission areas, but this is still controversial and should be explored in future studies (HASTINGS & D’ALESSANDRO, 2000; HASTINGS & WATKINS, 2005; TALISUNA et al., 2002). Selecting an effective first-line therapy is only the first step in the decision-making process for the implementation of a new treatment policy. Other activities include
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considerations of financing, diagnostics (clinical vs. laboratory confirmation), development of guidelines, training of health workers, advocacy, drug procurement, drug distribution, quality assurance, regulation and pharmacovigilance (Rational Pharmaceutical Management Plus Program, 2005; WILLIAMS et al., 2004). An ideal antimalarial drug combination should be cheap, administered over 3 days (at most), safe and have an effect on all stages of the parasite, including gametocytes (KREMSNER & KRISHNA, 2004). Our meta-analysis found evidence for the preference of AQ+SP over AS+SP, and AL over AQ+SP. Compared with AQ+SP, all the ACTs evaluated significantly reduced gametocyte carriage, a beneficial property of artemisinin derivatives that may be useful for transmission reduction (PRICE et al., 1996; SUTHERLAND et al., 2005). Our results indicate that for countries changing from SP, alternatives include AQ+AS or AL. None of these combinations is perfect. AQ+SP is currently not co-formulated, but the once-daily dosing may enhance adherence, although increasing resistance to AQ monotherapy may shorten the useful therapeutic life of the combination. AL is currently the only co-formulated ACT, but the high cost and twice-daily dosing may cause problems with adherence. Of the alternatives, AQ+AS may be a rational choice for first-line therapy, reserving the more costly AL for those who fail therapy with AQ+AS (second-line) and quinine for severe malaria. The efficacies of AQ and SP are still high in many areas of the West African region, and in those settings AQ+SP or AS+SP should be considered as first-line therapy and AQ+AS as second-line. Compared with ACTs, AQ+SP was more effective at reducing the incidence of new infections (data not shown), implying that in areas with high malaria transmission an ACT policy should be accompanied by an integrated programme that includes vector control interventions. The implementation of a malaria control programme using effective vector control (DDT spraying) and treatment with AL has resulted in a marked reduction in malaria morbidity and mortality in KwaZulu-Natal in South Africa (BARNES et al., 2005). Combination therapy will inevitably be more costly compared with either CQ or SP monotherapy. Consequently, cost is the main reason for selecting to implement an interim option or delaying the switch to ACT in most malaria-endemic settings. Currently, ACTs cost up to 10 times the price of CQ or SP (ARROW et al., 2004). A recent cost-effectiveness analysis has compared the effect of moving from the current CQ or SP monotherapy to ACT and moving to ACT through an affordable although partially effective (e.g. AQ+SP) interim antimalarial regimen (LAXMINARAYAN, 2004). An interim regimen was only cost-effective in the short-term (<5 years). The main caveat would be the need to change policy again within a short time, which is a time-consuming and expensive process. However, considering among other factors the logistical implications of changing a treatment policy as well as the malaria-specific morbidity and mortality averted it was more cost-effective to move straight to an ACT regimen (LAXMINARAYAN, 2004). The Global Fund for HIV/AIDS, tuberculosis and malaria (GFATM) is one initiative that provides support to malaria-endemic countries for expanding access to ACT and accelerating the change in policy to ACTs. Some countries may be hesitant to accept the GFATM support owing to lack of structures to sustain the purchase and distribution of ACTs once this support ends. A possible solution to the high cost of ACTs is a global subsidy at the high levels of drug procurement (ARROW et al., 2004).
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Our review has several limitations. We found only a small number of studies, with a preponderance of trials from the Eastern Africa region where SP resistance is increasingly widespread. There was only one study (Study III) from West Africa, conducted in an area with relatively high SP sensitivity and therefore our conclusions may not apply to other settings with sub-optimal therapeutic efficacy of AQ or SP. Similarly, there was only one study that compared AQ+SP with AL (Study IV). Reporting of adverse events, haemoglobin or background failure rates for SP and AQ was not consistently done in all the trials that we found. Only two of the studies (Studies III, VI) had performed a double-blind design. For the primary outcome, we used an intention-to-treat analysis, which may have underestimated the treatment effect. Several questions remain unanswered. The safety of ACTs is not established for infants, pregnant women and patients infected with HIV. Whether the reduction in malaria transmission observed in Southeast Asia following widespread deployment of AS plus mefloquine would be experienced with ACTs in areas of high malaria inoculation is still unknown. Similarly, there are no data that ACTs will delay the emergence of drug resistance in sub-Saharan Africa. Efficacy data alone are not sufficient for changing treatment policy; only limited data are available on the effectiveness of ACTs. The role of ACTs in home management of malaria (fever) or in intermittent presumptive therapy is still unclear. The efficacy of AL should be studied in other settings: there are unpublished data showing that it may perform differently in settings with higher AQ+SP efficacy. Similarly, there is an urgent need to evaluate other co-formulated ACTs, e.g. dihydroartemisinin-piperaquine, which is in the pipeline. There is also evidence of declining efficacy of AQ+SP in some settings. Overall, for malaria control in sub-Saharan Africa, effective tools (e.g. insecticide-treated bed nets, intermittent preventive treatment and combination therapies) have become available, and there is a global interest to expand coverage and to maximise impact. In conclusion, our results indicate that AQ+SP is inferior to AL, superior to AS+SP, but comparable with AQ+AS. There is an urgent need to evaluate the utility of combining ACTs with vector control interventions. At best, the AQ+SP combination should be considered as an interim regimen, and it may play an important role in settings where both components have maintained high efficacy, where malaria diagnostics are unavailable or when there are shortages of ACTs.
ACKNOWLEDGEMENTS This work was supported by Pfizer Global Pharmaceuticals. We acknowledge the comments of Drs Anne Gasasira, Ambrose Talisuna and Francois Nosten on earlier drafts of this manuscript. We thank the Director, Kenya Medical Research Institute (KEMRI), for permission to publish the results of this study.
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Chapter 3.2
Artesunate plus Sulfadoxine-Pyrimethamine for treatment of
uncomplicated malaria in Kenyan children: A randomised, double-
blind, placebo- controlled trial
Published as: Transactions of the Royal Society of Tropical Medicine and Hygiene 2003; 97: 585-91
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Artesunate plus Sulfadoxine-Pyrimethamine for uncomplicated
malaria in Kenyan children: A randomised, double-blind, placebo- controlled trial
Charles O. Obonyo, MSc1; Francis Ochieng, MBChB2; Walter R.J. Taylor, MRCP3; Samuel A. Ochola, MBChB4; Kefas Mugitu, MSc5; Piero Olliaro, MD PhD3; Feiko ter Kuile, MD, PhD1, 6 ; Aggrey J. Oloo, MBChB1
Institutional affiliations: 1= Centre for Vector Biology and Control Research, Kenya Medical Research Institute, KISUMU, KENYA 2= Siaya District Hospital, SIAYA, KENYA 3= UNDP/World Bank/ Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, SWITZERLAND 4=National Malaria Control Programme, Kenyan Ministry of Health, NAIROBI, KENYA 5= Ifakara Health Research and Development Centre (IHRDC), IFAKARA, TANZANIA 6= Unit of Infectious Diseases and Tropical Medicine, AMC, University of Amsterdam, AMSTERDAM, NETHERLANDS Corresponding author: Charles O. Obonyo Centre for Vector Biology and Control, Kenya Medical Research Institute, P.O. Box 1578-40100, KISUMU, KENYA Phone: 254 57 2022924 Cellphone: 254 733 837969 Fax: 254 57 2022981 Email: [email protected]
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ABSTRACT Plasmodium falciparum has developed resistance to almost all routinely used antimalarial drugs. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine as first-line treatment of uncomplicated malaria infection in Kenya but resistance to SP is already reported. The addition of artemisinin-derivatives to SP may delay the development of drug resistance, improve cure rates and reduce transmission. The efficacy and safety of artesunate plus SP in the treatment of uncomplicated falciparum malaria was evaluated in a randomised trial of 600 children at Siaya District Hospital, western Kenya. Children < 5 years of age were randomly assigned to receive SP alone (1.25mg/kg based on pyrimethamine), or in combination with either 1 or 3 days of artesunate (4mg/kg/day). Parasitological failure by days 14 and 28 (PCR-corrected for new infections) were the primary endpoints. Treatment failure rates by day 14 were 25.5% in the SP alone group, 16.2% (∆ -9.3% [-17.3% to -1.2%], p<0.027) in the one-dose artesunate group and 9.4% (∆ –16.2% [-23.6% to –8.7%], p<0.0001) in the 3-dose artesunate group. Corresponding rates by day 28 were 46.0% in the SP alone group, 38.2% (∆ –7.8% [-17.7% to 2.1%], p=0.16) in the one-dose group and 26.0% (∆ –20.0% [-29.4% to -10.6%], p<0.001) in the three-dose group. Artesunate-SP combination was well tolerated. There were no serious drug-related adverse events. Parasite clearance and gametocyte carriage were reduced significantly in both combination arms compared to SP alone. Three days of artesunate were required to reduce significantly the risk of treatment failure by day 28. However, the high background rate of parasitological failure with SP may make this combination unsuitable for widespread use in Kenya. Key words: Malaria, Child, Artesunate, Drug combinations, Clinical trial, Kenya
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INTRODUCTION Plasmodium falciparum, resistant to most standard antimalarial drugs, poses a major problem for the treatment of malaria. Several countries in sub-Saharan Africa including Kenya, Malawi, Tanzania, and South Africa have replaced chloroquine with sulfadoxine/pyrimethamine (SP) as the first line drug for the treatment of uncomplicated falciparum malaria. Both the long unmatched half-lives of sulfadoxine and pyrimethamine (mean 180 hours and 95 hours, respectively) and the mechanism of resistance (single point mutations) favour the selection of resistant parasites (WATKINS and MOSOBO, 1993; HASTINGS et al., 2002; NZILA et al., 2000). In other areas of the world where SP replaced chloroquine, such as, south-east Asia, resistance to SP developed within a few years of its introduction. There is concern that in Africa the effective life of SP may be equally limited. SP has been used officially in East Africa for less than 5 years and already resistance is present, resulting in a decrease in the effectiveness of this drug (RONN et al., 1996; ANABWANI et al., 1996; VAN DILLEN et al., 1999; GORISEN et al., 2000; OGUTU et al., 2000). In addition, alternatives to SP are few, costly and may have more adverse effects. Protection of drugs against the development of resistance is a key factor in the fight against malaria. One strategy that may achieve this objective is the use of drug combinations with independent modes of action. The concept that resistance could be delayed or prevented by combining drugs with different targets was first developed in the treatment of tuberculosis (GROSETT, 1980), and has been adopted widely for the treatment of HIV, leprosy, and cancer. Artemisinin-based drug combinations have been proposed as an option for treatment of drug-resistant malaria (WHITE and OLLIARO, 1996). The artemisinins are currently the most potent of antimalarials, and to date no clinical resistance has been documented. The basis for adopting artemisinin-based drug combinations is the ability of the artemisinin to reduce significantly the initial parasite biomass, leaving only a small residuum of parasites to be eliminated by high concentrations of the companion drug. This minimises the risk of parasite exposure to sub- optimal antimalarial drug levels, thus, reducing the risk of selection of resistant strains [WHITE, 1999]. Furthermore, because the artemisinins reduce gametocyte carriage their use may also lead to a reduction in malaria transmission (PRICE et al., 1996). In Thailand, an area of low malaria transmission, the introduction of the combination of artesunate plus mefloquine for the treatment of multi-drug resistant falciparum malaria has resulted in an improvement in cure rates, reduction in malaria transmission and a sustained high efficacy of mefloquine (PRICE et al., 1996; NOSTEN et al., 2000). As of today, only one study has been published from Africa that evaluated the effect of artesunate-SP in combination. In that study, in The Gambia, children with uncomplicated falciparum malaria treated with 3 days of artesunate-SP combination had a faster resolution of fever, parasite clearance and gametocyte carriage compared to those on SP alone (VON SEIDLEIN et al., 2000). SP in vivo efficacy was high in the Gambian setting when the trial was undertaken. It is not known whether these findings would apply to areas of sub-Saharan Africa where parasitological resistance to SP is already substantial, or areas with higher malaria transmission. As a first step to the possible deployment of artemisinin-based
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combinations in sub-Saharan Africa, there is need to study the safety and efficacy of these combinations. We therefore evaluated in a randomised, double-blind, placebo-controlled trial, the efficacy, safety and tolerability of artesunate plus SP compared to SP alone in the treatment of uncomplicated falciparum malaria in western Kenya. This study was part of a multicentre trial sponsored by UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) to assess the role of artesunate-based combinations for treatment of uncomplicated falciparum malaria. MATERIALS AND METHODS Study site The study was conducted between October 1999 and March 2000, at Siaya District hospital, a government health facility serving a rural population of approximately 600,000 people in Siaya District, western Kenya. The area has intense P. falciparum malaria transmission occurring throughout the year, with peak transmission associated with the two rainy seasons (March through June, and September through October). The entomological inoculation rate is estimated at 100-300 per person-year (BEIER et al., 1994). SP has been used in this hospital as second-line treatment of uncomplicated falciparum malaria since 1992. In 1999, there was a 27% in vivo parasitological failure rate in the surrounding community 7 days after treatment using SP in children aged less than 5 years (TER KUILE, unpublished data). Patient screening and recruitment Children under 5 years of age with a history of fever attending the hospital’s outpatient department were referred to the study team for evaluation. They were eligible for inclusion into the study if they had a consenting guardian, weighed at least 5.0 kg, had a history of fever during the preceding 48 hours, and had a smear-confirmed monoinfection with P. falciparum of at least 4,000 asexual parasites/ mm3. Children were excluded if they had mixed plasmodial infections, signs of severe malaria (WARRELL et al., 1990) or danger signs (e.g. inability to drink, repeated vomiting, convulsions, lethargy or abnormal sleepiness), a history of allergy to any of the study drugs, evidence of chronic disease (heart, liver, renal, malnutrition) or a clear history of an adequate malaria treatment in the preceding 72 hours. Specifically, children were excluded if they had a recent history of treatment using a drug with antimalarial activity e.g. cotrimoxazole, erythromycin, tetracycline or doxycycline. Children recently treated with chloroquine were included.
On admission to the study, a standardised medical history was taken and a clinical examination performed. The children were weighed, axillary temperatures taken (using a digital thermometer) and capillary blood samples obtained for malaria smears, haemoglobin determination and filter paper blots for parasite genotyping. From the first 70 children, a 2.0mL blood sample was taken by venipuncture for a full blood cell count and biochemistry (creatinine, total bilirubin and alanine aminotransferase). These were repeated on days 7 and 28 after enrolment.
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Study design, randomization and treatment We used a randomised, placebo-controlled, double-blind trial design. Parasitological failure rate by day 28 after starting treatment was the primary endpoint used for computing the sample size. On the assumption of a 15% failure rate with SP and 5% with artesunate plus SP combination, we required 200 patients (after 10% adjustment for attrition) in each treatment arm to detect this 10% difference in cure rate with 80% power using a two-sided alpha of 0.05. The randomisation code was computer-generated in blocks of 12. Patients were randomised to receive SP (Fansidar®, 500mg/25mg, Hoffman-La Roche, Basel, Switzerland) plus placebo (SP alone group); SP plus one dose of artesunate and 2 doses of placebo (AS1 group); or SP plus one dose of artesunate daily for three days (AS3 group). Artesunate (Arsumax 50mg, Sanofi-Synthélabo, France) and placebo tablets, of exact size, colour and shape were prepacked in aluminium sachets and serially labelled with the randomisation number. There were four drug sachets, one for each of days 0, 1, 2 and an extra for study drug replacement. Both artesunate (4mg/kg body weight) and SP (single dose, 25mg/kg of the sulfadoxine and 1.25mg/kg of the pyrimethamine) were administered orally by a nurse in the clinic. Children were observed for 30 minutes following drug administration for vomiting. Those who vomited within 30 minutes received a replacement dose of the study drugs, and were observed for another 30 minutes. Further vomiting resulted in study withdrawal and parenteral treatment. If the axillary temperature was ≥ 38.00C paracetamol was dispensed to be administered every 8 hours for 2 days. Parents, children, clinicians and investigators remained masked to the treatment allocation throughout the study. Patient follow-up Children were followed up for 28 days. They returned daily to the hospital for evaluations until parasites cleared. Thereafter, they were seen weekly, i.e. on days 7, 14, 21 and 28. Guardians were encouraged to return at other times if their children were unwell or developed a fever. At each follow-up visit, children were clinically assessed, an adverse events questionnaire was completed, temperatures were taken and capillary blood samples were obtained by finger-prick. If children did not return for scheduled follow-up visits, they were visited at home. Children who failed treatment received rescue treatment and were withdrawn from the study. A treatment failure was defined as the development of any of the following: (i) danger sign or signs of severe malaria, or a clinical requirement for parenteral treatment, (ii) rising or unchanged parasitaemia at 48 h, (iii) day 3 parasitaemia ≥ 25% of enrollment parasitaemia and patient unwell, (iv) day 4 parasitaemia ≥ 25% of enrollment parasitaemia; (v) any parasitaemia on day 7; (vi) recurrent parasitaemia at any time; (vii) any adverse event requiring treatment withdrawal. Rescue treatment consisted of oral amodiaquine (25 mg/kg as 10 mg/kg on days 0 and 1, and 5 mg/kg on day 2) for uncomplicated malaria and parenteral quinine for severe malaria. Ethical considerations This study was approved by the Ethical Review Committee of the Kenya Medical Research Institute, Nairobi, Kenya and also by the WHO Steering Committee for
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Research Involving Human Subjects. Written informed consent was obtained from all parents or guardians of children participating in the study. Laboratory procedures Haemoglobin (Hb) concentration was measured using a Hemocue machine® (Mission Viejo, CA, USA). The total blood cell count and Hb for the first 70 children was done using Coulter counter. Thick and thin blood smears were stained with 3% Giemsa for 30 minutes and read by microscopists who were blinded to treatment allocation and clinical outcomes. Parasite density was calculated as the number of parasites counted per 200 white blood cells (WBC) on a thick smear assuming a mean WBC count of 8000 per µL. If P. falciparum gametocytes were detected, a gametocyte count was done per 1000 leukocytes. Serum alanine aminotransferase, creatinine and total bilirubin were measured using commercial kits (Boehringer Ingelheim, Germany). If a child had recurrent parasitaemia, blood samples (blotted on Isocode stixTM, Schleicher and Schuell, Dassel, Germany) from the enrolment and recurrent episodes were genotyped by the polymerase chain reaction (PCR) for merozoite surface protein (MSP 1 and MSP 2), and glutamate rich protein (GLURP) to distinguish recrudescence of the original parasite strain from reinfection with a new parasite strain (SNOUNOU and BECK, 1998). In addition point mutations at codons 51, 59 and 164 of the dihydrofolate reductase (DHFR) gene and at codons 437, 540 and 581 of the gene for dihydropteroate synthetase (DHPS) were detected by allele-specific PCR and restriction fragment length polymorphism (RFLP) as previously described (DURAISINGH et al., 1998). In our study we did not routinely include the detection of point mutation at codon 108 of DHFR, because we assumed that subsequent point mutations at codons 51, 59 or 164 almost never occur before this mutation. Parasite genotyping for DHFR and DHPS was restricted to children who had recurrent parasitaemia between 14 and 28 days after enrolment. Outcomes The two primary endpoints were defined as parasitological failure rate by days 14 and 28. The day 28 failure rate was adjusted using the results of PCR genotyping to differentiate recurrent parasitaemia after day 14 from a re-infection. A recurrent parasitaemia was classified as either a recrudescent (treatment failure) or a new infection (cure). Failure after day 14 was defined as a recurrent parasitaemia with the same genotype as the initial parasitaemia occurring between day 14 and 28, inclusive. Missing PCR results (due to missing samples, a failed PCR analysis, or unequivocal PCR results), were analysed in 2 ways: as treatment failures, or excluded from the analysis. The secondary endpoints were fever (defined as an axillary temperature ≥ 37.50C) resolution rates, parasite clearance rates, change in haemoglobin from day 0 to 28, and presence of gametocytes on days 7, 14, 21 and 28. Drug safety and tolerability were evaluated clinically and by laboratory tests. An adverse event was defined as a sign, symptom, intercurrent illness, or abnormal laboratory value not present on day 0 that occurred during follow-up. The relationship to the study drug was determined by the clinicians in the field and designated as definite, probable, possible, unlikely, not
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related or unknown. A serious adverse event was defined as lethal, life threatening, and/or requiring hospital admission (EDWARDS and ARONSON, 2001). Statistical analysis Patients’ crude data were recorded on the case record form, double-entered and validated using Epi-Info 6.04d (Centers for Disease Control, Atlanta, GA). Data were analysed using SPSS version 11.0 (SPSS Inc., Chicago, IL). The analysis excluded children who were wrongly randomised or lost to follow up. Proportions were compared between treatment groups using the chi-square test. For all pair wise comparisons of failure rates, the SP alone group formed the reference category and results are presented as risk differences (∆), together with their 95% confidence intervals (CI). Normally distributed continuous variables were compared using the Student’s t-test and analysis of variance (ANOVA). Data not conforming to a normal distribution were compared using the Kruskal-Wallis one-way ANOVA. For some analyses we pooled data for the two artesunate groups, since they received the same treatments on day 1. All reported p values are two-tailed. RESULTS Baseline characteristics A total of 2,492 children presenting to the trial site during the study period with a history of fever or measured fever were screened and 600 eligible children were enrolled. The baseline characteristics of enrolled children are shown in table 1. The treatment groups were similar in distribution of children by age, gender, clinical features and parasite density. Withdrawals Four children randomised in error were excluded from the efficacy analysis: two [AS1 (n=1), AS3 (n=1)] had severe anaemia (Hb <5.0g/dl), one child (SP alone group) had persistent vomiting and another child (AS1 group) had both severe anaemia and persistent vomiting. A total of 22 [SP alone (n=7), AS1 (n=6), AS3 (n=9)] children were lost to follow-up: 13 on day 7, 5 on day 14 and 4 on day 28. Three children [AS3 (n=2), AS1 (n=1)] were absent on day 7, but were seen on day 14. Three [AS3 (n=2), SP alone (n=1)] others were absent on day14 and were seen on day 28. Twelve children [AS3 (n=4), AS1 (n=3), SP alone (n=5)] did not receive the full course of treatment because of either loss to follow up (n=7) or early withdrawal (n=5). Of these, 7 missed treatment on day 1, and a further 5 on day 2. Treatment outcome was known for 96% (578 of 600) by day 7, 97% (581of 600) by day 14 and 95% (572 of 600) by day 28. Early treatment response During the week following treatment, there were 31 treatment failures: 21/191 (11.0%) in the SP alone group, 6/194 (3.1%) in the AS1 group and 4/193 (2.1%) in the AS3 group. The risk of failure was significantly reduced among those receiving an artesunate combination: AS3 vs. SP alone [risk ratio [RR] =0.19 (95%CI 0.07 to 0.54), p<0.0001]; AS1 vs. SP alone [RR=0.28 (95%CI 0.12 to 0.68), p<0.001]. Five [SP alone (n=2), AS1 (n=1), AS3 group (n=2)] of these developed severe malaria or danger signs, five (SP alone) had day 2 parasitaemia ≥ 25% of day 0, five [SP alone (n=4), AS1 (n=1)],
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Table 1. Baseline characteristics of study children with uncomplicated malaria attending a district hospital, western Kenya, October 1999 to March 2000.
Treatment group
SP alone (n=200)
1-day Artesunate plus SP (n=200)
3-day Artesunate plus SP (n=200)
Male/female 97/103 105/95 104/96 Age (years) 1.4 (1.1) 1.5 (1.2) 1.3 (1.0) Body weight (kg) 9.4 (3.0) 9.6 (3.2) 9.2 (2.8) Temperature (0C) 38.0 (1.2) 37.8 (1.2) 37.8 (1.2) Parasite count/µL (range)
19172 (3360-77880)
19858 (4040-100720) 20429 (4040-86040)
Gametocyte prevalence (%)
14.5% 16.5% 12.0%
Haemoglobin (g/dL) 8.4 (1.8) 8.4 (2.0) 8.4 (1.8) Leucocyte count (x109/L)
10.8 (4.1) 10.0 (3.9) 11.0 (3.5)
ALT (IU/L) 18.8 (6.7) 13.4 (2.8) 11.4 (3.6) Creatinine (µmol/L) 0.5 (0) 0.5 (0) 0.5 (0) Total bilirubin (µmol/L)
1.6 (0.4) 1.0 (0.4) 1.2 (0.6)
SP, sulfadoxine-pyrimethamine. Data are presented as mean ± SD except for parasite count [geometric mean (range)] and gametocyte prevalence (%). had day 3 parasitaemia ≥ 25% of day 0, 13 [AS1 (n=4), SP alone (n=9)], had persistent parasitaemia on day 7, two (AS3) used other drugs with antimalarial activity and one (SP alone) developed an adverse event (vomiting). Day-14 treatment failure By day 14 the parasitological failure rates for AS3 vs. SP alone and AS1 vs. SP alone were 18/192 (9.4%) vs. 49/192 (25.5%) [∆–16.2% (95%CI -23.6% to –8.7%), p<0.0001], and 32 /197 (16.2%) vs. 49/192 (25.5%) [∆–9.3% (95% CI –17.3% to –1.2%), p<0.027], respectively (Table 2) Day-28 treatment failure The corresponding day 28 crude failure rates were 90/192 (46.9%) vs. 123/189 (65.1%) [∆–17.8% (95%CI -27.6% to –8.0%), p<0.0001], and 114/191 (59.7%) vs. 123/189(65.1%) [∆ -5.3% (95%CI -15.0% to 4.4%), p=0.30], respectively (Table 2). A total of 291 children developed recurrent parasitaemia during the follow-up. Sixty-five occurred by day 14 and 226 after day 14. Of those occurring after day 14, 210 (93%) were genotyped: 57 [AS3 (n=13), AS1 (n=21), SP alone (n=23)] were recrudescent, 117
[AS3 (n=40), AS1 (n=41), SP alone (n=36)] were re-infections and the rest had no results [AS3 (n=13), AS1 (n=14), SP alone (n=10)]. The day 28 failure rates adjusted for PCR were significantly higher in the SP alone arm compared to the AS3 arm. They were also higher in the SP alone arm than in the AS1 arm, although not significantly (Table 2). Parasite and fever clearance Children receiving an artesunate-SP combination cleared their parasitaemia faster than those who received SP alone (Figure 1). The two AS arms had similar clearance rates. The rate of parasite clearance was about twice for those on AS3 [rate ratio [RR] 1.98 (95% CI 1.5 to 2.60), p<0.0001] and about 1.2 times for those on AS1 [RR 1.19 (95% CI 0.91 to 1.56), p=0.19] compared to those on SP alone. For instance, on day 1, 190/198 (96%) treated with SP alone compared to 252/396 (63.6%) treated with an artesunate combination were still parasitaemic (χ2 =72.0, p<0.001) (Figure 1).
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
10 0
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S tu d y d a ys
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A S 3
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S P a lo ne
Figure 1. Rate of parasite clearance: the proportions (%) of children with malaria parasitaemia during the first week after treatment with sulfadoxine-pyrimethamine (SP) alone or in combination with either one or three days of artesunate (AS1 or AS3). Verical bars indicate 95% CI. Fever clearance was similarly faster among children who received an artesunate-SP combination compared to those who received SP alone. On day 1, 36/197(18.3%) of children treated with SP alone were still febrile compared to 17/396 (4.3%) treated with an artesunate combination (χ2 =31.6, p<0.001). Corresponding proportions on day 2, were 32/196 (16.3%) treated with SP alone, 6/199 (3.0%) treated with AS1 and 5/196 (2.6%)
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treated with AS3. Gametocyte carriage On day 0, gametocytes were detected in only 86/600 (14.3%) children. The proportion of children with gametocytes during follow up increased significantly among those treated with SP alone on day 7, peaked on day 14 and then fell (Figure 2). Those treated using an artesunate-SP combination had a marked decrease in gametocyte prevalence during the follow-up period. By day14, the gametocyte prevalence for AS3 vs. SP alone and AS1 vs. SP alone were 6/186 (3.2%) vs. 65/172 (37.8%) [∆ –34.6% (95% CI -42.2% to –26.9%), χ2 =67.2, p<0.0001], and 10 /191 (5.2%) vs. 65/172 (37.8%) [∆ –32.6% (95% CI –40.5% to –24.7%), χ2=58.5, p<0.0001], respectively. The corresponding rates for day 28 were 0/129 (0%) vs. 5/101(4.95%) [∆–4.95% (95% CI -9.5% to –0.44%), χ2 = 6.53, p=0.011], and 3/113 (2.7%) vs. 5/101 (4.95%) [∆–2.3% (95%CI –7.5% to 2.8%), χ2 =0.78, p=0.376], respectively. Table 2. Parasitological failure rates on days 14 and 28 for study children with uncomplicated malaria treated with sulfadoxine-pyrimethamine (SP) alone or in combination with either one or three days of artesunate (AS1 or AS3).
Failure rate (%) Risk difference a (95% CI) P value
Efficacy on day 14 AS3-SP 18/192 (9.4) -16.2 (-23.6, -8.7) <0.001
S1-SP 32/197 (16.2) -9.3 (-17.3, -1.2) 0.027 SP alone 49/192 (25.5) -- ---- ----
Efficacy on day 28* AS3-SP 90/192 (46.9) -18.2 (-28.0, -8.4) <0.001 AS1-SP 114/191 (59.7) -5.4 (-15.1, 4.3) 0.30 SP alone 123/189 (65.1) --- ---- -----
Efficacy on day 28¶ AS3-SP 50/192 (26.0) -20.0 (-29.4, -10.6) <0.001 AS1-SP 73/191 (38.2) -7.8 (-17.7, 2.1) 0.16 SP alone 87/189 (46) ---- ---- ----
Efficacy on day 28‡ AS3-SP 37/179 (20.7) -21.8. (-31.2, -12.5) <0.001 AS1-SP 59/178 (33.1) -9.4 (-19.4, 5.9) 0.067 SP alone 77/181 (42.5) ---- ----- ----
a Risk differences are for AS3-SP vs. SP alone and AS1-SP vs. SP alone. * No PCR correction ¶ Unresolved PCR results treated as failures in the analysis ‡ Unresolved PCR results excluded from the analysis Haemoglobin change The mean Hb at enrolment in each treatment arm was 8.4g/dl. By 28, the mean Hb (± SD) increased to 10.2 ± 1.6, 9.9 ± 1.5 and 10.2 ± 1.6 g/dl for those on AS3, AS1 and SP alone,
respectively (F-statistic=1.375, d.f =2, p=0.254). Correspondingly, on day 28, the mean change in Hb (± SD) from day 0 was 1.65 ± 1.6, 1.61 ± 1.8 and 1.62 ± 1.7, respectively (F-statistic=0.017, d.f =2, p=0.983). Parasite genotyping for the molecular markers of SP resistance Seventy-four paired samples were analysed. The prevalence of DHFR mutations in the pre-treatment samples were: 74/74 (100%) for Ile-51, and 46/74 (62.2%) for Arg-59. DHPS mutation rates were 50/73 (68.5%) for Gly-437, 56/73 (76.7%) for Glu-540, and 4/70 (5.4%) for Gly-581. Corresponding prevalence rates in the recurrent parasitaemia post-treatment was 74/74 (100%) for Ile-51, 48/74 (64.5%) for Arg-59 (p=0.732), 61/73 (83.9%) for Gly-437 (p=0.032), 65/73 (88.5%) for Glu-540 (p=0.048) and 6/70 (8.1%) for Gly-581 (p=0.512). Mutation in the164 allele (Ile-164 to Leu-164) was not found in any sample.
0
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15
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25
30
35
40
45
0 7 14 21 28STUDY DAY
PRO
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AEM
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)
AS3AS1SP ALONE
Figure 2. Prevalence of gametocyte carriage: the proportion (%) of children who had gametocytes on specified follow-up days after treatment with sulfadoxine-pyrimethamine (SP) alone or in combination with either one or three days of artesunate (AS1 or AS3). Vertical bars indicate 95%CI. Adverse events The three drug regimens were well tolerated. There were no clinically significant changes in haematological and biochemical parameters (data not shown). The proportion of children developing any adverse event, irrespective of drug relationship, was significantly
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more among those on AS3. These were 122/200 (61%) in the SP alone group, 126/200 (63%) in the AS1 group and 151/200 (76%) in the AS3 group (χ2=11.09, df 2, p=0.0039). The proportion of children developing skin rashes were: 8/122 (6.6%) for SP alone, 6/126 (4.8%) for AS1 and 2/151 (1.3%) for AS3 [χ2 for trend=4.774, p=0.0289]. All reported rashes were mild, papular eruptions that resolved with chlorpheniramine treatment. Three children developed serious adverse events requiring hospitalization or discontinuation of study treatment. None of these was attributed to the treatment received. One girl aged 9 months in the AS3 group died of severe pneumonia 10 days after enrolment. She had no parasites by day 7. Another child aged 17 months in the AS3 group developed severe anaemia after she received the full course of treatment. She was withdrawn on day 3, when she was admitted to the paediatric ward to receive a blood transfusion. One other child aged 12 months in the AS3 group was withdrawn on the first day of treatment because she repeatedly vomited the first dose of the study treatment. She was withdrawn for severe malaria (a danger sign), and hospitalized to receive parenteral quinine. DISCUSSION Early diagnosis and prompt institution of effective treatment remains the cornestone for malaria control, globally. However, SP alone for treating paediatric falciparum malaria in this area of intense transmission and emerging SP resistance was associated with high rates of parasitological resistance. The addition of artesunate to SP treatment resulted in improved cure rates, fever and parasite clearance and a marked reduction in gametocyte carriage. The drug combinations were well tolerated. SP continues to be used as a replacement for chloroquine as first line therapy for uncomplicated malaria in many countries of sub-Saharan Africa because of its low cost and simple dosing regimen. However, the emergence of resistance to SP has been rapid. This development will have an enormous impact on all countries in the sub-Saharan region in terms of increased morbidity and mortality, increased costs of malaria treatment and the choice of alternative drugs. In 1998, Kenya officially replaced chloroquine with SP as the drug of first choice for treatment of uncomplicated falciparum malaria; already, the level of resistance to SP in some areas of Kenya is unacceptably high (ANABWANI et al., 1996; VAN DILLEN et al., 1999; OGUTU et al., 2000; GORRISEN et al., 2000). We found high rates of parasitological resistance to SP during the 28 day follow up period, which was supported by the high prevalence of molecular markers of SP resistance. Moreover, patients treated with SP alone remained parasitaemic and febrile for a longer period and were more likely to be gametocytaemic. The level of parasitological resistance to SP on day 28 (46%) in our study site was significantly higher than the 19 to 38% found in other Kenyan sites (AMUKOYE et al., 1997; ANABWANI et al., 1996; OGUTU et al., 2000; GORRISEN et al., 2000; VAN DILLEN et al., 1999), as well as at other sites within the East African region (KAMYA et al., 2001; BIJL et al., 2000; WARSAME et al., 1999). In comparison to the previous studies evaluating the use of artesunate-SP combinations, the parasitological failure rates with SP alone at both days 14 and 28 (26 and 46%, respectively), at our trial site were markedly higher than the 3 and 6%, in Gambia (VON SEIDLEIN et al., 2000), or the 8.7 and 15.2% in Indonesia (TJITRA et al., 2001).
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In our study, over 80% of the children developing recurrent parasitaemia were infected with parasites that had the triple mutant dihydrofolate reductase alleles associated with high-level pyrimethamine resistance, a worrying finding. Their high prevalence rates in both the pre-and post-treatment samples probably indicates that the selection of these resistant genes is already occurring to a high degree in the population of Siaya. This finding may have implications for the adoption of alternative drugs acting on the antifolate pathway such as chlorproguanil-dapsone (LAPDAP), which is another promising antifolate drug in development. Although we did not find the mutation at point 164, the possibility that it is circulating at low prevalence cannot be ruled out (SIBLEY et al., 2001). The widespread use of sulfamethoxazole-trimethoprim (cotrimoxazole) in this area for treating childhood respiratory infections may also be contributing to the selection pressure for resistant parasites and may have accelerated the development of drug resistance to SP. Consistent with previous studies, the addition of three days of artesunate to SP alone treatment significantly improved cure rates by day 14 (VON SEIDLEIN et al., 2000; TJITRA et al., 2001). The addition of one day of artesunate did not produce significant benefit in cure rate but did improve the parasite clearance time, clinical recovery and gametocyte carriage. By day 28, the effect of the high background level of SP resistance and the intensity of malaria transmission was more evident. PCR helped to distinguish new from resistant infections. Nevertheless, even with three days of artesunate the failure rate was still high at 26% and already beyond the 25% threshold previously suggested for changing the antimalarial drug policy (BLOLAND et al., 1993). Hence, artesunate-SP combination is unlikely to rescue SP in western Kenya and we suggest that the optimal benefit of artesunate may be achieved by deploying it well before resistance to the companion drug has developed. Following treatment, children receiving SP alone had a greatly increased prevalence of gametocytes compared to those on artesunate-SP combination. There was no advantage of the three days of artesunate over one day, consistent with the findings from The Gambia (VON SEIDLEIN et al., 2000). Continued utilization of SP alone is likely to facilitate the transmission of SP-resistant parasite strains through the production of gametocytes, which have a survival advantage over drug-sensitive ones (HANDUNNETTI et al., 1996). In Thailand, the gametocytocidal effect of artesunate when combined with mefloquine resulted in a reduction in malaria transmission (PRICE et al., 1996). We did not study the effect of artesunate-SP combination on malaria transmission. The current approach among most African Ministries of Health of sequentially changing from one antimalarial drug to the next once resistance develops can no longer keep pace with the rate at which the parasite develops resistance. It is for this reason that artemisinin-based combination therapy has been advocated to delay the development of resistance (WHO 2001). The encouraging experience of using these drug combinations in south-east Asia cannot be extrapolated to sub-Saharan Africa where the epidemiology of malaria is diverse and where treatment practices vary. Hence, the role of artemisinin-based combinations should be evaluated more fully in sub-Saharan African settings. Further research is also required on the safety and cost-
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effectiveness of these combinations, and their effect on malaria transmission when deployed on a large-scale. The rapid decline of SP efficacy in western Kenya should serve as a warning to other countries designing malaria treatment policies. For malaria control in Kenya, there is already an urgent need to replace SP. The decision to change from SP is complex and requires more than efficacy and safety data (BLOLAND et al., 1999; FEVRE and BARNISH, 1999). It is currently unclear which artemisinin-based drug combination(s) would be suitable for Kenya and other countries experiencing poor efficacy of the two main first-line drugs (chloroquine and SP). To conclude, we evaluated the benefit of adding artesunate to a single dose of SP for the treatment of uncomplicated falciparum malaria in children residing in a setting with a high background resistance to SP. We found a significant improvement in the day 28 cure rate but only with three days of artesunate. SP resistance compromised the efficacy of the combination. AS-SP would not be a good choice for widespread use in Kenya. ACKNOWLEDGEMENTS We thank G. Shanks, the clinical monitor and M.H Corel (Sanofi-Synthélabo, France) for providing artesunate and placebo without charge. The following made special contributions to the study: Festus Okute and James S. Odera (microscopists), Peter O.Otieno and Eunice Kinyua (clinical officers), Ruth Otieno (study nurse); Frida Ondoro, Joshua Owino, Richard Odhiambo, Mike Juma, Billy Oduor, Miriam Auma (fieldworkers), Andrew Ndeda (driver) and Lillian Sewe and Jackline Mboga (data entry clerks). Dr Laurence Slutsker from the CDC/KEMRI Field station, Kisumu, Kenya, and two anonymous reviewers made useful comments on this manuscript. We thank the Director, KEMRI, for permission to publish these results. This study was supported by a grant from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland. Dr Feiko ter Kuile was supported by The Netherlands Foundation for the Development of Tropical Research (WOTRO), The Hague, The Netherlands. REFERENCES Amukoye E, Winstanley PA, Watkins WM, Snow RW, Hatcher J, Mosobo M,
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Hastings IM, Watkins WM, White NJ, 2002. The evolution of drug-resistant malaria: the role of drug-elimination half-life. Philosophical Transactions of the Royal Society of London B Biological Sciences, 357: 505-19
Kamya MR, Dorsey G, Gasasira A, Ndeezi G, Babirye JN, Staedke SG, Rosenthal PJ, 2001. The comparative efficacy of chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. Transactions of the Royal Society of Tropical Medicine and Hygiene, 90: 563-567
Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, et al., 2000. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet, 356: 297-302
Nzila AM, Nduati E, Mberu EK, Sibley HC, Monks SA, Winstanley PA, Watkins WM, 2000. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate pyrimethamine/sulfadoxine compared with the
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shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. Journal of Infectious Diseases, 181: 2023-8
Ogutu BR, Smoak BL, Nduati RW, Mbori-Ngacha DA, Mwathe F, Shanks GD, 2000. The efficacy of pyrimethamine-sulfadoxine (Fansidar) in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 94, 83—84
Price R, Nosten F, Luxemburger C, ter Kuile FO, Phaipun L, Chongsuphajaisiddhi T, White NJ, 1996. Effects of artemisinin derivatives on malaria transmissibility. Lancet, 347, 1654-58
Ronn A, Msangeni H, Mhia J, Wernsdorfer W, Bygberg I, 1996. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania. Transactions of the Royal Society of Tropical Medicine and Hygiene, 90, 179-81
Sibley CH, Hyde JE, Sims PFG, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM, 2001. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends in Parasitology, 17, 582-8
Snounou G and Beck H, 1998. The use of PCR genotyping in the assessment of recrudescence or reinfection after antimalarial drug treatment. Parasitology Today 14, 462-467
Tijtra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM, 2001. Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Java, Indonesia. American Journal of Tropical Medicine and Hygiene, 65, 309-317
Von Seidlein L, Milligan P, Pinder M, Bojang K, Anyalebechi C, Gosling R, et al., 2000. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double blind, randomized, controlled trial. Lancet 355, 352-357
Warrell DA, Molyneux ME, Beales PF, 1990. Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84: 1-65
Warsame M, Kilimali VAEB, Wernsdorfer WH, Lebbad M, Rutta AS, Ericsson O, 1999. Resistance to chloroquine and sulfadoxine-pyrimethamine in Plasmodium falciparum in Muheza district, Tanzania. Transactions of the Royal Society of Tropical Medicine and Hygiene, 93, 312-13
Watkins WM and Mosobo M, 1993. Treatment of Plasmodium falciparum malaria with pyrimethamine and sulfadoxine: a selective pressure for resistance is a function of long elimination half-life. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 75-9
White NJ and 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 B, 354, 739-49
WHO 2001. Antimalarial drug combination therapy. Report of a WHO technical consultation. Document WHO/CDS/RBM/2001.35
CHAPTER 4
ANTIMALARIA DRUG TREATMENT
OUTCOMES
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Chapter 4.1
The Mortality Consequences of the Continued Use of Chloroquine
in Africa: Experience in Siaya, Western Kenya
Published as: American Journal of Tropical Medicine and Hygiene 2003, 68: 386-90
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The Mortality Consequences of the Continued Use of Chloroquine
in Africa: Experience in Siaya, Western Kenya
Jane R. Zucker1, Trenton K. Ruebush II1,2, Charles Obonyo2, Juliana Otieno3, Carlos C. Campbell4 Author affiliation: 1 = Malaria Section, Epidemiology Branch, Division of Parasitic Diseases (DPD), National Center for Infectious Diseases (NCID), Centers for Disease Control and Prevention (CDC), Public Health Service (PHS), U.S. Department of Health and Human Services (DHHS), Atlanta, GA, USA 2 = Clinical Research Centre, Kenya Medical Research Institute, Nairobi, Kenya 3 = Siaya District Hospital, Siaya, Kenya 4 = formally with Malaria Branch, DPD, NCID, CDC, PHS, U.S. DHHS, Atlanta, GA, USA. Current affiliation: University of Arizona Health Sciences Center, Tucson, AZ, USA Address for correspondence: Dr. Jane R. Zucker New York City Department of Health, Immunization Program, 2 Lafayette Street, 19th floor, New York, NY 10007, USA; Phone: 212/676-2248, Fax: 212/676-2258; E-mail: [email protected]
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ABSTRACT In spite of increasing resistance, chloroquine is the primary drug used for treatment of malaria illness in most sub-Saharan African countries. We evaluated the effect of drug treatment policy on the case-fatality rates of children adjusting for differing distributions of malaria illness and severe anaemia. In 1991, 63% of children were treated with chloroquine while the remaining 37% were treated with a regimen that would eliminate and clear parasitaemia; case-fatality rates were 13% and 4.1%, respectively; the proportion of deaths attributable to chloroquine treatment was 69%. The trend in case-fatality rates for malaria decreased as an increased proportion of children received an effective treatment regimen; adjusted malaria case-fatality rates were 5.1%, 3.6%, and 3.3% in 1992, 1993, and 1994, respectively, when 85% of children in 1992 and 97% of children in 1993-1994 received effective therapy. These 4 years of data provide strong evidence that continued use of chloroquine in areas with resistance is contributing to excess Plasmodium falciparum-related deaths.
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INTRODUCTION A cornerstone of policies to reduce malaria-related morbidity and mortality in Africa has been early diagnosis and prompt, effective therapy (WHO 1993). The criteria used to define an effective regimen have been evolving and include assessments of parasitologic and clinical cures. Chloroquine is the primary drug used for treatment in most sub-Saharan African countries, even though there is increasing drug resistance. The rationale for its continued use is based on not only cost and availability, but also the observation that despite parasite resistance, chloroquine treatment is associated with rapid resolution of clinical symptoms and reduction in parasite density. However, clinical consequences of Plasmodium falciparum chloroquine resistance have also been recognized: persistent parasitaemia, return of clinical symptoms such as fever, and persistent anaemia despite drug treatment (BLOLAND et al., 1993; GREENWOOD 1987). In addition, a study among children hospitalized with malaria in a district hospital in Western Kenya showed a 3-fold higher risk of dying among those treated with chloroquine compared with patients treated with drugs to which P. falciparum was fully susceptible (ZUCKER et al., 1996). Children who received chloroquine treatment had a 33% case-fatality rate within 8 weeks of hospitalization compared with an 11% rate among those who received either pyrimethamine/sulfa, quinine, or 5 days of trimethoprim/sulfamethoxazole. Because of its striking effect on survival, pyrimethamine/sulfa has been provided since February 1992 as first-line therapy for children with malaria admitted to that hospital. The objective of this investigation was to evaluate the effect of changing drug treatment policy on the case-fatality rates of children hospitalized with malaria over a 4-year period. METHODS The study was conducted at Siaya District Hospital (SDH), a 200-bed Ministry of Health hospital serving a population of 600,000 in western Kenya. Children younger than 5 admitted to SDH’s 40-bed paediatric ward were studied, with informed consent obtained from the parent or guardian at the time of enrollment. The baseline period was from March through September 1991, corresponding to the months of highest malaria transmission. Follow-up study periods were during the same months in 1992 and 1994, and from June through September in 1993. Information collected from all children admitted included age, gender, admission haemoglobin, blood smear for malaria parasites, and outcome of hospitalization. Children received routine in-hospital evaluation and care by the SDH staff. The admission diagnosis assigned by the hospital staff and all treatments administered during hospitalization were recorded. Treatment decisions were made by the SDH medical staff assigned to care for pediatric patients. During the study period, chloroquine was the first-line drug for the treatment of malaria, according to Kenyan national policy. The treatment that each patient received for malaria was recorded for a systematically sampled subgroup of children who were enrolled in concurrent studies. This study was approved by the scientific steering and ethical review committees of the Kenya Medical Research Institute and the investigational review board of the U.S. Centers for Disease Control and Prevention.
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Laboratory procedures Haemoglobin was measured from a capillary fingerprick using a HemocueR* (Mission Viejo, CA) machine. Thick and thin blood smears were stained with 3% Giemsa for 30 minutes. The number and species of Plasmodium parasites were read per 300 white blood cells (WBC). Parasite density was calculated based on the number of WBC/mm3 determined by the complete blood count. If the WBC count was not available, parasite density was calculated using the population mean of 8,000 WBC/mm3. Analysis Data were analyzed using EpiInfo 5 (Centers for Disease Control and Prevention, Atlanta, GA) and SAS (SAS Institute, Inc., Cary, NC) statistical package software. Categorical variables were analyzed using frequency distributions, and differences among groups were assessed using χ2 or Fisher's exact tests, as appropriate. The Wilcoxon rank sum test or a two-tailed t-test was used to compare the distribution of continuous variables. Direct standardization was used to account for differing distributions of malaria and severe anaemia (defined as admission capillary haemoglobin < 5.0 g/dL) among children admitted each year (HENNEKENS and BURING, 1987). The 1991 admission data were used as the standard population. The adjusted number of deaths each year among children with malaria was calculated separately for children with haemoglobin < or > 5.0 g/dL, using the observed category-specific case-fatality rates for that year. Malaria case definition Because of the high prevalence of falciparum parasitaemia in this setting, (approximately 80%-90% of children in the community and over 60% of hospitalized children have a blood smear positive for asexual parasites of P. falciparum) the analysis was restricted to those children who met criteria for malaria illness (ZUCKER et al., 1996). The case definition for malaria illness used was: a parasite density of > 5000 parasites/mm3 and documented axillary temperature of > 37.5oC or a parasite density of > 20,000 parasites/mm3, irrespective of documented temperature. RESULTS During the 1991 baseline 6-month study period, a total of 1223 children less than 5 years of age were admitted to the pediatric ward. Among the children admitted, 467 (38%) met the case definition for malaria illness. There were 46 in-hospital deaths for an in-hospital case-fatality rate of 9.9% among children meeting the malaria case definition (Table 1). The corresponding number of children admitted during the 1992-1994 study periods were 1117, 970, and 1453, respectively; 62%-69% of children had a positive blood smear with asexual parasites of P. falciparum and the proportion of children meeting the malaria case definition varied from 25% to 38% (Table 1). The unadjusted case-fatality rates for children with malaria illness in 1992, 1993, and 1994 were 5.0%, 3.3%, and 2.8%, respectively.
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Table 1. Total number of children admitted to Siaya District Hospital and the number of children with parasitaemia, malaria illness, severe anaemia, and malaria-related deaths from 1991-1994: unadjusted data
1991* 1992* 1993† 1994*
Number admitted children 1223 1117 970 1453
Age (months): mean median
12.6 9
12.7 9
12.4 9
12.3 9
Number of children with a positive blood smear (%)
838 (69%)
731 (65%)
598 (62%)
1008 (69%)
Number of children with malaria illness (%)
467 (38%)
318 (29%)
245 (25%)
503 (35%)
Number of children with severe anaemia (%)
141 (30%)
88 (28%)
41 (17%)
96 (19%)
Total number of malaria-related Deaths (%)
46 (9.9%)
16 (5.0%)
8 (3.3%)
14 (2.8%)
* Admissions from March through September † Admissions from June through September The proportions used for standardizing the case-fatality rates were 55.7% for those children meeting the malaria case definition (467 in 199/total number of children with a positive blood smear in 1991) and 30% for the proportion of children with severe anaemia. Adjusted malaria case-fatality rates were 5.1%, 3.6%, and 3.3% in 1992, 1993, and 1994, respectively (Table 2). Cerebral malaria and hyperparasitaemia were uncommon manifestations of malaria in this setting, accounting for less than 2% of all children with malaria illness. In 1991, of the 467 children with malaria, 296 (63%) were treated with chloroquine alone, while the remaining 171 were treated with pyrimethamine/sulfa, quinine, or 5 days of trimethoprim/sulfamethoxazole. Children treated with chloroquine had a 13% case-fatality rate compared with 4.1% rate among those treated with the other three regimens; relative risk = 3.22 (95% CI: 1.47, 7.04). The proportion of malaria-related deaths attributable to chloroquine treatment was 69%. The case-fatality rate for malaria illness declined from 1991 through 1994 as the percentage of children who received an effective treatment regimen for malaria increased (Figure 1).
Table 2. Total number of children admitted to Siaya District Hospital and the number of children with parasitaemia, malaria illness, severe anaemia, and malaria-related deaths from 1991-1994: after standardization
1991* 1992* 1993† 1994*
Number of children with a positive blood smear 838 731 598 1008
Number of children with malaria illness (%) 467 (56%) 407 (56%) 333(56%) 561 (56%)
Number of children with severe anaemia (%) 141 (30%) 122 (30%) 100 (30%) 168 (30%)
Number of deaths among children with severe anaemia 17 11 5 12
Number of deaths among children with a haemoglobin level >
5.0 g/dl
29 10 7 7
Total number of malaria-related deaths (%) 46 (9.9%) 21 (5.1%) 12 (3.6%) 19 (3.3%)
* admissions from March through September † admissions from June through September
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9.9%
3.3%2.8%
5.0%37%
85%
97% 100%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
1991 1992 1993 1994
Year
case fa
tality r
ate
0%
20%
40%
60%
80%
100%
120%
case fatality rate effective treatment
Figure 1. Case-fatality rates and proportion of children receiving effective treatment for malaria, Siaya District Hospital
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DISCUSSION These results extend previous observations that chloroquine resistance is associated with increased clinical failures and hospitalizations for malaria, and clearly link drug resistance and malaria treatment with survival among hospitalized children (BLOLAND et al., 1993; ZUCKER et al., 1996; GREENBERG et al., 1989). During 1991, the proportion of deaths attributable to chloroquine treatment was 69%, indicating that two-thirds of deaths could have been prevented, a result supported by the decline in the malaria case-fatality rates observed from 1992 – 1994 in association with a change in treatment policy. These 4 years of data provide strong evidence that the continued use of chloroquine in areas with resistance is contributing to P. falciparum-related deaths. In this setting, the need to change drug treatment policy is apparent, but the real challenge is to recognize when first-line therapy is no longer effective before resistance is associated with significant malaria-related mortality. The controversy has been over identifying indicators to adequately monitor the consequences of resistance, including both parasitologic and clinical failures. Commonly used measurements to define responses to treatment have included parasitologic clearance at 72 hours, clinical status (recurrent fever) at 14 days, and hematologic recovery (WHITE & KRISHNA, 1989). At present, recommended standardized procedures in children younger than 5 include treatment at day 0 with follow-up parasite density and temperature measurements at days 3, 7, and 14 (WHO 1994; WHO 1996). This approach targets the nonimmune population at greatest risk for severe disease and provides information on the proportion of children who fail to eliminate their parasites and those who become ill again within a timeframe consistent with recrudescent infection rather than reinfection. Several sources have suggested that in vivo clinical failure rates of 14%--25% for a first-line treatment should indicate the need to change drug policy (WHO 1994; SCHAPIRA et al., 1993; SUDRE et al., 1992).
Factors in the decision on when to change the first-line treatment will include programmatic considerations, assessment of costs, available second-line agents, and the acceptable proportion of clinical failures (CAMPBELL 1991). The reluctance to abandon chloroquine is based, in part, on its low cost, wide availability, and acceptance. Chloroquine results in rapid initial improvement of clinical symptoms (e.g., headache and fever), which has contributed to its widespread acceptance and the perception that it remains effective, leading to an unwillingness of both health workers and patients to discontinue using chloroquine. The higher cost of second line treatment, such as Fansidar ® (pyrimethamine/sulfadoxine) or combination therapy with artemisinin derivatives, often is cited as prohibitive for most sub-Saharan African countries where the average health care expenditure per person is low. However, providing efficacious first-line treatment is more cost effective when compared with the cost of recurrent illness and retreatment where drug resistance levels are high (WHO 1994; SCHAPIRA et al., 1993; SUDRE et al., 1992). The higher cost of second-line drugs and combination
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treatment protocols, as well as concern about the development of drug resistance in the “next”-line drug, although valid concerns, cannot justify withholding life-saving treatment (WHITE et al., 1999). Of additional concern are observations suggesting that the use of chloroquine to treat chloroquine-resistant P. falciparum infections may lead to greater spread of the resistant strains because of enhanced gametocyte infectivity -- thus worsening the existing problem (HOGH et al., 1998). The ongoing monitoring of drug resistance also will be important to detect the development of resistance in the “next-line” drug used or to detect regained sensitivity to a drug that has not been used recently, as has been described for chloroquine, in order to develop rational drug treatment policies (BRANDTS et al., 2000). These observations in western Kenya were made in the context of routine care; except for providing antimalarial medications, there were no changes in the care or availability of supportive therapies during the study period. In this setting, the most prevalent manifestation of severe P. falciparum illness is severe anaemia. Overall, case-fatality rates were higher for severely anaemic children than those whose haemoglobin levels were greater than 5.0 g/dL, but the benefits of effective malaria therapy did not depend on haemoglobin level and also were demonstrated for survival at 8 weeks after hospitalization, suggesting a causal role for recrudescent parasitaemia (ZUCKER et al., 1996). The malaria case-fatality rates among children hospitalized at SDH were reduced to approximately the 3%-4% levels seen in developed countries and locations where cerebral malaria is more common (GREENBERG et al., 1990; MARSH et al., 1995). It is striking that in a different setting on the coast of Kenya, where 28% of children met the WHO criteria for cerebral malaria, the overall malaria case-fatality rate was 3.5% (MARSH et al., 1995; WHO 1990). These observations suggest that a case-fatality rate of between 3%--4% for malaria among hospitalized children, regardless of the case-mix of severe disease, may represent a useful measurement for monitoring overall quality of treatment (BARUTWANAYO et al., 1993). This observation will require validation from a number of different sites to determine its utility. This study was conducted in a health facility where laboratory testing was available, documentation of the treatment received was possible, and cause-specific mortality was obtained. The applicability of hospital-based observations to mortality patterns in the community may be questioned, as it is well recognized that the majority of malaria-related deaths among children occur outside a health facility (GREENWOOD et al., 1987). However, recent evidence from Senegal supports the belief that increasing chloroquine resistance is also causing increased malaria-related child morality at the community level (TRAPE et al., 1998). The need to ensure access to and availability of effective malaria treatment will be critical if we are to reduce the death toll caused by this disease (MARSH, 1998). Improved child survival in Africa will require more effective case management of malaria. Persistent parasitaemia from treatment with an inefficacious drug is associated with increased malaria-related mortality. While we try to understand the clinical consequences of parasite resistance, we must not lose sight of the most important of all clinical outcomes: death. Efficacious therapy does improve survival,
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and this strategy is practical for implementation in hospital settings in Africa. Chloroquine resistance has been reported from all countries in sub-Saharan Africa; children are being treated with chloroquine in settings where clinical failures already exceed 25% (HOGH et al., 1995; DEL NERO et al., 1994; KREMSNER et al., 1994; MHARAKURWA & MUGOCHI 1994; PREMJI et al., 1994; SCHREUDER et al., 1993). The debate about chloroquine drug resistance is no longer about the increased cost of second-line medications -- it is about the cost of life. We cannot justify allowing children to die in Africa because they are not receiving effective treatment. Acknowledgments: This paper is published with the permission of the Director, Kenya Medical Research Institute. We thank Johnson Awino, Solomon Twala, and Lucy Otieno for their participation in this study. Financial support: This work was partly supported by the World Health Organization (Global Programme on AIDS, Division of Diarrheal and Acute Respiratory Disease Control, and the Programme for Research and Training in Tropical Diseases). REFERENCES Barutwanayo M, Bassalia D, Birabuza A, Delacollette C, Keita M, Madji N, Maiga
AS, Maoude H, Ndihokubwayo H, Niangue J, Lemine SMOM, Yazipo ED, 1993. Malaria control in Africa: guidelines for the evaluation of national programs. United States Agency for International Development and U.S. Department of Health and Human Services, Atlanta, Publication No. 099-4243.
Bloland PB, Lackritz EM, Kazembe PN, Were JBO, Steketee 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, 932-37.
Brandts CH, Wernsdorfer WH, Kremsner PG, 2000. Decreasing chloroquine resistance in Plasmodium falciparum isolates from Gabon. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 554-56.
Campbell CC, 1991. Challenges facing antimalarial therapy in Africa. Journal of Infectious Diseases 163, 1207-11.
Del Nero L, Nebie I, Soudouem G, Pietra V, 1994. Chloroquine and sulfadoxine/pyrimethamine sensitivity in Burkina Faso. In vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine in Burkina Faso. Tropical and Geographical Medicine 46, 8-10.
Greenberg AE, Ntumbanzondo M, Ntula N, Mawa L, Howell J, Davachi F, 1989. Hospital-based surveillance of malaria-related paediatric morbidity and mortality in Kinshasa, Zaire. Bulletin of the World Health Organization 67, 189-96.
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Greenwood BM, 1987. Asymptomatic malaria infections - do they matter? Parasitology Today 3, 206-14.
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Hogh B, Thompson R, Hetzel C, Fleck SL, Kruse NAA, Jones I, Dgedge M, Barreto J, Sinden RE, 1995. Specific and nonspecific responses to Plasmodium falciparum blood-stage parasites and observations on the gametocytemia in schoolchildren living in a malaria-endemic area of Mozambique. American Journal of Tropical Medicine and Hygiene 52, 50-59.
Hogh B, Gamage-Mendis A, Butcher GA, Thompson R, Begtrup K, Mendis C, Enosse SM, Dgedge M, Barreto J, Eling W, Sindin RE, 1998. The differing impact of chloroquine and pyrimethamine/sulfadoxine upon the infectivity of malaria species to the mosquito vector. American Journal of Tropical Medicine and Hygiene 58, 176-182.
Kremsner PG, Winkler S, Brandts C, Neifer S, Bienzle U, Graninger W, 1994. Clindamycin in combination with chloroquine or quinine is an effective therapy for uncomplicated Plasmodium falciparum malaria in children from Gabon. Journal of Infectious Diseases 169, 467-7.
Marsh K, Forster D, Waruiru C, et al., 1995. Indicators of life-threatening malaria in African children. New England Journal of Medicine 332, 1399-1404.
Marsh K, 1998. Malaria disaster in Africa. Lancet 352, 92 Mharakurwa S and Mugochi T, 1994. Chloroquine-resistant falciparum malaria in an
area of rising endemicity in Zimbabwe. Journal of Tropical Medicine and Hygiene 97, 39-45.
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Schapira A, Beales PF, Halloran ME, 1993. Malaria: living with drug resistance. Parasitology Today 9, 168-73.
Schreuder HW, Wolters FL, de Vries G, Wetsteyn JC, 1993. Prospective in-vivo study of chloroquine resistance of Plasmodium falciparum in Zambian under-fives. Tropical and Geographical Medicine 45, 15-17.
Sudre P, Breman JG, McFarland D, Koplan JP, 1992. Treatment of chloroquine-resistant malaria in African children: a cost-effectiveness analysis. International Journal of Epidemiology 21, 146-54.
Trape JF, Pison G, Preziosi MP, Enel C, Desgrϑes du Loφ A, Delaunay V, Samb B, Lagarde E, Molez JF, Simondon F, 1998. Impact of chloroquine resistance on malaria mortality. C.R. Acad Sci Paris, Life Sciences 321, 689-697.
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White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK, Danis M, Greenwood BM, Anderson RM, Olliaro P, 1999. Averting a malaria disaster. Lancet 353, 1965-67.
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World Health Organization, 1990. Severe and complicated malaria. Eds. Warrell DA, Molyneux ME, Beales PF, eds. Transactions of the Royal Society of Tropical Medicine and Hygiene 84 (suppl. 2), 1-65.
World Health Organization, 1993. Implementation of the global malaria control strategy. Report of a WHO study group on the implementation of the global plan of action for malaria control 1993-2000. World Health Organization, Geneva; Technical Report Series no. 839.
World Health Organization, Division of Control of Tropical Diseases, 1994. Antimalarial drug policies: data requirements, treatment of uncomplicated malaria and management of malaria in pregnancy. Report of an informal consultation, Geneva, 14-18 March 1994. WHO/MAL/94.1070.
World Health Organization, Division of Control of Tropical Diseases, 1996. Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated falciparum malaria in areas of intense transmission. WHO/MAL/96.1077.
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, 655-660.
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Chapter 4.2
Effect of artesunate plus sulfadoxine-pyrimethamine on
haematological recovery and anaemia in Kenyan children with
uncomplicated falciparum malaria
Accepted for publication: Annals of Tropical Medicine and Parasitology
111
Effect of artesunate plus sulfadoxine-pyrimethamine on haematological recovery and anaemia in Kenyan children with uncomplicated falciparum
malaria
Charles O. Obonyo1, Walter Taylor2, Hakan Ekvall3, Akira Kaneko3, Feiko ter Kuile4, Piero Olliaro2, Anders Bjorkman3, Aggrey J Oloo1 Institutional Affiliation 1=Centre for Vector Biology and Control Research, Kenya Medical Research Institute, Kisumu, KENYA 2= UNICEF/UNDP/World Bank/Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, SWITZERLAND 3= Malaria Laboratory, Unit of Infectious Diseases, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, SWEDEN 4=Reproductive and Child Health Group, Liverpool School of Tropical Medicine and Hygiene, Liverpool, UK. Corresponding author: Charles O. Obonyo, Centre for Vector Biology and Control Research, Kenya Medical Research Institute, P.O. BOX 1578-40100, Kisumu, KENYA Phone: +254 57 2022924; Cell phone: +254 733837969; Fax: +254 572022981 Email: [email protected]
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ABSTRACT Malaria associated anaemia is a major public health problem. Treatment of uncomplicated malaria aims to clear parasites, relieve symptoms and effect haematological recovery. Data on the impact of antimalarial treatment efficacy on haematological recovery are few. Haematological recovery and anaemia prevalence were evaluated in 600 Kenyan children with uncomplicated falciparum malaria who were randomly assigned to one of 3 treatment groups: (1) SP alone [SP] (2) SP plus one dose of Artesunate [AS1], or (3) SP plus 3 doses of Artesunate [AS3]. We measured haemoglobin (Hb) on Days 0, 7, 14, 21 and 28 days after treatment. Haematological recovery was defined as a Day 28 Hb ≥ 11.0 g/dL. At enrolment 543/600 (91%) of the children were anaemic (Hb < 11.0g/dL) of whom 96/543 (18%) achieved haematological recovery. The prevalence of anaemia fell to 74% (252/340) by Day 28 (p=0.065). Compared to SP alone, neither artesunate regimen resulted in: (i) higher mean, Day 28 haemoglobins (10.2 g/dL [AS3] and 9.9g/dL [AS1] vs. 10.2g/dL [SP], p=0.254), (ii) higher proportions with haematological recovery (35/180 (19%) and 25/178 (14%) vs. 36/185 (20%), p=0.301), or (iii) reduction in anaemia rates (19% vs. 7% vs. 24%, p=0.40). On Day 7, AS3 treated children were more likely to have a larger drop in mean haemoglobin compared to AS1 or SP alone groups. Haematological recovery was more likely in older children who had mild anaemia at presentation and were parasitologically cured. Overall, haematological recovery rates were modest and not influenced by the more efficacious artesunate-based treatments. Other contributing factors to anaemia need to be explored more fully. Key words: malaria, anaemia, artemisinin, sulfadoxine-pyrimethamine, combination therapy
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1.0 INTRODUCTION Malaria-associated anaemia is a major public health problem especially among children in malaria endemic areas of sub-Saharan Africa. It is estimated that up to three quarters of African children in these regions are anaemic, mainly from malaria or iron deficiency (DeMAEYER and ADIELS-TEGMAN, 1985). Malaria-related anaemia is an important cause of paediatric morbidity and mortality, affecting an estimated 1.5 to 6 million African children and causing a case fatality rate of 15% (MURPHY and BREMAN, 2001). Increasing use of blood transfusions, the most common treatment for severe anaemia, compounds morbidity because of the risk of transmission of the human immunodeficiency virus (HIV). Other causes of paediatric anaemia include nutritional deficiencies (e.g. iron, folic acid, other micronutrients and protein-calorie malnutrition), genetic disorders of the red blood cell (e.g. hemoglobinopathies, thalassaemias and glucose-6-phosphate dehydrogenase [G-6-PD] deficiency), intestinal helminthes, and HIV infection. 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). Clinical studies have shown that poor haematological recovery was observed following treatment with chloroquine for uncomplicated falciparum malaria (BLOLAND et al., 1993; VERHOEFF et al., 1997; EKVALL et al., 1998). Failed treatment contributes to malarial anaemia because of persistent 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). Similarly, the previous gains achieved in reducing infant and childhood mortality in many malaria-endemic regions have been reversed with the emergence and intensification of antimalarial drug resistance (TRAPE et al., 1998; SNOW et al., 2001; TRAPE 2001; KORENROMP et al., 2003). One study has suggested that a reduction in the proportion of excess malaria-related deaths could be achieved by introducing effective antimalarial therapy (ZUCKER et al., 2003). The pathogenesis of malaria-associated anaemia is complex and multifactorial, and includes reduced red cell survival, haemolysis of parasitised and non-parasitised red cells, and bone marrow suppression (ABDALLA et al., 1980; EKVALL et al., 2001). Some antimalarial drugs are also haemato-toxic like the sulfa/pyrimethamine combinations, a folate antagonist, and chlorproguanil-dapsone, which cause haemolysis in G-6-PD deficient patients (SULO et al., 2001; ALLOUCHE et al., 2004). In animal studies, artesunate caused bone marrow suppression which manifest as a depression of the reticulocyte count. Depressed reticulocytosis has also been reported in humans (PRICE, 2000). There is also in vitro evidence of haemolysis caused by artemisinin and dihydroartemisinin, the main active metabolite of artesunate (GU et al., 1986). Experience with artemisinin-based combination therapies (ACTs) has shown that the rates of haematological recovery are similar to those of standard monotherapies despite improved cure rates (ADJUIK et al., 2002) while other studies have shown improved haematological recovery (Nosten F, unpublished data).
114
Prompt and effective treatment of malaria, the main strategy for global malaria control (WHO 1993), aims to clear parasites rapidly, relieve clinical symptoms and improve haemoglobin levels. The protocol developed by World Health Organization for the evaluation of antimalarial drug efficacy now includes haematological recovery as an efficacy endpoint (WHO 1996; WHO 2002). Lack of haematological recovery following antimalarial drug treatment coupled with significant parasitological and clinical failure has been proposed as sufficient evidence to consider a change in the treatment policy (BLOLAND et al., 1993; VERHOEFF et al., 1997; EKVALL et al., 1998; BLOLAND & ETTLING 1999). The impact of antimalarial drug resistance on haematological recovery has not been evaluated in sub-Saharan Africa. We hypothesise that using ACTs for acute, uncomplicated Plasmodium falciparum should result in greater haematological recovery because ACTs are more efficacious than standard monotherapies (ADJUIK et al., 2004). In the context of a randomised trial designed to evaluate the efficacy of combination therapy using Artesunate [AS] plus Sulfadoxine-Pyrimethamine [SP] versus SP alone for the treatment of uncomplicated falciparum malaria in western Kenya, we assessed the impact of these regimens and other determinants on haematological recovery. 2.0 PATIENTS AND METHODS 2.1 Study design The study procedures and findings of this randomised, double blind, placebo-controlled trial of the effect of SP plus AS for one or three days or SP alone in the treatment of uncomplicated malaria are detailed elsewhere (OBONYO et al., 2003). The study was conducted (October 1999-March 2000) at Siaya District hospital, western Kenya, an area of intense perennial transmission of predominantly P. falciparum (BEIER et al., 1994). Ethical approvals were obtained the Ethical Review Committee of the Kenya Medical Research Institute, Nairobi, Kenya and also from the WHO Steering Committee for Research Involving Human Subjects. Bbriefly, 600 children with clinical features of uncomplicated falciparum malaria attending the outpatient department at Siaya district hospital were enrolled into the randomised trial if they met the following inclusion criteria: were aged below 5 years, had a consenting guardian, weighed at least 5.0 kg, had a history of fever during the preceding 48hours, and a smear-confirmed monoinfection with P. falciparum of at least 4,000 asexual parasites/mm3. On admission to the study, the children were randomised in equal groups (i.e 200 children in each arm) to receive either: (1) SP (Fansidar®, 500mg/25mg, Hoffman-La Roche, Basel, Switzerland) plus placebo (SP alone group); (2) SP plus one dose of artesunate (Arsumax 50mg, Sanofi-Synthelabo, Gentilly-Cedex, France) (AS1 group); or (3) SP plus one dose of artesunate daily for three days (AS3 group). All the study drugs were administered by the study nurse. Doses of artesunate /placebo were 4mg/kg body weight/day, and for SP, 25 mg/kg based on sulfadoxine, given once. Parents provided the medical history and the children were clinically examined. Body weights and axillary temperatures were measured and capillary blood samples were obtained. Children were followed up for 28 days. To assess parasitological response to
115
treatment they were seen daily until parasites cleared. Thereafter, they were seen weekly, i.e. on days 7, 14, 21, and 28. At each follow up visit, children were assessed clinically, temperatures were taken and capillary blood samples were obtained by finger-prick. Malaria blood smears and haemoglobin was measured at study admission and again at each weekly visit. To determine hematological recovery, we measured haemoglobin for every child weekly until they failed therapy, got lost to follow-up and were withdrawn from participation in the study. If the axillary temperature was ≥38.00C paracetamol was administered. Parents, children, clinicians, microscopists and investigators remained masked to the treatment allocation throughout the study. Children who failed to respond adequately to the study treatment received rescue treatment using oral amodiaquine (25mg/kg as 10mg/kg on days 0 and 1, and 5mg/kg on day 2), for uncomplicated malaria or parenteral quinine for severe malaria and were withdrawn from the study. This means that children were withdrawn from the study as they met the treatment efficacy endpoints. Folic acid was not permitted in this study and iron supplementation was not routinely prescribed to the study participants, until the end of the study.
2.2 Laboratory procedures Haemoglobin (Hb) concentration was measured using a Hemocue machine® (Mission Viejo, CA, USA). Thick and thin blood smears were stained with 3% Giemsa for 30 minutes and read by trained microscopists. Parasite density was calculated as the number of parasites counted per 200 white blood cells (WBC) on a thick smear assuming a mean WBC count of 8000 per µL. P. falciparum gametocytes were counted against 500 WBC. Dried filter paper blood samples from children with recurrent parasitaemia between 15 and 28 days after treatment were used to perform parasite genotyping to distinguish recrudescence of the original parasite strain from reinfection with a new parasite strain (SNOUNOU & BECK, 1998). 2.3 Definitions and end points Anaemia was defined as haemoglobin (Hb) concentration <11.0g/dL and categorized as severe (Hb level < 5.0g/dL), moderate (Hb ≥ 5.0 to 7.9g/dL) and mild (Hb 8.0 to 10.9g/dL) anaemia. Persistent anaemia was defined as Hb that remained below 11g/dl for the duration of follow-up. Malnutrition (underweight) was defined as weight-for-age Z (WAZ) score below 2 standard deviations. High parasitaemia was defined as parasite density 20,000/µL. Febrile illness was considered prolonged if it had lasted more than 2 days. Parasitological cure was defined as complete clearance of parasites after treatment and absence of parasites on Day 28. Similarly, parasitological failure was defined as recurrent parasitaemia any time within the 28 days after treatment. The haematological endpoints were: (i) haematological recovery, (ii) anaemia prevalence, (iii) mean haemoglobin and mean change over time. Haematological recovery was defined as achieving haemoglobin level of at least 11.0g/dL in those with any degree of anaemia at the beginning of the study.
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2.4 Statistical analysis Data were analysed using SPSS version 12.0 (SPSS Inc., Chicago, IL). Weight-for-age z scores were computed using the 1978 CDC/WHO normalized version of the 1977 NCHS reference curves in Epi Info version 6.04d (Centres for Disease Control, Atlanta, GA). Normally distributed continuous data were compared by student’s t-test and analysis of variance or the corresponding non-parametric tests (Mann-Whitney U, Kruskal-Wallis) for skewed data. The association between two continuous variables was assessed using the Pearson’s rank correlation coefficient. Proportions were compared between treatment groups using the chi-square test. All reported p values are two-tailed and a value of <0.05 was considered statistically significant. Determinants of baseline anaemia (age, sex, body weight, nutritional status, splenomegaly, prolonged illness, a history of recent treatment with chloroquine, Day 0 asexual parasite density, high parasitaemia and Day 0 gametocytaemia.) and haematological recovery (Day 0 Hb, outcome: parsitological cure vs. failure, and recurrent parasitaemia) during follow-up (stratified by treatment received) were assessed by univariate and multivariate analyses. Variables found significant at p value <0.10 in the univariate analysis were entered into a multivariate logistic regression model. For all comparisons, the SP alone group served as the reference group. AS3 vs. AS1 were also compared. Time to haematological recovery was assessed by the survival analysis. 3.0 RESULTS 3.1 Patient characteristics The baseline characteristics of the 600 enrolled children were similar by arm (Table 1). The mean Hb at study admission was 8.41 g/dL (95% CI 8.26-8.56) for all the treatment arms combined. 3.2 Parasitological response Day 28, treatment failure rates, after excluding new infections by genotyping, were 46.0% [87/189, SP], 38.2% [73/191, AS1] (risk difference [∆] = -7.8%, 95% CI -17.7 to 2.1%, p= 0.16), and 26.0% [50/192, AS3] (∆= -20.0%, 95% CI -29.4 to -10.6%, p < 0.001). 3.3 Anaemia at enrolment and during follow-up At enrolment, 90.5% [543/600] of the children were anaemic (Hb<11.0g/dl); 4 (0.7%) had severe anaemia (inadvertent protocol violations), 251 (41.8%) had moderate and 288 (48%) had mild anaemia. Day 0 anaemia was correlated negatively with age (r = -0.180; p<0.01) and body weight (r = -0.203; p<0.001). From the multivariate logistic model, the following variables were found to be independent risk factors for Day 0 anaemia: (i) age > 36 months (adjusted odds ratio [AOR] = 5.65; 95% CI, 2.94-10.88, p<0.0001), (ii) a palpable spleen (AOR=3.10; 95%CI, 1.58-6.07, p=0.001), (iii) female gender (AOR=2.22; 95%CI, 1.21-4.05, p=0.010), and (iv) malnutrition (AOR=3.06; 95%CI, 1.15-8.12, p=0.025). There was no correlation between Day 0 anaemia and parasitaemia, high parasitaemia, presence of gametocytes, duration of fever or recent chloroquine treatment.
117
The overall proportion of anaemic children had fallen to 74% by Day 28: (i) 90% to 71% (AS3), 89% to 82% (AS1) and 93% to 69% (SP alone). The proportion of anaemic children during follow up was comparable across treatment groups except on Day 28 when there was a marginal difference across the three treatment groups (p=0.065). SP treated children had a significantly lower prevalence of anaemia compared to the AS1 arm (p=0.028), as did AS3 vs. AS1 treated children (p=0.05). The proportion of children with persistent anaemia during the follow-up period was 84.3% [506/600]. Persistent anaemia was similar across the 3 treatment groups (p=0.915). Persistent anaemia was negatively correlated with age (r = -2.12, p<0.0001), body weight (r = -0.203, p<0.0001) and the Day 0 Hb (r = -4.70, p<0.0001). Risk factors for persistent anaemia were: (i) age < 24months (AOR=7.22; 95%CI 3.65-14.29, p<0.0001), (ii) palpable spleen (AOR=2.34; 95%CI 1.22 – 4.48, p=0.011), (iii) Hb fall on Day 7 (AOR=3.58; 95%CI 1.93 – 6.64, p<0.0001), and (iv) parasitaemic on Day 2 (AOR=2.71; 95%CI 1.13-6.48, p=0.025). There was no correlation between gender, prolonged illness, Day 0 parasitaemia, gametocytaemia on Day 0 or high parasitaemia and persistent anaemia. The proportion of children with Hb<8.0g/dL was similar between those with treatment failure vs. success throughout the follow up period (p>0.50). 3.5 Haematological recovery and determinants By Day 28, only 17.7% [96/543] of children who were anaemic at enrolment attained full haematological recovery, as strictly defined. Their mean Hb was 11.8g/dL vs. 9.38g/dL for those without haematological recovery (p<0.0001). Proportions of children with haematological recovery were comparable between treatment groups: 19.4% [35/180], 14.0% [25/178] and 19.5% [36/185] in the AS3, AS1 and SP alone groups, respectively (P=0.301). A significantly higher proportion of children with mild anaemia at enrolment achieved haematological recovery compared to those with moderate anaemia: 28.5% [82/288] vs. 5.5% [14/223], OR= 6.85; 95% CI, 3.77- 12.4, p<0.0001. Haematological recovery rates were similar in children who failed to clear parasites by Day 3 vs. those who cleared (18.5% [85/459] vs. 15.9% [10/63], p=0.610), parasitological cure vs. failures (21.1% [47/223] vs. 15.3% [49/320], OR=1.48; 95%CI, 0.95-2.30, p=0.083), or those with Hb fall on Day 7 vs. those with Hb rise (18.5% [62/335] vs. 18.9% [31/164], p=0.915). The following factors were associated with haematological recovery in the univariate analysis: parasitological cure, age above 24months, febrile on Day 0, and mild anaemia at enrolment. Palpable spleen, malnutrition, gender, prolonged illness, recurrent parasitaemia, high parasitaemia or recent chloroquine treatment, were not significantly associated with haematological recovery. From the multivariate analysis, the following factors were independently associated with haematological recovery: parasitological cure (AOR=1.71; 95%CI, 1.04 - 2.79), mild anaemia at admission (AOR=5.73; 95%CI, 3.11- 10.54), and age above 24 months (AOR=2.68; 95%CI, 1.59 - 4.49). The mean times to haematological recovery were similar between the three arms: 19.0 (95%CI, 16.85-21.15), 17.1 (14.0-20.2), and 17.7 (15.3-20.0) days in the AS3, AS1, and SP groups, respectively. Children older than 24 months took significantly shorter
118
time to full haematological recovery compared to those younger than 24 months (14.9 vs. 20.3 days, p<0.0001). Children who were parasitologically cured took a significantly longer time to recover haematologically compared to those with parasitological failure (19.7 vs. 16.3 days, p=0.0145). Mildly and moderately anaemic children did not have significantly different times: 17.4 vs. 21.5 days (p=0.133). 3.6 Temporal patterns of haematological recovery Of the 543 anaemic children on Day 0, 24 had no serial haemoglobin measurements because they were withdrawn from the study during the week after enrolment. By Day 28, three different haematological outcomes emerged. The majority, 71.5% [371/519], never achieved haematological recovery, 18.5% [96/519] did, and 10% [52/519] children recovered temporarily and then became anaemic again. These outcomes were independent of Day 0 anaemia (details not shown). Of the 57 children without Day 0 anaemia, outcomes were known for 53: (i) 17 (32.1%) maintained normal Hbs, (ii) 24 (45.3%), developed anaemia and recovered from it, and (iii) 12 (22.6%) developed and remained anaemic. 3.4 Changes in haemoglobin concentrations over time Table 2 shows the evolution in the mean haemoglobin across the treatment groups during follow-up. Regardless of treatment received, there was an increase in the mean haemoglobin across all the treatment groups with an overall mean increase of 1.63g/dL (95%CI 1.45 to 1.81) by Day 28. There was no statistically significant difference in the mean haemoglobin across the treatment groups on Days 14, 21 and 28. However, on Day 7, children in the AS3 group had significantly lower mean haemoglobin compared to the SP alone group (p=0.038) but not compared to the AS1 group (p=0.144). On Day 28, parasitologically cured children had a significantly higher mean Hb compared to those with a parasitological treatment failure (10.21 vs. 9.75g/dL, p=0.016). Compared to moderately anaemic children those who had mild anaemia at enrolment had a significantly higher mean Hb on Day 28 (10.49 vs. 9.25g/dL, p<0.0001). Following treatment, the mean changes in haemoglobin from Day 0 were comparable across the treatment groups, except on Day 7, when children in the AS3 group had a significantly smaller mean difference (0.02g/dL) compared to either the SP alone (0.35g/dL, P=0.022) or AS1 (0.37, p=0.016) recipients. The mean change between AS1 and SP alone groups were comparable on Day 7 (p=0.939). On Day 28, there was no significant difference in the mean change in Hb across treatment groups (p=0.983), or between those with parasitological cure vs. those who failed therapy (1.46 vs. 1.69g/dL, p=0.262). However, children who were moderately anaemic at enrolment had a significantly higher difference in the mean Hb compared to those who had mild anaemia (2.53 vs. 1.20g/dL, p<0.0001).
Tabl
e 1.
Bas
elin
e ch
arac
teris
tics o
f the
stud
y po
pula
tion
Trea
tmen
tgro
up
SP
Alo
ne (n
=200
) 1-
day
Arte
suna
te p
lus S
P (n
=200
) 3-
day
Arte
suna
te p
lus S
P (n
=200
)
All
Ana
emic
N
on-a
naem
ic
N=1
85
N=1
5 A
llA
naem
ic
Non
-ana
emic
N
=178
N
=22
All
Ana
emic
N=1
80
Non
-ana
emic
N
=20
Mal
e/Fe
mal
e
97
/103
92
/93
5/10
105/
9596
/82
9/13
104/
9697
/83
7/13
Age
(mon
ths)
16
.9 (1
3.7)
16
.3 (1
3.1)
24
.3 (1
7.9)
17
.5(1
4.4)
17
.0 (1
3.5)
21
.1 (2
0.6)
16
.0 (1
2.3)
14
.7 (1
0.7)
27
.9 (1
9.2)
A
ge b
elow
24
mon
ths (
%)
147
(73.
5%)
140
(75.
6%)
7 (4
6.7%
) 15
1 (7
5.5%
) 13
6 (7
6.4%
) 15
(68.
2%)
156
(78%
) 14
6 (8
1%)
10 (5
0%)
Age
bel
ow 3
6 m
onth
s (%
) 17
7 (8
8.5%
) 16
6 (8
9.7%
) 11
(73.
3%)
169
(84.
5%)
154
(86.
5%)
15 (6
8.2%
) 18
2 (9
1%)
171(
95%
) 11
(55%
) B
ody
wei
ght (
kg)
9.4
(3.0
) 9.
3 (2
.8)
10.9
(4.5
) 9.
6 (3
.2)
9.5
(2.9
) 10
.8 (4
.5)
9.2
(2.8
) 8.
9 (2
.4)
12.0
(4.4
) Te
mpe
ratu
re (0
C)
38.0
(1.2
) 37
.9 (1
.2)
38.2
(1.3
) 37
.8 (1
.2)
37.7
(1.2
) 38
.2 (1
.0)
37.8
(1.2
) 37
.8 (1
.2)
37.6
(1.3
) Pa
rasi
te d
ensi
ty/µ
L
23,8
39
(154
04)
2422
7 (1
5469
) 19
058
(141
90)
25,6
43
(190
63)
2504
0 (1
9227
) 30
521
(173
12)
26,3
59
(181
08)
2593
2 (1
7803
) 30
196
(207
65)
Gam
etoc
yte
prev
alen
ce (%
) (1
4.5%
) 14
.6%
13
.3%
16
.5%
18
%
4.5%
12
.0%
12
.2%
10
%
Hae
mog
lobi
n (g
/dL)
8.
42(1
.7)
8.14
(1.5
) 11
.84
(0.9
) 8.
38 (1
.9)
7.95
(1.6
) 11
.88
(0.7
) 8.
42 (1
.8)
8.02
(1.5
) 11
.98
(0.8
) C
hlor
oqui
ne tr
eatm
ent (
%)
45 (2
2.5%
) 43
(23%
) 2
(13.
3%)
56 (2
8%)
52(2
9.2)
4(
18.2
) 43
(21.
5%)
41 (2
2.8)
2
(10%
) Pa
lpab
le sp
leen
(%)
91 (4
6%)
87 (4
7%)
4(26
.7%
) 10
0 (5
0%)
94 (5
2.8%
) 6
(27.
3%)
84 (4
2%)
81 (4
5%)
3 (1
5%)
Mal
nutri
tion
(%) W
AZ
-2SD
48
(24%
) 45
(24.
3%)
3(20
%)
37 (1
8.5%
) 37
(20.
8)
0 43
(21.
5%)
41(2
2.8%
) 2
(10%
) Pr
olon
ged
illne
ss
118
(59%
) 11
0 (5
9.5%
) 8
(53%
) 11
8 (5
9%)
109
(61.
2%)
9 (4
0.9)
11
7 (5
8.5)
10
5 (5
8.3)
12 (6
0%)
Hig
h pa
rasi
taem
ia
166
(83%
) 15
7 (8
4.9%
) 9
(60%
) 16
3 (8
1.5%
) 14
4 (8
0.9%
) 19
(86.
4%)
160
(80%
) 14
5 (8
0.6%
) 15
(75%
) A
naem
ia p
reva
lenc
e
Mild
ana
emia
(Hb
8 - >
11
g/dL
) 10
1 (5
0.5%
) 10
1 (5
0.5%
) 0
90 (4
5%)
90 (4
5%)
0 97
(48.
5%)
97 4
8.5%
) 0
Mod
erat
e an
aem
ia (5
- <
8g/d
L)
83 (4
1.5%
) 83
(41.
5%)
0 86
(43%
) 86
(43%
) 0
82 (4
1%)
82 (4
1%)
0
Seve
re a
naem
ia (<
5 g
/dL)
1
(0.5
%)
1(0.
5%)
0 2
(1%
) 2
(1%
) 0
1 (%
) 1
(0.5
%)
0 N
o an
aem
ia
15 (7
.5%
) 0
15 (7
.5%
) 22
(11%
) 0
22 (1
1%)
20 (1
0%)
0 20
(10%
)
Dat
a ar
e pr
esen
ted
as m
ean
±SD
, or a
s a p
erce
ntag
e, w
here
app
licab
le
120
Table 2. Mean Hb during follow up
Treatment regime
SP alone SP+AS1 SP +AS3
Hb day 0 No. 200 200 200 Mean ±SD 8.42±1.76 8.39±1.96 8.42±1.84 Hb Day 7 No. 177 186 187 Mean ±SD 8.82±1.62 8.71±1.67 8.46±1.67¶ Hb Day 14 No. 167 188 186 Mean ±SD 9.74±1.61 9.55±1.53 9.58±1.36 Hb Day 21 No. 140 157 175 Mean ±SD 9.98±1.39 9.95±1.35 9.99±1.42 Hb Day 28 No. 100 111 129 Mean ±SD 10.17±1.62 9.88±+1.49 10.19±+1.55 Hb difference (D7-D0) No. 179 186 187 Mean ±SD 0.35±1.44 0.37±1.43 0.02±1.32 ‡† Hb difference (D14-D0) No. 167 188 186 Mean ±SD 1.22±1.48 1.20±1.49 1.13±1.31 Hb difference (D21-D0) No. 140 157 175 Mean ±SD 1.44 ±1.58 1.63±1.56 1.46±1.40 Hb difference (D28-D0) No. 100 111 129 Mean ±SD 1.62 ±1.71 1.62 ±1.76 1.65 ±1.62
¶ The mean Hb in the AS3 group was significantly lower than in the SP alone group (p =0.038) ‡ There was a significant difference in mean Hb change between AS3 and SP alone (p=0.022) † There was a significant difference in mean Hb change between AS3 and AS1 (p=0.016)
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Although there was a rise in the mean haemoglobin over time for all arms, children sustained falls in Hb concentrations, especially on Day 7 (Table 3): 43.3% [81/187] of AS3 treated children had a significant fall in their haemoglobin compared to 32.8% [61/186] in the AS1 (p=0.036) and 34.8% [62/178] in the SP alone group (p=0.097). The mean Hb decrease on Day 7 was –1.17 g/dL (range –4.70 to –0.10) for all the groups combined. The greatest mean decrease occurred in the AS1 arm [–1.18 g/dL (range –4.70, -0.10)], which was significantly higher than the –1.14 g/dL (range –4.20, -0.10) in the AS3 group (p<0.001) or the –1.20 g/g/dL (range –3.60, -0.10) in the SP alone group (p<0.001). The proportion of children with a haemoglobin fall on day 7 ≥ 2.0 g/dL was comparable across treatment groups: 6.4% [12/187], 5.4% [10/186], 7.9% [14/178], in those treated with AS3, AS1 and SP alone, respectively (p=0.628). On Days 14 and 21, the proportions of children with a fall in Hb were similar but on Day 28 the AS3 arm had the smallest proportion of children with a fall on Hb (p=0.054). Three children with Day 0 moderate anaemia developed severe anaemia (Hb <5.0g/dL) but were clinically well and were treated with iron supplements. The lowest Hb (2.7g/dL) occurred on Day 3 in an AS3 treated child who was severely anaemic at enrolment (Hb 3.9g/dL); this child was admitted for a blood transfusion. In a multivariate analysis, the following factors were independently associated with a fall in Hb on Day 7: (i) high parasitaemia (AOR 2.33; 95%CI, 1.33-4.08, p=0.003), (ii) mild anaemia at presentation (AOR 3.65; 95%CI 2.39-5.56, P<0.0001), and (iii) age <24 months (AOR 1.67; 95%CI, 1.03- 2.71, p=0.036). 4.0 DISCUSSION We have found that anaemia in young African children with acute falciparum malaria was a significant health problem in this area of intense malaria transmission that has a high rate of SP and chloroquine resistance. Some 90% of children had mild (48%) or moderate (42%) anaemia. Haematological recovery was achieved by a minority of children (~18%), was independent of the drug regimen used, but was associated with older age, mild anaemia at disease presentation, and achieving parasitological cure. Never the less, the mean increase in Hb was modest, 1.63g/dL. We hypothesised that adding artesunate to SP would improve parasitological cure rates and rates of haematological recovery. Although three days of artesunate produced a higher cure rate than the other two regimens, it was still modest due to the high degree of background SP resistance. This difference was not seen in haematological recovery where all three regimens produced similar proportions of patients with haematological recovery and similar rises in mean Hb.
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Table 3. The risk of haemoglobin falling during follow up in children after treatment for uncomplicated malaria
Treatment regime
SP alone SP+AS1 SP +AS3
Day 7 No. (%) 62 (34.8%) 61 (32.8%) 81 (43.3%) Relative risk (95% CI) 1 0.94 (0.71-1.26) 1.24 (0.96 - 1.61)* Mean fall in Hb ± SD -1.20 ±0.88 -1.18 ±1.10 -1.14 ± 0.89 Day 14 No. (%) 36 (21.6%) 40 (21.3%) 35 (18.8%) Relative risk (95% CI) 1 0.99 (0.66 – 1.47) 0.87 (0.58-1.32) Mean fall in Hb ± SD -0.83± 0.72 -0.93± 0.69 -0.91± 0.64 Day 21 No. (%) 29 (20.7%) 24 (15.3% 26 (14.9%) Relative risk (95% CI) 1 0.74 (0.45 – 1.21) 0.72 (0.44-1.16) Mean fall in Hb ± SD -0.73 ±0.58 -0.84 ±0.59 -0.79± 0.82 Day 28 No. (%) 20 (20%) 23 (20.7%) 15 (11.6%) Relative risk (95% CI) 1 1.04 (0.61 – 1.77) 0.58 (0.31- 1.08) Mean fall in Hb ± SD 0.69 ±1.09 0.83 ±0.83 -1.35 ±1.13
* There was a significant difference in mean Hb drop between AS3 and AS1 (p=0.036) Several factors were associated with anaemia at presentation, notably younger age, a palpable spleen, and being malnourished. Haematological recovery was less likely in younger children, treatment failure, and the presence of moderate anaemia at presentation. These findings are consistent with those of Price et al., (2001) from Thailand, but we did not find a negative relationship between high Day 0 parasitaemia, Day 0 anaemia, and poor haematological recovery. The adverse effect of young age is probably related in part to a lack of malaria acquired immunity, a consequential increased risk of malaria and a reduced ability to clear parasites, poor nutritional status and possible co existing iron deficiency. Acquired immunity requires exposure to several infections and develops over several years (HVIID, 1998). Other studies have found that clearing parasites is a prerequisite to achieving haematological recovery (KEUTER et al., 1992; BLOLAND et al., 1993; VERHOEFF et al., 1997).
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Children in our study gained on average, 1.63g/dL of haemoglobin over 28 days. This Hb gain is appreciably higher compared to the mean rise of 0.5 g/dL from studies of insecticide treated (ITN) bednets in Africa (LENGELER 2004) and the 0.76g/dL achieved in studies of malaria control (a combination of ITNs and chemoprophylaxis) (GEERLIGS et al., 2003; KORENROMP et al., 2004). In comparison to other antimalarial drug efficacy studies the mean increase in Hb in our study was comparable to that of amodiaquine alone and combined with AS3 (ADJUIK et al., 2002), SP alone or in combination with one or three days of artesunate in the Gambia (VON SEIDLEIN et al., 2001), was less than that of SP plus AS3 (2.3 g/dL) or SP plus AS1 (1.9 g/dL) but similar to SP alone in Uganda (PRIOTTO et al., 2003). It was double the mean change obtained with chloroquine alone and combined with three days of artesunate in Burkina Faso (SIRIMA et al., 2003). The mean rise in Hb on day 14 and 28 were higher than those found in Malawi (VERHOEFF et al., 1997), Uganda (TALISUNA et al., 2004), The Gambia (VAN HENSBROEK et al., 1995) but lower than those found Cameroon (BASCO et al., 2002). Although mean Hb values had increased by study end, we observed that a sizeable minority of children had a fall in Hb compared to baseline that was most marked on Day 7 for the AS3 arm. Thereafter, the proportion of such children declined over time for all three arms. The AS3 associated Day 7 decline in Hb did not disadvantage this group for haematological recovery because by Day 28 the proportion of children with Hb recovery was comparable in all three arms, consistent with findings from Thailand (PRICE et al., 2001). The Day 7 decline in Hb we observed ranged from –4.70 to –0.10 g/dL for all three arms and is consistent with mean falls of ≥ -2.0 g/dL for SP and chlorproguanil dapsone on Day 7 (ALLOUCHE et al., 2004). Risk factors identified in the latter study were G6PD deficiency and a higher Day 0 temperature. For anaemic children with acute falciparum malaria, a further fall in haemoglobin may progress to life threatening severe anaemia necessitating blood transfusion. In our study one child was transfused and three others developed severe anaemia. Another finding was the variability in haemoglobin concentrations over time with a minority of children achieving haematological recovery whilst others were either persistently anaemic (72%) or became anaemic after a temporary period of having a normal Hb concentration (10%) or developed a new episode of anaemia following treatment and never recovered from it (23%). Clearly, Hb concentrations fluctuate differently over time in different individuals. Important factors for haematological recovery were a higher baseline Hb concentration, older age, and achieving parasitological cure. The pathophysiological basis of malaria induced anaemia and the dynamic Hb changes post treatment are poorly understood. Several mechanisms play a role, including enhanced clearance of both parasitised and non-parasitised red blood cells by the spleen, intravascular haemolysis, bone marrow suppression by persistent parasitaemia or cytokines, artesunate induced marrow suppression and/or direct haemolysis (GU et al., 1986; CAMACHO et al., 1998; EKVALL et al., 2001; EGAN
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et al., 2002). Chinese and Vietnamese studies have reported the occurrence of transient bone marrow suppression, manifesting as a transient reduction in reticulocyte counts in patients treated with artemisinin derivatives (HIEN and WHITE, 1993; CAO et al., 1997) but detailed data on these adverse events are lacking (PRICE et al., 1999; PRICE et al., 2001). The possible toxic effects of artesunate may outweigh the benefit of pitting, the process whereby young infected red cells are returned intact and without parasites to the circulation after passing through the spleen (CHOTIVANICH et al., 2000). In areas of high malaria transmission, like western Kenya, a high prevalence of asymptomatic parasitaemia with accompanying anaemia is common. The high prevalence of asymptomatic parasitaemia and anaemia in young children calls for a preventive rather than a curative strategy e.g. the use of insecticide-treated bed nets, intermittent preventive treatment (IPT), iron supplementation for infants and young children and deworming. More research is needed to assess the impact of these strategies but they should increase the background level of haemoglobin thus mitigating against the deleterious effects of acute malaria. Our results highlight a major limitation of the current malaria control strategy that is heavily based on case management of acute malaria. Children with high prevalence of malaria-associated anaemia arising probably from chronic asymptomatic parasitaemia may need repeated doses of an effective antimalarial therapy, combined with vector control. Our study and those of other workers have shown that the efficacy of an ACT depends strongly on the efficacy of the partner drug (ADJUIK et al., 2004; OBONYO et al., 2003). In our study, the high prevalence of SP resistance probably compromised the effect of the AS+SP combination in terms of parasitological cure and haematological recovery. We predict that the widespread deployment of a more effective ACT would result in greater parasitological, clinical, and haematological benefits. We did not routinely prescribe haematinics to children in our study and this may raise ethical questions. However, the prevailing recommendations on the routine supplementation of iron and folic acid as part of the package for treating uncomplicated malaria has been challenged by recent studies (VAN HENSBROEK et al., 1995; SAZAWAL et al., 2006). The proportion of paediatric anaemia in the tropics due to iron deficiency is not well known but previous studies with concomitant iron supplementation showed an improvement in Hb concentration compared to no iron in African children (VAN HENSBROEK et al., 1995). Folic acid did not produce enhanced haematological recovery in the same population. Our study had several limitations. We followed children up for 28 days and would have missed to detect further haematological recovery. In Thailand, 42 days was found to be necessary to capture full haematological recovery (PRICE et al., 2001), consistent with the current recommendations for extended follow up beyond 28 days for malaria drug efficacy studies (WHITE 2002; STEPNIEWSKA 2004). We did not sample the Hb on Day 3. Some studies have found Day 3 to be associated with the greatest fall in Hb (ALLOUCHE et al., 2004). We did not examine other predisposing factors to anaemia like intestinal worms, iron deficiency, sickle cell anaemia or G-6-PD deficiency. However, the prevalence of sickle cell trait and G-6-PD deficiency in
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the neighbouring study areas are 26% and 7%, respectively (MOORMAN et al., 2003). Whilst there are no accurate data on the prevalence of intestinal worms in Siaya, high prevalence rates with accompanying iron deficiency anaemia are common in many rural areas of Africa (FLEMING 1982; HERCBERG et al., 1986; HALL et al., 2001). Our study would have benefited from a more comprehensive haematological work-up, including reticulocyte counts, bilirubin levels, iron levels and full blood counts. More research is needed to assess the causes of anaemia in African children, the factors relevant in haematological recovery, and to explore their underlying mechanisms. To our knowledge, this study has provided for the first time insight into the dynamics of anaemia and haematological recovery in relation to artemisinin-based combination therapy for uncomplicated falciparum malaria in African children. Our results indicate that treatment using artesunate plus SP in our setting produced suboptimal cure rates and rates of haematological recovery. Parasitological cure was necessary for haematological recovery. ACKNOWLEDGEMENTS This work was supported by UNICEF/UNDP/World Bank/Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, SWITZERLAND. Sanofi-Synthelabo supplied artesunate tablets free of charge. We acknowledge the comments of Dr Francois Nosten on earlier drafts of this manuscript. We thank the Director, Kenya Medical Research Institute (KEMRI) for permission to publish the results of this study. REFERENCES Abdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M, 1980. The anaemia of P.
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CHAPTER 5
TRANSFUSION DECISIONS
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Chapter 5.1
Blood transfusions for severe malaria-related anaemia in Africa: a
decision analysis
Published as: American Journal of Tropical Medicine and Hygiene 1998, 59: 808-12
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Blood transfusions for severe malaria-related anaemia in Africa: a
decision analysis
Charles O. Obonyo MSc 1, 2, Ewout W.Steyerberg PhD 1, Aggrey J. Oloo MD 2, J. Dik F. Habbema PhD1 Institutional affiliations 1=Center for Clinical Decision Sciences, Dept. of Public Health, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands 2= Centre for Vector Biology and Control Research, Kenya Medical Research Institute, P.O. Box 1578, Kisumu, Kenya Corresponding author: E.W. Steyerberg, PhD, Center for Clinical Decision Sciences, Ee 2091, Dept. of Public Health, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, The NETHERLANDS
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ABSTRACT Severe childhood malarial anaemia is commonly treated using blood transfusion. Although transfusion may decrease short-term mortality, the risk of HIV transmission is considerable in Africa. We constructed a decision tree to weigh the short-term mortality benefit of transfusion against HIV infection risk. Probability estimates were derived from published studies. The base-case was a 2-year-old child with a 13.5 % mortality risk, to be transfused with screened or unscreened blood (1% or 13% HIV contamination risk respectively), with reduction of mortality to 5.5% by transfusion (odds ratio 2.7), and a 2.4 % risk of fatal transfusion complications. A sensitivity analysis was performed to assess the influence of variation in these estimates. If a child developed acquired immunodeficiency syndrome, survival was weighed as one-tenth of normal survival. For the base-case, we found that transfusion with screened blood provided a survival benefit of 5%. In contrast, transfusion with unscreened blood decreased survival by 2%. Patients with a mortality risk <5% derived no benefit from a transfusion with screened blood. Other important factors for the benefit of transfusion were the effectiveness of transfusion in reducing mortality and the risk of blood contamination. A blood transfusion was clearly beneficial if the mortality risk was high and the risk of contamination was low. Our findings can be used as a basis for a clinical transfusion policy that limits transfusions to situations in which they are likely to be beneficial. This will in turn optimize child survival and prevent unnecessary exposure of low risk children to the transfusion risks.
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INTRODUCTION With the risk of transmission of the human immunodeficiency virus (HIV-1), the use of blood transfusion in the management of severe paediatric anaemia has become an important clinical decision problem in Africa (AUBUCHON 1996; GREENBERG et al., 1988). Severe malaria-associated paediatric anaemia increasingly is a major cause of hospital admission and death as the spread of chloroquine-resistant Plasmodium falciparum malaria intensifies across the continent (BLOLAND et al., 1993; CAMPBELL 1991; HEDBERG et al., 1993). Subsequently, the demand for blood transfusions has increased. In some settings, 20-50 % of hospitalized children were transfused (LACKRITZ et al., 1992; DORWARD et al., 1989). The prevalence of HIV infection among blood donors has increased in most developing countries, and at least 10% of all African paediatric AIDS cases may have arisen from contaminated blood transfusions (GREENBERG et al., 1988; LACKRITZ et al., 1993; MHALU and RYDER, 1988; JAGER et al., 1990). Many African countries, particularly where P. falciparum malaria is endemic and HIV/AIDS is a major health issue, cannot maintain an adequate blood supply, and fail to screen all their donated blood (JAGER et al., 1990; GIBBS and CORCORAN, 1994; RYDER, 1992; NTITA et al., 1991). Even screened blood can be infectious, with a risk that depends on the background seroprevalence among the blood donors and on the quality of the screening (GIBBS and CORCORAN, 1994; WARD et al., 1988). The mortality from severe anaemia is known to be higher with more intense P. falciparum transmission patterns and patient characteristics like younger age, lower haemoglobin level and presence of respiratory distress or impaired consciousness (LACKRITZ et al., 1992; MARSH et al., 1995; MOLYNEUX et al., 1989; BREWSTER and GREENWOOD 1993; ZUCKER et al., 1996; COMMEY and DEKYEM, 1995; SNOW et al., 1994; PHILLIPS and PASVOL, 1992). A survival benefit of transfusion was found in an observational study in western Kenya (LACKRITZ et al., 1992), but the effectiveness of transfusions has unfortunately not been studied in randomized controlled trials. In this study, we examine when administration of a blood transfusion is beneficial, using decision analysis as a framework for synthesis of the available evidence (WEINSTEIN and FINEBERG, 1980). We weigh the risks of mortality with severe anaemia against complications and HIV risks associated with receiving a blood transfusion. This understanding will enable clinicians to perform informed risk-benefit evaluations prior to making any transfusion decisions. METHODS Model structure and assumptions A decision analysis model was constructed for the problem of whether or not to transfuse a severely anaemic child aged under 5 years with an acute P. falciparum
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malaria infection. Severe malarial anaemia was defined as Hb below 5 g/dl and any level of peripheral malaria parasitaemia. We structured the problem similar to a previously published decision tree (HEYMANN and BREWER, 1993)(Figure 1). Depending on the clinical presentation, the attending physician in consultation with the accompanying guardian decides on the need for a transfusion. When the strategy “Do not transfuse” is chosen, the patient may die from the pathological processes associated with anaemia and /or malaria or survive the acute phase of the disease. For transfusion, a blood unit is selected or a donor sought. In the short-term, the recipients may die from anaemia, malaria or non-HIV transfusion complications. The selected blood unit may be HIV contaminated. Even if screened, this status cannot usually be known with certainty, specifically due to laboratory error, limits in test sensitivity or window period (time between infection and detection of antibodies to HIV) (WARD et al., 1988). Surviving patients may acquire HIV infection and develop AIDS Treatment outcomes considered in this analysis were survival, death, or survival with AIDS In structuring this problem, we made a number of assumptions. We assumed that the decision to transfuse means immediate transfusion. In practice, the decision may take the form of either an immediate transfusion or one after a period of patient observation during which the patient’s state is monitored for deterioration. Second, the effectiveness of a transfusion is assumed to be equal for patients risking death from anaemia and patients risking death from malaria (particularly cerebral malaria). This may be reasonable since most of the risk factors overlap (e.g., impaired consciousness and respiratory distress) (MARSH et al., 1995). Third, we assumed that the patients had no HIV infection before treatment. Finally, we assumed that an effective antimalarial drug (e.g., quinine) had already been administered. Model quantification Probabilities of the occurrence of the different events in the decision analysis were based on published studies as identified with a MEDLINE search. Plausible ranges were defined for the probabilities, based on 95 % confidence intervals (CIs) or ranges found in the literature. To determine when the benefits of transfusion outweighed the risks, we assumed that short-term mortality was the worst outcome (valued as 0), and survival without AIDS the best (valued as 1). Young children may develop AIDS within 2 years and 50% may have died 5 years later (LEPAGE and HITIMANA, 1991). We therefore estimated that children with HIV and seroconversion to AIDS may have a life-expectancy of around a tenth the normal life-expectancy among African children (LEPAGE and HITIMANA, 1991). The outcome ‘AIDS’ was valued as 0.1, with a plausible range from 0, when AIDS is considered as bad as short-term mortality, to 0.2, when AIDS is regarded as equivalent to a fifth of normal survival. A sensitivity analysis was performed to gain insight in the effects of variation in the estimates on
137
the difference between survival with or without transfusion. Calculations were performed with the DATA 3.0 (TreeAge Software, Inc., Williamstown, MA) computer package. RESULTS A base-case patient was defined as a two-year-old boy with a haemoglobin level < 5 g/dL and an acute P. falciparum malaria infection. The probabilities that were used as estimates for this base-case patient are shown in the decision tree (Figure 1). Risk of in-hospital mortality with severe malarial anaemia We identified eight prospective hospital-based studies conducted in African settings that had reported mortality rates associated with severe malarial anaemia between 1990 and 1997 (SLUTSKER et al., 1994; LACKRITZ et al., 1992; MARSH et al., 1995; BREWSTER and GREENWOOD 1993; ZUCKER et al., 1996; CRAIGHEAD and KNOWLES 1993; HOLZER et al., 1993; NEWTON et al., 1997) (Table 1). The average risk of mortality was 12%, but the heterogeneity was significant (P<0.001, by chi-square test). When the studies were classified according to the local malaria transmission level, we observed that children residing in high transmission regions experienced the highest mortality rates (139 [17.2%] of 810 died), followed by moderate and low transmission areas (158 [13.5%] of 1,170 died and 130 [8.1%] of 1,602 died, respectively). This distinction according to transmission pattern explained a large proportion of the heterogeneity between the studies.
However, differences between studies from low and moderate transmission areas were still statistically significant (P<0.05, by chi-square tests). Furthermore, the case-mix in these studies included both children who received transfusions and others who did not. The actual mortality risk may thus be higher for those who were not transfused. In any specific malaria endemic region, individual risks of mortality may vary considerably depending on the clinical presentation of the patient. For instance, hospitalized children on the Kenyan coast, who had severe anaemia with respiratory distress, impaired consciousness or both experienced 16%, 8%, and 36% mortality rates respectively (MARSH et al., 1995). The mortality rate used for the decision model was 13.5 % for the base-case (intermediate transmission region), with a range from 3 to 30%.
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138
139
Table 1. Severe malarial anaemia mortality studies in Africa, 1990-1997
First author, year N Deaths (%) Transmission pattern
Lackritz, 1992 684 125 18.3 High Brewster, 1993 1,050 101 9.6 Low Craighead, 1993 155 15 9.7 Moderate Holzer, 1993 105 3 2.9 Moderate Slutsker, 1994 910 140 15.3 Moderate Marsh, 1995 506 25 4.9 Low Zucker, 1996 126 14 11.1 High Newton, 1997 46 4 8.7 Low Total 3,582 427 11.9 Transfusion benefits and risks The beneficial effect of a transfusion on in-hospital mortality was derived from a study in western Kenya. The observed odds ratio for in-hospital mortality, hereafter referred to as transfusion effectiveness, was 2.7 (95 % CI. 1.9 - 3.7) (LACKRITZ et al., 1992). This means that the mortality odds with transfusion were 2.7 times lower than the mortality odds without a transfusion. When the transfused blood is unscreened, the probability that it is HIV contaminated depends on the seroprevalence levels among the donor population. The probability that a screened unit of blood is HIV contaminated has been estimated at between 0.5 and 1% in Cote d’Ivoire, where HIV prevalence among blood donors was 11% (SARAVIT et al., 1992). These risks were 2.1% for screened blood (Lackritz EM and others, unpublished data) and 13.4% for HIV prevalence (LACKRITZ et al., 1993) in western Kenya. The plausible range for the probability of receiving HIV contaminated blood was set as 0.5 to 20%. For an unscreened unit, a 13.4% contamination risk was used in the base-case analysis. The probability that seroconversion occurs after receipt of HIV contaminated blood has been found to be 90% in the USA (DONEGAN et al., 1990), and 96% in Zaire (COLEBUNDERS et al., 1991). The probability of developing AIDS after seroconversion is around 80% (HEYMANN and BREWER, 1992). A 2.4% incidence of fatal acute transfusion complications was observed among transfused children in Kinshasa, Zaire (JAGER et al., 1990). Table 2 summarizes the estimates and plausible ranges used in the decision analysis. Transfusion decisions When we evaluated the decision tree for the base-case patient, transfusion with screened blood led to a 7.7% risk of in-hospital mortality and 0.7 % risk of acquiring AIDS, compared to 13.5% mortality without transfusion.
140
Table 2. Probability estimates and plausible ranges used in the decision analysis * HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome; † Values used in calculations for the base-case; ‡ 95% confidence intervals. Variable Baseline
estimate† Plausible range (%)
References
Mortality from untreated anaemia (moderate transmission level)
13.5%
3-30
See Table 1
Transfusion effectiveness (odds ratio) 2.7 1.9 – 3.7‡ 7 HIV contamination risk Screened blood
1.0%
0.5 - 20
9, 29
Unscreened blood 13.4% Probability of HIV seroconversion 90% 90-96 30,31 Probability of AIDS development 80% 78 – 95 32 Acute fatal complications risk 2.4% 1 - 4‡ 11
The survival benefit hence was 5.2%. If the blood was not screened, we expected an 8.9% risk of acquiring AIDS, and the survival with transfusion was lower than without (84.3% vs. 86.5%). We further varied each estimate over its plausible range. Three factors strongly influenced the benefit of transfusion: the blood contamination risk, the baseline mortality risk, and the transfusion effectiveness. For the base-case, transfusion was the optimal decision provided that either the blood contamination risk was <10%, the transfusion-reduced mortality had an odds ratio >1.3, or the baseline risk of mortality was >5%. A minimal influence on the transfusion decision was noted for the valuation of AIDS, or the risks of fatal complications, seroconversion to HIV infection, or development of AIDS; for these estimates, variation over the plausible ranges exerted a maximal survival difference of 1%. We examined eight possible scenarios based on all combinations of low and high values of the three most important factors. Table 3 shows that a transfusion is clearly beneficial if the baseline mortality risk is high and the blood contamination risks are low. A net benefit is also expected if all three factors are on their high values (scenario 4). In the other scenarios, transfusion leads to a lower survival. For instance, transfusion is not indicated for a severely anaemic child with a low risk of mortality, especially if only unscreened blood is available.
141
Table 3. Eight possible scenarios based on combinations of low (L) and high (H) plausible values for the HIV contamination risk in transfused blood, the anaemia mortality risk, and the transfusion effectiveness
Scenarios
1 2 3 4 5 6 7 8 HIV contamination L: 0.5%; H: 20%
H H H H L L L L
Anaemia mortality risk L: 3%; H: 30%
L L H H L L H H
Transfusion effectiveness L: OR=1.9; H: OR=3.7
L H L H L H L H
Survival differences (%) † (transfusion-no transfusion)
-13.4 -12.8 -0.7 +6.1 -1.3 -0.5 +9.4 +17.2
* HIV=human immunodeficiency virus; OR=odds ratio. † Positive values indicate that transfusion is the preferred strategy.
Finally, we varied the risks of blood contamination, the baseline mortality risk and the transfusion effectiveness in a three-way sensitivity analysis (Figure 2). The graph shows that for three levels of transfusion effectiveness, blood transfusion leads to a larger benefit in survival if the mortality risk is higher and the contamination risk lower. Also, at a constant blood contamination risk, the threshold (mortality risk) above which one would transfuse decreases with increasing transfusion effectiveness. Overall, we note that transfusion does not carry a survival benefit when HIV contamination risk is high. DISCUSSION In this analysis we examined when it is beneficial to administer a blood transfusion to African children with severe malarial anaemia. Three factors were found to have a major impact on this decision: the risk of mortality without a transfusion, HIV contamination risk of the blood products and the effectiveness of a transfusion in reducing mortality. We estimated the average risk of mortality with severe malarial anaemia to be about 12 %, but this figure varied considerably across reported studies. The heterogeneity between studies was partly explained by differences in the intensity of malaria transmission patterns (SNOW et al., 1994; GREENWOOD et al., 1991). Furthermore, the mortality risk may vary depending on several clinical characteristics, such as respiratory distress, impaired consciousness, age, Hb level, parasite density and co-morbidity (LACKRITZ et al., 1992; MARSH et al., 1995; MOLYNEUX et al.,
142
1989; BREWSTER and GREENWOOD 1993; ZUCKER et al., 1996; COMMEY and DEKYEM, 1995; SNOW et al., 1994; PHILLIPS and PASVOL, 1992). Although case management of severe malarial anaemia often includes the use of blood transfusion, this analysis reveals that the typical anaemic patient may expect to derive only a modest improvement in survival when transfused using screened blood. The short-term benefit depends on the baseline mortality risk and transfusion effectiveness. Transfusion was not beneficial when the patient’s risk of mortality without a transfusion was <5%. Because most deaths among severely anaemic children tend to occur within 12 hours of admission, it is important to identify those patients at high risk timely to allow for early intervention. When transfusion is delayed, the child already survived the immediate period and the remaining mortality risk will be lower. The effectiveness of blood transfusion has been found to be higher with a higher patient-specific mortality risk and an early administration of the transfusion (LACKRITZ et al., 1992). Decision making shortly after admission of the patient is hence required. This may best be achieved with the availability of a blood bank with screened blood. In clinical practice, the estimate of a reduction of the mortality with an odds ratio of 2.7 may be a starting point, while the impact of other assumptions of effectiveness can be explored with Figure 2. Randomized clinical trials are desired to provide further evidence on the benefits and risks of transfusion. Such studies might be considered for children with a moderate mortality risk, e.g. around 5 to 10%, since the benefit of a transfusion is unclear for these children. The definition of this risk group may however be difficult, and the conclusions might have limited generalizability. As expected, the likelihood of blood contamination with the HIV-1 virus had a crucial influence on the benefit of a transfusion. African children less than five years of age with acute malarial anaemia or sickle cell anaemia are the most frequent recipients of blood transfusion. For instance, at one hospital in western Kenya, children received 67% of all the administered transfusions (LACKRITZ et al., 1992). With the increasing prevalence of paediatric malaria-associated anaemia, blood screening therefore is a priority child survival issue (FOSTER and BUVE 1995). Most African countries have a policy of pre-transfusional blood screening, which may however be difficult to achieve in practice due to logistic and technical limitations. It has been observed that HIV contamination may be up to five times higher among units donated for replacement or by family members compared to banked blood from volunteer donors. Moreover, only banked blood will be available early during hospitalization, when transfusion may be most effective to increase survival (LACKRITZ et al., 1992; LACKRITZ et al., 1993). Because of the rising HIV prevalence among blood donors in most African settings, safe blood has become a scarce and costly resource. It was estimated to cost $14 to remove one HIV contaminated unit by blood screening in Kenya (Lackritz EM and others, unpublished data).
1015202530 Blood contamination (%)
Tra
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ates
of t
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enes
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rans
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on (m
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s [O
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=1.
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.7, a
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ighe
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an w
ithou
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.
144
Our analysis shows that using screened blood implies a substantial benefit compared to using unscreened blood (survival +5% versus -2%). Therefore, it may be expected that the cost-effectiveness of blood screening is favourable in the context of transfusion of severe malaria-related anaemia in African children. Our analysis indicates that unscreened blood should only be given in life-saving situations. This finding supports current transfusion policies that generally discourage the use of unscreened blood. We recommend continued intensification of efforts to ensure a safe blood supply by screening and recruitment of low-risk donors. Although this analysis was undertaken on a number of assumptions, it has enabled us to study important considerations relating to when a transfusion may be beneficial. The methodology that we adopted can be used to study other transfusion-transmissible infections, like hepatitis B and C. The results shown in Figure 2 may be applicable in all settings where malarial anaemia and transfusion-transmitted HIV-1 are important health problems. We note, however, that the specific probability estimates used in our analysis mainly originate from anglophone Africa, which may not be representative for all of Africa. Furthermore, this analysis did not consider the many non-clinical factors that trigger and influence the clinical decision to order transfusions. These may include the health-care provider’s perception and tolerance of risk, peer-pressure, and the availability of blood (BROWN et al., 1992; SCHATZ-SALEM et al., 1990). In conclusion, our study has provided a quantitative insight in the relevant considerations for making transfusion decisions in African children with severe malaria-related anaemia. This insight may support the development of clinical transfusion policies at a local level such that transfusions be limited to situations where they are likely to be beneficial. ACKNOWLEDGEMENT This research has been carried out as part of the MSc programme in Clinical Epidemiology of the NIHES, Erasmus University, Rotterdam, The Netherlands. We wish to acknowledge the contributions made by Frithjofna Abbink, Carina van Vliet, and Kitty van der Ploeg to this study. We appreciate comments by Dr Maribel Salas on earlier drafts. REFERENCES AuBuchon JP, 1996. The role of decision analysis in transfusion medicine. Vox Sang
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IS INTERMITTENT PREVENTIVE THERAPY IN
THE POST DISCHARGE PERIOD THE KEY TO
IMPROVING OUTCOME OF SEVERE
MALARIAL ANAEMIA IN AFRICAN
CHILDREN?
CHAPTER 6
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Severe malarial anaemia as a public health problem Malaria-associated anaemia is a major public health problem especially among children in malaria endemic areas of sub-Saharan Africa. In settings where malaria transmission is intense, severe malarial anaemia (haemoglobin level < 5.0g/dL and a positive blood smear for malaria parasites) is the major presentation of severe Plasmodium falciparum malaria, especially in very young children below 3 years of age (LACKRITZ et al., 1992; MARSH et al., 1995; GREENWOOD 1997). In these settings, severe malarial anaemia (SMA) is the leading cause of hospital admission and contributes substantially to paediatric mortality. Malaria-related anaemia affects an estimated 1.5 to 6 million African children, causing a case fatality rate of 15%, which translates to approximately 1 million deaths due to SMA in African children aged < 5 years annually (MURPHY and BREMAN, 2001). The contribution of severe anaemia to malaria-attributed mortality in children below five years of age is between 17 and 54% (SLUTSKER et al., 1994; MARSH et al., 1995; BIEMBA et al., 2000). Severe malarial anaemia and post-discharge mortality Majority of children with asymptomatic SMA are at low risk of mortality. The risk of mortality in SMA increases with presence of respiratory distress and /or impaired consciousness (LACKRITZ et al., 1992; MARSH et al., 1995; BOJANG et al., 1997a; ENGLISH et al., 2002). The average in-hospital mortality rate from SMA is 12%, but varies with intensity of malaria transmission (OBONYO et al., 1998). In western Kenya, an area of high malaria transmission in-hospital mortality in children with SMA is approximately 18%, which is similar to that reported in other areas with intense malaria transmission (LACKRITZ et al., 1992; BRABIN et al., 2001). The survival of severely anaemic children with respiratory distress can be improved by blood transfusion and for this category of children, transfusion decisions need to be optimized and resources mobilized to make safe blood available (LACKRITZ et al., 1992; LACKRITZ et al., 1997; OBONYO et al., 1998; ENGLISH et al., 2002). Follow-up studies show that children who complete the routine in-hospital treatment for severe anaemia (blood transfusion and antimalarials) have unacceptably high rates of rebound severe anaemia and post-discharge mortality, despite the initial significant clinical improvement during the in-hospital period (ZUCKER et al., 1996; LACKRITZ et al., 1997; SNOW et al., 2000). Children who survive an episode of severe anaemia represent a selected group at very high risk of rebound severe anaemia due to a combination of factors that may include parasite (e.g. virulence, drug resistance), host (age, immunity, genetic profile), environmental (e.g. transmission intensity) and socio-behavioral (e.g. access to treatment) factors affecting exposure to subsequent malaria infection. Only a few studies have reported on the mortality experiences of severely anaemic children who do not receive a transfusion. In Kenya, regardless of whether children received a transfusion or not, mortality rates for severely anaemic children, were high within 8 weeks post-discharge (LACKRITZ et al., 1997). The post discharge case fatality rate in children with severe anaemia was 16% within 8 weeks of hospitalisation and highest among children who received IV quinine followed by chloroquine (25%) compared with 10% among those who received more effective antimalarial combinations (7 days of quinine, or IV quinine
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plus oral SP or cotrimoxazole). However, partially effective antimalarial treatment (chloroquine) and persistent parasitaemia on discharge were strong predictors of subsequent out-of-hospital mortality (ZUCKER et al., 1996; LACKRITZ et al., 1997). Because most deaths occurred at home the cause of death could not be ascertained. Causes of post-discharge severe anaemia and mortality The prevalence of malaria-associated anaemia and mortality in African children is increasing, partly attributable to the increase in antimalarial drug resistance (HEDBERG et al., 1993; SLUTSKER et al., 1994; TRAPE et al., 1998; BJORKMAN 2002). It is likely that in the children with severe malarial anaemia, the initial rise in haemoglobin, resulting from blood transfusions and (partially) effective in-hospital antimalarial treatment, is negated by subsequent episodes of new or recrudescent malaria infections during the post-discharge period. It is known from studies in Thailand that full hematological recovery of a single episode of acute uncomplicated falciparum malaria that is diagnosed and treated effectively takes at least 42 days in patients that are radically cured (PRICE et al., 2001). This slow recovery in successfully treated patients may result from dyserythropoiesis and continued destruction of unparasitized erythrocytes after clearance of parasitaemia (LOOARESUWAN et al., 1987). Patients whose infections recrudesce take significantly longer to return to a normal hemoglobin level and by day 42 and are nearly 3 times more likely to be anaemic than successfully treated patients (PRICE et al., 2001; BLOLAND et al., 1993). Thus, both inadequate initial antimalarial treatment in-hospital resulting in persistence of parasitaemia and slow hematological recovery, as well as subsequent new infections resulting in additional haematological insult in partially recovered children are likely to contribute to post-discharge anaemia. The relative contribution of each needs to be determined but is likely to vary with the level of drug resistance and environmental (e.g. transmission season) and behavioural factors determining the risk of new infections during the recovery period. Survivors of a severe anaemia episode, are a high-risk group who may benefit significantly from interventions that prevent the development of subsequent malaria after discharge and result in sustained haematological improvements. Effective antimalarial therapy and haematological recovery Currently, the standard treatment for severe malarial anaemia in Kenya includes blood transfusion and parenteral quinine followed by oral quinine as soon as the child is able to take oral medication. After discharge, the remainder of the 7 day quinine course is typically completed at home. This often results in low compliance and low effectiveness because of unpleasant side effects of quinine and the complex 3 times daily oral dosing regimen. In many settings supplementary treatment with a single dose of oral sulfadoxine-pyrimethamine (SP) is therefore preferred over oral quinine. However, resistance to SP is rapidly intensifying and failure rates to SP monotherapy are now 65% by day 28 in many parts of Kenya (OBONYO et al., 2003). In addition, the efficacy of IV quinine followed by oral SP is not satisfactory: 20% of children treated with SP after 1 to 5 doses of IV Quinine failed therapy within 21 days of starting treatment in western Kenya (OGUTU et al., 2005). Artemisinin-based combination therapy (ACT) offers great promise in the treatment of malaria: ACT is likely to improve treatment efficacy, reduce gametocyte carriage rates, and may delay
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the development of resistance. ACT is better tolerated and may be more practical to give than quinine and hence, may maximise the potential to obtain radical cure and enhance haematological recovery. Effective therapy is also likely to improve survival (ZUCKER et al., 2003). Chemoprophylaxis or intermittent preventive treatment Targetted chemoprophylaxis prevents malaria morbidity but is no longer advocated in endemic areas due to the fear of accelerating the development of drug resistance and enhancing the loss of acquired immunity to malaria (GREENWOOD 1991; WHO 1993), leading to an increased risk of (rebound) malaria attacks after the intervention ceases (GREENWOOD et al., 1995; MENENDEZ et al., 1997). By contrast, two recent reviews of the available evidence conclude that malaria chemoprophylaxis may actually improve the mean haemoglobin, reduce the incidence of severe anaemia and does not produce any sustained impairment on the immunity (GEERLINGS et al., 2003; MEREMIKWU et al., 2005). Alternatively, intermittent preventive treatment (IPT) has been suggested for the prevention of malaria and malaria-associated severe anaemia in young children. Different from chemoprophylaxis, in IPT, a full curative dose of an effective antimalarial drug (preferably, one with a long half life) is administered at predefined intervals, regardless of the presence of parasites. This is likely to clear the parasites and induce prolonged periods of aparasitemia, protecting the child against new malarial infections (BRADLEY-MOORE et al., 1985; BJORKMAN et al., 1986; SHULMAN et al., 1999). In Tanzanian infants, IPT with SP or amodiaquine halved the incidence of moderate and severe anaemia in areas with intense malaria transmission (SCHELLENBERG et al., 2001; MASSAGA et al., 2003). However, the role of IPT in the initial treatment of severe anaemia and the subsequent prevention of repeat episodes in young children in malaria endemic areas remains to be established. Intermittent preventive treatment in the post-discharge period (IPTpd) Children who have experienced an episode of severe anaemia may be at special risk for another episode of anaemia if they are infected for a second time before their haemoglobin level has returned to normal (LACKRITZ et al., 1992; BOJANG et al., 1997b). We propose that ACT given as IPT in the post-discharge period (IPTpd) may reduce the risk of rebound severe anaemia and possibly mortality in children hospitalized with severe anaemia. Before widespread implementation of this proposed intervention, there is an urgent need to evaluate it in a randomised trial. Because there is currently no evidence to support the conduct of a trial designed to evaluate the effect of IPTpd on mortality, such a study should be performed in 2 phases. The first phase would provide the evidence for the efficacy of IPTpd on haematological recovery, while a subsequent trial should be large, and possibly multicentre, to document mortality benefits. The primary end-point will be mean haemoglobin measured at 3 months after discharge. Secondary endpoints could include the incidence of all sick child visits with clinical malaria, severe anaemia and all cause mortality.
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Future research If shown to work, the application of ACT as IPT in the post discharge (IPTpd) management of severe malarial anaemia is an innovative and potentially cost effective approach that may improve survival and reduce the risk of malaria-related morbidity in the post-discharge period. The intervention will provide a window period in which the bone marrow can recover and haemoglobin levels can increase to levels in the non-anaemic range. Consequently, the risk of subsequent haematological insults from malaria leading to severe anaemia could be reduced significantly. The choice of antimalarial drug for IPT will be crucial. The success of IPT will be improved by introduction of directly-observed treatment (DOT). Despite the great promise of IPTpd, prediction models already advice proceeding with caution as IPT may enhance the spread of drug-resistant malaria parasites in areas of intense transmission (O’MEARA et al., 2006). It will be important to establish surveillance systems for monitoring drug use patterns and the development of drug resistance. Studies of molecular markers of drug resistance will be useful for sounding early warning, when resistant strains emerge. The likelihood of a reduction in acquired immunity to malaria due to IPT will need to be evaluated. Implementation research studies will be required to determine the best delivery mechanisms by which IPT can be made available. Any attempts at malaria control that do not include the reduction of human-vector contact is bound to fail. Implementation of IPTpd should will therefore benefit from integration with vector control interventions. In conclusion, given the high prevalence of malarial anaemia in African children and the burden that this places on the healthcare system, we have argued that intermittent preventive therapy in the post-discharge period (IPTpd) using effective antimalarial drugs may go a long way in reducing the incidence of rebound anaemia, improving haematological recovery and possibly, the risk of death. REFERENCES Biemba G, Dolmans D, Thuma PE, Weiss G, Gordeuk VR, 2000. Severe anaemia in
Zambian children with Plasmodium falciparum malaria. Tropical Medicine and International Health 5, 9-16.
Bjorkman A, Brohult J, Pehrson PO, Willcox M, Rombo L, Hedman P, et al., 1986. Monthly antimalarial chemotherapy to children in a holoendemic area of Liberia. Annals of Tropical Medicine and Parasitology 80, 155-167
Bjorkman, A., 2002. Malaria associated anaemia, drug resistance and antimalarial combination therapy. International Journal of Parasitology 32, 1637-43
Bloland PB, Lackritz EM, Kazembe PN, Were JB, Steketee 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.
Bojang, K.A., van Hensbroek, M.B., Palmer, A, Banya, W.A., Jaffar, S., Greenwood, B.M., 1997a. Predictors of mortality in Gambian children with severe malaria anaemia. Annals of Tropical Paediatrics 17, 355-59.
Bojang KA, Palmer A, Boele van Hensbroek M, Banya WAS, Greenwood BM, 1997b. Management of severe malarial anaemia in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 91, 557-61
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Brabin BJ, Premji Z, Verhoeff F, 2001. An analysis of anaemia and child mortality. Journal of Nutrition 131, 636S-648S
Bradley-Moore AM, Greenwood BM, Bradley AK, Akintunde A, Attai ED, Fleming AF, et al., 1985. Malaria chemoprophylaxis with chloroquine in young Nigerian children. IV. Its effect on haematologic measurements. Annals of Tropical Medicine and Parasitology 79, 585-95
English M, Ahmed M, Ngando C, Berkley J, Ross, 2002. Blood transfusion for severe anaemia in children in a Kenyan hospital. Lancet 359, 494-5
Geerligs PD, Brabin BJ, Eggelte TA, 2003. Analysis of the effects of malaria chemoprophylaxis in children on haematological responses, morbidity and mortality. Bulletin of the World Health Organization 81, 205-16.
Greenwood BM, 1991. Malaria chemoprophylaxis in endemic regions. Target GAT, ed. Malaria: Waiting for the vaccine. Chicester: John Wiley and sons, 83-104.
Greenwood BM, David PH, Otoo-Forbes LN, Allen S, Alonso PL, Armstrong-Schellenberg JR, et al., 1995. Mortality and morbidity from malaria after stopping malaria chemoprophylaxis. Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 629-33
Greenwood, B.M., 1997. The epidemiology of malaria. Annals of Tropical Medicine and Parasitology 91, 763-9
Hedberg K, Shaffer N, Davachi F, Hightower A, Lyamba B, Paluku KM, et al., 1993. Plasmodium falciparum-associated anaemia in children at a large urban hospital in Zaire. American Journal of Tropical Medicine and Hygiene 48, 365-371
Lackritz EM, Campbell CC, Ruebush TK, Hightower AW, Wakube W, Steketee RW, Were JB, 1992. Effect of blood transfusion on survival among children in a Kenyan hospital. Lancet 340: 524-8.
Lackritz EM, Hightower AW, Zucker JR, Ruebush TK, Onudi CO, Steketee RW, et al., 1997. Longitudinal evaluation of severely anaemic children in Kenya: the effect of transfusion on mortality and hematologic recovery. AIDS 11, 1487-94.
Looareesuwan S, Merry AH, Phillips RE, Pleehachinda R, Wattanagoon Y, Ho M, et al., 1987. Reduced erythrocyte survival following clearance of malarial parasitaemia in Thai patients. British Journal of Haematology 67, 473-8.
Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, et al., 1995. Indicators of life-threatening malaria in African children. New England Journal of Medicine 332, 1399-404.
Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, et al., 2003. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet 361, 1853-60.
Menendez C, Kahigwa E, Hirt R, Vounatsou P, Aponte JJ, Font F, et al.,1997. Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet 350, 844-50
Meremikwu MM, Omari AAA, Garner P, 2005. Chemoprophylaxis and intermittent treatment for preventing malaria in children. The Cochrane Database of Systematic Reviews 2005, Issue 4, CD003756.DOI: 10.1002/14651858.CD003756.pub2.
Murphy, S.C. and Breman, J.G., 2001. Gaps in the African childhood malaria burden adding neurological sequelae, anaemia, respiratory distress, hypoglycaemia, and
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complications of pregnancy. American Journal of Tropical Medicine and Hygiene 64 (Suppl 1), 57-67
Obonyo CO, Steyerberg EW, Oloo AJ, Habbema JDF, 1998. Blood transfusions for severe malaria-related anaemia in Africa: a decision analysis American Journal of Tropical Medicine and Hygiene 59, 808-812
Obonyo CO, Ochieng F, Taylor WRJ, Ocholla SA, Mugitu K, Olliaro P, et al., 2003. Artesunate plus Sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomised, double-blind, placebo-controlled trial. Transactions of the Royal Society of Tropical Medicine and Hygiene 97, 585-91
Ogutu BR, Nzila AM, Ochong E, Mithwani S, Wamola B, Olola CH, et al., 2005. The role of sequential administration of sulphadoxine-pyrimethamine following quinine in the treatment of severe falciparum malaria in children. Tropical Medicine and International Health 10, 484-8.
O'Meara WP, Smith DL, McKenzie FE, 2006. Potential impact of intermittent preventive treatment (IPT) on spread of drug-resistant malaria. PLos Med 3, e141
Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, et al., 2001. Factors contributing to anaemia after uncomplicated falciparum malaria. American Journal of Tropical Medicine and Hygiene 65, 614-22.
Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, Mshinda H, Alonso P, 2001. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet 357: 1471-7.
Shulman CE, Dorman EK, Cutts F, Kawuondo K, Bulmer JN, Peshu N, Marsh K, 1999. Intermittent sulfadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomized placebo-controlled trial. Lancet 353, 622-36
Slutsker L, Taylor TE, Wirima JJ, Stekettee RW, 1994. In-hospital morbidity and mortality due to malaria-associated severe anaemia in two areas of Malawi with different patterns of malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 88: 548-51
Snow RW, Howard SC, Mung’ala-Odera V et al., 2000 Paediatric survival and re-admission risks following hospitalization on the Kenyan Coast. Tropical Medicine and International Health 5:377-383.
Trape JF, Pison G, Preziosi MP, Enel C, Desgrees du Lou A, Delaunay V, et al., 1998. Impact of chloroquine resistance on malaria mortality. C. R. Acad. Sci. III 321, 689-97
World Health Organization, 1993. Implementation of the global malaria control strategy: report of a WHO study group on the implementation of the global plan of action for malaria control 1993-2000. Technical Report Series No. 839. Geneva: World Health Organization.
Zucker JR, Lackritz EM, Ruebush TK, Hightower AW, Adungosi JE, Were JB, et al., 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.
Zucker JR, Ruebush TK, Obonyo C, Otieno J, Campbell CC, 2003. Mortality consequences of continued chloroquine use: experience in Siaya. American Journal of Tropical Medicine and Hygiene 68, 386-90
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CHAPTER 7
SUMMARY
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Anaemia is an inevitable consequence of Plasmodium falciparum malaria infection, especially in areas of high malaria transmission. In these settings, the group at high-risk for malaria-associated anaemia are infants and young children. Since the emergence of drug-resistant parasite strains, the frequency of occurrence of anaemia is rising. Simultaneously, the treatment of uncomplicated falciparum malaria is posing a formidable challenge, because malaria control programs have to move onto combination therapy, which is inevitably expensive. The purpose of treating a case of uncomplicated malaria is to cure the infection, prevent progression to complications, severity and death. Severe anaemia is a major complication of malaria in areas of intense perennial transmission, especially, among young children. Treatment decisions for severe anaemia have to be made carefully, because the common intervention, blood transfusion, has become a major risk factor for HIV transmission. This thesis describes how we identified the problem of malaria-associated anaemia in young Kenyan children and the steps we followed in finding possible solutions to this problem. In chapter 1 we introduce the problem of malaria-associated anaemia and the relationship with antimalarial drug resistance. In that chapter we also outline the major aims of the studies described in this thesis. In chapter 2, we presented two studies that show the prevalence and burden of malarial anaemia in Kenyan children. In chapter 2.1, data from 3586 children who participated in the screening phase of a randomized trial were used. We found that 80% of these children had anaemia (Hb<11.0g/dL) and 3% had severe anaemia. Risk factors for presenting to hospital with anaemia were malaria parasitaemia, young age, splenomegaly, malnutrition, previous ineffective therapy and lack of bednet use. Young children below 3 years of age were identified as the high-risk population: prevalence of anaemia was 83%, Hb < 8.0 g/dL was 34% and 4% were severely anaemic (Hb<5.0g/dL). Malaria parasitaemia was strongly associated with Hb < 8.0 g/dL. This initial study characterized the problem of anaemia and identified young children<3 years of age as the population at the highest risk for severe anaemia and malaria-associated anaemia. In chapter 2.2, we aimed to determine the burden of severe malarial anaemia on paediatric admissions and mortality. Using data from a retrospective record review, we found that severe malarial anaemia was a major cause of admission and in-hospital mortality in children below 3 years of age. In this hospital, 90% of all admissions had Hb < 11g/dL, 20% were severely anaemic and 20% of all admissions were transfused. Additionally, 12% of severely anaemic children died and 52% of the malaria-related mortality was due to severe anaemia. This audit highlights the magnitude of burden that severe malarial anaemia poses on the paediatric healthcare system in this area of intense malaria transmission and identifies children < 3 years as the target group for any interventions aimed at reducing the burden of malarial anaemia. These initial studies identified that malaria, a treatable and preventable infection, was an important risk factor for severe paediatric anaemia. We therefore set out to evaluate the efficacy of current antimalarial therapy and to identify alternative treatment options.
Chapter 3 describes 2 studies evaluating the role of artemisinin-based combination therapy in the treatment of uncomplicated falciparum malaria in African children. In chapter 3.1, we used the methods of meta-analysis to identify possible antimalarial
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drug treatment options. Due to the problem of antimalarial drug resistance, combination therapy is widely advocated for treatment of uncomplicated falciparum malaria. In these decisions, cost and availability are major issues. We therefore compared the efficacy of one non-artemisinin-based combination (amodiaquine plus sulfadoxine-pyrimethamine [SP]) with 3 sets of artemisinin-based combinations (ACT) using data from 4472 African children with uncomplicated malaria. Besides reduction of gametocyte carriage, we found no clear advantage of ACT over amodiaquine plus SP. In some settings, amodiaquine plus SP had inferior (to artemether-lumefantrine), similar (to artesunate plus amodiaquine) or superior (to artesunate plus SP) efficacy compared to ACT. The most efficacious ACT in our study was artemether-lumefantrine, consistent with the current recommendations. We conclude that alternative options to ACT, including amodiaquine plus SP, do exist and should be considered when malaria control programmes make treatment policy decisions. Although, artesunate plus SP was inferior to amodiaquine plus SP in the meta-analysis, in some situations it may be the most feasible treatment option. We had such a situation in Kenya where the antimalarial drug of choice at the time of the study was SP, which was failing at a rapid rate. Due to limited experience with ACTs, it was considered the best option to retard the progression of SP resistance by adding artesunate. In chapter 3.2, we described a randomized, double blind, placebo-controlled trial in 600 children with uncomplicated falciparum malaria who were treated with either one [AS1] or 3 days of Artesunate plus SP [AS3] and compared with SP alone. By day 14, it was already clear that SP failure rate was unacceptably high. Adding artesunate to SP did not markedly improve the efficacy of the combination and by day 28, the parasitological failure rates when corrected by parasite genotyping were 33.1%, 20.7%, and 42.5%, for those treated with AS1, AS3 and SP alone, respectively. Both AS3 and AS1 regimens significantly reduced gametocyte carriage, fever and parasite clearance. However, the high failure rate of SP compromised the efficacy of the artesunate combination, making it an unsuitable choice for widespread use in Kenya. We concluded that ACT probably works best when the artemisinin-derivative is introduced earlier on before resistance develops to the standard companion drug. For malaria control in Kenya, alternative antimalarial drug (combination) was urgently required. Paediatric anaemia is an inevitable consequence of any significant malaria infection. Survival and improvement of haemoglobin are important clinical outcomes of antimalarial drug therapy. Chapter 4 describes two studies of the outcome of treatment for uncomplicated falciparum malaria. In chapter 4.1, the impact of introducing effective antimalarial therapy on case fatality is described. We used data from the prospective in-hospital surveillance system collected over 4 years. During the 4 years an increasing proportion of hospitalized children received an effective antimalarial therapy and there was a significant reduction in case fatality rates (from 13% at baseline to 3.5%). These results support the introduction of effective malaria therapy and we conclude that the current debate about delaying the introduction of effective, though expensive second-line (combination) therapies is not simply the debate about money, but about the cost of life. In chapter 4.2, we describe the effect of therapy on haematological recovery and anaemia prevalence within 28 days of initiating treatment. We used data from the randomized trial described in chapter 3.2.
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At enrolment 91% of the children were anaemic and only 18% achieved haematological recovery by 28 days after treatment, with only a modest reduction in the prevalence of anaemia in all treatment arms. We had hypothesized that treatment with Artesunate plus SP would result in better haematological outcomes compared to SP alone. This was not the case, probably because of the high failure rates in all treatment arms, the short follow-up period and the natural history of haemoglobin fall that follows treatment due parasite clearance. Our study confirmed that parasitological cure was necessary for achieving haematological recovery. However, our results highlight a major limitation of the current malaria control policy based heavily on case management. Children with high prevalence of malaria-associated anaemia arising probably from chronic asymptomatic parasitaemia may need repeated doses of an effective preventive antimalarial therapy, combined with a vector control strategy.
Treatment of severe anaemia often includes blood transfusion – a costly and labour intensive intervention, which may save life but could also transmit a chronic disease [the human immunodeficiency virus (HIV)]. In chapter 5 we used the methods of decision analysis to determine the circumstances when routine blood transfusion for severe malarial anaemia provides a higher probability of survival compared to no transfusion. Three key factors were found to determine the beneficial effect of a transfusion: a high risk of mortality without a transfusion, low risk of HIV contaminating the blood supply and the likelihood of high transfusion effectiveness (in reducing mortality). We recommend that transfusions should be given early during hospitalization using blood screened for HIV. Given the huge problem of malaria and its association with anaemia in young children, we propose that the risk of severe anaemia, hospitalization, mortality or blood transfusion could be reduced by administration of intermittent preventive therapy using an effective antimalarial drug. In chapter 6, we propose that intermittent preventive therapy in the post-discharge period (IPTpd) may be a key intervention to improving the outcomes (survival, haematological recovery and the frequency of occurrence of anaemia) of children who have survived at least one episode of severe malarial anaemia. The proposed intervention will go a step beyond the scope of the currently available interventions (insecticide-treated bednets, IPT in infancy, and malaria case management) that aim to prevent the development of a new episode of severe anaemia. However, we note that the efficacy and safety of this intervention has not been evaluated in well-designed clinical trials and there are implementation problems that need to be worked out. In conclusion, malaria-associated anaemia is a potentially preventable cause of severe morbidity and mortality among children < 5years of age in western Kenya and in other parts of sub-Saharan Africa. Determining which children are at highest risk for severe anaemia, defining optimal treatment and prevention regimens, and identifying opportunities for earlier intervention may reduce the burden of disease and improve child survival. Our studies were undertaken at a time when most malaria control programmes were considering a switch from the current failing monotherapies to effective (though expensive) combination therapies. In part, our results assisted in prompting a change in the Kenyan treatment policy for uncomplicated malaria. Our
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meta-analysis will help policy-makers undertake evidence-based decisions on the choice of antimalarial drug for uncomplicated malaria. Our transfusion decision analysis will aid the development of transfusion guidelines, in the context of malaria and the risk of HIV transmission through the blood supply. The epidemiology of malaria-associated anaemia in western Kenya highlights that this is still a major public health problem and that current efforts are not making a significant impact. Even with the availability of proven tools like insecticide treated bed nets, and iron supplementation (and very soon, intermittent preventive treatment of infants), these interventions do not seem to reach the target groups. A better understanding of the root causes of antimalarial drug resistsance is urgently needed. The struggle continues.
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SAMENVATTIG
(DUTCH SUMMARY)
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Anemie is een onvermijdelijk gevolg van malaria-infecties door Plasmodium falciparum, vooral in gebieden waar zeer veel malaria voorkomt. De groep met het grootste risico op malariageassocieerde anemie zijn kinderen. Sinds het ontstaan van geneesmiddelresistente parasietstammen, neemt het aantal gevallen van anemie toe. Tegelijkertijd vormt de behandeling van ongecompliceerde falciparium malaria een geweldige uitdaging, omdat de malariacontroleprogramma’s gebruik moeten maken van combinatietherapieën, wat zondermeer gepaard gaat met hoge kosten. Het doel bij de behandeling van een ongecompliceerde malaria is de infectie te genezen, en te voorkomen dat complicaties gaan optreden, dat de ziekte ernstiger wordt en de patiënt overlijdt. Ernstige anemie is een belangrijke complicatie van malaria in gebieden waar langdurig malaria heerst, vooral onder jonge kinderen. De beslissing om een ernstige anemie te behandelen moet zorgvuldig worden genomen, omdat de gebruikelijke interventie, een bloedtransfusie, een belangrijke risicofactor is geworden voor HIV-besmetting. Dit proefschrift beschrijft hoe het probleem van malariageassocieerde anemie bij Kenyase kinderen is geïdentificeerd en de stappen die zijn genomen om mogelijke oplossingen voor dit probleem te vinden. In hoofdstuk 1 wordt het probleem van de malariageassocieerde anemie en zijn verband met resistentie tegen antimalariageneesmiddelen geïntroduceerd. In dit hoofdstuk worden ook de belangrijkste doelstellingen geschetst van de studies die in dit proefschrift worden beschreven. In hoofdstuk 2 worden twee studies gepresenteerd die de prevalentie en het aandeel van anemie ten gevolge van malaria bij Kenyase kinderen tonen. In hoofdstuk 2.1 wordt gebruik gemaakt van gegevens van 3586 kinderen die deelnamen aan de screeningsfase van een gerandomiseerde trial. Gevonden werd dat 80% van de kinderen leed aan anemie (Hb<11 g/dl) en 3% aan ernstige anemie. Risicofactoren om met anemie door te verwijzen naar een ziekenhuis, waren malariaparasitisme, een jonge leeftijd, splenomegalie, ondervoeding, een eerdere ineffectieve behandeling en het niet gebruiken van een klamboe. Kinderen beneden 3 jaar bleken de populatie met een hoog risico te zijn: de prevalentie van anemie was 83%, een Hb-gehalte < 8 g/dl kwam voor bij 34% van de populatie en 4% leed aan ernstige anemie (Hb<5 g/dl). Malariaparasitisme was sterk geassocieerd met een Hb-gehalte < 8 g/dl. Deze initiële studie karakteriseerde het anemieprobleem en identificeerde kinderen < 3 jaar als de populatie met het grootste risico op ernstige anemie en malariageassocieerde anemie. De doelstelling van hoofdstuk 2.2 was het bepalen van het aandeel van ernstige anemie ten gevolge van malaria in opnames op afdelingen kindergeneeskunde en aan het sterftecijfer. Door gebruik te maken van gegevens uit een retrospectieve review werd gevonden dat ernstige anemie ten gevolge van malaria een belangrijke reden was voor opname en overlijden in een ziekenhuis bij kinderen beneden 3 jaar. In het betreffende ziekenhuis had 90% van alle opgenomen kinderen een Hb-gehalte < 11 g/dl, 20% leed aan ernstige anemie en 20% kreeg een bloedtransfusie. Bovendien overleed 12% van de kinderen met een ernstige anemie, en was 52% van de sterftegevallen die verband hielden met malaria, te wijten aan een ernstige anemie. Dit onderzoek toont duidelijk de enorme belasting die ernstige anemie ten gevolge van malaria vormt voor gezondheidszorgsystemen voor kinderen in gebieden waar zeer veel malaria heerst, en identificeert kinderen < 3 jaar als de doelgroep voor
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interventies die zijn bedoeld om het aandeel van anemie ten gevolge van malaria te reduceren. Uit deze initiële studies kwam naar voren dat malaria, een te behandelen en te voorkomen infectie, een belangrijke risicofactor vormt voor ernstige anemie bij kinderen. Daarom werd besloten om de effectiviteit van de huidige antimalariabehandelingen te bestuderen en alternatieve behandelingsmogelijkheden te onderzoeken. Hoofdstuk 3 beschrijft 2 studies die de rol van een op artemisinine gebaseerde combinatietherapie bij de behandeling van ongecompliceerde falciparum malaria bij Afrikaanse kinderen onderzoeken. In hoofdstuk 3.1 wordt gebruik gemaakt van de meta-analyse methode om mogelijke behandelingen met antimalariageneesmiddelen te onderzoeken. Vanwege het probleem van de resistentie tegen antimalariageneesmiddelen bestaat er een sterke voorkeur voor combinatietherapie bij de behandeling van ongecompliceerde falciparum malaria. Bij de keuze van de geneesmiddelen zijn het kostenaspect en de beschikbaarheid van de geneesmiddelen van groot belang. Daarom werd de effectiviteit van één niet op artemisinine gebaseerde combinatie (amodiaquine met sulfadoxine-pyrimethamine [SP]) vergeleken met 3 op artemisinine gebaseerde combinaties (ACT), waarbij gebruik werd gemaakt van gegevens van 4472 Afrikaanse kinderen met ongecompliceerde malaria. Naast een reductie van het aantal gametocytdragers, werden geen duidelijke voordelen van ACT ten opzichte van amodiaquine met SP gevonden. In sommige settings had amodiaquine met SP een slechtere (ten opzichte van artemether-lumefantrine), een overeenkomstige (ten opzichte van artesunaat met amodiaquine) of een betere (ten opzichte van artesunaat met SP) effectiviteit in vergelijking met ACT. De ACT met de beste werking in onze studie was artemether-lumefantrine, wat overeenkomt met de huidige aanbevelingen. De conclusie was dat er alternatieve mogelijkheden voor ACT, waaronder amodiaquine met SP, bestaan en dat deze ter overweging dienen te worden genomen wanneer in malariacontroleprogramma’s beslissingen worden genomen met betrekking tot behandelingsstrategieën. Hoewel artesunaat met SP in de meta-analyse een slechtere werking vertoonde dan amodiaquine met SP, kan het in sommige gevallen de beste behandelingsoptie zijn. Een dergelijke situatie ontstond in Kenya waar op het moment van de studie gekozen was voor SP als antimalariageneesmiddel, maar de werking van SP in een snel tempo afnam. Vanwege een geringe ervaring met ACT’s, werd het toevoegen van artesunaat beschouwd als de beste optie om de progressie van SP-resistentie te vertragen. In hoofdstuk 3.2 wordt een gerandomiseerde, dubbelblinde placebo-gecontroleerde trial beschreven bij 600 kinderen met ongecompliceerde falciparum malaria die gedurende één dag [AS1] of drie dagen [AS3] werden behandeld met artesunaat met SP, en dit werd vergeleken met een behandeling met alleen SP. Na 14 dagen was al duidelijk dat de werking van SP onacceptabel snel afnam. Het toevoegen van artesunaat aan SP gaf geen duidelijke verbetering van de effectiviteit van de combinatie, en na 28 dagen bedroegen de parasitologische failure rates, gecorrigeerd voor parasietgenotype, 33,1%, 20,7% en 42,5% voor de patiënten die een behandeling hadden ondergaan van respectievelijk AS1, AS3 en SP alleen. Zowel AS3 als AS1 gaven een significante reductie van het aantal gametocytdragers, de koorts en de parasietklaring. De hoge failure rate van SP had echter een nadelige invloed op de effectiviteit van de artesunaatcombinatie, wat het ongeschikt maakt voor algemeen gebruik in Kenya. De
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conclusie was dat ACT waarschijnlijk het beste werkt wanneer de afgeleide van artemisinine eerder in de behandeling wordt opgenomen, nog voordat er resistentie tegen het standaard gebruikte geneesmiddel is ontwikkeld. Voor een controle van malaria in Kenya was dringend behoefte aan een alternatief antimalariageneesmiddel (of geneesmiddelencombinatie). Anemie bij kinderen is een onvermijdelijk gevolg van een significante malaria-infectie. Overleving en een verbetering van het hemoglobinegehalte zijn belangrijke klinische resultaten van een behandeling met antimalariageneesmiddelen. Hoofdstuk 4 beschrijft twee studies van de resultaten van de behandeling van ongecompliceerde falciparum malaria. In hoofdstuk 4.1 wordt het effect van de introductie van een effectieve antimalariabehandeling op de sterfte beschreven. Er werden gegevens gebruikt uit het prospectieve overzichtsysteem van ziekenhuizen die gedurende 4 jaar waren verzameld. Tijdens de 4 jaren ontving een toenemend aantal opgenomen kinderen een effectieve antimalariabehandeling en er trad een significante reductie van het aantal sterftegevallen op (van 13% als basislijn tot 3,5%). Deze resultaten ondersteunen de introductie van een effectieve malariabehandeling en er werd geconcludeerd dat de huidige discussie over het uitstellen van de introductie van effectieve, maar weliswaar dure, tweedelijns (combinatie-) behandelingen niet eenvoudigweg een discussie over geld is, maar een discussie over mensenlevens. In hoofdstuk 4.2 wordt het effect van een behandeling beschreven op het hematologische herstel en de prevalentie van anemie binnen 28 dagen na het begin van de behandeling. Er werden gegevens gebruikt uit de gerandomiseerde trial die in hoofdstuk 3.2 wordt beschreven. Bij binnenkomst leed 91% van de kinderen aan anemie. Bij slechts 18% werd 28 dagen na de behandeling een hematologisch herstel bereikt, en alle behandelingen gaven slechts een geringe reductie van de prevalentie van anemie. Verondersteld werd dat een behandeling met artesunaat met SP betere hematologische resultaten zou geven dan SP alleen. Dit bleek niet het geval te zijn, waarschijnlijk vanwege de hoge failure rates bij alle behandelingen, de korte follow-up periode en het natuurlijke ziekteverloop waarbij een daling van het hemoglobinegehalte optreedt vanwege parasietklaring die volgt na een behandeling. De studie bevestigde dat een parasitologische genezing noodzakelijk was om hematologisch herstel te bereiken. De resultaten brachten echter een belangrijke beperking naar voren van de huidige malariacontrolestrategie die sterk is gebaseerd op case management. Kinderen met een hoge prevalentie van malariageassocieerde anemie die waarschijnlijk voortkomt uit een chronische asymptomatische parasitemie, kunnen herhaalde doseringen nodig hebben van een effectieve preventieve antimalariabehandeling gecombineerd met een vectorcontrolestrategie. De behandeling van een ernstige anemie omvat vaak een bloedtransfusie – een kostbare en arbeidsintensieve interventie, die een leven kan redden, maar ook een chronische ziekte zou kunnen overbrengen [het humane immuundeficiëntievirus (HIV)]. In hoofdstuk 5 wordt gebruik gemaakt van beslissingsanalysemethoden om de omstandigheden te bepalen waaronder een routinematige bloedtransfusie voor ernstige anemie ten gevolge van malaria een grotere kans geeft op overleven dan wanneer geen bloedtransfusie zou worden uitgevoerd. Er werden drie sleutelfactoren gevonden die het gunstige effect van een transfusie bepaalden: een grote kans op
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overlijden wanneer geen bloedtransfusie wordt uitgevoerd, een kleine kans dat het toe te dienen bloed wordt besmet met HIV en de waarschijnlijkheid van een grote effectiviteit van de transfusie (bij het reduceren van de sterfte). Aanbevolen wordt om bloedtransfusies in een vroeg stadium van de ziekenhuisopname uit te voeren, waarbij gebruik wordt gemaakt van bloed dat is getest op de aanwezigheid van HIV. Gezien het immense malariaprobleem en zijn verband met anemie bij kinderen, wordt verondersteld dat het risico op een ernstige anemie, een ziekenhuisopname, overlijden of van een bloedtransfusie zou kunnen worden gereduceerd door een intermitterende preventieve behandeling toe te passen, waarbij gebruik wordt gemaakt van een effectief antimalariageneesmiddel. In hoofdstuk 6 wordt aangenomen dat een intermitterende preventieve behandeling in de post-discharge periode (IPTpd) een sleutelinterventie kan zijn voor de verbetering van de resultaten (overleving, hematologisch herstel en de anemiefrequentie) bij kinderen die tenminste één episode van ernstige anemie ten gevolge van malaria hebben overleefd. De voorgestelde interventie gaat een stap verder dan de momenteel beschikbare interventies (met een insecticide behandelde klamboes, IPT tijdens de jeugdjaren en case management van malaria) die tot doel hebben om de ontwikkeling van een nieuwe episode van ernstige anemie te voorkomen. Er moet echter worden opgemerkt dat de effectiviteit en de veiligheid van deze interventies niet is onderzocht in goed opgezette klinische trials, en dat er implementatieproblemen bestaan die nog moeten worden opgelost. Concluderend, malariageassocieerde anemie is een mogelijkerwijs te voorkomen oorzaak van ernstige morbiditeit en mortaliteit onder kinderen < 5 jaar in West-Kenya en in andere delen van Afrika beneden de Sahara. Bepalen welke kinderen het grootste risico lopen op een ernstige anemie, definiëren van optimale behandelings- en preventiekuren, en identificeren van mogelijkheden voor een vroege interventie kunnen bijdragen aan een reductie van het aandeel van deze ziekte en de overleving van de kinderen verbeteren. De studies werden uitgevoerd op een moment dat de meeste malariacontroleprogramma’s een overstap overwogen van de huidige, slecht werkende monotherapieën naar effectieve (alhoewel dure) combinatietherapieën. De resultaten hebben voor een deel bijgedragen aan het in gang zetten van een verandering van de Kenyase behandelingsstrategie voor ongecompliceerde malaria. De meta-analyse zal een hulp zijn voor beleidsmakers om op bewijzen gebaseerde besluiten te nemen bij de keuze van antimalariageneesmiddelen voor ongecompliceerde malaria. De beslissingsanalyse voor een bloedtransfusie zal de ontwikkeling van richtlijnen voor bloedtransfusies bevorderen met als context malaria en het risico van een HIV-besmetting via het toedienen van bloed. De epidemiologie van malariageassocieerde anemie in West-Kenya laat zien dat het nog steeds een belangrijk algemeen gezondheidsprobleem vormt, en dat de huidige pogingen om hier verandering in te brengen, geen significant effect hebben. Zelfs met de beschikking over middelen waarvan de goede werking is bewezen, zoals met een insecticide behandelde klamboes en ijzersupplementen (en zeer binnenkort intermitterende preventieve behandelingen van kinderen), lijken deze interventies de doelgroepen niet te bereiken. Er is dringend behoefte aan een beter begrip van de factoren die resistentie tegen antimalariageneesmiddelen veroorzaken. De strijd duurt voort.
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LIST OF CO-AUTHORS
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Willis Akhwale, Division of Malaria Control, Kenyan Ministry of Health Nairobi, Kenya Anders Bjorkman Department of Medicine, Karolinska Institute, Stockholm, Sweden Carlos Campbell, Arizona University, Arizona, USA Hakan Ekvall Department of Medicine, Karolinska Institute, Stockholm, Sweden DE Grobbee Julius Center for Health Sciences University Medical Center Utrecht Utrecht, Netherlands Dik Habemma Department of Public Health Erasmus University Medical Centre Rotterdam, Netherlands Elizabeth Juma Kenya Medical Research Institute, Kisumu, Kenya Akira Kaneko Department of Medicine, Karolinska Institute, Stockholm, Sweden Feiko ter Kuile Liverpool School of Tropical Medicine & Hygiene, Liverpool, UK Joseph Lau Tufts-New England Medical Centre Boston, USA Kefas Mugittu Ifakara Health and Development Centre, Ifakara, Tanzania
Francis Ochieng Siaya District Hospital, Siaya, Kenya Sam Ocholla Division of Malaria Control Kenyan Ministry of Health Nairobi, Kenya Bernhards Ogutu Kenya Medical Research Institute, Kisumu, Kenya Piero Olliaro WHO TDR, Geneva, Switzerland Aggrey J Oloo WHO/AFRO, Harare, Zimbabwe Juliana Otieno Nyanza Provincial General Hospital Kisumu, Kenya Trenton K Ruebush Centers for Disease Control, Atlanta, GA, USA Ewout Steyerberg Department of Public Health Erasmus University Medical Centre Rotterdam, Netherlands Walter Taylor WHO TDR, Geneva, Switzerland John Vulule Kenya Medical Research Institute, Kisumu, Kenya Jane Zucker New York City Department, New York, USA
ACKNOWLEDGEMENTS
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A thesis is never the work of one person. The studies presented in this thesis were the result of a joint effort over several years involving many people and institutions from different countries, all of whom I am sincerely grateful to. I wish to express my sincere gratitude to everyone who has contributed to this work in any way. For the purposes of brevity, I will not mention everyone by name but would like to specially thank the following people: Prof. Rick Grobbee, my promoter, for giving me the opportunity to do this PhD under his supervision. Thank you Rick, for your interest in my work and encouragement over the years. In Canada: Olli Miettinen has significantly influenced my epidemiological thinking. Thanks Olli, for keeping in touch. As you say, “it is students like you who give me a sense of purpose”. In Kenya: I thank all the parents of the Kenyan children who participated in the studies described in this thesis for their time, enthusiasm and patience. Your participation has contributed to knowledge that may be beneficial to future generations of African children when translated into preventive and treatment tools. I thank the administration and staff of Siaya district hospital for generously supporting the conduct of our studies over the years. My colleagues at the CVBCR/KEMRI Kisumu, for friendship, encouragement and support. My special thanks go to Dr Vulule, the current Centre Director, and Dr Oloo, the former director, for their unfailing administrative support. In The Netherlands: Dik Habbema, and Ewout Steyerberg, my mentor and research supervisors during the Masters degree programme. Dik and Ewout, played a special role in laying the foundation for the rest of this thesis and I thank you for maintaining a keen interest in my work. Special thanks to Giene, at Utrecht, who provided much more than administrative support. In the UK: Thanks Feiko for your friendship, collaboration, advice and support over the years. Your faith in me provided the encouragement to pursue a master’s degree in the first place, and thereafter, landed me my first clinical trial. In the USA: I would never have begun my scientific research career without the encouragement and support of Trenton Ruebush, who encouraged me to join KEMRI. Eve Lackritz and Jane Zucker introduced me to the research relating to paediatric anaemia, blood transfusion and mortality. Joseph Lau—thanks Joe, for teaching me all I know about meta-analysis and systematic reviews. Special thanks to Michael Bennish, John Wong, Harry Selker and Steve Pauker, for accommodating me during my Clinical research and informatics fellowship at Boston. In Sweden: Professor Anders Bjorkman, Drs Akira Kaneko and Hakan Ekvall, for your collaboration, encouragement and support. Akira, you deserve special thanks for encouraging me to pursue a PhD degree. I appreciate the opportunity of staying at
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your house when I visited Stockholm and greatly appreciate Yoko, for never tiring to make plenty of delicious food. In Switzerland: Bob Taylor, for friendship, collaboration and support over the years. I appreciate the warm welcome and music when I visited Geneva. Home: Joanne for your love, encouragement and unfailing support. My children, Eve, Mercy and Joseph for your company. My father Adrian Obonyo and mother Jane, for the opportunity to go to school and your support, encouragement and prayers through the years. Above all else, I thank God for the strength, wit and drive to complete this series of work.
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ABOUT THE AUTHOR
Charles Owuora Obonyo was born in South Nyanza district, western Kenya on 17th June 1965. In 1985, he completed his high school education at Maseno National School, and subsequently worked at the Tea Research Foundation of Kenya in Kericho, Kenya, for a year where he conducted a research study on, “Nitrate reductase levels predict the quality of a good cup of tea” in the Biochemistry department (head: Dr Owuor). In 1986 he began his medical training at the Kenya Medical Training Center, Nakuru, Kenya. He obtained a Diploma in Clinical Medicine in 1989. Following his internship at Siaya district hospital in western Kenya, he worked for the Kenyan Ministry of Health until 1991 when he joined
the Kenya Medical Research Institute (KEMRI). Between 1991 and 1995, he worked as the Clinical Officer on the epidemiological studies conducted collaboratively by KEMRI and the US Centers for Disease Control and Prevention (KEMRI/CDC) at Siaya district hospital. In 1996, through a scholarship from NUFFIC he joined the Netherlands Institute for Health Sciences (NIHES) at Erasmus University Rotterdam, The Netherlands, where he completed a master’s degree in Clinical Epidemiology. While at Rotterdam, his thesis research was “Blood transfusion for African children with severe malarial anaemia: A decision analysis” conducted at the Centre for Clinical Decision Sciences, Department of public health (head, Prof Dik Habbema). On return to Kenya, he began the series of studies described in this thesis. He interrupted these studies for 1 year to train as a pre-doctoral research fellow in clinical research and medical informatics at the Tufts University and the New England Medical Center, Boston, USA. He resumed the conduct of the studies described in this thesis in 2001. On completion of the Doctoral training, he would like to continue working as a clinical researcher and lecturer in Clinical Epidemiology. Other publications by the author:
1. Obonyo CO, Lau J. Efficacy of Haemophilus influenzae b vaccines in young children: A meta-analysis. European Journal of Clinical Microbiology and Infectious Diseases 2006, 25: 90-7
2. Holmgren G, Gil JP, Ferreira PM, Veiga MI, Obonyo CO, Bjorkman A. Amodiaquine resistant Plasmodium falciparum is associated with selection of pfcrt76T and pfmdr1 86Y. Infection, Genetics and Evolution 2006, 6: 309-14
3. Akhwale WS, Koji Lum J, Kaneko A, Eto H, Obonyo C, Bjorkman A, Kobayakawa T. Anaemia and malaria at different altitudes in the western highlands of Kenya. Acta Tropica 2004, 91:161-71
4. International Artemisinin Study Group. Artesunate combinations for treatment of malaria: a meta-analysis. Lancet 2004: 363: 9-17
5. Zucker JR, Perkins BA, Jafari H, Otieno JA, Obonyo CO, Campbell CC. Clinical signs for the recognition of children with moderate and severe anaemia; western Kenya. Bulletin of the World Health Organization 1997;75 (suppl 1): 97-102.
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6. Snow RW, Omumbo JA, Lowe B, Molyneux CS, Obiero JO, Palmer A, Weber MW, Pinder M, Nahlen B, Obonyo C, Newbold C, Gupta S, Marsh K. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349: 1650-54
7. Shah SN, Smith E, Obonyo CO, Kain KC, Bloland PB, Slutsker L, Hamel MJ. HIV immunosuppression and antimalarial efficacy: Sulfadoxine-pyrimethamine for treatment of uncomplicated malaria in HIV infected adults in Siaya, Kenya (accepted, Journal of Infectious Diseases).
8. Obonyo CO, Juma EA. Clindamycin plus quinine for treating uncomplicated malaria: a systematic review and meta-analysis. (To be published on The Cochrane Library Issue 1, 2007)
9. Obonyo CO, Griffith J, Selker H. Development of a prediction model for mortality in Kenyan children with severe malarial anaemia (submitted, Journal of Clinical Epidemiology)
10. Obonyo CO, Taylor WR, Otieno PO, Kinyua E, Vulule JM. The high prevalence of and risk factors for treatment failure with Sulfadoxine-pyrimethamine for uncomplicated malaria in children from western Kenya (submitted, Annals of Tropical Medicine and Parasitology)
11. Obonyo CO, Juma EA, Taylor WR. Prevalence of and risk factors for gametocyte carriage in Kenyan children with uncomplicated falciparum malaria (submitted, Transactions of the Royal Society of Tropical Medicine and Hygiene)
12. Obonyo CO. Factors associated with severe anaemia at admission in Kenyan children with Plasmodium falciparum malaria (submitted, Annals of Tropical Paediatrics)
13. Arudo J, Obonyo CO, Phillips-Howard PA, Nahlen BL, Hawley WA, Orago AS, Kachur SP. Verbal autopsy for under-five year old children exposed to intense malaria transmission in rural western Kenya (submitted, Tropical Medicine and International Health)
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