The Epidemiology and the burden of malaria in Mozambique Samuel José Alves Mabunda This work is dedicated to my family Universitat de Barcelona Facultat de Medicina Departament de Salut Pública The Epidemiology and the burden of malaria in Mozambique Tesi Presentada per Samuel José Alves Mabunda Per a optar al grau de Doctor en Medicina i Cirurgia Director de la tesi Pedro L. Alonso Fernández Barcelona 2006 TABLES OF CONTENTS Pages ACKNOWLEDGEMENTS.................................................................................................................... iv LIST OF TABLES.................................................................................................................................... v LIST OF FIGURES................................................................................................................................vii ABBREVIATIONS.................................................................................................................................viii ABSTRACT (English)........................................................................................................................................x (Spanish)....................................................................................................................................xvi 1.INTRODUCTION .................................................................................................................................. 1 1.1.THE HISTORY OF MALARIA …………………………………………………………..….…. 1 1.2. THE DISCOVERY ERA AND INITIAL ATTEMPS TO MALARIA CONTROL ………........ 3 1.3. GLOBAL ERADICATION CAMPAIGN ……………………………………………..…….…. 4 1.4. THE GARKI AND KISUMI PROJECTS ……………………………………………………..... 7 1.5. THE LIFE CYCLE OF HUMAN MALARIA PARASITES ………………………..………… 11 1.6. PATHOGENESIS AND CLINICAL MANIFESTATIONS OF MALARIA ……………….… 13 1.7. CLINICAL MANIFESTATIONS OF MALARIA ………………………………………….… 16 1.7.1. The incubation and pre-patient period ……………………………………………….…. 17 1.7.2. Uncomplicated malaria ………………………………………………………………..... 17 1.7.3. Clinical manifestations of severe malaria ……………………………………………... .18 1.7.4. Clinical manifestations of severe malaria in children ………………………………….. 18 1.7.5. Clinical manifestations of severe malaria in adults …………………………………….. 21 1.7.6. Clinical manifestations of severe malaria in pregnancy …………………………………22 1.8. MAIN PATHOLOGIC FEATURES IN VITAL ORGANIS ……………………………….… 23 2. THE EPIDEMIOLOGY OF MALARIA........................................................................................... 25 2.1. DISTRIBUTION AND DETERMINANTS OF MALARIA …………………………………. 25 2.1.1. The Natural Environment ………………………………………………………………..25 2.1.1.1. Temperature ……………………………………………………………………25 2.1.1.2. Humidity of the air …………………………………………………………….26 2.1.1.3. Rainfall and breeding places ……………………………………………………26 2.1.2. The Vectors …………………………………………………………………………………………27 2.1.2.1. Life cycle of anopheline mosquitoes …………………………………………..29 2.1.3. The Parasites ……………………………………………………………………………..31 2.1.3.1. The distribution of malaria parasites ………………………………………….. 32 2.1.3.1.1. Plasmodium vivax ..…………………………………………..……. 32 2.1.3.1.2. Plasmodium ovale …………………………………………………. 32 2.1.3.1.3. Plasmodium malariae ……………………………………………....34 2.1.3.1.4. Plasmoidum (Laverania) falciparum ……………………………..……. 35 2.1.3.1.5. Mixed infections ………………………………………………………… 35 2.2. THE HUMAN HOST …………………………………………………………………………… 35 2.2.1. Biological factors ……………………………………………………………………….. 35 3. MALARIA IN AFRICA ………………............................................................................................. 37 3.1. THE EPIDEMIOLOGY OF MALARIA IN AFRICA ………….…………………………..... 37 3.2. THE BURDEN OF MALARIA IN AFRICA …………………………………………………. 40 3.3. THE ECONOMIC AND SOCIAL IMPACT OF MALARIA IN AFRICA ………………….. .43 3.3.1. Social and Economic Toll ………………………………………………………………. 44 4. MALARIA DRUG RESISTANCE ………........................................................................................ 45 5. VECTOR RESISTANCE ………………............................................................................................ 47 i 6. GLOBAL CLIMATIC AND ENVIROMENTAL CHANGES ……………………………..…… 47 7. THE EPIDEMIOLOGY OF MALARIA IN MOZAMBIQUE ……………………………..…… 49 7.1. DISEASE BURDEN …………………………………………………………………………... 50 7.2. MALARIA AND PAST CONTROL ACTIVITIES IN MOZAMBIQUE …………………… 51 7.2.1. Parasite prevalence …………………………………………………………………….. 54 7.2.2. Malaria vectors …………………………………………………………………………. 55 7.2.3. Anti-malarial activities ………………………………………………………………….. 58 7.2.4. Some anti-malarial trials carried out in Mozambique …………………………….……. 62 8. THE CURRENT NATIONAL MALARIA CONTROL STRATEGIES …………….………… 63 8.1. MALARIA CONTROL CURRENT STATUS AND RECOMMENDATIONS ……….……. 63 8.2. CHALLENGES AND CONTROVERSIES IN THE FIELD OF …………..……….…..….… 63 8.2.1. Vaccines …………………………………………………………………………...…... 64 8.2.2. Parasite life cycle and vaccine strategies and targets …………………….……….…. 65 9. OBJECTIVES …………………………………………………………………………..………….. 70 9.1. GENERAL OBJECTIVE ……………………………………………………………………... 70 9.2. SPECIFIC OBJECTIVES ………………………………………………………………….… 70 10. MATERIAL AND METHODS ……………………………………….………………………..… 71 10.1. STUDY AREA …………………………………………………………………………….….71 10.1.1. Geographic, climatic and demographic characteristics ………………………….…. 71 10.1.2. The Climate …………………………………………………………………..………. 72 10.1.3. The rainfall pattern ……………………………………………………………….…... 74 10.2. DESIGN AND SAMPLING METHODS……………………………… …………………… 74 10.2.1. Stratificaton …………………………………………………………………………....74 10.2.2. Cluster Sampling Method ………………………………………………………………….…. 74 10.3. STUDY POPULATION …………………………………………………………………….. 76 10.4. THE CROSS SECTIONAL SURVEY ………………………………………………………. 78 10.4.1. Field Work Procedures ………………………………….... …………………………….. 78 10.5. LABORATORIAL METHODS ……………………………………………………………... 81 10.5.1. Blood smears –staining methods …………………….……………………..………... 81 10.5.2. Characteristics and qualitiy of stained blood smears …………………………………..… 81 10.5.3. Mosquito species identification and sporozoite detection ………………………………… 82 10.5.4. Main steps for DNA-Polymerase Chain Reaction (PCR)………………………….…... 82 10.5.5. Species identification of the An. gambiae complex by PCR ………………………………. 84 10.5.6. Species identification of the An. funestus group by PCR ……………………….…….. 84 10.5.7. Plasmodium sporozoites detection in Anopheles mosquitoes and estimation of infective rate ………………………………………………………. 85 10.6. DATA MANAGEMENT …………………………………………………………………….. 86 10.6.1. Data analysis ………………………………………….……………………..……… 86 10.6.2. Accounting for the sample design …………………….. ………………………………….… 87 10.6.3. Clinical malaria – establishment of case definition …………………………………….…. 88 10.6.4. Entomological inoculation rates ……………………………. ……………………………… 82 10.6.5. Definitions )……………………………………………………………………..….….. 89 11. RESULTS ………………………………….……………………………….……………….…..… 91 11.1. THE STUDY PROFILE ……………………………………………………………………... 91 11.2. DEMOGRAPHIC CHARACTERISTICS OF CHILDREN ……………………………….… 93 11.3. PREVALENCE AND INTENSITY OF MALARIA INFECTION AND ANAEMIA ……… 95 11.3.1. Overall prevalence of malaria parasite and geometric mean parasite density ……..….. 95 11.3.2. Prevalence of fever and fever associated with malaria parasites infection ………….… 97 11.3.3. Overall mean haemoglobin and prevalence of anaemia … ……………………………..… 98 ii 11.3.4. Overall prevalence of P. falciparum sexual forms ………………………………………... 99 11.3.5. Prevalence of Plasmodium malariae …………………………………………………..….. 100 11.3.6. Prevalence of mixed infection ………………………………………………………….…... 100 11.3.7. Attributable fraction of fever, clinical malaria case definition and its relation to age ………………………………………………………………………… 101 11.4. VARIATIONS ON THE PREVALENCE AND INTENSITY OF MALARIA INFECTION AND ANAEMIA ACROSS REGIONS ………………………………………………………103 11.4.1. Overall parasite prevalence and geometric mean parasite density …………………. .103 11.4.2. Prevalence of fever and fever associated with malaria parasites infection ……….… 106 11.4.3. Overall mean haemoglobin and prevalence of anaemia …………………………….… 107 11.4.4. Overall prevalence of P. falciparum sexual forms ………………………………….….. 111 11.4.5. Prevalence of Plasmodium malariae ………………………………………………….…. 112 11.4.6. Prevalence of mixed infection ………………………………………………………….…. 112 11.5. ESTIMATED NUMBER OF CHILDREN HARBOURING MALARIA PARASITE INFECTION AND ANAEMIA ACROSS THE COUNTRY …………………………….…. 113 11.6. CHARACTERISTICS OF PREGNANT WOMEN ………………………......………….… 115 11.7. PREVALENCE AND INTENSITY OF MALARIA INFECTION AND ANAEMIA ….… 116 11.7.1. Risk factors for malaria infection in pregnancy ……………………………………....… 119 11.7.2. Risk factors for anaemia in pregnancy …………………………………………………… 121 11.8. REGIONAL VARIATIONS ACROSS DIFFERENT STRATA …………………….…….. 123 11.9. ESTIMATED NUMBER OF WOMEN IN BEARING AGE HARBOURING MALARIA PARASITE INFECTION AND ANAEMIA ACROSS THE COUNTRY …………..……. 126 11.10. ENTOMOLOGICAL INOCULATION RATE ……………………………………..……. 128 12. DISCUSSION ………………………………………………………………………………..…… 130 12.1. PREVALENCE OF MALARIA PARASITES AND PARASITE DENSITY ………..…… 130 12.2. PREVALENCE OF ANAEMIA ……………………………………………………..…… 131 12.3. PREVALENCE OF CLINICAL MALARIA AND ESTABLISHMENT OF CASE DEFINITION …………………………………………………………………...……..133 12.4. PREVALENCE OF MALARIA PARASITES AND PARASITES DENSITY ……….. … 134 13. CONCLUSION ……………………………………………………………………...…………… 137 14. REFERENCES …………………………………………………………………….…………….. 139 Appendix 1............................................................................................................................................160 Appendix 2............................................................................................................................................162