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Clinical and Pathophysiological Aspects of Severe Falciparum Malaria

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Clinical and Pathophysiological Aspects of Severe Falciparum Malaria Open Research Online The Open University’s repository of research publications and other research outputs Clinical and pathophysiological aspects of severe falciparum malaria Thesis How to cite: Nguyen, Hoan Phu (2009). Clinical and pathophysiological aspects of severe falciparum malaria. PhD thesis The Open University. For guidance on citations see FAQs. c 2009 The Author https://creativecommons.org/licenses/by-nc-nd/4.0/ Version: Version of Record Link(s) to article on publisher’s website: http://dx.doi.org/doi:10.21954/ou.ro.000100a7 Copyright and Moral Rights for the articles on this site are retained by the individual authors and/or other copyright owners. For more information on Open Research Online’s data policy on reuse of materials please consult the policies page. oro.open.ac.uk CLINICAL AND PATHOPHYSIOLOGICAL ASPECTS OF SEVERE FALCIPARUM MALARIA Nguyen Hoan PhuMD, DTM&H A Thesis Submitted in Partial Fulfilment of the Requirement of the Open University, UK for the Degree of Doctor of Philosophy Wellcome Trust Major Overseas Programme Oxford University Clinical Research Unit Hospital for Tropical Diseases, Ho Chi Minh City Viet Nam August 2009 sxrre op sujk'fussicsiN : 1* S e e 1 2 , 0 0 ^ 5>R‘tc fip v ProQuest Number: 13889933 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13889933 Published by ProQuest LLC(2019). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ABSTRACT Malaria is a major global public health problem. One-fifth of the world's population is at risk of malaria and drug resistance is spreading. Nearly five times as many cases of malaria were reported in 2000 as tuberculosis, AIDS, measles and leprosy cases combined. In the time it takes to say the word "malaria," ten children will contract the disease and begin fighting for their lives. Since the cinchona alkaloids were introduced as a specific treatment for agues 350 years ago, the treatment of severe malaria has changed little and therapy remains largely empirical. Quinine and quinidine remain the drugs of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum, and with the spread of these resistant parasites, the usage of these drugs is increasing. In 1972 scientists in China discovered the antimalarial properties of a group of sesquiterpene lactone peroxides derived from the qinghao plant (Artemisia annua). The principal component, qinghaosu (artemisinin), and two derivatives - the water-soluble hemisuccinate artesunate and the oil-soluble artemether - are the most rapidly acting and potent of all antimalarial drugs. Although much research effort has been invested in optimizing antimalarial drug regimes, severe malaria remains a major cause of adult mortality in the Asiatic tropics. Despite many clinical trials reducing the mortality from severe malaria has proved difficult. Artemether has been shown to be as good as quinine but not better. This thesis set out to determine whether Artemether or Artesunate was the the better drug, how to manage acute renal failure in severe malaria, to design a severity score for malaria and assess whether there had been any change in the parasite clearance times in Viet Nam over a 18 year period. The results from a series of clinical trials and research from one hospital in Viet Nam are presented. This thesis undertook the following studies: 1. A randomised clinical trial of artesunate vs artemether in the treatment of severe malaria in adults in Viet Nam. 2. A randomized comparison of pumped venovenous haemofiltration and peritoneal dialysis in acute renal failure associated with severe infection. 3. Fluid management in severe malaria. 4. The stage of the development of the falciparum parasites at the time of clinical presentation with severe malaria is important in predicting outcome. 5. Development of a predictive score of outcome in adults with severe falciparum malaria. 6. Assessment of the efficacy of the artemisinin derivatives in the treatment of severe falciparum malaria in Viet Nam 1991-2008. 3 ACKNOWLEDGEMENTS I owe many thanks to all severe malaria patients who participated in the studies described in this thesis. I am indebted to them and their relatives. I am enormous grateful to Professor Nicholas John White, who came to Viet Nam in 1990 to set up the Malaria Research Unit - Wellcome Trust Clinical Research Unit in the Centre for Tropical Diseases - Ho Chi Minh City (HCMC). A special note of sincere thanks goes to Professor Tran Tinh Hien, Vice-Director of the Hospital for Tropical Diseases of HCMC. Twenty-nine years ago, he suggested I should work on Malaria, and he was a supervisor of my first thesis for the degree of Medical Doctor, for my second thesis for the degree of Specialist in Infectious Diseases and for this thesis as well. I would like to thank him for his guidance, invaluable advice, and never-ending support over almost three decades. I would like to express my sincere gratitude and deep appreciation to my supervisors, Professor Jeremy J. Farrar and Professor Nicholas P.J. Day, for their enthusiasm, supports both personal and professional, expertise and professional skills over the eighteen years. Without them this thesis would never have started and certainly never have been completed. Particular thanks go to all doctors, nurses, lab technicians, cleaners of the Malaria Research Unit and Oxford University Clinical Research Unit - Hospital for Tropical Diseases of HCMC for their assistance in clinical care and support of this thesis. 4 Special thanks also go to Dr Lee Sue, Dr Hoang Thi Thanh Hang and Dr Phung Quoc Tuan who helped me with the statistical analyses. I would like to thank Dr Keith Arnold, Dr Li Guo Qiao who firstly provided qinghaosu suppositories, artemether and artesunate for my hospital and my country and who helped to conduct the initial studies on malaria treatment. I am extremely grateful to the Wellcome Trust of Great Britain for helping to fund the work. Thanks must be given to my best friend, Nguyen Due Phong, for invaluable support and friendship. I appreciate the positive attitude that keeps me going. This thesis is dedicated to my Family, my Parents, my brothers, my sister for their abundant support. 5 DECLARATION Other than the assistance outlined in the acknowledgements, the work described in this thesis is my own work. I participated in designing, implementing, treating and caring for all patients involved in the studies, taking and preparing blood samples and blood smears, performing the peritoneal dialysis and haemofiltration, doing all parasite staging in peripheral blood smears, collecting specimens with autopsy from death patients, and conducting the follow-up examination of the patients. I have also been involved in all the data analysis. My work described in this thesis has not been submitted for a degree or other qualification to this or any other university. 6 LIST OF CONTENTS ABSTRACT ACKNOWLEDGEMENT DECLARATION LIST OF CONTENTS LIST OF FIGURES LIST OF TABLES ABBREVIATION CHAPTER 1 INTRODUCTION 1.1 Malaria 1.1.1 History of Malaria 1.1.2 Current malaria situation on the world 1.1.3 History of malaria in Viet Nam 1.1.4 Current malaria situation in Viet Nam 1.2 Malaria parasite 1.3 The pathophysiology of malaria 1.3.1 Parasite multiplication 1.3.2 Parasite biomass 1.3.3 Toxicity and Cytokines 1.3.4 Sequestration 1.3.5 Cytoadherence 1.3.6 Red cell deformability 1.3.7 Rosetting 1.3.8 Genetic Factors and Immunity 1.3.9 Permeability 1.3.10 Cerebral malaria 1.3.11 Renal failure 1.3.12 Hepatic dysfunction 1.3.13 Pulmonary oedema 1.3.14 Hypoglycaemia 1.3.15 Lactic acidosis 1.4 The clinical aspects of malaria 1.4.1 Asymptomatic infection 1.4.2 Uncomplicated malaria 1.4.3 Severe and complicated 1.4.3.1 Cerebral malaria 1.4.3.2 Acute renal failure 1.4.3.3 Jaundice 1.4.3.4 Hypotension 1.4.3.5 Metabolic acidosis 1.4.3.6 Acute pulmonary oedema 1.4.3.7 Hypoglycaemia 1.4.3.8 Black water fever 1.4.3.9 Haematological abnormalities 1.4.4 Malaria in pregnancy 8 1.5 Diagnosis 1.5.1 Conventional methods 1.5.2 Rapid diagnosis test 1.5.3 Other tests for malaria diagnosis 1.6 Laboratory findings 1.7 Antimalarial drugs CHAPTER 2 MALARIA IN VIET NAM AND THE RESEARCH SITE 2.1 Study sites 2.1.1 Geography 2.1.1.1 Climate 2.1.1.2 Population 2.1.1.3 Economy and environment 2.1.2 Health services 2.1.3 National Malaria Control Programme 2.1.4 Hospital for Tropical Diseases 2.1.5 Oxford University Clinical Research Unit 2.2 Aims of this thesis 2.3 Clinical methods. 2.3.1 Scientific and ethical approval 2.3.2 Patients, diagnosis and treatment CHAPTER 3 RANDOMIZED CONTROLLED TRIAL OF ARTESUNATE OR ARTEMETHER IN VIETNAMESE ADULTS WITH SEVERE FALCIPARUM MALARIA CHAPTER 4 RANDOMIZED COMPARISON OF PUMPED VENOVENOUS HAEMOFLTRATION AND PERITONEAL DIALYSIS IN ACUTE RENAL FAILURE ASSOCIATED WITH SEVERE INFECTION CHAPTER 5 FLUID MANAGEMENT IN SEVERE FALCIPARUM MALARIA CHAPTER 6 PARASITE STAGING AND PREDICTING OUTCOME IN SEVERE FALCIPARUM MALARIA CHAPTER 7 PREDICTIVE SCORE OF OUTCOME IN ADULTS WITH SEVERE FALCIPARUM MALARIA CHAPTER 8 ASSESSMENT OF THE EFFICACY OF ARTEMISININ DERIVATIVES IN THE TREATMENT OF SEVERE FALCIPARUM MALARIA IN VIET NAM (1991-2008) 10 CHAPTER 9 DISCUSSION REFERENCES APPENDICES LIST OF FIGURES Figure 1.1 Malaria in the world ...............................
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