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The Burden and Spectrum of Paediatric Severe Malaria and Aetiology of Dark Urine Syndrome in Eastern Uganda

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The Burden and Spectrum of Paediatric Severe Malaria and Aetiology of Dark Urine Syndrome in Eastern Uganda Open Research Online The Open University’s repository of research publications and other research outputs The Burden and Spectrum of Paediatric Severe Malaria and Aetiology of Dark Urine Syndrome in Eastern Uganda Thesis How to cite: Olupot-Olupot, Peter (2015). The Burden and Spectrum of Paediatric Severe Malaria and Aetiology of Dark Urine Syndrome in Eastern Uganda. PhD thesis The Open University. For guidance on citations see FAQs. c 2015 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.0000efe5 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 The Burden and Spectrum of Paediatric Severe Malaria and Aetiology of Dark Urine Syndrome in Eastern Uganda Dr. Peter Olupot-Olupot, MB.Ch.B, MPH A thesis submitted for the degree of Doctor of Philosophy The Open University September 2014 Sponsoring Establishment KEMRI-Wellcome Trust Programme, Kilifi (OU Affiliated Research Centre) JDiVrigr ci- SJisvniSS’i o»"'i "■ | <Dcrrc:'OG-tZ 2 . 0 1 £?- ProQuest Number: 13834846 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 13834846 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 From May 2011 - April 2012,1 prospectively conducted paediatric ward admissions surveillance (WSS) and described both the in-patient burden and clinical spectrum of severe P. falciparum malaria (SM) in children admitted to Mbale Regional Referral Hospital (Mbale RRH). Furthermore, epidemiology, clinical features and the outcomes of dark urine syndrome (DUS) were described using both retrospective dark urine epidemiological study (REDUES); (FEAST trial ISRCTN 69856593) and the prospective dark urine epidemiological study (PRODUES) nested in the WSS. Overall 10,208/23,217 (44.0%) children were enrolled in the WSS, a majority 87% were under 5 years of age. Malaria 6,714/10,208 (65.8%) and DUS 1,087/10,208 (10.6%) were among the common diagnoses. Neonatal conditions accounted for 947/9,551 (10.0%) admissions. The in-hospital mortality was high 655 (6.4%); with higher case fatality rate (CFR) 13.2% in neonates compared to 3.7% in older children, P=0.0001. The WHO criteria for surveillance of severe malaria were fulfilled in 662 admissions or 10% of all malaria cases. The common clinical presentations included respiratory distress 554/662 (83.7%), shock 411/662 (62.1%), clinical jaundice 177/662 (26.7%), severe anaemia 169/662 (25.5%), hyperlactataemia 134/662 (20.3%) and DUS 93/662 (14.0%); features similar to, but also varying from those reported from other settings. The mortality in SM was high 63/662 (9.5%) but consistent with other reports, with higher CFR in patients with multiple features. i Olupot-Olupot PhD Thesis Abstract In the REDUES, 394/3,170 (12.4%) had DUS with a majority 318/394 (81.0%) presenting to Eastern Uganda. Complications of DUS included clinical jaundice in 256/318 (80.5%) and severe anaemia (Hb <5g/dL) in 238/310 (77.0%). Current malaria infection 147/300 (49.0%) was lower than evidence of recent infection 192/246 (78.0%). G6PD was marginally higher in DUS 35/224 (15.6%) v 53/489 (10.8%) in those without DUS. Mortality at 48hours (10.4% v 8.9%, P=0.402) and at 28 days (12.3% v 9.9%, P=0.211) was similar in children with and without DUS respectively. PRODUES enrolled 268 strictly defined cases in whom use of antimalarials 129/268 (48.1%) and herbs 52/268 (19.4%) were common. Haemoglobinuria 92/165 (55.8%) and myoglobinuria 59/165 (36.0%), markers of massive haemolysis and muscle cell injury respectively were found; possibly related to the pathophysiology of malaria. In conclusion, the spectrum of SM in children at Mbale RRH was similar to, but also varied from current descriptions from other sites. The DUS was linked to malaria with innate characteristics and drugs being risk factors. Olupot-Olupot PhD Thesis Abstract List of abbreviations Abbreviation Meaning AARR Annual Average Reduction Rates AHG Anti-human Globin AIDS Acquired Immunodeficiency Syndrome APGAR Activity, Pulse, Grimace, Appearance & Respiration ARF Acute Renal Failure ART Antiretroviral Therapy BCS Blantyre Coma Scale CBC Complete Blood Count CFR Case Fatality Rate Cl Confidence Intervals CM Cerebral Malaria CNS Central Nervous System CRF Case Record Form CSF Cerebrospinal Fluid DNA Deoxyribonucleic Acid DRC Democratic Republic of the Congo DUS Dark Urine Syndrome EDTA Ethylenediaminetetraacetic Acid EIR Entomological Inoculation Rates ELISA Enzyme-linked Immunosorbant Assay Olupot-Olupot PhD Thesis List of Abbreviations ETAT Emergency Triage and Treatment FBC Full Blood Counts G6PD Glucose-6-Phosphate Dehydrogenase Deficiency Hb Haemoglobin HCC Hammersmith Colour Chart Hct Haematocrit HiB Haemophilus Influenza-B HIV Human Immunodeficiency Virus HIE Hypoxic Ischaemic Encephalopathy HMIS Health Management Information System HRP-2 Histidine Rich Protein - 2 ICD International Classification of Diseases IMCI Integrated Management of Childhood Illnesses IRR Incident Rate Ratio IV Intravenous JCRC Joint Clinical Research Centre Kg Kilogram Km Kilometre KWTRP KEMRI Wellcome Trust Research Programme LP Lumbar Puncture MDG Millennium Development Goals mg Milligram Olupot-Olupot PhD Thesis List of Abbreviations m g/Kg Milligrams per kilogram mm Millimetre mmHg Millimetres of Mercury mmol Millimoles MOH Ministry of Health, Uganda MOP Manual of Operations MTA Material Transfer Agreement MUAC Mid Upper Arm Circumference nPRBC Non-parasitised red blood cells °C Degree Centigrade OR Odds ratio P. Plasmodium PACU Paediatric Acute Care Unit PAR Paediatric Admission Record PCP Pneumocystis Carinii Pneumonia PCV Pneumococcal Conjugate Vaccine PEM Protein Energy Malnutrition PI Principal Investigator PIDC Paediatric Infectious Diseases Clinic pLDH Plasmodium Lactate Dehydrogenase pRBC Parasitised Red Blood Cells PRODUES Prospective Dark Urine Epidemiological Studies Olupot-Olupot PhD Thesis List of Abbreviations RBC Red Blood Cell RDT Rapid Diagnostic Test for malaria REDUES Retrospective Dark Urine Epidemiological Studies RPM Revolutions per Minute RR Relative Risk RSV Respiratory Syncytial Virus SA Severe Anaemia SAM Service availability Mapping SaC>2 Saturation of Oxygen SEA South East Asia SOP Standard Operating Procedure SSA Sub Saharan Africa TB Tuberculosis TIH Treatment Induced Hypoglycaemia TMB Tetramethyl Benzidine TNF-a Tumor Necrosis Factor-alpha UBOS Uganda Bureau of Statistics U5 Under 5 URTI Upper Respiratory Tract Infection V Versus WBC White Blood Cells WCC White Blood Cell Count WHO World Health Organization Olupot-Olupot PhD Thesis List of Abbreviations Dedication To my wife Harriet and our two lovely children Nissi and Libni. vii Olupot-Olupot PhD Thesis Dedication Acknowledgements First and foremost, I would like to give thanks to God. I know it is by His Grace that I am what I am and I have what I have! I am extremely grateful in a special way to my three supervisors, Professor Kathryn Maitland, my Director of Studies for her high quality professional guidance throughout this study. Professor Thomas N. Williams for his supervision and a very rare gift of constructive and highly productive interrogation of my research data. Professor Charles Karamagi for his supervision and patience through this rigorous process. You will remain special to me throughout my research career and I firmly say thank you so very much. I thank the SMAC and third party monitor (3PM) for all their input. Dr. Charles Engoru (3PM), thank you for your dedicated monitoring and guidance during this long journey. I am very thankful to all the members of my research team at the Mbale Regional Referral Hospital Clinical Research Unit (MCRU), including Dr. Julius Nteziyaremye, Dr. Martin Chebet, Ms. Rita Muhindo, Mr. Tonny Ssenyondo, the nursing and data entry teams. I recognize your support and I am proud of you. I would like to thank, in a special way the entire FEAST study team and its leadership steered by Professor Kathryn Maitland. The FEAST trial opened my research insight v jjj Olupot-Olupot PhD Thesis Acknowledgements and broke my small-research-cocoon into the world of big-research-exploits. What a transformation! I say thank you to the FEAST Trial Steering Committee (TSC) for permitting me to use the FEAST data for part of my thesis. I give special recognition and gratitude to Professor Thomas N. Williams for allowing me to process and analyze my study samples in his laboratory in Kilifi. This same gratitude goes to all his laboratory team without exception. Special mention includes Dr. Sophie Uyoga, Mr. Alex Macharia and Ms. Emily Nyatichi for their tireless efforts in the laboratory procedures. I sincerely thank Mr. Gideon Nyutu who helped with the database design and GPS data analysis. This contribution was vital for the completion of this study. I cherish the support and good working environment provided by the staff and administration of Mbale Regional Referral Hospital. In a special way I will mention Dr. Benon Wanume, the Hospital Director, Dr. J.S.O. Obbo, the Deputy Hospital Director, Dr. Crispus Tegu then Head of Department Paediatrics and Child Health, Dr. Andrew Kasoro the current head of Department Paediatrics and child health and all staff in the paediatric acute care unit.
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