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Rheumatic Heart Disease in Egypt

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Rheumatic Heart Disease in Egypt Rheumatic Heart Disease in Egypt Susy Natália Mohamed Kotit M.D. Supervised by Professor Sir Magdi Yacoub A thesis submitted for the award of Doctor of Philosophy (PhD) Imperial College London Faculty of Medicine National Heart and Lung Institute Imperial College London and Division of Tissue Engineering The Magdi Yacoub Institute Harefield Heart Science Centre Abstract Rheumatic Heart Disease remains one of the most neglected cardiac conditions in children and young adults around the world. The pathogenesis is complex and remains elusive, and the clinical characteristics vary around the world. This thesis concentrates on different aspects of the disease in Egypt, where it is known to have a high incidence. The methodology included epidemiological studies in school children in Aswan and investigation of RHD in a population with history of RF, using newly developed echocardiographic criteria. Concomitantly, the pattern of immune response in RF and RHD was determined in serum and excised valves. In this series RF presents in children and young adults, as well as adults, (0.2-44 years, 10.69 ± 6.24) with polyarthritis being the most common clinical presentation (87.9%) and recurrences of RF being very common (98.2%). RHD affected 23 in 1000 school children in Aswan with over 90% of the cases being subclinical and developed in up to 69.2% of the individuals with history of RF, predominantly as mitral regurgitation. Risk factors for the development and severity of RHD were shown to be low disease awareness, non-compliance to penicillin prophylaxis or a regimen of longer than 15-days. Resistance to antibiotic regimens, including Penicillin and Vancomicin seems to lead to development and recurrences of RF in Egypt. This series showed the presence of immune activation and ongoing immunological reaction in an apparently quiescent phase of the disease with distortion of normal valvular architecture, histology and composition. This work has served to define the epidemiology, pattern of disease, immune reponse and predisposing factors in a population with no previous data, also contributing to the improvement of the echocardiographic diagnostic criteria. Standardization of the criteria will allow comparison of prevalence in different areas and improve case detection. ―We don't believe in Rheumatic Fever or true love until the first attack...” (Adapted from: Marie Von Ebner-Eschenbach (Austrian novelist, 1830-1916)) This work is dedicated to my beloved father and mother, Mohamed and Maria do Céu Kotit Forgive me Forgive me for all missed occasions Holidays, birthdays, anniversaries Forgive me for not being there Every moment, every second, every day Forgive me for not sharing your joy and happiness And for not always showing how much I care Forgive me for not drying your tears Or talk you out of your fears Forgive me for not holding your hand When you most needed Forgive me for all missed kisses And the phone good night wishes But only my pillow knows How much my heart misses You’re always in my heart I’ll carry you with me all my life You are my safe port My shining star My home You are everything and more Susy Natália Acknowledgements First of all, I thank God, for guiding and supporting me. Studying at Imperial College and being able to research into a subject that is so important and affects the lives of so many people especially in my country was for me a unique privilege. I feel humbled and extremely fortunate to have been given this opportunity, and thank the Magdi Yacoub Institute and Magdi Yacoub Foundation for funding and supporting this research. I am sincerely indebted to my supervisor Professor Sir Magdi Yacoub for his inspiration, enthusiasm and constant guidance throughout the duration of my studies, and for giving me the freedom and support to develop my own ideas. I‘m deeply grateful to Dr Karim Said and Dr Amr ElFaramawy for their supervision, help and support as well as all my colleagues and personnel at the Aswan Heart Centre for their delighting involvement and care. My sincere gratitude to the nurses that accompanied me on my adventurous trips to the schools. I would like to express my gratitude to the Egyptian Ministry of Health and Education and the Governorate of Aswan, the schools and teachers of Aswan District for their help in the preparation and implementation of the community study, and to all collaborators at the Aswan Heart Centre, National Heart Institute, Harefield Heart Science Centre, Helmholtz Centre for Infection Research, and Imperial College London, for their valuable contributions to the studies. My special thank you to the individuals recruited and the school children of Aswan. Not enough words to explain how grateful I am to my parents for their unconditional love, care, understanding and support during this demanding period and throughout my whole life. A special dedication to my grandmother, Albertina, my little brother Magdy and someone special in my life, Ahmed Nabil. Table of contents Table of Contents CHAPTER 1 INTRODUCTION .................................................................................................. 19 1.1 Background ............................................................................................................................. 20 Summary ....................................................................................................................................... 20 1.2 Rheumatic Fever ..................................................................................................................... 22 1.2.1 Presentation ....................................................................................................................................... 23 1.2.2 Diagnosis ........................................................................................................................................... 24 1.2.3 Diagnostic tools ................................................................................................................................. 26 1.3 Rheumatic Heart Disease ........................................................................................................ 29 1.3.1 Clinical presentation .......................................................................................................................... 30 1.3.2 Risk factors......................................................................................................................................... 32 1.3.3 Prevention .......................................................................................................................................... 33 Secondary prevention .......................................................................................................................... 34 1.3.4 Screening............................................................................................................................................ 35 1.4 Echocardiography ................................................................................................................... 36 1.4.1 Echocardiographic criteria................................................................................................................ 36 1.5 Pathogenesis ............................................................................................................................ 39 1.5.1 Molecular mimicry ............................................................................................................................. 40 1.5.2 Cellular and humoral immune response ............................................................................................ 40 1.5.2.1 Cytokines ................................................................................................................................. 42 1.5.3 Cellular and humoral response in valvular tissue ............................................................................. 48 1.5.4 Valvular architecture ......................................................................................................................... 50 1.5.5 Structural and biochemical imaging techniques ................................................................................ 52 1.6 Streptococcal pathogenesis ..................................................................................................... 54 1.6.1 GAS .................................................................................................................................................... 55 1.6.1.1 Variety of M-types ................................................................................................................... 56 M protein amino (N)-terminus ............................................................................................................ 57 1.6.2 Group C streptococci (GCS) and group G streptococci (GGS)......................................................... 57 1.6.3 Streptococcal PARF peptide and human collagen IV ........................................................................ 58 Rheumatic Heart Disease in Egypt CHAPTER 2 AIMS AND PLAN OF INVESTIGATION ........................................................... 60 2.2 Plan of investigation ............................................................................................................... 62 DETERMINATION OF THE EPIDEMIOLOGICAL AND CLINICAL CHARACTERISTICS OF RF AND RHD ...........................................................................................................................................
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