Current status of serious fungal infections in Nigeria A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Faculty of Biology, Medicine and Health. 2017 Rita Okeoghene OLADELE School of Biological Sciences Division of Infection, Immunity anD Respiratory MeDicine CONTENTS Page LIST OF FIGURES ............................................................................................................ 6 LIST OF TABLES ............................................................................................................. 7 Abbreviations ............................................................................................................... 9 Abstract ...................................................................................................................... 11 Declaration ................................................................................................................. 12 Copyright Statement ................................................................................................... 12 The author .................................................................................................................. 13 Acknowledgements .................................................................................................... 14 Thesis structure .......................................................................................................... 16 Chapter 1 .................................................................................................................... 19 1.1 Introduction .......................................................................................................................... 19 1.2 Endemic mycosis - Histoplasmosis ........................................................................................ 25 1.2.1 Epidemiology ................................................................................................................. 25 1.2.2 Histoplasmosis in Nigeria ............................................................................................... 29 1.2.3 Diagnosis ........................................................................................................................ 31 1.2.3 Treatment ...................................................................................................................... 34 1.3 Pneumocystosis ................................................................................................................... 35 1.3.1 Epidemiology ................................................................................................................. 35 1.3.1.1 Burden in Africa ...................................................................................................... 36 1.3.2 Outbreaks ...................................................................................................................... 37 1.3.3 Clinical presentation ...................................................................................................... 38 1.3.4 Diagnosis ........................................................................................................................ 41 1.3.4.1 Microscopy .............................................................................................................. 42 1.3.4.2 PCR .......................................................................................................................... 43 1.3.4.3 β-1-3-D-glucan (BG) ................................................................................................ 44 1.3.4.4 S-Adenosyl-L-methionine (AdoMet) ....................................................................... 45 1.3.4.5 Lactate dehydrogenase (LDH) ................................................................................. 46 1.3.4.6 Culture .................................................................................................................... 46 1.3.5 Treatment ...................................................................................................................... 47 1. 4 Aspergillosis ......................................................................................................................... 49 1.4.1 Hypersensitivity/allergic disease .................................................................................... 50 1.4.2 Invasive aspergillosis (IA) ............................................................................................... 51 1.4.2.1 Diagnosing IA .......................................................................................................... 52 2 1.4.2.2 Laboratory diagnosis of IA ...................................................................................... 53 1.4.2.2.1 Biomarkers ........................................................................................................... 53 1.4.2.2.2 Other “biomakers” ............................................................................................... 54 1.4.2.2.3 PCR ....................................................................................................................... 55 1.4.3 Chronic pulmonary aspergillosis (CPA) .......................................................................... 56 1.4.3.1 Epidemiology .......................................................................................................... 56 1.4.4 Tracheobronchial aspergillosis ....................................................................................... 59 1.5 Cryptococcosis ...................................................................................................................... 59 1.5.1 Epidemiology ................................................................................................................. 59 1.5.2 Laboratory diagnosis ...................................................................................................... 62 1.5.3 Treatment ...................................................................................................................... 63 1.5.3 Treatment outcomes ..................................................................................................... 66 1.6. Rationale of research described in this thesis ..................................................................... 68 1.7. Aims of research .................................................................................................................. 68 1.7.1 - Specific aims ................................................................................................................ 69 References .................................................................................................................................. 69 Chapter 2 .................................................................................................................... 97 2.1 - Study 1 - Seroprevalence of cryptococcal antigenemia in HIV infected patients in Lagos, Nigeria ......................................................................................................................................... 97 2.2- Study 2 - Evaluation of chronic pulmonary aspergillosis (CPA) as a cause of smear-negative TB and or anti-TB treatment failure in HIV-infected Nigerians. ................................................ 100 2.3 Study 3 - Histoplasmosis in Africa ....................................................................................... 107 2.4 Study 4 - Histoplasmin skin sensitivity survey ..................................................................... 108 2.5 Study 5 - Intensive Care Unit acquired infections in the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. .............................................................................................................. 111 2.6 Study 6 – Invasive Candida infections in a Nigerian neonatal intensive care unit (NICU) .. 119 2.7 – Study 7 - A 12-year retrospective study of opportunistic fungal infections in HIV infected patients attending a PEPFAR clinic in Nigeria ........................................................................... 121 References ................................................................................................................................ 122 Chapter 3 .................................................................................................................. 124 Paper 1 = Seroprevalence of cryptococcal antigenemia in HIV infected patients in Lagos, Nigeria. Published as: Oladele R, Akanmu S, Nwosu A, Ogunsola F, Richardson MD, Denning DW. Prevalence of cryptococcal antigenemia in antiretroviral naïve and antiretroviral experienced HIV infected patients with CD4+ count below 250 cells/mm3 in Lagos, Nigeria. Open Forum Infect Dis 2016; 3:ofw055. ................................................................................... 124 Abstract ..................................................................................................................................... 124 Introduction .............................................................................................................................. 126 Methods .................................................................................................................................... 126 3 Results ....................................................................................................................................... 128 Discussion ................................................................................................................................