7KH3HULRGLF)HYHU $SKWKRXVVWRPDWLWLV3KDU\QJLWLVDQG FHUYLFDO$GHQLWLVV\QGURPHLQFKLOGUHQ &OLQLFDODQGLPPXQRORJLFDODVSHFWV -RVWHLQ$)¡UVYROO Dissertation for the degree of philosophiae doctor (PhD) at the University of Bergen Dissertation date: WK6HSWHPEHU 2 3 4 TABLE OF CONTENTS 1 Preface ...................................................................................................................... 9 1.1 Acknowledgements ........................................................................................... 9 1.2 Summary of thesis ........................................................................................... 11 1.3 List of papers ................................................................................................... 13 1.4 Abbreviations .................................................................................................. 15 2 General introduction ............................................................................................... 17 2.1 Historical background ..................................................................................... 17 2.2 The origin of the thesis .................................................................................... 19 2.3 A brief introduction to the immune system ..................................................... 20 2.3.1 The innate immune system ....................................................................... 22 2.3.2 The adaptive immune system ................................................................... 25 2.4 Cytokines ......................................................................................................... 29 2.4.1 Interleukin-1ȕ ........................................................................................... 30 2.4.2 Tumor necrosis factor ............................................................................... 31 2.4.3 Interferon-Ȗ ............................................................................................... 32 2.4.4 Interleukin-6 ............................................................................................. 32 2.4.5 Chemokines .............................................................................................. 33 2.5 Inflammation ................................................................................................... 35 2.5.1 Initiation of inflammation ......................................................................... 35 2.5.2 The inflammatory pathway ....................................................................... 35 2.6 Fever in children .............................................................................................. 38 2.7 Periodic fever .................................................................................................. 40 2.8 The PFAPA syndrome..................................................................................... 40 2.8.1 Diagnostic criteria ..................................................................................... 40 2.8.2 Clinical presentation and prognosis .......................................................... 41 2.8.3 Laboratory tests ........................................................................................ 42 2.8.4 PFAPA as a pathological entity ................................................................ 42 2.8.5 Medical and surgical treatment ................................................................ 44 2.9 Differential diagnoses to PFAPA .................................................................... 45 2.9.1 Infections .................................................................................................. 45 2.9.2 Cyclic Neutropenia ................................................................................... 47 5 2.9.3 Childhood malignancies ........................................................................... 47 2.9.4 Autoimmune diseases ............................................................................... 48 2.9.5 Autoinflammatory diseases ...................................................................... 48 2.10 Summary of the introduction ....................................................................... 53 3 Aims of the thesis ................................................................................................... 55 4 Subjects and methods ............................................................................................. 57 4.1 Catchment area ................................................................................................ 57 4.2 Subjects and diagnosis of PFAPA ................................................................... 57 4.3 Testing procedures .......................................................................................... 58 4.4 Laboratory analyses including evaluation of tonsils ....................................... 60 4.4.1 Microbiology ............................................................................................ 60 4.4.2 Blood samples (Paper I and II) ................................................................. 60 4.4.3 Tonsils (Paper III) ..................................................................................... 62 4.5 Ethical issues ................................................................................................... 62 4.6 Statistics ........................................................................................................... 63 5 Summary of results ................................................................................................ 65 5.1 Clinical characteristics, epidemiology and outcome (Paper I): ...................... 66 5.2 Immunological aspects of PFAPA assessed by blood tests (Paper II): ........... 68 5.3 Immunological aspects of PFAPA studied in tonsils (Paper III) .................... 72 6 Discussion .............................................................................................................. 73 6.1 Methodological considerations ....................................................................... 73 6.1.1 The PFAPA diagnosis .............................................................................. 73 6.1.2 Collection of clinical data ......................................................................... 76 6.1.3 Preparation and implementation of laboratory analyzes .......................... 76 6.1.4 Control groups .......................................................................................... 78 6.1.5 Statistical considerations .......................................................................... 79 6.2 Epidemiology and clinical characteristics (Paper I) ........................................ 81 6.2.1 Setting and incidence ................................................................................ 81 6.2.2 Clinical characteristics .............................................................................. 82 6.2.3 Outcome .................................................................................................... 85 6.3 Immunological aspects of PFAPA assessed by blood tests ............................ 86 6.3.1 Immunoglobulin D and hematologic parameters ..................................... 86 6.3.2 Cytokines, chemokines and soluble receptors .......................................... 88 6.3.3 Other perspectives .................................................................................... 91 6 6.4 Immunological aspects of PFAPA studied in tonsils ...................................... 92 7 Conclusion .............................................................................................................. 95 8 Future Perspectives: ............................................................................................... 96 9 Reference list .......................................................................................................... 97 10 Errata ................................................................................................................. 117 11 Appendix ........................................................................................................... 118 12 Paper number I-III ............................................................................................ 121 7 8 1 Preface 1.1 Acknowledgements This research project has been carried out with financial support from the Pediatric Department and the Department of research at the Stavanger University Hospital. First, I want to express my gratitude to all the participating children. Without them and their enthusiastic parents, this research would not have been possible. After years of studying the periodic fever, aphthous stomatitis and cervical adenitis syndrome, meeting a new child with this disorder still amazes me. My main supervisor Professor Knut Øymar at the Pediatric Department of Stavanger University Hospital, triggered my interest for medical research, when I was engaged in a small project almost 10 years ago. I’m deeply grateful for the wise guidance, continuous support and inspiration that he has offered me throughout this PhD project. His infinite patience and positive attitude made me believe that any problem can be solved, and made me focus on the goal not the obstacles. I want to thank my co-supervisor Professor Einar Klæboe Kristoffersen at the Department of Immunology and Transfusion Medicine, Haukeland University Hospital for his devotion to this project. He has given me important advice and constructive feedback.