Aus dem Centrum für Chronische Immundefizienz des Universitätsklinikums Freiburg im Breisgau The Characteristics of Viral Skin Infections in the Immunocompromised Host ________________________________________ I N A U G U R A L - D I S S E R T A T I O N zur Erlangung des Medizinischen Doktorgrades der Medizinischen Fakultät der Albert-Ludwigs-Universität Freiburg i. Br. Vorgelegt 2018 von Svenja Abel geboren in Emmendingen Dekan: Prof. Dr. Norbert Südkamp Erstgutachter: Prof. Dr. Bodo Grimbacher Zweitgutachterin: Dr. Siobhan Burns Jahr der Promotion: 2019 Contents Contents Contents ................................................................................................................................ I List of Figures ..................................................................................................................... III List of Tables ........................................................................................................................ V List of Abbreviations .......................................................................................................... VI 1 Introduction ................................................................................................................. 1 1.1 Skin Infections ........................................................................................ 1 1.2 Common Viral Skin Infections ............................................................... 1 1.2.1 Herpes Viruses ............................................................................. 1 1.2.2 Human Papilloma Virus ................................................................. 4 1.3 Viral Infections and Immune Response ................................................ 5 1.3.1 Immune Control of Viruses ............................................................ 5 1.3.2 Herpes simplex Infections ............................................................. 7 1.3.3 Varizella Zoster Infections ............................................................. 8 1.3.4 HPV Infections .............................................................................. 9 1.4 Primary immunodeficiencies (PID) with a Susceptibility to HSV or HPV Infections ....................................................................................................... 10 1.4.1 Onset in Childhood ..................................................................... 10 1.4.2 PID Onset in Adulthood ............................................................... 12 1.5 Treatment .............................................................................................. 15 1.5.1 HSV Treatment ........................................................................... 15 1.5.2 VZV Treatment............................................................................ 18 1.5.3 HPV Treatment ........................................................................... 20 2 Study Aims ................................................................................................................ 25 3 Materials and Methods .............................................................................................. 26 3.1 Recruitment of Participants ................................................................. 26 3.2 Ethical Approval and Consent Forms ................................................. 26 3.3 Study Design ........................................................................................ 26 3.3.1 Identification of Patients .............................................................. 26 3.3.2 Approaching Patients .................................................................. 27 3.3.3 Data Collection............................................................................ 27 3.3.4 Questionnaires ............................................................................ 29 3.3.5 Dermatology Quality of Life Index ............................................... 30 3.3.6 Isolation of PBMC from Whole Blood .......................................... 30 3.3.7 HPV Phenotyping ........................................................................ 31 3.4 Data Analysis ........................................................................................ 34 3.4.1 HPV Type Analysis ..................................................................... 34 I Contents 3.4.2 DLQI Analysis ............................................................................. 34 3.4.3 Blood Values Analysis ................................................................. 35 3.4.4 Treatment ................................................................................... 35 4 Results ....................................................................................................................... 37 4.1 Characteristics of Patients with Warts ................................................ 37 4.2 Characteristics of Patients with Herpes.............................................. 38 4.3 HPV Type Analysis ............................................................................... 41 4.4 Dermatology Quality of Life Index (DLQI) Analysis............................ 44 4.5 Blood Analysis...................................................................................... 50 4.5.1 Immunodeficiency Panel ............................................................. 51 4.5.2 T Cell Phenotyping ...................................................................... 55 4.5.3 B Cell Phenotyping ..................................................................... 55 4.5.4 Immunoglobulins ......................................................................... 57 4.6 Treatment .............................................................................................. 59 4.6.1 Warts Patients............................................................................. 59 4.6.2 Herpes Patients .......................................................................... 63 5 Discussion ................................................................................................................. 68 5.1 Clinical Features of Patients ................................................................ 68 5.1.1 Characteristics of Patients with Warts ......................................... 68 5.1.2 Characteristics of Patients with Herpes ....................................... 70 5.2 Immunology Features of Patients ....................................................... 72 5.3 Dermatology Quality of Life Index (DLQI) ........................................... 76 5.3.1 Patients with warts ...................................................................... 76 5.3.2 Herpes Patients .......................................................................... 78 5.4 Treatment of Patients ........................................................................... 80 5.4.1 Wart Patient’s Treatment ............................................................ 80 5.4.2 Herpes Patient’s Treatment......................................................... 83 6 Summary and Conclusion ........................................................................................ 87 7 Zusammenfassung ................................................................................................... 88 8 References .................................................................................................................. IX 9 Appendix.............................................................................................................. XXXVI 9.1 Blood Values Spreadsheet............................................................ XXXVI 9.2 Questionnaire Dermatology Quality of Life Index (DLQI) ................. XL 9.3 Questionnaire Herpes Patients ......................................................... XLII 9.4 Questionnaire Wart Patients .......................................................... XLVIII 9.5 Eidesstattliche Versicherung ............................................................. LIV 10 Acknowledgements................................................................................................... LV II List of Figures List of Figures Figure 1: β- and α-HPV type virus prevalence .............................................................. 42 Figure 2: HPV genotype distribution by anatomical location ......................................... 43 Figure 3: A. DLQI scores for warts and herpes patients; B. DLQI scores for warts and herpes patients divided into groups ........................................................ 45 Figure 4: Comparison between the herpes no outbreak cohort Q (1/1) and Q (1/2) groups and the herpes outbreak cohort ......................................................... 46 Figure 5: DLQI for when patients answer, “not at all” .................................................... 48 Figure 6: DLQI for when patients answer, “a little” ........................................................ 48 Figure 7: DLQI for when patients answer, “a lot” .......................................................... 49 Figure 8: DLQI for when patients answer, “very much” ................................................. 49 Figure 9: DLQI for when patients answer, “not relevant” .............................................. 50 Figure 10: Comparing lymphocyte count of the warts cohort (divided into CVID and no-PID patients in plot B), DOCK8 and IL7Ra deficient patients and herpes cohort ...............................................................................................