Final Report 2006 - ESPED · ESPED study group - reporting physicians (cf. Appendix A ) EURODIAB...

VARICELLA ZOSTER VIRUS INFECTION

Hospitalisations and Complications

in Children and Adolescents Germany, 2003–2004

Final Report 2006

EURODIAB

ICD-10

ESPED

Varicella Zoster Virus Infection

Hospitalisations and Complications in Children and Adolescents

Germany, 2003 - 2004

– Final Report –

April 2006

Principal Investigators: PD Dr. Johannes Liese, MSc Kinderklinik und Poliklinik im Dr. v. Haunerschen Kinderspital Lindwurmstr. 4 80337 Munich, Germany Tel: +49/89/5160 -3120, Fax: -3138 E-mail: [email protected] Prof. Dr. Rüdiger von Kries, MSc Institut für Soziale Pädiatrie, Epidemiologie und Jugendmedizin der LMU Munich Heiglhofstr. 63 81377 Munich, Germany Tel: +49/89/71009 -314, Fax: -315 E-mail: [email protected] Study Coordination: Dr. Veit Grote, MSc Kinderklinik und Poliklinik im Dr. v. Haunerschen Kinderspital Lindwurmstr. 4 80337 Munich, Germany Tel: +49/89/5160 -7798, Fax: -2951 E-mail: [email protected] Dr. Richela Fischer, MPH Eva Rosenfeld, MSc Institut für Soziale Pädiatrie, Epidemiologie und Jugendmedizin der LMU Munich Heiglhofstr. 63 81377 Munich, Germany Tel: +49/89/71009 -120, Fax: -315 E-mail: [email protected] Other Participating Institutions: ESPED Arbeitsgruppe der Kinderklinik der Heinrich-Heine-Universität Postfach 102244 40013 Düsseldorf, Germany Tel.: +49/211/81/162 -63, Fax: -62 ESPED study group - reporting physicians (cf. Appendix A ) EURODIAB Dr. Joachim Rosenbauer Deutsches Diabetes-Forschungsinstitut (German Diabetic Research

Centre) an der Heinrich-Heine Universität Auf’m Hennekamp 65 40225 Düsseldorf, Germany Tel. +49/211/3382-278 Supporters: Sanofi Pasteur MSD GmbH, Leimen, Germany GlaxoSmithKline Biologicals, Rixenart, Belgium GlaxoSmithKline GmbH & Co.KG, Munich, Germany

Final report – VZV hospitalisations in Germany page i

Contents

CONTENTS..................................................................................................................................................................I ABBREVIATIONS .................................................................................................................................................... V LIST OF TABLES ....................................................................................................................................................VI LIST OF FIGURES ..................................................................................................................................................IX

1 BACKGROUND................................................................................................................................................. 1 2 OBJECTIVES .................................................................................................................................................... 5

2.1 MAIN OBJECTIVE............................................................................................................................................. 5 2.2 SECONDARY OBJECTIVES ................................................................................................................................ 5

3 METHODS ......................................................................................................................................................... 6 3.1 GENERAL STUDY DESIGN................................................................................................................................ 6 3.2 PARTICIPATING INSTITUTIONS ......................................................................................................................... 6 3.3 ESPED: PAEDIATRIC HOSPITAL SURVEILLANCE............................................................................................. 7

3.3.1 ESPED: Structure ................................................................................................................................ 7 3.3.2 ESPED: Questionnaire ........................................................................................................................ 7 3.3.3 ESPED: Logistics ................................................................................................................................. 8 3.3.4 ESPED: Study population.................................................................................................................... 8 3.3.5 ESPED: Case definition....................................................................................................................... 8 3.3.6 ESPED: Study period........................................................................................................................... 9

3.4 EURODIAB: PRACTITIONER SENTINEL IN NORTH-RHINE WESTPHALIA ........................................................ 9 3.4.1 EURODIAB: Structure ........................................................................................................................ 9 3.4.2 EURODIAB: Study population.......................................................................................................... 10 3.4.3 EURODIAB: Case definition and study period................................................................................. 10

3.5 ICD10: PAEDIATRIC HOSPITAL SURVEILLANCE ............................................................................................ 10 3.5.1 ICD10 Background ............................................................................................................................ 10 3.5.2 ICD10 PILOT STUDY (Bavaria/ North-Rhine Westphalia 2003) ................................................... 10

3.5.2.1 ICD10 PILOT STUDY: Objectives.............................................................................................. 11 3.5.2.2 ICD10 PILOT STUDY: Study design.......................................................................................... 11 3.5.2.3 ICD10 PILOT STUDY: Structure and logistics ........................................................................... 11 3.5.2.4 ICD10 PILOT STUDY: Case definition ...................................................................................... 12

3.5.3 ICD10 STUDY in North-Rhine Westphalia 2003-2004 .................................................................... 13 3.5.3.1 ICD10 STUDY NRW 2003-2004: Structure................................................................................ 13 3.5.3.2 ICD10 STUDY NRW 2003-2004: Paediatric hospitals ............................................................... 13 3.5.3.3 ICD10 STUDY NRW 2003-2004: Objectives ............................................................................. 13 3.5.3.4 ICD10 STUDY NRW 2003-2004: Case definition ...................................................................... 13 3.5.3.5 ICD10 STUDY NRW 2003-2004: Categorising of ICD10 codes................................................ 14

3.6 DATA ANALYSIS ............................................................................................................................................ 15 3.6.1 Missing values .................................................................................................................................... 15

3.7 ETHICAL CONSIDERATIONS............................................................................................................................ 16 3.8 DATA PROTECTION ........................................................................................................................................ 16

Final report – VZV hospitalisations in Germany page ii

4 ESPED: RESULTS .......................................................................................................................................... 17 4.1 ESPED: PERFORMANCE AND DATA PROFILE ................................................................................................. 17 4.2 ESPED: VARICELLA HOSPITALISATIONS ...................................................................................................... 18

4.2.1 General characteristics....................................................................................................................... 18 4.2.2 Hospital stay ....................................................................................................................................... 19 4.2.3 Therapy............................................................................................................................................... 19

4.2.3.1 Acyclovir and antibiotics.............................................................................................................. 19 4.2.3.2 Surgery ......................................................................................................................................... 19

4.2.4 Underlying chronic diseases .............................................................................................................. 20 4.2.5 Clinical symptoms associated with varicella hospitalisations ........................................................... 21 4.2.6 Complications associated with varicella hospitalisations ................................................................. 22

4.2.6.1 Children without specific varicella-associated complications indicated ...................................... 24 4.2.6.2 Neurologic complications............................................................................................................. 25

4.2.6.2.1 Meningoencephalitis ............................................................................................................. 32 4.2.6.2.2 Cerebral infarct and vasculitis............................................................................................... 35

4.2.6.3 Skin infectious complications....................................................................................................... 40 4.2.6.4 Lower respiratory tract complications .......................................................................................... 40 4.2.6.5 Haematological complications ..................................................................................................... 41 4.2.6.6 Upper respiratory tract, ENT and eye complications.................................................................... 41 4.2.6.7 Gastrointestinal tract complications ............................................................................................. 41

4.2.6.7.1 Liver affection....................................................................................................................... 42 4.2.6.8 Reactive arthritis........................................................................................................................... 43 4.2.6.9 Complications due to other systemic bacterial infections............................................................. 43 4.2.6.10 Complications due to coagulation disorders and sequelae.................................................... 46 4.2.6.11 Other complications .............................................................................................................. 46

4.2.7 Risk factors for varicella complications ............................................................................................ 48 4.2.7.1 Age, complications and chronic disease....................................................................................... 48 4.2.7.2 Hospital stay, complications and chronic disease......................................................................... 48 4.2.7.3 Gender and complications ............................................................................................................ 50 4.2.7.4 Complications in immunocompromised children......................................................................... 50

4.2.8 Hospitalisations in patients with previous VZV-vaccination ............................................................ 52 4.2.9 Concomitant occurrence of varicella and herpes zoster ................................................................... 52 4.2.10 Sequelae associated with varicella ..................................................................................................... 53 4.2.11 Deaths associated with varicella ........................................................................................................ 54

4.3 ESPED: HERPES ZOSTER HOSPITALISATIONS................................................................................................ 60 4.3.1 General characteristics....................................................................................................................... 60 4.3.2 Hospital stay ....................................................................................................................................... 60 4.3.3 Therapy............................................................................................................................................... 61 4.3.4 Underlying chronic diseases .............................................................................................................. 61 4.3.5 Symptoms and localisation of rash .................................................................................................... 62 4.3.6 Complications associated with herpes zoster hospitalisations .......................................................... 63

Final report – VZV hospitalisations in Germany page iii

4.3.6.1 Skin infectious complications....................................................................................................... 64 4.3.6.2 Meningoencephalitis..................................................................................................................... 64 4.3.6.3 Other complications...................................................................................................................... 66

4.3.7 Risk factors for herpes zoster complications ..................................................................................... 66 4.3.7.1 Gender and complications ............................................................................................................ 66 4.3.7.2 Age, complications and chronic disease....................................................................................... 66 4.3.7.3 Hospital stay, complications and chronic disease......................................................................... 66 4.3.7.4 Complications in immunocompromised children......................................................................... 67

4.3.8 Sequelae associated with herpes zoster.............................................................................................. 67 5 EURODIAB: RESULTS.................................................................................................................................. 68

5.1 EURODIAB: PERFORMANCE........................................................................................................................ 68 5.2 EURODIAB: DESCRIPTION OF VARICELLA CASES ........................................................................................ 68 5.3 EURODIAB: DESCRIPTION OF HZ CASES..................................................................................................... 69

6 ICD10 PILOT STUDY (BAVARIA/NRW 2003): RESULTS ...................................................................... 70 6.1 ICD10 PILOT STUDY: PERFORMANCE ............................................................................................................ 70 6.2 ICD10 PILOT STUDY: GENERAL CHARACTERISTICS OF VARICELLA HOSPITALISATIONS................................. 71 6.3 ICD10 PILOT STUDY: HOSPITAL STAY OF VARICELLA HOSPITALISATIONS ..................................................... 71 6.4 ICD10 PILOT STUDY: COMPLICATIONS OF VARICELLA HOSPITALISATIONS.................................................... 71 6.5 ICD10 PILOT STUDY: CONCLUSIONS ............................................................................................................. 71

7 ICD10 STUDY NRW 2003-2004: RESULTS................................................................................................. 73 7.1 ICD10 STUDY NRW 2003-2004: PERFORMANCE AND DATA PROFILE ........................................................ 73 7.2 ICD10 STUDY NRW 2003-2004: VARICELLA HOSPITALISATIONS.............................................................. 74

7.2.1 General characteristics....................................................................................................................... 74 7.2.2 Underlying chronic diseases .............................................................................................................. 75 7.2.3 Classification of varicella hospitalisations by primary ICD10-diagnosis and underlying chronic disease ............................................................................................................................................................. 75 7.2.4 Complications ..................................................................................................................................... 76

7.2.4.1 Neurologic complications............................................................................................................. 77 7.2.4.2 Other systemic bacterial complications ........................................................................................ 78 7.2.4.3 Complications of the gastrointestinal tract ................................................................................... 78

7.2.5 Age, complications and chronic disease ............................................................................................ 78 7.2.6 Hospital stay, complications and chronic disease ............................................................................. 78

7.3 ICD10 STUDY NRW 2003-2004: HERPES ZOSTER HOSPITALISATIONS ....................................................... 81 7.3.1 General characteristics....................................................................................................................... 81 7.3.2 Underlying chronic diseases .............................................................................................................. 81 7.3.3 Classification of HZ hospitalisations by primary ICD10-diagnosis and underlying chronic disease . ............................................................................................................................................................. 82 7.3.4 Complications ..................................................................................................................................... 82

8 INCIDENCE ESTIMATES............................................................................................................................. 84 8.1 CAPTURE-RECAPTURE METHODOLOGY.......................................................................................................... 84

8.1.1 Background ........................................................................................................................................ 84 8.1.2 Assumptions........................................................................................................................................ 84

8.2 RESULTS OF CAPTURE-RECAPTURE ANALYSIS ............................................................................................... 86

Final report – VZV hospitalisations in Germany page iv

8.2.1 Comparison of hospitalisations: ESPED and EURODIAB.............................................................. 86 8.2.1.1 Varicella ....................................................................................................................................... 86 8.2.1.2 Herpes zoster ................................................................................................................................ 86

8.2.2 Comparison of hospitalisations: ESPED and ICD10-data ............................................................... 86 8.2.2.1 Varicella ....................................................................................................................................... 86

8.2.2.1.1 General characteristics .......................................................................................................... 86 8.2.2.1.2 Underlying chronic diseases ................................................................................................. 87 8.2.2.1.3 Complications ....................................................................................................................... 87

8.2.2.2 Herpes zoster ................................................................................................................................ 88 8.2.2.2.1 General characteristics .......................................................................................................... 88 8.2.2.2.2 Underlying chronic diseases ................................................................................................. 88 8.2.2.2.3 Complications ....................................................................................................................... 88

8.2.3 Comparison of hospitalisation in all three sources: Concluding remarks ....................................... 88 8.2.4 Matching............................................................................................................................................. 89

8.2.4.1 General ......................................................................................................................................... 89 8.2.4.2 Results of matching for varicella hospitalisations in NRW.......................................................... 89 8.2.4.3 Results of matching for HZ hospitalisations in NRW .................................................................. 91

8.2.5 Incidence estimates for varicella hospitalisations ............................................................................. 93 8.2.5.1 Two- and three source capture-recapture ..................................................................................... 93 8.2.5.2 Use of other methodologic approaches......................................................................................... 95

8.2.6 Incidence estimates for herpes zoster hospitalisations...................................................................... 96 8.2.6.1 Two- and three source capture-recapture ..................................................................................... 96 8.2.6.2 Use of other methodologic approaches......................................................................................... 97

9 SUMMARY ...................................................................................................................................................... 98 10 REFERENCES............................................................................................................................................... 103 11 FIGURES........................................................................................................................................................ 107 12 FINANCIAL DISCLOSURE ........................................................................................................................ 151 13 ACKNOWLEDGMENT................................................................................................................................ 152

APPENDIX A THE ESPED STUDY GROUP................................................................................................A-1

APPENDIX B PAEDIATRICIANS AND PAEDIATRIC HOSPITALS PARTICIPATING IN THE ICD10 PILOT STUDY AND ICD10 NRW 2003-2004 STUDY........................................................ B-1

APPENDIX C ICD10 CODES AND COMPLICATION CATEGORIES....................................................C-1

Final report – VZV hospitalisations in Germany page v

Abbreviations

CI Confidence interval ENT Ear, nose and throat ESPED Erhebungssystem Seltener Pädiatrischer

Erkrankungen in Deutschland (German Surveillance Unit for Rare Diseases in Childhood)

EURODIAB European Diabetes Study Group GDRC German Diabetic Research Centre HKI Department of Infectious Disease, Children's

Hospital, Ludwig-Maximilians-University Munich

HZ Herpes zoster ICD International Statistical Classification of

Diseases and Related Health Problems IQR Interquartile Range (25.-75- Percentile) KIZE Department of Paediatric Epidemiology,

Institute of Social Paediatrics and Adolescence Medicine, Ludwig-Maximilians-University Munich

NRW North Rhine-Westphalia PD Primary ICD diagnosis PY Person years SD Secondary ICD diagnosis VZV Varicella Zoster Virus WHO World Health Organisation

Final report – VZV hospitalisations in Germany page vi

List of Tables

Table 1. Incidence and expected number of hospitalisations in Germany in children under 16 years of age based on results of 27 studies from Europe and North America* ...............................4

Table 2. ESPED: Reasons for 89 false reports..............................................................................18

Table 3. ESPED: General characteristics of 918 varicella hospitalisations..................................18

Table 4. ESPED: Complications in 37 patients hospitalised with varicella undergoing surgical intervention....................................................................................................................................20

Table 5. ESPED: Chronic disease status and contribution to overall hospital days in 917 children hospitalised with varicella .............................................................................................................20

Table 6. ESPED: Other chronic diseases in 78 children hospitalised with varicella ....................21

Table 7. ESPED: Diagnosis in 68 immunocompromised children hospitalised with varicella ....22

Table 8. ESPED: Classification of 913 varicella hospitalisations into number of complication categories reported per case ..........................................................................................................23

Table 9. ESPED: Complication categories and contribution to overall hospital days in 913 children hospitalised with varicella (multiple nominations possible)...........................................24

Table 10. ESPED: Chronic disease status in 183 (20.0%) varicella hospitalisations without specific complications ...................................................................................................................25

Table 11. ESPED: Median age for varicella-associated complications (sorted by age; multiple nominations possible)....................................................................................................................27

Table 12. ESPED: Median hospital stay and varicella-associated complications in 909 children with varicella sorted by hospital days (multiple nominations possible) .......................................28

Table 13. ESPED: Use of intravenous antibiotics in 893 children with varicella-associated complications (% of all children with specific complications; multiple nominations possible)...29

Table 14. ESPED: Use of intravenous acyclovir in 893 children with varicella-associated complications (% of all children with specific complications; multiple nominations possible)...30

Table 15. ESPED: Start of exanthema in 811 children with varicella-associated complications (sorted by days since start of exanthema; multiple nominations possible) ...................................31

Table 16. ESPED: Results of VZV-specific liquor diagnostics in 52 children with meningoencephalitis......................................................................................................................33

Table 17. ESPED: Description of 16 patients with meningoencephalitis and additional varicella-associated complications ...............................................................................................................34

Table 18. ESPED: Characteristics of 6 patients with varicella-associated cerebral ischaemic infarct or vasculitis ........................................................................................................................39

Table 19. ESPED: Characteristics of 8 patients with varicella-associated osteomyelitis (grey) or septic arthritis ................................................................................................................................44

Table 20. ESPED: Characteristics of 9 patients with varicella-associated deep myositis (grey) or necrotising fasciitis........................................................................................................................45

Table 21. ESPED: Characteristics and diagnosis of 12 patients with other varicella-associated severe complications .....................................................................................................................47

Table 22. ESPED: Median age by categories of hospital stay in children hospitalised with varicella .........................................................................................................................................48

Final report – VZV hospitalisations in Germany page vii

Table 23. EPSED: Hospital stay and chronic disease (% of all children in category of hospital stay) in children hospitalised with varicella..................................................................................49

Table 24. ESPED: Hospital stay and complication category (% of all children in category of hospital stay) in children hospitalised with varicella (multiple nominations possible) ................50

Table 25. ESPED: Proportion of immunocompetent and immunocompromised children in complication categories (excluding children with no specific complication reported; multiple nominations possible)....................................................................................................................51

Table 26. ESPED: Characteristics of 7 patients with varicella and prior varicella immunisation 52

Table 27. ESPED: Possible sequelae in 78 hospitalised children with varicella ..........................53

Table 28. ESPED: Overview of 10 varicella-associated deaths....................................................59

Table 29. ESPED: General characteristics of 244 children hospitalised with herpes zoster ........60

Table 30. ESPED: Chronic disease status and contribution to overall hospital days hospitalised with varicella .................................................................................................................................61

Table 31. ESPED: Diagnosis in 78 immunocompromised children hospitalised with herpes zoster .............................................................................................................................................62

Table 32. ESPED: Complication category and contribution to overall hospital days in 243 children hospitalised with HZ (multiple nominations possible) ...................................................63

Table 33. ESPED: Results of VZV-specific liquor diagnostic in 22 children with herpes zoster-associated meningoencephalitis ....................................................................................................65

Table 34. EURODIAB: Reasons for 35 varicella and 23 herpes zoster false reports...................68

Table 35. ICD10 PILOT STUDY: Reasons for false reports .......................................................70

Table 36. ICD10 PILOT STUDY: Distribution of varicella cases according to case definition..71

Table 37. ICD10 STUDY: Reasons for false reports....................................................................74

Table 38. ICD10 STUDY: General characteristics of 728 varicella hospitalisations...................74

Table 39. ICD10 STUDY: Chronic disease status and median age and hospital stay in 728 children hospitalised with varicella...............................................................................................75

Table 40. ICD10 STUDY: Classification of varicella hospitalisations by primary ICD10-diagnosis and chronic disease status .............................................................................................76

Table 41. ICD10 STUDY: Classification of 728 varicella hospitalisations into complication categories.......................................................................................................................................76

Table 42. ICD10 STUDY: Complication categories and contribution to overall hospital days (multiple nominations possible) ....................................................................................................77

Table 43. ICD10 STUDY: Median age and hospital stay in 157 children with varicella-associated neurologic complications.............................................................................................77

Table 44. ICD10 STUDY: Median age and complication category of 728 children hospitalised with varicella (multiple nominations possible) .............................................................................79

Table 45. ICD10 STUDY: Median hospital stay and complication category of 728 children hospitalised with varicella (sorted by hospital stay; multiple nominations possible) ...................80

Table 46. ICD10 STUDY: General characteristics of 83 children hospitalised with HZ.............81

Table 47. ICD10 STUDY: Chronic disease status and median age and hospital stay of 83 children with HZ ...........................................................................................................................82

Final report – VZV hospitalisations in Germany page viii

Table 48. ICD10 STUDY: Classification of 83 HZ hospitalisations by primary ICD10-diagnosis and chronic disease status .............................................................................................................82

Table 49. ICD10 STUDY: Classification of 83 HZ hospitalisations into complication categories.......................................................................................................................................................83

Table 50. ICD10 STUDY: Median age and hospital stay by complication category of 83 children hospitalised with HZ .....................................................................................................................83

Table 51. Population of children under 17 years (not reaching their 17th birthday) of age by federal state [30] and number of ESPED reports ..........................................................................85

Table 52. Classification of 68 hospitals in NRW by participation (=reporting) in ESPED and ICD10-queries ...............................................................................................................................89

Table 53. Number of reported varicella cases by source and number of matches in NRW .........90

Table 54. Number of reports from 27 hospitals that participated in ESPED and ICD10 STUDY and which had reported at least one case with varicella from either source in NRW...................91

Table 55. Number of reported herpes zoster cases by source and number of matches in NRW ..92

Table 56. Number of reports from 27 hospitals that participated in ESPED and ICD10 STUDY and which had reported at least one case with HZ from either source in NRW ...........................93

Table 57. Incidence estimates for varicella hospitalisations using different calculation methods94

Table 58. Incidence estimates by age categories for varicella hospitalisations using three-source capture-recapture (EURODIAB+ESPED+ICD) in NRW (stratified analysis).............................95

Table 59. Incidence estimates for HZ hospitalisations using different calculation methods........96

Final report – VZV hospitalisations in Germany page ix

List of Figures

Figure 1. ESPED: Organisation of surveillance..........................................................................107

Figure 2. ESPED: Response rate of questionnaires ....................................................................107

Figure 3. ESPED: Seasonal distribution of cases reported to ESPED........................................108

Figure 4. ESPED: Data profile....................................................................................................109

Figure 5. ESPED: Distribution of 918 varicella cases by month and year .................................110

Figure 6. ESPED: Age distribution of 914 varicella cases .........................................................110

Figure 7. ESPED: Interval between start of exanthema and admission in 814 varicella cases ..111

Figure 8. ESPED: Duration of hospitalisation in 912 varicella cases.........................................112

Figure 9. ESPED: Symptoms in 909 varicella cases...................................................................113

Figure 10. ESPED: Symptoms and age at admission in 905 children with varicella (x= 25th and 75th percentile)............................................................................................................................113

Figure 11. ESPED: Symptoms and duration of hospital stay in 904 children with varicella (x= 25th and 75th percentile).............................................................................................................114

Figure 12. ESPED: Median age at admission, and complication category and underlying chronic disease in 909 children with hospitalised with varicella (x= 25th and 75th percentile) .............115

Figure 13. ESPED: Median hospital stay, and complication category and underlying chronic disease in 909 children hospitalised with varicella (x= 25th and 75th percentile) .....................115

Figure 14. ESPED: Complications in 913 varicella cases ..........................................................116

Figure 15. ESPED: Neurologic complications in 913 varicella cases ........................................117

Figure 16. ESPED: Symptoms in 52 children with meningoencephalitis and varicella .............118

Figure 17. ESPED: Skin infectious complications in 913 varicella cases ..................................119

Figure 18. ESPED: Microorganisms detected in 108 children with varicella-associated skin infectious complications..............................................................................................................120

Figure 19. ESPED: Complications and immunocompromised state in 913 children hospitalised with varicella ...............................................................................................................................121

Figure 20. ESPED: Distribution of 244 children with HZ by month and year ...........................122

Figure 21. ESPED: Age distribution in 243 children hospitalised with HZ ...............................123

Figure 22. ESPED: Interval between start of exanthema and admission in 217 children hospitalised with HZ ...................................................................................................................123

Figure 23. ESPED: Relation of age at primary VZV infection and eruption of herpes zoster rash in 74 children with known time of primary infection (distribution plot) ....................................124

Figure 24. ESPED: Hospital stay of 242 children hospitalised with HZ ....................................125

Figure 25. ESPED: Symptoms in 233 children hospitalised with HZ ........................................125

Figure 26. ESPED: Symptoms and median age in 232 children hospitalised with HZ (x= 25th and 75th percentile).....................................................................................................................126

Figure 27. ESPED: Symptoms and hospital stay in 224 children hospitalised with herpes zoster (x= 25th and 75th percentile) ......................................................................................................126

Final report – VZV hospitalisations in Germany page x

Figure 28. ESPED: Distribution of dermatomes affected in 226 children hospitalised with HZ127

Figure 29. ESPED: Complications in 243 children hospitalised with HZ ..................................128

Figure 30. ESPED: Median age, and complication category and underlying chronic disease in 242 children hospitalised with HZ (x= 25th and 75th percentile)...............................................128

Figure 31. ESPED: Median hospital stay, and complication category and underlying chronic disease in 241 children hospitalised with HZ (x= 25th and 75th percentile) ..............................129

Figure 32. ESPED: Complications and immunocompromised state in 243 children hospitalised with HZ .......................................................................................................................................129

Figure 33. EURODIAB: Age distribution in 107 children hospitalised with varicella ..............130

Figure 34. EURODIAB: Duration of hospitalisation in 107 children hospitalised with varicella.....................................................................................................................................................130

Figure 35. ICD10 PILOT STUDY: Results of medical chart review .........................................132

Figure 36. ICD10 PILOT STUDY: Age distribution of 105 children hospitalised with varicella.....................................................................................................................................................132

Figure 37. ICD10 PILOT STUDY: Duration of hospitalisation in 105 children hospitalised with varicella .......................................................................................................................................133

Figure 38. ICD10 PILOT STUDY: Complications in 105 children hospitalised with varicella 134

Figure 39. ICD10 STUDY: Distribution of 728 children hospitalised with varicella by month and year ..............................................................................................................................................135

Figure 40. ICD10 STUDY: Age distribution of 728 children hospitalised with varicella..........136

Figure 41. ICD10 STUDY: Distribution of 83 children hospitalised with HZ by month and year.....................................................................................................................................................137

Figure 42. ICD10 STUDY: Age distribution of 83 children hospitalised with HZ ....................138

Figure 43. Age distribution of ESPED (n=918) and EURODIAB (n=107) varicella cases .......138

Figure 44. Hospital stay of ESPED (n=918) and EURODIAB (n=107) varicella cases ............139

Figure 45. Chronic disease status of ESPED (n=918) and EURODIAB (n=107) varicella cases.....................................................................................................................................................139

Figure 46. Age distribution of ESPED (n=918) and ICD10 STUDY (n=728) varicella cases...140

Figure 47. Hospital stay of ESPED (n=918) and ICD10 STUDY (n=728)varicella cases.........140

Figure 48. Chronic disease status of ESPED (n=918) and ICD10 STUDY (n=728)varicella cases.....................................................................................................................................................141

Figure 49. Complications of varicella patients in ESPED (n=918)and ICD10 STUDY (n=728).....................................................................................................................................................142

Figure 50. Age distribution of herpes zoster patients in ESPED (n=244) and ICD10 STUDY (n=83) ..........................................................................................................................................143

Figure 51. Hospital stay in ESPED (n=244) and ICD10 STUDY (n=83) herpes zoster patients.....................................................................................................................................................143

Figure 52. Chronic disease status of herpes zoster patients in ESPED (n=244) and ICD10 STUDY (n=83)............................................................................................................................144

Figure 53. Complications of herpes zoster patients in ESPED (n=243) and ICD10 STUDY (n=83) ..........................................................................................................................................145

Final report – VZV hospitalisations in Germany page xi

Figure 54. Number of varicella reports in NRW from ESPED and EURODIAB in 2003/2004 146

Figure 55. Number of varicella reports in NRW from ESPED, EURODIAB, and ICD10 STUDY in 2003/2004................................................................................................................................147

Figure 56. Number of herpes zoster reports in NRW from ESPED and EURODIAB in 2003/2004....................................................................................................................................148

Figure 57. Number of herpes zoster reports in NRW from ESPED, EURODIAB, and ICD10 STUDY in 2003/2004 .................................................................................................................149

Figure 58. Expected number of varicella cases in children <= 16 years in different German studies..........................................................................................................................................150

1 Background

Final report – VZV hospitalisations in Germany page 1

1 Background

Varicella are the primary manifestation of a varicella zoster virus (VZV) infection. Varicella are

generally recognised as a relatively mild disease with rare complications. However, since

varicella affect virtually every child, they are also an important contributor to morbidity and

mortality [1-8], and to public health costs [9-19]. VZV infections can be prevented through a

safe and effective, attenuated, live viral vaccine [20].

The burden of varicella complications has been estimated in different national and international

studies. Most studies rely on hospitalisations due to varicella as a surrogate of varicella

complications. Reported incidences of hospitalisations differ markedly between areas, year and

source of data. Most reported incidences rely on one single data source, usually ICD hospital

discharge data. Some studies evaluated the specificity of the data using secondary sources, for

instance medical record reviews [21-29]. In Germany the incidence of varicella complications

has been estimated by two studies with contradicting results. There is an approximately 27-fold

difference in the incidence of varicella hospitalisations between both studies [30-32] (Table 1).

In a one-year surveillance of paediatric hospitals with the German Surveillance Unit for Rare

Diseases in Childhood (ESPED – Erhebungseinheit für Seltene Pädiatrische Erkrankungen in

Deutschland) Ziebold et al. [30] reported 119 varicella-related complications in hospitalised,

immuno-competent children and adolescents in 1997. Based on these cases a population-based

incidence of hospitalisations due to varicella in under 16 year old children was calculated to be

0.85/100,000 person years (py). (In the original article the incidence was erroneously published

with 8.5 / 100,000 py.) Permanent sequelae were reported in 6 children. There was no report of

any varicella-associated death.

However, it has to be to assumed that the true rate of complications is higher. First, this first

ESPED varicella study was restricted to severe complications. This becomes obvious in the

proportion of neurologic complications (61 %) as found by Ziebold et al, a proportion which is

much higher than in any other study published so far. Furthermore, only immuno-competent

children were included. Some of the most common complications such as cerebellitis were not

explicitly addressed in the questionnaire. A recall bias which leads to the reporting of more

severe cases in the ESPED system is highly probable. In addition, with an active surveillance a

certain degree of underreporting has to be assumed. In four different ESPED studies the degree

of underreporting has been estimated to be between 38% and 76% [33].

1 Background


In a second medical practice-based German study Wutzler et al. [31, 32] investigated 1334

varicella patients in all age groups. From 282 randomly selected medical practices in Germany 5

varicella patients each were retrospectively, randomly sampled out of all patients in each

practice. Among the 1334 patients, they found a complication rate of 5.7%. Bacterial

superinfections (2.4%), pneumonia/bronchitis (1%) and otitis media (0.9%) were the most

frequent complications. Based on 76 patients with complications and 11 hospitalised patients the

authors estimated the annual number of persons with varicella related complications and

hospitalisations in Germany to be 39720 and 5739, respectively. Ninety percent of the

complications and about 60 % of the hospitalisations (≈24/100,000 py) were observed in

children (personal communication Dr. Wagenpfeil). The data were collected retrospectively and

rely on only 11 hospitalisations in children and adults, rendering the estimate quite unstable.

Two Swiss studies are also of interest due to the regional proximity and/or methodological

approach. Jaeggi et al. [22] retrospectively identified 113 hospitalised varicella patients over a

ten year period in the canton of Bern, Switzerland, by ICD diagnosis and reviewed the medical

records. Based on the mean annual birth cohort in this area they estimated the hospitalization rate

as being 9 in 10,000 varicella cases (5.2/100,000 py).

From 2000 to 2003, Bonhoeffer et al. [29] used a similar surveillance unit to that of ESPED,

SPSU (Swiss Paediatric Surveillance Unit) [34]. Additionally, ICD10 data were used to identify

all admissions due to varicella. Every identified case was thoroughly validated by record review

and questionnaires were filled in by the researchers themselves. SPSU- and ICD10-data were

quite comparable and reporting bias to more severe cases in SPSU was excluded by the authors.

Applying capture-recapture techniques they estimated having about 100 admissions per year

(7.4/100,000 py) in Switzerland which would translate into about 1000 hospitalisations for

Germany in children up to the age of 16 years. It might be speculated that underreporting by

SPSU (44%) was underestimated since participation in the ICD10-data query was restricted to a

“representative” sample of 13 of 38 paediatric units in Switzerland. These hospitals might have

been well engaged in the SPSU and might have reported relatively more cases than non-

participating hospitals. On the other hand, Bonhoeffer et al. did not exclude the fraction of

patients that were hospitalised a week or more before a varicella exanthema erupted.

Since economic evaluations uniquely demonstrated a net economic benefit of universal VZV

vaccination, Canada and USA have been recommending a universal varicella-virus vaccination

since 1995 and 1996 [35, 36]. In 2003, 38 of 50 US states had implemented child care or school

entry requirements for varicella (“No vaccination – no access to school or daily child care”).

Several local and regional surveillance projects have been implemented simultaneously to the

1 Background


introduction of the general varicella vaccination in the USA. Seward et al. [37] implemented an

active, population-based surveillance project in three communities (Antelope Valley, California;

Travis County, Texas; and West Philadelphia, Pennsylvania). Data from the National Discharge

Surveys were analysed by Galil et al. [38] and Davis et al. [39]. Furthermore, two surveillance

studies on varicella-related mortality in children and adults have been conducted [40, 41]. All

these studies demonstrated a marked decline in incidence, hospitalisations and mortality.

Up to July 2004, varicella vaccination was recommended in Germany for particular risk groups

(and their contacts). In July 2004, the German Advisory Board for Immunisation (STIKO –

Ständige Impfkommission am Robert-Koch-Institut) added the VZV vaccination to the national

routine childhood vaccination schedule for all susceptible children, preferably at an age between

11 and 14-months-old in Germany [42]. Thus, Germany has been the first country in the

European Union to introduce general varicella vaccinations. Catch-up vaccinations for children

and adults are recommended.

In summary, varicella vaccinations have been shown to be very effective in reducing the medical

burden of VZV infections. However, a valid estimation of the incidence of VZV hospitalisations

and of VZV-related medical complications is lacking in Germany. To gather this information, it

is essential to furnish a more precise picture of the burden of VZV disease in Germany.

Furthermore, results of the present study will serve as a reliable baseline to validate the impact of

an universal varicella vaccination programme on hospitalisations and complications in the future.

1 Background


Table 1. Incidence and expected number of hospitalisations in Germany in children under 16 years of age based on results of 27 studies from Europe and North America*

* Age-specific incidences were standardised to the German population according to data of the Federal Statistics Office from 1999 (German population 0-16 years of age 13,837,935); in cases where the incidence was given as hospitalisation per case, 740000 cases of 0-16-year-old German children (90% of a birth cohort 1999) were assumed.

Study Country (Study Period) Source

Hospitalisations per 100,000 person years

Expected

hospitalisations in Germany

Ziebold 2001 Ger (1997) Hospital Surveillance 0.9 119

Deguen 1998 F (91-95) Practice Surveillance 0.9 126

Guess 1984 USA (62-81) ICD Hospital data / Medical record review 3.2 449

Joseph 1988 England/Wales (67-85) ICD Hospital data 4.7 655

Jaeggi 1998 CH (86-96) ICD Hospital data/ Medical record review 4.9 681

Guess 1986 USA (79-82) Household Survey 5.3 740

Bonhoeffer 2005 CH (00-03) Hospital Surveillance / Medical record review / ICD10 data

7.4 1025

Huse 1994 USA (80-90) ICD Hospital data 8.6 1184

Preblud 1981 USA (72-78) Household Survey 9.1 1258

Varughese 1988 Canada (83-84) Surveillance (Compulsory) 9.1 1263

Fornaro 1999 Italy (97) Practice Sentinel 9.6 1332

Peterson 1996 USA (90-94) Surveillance Hospitals / Medical record review 9.6 1332

Lin 2000 USA (86-95) ICD Hospital data 9.9 1372

Gil 2001 Spain (95-98) ICD Hospital data 10.1 1392

Galil 2002 USA (88-95) ICD Hospital data 12 1625

Seward 2002 USA (95-00) Surveillance Hospitals 12.4 1722

Roca 2000 Catalonia (99) Surveillance Hospitals / Medical record review 12.8 1776

Coplan 2001 USA (94) ICD Hospital data / Medical record review 14.3 1979

Rivest 2001 Canada (94-96) ICD Hospital data / Medical record review 15.5 2146

Ratner 2002 USA (88-95) ICD Hospital data 16.5 2287

Socan 2000 Slovenia (79-98) Surveillance (Compulsory) 16.9 2340

Fairley 1996 Scotland (89-90) Surveillance (Compulsory) 18.2 2517

Brisson 2001 England (95-96) ICD Hospital data 19.9 2748

Canada (79-97) ICD Hospital data 19.9 2748

Wutzler 2001 Ger (99) Practice Survey 24.7 3420

Choo 1995 USA (90-92) ICD in HMO / medical record review 27.3 3774

Yawn 1997 USA (81-94) Household survey / Epidemiological database review

29.4 4070

2 Objectives — Main Objective


2 Objectives

2.1 Main Objective The purpose of the study was to estimate the overall incidence of hospitalisations due to VZV

infections in children and adolescents between 0 and 16 years (from day of birth to day before

17th birthday) of age in Germany.

2.2 Secondary Objectives • To assess the type, severity, duration and outcome of VZV complications requiring

hospitalisation,

• To assess the impact of chronic diseases on the development of VZV complications,

• To assess the usefulness and practicability of ICD10 data for the implementation of a

long term hospitalisation surveillance system.

3 Methods — General Study Design


3 Methods

3.1 General Study Design The study was a surveillance study using three different surveillance sources, ESPED

(Erhebungssystem Seltener Pädiatrischer Erkrankungen in Deutschland; German Surveillance

Unit for Rare Diseases in Childhood), EURODIAB (European Diabetes Study Group), and

ICD10 data (International Classification of Diseases and Related Health Problems -10th

Revision).

ESPED data are specifically used to assess in clinical depth the severity of disease, the type of

complications, the duration of hospitalisations, the role of chronic diseases and

immunosuppression, as well as the diagnostic and therapeutic procedures applied.

Since underreporting of varicella complications by the ESPED system was assumed, a second

data source using a practised based sentinel in the federal state of North-Rhine Westphalia was

established. EURODIAB data were used for refined incidence estimates using capture-recapture

methods.

In a pilot-study ICD10-data were examined for their general accessibility and usefulness, and

their validity to capture varicella and herpes zoster cases. In an extended ICD10 study the data

were further analysed for their usefulness in refining incidence estimates by use of three-source

capture-recapture and for the possible implementation of a future surveillance system based on

ICD10-data.

3.2 Participating institutions Several institutions participate in the organisation of the study:

(A) Department of Infectious Disease at the Dr. v. Hauner Children's Hospital, Ludwig-

Maximilians-University Munich (HKI)

(B) Department of Paediatric Epidemiology, Institute of Social Paediatrics and Adolescent

Medicine, Ludwig-Maximilians-University Munich (KIZE)

(C) ESPED study centre, Düsseldorf (ESPED)

(D) ESPED hospitals and physicians (cf. Appendix A )

(E) EURODIAB study group at the German Diabetic Research Institute, Düsseldorf

(EURODIAB)

3 Methods — ESPED: Paediatric Hospital Surveillance


3.3 ESPED: Paediatric Hospital Surveillance

3.3.1 ESPED: Structure

The ESPED system has a similar structure as the British Paediatric Association Surveillance Unit

[43]. Established in 1992 to study the epidemiology of rare childhood diseases, ESPED is run

under the auspices of the German Society for Paediatrics and Adolescent Medicine. Current and

past ESPED projects can be found at http://www.esped.uni-duesseldorf.de.

Each month the study centre of ESPED in Düsseldorf is mailing a report card or is sending an E-

mail with up to 12 disease entities to all paediatric hospitals and departments in Germany to

determine, whether a patient has been hospitalised with any one of those entities. Depending on

the size and the structure, each hospital has one or several ESPED-representatives who are

responsible for the case findings within the hospital. The position of ESPED-representatives in

the hospital varies. They are sometime heads of the hospital, and sometimes consultants or senior

house officers. The process of case finding is not predetermined by ESPED. If a case was

reported, the responsible research centre (in this study: HKI) was informed by the ESPED study

centre and subsequently send a questionnaire to the hospital (Figure 1).

3.3.2 ESPED: Questionnaire

The questionnaire for varicella and herpes zoster hospitalisations (cf. Fehler! Verweisquelle

konnte nicht gefunden werden.) was jointly developed with paediatricians, epidemiologists and

statisticians. Each questionnaire carried a unique identification number and ESPED hospital

number, which was supplied by the ESPED study centre. It was structured into ten sections:

1) Identifiers of the patient

2) Hospital data and general identification of case

3) Permanent sequelae

4) Symptoms

5) Diagnostic procedures

6) Type of VZV complications

7) Type of herpes zoster complications

8) Therapy

9) Chronic diseases

10) VZV vaccinations

3 Methods — ESPED: Paediatric Hospital Surveillance


Anonymous medical discharge letters were requested for cases involving insufficient

documented questionnaires.

3.3.3 ESPED: Logistics

The coordinating study centre (HKI) was informed by the ESPED Study Centre about reported

varicella or herpes zoster patients. The study coordinators sent the above described questionnaire

to the physician acting as the ESPED-representative in the respective paediatric hospital or

department. A stamped return envelope and a small amount of sweets was attached to the

questionnaire which served as an incentive for the physician to fill in the questionnaire. If a

questionnaire was not returned, written reminders including a copy of the questionnaire were

sent in periodical intervals of about four weeks. After two written reminders the ESPED-

representative received a call from the study coordinators.

For tracking of reports some core data of returned questionnaires and reception date were entered

into a database upon receipt: Patient’s data (initials, month and year of birth, nationality, first

three numbers of the residential zip code), month and year of admission to the hospital, diagnosis

(acute varicella-infection, acute herpes zoster, or post-infectious varicella complication), and

address and name of the hospital contact person. Furthermore, information on double or false

reports were stored in this database. Thus, it was possible to track every report for reminders, to

clarify questions of ESPED representatives in the respective hospital, and to report the current

status of ESPED reports on a monthly basis. Double entry of the complete questionnaire was

performed by an external contractor (con-m, Munich, Germany). Before analysis extensive data

management and data cleaning was performed. To clarify uncertain information physicians who

filled in the questionnaires were called.

3.3.4 ESPED: Study population

For the ESPED surveillance, the study population includes all children and adolescents up to the

age of 16 years (< 17th birthday) in Germany (14,106,043 children in 2003).

3.3.5 ESPED: Case definition

All children should be reported by the ESPED hospital who were admitted for at least one day

for a condition presumed to be related to a VZV infection and/or with associated symptoms or

complications. In detail, the ESPED representatives were asked to report:

a) Acute VZV infection: Any child hospitalised with an acute, clinically overt VZV infection

with or without complications

3 Methods — EURODIAB: Practitioner Sentinel in North-Rhine Westphalia


b) Acute herpes zoster infection: Any child hospitalised with an acute, clinically overt herpes

zoster with or without complications

c) Post-infectious varicella complication: Any child hospitalised with a complication which is

presumed to be related to a previous varicella virus infection without current exanthema.

The coordinating study centre (HKI) excluded reported cases with an exanthema erupting more

than 6 days after hospitalisation. Patients reported as post-infectious varicella complication were

later classified as varicella cases by HKI.

3.3.6 ESPED: Study period

The data collection was performed between 1/1/2003 and 31/12/2004. The final report is based

on returned ESPED reporting cards and questionnaires of cases from the years 2003 and 2004.

3.4 EURODIAB: Practitioner Sentinel in North-Rhine Westphalia

3.4.1 EURODIAB: Structure

In 1988, the EURODIAB collaborative group established prospective registers of new patients of

insulin-dependent diabetes in children under 15 years of age in 26 geographically different

regions of Europe [44, 45]. The aim is to study the variation and time trends of diabetes in

Europe. The completeness of registration is estimated by capture-recapture methodology. The

German Diabetes Research Centre (GDRC) in Düsseldorf is participating in the EURODIAB

study. The GDRC has used ESPED since 1996 and a practice sentinel in North Rhine Westphalia

as a second data source. Practices were identified on a yearly basis through the two Medical

Associations of North Rhine-Westphalia ("Landesärztekammer Nordrhein" and

"Landesärztekammer Westfalen-Lippe"), where all practices have to be registered. Thus, about

10,500 practices of internal medicine, of general practitioners and paediatricians in North Rhine–

Westphalia were contacted twice a year (January and July) for the years 2003 and 2004. Each

practice received an information letter, a short questionnaire (cf. Fehler! Verweisquelle konnte

nicht gefunden werden.) and a return envelope. Each questionnaire carried a unique identifier

of the practice. The physician was asked to fill in a questionnaire for each patient up to 16 years

(< 17th birthday) of age who was known to have been hospitalised with varicella or herpes zoster

in the first and second half of the year, respectively. The questionnaire included identifiers, date

and reason for admission to a hospital, name of the hospital, main ICD diagnosis, permanent

sequelae resulting from varicella zoster virus infection or complications, baseline chronic

diseases and VZV vaccination status. The practices were asked to return (mostly by FAX) the

VZV questionnaire even if they did not know of a child.

3 Methods — ICD10: Paediatric Hospital Surveillance


3.4.2 EURODIAB: Study population

For the EURODIAB surveillance, the study population included all children and adolescents

from their birthday up their 17th birthday in North Rhine-Westphalia (3,248,227 children in

2003).

3.4.3 EURODIAB: Case definition and study period

Children who have been admitted to a paediatric hospital in NRW due to VZV infection or its

complication for at least one day. Inclusion criteria and study period were the same as in the

ESPED surveillance study.

3.5 ICD10: Paediatric Hospital Surveillance

3.5.1 ICD10 Background

ICD-data (International Classification of Diseases and Related Health Problems - 10th Revision)

were collected for years, mainly for statistical reasons, as hospitals are required by law to report

ICD diagnoses of each admission to the regional office of statistics. In 2000, however, it was

decided that, from 2005 on, hospital costs will be reimbursed based on Diagnosis Related

Groups (DRG) for each admitted patient, with a pre-phase in 2003 and 2004. According to §21

KHEntgG (Krankenhausentgeltegesetz; hospital reimbursement law) every hospital in Germany

has to deliver on a yearly basis age, gender, admission dates, ICD-codes, procedures, and a few

other patient characteristics of all inpatients to the DRG institute (http://www.g-drg.de/). ICD

codes are differentiated into a primary diagnosis (PD), which should be the main cause of

hospitalisation, and secondary diagnoses (SD) which have an impact on the hospital stay and the

intensity of care. According to these data, reimbursement rates that are based on DRG will be

calculated. Thus, there is currently a fundamental change in coding practice, and increased ICD

coding and potentially higher precision in the ICD coding system may be expected. In a first

step, we evaluated the usefulness and accessibility of ICD10 data in frame of a pilot study that

was limited to a couple of hospitals. In a second step, we contacted all hospitals in NRW that

were registered with ESPED.

3.5.2 ICD10 PILOT STUDY (Bavaria/ North-Rhine Westphalia 2003)

In order to support the hypothesis that ICD10 codes have become more reliable and more easy to

retrieve due to the new hospital reimbursement law, our research group initiated an ICD10 pilot

study capturing all hospitalisations with a varicella or herpes zoster ICD10 code. In 2003, ICD10

data on hospitalised children with VZV infections were evaluated in selected hospitals in Bavaria

and NRW.



3.5.2.1 ICD10 PILOT STUDY: Objectives

• Are ICD10 data specific, e.g. were children identified by ICD10 codes related to varicella

zoster virus infections really admitted to the hospital due to varicella virus infection?

• Is an ICD10-surveillance study technically feasible, especially with regard to the

willingness of hospitals to participate and the data management needed to pool existing

data files of a different origin?

• How much effort and how many resources (time and money) are needed to assess ICD

data?

3.5.2.2 ICD10 PILOT STUDY: Study design Within the pilot study a sample of 15 German paediatric hospitals was selected. The Bavarian

hospitals were chosen by proximity and the NRW hospitals were randomly sampled (stratified

by hospital size) from all NRW hospitals. Eleven hospitals sent all requested data that were used

for further evaluation. In 4 of these hospitals (Bavaria), a medical chart review was performed.

The study population covered all patients up to age 17 years (<17th birthday), identified by an

ICD10 code for varicella infection (B01.0-B01.9) or herpes zoster (B02.0-B02.9) in 2003 in any

diagnostic position (PD or SD) in one of the selected hospitals.

3.5.2.3 ICD10 PILOT STUDY: Structure and logistics The ICD10 pilot study was conducted in two steps. First, clinical directors of 15 Bavarian and

NRW paediatric hospitals were contacted by letter and asked whether they agreed in

participating in a study to evaluate if ICD10 data could serve as a surveillance tool for

hospitalised VZV cases. An agreement form was attached to the letter (here, they could also

name a person responsible for the necessary data query) as well as an information sheet on

technical details which could easily be passed through to the controlling staff and data

processing personnel.

If possible, data managers were contacted directly with regard to any technical problems. Clinic

directors, who had not responded, were contacted up to three times by letter and, finally, by way

of personal telephone calls. In some cases, the director agreed in participating in the study, but

extensive efforts had to be undertaken to receive the requested data.

The following data was requested: Date of birth, date of admission to and discharge from

hospital, gender, hospital’s patient number, first three numbers of the residential zip code, and all

primary and secondary diagnoses encoded in ICD10.



In each of the four participating Bavarian hospitals, ICD10-coded cases were evaluated by one

coordinator (Veit Grote) by medical record review using discharge letters and, if in doubt, all

other information in a medical record. Each case was categorised into a true or false VZV case

and into an admission associated and non-associated with VZV infection.

Of 6 selected paediatric hospitals in Bavaria, 4 participated in the study. In one clinic the internal

organisational structure and questions of reimbursement made participation impossible, and in

one clinic the responsible controller was unable to send the requested data. Of 9 selected

paediatric hospitals in NRW, 7 participated in the study, one declined and one sent data which

was incomplete and therefore not to be used for further data analysis. As each paediatric hospital

works with different data base systems, requested data had diverse data formats (MS-Excel, MS-

Access and MS-Word files with diverse fields of data and encoding of variables). Therefore

excessive data management tasks had to be performed. Before implementation of the study the

ICD-pilot study was approved by the local ethics committee and by the Bavarian data protection

agency.

3.5.2.4 ICD10 PILOT STUDY: Case definition For the definition of a varicella-associated hospital admission, at least one of the following

criteria had to be fulfilled (adapting the definition of Davis et al. [39]):

Varicella as the primary ICD10 diagnosis,

specific varicella-related complications such as varicella encephalitis (B01.1) and varicella

pneumonitis (B01.2) in any diagnostic position (in primary or one of the secondary diagnoses),

any ICD10 code for varicella in a person with an immuno-compromising condition likely to

necessitate hospitalisation for varicella (e.g. human immunodeficiency virus/acquired immune

deficiency syndrome, severe defect of T-cell immunity, organ recipient, malignancy, recipient of

chemotherapy),

any ICD10 code of varicella in a person with a condition or underlying chronic disease that may

increase the risk of varicella complications because of treatment of the condition (e.g.

rheumatoid arthritis, asthma, diabetes),

any code for a well-described potential complication of varicella in primary diagnosis and a

varicella ICD10 code in any subsequent secondary diagnosis.

All admissions that could not be categorised using the above-mentioned criteria were categorised

as non-varicella-associated hospital admissions.



3.5.3 ICD10 STUDY in North-Rhine Westphalia 2003-2004

3.5.3.1 ICD10 STUDY NRW 2003-2004: Structure Due to the positive experience with the ICD10-pilot study we decided to continue with an ICD10

surveillance study covering all paediatric hospitals in NRW (n=68). General logistics structure

and study population were the same as in the ICD10 pilot study. However, as an incentive to

participate in the study, the clinic or the responsible person received a reimbursement of €100 for

their efforts with the data query. Clinic directors, which had not responded, were contacted up to

three times by letter and, finally, by way of personal telephone calls.

The requested data included:

- Date of birth,

- date of admission to and discharge from hospital,

- gender,

- hospital’s patient number,

- first three numbers of the residential zip code,

- all primary and secondary diagnoses encoded in ICD10,

- procedures,

- DRG-codes,

- status of discharge.

3.5.3.2 ICD10 STUDY NRW 2003-2004: Paediatric hospitals Paediatric hospitals were defined as acute care clinics with paediatric wards. The list of these

hospitals was generated using all hospitals listed with ESPED in 2004 and excluding those

hospitals dealing exclusively with chronic patients or those for rehabilitation. Thus, there were

68 paediatric hospitals selected in NRW.

3.5.3.3 ICD10 STUDY NRW 2003-2004: Objectives

• Are ICD10-data a useful tool of surveillance?

• Can ICD10-data be used to refine incidence estimates with a three source capture-

recapture technique (ESPED, EURODIAB, ICD10-data)?

3.5.3.4 ICD10 STUDY NRW 2003-2004: Case definition Hospitals were asked to identify all admissions in their data base with the following criteria:

1. ICD10 code for varicella-infection (B01.0 – B01.9) or herpes zoster (B02.0 – B02.9) in

primary or secondary diagnoses at admission or discharge;

AND



2. birth date between 1. Jan. 1987 and 31. Dec. 2003 for the 2003 query and between 1. Jan.

1998 and 31. Dec. 2004 for the 2004 query;

AND

3. patients who had to be admitted to a paediatric ward.

For the definition of a varicella- or herpes zoster-associated hospital admission the criteria of the

case definition used within the pilot study were slightly changed. This should allow for a better

differentiation into varicella-associated and non-associated cases. Thus, all cases identified by

the hospitals with the following criteria were included (or excluded) for further analysis:

1. ICD10 code for varicella-infection (B01.0 – B01.9) or herpes zoster (B02.0 – B02.9) in

primary or secondary diagnoses at discharge,

AND

2. Age at admission <= 16 years (17th birthday not reached),

AND

3. Patients who had been admitted to a paediatric ward,

AND

4. Patient who has been admitted for at least one day,

AND

5. Patient who has been admitted in 2003 or 2004,

AND

6. Patient who has been admitted for the first time with a varicella or herpes zoster ICD10-

code in the same hospital within the respective year.

Excluded were patients with overt surgical codes in the primary diagnosis, who were not

considered to be associated with varicella (for instance, head wound, concussion of the brain,

fracture, etc.).

3.5.3.5 ICD10 STUDY NRW 2003-2004: Categorising of ICD10 codes Patients identified by the case definition were further categorised in 7 groups, hierarchically and

mutually exclusively similar to the method used by Davis et al. [39]:

1. Varicella or herpes zoster as the primary ICD10 diagnosis,

2. specific VZV / HZ complications as varicella meningitis (B01.0), varicella encephalitis

(B01.1), varicella pneumonitis (B01.2), HZ encephalitis (B02.0), HZ meningitis (B02.1),

ophthalmic zoster (B02.3), generalised HZ (B02.7) in the secondary diagnoses,

3. an immunocompromising medical condition likely to necessitate hospitalisation for VZV

/ HZ (for instance ALL),

3 Methods — Data analysis


4. chronic conditions such as juvenile idiopathic arthritis, atopic dermatitis or diabetes

mellitus making a hospitalisation for VZV / HZ more likely,

5. an VZV / HZ-associated complications (as of experience with the ESPED study, or

described in the literature) as a primary diagnosis and a code of B01.8, B01.9, B02.8 or

B02.9 as a secondary diagnosis,

6. other chronic conditions such as, for instance, epilepsy or chronic lung disease in the

primary diagnosis, and

7. other patients with B01.8, B01.9, B02.8 or B02.9 as a secondary diagnosis and with no

clearly defined diagnosis in the primary position that could be attributed to VZV / HZ,

those that were admitted as a prophylaxis (for instance, neonates), or those with side

effects of medications.

ICD10-codes for chronic conditions were categorised in 5 groups. Solid and haematologic

tumours, transplantations, HIV and other immunodeficiencies were classified to

immunocompromised conditions. Rheumatologic diseases were classified as an individual group

but later categorised as an immunocompromised condition. Furthermore, atopic dermatitis and

diabetes mellitus were categorised in distinct groups. The latter group was later combined with

all other chronic conditions like epilepsy, asthma, developmental delay etc.

3.6 Data analysis All data of ESPED, EURODIAB and ICD10 has been stored and analysed using Microsoft

Access and Microsoft Excel. Additionally, SAS (SAS Institute, Cary, NC) version 8.2 and Stata

8.2 (Stata Corp., College Station, Texas) were used for all data management tasks, statistical

analyses and graphics.

As most continuous outcomes were skewed to the right, medians with interquartile ranges (25. to

75. percentile) were used as a description of the average value and measures of variation

throughout the analysis. Pearson χ2 was used for statistical comparison of categorical data. For a

comparison of not normally distributed continuous outcomes the Kruskal-Wallis rank test (in

case of more than two categories) or a nonparametric K-sample test on the equality of medians

(in cases of two categories) was used. A nonparametric test developed by Cuzick [46] was used

to test for trends across ordered groups.

3.6.1 Missing values

Not all questions in the ESPED/EURODIAB questionnaires were completely filled in by the

respective physicians. Thus, reported numbers in the report may vary according the number of

3 Methods — Ethical considerations


missing values in the respective category. For instance, if gender was filled in in 912 of 918

varicella ESPED reports, the relative distributions and percentages were calculated using the 912

subjects with completed information on gender.

In ESPED data lacking clinical information in questions with “Yes” or “No” or “Possible”, a

“No” answer was assumed, if at least one answer (“Yes”, “No” or “Possible”) was filled in

within the respective section of the questionnaire (cf. Section 3.3.2). For instance, in 10 of 918

children hospitalised with varicella information on symptoms was given, or in five of 918 cildren

hospitalised with varicella and in one child hospitalised with herpes zoster no information on

complications was available. Thus, the relative frequency of symptoms or complications in

children hospitalised with varicella was based on 908 and 913 children, respectively.

3.7 Ethical considerations All study parts were approved by the ethical committee of the medical faculty of the Ludwig-

Maximilian University, Munich.

3.8 Data protection All questionnaires of the study, and logistics, contents and data storage of the ICD10 data query,

were approved by the Bavarian data protection agency.

4 Results — ESPED: Performance and data profile


4 ESPED: Results

4.1 ESPED: Performance and data profile In 2003 and 2004, 98% of all ESPED reporting cards and 93% of all questionnaires were

returned by the ESPED-hospitals (Figure 2). There were 452 reporting departments registered

with ESPED in December 2004 which were based in 368 hospitals with 21435 beds. Two-

hundred twenty-four (61%) of these 368 hospitals reported at least one varicella or herpes zoster

associated hospitalisation to ESPED, whereas 144 (39%) hospitals never reported any case to

ESPED. However, reporting hospitals represented about 72% of all paediatric hospital beds

registered in the ESPED system.

Questionnaires were returned on a median 32 [IQR: 21-49] days after the reported case had been

admitted to the hospital. Two percent of all questionnaires were returned more than one year

after admission. For one third of all 1443 reported patients at least one reminder had to be sent.

The number of reports declined during the summer and early spring months, reaching the lowest

number in September 2003 with 19 patients being reported. In 2004, 237 patients have been

reported in March and April (Figure 3).

The data profile for all of the following results is displayed in Figure 4. 1443 cases were reported

on ESPED reporting cards from January 2003 to December 2004. Sixty-nine reports were later

declared by the reporting hospital to be false or double reports. Ninety-four questionnaires were

not returned. Of 1280 patients with available questionnaires, 117 were excluded. Of these 117

cases 28 cases were double reports (including second reports in case of transferral) and 89 false

reports. Fifty-two of the 89 false reports were either considered to be unrelated to the existing

VZV infection, the exanthema had erupted more than six days after admission, or the age of the

children was older than 16 years (Table 2). One questionnaire was lost. Of the remaining 1162

questionnaires, 918 (79%) were children hospitalised with a diagnosis of varicella and 244

(21%) with a diagnosis of herpes zoster.

4 Results — ESPED: Varicella Hospitalisations


Table 2. ESPED: Reasons for 89 false reports

4.2 ESPED: Varicella Hospitalisations

4.2.1 General characteristics

There were 918 varicella-associated hospitalisations from January 2003 to December 2004 in

ESPED (Table 3). Five hundred of 912 children (55%) were male. The median age at admission

was 3.3 years (IQR: 1.4-5.2) with 561 (61%) children being younger than 5 years and 41 (5%)

children older than 10 years. 161 (18%) of all children were younger than 12 months of age

(Figure 6). Boys were slightly older than girls at admission, 4 (IQR 1.8-6.6) years versus 3.7

(IQR 1.6-6.7) (pmedian test<0.023). Eighty-one (50%), 210 (53%), 182 (59%) and 25 (61%) of the

children with an age of 0-1 year, 2-4 years, 5-10 and over 10 years were male, respectively.

Children were hospitalised at a median of 3 days after the exanthema had started. 17 (2%)

children were reported with admissions more than 2 weeks after the eruption of the exanthema,

referring to either late varicella complications or post-infectious varicella complications (Figure

7).

Table 3. ESPED: General characteristics of 918 varicella hospitalisations

Varicella Herpes zoster

(n=47) (n=42)

Hospitalisation unrelated to VZV or exanthema started > 6 days after admission 21 9

Age > 16 years* 8 14

Hospitalisation in 2002 or 2005 6 1

No VZV infection (e.g. Herpes simplex infection) 2 9

Ambulatory or ≤ 1 day admitted 10 9

* 17th birthday reached

Male:female 55% / 45%

Median age in years 3.3 (1.4-5.2)

Median hospital stay in days 5 (3-8) Median time start of exanthema to admission in days 3 (2-6)

i.v. acyclovir therapy 28%

i.v. antibiotic therapy 36%

immunocompromised 7%



4.2.2 Hospital stay

Children admitted for varicella remained a median of 5 (IQR 3 – 8) days in the hospital.

However, about 8% of the children stayed longer than 14 days (Figure 8). Immunocompetent

children were hospitalised for a shorter period than immunocompromised children (median 5 vs.

7 days). The relationship between length of hospital stay and type of complication is summarised

in Table 12.

4.2.3 Therapy

4.2.3.1 Acyclovir and antibiotics 247 of 894 children (28%) received intravenous acyclovir treatment, whereas 319 of 893

children (36%) received intravenous antibiotic treatment. 10% of the children received combined

intravenous antibiotic and intravenous acyclovir treatment. 55 (22%) of the children receiving

acyclovir remained in the hospital for longer than 7 days. Children with neurologic

complications were significantly more often (44% vs. 22%), and children with skin infectious

complications less frequently (20% vs. 30%) treated with i.v. acyclovir than other children with

varicella. The relationship of antibiotic and acyclovir therapy to complications is summarised in

Table 13.

4.2.3.2 Surgery 37 (4%) children had to undergo surgical intervention. Their median age and hospital stay was

3.4 years (IQR 2-4.5) and 12.5 days (IQR 7-18), respectively. Complications given in the

questionnaire for these patients are listed in Table 4.



Table 4. ESPED: Complications in 37 patients hospitalised with varicella undergoing surgical intervention

4.2.4 Underlying chronic diseases

Seven-hundred ten (78%) children had no underlying chronic disease, predisposing for an

increased risk of varicella complications. Such a condition was reported in 207 (23%) children

(Table 5). Of these 68 children (7%) were immunocompromised. Sixty-one (7%) children were

reported to have atopic dermatitis and 78 (9%) children had other chronic diseases. Table 6

indicates the diagnoses of children with other chronic diseases and Table 7 with

immunocompromised conditions. Of 78 children with other chronic diseases, neurologic (35%)

and chronic pulmonary diseases (17%) were the most frequent. Of 68 immunocompromised

children hospitalised with varicella, 16 (25%) children had leukaemia, 15 (22%) children

juvenile idiopathic arthritis under immunosuppressive treatment, and 36 (54%) children other

immunocompromised conditions.

Table 5. ESPED: Chronic disease status and contribution to overall hospital days in 917 children hospitalised with varicella

n %

Abscess 16 43% Necrotising fasciitis 5 14% Bacterial arthritis 3 8% Appendicitis 3 8% Adhesion ileus 1 3% Liver failure 1 3% Mastoiditis 1 3% Retina necrosis 1 3% Pneumonia with pleural effusion 1 3% Osteomyelitis 1 3% Haemorrhagic varicella 1 3% Purpura fulminans 1 3% Otitis media perforans (tube placement) 1 3% Phlegmon 1 3%

TOTAL 37 100%

Chronic disease status n % of all varicella patients

Sum of hospital days

% of all hospital days

No chronic disease 710 77.8% 4591 71.9% Other chronic disease 78 8.5% 817 12.8% Immunocompromised 68 7.4% 634 9.9% Atopic dermatitis 61 6.7% 340 5.3%

TOTAL 917 100% 6385 100%



Table 6. ESPED: Other chronic diseases in 78 children hospitalised with varicella

4.2.5 Clinical symptoms associated with varicella hospitalisations

The range of reported symptoms in children admitted with varicella was wide. Fever and feeding

difficulties were the most frequent symptoms with 75.4% and 51.2% of all children

demonstrating these findings, respectively. Neurologic symptoms were also frequent: Ataxia

(13.3%), convulsions (11.3%), reduced consciousness (8.8%), headaches (3.3%), focal

neurologic signs (3.2%), comatose states (0.4%) and other neurologic symptoms (4.0%), such as

meningeal signs or diplopia (Figure 9). Children with fever and feeding problems were

significantly younger than all other children, i.e. 2.9 (IQR 1.3 - 4.8) and 2.6 (IQR 1.1 - 4.4)

years, respectively. In contrast, children with headache (5.4 years; IQR 4.8 - 6.6), focal

neurologic symptoms (5.2 years; IQR 3.2 - 7.6), other neurologic symptoms (4.7 years; IQR 3.2 -

5.8), ataxia (4.7 years; IQR 3.3 - 6.2) and reduced consciousness (4.2 years; IQR 2.3 - 6.2) were

significantly older than all other children (Figure 10). Children with convulsions (4.0 days; IQR

3.0 - 8.0) had a significantly shorter hospital stay than all other children. On the other hand,

children with focal neurologic symptoms (12.0; IQR 7.0 - 18.0), pain (10.5; IQR 7.0 - 18.0),

ataxia (9.0; IQR 5.0 - 14.0), headache (8.0; IQR 5.0 - 13.0), reduced consciousness (8.0; IQR 3.0

- 14.0), and affection of a joint (7.0; IQR 5.0 - 16.0) stayed longer in hospital than all other

children (Figure 11).

n %

Neurologic diseases (e.g. epilepsia, psycho-motoric retardation) 27 (34.6%)

Chronic pulmonary diseases (e.g. Chronic lung disease, asthma) 13 (16.7%)

Cardiovascular diseases (e.g. congenital heart disease) 11 (14.1%)

Syndromes (e.g. trisomie 21) 10 (12.8%) Haematologic diseases (e.g. Immunthrombocytopenia, anemia) 6 (7.7%)

Other chronic diseases 6 (7.7%) Endocrine and metabolic diseases (e.g. diabetes mellitus) 5 (6.4%)

Total 78 100



Table 7. ESPED: Diagnosis in 68 immunocompromised children hospitalised with varicella

4.2.6 Complications associated with varicella hospitalisations

Reported varicella-associated complications were categorised into the following 10 groups:

1) Neurologic complications

2) Skin infectious complications

3) Upper respiratory tract, ENT and eye complications

Category of immunocompromised state

Diagnosis N n Median age in years

Median hospital stay in days

Leukaemia 16 4.8 8 Juv. chron. arthritis 15 4.6 7 Primary immuno-deficiency 8 4.2 7

X-SCID 2 autoimmune neutropenia 1

Chediale-Higashi-syndrome 1 hypogammaglobinaemia 1

Louis-Bar-syndrome 1 chronic granulomatosis 1 Hyper IgE syndrome 1

Tumour 8 3.9 7 neuroblastoma 2 X-histiocytosis 1

medulloblastoma 1 nephroblastoma 1

rhabdomyosarcoma 1 rhaboid brain tumour 1 sarcoma, paraspinal 1

Nephrotic syndrome 7 5.3 7 Previous organ transplantation 5 4.1 8

liver 2 kidney 2 heart 1

Autoimmune disease 4 6.3 13.5 Autoimmune hepatitis 1

Sharp-syndrome 1 undefined autoimmune disease

under steroid therapy 1

very severe aplastic anaemia 1 Hodgkin’s disease 1 4.8 4 Others 4 2.8 6.5

low IgG1 and IgG 1 persistent EBV infection 1

obstructive bronchitis with oral steroid therapy

1

HIV infection 1



4) Lower respiratory tract (pneumonia and bronchitis) complications

5) Gastrointestinal tract complications

6) Haematological complications

7) Reactive arthritis

8) Complications due to other secondary bacterial infections

9) Complications due to coagulation disorders

10) Other complications

5 of 918 children had lacking information in all complication categories and were considered to

have an unknown complication status. 3 of these children were immunocompromised, 1 child

had Down’s syndrome, and one child was also seen to have an unknown chronic disease status.

183 children (20.0%) had no specific complication indicated by the physicians. For these patients

all answers in the questionnaire asking for complications were answered with “no”. All other

patients were classified in one or more groups according to diagnoses given in the questionnaire.

59.9% of all patients were classified in one complication category, 20% in more than one

category (Table 8). Whereas each patient was possibly counted multiple times for each

complication category, any further classifications within these 10 complication categories were

mutually exclusive. Thus, if a patient had pyoderma and an abscess, he was classified to have an

abscess but not pyoderma, or if cerebellitis and encephalitis were reported as complications, only

the latter was classified. However, if a patient was reported with osteomyelitis and pyoderma he

was categorised as having other systemic bacterial and skin infectious complications.

Table 8. ESPED: Classification of 913 varicella hospitalisations into number of complication categories reported per case

N % Median age (years, IQR)

Hospital stay (days, IQR)

All varicella hospitalisations 913 (100%) 3.3 (1.4-5.2) 5 (3-8)

Included in only 1 complication category 550 (59.9%) 3.3 (1.5-5.2) 5 (3-8) 2 complication categories 145 (15.8%) 3.1 (1.4-4.8) 6 (4-10) 3 complication categories 21 (2.3%) 3.9 (1.7-4.8) 8 (4-13) 4 complication categories 7 (.3%) 5.4 (2.4-6.8) 12 (2-21) 5 complication categories 5 (.5%) 5.7 (4.5-7.4) 18 (17-29) 6 complication categories 2 (.2%) 6.8 (1.2-12.3) 25 (19-31) 7 complication categories 1 (.1%) 2.8 22

No specific complication recorded 183 (20.0%) 2.8 (1.1-5.1) 4 (2-5)



The most frequent complications were neurologic complications and skin infectious

complications (Table 9). 232 (25.4%) children had a neurologic complication, 212 (23.2%) a

skin infectious complications, 137 (15.0%) gastrointestinal tract complications, 108 (11.8%)

lower respiratory tract complications, 92 (10.1%) upper airway, ENT or eye complications, 64

(7.0%) haematological complications, 51 (5.6%) complications due to coagulation disorders, 41

(4.5%) complications due to other secondary bacterial infections, and 14 (1.5%) reactive

arthritis. 24 (2.6%) children had complications that could not be categorised in one of the above

groups (Figure 14).

Neurologic complications also demonstrated the highest medical burden in children with

varicella in terms of total hospital days. All children with neurologic complications stayed

together 2172 (34% of all 6385 hospital days of children with varicella) days in hospital (Table

9). No specific complication was recorded in 183 (20.0%) children with varicella. However,

these 183 patients contributed to only 12.1% of all hospital days. On the other hand, the 40

(4.4%) children with other systemic bacterial complications contributed to 11.7% of all hospital

days.

Table 9. ESPED: Complication categories and contribution to overall hospital days in 913 children hospitalised with varicella (multiple nominations possible)

4.2.6.1 Children without specific varicella-associated complications indicated The 183 children (20.0%) without specific complication recorded were slightly (pmedian-

test=0.410) younger 2.8 years (IQR 1.1-5.1) versus 3.3 years (IQR 1.5-5.2) (Figure 12) and had a

n % of all varicella patients



Neurologic 232 25.4% 2172 34.0% Skin infectious complications 212 23.2% 1477 23.1% Lower respiratory tract 108 11.8% 1175 18.4% Gastrointestinal tract 137 15.0% 918 14.4% No specific complication recorded 183 20.0% 775 12.1% Other systemic bacterial 40 4.4% 746 11.7% Haematologic 64 7.0% 667 10.4% Coagulation disorders 51 5.6% 651 10.2% Upper respiratory tract/ENT 92 10.1% 575 9.0% Other complications 24 2.6% 228 3.6% Reactive arthritis 14 1.5% 115 1.8%

All children 913 100% 6385 100%



significantly (pmedian-test<0.001) shorter hospital stay 4 days (IQR 2-5) versus 5 days (IQR 3-9)

than all other children with indicated complications (Figure 13).

Sixty-five of 183 patients (36%) had a chronic disease predisposing for varicella complications.

Of these 65, 38 were immunocompromised patients, 14 patients with atopic dermatitis and 13

with other chronic conditions (Table 10). They were treated with acyclovir in 97%, 15%, and

43%, and treated with antibiotics in 41%, 21% and 23%, respectively. Fifty-five of 179 (31%)

children without specific complication were treated with intravenous, 10 (6%) exclusively with

oral acyclovir. 29 (16%) patients received intravenous (n=6) or oral (n=23) antibiotics.

Ninety-three of 183 patients had neither a chronic disease nor were they treated with acyclovir or

antibiotics. Most of these 93 children were admitted either with symptoms of fever (13/14%) or

feeding problems (14/15%), or both combined (53/57%). Six (6%) patients had other symptoms.

The remaining 6 patients had no symptoms reported.

Table 10. ESPED: Chronic disease status in 183 (20.0%) varicella hospitalisations without specific complications

4.2.6.2 Neurologic complications

Among the 232 children with neurologic complications, the most frequent diagnoses were

cerebellitis seen in 72 (7.9%) children, febrile convulsion in 69 (7.6%) children,

meningoencephalitis in 52 (5.7%) children, cerebral convulsion in 21 (2.3%) children, and

syncope in 9 (1.0%) children. Six children (0.7%) were reported with cerebral vasculitis and/or

cerebral infarct. Three children had other neurologic complications, namely two children showed

a facial nerve paralysis and one a paralysis of the oculomotor nerve (Figure 15). The median age

of children with neurologic complications was 4.2 years (IQR 2.5-5.9) (Figure 12). Children with

neurologic complications remained a median of 6 (IQR 3-11) days in hospital, which was

significantly longer than all other children with varicella-associated hospitalisations (Figure 13).

44 (21%) children received i.v. antibiotic and 98 (44%) i.v. acyclovir treatment. 43% of all

children with cerebellitis and 89% of all children with meningoencephalitis received iv acyclovir

(Table 13, Table 14).

N % Median age in years (IQR)

Median hospital stay in days (IQR)

None 118 (64.5%) 1.9 (.8-4.4) 3 (2-4) Atopic dermatitis 14 (7.7%) 2.1 (1.3-4) 3 (2-5) Immunocompromised 38 (20.8%) 4.6 (3.2-6.5) 7 (5-9) Other chronic disease 13 (7.1%) 3.9 (2.6-11.3) 4 (3-6)



A magnetic resonance tomography was performed in 23% of all children with neurologic

complications, in 39% of all children with meningoencephalitis and in 29% of all children with

cerebellitis. An electroencephalogram was performed in 71% of all children with neurologic

complications. 69 of 188 (37%) EEG’s were pathologic. 42 of 69 (61%) showed decelerations,

15% focal and 6% generalised epileptic signs, and 36% showed other pathologic EEG changes.

Children with febrile convulsions were significantly younger than children with

meningoencephalitis with 2.3 years and 5.4 years, respectively (Table 11). Whereas children

with syncope remained for a median of 2 days, children with cerebellitis stayed on a median 7

days in hospital (Table 12). The interval between start of exanthema and admission was

significantly longer in children with cerebellitis than in children with febrile convulsion, 7 days

versus 1 day, respectively (Table 15).

Besides 5 children with ischaemic cerebral insult / vasculitis (see 4.2.6.2.2) there were 5 children

with a late onset of neurologic complications that presented more than 14 days after start of

varicella exanthema:

1. A 4.2 year old girl had facial nerve paralysis 17 days after start of VZV-exanthema.

Liquor diagnostics were unremarkable and liquor VZV-IgG and –IgM were negative.

VZV-PCR was not performed.

2. A 2.1 year old boy had three cerebral convulsions 15 days after start of VZV-exanthema.

On admission he still had newly developed varicella blisters. Liquor diagnostics were

normal and liquor VZV-PCR was negative.

3. A 3.9-year-old girl was diagnosed with cerebellitis 21 days after VZV exanthema. The

girl had fallen out of a loft bed, was admitted with a cerebral concussion and developed

overt ataxia on the next day. No liquor diagnostic was performed.

4. A 4.9-year-old boy was admitted 84 days after VZV exanthema with headache, light

aversion and paralysis of the abducent nerve. He had liquor pleocytosis and liquor VZV-

PCR was positive.

5. A 7-year-old girl was reported to have meningoencephalitis 35 days after VZV

exanthema. No VZV-specific diagnostics were performed.

Except the girl with a concussion and cerebellitis, all children were treated with intravenous

acyclovir.



Table 11. ESPED: Median age for varicella-associated complications (sorted by age; multiple nominations possible)

Category Complication N Median age IQR

Neurologic Syncope 9 9 (5.3 - 12.1) Neurologic Others 3 6.6 (4.2 - 14.5) Gastrointestinal tract Others 4 6.4 (2.8 - 10.4) Coagulation and sequelae Others 13 5.7 (3.8 - 7.1) Neurologic Cerebral vasculitis/infarct 6 5.6 (3.2 - 6.4) Neurologic Meningoencephalitis 52 5.4 (4.2 - 6.7) Neurologic Cerebral convulsion 21 5.3 (1.2 - 6.7)

Haematologic Thrombocytopenia with leuko- and/or erythrocytopenia (+ haemolysis) 17 5.1 (3.9 - 6.7)

Haematologic leuko- and/or erythrocytopenia 11 5 (1.0 - 6.7) Other systemic bact. infections Necrotising fasciitis 6 4.7 (1.9 - 5.6) Upper respiratory tract and ENT Pharyngitis/Tonsillitis 21 4.5 (2.5 - 5.3)

Neurologic Cerebellitis 71 4.4 (3.3 - 5.8) Coagulation and sequelae Haemorrhagic varicella 33 4.3 (2.0 - 6.8) Other systemic bact. infections Bact. arthritis 3 4.3 (0.8 - 10.8) Upper respiratory tract and ENT Lymphadenitis 10 4.1 (1.7 - 5.5) Coagulation and sequelae Purpura fulminans 5 4 (3.8 - 4.3) Other complications 24 3.9 (1.8 - 4.9) Haematologic Thrombocytopenia 35 3.8 (1.6 - 6.7) Skin infectious complications Others 9 3.8 (1.4 - 6.8) Gastrointestinal tract Affection of liver 14 3.6 (2.1 - 4.8) Lower respiratory tract Pneumonia 83 3.6 (1.6 - 5.7) Reactive arthritis 14 3.6 (1.5 - 4.8)

All children with varicella 909 3.3 (1.4 - 5.2) Skin infectious complications Phlegmon 51 3.1 (1.7 - 5.0) Other systemic bact. infections Osteomyelitis 6 2.9 (0.8 - 7.4) Skin infectious complications Abscess 35 2.8 (1.3 - 4.3) Skin infectious complications Pyoderma 100 2.6 (1.0 - 4.4) Other systemic bact. infections Sepsis 21 2.4 (0.9 - 4.0) Gastrointestinal tract Dehydration 29 2.3 (1.3 - 4.3) Neurologic Febrile convulsion 69 2.3 (1.6 - 3.4) Skin infectious complications Cellulitis 9 2.3 (1.2 - 3.3) Upper respiratory tract and ENT Otitis media 38 2.2 (1.3 - 3.9) Upper respiratory tract and ENT Conjunctivitis 18 2.2 (0.8 - 5.4) Skin infectious complications Staph.-SSS 6 2 (0.6 - 2.4) Upper respiratory tract and ENT Others 5 2 (0.8 - 2.5) Gastrointestinal tract Stomatitis 29 1.9 (1.4 - 4.8) Lower respiratory tract Bronchitis/Bronchiolitis 24 1.7 (0.8 - 3.9) Gastrointestinal tract Gastroenteritis 61 1.6 (0.9 - 3.4) Other systemic bact. infections Others 5 1.6 (1.5 - 2.8)



Table 12. ESPED: Median hospital stay and varicella-associated complications in 909 children with varicella sorted by hospital days (multiple nominations possible)

Category Complication N

Median hospital stay in days

IQR

Neurologic Syncope 9 2 (2.0 - 3.0) Gastrointestinal tract Stomatitis 29 3 (2.0 - 8.0) Lower respiratory tract Bronchitis/Bronchiolitis 24 3 (3.0 - 7.0) Gastrointestinal tract Dehydration 29 4 (3.0 - 9.0) Haematologic leuko- and/or erythrocytop. 12 4 (4.0 - 6.5) Neurologic Febrile convulsion 69 4 (3.0 - 5.0) Skin infectious complications Cellulitis 9 4 (4.0 - 8.0) Gastrointestinal tract Gastroenteritis 61 5 (3.0 - 7.0) Neurologic Cerebral convulsion 21 5 (3.0 - 9.0) Skin infectious complications Pyoderma 101 5 (3.0 - 7.0) Skin infectious complications Others 9 5 (2.0 - 7.0)

All children with varicella 909 5 (3 – 8) Upper respiratory tract,ENT,eye Otitis media 38 5 (4.0 - 8.0) Upper respiratory tract,ENT,eye Others 5 5 (4.0 - 6.0) Upper respiratory tract,ENT,eye Pharyngitis/Tonsillitis 21 5 (3.0 - 6.0) Upper respiratory tract,ENT,eye Lymphadenitis 10 5 (3.0 - 9.0) Reactive arthritis 14 5.5 (3.0 - 8.0) Upper respiratory tract,ENT,eye Conjunctivitis 18 5.5 (3.0 - 7.0) Gastrointestinal tract Others 3 6 (6.0 - 8.0) Other complications 24 6 (3.5 - 12.0) Skin infectious complications Phlegmon 51 6 (3.0 - 8.0) Gastrointestinal tract Affection of liver 14 7 (2.0 - 29.0) Haematologic Thrombocytopenia 35 7 (3.0 - 15.0) Lower respiratory tract Pneumonia 83 7 (5.0 - 12.0) Neurologic Cerebellitis 72 7 (4.0 - 11.0) Neurologic Others 3 7 (3.0 - 12.0) Coagulation and sequelae Others 13 8 (4.0 - 19.0)

Haematologic Thrombocytop. w/leuko- and/or erythrocytop. (+ haemolysis) 17 8 (4.0 - 19.0)

Skin infectious complications Staph.-SSS 6 8 (7.0 - 9.0) Skin infectious complications Abscess 36 8.5 (6.5 - 12.5) Coagulation and sequelae Haemorrhagic varicella 33 9 (6.0 - 13.0) Other systemic bact. infections Sepsis 20 11 (8.0 - 21.0) Neurologic Meningoencephalitis 52 13 (8.0 - 17.5) Neurologic Cerebral vasculitis/infarct 6 15 (12.0 - 21.0) Other systemic bact. infections Bact. arthritis 3 16 (12.0 - 35.0) Other systemic bact. infections Necrotising fasciitis 6 18 (14.0 - 19.0) Other systemic bact. infections Others 5 18 (10.0 - 25.0) Coagulation and sequelae Purpura fulminans 5 28 (18.0 - 41.0) Other systemic bact. infections Osteomyelitis 6 33.5 (14.0 - 41.0)



Table 13. ESPED: Use of intravenous antibiotics in 893 children with varicella-associated complications (% of all children with specific complications; multiple nominations possible)

Category Complication iv antibiotics n %

Other systemic bact. infections Others 5 100% Other systemic bact. infections Necrotising fasciitis 6 100% Other systemic bact. infections Bact. arthritis 3 100% Other systemic bact. infections Osteomyelitis 6 100% Skin infectious complications Abscess 33 92% Other systemic bact. infections Sepsis 19 91% Skin infectious complications Phlegmon 46 90% Skin infectious complications Cellulitis 8 89% Skin infectious complications Staph.-SSS 5 83% Coagulation and sequelae Purpura fulminans 4 80% Lower respiratory tract Pneumonia 66 79% Gastrointestinal tract Others 3 75%

Haematologic Thrombocytop. w/leuko- and/or erythrocytop. (+ haemolysis) 12 71%

Skin infectious complications Pyoderma 68 67% Coagulation and sequelae Haemorrhagic varicella 22 67% Neurologic Others 2 67% Upper respiratory tract,ENT,eye Lymphadenitis 6 60% Gastrointestinal tract Affection of liver 8 57% Upper respiratory tract,ENT,eye Pharyngitis/Tonsillitis 12 57% Haematologic Thrombocytopenia 18 51% Coagulation and sequelae Others 6 46% Reactive arthritis 6 43% Upper respiratory tract,ENT,eye Conjunctivitis 7 39% Neurologic Meningoencephalitis 20 39% Upper respiratory tract,ENT,eye Otitis media 14 37% Haematologic leuko- and/or erythrocytopenia 4 33% Other complications 8 33% Gastrointestinal tract Stomatitis 8 28% Lower respiratory tract Bronchitis/Bronchiolitis 6 25% Skin infectious complications Others 2 22% Neurologic Febrile convulsion 14 20% Upper respiratory tract, ENT, eye Others 1 20% Gastrointestinal tract Dehydration 5 17% Gastrointestinal tract Gastroenteritis 9 15% Neurologic Cerebral convulsion 2 10% Neurologic Cerebellitis 6 8% Neurologic Syncope 0 0% Neurologic Cerebral vasculitis/infarct 0 0%



Table 14. ESPED: Use of intravenous acyclovir in 893 children with varicella-associated complications (% of all children with specific complications; multiple nominations possible)

Category Complication iv acyclovir n % Neurologic Others 3 100% Neurologic Meningoencephalitis 46 89%

Haematologic Thrombocytop. w/leuko- and/or erythrocytop. (+ haemolysis) 12 71%

Gastrointestinal tract Affection of liver 8 57% Haematologic leuko- and/or erythrocytopenia 6 50% Other systemic bact. infections Osteomyelitis 3 50% Coagulation and sequelae Haemorrhagic varicella 15 46% Skin infectious complications Others 4 44% Neurologic Cerebellitis 31 43% Coagulation and sequelae Purpura fulminans 2 40% Neurologic Cerebral convulsion 8 38% Other systemic bact. infections Sepsis 8 38% Lower respiratory tract Pneumonia 29 35% Haematologic Thrombocytopenia 12 34% Neurologic Cerebral vasculitis/infarct 2 33% Other systemic bact. infections Bact. arthritis 1 33% Other complications 8 33% Skin infectious complications Staph.-SSS 2 33% Skin infectious complications Cellulitis 3 33% Upper respiratory tract,ENT,eye Conjunctivitis 6 33% Gastrointestinal tract Stomatitis 8 28% Skin infectious complications Pyoderma 27 27% Coagulation and sequelae Others 3 23% Upper respiratory tract,ENT,eye Otitis media 8 21% Gastrointestinal tract Dehydration 5 17% Gastrointestinal tract Gastroenteritis 9 15% Skin infectious complications Abscess 5 14% Reactive arthritis 2 14% Neurologic Syncope 1 11% Neurologic Febrile convulsion 7 10% Upper respiratory tract,ENT,eye Lymphadenitis 1 10% Upper respiratory tract,ENT,eye Pharyngitis/Tonsillitis 2 10% Lower respiratory tract Bronchitis/Bronchiolitis 2 8% Skin infectious complications Phlegmon 1 2% Gastrointestinal tract Others 0 0% Other systemic bact. infections Others 0 0% Other systemic bact. infections Necrotising fasciitis 0 0% Upper respiratory tract,ENT,eye Others 0 0%



Table 15. ESPED: Start of exanthema in 811 children with varicella-associated complications (sorted by days since start of exanthema; multiple nominations possible)

Category Complication N Start of exanthema before admission IQR

Neurologic Cerebral vasculitis/infarct 1 -2 Neurologic Febrile convulsion 60 1 (1 - 3) Coagulation and sequelae Others 10 1.5 (1 - 5) Neurologic Syncope 6 1.5 (0 - 3) Gastrointestinal tract Affection of liver 12 2.5 (0.5 - 5) Skin infectious complications Others 8 2.5 (1.5 - 5) Gastrointestinal tract Dehydration 27 3 (2 - 6) Gastrointestinal tract Stomatitis 28 3 (2.5 - 4.5) Gastrointestinal tract Gastroenteritis 58 3 (1 - 6) Haematologic leuko- and/or erythrocytopenia 12 3 (0 - 6) Haematologic Thrombocytop. w/leuko- and/or

erythrocytop. (+ haemolysis) 15 3 (1 - 5)

Lower respiratory tract Pneumonia 74 3 (1 - 6) Lower respiratory tract Bronchitis/Bronchiolitis 24 3 (1 - 5) Neurologic Cerebral convulsion 19 3 (1 - 4)

All children with varicella 811 3 (2 - 5) Other complications 19 3 (2 - 6) Reactive arthritis 11 3 (0 - 5) Skin infectious complications Abscess 31 3 (2 - 6) Upper respiratory tract, ENT, eye Otitis media 33 3 (2 - 4) Upper respiratory tract, ENT, eye Conjunctivitis 17 3 (2 - 4) Upper respiratory tract, ENT, eye Pharyngitis/Tonsillitis 18 3 (2 - 6) Upper respiratory tract, ENT, eye Others 5 3 (2 - 5) Coagulation and sequelae Haemorrhagic varicella 28 3.5 (1.5 - 5) Haematologic Thrombocytopenia 30 3.5 (2 - 5) Skin infectious complications Cellulitis 8 3.5 (1.5 - 5.5) Gastrointestinal tract Others 3 4 (4 - 6) Other systemic bact. infections Sepsis 20 4 (2.5 - 6) Skin infectious complications Pyoderma 91 4 (2 - 5) Skin infectious complications Staph.-SSS 6 4 (3 - 5) Upper respiratory tract, ENT, eye Lymphadenitis 10 4 (2 - 6) Neurologic Meningoencephalitis 45 5 (3 - 7) Other systemic bact. infections Others 4 5 (4 - 7) Skin infectious complications Phlegmon 49 5 (3 - 6) Other systemic bact. infections Necrotising fasciitis 6 5.5 (3 - 7) Coagulation and sequelae Purpura fulminans 5 6 (5 - 6) Neurologic Cerebellitis 54 7 (6 - 8) Other systemic bact. infections Bact. arthritis 3 7 (5 - 10) Other systemic bact. infections Osteomyelitis 4 8 (5.5 - 9) Neurologic Others 2 10 (3 - 17)



4.2.6.2.1 Meningoencephalitis 52 (6%) of 913 children were reported to have meningoencephalitis. 34 (65%) presented with

fever, 31 (60%) with feeding problems, 25 (48%) with ataxia, 24 (46%) with reduced

consciousness, 4 were in a comatose state. Convulsions (n=13, 25%), headaches (n=13, 25%)

and various other neurologic symptoms (n=14, 27%) were reported quite frequently. Of the latter

14 patients five were reported to have typical meningeal signs (Figure 16).

Admission occurred on a median of 5 days (IQR: 3-7) after the start of varicella exanthema. Age

at admission was on a median of 5.4 (IQR: 4.2-6.7) years. The children stayed for a median of 13

(IQR: 8-17.5) days and 40% remained in hospital for more than 14 days.

Of 52 children with meningoencephalitis, 36 (69%) had no further complication indicated. Of the

16 remaining patients with meningoencephalitis, 8 presented with pneumonia, 4 with sepsis, two

with purpura fulminans and one with osteomyelitis. A more detailed description of these 16

patients is given in Table 17.

Forty-five (87%) of all patients with meningoencephalitis had a lumbar puncture performed. 2 of

the 7 patients without lumbar puncture died (patient 9+12 of Table 17) before additional

diagnostic procedures could be performed. Both had convulsions and reduced consciousness, and

an MRT was performed in one that showed changes consistent with meningoencephalitis. Of the

other five patients 2 had a convulsion, 2 ataxia with reduced consciousness and one patient

reduced consciousness with transient spike waves in the EEG. Specific VZV liquor diagnostic

was performed in 31 patients, VZV-PCR and VZV-liquor antibodies were determined in 17 and

in 18 patients, respectively. In 7 of 17 liquor-tested children (41%), VZV-PCR was positive.

Eight of 16 (50%) liquors tested for VZV-IgG, and 8 of 11 tested for VZV-IgM were positive.

Overall, 16 of 31 (55%) children had either positive VZV-IgG, VZV-IgM, or VZV-PCR in

liquor (Table 16). Information on CSF/serum quotients for VZV-specific antibodies were not

available.



Table 16. ESPED: Results of VZV-specific liquor diagnostics in 52 children with meningoencephalitis

In 24 of 52 (46%) children bacterial cultures of liquor were tested. Twenty-two (92%) of the

cultures were sterile and one was positive with Micrococcus luteus which was considered to be a

contamination. In patient 6 (Table 17) with Streptococcal Toxic-Shock syndrome liquor was

positive for Strep. pyogenes.

PCR IgG IgM n Percent

nd nd nd 21 40% negative nd nd 8 15% positive nd nd 5 10%

nd positive positive 4 8% nd negative negative 3 6% nd negative nd 2 4% nd positive nd 2 4% nd nd positive 2 42%

negative negative nd 2 4% nd negative positive 1 2%

positive positive positive 1 2% positive positive nd 1 2%



Table 17. ESPED: Description of 16 patients with meningoencephalitis and additional varicella-associated complications

Age at admission (years)

Hospital stay (days)

Underlying chronic disease Death Complications beside meningoencephalitis

Patient 1 0 199 Prematurity yes Pneumonia, chronic lung disease, cerebral haemorrhage

Patient 2 1.1 5 None otitis media

Patient 3 1.2 19 None pneumonia, thrombocytopenia, cellulitis, stomatitis, protein S deficiency

Patient 4 1.7 41 None osteomyelitis, purpura fulminans

Patient 5 2.4 10 None pneumonia, sepsis, thrombocytopenia

Patient 6 4 18 None pneumonia, sepsis, purpura fulminans, Streptococcal Toxic-Shock Syndrome, gastroenteritis

Patient 7 4.3 9 None Pneumonia

Patient 8 4.3 14 None Dehydration

Patient 9 4.5 13 Acute lymphoblastic leukaemia yes sepsis, liver and kidney failure, haemorrhagic varicella, leucytopenia

Patient 10 4.5 9 None pyoderma, lymphadenitis

Patient 11 6.5 8 Atopic dermatitis otitis media

Patient 12 6.7 2 None yes pneumonia, thrombo- and leukocytopenia, haemorrhagic varicella

Patient 13 6.8 14 None Gastroenteritis

Patient 14 7.4 48 autoimmune disease / steroid therapy pneumonia, osteomyelitis, conjunctivitis

Patient 15 11.8 14 None side effect acyclovir (kidney failure)

Patient 16 12.3 31 Acute lymphoblastic leukaemia pneumonia, sepsis, haemorrhagic varicella, liver and kidney failure



4.2.6.2.2 Cerebral infarct and vasculitis Six patients were reported to have an ischaemic infarct and/or cerebral vasculitis associated with

varicella. Their median age was 5.6 years (range 1.9-8.5) and their median hospital stay was 15

days (range 11-44). Primary varicella infection had occurred between 2 days after and 4 months

before cerebral infarct or cerebral vasculitis (one case unknown, but at least one year before

infarct). The six patients are summarised in Table 18 and further described in the following

section.

1) This is a 1.9 year-old boy with an ischaemic right basal ganglia infarct 6 weeks after

varicella. Since the first months of life some motor retardation was known. The boy was

admitted for observation of a newly diagnosed tremor of both hands. Furthermore, the boy

had some ataxia (hands) of varying intensity and signs of infection of the upper respiratory

tract. On the second day some weakness in his left leg was observed and coxitis fugax was

diagnosed. However, on the third day a hemiparesis of his right leg developed. CT scan

showed signs of infarction of the left basal ganglia. The boy was transferred to a tertiary

care clinic, where also some weakness in his right arm was seen. Blood count with

differential, and extensive coagulation diagnostics were normal. Serum VZV-IgG and IgM

were positive. Liquor puncture was contaminated with blood and positive for VZV-PCR.

No acyclovir was given. He was discharged after 14 days in hospital. After discharge

intensive physical therapy has been continued. 2 months after discharge the boy had

spasticity in his right leg and arm. Despite marked improvement, he still could not walk

and mobility of his right arm and hand was restricted.

2) This is a 3.2 year-old girl with encephalopathy, cerebral vasculitis, and temporary right

hemiparesis and facial nerve paralysis about 4 months after varicella infection. The child’s

medical history is remarkable for a hospital admission for severe pneumonia with pleural

and pericardial effusion about one month after varicella infection (this hospitalisation was

not reported to ESPED). During this hospital stay a relative low lymphocyte, a relative high

B-lymphocyte and relative low T-suppressor cell count was documented together with a

reduced phagocyte function. However, no diagnosis was attributed to these findings and a

re-evaluation was recommended.

Two days before admission the girl had pain in her legs and was tired. On the next day, her

general health deteriorated and she also started to vomit. A diagnosis of upper respiratory

tract infection was given in an emergency room visit. One day later, the mother observed

that her child did not recognise her properly and seemed to be absent. On admission the girl



was non-responsive to voice, wailing and sensitive to touch, and she had a reduced

consciousness. She was diagnosed with encephalitis. Lab work revealed signs of an

inflammatory process with a leukocyte count of 20.4/nl (lymphocytes 15%, neutrophils

79%), a C-reactive protein (CRP) of 32 mg/l and an erythrocyte sedimentation rate (ESR)

of 109mm/ 1 hour. Liquor diagnostics showed pleocytosis (6,300 cells/ml, 98%

lymphocytes) with elevation of protein. Therapy with acyclovir was started. On the second

day in hospital a transient hemiparesis and central facial nerve paralysis on her right side

developed. MRT depicted changes in the cortex as found in vasculitis. EEG showed

general deceleration with accentuated focal changes over the left middle and posterior

hemisphere. Serum and liquor VZV-IgG and serum VZV-IgM were positive. Thus, a

encephalopathy due to varicella vasculitis was suspected. Dexamethason therapy was

added. Sixteen days after admission the girl was fully recovered and discharged without

any residual neurologic sequelae.

3) This is a 5.2 year-old boy with an ischaemic left basal ganglia infarct. First symptoms

developed about 8-9 weeks after varicella. The boy complained of weakness in his right

shoulder and arm. He was treated with ergotherapy. About one month later he complained

about abdominal pain. After vomiting he turned unconscious for a brief moment, and

showed afterwards weakness in his right arm and facial nerve paralysis. During admission

he also developed a total right hemiparesis. Blood count with differential, and extensive

coagulation diagnostics were normal. Serum VZV-IgG was positive (2,400 IU/l) and VZV-

IgM was negative. Liquor diagnostics were remarkable for a positive VZV-IgG (27 IU/l)

and a questionable positive VZV-IgM. Angio- and native computertomography showed an

acute ischaemic infarct of the left basal ganglia. The distal horizontal (M1) segment of the

A. media cerebri (ACM) could not be delineated in angio-CT and an occlusion or a high

grade stenosis was suspected. Angio-MRT 10 days and 24 days later showed first a patent

M1 segment with wall irregularities and than occlusion of the M1 segment. These

observations were interpreted as signs of a sub-acute process as in vasculitis. The boy was

treated with acetylsalicylic acid. No acyclovir was given. One month after admission he

had overt hemiparesis with facial nerve paralysis, understood many instructions but did not

respond to questions. Another two month later his aphasia and his motor skills had

improved, however, he showed overt spastic cerebral hemiparesis.

4) This is a 6 year old girl with an ischaemic left basal ganglia infarct two days prior to start

of varicella exanthema. The girl was admitted after an unobserved fall with motor

dysarthria, amnesia, paralysis of her left arm and ocular deviation to the left.



Computertomography yielded no pathology. As her general health deteriorated and

progressive urinary dysfunction was observed, she was transferred to a tertiary care clinic.

A MRT depicted ischaemic cerebral parenchyma in the supply area of the left arteria

cerebri media and a questionable thickening of the M1 segment. Transcranial and carotid

duplex ultrasonography were unremarkable. At first, the findings were interpreted as a

consequence of craniocerebral trauma. However, later during the third day after admission

a typical varicella rash developed. Serum VZV-IgG and IgM became positive 3 weeks

later. Liquor diagnostics were unremarkable including negative VZV-IgG and -IgM. No

VZV-PCR was performed. She was treated with acyclovir and heparin and discharged after

21 days for further physical therapy. One and half years later she still had a left spastic

cerebral paralysis grade 1 according the Gross Motor Function Classification System

(GMFCS).

5) This is a 6.4 year old boy with an ischaemic infarct of the right gyrus frontalis superior

(right A. cerebri anterior) about two weeks after varicella. The boy had suddenly collapsed

in kindergarten, had hardly been able to rise, had been trembling and groggily. He also had

held his left arm in a relieving posture. Several hours after this event he was presented in

the emergency room without any pathologic symptoms or signs. Blood count with

differential, and extensive coagulation diagnostics were normal besides a slightly elevated

cardiolipin antibody (72 U/ml). Serum VZV-IgM was positive and liquor VZV-IgG and

VZV-IgM negative. MRT showed an ischaemic infarct of the right gyrus frontalis superior

(3x1.5cm), angio-MRT of the circulus villisi and EEG were unremarkable. He was

discharged 14 days after admission without any sequelae.

6) This is a 8.5 year old girl with an ischaemic infarct in the supply area of the right arteria

cerebri media (right basal ganglia). The exact age of VZV infection is unknown but was

reported to have been about two years before admission. Two days before admission the

girl had acute onset of nausea, abdominal pain and vomiting. The next day she developed a

headache with pressure behind her eyes. On the day of admission she reported to have had

a rare perception of her environment, had a vertiginous attack and, subsequently, collapsed

without loss of consciousness. She also had numbness of her left leg, weakness in her left

arm, a left facial nerve paralysis, ataxia, dysarthria and confusion. On her way to the

hospital her condition improved dramatically. On admission she presented with a red left

eye but without any neurologic abnormalities beside some dizziness and hyperesthesia of

her left leg. Blood count with differential, triglycerides, cholesterol and coagulogram were

normal. However, D-dimers were slightly elevated (211 µg/l). Furthermore, she had an



elevated LP(a). VZV-IgG in serum was 2600 U/l and VZV-IgM was marginally elevated.

Liquor VZV-PCR and VZV-IgM were negative and VZV-IgG was elevated (327 U/l). She

had a slight liquor pleocytosis (44 leukocytes per µl). Transcranial ultrasound depicted a

high-grade stenosis of the right carotid sinus, the right proximal ACM and right arteria

carotis anterior. The MRT revealed a fresh infarct in the right basal ganglia. No acyclovir

was given. The girl was treated with acetylsalicylic acid and was discharged after 12 days

in good health with some general fatigue.



Table 18. ESPED: Characteristics of 6 patients with varicella-associated cerebral ischaemic infarct or vasculitis

Patient Gender

Age (years)

Hospital stay (days) Underlying chronic disease Localisation

VZV exanthema / infection before

admission Sequelae

1 m 1.9 14 psychosomatic retardation basal ganglia left 6 weeks spastic cerebral paralysis right arm and leg

2 f 3.2 16 possible primary immunodeficiency generalised cortical changes 4 months None

3 m 5.2 44 No basal ganglia left 8-9 weeks spastic cerebral paralysis right arm and leg, partial aphasia

4 f 6 21 No basal ganglia left 2 days after infarct spastic cerebral paralysis right arm and leg

5 m 6.4 14 No gyrus frontalis superior right 2 weeks None

6 f 8.5 12 apoprotein C resistance; high serum level of Lp(A) basal ganglia right Yes, time unknown Acetylsalicylic acid prophylaxis



4.2.6.3 Skin infectious complications Skin infectious complications were the second most common complications. They occurred in

212 of 913 children (23.2%) and i.v. antibiotic treatment was administered in 42 (20%) of these

children. 101 children (11.1% of all children with varicella) had pyoderma, 51 a phlegmon

(5.6%), and 9 (1%) a cellulitis. Six (0.7%) were diagnosed with staphylococcal scalded-skin

(Staph.-SSS) syndrome and 9 (1%) children showed other skin complications: Three children

with dermatitis, two children with erythema multiforme exsudativum, and one child each with

scrotal and lip swelling, with thrombophlebitis, urticaria, and genital ulcers (Figure 17).

The median age of children with skin infectious complications was 2.7 years (IQR 1.2-4.4)

(Figure 12). Complications due to Staph.-SSS occurred at a median age of 2 years in contrast to

children with other skin infectious complications which were seen to have occurred at a median

age of 3.8 years (Table 11). Children with skin infections remained a median of 6 (IQR 4-8) days

in hospital (Figure 13). Patients with an abscess stayed significantly longer in hospital compared

to all other children with skin infectious complications (pmedian test<0.001) (Table 12).

Children with skin infectious complications also significantly differed in terms of treatment.

Thirty seven percent of all children with pyoderma and 98% with phlegmon were treated with

oral or intravenous antibiotics (Table 13), whereas 73% of children with phlegmon and 59% with

pyoderma were treated with oral or intravenous acyclovir (Table 14).

Three of the 6 children with Staph.-SSS had atopic dermatitis. In five children the diagnosis was

confirmed by bacterial culture and in one child the diagnosis was established by the clinical

picture. The course of disease in children with Staph.-SSS was generally benign. However,

scarring of the face was reported as a possible sequela in one child.

108 positive microbiological specimens from the skin were reported. Staph. aureus (n=55, 51%)

and Strep. pyogenes (n=28, 26%) were the most frequent microorganisms isolated (Figure 18).

The causative agent for skin infectious complications changed significantly by age group.

Whereas the proportion of infections with Staph. aureus decreased from 68% (n=17) in the first

year of life to 39% (n=13) in children over 4 and up to ten-years-old, the proportion of infections

with Strep. pyogenes increased from 16% (n=4) to 30% (n=10) , respectively, in the same age

groups.

4.2.6.4 Lower respiratory tract complications 108 of 913 (11.8%) children presented with complications of the lower respiratory tract.

Pneumonia was the most frequent diagnosis occurring in 84 (9.2%) children. In 62 of 84 (74%)

children pneumonia was confirmed by X-ray. A differentiation into primary varicella or



secondary bacterial pneumonia was not performed in most cases. 14 (17%) of the 84 pneumonia

patients required treatment in an intensive care unit. Bronchitis or bronchiolitis were diagnosed

in 24 of 913 (2.6%) children. The median age of children with complications of the lower

respiratory tract was 3.3 years (IQR 1.3-5.4) (Figure 12). Children with complications of the

lower respiratory tract remained a median of 7 (IQR 3-11) days in hospital (Figure 13). 66 (79%)

children with pneumonia received i.v. antibiotic (Table 13) and 29 (35%) i.v. acyclovir treatment

(Table 14).

4.2.6.5 Haematological complications Haematological complications were diagnosed in 64 (7.0%) patients. 35 (3.8%) of these 64

children had only thrombocytopenia, 17 (1.9%) had a thrombocytopenia with leuko- and/or

erythrocytopenia (including those with accompanying haemolysis) and 12 (1.3%) had a leuko-

and/or erythrocytopenia alone. Children with haematological complications were admitted at a

median age of 4.3 years (IQR 2.4-6.7). The median hospital stay was 6.5 days (IQR 4-14) for

children with haematological complications. 13 of 64 (20%) children with haematological

complications were immunocompromised (see Section 4.2.7.4).

4.2.6.6 Upper respiratory tract, ENT and eye complications Complications of the upper respiratory tract, ear-nose-throat (ENT) and eyes were seen in 92

(10.1%) children. Among these otitis media was diagnosed in 38 (4.2%) children,

pharyngitis/tonsillitis in 21 (2.3%) children, conjunctivitis in 18 (2.0%), and lymphadenitis in 10

(1.1%) children. Five children had other complications of the upper respiratory tract and ENT:

One child each was reported with an unspecific infect of the upper respiratory tract,

pseudocroup, mastoiditis, rhinitis, and stenosing laryngotracheitis. The median age of children

with complications of the upper respiratory tract and ENT was 2.5 years (IQR 1.3-4.6). Children

with complications of the upper respiratory tract and ENT remained a median of 5 (IQR 3-7)

days in hospital.

4.2.6.7 Gastrointestinal tract complications

Among the 137 (15.0%) children with gastrointestinal complications, gastroenteritis was

diagnosed in 61 (9.2%) children, stomatitis in 29 (3.2%), dehydration in 29 (3.2%), liver

affection in 14 (1.5%), and other gastrointestinal complications in 4 (0.4%) of the children.

Among the children with other gastrointestinal complications, there were 3 children with

appendicitis and one child with pancreatitis. The median age of children with gastrointestinal

complications was significantly younger than all other children, 2.1 years (IQR 1.1-4.3) versus



3.4 years (IQR 1.5-5.3). Children with complications of the gastrointestinal tract remained a

median of 4 (IQR 3.0-7.5) days in hospital.

4.2.6.7.1 Liver affection Of the 14 patients with liver affection, there was no patient with reported Reye-syndrome. Three

patients with concomitant hepatitis died either of multi-organ failure, or of cardio-circulatory

failure and respiratory failure (cf. Section 4.2.11 and Table 28). Eight patients had hepatopathy

or hepatitis. An one year old, otherwise healthy, girl with an abscess of the left shoulder had

concomitant ascites, hepatomegaly and peripheral oedema. Two patients with reported liver

failure are further described in the following paragraphs.

1) A 2.1-year-old boy had liver failure requiring liver transplantation and developed aplastic

anaemia later in the course of disease requiring stem cell transplantation. Both siblings were ill

with varicella about three weeks before admission (exact dates not reported). Ten days before

admission, parents observed icteric changes of the sclera for the first time. He was admitted

because of progressive icterus with elevated transaminase levels. Two days later, an overt

varicella exanthema developed which persisted for 5 days. General health deteriorated and

transaminase levels further increased in the 11 days after admission and he was transferred to a

nearby university hospital for further therapy and diagnostics. Two days later, he was transferred

to another hospital for split-liver transplantation. Histology of the explanted liver showed

unspecific signs of inflammation with extensive liver dystrophy. As a possible indication for

varicella hepatitis, an unspecific portal infiltration of lymphocytes was seen. If a VZV-PCR of

liver tissue was performed, has not been reported. After extensive diagnostics, no clear cause for

liver failure was found. Five months after transplantation, the patient developed aplastic anaemia

and required allogen stem-cell transplantation about one year after his primary admission.

2) The second boy with a reported liver failure is a 12.3 year old boy with multi-organ

failure due to systemic varicella infection admitted on day 2 of the varicella exanthema. He was

diagnosed with common-ALL 20 months earlier and had been in remission for one year. He was

admitted with back pain in the morning, had a cerebral convulsion in the afternoon and was

transferred to the intensive care unit where he continued to have several cerebral seizures. The

next day his general condition deteriorated, he was diagnosed to have pneumonia and he was

electively intubated and ventilated for 16 days. Furthermore, circulatory instability and kidney

insufficiency developed. Catecholamines and dialysis were needed for 11 days and 16 days,

respectively. Concerning the reported liver failure, it was reported that transaminase levels had

increased and hepatomegaly with hydrocholecystis and ascites was observed. He was treated



with intravenous acyclovir beginning with admission on the intensive care unit. He was

discharged to a general paediatric ward after one month.

4.2.6.8 Reactive arthritis Fourteen (1.5%) children were diagnosed with reactive arthritis. 7 had coxitis, 5 gonarthritis, and

one child each polyarthritis and arthritis of the wrist joint. These children demonstrated a median

age of 3.6 years (IQR 1.5-4.8) and stayed a median of 5.5 (IQR 3-8) days in hospital.

4.2.6.9 Complications due to other systemic bacterial infections Other secondary bacterial infections were seen in 40 (4.4%) children. Among these, 21 (2.3%)

were diagnosed with sepsis and 6 (0.7%) with an osteomyelitis (Table 19). Six (0.7%) children

were reported with a necrotising fasciitis (Table 20) and 2 (0.2%) with a bacterial arthritis (Table

19). Five (0.5%) children presented with other systemic bacterial complications, namely one

child with endocarditis caused by Strep. pyogenes, one with lymphangitis (right foot) and three

children with deep myositis (Table 20). The median age of children with systemic bacterial

complications was 2.8 years (IQR 1.1-4.5). They remained a median of 16.5 (IQR 8-28) days in

hospital, significantly longer than all other children (pmedian-test<0.001). They also presented

significantly (pmedian-test=0.005) later after the start of VZV exanthema than all other children, 5

(IQR 3-7) versus 3 (IQR 2-5) days. 38 (95%) of 40 children were treated with intravenous

antibiotics. A 3.9-year-old boy with sepsis (Strep. pyogenes) and accompanying reactive

arthritis, thrombocytopenia, and anaemia was treated with oral antibiotics alone. A 3.1 old girl

with foudroyant sepsis was already dead before treatment could have started in the hospital (see

Table 28, Patient 3).

Twenty positive microbiological specimens from blood cultures were reported. Strep. pyogenes

(n=7, 33%) was the most frequent microorganism isolated. Other pathogens recorded were:

Staph. aureus (n=3), Strep. pneumonia (n=3), Staph. epidermidis (n=2), Streptococcus spp.

(n=1), Neisseria meningitidis Gr. B (n=1), Pseudomonas spp.(n=1), Salmonella spp. (n=1), and

gram-negative cluster cocci (n=1).



Table 19. ESPED: Characteristics of 8 patients with varicella-associated osteomyelitis (grey) or septic arthritis

Patient Gender

Age (years)


Underlying chronic disease Localisation

Start VZV exanthema / infection before

admission Pathogen Other complications / comment

1 m 0.5 14 none hip/femur 4 days Staph. aureus 2 m 0.8 35 none hip/femur 9 days none isolated pyogenic arthritis

3 m 1.7 41 none left foot 9 days N. meningitidis Gr. B sepsis, Waterhouse-Friedrichsen syndrome

4 m 4.1 7 none hip/femur 7 days None isolated osteomyelitis was suspected

5 m 7.4 32 none hip/femur (not known) Staph. aureus pyoderma

6 f 7.4 48 autoimmune disease / steroid therapy distal radius Blisters, no crusts at

admission Strep. pyogenes pneumonia, sepsis

7 m 4.3 12 none knee 5 days none isolated

8 f 10.8 16 none hip 10 days Strep. pyogenes skin abscess over hip with connection to joint



Table 20. ESPED: Characteristics of 9 patients with varicella-associated deep myositis (grey) or necrotising fasciitis

Patient Gender

Age (years)


Underlying chronic disease Localisation

Start VZV exanthema /

infection (days before

admission)

Pathogen Other complications Surgery

1 f 1.3 18 none thigh - None isolated reactive arthritis no

2 m 1.5 25 none thigh and forearm 9 Strep. pyogenes pyoderma no

3 f 6.4 10 none thoracic/flank 3 not tested phlegmon no

4 f 1 7 none thigh 8 Strep. pyogenes - no

5 f 1.9 24 none abdominal 5 Staph. aureus, Enterococcus ssp. phlegmon yes

6 f 4.3 14 mental and motoric retardation thigh 6 Strep. epidermidis (blood culture) abscess lower leg yes

7 m 5.1 19 none upper arm -1 Strep. pyogenes pneumonia, thrombocytopenia,

post-operative coagulation disorder

yes

8 m 5.6 18 none thoracic 3 Strep. pyogenes - yes

9 m 11.8 18 none lower jaw 7 Strep. pyogenes thrombocytopenia, DIC yes



4.2.6.10 Complications due to coagulation disorders and sequelae There were 51 (5.6%) children diagnosed with coagulation disorders. Among these 51 children

33 (3.8%) had haemorrhagic varicella, 5 (0.3%) purpura fulminans, and 13 (1.4%) children

showed other coagulation disorders and sequelae. Among the latter subgroup four children had

haematoma and petechiae together with thrombocytopenia, three children had pathologic

changes in PTT and INR, and one child each was diagnosed with an elevated lipoprotein a,

protein-S deficiency, disseminated intravascular coagulation (DIC), and a post-operative

coagulation disorder (child with necrotising fasciitis). Additionally, there were two children

categorised in this group who had haematemesis and haematuria. The children with coagulation

disorders were at a median of 4.4 years old (IQR 3.2-6.8) and stayed with a median of 9 days

(IQR 6-18) significantly longer in hospital than all other children (5 days, IQR 3-8).

4.2.6.11 Other complications Other complications, i.e. those complications not classified in the categories above, have been

diagnosed in 24 (2.6%) children. Six of these 24 children were hospitalised for undesirable

medical side effects, i.e. renal affection by acyclovir (2), overdose of dimetindenmaleat (2) and

paracetamol (1), and skin reaction to Tannosynt® (lotion against itching) (1). Six children

showed varicella-associtaed urologic complications, i.e. 4 children with urinary tract infection

and 2 children with retention of urine. A further 12 children with various other complications are

listed in Table 21.



Table 21. ESPED: Characteristics and diagnosis of 12 patients with other varicella-associated severe complications

Patient Gender Age (years)



infection (days before

admission)

Complication Other complications Underlying chronic disease

1 f 0.2 6 4 pericarditis gastroenteritis none

2 f 0.3 12 2 pericardial effusion - ASDII, PFO, PDA, hypoproteinemia

3 f 1.8 12 3 mononucleosis skin abscess, stomatitis, haemorrhagic varicella atopic dermatitis

4 - 2.3 3 - ventricular extrasystoles dedydration none

5 f 3.3 4 - parainfectious tendovaginitis - none

6 m 3.8 12 - retinal necrosis with atrophic optical nerve - none

7 f 4.1 19 9 graft-versus host reaction pyoderma, haemorrhagic varicella heart transplant

8 f 4.2 6 6 adrenal insufficiency thrombocytopenia mental retardation / cortical dysplasia

9 f 4.6 60 6 renal salt loosing syndrome cerebral convulsion cleft lip, persistent patent foramen ovale

10 m 5.3 8 0 relapse nephrotic syndrome - nephrotic syndrome (under steroid therapy)

11 f 14.8 12 - myocarditis death none

12 m 15.8 15 22 retinal necrosis - none



4.2.7 Risk factors for varicella complications

4.2.7.1 Age, complications and chronic disease The age at admission to the hospital correlated significantly (pchi-square<0.001) with the severity of

the course of disease, i.e. with the duration of hospitalisation. The proportion of children who

were hospitalised for more than 7 days was higher (38%) in the older age groups (>10-16 years

of age) than in infants (0-1 year) (25%) and toddlers (>1-4 years) (21%). The median age of

children hospitalised for 1-3 days was 3 years, whereas the age of children hospitalised for 15-21

days was 5.4 years (Table 22).

Table 22. ESPED: Median age by categories of hospital stay in children hospitalised with varicella

Figure 12 and Table 11 summarise the relationship between median age at admission and

complication categories and complications. Children with neurologic (4.2 years, IQR 2.5-5.9),

haematologic (4.3 years, IQR 2.4-6.7) complications as well as children with coagulation

disorders and sequelae (4.4 years, IQR 3.2-6.8) were each significantly older than all other

children with varicella, whereas children with gastrointestinal (2.1 years, IQR 1.1-4.3) and skin

infectious complications were significantly younger. All other differences in median age did not

reach statistical significance (Figure 12).

There were also statistically significant differences in age at admission by chronic disease status

(pmedian test<0.001). Whereas children with atopic dermatitis were admitted at a median age of 2.7

years (IQR 1.3-4.9), immunocompromised children were admitted at a median age of 4.6 years

(IQR 3.3.-6.7) (Figure 12). This probably reflects the younger age at manifestation of atopic

dermatitis and the older age at manifestation of chronic conditions with an immunocompromised

state.

4.2.7.2 Hospital stay, complications and chronic disease Figure 13, Table 12 and Table 24 summarise the relationship between hospital stay and

complications. The median hospital stay varied from 16 days for children with other systemic

Hospital stay (days) n Median age in years

(IQR)

1-3 291 3 (1.5-5) 4-7 371 3.1 (1.3-4.8) 8-14 175 3.8 (1.4-5.8) 15-21 44 5.4 (3.7-7.7) 22-199 27 3.8 (1.5-5.7)



bacterial infections to 4 days for children with complications of the gastrointestinal tract (Figure

13). A highly statistically significant (pKruskal-Wallis<0.001) longer hospital stay compared to all

other children was found for children with complications of the lower respiratory tract (7 days),

coagulation disorders and sequelae (9 days) and other systemic bacterial infections (16 days),

whereas a statistically significant shorter stay was seen only for children without recorded

specific complications (4 days). Also children with neurologic complications (6 days) stayed

significantly longer in hospital than all other children (pKruskal-Wallis=0.003). The differences for

these complications are reflected in the increasing proportion of children with a hospital stay of

0-7 days, 8-14 days, and over 14 days (Table 24). Thus, 136 of 662 (20.5%) children with a

hospital stay of less than 8 days but 34 of 72 (47.2%) children with a hospital stay of over 14

days had a neurologic complication.

Table 23. EPSED: Hospital stay and chronic disease (% of all children in category of hospital stay) in children hospitalised with varicella

Hospital stay

< 7 days 8-14 days > 14 days N n (%) n (%) n (%)

Atopic dermatitis 61 50 (7.5 %) 10 (5.7 %) 1 (1.4 %) Immunocompromised 64 34 (5.1 %) 25 (14.3 %) 6 (8.3 %) No chronic disease 707 527 (79.2 %) 124 (70.9 %) 56 (77.8 %) Other chronic disease 77 53 (8 %) 16 (9.1 %) 9 (12.5 %)

TOTAL 909 662 (72.8 %) 175 (19.3 %) 72 (7.9 %)



Table 24. ESPED: Hospital stay and complication category (% of all children in category of hospital stay) in children hospitalised with varicella (multiple nominations possible)

There were also highly statistically significant (pKruskal-Wallis<0.001) differences in duration of

hospital stay by chronic disease status (Table 23). Children with atopic dermatitis and no chronic

condition where hospitalised for a shorter time period (5 days) than children with other chronic

conditions and immunocompromised children (6 and 7 days, respectively) (Figure 13).

4.2.7.3 Gender and complications There was no significant correlation between gender of children and categories of hospital stay

as a correlation for severity of disease (pchi-square=0.65). 139 (55%), 93 (53%) and 43 (60%) of the

children with a hospital stay of 0-7 days, 8-14 days and over 14 days were male, respectively.

The only significant difference in the proportion of girls and boys within complication categories

was seen in the category “other complications” (see Section 4.2.6.11, page 46). 18 of 22 children

(82%) were female (pchi-square<0.001). Otherwise, boys had a borderline significant (pchi-square=0.07)

higher frequency of reactive arthritis (11/14, 79%).

4.2.7.4 Complications in immunocompromised children

Sixty-eight (7.4%) of all children hospitalised with varicella and 27 (3.7%) of all children

hospitalised with varicella and a specific complication reported were classified to be

immunocompromised. Immunocompromised children were admitted significantly more often

without an accompanying complication than immunocompetent children (58% vs. 17%). Thirty-

Hospital stay

< 7 days 8-14 days > 14 days N n (%) n (%) n (%)

Coagulation and sequelae 51 19 (2.9 %) 15 (8.6 %) 17 (23.6 %) Gastrointestinal tract 136 102 (15.3 %) 23 (13.1 %) 11 (15.3 %) Haematologic 64 36 (5.4 %) 13 (7.4 %) 15 (20.8 %) Lower respiratory tract 107 66 (9.9 %) 24 (13.7 %) 17 (23.6 %) Neurologic 232 136 (20.5 %) 62 (35.4 %) 34 (47.2 %) No specific complication recorded 182 164 (24.7 %) 17 (9.7 %) 1 (1.4 %) Other systemic bacterial 39 6 (0.9 %) 13 (7.4 %) 20 (27.8 %) Other complications 24 14 (2.1 %) 7 (4 %) 3 (4.2 %) Reactive arthritis 14 10 (1.5 %) 2 (1.1 %) 2 (2.8 %) Skin infectious complications 212 147 (22.1 %) 48 (27.4 %) 17 (23.6 %) Upper respiratory tract and ENT 92 71 (10.7 %) 17 (9.7 %) 4 (5.6 %)

All children 909 662 (72.8 %) 175 (19.3 %) 72 (7.9 %)



eight of 183 (21%) children with no specific complication were immunocompromised, whereas

27 of 730 (4%) with a reported complication were immunocompromised. Except for one child

with juvenile idiopathic arthritis under methotrexate therapy all immunocompromised children

with no specific complication reported were treated with acyclovir.

Table 25. ESPED: Proportion of immunocompetent and immunocompromised children in complication categories (excluding children with no specific complication reported; multiple nominations possible)

Complications due to coagulation disorders, haematologic complications, complications of the

lower respiratory tract, other systemic bacterial and other complications were significantly more

frequent, and neurologic and infectious skin complications were less frequently reported for

immunocompromised children than for immunocompetent children (Table 25, Figure 19).

All 7 immunocompromised children with complications due to coagulation disorders had

haemorrhagic varicella. Five children with other systemic bacterial complications had sepsis and

one had an osteomyelitis.

Thirteen of 64 (20%) immunocompromised children had a haematologic complication in contrast

to 51 of 703 (7%) immunocompetent children. Forty-one percent of all children with

thrombocytopenia in conjunction with leuko- and/or erythrocytopenia (often pancytopenia) were

immunocompromised. On the other hand, 23 of 35 (66%) children with thrombocytopenia alone

were immunocompetent children.

Four of 27 (15%) immunocompromised children had a neurologic complication, 3 had

meningoencephalitis and one a febrile convulsion. All 2 immunocompromised children with skin

infectious complications had pyoderma.

Immunocompetent Immunocompromised p-value

N=703 N=27

N n % n % Coagulation and sequelae 51 44 5% 7 22% <0.001 Gastrointestinal tract 137 132 19% 5 19% 0.973 Haematologic 64 51 7% 13 48% <0.001 Lower respiratory tract 108 96 14% 12 44% <0.001 Neurologic 232 228 32% 4 15% 0.054 Other systemic bacterial 40 34 5% 6 22% <0.001 Other complications 24 21 3% 3 11% 0.020 Reactive arthritis 14 14 2% 0 0% 0.459 Skin infectious complications 212 210 30% 2 7% 0.012 Upper respiratory tract and ENT 92 86 12% 6 22% 0.125



4.2.8 Hospitalisations in patients with previous VZV-vaccination

In seven hospitalised patients with varicella prior immunisation with a varicella vaccine was

reported. Five patients were immunocompromised (1 leukaemia, 1 hodgkin’s disease, 1

nephrotic syndrome, 1 juvenile idiopathic arthritis, 1 organ transplantation) and two patients had

no underlying chronic disease. The median age was 4.3 (range 1.1-10.7) years and the median

hospital stay was 6 (range 3-12) days. The time between vaccination and hospitalisation with

varicella ranged between 10 days and 8 years, with a median of 2 years. The largest time interval

of 8 years was reported for a patient who was vaccinated in 1995 in the USA. Information on

number of vaccinations and serologic response to vaccination was not available.

A 1.1 year old patient was hospitalised 10 days after varicella vaccination with varicella

complicated by pyoderma. Information on prior varicella exposure was not available. He was

immunocompetent and differentiation into wild- or vaccine-type VZV infection was not

performed. Three patients had no specific complication recorded. There were two patients with

pyoderma, and one each with meningoencephalitis and pneumonia (Table 26).

Table 26. ESPED: Characteristics of 7 patients with varicella and prior varicella immunisation

4.2.9 Concomitant occurrence of varicella and herpes zoster

In two patients physicians reported that patients had both clinical signs of varicella and herpes

zoster at the same time.

1) A 6 year old, healthy girl developed a herpes zoster rash two days before

admission. The rash was localised in the area of the left N. trigeminus and was

accompanied by pain. Acyclovir therapy was started by the paediatric practice.

She was admitted for vomiting and deteriorating general condition. During

hospital stay a typical, generalised but discrete varicella rash developed. The rash

Patient Age in years


Varicella-associated complication Underlying chronic disease Time since

vaccination

1 4.8 4 none hodgkin's disease 1 month

2 3.2 5 none juv. idiopathic arthritis 3 months

3 4.3 6 pyoderma leukaemia unknown

4 6.8 7 none nephrotic syndrome 3.7 years

5 3.2 8 pneumonia prior kidney transplantation 2 years

6 10.7 12 meningoencephalitis none 8 years

7 1.1 3 pyoderma none 10 days



was mainly localised over abdomen and the upper and lower limbs. After 4 days

in hospital she was discharged in good condition.

2) This is a 10.6 year old girl admitted for meningoencephalitis and cerebellitis. The

girl was an US citizen and immunised with varicella vaccine about 8 years earlier.

First atactic symptoms were observed about 5 days before admission. One day

before admission a varicella typical rash was observed on the right shoulder of the

patient. A concomitant rash in the elbow flexure was judged to be more typical

for herpes zoster. No further exanthema was observed. Serology (IgG+IgM) and

PCR were positive for VZV. She was treated with i.v. acyclovir. The patient was

discharged after 12 days in good health. This case may be either an atypical

presentation of varicella after prior immunisation, a presentation of herpes zoster

in two different dermatomes, or a concomitant occurrence of varicella and herpes

zoster as described by the reporting physician.

4.2.10 Sequelae associated with varicella

Sequelae were assessed at hospital discharge and there was no further regular follow-up.

Classification of a sequela was performed by the physician filling in the questionnaire.

In 894 children there were ten deaths (see 0) and 15 (1.7%) permanent sequelae reported. Ten of

the 15 children were reported to have scarring, one child each was reported to have ataxia, mitral

valve insufficiency due to endocarditis, visual restriction due to retina necrosis, liver

transplantation, and hemiparesis due to cerebral infarct. For 78 (8.7%) children, possible

sequelae were recorded as listed in Table 27.

Table 27. ESPED: Possible sequelae in 78 hospitalised children with varicella

n %

Scars 19 24.4% Ataxia / coordination disorder 17 21.8% Epilepsy 4 5.1% Cerebral nerve paralysis 3 3.8% Arthrosis 2 2.6% Hemiparesis / aphasia 1 1.3% Pulmonary defect 1 1.3% Dysesthesia face 1 1.3% Residuals of deep venous thrombosis 1 1.3% Epiphysal changes bacterial arthritis 1 1.3% Others, no specific cause reported 28 35.9%

TOTAL 78 100%



4.2.11 Deaths associated with varicella

A total of ten varicella-associated deaths were reported. 4 deaths in 2003 and 6 in 2004. Six of

them were considered to be immunocompetent. Three children had an acute lymphatic leukaemia

(ALL) and one child had low IgG and IgG1 serum levels documented for the first time during

the acute VZV illness. Two children had a congenital varicella syndrome. The median age at

presentation in the hospital was 5 years (range 0-14.8). All admitted patients received iv

acyclovir. The ten deaths are briefly described in Table 28 and the following section:

Patient 1. This female infant died at 8 months of age following complications of a

congenital varicella syndrome. The mother was exposed to varicella at 12 weeks

of gestational age and received i.m. VZV-immunoglobulins prophylactically 3

days after the start of exanthema while carrying her daughter. The mother

developed varicella in the 14th week of gestational age. She was not treated with

acyclovir. She presented in the 34th week of gestational age for amniocentesis

because of extensive polyhydramnios. Due to a silent cardiotocography a prompt

caesarean section was performed. A girl was born with an APGAR 4/6/8, a birth

weight of 2070 g and a length of 37 cm. Due to insufficient breathing, the child

had to be intubated shortly after birth and was never extubated during the course

of disease. In the right genital area and on the right sole of the foot, several

blisters were found. Furthermore, there were a couple of small white ulcerations

on the right side of the body. Otherwise, the girl had no further skin

manifestations or congenital malformations. Because of the history of varicella

exposure, extensive testing of VZV was performed. PCR was positive for VZV in

sputum, liquor, urine and blood. VZV was secreted in urine for three weeks.

Treatment with acyclovir and VZV immunoglobulins was initiated immediately.

However, the child deteriorated during the first day and had a cerebral

haemorrhage. After slow clinical stabilisation, the child developed chronic lung

disease and died at 8 months of age due to pulmonary insufficiency with

circulatory failure. The child never developed a cellular or humoral VZV-specific

immunity. However, in an extensive work-up, a humoral or cellular

immunodeficiency could be excluded. Thus, an immune-tolerance to VZV was

suspected. Post-mortem examination revealed VZV-DNA in brain and spinal cord

tissue, but not in any other organ.

Patient 2. This female infant died at an age of 39 days following complications of a

congenital varicella syndrome. The mother had developed varicella at 13 weeks



of gestation. Amniocentesis during the 15th week of gestation and an ultrasound

examination during the 19th week were seen to be unremarkable. At 28+5 weeks

of gestational age, a caesarean section was performed because of the silent

cardiotocography. With a birth weight of 730g, a length of 34 cm and an APGAR

of 4 with insufficient breathing, the child had to be intubated immediately. The

child had multiple skin lesions on both ankles, knees and hand joints, and on the

forehead. Furthermore, there were contractures to be observed on all joints and

only four digits on the right foot. The right eye was not developed. VZV-DNA

was detected in the pharynx and in the faeces. In the further course of disease, a

complete stenosis of the small intestine and liver dysfunction with calcifications

of the whole organ were diagnosed. As a prognosis was unfavourable, only

supportive therapy was administered. The girl died at the age of 39 days. No

autopsy was performed.

Patient 3. This 3.1-year-old, previously healthy girl died following fulminant sepsis during

day 4 of varicella. She was first presented at her paediatrician with high fever and

pharyngitis on the second day of the varicella exanthema. A rapid Strep A antigen

test was negative. With symptomatic therapy, the girl was seen to be fine during

the following two days and the fever was declining. In the evening of the fourth

day, a blood-filled, inguinal bulla was observed. Some hours later, the father

found the child to be dyspneic and comatose in her bed. Reanimation at home by

parents and by the emergency physician were unsuccessful. Autopsy was

performed. Death was attributed to fulminant sepsis. Haemorrhagic necrosis of

the skin and a super-infected varicella rash were found. There were no signs of

encephalitis or meningitis. Endovascular and intra-alveolar bacteria were

abundant with no inflammatory reaction.

Patient 4. This 3.4-year-old boy died on day 3 of the varicella exanthema. He was diagnosed

with acute lymphatic leukaemia during the course of acute disease. He presented

in the emergency room of a paediatric hospital with macrohaematuria, weakness

and varicella exanthema, that had started 1 day earlier. The white blood count was

91,000 / µl (81% blasts), and thrombocytes were reduced (67,000 / µl). The lactic

dehydrogenase (LDH) was elevated with 4,567 U/l. Due to the suspected

diagnosis of ALL (later: pre-T-ALL) the boy was transferred to the next oncology

unit at a university children’s hospital in a nearby city. Within one day his health

status progressively deteriorated and he had to be intubated for pulmonary



insufficiency. He died several hours later. In the post-mortem examination,

cardiac and circulatory failure with pulmonary leukostasis were the documented

causes of death. The spleen was necrotic. The capillary bed of the lungs was filled

with blasts, whereas all other capillary beds and interstitial tissues, beside the

bone marrow, were free of blasts. Electronic microscopy revealed herpes virus

within the lymphatic blasts. VZV-DNA was detected in all organs. It was

speculated that death was caused by the activation of blasts through varicella

virus infection, the following sequestration of blasts in the lungs and the

consecutive decrease in the pulmonary arterial flow.

Patient 5. This 4.5-year-old boy died on day 13 of varicella. He was admitted to an

oncology unit to start treatment for newly diagnosed common-ALL. It was known

that he had no history of varicella and had had contact to a friend with varicella 2

½ weeks before admission. However, the contact was reported to have been more

than two days before eruption of exanthema and again, a second time, after the

healing of all blisters. Nevertheless, the patient was isolated until day 28 after

potential exposure.

Chemotherapy was initiated. 6 weeks after potential exposure, the boy was

admitted with abdominal pain and several small cervical maculae (maximum 6-

10). The liver was enlarged and liver enzymes were elevated (LDH 500 U/l, AST

145 U/l, ALT 150 U/l; total bilirubin 2.0 mg/dl). Acyclovir (3x10 mg/kg body

weight /day) was initiated one day later for suspected primary varicella infection.

For the differential diagnosis of a hepatic vein occlusion syndrome with bacterial

infection, antibiotic (meropenem+vancomycin) treatment was initiated at

admission. One day later, the boy experienced a convulsion and was transferred to

the intensive care unit. On the third day after admission, MRT of the head showed

changes compatible with a CNS infection. Furthermore, PCR of skin probes were

positive for VZV and blood cultures were positive for salmonella. Liver enzymes

increased markedly. The dose of acyclovir was increased to 3 x 20 mg / kg body

weight, cidofovir and later foscavir were added. Intravenous antibiotic therapy

was continued with meropenem, teicoplanin and tobramycin. In the following

days varicella further progressed with 1,000,000 copies of VZV DNA /ml still

detected in blood serum, in spite of one week of i.v. acyclovir therapy. The

patient developed progressive renal failure, and the patient died of

cardiocirculatory failure 13 days after admission. No autopsy was performed.



Patient 6. This 5.4-year-old girl died of generalised VZV infection 6 days after the start of

fever and 3-5 days after the start of a papular rash. The girl had already been on

maintenance therapy for seven months (mercaptopurine and methotrexate) for

ALL in remission. She had no neutro or lymphopenia. She developed fever

without a specific infectious focus and ambulatory therapy with cefuroxim was

started. In the following days, a papular rash developed that was not initially

recognised as varicella. The general health deteriorated and the child was

admitted on day 5 of varicella. Tachycardia, dyspnoea (O2 saturation 81%) and a

generalised vesicular rash with haemorrhagic vesicles was noted. Immediate

therapy with acyclovir and cefotiam was started. After 12 hours, the child died of

respiratory failure. Autopsy showed morphologic signs of a generalised VZV

infection of the skin, lungs, liver, spleen and mucous membranes. VZV-PCR was

positive in specimens of the liver and the pharynx. Lung parenchyma showed

signs of shock lung with hyaline thrombi and membranes. Liver parenchyma

showed extensive degenerative and necrotic changes. There were no leukaemic

changes in any lymphatic tissue examined nor in the bone marrow.

Patient 7. This 6.7-year-old, previously healthy girl died of multi-organ failure 4 days after

varicella exanthema had started and two days after admission with pneumonia. A

few hours after admission, the child was intubated because of respiratory

insufficiency. Concurrently, liver failure developed with disseminated intravasal

coagulation and bleeding anaemia. Due to circulatory insufficiency, high doses of

catecholamines were required and renal failure developed. In the last hours, a

capillary-leak syndrome developed and any further intensive care measures were

seen to be unsuccessful. No autopsy was performed.

Patient 8. This 6.9-year-old, previously healthy boy died of Staph. aureus sepsis on day 5 of

varicella. He was already dead when transferred to the emergency room of the

hospital. During the five days before his death he was seen three times by

different paediatricians who had diagnosed varicella, but could not identify a

serious condition in the boy. Two days before his death he was seen for the last

time by his paediatrician. He was diagnosed with Staph. aureus pneumonia and

sepsis in the post-mortem autopsy. Several bullae and flaming red skin areas were

observed on the whole body.

Patient 9. This 13.3-year-old boy with psychomotor retardation due to neonatal asphyxia

died of respiratory and circulatory failure on day 9 of varicella. One week before



admission he developed a varicella exanthema that became haemorrhagic during

the week. He was admitted because of increasing dyspnoea with cyanosis of the

lips and high fever. X-ray of the lung showed subtotal opacification of both lungs

with effusion, consistent with varicella pneumonia. Intravenous treatment with

cefazolin and acyclovir was started. On the second day, the boy had to be

intubated due to progressive respiratory failure. Furthermore, disseminated

intravasal coagulation with bleeding anaemia developed and several red blood

cell and platelet concentrates were given. On the third day after admission, the

patient died of respiratory and circulatory failure. No autopsy was performed.

Patient 10. This 14.8-year-old girl developed a vesicular rash, at first on her back and later

generalised, accompanied with nausea and vomiting eight days before admission.

Two days before admission, dermatitis caused by Staphylococcus spp. was

suspected, a swab of a skin lesion was taken and therapy with cefaclor was

started. One day later, the specimen of the skin swab was reported to be positive

for Pseudomonas spp.. Additionally, thrombocytopenia was seen in the blood

count. On the next day, the condition of the girl worsened with weakness and

exercise-induced dyspnoea. She was admitted with suspected pseudomonas sepsis

that was not confirmed by the hospital. Over night her condition worsened and

she was seen to require oxygen. A lung x-ray showed signs of lung oedema.

Echocardiography was performed and a reduced left-ventricular function (about

17%) was observed. The patient was transferred to the cardiac intensive care unit

with suspected myocarditis. The exanthema with crusts and without blisters was

suspected as varicella and confirmed by a positive PCR of a swab of the skin

beneath a crusted lesion. For the treatment of cardiac failure, the patient required

treatment with an intra-aortal balloon pump (IABP) and ECMO (extracorporeal

membrane oxygenation) over several days. The patient’s condition stabilised, and

IABP and ECMO were terminated. However, after arterial catheter removal, an

acute reperfusion syndrome with hyperkalemia developed, which was

unmanageable and lead to cardiac failure and death 11 days after admission. No

autopsy was performed.



Table 28. ESPED: Overview of 10 varicella-associated deaths

Patient Gender

Age patient

died (years)


infection before death

Underlying chronic disease Diagnosis / complications Cause of death

1 F 0.7 8 months none atypical congenital varicella syndrome, no malformations, cerebral haemorrhage, BPD respiratory failure

2 F 0.1 39 days none congenital varicella syndrome, stenosis of small intestine, calcification of liver multi organ failure

3 F 3.1 4 days none sepsis with gram-positive cocci fulminant sepsis

4 M 3.4 3 days ALL (newly diagnosed, no therapy yet) pneumonia, haemorrhagic varicella

cardiac and circulatory failure with pulmonary leukostasis, disseminated

intravasal coagulation

5 M 4.5 13 days ALL (newly diagnosed, start

of therapy in incubation period)

hepatitis, meningo-enzephalitis cardio-circulatory failure

6 F 5.4 3-5 days ALL in remission pneumonia, hepatitis, haemorrhagic varicella respiratory failure

7 F 6.7 4 days none pneumonia, meningoencephalitis, haemorrhagic varicella multi-organ-failure

8 M 6.9 5 days none pneumonia, Strep. pyogenes sepsis respiratory failure

9 M 13.3 9 days

possible IgG+IgG1 deficiency; psychomotor retardation after neonatal

asphyxia

haemorrhagic varicella, pneumonia cardio-circulatory and respiratory failure

10 F 14.8 19 days juvenile myoclonic epilepsy myocarditis, ECMO cardio-circulatory failure

4 Results — ESPED: Herpes zoster Hospitalisations


4.3 ESPED: Herpes zoster Hospitalisations


In 2003 and 2004 244 children and adolescents hospitalised with herpes zoster were reported

(Table 29). There was no seasonal variation within and between the years 2003 and 2004 (Figure

20). One-hundred and twelve of 241 children (46%) were female. The median age at admission

was 9.0 years (IQR: 4.9-13.1) with a equal distribution over all age groups (Figure 21). 10

children each were admitted during their first and second year of life. Children were hospitalised

a median of 2 days after the exanthema had started. 10 of 217 children were reported with

admissions more than 1 week after the eruption of exanthema (Figure 22). Of these 10 children

four presented with skin infectious complications. There were three immunocompetent children

with dermatomal pain, one immunocompetent child with a prolonged rash (rash still existing

after 4 weeks), one child with pneumonia, and one child with a HZ relapse.

Table 29. ESPED: General characteristics of 244 children hospitalised with herpes zoster

Herpes zoster erupted a median of 4 years after primary VZV infection (n=74). Twenty-four

(32%) and 12 (16%) children had their primary VZV infection within their first and second year

of life, respectively. 35% (n=26) of all children, who had their primary VZV infection during the

first two years of life developed herpes zoster within 4 years (Figure 23). These data may be

subject to recall bias as Figure 23 could also suggest that varicella not more than 4 to 5 years

before herpes zoster and varicella in the first year of life are better remembered and documented

in the questionnaires.

4.3.2 Hospital stay

Once admitted, children remained an average of 7 days in hospital. However, 22 children (9%)

stayed longer than 14 days (Figure 15). Immunocompetent children were hospitalised for a

shorter period than immunocompromised children (median 6 vs. 8 days, p=0.02).

Male / female 54% / 46% Median age in years 9.0 (4.9-13.1) Median hospital stay in days 7 (5-10) Median time start of exanthema to admission in days 2 (0-4)

i.v. acyclovir therapy 81% i.v. antibiotic therapy 25% Immunocompromised 32%



4.3.3 Therapy

Two-hundred-thirteen (88%) children were treated with oral or intravenous acyclovir. One-

hundred-twenty-one children (50%) were treated with antibiotics. Fifty-three (22%) children

were treated with intravenous acyclovir and antibiotics. Twenty children had neither antibiotics

nor acyclovir, none of them was immunocompromised. Seventy-six of 77 (99%)

immunocompromised children were treated with acyclovir, 84% only intravenously. In contrast,

24 of 143 (17%) children without chronic conditions received no acyclovir at all and only 65%

received intravenous acyclovir exclusively.


One-hundred forty-four of 244 (59%) children admitted had no underlying chronic disease. 78

(32%) children were considered to be immunocompromised, 9 (4%) were reported to have atopic

dermatitis, and 13 (5%) had other chronic diseases. Immunocompromised patients contributed to

about 39% of all hospital days (Table 30).

Table 30. ESPED: Chronic disease status and contribution to overall hospital days hospitalised with varicella

Of the 78 immunocompromised children, almost 75% had a haemto-oncologic disease with

leukaemia being the most frequent diagnosis (Table 31). Of 13 children with other chronic

diseases, 5 (38%) children had a neurologic disease, one child each (8%) a chronic pulmonary

disease or a metabolic disorder, and 6 (46%) children various other chronic conditions.

n % of all HZ patients



None 144 59.3% 971 51.7%

Immunocompromised 78 32.1% 723 38.5%

Other chronic diseases 13 5.3% 112 6.0%

Atopic dermatitis 9 3.7% 73 3.9%

TOTAL 244 100% 1879 100%



Table 31. ESPED: Diagnosis in 78 immunocompromised children hospitalised with herpes zoster

4.3.5 Symptoms and localisation of rash

The most frequent symptoms in children with herpes zoster were pain, seen in 104 (45%) and

fever, seen in 85 (36%) children. Feeding problems were reported in 37 (16%) children. Thirty-

two (14%) children hospitalised with herpes zoster had eye involvement. Headache was noted in

32 (14%), gastrointestinal symptoms in 20 (9%), neurologic focal symptoms and signs in 17

(7%), other neurologic symptoms in 13 (6%), and ataxia in 8 (3%) children (Figure 25). Children

with pain (median age 11 years, IQR 6.5-14.3) were significantly older and children with feeding

problems (5.9 years, IQR 2.9-8.4) and fever (7.1 years, IQR 3.4-11.9) younger than other

children with herpes zoster (Figure 26). Hospital stay was generally longer in children with

neurologic symptoms, and statistically significant (each pmedian-test<0.001) for ataxia (15 days,

IQR 8-21), other neurologic (12 days, IQR 8-17) and focal neurologic symptoms (9 days, IQR 6-

16) (Figure 27).

Neuralgia was explicitly stated as a complication in 98 (40.3%) children. The frequency of

neuralgia was not related to dermatome location of the HZ rash (pchi-square=0.511). There was a

borderline significant difference in neuralgia frequency by chronic disease status (pchi-

square=0.051). Whereas 66 (44%) of 144 children with other chronic diseases had neuralgia, one

of 10 children with atopic dermatitis and 28 (36%) of 77 immunocompromised children were

seen to have suffered from neuralgia. Duration of neuralgia was limited to the time of HZ rash

most of the time. Four children were reported with neuralgia of 14 days, several weeks, two

months and at least 5 weeks (last contact with physician), respectively. One immunocompetent

child with facial nerve paralysis suffered from pain for about 14 days. All other three children

were immunocompromised and had a lumbal/sacral location of HZ rash.

n %

Leukaemia 34 (44%) Tumour 15 (19%) Hodgkin’s disease 9 (12%) Organ transplantation 7 (9%) Autoimmune disease 5 (6%) Juvenile idiopathic arthritis 3 (4%) Others 2 (3%) Nephrotic syndrom 2 (3%) Primary immuno-deficiency 1 (1%)

TOTAL 78 (100%)



Thoracic (43%) and trigeminal dermatomes (32%) were the most frequent skin localisations of

herpes zoster. A lumbal/sacral localisation of HZ rash was seen in 27 (12%) children. In 11 (5%)

children, two different dermatome areas were affected, mostly adjacent to the trigeminal and

cervical dermatomes. However, one immunocompetent child had lesions in non-adjacent

trigeminal and thoracic dermatomes. In 4% of all children, a cervical dermatome was affected

and the exanthema was considered to be generalised in 4% of all children with herpes zoster

(Figure 28).

4.3.6 Complications associated with herpes zoster hospitalisations

In 128 (53%) children no specific complication was recorded. These children contributed to 46%

of all hospital days in HZ patients (Table 32). Most of the children with no specific complication

were either immunocompromised and were treated with acyclovir (n=57, 24%), had pain (n=57,

24%), feeding problems (n=11, 5%), or had other symptoms such as fever or other chronic

conditions and were treated with acyclovir (n=24, 10%).

Table 32. ESPED: Complication category and contribution to overall hospital days in 243 children hospitalised with HZ (multiple nominations possible)

In 115 (47%) children a specific complication of herpes zoster was recorded. Super-infection of

the skin (n=42, 17%), ophthalmic zoster (n=29, 12%), 10 with keratitis, zoster oticus (n=23,

9%), 11 of these with facial nerve paralysis (Ramsay Hunt) and 3 with involvement of the

vestibular nerve, and meningoencephalitis (n=22, 9%) were the most frequent complications

(Figure 29).

n % of all HZ patients



No specific complication recorded 128 52.7% 857 45.6% Skin infectious complications 42 17.3% 361 19.2% Meningoencephalitis 22 9.1% 248 13.2% Ophthalmic zoster 29 11.9% 233 12.4% Zoster oticus 12 4.9% 90 4.8% Ramsay Hunt 11 4.5% 132 7.0% Generalised herpes zoster (Skin) 9 3.7% 85 4.5% Other complications 8 3.3% 65 3.5% Pneumonia 5 2.1% 49 2.6% Upper respiratory tract, ENT and eye 5 2.1% 26 1.4% Other neurologic 4 1.6% 23 1.2%

All children 243 100% 1879 100%



4.3.6.1 Skin infectious complications Of 42 children with complications of the skin 25 (10%) had pyoderma, 12 (5%) phlegmona, 3

(1%) cellulitis, and 2 other manifestations of the skin, i.e. one with an unspecific exanthema and

one with skin bullae.

In 27 of 42 skin infections microbiological testing of skin specimen was reported. Of these, 12

(44%) were sterile. Of 15 positive cultures 6 (40%) were positive for Staph. aureus. The

following other specimens were isolated: Bacillus ssp. 2, Staphylococcus ssp. 1, Streptococcus

ssp. 1, Staph. epidermidis 1, Strep. pneumonia 1, Strep. pyogenes 1, Pseudomonas putida 1,

gram-positive mixed culture 1.

4.3.6.2 Meningoencephalitis Because of the difficulty to assign patients to meningitis or encephalitis by questionnaire, and

because of the fact that many physicians reported the patients as belonging to both the meningitis

and the encephalitis groups, we combined all reports of meningitis and encephalitis into one

group. Thus, 22 (9%) children were reported to have meningoencephalitis. 14 (63%) presented

with headache, 8 (36%) with fever, 6 (27%) with meningeal signs and 3 (14%) with reduced

consciousness. 66% (n=12) of these children had a thoracic rash compared to 42% of all other

children with herpes zoster rash. However, this difference did not reach statistical significance

(pchi2=0.35). Age at admission was a median of 13.0 (IQR: 10.4-13.9) years, significantly older

than all other children with HZ (8.5 years; IQR 4.6-13.0). The children stayed on for a median of

10.5 (IQR: 7-15) days, that is longer than all other children hospitalised with HZ (6 years; IQR

5-9). The rash started on a median of 2 days before admission (range 7 before – 2 days after

admission). Two children had accompanying involvement of the facial nerve and zoster oticus

(Ramsay Hunt), 2 had accompanying skin infections and 1 child had accompanying ophthalmic

zoster.

MRT was performed in 8 of 21 (38%) and EEG in 14 of 20 (70%) patients with complete

information. Two of 8 MRT’s and 8 of 14 EEG’s were considered to be pathologic. In one MRT

signs of brain oedema and other local abnormalities and in another MRT local abnormalities

were observed. The eight pathologic EEG’s were as follows: 3 EEG’s with generalised

decelerations, two with generalised signs of dysfunction, one with focal epileptic signs, one with

generalised decelerations and focal epileptic signs, and one with focal decelerations.

Eighteen (82%) children received intravenous acyclovir and 16 (68%) oral or intravenous

antibiotics. Three children were treated neither with antibiotics nor acyclovir, and 4 children

were not treated with acyclovir.



The age of primary VZV infection was known in 8 children. Three of them had varicella in the

first year of life which is about the same proportion as in all other children with herpes zoster.

Aside from in a 12.3-year-old girl with fever, headache and meningeal signs at presentation, a

liquor puncture was performed in all other children with a diagnosis of meningoencephalitis. In

20 of 21 (95%) children VZV specific testing of the liquor by PCR or serology was performed

(Table 33). The one child without testing had a liquor cell count of 14 cells per ml, a liquor

protein of 95 mg /dl and a liquor glucose of 53 mg /dl. PCR was positive in 11 children (of 14

tested). Of the remaining children 6 were positive for VZV-IgG and one for VZV-IgM, and no

specific VZV-antibodies were tested in three further children. Bacterial cultures were negative in

all 16 children tested. However, a 11-year-old, immunocompetent girl developed a brain

empyema 3 weeks after primary herpes zoster meningoencephalitis and required surgery. Culture

of surgical drainage material revealed Pseudomonas spp. infection.

Table 33. ESPED: Results of VZV-specific liquor diagnostic in 22 children with herpes zoster-associated meningoencephalitis

Four children had no rash at all. Neither had they reported dermatomal pain as in herpes zoster

sine herpete. Two of four presented with reduced consciousness, 1 with headache and ataxia, and

one with a developmental delay. Aside from in one of these children with a very high liquor-

serum VZV-IgG ratio of 18 and a negative VZV-PCR, the proof of VZV reactivation was

incomplete. VZV-PCR was performed in none of the other patients. The diagnosis is based on an

increase of liquor-serum VZV-IgG ratio from 1.1 to 1.3 during acute disease in one child, a

liquor-serum VZV-IgG ratio of 2.1 in another, and sero-conversion of liquor VZV-IgG within

one year in a third child.

PCR IgG IgM n (N=22) Percent

nd nd nd 2 9.1%

positive nd nd 7 31.8% positive positive nd 3 13.6%

nd positive negative 3 13.6% negative nd nd 2 9.1%

nd positive nd 2 9.1% negative positive negative 1 4.6% positive negative positive 1 4.6%

nd negative negative 1 4.6%



4.3.6.3 Other complications Nine (4%) patients were considered to have generalised herpes zoster. However, all herpes zoster

manifestations were restricted to the skin. Of the five (2%) patients with complications of the

upper respiratory tract, ENT and eyes, three had swelling of regional lymph nodes and two a

conjunctivitis. Four children had other neurologic complications and symptoms, i.e. headaches

(2), convulsion (1) and tinnitus (1) with a concurrent zoster oticus without involvement of the

vestibular nerve. Of the seven patients categorised as “others”, 3 had signs of dehydration or

gastroenteritis, 2 immunocompromised patients had leukocytopenia, one suffered of side effects

of brivudin and one immunocompromised patient was treated for suspected sepsis.

4.3.7 Risk factors for herpes zoster complications

4.3.7.1 Gender and complications Aside from the fact that boys were hospitalised more often than girls (54% vs. 46%), there was

no indication that gender influenced the frequency and timing (by age or by eruption of

exanthema) of admission, hospital stay or therapy due to HZ. Except for generalised herpes

zoster (7% vs. 0%, pchi2=0.005), no complication was seen more often seen in boys than in girls.

4.3.7.2 Age, complications and chronic disease The 9 children with generalised herpes zoster and 42 children with skin infectious complications

were admitted at a median age of 4.7 years and 6.5 years, respectively. In contrast, children with

meningoencephalitis and zoster oticus were admitted at an age 13.0 and 10.6 years, respectively,

which is older than the median age of all children (9 years). The difference in age was only

statistically significant for meningoencephalitis (pmedian test<0.001) (Figure 30).

There were also statistically significant differences in age at admission by chronic disease status

(pmedian test<0.001). Whereas children with atopic dermatitis were admitted at a median age 3.5

years, immunocompromised children were admitted at a median age of 10.8 years (Figure 30).

4.3.7.3 Hospital stay, complications and chronic disease Children with meningoencephalitis (median hospital stay 10.5 days) were hospitalised for a

longer period than all other children (pmedian test<0.001). Also children with zoster oticus (8 days),

especially those with involvement of the facial nerve (10 days), had a longer hospital stay (pmedian

test=0.056) than all other children.

There were also statistically significant differences in duration of hospital stay by chronic disease

status (pmedian test<0.001). Children without and children with other chronic conditions where



hospitalised for a shorter time period (6 days) than children with atopic dermatitis and

immunocompromised children (8 days) (Figure 31).

4.3.7.4 Complications in immunocompromised children Immunocompromised children were admitted significantly more often without an accompanying

complication than immunocompetent children (76% vs. 42%). Within all patients with specific

complications generalised herpes zoster was seen significantly more often in

immunocompromised patients (25% vs. 4%, pchi2=0.002). Skin infections and pneumonia

manifested as often in immunocompromised as in immunocompetent children. However, zoster

oticus (11% vs. 22%), ophthalmic zoster (16% vs. 27%), meningoencephalitis (11% vs. 21%),

and complications of the upper respiratory tract, ENT and eyes (0% vs. 6%) were reported more

often in immunocompetent children. None of the latter differences, however, reached statistical

significance (Figure 32).

4.3.8 Sequelae associated with herpes zoster

There were two reports of permanent sequelae in 237 children with available information. Both

children still suffered from facial nerve paralysis several months after diagnosis. In 19 (8%)

children, possible permanent sequelae were recorded: 6 of 19 (32%) children with possible

permanent scaring, 5 (26%) with residual facial paralysis at discharge and up to 5 months after

discharge, and one (5%) child each with possible restricted hearing, with sequelae after ceratitis,

and one with possible sequelae following brain surgery. In five (26%) further patients, no

specific reason for possible permanent sequelae was given.

5 Results — EURODIAB: Performance


5 EURODIAB: Results

5.1 EURODIAB: Performance In the period 2003-2004, 22% (2292 / 10,432) of all practices responded on average in all four

biannual queries. The response rate was higher for paediatric practices than for general practices

and practices for internal medicine evaluated together, i.e. 43% (416 / 967) and 20% (1876 /

9465), respectively. The response of the paediatricians was the highest in the first six months of

the year 2003, during which 53% (501 / 947) had responded.

164 practices reported 183 patients. 125 patients were verified as cases, while 58 (31%) were

considered false reports. The reasons for 35 varicella and 23 herpes zoster false reports are listed

in Table 34. Reason for most false reports were either not undergoing in-patient treatment or age

older than 16 years (17th birthday already reached). In four children, a VZV infection could not

be confirmed and 3 cases did not occur during the relevant time period of 2003-2004. Three

children were admitted to adult hospitals/wards (not included in ESPED) and two children were

admitted to hospitals outside the NRW region. Three cases were double reports. Of 125 verified

cases, 107 were hospitalisation due to varicella and 18 due to herpes zoster.

Table 34. EURODIAB: Reasons for 35 varicella and 23 herpes zoster false reports

5.2 EURODIAB: Description of varicella cases Sixty-three (59%) of 107 varicella patients were male. The median age at admission was 3.6

years (IQR 1.8-5.1), with 11 children being older than 8 years, 17 children between 1-2 and 20

children between 4-5 years of age. Fourteen children had varicella within the first year of life

(Figure 33). Patients with varicella were hospitalised for a median of 6 days (IQR 3-8) (Figure

34). Most of the reported varicella cases (n=71, 68%) had no underlying chronic disease. Eight

Varicella n=35

Herpes zoster n=23

No in-patient treatment 23 13

Age > 16 years 1 6

No VZV infection 1 3

Admission not in 2003/2004 3 -

No children's hospital / ward 2 -

Hospital outside NRW 2 -

Double report 3 -

5 Results — EURODIAB: Description of HZ cases


(8%) children had atopic dermatitis, 5 (5%) were considered immunocompromised and 21 (20%)

children had another chronic disease. Four cases (4%) were reported with permanent sequelae,

while sequelae were uncertain in 12 cases (11%). Ninety (85%) children had no residual defects.

5.3 EURODIAB: Description of HZ cases Sixteen hospitalisations due to herpes zoster have been reported. Seven of them (44%) were

male. Median age at time of hospitalisation was 7.5 years (IQR 4.5-14). Children stayed in

hospital for a median of 6.5 days (IQR 4-8). Twelve children (75%) had no chronic underlying

disease; three children (19%) suffered from a chronic disease. The physicians reported one child

with atopic dermatitis and no immunocompromised child. No child had permanent sequelae.

6 Results — ICD10 pilot study: Performance


6 ICD10 pilot study (Bavaria/NRW 2003): Results

6.1 ICD10 pilot study: Performance In 4 hospitals, 76 patients were reported for 2003 (different time periods for each hospital) with

an ICD code for varicella or herpes zoster. Seventy-one of 76 cases were assessed by medical

chart review, as there was no medical chart available for 6 cases (8%). Four cases (5%) which

had an ICD10 code of VZV infection proved to be “false” or not associated with varicella

infection. One of these 4 children had no varicella infection and the other 3 were admitted for

other reasons than varicella. The latter 3 were also identified as false reports by mere evaluation

of ICD data due to overt surgical codes. Furthermore, 5 cases (6%) were classified as possibly

varicella-related hospitalisations (Figure 35).

All 11 hospitals participating in the pilot study reported 142 hospitalisations, i.e. 119 (84%) with

varicella and 23 (16%) with HZ. Of 119 reported varicella cases, 14 (13%) were false reports. 7

of these14 hospitalisations were considered to be unrelated to a varicella zoster virus infection, in

4 cases the age of the children was over 16 years, 2 children were treated ambulatory, and

hospital stay was not plausible in one case (discharge from hospital was earlier in time than

admission to the hospital, e.g. this represents a possible mistake at data entry on the hospital’s

site). Of 25 HZ reports 7 (28%) were false reports (Table 35).

Table 35. ICD10 PILOT STUDY: Reasons for false reports

Of all 105 hospitalised varicella cases 90 (85%) were considered to be related to varicella

infection according to the case classification: 39 (37%) of these had an ICD10 code for varicella

as the primary diagnosis and 51 (49%) had a varicella ICD10 code in any secondary diagnosis.

Fifteen (14%) of the hospitalised varicella cases were considered to probably not be associated

with varicella according to the case classification used. Herpes zoster hospitalisations less

frequently had an HZ ICD code in the PD (39%) and were more often classified as not being

associated with HZ (39%) (Table 36).

Varicella n=14

Herpes zoster n=7

Hospitalisation presumed to be unrelated to VZV 7 - Age > 16 years 4 6 Ambulatory or < 1 day admitted 2 1 Not plausible hospital stay 1 -

6 Results — ICD10 pilot study: General characteristics of varicella hospitalisations


Table 36. ICD10 PILOT STUDY: Distribution of varicella cases according to case definition

6.2 ICD10 pilot study: General characteristics of varicella hospitalisations The median age of the 105 reported children with VZV-associated hospitalisation was 3.3 years

(IQR 1.3 – 5.5), 58% of them were male (Figure 36).

6.3 ICD10 pilot study: Hospital stay of varicella hospitalisations The median duration of hospitalisation was 4 days (IQR 2 – 5) (Figure 37).

6.4 ICD10 pilot study: Complications of varicella hospitalisations The most frequent complications reported were gastrointestinal complications (32%, including

dehydration seen in 22%, neurologic complications (19%), and skin complications (17%) (Figure

38).

6.5 ICD10 pilot study: Conclusions All requested ICD10 data were available and retrievable. However, the effort to access these data

varied considerably depending on the software used by the hospital, the size of the hospital, and

the qualification of the person retrieving the data. Primary contact persons frequently did not

have the qualification for complex data queries and the full access to the hospital data due to

personal data protection rules. As patient data and medical data are stored in separate virtual

areas, at least two data queries were needed. Also the results of data sets sent to our institution

varied considerably, making the unification of data sets time-consuming.

As with all analyses of ICD-data, misattribution of ICD10 codes within the coding process may

occur. Furthermore, ICD10 encoded diagnoses do not deliver detailed medical information, e.g.

laboratory values and therapeutic procedures. Cases have to be evaluated with limited medical

information on disease categories and short descriptions of marked degrees of the disease.

However, we get basic information on type of complication. Added information on encoded

procedures and DRG codes could give a realistic impression of the spectrum of complications of

varicella infections.

Varicella n=105

Herpes zoster n=18

Hospitalisation related to VZV infection 90 (86%) 11 (61%) - ICD-code in primary diagnosis 39 (37%) 7 (39%) - ICD-code in secondary diagnosis and any ICD-code in primary diagnosis related to VZV 51 (49%) 4 (22%)

ICD-code VZV in secondary diagnosis; primary diagnosis not clearly related to VZV 15 (14%) 7 (39%)

6 Results — ICD10 pilot study: Conclusions


The specificity of the ICD10 data remains to some extent uncertain. In our pilot study, which

included a medical chart review, at least 80% of all identified cases, were true cases.

Nonetheless, sensitivity appears to be high as almost no other cases that were not included in the

ICD10 database were reported by ESPED. On the other hand, ICD10 data in the pilot study

identified six times as many cases as those reported by the ESPED surveillance system in the

respective hospitals during the same time period.

In summary, it can be assumed that ICD10 data have to a great extent proven to be sensitive and

specific. ICD10-data offer reliable medical information. The pilot study has also shown that an

ICD10 surveillance study is technically feasible. We therefore consider ICD-data to be an

efficient tool for the surveillance of hospitalisations and complications due to varicella-

infections.

7 Results — ICD10 STUDY NRW 2003-2004: Performance and data profile


7 ICD10 STUDY NRW 2003-2004: Results

7.1 ICD10 STUDY NRW 2003-2004: Performance and data profile 39 of 68 hospitals (57%), representing 55% of all paediatric hospital beds registered with ESPED

in NRW, agreed to participate in the study and transmitted the results of their data query. One of

them (with 70 hospital beds) had performed the data query, but it was reported that no child was

identified in 2003 and 2004 with an ICD-code (B01.0-B01.9 or B02.0-B02.9), neither in the

primary diagnosis nor in any secondary diagnoses. Two directors of paediatric hospitals who had

participated in the ICD10 pilot study did not participate in the ICD10-study 2003-2004. Thus,

the data of these hospitals could be included for analysis only for the year 2003. Heads of three

other paediatric hospitals agreed in participating in the study, but we never received the data files

despite numerous phone calls, possibly due to a lack of communication flow within the hospital

or due to personal incapability. In nine cases we got explicit rejections to participate in the study

for various reasons. In four of these 9 cases it was stated that the amount of work was too large

and the rejection had to be made due to financial reasons, and in two cases no reason was given

for the rejection. Further reasons for rejections were: Incapability to perform the necessary data

query, no possibility of data transmission, misunderstanding concerning the purpose of the study

(one director was worried about the fact that the study could have been implemented as a

mission of pharmaceutical industry to promote varicella vaccination).

Overall we received data from 933 hospitalisations possibly associated with VZV infection.

There were 820 (88%) varicella and 96 (10%) herpes zoster hospitalisations. Eleven patients had

no ICD10 code for varicella or herpes zoster at discharge (but at admission). Additionally, six

patients each had a VZV- or HZ-ICD10-code in the primary diagnosis and an HZ or VZV ICD10

code in a secondary diagnosis. These cases could not be clearly grouped as VZV or HZ cases.

However, neither were they considered to be false reports. Data from these cases were analysed

for matching purposes with ESPED and EURODIAB data (see Section 8.2.4). (Two of these

cases were later categorised as varicella cases through matching with ESPED data. The other 4

patients might be patients with co-presentation of varicella and herpes zoster which was also

seen in two ESPED patients (cf. Section 4.2.9).

A median of 2 (IQR 1-4) secondary diagnoses were given together with a primary diagnosis.

Forty-two of 820 (5%) varicella hospitalisations and 18 of 93 (19%) herpes zoster

hospitalisations had no secondary diagnosis. Seven-hundred-fifteen distinct ICD10 codes and

different German ICD10-SGB-V coding versions were used (2003, 2004 and 2005). Four codes

could not be identified as valid ICD10 codes.

7 Results — ICD10 STUDY NRW 2003-2004: Varicella Hospitalisations


We excluded 117 hospitalisations for various reasons. Eleven patients had no ICD10 code for

varicella or herpes zoster in any discharge diagnosis. Reasons for further 106 excluded

hospitalisations are listed in Table 37. Overall 90 of 802 (11%) varicella and 13 of 82 (14%)

herpes zoster hospitalisations were excluded. Thus, there were 728 varicella and 83 herpes zoster

hospitalisations for further analysis.

Table 37. ICD10 STUDY: Reasons for false reports

7.2 ICD10 STUDY NRW 2003-2004: Varicella Hospitalisations


There were 728 varicella-associated hospitalisations from January 2003 to December 2004

reported by 38 hospitals in NRW (Table 38). With two hospitals not reporting in 2004 but in

2003 the number of varicella hospitalisations was evenly distributed between the years 2003

(50% of all cases) and 2004. Seventy-five percent of all hospitalisations occurred in the first six

months of the year (Figure 39).

Birth day was not reported by 3 hospitals. Instead these hospitals reported completed age in full

years and age in days for the first year of life. Gender was not reported by one hospital and not

for all cases by two hospitals. Thus, information on gender was available for 692 (95%) of all

hospitalisations.

Table 38. ICD10 STUDY: General characteristics of 728 varicella hospitalisations

Boys (57%) were more often hospitalised than girls (43%). The median age was 3 (IQR 1-5)

years with 70% of all children being younger than 5 years of age (Figure 40). Boys (3 years; IQR

1-5) were on a median slightly older than girls (2 years; IQR 1-4) (pmedian test<0.037). One-

Varicella n=93

Herpes zoster n=13

Hospitalisation presumed to be unrelated to VZV 51 2 Age > 16 years 6 6 < 1 day admitted 23 2 Admission in 2002 or 2005 10 - Re-admission 3 3

Male / female 57% / 43% Median age in years 3 (1-5) Median hospital stay in days 4 (2-7) Immunocompromised 5%



hundred-forty-two (55%), 147 (57%), 86 (59%) and 19 (63%) of the children with ages of 0-1

year, 2-4 years, 5-10 and over 10 years were male, respectively.


No chronic underlying condition was coded for 582 of 728 (80%) varicella hospitalisations. An

ICD10-code for atopic dermatitis was reported for 22 (3%) children. An immunocompromised

condition was reported for 44 (6%) children, including 12 children with rheumatologic diseases.

Eighty-three (11%) children had other chronic conditions. Age and hospital stay varied

significantly (pmedian-test<0.001) by chronic disease status. Immunocompromised children (4

years) were older and children with no chronic condition (2 years) and atopic dermatitis (1.5

years) were younger than the median of all children (3 years). The hospital stay was longer for

children with an immunocompromised condition (6 days) and children with other chronic

conditions (7 days) than the median of all children (4 days) (Table 39).

Table 39. ICD10 STUDY: Chronic disease status and median age and hospital stay in 728 children hospitalised with varicella

7.2.3 Classification of varicella hospitalisations by primary ICD10-diagnosis and

underlying chronic disease

Three-hundred thirty-eight of 728 (46%) varicella hospitalisations had a varicella code in the PD

and 389 (54%) a varicella code in a SD. VZV-associated complications were coded in 280 (38%)

of all hospitalisations as a PD. One-hundred-ten (15%) hospitalisations were categorised in other

groups (Table 40).

n % Median age in years (IQR)


None 582 80.0% 2 (1 - 4) 4 (2 - 6) Other chronic condition 80 11.0% 3 (1 - 5) 7 (3 - 9) Immunocompromised condition 44 6.0% 4 (3 - 6) 6 (5 - 8) Atopic dermatitis 22 3.0% 1.5 (0 - 3.5) 3.5 (2 - 5.5)



Table 40. ICD10 STUDY: Classification of varicella hospitalisations by primary ICD10-diagnosis and chronic disease status

7.2.4 Complications

Reported varicella-associated complications were categorised into 10 groups according to the

ESPED study (cf. Section 4.2.6) plus an additional category for co-infections (cf. Appendix C ).

195 children (26.8%) had no specific complication indicated by ICD-codes. All other patients

were classified in one or more groups according to diagnoses given in ICD-codes. 50.1% of all

cases were classified in one complication category, 23.2% in more than one category (Table 41).

Table 41. ICD10 STUDY: Classification of 728 varicella hospitalisations into complication categories

The most frequent complications were gastrointestinal tract complications and neurologic

complications. Two-hundred-one of 728 (28%) children had a gastrointestinal tract complication,

139 (19%) a neurologic complications, 123 (17%) complications of the upper respiratory tract,

ENT and eyes, 94 (13%) skin infectious complications, 87 (12%) lower respiratory tract

complications, 15 (2%) complications due to other systemic bacterial infections, 17 (2%)

complications due to coagulation disorders, 9 (1%) haematological complications, 8 (1%) a co-

n %

VZV in PD 338 46.5% VZV-meningoencephalitis/-pneumonia in SD 13 1.8% Immunocompromised condition in PD + VZV in SD 14 1.9% Rheumatic disease/DM/AD in PD + VZV in SD 19 2.6% VZV complication in PD 280 38.5% Other chronic condition in PD + VZV in SD 24 3.3% Other chronic condition in SD + VZV in SD 4 0.6% Others in PD + VZV in SD 36 5.0%

TOTAL 728 100.0%

n % Median age (years, IQR)


All varicella hospitalisations 728 100% 3 (1 - 5) 4 (2 - 7) Included in only 1 complication category 364 50.1% 3 (1 – 4.5) 4 (2 - 7) 2 complication categories 142 19.5% 3 (1 - 4) 5 (3 - 7) 3 complication categories 20 2.8% 1.5 (1 – 3.5) 6.5 (3.5 – 11) 4 complication categories 6 0.8% 1 (1 - 3) 9.5 (9 - 15) 5 complication categories 1 0.1% 1 7

No associated VZV complication coded 195 26.8% 2 (0 - 5) 3 (2 - 6)



infection and 5 (1%) reactive arthritis. 39 (5%) children had complications that could not be

categorised in one of the above groups (Table 42).

Table 42. ICD10 STUDY: Complication categories and contribution to overall hospital days (multiple nominations possible)

7.2.4.1 Neurologic complications There were 139 (19%) neurologic complications coded. A meningoencephalitis was coded for 57

(7.8%) patients, febrile seizures for 48 (6.6%), cerebral convulsion for 13 (1.8%) and facial

nerve paralysis for 4 (0.6%) patients. Seventeen (2.3%) patients had other neurologic

complications. An ICD code for cerebellitis does not currently exist. However, ICD10 codes for

ataxia with a diagnosis of varicella suggest cerebellitis in 12 (1.7%) children. As these codes are

unspecific, the respective patients were summarised in the group of other neurologic

complications.

Children with febrile seizures were significantly younger. Children with meningoencephalitis

and facial nerve paralysis stayed longer in hospital than all other children (Table 43).

Table 43. ICD10 STUDY: Median age and hospital stay in 157 children with varicella-associated neurologic complications

n % Sum of hospital days


Gastrointestinal tract 201 27.7% 996 25.2% Neurologic 139 19.1% 760 19.2% Upper respiratory tract, ENT and eyes 123 16.9% 610 15.4% Skin infectious complications 94 12.9% 625 15.8% Lower respiratory tract 89 12.2% 766 19.4% Other complications 39 5.4% 291 7.4% Coagulation and sequelae 17 2.3% 141 3.6% Other systemic bacterial 15 2.1% 290 7.3% Haematologic 9 1.2% 41 1.0% Co-infection 8 1.1% 68 1.7% Reactive arthritis 5 0.7% 38 1.0%

No associated VZV complication coded 195 26.8% 930 23.5%

All children 728 100% 3956 100%

n % Median age in years (IQR) Median hospital stay in days

Meningoencephalitis 57 7.8% 4 (2-5) 5 (2-9) Febrile seizure 48 6.6% 2 (1-3) 4 (2-5.5) Cerebral convulsion 13 1.8% 4 (2-5) 3 (2-5) Facial nerve paralysis 4 0.6% 3 (2-4) 13.5 (9.5-21.5) Other neurologic complications 17 2.3% 5 (3-6) 3 (1-4)



7.2.4.2 Other systemic bacterial complications Of 15 children with other systemic bacterial complications, 7 had a sepsis, 5 an osteomyelitis and

2 a fasciitis. One patients had an infectious myositis.

7.2.4.3 Complications of the gastrointestinal tract There were 87 (12%) children coded with gastroenteritis, 19 (3%) with stomatitis and 84 (12%)

with dehydration. Eleven (2%) children had other gastrointestinal complications.

7.2.5 Age, complications and chronic disease

Children with complications of the gastrointestinal tract were significantly (pkwallis=0.031)

younger than all other children, i.e. 2 (IQR: 1-4) years versus 3 (IQR: 1-5) years. Especially

children with gastroenteritis (1 year, IQR 0-3) and dehydration (2 years, IQR 1-4.5) were

younger than all other children. Children with haematologic (pkwallis=0.006) and neurologic

complications (pkwallis=0.027), complications due to coagulation disorders (pkwallis=0.031) and

with complications of the upper respiratory tract, ENT and eyes (pkwallis=0.023) each differed

significantly in their age distribution and were each older compared to all other children. The

median age for hospitalisation of children with a haematologic complication was 5 (IQR 4-6)

years, whereas 269 of 718 (37%) children without haematologic complications were a median of

3 years of age (IQR 1-5). There was no child with a haematologic complication under one year

of age (Table 44).

7.2.6 Hospital stay, complications and chronic disease

Patients with skin infectious complications, lower respiratory tract infections and other systemic

bacterial infections stayed in hospital significantly (each pkwallis<0.001) longer than other

children with varicella, 5 (IQR 4-8) days, 7 (4-10), and 14 (7-27) days each vs. 4 (2-6) days

(Table 45).



Table 44. ICD10 STUDY: Median age and complication category of 728 children hospitalised with varicella (multiple nominations possible)

N % Age in years (categories) Median age in years (IQR)

0-1 >1-4 5-10 11-16

Gastrointestinal tract 201 27.6% 84 (31.2%) 72 (26.3%) 40 (25.8%) 5 (16.7%) 2 (1 - 4) Neurologic 139 19.1% 37 (13.8%) 64 (23.4%) 34 (21.9%) 4 (13.3%) 3 (1 - 5) Upper respiratory tract and ENT 123 16.9% 52 (19.3%) 51 (18.7%) 20 (12.9%) 0 (0%) 2 (1 - 4) Skin infectious complications 94 12.9% 34 (12.6%) 38 (13.9%) 19 (12.3%) 3 (10.0%) 2 (1 - 4) Lower respiratory tract 89 12.2% 41 (15.2%) 32 (11.7%) 12 (7.7%) 4 (13.3%) 3 (0 - 4) Other complications 39 5.4% 13 (4.8%) 17 (6.2%) 9 (5.8%) 0 (0%) 3 (1 - 4) Other systemic bacterial 15 2.1% 4 (1.5%) 8 (2.9%) 3 (1.9%) 0 (0%) 2 (1 - 4) Coagulation and sequelae 17 2.3% 3 (1.1%) 9 (3.3%) 4 (2.6%) 1 (3.3%) 4 (3 - 5) Haematologic 9 1.2% 0 (0%) 3 (1.1%) 6 (3.9%) 0 (0%) 5 (4 - 6) Co-infection 8 1.1% 4 (1.5%) 2 (.7%) 2 (1.3%) 0 (0%) 2.5 (0.5 - 4.5) Reactive arthritis 5 0.7% 0 (0%) 3 (1.1%) 2 (1.3%) 0 (0%) 3 (3 - 5)

No complication coded 195 26.8% 84 (31.2%) 51 (18.7%) 44 (28.4%) 15 (50%) 2 (0 - 5)

All children 728 100.0% 269 (37.0%) 273 (37.6%) 155 (21.3%) 30 (4.1%) 3 (1 - 5)



Table 45. ICD10 STUDY: Median hospital stay and complication category of 728 children hospitalised with varicella (sorted by hospital stay; multiple nominations possible)

N % Median hospital stay in days (categories) Median hospital stay in days (IQR)

1-3 4-7 8-14 >14 Gastrointestinal tract 201 27.7% 93 (29.0%) 80 (28.9%) 22 (24.2%) 63 (15.8%) 4 (2 - 6) Neurologic 139 19.1% 63 (19.6%) 46 (16.6%) 22 (24.2%) 8 (21.1%) 4 (2 - 7) Upper respiratory tract and ENT 123 16.9% 58 (18.1%) 49 (17.7%) 12 (13.2%) 4 (10.5%) 4 (2 - 6) Haematologic 9 1.2% 4 (1.2%) 3 (1.1%) 2 (2.2%) 0 (0%) 4 (3 - 5) Other complications 39 5.4% 13 (4.0%) 16 (5.8%) 6 (6.6%) 4 (10.5%) 5 (2 - 8) Reactive arthritis 5 0.7% 2 (.6%) 2 (.7%) 0 (0%) 1 (2.6%) 5 (3 - 6) Skin infectious complications 94 12.9% 20 (6.2%) 46 (16.6%) 22 (24.2%) 6 (15.8%) 5 (4 - 8) Coagulation and sequelae 17 2.3% 5 (1.6%) 5 (1.8%) 6 (6.6%) 1 (2.6%) 6 (3 - 10) Co-infection 8 1.1% 1 (.3%) 4 (1.4%) 2 (2.2%) 1 (2.6%) 6.5 (4.5 - 11) Lower respiratory tract 89 12.2% 19 (5.9%) 32 (11.6%) 27 (29.7%) 11 (29.0%) 7 (4 - 10) Other systemic bacterial 15 2.1% 0 (0%) 5 (1.8%) 3 (3.3%) 7 (18.4%) 14 (7 - 27)

No complication coded 195 26.8% 57 (17.8%) 53 (19.1%) 10 (11.0%) 7 (18.4%) 4 (2 - 7)

All children 728 100.0% 269 (37.0%) 273 (37.6%) 155 (21.3%) 30 (4.1%) 4 (2 - 7)

7 Results — ICD10 STUDY NRW 2003-2004: Herpes zoster Hospitalisations


7.3 ICD10 STUDY NRW 2003-2004: Herpes zoster Hospitalisations


There were 83 herpes zoster associated hospitalisations from January 2003 to December 2004

reported by 38 hospitals in NRW (Table 29). With two hospitals not reporting in 2004 but in

2003 the number of HZ hospitalisations was evenly distributed between the years 2003 (51% of

all cases) and 2004 (49%). Sixty-three percent of all hospitalisations occurred in spring and

summer months. However, the distribution of herpes zoster cases over the year did not

statistically depart from a normal distribution (Figure 41).

Birth day was not reported by 3 hospitals. Instead these hospitals reported completed age in full

years and age in days for the first year of life. Gender was not reported by one hospital and not

for all cases by two hospitals. Thus, information on gender was available for 81 (98%) of all HZ

hospitalisations.

Table 46. ICD10 STUDY: General characteristics of 83 children hospitalised with HZ

Boys (51%) were hospitalised as often as girls (49%). The median age was 8 (IQR 4-12) years

with no child reported in the first year of life (Figure 42). Boys and girls did not differ in respect

to age at admission or duration of hospital stay.


No chronic underlying condition was coded for 58 of 83 (73%) HZ hospitalisations. An ICD10-

code for atopic dermatitis was reported for 2 (2%) children. An immunocompromised condition

was reported for 17 (20%) children, including one child with rheumatologic disease. Three (4%)

children had other chronic conditions. Age at admission did not vary significantly (pkwallis>0.05)

by chronic disease status. However, duration of hospital stay significantly (pkwallis=0.015)

differed by chronic disease status. Immunocompromised children stayed in hospital a median of

8 (IQR 6-12) days, in contrast children without a chronic disease stayed 5 (IQR 4-7) days (Table

47).

Male / female 51% / 49% Median age in years 8 (4-12) Median hospital stay in days 6 (4.5-8) Immunocompromised 20%



Table 47. ICD10 STUDY: Chronic disease status and median age and hospital stay of 83 children with HZ

7.3.3 Classification of HZ hospitalisations by primary ICD10-diagnosis and

underlying chronic disease

Fifty-three of 83 (64%) HZ hospitalisations had an HZ code in the primary position and 30

(36%) an HZ code in a second position. HZ-associated complications were coded in 13 (16%) of

all hospitalisations as a PD. Seventeen (20%) hospitalisations were categorised in other groups

(Table 48).

Table 48. ICD10 STUDY: Classification of 83 HZ hospitalisations by primary ICD10-diagnosis and chronic disease status

7.3.4 Complications

Thirty-two of 83 children (38.6%) had no specific complication to be indicated by ICD-codes.

Twenty-nine of these 32 patients (91%) had an HZ code (B02.8 or B02.9) in the primary

diagnosis, two had an immunocompromised condition and HZ in a second diagnosis and one had

another chronic condition in the primary diagnosis. All other 51 (61.4%) patients were classified

in one or more groups according to diagnoses given in ICD-codes. 36.1% of all cases were

classified in one complication category, 26.3% in more than one category (Table 49).

n % Median age in years (IQR)


None 61 73.5% 8 (5 - 12) 5 (4 - 7) Other chronic condition 3 3.6% 7 (4 - 14) 6 (2 - 6) Immunocompromised condition 17 20.5% 7 (4 - 13) 8 (6 - 12) Atopic dermatitis 2 2.4% 5 (3 - 7) 5.5 (5 - 6)

n %

HZ in PD 53 63.9% HZ meningoencephalitis/ophthalmic zoster / generalised zoster in SD 8 9.6%

Immunocompromised condition in PD + HZ in SD 7 8.4% Rheumatic disease/DM/AD in PD + HZ in SD - - HZ complication in PD + HZ in SD 13 15.7% Other chronic condition in PD + HZ in SD 1 1.2% Other in PD + HZ in SD 1 1.2%

TOTAL 83 100.0%



Table 49. ICD10 STUDY: Classification of 83 HZ hospitalisations into complication categories

Ophthalmic zoster (n=16, 19%) and neurologic complications (n=15, 18%), including 6 (7%)

patients with meningoencephalitis, were the most frequently coded complications for HZ.

Complications of the gastrointestinal tract were seen in 11 (13%) children. Skin infectious

complications were coded in 9 (11%) patients, complications of the upper respiratory tract, ENT

and eyes in 10 (12%), complications of the lower respiratory tract in 6 (7%), generalised zoster

in 3 (4%), other systemic bacterial complications in 3 (4%) and haematologic complications in 2

(2%) patients. Ten (12 %) children had complications that could not be categorised in one of the

above groups (Table 50).

Age and hospital stay varied by complication category (Table 50). However, statistically

significant differences were only seen for children with lower respiratory tract infections. These

children were younger than all other children, 2.5 (2-4) vs. 8(5-12) years.

Table 50. ICD10 STUDY: Median age and hospital stay by complication category of 83 children hospitalised with HZ

n % Median age (years, IQR)


All HZ hospitalisations 83 100% 8 (4 - 12) 6 (4.5 - 8)

Included in only 1 complication category 30 36.1% 7 (4 - 12) 6 (5 - 7) 2 complication categories 10 12.5% 12 (11 - 13) 7.5 (5 - 16) 3 complication categories 8 10.0% 1.5 (1 - 3) 8.5 (6.5 - 13) 4 complication categories 3 3.8% 8 (4 - 13) 6 (5 - 11)

No associated HZ complication coded 32 38.6% 8 (6 - 12) 5 (3 - 7)

n % Median age (IQR) Median hospital stay in days (IQR)

Ophthalmic zoster 16 19.3% 6 (3 - 12) 7 (5.5 - 11) Gastrointestinal tract 11 13.3% 8 (1 - 13) 8 (5 - 11) Other complications 10 12.0% 10 (5.5 - 12) 7 (2 - 11) Upper respiratory tract, ENT, and eyes 10 12.0% 4 (3 - 8) 6 (5 - 6) Other neurologic 9 10.8% 9 (4 - 12) 6.5 (5 - 16) Skin infectious complications 9 10.8% 3 (2 - 12) 7 (5 - 9) Meningoencephalitis 6 7.2% 10 (1 - 12) 6 (5 - 16) Lower respiratory tract 6 7.2% 2.5 (2 - 4) 9 (5 - 20) Generalised zoster 3 3.6% 7 (3 - 14) 8 (7 - 10) Other systemic bacterial 3 3.6% 13 (1 - 13) 11 (3 - 51) Haematologic 2 2.4% 12 (11 - 13) 9.5 (8 -11)

8 Incidence estimates — Capture-recapture methodology


8 Incidence estimates

8.1 Capture-recapture methodology

8.1.1 Background

The aim of the capture-recapture methodology is to estimate the degree of underreporting in

different surveillance sources. With application of capture-recapture methods, therefore, the true

incidence of hospitalisations for children with varicella can be estimate by using lists of cases

from at least two sources. The cases which have been captured by each source alone and the

overlapping cases ascertained by at least two sources are the basis of this estimation. The

research project was initially planned to use two well established surveillance sources, ESPED

and EURODIAB for a two-source capture-recapture model restricted to the largest Bundesland

North-Rhine-Westfalia. During the study the usefulness of an additional potential surveillance

source, resulting from hospital-documented ICD10-data, were analysed in a pilot project (cf.

Section 6. ICD10 pilot study (Bavaria/NRW 2003): Results). Since the results of the pilot project

were promising, ICD 10 data were used as a third source in NRW and incorporated in additional

two-source and three-source incidence estimates.

8.1.2 Assumptions

Applying capture-recapture methods, several underlying assumptions have to be considered. The

independence between the two sources is a prerequisite for a valid estimation. It can be violated

if

• linking of the source is incomplete or false, i.e. identifiers of cases are insufficiently

unique,

• the probabilities to capture a case are heterogeneous, i.e. regional variation in notification

behaviour,

• one notification source influences another source, i.e. positive serology (laboratory

surveillance) leads to the hospitalisation of the case.

Therefore, the sources have to be chosen in such a way that the dependency between the sources

is minimal. The study population under study is assumed to be "closed", while the study period

and area are the same in both sources, and each case is diagnosed accurately.

In the present study, prerequisites for applying capture-recapture methods to the lists of cases are

taken into consideration as far as possible.

8 Incidence estimates — Capture-recapture methodology


The study population - a population of 3,248,227 children and adolescents up to 16 years of age

in NRW - represents 22.9% of the total German population. A proportion of 22.2% of all ESPED

reports (n=298) derived from the study population in NRW seems to indicate that there is little

regional variation in the reporting of hospitalisations for children with VZV infection (Table 51).

Table 51. Population of children under 17 years (not reaching their 17th birthday) of age by federal state [30] and number of ESPED reports

The probabilities of capturing a case could be heterogeneous in both sources, i.e. ascertained

cases by ESPED do not have the same "catchability" as EURODIAB cases (or ICD10 cases).

Even though the sources might be statistically independent, heterogeneities represent possible

limitations of application of capture-recapture methodology within this study. However, as the

amount of information on EURODIAB case characteristics was limited due to study design,

heterogeneities in reported cases between ESPED and EURODIAB could only be analysed by a

few key characteristics. ICD10-data on the other hand are methodologically different as they are,

first, not based on recall and, second, the process of coding of a clinical diagnosis into ICD10

codes is different from filling in a medical questionnaire.

North Rhine-Westphalia is not a "closed" population. Individuals can migrate into the area or be

lost because of death or migration out of the area, and children living in the area might be

hospitalised in another neighbouring land (or the other way around). Most of the populations

studied in epidemiology with capture-recapture methods are not closed. However, migration and

death are not considered to have a big impact on catchability in this study setting.

Land Population of

children under 17 years in 1000

Percent of all children < 17 years in Germany

Percent of all ESPED reports

(N=1443)

Number of validated cases

Percent of all validated cases

BE 494.4 3.5% 3.7% 43 3.7% BR 372.2 2.6% 2.2% 29 2.5% BW 1964 13.9% 13.0% 156 13.4% BY 2234.1 15.8% 17.1% 211 18.2% HB 102.6 0.7% 0.7% 2 0.2% HE 1046.7 7.4% 3.5% 35 3.0% HH 261.1 1.9% 2.7% 36 3.1% MV 253 1.8% 4.9% 42 3.6% NI 1467.6 10.4% 8.3% 106 9.1%

NRW 3248.2 23% 22.6% 258 22.2% RP 727 5.2% 5.1% 54 4.6%

SAC 583 4.1% 6.3% 80 6.9% SAH 346.6 2.5% 3.1% 33 2.8% SH 505.9 3. 6% 2.6% 24 2.1% SL 172.3 1.2% 1.9% 23 2.0% TH 327.4 2.3% 2.2% 30 2.6%

Total 14106.0 100% 100% 1162 100%

8 Incidence estimates — Results of capture-recapture analysis


8.2 Results of capture-recapture analysis

8.2.1 Comparison of hospitalisations: ESPED and EURODIAB

8.2.1.1 Varicella There were 918 varicella hospitalisations in Germany reported by ESPED and 107 varicella

hospitalisations reported by EURODIAB in NRW. Boys were overrepresented in varicella-

associated hospitalisations reported by both ESPED and EURODIAB, 500 (55%) and 63 (59%),

respectively. The age distribution of varicella cases was quite similar among the cases of the two

sources (Figure 43). Children with varicella reported by ESPED tended to stay in hospital for a

shorter period of time (median 5 versus 6 days) (Figure 44). However, this difference did not

reach statistical significance (pmedian-test=0.053). Whereas the majority of children had no chronic

disease in ESPED and EURODIAB, the proportion of children with chronic disease was higher

in the latter source (32% in EURODIAB versus 23% in ESPED), but the difference did not reach

statistical significance (pchi-square=0.134) (Figure 45). One possible reason for a higher proportion

of children hospitalised due to varicella zoster virus infection with chronic disease in

EURODIAB could be a recall bias: Physicians in internal medicine, paediatric and general

practices tend to report cases with underlying diseases more often. They usually have been seen

by the physician more often than children without a chronic disease.

8.2.1.2 Herpes zoster Girls represented 47% (n=112) of all hospitalisations in ESPED and 56% (n=9) in EURODIAB.

The median age was 9.1 (IQR 4.9-13.1) and 7.6 (4.8-14.6), and the median hospital stay 7 days

(5-10) and 6.5 (4-8) in ESPED and EURODIAB, respectively. A chronic disease was reported

for 100 (41%) children in ESPED and 4 (25%) in EURODIAB. None of these differences,

however, reached statistical significance.

8.2.2 Comparison of hospitalisations: ESPED and ICD10-data

8.2.2.1 Varicella

8.2.2.1.1 General characteristics Boys were overrepresented in varicella-associated hospitalisations reported through ESPED and

ICD10-data, 500 (55%) and 395 (57%), respectively. Age distribution was similar among the

cases of the two sources (Figure 46). Children with varicella reported through ESPED stayed

significantly (pmedian-test<0.001) longer in hospital than children reported through ICD10-data, 5

(IQR 3-8) days and 4 (2-7) days, respectively (Figure 47).



8.2.2.1.2 Underlying chronic diseases Children also showed a small but statistically significant (pchi-square=0.002) difference in respect

to chronic disease status (Figure 48). Sixty-eight (7%) children with varicella were reported in

ESPED to be immunocompromised and 78 (9%) children had other chronic diseases. In ICD10-

data, in contrast, 44 (6%) of 730 varicella hospitalisations were immunocompromised and 80

(11%) had other chronic diseases.

Comparing 144 cases reported by both ESPED and ICD10-data with respect to their chronic

disease status, in only 8 (6%) patients the classification was not corresponding in both sources.

Three patients were reported in ESPED to have atopic disease and had no chronic disease code

in ICD10-data, one patient had a ventricular peritoneal shunt and one patient a genetic syndrome

that was not coded in ICD10-data. One patient had a ICD10-code for a malignant tumour of the

peripheral nervous system, but no chronic underlying disease reported in ESPED. Two patients

with cerebral convulsions reported as a complication in ESPED were coded with ICD10 codes of

epilepsy in ICD10-data.

8.2.2.1.3 Complications A comparison of complication categories reported in ESPED and coded in ICD10-data is shown

in Figure 49. In ESPED 183 of 913 (20%) children were reported without any specific varicella-

associated complication. In ICD10-data 195 of 728 (27%) were coded without any specific

varicella-associated complication.

The most striking difference is the high proportion of gastrointestinal complications coded in

ICD10-data (28%) and the comparatively lower proportion reported in ESPED (15%).

Gastroenteritis was reported in 7% of all children with varicella in ESPED and in 12% of the

ICD10-data. Stomatitis was reported for 29 (3%) children in ESPED and 19 children (3%) in

ICD10-data. However, dehydration was coded in 12% with the ICD10-data. In contrast, it was

only reported in 3% of ESPED varicella hospitalisations. However, feeding problems (as a

symptom, no specific complication) were reported for 51% of all varicella hospitalisations in

ESPED data. Thus, the difference in frequency of complications of the gastrointestinal tract

might be explained by methodological differences. Possibly quite a few of these patients with

feeding problems were coded in ICD10-data as dehydration. Furthermore, it may be speculated

that especially those patients with less severe complications like dehydration or gastroenteritis

were not reported in ESPED.

Also neurologic complications (19%), infectious skin manifestations (13%), complications of

coagulation disorders (2%) and other systemic bacterial complications (2%) were less frequently



coded in ICD10-data than reported in ESPED, 25%, 23%, 6% and 4%, respectively. On the other

hand, complications of the lower respiratory tract (12%) had the same frequency in ICD10 and

ESPED data.

8.2.2.2 Herpes zoster

8.2.2.2.1 General characteristics Boys and girls were about evenly represented without statistical difference in HZ associated

hospitalisations reported through ESPED and ICD10-data, i.e. 112 (46%) and 40 (49%) being

female, respectively. Age was quite equally distributed over the cases of the two sources (Figure

50). In ICD10, however, children with HZ were slightly younger (8 years, IQR 4-12) than in

ESPED (9 years, 4-13) (pmedian-test=0.283). Children with HZ reported through ESPED stayed

significantly (pmedian-test=0.047) longer in hospital than children reported through ICD10-data, 7

(IQR 5-10) days and 6 (5-8) days, respectively (Figure 51).

8.2.2.2.2 Underlying chronic diseases There were no statistically significant differences between ICD10 and ESPED HZ-

hospitalisations concerning chronic disease status (pchi-square= 0.376). However, whereas 78

(31%) children were considered to be immunocompromised in ESPED, ICD10-data suggested

an immunocompromised status for 17 (21%) children (Figure 52).

8.2.2.2.3 Complications A comparison of complication categories reported in ESPED and coded in ICD10-data is shown

in Figure 53. Of 243 ESPED reports 128 (53%) had no specific complication recorded. In

ICD10-data 30 of 83 (38%) had no specific complication coded. Meningoencephalitis and

generalised herpes zoster had about the same frequency in ESPED and ICD10-data. Skin

infectious complications had a lower frequency (17% vs. 11%) in ICD10-data, and all other

complication were more frequently seen in ICD10-data.

Complications of the gastrointestinal tract were recorded in 3 of 243 (1%) HZ cases in ESPED

but in 11 of 83 (14%) HZ cases in ICD10-data. Ophthalmic zoster was reported for 29 (12%)

children in ESPED and 16 (19%) in ICD10-data.

8.2.3 Comparison of hospitalisation in all three sources: Concluding remarks

Overall, we have similar results in all three data sources with few differences, especially between

ESPED and ICD10-data. It seems that more severe cases are overrepresented in ESPED and

EURODIAB. In ESPED hospital stay was longer than in ICD10-data, the proportion of children

without specific complications was lower, and cases, that are considered to be less severe - those



with gastroenteritis or dehydrations - were less frequently reported. This observation is

methodologically plausible since ESPED and EURODIAB both rely on recall by reporting

physicians and are, therefore, more prone to capture severe cases that are probably more easily

remembered.

8.2.4 Matching

8.2.4.1 General Extensive automated and manual matching was performed to generate lists of matching cases,

those cases captured by two or even three sources. As matching criteria, hospital name, birth

month and year, admission and discharge dates, and VZV/HZ were primarily used. In cases of

doubt, gender, zip code and available information on complications were used.

Fifteen hospitals (22%) in NRW did neither participate (no reports) in ESPED nor in ICD10, and

53 (78%) of all hospitals in NRW reported varicella or herpes zoster cases through ESPED or

ICD10 (Table 52).

Table 52. Classification of 68 hospitals in NRW by participation (=reporting) in ESPED and ICD10-queries

Three potential matches were not considered as such. All three were coded as varicella in

ESPED and herpes zoster in ICD10-data. As the researchers could not decide if the case had

varicella or herpes zoster, it was decided to leave these patients as non-matching, individual

cases.

8.2.4.2 Results of matching for varicella hospitalisations in NRW

850 individual varicella reports were identified by ESPED, ICD10-data and EURODIAB in

NRW. An overview on the number of cases captured by each source and by a combination of

sources is shown in Table 53 and Figure 55. ICD10-data alone captured 730 cases or 86% of all

850 cases. ESPED, however, captured only 25% (n=212) of all reported cases in NRW. One-

hundred seventy-four of these 850 (20%) cases were matches and were reported by at least two

Hospitals (N=68)

Hospital beds in NRW

(N=4987) n % %

Only ICD 11 16.2% 14.4%

ICD + ESPED 27 39.7% 43.2%

Only ESPED 15 22.1% 25.0% No participation / no case reported 15 22.1% 17.5%



sources. Eighteen (2%) patients were captured by all three sources, 49 cases were captured by

ICD10-data and EURODIAB, 24 by ESPED and EURODIAB and 144 by ICD and ESPED.

Table 53. Number of reported varicella cases by source and number of matches in NRW

Twenty-seven hospitals that participated in ESPED and in the ICD10-data query reported 581

individual varicella hospitalisations, including 144 hospitalisations that were reported by both

sources. The number of reports in ICD and ESPED is listed for each participating hospital in

Table 54. Each hospital reported on a median 18 cases. Twenty-nine percent of all cases were

reported through ESPED. Eighty-five percent of all ESPED caeses were also reported through

ICD10-data.

Cases (n)

% of all cases (three sources)

Proportion of ESPED

cases

Proportion of EURODIAB

cases

Proportion of ICD cases

Matches(n)

Proportion of matches

ESPED 212 25% 100% - - - -

EURODIAB 107 13% - 100% - - -

ICD 730 86% - - 100% - -

ESPED-EURODIAB 295 35% 72% 36% - 24 8%

ESPED-ICD 798 94% 27% - 92% 144 18%

EURODIAB-ICD 788 93% - 14% 93% 49 6%

ESPED-EURODIAB-ICD 850 100% 25% 13% 86% 18 2%



Table 54. Number of reports from 27 hospitals that participated in ESPED and ICD10 STUDY and which had reported at least one case with varicella from either source in NRW

8.2.4.3 Results of matching for HZ hospitalisations in NRW One-hundred twenty-four individual HZ reports were identified by ESPED, ICD10-data and

EURODIAB in NRW. An overview on the number of cases captured by each source and by a

combination of sources is shown in Table 55 and Figure 57. ICD10-data alone captured 83 cases

or 67% of all 124 cases. ESPED, however, captured only 38% (n=46) of all reported cases in

NRW. Twenty of these 124 (16%) cases were matches and were reported by at least two

sources. One patient (1%) was captured by all three sources. Two patients each were captured by

Hospital no. All reports ICD ESPED

Percent of ESPED cases also reported

by ICD10

Hospital beds

All reports per 100 hospital

beds

ESPED reports per 100 hospital

beds

n n % of all % n

1 65 62 52% 91% 175 37.1 19.4 2 54 51 18% 70% 230 23.9 4.4 3 40 36 25% 60% 120 33.3 8.3 4 38 38 39% 100% 80 48.8 18.8 5 30 27 17% 40% 112 26.8 4.5 6 29 26 24% 57% 98 29.6 7.1 7 25 25 32% 100% 50 50.0 16.0 8 23 21 22% 60% 80 28.8 6.3 9 23 23 30% 100% 70 32.9 10.0

10 21 21 38% 100% 90 23.3 8.9 11 21 21 38% 100% 95 22.1 8.4 12 20 20 10% 100% 55 36.4 3.6 13 19 18 39% 86% 40 45.0 17.5 14 18 18 22% 100% 95 19.0 4.2 15 17 16 100% 94% 46 37.0 37.0 16 16 15 31% 80% 51 31.4 9.8 17 16 15 6% 0% 90 17.8 1.1 18 15 14 13% 50% 33 45.5 6.1 19 14 14 21% 100% 142 9.9 2.1 20 13 13 15% 100% 45 28.9 4.4 21 13 12 23% 67% 42 31.0 7.1 22 11 11 9% 100% 102 10.8 1.0 23 11 11 18% 100% 30 36.7 6.7 24 10 10 0% - 48 20.8 0 25 9 9 22% 100% 50 18.0 4.0 26 6 6 0% - 50 12.0 0 27 4 3 25% 0% 32 9.4 3.1

TOTAL 581 556 29% 85% 2151 27.0 7.9



ICD10-data and EURODIAB, and by ESPED and EURODIAB, and 18 (15%) patients by ICD

and ESPED.

The 27 hospitals that participated in ESPED and in the ICD10-data query reported 93 individual

HZ hospitalisations including 18 hospitalisations that were reported by both sources. The number

of reports in ICD and ESPED is listed for each hospital in Table 56. Each hospital reported on a

median 3 cases. Thirty-three percent of all reports were made through ESPED. Fifty-five percent

of all ESPED reports were also reported through ICD10-data.

Table 55. Number of reported herpes zoster cases by source and number of matches in NRW

Cases (n)

% of all cases (three sources)

Proportion of ESPED

cases

Proportion of EURODIAB

cases

Proportion of ICD cases

Matches(n)

Proportion of matches

ESPED 46 38% 100% - - - -

EURODIAB 16 13% - 100% - - -

ICD 83 67% - - 100% - -

ESPED-EURODIAB 60 50% 77% 27% - 2 3%

ESPED-ICD 111 90% 43% - 74% 18 15%

EURODIAB-ICD 97 78% - 17% 85% 2 2%

ESPED-EURODIAB-ICD 124 100% 38% 13% 67% 1 1%



Table 56. Number of reports from 27 hospitals that participated in ESPED and ICD10 STUDY and which had reported at least one case with HZ from either source in NRW

8.2.5 Incidence estimates for varicella hospitalisations

8.2.5.1 Two- and three source capture-recapture Figure 54 illustrates that 188 varicella cases were reported in NRW in 2003 and 2004 by ESPED

alone and 83 cases reported by EURODIAB alone. 24 cases have been reported both by ESPED

and EURODIAB, i.e. a total of 295 cases have been found by both sources. Applying capture-

recapture methodology for two-sources using a calculation proposed by Chapman [47] we can

estimate that from all true cases in NRW, ESPED captured 23% (95% CI: 18 - 34), EURODIAB

Hospital All reports ICD ESPED

Percent of ESPED cases also reported

by ICD10

Hospital beds

All reports per 100 hospital

beds

ESPED reports per 100 hospital

beds

n n % % n

5 12 4 75% 11% 112 10.7 8.0 3 9 8 33% 67% 120 7.5 2.5 1 7 7 43% 100% 175 4.0 1.7

19 7 6 29% 50% 142 4.9 1.4 12 6 6 0% - 55 10.9 0 13 6 6 17% 100% 40 15.0 2.5 24 6 5 33% 50% 48 12.5 4.2 16 4 4 50% 100% 51 7.8 3.9 2 3 3 0% - 230 1.3 0

10 3 3 33% 100% 90 3.3 1.1 11 3 3 0% - 95 3.2 0 14 3 3 67% 100% 95 3.2 2.1 22 3 3 0% - 102 2.9 0 26 3 2 33% 0% 50 6.0 2.0 27 3 3 33% 100% 32 9.4 3.1 6 2 2 50% 100% 98 2.0 1.0 8 2 2 50% 100% 80 2.5 1.3 9 2 2 0% - 70 2.9 0

25 2 2 0% - 50 4.0 0 4 1 0 100% 0% 80 1.3 1.3 7 1 1 0% - 50 2.0 0

15 1 1 0% - 46 2.2 0 17 1 1 0% - 90 1.1 0 18 1 1 100% 100% 33 3.0 3.0 20 1 0 100% 0% 45 2.2 2.2 21 1 0 100% 0% 42 2.4 2.4 23 0 0 - - 30 - -

TOTAL 93 78 33% 55% 2151 4.3 1.5



12% (95% CI: 9 – 17), and both sources 32% (95% CI: 24 – 47). The number of true varicella

cases per year in NRW can be estimated to be 460 (95% CI: 314 - 605). Given a population of

3,248,227 children in NRW (in 2003) up to the age of 16 (< 17th birthday) years, the incidence of

hospitalisations due to VZV can be estimated to be 14.1 (95% CI: 9.7 – 18.6) per 100,000

children. Applying this incidence to the total German population up to the age of 16 (14,106,043

children in Germany), results in an estimated number of 1996 (1363-2629) varicella

hospitalisations per year in this age group. The results of all further two-source capture-recapture

estimates combining ESPED and ICD10-data, or EURODIAB and ICD10-data are given in

Table 57. Using all three sources for capture-recapture (Figure 55) and applying an independent

log-linear model the incidence estimate increases to 18.7 (95% CI: 17.5 – 20.2) in NRW. The

expected number of varicella hospitalisations in Germany can be then estimated to 2640 (95%

CI: 2471 – 2855) per year. (Table 57).

Table 57. Incidence estimates for varicella hospitalisations using different calculation methods

Using age stratified three source capture-recapture techniques the incidence of varicella

hospitalisations is highest in the age group of children under one year of age 96.5 (89.3-110.6) /

100,000 children, and lowest in the age group of children between 11-17 yeras age 2.3 (1.8-3.7)

/ 100,000 (Table 58).

Case finding method Cases per yearPopulation <=

16 years in 2003

Incidence estimate per 100,000 children

Estimated number of hospitalised children under 16 years of age

in Germany

Germany: ESPED varicella cases 918 / 2 = 459 14,106,043 3.3 459

NRW: ESPED varicella cases 212 / 2 = 106 3,248,227 3.3 460

NRW: ESPED + EURODIAB cases 295 / 2 = 148 3,248,227 4.5 641

NRW: Using two-source capture-recapture (ESPED+EURODIAB)

14.1 (95% CI:9.7 – 18.6)

1996 (95% CI: 1363 – 2629)

NRW: Using two-source capture-recapture (ESPED+ICD)

16.5 (95% CI: 15.2 – 17.9)

2330 (95% CI: 2138 – 2521)

NRW: Using two-source capture-recapture (EURODIAB+ICD)

24.3 (95% CI: 19.6 – 29.0)

3427 (95% CI: 2761 – 4092)

NRW: Using three-source capture-recapture (ESPED+EURODIAB+ICD)

18.7 (95% CI: 17.5 – 20.2)

2640 (95% CI: 2471 – 2855)



Table 58. Incidence estimates by age categories for varicella hospitalisations using three-source capture-recapture (EURODIAB+ESPED+ICD) in NRW (stratified analysis)

The total estimated underreporting of varicella hospitalisations of 69.9% is a result of a

combined effect: (1) Underreporting of varicella hospitalisations within hospitals that

participated in ESPED, and (2) non-participation of hospitals in both surveillance systems (60%

of all ESPED hospitals in NRW participated in ICD or ESPED). Underreporting affects ESPED

relatively more than the ICD-10 reports, which are not as strongly based on recall as the ESPED

system.

8.2.5.2 Use of other methodologic approaches For sensitivity analysis we took the number of reports and hospital beds of reporting hospitals

into account. We considered the reporting hospitals to be representative of all hospitals in NRW,

took the number of cases captured by ICD and ESPED (n=798/2 per year) and adjusted for the

fact that the reporting hospitals only represented 82.5% of all hospital beds in NRW (Table 52)

(n=798/2/0.825=493), and used the same population basis as in Table 57 to calculate the

incidence in NRW and the expected number of hospitalisations in Germany. Thus, we would

expect an incidence of 14.9 /100,000 or 2,100 children hospitalised with varicella in Germany.

In a further approach we took the average number of cases per 100 hospital beds calculated from

those 27 hospitals participating in ESPED and ICD (n=7.9) (Table 54), and multiplied this

number by the total of paediatric hospital beds in Germany (n=21,435). This calculation yielded

an incidence of 20.5 / 100,000 children, which would result in 2894 hospitalised children per

year for Germany. However, this assumes on average an equal number of varicella

hospitalisations among paediatric beds in Germany and those participating in ESPED and the

ICD-query in NRW. Furthermore, in those 21,435 paediatric hospital beds in Germany registered

Observed varicella hospitalisations in

NRW

Estimated underreporting of all

three sources

Incidence estimate per 100,000 children (95%

CI)

Estimated number of hospitalised children up to

16 years of age in Germany (95% CI)

< 1 year 261 84.7% 96.5 (89.3 – 110.6) 681 (631 –- 781)

1-4 years 329 67.8% 47.6 (42.9 – 54.6) 1066 (960 – 1222)

5-10 years 219 68.0% 14.3 (12.8 – 12.8) 683 (609 – 795)

11-17 years 41 61.2% 2.3 (1.8 – 3.7) 147 (112 – 239)

All Ages 850 69.9% 18.7 (17.5 – 20.2) 2640 (2469 - 2849)



with ESPED some facilities for rehabilitation or hospitals with only neonatal care units are

included that are not expected to report varicella cases.

In conclusion, we consider the three source capture-recapture estimate of 2640 (95% CI: 2469 -

2849) children hospitalised due to varicella per year in Germany as the most reliable estimate.

8.2.6 Incidence estimates for herpes zoster hospitalisations

8.2.6.1 Two- and three source capture-recapture Reliable incidence estimates are difficult to obtain for herpes zoster, as the number of cases is

relatively low. We have 244 herpes zoster cases from all ESPED hospitals in Germany, and 46

cases reported by ESPED for NRW. There were 44 cases by ESPED alone, 14 by EURODIAB

alone, and 2 cases captured by both sources, amounting to a total of 60 cases from both sources

in NRW (Figure 56). Using two-source capture-recapture, an incidence of 4.1 (95% CI 0.6 – 7.6)

can be estimated. The results of all further two-source capture-recapture estimates combining

ESPED and ICD10-data, or EURODIAB and ICD10-data are given in Table 59. Using a three-

source independent log-linear model the incidence estimate is unchanged at 4.1 /100,000 (95%

CI 3.2 – 5.9) children, corresponding with 584 (447 - 827) HZ hospitalisations in Germany

(Table 59).

Table 59. Incidence estimates for HZ hospitalisations using different calculation methods

Case finding method Cases per yearPopulation <=

16 years in 2003

Incidence estimate per 100,000 children

Estimated number of hospitalised children under 16 years of age

in Germany

Germany: ESPED herpes zoster cases 244 / 2 = 122 14,106,043 0.9 122

NRW: ESPED herpes zoster cases 46 / 2 = 23 3,248,227 0.7 100

NRW: ESPED + EURODIAB cases 60 / 2 = 30 3,248,227 0.9 109

NRW: Using two-source capture-recapture (ESPED+EURODIAB) 4.1

(95% CI: 0.6 – 7.6) 576

(95% CI: 79 – 1074)

NRW: Using two-source capture-recapture (ESPED+ICD) 3.2

(95% CI: 2.2 – 4.1) 449

(95% CI: 315 – 583)

NRW: Using two-source capture-recapture (ICD+EURODIAB) 7.3

(95% CI: 0.9 – 13.7) 1031

(95% CI: 129 – 1934)

NRW: Using three-source capture-recapture (ESPED+EURODIAB+ICD) 4.1

(95% CI: 3.2 – 5.9) 584

(95% CI: 447 – 827)



8.2.6.2 Use of other methodologic approaches Analogous to the approach taken for varicella hospitalisations we took the number of reports and

hospital beds of reporting hospitals into account. We considered the reporting hospitals to be

representative of all hospitals in NRW, took the number of cases captured by ICD and ESPED

(n=124/2 per year) and adjusted for the fact that the reporting hospitals only represented 82.5%

of all hospital beds in NRW (Table 52) (n=124/2/0.825), and used the same population basis as

in Table 59 to calculate the incidence in NRW and the expected number of hospitalisations in

Germany. Thus, we would expect an incidence of 2.3 /100,000 and 326 children in Germany

hospitalised with HZ.

In another approach we took the average number of cases per 100 hospital beds calculated from

those 27 hospitals participating in ESPED and ICD (n=1.5) (Table 56), and multiplied this

number by the total of paediatric hospital beds in Germany (n=21,435). Here the incidence was

calculated to be 3.3 / 100,000, resulting in 461 hospitalised children per year for Germany.

9 Summary


9 Summary

The presented study provides, for the first time, a complete overview of the burden of varicella

zoster virus hospitalisations and complications in Germany prior to the introduction of general

varicella vaccinations in children in July 2004. This study report first provides a detailed

description of 1162 children hospitalised due to varicella (n=918/76%) and herpes zoster

(n=244/24%). These hospitalisations were reported from 368 paediatric hospitals within the

nationwide hospital-based ESPED surveillance system between January 2003 and December

2004. Secondly, this study report provides precise estimates of the incidence of varicella and

herpes zoster hospitalisations, combining the results of three case surveillance sources performed

in parallel in North-Rhine Westphalia (NRW), the most populous “Bundesland” (Federal State)

in Germany with a population of 3,248,227 persons under the age of 17 years. First of all, the

ESPED hospital-based system, secondly, the EURODIAB practice sentinel network including

10,500 medical practices and, thirdly, the ICD10 surveillance study, involving extensive ICD10

data surveillance carried out in 68 paediatric hospitals in NRW. These independent surveillance

systems were the basis for three-source capture-recapture analyses performed in order to attain

precise incidence estimates and to account for possible under-reporting within the ESPED study.

In the nationwide ESPED surveillance, 500 (55 %) of a total of 918 hospitalised children with

varicella were male. In the literature, several studies have also reported a preponderance of boys

affected by varicella complications [22, 24, 29, 30, 48, 49]. However, data on sero-epidemiology

show that there is no difference between boys and girls in the incidence of varicella [50, 51]. The

reason for the higher complication rate for varicella in boys remains unclear. The median age of

the 918 hospitalised children with varicella was 3.3-years-old (IQR: 1.4-5.2) and 18% of all

varicella hospitalisations were seen to have occurred during the first year of life. The median

hospital stay was 5 days (IQR: 3-8). A considerable number of children, however, were

hospitalised for more than 7 days (27%) and some for even longer than 14 days (8%). Children

5-10-years-old (35%, 311/914) and 11-16-years-old (5%, 42/914) were significantly

overrepresented in the group of children that had been hospitalised with varicella for more than

14 days, demonstrating 51% and 11% of the hospitalisations, respectively. Therefore, it may be

assumed that older children had a higher risk for a severe and prolonged varicella hospitalisation

than did younger children.

Whereas 77% of the hospitalised children were reported as healthy, an underlying chronic disease

was reported in 207 children (23%): Immunosuppression in 7%, atopic dermatitis in 7%, and

9 Summary


other chronic diseases in 9% of the cases. Among the hospitalised children with

immunosuppression, about 60% had no specific complication indicated and were probably

admitted for primary intravenous antiviral treatment. However, complications due to coagulation

disorders, complications of the lower respiratory tract and other systemic bacterial infections were

seen more frequently in immunocompromised children than in immunocompetent children.

Interestingly, in contrast, neurologic and skin infectious complications were more frequently

reported among immunocompetent children.

The most frequent varicella-associated symptoms among all 918 hospitalised children were fever

(75.4%), feeding problems (51.2%), ataxia (13.3%), convulsions (11.3%) and reduced

consciousness (8.8%).

The spectrum of recorded varicella complications was wide and included almost any organ

system. Neurological complications (25.4%), skin infections (23.2%) and problems involving the

gastrointestinal tract (15.0%) were the most frequent complications. Remarkable was the

relatively high frequency of varicella-associated gastrointestinal complications (15%), such as

gastroenteritis or dehydration. Forty-seven percent of all varicella cases hospitalised for more

than 14 days were children with neurologic complications. Among the 918 hospitalised children,

143 children (16%) demonstrated a very severe clinical course of their varicella infection,

presenting the following 172 clinical diagnoses: Secondary systemic bacterial infections (i.e.

sepsis, osteomyelitis, septic arthritis, necrotising fasciitis) (n=40), coagulation disorders and

sequelae (i.e. purpura fulminans and haemorrhagic varicella) (n=51), meningoencephalitis

(n=52), cerebral infarcts or vasculitis (n=6), pneumonia requiring intensive care treatment

(n=14), deep phlegmons (n=2), retinal necrosis (n=2), pericarditis (n=2), myocarditis (n=1), liver

transplantation (n=1), and mastoiditis (n=1). However, also a considerable number of the 72

children with varicella cerebellitis, considered by many physicians as a benign complication,

remained in hospital more than 7 days (49%) or even more than 14 days (11%). No specific

complication was reported for 183 (20%) children. About two thirds of these patients were of a

younger age and were hospitalised with fever or feeding difficulties. About one third of these

children was immunocompromised, had atopic dermatitis or chronic diseases and were probably

hospitalised for intravenous acyclovir therapy in order to prevent complications.

In 15 children (1.7%), varicella-related, permanent sequelae were reported. Ten of the 15

children were reported to have scarring, one child each was reported to have ataxia, mitral valve

insufficiency due to endocarditis, visual restriction due to retina necrosis, liver transplantation,

and hemiparesis due to a cerebral infarct. For a further 78 (8.7%) children, possible sequelae

were recorded as listed in Table 27. During the two-year study period, 10 varicella-associated

9 Summary


deaths were reported, 6 in immunocompetent and 4 in immunocompromised children. The

number of observed deaths, the estimated mortality (0.04 / 100,000 children < 17 years of age)

and the estimated lethality (0.07 / 10,000 VZV cases) are within the range of estimates found in

other countries [42].

Initially, participation of ESPED hospitals was thought to be very good, highlighted by response

rates well over 90% in response to monthly ESPED-cards and sent-out questionnaires. However,

applying capture-recapture analysis, it was estimated that only about 17% (95% CI: 16-19) of all

hospitalised cases due to varicella were reported by ESPED. Underreporting of varicella

hospitalisations by the ESPED system may principally be due to two major reasons: First of all,

not all paediatric hospitals participated in the ESPED system. Only 224 of 368 (61%) hospitals

and paediatric wards that are registered with ESPED ever reported a hospitalised varicella case.

Since varicella hospitalisations are a relatively frequent event, it seems highly improbable that no

hospitalisation had occurred in the 39% of non-reporting hospitals. Secondly, among those

hospitals reporting at least one case, there is a high probability that severe hospitalised varicella

cases were more likely to be reported than less severe cases that are hospitalised only for a short

period of time. This recall bias may especially affect a relatively frequent disease like varicella.

Assuming a total incidence of 735,000 varicella cases / year in Germany (corresponding to the

annual birth rate), varicella hospitalisation occurred in 3.3/100,000 children/year or in about 6

cases per 10,000 varicella cases as based upon ESPED reports alone. Under the assumption of

complete ascertainment by ESPED and EURODIAB, a hospitalisation incidence of 4.5/100,000

children was calculated. This is about four times higher than the estimate provided by an earlier

ESPED survey from 1999 [30], which included only severe complications and had other

methodological limitations. Using capture-recapture analyses of all three surveillance sources

performed in NRW, an incidence of 18.7 (95% CI: 17.5 – 20.2) varicella hospitalisations /

100,000 children / year was estimated. Extrapolating this incidence to the whole German

population of children < 17-years-old resulted in an estimate of 2640 (95% CI: 2471 – 2855)

varicella-related hospitalisations per year. Thus, about 36 (95% CI: 34-39) hospitalisations per

10,000 varicella cases per year may be expected. Assuming about 2600 varicella hospitalisations

per year and an average hospital stay of 5.6 days (ICD+ESPED NRW) or 7 days (ESPED

Germany), about 15,000-18,000 hospital days per year can be expected to be related to varicella.

The obtained incidence estimate of 18.7 /100,000 person-years is in the upper middle of the

range of estimated incidences of varicella hospitalisations in different areas of Europe and North

America [21-28, 30-32, 37, 38, 52-63] (range 0.85-29.4 / 100,000 - Table 1). It is, however,

approximately 25% lower than the result obtained from the EVITA study of Wutzler et al. [32]

9 Summary


(Figure 58). The EVITA study was based on a retrospective practice survey, extrapolating the

incidence estimate only from 11 hospitalised varicella cases.

Among the 1162 children reported in ESPED, 244 (24%) were hospitalised with herpes zoster.

In general, herpes zoster is considered to be a localised skin disease mainly affecting adults and

immunocompromised children. Contrary to the general perception, the majority of

hospitalisations in children with herpes zoster involved immunocompetent children. Among

children hospitalised with herpes zoster, 144 (59%) were without underlying chronic disease.

Immunocompromised children did not seem to have specific complications more frequently,

with the exception of a generalisation of HZ rash, which was seen to have occurred in 25%.

Furthermore, the results showed that herpes zoster is not restricted to skin affections. Especially

such neurological complications as meningoencephalitis or facial nerve paralysis were seen to

have occurred in up to 15% of the children hospitalised with herpes zoster. Finally, even though

children hospitalised with herpes zoster can be severely ill, permanent sequelae were rarely

reported. Facial nerve paralysis in conjunction with zoster oticus (Ramsay Hunt) was the major

complication of HZ, occurring in 5% of the hospitalised children.

The incidence of herpes zoster hospitalisation was estimated to be 4.1 (95% CI 3.2-5.9) /

100,000 children/year using the three source capture-recapture method. This translates into an

estimated number of 584 (95% CI: 447 – 827) HZ hospitalisations per year in Germany.

A further objective of this study was to evaluate ICD10 data as a possible future tool for long-

term surveillance regarding varicella complications. ICD10 data confirmed the relatively large

degree of underreporting in the ESPED system, initially documented by the two-source

EURODIAB-ESPED capture-recapture analysis. This is in accordance with the clearly increased

sensitivity of ICD10 data, which identified about 3-times more children with varicella

hospitalisations than ESPED in those hospitals that had participated and reported cases both in

ESPED and the ICD10 data query. A comparison of ICD10 data and ESPED-data confirmed -

especially in children with less severe complications, i.e. young children with fever and feeding

problems, or children with VZV-associated gastroenteritis or dehydration - that these cases had

been underreported in the ESPED-system, most probably due to recall bias. Aside from this

observation, ICD10 data yielded similar results as that found in the ESPED surveillance system

concerning age distribution, hospital stay, chronic underlying disease status and VZV-associated

complications, and therefore proved to be a useful tool for future surveillance.

This study on hospitalisations and complications of varicella zoster virus infections in Germany

provides, for the first time, a precise and detailed picture of the burden of complicated VZV

9 Summary


infections in Germany in children up to 16 years of age. The use of a three-source capture-

recapture method resulted in the most reliable incidence estimate of varicella hospitalisations in

German children so far. These data are especially important in the view of the recent

introduction of a general varicella vaccination for all children during their second year of life.

They will serve as a baseline for future surveillance of changes in VZV epidemiology as well as

epidemiology-based public health decisions with regard to measures necessary for obtaining

sufficient vaccination coverage.

10 References


10 References

1. Aebi C, Ahmed A, Ramilo O (1996) Bacterial complications of primary varicella in children. Clin Infect Dis;23(4):698-705.

2. Chen TM, George S, Woodruff CA, Hsu S (2002) Clinical manifestations of varicella-zoster virus infection. Dermatol Clin;20(2):267-+.

3. Fleisher G, Henry W, McSorley M, Arbeter A, Plotkin S (1981) Life-Threatening Complications of Varicella. Amer J Dis Child;135(10):896-899.

4. Floret D (1998) Varicella in immunocompetent children: Complications and risk factors. Med Mal Infec;28(11):775-781.

5. Jackson MA, Burry VF, Olson LC (1992) Complications of varicella requiring hospitalization in previously healthy children. Pediatr Infect Dis J;11(6):441-445.

6. Michel JL, Perrot JL, Cambazard F (1998) Severe varicellas in children. Nouv Dermatol;17(10):670-672.

7. Meyer PA, Seward JF, Jumaan AO, Wharton M (2000) Varicella mortality: Trends before vaccine licensure in the United States, 1970-1994. J Infec Dis;182(2):383-390.

8. Preblud SR (1986) Varicella - Complications and Costs. Pediatrics;78(4):728-735.

9. Law B, Fitzsimon C, Ford-Jones L, McCormick J, Riviere M (1999) Cost of chickenpox in Canada: Part II. Cost of complicated cases and total economic impact. Pediatrics;104(1):7-14.

10. Law B, Fitzsimon C, Ford-Jones L, MacDonald N, Dery P, Vaudry W, et al. (1999) Cost of chickenpox in Canada: Part I. Cost of uncomplicated cases. Pediatrics;104(1):1-6.

11. Brisson M, Edmunds WJ (2002) The cost-effectiveness of varicella vaccination in Canada. Vaccine;20(7-8):1113-1125.

12. Brisson M, Edmunds WJ (2003) Varicella vaccination in England and Wales: cost-utility analysis. Arch. Dis. Child.;88(10):862-869.

13. Scuffham PA, Lowin AV, Burgess MA (1999) The cost-effectiveness of varicella vaccine programs for Australia. Vaccine;18(5-6):407-415.

14. Scuffham P, Devlin D, Eberhart-Phillips J, Wilson-Salt R (1999) The cost-effectiveness of introducing a varicella vaccine to the New Zealand immunisation schedule. Soc Sci Med;49(6):763-779.

15. Saddier P, Floret D, Guess HA, Durr F, Peyrieux JC, Weber DJ, et al. (1998) Cost of varicella in France: A study in day care centers. J Infec Dis;178:S58-S63.

16. Lieu TA, Cochi SL, Black SB, Halloran ME, Shinefield HR, Holmes SJ, et al. (1994) Cost-Effectiveness of a Routine Varicella Vaccination Program for United-States Children. Jama-J Am Med Assn;271(5):375-381.

17. Beutels P, Clara R, Tormans G, Van Doorslaer E, Van Damme P (1996) Costs and benefits of routine varicella vaccination in German children. J Infect Dis;174(Suppl. 3):S335-S341.

18. Ferson MJ (1992) Health and Economic Cost of Chickenpox in Child-Care. Med J Australia;156(5):364-364.

19. Ferson MJ, Shen WL, Stark A (1998) Direct and indirect costs of chickenpox in young children. J Paediatr Child Health;34(1):18-21.

20. Skull SA, Wang EEL (2001) Varicella vaccination - a critical review of the evidence. Arch Dis Child;85(2):83-90.

10 References


21. Guess HA, Broughton DD, Melton LJ, Kurland LT (1984) Chickenpox Hospitalizations among Residents of Olmsted County, Minnesota, 1962 through 1981 - a Population-Based Study. Amer J Dis Child;138(11):1055-1057.

22. Jaeggi A, Zurbruegg RP, Aebi C (1998) Complications of varicella in a defined central European population. Arch Dis Child;79(6):472-477.

23. Peterson CL, Mascola L, Chao SM, Lieberman JM, Arcinue EL, Blumberg DA, et al. (1996) Children hospitalized for varicella: A prevaccine review. J Pediat;129(4):529-536.

24. Roca J, Dominguez A, Moraga FA, Jane M, Navas E, Salleras L (2000) Pediatric complications of varicella requiring hospitalization in Catalonia. Pediatr Catalana;60(5):234-237.

25. Coplan P, Black S, Rojas C, Shinefield H, Ray P, Lewis E, et al. (2001) Incidence and hospitalization rates of varicella and herpes zoster before varicella vaccine introduction: A baseline assessment of the shifting epidemiology of varicella disease. Pediatr Infect Dis J;20(7):641-645.

26. Rivest P, Bedard L, Valiquette L, Mills E, Lebel HM, Lavoie G, et al. (2001) Severe complications associated with varicella: Province of Quebec, April 1994 to March 1996. Can J Infect Dis;12(1):21-26.

27. Yawn BP, Yawn RA, Lydick E (1997) Community impact of childhood varicella infections. J Pediat;130(5):759-765.

28. Choo PW, Donahue JG, Manson JE, Platt R (1995) The Epidemiology of Varicella and Its Complications. J Infec Dis;172(3):706-712.

29. Bonhoeffer J, Baer G, Muehleisen B, Aebi C, Nadal D, Schaad UB, et al. (2005) Prospective surveillance of hospitalisations associated with varicella-zoster virus infections in children and adolescents. Eur J Pediatr;164(6):366-70.

30. Ziebold C, von Kries RD, Lang R, Weigl J, Schmitt HJ (2001) Severe complications of varicella in previously healthy children in Germany: A 1-year survey. Pediatrics;108(5):art. no.-e79.

31. Wutzler P, Neiss A, Banz K, Tischer A (2002) Ist eine Elimination der Varizellen durch eine allgemeine Impfung möglich? [Will Routine vaccination eliminate varicella?]. Deutsches Aertzeblatt;99(15):1024-9.

32. Wutzler P, Neiss A, Banz K, Goertz A, Bisanz H (2002) Can varicella be eliminated by vaccination? Potential clinical and economic effects of universal childhood varicella immunisation in Germany. Med Microbiol Immunol (Berl);191(2):89-96.

33. von Kries R, Heinrich B, Hermann M (2001) German paediatric surveillance unit (ESPED). Monatsschr Kinderheilk;149(11):1191-+.

34. Zimmermann H, Desgrandchamps D, Schubiger G (1995) The Swiss paediatric surveillance unit (SPSU). Soz Praventivmed;40(6):392-395.

35. Centers for Disease Control and Prevention (1996) Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep;45(Rr-11):1-36.

36. American Academy of Pediatrics (1995) Recommendations for the use of live attenuated varicella vaccine. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics;95(5):791-6.

37. Seward JF, Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX, et al. (2002) Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA;287(5):606-11.

38. Galil K, Brown C, Lin F, Seward J (2002) Hospitalizations for varicella in the United States, 1988 to 1999. Pediatr Infect Dis J;21(10):931-5.

39. Davis MM, Patel MS, Gebremariam A (2004) Decline in varicella-related hospitalizations and expenditures for children and adults after introduction of varicella vaccine in the United States. Pediatrics;114(3):786-792.

10 References


40. McCoy L, Sorvillo F, Simon P (2004) Varicella-Related Mortality in California, 1988-2000. Pediatric Infectious Disease Journal;23(6):498-503.

41. Nguyen HQ, Jumaan AO, Seward JF (2005) Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med;352(5):450-8.

42. Ständige Impfkommission (STIKO) (2004) Empfehlungen der Ständigen Impfkommission (STIKO). Epidemiologisches Bulletin;2004(30):235-50.

43. Verity C, Preece M (2002) Surveillance for rare disorders by the BPSU. The British Paediatric Surveillance Unit. Arch Dis Child;87(4):269-71.

44. Green A, Brutti G, Patterson CC, Dahlquist G, Soltesz G, Schober E, et al. (2000) Variation and trends in incidence of childhood diabetes in Europe. Lancet;355(9207):873-876.

45. Green A, Gale EA, Patterson CC (1992) Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE Study. Lancet;339(8798):905-9.

46. Cuzick J (1985) A Wilcoxon-type test for trend. Stat Med;4(1):87-90.

47. Chapman D (1952) Inverse, multiple and sequential censuses. Biometrics;8:286-306.

48. Law B, MacDonald N, Halperein S, Scheifele D, Dery P, Jadavji T, et al. (2000) The Immunization Monitoring Program Active (IMPACT) prospective five year study of Canadian children hospitalized for chickenpox or an associated complication. Pediat Inf Dis J;19(11):1053-1059.

49. Somekh E, Maharashak N, Shapira Y, Greenberg D, Dagan R (2000) Hospitalization for primary varicella-zoster virus infection and its complications in patients from southern Israel. Infection;28(4):200-204.

50. Wutzler P, Farber I, Wagenpfeil S, Bisanz H, Tischer A (2001) Seroprevalence of varicella-zoster virus in the German population. Vaccine;20(1-2):121-124.

51. Thiry N, Beutels P, Shkedy Z, Vranckx R, Vandermeulen C, Wielen MV, et al. (2002) The seroepidemiology of primary varicella-zoster virus infection in Flanders (Belgium). Eur J Pediatr;161(11):588-93.

52. Deguen S, Chau NP, Flahault A (1998) Epidemiology of chickenpox in France (1991-1995). J Epidemiol Community Health;52:46S-49S.

53. Joseph CA, Noah ND (1988) Epidemiology of chickenpox in England and Wales, 1967-85. Br Med J;296(6623):673-676.

54. Guess HA, Broughton DD, Melton LJ, Kurland LT (1986) Population-Based Studies of Varicella Complications. Pediatrics;78(4):723-727.

55. Preblud SR (1981) Age-Specific Risks of Varicella Complications. Pediatrics;68(1):14-17.

56. Varughese PD (1988) Chickenpox in Canada, 1924-87. Can Med Assoc J;138(2):133-134.

57. Fornaro P, Gandini F, Marin M, Pedrazzi C, Piccoli P, Tognetti D, et al. (1999) Epidemiology and cost analysis of varicella in Italy: results of a sentinel study in the pediatric practice. Italian Sentinel Group on Pediatric Infectious Diseases. Pediatr Infect Dis J;18(5):414-9.

58. Lin F, Hadler JL (2000) Epidemiology of primary varicella and herpes zoster hospitalizations: The pre-varicella vaccine era. J Infec Dis;181(6):1897-1905.

59. Gil A, Oyaguez I, Carrasco P, Gonzalez A (2001) Epidemiology of primary varicella hospitalizations in Spain. Vaccine;20(3-4):295-298.

60. Fairley CK, Miller E (1996) Varicella-Zoster virus epidemiology - A changing scene? J Infec Dis;174:S314-S319.

10 References


61. Ratner AJ (2002) Varicella-related hospitalizations in the vaccine era. Pediatr Infect Dis J;21(10):927-31.

62. Socan M, Kraigher A, Pahor L (2001) Epidemiology of varicella in Slovenia over a 20-year period (1979-98). Epidemiol Infect;126(2):279-283.

63. Brisson M, Edmunds WJ, Law B, Gay NJ, Walld R, Brownell M, et al. (2001) Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect;127(2):305-314.

11 Figures


11 Figures

Figure 1. ESPED: Organisation of surveillance

Figure 2. ESPED: Response rate of questionnaires

93.4%mean

020

4060

8010

0R

espo

nser

ate

in %

01/2003 04/2003 07/2003 10/2003 01/2004 04/2004 07/2004 10/2004 12/2004Month

Date:30/11/2005

11 Figures


Figure 3. ESPED: Seasonal distribution of cases reported to ESPED

050

010

0015

00C

umul

ativ

e nu

mbe

r of c

ases

050

100

150

Num

ber o

f cas

es p

er m

onth

Jan

Feb Mar AprMay Ju

n Jul

Aug Sep OctNov Dec Ja

nFeb Mar Apr

May Jun Ju

lAug Sep Oct

Nov Dec

Month

per month cumulativeDate:30/11/2005

Reported cases N=1443

11 Figures


Figure 4. ESPED: Data profile

1443 ESPED-reports

69 false or double reports by hospital

94 non-returnedquestionnaires

69 false or double reports by hospital

94 non-returnedquestionnaires

1280 returned questionnaires

1162 complete cases

117 false ordouble reports

1 missingquestionnaire

79 % 21 %

918 varicella 244 herpes zoster79 % 21 %

918 varicella 244 herpes zoster

11 Figures


Figure 5. ESPED: Distribution of 918 varicella cases by month and year

020

4060

8010

012

014

0N

umbe

r of c

hild

ren

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Varicella (n=918)

2003 2004

Figure 6. ESPED: Age distribution of 914 varicella cases

05

1015

20P

erce

nt o

f chi

ldre

n

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17Age in years

IQR: Interquartile range=25. - 75. Quartile

Median age 3.3 Jahre (IQR:1.4 - 5.2)

11 Figures


Figure 7. ESPED: Interval between start of exanthema and admission in 814 varicella cases 0

5010

015

020

025

0N

umbe

r of c

hild

ren

Days afteradmisson

Days before admisson6-3 2-0 0-1 2-3 4-5 6-7 8-14 15-21 22-124

Start of exanthemaIQR: Interquartile range=25. - 75. Quartile

Median 3 Tage (IQR: 2 - 6)

11 Figures


Figure 8. ESPED: Duration of hospitalisation in 912 varicella cases 0

1020

3040

Per

cent

of c

hild

ren

1-3 4-7 8-14 15-21 22-199Days in hospital


Median 5 days (IQR: 3 - 8)

11 Figures


Figure 9. ESPED: Symptoms in 909 varicella cases

441517182029303336

568086103121

465685

0 200 400 600 800Number of children

Cardiac (0.4 %)Comatose state (0.4 %)

Pain (1.7 %)Affection of a joint (1.9 %)

Signs of bleeding disorders (2.0 %)Eye involvement (2.2 %)

Neurological focal (3.2 %)Headache (3.3 %)Unspecific (3.6 %)

Other neurological (4.0 %)Upper respiratory infection (6.2 %)

Reduced consciousness (8.8 %)Gastrointestinal (9.5 %)

Convulsion (11.3 %)Ataxia (13.3 %)

Feeding problems (51.2 %)Fever (75.4 %)

Figure 10. ESPED: Symptoms and age at admission in 905 children with varicella (x= 25th and 75th percentile)

0 5 10 15Age in years

HeadacheComatose state

Neurological focalUnspecific

Signs of bleeding disordersOther neurological

AtaxiaPain

Reduced consciousnessAffection of a joint

GastrointestinalCardiac

FeverConvulsion

Eye involvementUpper respiratory infection

Feeding problems

11 Figures


Figure 11. ESPED: Symptoms and duration of hospital stay in 904 children with varicella (x= 25th and 75th percentile)

0 10 20 30Days in hospital

Comatose stateNeurological focal

CardiacPain

AtaxiaReduced consciousness

HeadacheSigns of bleeding disorders

Affection of a jointEye involvement

Upper respiratory infectionUnspecific

Other neurologicalGastrointestinal

FeverFeeding problems

Convulsion

11 Figures


Figure 12. ESPED: Median age at admission, and complication category and underlying chronic disease in 909 children with hospitalised with varicella (x= 25th and 75th percentile)

0 2 4 6 8Age in years

ImmunocompromisedOtherNone

Atopic dermatitis

Coagulation and sequelaeHaematologic

NeurologicOthers

Reactive arthritisLower respiratory tract

Other systemic bacterialNo specific complication recorded (VZV)

SkinUpper respiratory tract and ENT

Gastrointestinal tract

Figure 13. ESPED: Median hospital stay, and complication category and underlying chronic disease in 909 children hospitalised with varicella (x= 25th and 75th percentile)

0 5 10 15 20 25Days in hospital

ImmunocompromisedOtherNone

Atopic dermatitis

Other systemic bacterialCoagulation and sequelae

Lower respiratory tractHaematologic

SkinOthers

NeurologicReactive arthritis

Upper respiratory tract and ENTNo specific complication recorded (VZV)

Gastrointestinal tract

11 Figures


Figure 14. ESPED: Complications in 913 varicella cases

14

24

40

51

64

92

108

137

212

232

0 50 100 150 200 250Number of children

Reactive arthritis (1.5 %)

Others (2.6 %)

Other systemic bacterial (4.4 %)

Coagulation and sequelae (5.6 %)

Haematologic (7.0 %)

Upper respiratory tract and ENT (10.1 %)

Lower respiratory tract (11.8 %)

Gastrointestinal tract (15.0 %)

Skin (23.2 %)

Neurologic (25.4 %)

Percent of all children in brackets

11 Figures


Figure 15. ESPED: Neurologic complications in 913 varicella cases

3

6

9

21

52

69

72


Others (0.3 %)

Cerebral vasculitis/infarct (0.7 %)

Syncope (1.0 %)

Cerebral convulsion (2.3 %)

Meningoencephalitis (5.7 %)

Febrile convulsion (7.6 %)

Cerebellitis (7.9 %)


11 Figures


Figure 16. ESPED: Symptoms in 52 children with meningoencephalitis and varicella

1

2

4

6

6

9

9

13

13

24

25

31

34

0 10 20 30 40

Eye involvement (1.9 %)Pain (3.8 %)

Comatose state (7.7 %)Other neurological (11.5 %)

Unspecific (11.5 %)Gastrointestinal (17.3 %)

Neurological focal (17.3 %)Convulsion (25.0 %)Headache (25.0 %)

Reduced consciousness (46.2 %)Ataxia (48.1 %)

Feeding problems (59.6 %)Fever (65.4 %)

11 Figures


Figure 17. ESPED: Skin infectious complications in 913 varicella cases

6

9

9

36

51

101


Staph.-SSS (0.7 %)

Cellulitis (1.0 %)

Others (1.0 %)

Abscess (3.9 %)

Phlegmon (5.6 %)

Pyoderma (11.1 %)


11 Figures


Figure 18. ESPED: Microorganisms detected in 108 children with varicella-associated skin infectious complications

020

4060

Num

ber o

f spe

cim

en

Staph.

aureu

s

Strep.

pyog

enes

Enteroc

occu

s ssp

.

Strepto

cocc

us ss

p.

Staphy

lococ

cus s

sp.

others

Strep.

pneu

monia

Staph.

epide

rmidi

s

11 Figures


Figure 19. ESPED: Complications and immunocompromised state in 913 children hospitalised with varicella

1413134 644 751 1385 693 12130 5210 2228 4

0 50 100 150 200 250

Reactive arthritis (0.0 %)Others (12.5 %)

Other systemic bacterial (15.0 %)Coagulation and sequelae (13.7 %)

Haematologic (20.3 %)Upper respiratory tract and ENT (6.5 %)

Lower respiratory tract (11.1 %)Gastrointestinal tract (3.6 %)

Skin (0.9 %)Neurologic (1.7 %)

Percent of immunocompromised children in brackets

68 ( 7.4%) of all children are immunocompromised

Not immunocompromisedImmunocompromised

11 Figures


Figure 20. ESPED: Distribution of 244 children with HZ by month and year

05

1015

2025

Num

ber o

f chi

ldre

n


Herpes zoster (n=244)

2003 2004

11 Figures


Figure 21. ESPED: Age distribution in 243 children hospitalised with HZ

02

46

810

Per

cent

of c

hild

ren

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17Age in years


Median age 9.1 (IQR:4.9 - 13.1)

Figure 22. ESPED: Interval between start of exanthema and admission in 217 children hospitalised with HZ

020

4060

80N

umbe

r of c

hild

ren

Days afteradmisson

Days before admisson6-3 2-0 0-1 2-3 4-5 6-7 8-14 15-21

Start of exanthemaIQR: Interquartile range=25. - 75. Quartile


11 Figures


Figure 23. ESPED: Relation of age at primary VZV infection and eruption of herpes zoster rash in 74 children with known time of primary infection (distribution plot)

05

1015

Yea

rs a

fter p

rimar

y in

fect

ion

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -12Age at primary infection

11 Figures


Figure 24. ESPED: Hospital stay of 242 children hospitalised with HZ

010

2030

40P

erce

nt o

f chi

ldre

n

1-3 4-7 8-14 15-21 22-36Days in hospital


Median 7 Tage (IQR: 5 -10)

Figure 25. ESPED: Symptoms in 233 children hospitalised with HZ

1

1

3

5

5

8

11

13

17

20

32

32

37

85

104


Affection of a joint (0.4 %)Comatose state (0.4 %)

Upper respiratory infection (1.3 %)Convulsion (2.1 %)

Reduced consciousness (2.1 %)Ataxia (3.4 %)

Unspecific (4.7 %)Other neurological (5.6 %)Neurological focal (7.3 %)

Gastrointestinal (8.6 %)Eye involvement (13.7 %)

Headache (13.7 %)Feeding problems (15.9 %)

Fever (36.5 %)Pain (44.6 %)

11 Figures


Figure 26. ESPED: Symptoms and median age in 232 children hospitalised with HZ (x= 25th and 75th percentile)

0 5 10 15 20Age in years

Affection of a jointUnspecificHeadache

Other neurologicalGastrointestinal

PainReduced consciousness

Neurological focalUpper respiratory infection

AtaxiaEye involvement

FeverFeeding problems

ConvulsionComatose state

Figure 27. ESPED: Symptoms and hospital stay in 224 children hospitalised with herpes zoster (x= 25th and 75th percentile)

0 5 10 15 20Days in hospital

AtaxiaOther neurologicalAffection of a jointNeurological focal

Reduced consciousnessUpper respiratory infection

UnspecificHeadache

ConvulsionComatose stateGastrointestinal

Eye involvementFever

Feeding problemsPain

11 Figures


Figure 28. ESPED: Distribution of dermatomes affected in 226 children hospitalised with HZ

43%

32%

12%

5%4%4%

thoracal trigeminal lumbal/sacralothers generalised (Skin) cervical

11 Figures


Figure 29. ESPED: Complications in 243 children hospitalised with HZ

4

5

5

8

9

11

12

22

29

42

0 10 20 30 40

Other neurologic (1.6 %)

Pneumonia (2.1 %)


Others (3.3 %)

Generalised herpes zoster (Skin) (3.7 %)

Ramsay Hunt (4.5 %)

Zoster oticus (4.9 %)

Meningoencephalitis (9.1 %)

Ophthalmic zoster (11.9 %)

Skin (17.3 %)


Figure 30. ESPED: Median age, and complication category and underlying chronic disease in 242 children hospitalised with HZ (x= 25th and 75th percentile)

0 5 10 15Age in years

ImmunocompromisedNoneOther

Atopic dermatitis

MeningoencephalitisOther neurologic

Upper respiratory tract and ENTRamsay HuntZoster oticus

No specific complication recorded (HZ)Pneumonia

OthersOphthalmic zoster

SkinGeneralised herpes zoster (Skin)

11 Figures


Figure 31. ESPED: Median hospital stay, and complication category and underlying chronic disease in 241 children hospitalised with HZ (x= 25th and 75th percentile)

0 5 10 15 20Days in hospital

ImmunocompromisedAtopic dermatitis

OtherNone

MeningoencephalitisRamsay HuntZoster oticus

PneumoniaOphthalmic zoster

Generalised herpes zoster (Skin)Others

SkinUpper respiratory tract and ENT

No specific complication recorded (HZ)Other neurologic

Figure 32. ESPED: Complications and immunocompromised state in 243 children hospitalised with HZ

44 155 34 510 111 120 226 335 7

0 10 20 30 40

Other neurologic (0.0 %)Pneumonia (20.0 %)

Upper respiratory tract and ENT (0.0 %)Others (37.5 %)

Generalised herpes zoster (Skin) (55.6 %)Ramsay Hunt (9.1 %)Zoster oticus (8.3 %)

Meningoencephalitis (9.1 %)Ophthalmic zoster (10.3 %)

Skin (16.7 %)

Percent of immunocompromised children in brackets

78 (32.0%) of all children are immunocompromisedand 19 (16.5%) of all children with specific complication

Not immunocompromisedImmunocompromised

11 Figures


Figure 33. EURODIAB: Age distribution in 107 children hospitalised with varicella

05

1015

20P

erce

nt o

f chi

ldre

n

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17Age in Years

IQR: Interquartile range=25th - 75th quartile

Median age 3.6 years [IQR:1.8 - 5.1]

Figure 34. EURODIAB: Duration of hospitalisation in 107 children hospitalised with varicella

11 Figures


010

2030

4050

Per

cent

of c

hild

ren

1-3 4-7 8-14 15-21Days hospitalised


Median 6 days [IQR: 3 - 8]

11 Figures


Figure 35. ICD10 PILOT STUDY: Results of medical chart review

81 6 8 5

67 33

100

78 17 6

85 53 8

0 20 40 60 80 100Percent

All hospitals (n=78)

K (n=15)

J (n=5)

I (n=18)

H (n=40)

correct uncertainno medical record available false

Child admitted for VZV-infection

Figure 36. ICD10 PILOT STUDY: Age distribution of 105 children hospitalised with varicella

05

1015

Per

cent

of c

hild

ren

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16Age in Years



11 Figures


Figure 37. ICD10 PILOT STUDY: Duration of hospitalisation in 105 children hospitalised with varicella

010

2030

4050

Per

cent

of c

hild

ren

1-3 4-7 8-14 15-21 22-66Days hospitalised



11 Figures


Figure 38. ICD10 PILOT STUDY: Complications in 105 children hospitalised with varicella

Others (4%)

Hematological (5%)

Lower respiratory tract (10%)

Respiratory tract/ENT (14%)

Skin infections (17%)

Neurological (19%)

Gastrointestinal (32%)


Multiple nominations possible

11 Figures


Figure 39. ICD10 STUDY: Distribution of 728 children hospitalised with varicella by month and year

020

4060

8010

012

0N

umbe

r of c

hild

ren


Varicella (n=728)

2003 2004

11 Figures


Figure 40. ICD10 STUDY: Age distribution of 728 children hospitalised with varicella

05

1015

20P

erce

nt o

f chi

ldre

n

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17Age in years


Median age 3 (IQR: 1 - 5)

11 Figures


Figure 41. ICD10 STUDY: Distribution of 83 children hospitalised with HZ by month and year

05

1015

Num

ber o

f chi

ldre

n


Herpes zoster (n=83)

2003 2004

11 Figures


Figure 42. ICD10 STUDY: Age distribution of 83 children hospitalised with HZ

05

1015

Per

cent

of c

hild

ren

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17Age in years



Figure 43. Age distribution of ESPED (n=918) and EURODIAB (n=107) varicella cases

05

1015

20P

erce

nt o

f chi

ldre

n

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10-11-12-13-14-15-16-17Age in years


Median age 3.3 (IQR:1.4 - 5.2)

05

1015

20P

erce

nt o

f chi

ldre

n

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10-11-12-13-14-15-16-17Age in Years



ESPED EURODIAB

11 Figures


Figure 44. Hospital stay of ESPED (n=918) and EURODIAB (n=107) varicella cases

010

2030

4050

Per

cent

of c

hild

ren

1-3 4-7 8-14 15-21 22-199Days in hospital



010

2030

4050

Per

cent

of c

hild

ren

1-3 4-7 8-14 15-21Days hospitalised



Figure 45. Chronic disease status of ESPED (n=918) and EURODIAB (n=107) varicella cases

020

4060

80P

erce

nt o

f chi

ldre

n

NoneAtopic dermatitis

ImmunocompromisedOther

020

4060

80P

erce

nt o

f chi

ldre

n

No chronic diseaseAtopic dermatitis

Immune compromisedOther chronic disease

ESPED EURODIAB

ESPED EURODIAB

11 Figures


Figure 46. Age distribution of ESPED (n=918) and ICD10 STUDY (n=728) varicella cases 0

510

1520

Per

cent

of c

hild

ren

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10-11-12-13-14-15-16-17Age in years


Median age 3.3 (IQR:1.4 - 5.2)

05

1015

20P

erce

nt o

f chi

ldre

n

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10-11-12-13-14-15-16-17Age in years



Figure 47. Hospital stay of ESPED (n=918) and ICD10 STUDY (n=728)varicella cases

010

2030

40P

erce

nt o

f chi

ldre

n

1-3 4-7 8-14 >14 daysDays in hospital



010

2030

40P

erce

nt o

f chi

ldre

n




ESPED ICD10 STUDY

ESPED ICD10 STUDY

11 Figures


Figure 48. Chronic disease status of ESPED (n=918) and ICD10 STUDY (n=728)varicella cases

020

4060

80P

erce

nt o

f chi

ldre

n



020

4060

80P

erce

nt o

f chi

ldre

nnone

atopic dermatitisimmunocompromised

others

ESPED ICD10 STUDY

11 Figures


Figure 49. Complications of varicella patients in ESPED (n=918)and ICD10 STUDY (n=728)

14

24

40

51

64

92

108

137

212

232


Reactive arthritis (1.5 %)

Others (2.6 %)

Other systemic bacterial (4.4 %)

Coagulation and sequelae (5.6 %)

Haematologic (7.0 %)


Lower respiratory tract (11.8 %)

Gastrointestinal tract (15.0 %)

Skin (23.2 %)

Neurologic (25.4 %)


5891517

398794

123139

201


Reactive arthritis (0.7)Co-infection (1.1)

Haematologic (1.2)Other systemic bacterial (2.1)

Coagulation and sequelae (2.3)Others (5.4)

Lower respiratory tract (12.0)Skin (12.9)

Upper respiratory tract and ENT (16.9)Neurologic (19.1)

Gastrointestinal tract (27.6)


ESPED

ICD10 STUDY

11 Figures


Figure 50. Age distribution of herpes zoster patients in ESPED (n=244) and ICD10 STUDY (n=83)

05

1015

Per

cent

of c

hild

ren

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10-11-12-13-14-15-16-17Age in years


Median age 9.1 (IQR:4.9 - 13.1)

05

1015

Per

cent

of c

hild

ren

0-1 -2 -3 -4 -5 -6 -7 -8 -9 -10-11-12-13-14-15-16-17Age in years



Figure 51. Hospital stay in ESPED (n=244) and ICD10 STUDY (n=83) herpes zoster patients

010

2030

4050

Per

cent

of c

hild

ren



Median 7 days (IQR: 5 -10)

010

2030

4050

Per

cent

of c

hild

ren




ESPED ICD10 STUDY

ESPED ICD10 STUDY

11 Figures


Figure 52. Chronic disease status of herpes zoster patients in ESPED (n=244) and ICD10 STUDY (n=83)

020

4060

80P

erce

nt o

f chi

ldre

n



020

4060

80P

erce

nt o

f chi

ldre

nnone

atopic dermatitisimmunocompromised

others

ESPED ICD10 STUDY

11 Figures


Figure 53. Complications of herpes zoster patients in ESPED (n=243) and ICD10 STUDY (n=83)

455

891112

2229

42

0 10 20 30 40

Other neurologic (1.6 %)Pneumonia (2.1 %)

Upper respiratory tract and ENT (2.1 %)Others (3.3 %)

Generalised herpes zoster (Skin) (3.7 %)Ramsay Hunt (4.5 %)Zoster oticus (4.9 %)

Meningoencephalitis (9.1 %)Zoster ophthalmicus (11.9 %)

Skin (17.3 %)


233

66

99

1010

1116

0 5 10 15Number of children

Haematologic (2.4)Generalised (3.6)

Other systemic bacterial (3.6)Lower respiratory tract (7.2)

Meningoencephalitis (7.2)Other neurologic (10.8)

Skin (10.8)Others (12.0)

Upper respiratory tract and ENT (12.0)Gastrointestinal tract (13.3)Zoster ophthalmicus (19.3)


ESPED

ICD10 STUDY

11 Figures


Figure 54. Number of varicella reports in NRW from ESPED and EURODIAB in 2003/2004

11 Figures


Figure 55. Number of varicella reports in NRW from ESPED, EURODIAB, and ICD10 STUDY in 2003/2004

11 Figures


Figure 56. Number of herpes zoster reports in NRW from ESPED and EURODIAB in 2003/2004

11 Figures


Figure 57. Number of herpes zoster reports in NRW from ESPED, EURODIAB, and ICD10 STUDY in 2003/2004

11 Figures


Figure 58. Expected number of varicella cases in children <= 16 years in different German studies

ESPED 03/04 (Capture-Recapture)

ESPED 97ESPED 03/04

EVITA 00

Statistisches Bundesamt (GER)

010

0020

0030

0040

00

Number ofexpected cases

German studies Other studiesESPED 03/04 95% CI

12 Financial disclosure


12 Financial disclosure

The study was supported by an unrestricted financial grant from GlaxoSmithKline Biologicals

(Rixenart, Belgium), GlaxoSmithKline GmbH & Co.KG (Munich, Germany) and Sanofi Pasteur

MSD GmbH (Leimen, Germany). Funding included the positions of one full-time epidemiologist

(Dr. Veit Grote) for 39 months and one half-time epidemiologist for 36 months (position shared

by Dr. Richela Fischer / Eva Rosenfeld). Furthermore, funding included all administrative,

technical and material costs and fees, necessary for ESPED, EURODIAB and ICD-10 data

surveillance. The authors received a financial support for travel expenses for the presentation of

study results at national and international conferences. The sponsors of the study had no decisive

role in study design, data collection, data analysis, data interpretation and writing of the report.

13 Acknowledgment


13 Acknowledgment

♦ We are most grateful to all voluntary and committed physicians of the ESPED STUDY

GROUP (cf. Appendix A ) and of EURODIAB, and all paediatricians and controllers of

the hospitals participating in the ICD10 study (cf. Appendix B ) reporting their patients

and contributing the important clinical information, without whom this study would not

have been possible.

♦ We like to thank Beate Heinrich, secretary of ESPED, for her dedication to ESPED, her

patience and help.

♦ We appreciate the continuous logistical and technical help of Regina Pointner (Dr. von

Haunersches Kinderspital)

♦ We respectfully acknowledge the assistance, support and cooperation of Joachim

Rosenbauer of EURODIAB.

♦ We would like to thank Helmtrud Bisanz, Thomas Breuer, Thomas Verstraeten, Michael

Greenberg and Roland Saenger from GlaxoSmithKline and Sarah Jow, Erika Harzer,

Denise Vetter and Gabrielle Breugelmans from Sanofi Pasteur MSD GmbH and for their

advices, input and support throughout the study.

♦ We especially thank Helmtrud Bisanz for her critical revision of the final study report.

♦ We would also like to acknowledge the contributions through discussions with members

of the Deutsche Vereinigung zur Bekämpfung von Viruskrankheiten (DVV; German

Association for Combating Viral Infections), in particular we like to thank Peter Wutzler.

♦ We also like to thank Bernd H. Belohradsky for his valuable comments and discussions

throughout the study.

Appendix A

Final report – VZV hospitalisations in Germany page A-1

Appendix A The ESPED study group

Following physicians have contributed ESPED reports:

Aalen: Weiß; Leuthe-Vogel; Töpke; Andritschky; Toth - Ahlen: Joachim; Staender; Scholz - Altötting: Huber; Amanatidis; Arjonto; Conen; Schmid - Amberg: Urban; Joppich - Annaberg-Buchholz: Meyer - Apolda: Rieger - Arnsberg: Rey - Arnstadt: May; Stein - Aschaffenburg: Erhardt; Mittermayer; Ohlig - Aschersleben: Salheiser - Aue: Frey; Praedicow - Augsburg: Welzenbach; Schlick; Westphal; Engelmann; Buheitel; Schikor; Fischer; Heidemann; Blichle; Emminger; Flüthorn - Bad Kissingen: Menendez-Castro - Bad Saarow-Pieskow: Sparr - Bad Salzungen: Georgi-Rubner; Leonhardt - Baden-Baden: Pizard-Weyrich - Bamberg: Glöckel; Dachert; Niedermeier; Windschall; Reisig - Bayreuth: Neukirchner; Pohl - Bergen/Rügen: Hirsch; Gesser - Berlin: Stationen 41,44,45; Schunck; Trommler; Fitzner; Seyyedi; Muldenburger; Götte; Dörffel; Lange; Gaedicke; Fitzner; Schöntube; Henning; Thies - Bernau: Stetter - Bernburg: Filz - Bielefeld: Remberg; Scharenberg; Knauss; Josch; Jorch; Janßen; Polster; Ashmas; Reiprich - Bitterfeld: Lübbe - Bocholt: Winter - Bochum: Rothoeft; Lilienthal - Bonn: Franz; Franke - Borna: Möckel - Braunschweig: Marx - Bremen: Simic-Schleicher - Bremerhaven: Kröhn; Renneberg - Böblingen: Teufel - Celle: Kirschstein; Schönfeldt; Wilke - Chemnitz: Wagner; Hofmann; Schröter - Coburg: Schamberger; Salinger; Frank - Cottbus: Stolz; Erler; Möbius; Schneider-Kulle - Damme: Blomer - Darmstadt: Pingel; Matthes; Lettgen - Datteln: Wiesel; Meral; Plumpe; Sousa de; Balci; Trebst; Ertelt; Hornschuh; Andler - Delmenhorst: Steidel - Demmin: Richter; Kritzler - Dessau: Marby - Dinslaken: Carsten - Dresden: Jürgens; Biereder; Böhme - Duisburg: Wangemann; DiMaio; Rech - Düren-Birkesdorf: Eßer; Arpel; Werth - Düsseldorf: Groninger; Erbler; Bernbeck; Weinspach; Wiemann; Schroten; Beltz; Groth; Heusch; Göbel; Rosenbaum; Heinrich; Stannigel; Janßen; Dilloo - Eberswalde-Finow: Miroslau; Seidel - Eckernförde: Lemke; Ott; Gerhardt - Eisenach: Kasper - Eisenhüttenstadt: Darr - Emden: Janssen; Wosnitza - Erfurt: Weinmann; Lemmer; Schulze - Erlangen: Paulides - Essen: Bonzel; Tschiedel; Lin; Wallot; Neudorf; Kömen; Deimling v.; Hauffa; Gartig; Remus; Knauer; Wirth; Vester - Esslingen: Partsch - Frankfurt: Fischer; Latta; Hansen - Frankfurt-Höchst: Schrod; Scheckenbach; Christiansen; Pons - Freiburg i. Br.: Budde; Meng; Forster; Pohl; Brandis; Schwieger; Dorn; Berner - Freudenstadt: Walka; Böse; Halbsguth; Mattes - Fulda: Werner - Gardelegen: Genseke - Garmisch-Partenk.: Schoof; Miller - Geldern: Lammert - Gelnhausen: Schürmann - Gelsenkirchen: Lautner; Wirth - Gera: Natho; Knöll - Giessen: Bremer - Gifhorn: Mutlak - Glauchau: Thiele - Gotha: Greßmann - Greifswald: Wiersbitzky; Bruns - Greiz: Lietz - Göppingen: Frische; Stempfle; Thiele - Göttingen: Rostasy; Bartmus; Brockmann; Withut; Hammersen; Herting - Güstrow: Trapp - Hagen: Schimmel - Hagenow: Mandelkow - Halberstadt: Puhrer - Haldensleben: Knauer-Schiefer - Halle: Brinkmann; Merkel; Wittlinger; Föll; Horneff; Hühn - Hamburg: Akkert; Ullrich; Bentfeld; Baumann; Beutel; Schneider; Hellwege - Hamburg-Rahlstedt: Richter; Zweyrohn; Willig; Püst; Katheika; Brandau; Lepler; Clemen; Weitbrecht; Frank; Peters; Meyer - Hameln: Möller; Tschochner; Schier; Blanckenburg v.; Hedemann; Jänsch; Jeremie - Hannover: Ure; Thon; Offner; Maecher; Müller-Deile; Welte; Hardt v. der; Grigull - Heidelberg: Grulich-Henn; Bär; Springer; Linderkamp; Bosse; Heinrich - Heidenheim: Schweizer; Mourkis; Reininghaus; Haux; Bäuerle; Ertelt; Radike - Heilbronn: Bornschein - Herdecke: Längier; Winkhaus - Hildesheim: Bejo; Balke; Heithorn; Basoglu; Kerstan - Hof/Saale: Schnier; Schikor; Ponader - Homburg/Saar: Shamdeen; Sitzmann - Hoyerswerda: Mothes; Frenzel - Höxter: Klimpel; Wandelt; Storkebaum; Dörfel - Idar-Oberstein: Prellberg; Dummer; Rieger - Iserlohn: Knust - Kaiserslautern: Gutwein - Karlsruhe: Linz; Bauer; Möllmann; Brands; Kühr; Scholten - Kassel: Kassel: Eichholt; Conze; Lenz; Wilken; Kolb; Wright; Keller; Tegtmeyer; Hellwig - Kaufbeuren: Kempf; Rubens - Kempten: Peke; Franke - Kiel: Claaß; Timke; Klöpper; Sieck; Kramer; Ankermann; Stephani - Kirchen: Fischer - Koblenz: Rister; Metzler; Krech; Schlap;

Appendix A

Final report – VZV hospitalisations in Germany page A-2

Schlags - Krefeld: Albach; Schulte-Wissermann; Thiel; Wessel; Fibau; Müller - Köln: Knoop - Köln-Porz: Heesen; Pigulla; Wiater; Ecken - Königs Wusterhausen: Weiss - Landau/Pfalz: Pelzer; Bensch - Landsberg am Lech: Oliver Wiese - Leer: Hertel - Leipzig: Richter; Bernhard; Vetterlein; Künzel; Liedemann; Lenk; Scholz; Struss; Schille; Reich; Borte; Hügle; Scholbach; Bierbach; Keller - Leisnig: Liebscher - Leverkusen: Durmaz; Breitenbach; Podlinski; Groneck; Meister; Werthenbach - Lingen: Bosse - Lippstadt: Uhlig - Ludwigsburg: Brand; Kunisch - Ludwigshafen: Dominick; Ponstingl; Klius - Ludwigslust: Wässer - Lutherst. Wittenberg: Kändler - Lörrach: Henzler-LeBoulanger; Hassan - Lübben: Stefspal - Lübeck: Dommer; Schlutz; Hinüber v.; Bucsky; Wagner - Lüdenscheid: Weber - Lüneburg: Kietzell - Magdeburg: Mittler; Mohnike; Wiemann; Aumann; Gleißner - Mainz: Fersterer; Miebach; Mani; Sonnenschein; Uni-Kinderklinik; Wolf; Wenzel; Kamin; Wendt; Fabian; Russo - Mannheim: Warnecke; Witsch; Waag - Marburg: Sprang; Bergmann; Schäfer; Jüttner; Berwanger; Schaller-Bahs; Kömhoff; Seyberth; Sassen - Mechernich: Ramolla; Hellmann-Mersch - Meißen: Drubig - Meppen: Peters - Merseburg: Schobeß; Beier - Minden: Eisberg - Moers: Pistor; Stiegler; Poss - Mönchengladbach: Kern - Munich: Stojanov; Glöckner-Pagel; Pfünder; Schmid; Broekaert; Härtle; Kumlien; Graubner; Walter v.; Dincer; Müller; Brunnhölzl; Genzel; Schwarz; Bidlingmaier; Baethmann; De Negri; Warncke; Benz; Landgraf; Nicolai; Gehrmann; Bufler - Münster: Hartmanis; Böswald; Marquardt; Ritter; Reich; Flotmann; Tebbe; Schuster; Krins; Denecke; Schmidt; Kurlemann - Naumburg: Leich - Nebel/Amrum: Paul - Neubrandenburg: Liskewitsch; Kinder; Feickert; Manzke - Neuburg / Donau: Stenzel; Richter - Neumünster: Seitz - Neunkirchen/Saar: Schofer; Brassel; Schäfer; Hüttel; Hüttel; Burgard; Mischo; Feldmann-Ulrich; Mitsinga - Neuruppin: Lutz-Dettinger - Neuss: Mampe; Kühl - Neustadt a. Rbg.: Arens; Barthauer - Neuwied: Fremerey - Nordhausen: Hempel - Nordhorn: Hewing; Bongartz; Pfefferkorn - Nürnberg: Schwarzer; Hinrichs; Horn; Schwager; Engelhardt; Schmidt; Joachim; Scheurlen; Rühl; Jennewein; Schneiderbanger - Offenburg: Hoffmann - Oldenburg: Schulze-Becking; Harding - Osnabrück: Barkmeyer; Edentfeld - Paderborn: Jost; Dohle; Storm - Papenburg: Erdmann - Parchim: Linke - Pasewalk: Brechlin - Passau: Staudt; Böcking; Baumgartner - Perleberg: Ruschke - Pforzheim: Rastetter; Reiter; Müller - Plauen: Schilbach; Raisen v.; Quietzsch - Potsdam: Dohmen; Westhues; Behl - Prenzlau: Boldis - Rathenow: Steddin - Ravensburg: Ferrari; König; Krämer - Regensburg: Segerer - Remscheid: Vorbeck - Rendsburg: Steiner - Reutlingen: Trefz; Beck; Dieterle; Schmidke; Freudenberg - Rheine: Wiemann; Schäper; Hoffmann; Heermann; Marx - Rodewisch/Vogtl.: Baumann - Rostock: Walther; Neubauer; Willers - Rotenburg: Hahn - Rüdersdorf: Schultz - Saalfeld: Maak - Saarbrücken: Möller; Fricke; Ihlmann - Saarlouis: Tzonos; Orth - Salzgitter: Metze - Salzwedel: Schellenberg - Sankt Augustin: Bartmann; Herrmann; Deimling v. - Schleswig: Brandis - Schweinfurt: Giesen - Schwelm: Grossmann - Schwäbisch Gmünd: Koch; Schädel - Siegen: Leuthold; Turian; Burghard - Singen: Trechow - Speyer: Zinn; Steiner - Starnberg: Hollunder; Förster; Tratzmüller - Stolberg: Hundemeer - Stuttgart: Wörle; Cegla - Suhl: Graf; Pietzak-Büttner - Trier: Lussem; Rauh; Stolzis - Tübingen: Wolff; Eyrich; Rebmann; Binder - Uelzen: Hebestreit; Kapp - Vechta: Scheppokat; Ahrens; Scholz-Jordan; Casper; Papke; Franzke; Steinborn; Mayer - Villingen-Schwenning: Schwanz - Waiblingen: Kratz; Strotbeck; Bernbeck - Waren/Müritz: Flägel - Weiden i.d. Opf.: Unterreithmeier; Schreyer; Lachmann; Schuwirth - Weimar: Köhler - Weißenfels: Knopp - Wermsdorf: Boudriot - Wesel: Berdel; Kardorff - Wiesbaden: Weitzel; Beron - Wilhelmshaven: Kusbohm; Meyer - Wismar: Koepp - Wittlich: Kriewitz - Wolfsburg: Langelittig - Worms: Teßmer; Kummer-Schwarz; Skopnik; Ogul - Wuppertal: Kerkhoffs; Studnitz v. - Würzburg: Kreth; Wirbelauer; Hebestreit; Doerck - Zittau: Verbeek.

Appendix B

Final report – VZV hospitalisations in Germany page B-1

Appendix B Paediatricians and paediatric hospitals participating in the ICD10 PILOT STUDY and ICD10 NRW 2003-2004 STUDY

Dr. Häusler, Universitätsklinikum der RWTH, Aachen; Dr. Krüger, St.Franziskus-Hospital, Ahlen; Dr. Rey, Karolinen-Hospital, Arnsberg; Dr. von Andrian, Kinderklinik Klinikum Augsburg, Augsburg; Prof. Dr. Otte, Evangel. Krankenhaus Bielefeld, Bielefeld; Dr. Winter, St. Agnes-Hospital, Bocholt; Prof. Dr. Rieger, Univ.-Kinderklinik, Bochum; Prof. Dr. Lentze, Univ.-Kinderklinik, Bonn; Dr. Buderus, St.Marien-Hospital, Bonn; Dr. Günther, Marienhospital , Bottrop; Dr. Gerleve, St.-Vincenz-Hospital, Coesfeld; Prof. Dr. Andler, Vestische Kinderklinik, Datteln; Dr. Kluitmann, St.-Vinzenz-Hospital, Dinslaken; Prof. Dr. Wagner, Klinikum Dortmund gGmbH, Dortmund; PD Dr. Trotter, Klinikum Duisburg, Duisburg; Dr. Keller-Röttger, Krankenhaus Düren, Düren; Prof. Dr. Mayatepek, Univ.-Kinderklinik, Düsseldorf; PD Dr. Frhr. von Lilien-Waldau, Diakoniewerk Kaiserswerth, Düsseldorf; Prof. Dr. Schweitzer-Krantz, Evang. Krankenhaus, Düsseldorf; Dr. Dreher, St.Clemens-Hospital, Geldern; Dr. Evers, Marienhospital, Gelsenkirchen; Dr. Pretel, Kreiskrankenhaus, Gummersbach; Dr. Tautz, Gemeinschaftskrankenhaus, Herdecke; Dr. Klimpel, St.-Ansgar-Hospital, Höxter; Dr. Rübo, St.-Antonius-Hospital, Kleve; Prof. Dr. Weiß, Städt. Krankenhaus Riehl, Köln; Dr. Wiater, Krankenhaus Porz, Köln-Porz; Prof. Dr. Groneck, Klinikum Leverkusen, Leverkusen; Dr. Uhlig, Evang. Krankenhaus, Lippstadt; Dr. Schriever, Kreiskrankenhaus, Mechernich; Prof. Dr. Kölfen, Elisabeth-Krankenhaus, Mönchengladbach; Herr Antonic, Kinderklinik Dritter Orden, München; Herr Raisinger, Städt. Krankenhaus München-Harlaching, München; Herr Huith, Dr. von Haunersches Kinderspital, LMU, München; Prof. Dr. Harms, Univ.-Kinderklinik, Münster; Dr. Uekötter, Clemenshospital, Münster; Dr. Böswald, St.-Franziskus-Hospital, Münster; Prof. Dr. Kühl, Lukaskrankenhaus, Neuss; Dr. Ibach, Sana-Klinikum Remscheid, Remscheid; Dr. Hoffmann, Mathias-Spital, Rheine; Dr. Soditt, Städt. Krankenhaus, Solingen; PD Dr. Kentrup, Bethlehem-Krankenhaus, Stolberg; Dr. El Hamid, Kreiskrankenhaus, Waldbröl; Prof. Dr. Berdel, Marienhospital, Wesel; Prof. Dr. Wirth, Helios-Klinikum Barmen, Wuppertal.

Appendix C

Final report – VZV hospitalisations in Germany page C-1

Appendix C ICD10 codes and complication categories

Following ICD10 codes have been classified into respective complication categories (ICD10 codes partially abbreviated to 5 characters, ICD10 text abbreviated to 80 characters):

1 Neurologic complications

A39.0 /* Meningitis durch Meningokokken */ A86 /* Virale Meningoenzephalitis */ A87.8 /* Meningitis durch Arboviren */ G00.9 /* Bakterielle Meningitis a.n.k. */ G02.0 /* Meningitis bei anderenorts klassifizierten Viruskrankheiten */ G03.9 /* Basalmeningitis */ G04.9 /* Chronisch-entzündlicher ZNS-Prozeß */ G05.1 /* Enzephalitis, Myelitis und Enzephalomyelitis bei anderenorts klassifizierten Vir */ G08 /* Eitrige intrakranielle Phlebitis des Venensinus */ G11.1 /* Früh beginnende zerebellare Ataxie */ G11.2 /* Spät beginnende zerebellare Ataxie */ G25.3 /* Myoklonus */ G44.2 /* Migränoide Spannungskopfschmerzen */ G51.0 /* Fazialisparese */ H47.0 /* Optikopathie durch Alkohol */ H49.0 /* Lähmung des Nervus oculomotorius [III. Hirnnerv] */ H49.2 /* Lähmung des Nervus abducens [VI. Hirnnerv] */ I95.0 /* Idiopathische Hypotonie */ I95.1 /* Orthostatische Hypotonie */ R26.0 /* Ataktischer Gang */ R27.0 /* Ataxie */ R55 /* Sympathikovasaler Anfall */ R56.0 /* Fieberanfall */ R56.8 /* Zerebraler Krampfanfall */

2 Skin

A26.8 /* Disseminiertes Erysipeloid */ A46 /* Gesichtserysipel */ A49.0 /* Infektion durch Staphylokokken a.n.k. */ H05.0 /* Akute Orbitaentzündung */ H60.0 /* Gehörgangsfurunkel */ K61.2 /* Anorektaler Abszeß */ L01.0 /* Impetigo contagiosa */ L01.1 /* Sekundäre Impetiginisation einer Dermatose */ L02.0 /* Hautabszeß des Gesichts */ L02.1 /* Nackenfurunkel */ L02.2 /* Brustdrüsenfurunkel */ L02.3 /* Steißbeinabszeß */ L02.4 /* Armabszeß */ L02.8 /* Kopfabszeß */ L02.9 /* Karbunkel */ L03.0 /* Phlegmone an Fingern und Zehen */ L03.01 /* Paronychie */ L03.1 /* Phlegmone an sonstigen Teilen der Extremitäten */

Appendix C


L03.2 /* Gesichtsphlegmone */ L03.3 /* Rumpfphlegmone */ L03.8 /* Kopfhautphlegmone */ L03.9 /* Akute Phlegmone */ L08.0 /* Pyodermie a.n.k. */ L08.8 /* Perifollikulitis */ L08.9 /* Unterhautinfektion */ L22 /* Windeldermatitis */ L30.3 /* Ekzematoide Dermatitis */ N48.1 /* Gangränöse Balanitis */ N76.4 /* Vulvakarbunkel */ R02 /* Beingangrän */

3 Lower respiratory tract

B01.3 /* Varizellenpneumonie */ J12.9 /* Viruspneumonie */ J15.7 /* Pneumonie durch Mycoplasma pneumoniae */ J15.8 /* Sonstige bakterielle Pneumonie */ J15.9 /* Bakterielle Pneumonie */ J17.1 /* Pneumonie bei anderenorts klassifizierten Viruskrankheiten */ J18.0 /* Bronchopulmonale Infektion */ J18.1 /* Fibrinöse Pneumonie */ J18.8 /* Segmentpneumonie */ J18.9 /* Hämorrhagische Lungenentzündung */ J20.5 /* Akute Bronchitis durch Respiratory-Syncytial-Viren [RS-Viren] */ J20.9 /* Akute Laryngotracheobronchitis */ J21.0 /* Akute Bronchiolitis durch Respiratory-Syncytial-Viren [RS-Viren] */ J21.9 /* Akute Bronchiolitis */ J22 /* Fieberhafte Infektion der Luftwege */ J40 /* Superinfizierte spastische Bronchitis */ J44.0 /* Chronische asthmatische Bronchitis mit akuter Infektion der unteren Atemwege */ J46 /* Status asthmaticus */ J80 /* Adult respiratory distress syndrome [ARDS] */ J90 /* Bakterielle Pleuritis exsudativa */ J93.9 /* Pneumothorax */

4 Haematologic

D59.9 /* Akute hämolytische Anämie */ D69.5 /* Sekundäre Thrombozytopenie */ D69.6 /* Thrombozytopenie, nicht näher bezeichnet */

5 Others

A60.0 /* Vaginitis durch Herpesviren */ B99 /* Infektionskrankheit */ D43.4 /* Unsichere Neubildung des Rückenmarks */ D61.1 /* Arzneimittelinduzierte aplastische Anämie */ G47.0 /* Hyposomnie */ H04.5 /* Tränensackhydrops */ H33.2 /* Seröse Netzhautablösung */ I88.0 /* Unspezifische mesenteriale Lymphadenitis */

Appendix C


L04.2 /* Akute Lymphadenitis der oberen Extremität */ M25.4 /* Gelenkerguß */ M79.9 /* Krankheit des Weichteilgewebes, nicht näher bezeichnet */ N00.4 /* Akutes nephritisches Syndrom mit diffuser endokapillär-proliferativer Glomerulon */ N10 /* Akute tubulointerstitielle Nephritis */ N32.8 /* Blasenfibrose */ N39.0 /* HWI */ N76.0 /* Akute Kolpitis */ N76.2 /* Akute Vulvitis */ N77.1 /* Vaginitis, Vulvitis oder Vulvovaginitis bei anderenorts klassifizierten infektiö */ P92.2 /* Trinkunlust beim Neugeborenen */ R33 /* Harnsperre */ R65.0 /* FALSCH */ T45.0 /* Vergiftung durch Antiallergika */ T47.7 /* Vergiftung durch Emetika */ T50.9 /* Tablettenintoxikation */

6 Upper respiratory tract, ENT and eye

A38 /* Scharlach */ B30.8 /* Newcastle-Keratokonjunktivitis */ H01.0 /* Chronische Blepharitis */ H10 /* Konjunktivitis */ H10.0 /* Mukopurulente Konjunktivitis */ H10.2 /* Konjunktivitis durch chemisch-physikalische Einflüsse */ H10.5 /* Blepharokonjunktivitis */ H10.8 /* Bakterielle Bindehautentzündung */ H10.9 /* Ophthalmie */ H11.8 /* Bindehautschwellung */ H20.0 /* Fibrinöse Iritis */ H20.9 /* Keratoiritis */ H30.0 /* Zentrale Uveitis posterior */ H35.0 /* Retinopathie Augenhintergrund und Veränderung Netzhautgefäße */ H60.9 /* Gehörgangsentzündung */ H65.0 /* Akute seröse Otitis media */ H65.1 /* Akute exsudative Otitis media */ H65.9 /* Nichteitrige Otitis media */ H66.0 /* Akute eitrige Otitis media */ H66.4 /* Pyotympanon */ H66.9 /* Perforierte Otitis media */ I88.9 /* Lymphadenitis */ I89.1 /* Lymphangitis */ J00 /* Epipharyngitis */ J01.0 /* Sinusitis maxillaris akut */ J02.8 /* Pharyngitis durch Staphylokokken */ J02.9 /* Akute Pharyngitis */ J03.8 /* Akute Angina */ J03.9 /* Zungengrundangina */ J04.2 /* Laryngotracheitis */ J05.0 /* Croup - s.a. Laryngitis, obstruktiv,akut */ J06.8 /* Akute Sinupharyngitis */ J06.9 /* Husten bei grippalem Infekt */

Appendix C


J35.0 /* Chronische Tonsillitis */ J35.2 /* Adenoide Wucherung */ J39.1 /* Pharynxabszeß */ L04.0 /* Halsdrüsenentzündung */ L04.9 /* akute Lymphangitis onA */ M43.6 /* Tortikollis */

7 Gastrointestinal tract

A02.0 /* Enteritis durch Salmonellen */ A08.0 /* Enteritis durch Rotaviren */ A08.3 /* Diarrhoe durch Enteroviren */ A08.4 /* Virusenteritis */ A09 /* Akute Enterokolitis */ B00.2 /* Pharyngotonsillitis herpetica */ B00.8 /* Ösophagitis bei Herpes */ E86 /* Anhydrämie */ K12.0 /* Orale rezidivierende Aphthen */ K12.1 /* Stomatitis ulcerosa */ K35.1 /* Akute Appendizitis mit Peritonealabszeß */ K35.9 /* Akute Appendizitis */ K52.9 /* Chronische Gastroenteritis */ K59.0 /* Obstipation */

8 Reactive arthritis

M02.9 /* Reaktive Arthritis, nicht näher bezeichnet */ M13.9 /* Arthritis, nicht näher bezeichnet */ M13.1 /* Monarthritis, anderenorts nicht klassifiziert */ M02.8 /* Sonstige reaktive Arthritiden */

9 Coagulation and sequelae

D69.0 /* Purpura und sonstige hämorrhagische Diathesen */ D69.3 /* Idiopathische thrombozytopenische Purpura */ K62.5 /* Analhämorrhagie */ K92.0 /* Hämatemesis */ K92.1 /* Meläna */ K92.2 /* Darmblutung */ R23.3 /* Spontane Ekchymose */ D65 /* Disseminierte intravasale Gerinnung */ I80.2 /* Tiefe Venenthrombose */

10 Other systemic bacterial

A39.4 /* Sepsis durch Meningokokken */ A40.0 /* Sepsis durch Streptokokken Gruppe A */ A41.0 /* Sepsis durch Staphylococcus aureus */ A41.2 /* Sepsis durch Staphylokokken */ A41.5 /* Sepsis durch gramnegative Erreger */ A41.8 /* Sonstige näher bezeichnete Sepsis */ A41.9 /* Pyämie */ M00.9 /* Eitrige Arthritis, nicht näher bezeichnet */ M60.0 /* Infektiöse Myositis */

Appendix C


M71.1 /* Sonstige infektiöse Bursitis (Fussballenentzündung) */ M72.5 /* Fasziitis, anderenorts nicht klassifiziert */ M72.69 /* Nekrotisierende Fasziitis: Nicht näher bezeichnete Lokalisationen */ M86.0 /* Akute hämatogene Osteomyelitis */ M86.1 /* Sonstige akute Osteomyelitis */ M86.9 /* Osteomyelitis, nicht näher bezeichnet */ N45.9 /* Septische Orchitis */

11 Co-infection

A37.0 /* Keuchhusten durch Bordetella pertussis */ A69.2 /* Lyme-Krankheit */ B26.8 /* Mumps */ B27.0 /* Pfeiffer-Drüsenfieber */ B86 /* Skabies */ J11.1 /* Grippe [Influenza] mit Seitenstrangangina */

Final Report 2006 - ESPED · ESPED study group - reporting physicians (cf. Appendix A ) EURODIAB...

Documents

Transcript of Final Report 2006 - ESPED · ESPED study group - reporting physicians (cf. Appendix A ) EURODIAB...