The Development of Strategies to Reduce Infection-Related Deaths among Immunocompromised Children in England

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Acknowledgement

I would take this opportunity to thank my research supervisor, family and friends for their support and guidance without which this research would not have been possible.

DECLARATION

I, [type your full first names and surname here], declare that the contents of this dissertation/thesis represent my own unaided work, and that the dissertation/thesis has not previously been submitted for academic examination towards any qualification. Furthermore, it represents my own opinions and not necessarily those of the University.

Signed __________________ Date _________________

ABSTRACT

Background. Children with cancer have an increased susceptibility to influenza infection. The objective of this study was to assess the immunogenicity of pandemic (H1N1) 2009 vaccine in children with cancer.

Methods. Children were recruited from the Royal Marsden Hospital, England, during November 2009. The vaccination schedule consisted of 2 doses of an AS03B-adjuvanted vaccine given at days 0 and 21. Serological analysis was performed on blood samples obtained at day 0 and day 42. The primary immunological end point was the seroconversion rate, which was defined as the proportion of subjects with an individual 4-fold increase in hemagglutination inhibition titer and a postvaccination hemagglutination inhibition titer =1:32.

Results. Fifty-four children with a median age of 6.3 years (range, 1.4-16.6 years) were vaccinated and had samples taken for serological analysis. Twenty-four (44.4%) of 54 children demonstrated seroconversion. Seroconversion rates were 33.3% (9 of 27) among children with acute lymphoblastic leukemia, 36.4% (4 of 11) among those with lymphoma or other leukemias, 66.7% (6 of 9) among those with brain tumors, and 71.4% (5 of 7) among those with other solid tumors. Seroconversion occurred in 4 (28.6%) of 14 children receiving acute lymphoblastic leukemia maintenance therapy. Univariate analysis showed significantly higher responses among children with solid tumors, compared with those with hematological malignancies (11 [68.8%] of 16 vs 13 [34.2%] of 38; Pp.03), and among those not receiving treatment, compared with those receiving treatment (7 [87.5%] of 8 vs 17 [37.0%] of 46; Pp.02). Multivariable analysis showed that age, cancer type, and lymphopenia did not influence seroconversion rates.

Conclusion. These data suggest that this AS03B-adjuvanted pandemic (H1N1) 2009 vaccine can induce limited but useful protective immune responses in children with cancer.

Table of Contents

ACKNOWLEDGEMENTII

DECLARATIONIII

ABSTRACTIV

CHAPTER 1: INTRODUCTION1

Pathogenesis1

Cell-Mediated Immunity2

Phagocytes7

Complement8

Aspergillus10

Cytomegalovirus12

CHAPTER 2: LITERATURE REVIEW14

Treatment of respiratory infections in four different immunocompromised situations32

Situation 132

Situation 234

Situation 334

Situation 435

Vaccines: Plain Polysaccharide Versus Protein-Conjugated42

Immune System Deficiencies And Vaccine Recommendations45

Pneumococcal Vaccination46

CHAPTER 3: METHODOLOGY49

Research Design49

Research Method50

Rationale for Methodology50

Overview of Qualitative and Quantitative Research Approaches51

Secondary Data52

Literature Search52

Research Instrument53

Qualitative Data Analysis53

CHAPTER 4: RESULTS57

Vaccine Adverse Events60

Seroconversion Rate by HAI.61

Pre- and Postvaccination GMTs and Fold Increases63

CHAPTER 5: DISCUSSION65

Live Vaccines72

Inactivated Vaccines And Passive Immunization73

Primary Immunodeficiencies73

Solid Organ Transplant Recipients75

HIV Infection78

CHAPTER 6: CONCLUSION82

Dominant Organisms Associated With Infection84

Initial Evaluation Of Fever87

Management Of Infectious Complications88

REFERENCES90

CHAPTER 1: INTRODUCTION

Infections are an important source of morbidity and mortality in the immunocompetent host but immunocompromised patients pose a greater challenge as their susceptibility to infection and poor ability to combat infection puts them at a much greater risk. As increasing numbers of patients with congenital immunodeficiencies are identified, and patients ...