Paediatrics (RCH) - Theses
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ItemThe epidemiology of egg allergy and other IgE-mediated food allergies in infants( 2010)IgE-mediated food allergy often develops early in life and has a major impact on the quality of life of the child and its family. Recent increases in the prevalence of food allergy, which have occurred too rapidly to be explained by genetic factors alone, suggest that environmental factors may play an important role. Potential candidates include maternal and infant diet and infant microbial exposures. However, few studies to date have examined risk factors for food allergies. I investigated the prevalence and risk factors for egg allergy, the most common IgE-mediated food allergy in infants, within the HealthNuts study. HealthNuts is an ongoing population-based cross-sectional study of 12-month-old infants in Melbourne, Australia. As part of the study, parents reported on infant feeding and other environmental exposures. All infants subsequently received a skin prick test for four foods including egg white and those with a wheal size ≥ 1mm underwent an oral food challenge with raw egg white. This thesis includes data from the first 2,600 infants included in the study, which is due to complete recruitment in April 2011. Among infants participating in the HealthNuts study, there was a high prevalence of egg allergy (9.3%, 95% CI 8.2-10.5). There was no evidence that maternal dietary factors were associated with infant egg allergy. Of the infant dietary factors examined, only timing of egg introduction was associated with egg allergy risk. Introduction of cooked egg into the infant diet at 4-6 months of age was associated with a 3-fold decreased risk of egg allergy compared with introduction after 12 months of age. Other infant dietary factors previously suggested to be associated with general allergy risk, namely duration of breastfeeding and age at introduction of first solid foods, were not associated with egg allergy. Factors previously associated with increased microbial exposure, including siblings, childcare and pet ownership, were associated with a reduced risk of egg allergy. There was evidence of a dose-response effect for siblings and egg allergy, with an increasing number of siblings associated with a further reduction in egg allergy: one sibling, OR0.72 (95% CI 0.53-0.97), two siblings OR 0.57 (95% CI 0.35-0.92) and three or more siblings OR 0.47 (95% CI 0.20-1.09). Attending childcare before 7 months of age was associated with a reduced risk of egg allergy compared with never having attended childcare (OR 2.05, 95% CI 0.97-4.35), while there was no evidence of a protective effect of childcare attendance between 7-12 months of age. Having either a cat or dog at home at one year of age was associated with a reduced risk of egg allergy among infants with a history of eczema (OR 0.49, 95% CI 0.31-0.78) but not among those without a history of eczema (OR 1.01, 95% CI 0.62-1.62). My results show that egg allergy is common in infants and suggest several possible risk factors related to infant diet and potentially microbial exposures which may help to explain recent rise in food allergy prevalence. The protective effect of introduction of egg at 4-6 months of age has implications for infant feeding guidelines internationally and, if confirmed, suggests that changes in infant feeding practices could have the potential to reduce the prevalence of egg allergy.
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ItemAlternative pneumococcal vaccination schedules for infants in Fiji and pneumococcal epidemiology( 2010)This thesis documents the pneumococcal disease burden and the results of a Phase II pneumococcal vaccine trial in the low middle income country, Fiji. The overall objective was to gather sufficient evidence for the Fiji Ministry of Health to decide whether to introduce the pneumococcal vaccination into its national schedule and define an appropriate and affordable vaccination strategy. The nasopharynx is the main reservoir for pneumococci and plays an important role in the spread of the organism. Studies of nasopharyngeal carriage offer insights into the pneumococcal disease burden in a community, particularly for potential serotypes which may cause pneumonia, and are a convenient way of determining the level of antibiotic resistance among pneumococcal isolates circulating in a population. The first study, a cross-sectional pneumococcal nasopharyngeal carriage survey of healthy children aged 3-13 months, was undertaken to document the prevalence of pneumococcal nasopharyngeal carriage, risk factors for carriage, serotypes and antimicrobial susceptibility patterns of carried pneumococci in healthy young children in Fiji (Chapter 3). Pneumococcal nasopharyngeal carriage was common in Fijian children. Penicillin resistance was documented for the first time, and, as a result, first-line treatment for meningitis was altered. A low proportion of carriage serotypes were included in the 7-valent pneumococcal conjugate vaccine. Invasive pneumococcal disease is an important cause of morbidity and mortality, particularly in the very young and the elderly. The introduction of the 7-valent pneumococcal conjugate vaccine in the national immunisation schedule in the USA has resulted in an impressive reduction in infant invasive pneumococcal disease. In addition, the vaccine has had a more than expected herd immunity effect on invasive pneumococcal disease in the elderly and other age groups. Chapter 4 reports on a study that aimed to document age-specific burden of invasive pneumococcal disease including clinical syndromes, underlying conditions, serotype distribution, and the potential protection against invasive pneumococcal disease and chest X-ray confirmed pneumonia by 7-valent pneumococcal conjugate vaccine in Fiji. The annual invasive pneumococcal disease incidence was comparable to countries of similar socioeconomic status. Being indigenous Fijian was an independent risk factor for disease. Underlying conditions were common and the case fatality rate was high particularly in the elderly population. For every, 1.930 and 128 infants vaccinated, one death and one case respectively, would be prevented in those <5 years, by introduction of universal immunisation with the 7-valent conjugate vaccine. A Phase II vaccine trial was undertaken to document the safety, immunogenicity and impact on pneumococcal carriage of various pneumococcal vaccination regimens combining one, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine in infancy (Chapters 5 to 10). In order to broaden the serotype coverage, the additional benefit of a booster of 23-valent pneumococcal polysaccharide vaccine at 12 months of age was also assessed. To address the theoretical concerns of hyporesponsiveness to 23-valent pneumococcal polysaccharide vaccine following re-challenge, the immunological responses at 17 months of age to a small challenge dose of 20% of 23-valent pneumococcal polysaccharide vaccine (mPPS) in children who had or had not received the 23-valent pneumococcal polysaccharide vaccine at 12 months of age was undertaken. The immunogenicity following a 2 or 3 dose 7-valent pneumococcal conjugate vaccine primary series was similar for many serotypes. A single 7-valent pneumococcal conjugate vaccine dose would offer protection in the first 12 months of life for many serotypes. The one or 2 dose 7-valent pneumococcal conjugate vaccine schedules induced immunologic memory, with memory responses following 23-valent pneumococcal polysaccharide vaccine being most profound for children who had received only a single dose of 7-valent pneumococcal conjugate vaccine previously, compared with the 2 or 3 dose groups. Following the 23-valent pneumococcal polysaccharide vaccine booster, there were significant responses for all 23 serotypes which persisted for at least 5 months following vaccination. However despite higher antibody concentration at 17 months in children who had received 23-valent pneumococcal polysaccharide vaccine at 12 months, the response to a re-challenge was poor to all 23 serotypes compared to children who did not receive the 12 month 23-valent pneumococcal polysaccharide vaccine. This indicates immunological hyporesponsiveness or non-responsiveness. This effect occurred regardless of pre-mPPS antibody levels and prior 7-valent pneumococcal conjugate vaccine exposure. The addition of 23-valent pneumococcal polysaccharide vaccine at 12 months had no impact on carriage, despite the substantial boosts in antibody levels observed and despite significantly higher opsonophagocytic activity and antibody avidity comparing pre- and post-levels. In summary, a substantial burden of pneumococcal disease in Fiji was found. The 7-valent pneumococcal conjugate vaccine would provide limited coverage of invasive disease compared to its use in affluent countries. Two doses of 7-valent pneumococcal conjugate vaccine have similar immunogenicity as 3 doses although a single dose still provides some protection. The 23-valent polysaccharide vaccine booster was found to be immunogenic but re-challenge resulted in hyporesponsiveness. Further research evaluating the potential of reduced dose schedules using the newer conjugate vaccines with an early conjugate booster would be recommended.