Paediatrics (RCH) - Theses
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ItemEpidemiology of pneumococcal carriage and transmission in Fiji, before and after the introduction of the ten valent pneumococcal conjugate vaccine( 2022)Streptococcus pneumoniae (the pneumococcus) is responsible for substantial global morbidity and mortality in children younger than five years. The burden of pneumococcal disease is highest in low and middle income countries. Nasopharyngeal carriage of pneumococci is common and primarily asymptomatic but is responsible for transmission and precedes pneumococcal disease. There are approximately 100 different pneumococcal serotypes distinguished by the presence and diversity of a polysaccharide capsule. Pneumococcal conjugate vaccines (PCV) protect against the transmission and carriage of common disease-causing serotypes. Differences in the pneumococcal carriage and disease burden by country, ethnicity, age, and social determinants of health have been reported. Little is known about transmission and whether risk factors vary by setting. Understanding the varied epidemiology of pneumococcal carriage risk factors and transmission routes is essential to developing, evaluating, and comparing public health intervention policies, including PCV. This thesis addresses some outstanding questions about pneumococcal carriage risk factors and transmission post-PCV introduction and is set in Fiji. The Fijian Government introduced the ten valent PCV (PCV10) into the Fijian infant immunisation program in October 2012. Before introducing PCV10, the odds of pneumococcal nasopharyngeal carriage were significantly greater among Indigenous (iTaukei) Fijian toddlers aged 3 – 13 months compared with their Fijian of Indian Descent counterparts. Similarly, the risk of developing invasive pneumococcal disease (IPD) was significantly greater among iTaukei than FID. My thesis consists of an Introduction (Chapter 1) and four studies: a systematic review of risk factors for pneumococcal carriage and a summary of pneumococcal carriage rates, stratified by country income classification; an analysis of factors associated with pneumococcal carriage and density in Fiji; an investigation of the social contact, ethnicity, and pneumococcal carriage and density in Fiji; and a comparison of pneumococcal carriage by infant mode of delivery among Fijian infants too young for PCV vaccination. The chapters of my thesis that focus on pneumococcal carriage epidemiology use data obtained from a PCV impact evaluation study. Chapter 2, a systematic review, found that although pneumococcal carriage rates were highest in low income classifications, risk factors for pneumococcal carriage were similar across income classifications. Most risk factors would not be modifiable directly. Rather, public health interventions aimed at mitigating the adverse impact of some social determinants of health would be of benefit. Chapter 2 contributes new information regarding pneumococcal carriage risk factors and proposes variables to consider for collection in future community pneumococcal carriage surveys. PCV reduces vaccine serotype carriage and disease. However, it is essential to contemplate interventions to reduce overall carriage, particularly in some low and middle income countries, where high vaccine type carriage rates may persist or where carriage of non-vaccine serotypes replaces that of vaccine serotypes following PCV introduction. Notably, there was an identified knowledge gap surrounding the impact of PCV on risk factors for pneumococcal carriage in low and middle income countries of the Asia-Pacific region. Chapter 3 describes the risk factors for pneumococcal carriage and density in Fiji, one year pre- and up to three years post-introduction of ten valent PCV (PCV10). This work showed that Indigenous iTaukei (iTaukei) ethnicity, compared with Fijian of Indian Descent (FID), was a key risk factor for pneumococcal carriage despite high PCV10 coverage rates across the groups. Higher median pneumococcal density was associated with upper respiratory tract infection symptoms and young age. The positive association between Indigenous Fijian ethnicity and pneumococcal carriage, coupled with anecdotal observations, led to the hypothesis that differences in pneumococcal carriage between the ethnic groups may be due to differences in social contact. Chapter 4 determined whether there were any differences in the frequency and intensity of social contact between the two main ethnic groups in Fiji; and if any differences in social contact were associated with differences in pneumococcal carriage. This analysis showed that iTaukei had a greater frequency and intensity of social contact than FID. Physical, not conversational, contact was associated with pneumococcal carriage. Ethnicity-based differences in social contact patterns did not explain differences in pneumococcal carriage rates by ethnicity observed in Chapter 3. While contact between and with young children is a risk factor for pneumococcal carriage via horizontal transmission, little is understood about transmission and early onset carriage and disease. Chapter 5 describes and compares pneumococcal carriage and density by infant mode of delivery in Fijian infants too young to be PCV10-vaccinated. Infants born by vaginal delivery had higher pneumococcal carriage prevalence, range of detected serotypes, and odds of pneumococcal carriage than those born by Caesarean section. These findings raise a vertical transmission hypothesis. This PhD fills several pneumococcal carriage knowledge gaps and has implications for future research. It has provided a global summary of hypothesis-generating studies that will be of value for future research into causal relationships between risk factors and carriage of pneumococci. Importantly, my PhD highlights that in addition to using PCVs to control pneumococcal disease, efforts to reduce and control respiratory virus transmission and address social determinants of health are essential. My PhD also shows that catch-up campaigns may be necessary to control vaccine serotypes in higher prevalence settings. In such settings, reducing vaccine serotype transmission may take a long time due to a relative shift in the higher carriage rate of vaccine serotypes to older age groups, resulting in ongoing circulation. The role of a catch-up campaign with PCV introduction needs to be determined, as vaccine serotype transmission may persist for some time with a birth cohort only roll out. Transmission of pneumococci is complex, and host factors also play a role. However, household size is a crucial consideration, as is ensuring infants too young to be vaccinated in low and middle income countries are protected by herd immunity or by an earlier first dose of PCV.
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ItemFiji integrated therapy – safety and efficacy of community control strategies for lymphatic filariasis and scabies in Fiji( 2022)Neglected tropical diseases (NTDs) are a collection of 20 diseases recognised by the World Health Organization (WHO) as causing significant harm to the health, social engagement and economic potential of billions of people living in poverty, predominantly in the tropics. Both lymphatic filariasis (LF) and scabies are NTDs. One effective approach to reduce the burden of NTDs in endemic communities is annual mass drug administration (MDA). This strategy involves providing free medication to all community members regardless of infection status at the same time. Lymphatic filariasis (LF) is a caused by the nematode Wuchereria bancrofti, transmitted between humans by mosquitoes. Chronic complications of LF include irreversible lymphoedema and hydroceles. Lymphatic filariasis remains endemic in areas of Fiji, despite regular annual MDA using diethylcarbamazine and albendazole (DA) since 2000. Experts in the field hypothesised that adding ivermectin to DA would improve the efficacy of the MDA and help accelerate towards the goal of elimination of LF as a public health problem. Scabies is a pruritic rash caused by the microscopic mite Sarcoptes scabiei variety hominis. Secondary bacterial infections from Staphylococcus aureus and Streptococcus pyogenes are common and can lead to local skin infections, sepsis and auto-immune complications including glomerulonephritis and potentially rheumatic fever. Scabies is endemic in Fiji with an estimated national prevalence of scabies of 18%. Scabies can be successfully controlled with two-dose ivermectin-based MDA. Experts in the field have highlighted evaluation of one-dose ivermectin-based MDA as a priority, because if non-inferior to a two-dose schedule it would reduce barriers to implementation of scabies control efforts. The Fiji Integrated Therapy study was initiated to evaluate the impact of MDA with ivermectin, diethylcarbamazine and albendazole, known as IDA, on 2 remote islands within the Eastern Division of Fiji where LF and scabies are co-endemic. Data arising from this cluster randomised controlled study underpins this thesis. There are 3 main components: 1) safety of IDA; 2) efficacy of IDA for LF and 3) evaluation of community control strategies for scabies. The first part of the thesis evaluates the safety of IDA MDA compared to DA. Adverse events were monitored for the first 7 days after treatment. Six hundred (16.7%) participants experienced an adverse event with no difference between treatment groups. Most (93.2%) symptoms were graded as mild with no serious events attributable to treatment. Participants with microfilaremia were more likely to experience an adverse event (43.2% versus 15.7%). The second part of the thesis reports on the efficacy of IDA compared to DA for LF. Contrary to IDA efficacy studies in other countries with different transmission profiles, we found no difference between treatment groups for clearance of microfilaremia 12 months after treatment (DA 69.2% versus IDA 62.5%). There was no difference in community prevalence of LF at 12 months. The possible reasons for this unexpected finding are discussed. The third part of the thesis addresses the effectiveness of different community control strategies for scabies. One-dose ivermectin-based MDA was non-inferior to two-dose ivermectin-based MDA for reduction in community prevalence of scabies at 12 months. Screen and treat with permethrin for individuals with scabies and their household contacts was also non-inferior, however this approach would be labour intensive and expensive and unlikely to be feasible at scale. Overall, IDA MDA was well tolerated and effective in reducing the community prevalence of LF and scabies in endemic communities in Fiji. The lack of benefit by the addition of ivermectin on LF in Fiji needs further exploration in similar transmission settings to understand the possible reasons for this finding. The success of one-dose ivermectin-based MDA for the control of scabies needs further research to determine if it can be replicated in urban and non-island settings. The findings from this thesis have informed LF and scabies control policy within Fiji, the Pacific region, and globally.
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ItemIvermectin-based mass drug administration for the serious bacterial complications of scabies( 2022)Scabies is a skin disease caused by the mite Sarcoptes scabiei var. hominis, which is especially prevalent in populations experiencing overcrowding and poverty. Recognised as a neglected tropical disease by the World Health Organization in 2017, scabies is characterised through skin lesions and intense itch. The host is made vulnerable to secondary bacterial infection through skin breaches, scratching and inhibition of the complement system via mite secretions. Bacterial infection predominantly caused by Staphylococcus aureus and/or Group A Streptococcus most commonly manifesting as impetigo can complicate scabies. Impetigo can progress to more complicated skin and soft tissue infection, invasive bacterial infection and post streptococcal sequelae which cause significant morbidity and mortality. Previous studies in the Pacific Islands, including in Fiji, demonstrated that ivermectin-based mass drug administration substantially reduces scabies prevalence by approximately 90%, and leads to a concomitant reduction in impetigo prevalence by 60% to 70%. The focus of this thesis was to determine if ivermectin-based mass drug administration also leads to a reduction in the more serious bacterial complications of scabies. The studies and intervention described in this thesis take place in Fiji’s Northern Division (population ~131,914 in 2017). Four studies are reported in the thesis. The first study investigated the burden of hospitalisations for skin and soft tissue infections using prospective surveillance at the referral hospital of the Northern Division, and found a very high population incidence of 647 admissions per 100,000 person-years (95% CI 571-660). The second study investigated the burden of invasive infections caused by S. aureus and group A Streptococcus, using prospective surveillance also at the referral hospital, and found a high incidence at 45.2 and 12.3 per 100,000 person-years, respectively. The third study investigated the incidence of primary healthcare presentations for scabies and skin and soft tissue infections using a prospective surveillance system established at all primary healthcare facilities in the Northern Division, and found that there were 13,736 presentations over 50 weeks, equivalent to a population incidence of 108 presentations per 1000 person-years. The final major study investigated the impact of ivermectin-based mass drug administration on the bacterial complications of scabies. Ivermectin-based mass drug administration was deployed across the whole of the Northern Division. Coverage of mass drug administration was high – with the first dose achieving 97% and the second dose 87% coverage. The primary outcome measure was the annual incidence of hospitalisations for skin and soft tissue infections, with the study finding that the incidence declined significantly by 17% in the year after mass drug administration (from 467 to 388 per 100,000, incidence rate ratio 0.83 95% confidence intervals 0.74% to 0.94%). This finding was supported by a reduction in the annual incidence of primary healthcare presentations by 21%, and by a reduction in scabies and impetigo prevalence by 29% and 60% respectively. There was no decrease in the incidence of invasive infections and post streptococcal sequelae. Overall, this thesis demonstrates that scabies control through mass drug administration can lead to a reduction in the incidence of bacterial skin and soft tissue infections, measured as a fall in healthcare utilisation and community prevalence. These results are encouraging and provide further evidence of the broader benefits of scabies control via mass drug administration. In settings where scabies is endemic and where resources are limited and health priorities compete, this thesis highlights the underestimated burden of scabies and strengthens the case for policy targeting control of this neglected tropical disease.