Abstract
Acute rheumatic fever (ARF) is a preventable immune mediated condition triggered in response to Group A Streptococcus (GAS) pharyngitis. Rheumatic heart disease (RHD) can result from a single episode of ARF and is particularly likely to occur following recurrent episodes. RHD is a serious condition which can lead to cardiac failure, stroke and early death. ARF is highly topical in New Zealand (NZ). Despite being almost eradicated from the NZ European population, ARF continues to impose an important and inequitable burden of disease in Māori and Pacific peoples. An ambitious national ARF prevention programme (RFPP) was recently implemented, with the aim of substantially reducing ARF incidence rates. Gaps in knowledge around ARF risk factors and pathogenesis impair the ability to implement prevention and control programmes that effectively reduce the burden of disease, however. Consequently the University of Otago (NZ) has recently started work on an ARF case-control study (‘RFRF study’) which aims to identify potentially modifiable risk factors and shed light into important pathogenic pathways.
This thesis contains four major aims, addressed in four parts (A-D). These aims are:
Aim 1. To assess the population exposure to GAS pharyngitis, its importance as an initiator of ARF, and risk factors for progression to ARF in NZ (addressed in parts B and C);
Aim 2. To assess the likely true incidence of ARF and identify potential risk factors for this disease in NZ (addressed in parts A and D);
Aim 3. To identify factors influencing progression from ARF to RHD (addressed in Part D);
Aim 4. To identify opportunities for reducing the incidence, inequities and impact of ARF in NZ and identify improvements to surveillance, evaluation and research to support these processes (addressed throughout the thesis).
Part A collates existing knowledge of ARF risk factors and systematically describes the epidemiology of ARF in NZ. A wide array of risk factors have been identified in the international literature, albeit fairly inconsistently. Evidence for these risk factors is grouped according to which aspect of the causal pathway it relates to. This work helped identify hypotheses which the RFRF study went on to test in the NZ population. National epidemiological analyses emphasize the dramatic ethnic and socioeconomic inequities in occurrence rates. Highlighting which NZ populations are most affected by ARF has clear indications for RFRF study case recruitment methods.
Part B investigates the role of GAS pharyngitis as the main initiator of ARF. If this was the sole initiator of ARF, then one would expect its distribution to reflect that of ARF (albeit on a much larger scale, as ARF occurs far less frequently than GAS pharyngitis). Part B investigates this hypothesis using a review of the international literature and in-depth analyses to describe the epidemiology of GAS pharyngitis key area of NZ (Auckland). It appears that around half of all children presenting to primary healthcare with sore throat symptoms and a GAS culture-positive (GAS+ve) throat swab actually have GAS pharyngitis (as opposed to GAS carriage with coincidental viral infection). Inequities in the burden of GAS pharyngitis do not reflect the astounding ethnic inequities in the occurrence of ARF. This implies that other factors may play key roles in promoting disease progression to ARF, which Parts C and D explore. These are important lessons to be learnt from the RFPP regarding the refinement of future prevention interventions, particularly around the need to target high-risk children appropriately.
Part C uses linked data to investigate the association between GAS pharyngitis and ARF, with the emphasis on potential interventions that could stop disease progression. GAS+ve pharyngitis is firmly associated with the development of ARF. By contrast, pharyngitis with Group C or Group G Streptococcus is not. The clear association between GAS pharyngitis and ARF further highlights the need for primary prevention strategies to appropriately target high-risk children.
Part D first describes the epidemiology of ARF in NZ with a view to improving national surveillance, and secondly considers ARF through a public health policy and prevention lens, again with an emphasis on lessons from the RFPP. Despite recent surveillance improvements, under-notification of cases and misdiagnoses continue to present problems. A national case register could provide standardised surveillance information and perform critical case management functions. The RFRF study pilot is described here, which showed that poor living conditions very commonly preceded ARF in the study sample. Interventions that improve housing conditions and reduce home crowding have potential to reduce rates of ARF and avert a significant burden of other preventable child morbidity and early death. This approach was not a key strategy of the RFPP, but may be important for future interventions. Disease progression, from initial hospitalisation for ARF through to ARF recurrence, RHD and death, is also explored in Part D. Māori and Pacific ARF cases are especially at risk of these outcomes. This indicates that failures in the delivery of secondary prophylaxis is an issue affecting known ARF cases. Around 65% of recently diagnosed RHD cases had no history of prior hospitalisation for ARF. This indicates that improved approaches to case finding are needed, or that broader approaches to ARF prevention are required.
Major findings of this thesis are that firstly, GAS pharyngitis does appear to be the major initiator of ARF in NZ. Secondly, ARF primary prevention interventions must be appropriately targeted to groups likely to benefit the most, and thirdly, potentially modifiable environmental risk factors may have a key role in promoting GAS pharyngitis and disease progression to ARF. There are two major themes running throughout this doctoral thesis: 1) Lessons learnt from the RFPP, and 2) Preparing for the RFRF study. The ultimate goal of this thesis is to provide high quality evidence to support policies, programmes and practices to reduce rates and inequities in the incidence and impact of ARF in NZ. A number of recommendations for improved ARF control and prevention are made based on findings from this thesis and are supported by international literature.