The impact of the 2009 influenza pandemic and other recent epidemics are still being assessed. Appropriate allocation of protection and control strategies depend on accurate estimation of disease burden, with high risk groups generally being a key focus especially for distribution of influenza vaccine to maximize the disease burden prevented per vaccine when resource is limited. Therefore, better understanding the impact of influenza and control of influenza among the high risks groups with greater burden is particularly important. In this thesis, I estimated the years of life lost (YLL) associated with influenza correcting for underlying risk factors in addition to age and provided a new methodology for disease burden estimation of influenza. I focused on three vaccine target groups - healthcare workers (HCWs), cancer patients and obese people - to estimate the influenza impact and control among them using multiple approaches. I applied a new comprehensive method to take into account the shorten life expectancy for influenza deaths with underlying risk factors compared to general population by adding excess hazards of these risk factors in the baseline life tables, finally correcting for 25% overestimation of YLL associated with 2009 pandemic. For vaccine target groups, I analyzed the serum data from a cross-sectional study and found there was no occupation-related excess infection risk for unvaccinated HCWs following the first wave of the 2009 pandemic, supporting the effectiveness of the intensive protection and control strategies in Hong Kong. However, the reasons for the unexpectedly poor immune response observed in this study for HCWs with receipt of the 2009 pandemic influenza vaccine requires further exploration. In a large elderly cohort study with follow-up period of 1998-2012, I identified substantial impact of influenza on cancer mortality and several risk factors particularly aggravating effect of influenza on cancer mortality. With the data from this elderly cohort study, I also found that obesity was an independent risk factor for increased respiratory mortality associated with seasonal influenza. The findings from this research have provided new evidence on high risk groups who were more vulnerable to severe outcomes after influenza infection. The insights gained suggest that effective protection policy, including an influenza vaccine program, should be prudently applied for HCWs, cancer patients (especially those with certain risk factors), and obese people during epidemics and pandemics. / published_or_final_version / Public Health / Doctoral / Doctor of Philosophy

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

The burden and behaviour of influenza in Southeast Asia is poorly charac- terised, leading to uncertainty about the importance of influenza as a local health problem and the role of Southeast Asia in the global epidemiology of influenza. Prospective community-based studies have provided fundamental insights into the epidemiology of influenza in temperate regions; therefore a household-based cohort study was established with the aim of determining the intensity and characteristics of influenza transmission in a semi-rural tropical setting. The primary results of the cohort study are presented, along with the results of a survey of social contact patterns in the cohort and a mathemati- cal model of the spread of pandemic influenza A/H1N1/2009 in Vietnam that utilises data from the cohort. Highly pathogenic avian influenza A/H5N1 remains endemic in poultry in parts of Southeast Asia and continues to infect humans. Marked familial clustering of human H5N1 cases has led to speculation that susceptibility to H5N1 infection may have a host genetic component. The epidemiological data that led to the hypothesis of genetic susceptibility to H5N1 is summarised, whilst the evidence for a role of host genetics in susceptibility to influenza in general is systematically reviewed. A genome-wide case-control genetic association study was conducted in Vietnam and Thailand to test the hypothesis of genetic susceptibility to H5N1 infection, and the results are presented. This work provides new data and understanding of the patterns and deter- minants of inter-pandemic, pandemic, and avian influenza epidemiology. The cohort study has added to the body of knowledge that is accruing on the burden and epidemiology of influenza in the tropics by providing community level data that were previously absent. The genetics study has provided the first direct evidence of genetic loci associated with susceptibility to H5N1 and opens new avenues of research to test these findings and their relevance to the pathogenesis of H5N1 and other types of influenza.

published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Influenza causes substantial morbidity and mortality yearly in both temperate and tropical regions, as well as sporadic and potentially severe pandemics. Although vaccines for seasonal influenza exist, most options for controlling influenza outbreaks are reactive in nature. Sufficiently accurate and well-calibrated forecasts, on the other hand, could allow public health practitioners, medical professionals, and the public to respond to unfolding influenza outbreaks proactively. For example, hospitals could prepare additional beds for a predicted surge, and public health experts could redouble vaccination efforts. Recently, skillful forecasts have been developed for a range of infectious diseases, including influenza, but this work has been limited to only a few countries. In this dissertation, we explore the potential for generating accurate influenza forecasts using a publicly-available dataset of country-level epidemiologic and virologic surveillance data. In Chapter 2, we use a combined model-inference system to generate retrospective forecasts for 64 countries in both temperate and tropical climates. We show that forecast accuracy is significantly better in countries with temperate climates, and that inclusion of environmental forcing, specifically modulation of viral transmissibility due to variability of absolute humidity conditions, also improves forecast accuracy in temperate climates. In Chapter 3, we develop a metapopulation model of twelve European countries using data on international air travel and commuting. We find that this model is unable to produce more skillful forecasts than those produced for individual countries in isolation. We make recommendations for improvements in data collection and reporting that may increase the success of similar modeling efforts in the future. In Chapter 4, we assess the performance of real-time forecasts generated for 37 countries over two influenza seasons and discuss the potential for their use in public health decision making. Finally, in Chapter 5 we describe the results of a small survey of public health practitioners in the United States. We find that the majority of respondents desire more effective communication between modelers and public health practitioners, and we discuss the importance of regular and improved communication in advancing the practical use of forecasts as public health decision making tools. This dissertation advances the science of influenza forecasting by demonstrating that skillful retrospective and real-time forecasts can be generated for many countries where previous forecasting efforts are either minimal or absent. However, it is vital that data quality issues be addressed if further progress is to be made. Future work should focus in particular on climatic drivers of influenza in the tropics and subtropics, on the role of human travel at various spatial scales, and on the development of regional and local forecasting capacity. Additionally, dedicated collaboration between modelers and public health practitioners will be instrumental for motivating and informing the use of forecasts in combating influenza outbreaks.

published_or_final_version / Community Medicine / Master / Master of Public Health

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy Johannesburg, October 2014 / Introduction Data on the burden of influenza-associated hospitalisation and mortality in relation to other aetiologies of pneumonia as well as risk groups for severe and complicated disease are important to guide influenza prevention policy. Materials and methods We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods from monthly age-specific mortality data using Serfling regression models. For individuals aged ≥65 years from South Africa and the United States of America (US) we evaluated influenza-related deaths due to all causes, pneumonia and influenza (P&I) and other influenza-associated diagnoses for 1998-2005. For adults with acquired immune deficiency syndrome (AIDS) aged 25-54 years in South Africa (1998-2005) and the US (pre-highly active antiretroviral therapy (HAART) era: 1987-1994; HAART era: 1997-2005) we estimated deaths due to all-causes and P&I. We prospectively enrolled individuals with severe acute respiratory illness (SARI) at six hospitals in four provinces of South Africa from 2009-2012. Using polymerase chain reaction, respiratory samples were tested for ten respiratory viruses and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with available population denominators. Results Age-standardised excess mortality rates amongst seniors were higher in South Africa than in the US (545 vs. 133 per 100,000 for all-causes, p<0.001; 63 vs. 21 for P&I, p=0.03). The mean percent of winter deaths attributable to influenza was 16% in South Africa and 6% in the US, p<0.001. For all respiratory causes, cerebrovascular disease and diabetes age-standardised excess death rates were 4- to 8-fold greater in South Africa than in the US, and the percent increase in winter deaths attributable to influenza was 2- to 4-fold higher. In the US pre-HAART, influenza-related mortality rates in adults with AIDS were 150- (95% confidence interval (CI) 49-460) and 208- (95% CI 74-583) times greater than in the general population for all-cause and P&I respectively and 2.5- (95% CI 0.9-7.2) and 4.1- (95% CI 1.4-13) times higher than in seniors. Following HAART introduction, influenza-related mortality in adults with AIDS dropped 3-6 fold but remained elevated compared to the general population (all cause relative risk (RR) 44, 95% CI 16-12); P&I RR 73, 95% CI 47-113). Influenza-related mortality in South African adults with AIDS was similar to that in the US in the pre-HAART era. From 2009-2012 we enrolled 8723 children age <5 years with SARI. The human immunodeficiency virus (HIV) prevalence among tested children was 12% (705/5964). The overall prevalence of respiratory viruses identified was 78% (6517/8393), which included 26% (n=2216) respiratory syncytial virus (RSV) and 7% (n=613) influenza. The annual incidence of SARI hospitalisation in children age <5 years ranged from 2530-3173 per 100,000 and was 1.1-3-fold greater in HIV-infected than HIV-uninfected children. In multivariable analysis, compared to HIV-uninfected children, HIV-infected children were more likely to be hospitalised >7 days (odds ratio (OR) 3.6, 95% CI 2.8-5.0) and had a 4.2-fold (95% CI 2.6-6.8) higher case-fatality ratio. From 2009-2012, we enrolled 7193 individuals aged ≥5 years with SARI. HIV-prevalence was 74% (4663/6334) and 9% (621/7067) tested influenza positive. The annual incidence of SARI hospitalisation in individuals age ≥5 years ranged from 325-617 per 100,000 population and was 13 to 19-fold greater in HIV-infected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (OR 2.1, 95% CI 1.3-3.2), have pneumococcal infection (OR 2.2, 95% CI 1.6-2.9), be hospitalised for longer (>7 days rather than <2 days OR 2.4, 95% CI 1.8-3.2) and had a higher case-fatality ratio (8% vs. 5%; OR 1.6, 95% CI 1.2-2.2), but were less likely to be infected with influenza (OR 0.6, 95% CI 0.5-0.8). Influenza was identified in 9% (1056/11925) of patients of all ages enrolled in SARI surveillance from 2009-2011. Among influenza case-patients, 44% (358/819) were HIV-infected. Age-adjusted influenza-associated SARI incidence was 4-8 times greater in HIV-infected (186-228 per 100,000 population) than HIV-uninfected (26-54 per 100,000 population). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals with influenza-associated SARI were more likely to have pneumococcal co-infection (OR 2.3, 95% CI 1.0-5.0), influenza type B than type A (OR 1.6, 95% CI 1.0-2.4), be hospitalised for 2-7 days (OR 2.8 95% CI 1.5-5.5) or >7 days (OR 4.5, 95% CI 2.1-9.5) and more likely to die (OR 3.9, 95% CI 1.1-14.1). Discussion and conclusions The mortality impact of seasonal influenza in the South African elderly may be substantially higher in an African setting compared to the US. Adults with AIDS in South Africa and the US experience substantially elevated influenza-associated mortality rates, which although lessened by widespread HAART treatment does not completely abrogate the heightened risk for influenza illness. HIV-infected children and adults also experience substantially elevated incidence of hospitalisation for influenza-associated SARI and have higher case-fatality ratios. Influenza is commonly detected amongst children (7%) and adults (9%) with SARI. Less frequent identification of influenza amongst HIV-infected than -uninfected individuals aged ≥5 years likely reflects increased relative burden and role of other opportunistic pathogens such as pnuemococcus and Pneumocystis jirovecii. Improved access to HAART for HIV-infected individuals and vaccination against influenza virus amongst HIV-infected individuals, young children and the elderly, where the influenza burden is great may reduce the high burden of hospitalisations and mortality associated with influenza.