James Wood

Risk Factors for Tuberculosis

The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli.

Cost-effectiveness analyses of human papillomavirus vaccination

With a human papillomavirus (HPV) vaccine soon to become available for widespread use, several studies have modelled the cost-effectiveness of vaccination. These pioneer studies are likely to be influential on the design of further analyses, and we have therefore summarised and critically reviewed the strengths and limitations of their methods and assumptions. Despite a lack of transparency in some key elements, the most influential assumptions were identified as relating to vaccine effectiveness, cervical screening, and model design. Although the studies suggest that the introduction of an HPV vaccine could be cost effective compared with current practice in the USA, there is still substantial uncertainty around key variables, and model validation seems insufficient. The desirability of vaccinating boys in addition to girls has been explored in only one study. Further refinements to model design and epidemiological variables of (type-specific) HPV disease progression, and expansions on the options for vaccine use, are required for policy making.

Influenza-related hospitalisation and death in Australians aged 50 years and older

Summary Estimating the true burden of influenza is problematic because relatively few hospitalisations or deaths are specifically coded as influenza related. Statistical regression techniques using influenza and respiratory syncytial virus surveillance data were used to estimate the number of excess hospitalisations and deaths attributable to influenza. Several International Classification of Diseases 10th Revision (ICD-10) groupings were used for both hospitalisation and mortality estimates, including influenza and pneumonia, other respiratory disorders, and circulatory disorders. For Australians aged 50–64 years, the annual excess hospitalisations attributable to influenza were 33.3 (95%CI: 23.2–43.4) per 100,000 for influenza and pneumonia and 57.6 (95%CI: 32.5–82.8) per 100,000 for other respiratory disorders. For Australians aged ≥65 years, the annual excess hospitalisations attributable to influenza were 157.4 (95%CI: 108.4–206.5) per 100,000 for influenza and pneumonia and 282.0 (95%CI: 183.7–380.3) per 100,000 for other respiratory disorders. The annual excess all-cause mortality attributable to influenza was 6.4 (95%CI: 2.6–10.2) per 100,000 and 116.4 (95%CI: 71.3–161.5) per 100,000, for Australians aged 50–64 years and those aged ≥65 years, respectively. In the age-group ≥65 years, a significant association was found between influenza activity and circulatory mortality. We conclude that influenza is responsible for a substantial amount of mortality and morbidity, over and above that which is directly diagnosed as influenza in Australians aged ≥50 years.

Impact of Emerging Antiviral Drug Resistance on Influenza Containment and Spread: Influence of Subclinical Infection and Strategic Use of a Stockpile Containing One or Two Drugs

Background Wide-scale use of antiviral agents in the event of an influenza pandemic is likely to promote the emergence of drug resistance, with potentially deleterious effects for outbreak control. We explored factors promoting resistance within a dynamic infection model, and considered ways in which one or two drugs might be distributed to delay the spread of resistant strains or mitigate their impact. Methods and Findings We have previously developed a novel deterministic model of influenza transmission that simulates treatment and targeted contact prophylaxis, using a limited stockpile of antiviral agents. This model was extended to incorporate subclinical infections, and the emergence of resistant virus strains under the selective pressure imposed by various uses of one or two antiviral agents. For a fixed clinical attack rate, R 0 rises with the proportion of subclinical infections thus reducing the number of infections amenable to treatment or prophylaxis. In consequence, outbreak control is more difficult, but emergence of drug resistance is relatively uncommon. Where an epidemic may be constrained by use of a single antiviral agent, strategies that combine treatment and prophylaxis are most effective at controlling transmission, at the cost of facilitating the spread of resistant viruses. If two drugs are available, using one drug for treatment and the other for prophylaxis is more effective at preventing propagation of mutant strains than either random allocation or drug cycling strategies. Our model is relatively straightforward, and of necessity makes a number of simplifying assumptions. Our results are, however, consistent with the wider body of work in this area and are able to place related research in context while extending the analysis of resistance emergence and optimal drug use within the constraints of a finite drug stockpile. Conclusions Combined treatment and prophylaxis represents optimal use of antiviral agents to control transmission, at the cost of drug resistance. Where two drugs are available, allocating different drugs to cases and contacts is likely to be most effective at constraining resistance emergence in a pandemic scenario.

Influenza-attributable mortality in Australians aged more than 50 years: a comparison of different modelling approaches.

This study aimed to compare systematically approaches to estimating influenza-attributable mortality in older Australians. Using monthly age-specific death data together with viral surveillance counts for influenza and respiratory syncytial virus, we explored two of the most frequently used methods of estimating excess influenza-attributable disease: Poisson and Serfling regression models. These approaches produced consistent age and temporal patterns in estimates of influenza-attributable mortality in older Australians but some variation in the magnitude of the disease burden. Of Australians aged >50 years, average annual estimated influenza-attributable deaths (all cause) ranged from 2314 to 3457 for the Serfling and Poisson regression models, respectively. The excess influenza-attributable disease burden was substantial under all approaches.

Management of blunt splenic trauma

1. Non-operative management of splenic trauma also includes splenic artery embolisation. By making a literature search using PubMed and the Cochrane Library, we were unable to identify any reports from the UK of experience on angio-embolisation for splenic trauma. We recently managed successfully, with proximal splenic artery embolisation, an 85-year-old woman with grade III splenic injury and extensive haemoperitoneum after a fall at home. Nevertheless, there is extensive literature on the topic, mostly North American. Arteriography and embolisation is routinely performed in many trauma centres, and has proved to be a safe and useful investigation and therapeutic intervention.1 Despite this, there is still much to be said as to its precise role. Embolisation for lowgrade injuries is probably unnecessary as these patients may do just as well without it. Patients with higher grade splenic injuries may benefit more as embolisation can result in an increased rate of successful non-operative management. Some reports have questioned the value of indiscretionary embolisation, or have suggested that only specific subgroups of patients may benefit.2,3 A multicentre, randomised, controlled trial is necessary to give answers as to which subgroups of non-operative management patients would benefit from embolisation.

Induction of antibody responses to African horse sickness virus (AHSV) in ponies after vaccination with recombinant modified vaccinia Ankara (MVA).

Background African horse sickness virus (AHSV) causes a non-contagious, infectious disease in equids, with mortality rates that can exceed 90% in susceptible horse populations. AHSV vaccines play a crucial role in the control of the disease; however, there are concerns over the use of polyvalent live attenuated vaccines particularly in areas where AHSV is not endemic. Therefore, it is important to consider alternative approaches for AHSV vaccine development. We have carried out a pilot study to investigate the ability of recombinant modified vaccinia Ankara (MVA) vaccines expressing VP2, VP7 or NS3 genes of AHSV to stimulate immune responses against AHSV antigens in the horse. Methodology/Principal Findings VP2, VP7 and NS3 genes from AHSV-4/Madrid87 were cloned into the vaccinia transfer vector pSC11 and recombinant MVA viruses generated. Antigen expression or transcription of the AHSV genes from cells infected with the recombinant viruses was confirmed. Pairs of ponies were vaccinated with MVAVP2, MVAVP7 or MVANS3 and both MVA vector and AHSV antigen-specific antibody responses were analysed. Vaccination with MVAVP2 induced a strong AHSV neutralising antibody response (VN titre up to a value of 2). MVAVP7 also induced AHSV antigen–specific responses, detected by western blotting. NS3 specific antibody responses were not detected. Conclusions This pilot study demonstrates the immunogenicity of recombinant MVA vectored AHSV vaccines, in particular MVAVP2, and indicates that further work to investigate whether these vaccines would confer protection from lethal AHSV challenge in the horse is justifiable.

Modelling the impact of one-dose vs. two-dose vaccination regimens on the epidemiology of varicella zoster virus in Australia

We examined the impact of one-dose vs. two-dose vaccination strategies on the epidemiology of varicella zoster virus (VZV) in Australia, using a mathematical model. Strategies were assessed in terms of varicella (natural and breakthrough) and zoster incidence, morbidity, average age of infection and vaccine effectiveness (VE). Our modelling results suggest that compared to a one-dose vaccination strategy (Australias current vaccination schedule), a two-dose strategy is expected to not only produce less natural varicella cases (5% vs. 13% of pre-vaccination state, respectively) but also considerably fewer breakthrough varicella cases (only 11.4% of one-dose strategy). Therefore a two-dose infant vaccination programme would be a better long-term strategy for Australia.

The potential cost-effectiveness of infant pneumococcal vaccines in Australia.

Over the last decade infant pneumococcal vaccination has been adopted as part of routine immunisation schedules in many developed countries. Although highly successful in many settings such as Australia and the United States, rapid serotype replacement has occurred in some European countries. Recently two pneumococcal conjugate vaccines (PCVs) with extended serotype coverage have been licensed for use, a 10-valent (PHiD-CV) and a 13-valent (PCV-13) vaccine, and offer potential replacements for the existing vaccine (PCV-7) in Australia. To evaluate the cost-effectiveness of PCV programs we developed a static, deterministic state-transition model. The perspective for costs included those to the government and healthcare system. When compared to current practice (PCV-7) both vaccines offered potential benefits, with those estimated for PHiD-CV due primarily to prevention of otitis media and PCV-13 due to a further reduction in invasive disease in Australia. At equivalent total cost to vaccinate an infant, compared to no PCV the base-case cost per QALY saved were estimated at A

Cost-effectiveness of pharmaceutical-based pandemic influenza mitigation strategies.

64,900 (current practice, PCV-7; 3+0), A