Person:

Murray, Megan

Background: Mathematical models of tuberculosis (TB) transmission have been used to characterize disease dynamics, investigate the potential effects of public health interventions, and prioritize control measures. While previous work has addressed the mathematical description of TB natural history, the impact of demography on the behaviour of TB models has not been assessed. Methods: A simple model of TB transmission, with alternative assumptions about survivorship, is used to explore the effect of age structure on the prevalence of infection, disease, basic reproductive ratio and the projected impact of control interventions. We focus our analytic arguments on the differences between constant and exponentially distributed lifespans and use an individual-based model to investigate the range of behaviour arising from realistic distributions of survivorship. Results: The choice of age structure and natural (non-disease related) mortality strongly affects steady-state dynamics, parameter estimation and predictions about the effectiveness of control interventions. Since most individuals infected with TB develop an asymptomatic latent infection and never progress to active disease, we find that assuming a constant mortality rate results in a larger reproductive ratio and an overestimation of the effort required for disease control in comparison to using more realistic age-specific mortality rates. Conclusions: Demographic modelling assumptions should be considered in the interpretation of models of chronic infectious diseases such as TB. For simple models, we find that assuming constant lifetimes, rather than exponential lifetimes, produces dynamics more representative of models with realistic age structure.

Background: The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans. Methods and Findings: We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains. Conclusions: The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance should be considered in pandemic planning and monitored closely during a pandemic.

Background: Tuberculosis is the leading cause of death in South Africa by death notification, but accurate diagnosis of tuberculosis is challenging in this setting of high HIV prevalence. We conducted limited autopsies on young adults dying in a single public hospital in the province of KwaZulu-Natal between October 2008 and August 2009 in order to estimate the magnitude of deaths attributable to tuberculosis. Methods and Findings: We studied a representative sample of 240 adult inpatients (aged 20–45 years) dying after admission to Edendale Hospital. Limited autopsies included collection of respiratory tract secretions and tissue by needle core biopsies of lung, liver, and spleen. Specimens were examined by fluorescent microscopy for acid-fast bacilli and cultured in liquid media; cultures positive for M. tuberculosis were tested for drug susceptibility to first- and second-line antibiotics. Ninety-four percent of our study cohort was HIV seropositive and 50% of decedents had culture-positive tuberculosis at the time of death. Fifty percent of the participants were on treatment for tuberculosis at the time of death and 58% of these treated individuals remained culture positive at the time of death. Of the 50% not receiving tuberculosis treatment, 42% were culture positive. Seventeen percent of all positive cultures were resistant to both isoniazid and rifampin (i.e., multidrug resistant); 16% of patients dying during the initiation phase of their first ever course of tuberculosis treatment were infected with multidrug-resistant bacilli. Conclusions: Our findings reveal the immense toll of tuberculosis among HIV-positive individuals in KwaZulu-Natal. The majority of decedents who remained culture positive despite receiving tuberculosis treatment were infected with pansusceptible M. tuberculosis, suggesting that the diagnosis of tuberculosis was made too late to alter the fatal course of the infection. There is also a significant burden of undetected multidrug-resistant tuberculosis among HIV-coinfected individuals dying in this setting. New public health approaches that improve early diagnosis of tuberculosis and accelerate the initiation of treatment are urgently needed in this setting.