Unintended consequences and the paradox of control: Management of emerging pathogens with age-specific virulence.

We project forward total Zika virus disease (ZVD) under varying hazards of infection and consider how the age distribution of disease burden varies between these scenarios. Pathogens with age structured disease outcomes, such as rubella and Zika virus, require that management decisions consider their impact not only on total disease incidence but also on distribution of disease burden within a population. Some situations exhibit a "paradox of control" in which reductions of overall transmission decrease the total incidence but increase the incidence of severe disease. This happens because of corresponding increases in the average age of infection. Beginning with the current population structure and demographic rates of Brazil, we project forward total ZVD burden as measured by cases occurring in pregnant women and document the scenarios under which a paradox of control for ZVD management emerges. We conclude that while a paradox of control can occur for ZVD, the higher total costs from increasing the average age of infection will only be realized after several decades and vanish under conservative discounting of future costs. This indicates that managers faced with an emerging pathogen are justified to prioritize current disease incidence over potential increases in severe disease outcomes in the endemic state

Brazilian population pyramid, 2015.

<p>Brazil’s population currently has the bulk of its mass in reproductive-age individuals, complicating any recommendation to delay childbearing.</p

Intermediate levels of ZVD hazard lead to the largest number of at-risk births.

<p>When annual discounting of 1.1% or greater is applied to future cases, the total weighted cost of ZVD increases monotonically with annual hazard. The gray region indicates the range of discounting rates commonly used in social policy [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005997#pntd.0005997.ref023" target="_blank">23</a>].</p

Intermediate levels of ZVD hazard lead to the largest number of at-risk births.

<p>When annual discounting of 5.5% or greater is applied to future cases, the total weighted cost of ZVD increases monotonically with annual hazard.</p

The paradox of control seen in the endemic setting is a function of equilibrium disease burden, and therefore insensitive to discounting.

<p>For illustrative purposes we include the range of common discounting rates in the gray shaded region.</p

“Developing” age pyramid.

<p>In a setting with far more children (proportionally) there is less cost, and more potential benefit, to higher ZVD hazards providing a “natural vaccine” to ZVD infection during pregnancy.</p

Age-specific fertility rates.

<p>Age-specific Brazilian fertility rates as of 2012 in five-year intervals, with a smoothing spline fit to obtain annual resolution.</p

Since the population in the endemic setting begins with partial immunity, annual disease burden is already at equilibrium and fluctuations are primarily due to demographic rates.

<p>A clear paradox of control appears in which reductions in attack rate monotonically increase the mean age of infection and therefore relative burden in at-risk age classes.</p

Since most individuals in this hypothetical developing population are below reproductive age, costs of ZVD tend to be higher in the future than in the case of Brazilian demography.

<p>The left panel shows absolute number of annual ZVD cases in pregnant women under varying hazard rates, while the right panel shows cumulative number of cases. This assumes the starting population age distribution is exponential and begins with all individuals susceptible.</p