Mapping infectious disease mortality onto the within-host dynamics of pathogen growth

Infectious diseases remain a major cause of global mortality, yet basic questions concerning the relationship between within-host processes governing pathogen burden (pathogen replication, immune responses) and epidemiological patterns of mortality remain obscure. In standard epidemiological models of bacterial and viral infections (‘compartmental models’), pathogen-induced mortality is described as a constant risk factor, unchanging with time since infection or the dynamics of the pathogen population inside the host. Here we review experimental data illustrating the failure of this assumption, with multiple infection models highlighting an accelerating risk of death with time since infection. Next, we show that the dynamics of infection-mediated death are phenomenologically similar to the dynamics of all-causes death, captured by an exponentially increasing instantaneous mortality or ‘hazard’ (a Gompertz function). We then sketch a series of within-host pathogen models and highlight that multiple models are consistent with existing Gompertz-like infection mortality data, including: (1) exponential pathogen growth and a linear mapping between pathogen density and host hazard, and (2) linear pathogen growth and an exponential mapping between pathogen density and host hazard. We review critical experimental questions that our work highlights, requiring additional non-invasive data on pathogen burden throughout the course of infection, and end with a discussion on the unpicking of the mechanistic and dynamical basis of accelerating mortality risk during the course of human infections.