Impact of waning acquired immunity and asymptomatic infections on case-control studies for enteric pathogens

Case-control studies of outbreaks and of sporadic cases of infectious diseases may provide a biased estimate of the infection rate ratio, due to selecting controls that are not at risk of disease. We use a dynamic mathematical model to explore biases introduced in results drawn from case-control studies of enteric pathogens by waning and boosting of immunity, and by asymptomatic infections, using Campylobacter jejuni as an example. Individuals in the population are either susceptible (at risk of infection and disease), fully protected (not at risk of either) or partially protected (at risk of infection but not of disease). The force of infection is a function of the exposure frequency and the exposure dose. We show that the observed disease odds ratios are indeed strongly biased towards the null, i.e. much lower than the infection rate ratio, and furthermore even not proportional to it. The bias could theoretically be controlled by sampling controls only from the reservoir of susceptible individuals. The population at risk is in a dynamic equilibrium, and cannot be identified as those who are not and have never experienced disease. Individual-level samples to measure protective immunity would be required, complicating the design, cost and execution of case-control studies.