Declaring a tuberculosis outbreak over with genomic epidemiology

Abstract

We report an updated method for inferring the time at which an infectious disease was transmitted between persons from a time-labelled pathogen genome phylogeny. We applied the method to 48 Mycobacterium tuberculosis genomes as part of a real-time public health outbreak investigation, demonstrating that although active tuberculosis (TB) cases were diagnosed through 2013, no transmission events took place beyond mid-2012. Subsequent cases were the result of progression from latent TB infection to active disease, and not recent transmission. This evolutionary genomic approach was used to declare the outbreak over in January 2015.

Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

“…With time of exposure to an active TB case pinpointed within a two week period, and sometimes to a single day, Poulsen determined that these clinical features accompany TST conversion within 6 weeks of exposure (14,34,44). While these clinical features of initial M.tb infection are transient and not specific to M.tb infection, a method to determine that a person is currently in the first 1-2 years post initial infection would have great prognostic value for nearfuture TB disease and could allow real-time geospatial mapping of recent TB transmission in communities (14,15,17,(34)(35)(36)(37). In our proof of concept analysis, we sought to determine whether it is possible to develop an RNA-based blood test to detect recent exposure or infection with M.tb.…”

“…To determine whether our findings in mice and cynomolgus macaques could translate to humans, several points are important to consider. While a recent study in the United States and Canada showed that recent contacts of active TB cases are at highest risk of TB disease in the first 1-3 months after the diagnosis of the TB index case, studies in other countries and other time periods show that the highest risk is in the first 1-2 years, with most cases accruing more than 2-3 months after a documented exposure (14,17,(34)(35)(36)(37). A recent vaccine study in rhesus macaques showed that BCG-induced immunity to M.tb delays IGRA conversion in a repeated limiting-dose M.tb challenge model (38).…”

De Novo Mutations Resolve Disease Transmission Pathways in Clonal Malaria

“…Even on a wider 377 geographic scale, where comprehensive sampling of an outbreak cannot be guaranteed, 378 the approach demonstrated here can generate concrete recommendations for public 379 health authorities. Transmission-network reconstructions of a tuberculosis outbreak in disease, rather than active transmission, with the direct result that the outbreak was declared over, a conclusion that was reached solely by comparison of the rate of de 383 novo mutation between samples (Hatherell et al 2016). Adapting such a capacity to 384 malaria would have major implications for elimination efforts: malaria elimination within a 385 country is defined as zero incidence of indigenous cases (WHO 2016) and the ability to 386 distinguish a chain of transmission from repeated importations without recourse to a 387 multi-country dataset could be a key capacity for the WHO Global Malaria Program.…”

A brief primer on genomic epidemiology: lessons learned fromMycobacterium tuberculosis

“…For a reportable disease like TB, with nearly exclusive human‐to‐human transmission, and in a well‐resourced, low‐incidence setting where culture is routinely used in diagnosis, this is often achievable. For example, in a recent British Columbia TB outbreak, we obtained Mtb DNA from 48 of 52 outbreak cases . For non‐notifiable diseases and/or those involving food‐ or water‐borne transmission or nonhuman hosts, the outbreak may be insufficiently represented by the available samples.…”

“…For example, in a recent British Columbia TB outbreak, 36 we obtained Mtb DNA from 48 of 52 outbreak cases. 37 For nonnotifiable diseases and/or those involving food-or water-borne transmission or nonhuman hosts, the outbreak may be insufficiently represented by the available samples.…”