The Epidemiological Importance of Subclinical Tuberculosis. A Critical Reappraisal

Abstract

From Chlamydia (1) to malaria (2) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (3), it is increasingly recognized that individuals without recognizable symptoms play an important role in the transmission of infectious pathogens. To date, however, this paradigm has largely not been applied to Mycobacterium tuberculosis (Mtb) even though many people with prevalent tuberculosis (TB) do not experience symptoms. The World Health Organization has adopted ambitious targets to end the TB epidemic, including a 90% reduction in incidence from 2015 to 2035. The corresponding End TB Strategy focuses on the early diagnosis and treatment of individuals with recognizable symptoms and treatment of latent TB infection in people at high risk (4). However, these targets may not be achievable without increased attention to averting transmission from the millions of people who have subclinical TB. Historically, TB has been conceptualized by some as consisting of latent infection (asymptomatic and noninfectious) and active disease (symptomatic and infectious). Recently, others have articulated this as a false dichotomy that masks a broader spectrum of disease, including incipient and subclinical stages (Figure 1) (5, 6). Yet subclinical TB is still frequently conceptualized as both noninfectious and as part of a “progression of disease activity” (5) that ultimately leads to recognizable symptoms (7). Under this paradigm, early diagnosis and treatment of people with symptomatic TB is capable of averting the vast majority of transmission events. If, however, a large fraction of Mtb transmission originates from people who do not have recognizable symptoms, then finding and treating these individuals (for example, by screening for TB with algorithms that do not rely on symptom screening) may be necessary to achieve major reductions in TB incidence by 2035.