Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection

Abstract

SUMMARYTuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.

Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

“…This has been defined by the WHO as the prolonged asymptomatic phase of early disease during which pathology evolves, prior to clinical presentation as active disease 8 . This definition encompasses the incipient and subclinical phases described by others 9 . This phase in the natural history of TB, between latent infection and active disease, is highly attractive as a target for novel prognostic TB diagnostic tests in the hope of improving PPV for incident TB, while still offering an opportunity to prevent TB-related morbidity and mortality and interrupt onward transmission 9 .…”

“…This definition encompasses the incipient and subclinical phases described by others 9 . This phase in the natural history of TB, between latent infection and active disease, is highly attractive as a target for novel prognostic TB diagnostic tests in the hope of improving PPV for incident TB, while still offering an opportunity to prevent TB-related morbidity and mortality and interrupt onward transmission 9 . This has led to the WHO producing a target product profile (TPP) for incipient TB diagnostics, stipulating minimum sensitivity and specificity of 75% and optimal sensitivity and specificity of 90%, over a two-year time period 8 .…”

Escaping the Plato's cave of latent tuberculosis testing: a path for developers of predictive tests for risk of tuberculosis

“…The vision is driven by the availability of shorter treatment regimens (e.g. using a 12-dose once-weekly rifapentine and isoniazid combination [10]), but in particular also by a recognition that the old binary paradigm of "LTBI" and "active TB disease" has fallen and new diagnostic opportunities seem within the technical reach of developers [11,12].…”

“…The infected individuals' position in this spectrum is determined by the ability to control bacillary replication, which again is dynamic and influenced by factors such as nutritional status, HIV infection and compliance to anti-TB treatment [11,13]. The spectrum paradigm includes a central postulate that, prior to clinical presentation with active TB disease, there might be a prolonged asymptomatic phase of incipient TB (subclinical disease), during which pathology develops [11,12].…”

“…Based on these assumptions, diagnostic tests for the identification of latent infection can conceptually be categorised as persistent infection tests (PITs) (a space largely covered by the current diagnostic portfolio for LTBI) and tests detecting incipient TB (ITTs) [12,14]. A therapeutic intervention directed by ITTs (with or without the requirement of a two-step approach with an initial rule-out PIT) would be the most cost-effective and safe approach to programmatic management of LTBI,the "holy grail" for test developers.…”