Quaterly Medical Review
Tuberculosis elimination and the challenge of latent tuberculosis

https://doi.org/10.1016/j.lpm.2017.01.015Get rights and content

Summary

Latent tuberculosis infection (LTBI) affects one third to one fourth of the human population and is the reservoir for a significant proportion of emerging active tuberculosis (TB) cases, especially in low incidence countries. The World Health Organization launched in 2015 the END-TB strategy that aims at TB elimination and promotes, for the first time ever, the management of LTBI. The preventive package, basically consisting of testing and treatment for LTBI in groups at high risk of reactivation, is a mainstay of the first pillar of the strategy, alongside prompt diagnosis and early treatment of both drug-susceptible and drug-resistant TB disease. Testing and treatment for LTBI should be pursued with a programmatic perspective. This implies strong political commitment, adequate funding and an effective monitoring and evaluation system. People living with HIV and children under five years of age who are household contact of a contagious TB cases are primarily targeted in all epidemiological setting. In high resource and low incidence setting, additional at risk populations should also be the target for systematic LTBI testing and treatment. Research is urgently needed to develop diagnostic tests with higher predictive value to identify individuals that progress from infection to disease. Similarly, shorter and safer treatment regimens are needed to make the trade-off between potential benefits and harms more favourable for an increasing proportion of infected individuals.

In this issue

World Tuberculosis Day 2017: strengthening the fight against tuberculosis.

I. Solovic (Slovakia) et al.

Breaking the barriers: migrants and tuberculosis.

G. Sotgiu (Italy) et al.

Tuberculosis elimination and the challenge of latent tuberculosis.

A. Matteelli (Italy) et al.

The cursed duet today: tuberculosis and HIV-co-infection.

S. Tiberi (UK) et al.

The challenge of the new tuberculosis drugs.

S. Tiberi (UK) et al.

Agents of change: the role of healthcare workers in the prevention of nosocomial and occupational tuberculosis.

R.R. Nathavitharana (USA) et al.

Introduction

Tuberculosis (TB) is among the leading infectious causes of morbidity and mortality worldwide, with as many as 10.4 million new cases and 1.8 million deaths (including 0.4 million among people living with human immunodeficiency virus infection, PLHIV) estimated to have occurred in 2015 [1].

Approximately one-third to one-quarter of the global population is estimated to have latent tuberculosis infection (LTBI), a condition in which mycobacteria remain in the host in a dormant state without causing any sign or symptom [2], [3], [4], [5]. Since latently infected individuals are asymptomatic and noncontagious, the exact magnitude of LTBI prevalence is hard to measure and can only be estimated through mathematical models based on the average risk of acquiring the infection and the transmission potential of active pulmonary TB cases in different contexts. The majority of individuals with LTBI remain in this condition long life and are mostly unaware of it, but 5–15% may reactivate and progress to active disease, more commonly within the 2–5 years after infection [6]. Reactivation usually occurs under the influence of a number of risk factors that disrupt the immunological response thus hindering mycobacterial containment [4]. Being the most important source of new TB cases (especially in low burden countries), the submerged pool of latently infected subjects constitutes a priority target in the fight against TB. High-risk populations have been defined and tailored interventions need to be implemented to reach the future elimination goals as outlined in the post-2015 Agenda [7], [8]. Whilst donors and policy makers traditionally were concerned on detection and treatment of active TB cases only, prevention is now gaining growing attention at strategic level.

Besides PLHIV and under-five child contacts of pulmonary TB cases, who had been already recognized as the most vulnerable groups to be prioritised both in high- and low-incidence settings, other at-risk categories should be targeted by systematic LTBI testing and treatment in high- and upper-middle-income countries with a low TB burden [9], [10], [11], [12].

We hereby provide an overview on the significance and implications of LTBI and discuss public health interventions in the context of the new TB elimination strategy [13].

Section snippets

The role of TB prevention within the END-TB strategy

The World Health Organization (WHO) launched the END-TB strategy in 2014, adopting a completely new approach to the fight against TB. The strategy's very ambitious goals were to consolidate and further expand what had already been achieved under the previous strategies in accordance with the Millennium Development Goals (MDGs) for 2015 [7], [8], [14]. To reach TB elimination by 2035, three goals need to be achieved: a 95% decline in TB mortality, a 90% reduction in TB incidence (down to less

The two-pronged approach for the management of LTBI

The epidemiology of underlying TB, the burden of latent TB infection among risk groups and the likelihood of progression of latent infection to active clinical tuberculosis disease in the risk groups determine the policies that govern the programmatic management of LTBI [15]. Patients with pulmonary TB are the primary source of all new tuberculosis infections. The severity of disease in an index case and the closeness of the contact is correlated with the risk of developing infection and

LTBI diagnosis

A gold standard test for the diagnosis of LTBI does not exist. Tuberculosis infection can be measured by in vivo and in vitro assays that, by detecting memory T-cell response, are capable to detect the host sensitisation to M. tuberculosis antigens. However, such tests do not provide evidence regarding the stage and potential of progression from infection to disease. They are generally considered as acceptable but imperfect tests [39]. Commercially available tests to measure LTBI include in vivo

LTBI treatment

Treatment of LTBI is designed to prevent the progression of asymptomatic tuberculosis infection to clinical active tuberculosis disease. The choice of the most appropriate treatment regimen should primarily be based on the evidence around efficacy and safety. However, from a programme perspective, other considerations are also important, including acceptability, costs, feasibility and risk of fostering drug resistance during treatment. Safety is particularly important in this context as all

Concluding remarks

Reaching the targets of the END-TB strategy will be possible if the annual reduction of TB incidence increases to 10% and above. Achieving this result will require a multifaceted approach but will not be possible without systematic screening of high-risk populations and preventive treatment of individuals who test positive. National TB plans will need to incorporate systematic testing and treatment of carefully identified populations into their programmatic activities using available diagnostic

Disclosure of interest

the authors declare that they have no competing interest.

References (72)

  • World Health Organization

    Global tuberculosis report 2016

    (2016)
  • C. Dye et al.

    Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project

    JAMA

    (1999)
  • R.M. Houben et al.

    The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling

    PLoS Med

    (2016)
  • J.M. Achkar et al.

    Incipient and subclinical tuberculosis: defining early disease states in the context of host immune response

    J Infect Dis

    (2011)
  • E. Guirado et al.

    Characterization of host and microbial determinants in individuals with latent tuberculosis infection using a human granuloma model

    mBio

    (2015)
  • H. Getahun et al.

    Latent Mycobacterium tuberculosis infection

    N Engl J Med

    (2015)
  • C.J. Murray

    Shifting to Sustainable Development Goals – implications for global health

    N Engl J Med

    (2015)
  • World Health Organization

    Guidelines on the management of latent tuberculosis infection

    (2015)
  • World Health Organization

    Implementing the END-TB Strategy: the essentials

    (2015)
  • World Health Organization

    Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings

    (2011)
  • World Health Organization

    Recommendations for investigating contacts of persons with infectious tuberculosis in low- and middle-income countries

    (2012)
  • R. Diel et al.

    Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination

    Eur Respir J

    (2013)
  • M. Lomazzi et al.

    The Millennium Development Goals: experiences, achievements and what's next

    Global Health Action

    (2014)
  • H. Getahun et al.

    Advancing global programmatic management of latent tuberculosis infection for at risk populations

    Eur Respir J

    (2016)
  • K. Lonnroth et al.

    Towards tuberculosis elimination: an action framework for low-incidence countries

    Eur Respir J

    (2015)
  • L. D’Ambrosio et al.

    Tuberculosis elimination: theory and practice in Europe

    Eur Respir J

    (2014)
  • M. Schito et al.

    Translating the Tuberculosis Research Agenda: much accomplished, but much more to be done

    Clin Infect Dis

    (2015)
  • H.A. Fletcher et al.

    TB vaccine development and the END-TB Strategy: importance and current status

    Trans R Soc Trop Med Hyg

    (2016)
  • G.W. Comstock et al.

    The prognosis of a positive tuberculin reaction in childhood and adolescence

    Am J Epidemiol

    (1974)
  • P.A. Selwyn et al.

    A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection

    N Engl J Med

    (1989)
  • J. Keane et al.

    Tuberculosis reactivation during immunosuppressive therapy in rheumatic diseases: diagnostic and therapeutic strategies

    Curr Opin Rheumatol

    (2008)
  • A. Sidhu et al.

    Outcome of latent tuberculosis infection in solid organ transplant recipients over a 10-year period

    Transplantation

    (2014)
  • K.A. Al-Anazi et al.

    Infections caused by Mycobacterium tuberculosis in recipients of hematopoietic stem cell transplantation

    Front Oncol

    (2014)
  • E.L. Corbett et al.

    HIV infection and silicosis: the impact of two potent risk factors on the incidence of mycobacterial disease in South African miners

    AIDS

    (2000)
  • A.I. Christopoulos et al.

    Risk factors for tuberculosis in dialysis patients: a prospective multi-center clinical trial

    BMC Nephrol

    (2009)
  • I. Baussano et al.

    Tuberculosis incidence in prisons: a systematic review

    PLoS Med

    (2010)

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      Citation Excerpt :

      In humans, TB is mainly caused by M. tuberculosis sensu stricto (Mtbss), and M. africanum (Maf) herein referred to as human-adapted MTBC (hMTBC) (Gagneux et al., 2006, Kamerbeek et al., 1997). Nevertheless, animal species such as M. bovis and M. orygis occasionally cause TB in humans, resulting in zoonotic TB (Jenkins, 2011, Otchere et al., 2019, Rossi et al., 2015), which is seen chiefly in major livestock producing communities (Matteelli et al., 2017, Müller et al., 2009). The hMTBC cluster in lineages (L) and sub-lineages are characterized by extensive sequence polymorphisms, single nucleotide polymorphisms, and insertion sequence polymorphisms.

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