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Mycobacterium tuberculosis is a significant human pathogen that can cause asymptomatic latent tuberculosis infection. Approximately 5% to 15% of patients with latent tuberculosis cases will reactivate across their lifetime, progressing to active tuberculosis disease and potentially transmitting this pathogen throughout the community. To avoid the personal and public health concerns related to tuberculosis reactivation, identifying and treating patients with latent tuberculosis infections is critical, even in low-incidence regions such as the United States. This activity reviews the etiology, pathophysiology, and epidemiology of latent tuberculosis infection, the steps in evaluating and diagnosing patients with latent tuberculosis infection, and the standard therapeutic regimens, including their adverse effects, for this disease process. The activity also highlights the importance and benefit of interprofessional teams in improving treatment adherence and outcomes for patients with latent tuberculosis infection and curbing the progression rates to active tuberculosis. Objectives: Identify individuals at an increased risk of progression from latent tuberculosis infection to active tuberculosis. Employ diagnostic testing and risk-based calculators to identify patients who may benefit from treatment for latent tuberculosis infection. Select a patient-appropriate treatment regimen for latent tuberculosis infection. Develop and implement effective interprofessional team strategies to improve outcomes for patients with latent tuberculosis infections. Access free multiple choice questions on this topic.

Mycobacterium tuberculosis is a significant human pathogen. This bacterium primarily causes pulmonary disease but can spread to involve any organ and manifest as acute, chronic, or latent infection.[1] Tuberculosis is a global disease, but the disease burden disproportionately impacts low-income countries and vulnerable populations, including those who are homeless or unsheltered, incarcerated, or who use intravenous drugs.[2] The financial burden of tubercular illness and treatment can consume livelihoods among these populations.[3] In high-income countries with a low prevalence of tuberculosis, public health interventions focus on detecting and treating patients with latent tuberculosis (TB) infection.[4] Latent TB infection may reactivate to cause active and infectious TB disease that can spread throughout the population. Identification and characterization of individuals with latent TB infection and at risk of reactivation is imperative for public health but requires balancing the benefits of therapy with potential harms. For a comprehensive discussion of the epidemiology, etiology, pathophysiology, histopathology, evaluation, and management of tuberculosis, please see StatPearls' companion topic, "Tuberculosis."

The bacterium Mycobacterium tuberculosis is the causative agent of TB disease. The genus Mycobacterium contains many nontuberculous mycobacteria (NTM), but all mycobacteria are bacilli with a cell envelope containing high levels of mycolic acids.[5] The unique cell envelope of mycobacteria is impervious to Gram stain; visualization with light microscopy requires acid-fast stains such as the auramine-rhodamine or Ziehl-Neelsen stains.[6][7] Mycobacteria are aerobic and slow-growing; several weeks of culture may be required to achieve a positive result.[8] The identification of M tuberculosis isolated from culture is typically based on morphologic and biochemical characteristics. Rapid diagnostic techniques such as nucleic acid amplification testing may be performed for the identification of M tuberculosis and can target gene sequences known to confer drug resistance.[7]

Approximately one-third of the global population is infected with M tuberculosis. Despite being a treatable and curable condition, TB kills approximately 1.5 million people annually worldwide.[9] However, the burden of infection disproportionately falls on low-income countries. High rates of infection, defined as greater than 300 per 100,000 population per year, are seen in India and countries in sub-Saharan Africa. Tuberculosis rates in Eastern Europe are as high as 154 per 100,000 population per year.[2] Countries with a low incidence of TB infection, such as the United States, are defined by an incidence of TB of less than 100 per 100,000 population per year.[9] A majority of cases in the United States occur in people who were born overseas. The incidence of TB is higher in males than females; in one study, the pulmonary TB rate in males was 31.8 cases per 100,000 person-years compared to 20.1 cases per 100,000 person-years in females.[10] Approximately 12% of newly diagnosed global TB occurs in people coinfected with HIV; the interpretation of interferon-gamma diagnostic results can be affected by the degree of HIV-induced immunosuppression.[11][12][13] Following inhalational exposure to the bacterium, approximately 5% to 15% of infected individuals will develop active TB during their lifetime. While latency may last for decades following infection, most patients who progress to active TB disease do so within the first 2 years following exposure.[14][15]

Inhalation of the M tuberculosis bacterium is met by varying immune responses between hosts. The immune response in some patients, particularly those who are immunocompetent, is characterized by the elimination of the bacterium by alveolar macrophages. In other patients, the innate immune system in the lungs produces a granulomatous reaction to contain the bacterium called a tubercle.[16] A spectrum of containment from latent tuberculosis infection to active tuberculosis disease correlates with the bacteria escaping from the tubercle according to host-pathogen interactions.[17][16] A bacteremic phase may occur, particularly in those with HIV, and mycobacteria may hematogenously spread to any organ.[18] The definition of latent TB infection is evidence of immunological response to M tuberculosis without evidence of clinical disease.[19] In the absence of treatment, the risk of reactivation of latent tuberculosis infection is 5% to 15% across the lifetime of the infected patient.[20] However, this risk varies depending on the coincident pathogen, host, and environmental factors. Bacterial pathogenic factors include the varied virulence of different clades of M tuberculosis that co-evolve with human host populations and differences in progression to active disease between species within the M tuberculosis complex.[14] Host factors that increase the risk of progression to active TB disease include immunosuppression and advancing age. The age-related decline in the immune response, mutations in Toll-like receptors, T-cell depletion, and changes in the expression of cytokines such as interferon-gamma and tumor necrosis factor.[9] Patients utilizing biological therapies for rheumatological diseases may also be at increased risk of reactivation from latent TB, as these treatments affect key cytokine responses in cellular immunity.[21] Other conditions that decrease the immune response and are risk factors for progression to active TB include HIV infection, diabetes, smoking, malignancy, corticosteroid use, and solid organ or hematological transplant.[21] Bacterial factors include the varied virulence of different clades of M tuberculosis that co-evolve with human host populations and differences in progression to active disease between species within the M tuberculosis complex.[14]

Patients with latent TB infection are asymptomatic.[19] Therefore, obtaining a medical history is dual-purposed: identifying patients with indications for testing for latent TB infection and excluding active tuberculosis disease. Indications for latent TB infection testing include patients at high risk of reactivation in low-incidence countries, patients at high risk of a new TB infection, or patients at moderate-to-high risk of reactivation in a high-incidence area.[22] A thorough exploration of risk factors for reactivation is required; these risk factors include a personal history of hematological or solid organ transplantation, dialysis, silicosis, anti-tumor necrosis factor treatment, and HIV coinfection.[21] Additionally, individuals of all ages who are in contact with patients with active TB infection are at a significantly increased risk of developing a new TB infection. Symptoms that may indicate active TB disease include a cough for more than 2 weeks, shortness of breath, hemoptysis, chest pain, fevers, night sweats, and weight loss.[22] People at high risk for exposure to cases of pulmonary TB include prisoners, healthcare workers, homeless persons, illicit drug users, those with silicosis, and people who have emigrated from high TB incidence to low-incidence countries.[4][23][24] The physical examination should focus on identifying features of active TB disease, including pulmonary and extrapulmonary signs. Weight loss, sputum jars of hemoptysis, fevers, and diaphoresis may be indicative of active TB disease. Extrapulmonary signs include lymph node enlargement, skin changes such as erythema nodosum or panniculitis, pallor indicative of anemia, meningeal, peritoneal, and osteoarticular signs.[22] Features that may predispose risk for reactivation seen on examination include intravascular catheters or arteriovenous fistulas for dialysis, signs of organ transplantation and treatment, and steroid-related changes.

No single test can accurately distinguish between active and latent TB disease. The diagnosis of latent TB infection relies on evidence of cellular immune response to M tuberculosis and the reasonable exclusion of active TB disease. Immune-Based Testing Immune-based tests include the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). TST and IGRA are frequently utilized in high-income, low-incidence countries where the Bacille Calmette–Guérin (BCG) vaccine is less often used for population-based management of TB.[25] The TST and IGRA should lack the sensitivity and specificity to detect active TB and should not be used to diagnose active TB; mycobacterial culture and molecular methods are used for this purpose.[26] The TST involves intradermal administration of a small volume of tuberculin antigens (tuberculoprotein preparation, or PPD) to allow for T-cell–mediated recognition and induration formation secondary to TB-sensitised T cells.[27] Developing skin test conversion following active M tuberculosis infection may take up to 12 weeks.[28] Approximately 50% of individuals with past exposure to M tuberculosis do not react when challenged with a TST; this may represent a failure of TH1-driven cellular immunity or that infection with the mycobacterium did not occur.[29] If cellular immunity is intact and the patient has previously been exposed to the antigens, a delayed-type hypersensitivity reaction will result in induration and erythema.[30] Patients return 2 to 5 days following PPD administration for measurement of skin induration by a skilled clinician.

The TST involves intradermal administration of a small volume of tuberculin antigens (tuberculoprotein preparation, or PPD) to allow for T-cell–mediated recognition and induration formation secondary to TB-sensitised T cells.[27] Developing skin test conversion following active M tuberculosis infection may take up to 12 weeks.[28] Approximately 50% of individuals with past exposure to M tuberculosis do not react when challenged with a TST; this may represent a failure of TH1-driven cellular immunity or that infection with the mycobacterium did not occur.[29] If cellular immunity is intact and the patient has previously been exposed to the antigens, a delayed-type hypersensitivity reaction will result in induration and erythema.[30] Patients return 2 to 5 days following PPD administration for measurement of skin induration by a skilled clinician. The TST is not specific for M tuberculosis. Falsely positive results may occur in patients exposed to environmental NTM, vaccinated with the BCG vaccine, or with past exposure to M tuberculosis but have cleared the infection. Incorrect TST technique or interpretation may also contribute to a false-negative result. NTM that are cross-reactive with the TST include Mycobacterium avium-intracellulare, Mycobacterium simiae, Mycobacterium scrofulaceum, and Mycobacterium kansasii. M kansasii and M avium-intracellulare complex can cause clinically significant pulmonary infections, particularly in patients with underlying structural lung disease.[31][32] However, globally, NTM is a less important cause of false-positive TST results, except in areas of higher NTM but low M tuberculosis prevalence.[33] False-negative results may occur in patients who have impaired cellular immunity. [34] The IGRA is a blood test that measures in vitro cellular responses to M tuberculosis-specific antigens not found in the BCG vaccine or most NTM.[34][35] Three tubes of blood are required to perform an IGRA: a negative control, a positive control with phytohemagglutinin, and a tube specific for M tuberculosis antigens.[27] The blood is incubated for up to 24 hours and separated into plasma; results are released as positive, negative, or indeterminate. Unlike the TST, IGRA tests will not react to prior BCG vaccinations or NTM.[36]

The IGRA is a blood test that measures in vitro cellular responses to M tuberculosis-specific antigens not found in the BCG vaccine or most NTM.[34][35] Three tubes of blood are required to perform an IGRA: a negative control, a positive control with phytohemagglutinin, and a tube specific for M tuberculosis antigens.[27] The blood is incubated for up to 24 hours and separated into plasma; results are released as positive, negative, or indeterminate. Unlike the TST, IGRA tests will not react to prior BCG vaccinations or NTM.[36] IGRA has a higher specificity than TST for M tuberculosis exposure but is more expensive and resource-intensive in many countries.[37] However, emerging evidence in high-income countries shows that IGRAs can be cost-effective for detecting latent TB infection in high-risk populations.[37][38] A false-negative IGRA can occur in patients with central nervous TB infection or an impaired immune response, including older patients or those with an innate or acquired interferon-gamma deficiency.[39][40] False positive IGRA results may occur secondary to specimen contamination with live TB organisms.[41] An indeterminate result may be secondary to reduced immune responses to the mitogen control, as in immunosuppression, or secondary to elevated interferon-gamma in the negative controls, such as the presence of heterophile antibodies, incorrect antigens, or autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis.[22][42] There is limited utility to using TST or IGRA when monitoring the response to TB treatment. Though there may be a decline in IGRA-positive rates after TB treatment, many cases remain positive despite latent TB therapy.[43][44] Similarly, TST measures the hypersensitivity of T-cell responses to tuberculin rather than as a treatment response or immunity measure.[30] Chest Radiography and Sputum Samples A chest radiograph may be adequate to exclude active tuberculosis in patients without symptoms of TB disease. However, patients with clinical or radiological abnormalities should be further investigated for TB disease or other conditions. Other conditions that may mimic TB include silicosis, malignancy, sarcoidosis, autoimmune causes such as rheumatoid arthritis and vasculitis, and infections including NTM, Nocardia, Cryptococcus, Histoplasma, and Aspergillus.[45][46][47][48][49]

A chest radiograph may be adequate to exclude active tuberculosis in patients without symptoms of TB disease. However, patients with clinical or radiological abnormalities should be further investigated for TB disease or other conditions. Other conditions that may mimic TB include silicosis, malignancy, sarcoidosis, autoimmune causes such as rheumatoid arthritis and vasculitis, and infections including NTM, Nocardia, Cryptococcus, Histoplasma, and Aspergillus.[45][46][47][48][49] Another test for active TB is the evaluation of 3 early morning sputum samples for acid-fast staining, mycobacterial culture, and nucleic acid amplification testing.[22] Identifying M tuberculosis on a sputum sample is diagnostic for active TB infection; such a patient can infect others and requires isolation. This situation also requires public health notification for contact tracing to limit community transmission of TB.[50] Patients with isolated extrapulmonary manifestations of TB are noninfectious.[51]

Mycobacteria such as M tuberculosis are intrinsically resistant to most commonly used antibiotics.[52] The treatment regimen for latent TB infection typically comprises 1 or 2 drugs active against mycobacteria.[53] In comparison, the standard treatment regimen for sensitive pulmonary TB disease is much more complex: rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months, and if testing confirms susceptibility to rifampicin and isoniazid, continuation of those 2 drugs for an additional 4 months with cessation of the pyrazinamide and ethambutol.[53][54] Susceptibility testing cannot be used to guide treatment for latent TB as M tuberculosis cannot be cultured.[55] Individuals in close contact with patients with multidrug-resistant TB (MDR-TB) are more likely to have latent TB, and close contacts with active TB are more likely to have MDR-TB themselves.[56][57] Despite this, the evidence to inform best practices regarding managing close contacts of MDR-TB is limited.[56] Given the lack of evidence of better treatment outcomes in treating latent TB based on MDR-TB close contact susceptibilities, the selection of latent TB management in these cases has been guided by expert opinion and the discretion of the treating clinician on the individual risk of acquiring MDR-TB.[58][59] The goal of latent TB infection treatment is to prevent progression to active disease. Given that most patients will not reactivate during their lifetime if untreated, the risk of this progression must be balanced against the risk of toxicity from treatment, particularly hepatotoxicity with isoniazid-based therapy.[60][61] To assist clinicians in evaluating this risk-benefit equation, several clinical calculators have been developed to estimate the likelihood that the patient has true-positive testing for latent TB, their risk of reactivation, and their risk of serious hepatotoxicity from the treatment of latent TB.[62][63] The 3 most commonly utilized regimens for the treatment of latent tuberculosis are rifampicin monotherapy daily for 3 to 4 months, rifampicin or rifapentine plus isoniazid for 3 to 4 months, or isoniazid monotherapy daily for 6 to 9 months.[53] Choosing among these regimens is influenced by cost, efficacy, likelihood of adherence, and adverse effects, including hepatotoxicity.

The 3 most commonly utilized regimens for the treatment of latent tuberculosis are rifampicin monotherapy daily for 3 to 4 months, rifampicin or rifapentine plus isoniazid for 3 to 4 months, or isoniazid monotherapy daily for 6 to 9 months.[53] Choosing among these regimens is influenced by cost, efficacy, likelihood of adherence, and adverse effects, including hepatotoxicity. Isoniazid is an antimycobacterial antibiotic that inhibits the synthesis of the mycolic acids essential for the cell envelope of mycobacteria.[64] Isoniazid is cheaper than rifamycin but carries a higher risk of adverse effects. The rifamycins are a class of antibiotics that inhibit bacterial DNA-dependent RNA-polymerase and are active against a broad range of bacteria, including mycobacteria.[65] The rifamycins most useful for treating latent TB are rifampicin and rifapentine; rifapentine has a longer half-life and can be dosed weekly.[66] The protective efficacy of established regimens for latent TB ranges from 60% to 90% for up to 19 years.[67] In persons with HIV infection in areas with a high incidence of tuberculosis, the optimal duration of therapy for latent TB infection is not well established due to the risks of repeated or ongoing exposure and host immune status changes.[68][69]

Diagnosing latent TB infection can be challenging. No single test is adequate for diagnosis, and assessing for the condition requires careful clinical and radiological evaluation and interpretation of immunological tests. Patients with latent TB infection are asymptomatic by definition and detected solely through screening. The most pertinent differential diagnoses are active or previously treated TB disease and other NTM infections that predispose to falsely positive immune-based tests.[34] Active Tuberculosis Disease The minimum requirement for the exclusion of active TB disease is the patient is asymptomatic of TB disease with a normal chest radiograph.[70] If there is uncertainty, obtaining three early morning sputum samples for acid-fast staining, mycobacterial culture, and nucleic acid amplification testing must be considered. Signs or symptoms of extrapulmonary TB disease may require imaging, biopsy, and lumbar puncture. Resolved Tuberculosis Infection Asymptomatic patients with immunological evidence of prior exposure to M tuberculosis characterized by a positive TST or IGRA may have had a previously treated or cleared TB infection. Obtaining a careful timeframe of prior exposures and treatment history is critical. The decision to treat latent TB infection is often a patient-specific risk-benefit analysis; clinical calculators may assist the clinician.[62][63] Bacille Calmette–Guérin (BCG) Vaccination The TST is not specific for M tuberculosis, and false-positive results may occur in those vaccinated with BCG as derived from M bovis.[34] Nontuberculous Mycobacterial Infection The TST is not specific for M tuberculosis, and false-positive results may occur for those exposed to environmental NTM, such as M avium-intracellulare complex, M simiae, M scrofulaceum, and M kansasii.[31][32]

One of the most significant challenges in the treatment of latent TB infection is the difficulty in achieving an accurate diagnosis. The current diagnostic tests for M tuberculosis rely on cellular immune responses to prior exposure to antigens produced by the bacteria. These tests, particularly the TST, can be positive in patients who have cleared the infection and those with active pulmonary disease.[71] Next-generation diagnostics under development include immunodiagnostic biomarkers that seek to improve the capacity to differentiate latent TB infection.[32]

Treating latent TB infection kills the mycobacteria before the development of active TB disease. The protective efficacy of established regimens for treating latent TB infection ranges from 60% to 90%.[88][89] Without treatment, 5 % to 15% of patients with latent TB infection will reactivate during their lifetime.[20] While there are known host, pathogen, and environmental factors that will put some individuals at higher risk, it is impossible to perfectly predict which patients will go on to have TB disease.[9][21] This equates to 90% of patients treated for latent TB infection are exposed to the adverse effects of treatment without benefit; careful assessment of patients is required before commencing therapy for latent TB infection.

Minimizing the risk of harm from the treatment of latent TB infection is imperative and is best accomplished through monitoring liver function in patients at increased risk of hepatotoxicity during regular clinic or case management visits.[81] The concerns regarding the risk of increasing drug resistance by treating latent TB infection have not been validated by comprehensive, systematic meta-analyses. [81][90] However, drug resistance surveillance systems should be in place to monitor for this potential outcome.[91]

Medication adherence is one of the significant variables in successfully treating latent TB infection. There has been a clinical shift to shorter and less complex treatment regimens to increase medication adherence.[92] Peer support, case management, and educational interventions also improve medication adherence.[93] Educating patients about the nature of TB infection and the importance of treatment promotes patient engagement and medication adherence. Patients must be counseled regarding the potential adverse effects of treatment, including the risk of hepatotoxicity and when to seek additional care.

In high-income, low-tuberculosis prevalence regions like the United States, where population-wide screening data for preventing active TB is lacking, public health interventions prioritize testing high-risk individuals and those prone to TB progression or new infections.[94][95] TB-oriented clinics and public health services are pivotal in screening close contacts of active TB cases. Yet, services led by rheumatologists, primary care practitioners, sexual health services, and clinicians aid vulnerable populations in identifying high-risk patients and referring them for further assessment and treatment.[96][97][98][99] Interprofessional collaboration involving pharmacists, nurses, and social workers significantly enhances patient safety and treatment outcomes. Pharmacists contribute expertise in treatment regimens for latent TB, managing risks like hepatotoxicity and drug interactions with rifamycin-containing therapies. TB-trained nurses or cultural health workers also aid in case management, optimizing medication adherence, and monitoring treatment-related adverse effects to ensure patient well-being. This integrated approach across healthcare disciplines is crucial in effectively managing latent TB in low-prevalence areas. Screening for and treating latent TB infection in high-income, low-incidence countries demands a coordinated and interprofessional approach involving physicians, advanced practice practitioners, nurses, pharmacists, and other health professionals. A comprehensive knowledge of and competence in TB screening methods, including interpreting TST and IGRA results, is required. Effective interprofessional communication, particularly surrounding social determinants and barriers to treatment, supports holistic patient care and improves outcomes. In high-income, low-incidence countries, the challenge lies in maintaining vigilance despite lower prevalence rates. Effective teamwork, continuous education, standardized protocols, and a patient-centered approach bolstered by ethical considerations are pivotal in achieving successful screening, treatment, and improved outcomes for patients with latent TB infection.