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Tuberculosis Last updated: June 16, 2023

Summary

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis, which typically affects the lungs. It is a common infectious cause of morbidity and
mortality worldwide. Primary infection, transmitted via airborne aerosol droplet nuclei, is often initially asymptomatic. M. tuberculosis infection is typically
dormant (latent TB infection; LTBI) because of intact innate and cellular immune responses. If the immune system is compromised, however, reactivation of
the infection may occur and lead to active TB. Patients with active disease characteristically present with fever, weight loss, night sweats, and a productive
cough (with or without hemoptysis) that does not respond to conventional antibiotic therapy. The infection may spread hematologically to any organ, causing
extrapulmonary TB. However, disseminated disease is rare, occurring in severely immunocompromised individuals. If active TB infection is suspected, imaging
should be obtained as well as microscopy, cultures, and/or polymerase chain reaction (PCR) to identify M. tuberculosis. The treatment of tuberculosis is
prolonged due to the slow growth of M. tuberculosis, its concealment in macrophages, and the inability of drugs to easily penetrate its cell wall. Standard
treatment includes combination therapy with rifampin, isoniazid, ethambutol, and pyrazinamide for two months, followed by rifampin and isoniazid for an
additional four months. Patients with suspected LTBI should be tested using the tuberculin skin test (TST) or interferon-γ release assay (IGRA) and treated
accordingly. Treatment of LTBI reduces the risk of active infection in up to 90% of cases and, therefore, plays a crucial role in the prevention of active TB.

Overview

Types of tuberculosis

Characteristics Primary tuberculosis (primary infection) Reactivation tuberculosis (secondary infection) [1]

Latent tuberculosis infection (LTBI) Active primary tuberculosis [3]

[2]

Definition A state of constant immune Active TB disease occurring after first-time exposure to Active TB developing after endogenous
response stimulation due to M. tuberculosis (only in 1–5% of cases) reactivation of latent TB or exogenous
M. tuberculosis antigens, with no reinfection
signs of active TB

Features Asymptomatic Can be symptomatic Symptomatic

Not contagious Contagious Contagious

The risk of reactivation is 5–10% Progressive primary tuberculosis is a severe form of disease Reactivation tuberculosis has a predilection for
during the course of a lifetime. seen in individuals with impaired immune systems (e.g., HIV, the upper lobe and typically manifests with
[4] malnutrition) or immature immune systems (e.g., young cavitation (M. tuberculosis is a highly aerobic
children). [1] bacteria) [5]

Diagnostics Tuberculin skin test (TST) or Microbiological confirmation: acid-fast staining, PCR, and culture
interferon-γ release assay (IGRA)
Imaging: chest x-ray or CT chest

Treatment Preferred regimens Intensive phase: rifampin PLUS isoniazid, pyrazinamide, and ethambutol for 2 months
Isoniazid PLUS rifapentine Continuation phase: rifampin PLUS isoniazid for 4 months
weekly for 3 months
OR rifampin daily for 4 months
OR isoniazid PLUS rifampin
daily for 3 months

Alternative regimen: isoniazid

daily for 6 or 9 months

Active tuberculosis

Definition: any TB infection with symptoms and signs of disease, including primary TB and reactivation of latent TB [1][6][7]

Features [1]

Pulmonary TB: the most common form of active TB

Extrapulmonary TB: The most common forms are TB lymphadenitis and pleural tuberculosis.

Diagnostics: confirmed if bacilli are present in respiratory secretions or other tissues, and subsequent microbiological testing and imaging results are
consistent with active TB [7][8]

Treatment
[9]
Combination of antibiotics, most commonly given for 6 months

Occasionally, invasive procedures (e.g., drainage for pleural TB) or surgery (e.g., lobectomy for drug-resistant TB) may be necessary. [9][10]

Drug-resistant tuberculosis [11]

Definition: a form of TB that is resistant to one or more antitubercular agents

Types

Rifampin-resistant tuberculosis (RR-TB): resistance to rifampin with or without resistance to other antitubercular drugs

Monoresistant TB: resistance to one of the first-line antitubercular drugs

Multidrug-resistant tuberculosis (MDR-TB ): resistance to both isoniazid and rifampin

Extensively drug-resistant tuberculosis (XDR-TB ): resistance to any single fluoroquinolone and at least one of the second-line injectable drugs (e.g.,
amikacin, kanamycin, or capreomycin) in addition to MDR-TB

Causes

Incorrect drug combination therapy

Inadequate duration or dosage of drug therapy

Poor treatment adherence

Poor quality of drugs

Close contact with an individual with drug-resistant TB

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Epidemiology

United States [12]

The incidence of TB infection in the US has been slowly declining.

The incidence rate for 2018 was 2.8 cases per 100,000 population.

Two-thirds of new TB cases reported in the US in 2019 were in individuals born outside the US.

The prevalence of LTBI in the United States is estimated to be 5% [13]

Worldwide [14]

A leading cause of death from a single infectious agent

The overall incidence and prevalence have been declining.

The incidence rate for 2018 was 132 cases per 100,000 population.

One-fourth of the world's population has latent TB.

[15]
The sex ratio varies across countries and communities and largely depends on social and cultural factors.

Countries with the highest incidence of TB: India, Indonesia, China, the Philippines, Bangladesh, Nigeria, Pakistan, and South Africa

The incidence of multidrug-resistant TB is steadily rising.

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Mycobacteria

Species

Mycobacterium species that cause tuberculosis are collectively known as the Mycobacterium tuberculosis complex, which includes:

Mycobacterium tuberculosis

Mode of transmission: spread via aerosol droplet nuclei

Reservoir: predominantly humans

Disease: all forms of tuberculosis

Mycobacterium bovis

Mode of transmission: predominantly via ingestion of contaminated cow's milk

Reservoir: predominantly cattle

Disease: gastrointestinal tuberculosis in humans

Mycobacterium africanum: common cause of tuberculosis in West, Central, and East Africa [1]

Mycobacterium microti

Features of Mycobacterium tuberculosis

Type: facultative intracellular rod-shaped bacteria

[16][17]
Gram stain: does not stain well

Special stains
[18]
Ziehl-Neelsen stain: acid-fast bacilli appear pink

Auramine-rhodamine stain [19]

Acid-fast bacilli appear reddish-yellow on fluorescence microscopy.

Used as a screening tool because of high sensitivity and low cost

Culture mediums for growth

Löwenstein Jensen medium

Middlebrook medium

Rapid automated broth culture

Mechanism of resistance
[20]
Remains viable in airborne droplet nuclei and soil

Able to survive in acidic conditions [21]

Virulence factors: See “Pathophysiology” below.

Risk factors for tuberculosis exposure [22]

Working in the health care industry

Migration from countries with a high TB incidence (≥ 100 cases per 100,000 population) [23]

Frequent travel to countries with a high TB burden

Close contact with a patient with active TB infection

Crowded living conditions (e.g., prisons)

Homelessness

Pathophysiology

Primary tuberculosis [1][24][25]

Innate immune response

Exposure to M. tuberculosis

Individuals with M. tuberculosis infection disperse droplet nuclei that contain bacilli via sneezing or coughing.

Inhaled droplet nuclei reach the terminal alveoli and are taken up by the alveolar macrophages.

Entry into macrophages

Mycobacterial cell wall contains pathogen-associated molecular patterns (PAMPs) such as lipoarabinomannan and lipomannan.

Alveolar macrophages recognize M. tuberculosis PAMPs via toll-like receptors (TLRs)

Activation of TLRs leads to the production of proinflammatory cytokines (e.g., IL-1, IL-12, TNF-α) and phagocytosis of mycobacteria.

Replication within macrophages

Typically, phagocytosed organisms reside within a phagosome to undergo intracellular killing via the following steps:
[26]
Phagosome maturation: acidification using a proton pump system

Fusion of phagosome and lysosome: mediated by increased intracellular calcium levels [27]

Killing of bacteria by reactive oxygen species (ROS), reactive nitrogen intermediates (RNI), and lysosomal enzymes

M. tuberculosis survives within macrophages because of the inhibition of both phagosome maturation and phagolysosome fusion

Virulence factors involved include: [17]

Cord factor (trehalose-6,6'-dimycolate): a surface glycolipid that causes serpentine cord-like growth, inhibits neutrophil migration, and induces TNF-α
[28][29]
release to stimulate activated macrophages to form granulomas

Sulfatides: surface glycolipids that inhibit phagolysosome fusion [30]

Lipoarabinomannan: a lipoglycan that induces TNF-α release from macrophages and scavenges ROS

Catalase-peroxidase: an enzyme that catalyzes the destruction of ROS and H2O2

Macrophage lysis and release of bacteria

Following replication in the alveolar macrophages, the released bacteria attack uninfected macrophages to spread infection.

Dendritic cells migrate to the site of infection and process mycobacterial antigens.

Some bacteria enter the bloodstream, causing bacteremia and seeding multiple organs.

Cellular immune response

Th1 cell activation

Dendritic cells present mycobacterial antigens complexed with MHC 2 to naive T cells

Activated CD4+ T cells migrate to the focus of infection (type IV HSR).

Macrophage activation and bacterial killing

Activated CD4+ T cells release IFN-γ

IFN-γ acts on macrophages to enable bacterial killing via the following mechanisms:

Promotion of phagosome maturation

Enhanced RNI production

Autophagy

Granulomatous inflammation and tissue destruction

IFN-γ-activated macrophages secrete TNF-α.

TNF-α promotes the aggregation of macrophages and T cells to form granulomas, affecting the lungs and regional lymph nodes

Destruction of M. tuberculosis-infected macrophages causes central caseous necrosis and tissue damage.

Granuloma limits the spread of infection.

Ghon focus: a granuloma typically located in the middle/lower lung lobes.

Ghon complex: formed by the Ghon focus, regional lymph node, and the linking lymphatic vessels

Disease progression

Sufficient immune response

Most of the bacteria are killed.

Some bacteria may persist, causing LTBI.

The granulomas in the Ghon complex undergo fibrosis and calcification to form the Ranke complex.

Deficient immune response (e.g., HIV, malnutrition)

Failure of granulomas to limit infection

Progressive primary TB causing progressive lung disease, bacteremia, and miliary TB

Secondary tuberculosis [25]

Latent TB: Dynamic equilibrium is maintained between the host immune response and M. tuberculosis.

Reactivation of disease: due to weakening of immune response (e.g., resulting from HIV, TNF-α inhibitor therapy)

Disease progression

Caseating granulomas with central necrosis and Langhans giant cells are characteristic features.

Usually affects the upper lobes of the lungs because of higher oxygen tension

Can also affect other organs (due to seeding of organs in primary tuberculosis)

Prior sensitization to mycobacterial antigens results in a stronger inflammatory response, causing extensive tissue destruction, cavitation, and scarring.

Clinical features

Latent tuberculosis infection does not typically manifest with symptoms. Patients with primary TB are commonly asymptomatic.
Pulmonary tuberculosis [1]

Systemic

Low-grade fever with night sweats

Weight loss (often severe), anorexia

Decreased appetite

Malaise, weakness

Pulmonary

Non-productive cough

Symptoms of progression: productive cough with purulent sputum, hemoptysis

Shortness of breath
[31]
Pleuritic chest pain

Clinical examination: Findings are nonspecific.

General: pallor, clubbing (advanced disease), generalized wasting

Chest examination: Findings vary depending on the type and degree of pulmonary involvement.

Consolidation: dullness on percussion, crackles, diminished breath sounds

Cavitation: hyperresonance on percussion, amphoric breath sounds

Bronchial obstruction: rhonchi

Pleural effusion and/or empyema: dullness on percussion, diminished breath sounds

Other possible findings: erythema nodosum, phlyctenular conjunctivitis

Depending on the degree of immunosuppression, TB in HIV-positive individuals may progress atypically or more rapidly.

Always consider TB as a differential diagnosis in a young individual with hemoptysis and if treatment for other pulmonary conditions (e.g.,
pneumonia) does not improve symptoms.

Extrapulmonary tuberculosis
See “Extrapulmonary tuberculosis” for respective clinical features.

Diagnostics

This section reviews the diagnosis of active tuberculosis infection. For screening and diagnosis of latent TB, see the section “Latent tuberculosis.”
Approach [7]

Initial workup in all patients

Focused patient history (e.g., exposure to individuals with TB, history of visiting or living in countries with a high TB burden)

Microbiological studies

Initial tests: microscopy examination for acid-fast bacilli (AFB), nucleic acid amplification test (NAAT)

Confirmatory test: mycobacterial culture (gold standard)

Drug susceptibility testing: indicated in certain circumstances to identify resistant mycobacteria

Consider CT chest or CXR

Suspicion for extrapulmonary TB: Additional invasive procedures (e.g., lymph node biopsy, thoracocentesis) may be required for bacteriological
confirmation (see “Extrapulmonary TB”). [32]

Lung cancer is an important differential diagnosis of pulmonary TB. Start investigations for malignancy in any patient with systemic symptoms
(e.g., weight loss, persistent fevers, anorexia) and abnormal imaging.

TST and IGRA are screening tests for latent TB and do not aid in the diagnostics of active TB. [7]

Laboratory studies [1]

Laboratory findings are mostly unspecific but can provide important information during initial diagnostic stages. Possible findings include:

CBC: mild leukocytosis (common) , anemia (in advanced disease)

BMP: mild hyponatremia

Liver chemistries: ↑ in concomitant liver disease; useful as a baseline prior to treatment [33]

Other nonspecific findings: ↑ ESR, pyuria in renal disease [33]

Microbiological studies [7]

Confirmation of the presence of tuberculosis bacilli in different samples is done by direct visualization, positive culture, or by detecting genetic material.
Samples used for testing include: [7]
[7][34][35]
Sputum samples (most common): Obtain ≥ 3 samples separated by 8 to 24-hour intervals (should include at least one early morning sample).
[35]
Induced sputum
[36]
Gastric lavage

Bronchoalveolar lavage
[7]
Extrapulmonary TB suspected: Fluid specimens or tissue samples should be sent for cell count, chemistries, AFB smear microscopy, and NAAT.

Because sputum induction carries a high risk of transmission to health care workers, the procedure must be performed under strict infection
control precautions. [37]

Microbiological tests for active TB [7][38]

Test Description Advantages Disadvantages

Acid-fast Ziehl Neelsen stain or Rapid detection Low sensitivity [38]

auramine rhodamine stain are used.
bacilli smear Inexpensive Cannot differentiate M. tuberculosis from other
microscopy nontuberculous mycobacteria [39]

Both viable and nonviable mycobacteria will stain.

[40]

Nucleic acid For initial testing (along with High specificity and sensitivity (lower Requires laboratory equipment and trained staff,
AFB smear microscopy and culture) if sensitivity in individuals with a negative AFB which may make use in resource-limited settings more
amplification
clinical suspicion is high smear) [38] difficult
test
Used for confirmation of AFB positive Rapid diagnosis Both viable and nonviable mycobacteria are
smears [7] detectable. [37]
Rapid detection of drug-resistant strains
[38]

Low cross-reactivity with

nontuberculous mycobacteria [38]

Culture Gold standard diagnostic test High sensitivity [38] Takes 2 to 6 weeks for positive cultures to develop
[38]
Provides information on drug susceptibility Species identification
Delays the initiation of treatment, especially
Identification of drug resistance
drug-resistant TB

Request AFB and cultures of every sample obtained; request NAAT for the initial respiratory sample along with microscopy and culture if
clinical suspicion is high. [7]

Drug susceptibility testing [7]

Standard culture: used to assess for drug susceptibility in most patients; results are available after several weeks.

Rapid molecular testing : for select patients at high risk of resistant tuberculosis [7]

History of previously treated tuberculosis

Contact with individuals with MDR-TB

HIV infection
[7]
Patients born or having lived for ≥ 1 year in a country with moderate to high TB incidence or high MDR-TB prevalence

A negative AFB smear microscopy result does not rule out pulmonary TB and a confirmatory culture should be obtained. [7]

Imaging [7][8][41]

Indications: often performed as part of the diagnostic workup of patients with respiratory symptoms

Modalities: x-ray or CT chest

Findings

Highly variable and nonspecific, but can help narrow the differential diagnosis

In primary TB, chest x-ray is often normal.

Chest imaging findings in active TB [33][41]

Primary TB (middle/lower lobes) Postprimary (reactivation) TB

Chest x-ray Consolidation (homogeneous with ill-defined borders) Consolidation (patchy or confluent)
Hilar lymphadenopathy (commonly unilateral) Fibrocaseous cavitary lesions in upper lobes
Ghon complex Calcifications

Pleural effusion
Cavitation (rare)

CT chest Enlarged lymph nodes with low-attenuation center indicating central necrosis [8] Thick-walled cavities without an air-fluid level

Tree-in-bud pattern

Extensive cavitation can lead to areas of bronchiectasis and damaged lung areas can be colonized with Aspergillus spp., leading to
aspergillomas, sometimes referred to as fungus balls. [33]

Normal imaging does not rule out TB. Although radiographic changes are common in immunocompetent patients, individuals who are
immunocompromised can have normal imaging findings. [8][32][41]

HIV and TB coinfection

Diagnosing TB in patients with HIV coinfection is challenging because these individuals often have a negative AFB smear and commonly have atypical imaging
findings resulting from paucibacillary disease due to a reduced immune response. Different measures can be used to increase diagnostic sensitivity. [32][37]

Advanced testing in patients with HIV (not widely available) [37]

For most patients: fluorescent AFB smear microscopy , specialized culture mediums

For patients with severe disease and those with a CD4 count < 100 cells/mm3: lateral flow urine lipoarabinomannan assay [42][43][44]
[37]
In resource-limited settings: a lower threshold for defining smear positivity and consideration of empiric treatment may be necessary

In patients with HIV, the sensitivity of routine initial microbiological studies may be low; additional investigations may be required.

Obtain HIV tests in all patients with suspected (rather than confirmed) TB, as this can help to interpret test results. [37]

Differential diagnoses

Pulmonary TB

Typical pneumonia

Atypical pneumonia

COVID-19 pneumonia

Lung cancer

Lung abscess

Interstitial lung disease

See “Differential diagnosis of granulomatous disease.”

Sarcoidosis

Hodgkin lymphoma

Non-Hodgkin lymphoma

Pneumoconiosis

Granulomatosis with polyangiitis

Histoplasmosis

See “Nontuberculous mycobacterial infections” and “Mycobacterium avium complex infection.”

Brucellosis

Tularemia

Extrapulmonary TB

Leprosy

Syphilis

Erythema nodosum

Lymphoma

Multiple myeloma

Rheumatoid arthritis

Systemic lupus erythematosus

The differential diagnoses listed here are not exhaustive.

Treatment

This section reviews the treatment of active tuberculosis. For the treatment of latent TB, see the section “Latent tuberculosis.”
General principles [1][9]

Goals

Reduction of disease severity and risk of transmission

Eradication of all bacilli to achieve sustained cure without relapse following completion of treatment

Prevention of drug resistance during therapy

Infection control measures

[45]
Case notification: mandatory reporting to local health department

Airborne precautions: should include a surgical mask for the patient and adequate personal protective equipment (including respirators) for medical staff
[46]
and caregivers

Contact tracing: See “Prevention” section for testing indications.

Indications for treatment [9]

Confirmed active TB

Positive culture for M. tuberculosis

Positive NAAT (with positive or negative AFB smear microscopy)

Suspected active TB: Consider empiric treatment in all patients pending test results.

Factors favoring empiric treatment: high risk of disease progression and/or dissemination , imaging consistent with active TB, positive screening ,
critically ill patients, high transmission risk

Factors favoring delayed therapy: no known TB exposure, high risk of therapy side effects, negative NAAT (with positive or negative
AFB smear microscopy)

Empiric treatment with standard antituberculosis therapy is indicated in most cases in which active infection is suspected. [9]

Pretreatment evaluation [9]

Clinical assessment

Nutritional assessment

Symptom review

Eye exam: visual acuity and color discrimination

Microbiology: sputum smear microscopy and culture, drug susceptibility testing

Imaging: chest x-ray or other chest imaging

Laboratory studies

All patients: liver chemistries; , platelet count, creatinine, HIV screening

Depending on risk: hepatitis B and hepatitis C screening, diabetes screen

Antituberculosis therapy

Standard antituberculosis therapy [9]

[9]
Intensive phase: 2 months of rifampin: PLUS isoniazid , pyrazinamide , and ethambutol
[9]
Continuation phase: 4 months of rifampin: PLUS isoniazid

Adjuvant treatment: : Pyridoxine ; to prevent vitamin B6 deficiency resulting from isoniazid (promotes pyridoxine excretion) for all individuals at risk of
[9]
neuropathy

Additional considerations

Self-administered and daily dosages are preferred

Directly observed therapy (DOT; standard practice): Health care personnel observe the patient taking the medication.

Restart full treatment if there is an interruption of ≥ 14 days during the intensive phase.

Standard first-line therapy consists of 6 months with isoniazid and rifampin plus ethambutol and pyrazinamide during the first 2 months.

"RIPE": Rifampin, Isoniazid, Pyrazinamide, and Ethambutol

 The long duration of treatment for active TB requires patient-centered coordination with primary care and specialist services and
directly observed therapy (DOT) to ensure adherence. [47]

Treatment of drug-resistant TB disease [10]

This includes MDR-TB and XDR-TB . Consultation with infectious disease experts is required.

Agents

Oral: later-generation fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline, linezolid, clofazimine, cycloserine

IV: amikacin, streptomycin, and carbapenem with amoxicillin-clavulanic acid

[10]
Phases of treatment: Combine at least 5 drugs for the intensive phase, and at least 4 drugs for the continuation phase.

Role of surgery: Elective partial lung surgery can be beneficial.

Treatment of extrapulmonary TB [9]

Treatment of extrapulmonary TB is usually guided by experts, and the choice of agents and duration of treatment are dependent on the site of manifestation.

Standard antituberculosis therapy: used for lymph node, pleural, miliary, pericardial, adrenal, gastrointestinal, and genitourinary TB

Extended regimens

TB meningitis

2 months of 4-drug intensive phase, followed by 7–10 months of continuation phase with isoniazid and rifampin

Adjunctive glucocorticoid treatment with dexamethasone or prednisolone for 6–8 weeks

Pott disease and other bone and joint TB: treatment duration of at least 9 months; surgery may be necessary.

Consultation with a specialist is always advised in all patients with extrapulmonary TB, especially for miliary disease.

Side effects of antituberculosis agents [9]

Mild side effects can usually be managed with symptomatic treatment, while more severe side effects (e.g., significant hepatotoxicity, optic neuritis) usually
require one or more drugs to be discontinued and replaced in consultation with a specialist.

General side effects: may be caused by any of the drugs commonly used in standard antituberculosis therapy

Hepatotoxicity (most common serious side effect)

Rash, pruritus

GI symptoms

Allergic and nonallergic hypersensitivity reactions

Specific side effects of antituberculosis drugs [9]

Isoniazid Asymptomatic elevation of transaminases

Cytochrome P450 inhibition: leading to interactions with numerous drugs, including antiretroviral agents, cardiovascular agents, and antibiotics
Less common
Drug-induced lupus

Vitamin B6 deficiency: sideroblastic anemia, peripheral neuropathy [48]

CNS toxicity: psychosis, ataxia, precipitation of benzodiazepine-refractory seizures with high doses of isoniazid [49][50][51]

Others: anion gap metabolic acidosis, pellagra, optic neuritis [9][49][52]

Rifampin Transient asymptomatic elevation of bilirubin, clinical hepatitis with a cholestatic injury pattern
Cytochrome P450 induction: leading to important interactions with ART in patients with HIV (therefore, rifabutin is preferred)
Orange discoloration of body fluids (e.g., urine, tears)

Thrombocytopenia
False-positive result on urine opiate screening

Pyrazinamide Greatest hepatotoxicity potential

Hyperuricemia [9]

Arthralgia
Photosensitivity

Ethambutol Optic neuritis (reversible red-green color blindness)

Hyperuricemia [53]

Rifampin and isoniazid alter the efficacy of drugs metabolized by cytochrome P450 (especially protease inhibitors, NNRTIs, OCPs, warfarin,
sulfonylureas).

Monitoring [9][45]
Monthly follow-ups are recommended in all patients receiving antituberculosis treatment for active TB or LTBI.

All patients

Assess adherence to therapy.

Perform a symptom review and screen for clinical features of active TB.

Monitor for side effects.

Patients with active TB

Sputum smear microscopy and culture

Weight and vision assessment

Laboratory studies: If indicated, obtain liver chemistries, platelet count, and creatinine.

Advise patients to self-monitor for features that suggest hepatitis (e.g., jaundice, fatigue, anorexia, abdominal pain) and seek prompt medical
attention if any of them arise. [45]

Latent tuberculosis infection

Description

A state of constant immune response stimulation due to M. tuberculosis antigens, with no signs of active TB infection

Individuals with latent TB are asymptomatic and not contagious.

M. tuberculosis remains dormant within the host and may be reactivated once the immune system becomes compromised (e.g., by high doses of
glucocorticoids or chemotherapeutic agents, HIV infection).

Epidemiology [13]

The prevalence of LTBI in the United States is estimated to be 5%

5–10% of untreated cases progress to active TB if left untreated.

Diagnosis [7][45]

[7][54][55]
Screening for LTBI

The decision of whether to test an individual should be carefully considered based upon the likelihood of someone having LTBI, the likelihood of progression
of LTBI to active TB, and the potential benefit of therapy.

Individuals with a high likelihood of LTBI (i.e., high risk of TB exposure; see also “Risk factors for tuberculosis”) [7][45]

Known contact with AFB smear-positive individual

[55]
Individuals born in or former residents of countries with a high TB burden (> 20 cases per 100,000 population)

People who live or work in high-risk settings (e.g., correctional facilities, long-term care facilities or nursing homes, homeless shelters)

Health-care workers who care for patients at increased risk for TB disease

Children (< 18 years of age) exposed to adults at increased risk for tuberculosis infection

Individuals with a high likelihood of progression from LTBI to active TB [7][45]

High risk factors:

HIV infection

Immunosuppressive therapy, including: [56]

[57][58]
Corticosteroid therapy
[59]
TNF-α inhibitor therapy (e.g., infliximab)

Others: methotrexate, cyclosporine; drugs used for organ transplant and stem cell transplant recipients

Silicosis

Age < 5 years

Prior TB infection

Intermediate risk factors: diabetes, chronic kidney disease; , IV drug use

Other risk factors:

[60]
Smoking
[61]
Heavy alcohol consumption

Malnutrition, low body mass index

[62]
Advanced age

Malignancy

Gastrectomy or jejunoileal bypass

All patients with HIV should be screened for LTBI, regardless of additional risk factors. [45]

All individuals due to start immunosuppressive therapy should be screened for LTBI. [56]

Selection of screening test [7]

[45]
Most patients: IGRA (preferred in those who have had the BCG vaccine) or TST

Patients with HIV, children aged < 5 years, immunocompromised patients

TST and chest x-ray

OR IGRA and chest x-ray

Screening tests for LTBI [7]

Tuberculin skin test (purified protein derivative test, Mantoux test) [63] Interferon-γ release assay (IGRA) [64]

Mechanism Tests cell-mediated immunity against M. tuberculosis via Tests cell-mediated immunity against M. tuberculosis-specific antigens by
delayed hypersensitivity reaction (type IV HSR) mounted by T cells measuring the amount of IFN-γ released by T cells using ELISA

Procedure Step 1: 0.1 mL (or 5 units) of purified protein derivative (PPD) injected QuantiFERON-TB Gold In-Tube (QFT) assay: Whole blood is drawn into
intradermally on the volar surface of the forearm resulting in wheal formation three test tubes in the following order: [65]
Step 2: transverse diameter of palpable induration checked 48–72 hours later 1. Negative control tube

2. TB antigen test tube

3. Positive control tube containing mitogen

T-SPOT.TB assay: One sample of whole blood is required. [64]

Benefits Inexpensive Only requires a single office visit

Preferred test in children < 5 years of age [7] Preferred test in individuals with prior BCG vaccination

Results are available within 24 hours. [45]

Limitations Does not differentiate between active and latent TB No differentiation between active and latent TB

Variability in test interpretation [64] Expensive [45]

Requires two office visits Errors in collecting and transporting blood can decrease accuracy. [13]

False positives resulting from either of the following:

Prior BCG vaccination
Exposure to nontuberculous mycobacteria
False negatives are possible in patients with any of the following:
Sarcoidosis [66]

Immunosuppressed state (anergy)

Age < 6 months
Recent (within 8–10 weeks) or very old (many years) TB infection
Recent live-virus vaccination

Disseminated TB disease

Interpretation of results [7][45]

IGRA

Positive: TB infection is likely

Negative: TB infection is unlikely, but cannot be excluded

Indeterminate: can occur in inflammation or infection; and/or immunosuppressed states (e.g., due to immunomodulatory medications and/or HIV
infection), and a repeat IGRA or TST can be useful [67]

TST: Depending on patient characteristics, a TST can be positive with an induration ≥ 5 mm, ≥ 10 mm, or ≥ 15 mm.

For healthy individuals with no risk factors, an induration < 15 mm is considered negative for TB.

Positive TST according to induration diameter [45]

≥ 5 mm Individuals exposed to AFB smear-positive case

Individuals with HIV

Individuals with clinical or radiographic evidence of active or prior TB

Individuals with organ transplants or receiving immunosuppressive therapy

≥ 10 mm Individuals who have moved within the last 5 years from a country with a high TB burden (> 20 cases per 100,000 population) [7]

Individuals living or working in high-risk settings (e.g., homeless shelters, prisons)

Individuals who inject drugs
Mycobacteriology laboratory workers

Individuals with illnesses such as diabetes and CKD

Children < 5 years of age
Children who have had contact with adults in high-risk categories

Individuals with low BMI

≥ 15 mm All otherwise healthy individuals with no known risk factors [68]

The diagnosis of LTBI is based on a positive screening result in patients with a medical history and physical examination consistent with latent
disease, once active TB has been excluded. [13]

If screening for LTBI is positive, it is still necessary to exclude active TB prior to starting treatment for LTBI because neither screening test can
differentiate between active and latent infection. [13]

Further evaluation

Management of individuals screened for TB [69]

Initial management Further management

Positive IGRA or TST Chest x-ray to exclude active TB Chest x-ray is normal: Treat for LTBI.
Individuals with low risk: Diagnosis can be confirmed with dual testing using the same Chest x-ray is abnormal: Work up for active TB.
or a different testing method. [70]

IGRA or If < 8–10 weeks Immunocompetent individuals and children ≥ 5 years of age: no treatment; repeat Repeat screening test is positive: chest x-ray
screening test 8–10 weeks following exposure. Chest x-ray is normal: Treat for LTBI.
TST since exposure
Immunocompromised individuals and children < 5 years of age: Start treatment for Chest x-ray is abnormal: Work up for active TB.
negative
LTBI until TST or IGRA is repeated 8–10 weeks following exposure. Repeat screening test is negative
No treatment is required; stop treatment if
already initiated.

HIV patients: Consider completing LTBI

treatment if exposed to an individual with
active TB.

If > 8–10 weeks No further evaluation is required.

since exposure

If health care workers are exposed to an individual with active TB without adequate personal protective equipment, IGRA or TST must be
performed immediately and repeated after 8–10 weeks if the initial test is negative. [71]

Special situations [45]

HIV infection: Screen for LTBI at the time of diagnosis and repeat annually in patients at risk of exposure.

BCG vaccine: may cause false-positive results in TST; if available, IGRA is preferred.

Screening prior to starting immunosuppressive therapy: Follow the usual screening algorithm, but consider a second test if the initial screening test is
[72]
negative.

Individuals who are periodically tested with TST

TST results may be affected by booster phenomenon

Consider two-step TST in select cases to avoid misinterpretation; two-step testing is not required if IGRA is used as a baseline test.

Method: initial baseline TST and a second TST 1–3 weeks later
[73]
Interpretation: Repeat TST is considered positive if TST conversion occurs.

Negative repeat TST: LTBI is unlikely and no further management is required.

Positive repeat TST: A boosted reaction has occurred and LTBI is likely and requires further management.

Treatment

The primary goal of the treatment of latent TB is to prevent reactivation to active TB.

Pretreatment considerations [45]

Medical and drug history

Baseline liver chemistries (for all individuals at risk of liver injury)

Exclusion of active TB: Patients should have no clinical or radiological evidence of TB.

Most patients: Obtain AFB smear microscopy ONLY if symptoms or radiological features are identified.

Patients with HIV: Consider AFB smear microscopy regardless of symptoms or radiological features.

Case notification: Reporting to the local health department is advised and may be mandatory in some locations.

Infection control: Airborne precautions are not required once active pulmonary TB has been excluded. [74]

Patient education: Provide information about treatment and its side effects, methods available to support adherence to therapy, and instructions to seek
medical attention if side effects occur.

Pharmacotherapy of LTBI [45]

Pharmacological therapy: indicated for patients with positive IGRA or TST after active TB has been excluded

Select a regimen based on the length of treatment, drug tolerance, pharmacological interactions, and HIV status.

Drug regimens for treatment of LTBI [45]

Detailed regimen Indications

Short Once-weekly isoniazid PLUS once-weekly rifapentine for 3 months (abbreviation: 3HP) Most patients > 2 years of age
[45]
regimens Select patients with HIV/AIDS

PLUS pyridoxine (for all individuals at risk of peripheral neuropathy from INH) [45]

Once-daily rifampin for 4 months (abbreviation: 4R) [45] HIV-negative patients of any age who:
Are unable to tolerate INH
OR have been exposed to INH-resistant TB

Long regimens Once-daily isoniazid for 6 months (abbreviation: 6H) [45] Most patients with HIV

[45] Patients of any age with contraindications for rifamycins

Once-daily isoniazid for 9 months (abbreviation: 9H)
[75]
PLUS pyridoxine (for all individuals at risk of peripheral neuropathy from INH) [45]

Rifampin and rifapentine are not interchangeable and clinicians and pharmacists should be careful to prescribe and administer the correct drug.

Extrapulmonary tuberculosis

This section provides an overview of the most common types of extrapulmonary tuberculosis.
Tuberculous lymphadenitis [76]

Pathophysiology

Hematogenous dissemination following primary TB

Local extension of infection from the affected organ

Sites of lymph node involvement

Cervical

Inguinal

Axillary

Clinical features

Constitutional symptoms
[77]
Lymphadenopathy: Findings vary depending on the stage of lymphadenitis.

Lymphadenitis: firm, mobile, and discrete lymph nodes

Periadenitis: rubbery and fixed lymph nodes

Cold abscess: soft and fluctuant lymph nodes

Draining sinus tract

Diagnostics

Ultrasound or CT: matted lymph nodes with a necrotic center

FNAC: acid-fast staining, PCR, and culture

Lymph node biopsy: histopathology

Treatment: See “Treatment of active TB.”

Tuberculous hilar lymphadenopathy [1][78]

Pathophysiology

Lymphatic spread of M. tuberculosis from the lung during primary TB infection

Bronchus compression

Total: causes distal airway collapse

Partial: causes ball-valve effect and hyperinflation

Clinical features

Commonly seen in children

Wheezing

Mostly asymptomatic

Diagnostics: chest x-ray or CT

Unilateral or bilateral enlarged hilar lymph nodes

Lung atelectasis

Hyperinflation

Treatment: See “Treatment of active TB.”

Tuberculous pleurisy [79]

Pathophysiology

Direct spread of infection from the lungs

Hematogenous spread

Delayed hypersensitivity reaction in the pleural space due to mycobacterial antigen

Clinical features

Constitutional symptoms

Nonproductive cough

Intensive (pleuritic) chest pain

Dyspnea

Diagnostics

Imaging

Chest x-ray: unilateral pleural effusion

Chest ultrasound or CT: loculated effusion with septations; pleural thickening

Thoracentesis: pleural fluid analysis [80]

Exudative type (Light criteria)

pH: < 7.4

Glucose: < 60 mg/dL

↑ Adenosine deaminase

Rich in lymphocytes

Microbiology: acid-fast staining, PCR, and culture

Sputum smear examination: acid-fast staining

Treatment

Therapeutic thoracentesis for symptom relief

See “Treatment of active TB.”

Miliary tuberculosis [81]

Definition: a form of TB with multiorgan involvement that manifests with granulomatous lesions (resembling millets) as a result of lymphohematogenous
dissemination of bacilli from a pulmonary or extrapulmonary source

Epidemiology: ∼ 20% of extrapulmonary TB cases [82]

Pathophysiology: primary infection or reactivation

Common sites of involvement: lungs, spleen, liver, lymph nodes, adrenals, meninges, vertebrae (Pott disease), joints and long bones, and choroid

Clinical features: mostly nonspecific

Cough and dyspnea

Constitutional symptoms

Lymphadenopathy

Hepatosplenomegaly

Tuberculosis miliaria cutis disseminata

Diagnostics: requires a high index of clinical suspicion

Fundoscopy: choroid tubercles

Microbiology: sputum, body fluids, and tissue

Acid-fast staining

PCR

Culture

Blood

↑ ESR and CRP

CBC: anemia, leukopenia

LFT: elevated transaminases and bilirubin

Electrolytes: hyponatremia, hypercalcemia

TST: negative

Imaging
[82]
Chest x-ray: multiple small nodules (< 2 mm) with an appearance resembling millet seeds

Ultrasound: pleural effusion, ascites, hepatic or splenic lesions

CT: lung nodules, enlarged hilar lymph nodes

Brain MRI: meningeal and/or basal cistern enhancement, hydrocephalus, tuberculoma

Echocardiography: pericardial effusion

Treatment: See “Treatment of active TB.”

Tuberculous meningitis

For clinical presentation and diagnostics, see “Tuberculous meningitis.”

For therapeutic options, see “Treatment of active TB.”

Pericardial tuberculosis [83][84]

Pathophysiology

Hematogenous spread from the site of primary infection

Retrograde lymphatic spread from hilar lymph nodes

Stages

Stage 1: fibrinous exudate containing neutrophils and mycobacteria

Stage 2: serosanguineous effusion with lymphocytes

Stage 3: absorption of effusion and caseating granulomas

Stage 4: scarring with calcification

Types

Pericardial effusion (rarely, cardiac tamponade)

Constrictive pericarditis

Effusive-constrictive pericarditis

Clinical features

Constitutional symptoms

Chest pain

Cough

Dyspnea

Physical examination findings: See “Clinical features” in “Pericardial effusion and cardiac tamponade” and “Pericarditis.”

Diagnostics

ECG: nonspecific ST-T changes

Imaging

Chest x-ray: enlarged cardiac silhouette or calcification

Echocardiography: effusion or diminished wall motility

Pericardiocentesis

Analysis: exudative, blood-stained

Microbiology: acid-fast staining, PCR, and culture

↑ Adenosine deaminase

Treatment

See “Treatment of active TB.”

Therapeutic pericardiocentesis

Adrenal tuberculosis [85]

Clinical features: See “Adrenal insufficiency.”

Diagnostics

CT/MRI: bilateral enlargement or calcification of adrenal glands

See “Diagnostics” below.

Management

Corticosteroid replacement

See “Treatment of active TB.”

Rifampin can precipitate an acute adrenal crisis in patients with undetected adrenal insufficiency due to tuberculosis.

Cutaneous tuberculosis [81][86]

Classification: based on pathogenesis, morphology of the lesion, and histopathological features

Types of cutaneous TB

Type Pathophysiology Clinical features Histopathology

features

Exogenous source of TB

Primary inoculation TB ( Inoculation of M. tuberculosis via broken skin or mucosa Firm and nontender ulcer Granulomatous
inflammation
tuberculous chancre) Individual has no prior immunity against TB Lymph node enlargement and
with
abscess formation that heals
caseous necrosis
with calcification
Acid-fast bacilli

Postprimary inoculation Inoculation of M. tuberculosis via broken skin or mucosa Hyperkeratotic papule Hyperkeratosis

TB ( Individual has prior immunity against TB No lymphadenopathy

tuberculosis verrucosa
cutis
)

Endogenous source of TB

Scrofuloderma Contiguous involvement of skin overlying structures (e.g., lymph node, joint, Firm nodule or swelling that Granulomatous
epididymis) infected with TB ulcerates to form a discharging inflammation
sinus tract with
caseous necrosis

Autoinoculation M. tuberculosis inoculated into orifices when secretions are expectorated (e.g., Site: oral cavity or Acid-fast bacilli
pulmonary TB) or passed (e.g., genitourinary or gastrointestinal TB) perineal region
Tender ulcers

Hematogenous source of TB

Lupus vulgaris Individuals previously sensitized to TB with a high degree of sensitivity Site: face or neck Nonspecific features
Plaques or nodules with
ulceration or scarring
Diascopy: apple jelly nodules

Tuberculosis miliaris Acute dissemination of M. tuberculosis from the primary focus of infection (e.g., Site: trunk, thighs, buttocks, Nonspecific
lungs, meninges) in individuals with impaired immunity (e.g., as a result of measles genitalia inflammation with
cutis disseminata
or HIV infection) necrotizing
Widespread papules and
vasculitis
crusted vesicles
Acid-fast bacilli

Tuberculous gumma ( Subacute dissemination of M. tuberculosis in immunocompromised individuals Multiple skin nodules that may Granulomatous
ulcerate to form discharging inflammation
metastatic tuberculous
sinus tract with
abscess caseous necrosis
)
Acid-fast bacilli

Tuberculid

Variable forms Unknown Papules or nodules with Nonspecific

ulceration and scarring inflammation
No acid-fast bacilli

Diagnostics: skin biopsy for histopathology, acid-fast staining, and culture

Treatment: See “Treatment of active TB.”

Gastrointestinal tuberculosis [87][88]

Pathophysiology

Ingestion of infected milk or sputum

Hematogenous spread resulting from primary pulmonary TB

Contiguous spread via affected lymph nodes

Sites of involvement: See “Types of gastrointestinal TB” below.

Types of gastrointestinal TB

Site of involvement Clinical features Diagnostics Differential diagnosis

Peritoneum Abdominal pain Abdominal ultrasound: loculated ascites with septations Peritoneal
carcinomatosis
Ascites CT abdomen
Lymphadenopathy with central necrosis Ovarian cancer
Fever and weight loss
Peritoneal thickening

Ascitic fluid analysis

Predominant lymphocytes
Low SAAG ascites
↑ Adenosine deaminase

Esophagus Dysphagia Barium swallow: stricture, fistula, traction diverticula Esophageal carcinoma

Retrosternal chest Endoscopy: ulceration Sarcoidosis

pain CT chest: mediastinal lymphadenopathy

Stomach Epigastric pain Upper GI endoscopy: ulceration, pyloric stenosis Gastric carcinoma

Fever and weight loss Gastric lymphoma

Crohn disease

Jejunum and ileocecal Small bowel Abdominal x-ray Crohn disease

obstruction Dilated bowel loops with multiple air fluid levels (intestinal obstruction)
region
Free air under the diaphragm (perforation)
Barium follow-through study: multiple strictures, matted bowel loops
CT abdomen
Bowel wall thickening

Exophytic growth in the ileocecal region

Mesenteric lymphadenopathy

Colorectal Abdominal pain Barium enema: strictures, fistula Crohn disease

Weight loss Colonoscopy Colon carcinoma

Transverse and superficial ulcers with yellow exudates and surrounding hyperemic
Loss of appetite Pseudomembranous
mucosa colitis
Altered bowel habits
Friable mucosal nodules
Annular and short segment strictures (< 3 cm)

Treatment

Surgical: for intestinal obstruction, perforation, fistula, abscess

Medical: See “Treatment of active TB.”

Urogenital tuberculosis [81][89]

Renal and urologic TB

Pathophysiology

Hematogenous spread of infection to the kidneys as a result of primary pulmonary TB that is reactivated in immunosuppressed states

Ureters and bladder are infected when bacteria are excreted in urine.

Common sites of involvement

Kidneys

Ureters

Bladder

Clinical features

Constitutional symptoms

Flank pain

Hematuria

Storage symptoms

Increased frequency of voiding

Nocturia

Urgency

Hypertension

Recurrent UTIs unresponsive to antibiotic therapy

Diagnostics

Urine examination

Analysis: hematuria, sterile pyuria, proteinuria

Microbiology: acid-fast staining, PCR, and culture

Imaging: CT or IV urography

Renal scarring

Hydroureteronephrosis

Calcification involving the entire urinary tract

Multiple ureteral strictures

Bladder wall thickening and fibrosis

Cystoscopy

Ulceration

Granuloma

Fibrosis

Treatment

Medical: See “Treatment of active TB.”

Ureteral stenting for strictures

Surgery

Total or partial nephrectomy

Bladder augmentation

Male genital tract TB

Pathophysiology

Hematogenous spread of infection to the epididymis and prostate

Extension of infection from the epididymis to the testis, vas deferens, seminal vesicles, and ejaculatory ducts

Common sites of involvement

Epididymis

Testis

Prostate

Vas deferens, seminal vesicles, and ejaculatory duct

Clinical features

Scrotal mass (can be painful or painless)

Scrotal sinus tract with watery discharge

Infertility

Increased urinary frequency, nocturia, and hematospermia

Recurrent prostatitis or epididymitis unresponsive to antibiotic therapy

Diagnostics

Urine examination

Analysis: hematuria, sterile pyuria

Microbiology: acid-fast staining, PCR, and culture

Scrotal ultrasound

Calcification

Hydrocele

Diffuse or nodular enlargement of the epididymis

Transrectal ultrasound: calcification in prostate and seminal vesicles

Treatment: See "Treatment of active TB.”

Female genital tract TB [90]

Pathophysiology: hematogenous spread of infection as a result of primary pulmonary TB that is reactivated in immunosuppressed states

Common sites of involvement

Ovaries

Fallopian tubes

Endometrium

Clinical features

Constitutional symptoms

Menstrual irregularities

Abdominal pain

Infertility

Adnexal mass on pelvic examination

Diagnostics

Menstrual fluid or endometrial curettage sample: acid-fast staining, PCR, and culture

Imaging

Ultrasound/CT: tuboovarian abscess

Hysterosalpingography: occluded fallopian tubes, hydrosalpinx, calcification

Hysteroscopy: adhesions and obliterated uterine cavity

Treatment

Medical: See “Treatment of active TB.”

Surgery: drainage of tuboovarian abscess

Pott disease [81]

Pathophysiology

Hematogenous dissemination of infection to vertebral bodies following primary TB

Infection from vertebral bodies spreads to the intervertebral disk, causing destruction and collapse of the disk

Common sites of involvement: thoracic and lumbar vertebrae

Clinical features

Constitutional symptoms

Back pain

Spinal tenderness

Kyphosis

Gibbus deformity

Neurological deficit (e.g., paraplegia)

Diagnostics

Imaging: x-ray, CT, or MRI of the spine

Involvement of multiple vertebrae

Osteoporosis of vertebral endplate

Disk space narrowing

Lytic lesions in the anterior vertebral body

Collapse of the vertebral body

Enlarged psoas muscle shadow (psoas abscess)

Spinal cord compression (seen on MRI)

See “Diagnostics of active TB.”

Treatment

Surgical: abscess drainage and/or spinal stabilization are indicated in patients with worsening or severe neurological deficits and spinal instability.

Medical: See “Treatment of active TB.”

Pathology

Gross pathology [24]

Multiple granulomas coalesce as grayish-white areas with necrotic centers that have a cheese-like appearance.

Calcification and fibrosis are visible in healed lesions.

Ghon complex

Lung parenchyma: gray-white areas of consolidation

Hilar lymph nodes: caseous necrosis

Histopathology [24]
Caseating tuberculous granulomas are pathognomonic of reactivation (secondary) tuberculosis.

Center: area of necrosis

Periphery: epithelioid histiocytes and Langhans giant cells

Although caseating tuberculous granulomas are a sign of a functioning immune system in TB infection, they do not necessarily indicate TB
infection because other mycobacteria (including tuberculoid leprosy) and tertiary syphilis manifest similarly.

Histopathology of other types of tuberculosis

Acinar nodular tuberculosis: merging of multiple epithelioid granulomas into macroscopically visible areas of necrosis

Miliary tuberculosis: single, small, and nodular foci without central necrosis

Urogenital tuberculosis [91]

Step-like progression with an initial singular focus of tuberculosis

Gradually increasing destruction of the renal calyces

During the end stage, the kidney appears to have homogeneous, sac-like collections of calcified caseous material on plain abdominal x-ray (known as
“putty kidney").

Complications

Rasmussen aneurysm: inflammatory pseudoaneurysm of a branch of the pulmonary artery lying adjacent to a tuberculous cavity and manifesting with
hemoptysis

Massive hemoptysis: due to erosion of blood vessels overlying a lung cavity, Rasmussen aneurysm, or aspergilloma

Lung cavitation

Lung fibrosis

Aspergilloma

Pneumothorax

Bronchiectasis

Fibrosing mediastinitis

Venous thromboembolism

We list the most important complications. The selection is not exhaustive.

Prevention

Bacillus Calmette-Guérin vaccine (BCG) [92]

Composition: live attenuated strain of M. bovis

Administration: 0.3 mL of reconstituted vaccine using a multiple puncture device over the deltoid region

Indications

Countries with a high TB burden: all newborns at birth [93]

[93]
Countries with a low TB burden

Children with a negative TST and who have come into contact with adults with untreated/inadequately treated TB or drug-resistant TB (if the child
cannot take long-term medication for infection)

Health care workers continually exposed to individuals with drug-resistant TB

Other uses: intravesical chemotherapy in superficial bladder cancer

Benefits: protects against tuberculous meningitis and miliary TB in children [94]

Adverse effects

Localized lymphadenitis and abscess

Disseminated TB disease

Contraindications

Immunocompromised individuals

Pregnancy

The BCG vaccine is not widely used in the US and is only given to very select people in consultation with a TB expert. [95]

Disinfectants active against M. tuberculosis [96]

Hydrogen peroxide

Phenol

Iodophor

Chlorine-based solutions

Glutaraldehyde

Contact tracing and postexposure management [69]

Contact tracing is standard practice in resource-rich countries. Contact tracing and treatment are usually prioritized in cases involving patients with highly
infectious TB, vulnerable contacts, or high-risk exposures. [69][97]

Exposure risk assessment

Factors that increase contagiousness of the index case

Pulmonary or laryngeal TB

Positive sputum smear microscopy

Cavitary lesions on chest x-ray

Untreated or inadequately treated TB

Factors that increase contacts' vulnerability to infection

Age < 5 years

Immune status: HIV infection, corticosteroid use

Comorbid conditions

Type of exposure: intensity, frequency, duration of exposure

Management of contacts

Symptomatic contacts: Obtain sputum smear microscopy and chest x-ray and manage according to results.

Asymptomatic contacts: Screening tests are indicated, see “Latent tuberculosis” for recommendations on test selection and next steps.

Offer HIV testing to all contacts if HIV status is unknown. [69]

Contact tracing is recommended if the index case has pulmonary or laryngeal TB or has a positive AFB smear. [69]

Postexposure management in health care settings [71]

All US health care workers are screened for LTBI at the beginning of their employment.

Health care workers with previous documented LTBI or active TB do not need a screening test after exposure and should be evaluated if features of
active TB develop.

Special patient groups

Management of TB in pregnant individuals [9][45][98]

General [45][98]

The diagnostic workup is the same as for nonpregnant individuals.

Indications for TB testing include:

Symptoms of TB

Risk factors for TB

A high likelihood of progression from LTBI to active TB (see “Screening for LTBI”)

Abdominal shielding should be used to protect the fetus when performing chest x-rays.

Liver transaminases should be monitored in patients receiving isoniazid due to an increased risk of isoniazid-induced hepatotoxicity during pregnancy and
the postpartum period.

Latent TB [45][98]

Active TB must to be ruled out by symptom review and chest x-ray before initiating treatment for LTBI.

Treatment can be delayed until 2–3 months postpartum for women who are not at increased risk of developing active TB.

Treatment should not be delayed in patients at high risk of developing active TB.

Drug regimens for treatment of LTBI in pregnant women [45]

Detailed regimen

Short regimens Isoniazid and rifampin once daily for 3 months (abbreviation: 3HR) PLUS pyridoxine

Rifampin once daily for 4 months (abbreviation: 4R)

Long regimens Isoniazid once daily for 6 months (abbreviation: 6H) or 9 months (abbreviation: 9H) PLUS pyridoxine

The 3HP regimen (once-weekly isoniazid and once-weekly rifapentine) is not recommended for pregnant women or women planning to
become pregnant during the treatment period due to lack of data on safety during pregnancy. [45]

Active TB [9][98]

Special considerations
[9]
Pyrazinamide use during pregnancy is controversial and should only be considered if the potential benefits outweigh the potential risks.

If pyrazinamide is not used, pregnant patients with drug-susceptible pulmonary TB should be treated for at least 9 months.

For extrapulmonary or drug-resistant TB, seek specialist advice. [10]

Standard first-line regimen

Intensive phase: daily rifampin, isoniazid, and ethambutol for 2 months

Continuation phase: daily rifampin and isoniazid for 7 months

Adjuvant treatment: pyridoxine to prevent vitamin B6 deficiency

Active TB [9][98]

Standard first-line regimen

Intensive phase: daily rifampin, isoniazid, and ethambutol for 2 months

Continuation phase: daily rifampin and isoniazid for 7 months

Adjuvant treatment: pyridoxine to prevent vitamin B6 deficiency

Extrapulmonary or drug-resistant TB: Seek specialist advice. [10]

Special considerations on pyrazinamide

While the WHO recommends pyrazinamide as part of the standard treatment regimen for pregnant women, the CDC and FDA does not recommend its
routine use in pregnant women due to a lack of studies in animals as well as humans. [9][98]

If pyrazinamide is not used, pregnant patients with drug-susceptible pulmonary TB should be treated for at least 9 months.

Standard first-line therapy for pregnant patients consists of 9 months with isoniazid and rifampin plus ethambutol during the first 2 months.

Streptomycin, kanamycin, amikacin, capreomycin, and fluoroquinolones are contraindicated during pregnancy.

Management during the postpartum period [9][98][99]

Isolation: Mothers do not need to isolate themselves from their babies after birth but should wear a surgical mask.

Breastfeeding recommendations

Breastfeeding should be encouraged in women receiving treatment with standard first-line agents.

Mothers should be informed that rifampin can cause harmless orange discoloration of breastmilk.

Exclusively breastfed infants should also receive prophylactic pyridoxine if the mother is taking isoniazid.

Complications of TB during pregnancy [99]

Maternal

Preeclampsia

Eclampsia

Antepartum hemorrhage

Miscarriage

Fetal

Intrauterine growth restriction

Preterm birth

Low birth weight

Increased risk of vertical HIV transmission [100]

Congenital TB (rare)

Perinatal death

Related One-Minute Telegram

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