Tuberculosis (TB) (see the image below), a multisystemic disease with myriad presentations and

manifestations, is the most common cause of infectious diseaserelated mortality worldwide. Although TB
rates are decreasing in the United States, the disease is becoming more common in many parts of the
world. In addition, the prevalence of drug-resistant TB is increasing worldwide.

Anteroposterior chest radiograph of a young patient who presented to the

emergency department (ED) with cough and malaise. The radiograph shows a classic posterior segment right upper
lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine
(remotemedicine.org).

See 10 Travel Diseases to Consider Before and After the Trip, a Critical Images slideshow, to help identify
and manage infectious travel diseases.

Essential update: FDA approves rifapentine for latent TB infection

The antimycobacterial rifapentine (Priftin), which was previously approved for use against active pulmonary
TB caused by Mycobacterium tuberculosis, has now been approved by the US Food and Drug
Administration (FDA) for use, in combination with isoniazid, in the treatment of latent TB infection. Therapy
was approved for patients aged 2 years or older who are at high risk of progression to TB disease. [1, 2]
FDA approval for the new indication was partially based on a randomized study of more than 6000 patients
in which a 12-dose, once-weekly regimen of directly observed therapy (DOT) with rifapentine plus isoniazid
was compared with a regimen consisting of 9 months of self-administered daily isoniazid. The cumulative
rate of tuberculosis disease development was 0.16% in the rifapentine-isoniazid group (5 out of 3074
patients), compared with 0.32% in the isoniazid group (10 out of 3074 patients). [1, 2]

Signs and symptoms

Classic clinical features associated with active pulmonary TB are as follows (elderly individuals with TB
may not display typical signs and symptoms):

Cough
Weight loss/anorexia
Fever
Night sweats
Hemoptysis
Chest pain (can also result from tuberculous acute pericarditis)
Fatigue
Symptoms of tuberculous meningitis may include the following:

Headache that has been either intermittent or persistent for 2-3 weeks
Subtle mental status changes that may progress to coma over a period of days to weeks
Low-grade or absent fever
Symptoms of skeletal TB may include the following:

Back pain or stiffness

Lower-extremity paralysis, in as many as half of patients with undiagnosedPott disease
Tuberculous arthritis, usually involving only 1 joint (most often the hip or knee, followed by the
ankle, elbow, wrist, and shoulder)
Symptoms of genitourinary TB may include the following:

Flank pain
Dysuria
Frequent urination
In men, a painful scrotal mass, prostatitis, orchitis, or epididymitis
In women, symptoms mimicking pelvic inflammatory disease
Symptoms of gastrointestinal TB are referable to the infected site and may include the following:

Nonhealing ulcers of the mouth or anus

Difficulty swallowing (with esophageal disease)
Abdominal pain mimicking peptic ulcer disease (with gastric or duodenal infection)
Malabsorption (with infection of the small intestine)
Pain, diarrhea, or hematochezia (with infection of the colon)
Physical examination findings associated with TB depend on the organs involved. Patients with pulmonary
TB may have the following:

Abnormal breath sounds, especially over the upper lobes or involved areas
Rales or bronchial breath signs, indicating lung consolidation
Signs of extrapulmonary TB differ according to the tissues involved and may include the following:

Confusion
Coma
Neurologic deficit
Chorioretinitis
Lymphadenopathy
Cutaneous lesions
The absence of any significant physical findings does not exclude active TB. Classic symptoms are often
absent in high-risk patients, particularly those who are immunocompromised or elderly.
See Clinical Presentation for more detail.

Diagnosis
Screening methods for TB include the following:

Mantoux tuberculin skin test with purified protein derivative (PPD) for active or latent infection
(primary method)

In vitro blood test based on interferon gamma release assay (IGRA) with antigens specific
for Mycobacterium tuberculosis for latent infection
Obtain the following laboratory tests for patients with suspected TB:

Acid-fast bacilli (AFB) smear and culture using sputum obtained from the patient: Absence of a
positive smear result does not exclude active TB infection; AFB culture is the most specific test for TB

HIV serology in all patients with TB and unknown HIV status: Individuals infected with HIV are at
increased risk for TB
Other diagnostic testing may warrant consideration, including the following:

Specific enzyme-linked immunospot (ELISpot)

Nucleic acid amplification tests
Blood culture
Positive cultures should be followed by drug susceptibility testing; symptoms and radiographic findings do
not differentiate multidrug-resistant TB (MDR-TB) from fully susceptible TB. Such testing may include the
following:

Direct DNA sequencing analysis

Automated molecular testing
Microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays
Additional rapid tests (eg, BACTEC-460, ligase chain reaction, luciferase reporter assays,
FASTPlaque TB-RIF)
Obtain a chest radiograph to evaluate for possible associated pulmonary findings. The following patterns
may be seen:

Cavity formation: Indicates advanced infection; associated with a high bacterial load
Noncalcified round infiltrates: May be confused with lung carcinoma
Homogeneously calcified nodules (usually 5-20 mm): Tuberculomas, representing old infection
Primary TB: Typically, pneumonialike picture of infiltrative process in middle or lower lung regions
Reactivation TB: Pulmonary lesions in posterior segment of right upper lobe, apicoposterior
segment of left upper lobe, and apical segments of lower lobes
TB associated with HIV disease: Frequently atypical lesions or normal chest radiographic findings
Healed and latent TB: Dense pulmonary nodules in hilar or upper lobes; smaller nodules in upper
lobes
Miliary TB: Numerous small, nodular lesions that resemble millet seeds
Pleural TB: Empyema may be present, with associated pleural effusions
Workup considerations for extrapulmonary TB include the following:
Biopsy of bone marrow, liver, or blood cultures
If tuberculous meningitis or tuberculoma is suspected, perform lumbar puncture
If vertebral ( Pott disease) or brain involvement is suspected, CT or MRI is necessary
If genitourinary complaints are reported, urinalysis and urine cultures can be obtained
See Workup for more detail.

Management
Physical measures (if possible or practical) include the following:

Isolate patients with possible TB in a private room with negative pressure

Have medical staff wear high-efficiency disposable masks sufficient to filter the bacillus
Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after
approximately 2-4 weeks of treatment)
Initial empiric pharmacologic therapy consists of the following 4-drug regimens:

Isoniazid
Rifampin
Pyrazinamide
Either ethambutol or streptomycin [3]
Special considerations for drug therapy in pregnant women include the following:

In the United States, pyrazinamide is reserved for women with suspected MDR-TB
Streptomycin should not be used
Preventive treatment is recommended during pregnancy
Pregnant women are at increased risk for isoniazid-induced hepatotoxicity
Breastfeeding can be continued during preventive therapy
Special considerations for drug therapy in children include the following:

Most children with TB can be treated with isoniazid and rifampin for 6 months, along with
pyrazinamide for the first 2 months if the culture from the source case is fully susceptible.

For postnatal TB, the treatment duration may be increased to 9 or 12 months

Ethambutol is often avoided in young children

Special considerations for drug therapy in HIV-infected patients include the following:

Dose adjustments may be necessary [4, 5]

Rifampin must be avoided in patients receiving protease inhibitors; rifabutin may be substituted
Considerations in patients receiving antiretroviral therapy include the following:
Patients with HIV and TB may develop a paradoxical response when starting antiretroviral therapy
Starting antiretroviral therapy early (eg, < 4 weeks after the start of TB treatment) may reduce
progression to AIDS and death [6]

In patients with higher CD4+ T-cell counts, it may be reasonable to defer antiretroviral therapy until
the continuation phase of TB treatment [7]
Multidrug-resistant TB
When MDR-TB is suspected, start treatment empirically before culture results become available, then
modify the regimen as necessary. Never add a single new drug to a failing regimen. Administer at least 3
(preferably 4-5) of the following medications, according to drug susceptibilities:

An aminoglycoside: Streptomycin, amikacin, capreomycin, kanamycin

A fluoroquinolone: Levofloxacin (best suited over the long term), ciprofloxacin, ofloxacin
A thioamide: Ethionamide, prothionamide
Pyrazinamide
Ethambutol
Cycloserine
Terizidone
Para-aminosalicylic acid
Rifabutin as a substitute for rifampin
A diarylquinoline: Bedaquiline
Surgical resection is recommended for patients with MDR-TB whose prognosis with medical treatment is
poor. Procedures include the following:

Segmentectomy (rarely used)

Lobectomy
Pneumonectomy
Pleurectomy for thick pleural peel (rarely indicated)
Latent TB
Recommended regimens for isoniazid and rifampin for latent TB have been published by the US Centers
for Disease Control and Prevention (CDC)[8] : An alternative regimen for latent TB is isoniazid plus
rifapentine as directly observed therapy (DOT) once-weekly for 12 weeks [9, 2] ; it is not recommended for
children under 2 years, pregnant women or women planning to become pregnant, or patients with TB
infection presumed to result from exposure to a person with TB that is resistant to 1 of the 2 drugs.
See Treatment and Medication for more detail.

Background
Tuberculosis (TB), a multisystemic disease with myriad presentations and manifestations, is the most
common cause of infectious diseaserelated mortality worldwide. The World Health Organization (WHO)
has estimated that 2 billion people have latent TB and that globally, in 2009, the disease killed 1.7 million
people.[10] (See Epidemiology.)[11]
Although TB rates are decreasing in the United States, the disease is becoming more common in many
parts of the world. In addition, the prevalence of drug-resistant TB is also increasing worldwide. Coinfection
with the human immunodeficiency virus (HIV) has been an important factor in the emergence and spread of
resistance.[12] (See Treatment.)
Mycobacterium tuberculosis, a tubercle bacillus, is the causative agent of TB. It belongs to a group of
closely related organismsincluding M africanum, M bovis, and M microti in the M tuberculosis complex.
(See Etiology.) An image of the bacterium is seen below.

Under a high magnification of 15549x, this scanning electron micrograph

depicts some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive
Mycobacterium tuberculosis bacteria. As an obligate aerobic organism, M. tuberculosis can only survive in an
environment containing oxygen. This bacterium ranges in length between 2-4 microns, with a width between 0.2-0.5
microns. Image courtesy of the Centers for Disease Control and Prevention/Dr. Ray Butler.

The lungs are the most common site for the development of TB; 85% of patients with TB present with
pulmonary complaints. Extrapulmonary TB can occur as part of a primary or late, generalized infection.
(See Pathophysiology and Presentation.)
The primary screening method for TB infection (active or latent) is the Mantoux tuberculin skin test with
purified protein derivative (PPD). An in vitro blood test based on interferon-gamma release assay (IGRA)

with antigens specific for M tuberculosis can also be used to screen for latent TB infection. Patients
suspected of having TB should submit sputum for acid-fast bacilli (AFB) smear and culture. (See Workup.)
The usual treatment regimen for TB cases from fully susceptible M tuberculosisisolates consists of 6
months of multidrug therapy. Empiric treatment starts with a 4-drug regimen of isoniazid, rifampin,
pyrazinamide, and either ethambutol or streptomycin; this therapy is subsequently adjusted according to
susceptibility testing results and toxicity. Pregnant women, children, HIV-infected patients, and patients
infected with drug-resistant strains require different regimens. (See Treatment and Medication.)
Laws vary from state to state, but communicable-disease laws typically empower public health officials to
investigate suspected cases of TB, including potential contacts of persons with TB. In addition, patients
may be incarcerated for noncompliance with therapy.
New TB treatments are being developed,[13] and new TB vaccines are under investigation. (See
Epidemiology and Treatment.)

Historical background
TB is an ancient disease. Signs of skeletal TB (Pott disease) have been found in remains from Europe from
Neolithic times (8000 BCE), ancient Egypt (1000 BCE), and the pre-Columbian New World. TB was
recognized as a contagious disease by the time of Hippocrates (400 BCE), when it was termed "phthisis"
(Greek fromphthinein, to waste away). In English, pulmonary TB was long known by the term
consumption. German physician Robert Koch discovered and isolated M tuberculosis in 1882.
The worldwide incidence of TB increased with population density and urban development, so that by the
Industrial Revolution in Europe (1750), it was responsible for more than 25% of adult deaths. In the early
20th century, TB was the leading cause of death in the United States; during this period, however, the
incidence of TB began to decline because of various factors, including the use of basic infection-control
practices (eg, isolation).

Resurgence of TB
The US Centers for Disease Control and Prevention (CDC) has been recording detailed epidemiologic
information on TB since 1953. Beginning in 1985, a resurgence of TB was noted. The increase was
observed primarily in ethnic minorities and especially in persons infected with HIV. TB control programs
were revamped and strengthened across the United States, and rates again began to fall. (See
Epidemiology.)
As an AIDS (acquired immunodeficiency syndrome)related opportunistic infection, TB is associated with
HIV infections, with dual infections being frequently noted. Globally, coinfection with HIV is highest in South
Africa, India, and Nigeria. Persons with AIDS are 20-40 times more likely than immunocompetent persons
to develop active TB.[14] Correspondingly, TB is the leading cause of mortality among persons infected with
HIV.[15]
Worldwide, TB is most common in Africa, the West Pacific, and Eastern Europe. These regions are plagued
with factors that contribute to the spread of TB, including the presence of limited resources, HIV infection,
and multidrug-resistant (MDR) TB. (See Epidemiology.)

Drug-resistant TB
MDR-TB is defined as resistance to isoniazid and rifampin, which are the 2 most effective first-line drugs for
TB. In 2006, an international survey found that 20% ofM tuberculosis isolates were MDR.[15] A rare type of
MDR-TB, called extensively drug-resistant TB (XDR-TB), is resistant to isoniazid, rifampin, any
fluoroquinolone, and at least one of 3 injectable second-line drugs (ie, amikacin, kanamycin, or
capreomycin).[10] XDR-TB resistant to all anti-TB drugs tested has been reported in Italy, Iran, and India. [16]
Multiple factors contribute to the drug resistance of M tuberculosis, including incomplete and inadequate
treatment or adherence to treatment, logistical issues, virulence of the organism, multidrug transporters,
host genetic factors, and HIV infection. A study from South Africa found high genotypic diversity and
geographic distribution of XDR-TB isolates, suggesting that acquisition of resistance, rather than
transmission, accounts for between 63% and 75% of XDR-TB cases. [17]
Statistics
In a 2008 report by the WHO, the proportion of TB cases in which the patient was resistant to at least 1
antituberculosis drug varied widely among different regions of the world, ranging from 0% to over 50%; the

proportion of MDR-TB cases ranged from 0% to over 20%. The WHO calculated that the global populationweighted proportion of MDR-TB was 2.9% in new TB cases, 15.3% in previously treated patients, and 5.3%
in all TB cases.[18]
In the United States, the percentage of MDR-TB cases has increased slowly, from 0.9% of the total number
of reported TB cases in 2008 to 1.3% of cases in 2011. Although the percentage of US-born patients with
primary MDR-TB has remained below 1% since 1997, the proportion of cases in which the patient was
foreign born increased from 25.3% in 1993 to 82.7% in 2011. [19]
XDR-TB is becoming increasingly significant.[18] According to the US National TB Surveillance System
(NTSS), between 1993 and 2006 a total of 49 cases (3% of evaluable MDR-TB cases) met the revised
case definition for XDR-TB. The largest number of XDR-TB cases was found in New York City and
California.
Cure rate
The cure rate in persons with MDR-TB is 50-60%, compared with 95-97% for persons with drugsusceptible TB.[15] The estimated cure rate for XDR-TB is 30-50%.[10] In people who are also infected with
HIV, MDR-TB and XDR-TB often produce fulminant and fatal disease; time from TB exposure to death
averages 2-7 months. In addition, these cases are highly infectious, with conversion rates of as much as
50% in exposed health-care workers.

Global surveillance and treatment of TB

As previously stated, multidrug resistance has been driven by poor compliance with TB therapies , resulting
in difficulties in controlling the disease. Consequently, a threat of global pandemic occurred in the late
1980s and early 1990s. Reacting to these signals, the WHO developed a plan to try to identify 70% of the
world's cases of TB and to completely treat at least 85% of these cases by the year 2000.
Out of these goals were born major TB surveillance programs and the concept of directly observed therapy
(DOT), which requires a third party to witness compliance with pharmacotherapy. With worldwide efforts,
global detection of smear-positive cases rose from 11% (1991) to 45% (2003), with 71-89% of those cases
undergoing complete treatment.

Approach to TB in the emergency department

Despite the importance of early isolation of patients with active TB, a standardized triage protocol with
acceptable sensitivities has yet to be developed.[20] Moran et al demonstrated that among patients with
active TB in the emergency department (ED), TB was often unsuspected, and isolation measures were not
used.[21] The difficulty in establishing such a protocol only highlights the importance of the emergency
physicians role in the prompt identification and isolation of active TB.
A large percentage of ED patients are at increased risk for having active TB, including homeless/shelterdwelling patients, travelers from endemic areas, immunocompromised patients, health-care workers, and
incarcerated patients. Therefore, emergency physicians must consider the management and treatment of
TB as a critical public health measure in the prevention of a new epidemic. [22]
For high-risk cases, prehospital workers can assist in identifying household contacts who may also be
infected or who may be at high risk of becoming infected.
Prehospital workers should be aware that any case of active TB in a young child indicates disease in 1 or
more adults with close contact, usually within the same household. TB in a child is a sentinel event
indicating recent transmission.

Extrapulmonary involvement in TB
Extrapulmonary involvement occurs in one fifth of all TB cases; 60% of patients with extrapulmonary
manifestations of TB have no evidence of pulmonary infection on chest radiographs or in sputum cultures.

Cutaneous TB
The incidence of cutaneous TB appears low. In areas such as India or China, where TB prevalence is high,
cutaneous manifestations of TB (overt infection or the presence of tuberculids) have been found in less
than 0.1% of individuals seen in dermatology clinics.

Ocular TB

TB can affect any structure in the eye and typically presents as a granulomatous process. Keratitis,
iridocyclitis, intermediate uveitis, retinitis, scleritis, and orbital abscess are within the spectrum of ocular
disease. Choroidal tubercles and choroiditis are the most common ocular presentations of TB. Adnexal or
orbital disease may be seen with preauricular lymphadenopathy. Because of the wide variability in the
disease process, presenting complaints will vary.
Most often, patients will complain of blurry vision that may or may not be associated with pain and red eye.
In the rare case of orbital disease, proptosis, double vision, or extraocular muscle motility restriction may be
the presenting complaint. Preseptal cellulitis in children with spontaneous draining fistula may also occur. In
cases of both pulmonary and extrapulmonary TB, there may be ocular findings without ocular complaints.
In patients with confirmed active pulmonary or active, nonocular extrapulmonary TB, ocular incidence
ranges from 1.4-5.74%. In HIV patients, the incidence of ocular TB may be higher, with a reported
prevalence of from 2.8-11.4%.

Patient education
Patient information on TB can be found at the following sites:

CDC Tuberculosis (TB)

World Health Organization Tuberculosis
For patient education information, see the Infections Center, as well asTuberculosis.

Pathophysiology
Infection with M tuberculosis results most commonly through exposure of the lungs or mucous membranes
to infected aerosols. Droplets in these aerosols are 1-5 m in diameter; in a person with active pulmonary
TB, a single cough can generate 3000 infective droplets, with as few as 10 bacilli needed to initiate
infection.
When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The organisms grow
for 2-12 weeks, until they reach 1000-10,000 in number, which is sufficient to elicit a cellular immune
response that can be detected by a reaction to the tuberculin skin test.
Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their
antigenicity is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D,
which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes
When a person is infected with M tuberculosis, the infection can take 1 of a variety of paths, most of which
do not lead to actual TB. The infection may be cleared by the host immune system or suppressed into an
inactive form called latent tuberculosis infection (LTBI), with resistant hosts controlling mycobacterial growth
at distant foci before the development of active disease. Patients with LTBI cannot spread TB.
The lungs are the most common site for the development of TB; 85% of patients with TB present with
pulmonary complaints. Extrapulmonary TB can occur as part of a primary or late, generalized infection. An
extrapulmonary location may also serve as a reactivation site; extrapulmonary reactivation may coexist with
pulmonary reactivation.
The most common sites of extrapulmonary disease are as follows (the pathology of these lesions is similar
to that of pulmonary lesions):

Mediastinal, retroperitoneal, and cervical (scrofula) lymph nodes - The most common site of
tuberculous lymphadenitis (scrofula) is in the neck, along the sternocleidomastoid muscle; it is usually
unilateral and causes little or no pain; advanced cases of tuberculous lymphadenitis may suppurate and
form a draining sinus
Vertebral bodies
Adrenals
Meninges
GI tract
Infected end organs typically have high regional oxygen tension (as in the kidneys, bones, meninges, eyes,
and choroids, and in the apices of the lungs). The principal cause of tissue destruction from M
tuberculosis infection is related to the organism's ability to incite intense host immune reactions to antigenic
cell wall proteins.

Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary systemic
tubercular infection. There is some debate with regard to whether molecular mimicry, as well as a
nonspecific response to noninfectious tubercular antigens, provides a mechanism for active ocular
inflammation in the absence of bacterial replication.

TB lesions
The typical TB lesion is an epithelioid granuloma with central caseation necrosis. The most common site of
the primary lesion is within alveolar macrophages in subpleural regions of the lung. Bacilli proliferate locally
and spread through the lymphatics to a hilar node, forming the Ghon complex.
Early tubercles are spherical, 0.5- to 3-mm nodules with 3 or 4 cellular zones demonstrating the following
features:

A central caseation necrosis

An inner cellular zone of epithelioid macrophages and Langhans giant cells admixed with
lymphocytes

An outer cellular zone of lymphocytes, plasma cells, and immature macrophages

A rim of fibrosis (in healing lesions)

Initial lesions may heal and the infection become latent before symptomatic disease occurs. Smaller
tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve tubercles and larger
lesions are surrounded by a fibrous capsule. Such fibrocaseous nodules usually contain viable
mycobacteria and are potential lifelong foci for reactivation or cavitation. Some nodules calcify or ossify and
are seen easily on chest radiographs.
Tissues within areas of caseation necrosis have high levels of fatty acids, low pH, and low oxygen tension,
all of which inhibit growth of the tubercle bacillus.
If the host is unable to arrest the initial infection, the patient develops progressive, primary TB with
tuberculous pneumonia in the lower and middle lobes of the lung. Purulent exudates with large numbers of
acid-fast bacilli can be found in sputum and tissue. Subserosal granulomas may rupture into the pleural or
pericardial spaces and create serous inflammation and effusions.
With the onset of the host immune response, lesions that develop around mycobacterial foci can be either
proliferative or exudative. Both types of lesions develop in the same host, since infective dose and local
immunity vary from site to site.
Proliferative lesions develop where the bacillary load is small and host cellular immune responses
dominate. These tubercles are compact, with activated macrophages admixed, and are surrounded by
proliferating lymphocytes, plasma cells, and an outer rim of fibrosis. Intracellular killing of mycobacteria is
effective, and the bacillary load remains low.
Exudative lesions predominate when large numbers of bacilli are present and host defenses are weak.
These loose aggregates of immature macrophages, neutrophils, fibrin, and caseation necrosis are sites of
mycobacterial growth. Without treatment, these lesions progress and infection spreads.

Etiology
TB is caused by M tuberculosis, a slow-growing obligate aerobe and a facultative intracellular parasite. The
organism grows in parallel groups called cords (as seen in the image below). It retains many stains after
decoloration with acid-alcohol, which is the basis of the acid-fast stains used for pathologic identification.

Acid-fast bacillus smear showing characteristic cording in Mycobacterium

tuberculosis.

Mycobacteria, such as M tuberculosis, are aerobic, nonspore-forming, nonmotile, facultative, curved

intracellular rods measuring 0.2-0.5 m by 2-4 m. Their cell walls contain mycolic, acid-rich, long-chain
glycolipids and phospholipoglycans (mycocides) that protect mycobacteria from cell lysosomal attack and
also retain red basic fuchsin dye after acid rinsing (acid-fast stain).

Transmission
Humans are the only known reservoir for M tuberculosis. The organism is spread primarily as an airborne
aerosol from an individual who is in the infectious stage of TB (although transdermal and GI transmission
have been reported).
In immunocompetent individuals, exposure to M tuberculosis usually results in a latent/dormant infection.
Only about 5% of these individuals later show evidence of clinical disease. Alterations in the host immune
system that lead to decreased immune effectiveness can allow M tuberculosis organisms to reactivate, with
tubercular disease resulting from a combination of direct effects from the replicating infectious organism
and from subsequent inappropriate host immune responses to tubercular antigens.
Molecular typing of M tuberculosis isolates in the United States by restriction fragment-length
polymorphism analysis suggests more than one third of new patient occurrences of TB result from personto-person transmission. The remainder results from reactivation of latent infection.
Verhagen et al demonstrated that large clusters of TB are associated with an increased number of
tuberculin skin testpositive contacts, even after adjusting for other risk factors for transmission. [23] The
number of positive contacts was significantly lower for index cases with isoniazid-resistant TB compared
with index cases with fully-susceptible TB. This suggests that some TB strains may be more transmissible
than other strains and that isoniazid resistance is associated with lower transmissibility.

Extrapulmonary spread
Because of the ability of M tuberculosis to survive and proliferate within mononuclear phagocytes, which
ingest the bacterium, M tuberculosis is able to invade local lymph nodes and spread to extrapulmonary
sites, such as the bone marrow, liver, spleen, kidneys, bones, and brain, usually via hematogenous routes.
Although mycobacteria are spread by blood throughout the body during initial infection, primary
extrapulmonary disease is rare except in immunocompromised hosts. Infants, older persons, or otherwise
immunosuppressed hosts are unable to control mycobacterial growth and develop disseminated (primary
miliary) TB. Patients who become immunocompromised months to years after primary infection also can
develop late, generalized disease.

Risk factors
The following factors help to determine whether a TB infection is likely to be transmitted:

Number of organisms expelled

Concentration of organisms
Length of exposure time to contaminated air
Immune status of the exposed individual
Infected persons living in crowded or closed environments pose a particular risk to noninfected persons.
Approximately 20% of household contacts develop infection (positive tuberculin skin test). Microepidemics
have occurred in closed environments such as submarines and on transcontinental flights. Populations at

high risk for acquiring the infection also include hospital employees, inner-city residents, nursing home
residents, and prisoners.
The following factors increase an individuals risk of acquiring active tuberculosis:

HIV infection
Intravenous (IV) drug abuse
Alcoholism
Diabetes mellitus (3-fold risk increase)
Silicosis
Immunosuppressive therapy
Tumor necrosis factoralpha (TNF-) antagonists
Cancer of the head and neck
Hematologic malignancies
End-stage renal disease
Intestinal bypass surgery or gastrectomy
Chronic malabsorption syndromes
Low body weight - In contrast, obesity in elderly patients has been associated with a lower risk for
active pulmonary TB [24]

Smoking - Smokers who develop TB should be encouraged to stop smoking to decrease the risk
of relapse [25]

Age below 5 years

TNF antagonists and steroids
Treatment with tumor necrosis factoralpha (TNF-) antagonists, which is used for rheumatoid arthritis,
psoriasis, and several other autoimmune disorders, has been associated with a significantly increased risk
for TB.[26] Reports have included atypical presentations, extrapulmonary and disseminated disease, and
deaths. Patients scheduled to begin therapy with a TNF- antagonist should be screened for latent TB and
counseled regarding the risk of TB.
Immunosuppressive therapy includes long-term administration of systemic steroids (prednisone or its
equivalent, given >15 mg/day for 4 wk or more) and/or inhaled steroids. Brassard and colleagues reported
that inhaled steroids, in the absence of systemic steroids, were associated with a relative risk of 1.5 for TB.
[27]

TB in children
In children younger than 5 years, the potential for development of fatal miliary TB or meningeal TB is a
significant concern. Osteoporosis, sclerosis, and bone involvement are more common in children with TB
than in adults with the disease. The epiphyseal bones can be involved because of their high vascularity.
Children do not commonly infect other children, because they rarely develop cough and their sputum
production is scant. However, cases of child-child and child-adult TB transmission are well documented.
(See Pediatric Tuberculosis for complete information on this topic.)

Genetic factors
The genetics of tuberculosis are quite complex, involving many genes. Some of those genes involve
important aspects of the immune system, while others involve more specific mechanisms by which the
human body interacts with mycobacterium species. The genes that follow have polymorphisms that are
associated with either susceptibility to or protection from tuberculosis. Additionally, regions such as 8q12q13 are associated with increased risk, although an exact mechanism or candidate gene has not yet been
found.
NRAMP1
In a study from Africa, 4 different polymorphisms of the NRAMP1 gene were associated with an increased
risk for TB. Subjects who possessed a certain 2 of those polymorphisms (located in an intron and in a
region upstream from the coding region) were at particular risk for contracting TB. [28] The association
ofNRAMP1 with risk of TB has been replicated in subsequent studies.[29, 30]
SP110

The product of this gene interacts with the interferon system and as such is an important aspect of the
immune response. A study of 27 different polymorphisms in this gene found 3 that were associated with
increased risk of TB; 2 of these polymorphisms were intronic and the third was a missense mutation in
exon 11.[31]
CISH
The product of this gene functions to suppress cytokine signaling, which is important for inflammatory
signaling. One study found that a single-nucleotide polymorphism upstream from CISH was associated with
susceptibility to TB, malaria, and invasive bacterial disease. The same study found that leukocytes of
persons who had the risk variant for CISH had a decreased response to interleukin 2.[32]
IRGM
The expression of this gene is induced by interferon, and the product is involved in the control of
intracellular mycobacteria. One study found that homozygosity for a particular polymorphism in the
promoter region of IRGM confers protection against TB, but only in persons of European ancestry. In vitro
analyses showed increased expression of the IRGM gene product with the promoter variant, further
underscoring the importance of this gene in the immune response to mycobacterial infection. [33]
IFNG
Interferon gamma is a cytokine that has an important role in the immune response to intracellular
infections, including viral and mycobacterial infections. One particular polymorphism near a microsatellite in
this gene is associated with increased expression of the IFNG gene and increased production of interferon
gamma. An association study found evidence that this polymorphism was related to protection against TB.
[34]

IFNGR1
The product of IFNGR1 is part of a heterodimeric receptor for interferon gamma. This has important
implications for the response of this part of the immune system in the defense against certain infections.
A region of homozygosity in the region of the IFNGR1 gene has been found in a group of related children in
southern Europe who were known to have a predisposition to mycobacterial infection; this predisposition,
which had resulted in death in three children and chronic mycobacterial infection in a fourth, was felt to be
autosomal recessive.[35] Subsequent sequencing of the gene showed a nonsense mutation that resulted in a
nonfunctional gene product.[36]
TIRAP
The TIRAP gene produces a protein that has several functions in the immune system. A study of 33
polymorphisms in the TIRAP gene found that heterozygosity for a serine-to-leucine substitution was
associated with protection again invasive pneumococcal disease, bacteremia, malaria, and TB. [37]
CD209
The product of the CD209 gene is involved in the function of dendritic cells, which are involved in the
capture of certain microorganisms. An association was found between susceptibility to TB and a
polymorphism upstream from the CD209 gene in a multiracial South African population.[38]

Epidemiology
Occurrence in the United States
With the improvement of living conditions and the introduction of effective treatment (streptomycin) in the
late 1940s, the number of patients in the United States reported to have TB began to steadily decline
(126,000 TB patients in 1944; 84,000 in 1953; 22,000 in 1984; 14,000 in 2004), despite explosive growth in
the total population (140 million people in 1946, 185 million in 1960, 226 million in 1980).
On a national level, the incidence of TB is at an all-time low. Since the 1992 TB resurgence peak in the
United States, the number of TB cases reported annually has decreased by 61%.
In 2011, 10,528 TB cases (a rate of 3.4 cases per 100,000 population) were reported in the United States,
representing a 5.8% decline in the number of reported TB cases and a 6.4% decline in the case rate,
compared with 2010.[19]

California, New York, Texas, and Florida accounted for half of all TB cases reported in the United States in
2011. Cases in foreign-born persons made up 62% of the national case total; foreign-born Hispanics and
Asians together represented 80% of TB cases in foreign-born persons and accounted for 50% of the
national case total. The top five countries of origin for foreign-born persons with TB were Mexico, the
Philippines, India, Vietnam, and China.
Among racial and ethnic groups, the largest percentage of total cases was in Asians (30%), followed by
Hispanics (29%) and non-Hispanic blacks/African Americans (15%). However, blacks/African Americans
represented 39% of TB cases in US-born persons. [19]
There were 529 deaths from TB in 2009, the most recent year for which these data are available.

International statistics
Globally, more than 1 in 3 individuals is infected with TB.[39] According to the WHO, there were 8.8 million
incident cases of TB worldwide in 2010, with 1.1 million deaths from TB among HIV-negative persons and
an additional 0.35 million deaths from HIV-associated TB. In 2009, almost 10 million children were
orphaned as a result of parental deaths caused by TB. [40]
Overall, the WHO noted the following[40] :

The absolute number of TB cases has been falling since 2006 (rather than rising slowly, as
indicated in previous global reports)

TB incidence rates have been falling since 2002 (2 years earlier than previously suggested)

Estimates of the number of deaths from TB each year have been revised downwards
The 5 countries with the highest number of incident cases in 2010 were India, China, South Africa,
Indonesia, and Pakistan. India alone accounted for an estimated 26% of all TB cases worldwide, and China
and India together accounted for 38%.[40]

Race-related demographics
In 2011, only 16% of TB cases in the US occurred in non-Hispanic whites; 84% occurred in racial and
ethnic minorities, as follows[19] :

Hispanics - 29%
Asians - 30%
Non-Hispanic blacks/African Americans - 23%
American Indians/native Alaskans - 1%
Native Hawaiians/other Pacific Islanders 1%
However, race is not clearly an independent risk factor, as foreign-born persons account for 77% of TB
cases among Hispanics and 96% of TB cases among Asians, but only 29% of TB cases among blacks.
This skewed distribution is most likely due to socioeconomic factors.

Sex-related demographics
Despite the fact that TB rates have declined in both sexes in the United States, certain differences exist. TB
rates in women have declined with age, but in men, rates have increased with age. In addition, men are
more likely than women to have a positive tuberculin skin test result. The reason for these differences may
be social, rather than biologic, in nature.
The estimated sex prevalence for TB varies by source, from no sex prevalence to a male-to-female ratio in
the United States of 2:1.

Age-related demographics
Higher rates of TB infection are seen in young, nonwhite adults (peak incidence, 25-40 y) than in white
adults. In addition, white adults manifest the disease later (peak incidence, age 70 y) than do nonwhite
persons.
In the United States, more than 60% of TB cases occur in persons aged 25-64 years; however, the agespecific risk is highest in persons older than 65 years. [40]TB is uncommon in children aged 5-15 years.

Prognosis
Full resolution is generally expected with few complications in cases of non-MDR- and non-XDR-TB, when
the drug regimen is completed. Among published studies involving DOT treatment of TB, the rate of

recurrence ranges from 0-14%.[41] In countries with low TB rates, recurrences usually occur within 12
months of treatment completion and are due to relapse. [42] In countries with higher TB rates, most
recurrences after appropriate treatment are probably due to reinfection rather than relapse. [43]
Poor prognostic markers include extrapulmonary involvement, an immunocompromised state, older age,
and a history of previous treatment. In a prospective study of 199 patients with TB in Malawi, 12 (6%) died.
Risk factors for dying were reduced baseline TNF- response to stimulation (with heat-killed M
tuberculosis), low body mass index, and elevated respiratory rate at TB diagnosis. [44]

Cutaneous tuberculosis
Cutaneous tuberculosis (TB) is essentially an invasion of the skin by Mycobacterium tuberculosis,
the same bacteria that cause TB of the lungs (pulmonary TB). Cutaneous TB is a relatively
uncommon form of extrapulmonary TB (TB infection of other organs and tissues). Even in
countries such as India and China where TB still commonly occurs, cutaneous outbreaks are rare
(<0.1%).

Types of cutaneous TB
Several different types of cutaneous TB exist. Direct infection of the skin or mucous membranes
from an outside source of mycobacteria results in an initial lesion called the tuberculous chancre.
The chancres are firm shallow ulcers with a granular base. They appear about 2-4 weeks after
mycobacteria enter through broken skin. The immune response of the patient and the virulence of
the mycobacteria determine the type and severity of cutaneous TB.

Types of cutaneous

Features

TB

TB verrucosa cutis

Lupus vulgaris

Scrofuloderma

Miliary TB

Occurs after direct inoculation of TB into the skin in someone who has been previous

Presents as a purplish or brownish-red warty growth

Lesions most often occur on the knees, elbows, hands, feet and buttocks

Lesions may persist for years but can clear up even without treatment

Persistent and progressive form of cutaneous TB

Small sharply defined reddish-brown lesions with a gelatinous consistency (called app

Lesions persist for years, leading to disfigurement and sometimes skin cancer

Skin lesions result from direct extension of underlying TB infection of lymph nodes, b

Often associated with TB of the lungs

Firm, painless lesions that eventually ulcerate with a granular base

May heal even without treatment but this takes years and leaves unsightly scars

Chronic TB infection that has spread from the primary infection (usually in the lungs)
bloodstream

Tuberculid

Skin lesions are small (millet-sized) red spots that develop into ulcers and abscesses

More likely in immunocompromised patients, eg HIV, AIDS, cancer

The patient is generally sick

Prognosis is poor (many patients die even if diagnosed and treated)

Generalised exanthem in patients with moderate or high degree of immunity to TB be

Usually in good health with no identifiable focus of active TB in skin or elsewhere

Erythema induratum (Bazin disease) presents as recurring nodules or lumps on the b

ulcerate and scar. It is a type of nodular vasculitis.

Papulonecrotic tuberculid results in crops of recurrent crusted skin papules on knees,

with scarring after about 6 weeks.

Lichen scrofulosorum is an extending eruption of small follicular papules in young per

Cutaneous tuberculosis

Lupus vulgaris

Lupus vulgaris

Erythema induratum

Innoculation tuberculosis

Tuberculosis verrucosa cutis Scrofuloderma

More images of tuberculosis ...

What tests are available?

The diagnosis is usually made or confirmed by characteristic histopathological features on skin
biopsy. Typical tubercles are caseating epithelioid granulomas that contain acid-fast bacilli. These
are detected by tissue staining, culture and polymerase chain reaction (PCR).
Other tests that may be necessary include:

Tuberculin skin test (Mantoux)

Quantiferon-Gold blood test

Sputum culture (it may take a month or longer for results to be reported)

Chest X-ray & other radiological tests for extrapulmonary infection.

Interferon gamma release assays (IGRA)

Severe Mantoux test reactions (active TB)

What is the treatment of cutaneous TB?

Patients with pulmonary or extrapulmonary TB disease need to be treated with antitubercular
drugs. This usually involves a combination of antibiotics (isoniazid,rifampicin, pyrazinamide and
ethambutol) given over a period of several months and sometimes years.
Patients with TB infection but no active disease must also be treated with antitubercular drugs to
prevent development of active disease.
Occasionally surgical excision of localised cutaneous TB is recommended.