Tuberculosis (TB)

Tuberculosis (TB), a multisystemic disease with myriad presentations and manifestations, is the most common cause of infectious disease–related 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. ^[13] (See Epidemiology.) ^[14]

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. ^[15] (See Treatment.)

Mycobacterium tuberculosis, a tubercle bacillus, is the causative agent of TB. It belongs to a group of closely related organisms—including 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.

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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 tuberculosis isolates 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, ^[16] 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 from phthinein, 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. ^[17] Correspondingly, TB is the leading cause of mortality among persons infected with HIV. ^[18]

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% of M tuberculosis isolates were MDR. ^[18] 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). ^[13] XDR-TB resistant to all anti-TB drugs tested has been reported in Italy, Iran, and India. ^[19]

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. ^[20]

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 population-weighted proportion of MDR-TB was 2.9% in new TB cases, 15.3% in previously treated patients, and 5.3% in all TB cases. ^[21]

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. ^[22]

XDR-TB is becoming increasingly significant. ^[21] 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 drug-susceptible TB. ^[18] The estimated cure rate for XDR-TB is 30-50%. ^[13] 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. ^[23] 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. ^[24] The difficulty in establishing such a protocol only highlights the importance of the emergency physician’s 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/shelter-dwelling 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. ^[25]

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 as Tuberculosis.

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 μm 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.

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.

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Mycobacteria, such as M tuberculosis, are aerobic, non–spore-forming, nonmotile, facultative, curved intracellular rods measuring 0.2-0.5 μm by 2-4 μm. 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 person-to-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 test–positive contacts, even after adjusting for other risk factors for transmission. ^[26] 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 individual’s risk of acquiring active tuberculosis:

• HIV infection

• Intravenous (IV) drug abuse

• Alcoholism

• Diabetes mellitus (3-fold risk increase)

• Silicosis

• Immunosuppressive therapy

• Tumor necrosis factor–alpha (TNF-α) 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 ^[27]

• Smoking - Smokers who develop TB should be encouraged to stop smoking to decrease the risk of relapse ^[28]

• Age below 5 years

TNF antagonists and steroids

Treatment with tumor necrosis factor–alpha (TNF-α) antagonists, which is used for rheumatoid arthritis, psoriasis, and several other autoimmune disorders, has been associated with a significantly increased risk for TB. ^[29] Reports have included atypical presentations, extrapulmonary and disseminated disease, and deaths. Patients scheduled to begin therapy with a TNF-α 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. ^[30]

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 8q12-q13 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. ^[31] The association of NRAMP1 with risk of TB has been replicated in subsequent studies. ^{[32, 33]}

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. ^[34]

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. ^[35]

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. ^[36]

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. ^[37]

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. ^[38] Subsequent sequencing of the gene showed a nonsense mutation that resulted in a nonfunctional gene product. ^[39]

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. ^[40]

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. ^[41]

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. ^[22]

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

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%. ^[42] In countries with low TB rates, recurrences usually occur within 12 months of treatment completion and are due to relapse. ^[43] In countries with higher TB rates, most recurrences after appropriate treatment are probably due to reinfection rather than relapse. ^[44]

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-α response to stimulation (with heat-killed M tuberculosis), low body mass index, and elevated respiratory rate at TB diagnosis. ^[45]