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Tuberculosis (TB) poses a serious threat to public health throughout the world

Tuberculosis (TB) poses a serious threat to public health throughout the world but disproportionately afflicts low-income nations. Persons in close contact with a patient with active pulmonary TB and those from endemic regions of the world are at highest risk of primary infection, whereas patients with compromised immune systems are at highest risk of reactivation of latent TB infection (LTBI). Tuberculosis can affect any organ system. Clinical manifestations vary accordingly but often include fever, night sweats, and weight loss. Positive results on either a tuberculin skin test or an interferon-γ release assay in the absence of active TB establish a diagnosis of LTBI. A combination of epidemiological, clinical, radiographic, microbiological, and histopathologic features is used to establish the diagnosis of active TB. Patients with suspected active pulmonary TB should submit 3 sputum specimens for acid-fast bacilli smears and culture, with nucleic acid amplification testing performed on at least 1 specimen. For patients with LTBI, treatment with isoniazid for 9 months is preferred. Patients with active TB should be treated with multiple agents to achieve bacterial clearance, to reduce the risk of transmission, and to prevent the emergence of drug resistance. Directly observed therapy is recommended for the treatment of active TB. Health care professionals should collaborate, when possible, with local and state public health departments to care for patients with TB. Patients with drug-resistant TB or coinfection with human immunodeficiency virus should be treated in collaboration with TB specialists. Public health measures to prevent the spread of TB include appropriate respiratory isolation of patients with active pulmonary TB, contact investigation, and reduction of the LTBI burden.


Sociodemographic risk factors for TBI include recent residence in an endemic region of the world, low socioeconomic position, being a member of a racial or ethnic minority (in the United States), homelessness, residency or employment at high-risk facilities (eg, correctional facilities, homeless shelters, skilled nursing facilities), and employment as a health care worker caring for patients with TB.

TRANSMISSION

Tuberculosis is transmitted through droplet aerosolization by an individual with active pulmonary disease. The highest risk of transmission occurs among patients with cavitary or positive acid-fast bacilli (AFB) smears12; however, patients with negative smears but positive cultures may still transmit the disease.13

Host factors dramatically influence which of those exposed to TB are most likely to contract primary disease or progress to active disease. Those with greater susceptibility include persons with immune systems that have been compromised through either diseases, such as HIV infection and hematologic and reticuloendothelial malignancies, or through immunosuppressive medications, such as corticosteroids, tumor necrosis factor α inhibitors, calcineurin inhibitors, and cytotoxic chemotherapeutic agents. Furthermore, patients with chronic diseases, such as diabetes, chronic kidney disease, and silicosis, are at elevated risk. Finally, age younger than 4 years, long-term malnutrition, and substance abuse are independent risk factors for disease.3

CLINICAL MANIFESTATIONS

Pulmonary TB

Primary Pulmonary TB. Symptoms occurring around the time of inoculation are referred to as primary pulmonary TB. Symptoms are generally mild and include low-grade fever.14,15 Two-thirds of persons with primary pulmonary TB remain asymptomatic. Physical examination findings are generally unremarkable, and the most common radiographic finding is hilar adenopathy.16 Less common radiographic findings include pulmonary infiltrates in the mid and lower lung field.

Reactivation TB. Approximately 90% of TB cases among adults can be attributed to reactivation TB. Symptoms present insidiously, most commonly with fever, cough, weight loss, fatigue, and night sweats. Less common symptoms include chest pain, dyspnea, and hemoptysis. Physical examination findings are nonspecific and may include rales or signs of pleural effusion (eg, dullness to percussion). Chest radiography demonstrates infiltrates in the apical-posterior segment of the upper lobes, and up to 20% of these infiltrates are associated with cavities characterized by air-fluid levels. Although not specific for TB, apical computed tomographic findings may show a “tree in bud” morphology manifested by centrilobular lesions, nodules, and branching linear densities.17,18 Among the roughly 15% of patients who present without upper lung field infiltrates, a variety of radiographic findings have been described, including lower lung infiltrates (especially superior segments), nodules, effusions, and hilar adenopathy. Finally, up to 5% of patients with active pulmonary disease may have normal findings on chest radiography.19,20 This is particularly worth noting among patients coinfected with HIV, who are more likely to have atypical (eg, less predisposition for upper lobes) or normal findings on chest radiography.21

Endobronchial TB. Endobronchial TB develops as the direct extension of TB from a pulmonary parenchymal source or sputum inoculation into the bronchial tree.22 Symptoms may include barking cough with sputum production, and examination may reveal rhonchi and wheezing23,24; the wheezing may lead to misdiagnosis of asthma.25 Diagnosis and response to therapy may be assessed through bronchoscopy.26


Extrapulmonary TB

Extrapulmonary TB accounts for roughly 15% of TB cases among immunocompetent hosts27 and for 50% to 70% of cases that occur in the context of coinfection with HIV.28-30 In low-incidence countries, immigrants from endemic countries are much more likely to present with extrapulmonary TB.31-33 As a rule, TB can present in any organ system; therefore, vigilance and examination for extrapulmonary disease are important for all persons being evaluated for TBI. A summary of the most common presentations of extrapulmonary TB follows

Diagnosis of Common Extrapulmonary TB Manifestations

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Tuberculous Lymphadenitis. Up to 40% of extrapulmonary TB cases are attributable to tuberculous lymphadenitis.27 It presents most commonly in the cervical lymph nodes, followed by the mediastinal and axillary nodes.34,35 A typical presenting symptom is long-term, unilateral, nontender lymphadenopathy; systemic symptoms are often absent.36 On examination, the node is typically matted and adherent to surrounding structures.36,37 If tuberculous lymphadenitis is clinically suspected, fine-needle aspiration should be pursued, followed by lymph node biopsy if the aspiration is nondiagnostic.38,39

Pleural TB. Accounting for roughly 4% of all TB cases, pleural TB is the second leading cause of extrapulmonary TB.40 In addition to constitutional symptoms, patients may present with nonproductive cough and pleuritic chest pain.41 Chest radiography typically shows a unilateral effusion, and pleural fluid analysis shows lymphocyte-predominant exudative features with low glucose levels and low pH.42 Pleural fluid culture is positive in only roughly 30% of cases, whereas the combination of histology and culture from a closed pleural biopsy specimen yields a diagnosis in most cases.43


New Technology

Several recently developed tests for TB, including molecular drug resistance, have the potential for providing rapid diagnosis and targeted treatment.91,92 These fully automated tests provide rapid drug-resistance testing for RIF and INH; however, they require sophisticated technology and are currently available only at reference laboratories.93


Other Considerations

At the start of LTBI therapy, baseline measurements of serum aspartate aminotransferase, alanine aminotransferase, and bilirubin are recommended for patients who have a history of liver disease (eg, hepatitis B or C, alcoholic hepatitis, or cirrhosis), use alcohol regularly, have risk factors for chronic liver disease, are infected with HIV, are pregnant, or have given birth within the past 3 months.76 All patients diagnosed as having LTBI should be offered voluntary HIV counseling and testing.


All patients with active TB should receive counseling and be tested for HIV infection. Serologic tests for hepatitis B and C should be performed for patients with risk factors such as injection drug use, foreign birth, and HIV infection. Susceptibility testing for INH, RIF, ethambutol (EMB), and pyrazinamide (PZA) should be performed on any initial culture that is positive. Susceptibility testing to the second-line drugs should be performed on specimens from patients who have had previous therapy, are known to have resistance to first-line drugs, are contacts of patients with drug-resistant TB, or have persistently positive cultures 3 months or more after starting treatment. Baseline measurements of platelet count and serum aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and serum creatinine levels are recommended for all patients starting TB treatment.68

TREATMENT

Latent TB Infection

Treatment for LTBI is recommended for persons deemed to be at relatively high risk of developing active TB (Table 2) and should be initiated only after active TB has been excluded by clinical and radiographic evaluations. Failure to rule out TB may result in inadequate treatment and development of drug resistance. For most patients, treatment with INH for 9 months is preferred (Table 4).76,94 Pyridoxine supplementation (25 mg/d) to INH is recommended for patients at an increased risk of neuropathy, including those with preexisting peripheral neuropathy, nutritional deficiency, diabetes mellitus, HIV infection, renal failure, alcoholism, or thyroid disease and those who are pregnant or breast-feeding. Intermittent treatment (ie, a twice-weekly regimen) should only be performed as directly observed therapy (DOT). Due to the high rates of hospitalization and death from liver injury, the combination of RIF and PZA is no longer recommended for the treatment of LTBI.94

Treatment Regimens for Latent Tuberculosis Infection

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Active TB

Patients with active TB should be treated with multiple agents to achieve bacterial clearance, to reduce the risk of transmi

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LTBI

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