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Tuberculosis

General

Tuberculosis (TB) is caused by organisms of the Mycobacterium tuberculosis complex. The complex includes M. tuberculosis (MTB), the most frequent and important agent of human mycobacterial disease, and M. bovis, previously an important cause of disease acquired via ingestion of unpasteurized milk. MTB is a thin aerobic bacterium that is neutral on Gram's staining but that, once stained, is acid-fast뾦.e., it cannot be decolorized by acid alcohol because of the cell wall's high content of mycolic acids and other lipids.

Epidemiology

?It is estimated that >8.5 million new cases of TB occurred worldwide in 2001, mostly in developing countries. In 2000, 1.8 million deaths due to TB are estimated to have occurred. The HIV epidemic has had a major impact on TB, increasing the number of cases by several fold in the developing world. Increased rates of TB in the United States during the late 1980s were related to immigration, HIV disease, social problems (e.g., homelessness), and the emergence of multidrug-resistant (MDR) MTB. Rates have since decreased as a result of strong TB control programs. In the United States, TB tends to be a disease of elderly persons, HIV-infected young adults, immigrants, and the poor.

?MDR TB is defined as that caused by strains resistant to isoniazid and rifampin, but it is often associated with resistance to other drugs as well. MDR TB cases are generally few in North America and Europe but are more common among immigrants from certain developing areas (e.g., the former Soviet Union, Southeast Asia).

?Disease from a pt with infectious pulmonary TB is most commonly spread by droplet nuclei that are aerosolized by coughing, sneezing, or speaking. Droplets may be suspended in air for several hours. Transmission is determined by the intimacy and duration of contact with a pt with TB, the degree of infectiousness of that pt, and the shared environment. Pts with cavitary disease are usually most infectious, with as many as 105 acid-fast bacilli (AFB) per milliliter of sputum.

?Risk factors for development of active disease after MTB infection include recent acquisition (within the preceding year), comorbidity (e.g., HIV disease, diabetes, silicosis, immunosuppression, gastrectomy), malnutrition, and presence of fibrotic lesions.

Pathogenesis

AFB that reach alveoli are ingested by activated macrophages. If the bacilli are not contained, they multiply, lyse the macrophages, and spread to nonactivated monocytes. Macrophages may transport bacilli to regional lymph nodes, from which dissemination throughout the body may occur. About 2? weeks after infection, delayed-type hypersensitivity (DTH) destroys nonactivated macrophages that contain multiplying bacilli, and a macrophage-activating response activates cells capable of killing AFB. DTH is the basis for the PPD skin test. A granuloma forms at the site of the primary lesion and at sites of dissemination. The lesions can then either heal by fibrosis or undergo further evolution. Despite "healing," viable bacilli can remain dormant within macrophages or in the necrotic material for years. Cell-mediated immunity confers partial protection against TB. Cytokines secreted by alveolar macrophages contribute to disease manifestations, granuloma formation, and mycobacterial killing.

Clinical Features

Pulmonary TB

? TB is limited to the lungs in >80% of cases in HIV-negative pts.

1. Primary disease: The initial infection is frequently located in the middle and lower lobes. The primary lesion usually heals spontaneously, and a calcified nodule (Ghon lesion) remains. Hilar and paratracheal lymphadenopathy are common. In immunosuppressed pts and children, primary disease may progress rapidly to clinical disease, with cavitation, pleural effusions, and hematogenous dissemination.

2. Postprimary (adult-type, reactivation, or secondary) disease: Usually localized to the apical and posterior segments of the upper lobes and the superior segments of the lower lobes.

a. Early symptoms of fever, night sweats, weight loss, anorexia, malaise, and weakness are nonspecific and insidious.

b. Cough and purulent sputum production, often with blood streaking, occur. Occasionally, massive hemoptysis follows erosion of a vessel located in the wall of a cavity.

c. Disease can be limited, or extensive cavitation may develop. Extensive disease may cause dyspnea and respiratory distress.

? Extrapulmonary TB

? Any site in the body can be involved. Up to two-thirds of HIV-infected pts with TB have extrapulmonary disease.

1. Lymphadenitis occurs in >25% of extrapulmonary TB cases, especially among HIV-infected pts. Painless swelling of cervical and supraclavicular nodes (scrofula) is typical. Early on, nodes are discrete but can be inflamed with a fistulous tract. Fine-needle aspiration or surgical biopsy of the node is required for diagnosis. AFB smears are positive in ~50% of cases and cultures in 70?0%.

2. Pleural involvement is common in primary TB, resulting from penetration of bacilli into the pleural space.

a. DTH in response to these bacilli can result in effusion. Fluid is straw-colored and exudative, with protein levels >50% of those in serum, normal to low glucose levels, a usual pH of <7.2, and pleocytosis (500?500 cells per microliter). Mononuclear cells are most common, although neutrophils may be present early in disease, and mesothelial cells are rare or absent. Pleural biopsy is often required for diagnosis, with up to 70% of biopsy cultures positive.

b. Empyema is less common and is usually a result of the rupture of a cavity with many bacilli into the pleural space.

3. In genitourinary disease, local symptoms predominate (e.g., frequency and dysuria). Calcifications and ureteral strictures can be seen. In >90% of cases, urinalysis shows pyuria and hematuria with negative bacterial cultures; in 90% of cases, culture of three morning urine specimens is diagnostic. Genital TB is more common among women than among men. Fallopian tube and uterine disease can cause infertility.

4. Skeletal disease: The spine, hips, and knees are the most common sites. Spinal TB (Pott's disease) often involves three or more adjacent vertebral bodies; in adults, lower thoracic/upper lumbar vertebrae are usually affected. Disease spreads to adjacent vertebral bodies, destroying the intervertebral disk and causing collapse of vertebral bodies in advanced disease (kyphosis, gibbus). Paravertebral cold abscesses may form.

5. Meningitis occurs most often in young children and HIV-seropositive pts. Disease typically evolves over 1? weeks.

a. Cranial nerve involvement (particularly of the ocular nerve) and hydrocephalus are common.

b. The CSF has a high lymphocyte count, an elevated protein level, and a low glucose concentration. Cultures are positive in 80% of cases.

c. Neurologic sequelae can be reduced with adjunctive glucocorticoids administered along with treatment for TB.

6. Gastrointestinal disease affects the terminal ileum and cecum, causing abdominal pain and diarrhea, and can present with a clinical picture similar to that of Crohn's disease. A palpable mass and bowel obstruction may occur. Peritonitis presents with fever, abdominal pain, and ascites that is exudative with a high protein content and lymphocytic leukocytosis. Peritoneal biopsy is usually required for diagnosis.

7. Pericarditis is characterized by an acute or subacute onset of fever, dull retrosternal pain, and sometimes a friction rub. Effusion is common. Chronic constrictive pericarditis is a potentially fatal complication, even in treated pts. Adjunctive glucocorticoids may help manage acute disease but do not seem to reduce constriction.

8. Miliary disease arises from hematogenous spread of MTB throughout the body. Lesions are small (1- to 2-mm) granulomas, and symptoms are nonspecific. Hepatomegaly, splenomegaly, lymphadenopathy, and choroidal tubercles of the eye may occur.

? HIV-Associated TB

? The manifestations of TB vary with the stage of HIV infection. When cell-mediated immunity is only partly compromised, pulmonary TB presents as typical upper-lobe cavitary disease. In late HIV infection, a primary TB-like pattern may be evident, with diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoracic lymphadenopathy. An immune reconstitution syndrome may occur when antiretroviral therapy is initiated. Symptoms and signs of TB are exacerbated as a consequence of improving immune function.

Diagnosis

?Maintain a high index of suspicion, perform appropriate radiographic studies, and obtain appropriate clinical specimens.

?Examine diagnostic specimens for AFB with auramine-rhodamine stain and fluorescence microscopy.

?Isolate and identify MTB on culture. New liquid media and nucleic acid probes for species identification have decreased the time for diagnostic confirmation to 2? weeks.

?Nucleic acid amplification is useful to confirm MTB as the species in AFB-positive sputa. It may be useful in other settings but is hampered by a sensitivity lower than that of culture (although higher than that of AFB smear microscopy).

?The results of drug susceptibility testing are most rapid if liquid medium is used.

?PPD skin testing is of limited value in active disease because of low sensitivity and specificity.

Treatment

Drugs

? First-Line Agents

?Rifampin: the most important and potent antituberculous agent. The standard dosage in adults is 600 mg/d. The drug distributes well throughout body tissues, including inflamed meninges. It turns body fluids (e.g., urine, saliva, tears) red-orange and is excreted through bile and the enterohepatic circulation. Rifampin is usually well tolerated but may cause GI upset. In pts with underlying chronic liver disease (e.g., alcoholics, the elderly), the drug can cause hepatitis. Rash, anemia, and thrombocytopenia are less common side effects. Of note, rifampin is a potent inducer of hepatic microsomal enzymes and decreases the half-life of many other drugs. Although relevant clinical data are less abundant than for rifampin, rifabutin뾞 closely related agent뾪ay be as effective, eliciting fewer drug interactions.

?Isoniazid (INH): the best agent available after rifampin. The usual adult dosage is 300 mg/d or 900 mg 2 or 3 times per week. INH is distributed well throughout the body and infected tissues, including CSF and caseous granulomas. The most important toxicities are hepatotoxicity and peripheral neuropathy. INH-associated hepatitis is idiosyncratic and increases with age, alcohol use, pregnancy or the postpartum period, and concomitant use of rifampin. Because peripheral neuropathy can result from interference with pyridoxine metabolism, pyridoxine (25?0 mg/d) should be given.

?Pyrazinamide: The usual dosage is 25 mg/kg daily. The drug distributes well throughout the body, including the CSF. At current doses, hepatotoxicity is no greater than with INH or rifampin. Hyperuricemia and뾦n rare cases뾤out can occur.

?Ethambutol: The least potent first-line agent, ethambutol is usually given at a dosage of 15 mg/kg daily. It is distributed throughout the body but reaches only low levels in CSF. At higher doses, retrobulbar optic neuritis can occur, causing central scotoma and impairing both visual acuity and the ability to see green.

? ? Other Effective Agents

?Fluoroquinolones: Levofloxacin, ciprofloxacin, moxifloxacin, and gatifloxacin have good, broad antimycobacterial activity.

?Streptomycin: The usual adult dose is 0.5?.0 g IM daily or 5 times per week. Streptomycin is similar to other aminoglycosides but is less nephrotoxic. Ototoxicity affects both hearing and vestibular function.

?Second-line agents are uncommonly used but may be needed in disease caused by MDR strains of MTB.

? ? Regimens

? See Table 102-1.

?Bacteriologic evaluation is the preferred method of monitoring response to treatment. Virtually all pts should have negative sputum cultures by the end of 2? months of treatment. If the culture remains positive, treatment failure and drug resistance should be suspected.

?Drug resistance may be either primary (i.e., infection caused by a strain resistant prior to therapy) or acquired (i.e., resistance arising during treatment because of an inadequate regimen or the pt's noncompliance).

?Nonadherence to the regimen is the most important impediment to cure. Use of directly observed treatment and fixed-drug-combination products should be considered.

?Close monitoring for drug toxicity should take place during treatment and should include baseline LFTs and monthly questioning about possible hepatitis symptoms. High-risk pts should have LFTs monitored during treatment if baseline results are abnormal.

Prevention

?Vaccination: An attenuated strain of M. bovis, bacille Calmette-Gu?in (BCG), protects infants and young children from serious forms of TB. Its efficacy is unclear in other situations.

?Treatment of latent infection: Candidates for chemoprophylaxis are usually identified by PPD skin testing. Positive skin tests are determined by reaction size and risk group (Table 102-2), and, if the test is positive, drug treatment is considered (Table 102-3). INH should not be given to persons with active liver disease.

Tuberculin Reaction Size, Treatment of Latent Tuberculosis Infection

Table 102-2

Risk Group Tuberculin Reaction Size, mm HIV-infected persons or persons receiving immunosuppressive therapy ≥5 Close contacts of tuberculosis patients ≥5a Persons with fibrotic lesions on chest radiography ≥5 Recently infected persons (≤2 years) ≥10 Persons with high-risk medical conditionsb ≥10 Low-risk personsc ≥15 aTuberculin-negative contacts, especially children, should receive prophylaxis for 2 to 3 months after contact ends and should then be retested with PPD. Those whose results remain negative should discontinue prophylaxis. HIV-infected contacts should receive a full course of treatment regardless of PPD results.

? ? bIncludes diabetes mellitus, some hematologic and reticuloendothelial diseases, injection drug use (with HIV seronegativity), end-stage renal disease, and clinical situations associated with rapid weight loss.

? ? cDecision to treat should be based on individual risk/benefit considerations.

1. renal tuberculosis의 증상: 치료에 반응하지 않고 오래 계속되는 chronic cystitis / sterile pyuria / gross or microscopic hematuria / nontender enlarged epididymis with beaded or thick vas deferens / chronic draining scrotal sinus / thickened seminal vesicles / general myalgia, fever, fatigue, wt loss

2. 경부 결핵성 림프절 절제술의 적응증: 결핵성 림프절염과 다른 질환과의 확실한 감별을 위해 / 농양이 형성되어 병소 주위 피부 파열 위험 있을 때 / 누공을 형성한 경우

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