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Tuberculosis: Clinical Syndromes

PULMONARY TUBERCULOSIS

The most common syndrome in adults is pulmonary TB, which accounts for ~ 80% of cases of active disease.

Clinical Findings

Signs and Symptoms

Symptoms of infection consist of fatigue, weight loss, fever, night sweats, and a productive cough. Most children who are infected with TB usually have no symptoms. Early symptoms can also include hemoptysis, which also occurs later in the disease when there is significant necrosis of lung parenchyma or if previous cavitations erode into arterioles. Patients with subpleural parenchymal inflammation with pleural membrane involvement or with TB pleuritis without parenchymal disease can experience pleuritic chest pain. Severe shortness of breath is not common. However, extensive pulmonary tuberculosis can cause respiratory failure.

Tuberculosis

Laboratory Findings

Routine laboratory test abnormalities are not common. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone can be seen in some patients with pulmonary TB. However, adrenal involvement with TB can cause adrenal insufficiency, which may also be present with hyponatremia. Anemia secondary to this chronic disease is common.

Imaging

Pulmonary TB usually produces infiltrates observable on chest x-rays, but occasionally, chest x-rays are normal. Primary TB is the disease that develops before the development of an immune response to the bacillus. Primary TB has different characteristics than secondary reactivation of a pulmonary TB disease. Primary TB usually involves the lower lobes. Five percent of cases show a lobar or segmental infiltrate associated with ipsilateral hilar adenopathy. Fifteen percent of cases may have bilateral hilar adenopathy, but this is more commonly unilateral. A pleural effusion may also be present.

Children with primary pulmonary TB often have hilar adenopathy and occasionally a lower-lobe infiltrate that can be seen on chest x-ray. Secondary or reactivation TB, which is by far the most common presentation, characteristically involves the lung apices (posterior apical segments) or, rarely, the superior segments of the lower lobes. This is seen in 95% of patients with localized pulmonary TB. The typical parenchymal pattern is cavitary lesions with associated air space consolidation of a patchy or confluent nature.

Old, healed pulmonary TB lesions can produce fibrosis or calcific lesions on chest x-ray. These lesions can cause volume loss or contraction of the involved lobe. Cavities also may persist. New infiltrates or masses in areas of old tuberculosis infections may represent carcinoma, bacterial infection, hemorrhage, mycetoma, or recurrence of TB.

Differential Diagnosis

Differential diagnosis of pulmonary TB includes other atypical mycobacterium infections (Mycobacterium avium complex or M kansasii) and viral infections (see site).

Complications

Complications of pulmonary TB include lung bulla formation, poor lung function, overwhelming infection, and death.

EXTRAPULMONARY TUBERCULOSIS

Extrapulmonary TB accounts for ~ 20% of cases of active tuberculosis. Extrapulmonary TB is more common in immunocompromised patients and in infants and young children. Of these extrapulmonary sites, meningeal and lymphatic locations for disease are more common in infants and young children. In adolescents, the extrapulmonary sites tend to be the pleura, genitourinary tract, or peritoneum. Overall, the most common extrapulmonary site of TB in children is in the lymphatic system.

Other sites of infection in adults can include pleura, genitourinary tract, gastrointestinal tract, bone, meninges, peritoneum, and adrenals. When the M tuberculosis bacillus infects the lung, it often disseminates and involves multiple organs, including the bone marrow. This is called disseminated or miliary tuberculosis, but it may be asymptomatic. Extrapulmonary TB develops when the bacillus overwhelms the immune system and disseminates by way of the lymphatics, the bloodstream, or both. In these cases, disease is documented by biopsy, positive blood cultures, or both.

Signs and symptoms of extrapulmonary TB depend on the organ system involved. Weight loss, night sweats, and fever are the classic but nonspecific signs of tuberculosis. Clinicians should do blood cultures as well as biopsy and culture of the suspected tissue.

TUBERCULOSIS IN PATIENTS WITH HIV INFECTION

HIV patients can have a wide variety of organ system involvement. In early HIV infection, pulmonary TB can be a presenting infection and an AIDS-defining illness. In advanced HIV infection, dissemination is common. A variety of unusual sites of infection have been documented, including brain, pericardium, and other more common extrapulmonary sites such as those for peritoneal and gastric TB. Overall, the most common site of TB disease in an HIV-positive patient is pulmonary; however, these patients are at increased risk for developing disseminated disease (Box 2).

Diagnosis

Diagnoses of extrapulmonary and pulmonary TB are the same. A skin test (PPD) is used to prove infection: 0.1 mL of PPD is placed intradermally on the volar surface of the forearm by means of a 26-gauge needle. At 48-72 h after injection, the diameter of induration, not erythema, is measured. A positive skin test reaction is caused by a delayed-type hypersensitivity response, which is directed at the TB protein antigens. Other tests include demonstration of the bacillus by means of culture or AFB smear of affected organs or blood culture in disseminated disease.

Interpreting Tuberculin Skin Tests

The criteria vary for interpreting a PPD test as positive. An induration = 5 mm is considered positive in patients who are at high risk of infection and developing disease; these include patients with known or suspected HIV infection, which includes all injection drug users. This group also includes close contacts of patients with active disease and patients with a chest x-ray suggestive of previously inactive tuberculosis. An induration of = 10 mm is considered positive in patients who are at intermediate risk of infection and developing TB.

This group includes known HIV-negative injection drug users, immigrants from high-prevalence countries (such as Asia and Mexico), residents of long-term care or correctional facilities, locally identified high-prevalence groups (migrant workers, the homeless, and high-risk racial or ethnic groups), and children = 4 years old. Patients also at intermediate risk of TB include those with an immunosuppressive illness other than HIV or those receiving immunosuppressive therapy. These include patients with diabetes, renal failure, or hematologic malignancies or those receiving steroids on a long-term basis (> 15 mg of prednisone/d). Finally, an induration of = 15 mm is considered positive in patients with no known risk of developing TB or being infected with TB.

False-positive PPDs

False-positive results can occur in two situations. Patients who are infected with atypical mycobacteria such as M avium or M kansasii may have false-positive PPD results. Bacillus Calmette-Guerin (BCG) vaccination can also cause a positive result. However, a history of prior BCG vaccination should be ignored when one is interpreting skin test results in individuals with a high likelihood of being infected with M tuberculosis.

False-negative PPDs

False-negative results are much more common. In patients with distant infection, reactivity to a PPD test can decrease over time. These patients may require a “boost” PPD given 2 weeks after the first injection. There are multiple other factors to consider that cause a false-negative reaction (Table 1). Patients with coexisting diseases can also have false-negative reactions. In these patients, administration of other antigens such as those for Candida infection and mumps may be used to rule out anergy. However, some patients can have selective PPD nonreactivity.

Bacteriologic Evaluation

Smears and cultures of sputum are the most reliable ways to diagnose active pulmonary tuberculosis. Three separate early-morning sputum samples should be collected for AFB staining. Cultures should be performed on all specimens of patients suspected of having tuberculosis. Because M tuberculosis grows so slowly, it may take = 6 weeks to identify the organism by culture. Drug susceptibility testing should be done on all positive cultures. In extrapulmonary TB, AFB stains and cultures are done on the infected tissue.

Polymerase Chain Reaction (PCR) Technique

Rapid diagnosis by the PCR technique is another option for the diagnosis of TB. It is commercially available and recently received approval by the U.S. Food and Drug Administration. PCR is approved only for testing AFB-positive sputum smears. In a research setting, PCR’s specificity and sensitivity are > 95%. It does not take the place of acid-fast smears or mycobacterial cultures. Many more studies must be performed to better define the utility of PCR in the clinical setting.

Treatment

Treatments of active extrapulmonary and pulmonary TB are the same. Treatment should be started presumptively before diagnosis in patients with severe disease thought to be TB. Treatment usually does not reduce the isolation rate of AFB in the first several days. In patients with less severe disease or those who present diagnostic dilemmas, therapy can be withheld until a diagnosis is made or until several specimens have been collected.

Patients should be started initially on a four-drug regimen until drug susceptibility tests are finalized, unless the patient is from an area where drug resistance is very low. Most communities in the United States have a > 4% incidence of cases resistant to at least one drug. However, if a community has a < 4% resistance rate, an initial three-drug regimen is acceptable.

Choice of Treatment Regimen

There are several available regimens for treatment (Box 3). Several considerations should be made when deciding on a particular regimen. These include the probability of primary resistance, previous treatment for tuberculosis, patient compliance, other coexisting illnesses, drug susceptibility of the organism, and history of hypersensitivity to or side effects of antituberculosis drugs. The risk factors for drug resistance include > 4% of INH resistance in the community, prior treatment with INH, exposure to a known drug-resistant case, immigration from countries with a high incidence of drug resistance (countries in Asia, Africa, or Central or South America), HIV coinfection, and intravenous drug use. These patients should be placed on an initial four-drug regimen (Table2).

Tuberculosis treatment is based on three basic principles. Regimens for treatment of the disease must contain multiple drugs to which the organism is susceptible. The medications must be taken regularly. Finally, drug therapy must continue for an extended period because of the slow growing nature of the M tuberculosis bacillus.

If patients do not take their medications regularly, many adverse consequences can result. M tuberculosis can develop resistance. It can take a long time for the patient to become noninfective or for the disease to be contained. These factors are why DOT was introduced. Some experts advocate that DOT should be used in all patients. However, this would be an expensive burden on the public health system. Most physicians use DOT for patients who have a history of noncompliance, risk factors for noncompliance such as substance abuse, and multidrug-resistant TB.

Monitoring During Treatment

While treating patients for tuberculosis, clinicians should monitor for clearing of the organism and for side effects of the medication. Before treatment is begun, laboratory tests of liver and renal functions should be performed and a baseline blood count obtained. If a patient is starting on pyrazinamide, a baseline uric acid level should be established. If a patient is to be treated with ethambutol, visual acuity and red-green color perception should be checked because this drug is known to produce optic neuritis. Ethambutol should not be used in children who are too young to report vision changes (Table 3).

Follow-up

Monthly follow-up should be done to check for symptoms of toxicity or disease progression. The patient with TB (pulmonary or extrapulmonary) should have a follow-up sputum monthly until the M tuberculosis culture is negative. Successful drug therapy using a combination regimen should eradicate the TB bacillus from the sputum of ~ 85% of patients in 2 months and ~ 100% of patients within 6 months. It is therefore important to obtain a sputum TB culture after the first 2-3 months of treatment and again after 6 months of treatment to document the negative cultures. If organisms are still present in the sputum after 3 months of treatment, patients should be evaluated for noncompliance, poor absorption of medications, or resistance of organisms. These patients should be referred to a tuberculosis specialist, as should patients for whom therapy has failed, patients with known drug-resistant organisms, and patients with complicated drug toxicities secondary to the treatment regimen.

Prevention & Control

The key to prevention and control of TB centers on preventing exposure and, if infection occurs, preventing disease progression (Box 4). It is important to prevent exposure of the surrounding population to a patient with active tuberculosis. Thus isolation of patients with suspected TB is critical. Isolation can be achieved at home, if the patient lives alone, or in a special room in the hospital. Isolation rooms should have negative pressure and have six exchanges of air per hour with no recirculation of that air within the hospital. These rooms also should have ultraviolet lights to kill the bacilli in that room. Any patient with a cough and an infiltrate consistent with TB on a chest x-ray should always be isolated. Before a patient can be removed from isolation, three negative sputum AFB smears should be obtained. If the patient’s disease is TB, the patient can be removed from isolation when the sputum AFB smear quantification decreases significantly (ie, 4+ to 1+). Masks have been a mainstay in preventing infection in health care workers, but efficacy remains unproven. The bacillus is spread from an infected patient by way of airborne droplets with active pulmonary disease only. Extrapulmonary TB is not contagious except when health care workers directly handle infected specimens (see below).

Prevention of disease in patients exposed to tuberculosis is important. It is accomplished by preventive therapy with INH. Patients who are at risk of infection have either a positive PPD, a history of exposure such as household contacts with a patient who has active TB, or both. A patient with a positive PPD test should have a screening chest x-ray. If signs of active disease are present, a screening sputum evaluation should be done. The risk of having infection is extremely high in children who are the household contacts. Known exposed children < 6 years of age should have a chest x-ray done even if the PPD is negative, since these children can have a severe course if active TB is left untreated. If a household contact’s first PPD is negative, another PPD should be placed in 8-12 weeks (which, if the patient has been truly exposed, should be positive at this time). If the second PPD is negative, preventative therapy can be stopped if the patient is no longer in danger of being exposed.

Prevention Among Health Care Workers

Health care workers should have regular PPD checks unless they have a history of PPD positivity. Most centers recommend yearly PPDs. PPDs should be placed on anyone who is a household contact of a patient with active TB or anyone who has had close contact with an active case of TB. Also, patients who are in extended-care facilities or correctional facilities should have a PPD at the time of initial placement because of the high risk of infecting a large group of people.

Patients who qualify for preventative therapy should receive INH, 300 mg by mouth daily for a minimum of 6 months (Table 61-4). If the patient has radiographic evidence of previous tuberculosis, he or she should be treated with INH for 12 months. Children should be given a dose of INH of 10 mg/kg/d to a maximal dose of = 300 mg/d. People receiving INH for prevention should be monitored monthly for signs of INH toxicity. Patients with symptoms of hepatitis, such as gastrointestinal complaints, jaundice, anorexia, or some combination of these symptoms, should have liver function tests performed. If those tests are abnormal, INH should be stopped. Patients with an increased risk of INH hepatitis should have their liver function checked regularly. These patients include those > 35 years of age, alcohol users, and those with preexisting liver disease. INH therapy should not be given to patients with active liver disease or to pregnant women. It is important to remember that patients with radiographic evidence of tuberculosis must be first evaluated for active disease before beginning preventative treatment.

If a person has a high risk of exposure to INH- or rifampin-resistant organisms, the data for the efficacy of preventative therapy are limited. If the risk of infection with INH-resistant organisms is high and the patient would be unable to tolerate the disease, rifampin should be used. If the patient was exposed to INH- and rifampin-resistant organisms, a multidrug preventive therapy should be used. Each case must be assessed individually (Table 5).

BCG vaccination has been used in some countries to improve the ability of a person who is acutely infected with Mycobacterium TB to contain the infection. The reported effectiveness of BCG vaccination varies, and the indications for use are limited. In the United States, the only people who might benefit from a BCG vaccination could be people who are repeatedly exposed to TB. Because BCG will cause a PPD test to be positive, it can complicate the diagnosis of a TB infection. However, the history of a BCG vaccination should be ignored when a PPD is placed, and the patient should be treated based on the guidelines in Table 61-4 or the patient’s symptoms of active disease.

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