Approach to the Patient with Tuberculosis

Benjamin Davis

The primary care physician most commonly encounters tuberculosis (TB) as a positive tuberculin screening test in the absence of active infection (see Chapter 38). However, the physician must remain vigilant for the signs and symptoms of active TB, which are changing as a consequence of its changing epidemiology. Active disease is increasingly a consequence of acute infection rather than of reactivation of latent disease. The classical clinical findings are less likely, and atypical presentations are becoming more prevalent, especially in immunocompromised hosts. The rapid diagnosis and treatment of TB may be impaired by several factors, including inadequate sensitivity of skin testing and sputum smears, a wide variety of clinical presentations, the several weeks required to obtain confirmatory cultures and antibiotic sensitivities, and the emergence of drug-resistant strains.

These challenges necessitate close collaboration with expert infectious disease consultants and relevant departments of public health. This chapter focuses on the role of the primary care physician, which entails initial diagnosis, implementation of a basic first-line antibiotic program pending culture results, and minimizing the risk of transmission to others.

PATHOPHYSIOLOGY AND EPIDEMIOLOGY (1, 2, 3, 4, 5, 6 and 7)

Virtually all cases are acquired through person-to-person aerosol transmission of a nonmotile, acid-fast, gram-positive rod. People with active pulmonary infection shed infected droplets, which are then aerosolized into the environment. Because most infectious patients discharge relatively few organisms, casual contacts are at low risk for infection, and most secondary cases occur among household members, schoolmates, or other close contacts of the index case. TB is more common in immigrants and population groups in which crowding, poverty (especially homelessness), or a high risk for HIV infection is common (see Chapter 38). Among HIV-infected patients, the risk for disease after infection is increased 1,000-fold. Serious outbreaks (with attack rates of 10%) have been reported among patients in hospital wards with a large concentration of AIDS patients. Risk is also high among health care workers attending to such patients. Epidemiologic predictors of extensively drug-resistant pulmonary TB include previous treatment, alcohol abuse, and homelessness. Increased risk of multidrug-resistant disease is found among those with previous treatment, age less than 65 years, or recent immigration.

Most persons harboring the tubercle bacillus mount an immune response sufficient to prevent progression from primary infection to clinical illness; they manifest a positive skin test result. About 5% of infected persons fail to contain the primary infection and progress to active primary disease within 2 years of initial infection. The proportion of infected persons who progress is much higher among HIV/AIDS patients. In the past, primary infection occurred almost entirely in childhood; however, as the epidemiology of TB has changed (see Chapter 38), primary TB is now also seen in adults, particularly among elderly nursing home residents and in patients coinfected with HIV.

Another 5% of infected patients (again, a higher proportion of AIDS patients) experience reactivation of latent endogenous infection, most often within 2 to 4 years of the initial infection or at times of lowered host resistance. However, reactivation can occur many decades after initial infection, as reported among elderly nursing home residents. More than one fifth of patients with reactivated disease have histories of inadequately treated clinical TB. In many instances, a discrete insult to host defenses, such as steroid therapy, alcoholism, malnutrition, neoplastic disease, HIV infection, or gastrectomy, can be implicated, but at times, it is impossible to identify the reason for reactivation.

Previously, the vast majority of active TB cases in the United States were thought to represent reactivation of latent disease, but the advent of polymerase chain reaction technology and molecular epidemiology reveals a different picture. Utilizing these techniques, studies from large metropolitan centers such as San Francisco and New York City revealed 35% to 40% of active TB cases were newly acquired infections. Although the HIV/AIDS epidemic accounts for some of this change in epidemiology, it is clear that clinical disease develops soon after infection in more immunologically “normal” persons than was previously thought.

CLINICAL PRESENTATION AND COURSE (1, 2, 3, 4, 5, 6, 7 and 8)

Primary Infection

As noted, more than 90% of patients are entirely asymptomatic at the time of primary infection and can be identified only through conversion of the tuberculin skin test from negative to positive or whole-blood interferon-gamma release assay (IGRA) test. The majority of these patients have normal findings on chest radiography. Among the 10% who progress directly to symptomatic disease, four broad syndromes can be identified: (a) Atypical pneumonia is the most common, characterized by fever and nonproductive cough. Chest x-ray films may show unilateral lower lobe patchy parenchymal infiltrates or paratracheal or hilar adenopathy. Although such patients should receive full antituberculous chemotherapy when the disease is diagnosed (see later discussion), it usually resolves even without treatment. (b) Tuberculous pleurisy and effusion are accompanied by fever, cough, pleuritic chest pain, and occasionally dyspnea. Chest x-ray films reveal unilateral pleural effusions, often without identifiable parenchymal lesions. The tuberculin test result is almost always strongly positive. Diagnosis depends on examination and culture of the pleural fluid or on percutaneous needle biopsy of the pleura because sputum cultures are positive for organisms in only 30% of such cases. (c) Direct progression from primary disease to upper lobe involvement is another presentation. (d) Early systemic dissemination, which used to be seen exclusively in children, now occurs in HIV-infected patients.

Reactivation (Postprimary) Tuberculosis

Notwithstanding our greater understanding of primary disease, this is still the most common clinical form of TB. Symptoms usually begin insidiously and progress during a period of many weeks or months before diagnosis. Constitutional symptoms are often prominent, including anorexia, weight loss, and night sweats. Most patients have low-grade fever, but higher temperatures and even chills may be seen occasionally when the disease progresses more rapidly. In addition, most patients present with pulmonary symptoms, including cough and sputum production. Dyspnea is relatively uncommon in the absence of underlying
chronic lung disease. A frequent complaint is hemoptysis, often in the form of bright red streaks of blood caused by bronchial irritation. Although physical examination findings are usually nondiagnostic, chest x-ray films are highly suggestive of the diagnosis. Typical features include infiltration in the posterior apical pulmonary segments, which may be unilateral or bilateral and progresses to frank cavitation. Apical lordotic views and chest tomography may help to document cavitary disease. Occasionally, postprimary TB may involve the lower lung fields, and, in rare instances, the chest radiographic appearance may be normal. The tuberculin skin test result is positive in about 80% of patients with reactivation TB; patients with advanced disease are often malnourished and thus anergic.

Extrapulmonary Tuberculosis

Approximately 20% of all newly recognized cases of TB in the United States are extrapulmonary. Although the frequency of pulmonary TB is constant, the incidence of extrapulmonary disease is increasing, largely among HIV-positive patients (see later discussion). Although the clinical features of extrapulmonary TB vary widely, certain generalizations are possible. Past history is not a reliable guide to the diagnosis. Only 25% of patients have a past history of TB; of these, virtually all have been inadequately treated. A long latent period between the first episode of infection and the extrapulmonary presentation is typical. Approximately 50% of patients with extrapulmonary disease have entirely normal chest radiographic findings; most of the others have stigmata of old, inactive pulmonary disease, and a minority has coexisting active pulmonary infection. Although extrapulmonary disease can involve all organ systems, either singly or in various combinations, the most commonly affected areas are the genitourinary tract, the musculoskeletal system, and the lymph nodes.

The most common type of extrapulmonary TB is infection of an individual organ system. The patient is most often afebrile and can be entirely free of constitutional complaints. The illness typically pursues an indolent course characterized by local organ dysfunction and eventual destruction rather than by progressive general decline. In fact, the clinical presentation in these persons more often suggests neoplastic disease than infection. The tuberculin skin test result is almost always positive. Clinical syndromes in this category include genitourinary TB, tuberculous arthritis and osteomyelitis, and tuberculous lymphadenitis.

HIV-positive patients with TB may experience extrapulmonary disease and dissemination early on. When CD4 cell counts are well preserved (see Chapter 13), tuberculous infection usually causes pulmonary disease that resembles TB in HIV-negative persons. However, in more severely immunocompromised HIV patients, TB is often disseminated at presentation. A high incidence of tuberculous meningitis has been reported among HIV-positive patients, often in conjunction with diffuse lymphadenopathy. The occurrence of pulmonary or extrapulmonary TB in patients with HIV infection fulfills the criteria for the diagnosis of AIDS.

In HIV-infected patients with disseminated disease, the result of the purified protein derivative skin test is often negative. Chest radiographic findings are normal in more than 10% of patients. When infiltrates do occur, they are often nonspecific and involve the lower lobes. Despite these atypical features, the diagnosis can usually be established, if suspected, without much difficulty by visualizing or culturing the causative organism from the sputum or extrapulmonary sites.

DIAGNOSIS (1,6,9, 10, 11, 12 and 13)

Diagnosis of TB has two components: diagnosis of infection with Mycobacterium tuberculosis and diagnosis of active disease.

Diagnosis of Infection

Tuberculin skin testing (TST) and the newer whole-blood interferon-gamma-release assay (IGRA) tests are the principle means of diagnosis for infection (see Chapter 38). A positive TST or IGRA test result does not by itself prove the presence of active disease, but it does indicate that infection has occurred. There is some evidence that IGRA positivity may be more predictive of developing active disease than TST positivity, especially in younger recent contacts. Promising results have been reported with a nucleic acid amplification test for rapid diagnosis of TB (sensitivity 98%, specificity 73%) and for identification of rifampin resistance

Negative tuberculin and IGRA reactions have been documented in upwards of 20% of patients with active TB, particularly those with overwhelming or advanced disease, immunosuppression, or debility. In HIV-positive patients, especially those with low CD4 cell counts, the rate of false-negative skin test results has been as high as 50%.

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