From American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003:52:1-77 [erratum appears in MMWR Recomm Rep 2005;53:1203; dosage error in text].

Box 181.1

Populations at Risk for Contracting Tuberculosis

Adapted from American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005;172:1169-1227.

Early stages of infection are most often asymptomatic in the normal host. Unless cell-mediated immunity is impaired, symptoms may manifest only after reactivation of the infection. Patients may present with a combination of systemic symptoms including cough, fatigue, fever, anorexia, malaise, and weight loss. An indolent cough that has progressed over more than 2 weeks should raise the clinical suspicion of pulmonary TB.⁵ Hemoptysis signifies erosion into the bronchial tree and is unlikely to be an early symptom of pulmonary TB. When the clinical suspicion is raised, the physical findings in pulmonary TB may include fever, pleural effusion, focal pneumonic ausculatory findings, and adenopathy.

Variations

Extrapulmonary manifestations clinically conform to the site of infection, and care should be taken to include TB in the differential diagnosis in patients who present with the following conditions:

• Diffuse adenopathy of the neck (scrofula)

• Recurrent urinary tract infections, scrotal mass, prostatitis, epididymitis, or orchitis (genitourinary TB)

• Headache, fever, meningeal signs, or altered mental status (TB meningitis)

• Focal neurologic deficits, cranial nerve abnormalities, cerebellar dysfunction, or seizure (central nervous system tuberculomas)

• Joint or spinal pain (Pott disease)

• Chest pain or dullness to percussion (pleural TB)

• Multiple organ system disease (disseminated TB)

Differential Diagnosis

Depending on the clinical symptoms at presentation, TB may mimic numerous systemic diseases. Radiographic findings, sputum smears, and skin tests help in the diagnosis of TB. The “gold standard” diagnostic test is culture, and results may not be available for several weeks (Table 181.2).

Table 181.2 Differential Diagnosis of Tuberculosis

Extrapulmonary Tuberculosis

HIV, Human immunodeficiency virus.

Red Flags

• Failure to consider extrapulmonary tuberculosis in the differential diagnosis

• Tuberculosis in immunocompromised patients or those at the extremes of age

• Tuberculosis in patients with risk factors for multidrug-resistant tuberculosis

• Patients with social concerns who may not be able to fulfill directly observed therapy

Diagnostic Testing

Latent TB in asymptomatic patients is clinically difficult to identify. Targeted population screening has been advocated as a means to identify early disease while it is still in the more easily treated latent period. Current recommendations are to perform a PPD skin test on patients who would benefit from therapy for latent TB and who are at high risk of developing active TB (Box 181.2).⁶ Currently, the foundation of screening is skin testing with PPD in patients at risk for TB. Patients who harbor latent TB and who have intact cellular immunity demonstrate a hypersensitivity reaction at the site of PPD placement that can be graded and evaluated with a well-established scale reflecting positivity or negativity (Table 181.3).⁶ This type of screening is not particularly sensitive in immunocompromised patients, older patients, newly infected patients, or very young children. Additionally, the PPD test lacks the specificity to distinguish among other Mycobacterium infections.⁷ Newer whole-blood antigen-stimulated interferon-γ release assays are available that have high sensitivity and specificity, are not affected by prior bacille Calmette-Guérin vaccination, and do not have a waning response over time.^4,⁷ As genomic testing becomes more widely available, the ability to predict disease progression based on the genetic expression of an individual patient may play an important role in diagnosis.⁸

Box 181.2

Indications for a Purified Protein Derivative Skin Test

TB, Tuberculosis.

From Myers JP. New recommendations for the treatment of tuberculosis. Curr Opin Infect Dis 2005;18:133-40.

Table 181.3 Evaluation of Purified Protein Derivative Skin Testing Results

INDURATION SIZE	CONSIDERED POSITIVE IN
≥5 mm	Recent contact with TB-positive patient Chest radiographic findings consistent with prior TB HIV-infected patients Immunosuppressed patients Organ transplant recipients

≥10 mm

Recent immigrants from countries with a high prevalence of TB

Intravenous drug users

Homeless and low-income populations

Residents or employees of nursing homes, hospitals, homeless shelters, correctional facilities

Risk factors for reactivation TB (diabetes, renal failure, malignant disease)

Medically underserved populations

Children < 4 years old

Children and adolescents exposed to TB-positive adult

≥15 mm People with no risk factors

HIV, Human immunodeficiency virus; TB, tuberculosis.

From Myers JP. New recommendations for the treatment of tuberculosis. Curr Opin Infect Dis 2005;18:133-40.

The advent of auscultation and radiography greatly advanced the diagnosis of TB in the eighteenth and nineteenth centuries.⁹ Despite technical advances in diagnostic tests, history, physical examination, and conventional radiography remain cornerstones in the diagnosis of TB in the emergency department (ED). Frequently, patients who present to the ED with symptoms of pulmonary or extrapulmonary TB have limited prior access to care, and heightened suspicion is required. Once a history is obtained that suggests active pulmonary disease, patients should be isolated (in a negative-pressure room, if possible), and a chest radiograph should be obtained. The identification of an upper lobe infiltrate suggests the presence of active disease (Figs. 181.1 and 181.2). Chest radiography is not highly sensitive, particularly in the immunocompromised patient, in whom reticulonodular and miliary patterns of disease may be present.¹⁰ The clinical syndrome of normal chest radiographs with sputum culture-positive TB is well described in patients with human immunodeficiency virus (HIV) infection and low CD4 counts.¹¹ In these patient populations, a high clinical suspicion for disease mandates that sputum studies be ordered.

Fig. 181.1 Right upper lobe cavitary lesion.

Fig. 181.2 Left lower lobe infiltrate with effusion.

Unfortunately, sputum Gram stain with carbolfuchsin and phenol or auramine O staining for the identification of acid-fast bacilli (AFB) is unreliable in the ED evaluation of patients suspected to have TB. In addition to the variability in performance inherently linked to the skill of the laboratory technical staff, and the availability of rapid test results at all times of day, the sensitivity of a single AFB smear remains low (<50%), far too low for the safe discharge of the high-risk patient.¹² This situation necessitates further management by the inpatient team or close follow-up with the local health department for further sputum smears in those patients who are deemed safe for discharge. The additive value of three morning sputum smears is helpful for excluding the diagnosis of active pulmonary TB. When AFB smears are identified, distinguishing among Mycobacterium species is not possible, and the definitive diagnosis should be confirmed with sputum culture.

Sputum culture is not part of the ED evaluation of a patient with suspected TB. Cultures traditionally take 4 to 8 weeks to grow. Cultures are sensitive in more than 80% of cases of infiltrative pulmonary TB and in more than 90% of cases of cavitary TB.¹³ Newer methods of radiometric culture systems with radiolabeled carbon-14 yield faster results (1 to 3 weeks).

The advent of nucleic acid amplification tests and of polymerase chain reaction identification greatly increased the sensitivity (97% to 99%) for the diagnosis of TB from a single sample, and accurate results can be obtained in hours. Additional strain typing for M. tuberculosis with restriction fragment length polymorphism is available to identify the organism’s DNA.¹⁴ Even for large centers, these tests are time and resource consuming to perform on an as-needed basis, and they are impractical for use in the ED work-up of patients with suspected TB. The utility of these newer tests in smear-negative individuals has been called into question with reports of lower sensitivities (70%) in this population.¹⁵

Extrapulmonary TB is often confirmed by biopsy of affected tissues and lymph nodes. Blood culture, urine culture, and culture of other body fluids are used to aid in the diagnosis of extrapulmonary TB, with varying sensitivities, depending on the host and the site of culture. The diagnosis of pleural TB is facilitated with pleural biopsy and culture; yields are 86% in immunocompetent patients and 47% in immunocompromised patients.¹⁶

Ultimately, the diagnosis of TB remains firmly grounded in the clinician’s analysis. A high suspicion of disease, coupled with appropriate testing for the given presentation, will translate into clinical success (Fig. 181.3).¹⁷

Fig. 181.3 Algorithm for patients suspected to have tuberculosis (TB).

AFB, Acid-fast bacillus; Neg, negative; Pos, positive; PPD, purified protein derivative.

Procedures

Historically, bleeding, leeches, cupping, application of animal excrement, “touching” by kings, pleurocentesis, and the isolation of patients in sanatoriums were used to treat TB. More modern medical times have seen the use of surgical pneumonectomy, thoracoplasty, pneumothorax, and phrenic nerve interruption as potential therapeutic procedures.⁹ The only procedure infrequently used today is surgical resection.

Treatment and Disposition

Pulmonary Tuberculosis

Prevention of the spread of TB is paramount in the treatment regimen, and involvement of the local health department ensures a higher success rate. Empirically in the ED, start patients with suspected TB on a drug regimen after obtaining sputum for AFB smears and cultures.

Treatment consists of two phases: the initiation (bactericidal) phase, lasting 2 months; and the continuation (sterilizing) phase, usually lasting 4 to 7 months. Because of the risk of multidrug-resistant organisms, at least two drugs should be used. The American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America recommend an initial four-drug cocktail of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (ETH) for 2 months (Table 181.4).⁴ Directly observed therapy increases completion rates for pulmonary TB and prevents the spread of disease.¹⁸^–²⁰

Table 181.4 Antituberculosis Medications

Immunocompetent patients become noninfectious 2 to 4 weeks after initiating therapy if the organism is susceptible. If the initial treatment regimen fails, then at least two additional drugs should be added.²⁰ Usually, PZA or another first-line agent is coupled with a second-line agent such as ethionamide or a fluoroquinolone.⁵

Special Populations

Patients Infected With Human Immunodeficiency Virus

Because of specific drug interactions and resistance, HIV-infected patients present a challenge to standard treatment protocols. Many of the anti-TB drugs have overlapping toxicities with the antiretroviral agents, and some anti-TB drugs may decrease the concentration of certain antiretroviral agents as a result of cytochrome system interactions.²¹ HIV-infected patients should not receive once-weekly INH-RIF combinations because of high relapse rates. Patients with CD4 counts lower than 100 cells/mL should receive the anti-TB regimen at least three times a week because of the potential for RIF resistance. If sputum cultures are still positive at 2 months, the continuation phase of treatment may need to be extended to 7 months.²⁰ Coordination with the infectious disease specialist during treatment of these patients is important.

Multidrug-Resistant Organisms

By definition, multidrug-resistant TB is disease that is resistant to two or more first-line agents, usually INH and RIF. Multidrug-resistant TB results from improper treatment regimens, noncompliance with therapy, and spontaneous mutations of the mycobacterium (Box 181.3).⁴ These patients should be treated with alternative drug regimens that include at least three drugs to which the organism is susceptible and that have not been previously administered. Ideally, one of these drugs should be injectable.⁴

Box 181.3

Risk Factors for Multidrug-Resistant Tuberculosis

Human immunodeficiency virus infection

Intravenous drug use

Recent immigration from a country with a prevalence of multidrug-resistant TB

Cavitary lung lesion

Homelessness

Incarceration

History of gastrectomy or ileal bypass

Prior failed TB treatment

Noncompliance with treatment regimen

TB, Tuberculosis.

From American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005;172:1169–227.