Epidemiology

The World Health Organization (WHO) estimates that one-third of the world’s population is latently infected with Mycobacterium tuberculosis.¹ From this pool, approximately 9 million active tuberculosis (TB) cases emerge annually, resulting in 2 million deaths and making TB the second leading cause of death by an infectious agent worldwide.² The vast majority of TB cases (95%) occur in the developing world. Incidence rates exceed 300 cases per 100,000 persons throughout sub-Saharan Africa, the Indonesian and Philippine archipelagos, Afghanistan, Bolivia, and Peru.^1,3 Areas with the most cases per year include densely populated India (2 million cases per year) and China (1.3 million cases per year).

In the United States, the TB rate continues to decline, with 3.8 new cases per 100,000 reported in 2009, the lowest rate recorded since national reporting began in 1953. Foreign-born persons and racial/ethnic minorities continue to bear a disproportionate burden of TB disease in the United States. In 2008, the TB rate within the foreign-born population in the United States was 10 times higher than in U.S.-born persons.⁴ TB rates among Hispanics and blacks were nearly eight times higher than among non-Hispanic whites, and rates among Asians were nearly 23 times higher than among non-Hispanic whites. Among U.S.-born racial and ethnic groups, the greatest racial disparity in TB rates was seen in the black population, who are seven times more likely to develop active TB than U.S.-born whites. Other groups at increased risk for active TB include prisoners, the homeless, and human immunodeficiency virus (HIV)-positive individuals.

The acquired immunodeficiency syndrome (AIDS) epidemic has contributed significantly to the rise in TB cases worldwide, with about 1.5 million individuals with active TB per year co-infected with HIV. HIV increases the risk of developing TB by 20.6-fold in countries where the prevalence of HIV is more than 1% in the general population.⁵ Co-infection with HIV contributes significantly to TB-related mortality.

The Serious Problem of Highly Drug-Resistant Tuberculosis

Drug-susceptible TB is readily curable provided adherence to medications is followed. However, drug-resistant TB requires a significantly longer course of antibiotics coupled with second-line agents that often are accompanied by difficult-to-tolerate side effects. More importantly, highly drug-resistant TB is associated with significant increase in morbidity and mortality. In the early 1990s, substantial levels of drug resistance began emerging in urban parts of the United States.⁶ Although the incidence of drug-resistant TB has diminished in the United States, it is increasingly problematic in many parts of the world.⁷

Multidrug-resistant TB (MDR-TB) is defined as resistance to two of the most powerful first-line anti-TB drugs, isoniazid (INH) and rifampin (RIF). Isolates that are resistant to multiple other combinations of anti-TB drugs but not to INH or RIF are not classified as MDR-TB. It is estimated that of the 9 million new cases of TB per year in the world, 500,000 are due to MDR-TB. Whereas drug-resistant TB is increasing at an alarming rate worldwide, particularly in India and China, prevalence in the United States decreased between 1991 and 2006 from 3.5% to 1.1%.⁸ MDR-TB disproportionately affects foreign-born individuals, accounting for 0.4% of TB cases occurring in U.S.-born persons and 1.3% in foreign-born individuals.⁹

Extensively drug-resistant tuberculosis (XDR-TB) is defined as resistance to INH, RIF, any fluoroquinolone, and to a second-line injectable (amikacin, kanamycin, or capreomycin). XDR-TB has emerged with a wide geographic distribution, including the United States, and is associated with worse treatment outcomes than MDR-TB, especially in those co-infected with HIV.^7,10–15

Tuberculosis in the Intensive Care Unit

TB patients requiring intensive care unit (ICU) care represent 1% to 3% of all patients with active TB. Most studies of TB patients requiring ICU admission are retrospective and frequently include a disproportionate number of HIV-positive individuals. TB should be considered in the differential diagnosis of critically ill patients, particularly in foreign-born individuals who emigrated from countries with a high prevalence of TB. With the increased use of tumor necrosis factor alpha (TNF-α) antagonists and other immunosuppressive agents, ICU physicians are more likely to encounter patients with non-classical features of TB. In this chapter, selected critical care issues in TB are discussed. Some disease forms, such as renal and peritoneal TB, are omitted because they are less likely to be seen in the ICU.

Pulmonary Tuberculosis

Pulmonary disease is by far the most common manifestation of active TB and of TB requiring ICU admission. Pulmonary disease may be due to a primary infection or to reactivation disease.

Primary infection occurs following airborne implantation of tubercle bacilli into the lungs. M. tuberculosis spreads from the lungs to hilar lymph nodes, and then throughout the bloodstream (Figure 142-1). Although primary infection is usually asymptomatic in adults, it can present with fever, hilar adenopathy, lung infiltrates, pleural effusions, and even severe pulmonary disease that may mimic viral or bacterial pneumonia, which may delay the diagnosis of TB. In severely immunocompromised patients, primary TB may be aggressive and become disseminated. Pleural TB is usually a manifestation of primary TB, although it may also occur with reactivation disease. Pleural TB can present as pleuritis or empyema. Pleural biopsy specimens are more likely to yield positive cultures than pleural fluid.

Figure 142-1 Representation of a primary infection of TB and occult dissemination. Largely asymptomatic, dissemination of M. tuberculosis following primary infection occurs when infected mononuclear cells migrate throughout the body, particularly to lung apices, kidneys, bone growth plates, and vertebrae, resulting in latent infection.

Most cases of active TB are due to reactivation of latent TB infection (LTBI). Active TB develops in about 10% of immunocompetent individuals with LTBI and tends to occur within the first 2 years of the initial infection. Typically, reactivation TB is a subacute fibrocavitary pneumonia involving the upper lobes and/or superior segments of the lower lobes. However, reactivation TB can involve any organ system and can present in a fulminant fashion with respiratory failure.¹⁶

There are some common clinical characteristics of TB patients who require ICU care. In a study of 58 ICU patients with confirmed TB, 22 (37.9%) required mechanical ventilation, and 15 (25.9%) died in the hospital.¹⁷ The factors independently associated with mortality were acute renal failure, need for mechanical ventilation, chronic pancreatitis, sepsis, acute respiratory distress syndrome (ARDS), and nosocomial pneumonia.¹⁷ Both primary and reactivation TB can cause bilateral alveolar infiltrates, hypoxic respiratory failure, and ARDS.^16,18 In another study of patients hospitalized with pulmonary TB, six factors were shown to be associated with respiratory failure or death: lymphopenia, advanced age, concomitant smear-positive extrapulmonary TB, alcoholism, a high percentage of neutrophils on the peripheral white blood cell count, and lack of radiographic cavitation.¹⁹ Laboratory findings of anemia and hypoalbuminemia have been shown to be predictors for death in patients with respiratory failure due to TB.²⁰ However, these findings are not specific to TB and commonly present in the critically ill.

Consolidation is the most frequent radiographic pattern of patients with pulmonary TB who are admitted to the ICU.²¹ Because this radiographic pattern is highly nonspecific, chest x-rays are often unhelpful in raising the suspicion for TB. Consolidation on initial chest radiograph has also been shown to be a strong independent risk factor for in-hospital mortality.²² One possible reason for this is a delay in the diagnosis; clinicians may be more prone to favor a diagnosis of non-tuberculous pneumonia in the absence of cavitation or miliary pattern. Another is that consolidation may be an indication of a suboptimal immune response to the infection. Pulmonary gangrene, which carries a mortality of up to 75%, can ensue when rapid progression of infiltrate causes vascular damage and death of lung tissue.²³ Other life-threatening complications of pulmonary TB include hemoptysis, spontaneous pneumothoraces, bronchopleural fistulas, and empyema. Not unexpectedly, delayed recognition and treatment of nosocomial pneumonia complicating TB in patients requiring mechanical ventilation has a significant adverse effect on survival.²⁴

Perhaps the best safeguard to prevent missing a diagnosis of pulmonary or disseminated TB in the critically ill is to maintain a high index of suspicion of it in at-risk individuals (e.g., foreign-born or immunosuppressed patients). Studies have shown that the presence of diffuse infiltrates consistent with ARDS and acute respiratory failure may cause physicians to inappropriately dismiss the diagnosis of TB.^25–27 Older individuals (≥65 years) or patients with AIDS may also have delayed diagnosis of TB, due in part to atypical presentations.^28,29

Hospital mortality has been reported to be 60% for patients with respiratory failure due to pulmonary TB.²² Hence, despite being a relatively rare cause of respiratory failure in ICU patients, pulmonary TB carries a poor prognosis. Early recognition of the infection is essential to reduce mortality and prevent nosocomial spread of M. tuberculosis.²⁷

Disseminated Tuberculosis

Disseminated, or “miliary,” TB is more likely to occur in the very young and very old and in patients with underlying diseases such as HIV. It may result from either primary or reactivation TB. Disseminated TB typically presents subacutely with symptoms present for days to months, but it can manifest fulminantly with septic shock and multiorgan failure.³⁰ Typical presenting signs and symptoms include fever, malaise, weight loss, dyspnea, and hypoxia.

The chest radiograph (Figure 142-2, A) and computed tomography (CT) scan (see Figure 142-2, B) show a typical miliary pattern manifested by a profusion of diffuse small (<2 mm) nodules that resemble the size and uniformity of millet seeds (see Figure 142-2, C). In some cases of disseminated disease, the chest radiograph may appear normal. Virtually any organ may be involved, including the adrenals, brain, meninges, liver, pancreas, eyes, urinary tract, and skin. Bone marrow involvement by TB commonly manifests with anemia, leukemoid reaction, and thrombocytosis. The diagnosis of miliary TB can be difficult. If disseminated TB is suspected, sputum smears should be obtained even if lung disease is not apparent. Biopsy and culture of affected tissue(s), such as the bone marrow, are often required. Culture of blood, urine, and/or stool may be positive, especially in HIV-positive patients.³⁰

Figure 142-2 Miliary TB.

A, Chest radiograph of patient with miliary TB. B, Chest computed tomography (CT) scan of same patient. Both show characteristically small (<2 mm) nodules thought to resemble millet seeds (C). Note that millet seeds are about 2 mm in diameter.

Neurologic Tuberculosis

Tuberculous Meningitis

TB meningitis is rare in developed countries, with approximately 300 to 400 cases in the United States each year. It occurs via rupture of a subependymal tubercle that has seeded and formed during primary infection or disseminated disease. Individuals at high risk for TB meningitis include very young children with primary TB and older patients with immunodeficiency disorders such as HIV. Most patients with TB meningitis will have no known history of TB, but evidence of extrameningeal disease (e.g., pulmonary, urinary, etc.) can be found in about half of these patients.^31,32 The tuberculin skin test is positive in only about 50% of patients with TB meningitis.

TB meningitis is typically a subacute disease. In one review of 58 cases, symptoms were present for 1 day to 9 months, with a median of 10 days prior to diagnosis.³¹ A prodromal phase of low-grade fever, malaise, headache, dizziness, vomiting, and/or personality changes may persist for 2 to 3 weeks before the patient presents for medical care. Typical findings at presentation include severe headache, altered mental status, stroke, hydrocephalus, and cranial neuropathies. These clinical features are the result of basilar meningeal fibrosis and vascular inflammation.³³ Classic features of bacterial meningitis such as stiff neck and fever may be absent. When allowed to progress, coma and seizures may ensue.

The diagnosis of TB meningitis can be difficult and may be based only on clinical findings without definitive microbiological proof. Certain clinical characteristics such as longer duration of symptoms (>6 days), moderate cerebrospinal fluid (CSF) pleocytosis, and the presence of focal deficits increase the probability of TB meningitis.^34,35 Characteristic CSF findings of TB meningitis include:

• Leukocytosis with predominance of lymphocytes. White blood cell counts are usually between 100 and 500 cells/µL. Lower white blood cell counts and neutrophil predominance may be seen very early in the course of disease.

• Elevated protein levels, usually between 100 and 500 mg/dL

• Low glucose, typically less than 45 mg/dL

CSF samples should be sent for acid-fast smears, but this is associated with low sensitivity (<20%). Large volumes (10-15 mL) from several daily lumbar punctures are often needed for a microbiological diagnosis. Sensitivity is increased if four spinal taps are performed. Culture can take weeks and is also associated with low sensitivity. Stereotactic biopsy can be performed if tissue samples are needed. Mycobacterial antigens by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay have been detected in the CSF of patients with TB meningitis.³⁶

Recent meta-analysis calculated that commercial nucleic acid amplification (NAA) assays used for the diagnosis of TB meningitis were 56% sensitive and 98% specific.^37,38 Unfortunately, considerable variability in sensitivity and specificity among tests from different laboratories makes it more difficult to interpret results. Most studies conclude that commercial NAA tests can confirm TB meningitis but cannot rule it out.³⁹ Thus a negative test neither excludes the diagnosis nor obviates the need for continued empirical therapy if the clinical suspicion is high. Comparisons of NAA and microscopy/culture using large volumes of CSF have indicated that the sensitivity of microscopy was similar to NAA for the diagnosis of TB meningitis, and repeated testing gave the highest diagnostic yield.⁴⁰ The sensitivity of CSF microscopy and culture falls rapidly after the start of treatment, whereas mycobacterial DNA may remain detectable within the CSF up to a month after the start of treatment.⁴¹

Magnetic resonance imaging (MRI) often reveals basilar meningeal enhancement (Figure 142-3) and/or hydrocephalus.³² Hypodensities due to cerebral infarcts, and ring or nodular enhancing lesions can also be seen. MRI is superior to CT for evaluating the brainstem and the extent of lesions.

Figure 142-3 Tuberculous meningitis.

A, T₁-weighted transverse magnetic resonance image (MRI) of the brain. B, Sagittal MRI of base of brain and spinal cord in patient with tuberculous meningitis. Note enhanced meninges (arrows) in basilar regions of brain, brainstem, and spinal cord.

The outcome of TB meningitis is improved by timely treatment. Thus empirical treatment is warranted when risk factors and clinical features are suggestive of this diagnosis, even before microbiological confirmation. Chemotherapy for TB meningitis follows the model of short-course chemotherapy for pulmonary TB—an induction phase followed by a continuation phase. But unlike pulmonary TB, the optimal drug regimen and duration of each phase of treatment are not clearly established. INH and RIF remain the most essential drugs. INH penetrates the CSF freely and has potent early bactericidal activity.^42–44 RIF penetrates the CSF less well (maximum concentrations around 30% of plasma), but the high mortality from RIF-resistant TB meningitis has confirmed its central role in the treatment of CNS disease.⁴⁵ INH, RIF, and pyrazinamide are considered mandatory at the beginning of TB meningitis treatment, and some centers use all three drugs for the duration of therapy.⁴⁶ There are no data from controlled trials to guide choice of the fourth drug. Most authorities recommend either streptomycin or ethambutol, although neither penetrates the CSF well in the absence of inflammation, and both can produce significant adverse reactions. Therapy should be continued for 9 to 12 months.

Adjunctive corticosteroid treatment of TB meningitis has been recommended for more than 50 years, but there has been long-standing concern that corticosteroids may reduce the penetration of anti-TB drugs into the CNS.³³ A recent Cochrane systematic review and meta-analysis of 7 randomized controlled trials involving 1140 participants (with 411 deaths) concluded that corticosteroids improved outcome in HIV-negative children and adults with TB meningitis, but the benefit in HIV infected individuals remains uncertain.⁴⁷ The results were heavily influenced by a study performed in 545 Vietnamese adults with TB meningitis which observed that treatment with dexamethasone was associated with a significantly reduced risk of death.⁴⁸ However, there was no demonstrable improvement in the combined endpoint of death or severe disability at 9-month follow-up. The survival benefit associated with corticosteroid therapy may have been due in part to a reduction in severe adverse events (9.5% versus 16%), particularly hepatitis, that necessitated changes in anti-TB drug regimens. No mortality benefit from dexamethasone was evident in 98 HIV-infected patients included in the study.⁴⁸

Because there are no controlled trials comparing different corticosteroid regimens, the choice should be based on those found to be effective in published trials. One recommended regimen for adults is dexamethasone, 12 mg a day for 3 weeks, followed by gradual taper over the next 3 weeks.⁴⁹ In the large study from Vietnam, patients with mild disease received intravenous (IV) dexamethasone, 0.3 mg/kg/d × 1 week, 0.2 mg/kg/d × 1 week, and then 4 weeks of tapering oral therapy.⁴⁸ For patients with more severe TB meningitis, IV dexamethasone was given for 4 weeks (1 week each of 0.4 mg/kg/d, 0.3 mg/kg/d, 0.2 mg/kg/d, and 0.1 mg/kg/d), followed by 4 weeks of tapering oral dexamethasone therapy.⁴⁸

Prognosis of TB meningitis largely depends on neurologic status at the time of presentation and time to treatment initiation. Most patients will die in 5 to 8 weeks if not treated. Various case series indicate a mortality rate between 7% and 65% in developed countries and up to 69% in underdeveloped areas.^31,32,50 Neurologic sequelae occur in up to 50% of survivors.⁵⁰ Mortality risk is highest in those with comorbidities, severe neurologic involvement on admission, rapid progression of disease, and being elderly.

Cardiovascular Tuberculosis

Tuberculosis in HIV-Positive Patients

HIV is the most important host risk factor for active TB.⁶¹ In many developing countries, TB is the most common opportunistic infection associated with HIV. The estimated annual risk for active TB among persons with LTBI in the general population is 12.9 per 1000 person-years. In contrast, rates of progression to active TB among HIV-infected persons with LTBI range from 35 to 162 per 1000 person-years. Because TB may be an initial manifestation of HIV infection, all patients with TB should be tested for HIV. The WHO estimates that TB causes death in 13% of persons with AIDS.⁶²

The mechanism of increased TB susceptibility in HIV positive persons is incompletely understood. Unlike other AIDS-related opportunistic infections, CD4⁺ count is not always a reliable predictor of increased risk for TB disease. Alveolar macrophages (AM) are important components of an effective immune response to TB,⁶³ and AM apoptosis represents a critical host defense mechanism that promotes M. tuberculosis elimination. In this context, one possible reason HIV increases susceptibility to TB is that HIV-infected AM have a reduced apoptotic response to M. tuberculosis compared to AM from healthy individuals.^64,65

When the CD4⁺ count is above 350 cells/µL, pulmonary TB in AIDS patients is more likely to present with typical chest radiograph findings of upper lobe fibrocavitary disease.⁶⁶ However, as the CD4⁺ count decreases, pulmonary TB tends to manifest with more atypical radiographic manifestations such as mediastinal adenopathy, diffuse miliary or nodular infiltrates, focal lower zone infiltrates, and lack of cavitation. Extrapulmonary TB is more common among HIV-positive patients, occurring in up to 70% of patients. Disease involving the lymph nodes is especially common. Other extrapulmonary manifestations include miliary disease, TB sepsis, and CNS disease.²⁸ Empirical treatment may be necessary before the diagnosis is confirmed. If rapid diagnosis is needed, NAA tests can be used, although these tests are more accurate in smear-positive cases.

After initiating highly-active antiretroviral therapy (HAART) in severely immunosuppressed patients, those with subclinical or recently diagnosed TB may display a paradoxical reaction, where there is an apparent clinical worsening of TB while on appropriate anti-TB treatment.^67–69 This phenomenon, also known by the more descriptive name of immune reconstitution inflammatory syndrome (IRIS), can manifest as early as 7 days after starting HAART. Signs and symptoms include fever, weight loss, and evidence of local inflammatory reactions such as lymphadenitis and worsening pulmonary disease such as increased pulmonary consolidation, nodules, and effusions. Histologically, a vigorous suppurative and necrotizing granulomatous reaction occurs, with or without caseation; cultures of infected material are almost invariably positive.

Treatment of TB in patients with HIV is similar to that in HIV-negative patients but is often complicated by drug interactions between TB medications and antiretrovirals.⁷⁰ The protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) can either induce or inhibit activity of the P450-3A (CYP3A) system. RIF can increase activity of CYP3A, leading to decreased levels of several antiretrovirals. Rifabutin is a less potent inducer of the CYP3A system and is associated with less drug-drug interactions, but dose adjustments may be needed. Despite these potential drug interactions, a RIF-based regimen should be used whenever possible. Patients with liver disease such as hepatitis C may be at increased risk for drug-induced hepatotoxicity. Another treatment issue in HIV-TB co-infection is that patients may fail to properly absorb the anti-TB drugs, which may increase the risk of treatment failure, relapses, and acquired drug resistance.⁷¹

Because of increased risk of RIF resistance, patients with HIV should not receive once weekly INH-rifapentine in the continuation phase of treatment. Twice-weekly INH-RIF or INH-rifabutin should be avoided when the CD4⁺ cell count is less than 100/µL. Treating drug-susceptible pulmonary TB in HIV-positive individuals for 9 months rather than the standard 6 months is associated with lower relapse rates.^72,73 Recommendations regarding treatment of TB in HIV patients are frequently revised as new drugs and information become available. The following websites can assist with treatment decisions and information on drug-drug interactions:

If a patient develops IRIS while on HAART, it is generally recommended that HIV therapy be continued during TB treatment whenever possible, because IRIS is usually self-limited. However, more severe IRIS may require addition of corticosteroids and/or temporary discontinuation of HAART. In patients who are not already on HAART, it is usually advisable to delay HIV treatment for at least 4 to 8 weeks after TB therapy is initiated.

Tuberculosis and Immunomodulatory Therapies

TNF-α plays a central role in the pathogenesis to various inflammatory disorders and in the pathophysiologic response to many infections. TNF-α is produced predominantly by macrophages and lymphocytes and is active both as a membrane-bound and soluble protein.^74,75 In several animal models, TNF-α plays an essential part in the host defense to TB.⁷⁶ One mechanism by which TNF-α potentiates host defense is by its ability to induce apoptosis of infected cells. Macrophage apoptosis helps to contain M. tuberculosis by maintaining granuloma integrity, increasing efficiency of antigen presentation, and promoting killing of intracellular M. tuberculosis.⁷⁷ Administration of antibodies neutralizing TNF-α resulted in reactivation of TB in a mouse model.⁷⁸ Interruption of the normal TNF-α controlled response to TB reduces apoptosis, disrupts granuloma integrity, and predisposes to disseminated infection.

TNF-α antagonists are increasingly used for the treatment of various chronic inflammatory disorders. Currently licensed TNF-α antagonists fall into two main types: monoclonal neutralizing anti-TNF-α antibodies and soluble p75 subunits of the TNF-α receptor (TNFα-R). The soluble TNFα-Rs antagonize TNF-α function by acting as decoys to bind TNF-α. Three monoclonal anti-TNF-α antibodies (infliximab, adalimumab, and certolizumab pegol) and two TNFα-Rs (etanercept and abatacept) are in clinical use. Patients treated with TNF-α blockers have a TB incidence rate of 1.17 per 1000 patient-years, 12.2 times that of the general population.⁷⁹ Almost all of these cases are due to reactivation of LTBI.

Important differences have emerged among the TNF-α antagonists in regard to the risks of reactivation TB. Consistently, the excess risk is associated with infliximab and adalimumab rather than etanercept. For example, compared with etanercept, infliximab is associated with a two- to sevenfold greater risk of TB, shorter time to TB onset (17 versus 48 weeks), and a higher proportion of TB cases with disseminated or extrapulmonary disease (25 versus 10%).^80,81 It is not entirely clear why the neutralizing antibodies to TNF-α put people at greater risk of reactivation TB than soluble TNF-α receptors. Possible reasons include a longer duration of action of infliximab and adalimumab and their ability to bind to membrane-bound TNF-α with greater affinity than etanercept.⁷⁴ As a result, infliximab can induce death in T cells that express the membrane-bound TNF-α, whereas etanercept cannot. In addition, anti-TNF-α antibodies can inhibit T-cell activation and interferon gamma (IFN-γ) production, whereas etanercept cannot. Thus the pharmacokinetic and biological differences between the two main types of TNF-α antagonists may account for the greater susceptibility to intracellular pathogens with the use of the anti- TNF-α antibodies.^74,82

Antagonists to other inflammatory cytokines are also being used in the management of patients with rheumatologic and inflammatory disorders. Interleukin 1 (IL-1) receptor antagonist (IL-1Ra) is the naturally occurring protein that prevents the action of IL-1 and IL-1β by competitively binding to IL-1R. Anakinra is a recombinant human form of IL-1Ra. In a case report, anakinra was associated with reactivation TB.⁸³

Diagnosis of Tuberculosis

When TB is suspected, the first diagnostic test should be microscopic examination and culture for mycobacteria of relevant body fluids or tissues. Several specimens are often required, especially for CNS disease.

Patients with suspected pulmonary TB should be placed in respiratory isolation until three sputa are collected, separated by at least 8 hours between samples, for acid-fast bacteria (AFB) and culture. Because patients with extrapulmonary disease may also have occult pulmonary disease, it is generally recommended that sputum smears be sent on these patients regardless of chest radiographic findings.

Because acid-fast smear does not differentiate between M. tuberculosis and non-tuberculous mycobacteria, culture is used to confirm species and determine drug susceptibility. Simultaneous culture on both liquid and solid media is recommended. Liquid medium such as the newer BACTEC system allows growth of the organism in about 14 days, whereas growth takes 3 to 6 weeks on solid media (Lowenstein-Jensen or Middlebrook 7H11). Once sufficient growth is obtained, species identification can be obtained via conventional biochemical tests or more rapid tests such as nucleic acid probes, high-performance liquid chromatography (HPLC), the NAP test (p-nitro-acetylamino-β-hydroxypropiophenone), or molecular tests. Only experienced laboratories should complete susceptibility testing on culture-positive specimens. Molecular fingerprinting by restriction fragment length polymorphism (RFLP) can be used to distinguish strain types when laboratory contamination is suspected.

Although rapid and inexpensive, acid-fast smear microscopy is limited by its poor sensitivity (~50% sensitivity in culture-confirmed pulmonary TB cases) and suboptimal specificity (50%-80%) in settings where nontuberculous mycobacteria are commonly isolated.^84–86 NAA testing has become a routine procedure in many settings, because NAA tests can reliably detect M. tuberculosis in specimens 1 or more weeks earlier than culture.⁸⁵ Because of the increasing use of NAA tests and the potential impact on patient care and public health, the Centers for Disease Control and Prevention (CDC) and the Association of Public Health Laboratories (APHL) made recommendations for using NAA tests for laboratory confirmation of TB. CDC recommends that NAA testing be performed on at least one respiratory specimen from each patient in whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB control activities.^87,88

Treatment of Tuberculosis

Standard treatment of adults with drug-susceptible TB is a three- or four-drug regimen for at least 6 months.^89,90 The typical course of therapy for drug-susceptible disease is 2 months of INH, RIF, pyrazinamide (PZA), and ethambutol (EMB) (initial phase), followed by 4 months of INH and RIF (continuation phase) (Tables 142-1 and 142-2). A 9- to 12-month regimen is suggested for TB meningitis, for pulmonary TB that is slow to respond to therapy (e.g., those with cavitary lesions and persistent sputum culture positivity even after 2 months of an appropriate four-drug regimen), or when PZA is not used in the induction regimen. EMB can be discontinued when drug susceptibility studies show sensitivity to INH and RIF. Streptomycin (SM) can be used instead of EMB if resistance is unlikely or susceptibility is shown. The continuation phase can be daily therapy, twice-weekly therapy, or thrice-weekly therapy for drug-susceptible TB (see Table 142-1). See the HIV section for details of treating TB in HIV-positive patients. Specific guidelines including information on first- and second-line agents have been published by the CDC.⁹¹

TABLE 142-1 Current Regimens for Treatment of Drug-Susceptible Tuberculosis

BIW, twice weekly; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; SM, streptomycin; TIW, thrice weekly.

^* The daily regimen is employed when patients self-administer their drugs. There is enough redundancy that if patients miss some of their doses, the outcome will remain acceptable.

^† The intermittent regimens are intended for directly-observed therapy (DOT). Regimen (a) entails a total of 62 doses and has yielded over 95% success rates for the past 22 years in Denver, Colorado.⁹⁷ Regimen (b) involves 78 doses and has also resulted in success rates of approximately 95% in Hong Kong, where it is the standard regimen.⁹⁸

When MDR-TB is suspected or confirmed, additional drugs that may be used include amikacin, a fluoroquinolone (levofloxacin, moxifloxacin), capreomycin, ethionamide, cycloserine, and/or para-aminosalicylic acid. Local public health departments should be contacted to meet reporting requirements and will usually be responsible for treatment monitoring. Directly observed therapy (DOT) should be implemented whenever possible. Patients with MDR-TB require DOT and longer therapy (generally 18 months of treatment after the last negative sputum culture). Surgical resection after 2 to 3 months of treatment may improve outcome.⁹¹

Parenteral therapy may be required in ICU patients and is recommended for patients with fulminant disease (Table 142-3). INH and RIF are available in parenteral forms; EMB and PZA are not. Other active medications available for IV use include the aminoglycosides, fluoroquinolones, and capreomycin. In patients with renal failure, dose adjustments are required for those taking EMB, PZA, cycloserine, an aminoglycoside, capreomycin, or a fluoroquinolone. INH and PZA should probably be withheld in the setting of severe liver failure. An expert in the treatment of TB should be consulted when treating the complicated ICU patient or those with MDR-TB.

TABLE 142-3 Selected Parenteral Medications Used in Treating Tuberculosis⁹¹

Notes: Table shows routine daily dosing. Dosages may differ in children and in patients in intermittent therapy. Persons over age 59 should receive the lower dose for aminoglycosides (750 mg).

IM, intramuscular; IV, intravenous, PO, oral.

Corticosteroids are generally recommended in the treatment of several TB conditions, including TB meningitis and pericarditis, as discussed above.⁹² Their role in patients with respiratory failure due to TB and in patients with severe AIDS-associated TB has not been proven, but many have used corticosteroids for these conditions. Typical therapy includes prednisone, 40 to 80 mg per day, tapered over a few weeks.

Risk to Healthcare Workers

An awareness that caring for TB patients poses a risk to healthcare workers (HCWs) did not emerge until the 1950s and 1960s when studies established that M. tuberculosis infection was transmitted by the airborne route.⁹³ However, occupational transmission received little attention until numerous outbreaks of TB and MDR-TB occurred in U.S. and European hospitals in the late 1980s and early 1990s.⁹⁴ At that time, more than 20 HCWs became ill with MDR-TB, and at least 10 died.⁹⁵ Hundreds of HCWs may be latently infected with MDR-TB and thus represent a relatively large reservoir of individuals at risk for future reactivation MDR-TB.

Pulmonologists are at higher risk for occupational exposure to TB compared to other medical specialists. Atypical presentations of TB can put providers at increased risk when TB is not suspected and proper precautions are not taken.⁹⁶ Bronchoscopy requires close contact with patients and provokes coughing, which likely contributes to the tuberculin skin test conversion rate of 11% among pulmonary fellows.⁹⁶ DMF-HEPA respirators should be used when performing bronchoscopy on patients with known or suspected TB.⁹⁶

In HCWs with negative tuberculin skin test reactions who undergo repeat testing, an increase in reaction size of more than 10 mm within a period of 2 years should be considered a skin test conversion indicative of recent infection with M. tuberculosis. Because tuberculin skin test conversion typically occurs 3 to 8 weeks after primary infection, skin testing should be performed at least 3 weeks following exposure.

HCWs with potential exposure should be monitored for symptoms and, unless known to have a positive tuberculin skin test at baseline, skin testing or an IFN-γ release assay should be performed as soon as possible after the exposure to establish a baseline. If initial screening is negative, testing should be repeated 8 to 10 weeks following exposure and, if found to be positive, treatment for LTBI is recommended.