pcr12017.htm

The Clinical Challenge of Tuberculosis: A State-of-The Art Review of Diagnostic Strategies, Atypical Presentations, and Treatment Guidelines

Authors: Dawn Demangone, MD, Assistant Professor of Medicine, Division of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA, David Karras, MD, Assistant Professor of Medicine, Director of Research, Division of Emergency Medicine, Temple University, Philadelphia, PA.

Editor: Gideon Bosker, MD, Assistant Clinical Professor, Yale University School of Medicine.

Peer Reviewer: Katherine L. Heilpern, MD, Assistant Professor, Division of Emergency Medicine, Emory University School of Medicine, Atlanta, GA.

Editor’s Note—Since 1985, the number of new tuberculosis cases in the United States has risen about 18% annually.1 Many consider the resurgence of this disease to be a failure of the American health care system or a symptom of government cuts in health care spending and social programs. Probably, the most important factor in the rise of tuberculosis, however, is the rapid increase in the number of immunocompromised hosts.2 The present epidemic of tuberculosis is largely a by-product of AIDS, whose victims frequently live in crowded conditions and can easily transmit the disease to immunocompetent individuals.

Coincident with the rise in the number of tuberculosis cases is a striking increase in multidrug-resistant strains of the organism. Poor compliance with antibiotic therapy has led to a crisis of drug-resistant tuberculosis, long a common problem in developing countries but uncommon in the United States prior to the 1990s.3 Nationally, more than 14% of new tuberculosis cases are resistant to at least one drug, and fully one-third of isolates in New York City are isoniazid-resistant.3 Multidrug-resistant strains pose a serious threat not only to the control of the disease in the population but also to health care workers.

With these issues in focus, this article reviews the epidemiology and pathogenesis of tuberculosis. The authors discuss diagnostic options and unusual clinical presentations of this protean disease as well as specific manifestations in high-risk subgroups. In addition, the most current tuberculosis treatment recommendations of the Centers for Disease Control and Prevention are described. Finally, this review provides detailed discussions about TB-related issues, including prophylaxis of exposed health-care workers and infection control.

Epidemiology

Infection with Mycobacterium tuberculosis continues to be a worldwide problem. Approximately one-third of the world population is currently infected.4 Ten million newly infected individuals are diagnosed each year, resulting in 30 million cases of active tuberculosis and 3 million deaths annually. Infection with M. tuberculosis is responsible for 6% of deaths worldwide.5

The recent resurgence in tuberculosis in the United States has been attributed to immigration from endemic areas, homelessness, intravenous drug use, and, perhaps most importantly, the HIV epidemic.1,6,7 Infection with tuberculosis is frequent among the elderly, institutionalized individuals (such as those in nursing homes and prisons), the urban poor, minority groups, and those infected with HIV. Non-whites have twice the risk of infection, with the highest rates in blacks and immigrants from regions with high tuberculosis prevalence, including Asia, Africa, Latin America, and the Caribbean.8,9 Children of immigrants have a four-fold increased infection rate over children with U.S.-born parents.7 The largest concentration of cases is between the ages of 25 and 44 years, and males are infected 2.5 times more frequently than females.5,7 In 1992, African-American men between 35 and 44 years of age had a rate of tuberculosis infection 53 times the national average.5

Transmission

Mycobacteria are slow-growing aerobic rods with characteristic cell-wall lipids that account for their acid-fast staining properties. Four subspecies of mycobacteria make up the "tuberculosis complex," each of these organisms can cause tubercular disease: M. tuberculosis, M. microti, M. africanum, and M. bovis. M. tuberculosis accounts for the majority of human disease.1,6,10

Transmission occurs primarily through inhalation of aerosolized bacilli. While as few as 1-10 bacilli entering the alveoli can cause infection, only about one-fifth of exposed individuals become infected.2,11 After a sneeze or cough by an infectious individual, aerosolized microdroplets are expelled into the environment. Large droplets are usually trapped in the upper airway, which contain multiple mechanical barriers resistant to infection.12 However, the droplets may partially evaporate into droplet nuclei and remain suspended in air for extended periods of time, where they are easily carried by air currents. These droplet nuclei are very small particles of the right size (1-5 mm), contain 1-3 tubercle bacilli, and have about a 50% chance of reaching the alveoli after inhalation. Micrometer-sized particles evade the mucociliary apparatus. Because they are too small to be entrapped, they can reach alveoli and produce infection. In addition, it should be stressed that droplet nuclei can remain suspended in a room, even if the patient is no longer present, an important factor when it comes to infection control measures.

Establishment of infection is influenced by many factors, including the intensity of exposure, the number of bacilli to reach the alveoli, viability of the bacilli, and the microbicidal activity of host alveolar macrophages.13 Specific infectious sites are associated with higher rates of transmission: patients with laryngeal tuberculosis, endobronchial disease, or extensive cavitary pulmonary disease are considered highly infectious, while extra-pulmonary tuberculosis is typically not considered transmissible.9 Tuberculosis is more effectively transmitted when acid-fast bacilli are present in the infected individual’s sputum, when exposure occurs in a small, enclosed space, or occurs in rooms that do not have adequate ventilation and there is recirculation of contaminated air.9 Nosocomial transmission is more common when the prevalence of tuberculosis is high in the community, there exists close contact with infectious individuals, and with the performance of certain procedures, notably endotracheal intubation, bronchoscopy, respiratory secretion suctioning, open abscess irrigation, and autopsy.9 The most important host factor bearing on an exposed individual’s susceptibility to infection is previous mycobacterial infection, which protects against re-infection. Genetic predisposition and the presence of underlying disease may also affect the risk of infection.2 Among factors predisposing to tuberculosis infection, the most important are HIV infection, end-stage renal disease, cancer, diabetes, malnutrition, corticosteroid use, and intravenous drug use.15

Primary Infection

Once present in the alveoli, the bacilli may replicate extracellularly or, more typically, are ingested by alveolar macrophages where they are either killed or replicated intracellularly. If infection is established, localized granulomas, or tubercles, develop within 2-6 weeks and are characterized by caseation necrosis and calcification. The bacilli are also transported to regional lymph nodes, where the infection may also be contained. Evidence of this primary infection is the "Ghon complex," defined as a peripheral lung lesion (the tubercle) and calcified hilar lymph nodes.2,15,16,17

Some individuals develop clinically apparent primary tuberculosis with fever, cough, and infiltrates on chest radiograph. Others will develop symptoms of pleurisy with an effusion, representing a local hypersensitivity reaction to the tubercle bacilli. Usually, however, the immune system limits replication and spread of the bacilli during this primary infection. Patients are typically asymptomatic, although the organisms may remain viable and dormant for many years. In these individuals, the only indication of primary infection is conversion to a positive reaction to the tuberculin purified protein derivative (PPD) skin test. Acid-fast bacilli are not present in the sputum.2

Tubercle bacilli may also enter the bloodstream via the thoracic duct, resulting in widespread dissemination. However, the majority of bacilli do not survive hematogenous dissemination. Tuberculosis requires high amounts of oxygen and blood flow to maintain viability and the ability to grow. These environmental requirements are readily available in the apical or posterior segments of the upper lobes of the lungs, superior segment of the lower lobes of the lungs, and, less commonly, the renal cortex, meninges, long bone epiphyses, and vertebrae.

Reactivation Disease

Reactivation of tuberculosis is the most common form of clinically apparent disease. Immunocompetent individuals with tuberculosis infection will have a 10% chance of developing reactivation disease during their lifetimes.13 The risk appears to be greatest during the initial two years following exposure and is highest in young adults. In immunocompromised individuals and the pediatric population, transition to active disease may occur rapidly.13,14 Overall, in HIV positive patients, the risk of acquiring active TB is approximately 10% per year.15

Reactivation tubercular disease occurs after a variable latent period when the immune system can no longer contain foci of dormant bacilli. Typical triggers for reactivation are advancing age, malignancy, AIDS, corticosteroid therapy, viral illness, malnutrition, and even emotional stress.2 Disease is accompanied by the signs and symptoms of a chronic wasting illness in the majority of patients. Individuals may experience generalized, nonspecific symptoms such as malaise, night sweats, low grade fever, weight loss, as well as symptoms specific to the site where reactivation occurs.4,8,11,15,19

Pulmonary Disease

Eighty percent of individuals with reactivation tuberculosis exhibit pulmonary disease. Most commonly, the apical and posterior segments of the upper lobes or the superior segments of the lower lobes are involved. Disease may range from virtually no symptoms to severe, destructive disease. Without effective therapy, active pulmonary tuberculosis pursues a progressive and chronic course. The overall death rate of untreated pulmonary disease may be as high as 60%, with a median time to death of 2.5 years after onset. With proper treatment, diseased areas may heal with very little permanent damage.4,8,15

Chronic cough with scant sputum production and hemoptysis are the principal respiratory symptoms. Hemoptysis is typically limited to blood streaking of sputum. As the pulmonary lesions progress, they undergo central caseation necrosis. Pulmonary architecture may be lost and there may be pulmonary fibrosis, volume loss, and upward retraction of the lungs. The lesions can erode into bronchi, with resultant spread throughout the airways and bleeding. Bronchopulmonary fistulas may cause severe respiratory compromise and require operative management. Cavitary lesions can also rupture into the pleural space causing empyemas, which require surgical drainage. The lesions may also erode into pulmonary blood vessels. "Rasmussen’s aneurysm," or rupture of a terminal pulmonary artery into a cavitary site, is a catastrophic complication.4,8,11,15,19

Extrapulmonary Disease

Tubercle bacilli may reach a number of extrapulmonary sites through hematogenous or lymphatic dissemination. Extrapulmonary tuberculosis may develop during the primary tuberculosis infection or with reactivation disease. It may present with localized symptoms, reflecting focal infection, or with dramatic systemic symptoms, most notably in the case of miliary tuberculosis.2,11 Extrapulmonary disease, regardless of site, tends to respond well to systemic antituberculosis medical therapy.

Miliary tuberculosis results from hematogenous spread of tubercle bacilli, with tuberculous lesions developing synchronously throughout the body. Patients typically experience generalized symptoms of fever, chills, and weight loss. Although a cough may be present, acid-fast organisms will rarely be seen in the sputum. When occurring during reactivation disease, miliary tuberculosis progresses in a much more destructive and fulminant pattern.8 On physical exam, hepatomegaly, splenomegaly, and adenopathy may be apparent. Patients generally become ill-appearing prior to the development of the characteristic radiographic findings. Diagnosis can be made via bronchoscopy, bronchial alveolar lavage, or bone marrow biopsy.11

Pleural disease typically has an abrupt onset and is characterized by significant pleuritic pain. Young individuals without evidence of pulmonary tuberculosis infection are most likely to develop pleurisy. If left untreated, the symptoms resolve spontaneously; however, two-thirds of these patients progress to active pulmonary disease within five years.8 Asymptomatic pleural effusions commonly occur with reactivation disease as a peripheral lesion erodes into the pleural space.

Pericarditis may present with fever, pericardial pain, and possibly a pericardial friction rub. As with pericarditis of other etiologies, complications can include pericardial tamponade and chronic constrictive cardiac dysfunction.11

Peritonitis presents with ascites and is frequently erroneously attributed to cirrhosis. The course is insidious in onset and indolent in nature. Acid-fast stains as well as cultures of the ascitic fluid are rarely positive, making diagnosis difficult.

Laryngeal tuberculosis is of special concern as it is highly infectious. It develops in association with advanced pulmonary disease. The laryngeal mucosa is seeded with infectious bacilli that are expelled with expectoration. The infection may be a superficial ulceration or granuloma, but other structures including the epiglottis or hypopharynx may also be affected. The chief complaint, in addition to pulmonary symptoms, is typically hoarseness.2,8,11,17,20

Lymph node infection (adenitis) secondary to tuberculosis may occur anywhere but is most common in the cervical chain. Scrofula is a chronic lymphadenitis of the cervical nodes, usually located just inferior to the mandible. The nodes are non-tender and initially have a rubbery consistency but harden as infection progresses. Chronic infection may lead to draining cutaneous fistulas.11,17,20

Skeletal System. Tuberculosis may infect any bone but is frequently found in the long bone epiphyses, particularly those of large weight-bearing bones, and in the vertebral bodies. Pott’s disease, infection of the vertebral bodies, most commonly affects the mid-thoracic region and may present as spontaneous compression fractures and associated spinal cord injury.2,4,8,15,17,20

Genitourinary System. Renal tuberculosis presents with hematuria or microscopic sterile pyuria. If untreated, patients can develop cavitation and permanent destruction of the renal parenchyma, in addition to scarring and strictures of the ureters and bladder. The prostate, seminal vesicles, and epididymis may all be infected, becoming edematous and indurated but remaining non-tender. Tuberculosis salpingitis can result in sterility.

Central nervous system (CNS) infection is more likely to be acute in children and chronic in adults. Acute infection is characterized by typical signs and symptoms of meningitis: fever, headache, neck stiffness. Chronic infection manifests with similar signs and symptoms; however, the course may be more indolent. Interestingly, approximately 30% of patients with chronic meningitis exhibit cranial nerve deficits. Cranial nerve deficits are caused by spread of infection to the meninges, where a basilar meningitis can develop. Focal tuberculomas can produce focal neurologic deficits that can include cranial nerve palsies ranging from hoarseness to diplopia and visual disturbances.2,4,8,11,17,20

Diagnosis

Infection with M. tuberculosis is sometimes difficult to diagnose due to the variety of presentations and the time required for cultures to develop. However, it is an important consideration, as proper isolation procedures and diagnostic measures should be undertaken as quickly as possible. Pulmonary tuberculosis should be considered in any patient demonstrating the characteristics described in Table 1.9 Immediate steps, including facial masks and isolation procedures, should be implemented to limit the spread of infection when tuberculosis is suspected.

Laboratory Diagnosis. Samples of sputum or other body fluids suspected of infection should be sent for both acid-fast stain and tuberculosis culture. While up to 80% of patients with active pulmonary infection will demonstrate acid-fast organisms on the initial sputum smear, a negative acid-fast-stain does not eliminate the possibility of infection.8 Sputum culture is the "gold standard" for diagnosing tuberculosis infection, but it can require 3-6 weeks to obtain final results.11 Blood cultures for mycobacteria may be obtained; while cultures are positive in the minority of patients, they may yield a diagnosis faster than sputum cultures.21 Newer, commercially available DNA probes that use polymerase chain reactions (PCR) are available for more rapid identification of tuberculosis in sputum, tissue specimen, and blood samples.22-24 Their use is limited by cost and the time required to obtain results.

To ensure identification, smears and cultures should be performed on three different days in patients with high risk of infection.9 If sputum is not available, samples may be obtained via nasotracheal aspiration, bronchoscopy, bronchoalveolar lavage or early morning gastric aspiration. Positive acid fast-stains are unusual with tuberculosis-related pleural effusions. Occasionally surgical biopsy of an infected site is indicated (particularly with tuberculous adenitis) and a microbiologic diagnosis is made from the biopsy specimen. All cultures should have susceptibility testing performed as well.

Other laboratory studies generally yield nonspecific results. The CBC may show a minor anemia and monocytosis of between 8-12%. The sedimentation rate is typically elevated. Patients with miliary tuberculosis may also develop hyponatremia, thrombocytopenia, and leukopenia. Cerebrospinal fluid (CSF) analysis must be performed if tuberculous meningitis is suspected. Infected CSF shows low glucose and high protein levels, while cell counts reveal granulocytosis in acute disease and lymphocytosis with chronic disease.11 It should be stressed that the diagnosis of tuberculous meningitis is difficult to make, and that additional quantities of CSF may be required to enhance culture results and improve yield of AFB positive smears. Analysis of tuberculous pleural effusions shows exudative properties with low pH, low glucose, and high protein. Again, granulocytes predominate in acute effusions, lymphocytes in chronic effusions.

Chest radiographs are critical to the diagnosis of pulmonary tuberculosis. While serial films are generally necessary to distinguish active from non-active infection, a single chest x-ray can be invaluable in identifying potentially infectious individuals. The classic finding in symptomatic primary infection is a small, parenchymal infiltrate in any region of the lung associated with unilateral hilar adenopathy. As the primary infection resolves, this lesion calcifies into a nodule. Other patients with primary infection may exhibit unilateral pleural effusions or no radiologic abnormalities at all.

The chest x-ray in patients with reactivation pulmonary tuberculosis classically demonstrates infiltrates in the apical and posterior segments of the upper lobes or in the superior segments of the lower lobes. Cavitation is frequently present in regions of substantial infiltration. Lordotic views, taken in an anterior-posterior fashion with the patient leaning backward against the x-ray plate, allow better visualization of the lung apices and may be helpful in identifying infiltrate in regions that may be obscured by the upper ribs or the clavicles.25 The typical finding in miliary tuberculosis are soft, fine, uniformly distributed nodules throughout both lung fields.

As the tubercular lesions heal, fibrotic scarring with loss of pulmonary volume is apparent. The lungs and hilar regions may be retracted upward and medially, the trachea may be deviated and atelectasis may be present. Atypical chest x-ray findings may manifest more frequently in certain patient populations, particularly the immunocompromised, and are discussed in the section on special considerations.

Skin Testing. The Mantoux skin test is used to measure delayed-type hypersensitivity to the tubercle bacillus. It is commonly referred to as the "PPD," as tuberculosis purified protein derivative is introduced beneath the skin of the volar or dorsal aspect of the forearm. The test is a reliable method of recognizing prior infection, however, it is neither perfectly sensitive nor specific.9 The test should be interpreted by trained individuals 48-72 hours following placement. The diameter of the region of induration, not erythema, should be measured. Table 2 describes criteria for positive reactions.9

False-positive reactions are possible as a result of exposure to non-pathological mycobacterial disease (e.g., M. avium complex), but not as a result of allergy to PPD components or previous testing. False-negative reactions are seen with advancing age, in individuals who have received BCG, have had recent tuberculosis infection, and are immunosuppressed.8 In fact, as many as 25% of all individuals with active tuberculosis may have a negative skin test at the time of initial presentation due to transient immunosuppression, and the majority of patients with miliary tuberculosis will have negative tests.2 Such individuals may be responsive to skin testing performed a few weeks later. This is called the "booster phenomenon." An anergy panel (skin testing with antigens to which most individuals will be hypersensitive) should be performed when a PPD test is negative in a patient suspected of having tuberculosis.

Treatment

Post-Exposure Prophylaxis. Because tuberculosis is a disease of relatively low communicability, post-exposure prophylaxis is generally not indicated unless the PPD skin test is positive. The exception to this is in children younger than 5 years of age, in whom empiric therapy with isoniazid (10 mg/kg/d) is indicated after tuberculosis exposure. Therapy may be discontinued if the PPD is negative at three months. Immunocompetent adults who remain PPD negative do not require empiric therapy.

Positive PPD Test. Prophylactic therapy should be considered for individuals with positive PPD reactions and negative chest x-rays. Criteria for initiating preventative treatment are listed in Table 3.9 The potential risks and benefits of prophylactic therapy should be analyzed and may differ between patients. The likelihood of a positive PPD secondary to tuberculosis, and not other mycobacterial infection, should be assessed. The risk of progression to active disease should be weighed against the very small risk of hepatitis or other adverse reaction to drug therapy. Because health care workers are at higher risk for contracting tuberculosis and have the potential to transmit infection to large numbers of ill individuals, special considerations are made when determining whether to offer preventative treatment to this group.

Specific recommendations for medical prophylaxis are described in Table 4.9 If the risk of primary infection with multi-drug resistant tuberculosis is high, multi-drug preventative therapy should be considered.9 In individuals with positive reactions to PPD and chest radiographs demonstrating either silicosis or fibrotic disease, but who are without evidence of active infection, preventative therapy with isoniazid and rifampin for four months, or isoniazid alone for 12 months is acceptable.9

Treatment of Active Disease. Single-drug therapy is no longer recommended because of the prevalence of drug-resistant tuberculosis. Currently, four-drug initial therapy is recommended until specific susceptibilities of isolates are known. Table 5 and Table 6 outline specific therapeutic regimens.9,16 Adherence to these guidelines will effectively treat at least 95% of patients.16 Additionally, sputum culture conversion to negative will occur more rapidly using a four- rather than three-drug regimen.16 Approximately 85% of patients will become culture negative within two months of starting therapy.4,15 Administration of drugs in a directly observed therapy program increases the effectiveness of therapy and may benefit individuals in whom compliance is questionable. Practitioners should consult other sources for information regarding medicolegal considerations pertaining to quarantine, mandatory hospitalization, and noncompliance with treatment.

Special Considerations

Tuberculosis in HIV Infection. Infection with HIV has played an important role in the recent resurgence of tuberculosis. Infection with tuberculosis is 500 times more common in AIDS patients than the general population. The demographic groups with the highest increase in prevalence of HIV infection, that is black and Hispanic males between 25-44 years of age, have also demonstrated the largest increase in tuberculosis infection. Additionally, cities and states with large numbers of HIV-infected persons have the largest increase in tuberculosis infection.6 In the United States, co-infection is most frequent in those patients who acquired HIV via intravenous drug use, or in immigrants from Haiti or Central Africa.12 The risk of development of active disease is 10% per year in these groups, compared to a 10% lifetime risk in immunocompetent individuals.13

Active tuberculosis infection develops in more than half of AIDS patients previously infected with tuberculosis. Tuberculosis typically presents sooner than other AIDS-defining illnesses, thus making it an AIDS-defining illness in HIV-positive individuals.6,8,11 Patients with co-infection progress faster to active tuberculous disease following primary exposure than do HIV-negative patients.6 Mortality rates of co-infection can be as high as 14-44%.11

Impaired host immunity is the most likely cause of the high morbidity and mortality of co-infection. Macrophage microbicidal activity is abnormal in AIDS patients, due to a lack of activation factors supplied by CD4+ cells.1 It has also been suggested that tuberculosis may increase the active expression of HIV, thereby further weakening an already impaired immune system.4 Interpretation of the PPD skin test can certainly be confused by this immunodeficient state. Of patients with culture proven infection and CD4+ counts greater than 100, only 64% displayed positive reactions to PPD. That percentage dropped to 0% in patients with CD4+ count less than 100.13 Thus, a negative reaction to PPD does not rule out infection. HIV-positive patients suspected of tuberculosis infection should receive anergy panel testing to assess the effectiveness of their immune response when their PPD is negative.

The vast majority of AIDS patients with tuberculosis will develop pulmonary manifestations of disease. However, tuberculosis may be difficult to distinguish from other HIV-related pulmonary infections.5 Other considerations include Kaposi’s sarcoma, lymphoma, fungal infections, and Pneumocystis carinii. Approximately half of patients display atypical patterns on chest x-ray, but in the majority, the pattern is suggestive of tuberculosis.8,13,26 The most frequent findings are hilar adenopathy, pleural effusion, predominate upper lobe infiltrate, miliary pattern, or cavitation.13 Patterns consistent with miliary disease are more common after the CD4+ count falls below 100, whereas cavitation and pleural effusion are more common when CD4+ counts are higher than 200. The presence of HIV infection does not affect the frequency with which sputum cultures are positive for acid-fact bacilli.27 Mycobacterial bacteremia, however, may be more common in HIV-infected patients, adding to the diagnostic yield of blood cultures in these individuals.21

The rate of extrapulmonary tuberculosis is very high in HIV-infected individuals: 70% of AIDS patients with TB exhibit extrapulmonary manifestations of primary infection or reactivation.8,26 There appears to be an inverse relationship between the frequency of extrapulmonary disease and CD4+ counts: 64% of patients with CD4+ counts less than 100 experience extrapulmonary disease, compared to 37% in those with counts greater than 200. Most frequently, extrapulmonary disease is manifested by lymphadenitis and bacteremia. It should be stressed that fever is often absent in HIV-infected patients, and that the presentation may be limited to headache in a non-toxic appearing patient. Thus, blood cultures should be performed in addition to other studies in all patients with suspicion of tuberculosis infection.13 Patients commonly present with tender adenopathy, fever, and weight loss. Overall, blood cultures are positive in 26-42% of AIDS patients with active tuberculosis, but again this rate varies inversely with CD4+ count. Meningitis is not uncommon, with a five-fold higher rate than in patients without associated HIV infection. CNS mass lesions and intraparenchymal disease are also more common.13

Treatment. Response to tuberculosis therapy in HIV-infected patients is similar to that in immunocompetent individuals.28,29 Treatment of active disease is therefore the same as that outlined for the general population in Table 6. The American Thoracic Society/CDC guidelines stipulate that a slow or suboptimal response—clinically or microbiologically—may necessitate prolonging the treatment course. AIDS patients experience an increased incidence of adverse drug reactions, which may lead to alteration of treatment regimens.26,29 Malabsorptive states can certainly impair the absorption of antituberculosis medications in HIV-infected individuals, although dosage adjustment is not recommended at this time.30 Treatment failure rates vary between 0-16%, and of those patients with an adequate response, 0-15% will relapse.11 There is a significant potential for interaction with anti-HIV medications and thus regimens often require adjustment. Protease inhibitor therapy should be stopped during tuberculosis treatment.28 Long-term anti-tuberculous maintenance therapy is not recommended.29

Multidrug-Resistant Tuberculosis

Perhaps the most concerning aspect of the recent resurgence of tuberculosis is the increasing occurrence of drug resistant strains. Multidrug-resistant tuberculosis (MDR-TB) is defined as resistance to both isoniazid and rifampin, and possibly other drugs.31 Incomplete, sporadic or erratic treatment of tuberculosis creates selective influences favoring growth of drug resistant bacilli over those which are susceptible.1,31 Other factors contributing to the rise in drug resistance are inappropriate therapy, the change from in-patient to poorly supervised out-patient management, delay in diagnosis, ineffective infection control, and transmission in institutionalized settings.1,3,6

The strongest predictor of the presence of MDR-TB is previous treatment with anti-tuberculous medications.6,31 Yet, at least 15% of newly diagnosed cases of tuberculosis are due to infection with MDR strains. A study conducted in New York City demonstrated that 79% of MDR-TB infections represented primary disease.32 In a 1991 CDC survey, 14.2% of tuberculosis cases were resistant to at least one drug.3 Of the resistant strains, more than half were resistant to one drug, one-quarter were resistant to two drugs, and 4% were resistant to five or more drugs. Drug-resistant strains are concentrated in large, urban regions: New York City had 54 times the rate of MDR-TB as the rest of the country. Minorities have a dramatically higher rate of MDR-TB. Transmission of MDR-TB to health care workers has been described, as has nosocomial transmission of MDR-TB via contaminated bronchoscopes.1,3,6,33

Pulmonary disease develops in more than 90% of patients with active MDR-TB.3 These patients are more likely than drug-susceptible patients to have positive acid fast smears and are more likely to transmit infection to other individuals.3 In some outbreaks of MDR-TB, up to 96% of patients with active disease are also HIV infected.13,34 Immunocompromised patients develop disease much more rapidly, with a median time to death of 4-16 weeks, and have a mortality as high as 89%.3,6 Other predictors of MDR-TB disease include persistent fever lasting more than two weeks and presence of hilar or mediastinal lymphadenopathy.6

Treatment should be based on the local rates of drug resistance. In regions with rates of MDR-TB higher than 4%, all patients with newly diagnosed tuberculosis should be treated with at least four drugs until susceptibility results are available. In regions with rates under 4%, treatment with three drugs is appropriate.6,31 Treatment strategies are outlined in Table 6.1,16

Tuberculosis in Children

The rise in tuberculosis in the pediatric population reflects the increase in adult transmission.35 Tuberculosis is present primarily in minority children living in large urban regions. While the majority are born in the United States, they may have parents who immigrated from endemic regions. There appears to be no gender predilection.18 Approximately 60% of infected children are younger than 5 years—those who are at highest risk to develop active disease.18

Diagnosing tuberculosis in children can be difficult, and similar studies should be obtained on children as in the adult population. Skin testing with PPD should be interpreted in the same manner as adults, but 5% of children with culture-proven tuberculosis have negative reactions to PPD.10 Chest x-ray findings mimic those of adults, with presence of a Ghon complex indicating healed primary infection.35 Sputum or other appropriate cultures should be obtained, including early morning gastric aspiration in children unable to produce adequate sputum cultures. All cultures should have susceptibility testing performed.

The primary infection is commonly asymptomatic, manifesting only as a positive PPD reaction with normal chest x-ray.17 Progression to active disease is more frequent in infants and immunocompromised children, possibly due to their less developed or impaired immune systems. Active pulmonary disease develops in 40% of untreated children less than 1 year old, 24% of children 1-5 years old, and 15% of children 11-15 years old.14

Progressive primary pulmonary infection occurs when the primary peripheral infectious focus forms a large caseous lesion, which may drain into a bronchus, forming a cavitary lesion and leading to disseminated disease.17 These children appear ill, with fever, weight loss, malaise, and chronic cough.17 Chest x-ray findings are similar to those of adults. Uncommonly, children develop chronic pulmonary tuberculosis which is analagous to reactivation pulmonary tuberculosis in adults.

The pediatric population demonstrates a higher rate of extrapulmonary tuberculosis than adults, with 30% of children with active tuberculosis developing extrapulmonary disease.18 Lymphadenitis is the most common, followed by meningeal, pleural, miliary, musculoskeletal, and other infection manifestations.17 The hilar and mediastinal nodes are most commonly affected and can become significantly enlarged, leading to bronchial obstruction.18

Tuberculous meningitis is the most common cause of pediatric death due to tuberculosis.17 It is most frequent in children below the age of 6 years, and develops within 3-6 months from the time of primary infection.18 Disease is characterized by an insidious onset over 1-3 weeks and consists of three stages. Stage 1 typically occurs over 1-2 weeks and demonstrates non-specific signs and symptoms of fever, anorexia, emesis, personality changes, apathy, and loss of play interest. During this stage, no neurologic deficits are evident. Stage 2 begins as intracranial pressure increases, with signs of meningeal irritation and cerebral dysfunction such as drowsiness, emesis, stiff neck, seizures, tremors, and slurred speech. Focal neurological deficits, such as asymmetric pupils and cranial nerve palsies, may be present. Stage 3 is characterized by obtundation, decerebrate or decorticate posturing, irregular respirations, and coma.17

Another serious complication of disseminated disease in children is miliary tuberculosis. Infants appear to be at highest risk. Disease is characterized by acute onset of fever, lethargy, anorexia, and generalized weakness. Respiratory signs and symptoms are usually absent. Physical exam may reveal hepatomegaly, splenomegaly, and lymphadenopathy. One-third to one-half of patients with miliary disease will also develop meningitis.

Transmission Prevention

Minimizing the risk of exposure to and transmission of tuberculosis is a concern to all health care workers. PPD conversion in health care workers is not infrequent and occurs with both drug-susceptible and drug-resistant strains of tuberculosis. As primary care physicians, the likelihood of caring for patients with active and potentially transmittable disease is high. Thus, proactive measures must be taken to prevent exposure and transmission.

Effective tuberculosis control policies should exist in all facilities. Three levels of preventative measures should be used to minimize the risk of transmission.

Level I-Administrative Measures. This first level of transmission prevention attempts to reduce risk through education of health care workers and implementation of policies to identify and isolate potentially infectious individuals.9 Education and training regarding effective preventative measures (e.g., respiratory protection and proper use of isolation rooms) should be provided to all health care workers.9 Policies outlining identification and isolation of high-risk patients should be developed, implemented, and emphasized. Additionally, annual PPD screening of all health care workers should be performed, except in areas with high risk of exposure. These areas require PPD screening on a bi-annual basis.

Level II-Environmental/Engineering Controls. Effective environmental controls can significantly reduce risk of transmission but do not completely eliminate risk. These interventions help contain the spread and reduce the number of infectious droplet nuclei present in the air.

Source control is important in reducing transmission. Once high-risk patients are identified, they should be instructed to cover their mouth and nose when coughing and sneezing; a surgical mask may be placed on the patient for the same purpose. These interventions are not entirely effective in preventing dissemination of droplet nuclei.

High-risk patients should be placed in an adequate, single-patient, isolation room. Negative pressure rooms prevent flow of droplet nuclei into adjacent areas of the facility. The door should remain closed and, if possible, an anteroom with relatively positive pressure should separate the isolation room from the common corridor. Adequate ventilation is perhaps the most important intervention, and at least six complete room air exchanges per hour are necessary.9 The exhaust from the rooms should be filtered via high-efficiency particulate filters and directed outside the building. The exhaust should never be recirculated into the general facility ventilatory system.

Mycobacteria were first hypothesized to be susceptible to ultraviolet (UV) germicidal irradiation after the observation that tuberculosis was rarely transmitted outdoors during daylight. While research has demonstrated the ability of UV light to destroy bacilli, no clinical trials have proven its efficacy in the clinical setting.12 Despite this, UV light is widely used as an adjunct to air exchange. The source light should be placed above eye level (to prevent keratitis) and in a location where room air has maximal exposure.

Level III-Personal Respiratory Equipment. Use of personalized, fitted masks with efficient filters by health care workers is required by OSHA to further discourage transmission. However, their use remains controversial as their safety and efficacy have yet to be proven.16

Summary

Tuberculosis presents many different faces and requires customized treatment and diagnostic strategies depending upon the patient subgroup in which the disease is encountered. Primary care physicians must be able to recognize the wide spectrum of possible clinical presentations and measures for disease prevention. Finally, the physician must be aware of indications for treatment and prophylaxis and the problems posed by multi-drug resistant TB.

References

1. Kent JH. The epidemiology of multidrug-resistant tuberculosis in the United States. Med Clin North Am 1993;77:1391-1409.

2. Ellner JJ. Tuberculosis. In: Kelley WN, ed. Textbook of Internal Medicine. New York: Lippincott; 1989:1569-1577.

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Physician CME Questions

50. The most common clinical manifestation of tuberculosis infection is:

a. primary pulmonary disease.

b. reactivation pulmonary disease.

c. extrapulmonary disease.

d. disseminated disease.

51. In children, tuberculosis differs in the following way:

a. progression to active disease is more common.

b. PPD skin testing is less reliable.

c. tuberculosis meningitis is extremely rare.

d. chest x-ray findings differ from those in adults.

52. Each of the following is considered a risk factor for tuberculosis except:

a. prolonged cough.

b. tuberculosis exposure.

c. unexplained fever.

d. history of bacterial pneumonia.

53. Tuberculosis associated with HIV infection requires special considerations because:

a. extrapulmonary disease is more common.

b. drug therapy is different.

c. PPD skin testing is likely to cause tissue necrosis.

d. AFB smears of the sputum are likely to be falsely positive.

54. The most common cause of death in children with TB is:

a. osteomyelitis.

b. tuberculosis meningitis.

c. miliary TB.

d. sepsis.

e. None of the above

55. Extrapulmonary disease is seen in approximately what percentage of children?

a. 10%

b. 20%

c. 30%

d. 40%

e. 50%

56. Each of the following has been implicated in the resurgence of tuberculosis except:

a. the AIDS epidemic.

b. drug-resistant strains of bacteria.

c. less effective generic drug preparations

d. cutbacks in tuberculosis treatment programs.