Tuberculosis and Nontuberculous Mycobacterial Diseases

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[edit] Tuberculosis and Nontuberculous Mycobacterial Diseases

David Rosenzweig

[edit] TUBERCULOSIS

[edit] Epidemiology

In the twentieth century the incidence of tuberculosis in the United States continuously declined until 1985. Between 1900 and 1985 annual tuberculosis mortality dropped from 200 to less than two per 100,000 population, more than a hundredfold decrease. From 1985 to 1993 the cases increased, but since then the decrease has resumed, and in 1997 the incidence was less than 20,000 new cases for the first time. Although declines have occurred worldwide, tuberculosis remains the most important fatal infection, accounting for 3 million deaths annually. Most deaths (2.5 million) occur in developing nations, where tuberculosis accounts for 6.7% of all deaths, 18.5% of deaths among persons 15 to 59 years of age, and 26% of all preventable deaths. Those who have been infected by Mycobacterium tuberculosis (i.e., tuberculin reactors) number almost 2 billion, more than one third of humankind.

Recently tuberculosis has been resurgent both in the United States and throughout the world, especially in Africa and Asia. Fueled by the acquired immunodeficiency syndrome (AIDS) epidemic and such factors as immigration, poverty, homelessness, and deterioration of public health programs, substantial increases in tuberculosis have occurred. In the United States these increases or outbreaks have been focused in larger cities and particularly in closed institutions (shelters, penal institutions, nursing homes, hospitals). Also, the age incidence of tuberculosis cases has shifted from elderly persons to younger adults, especially in minority populations, implying greater recent infection in these groups (Fig. 74-1). The problem has been compounded by an increase in drug-resistant cases. Drug resistance is especially prominent in Asia, Africa, Russia and other parts of eastern Europe, and Latin America, as well as the United States, but with modern travel, no part of the world is spared from drug resistance problems.

Figure 74-1 Age distribution of reported tuberculosis cases by year of report, United States, 1985-1990. (From Jereb JA et al: MMWR 40:23, 1991.)

[edit] Etiology

In 1882 Robert Koch first demonstrated that tuberculosis is an infectious disease caused by M. tuberculosis. The bacillus is a rod 1 to 4 μm long with a waxy cell wall that accounts for its resistance to acid-stain decoloring, referred to as acid fastness. The organism is hardy, requiring minimal nutrients for culture and able to survive adverse conditions for long periods. A closely related organism, M. bovis, can cause bovine tuberculosis, a similar illness, but this infection has virtually disappeared from the United States due to elimination of its source in infected dairy herds and pasteurization of milk products.

[edit] Natural History

Airborne spread from an infected person, the usual mode of infection, is especially likely to occur during aerosolization of droplets in speaking, singing, coughing, or sneezing. Such droplets quickly evaporate to droplet nuclei, which are capable of penetrating deeply into the respiratory tract. Infected droplet nuclei of 1 to 5 μm can penetrate and be deposited at the alveolar level, where infection is likely to occur, especially with repeated exposure and close household contact.

Initially the host mounts no defense and the mycobacteria multiply, but within days, cellular and humoral defense mechanisms develop. At first, organisms are lysed within macrophages, and mycobacterial antigens become accessible to T and B lymphocytes. Sensitized T lymphocytes secrete lymphokines, which attract and enhance macrophage activity, making phagocytosis and bacterial killing much more effective. This process occurs over 4 to 6 weeks and parallels the development of tuberculin reactivity. This reaction, which depends on activated T lymphocytes, appears 3 to 12 weeks (mean 6 weeks) after inoculation.

The stage of primary tuberculosis also appears at about this time. It may be subclinical and is usually nonspecific with symptoms of fever and cough, which subside over 2 to 3 weeks. If tuberculosis is suspected and the patient is evaluated, the chest radiograph may show a middle or lower segmental infiltrate and enlarged hilar lymph nodes. Children may have atelectasis from lymph node compression. Mycobacterial stains and cultures of respiratory specimens, sputum, or bronchial lavage may be negative in more than half the cases because the organisms are still relatively few at this stage. Transient mycobacteremia occurs during primary tuberculosis, however, seeding distant sites for potential later reactivation of disease, most often the pulmonary apex, renal cortex, epiphyses of long bones, and meninges.

Primary tuberculosis can then spontaneously subside and lead to several outcomes: (1) no further disease and no residual lesions, or only a calcified parenchymal nodule and ipsilateral hilar lymph node calcification; this is called the primary complex; (2) manifestations of progressive primary infection with development of pleural effusion or mediastinal and cervical lymphadenitis (see Extrapulmonary Tuberculosis); (3) more serious life-threatening dissemination with development of miliary or meningeal tuberculosis; or (4) a dormant phase with development of reactivation disease years or decades later in distant sites, most frequently the lung apex. The immunocompromised host, especially with human immunodeficiency virus (HIV), is much more likely to develop progressive primary disease and extrapulmonary disseminated stages than the otherwise healthy host.

Conventional wisdom and historic data indicate that once infected an individual is relatively immune from subsequent new infection, and that later recurrences or relapses are caused by endogenous reactivation of the original strain. Recent data, however, show that this relative immunity can be overcome. In certain closed institutions (e.g., nursing homes, prisons) where exposure may be heavy, exogenous new infection with different strains may be identified. In AIDS patients during treatment for drug-susceptible tuberculous disease, new drug-resistant strains have emerged, reversing a favorable course.

[edit] Clinical Features

Tuberculosis disease is characteristically chronic or recurrent, but its manifestations range from an inapparent or subclinical infection in the majority of those affected to an acute and rapidly progressive illness, especially in immunocompromised hosts or small children.

[edit] Pulmonary Tuberculosis.

Systemic manifestations are usually present. Fever occurs in 50% to 80% of patients, and malaise, weight loss, and night sweats also occur frequently. More than 85% of all forms of tuberculosis are pulmonary, so respiratory symptoms, especially cough, are common. The cough may be nonproductive in early stages, but patients may produce sputum later and less often, may experience hemoptysis. Pleuritic pain is occasionally seen even if overt pleural effusion is absent. Dyspnea, if present, is an ominous feature seen with widespread advanced disease. Crackles and bronchial breath sounds may be present, but more often there are no abnormal findings, even in well-developed pulmonary disease. Fatalities occur from wasting (consumption), hemorrhage, or respiratory failure.

Notable laboratory abnormalities include leukocytosis in 10% to 20% of patients, anemia in at least 10%, and hyponatremia in 10% to 15%. Anemia is more likely in more advanced disease and may be a sign of dissemination. Occasionally, anemia or pancytopenia may result from direct bone marrow involvement. Hyponatremia is usually of the normovolemic type and is a result of inappropriate antidiuretic hormone (ADH) secretion, marked by hyperosmolar urine in the presence of hyposmolar plasma. Hyponatremia is more often seen in advanced disease. Because these manifestations are nonspecific and often insensitive, a high index of suspicion may be needed for diagnosis. Screening and a careful diagnostic approach are justified in groups at high risk for tuberculosis (Box 74-1).

[edit] Extrapulmonary Tuberculosis.

Tuberculosis can involve almost any organ, but only the more common types are discussed here. Extrapulmonary involvement is present in about 15% of all patients but is much more likely in immunocompromised hosts.

[edit] Pleuritis.

Tuberculous pleural effusion results from a perforation of a subpleural focus of tuberculosis into the pleural space. The chest radiograph demonstrates an underlying parenchymal infiltrate, representing active pulmonary tuberculosis in only a minority of cases of tuberculous pleuritis. The purified protein derivative (PPD) skin test reaction may be temporarily suppressed, so when tuberculous pleuritis is suspected despite a negative PPD, the test should be repeated later. Evaluation of patients with suspected tuberculous pleural effusions includes sputum smear and culture, smear and culture of pleural fluid, and percutaneous pleural biopsy analyzed by smear, culture, and histopathology. The fluid features are characteristically a mononuclear cell and serous exudate. An elevated adenosine deaminase level may also be a helpful and specific marker. The analysis of the pleural fluid and pleural biopsy specimens diagnoses more than 90% of tuberculous pleural effusions, although the yield of pleural fluid culture alone is less than 25% (see Chapter 79 ). Diagnosis by thorascopic biopsy is occasionally needed. Untreated, most tuberculous pleural effusions spontaneously resolve in several weeks, although 65% of patients will develop active pulmonary tuberculosis within 5 years, underscoring the importance of diagnosis and treatment.

[edit] Lymphadenitis.

Hilar lymph node involvement with enlargement is a frequent sequela of primary tuberculosis. In children it can cause bronchial compression with atelectasis. Hilar and mediastinal lymphadenitis is also common in immunocompromised adults, especially HIV-infected patients.

Cervical lymphadenitis, formerly scrofula, presents as a firm group of supraclavicular or anterior nodes that are usually nontender and matted. Ulceration with sinus tracts is a later development. Diagnosis is usually made by aspiration or excision of the involved area. Granulomatous cervical lymphadenitis in younger children is rarely caused by tuberculosis in the United States. Most such cases now are caused by Mycobacterium avium-intracellulare complex (see later discussion).

[edit] Tuberculosis of Bone.

This may involve the spine (Pott's disease) or the epiphyses of larger long bones, especially at the knees or hips, and occasionally the wrists or elbows. The lumbar spine is more frequently involved than the dorsal spine, and involvement of the cervical spine is rare. Manifestations include pain, compression fracture and deformity, and radiculopathy from compression. The gibbous deformity with sharp spinal angulation is characteristic. Diagnosis is usually suspected from the clinical and radiographic features. Early x-ray changes include soft tissue swelling, subchondral osteoporosis, cystic sclerosis, and later involvement of the synovial space. Diagnosis is best made by needle aspiration and occasionally by open biopsy.

[edit] Meningitis.

Meningitis is the most common type of central nervous system tuberculosis. This dreaded disease was uniformly fatal before chemotherapy became available, and even with prompt and adequate treatment today, permanent sensory, motor, and cognitive impairment may be unavoidable; mortality may reach 40%. Usual features are basilar meningitis and cranial nerve involvement with headache, stiff neck, and obtundation. Lumbar puncture shows 100 to 1000 leukocytes, with lymphocytes predominant in two thirds of patients. Protein concentrations are high and glucose concentrations usually low. Acid-fast stains are positive in only 10% to 20% of patients, with culture confirmation later in 50% to 75%. Evidence indicating pulmonary or other forms of tuberculosis can assist diagnosis. If the diagnosis is suspected, early empiric therapy is prudent and may be lifesaving.

[edit] Disseminated or Miliary Tuberculosis.

This may also carry a grave prognosis. Systemic manifestations are prominent, with fever, weakness, and malaise. Anemia or pancytopenia often occurs because of marrow involvement. The name miliary is derived from the characteristic innumerable fine nodules of uniform size (millet seeds) that appear on chest radiograph or on cut section of the lung at autopsy. In its earlier stages, however, the x-ray shadows may be inapparent. High-resolution computed tomography (CT) scanning can demonstrate such shadows more sensitively than plain films. Diagnosis can be made in half of cases by sputum examination, but invasive procedures, especially transbronchial lung biopsy and bone marrow biopsy, offer a much more reliable yield and should be considered early.

In addition to increased frequency of disseminated or extrapulmonary disease, the immunocompromised host, especially if HIV infected, exhibits many features of tuberculosis that differ from those in the immunocompetent host (Table 74-1).

Table 74-1 Host Response Differences in Tuberculosis

[edit] Diagnostic Testing

[edit] Microbiology.

The microbiology laboratory is essential for confirming the diagnosis by identification of M. tuberculosis as well as for following the course of disease by documenting the disappearance of organisms with successful therapy. In pulmonary disease the sputum first expectorated in the morning is the preferred specimen, usually on 3 successive days. If such sputum is unobtainable, sputum induction using hypertonic 3% saline aerosol is an alternative. If necessary, the next step is fiberoptic bronchoscopy with sampling by bronchoalveolar lavage, brushing, or biopsy of affected segments.

The initial examination is the acid-fast stain. Specimens generally give best results if they are examined after predigestion. Fluorescent stains using auramine-rhodamine improve the sensitivity and rapidity with which the slide can be screened, but false-positive results do occur, so a positive fluorescent specimen should be confirmed by the standard Ziehl-Neelsen or Kinyoun stain. A positive acid-fast stain does not identify M. tuberculosis, since all other mycobacteria as well as Nocardia species are acid fast. Acid-fast stains require a fairly heavy population of organisms for detection and thus may be falsely negative. Culture methods increase sensitivity, since 40% to 60% of eventual isolates may be negative on initial stains.

Classic culture methods require 3 to 8 weeks for identifiable growth. Because of this inordinate delay, other techniques, especially the Bactec methods, are being used to accelerate growth and provide identification in 10 to 14 days. These techniques are available in larger hospital and state reference laboratories. Genetic techniques (e.g., RNA sequencing, gas-liquid chromatography, high-performance liquid chromatography) offer more precise and rapid identification in hours or days. The polymerase chain reaction technique offers promise as a rapid and sensitive test.

Drug susceptibility studies complement culture techniques. The proportion-plate method is being replaced by the more rapid and reliable broth (Bactec) technique. With recent increases in drug-resistant strains, susceptibility studies must be conducted on all initial isolates and must be repeated if organisms are still recovered after 2 to 3 months of treatment. The recent complete decoding of the tubercle bacillus genome holds great promises for advances in diagnostic methods as well as in drug and vaccine development.

[edit] Radiography.

Routine chest radiography is highly sensitive for recognition of pulmonary tuberculosis. Supplementary x-ray techniques, especially CT scans, can give additional information in areas that are difficult to visualize with conventional films, such as the mediastinal, retrocardiac, or apical zones, which can be obscured by overlying structures. The characteristic features are nodular infiltrates and cavitation. Air-fluid levels are uncommon in cavities but suggest another problem (e.g., lung abscess). In later stages, when healing occurs, signs of fibrosis may include loss of volume, linear shadows, and traction deformities of the hilum and mediastinum. The most common areas of involvement are the apical and posterior segments of upper lobes and superior segments of lower lobes. Adjacent pleural thickening often occurs (Fig. 74-2, A). A normal chest radiograph may occur rarely in pulmonary tuberculosis, as in an isolated endobronchial lesion or a very early miliary stage.

Figure 74-2 A, Common features of pulmonary tuberculosis, with bilateral upper zone nodular infiltrates and cavitation. Small airfluid level in right midzone cavity is unusual. Target shadows are electrocardiographic lead artifacts. B, Tuberculosis in acquired immunodeficiency syndrome. Hilar and paratracheal lymph node enlargement is prominent, with faint infiltrate in lung apex. C, Tuberculosis in AIDS. Bilateral infiltrates resemble segmental pneumonitis, with moderate hilar node enlargement.

In primary tuberculosis the radiographic picture is different and less specific. Infiltrates without nodularity, usually in the middle or lower zones, are seen. Hilar lymph node enlargement is a common feature. Lymphadenopathy is prominent in immunosuppressed patients, especially those with AIDS, and parenchymal infiltrates may be poorly defined, without nodularity or cavity formation (Fig. 74-2, B and C). Tuberculosis in AIDS can also have an interstitial pattern and be confused with Pneumocystis carinii pneumonia (Box 74-2).

[edit] Histology.

The characteristic lesion of tuberculosis is the formation of granulomas, which represent aggregations of inflammatory cells, principally macrophages, many of which assume epithelioid forms and join to create giant cells. Caseation necrosis is a prominent feature. These features are not specific for tuberculosis and may be seen in infectious granulomas caused by fungi or other mycobacteria. Granulomas without caseation may be found in sarcoidosis and foreign bodies or as an adjacent reaction to neoplastic and inflammatory diseases. Specific recognition of the tuberculous granuloma depends on demonstration of the organism by stain or culture of this tissue, as well as on clinical circumstances. In the immunocompromised host, granulomas may not be seen or may be poorly formed, and the inflammatory response may be modest. In such cases the organisms may be abundant on tissue stains.

[edit] Tuberculin Test.

The tuberculin reaction is the classic example of delayed hypersensitivity immune response. Tuberculin, an extract of killed tubercle bacilli, is now well standardized as PPD, and its activity is measured by bioassay. The standard test is the intradermal administration in the volar forearm of 5 units diluted to 0.1 ml (Mantoux test). The reaction is read at 48 to 72 hours as diameter of induration, not erythema. A positive reaction can be interpreted as infection with M. tuberculosis. The infection may be recent or remote, since persistence of reactivity is the rule. Up to 10% of reactors, however, may become negative on retesting a decade or more later.

The tuberculin test is plagued by uncertainties related to both sensitivity and specificity. In a diagnostic setting, sensitivity is as low as 70%, and false-negative results are likely when the diagnosis is most important: in overwhelming disease, in immunocompromised hosts, in elderly patients, and in sarcoidosis (Box 74-3). Cutaneous anergy may be present in such cases. Anergy is assessed by simultaneous intradermal testing with common antigens, such as mumps, tetanus toxoid, Candida, and Trichophyton. Unfortunately, anergic reactions offer little information. Specificity problems result from cross-reactivity with other mycobacterial infection (a common regional problem, especially in the southeastern United States) or with prior bacille Calmette-Guérin (BCG) vaccination. Such cross-reactivity usually gives weak reactions of 5 to 10 mm. In epidemiologic testing of healthy populations, tuberculin sensitivity is more reliable than for diagnostic use. In case contact surveys or employment screening programs the test is uniquely valuable.

Another difficulty is the booster phenomenon. A host who is weakly reactive may have an enhanced reaction on retesting a month or a year later. Since the implication is newly acquired vs. remote infection, interpretation can be confusing. This phenomenon is often seen in elderly patients and in annual nursing home surveys. One technique for clarifying the booster phenomenon is double testing, or repeating a negative test after 1 week. A positive reaction on second test represents a boost rather than a true conversion. This method is useful in screening persons over 60 years old.

Because of these difficulties, the American Thoracic Society has proposed a scaled interpretation of tuberculin tests based on clinical circumstances (Box 74-4). Although this interpretation formula is an improvement over the previous standard of 10-mm induration as the uniform positive threshold, the test still has intrinsic defects (e.g., 10% to 25% of AIDS patients have false-negative tests even at the 5-mm induration threshold).

[edit] Management

Comprehensive management of any contagious disease includes effective treatment of the source case as well as evaluation, prevention, and treatment of contacts. The cornerstone of effective treatment is multidrug chemotherapy, but the public health measures of contact surveys, isolation methods, and ensuring that the patient completes treatment are also important.

Tuberculosis is a reportable disease. Every case must be reported to the local health department when the diagnosis is made, but it is good policy to report cases even when tuberculosis is suspected but not proved. The public health officer should serve as a consultant to the primary care physician and is helpful in initiating the contact surveys of the patient's household and, if necessary, the patient's place of employment. Contact surveys begin as tuberculin testing followed by chest x-ray studies for reactors to evaluate them for active disease. A second round of tuberculin testing after 6 to 8 weeks is prudent for nonreactors to detect those who may have been very recently infected but who were not yet reactive on the initial survey. Preventive treatment is appropriately offered for contact reactors without evidence of clinical or radiographic disease. The health department also helps promote the successful completion of a prolonged course of patient treatment.

The decision for hospitalization is based on clinical circumstances. If the patient has pronounced symptoms and is seriously ill, if the patient requires extensive expedited diagnostic testing, or if drug resistance is suspected, hospitalization is indicated. On the other hand, many mildly ill patients can be managed at home. The hazard to household contacts is greatest before the diagnosis is made. Once effective treatment is begun, contagiousness rapidly decreases.

[edit] Chemotherapy.

Successful chemotherapy is based on the prolonged use of multiple effective drugs. The earliest lesson in treatment of tuberculosis with streptomycin in 1946 was that early success but late relapse occurred because of the selective emergence of resistance of the organisms to a single drug. With the use of multiple drugs, and especially since the use of isoniazid-rifampin (INH-RIF) combinations, this risk of acquired drug resistance has been minimized. Prolonged uninterrupted treatment is needed because persistent, slowly growing or dormant bacilli can only be eliminated slowly, even though the main population of rapidly dividing organisms quickly responds to therapy.

Several large drug trials sponsored by the U.S. Public Health Service and the British Medical Research Council showed that the ideal course of therapy can be as short as 6 months, if it has an intensive early three-drug phase followed by 4 months of INH-RIF. In the intensive phase, daily treatment is needed, but later the schedule may be daily or twice weekly. Demonstrated success in these drug trials included 95% or higher initial clearance of the disease, as well as freedom from relapse over 1 to several years after treatment. These trials established the standard of treatment as an initial 2 months of daily INH-RIF and pyrazinamide (PZA) followed by 4 months of INH and RIF either daily or two or three times weekly. If PZA cannot be tolerated, an alternative is INH-RIF for a 9-month course. Intolerance or drug resistance to either of the major drugs requires addition of two other drugs, usually ethambutol and streptomycin, and a more prolonged course of 12 to 18 months. These treatment programs need not be altered for extrapulmonary tuberculosis. In HIV-infected patients a minimum of 9 months is customary, although standard courses are likely to be effective (Table 74-2).

Table 74-2 Recommended Drug for Treatment of Tuberculosis

✢In persons over age 60, daily dosage of streptomycin should be limited to 10 mg/kg with maximum of 750 mg.

The recognition of drug-resistant strains affects the approach to therapy. In 1997 INH resistance occurred in 7.8% and INH-RIF resistance in 1.4% of cases in the United States. Substantially higher resistance rates were reported in California, Florida, New Jersey, and New York City, and 35 states reported INH resistance rates of 4% or higher. Thus an initial fourth drug, ethambutol or streptomycin, should be added in any region where INH resistance rates are greater than 4% or unknown. Treatment is then modified later based on susceptibility results, with reversion to standard regimens if resistance is not found and prolonged 18-month regimens if INH or RIF resistance is confirmed. Re-treatment of failed cases or treatment of multidrug-resistant cases is not the province of primary care, and cases should be referred. Treatment of diseases resistant to both INH and RIF is difficult, requiring less effective, more toxic drugs and prolonged administration.

Patient monitoring is necessary to ensure the safety and effectiveness of treatment. The patient should be seen at least monthly to discuss disease symptoms and side effects of therapy. For pulmonary tuberculosis, sputum studies should be done monthly for 3 months or until negative, at conclusion of treatment, and 3 to 6 months after treatment. Chest radiographs during therapy are desirable but not imperative because symptomatic and bacteriologic status indicators are more valuable; radiographic appearance should improve, but signs such as closure of cavities are not essential for success. Initial baseline complete blood count, blood urea nitrogen, liver enzymes, visual testing (for ethambutol), and uric acid (for PZA) are recommended. Since the three standard drugs are all potentially hepatotoxic, periodic monthly liver enzymes should be measured. Although modest elevations often subside with continued therapy, careful follow-up is necessary, but not discontinuance of treatment.

The most important and common reason for therapeutic failure is patient noncompliance. Education is helpful; the patient should understand the nature of the disease and the need for adhering to prolonged treatment, long after feeling well. Another measure of proven effectiveness is supervised or directly observed therapy; a caregiver or dedicated family member dispenses each dose and observes the patient ingesting it. This method is most conveniently adapted for intermittent, thrice-weekly dosing. Directly observed therapy is appropriate for any patient who may be noncompliant. Although alcoholics and drug users might seem to be noncompliant groups, no basis exists for predicting compliance from any social, economic, or educational group. Given the gravity of the reemergence of tuberculosis, the recommendation is that all therapy should be directly observed. This advice applies to any setting where compliance is less than 90% or is unknown, or virtually everywhere. Involuntary confinement or other coercive measures are rarely used. Any measure that simplifies treatment (e.g., twice-weekly or thrice-weekly dosing) can improve compliance. Fixed-combination tablets containing INH-RIF or INH-RIF-PZA discourage taking only part of the regimen. Pyridoxine is often routinely given to prevent the rare INH-induced peripheral neuropathy; the patient may then take only the vitamins, however, so routine use of pyridoxine can be counterproductive. The best tactic is to “keep it simple.”

Drug toxicity or intolerance accounts for much fewer treatment failures than patient compliance. Hepatotoxicity, even with three potentially toxic drugs (INH-RIF-PZA), occurs in less than 4% of cases but is seen more frequently in patients with preexisting liver disease. PZA usually produces hyperuricemia but rarely symptomatic gout. Optic neuritis caused by ethambutol is rare if the initial dosage of 25 mg/kg/day is reduced to 15 mg/kg/day after the first 6 weeks of use.

Adjunctive surgery has a minor role in tuberculosis treatment today. Occasional patients may require drainage of tuberculous empyema, decompression of constrictive pericarditis, or relief of neurocompression in spinal tuberculosis, but these are performed for specific reasons to improve organ function. Surgery could have a renewed role in multidrug-resistant disease, but this has yet to be demonstrated because successful surgery is not an alternative but an adjunct to effective chemotherapy.

[edit] Treatment of Children and Pregnant Women.

Treatment of children is similar to that for adults in combinations and duration of treatment (see Table 74-2). Treatment of tuberculosis in pregnant women is essential and should not be deferred. The preferred initial treatment is INH-RIF and ethambutol. The teratogenicity of PZA is undetermined, so it should not be used unless resistance to other drugs is demonstrated or likely. Streptomycin is ototoxic to the fetus and should not be administered unless other options are lacking.

[edit] Preventive Treatment.

Approximately 10% of persons who have been infected by the tubercle bacillus but have no disease (i.e., tuberculin reactors who have no active disease on radiographs) develop tuberculous disease at some point in their lifetime. This risk is greater within the year after infection and in immunosuppressed patients, such as those taking corticosteroids or chemotherapy, and patients with diabetes or cancer. The risk is extremely high in HIV-infected patients, 40 to 100 times that of the normal population. Several large field trials in the 1960s showed that INH given daily for 6 to 12 months provides effective protection in 80% to 90% of patients against this risk and that the protection endures in follow-up over at least a decade; subsequently, however, the hepatotoxic hazard of INH has curtailed its use in this setting. INH hepatotoxicity risk increases with patient age. The incidence is 2% to 3% in those over age 60, 1% in younger adults, and virtually nonexistent in children. INH is still recommended for most tuberculin reactors without disease, except those at lowest risk (Box 74-5). INH preventive treatment in the HIV-infected tuberculin reactor is strongly recommended. Other indications for such treatment in HIV patients include anergy and no apparent disease but high risk, as shown by a previous positive reaction, exposure to a patient with tuberculosis, a chest radiograph compatible with healed tuberculosis, or high likelihood of exposure (e.g., Haitian or Mexican immigrants, injection drug users).

Alternatives to INH have never been studied in a controlled way. If INH is indicated but cannot be given because of intolerance or suspected INH resistance, RIF would be the next drug of choice. Other inferior options include ofloxacin and ethambutol. BCG vaccine has uncertain and variable effectiveness. It is not used for tuberculin reactors and has no clear role for tuberculosis prevention in the United States. In addition, BCG is a live vaccine capable of causing progressive disease in immunocompromised patients, so it is clearly contraindicated in HIV disease.

[edit] Control Measures.

With the reemergence of heightened risk of tuberculous infection, physicians in health care facilities and other close environments should know and help implement effective surveillance and preventive measures (Box 74-6).

[edit] NONTUBERCULOUS MYCOBACTERIAL DISEASES

Several dozen species of mycobacteria have been identified since the tubercle bacillus itself was discovered. Most are found in the environment. Many are saprophytes, and some are pathogenic for fish, amphibia, or birds; only a few species are important to humans. All are less virulent than M. tuberculosis and are most often seen as opportunistic infections. The most common and important group is M. avium-intracellulare complex (MAC); others include M. kansasii, M. marinum, and rapid growers such as M. fortuitum-chelonae complex. Laboratory differentiation is based on colonial morphology, growth rates, and a biochemical test battery, but genetic testing for rapid identification of MAC vs. M. tuberculosis is now replacing the cumbersome biochemical testing.

[edit] Diseases from Mycobacterium Avium-intracellulare Complex

[edit] Chronic Pulmonary Disease.

MAC infection usually occurs in middle-aged men more often than women and may mimic pulmonary tuberculosis but has distinctive features. Respiratory symptoms often occur, but systemic symptoms are uncommon. Disease and progression are indolent, and radiographic features are usually limited to lung parenchyma, with thin-walled cavities and thickening of overlying pleura but rarely pleural effusion. Primary stages are rarely seen, and involvement usually occurs in a portion of the lung previously damaged by chronic bronchitis or bronchiectasis, emphysema, healed tuberculosis, or silicosis. Another distinct form of disease, with interstitial involvement and nodular bronchiectasis in the middle and lower zones, is seen in older women without preexisting lung disease. Extrapulmonary involvement is rare, but occasional cases of bone and joint disease occur. Because the MAC organisms may be casual isolates rather than disease producers, a firm diagnosis requires several criteria, including repeated isolates of the same organism over days or weeks in reasonable numbers, as well as a compatible radiographic and clinical picture.

Because of drug resistance, treatment is often of uncertain benefit. In mild disease, observation alone may be the best choice. In symptomatic cavitary disease, effective treatment often requires three or more drugs and a prolonged course of up to 2 years. If possible the choice of drugs should be guided by susceptibility studies. An initial recommended combination is clarithromycin or azithromycin, rifabutin or rifampin, and ethambutol, with an option of streptomycin initially. Adjunctive surgical resection can be beneficial if disease is well localized and the patient has acceptable surgical risks.

[edit] Cervical Lymphadenitis.

This disease presents in children ages 1 to 5 as chronic nontender enlarged lymph nodes in the anterior or posterior chain. Cervical lymphadenitis is probably acquired by oral ingestion of contaminated materials from floors. It is a much more common cause of granulomatous lymphadenitis in children than is tuberculosis. Diagnosis is made by identification of the organisms from aspirated or resected material. The preferred treatment is complete surgical excision. Drugs are weakly effective, and untreated disease often progresses to draining fistulae or disfiguring scars.

[edit] Disseminated MAC Disease.

This devastating disease occasionally occurs in immunosuppressed transplant or cancer patients, but its chief importance is in the late stages of AIDS. Disseminated MAC disease is marked by high fever, weakness, diarrhea, and pancytopenia that carries a poor prognosis. It is seen when marker CD4 T-lymphocyte counts are less than 50/mm³ (often below 10) and may occur in 20% to 40% of late-stage AIDS patients. Diagnosis is most reliably made by blood or marrow culture. Stool cultures are usually positive as well but alone are inconclusive for diagnosis. If untreated, median life expectancy is 4 months. Survival can be doubled with multidrug treatment, similar to that used in chronic pulmonary disease. Drug toxicity often occurs, with special problems from antiviral/rifampin interactions. MAC prophylaxis using azithromycin is recommended in AIDS patients with CD4 counts less than 100/mm³ (see Chapter 32 ).

[edit] Mycobacterium kansasii Infections

Although MAC can be widely found in the environment in soils and bodies of water, M. kansasii is rarely found in nature but can be found sporadically in tap water. The organism is beaded and larger than other mycobacteria, so an experienced microscopist can identify it from acid-fast stains alone. It shows the peculiar culture characteristic of pigmentation only if grown in light (photochromogen). M. kansasii shows limited virulence for humans. As with MAC, it can cause chronic pulmonary disease and disseminated disease in AIDS as well as the rare bone or joint disease. M. kansasii differs from MAC most importantly in its favorable response to therapy. Rifampin is highly effective in treatment, and the recommended current regimen is rifampin, isoniazid, and ethambutol for at least 9 months.

[edit] Mycobacterium marinum Cutaneous Infections

M. marinum infections occur as nodular ulcerations in swimmers (swimmers' itch), in fish processors, or from cleaning fish tanks (fish tank granuloma). Diagnosis is made by skin biopsy and identification of the organism. The disease may heal spontaneously, but deep infection should be treated for at least 3 months. The organism is usually susceptible to clarithromycin, sulfonamides, tetracycline, rifampin, and ethambutol, and monotherapy or a rifampin-ethambutol combination is appropriate.

[edit] Infections from Rapid-growing Mycobacteria

Rapid-growing mycobacteria, especially M. fortuitumchelonae complex, are most important in wound infections and in contamination of implanted prosthetic materials, especially breast implants, long-term catheters, porcine heart valves, and bone wax. Occasional ocular or cutaneous infections are also seen, along with pulmonary disease resembling MAC. Diagnosis is usually evident; organisms are easy to grow, and cultures mature in 3 to 7 days. Successful treatment usually involves removal of prosthetics and wide excision of infected tissue. Chemotherapy is of variable effectiveness, but drugs, including amikacin, tobramycin, cefoxitin, sulfamethoxazole, imipenem, and ciprofloxacin, are likely to have some benefit.

[edit] ADDITIONAL READINGS

• JB BassJr, American Thoracic Society: Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359.
• Core curriculum on tuberculosis: what the clinician should know ed 3. Washington, DC: US Department of Health and Human Services; 1994:
• MC Raviglione, DE Snider, A Kochi: Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. JAMA 1995; 273:220.
• RJ Wallace, American Thoracic Society: Diagnosis and treatment of disease caused by non-tuberculous mycobacteria. Am J Respir Crit Care Med 1997; 156:S1.