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Harrison’s Manual of Medicine



Other Mycobacterial Infections

Disseminated NTM Infections in AIDS and Other Immunodeficiencies

Localized Infections due to NTM

Mycobacteria are distinguished by their surface lipids, which cause them to be acid-fast in the laboratory. They may be divided into several groups: the M. tuberculosis complex (M. tuberculosis, M. bovis, and M. africanum), members of which cause tuberculosis (TB); M. leprae, which causes leprosy; and the nontuberculous mycobacteria (M. avium and others), a heterogeneous group that causes disseminated disease in immunocompromised hosts and a variety of local infectious syndromes in both immunocompromised and immunocompetent individuals. The vast majority of TB cases are caused by M. tuberculosis.
EPIDEMIOLOGY   Beginning in the mid-1980s in many industrialized countries, the number of TB case notifications, which had been falling steadily, stabilized or began to increase. A number of factors were implicated in the resurgence of TB in the U.S. in 1986–1992, including the AIDS epidemic; immigration from high-prevalence areas of the world; social problems such as poverty, homelessness, and drug abuse; and the emergence of multidrug-resistant (MDR) TB. With the implementation of stronger control programs, the number of cases began to decrease in 1993. In 1998, 18,361 cases of TB were reported—a 31% decrease from the 1992 peak. Currently in the U.S., TB tends to be a disease of the elderly, of young adults with HIV infection, of immigrants, and of the economically disadvantaged. In certain developing areas of the world, the HIV epidemic is responsible for the doubling or even tripling of the numbers of TB cases reported over the past decade; if the worldwide TB control situation remains as it is, the annual incident cases of TB may increase by 40% by 2020. M. tuberculosis is transmitted from person to person by droplet nuclei that are aerosolized by coughing, sneezing, or speaking. The infectivity of a given case correlates with the concentration of organisms in expectorated sputum, the extent of pulmonary disease, the frequency of cough, and the intimacy and duration of contact.
PATHOGENESIS   After entry into the lungs in aerosolized droplets, tubercle bacilli are ingested by macrophages and transported to regional lymph nodes. From there, they disseminate widely. Whether in the lung, lymph nodes, or sites of dissemination, lesions are contained by a delayed-type hypersensitivity (DTH) response (the tissue-damaging response) and by the cell-mediated macrophage-activating response. The development of host immunity and DTH to M. tuberculosis is evidenced by acquisition of skin-test reactivity to tuberculin purified protein derivative (PPD). The PPD skin test is the only test that reliably detects M. tuberculosis infection in asymptomatic persons. With the development of specific immunity and the accumulation of large numbers of activated macrophages at the sites of infection, granulomatous lesions (tubercles) form. The organisms survive within macrophages or necrotic material but do not spread further; reactivation (postprimary disease) may occur at a later time. In some cases, the immune response is inadequate to contain the infection, and symptomatic, progressive primary disease develops.
CLINICAL MANIFESTATIONS   TB is usually classified as pulmonary or extrapulmonary. In the absence of HIV infection, >80% of cases involve the lungs only. In the presence of HIV, up to two-thirds of pts with TB have either extrapulmonary disease alone or both pulmonary and extrapulmonary disease.
Pulmonary TB   Pulmonary tuberculous disease may be categorized as primary or postprimary.

Primary disease is often seen in children and is frequently localized to the middle and lower lung zones. In the majority of cases, the lesion heals spontaneously and may later be evident as a small calcified nodule (Ghon lesion). In children and in persons with impaired immunity (e.g., malnutrition, HIV infection), primary disease may progress rapidly and may evolve in different ways (pleural effusion, acute cavitation, bronchial compression by enlarging lymph nodes, miliary TB, or tuberculous meningitis).

Postprimary disease results from endogenous reactivation of latent infection and is usually localized to the apical and posterior segments of the upper lobes; in addition, the superior segments of the lower lobes are frequently involved. The extent of parenchymal involvement varies greatly, from the development of small infiltrates to extensive cavitary disease. Massive involvement and coalescence of lesions may produce tuberculous pneumonia; up to one-third of untreated pts succumb within a few weeks or months, others experience spontaneous remission, and still others have disease that follows a chronic, progressively debilitating course (“consumption”). Early signs and symptoms are often nonspecific and insidious (fever, night sweats, malaise, weight loss). Cough and blood-streaked sputum eventually develop in the majority of cases. Massive hemoptysis may occur. Physical findings are of limited diagnostic utility. The classic tuberculous amphoric breath sounds may be heard over areas with large cavities.
Extrapulmonary TB   The extrapulmonary sites most commonly involved are the lymph nodes, pleura, genitourinary (GU) tract, bones and joints, meninges, and peritoneum. Virtually any organ system may be affected.

Tuberculous lymphadenitis occurs in >25% of cases of extrapulmonary TB and is particularly common among HIV-infected pts. The involved nodes are most commonly those at cervical and supraclavicular sites and are swollen, discrete, and painless. Fistulous drainage of caseous debris may occur. Systemic symptoms usually develop only in HIV-infected pts. Concomitant pulmonary disease may or may not exist.

Pleural involvement is common during primary TB and results from DTH to bacilli in the pleural space; these organisms are typically few in number. The effusion produced may be small and asymptomatic or large with associated fever, pleuritic chest pain, and dyspnea. The pleural fluid is straw- colored, with a protein content that is >50% of the serum value, a normal or low glucose level, a pH of <7.2, and detectable WBCs (usually 500– 2500/µL). Pleural biopsy is often required for diagnosis and reveals granulomas or a positive culture in up to 70% of cases. This form of pleural TB responds well to chemotherapy and may resolve spontaneously. Tuberculous empyema is less common, results from rupture of a tuberculous cavity into the pleura, and may lead to severe pleural fibrosis and restrictive lung disease.

Genitourinary TB accounts for 15% of extrapulmonary cases, may involve any part of the GU tract, and is usually due to hematogenous seeding following primary infection. UA is abnormal in 90% of cases, with culture- negative pyuria and dysuria. Local symptoms predominate. In women, genital TB (fallopian tubes, endometrium) may cause infertility or menstrual irregularities. Men may develop epididymitis, orchitis, or prostatitis. These infections at GU sites respond well to chemotherapy.

Skeletal TB is responsible for ~10% of extrapulmonary cases in the U.S. Weight-bearing joints (spine, hips, knees) are affected most often. Spinal TB (Pott’s disease) often involves adjacent vertebral bodies and destroys the intervertebral disk. Spinal cord compression by a tuberculous abscess or lesion is a medical emergency. In advanced Pott’s disease, vertebral collapse may lead to kyphosis. Skeletal TB responds to chemotherapy, although severe cases may require surgery.

Central nervous system TB accounts for 5% of extrapulmonary cases and occurs most often in young children and in HIV-infected pts. Tuberculous meningitis results either from hematogenous spread or from rupture of a subependymal tubercle into the subarachnoid space. The disease may present acutely or subacutely. Cranial nerve palsies (particularly of ocular nerves) and hydrocephalus are common. CSF examination reveals lymphocytic pleocytosis (with PMNs sometimes predominating early on), an elevated protein level (100–800 mg/dL), and hypoglycorrhachia. Repeated CSF examinations increase the diagnostic yield; CSF culture is positive in up to 80% of cases. While the disease responds to chemotherapy, neurologic sequelae are common. Glucocorticoids enhance survival and decrease neurologic sequelae.

Gastrointestinal TB may affect any portion of the GI tract. The terminal ileum and cecum are the sites most commonly involved. Abdominal pain, diarrhea, obstruction, hematochezia, and a palpable abdominal mass are common findings. Cases with intestinal-wall ulcerations and fistulae may simulate Crohn’s disease. Surgical intervention is required in most cases. Tuberculous peritonitis presents as fever, abdominal pain, and ascites; ascitic fluid is exudative, with an elevated protein level and—in most cases— lymphocytic pleocytosis. Peritoneal biopsy is often needed to make the diagnosis.

Pericardial TB is frequently a disease of the elderly but is also common in HIV-infected pts. An effusion often develops and is exudative with a high leukocyte count; culture reveals TB in ~30% of cases. Without treatment, pericardial TB is fatal. Despite treatment, chronic constrictive pericarditis may develop.

Miliary TB is due to hematogenous spread and may represent either newly acquired infection or reactivation of latent disease. Clinical manifestations are nonspecific and protean. Fever, night sweats, anorexia, weakness, and weight loss characterize the majority of cases. Hepatomegaly, splenomegaly, lymphadenopathy, and choroidal (ocular) tubercles may occur. A high index of suspicion is required for the diagnosis; PPD results may be negative in up to 50% of untreated cases, and sputum smears are negative in 80%.
HIV-Associated TB   TB is an important opportunistic infection among HIV-infected persons worldwide. As of 1997, ~10 million persons in developing countries were coinfected with HIV and tubercle bacilli. In the U.S., coinfection is common among IV drug users and some minorities. The manifestations of TB in HIV-infected pts vary with the stage of the HIV infection. When cell-mediated immunity is only partly compromised, pulmonary TB presents as typical upper-lobe cavitary disease. In late HIV infection, a primary TB- like pattern may be evident, with diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoracic lymphadenopathy. Extrapulmonary TB occurs frequently in HIV-infected pts (at a rate of 40–60% in some series). Common syndromes include lymph nodal, disseminated, pleural, and pericardial TB as well as mycobacteremia and tuberculous meningitis. In pts in whom highly active antiretroviral therapy (HAART) has recently been started, symptoms and signs of TB may be exacerbated as a consequence of improving immune function. The diagnosis of TB in HIV-infected pts may be rendered difficult by PPD anergy and atypical radiographic and histologic manifestations.
DIAGNOSIS   Initial suspicion of pulmonary TB is often based on abnormal CXR findings in a symptomatic pt. The classic picture is that of upper lobe infiltrates and cavitary disease; however, virtually any pattern may be seen. A diagnosis of active infection is established by the demonstration of acid-fast organisms in sputum, bodily fluids, or tissues. The fluorescent auramine-rhodamine stain is used by most modern laboratories. Traditional acid-fast stains are also useful but are more time-consuming. Primary isolation in culture may require 4–8 weeks. Radiometric growth detection and nucleic acid probe identification make it possible to isolate the infecting organism and identify it to the species level within 2–3 weeks. Sputum induction may be useful when a pt is unable to produce a sputum sample spontaneously, and bronchoalveolar lavage increases the diagnostic yield over that obtained with expectorated sputum alone. Similarly, sampling of bodily fluids (pleural, pericardial, peritoneal, cerebrospinal) or tissue biopsy (of pleura, pericardium, peritoneum, liver, or bone marrow) is appropriate for suspected extrapulmonary or disseminated disease. Blood from HIV-infected pts with suspected TB should be cultured for the organism. The PPD skin test is useful in screening for prior mycobacterial infection. The Mantoux method is most reliable and should be read at 48–72 h as the transverse diameter of induration (not erythema) in millimeters.
PREVENTION   The best way to prevent TB is to diagnose cases rapidly and administer appropriate treatment until cure. Preventive chemotherapy is of value; recommendations for the treatment of latent TB infection, based on PPD result, are given in Table 97-1.

Table 97-1 Tuberculin Reaction Size and Treatment of Latent Tuberculosis Infection

Recommendations for the treatment of TB are summarized in Table 97-2 and Table 97-3. Treatment generally consists of isoniazid (INH) for 9 months. Shorter-course rifampin-based treatment has been shown to be effective in HIV-infected pts. Symptoms are alleviated in most cases within 2–3 weeks, but sputum conversion may take 3 months. Drug resistance is a serious problem and may be either primary (i.e., infection caused by a strain that is resistant before the start of treatment) or acquired (i.e., resistance arising during treatment because the regimen is inadequate or the pt is noncompliant). Rates of resistance to both INH and rifampin (from MDR strains) are generally low in North America and Europe. Immigrants with TB acquired in certain developing areas (e.g., the former USSR, Haiti, Southeast Asia, and many parts of Latin America) commonly have MDR disease. A high index of suspicion, prescription of adequate chemotherapeutic regimens, education of pts, direct observation of therapy, and close and careful follow-up of pts are all crucial in maximizing cure rates and minimizing the spread of MDR strains.

Table 97-2 Dosage Recommendations for Initial Treatment of Tuberculosis in Adultsa

Table 97-3 Recommended Regimens for the Treatment of Tuberculosis

ETIOLOGY   Leprosy (Hansen’s disease), which is caused by M. leprae, is a chronic granulomatous infection that attacks skin and peripheral nerves.
EPIDEMIOLOGY   There are currently 1.5–8 million pts with leprosy worldwide. Leprosy is almost exclusively a disease of the developing world, affecting areas of Asia, Africa, Latin America, and the Pacific. The disease most often affects the rural poor; cases in India, Brazil, Bangladesh, Indonesia, and Myanmar represent >80% of the total. About 100–200 new infections are diagnosed in the U.S. each year. Leprosy can present at any age, but peak onset is in the second and third decades of life. The route of transmission remains uncertain and may be multiple; nasal droplet infection, contact with infected soil, and insect vectors have been considered the prime candidates. The incubation period is usually 5–7 years but may be several decades.
CLINICAL MANIFESTATIONS   The wide spectrum of clinical and histologic manifestations of leprosy is attributable to the variability of the immune response to M. leprae. The spectrum from tuberculoid leprosy to lepromatous leprosy is associated with an evolution from localized to more generalized disease manifestations and an increasing bacterial load. Where a pt presents on the clinical spectrum largely determines prognosis, complications, and the intensity of antimicrobial therapy required.
Tuberculoid Leprosy   At the less severe end of the spectrum is tuberculoid leprosy, which encompasses polar tuberculoid (TT) and borderline tuberculoid (BT) disease. The hallmark of tuberculoid disease is one or a few hypopigmented, sharply demarcated macular lesions that enlarge by peripheral spread, are densely hypesthetic, and have lost sweat glands and hair follicles. Nerves become involved early and may be palpable. Neuritic pain may be prominent. On histologic section, bacilli are frequently absent or difficult to detect. TT leprosy may resolve spontaneously, but BT leprosy does not.
Lepromatous Leprosy   At the more severe end of the leprosy spectrum is lepromatous disease, which encompasses the polar lepromatous (LL) and borderline lepromatous (BL) forms. In lepromatous leprosy, bacilli are numerous in the skin, in peripheral nerves, in the circulating blood, and in all organs except the lungs and the CNS. However, pts remain afebrile and without major organ dysfunction. The initial lesions of lepromatous leprosy are skin-colored or slightly erythematous papules or nodules. New lesions may appear and coalesce. Later, pts present with symmetrically distributed skin nodules, raised plaques, or diffuse dermal infiltration, which, when on the face, results in leonine facies. Late manifestations include loss of eyebrows and eyelashes, pendulous earlobes, and dry scaling skin. Nerve enlargement and damage tend to be symmetric and are more insidious but ultimately more extensive than in tuberculoid leprosy. Pts with LL leprosy have symmetric acral distal peripheral neuropathy. They may also have symptoms related to involvement of the upper respiratory tract (nasal stuffiness, epistaxis, obstructed breathing), the anterior chamber of the eye, and the testes.
DIAGNOSIS   Leprosy should be suspected when a pt from an endemic area has suggestive skin lesions or peripheral neuropathy. The diagnosis should be confirmed by histology. Skin biopsy of lesions is generally diagnostic.

Pts are classified as multibacillary if they have ³5 skin lesions and as paucibacillary if they have <5 skin lesions. The World Health Organization recommends that paucibacillary adults be treated with dapsone (100 mg PO qd) and (under supervision) with rifampin (600 mg PO each month) for 6 months. Multibacillary adults should be treated without supervision with dapsone (100 mg PO qd) plus clofazimine (50 mg PO qd) and under supervision with rifampin (600 mg each month) plus clofazimine (300 mg each month) for 1 year. With effective therapy, lesions of lepromatous leprosy flatten within 2 months and resolve in a few years, while those of tuberculoid leprosy may disappear, improve, or remain unchanged.

Mycobacteria other than members of the M. tuberculosis complex and M. leprae are termed atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), or nontuberculous mycobacteria (NTM). In contrast to M. tuberculosis, NTM are ubiquitous in the environment.
Disseminated NTM Infections in AIDS and Other Immunodeficiencies
ETIOLOGY   The M. avium complex (MAC, consisting of M. avium and M. intracellulare) is a microbiologic designation retained in clinical practice but rendered obsolete by modern molecular diagnostic methods. The majority of mycobacterial infections in immunocompromised hosts in the U.S., including essentially all those formerly attributed to MAC, are caused by M. avium. M. genavense is an occasional cause of similar infections.
EPIDEMIOLOGY AND HOST FACTORS   Infection is probably acquired by the oral route. There is no evidence for nosocomial person-to-person spread. Disseminated infections with NTM almost exclusively affect severely immunosuppressed pts, usually those with AIDS. Rare cases occur in transplant recipients and in pts with leukemia (especially hairy cell leukemia), lymphoma, or certain congenital immunodeficiencies. In pts with AIDS, NTM infection is a late event: AIDS pts whose CD4 cell counts have been <10/µL for 1 year have a 40% probability of having a blood culture positive for NTM.
CLINICAL MANIFESTATIONS   No distinctive diagnostic features exist. Disseminated NTM infection should be suspected on the basis of prolonged fever and weight loss. Abdominal lymphadenopathy and/or hepatosplenomegaly may be evident either clinically or radiographically; diarrhea and abdominal pain may also be present. Anemia and leukopenia are frequent concomitants and may or may not be etiologically related to NTM. Suspicion of the diagnosis should prompt the performance of blood cultures.
DIAGNOSIS   Blood cultures on special media are the cornerstone for the diagnosis of NTM infection. Two or three such cultures are usually sufficient. With the liquid Bactec system, positive results may be obtained within 7–14 d; the detection of M. genavense may require much longer. Acid-fast stains of liver or bone marrow biopsy material may permit a more rapid presumptive diagnosis. The yield of liver biopsy approaches 50% in pts with unequivocally abnormal LFTs but is much lower in pts with negative blood cultures and normal or nearly normal LFTs.

The agents most active against MAC are the macrolides clarithromycin and azithromycin. Monotherapy may lead to resistance and should therefore be avoided. The preferred regimen for treatment of disseminated MAC infection is the combination of clarithromycin (1 g bid), ethambutol (900 mg qd), and rifabutin (300–600 mg qd). Alternative agents include clofazimine, rifampin, ciprofloxacin, and amikacin. It is not clear how long therapy needs to be administered. In pts whose symptoms have lessened, whose blood cultures have become negative, and whose CD4 lymphocyte counts have recovered to >100/µL with HAART, it is reasonable to discontinue antimycobacterial treatment. The best approach to prevention of MAC infections is the prevention and reversal of immunodeficiency by HAART. In pts without an adequate response to HAART and with a CD4 cell count of <100/µL, anti-MAC prophylaxis with rifabutin (300 mg qd), clarithromycin (500 mg qd or bid), or azithromycin (1200 mg weekly) is a reasonable choice.

Localized Infections due to NTM
PULMONARY DISEASE   Preexisting lung disease (e.g., chronic obstructive pulmonary disease, cancer, previous TB, bronchiectasis, cystic fibrosis, or silicosis) is the main predisposing factor for NTM pulmonary disease. The organisms most frequently involved are M. intracellulare, M. avium, and M. kansasii. Accurate identification to the species level is important; both clinical significance and therapeutic strategies differ with the organism. M. avium rarely causes significant pulmonary disease in pts with AIDS. Its isolation from sputum in the absence of radiographic changes is usually without significance. On the other hand, the isolation of M. kansasii, which causes a pulmonary TB-like illness, is clinically significant. Most pts with NTM lung infection present with chronic cough, low-grade fever, and malaise. Hemoptysis may develop. Minimal diagnostic criteria include a pulmonary infiltrate of indeterminate cause and the repeated isolation from sputum of multiple colonies of the same strain of NTM.

Pts with minimal disease do not need treatment. Likewise, solitary nodular NTM disease identified upon surgical resection requires no further treatment. Most other pts with pulmonary NTM disease are treated with antimicrobial agents; they may require surgery as well. The regimens used in therapy for disseminated MAC infection are preferred for the treatment of localized infection with M. avium or M. intracellulare as well. Infection with M. kansasii is treated with INH (300 mg/d), rifampin (600 mg/d), and ethambutol (15– 25 mg/kg qd). Most pts are treated for 18–24 months.

LYMPHADENITIS   This disease occurs most often in children 1–5 years old and is characterized by painless swelling of one node or a group of nodes, with fistulas to the skin. The anterior cervical chain is often affected. M. scrofulaceum and MAC organisms are the most common agents. Once TB has been excluded, the treatment of choice is surgical excision.
SKIN DISEASES   Swimming-Pool and Fish-Tank Granuloma   The causative organism is almost always M. marinum, and the usual incubation period is 2–3 weeks. After contact with a contaminated tropical fish tank, swimming pool, or saltwater fish, a small violet nodule or pustule appears at a site of minor trauma. The lesion may evolve into a crusted ulcer or small abscess. Dissemination may occur. In cases of persistence or dissemination, rifampin (300–600 mg/d) in combination with ethambutol (15–25 mg/kg qd), TMP- SMZ (160/800 mg bid), or minocycline (100 mg/d) may be tried for at least 3 months.
Buruli Ulcer   This entity occurs in the tropics and is due to M. ulcerans. Disease begins as a pruritic nodule, which then ulcerates; the course is prolonged. Excision constitutes the usual therapy.
INFECTIONS LINKED TO INJECTIONS AND SURGERY   Occasionally, mycobacteria are isolated from nodular skin lesions of hospitalized pts, particularly those who are immunosuppressed. Many cases are linked to injections (e.g., in diabetic pts) or follow surgery (e.g., in ophthalmologic or cardiac pts). These infections are usually due to the rapidly growing and notoriously resistant M. fortuitum complex (M. fortuitum, M. chelonae, or M. abscessus). Debridement is best combined with the administration of two or three antimicrobial agents (selected from amikacin, ciprofloxacin, sulfonamides, clofazimine, and clarithromycin).

For a more detailed discussion, see Raviglione MC, O’Brien RJ: Tuberculosis, Chap. 169, p. 1024; Gelber RH: Leprosy (Hansen’s Disease), Chap. 170, p. 1035; and Hirschel B: Infections due to Nontuberculous Mycobacteria, Chap. 171, p. 1040, in HPIM-15.


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