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Author: John Ross, M.D.
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1. Pathogenesis

Infection with M. tuberculosis is usually acquired from inhalation of tiny airborne droplets (“droplet nuclei”) or free-floating bacilli. Droplet nuclei arise from the cough of an infected person. Because of their small size, the droplets remain suspended in air for hours. Rarely, TB is acquired from a draining wound, at autopsies, or by ingestion of contaminated milk.

Infectivity is greatest in patients with cavitary disease. (Cavities contain huge numbers of bacteria, up to 109 bacilli. This huge burden of organisms is why combination therapy must be given for several months to prevent resistance.) A positive “acid-fast” (Ziehl-Neelsen) stain is a sensitive test for infectivity. Patients with negative sputum smears are not infectious and need not be isolated. (Occasional patients with early TB may have negative smears, but positive cultures.)

Primary infection arises after droplet inhalation, usually into a lower lobe (because lower lobes are better ventilated than upper lobes). When an alveolar macrophage ingests a bacillus, it may be able to destroy it. If not, the bacillus multiplies in the macrophage, which bursts, and infection spreads to the regional lymphatics. From there, bacilli may jump into the bloodstream (“silent bacillemia”), establishing latent tuberculosis foci throughout the body, which can persist for decades. These foci may reactivate later, especially in areas of high oxygen tension, such as the lung apices, kidneys and meninges. All this occurs with few or no symptoms.

As the weeks pass, cell-mediated immunity (CMI) develops, with granuloma formation. One manifestation of CMI is the delayed cutaneous hypersensitivity reaction to purified protein derivative from killed organisms, the “PPD test”.

The vast majority (95%) of patients will contain the infection through CMI. A small proportion, mainly neonates, the very elderly, or immunosuppressed, will suffer from progressive primary infection – either primary TB pneumonia, or disseminated (miliary) disease. About 25% of those who suppress the infection will show a healed “Ghon complex” on chest x-ray (a calcified scar in the lung parenchyma as well as the regional lymph node).

Of all infected persons, about 4-8% will experience recrudescence of the TB infection at some time after the primary infection – with about half of these recrudescences occurring in the first year after infection. (That is why recent contact with a person with active TB or recent skin test conversion are strong indications for giving INH prophylaxis.) The other half will have their recrudescence at some later date, usually when CMI is diminished because of old age, steroids, anti-TNF blockers, or other medical conditions.

Recrudescence usually occurs at sites seeded during the silent bacillemia, especially the apex of the lung.The most common presentation of TB is an apical lung infiltrate, often with fibrosis and cavitation. Pathologically, reactivation TB is characterized by caseating necrosis within granulomas. Liquefaction of caseation necrosis forms cavities containing enormous numbers of TB bacilli. In these patients, CMI causes tissue damage to the host, without being robust enough to contain TB infection.

The symptoms of TB are mainly caused by cytokine release as a result of CMI, namely, fever, sweats, weight loss, as well as symptoms from local inflammation (cough, hemoptysis, bone pain, etc). Highly immunosuppressed patients may have few symptoms. Moreover, symptoms in immunocompetent patients may be relieved by the administration of drugs that suppress CMI, such as corticosteroids.

The diagnosis of TB should be suspected on the basis of typical symptoms (prolonged cough, fever, night sweats, weight loss, hemoptysis, apical lesion on chest x-ray) – and the suspected patient should be placed in isolation until the diagnosis is made or disproven. TB is prevalent in certain populations (see slide titled High Risk Populations). Among foreign-born persons, active TB usually arises from infection acquired years earlier. Among US-born persons, it often indicates recent infection.

The tuberculin skin test indicates past infection, not active disease. It is negative in infected patients who have defective CMI for any reason, and in 10-20% of infected patients for no apparent reason. It is most useful for detecting “latent” TB infection (LTBI). By contrast, the diagnosis of active tuberculosis is best made by identifying acid-fast bacteria (by smear or culture) in bodily samples or by demonstrating granulomas (preferably with caseation) on biopsies. However, other diseases may cause granulomas and some other microbes are acid-fast so that, short of actually growing the microorganisms in culture, the diagnosis must be made on the basis of high probability rather than proof.

Interpretation of a positive PPD in the patient with suspected latent TB is complicated and depends on the a priori likelihood of TB and the presumed ability of the patient to mount a delayed hypersensitivity reaction. As little as 5 mm of induration is indicative of latent TB in HIV-infected patients, close contacts of patients with active TB, patients with upper lobe scarring, or patients on chronic prednisone. Ten mm is required in patients with moderate risk of exposure (born in endemic area, homeless, injection drug user, health care worker) or some potential impairment of CMI (steroids, malnutrition, certain medical illnesses such as ESRD, DM). Other patients should not be tested at all or, if tested, require 15 mm of induration to qualify as having latent TB.

2. Extrapulmonary TB

One general feature of extrapulmonary TB is that AFB (acid-fast bacilli) are scanty, compared to cavitary TB. AFB are often not seen on biopsy or grown on culture, so the diagnosis is often presumptive, based on the clinical syndrome, presence of granulomas on biopsy, and PPD positivity. Only about 50% of patients with extrapulmonary TB have simultaneous active pulmonary TB. Although TB may affect any organ, some extrapulmonary presentations are characteristic.

Cervical lymphadenitis (scrofula): painless lymph node swelling in the neck; may lead to purulent drainage; less than 20% are systemically ill; more common in women by a 2:1 ratio (pulmonary TB somewhat more common in men); PPD usually strongly positive.

Renal TB: suspect in patients with sterile pyuria and renal calcification; dysuria and hematuria common; most are afebrile.

Peritoneal TB: may mimic ovarian cancer, or carcinomatous peritonitis, with numerous peritoneal implants; may occur in “wet” or “dry” forms (with or without ascites); diagnosis may be missed in alcoholics. Very low yield of peritoneal fluid AFB stains, diagnosis usually made by biopsy of implants.

Meningeal TB: subacute onset of fever and headache in adults; lymphocytic pleocytosis in CSF; basilar meningitis with cranial nerve palsies. TB in the CNS may also present as a ring-enhancing cerebral mass lesion (“tuberculoma”).

Vertebral TB (Pott’s disease of the spine): usually affects thoracic spine, perhaps because of lymphatic drainage from chest; associated with large paravertebral “cold” abscess, which may track along the psoas muscle. May result in severe spinal deformity (as in the poet Alexander Pope).

3. TB and HIV

TB in the USA declined steadily from the 1930s until the mid-1980s (because of public health measures and rising living standards, as well as anti-TB drugs), but then began to rise, because of the HIV epidemic and misguided public health budget-cutting. TB resistant to multiple drugs also appeared. Because of increased public health measures (including “directly-observed therapy” for TB) the disease is falling again.

Whereas the incidence of active TB in immunocompetent infected patients is about 4-8% over a lifetime, that in HIV patients is about 8% per year! Because it is a virulent infection, TB often affects patients with HIV early in their HIV disease (unlike true opportunistic infections which present when the CD4 count has dwindled). Moreover, TB in HIV-infected patients often presents in extrapulmonary locations.

4. “Atypical” mycobacterial infections

There are numerous “atypical” mycobacterial species. In contrast to M. tuberculosis, they arise from environmental sources, and are not spread from person to person.Patients with these infections do not have to be isolated. They may not respond to therapy for typical TB.

4.1. Atypical mycobacterial species.

4.1.1. M. marinum

M. marinum (“fish tank granuloma” or “swimming pool granuloma”) usually presents as a slow-growing, indurated skin infection, especially in fish fanciers. (For unclear reasons, this pathogen is a favorite on board examinations.) Clarithromycin or minocycline are preferred.

4.1.2. M. avium intracellulare

M. avium intracellulare (called MAC or MAI) causes disseminated infection in advanced AIDS, but may also mimic TB in immunocompetent patients with chronic obstructive pulmonary disease (COPD).

4.1.3. M. fortuitum and M. chelonae

While most mycobacteria grow slowly in the lab (taking weeks to form colonies), some are “rapid growers”, such M.fortuitum and M. chelonae.M. fortuitum was recently implicated in outbreaks of soft tissue infection associated with nail salons

5. Ancillary Material

5.1. Readings

5.1.1. Required

  • Schaechter Textbook, Chapter 23, pages 230-240

5.1.2. Recommended

  • Jasmer RM, Nahid P, Hopewell PC. Latent tuberculosis infection. New Eng J Med 2002; 347:1860-66.
  • Geng E, Kreiswirth B, Driver C, et al. Changes in the transmission of tuberculosis in New York City from 1990- 1999. New Eng J Med 2002; 346:1453-8.
  • Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. New Eng J Med 1999; 340:367-73.
  • Horsburgh CR. Priorities for the treatment of latent tuberculosis infection in the United States. New Engl J Med 2004; 350:2060-7.