Tuberculosis and other mycobacterial infections
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Tuberculosis and other Mycobacterial Infections. Charles S. Bryan, M.D. November 27, 2007. Tuberculosis: current problems. About 3.8 million cases per year; 90% (and 98% of the 3 million deaths) are in developing countries Multidrug resistance (“MDR-TB”)

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Tuberculosis and other mycobacterial infections l.jpg

Tuberculosis and other Mycobacterial Infections

Charles S. Bryan, M.D.

November 27, 2007


Tuberculosis current problems l.jpg
Tuberculosis: current problems

  • About 3.8 million cases per year; 90% (and 98% of the 3 million deaths) are in developing countries

  • Multidrug resistance (“MDR-TB”)

  • AIDS: atypical presentations and distribution

  • Nosocomial spread

  • Foreign-born



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Number and percentage of cases of TB among foreign-born persons, by year of diagnosis, USA, 1986-2003


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TB incidence among five racial/ethnic populations, USA, 2003 persons, by year of diagnosis, USA, 1986-2003


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Mycobacterium tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • An obligate aerobe: prefers P02 of 130 torr

  • Replicates every 20 hours

  • Natural resistance to one drug is one in every 105 to 107 cells

  • Natural resistance to two or more drugs is 1 in every 109 to 1012 cells


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Tuberculosis: the basics persons, by year of diagnosis, USA, 1986-2003

  • The Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum

  • Transmitted primarily by airborne droplet nuclei

  • Persons with positive AFB sputum smears are especially effective transmitters

  • Between 5% and 15% of infected persons will develop active disease (involving any organ) within two years


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Tuberculosis: the basics (2) persons, by year of diagnosis, USA, 1986-2003

  • Populations at increased risk of infection: medically-underserved, low-income groups; immigrants; residents of long-term care or correctional facilities

  • Infected persons with increased risk of active disease: close contacts of cases; children < 5 years old; persons with chronic diseases (renal failure; silicosis; diabetes); immunosuppressed; HIV-positive persons


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Immunology of tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • Tubercle bacillus + macrophages --> processed antigen

  • Antigen recognition by lymphocytes --> activated lymphocytes --> lymphokines

  • Lymphokines--> attraction, stimulation, and retention of macrophages at antigen site

  • Activated macrophages--> lytic enzymes with mycobactericidal but also tissue-necrosing capacity


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Immunology of tuberculosis (2) persons, by year of diagnosis, USA, 1986-2003

  • Interferon-gamma probably stimulates macrophages to produce interferon-alfa and 1,25-dihydroxyvitamin D, both of which are mycobacterial inhibitors

  • Cytokines secreted by alveolar macrophages: interleukin 1 (fever); interleukin 6 (hyperglobulinemia), and tumor necrosis factor alpha (killing of organisms, granuloma formation, fever and weight loss)


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Pathogenesis of tuberculosis persons, by year of diagnosis, USA, 1986-2003


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Primary tuberculous infection persons, by year of diagnosis, USA, 1986-2003

  • Inhalation leads to infection at periphery of middle lung zone

  • Pneumonia 2 to 6 weeks after infection followed by lymphohematogenous dissemination

  • Cell-mediated immunity (manifested by positive PPD) usually contains the infection

  • Some organisms remain viable


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Reactivation of tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • Occurs most often in persons > 50 years of age; more common in men

  • Higher risk in elderly persons and in those with malnutrition, diabetes mellitus, post-gastrectomy, immunocompromise, alcoholism, HIV infection, or corticosteroid therapy


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Residua of primary infection persons, by year of diagnosis, USA, 1986-2003

  • Ghon complex (after Anton Ghon, German bacteriologist): calcified peripheral focus of tuberculous infection with calcified regional (hilar) lymph node (also called Ranke complex)

  • Simon focus (after Georg Simon, German pediatrician): focus at apex of lung, containing viable organisms and manifested on x-ray as “fibrous cap”


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Axioms on Simon foci persons, by year of diagnosis, USA, 1986-2003

  • “If humans did not have apices to their lungs, the tubercle bacillus would not have survived as a human pathogen.”

  • “Once a Simon focus has formed, one will eventually die of tuberculosis if something else doesn’t cause death first.”


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Progression to active tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • One year after infection: approximately 5%

  • Thereafter: approximately 5% (lifetime)

  • It now seems that many people eventually outlive their tubercle bacilli and are consequently vulnerable to reinfection (Stead, studies in Arkansas, early 1980s)

  • Tuberculin-positive persons with HIV infection: risk is 7% to 10% per year


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Insights from genotyping of persons, by year of diagnosis, USA, 1986-2003M. tuberculosis isolates (N Engl J Med 2003; 349: 1149-1155)

  • Previously, it was thought that 90% of TB cases in industrialized nations resulted from reactivation of infection acquired in remote past.

  • It now seems that recent transmission causes 40% to 50% of TB cases in urban areas.


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The cavity (1) persons, by year of diagnosis, USA, 1986-2003

  • Formation of the cavity is the pivotal event in the evolution of pulmonary tuberculosis.

  • Mortality of cavitary pulmonary tuberculosis without treatment approaches 90%.

  • All therapies prior to 1948 were aimed at closing cavities.


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The cavity (2) persons, by year of diagnosis, USA, 1986-2003

  • Even healed, cavities are unstable.

  • The walls of cavities contain extensive sheets of bacilli (up to 1011 bacilli/gram).

  • The cavity is thinnest at the point of penetration of bronchi.

  • Open cavities may persist for years, constantly draining bacilli into the rest of the bronchial tree.


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Complications of pulmonary tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • Cough, fever, night sweats, weight loss, anemia

  • Massive hemoptysis (erosion of a vessel in the wall of a cavity; a dilated vessel in a cavity (Rasmussen’s aneurysm; or an aspergilloma)

  • Progressive pulmonary disease, rarely ARDS

  • Hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH)


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Major syndromes of extrapulmonary tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • Disseminated (miliary) tuberculosis

  • “Serosal” tuberculosis (anatomic spaces or cavities): pleurisy, pericarditis, meningitis, peritonitis, arthritis

  • Tuberculosis of solid organs: renal (genitourinary), osteomyelitis, adrenal glands (Addison’s disease), lymph nodes


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Miliary tuberculosis: diagnostic aids persons, by year of diagnosis, USA, 1986-2003

  • Repeat physical examination: choroidal tubercles, palpable lymph nodes

  • Repeat CXR and tuberculin test

  • Cultures: sputum (up to 63% positive), urine, bone marrow, CSF, gastric aspirate, pleural fluid

  • Biopsy: palpable nodes, marrow, liver

  • Therapeutic trial


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“Cryptic miliary tuberculosis” persons, by year of diagnosis, USA, 1986-2003

  • An occult illness with gradual decline in general health

  • Often no significant fever

  • Non-reactive tuberculin skin test

  • Normal chest x-ray


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Frequency order of extrapulmonary sites persons, by year of diagnosis, USA, 1986-2003

1. Lymph node

2. Pleura

3. Genitourinary tract

4. Bone and joints

5. Meninges

6. Peritoneum


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Tuberculous pleurisy persons, by year of diagnosis, USA, 1986-2003

  • Subpleural focus ruptures into the pleural space

  • Usually younger adults, 3 to 7 months after primary tuberculous infection

  • Abrupt or insidious onset. DDx: pneumonia, pulmonary infarct, tumor, others

  • Natural history untreated: 65% of 141 patients developed active tbc (Roper & Waring)


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Tuberculous meningitis persons, by year of diagnosis, USA, 1986-2003

  • Rupture of subependymal tubercle into subarachnoid space (“Rich focus”; Rich and McCormack, 1933)

  • The intrathecal tuberculin reaction (instillation of PPD material into CSF of PPD-positive volunteers)

  • Usually occurs within first 6 months of infection; now seen in older adults


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Tuberculous pericarditis persons, by year of diagnosis, USA, 1986-2003

  • Rupture of a tuberculous mediastinal lymph node into the pericardial sac

  • Mortality 80% to 90% without treatment. Major problems even with appropriate Rx

  • Diagnosis is difficult to make short of total pericardiectomy

  • Constrictive pericarditis

  • Can extend into myocardium --> fiber atrophy


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Tuberculous peritonitis persons, by year of diagnosis, USA, 1986-2003

  • Onset is usually insidious. Mortality 45% to 55% untreated but as low as 0% to 4% with treatment

  • Polar types: plastic or adhesive type (“doughy abdomen”) and exudative or serous peritonitis with ascites

  • Presentations: debilitating FUO; chronic abdominal pain; ascites of unknown origin


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Tuberculous arthritis persons, by year of diagnosis, USA, 1986-2003

  • Tuberculous focus in bone ruptures into joint space; trauma predisposes

  • Adults: spine 50%, hips 15%

  • Children: Knees 15%

  • Insidious joint pain and swelling, most often involving large weight-bearing joints

  • Absence of proteolytic enzymes explains preservation of joint space


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Genitourinary tuberculosis persons, by year of diagnosis, USA, 1986-2003

  • Tubercle of the glomerulus ruptures into the calyceal system

  • May progress to involve the entire kidney (“autonephrectomy”) and/or may spread throughout the GU tract (prostatitis, epididymitis, salpingitis)

  • Insidious onset


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Tuberculous osteomyelitis persons, by year of diagnosis, USA, 1986-2003

  • Subchondral osteoporosis with surrounding ring of sclerosis

  • Spine: anterior involvement of vertebral bodies with disk collapse (Pott’s disease)

  • Suspect: Monoarticular arthritis of insidious onset; paraspinous mass; back pain


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Tuberculosis of the adrenal glands (Addison’s disease) persons, by year of diagnosis, USA, 1986-2003

  • Tuberculosis formerly the major cause of the disease as described by Thomas Addison (now rare; most common cause is idiopathic [autoimmune])

  • Wasting, hyperpigmentation, low blood pressure, hyponatremia, hyperkalemia


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Tuberculosis in HIV-positive patients persons, by year of diagnosis, USA, 1986-2003

  • Present in 5% to 35% of patients diagnosed with AIDS

  • Precedes diagnosis of AIDS in 67% of patients

  • Although most of these cases result from reactivation, CXR often resembles progressive primary tuberculosis

  • Multiple drug resistance a major problem


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AFB smears persons, by year of diagnosis, USA, 1986-2003

  • Three morning specimens

  • Fluorescent methods are more sensitive than traditional Kinyoun or Ziehl-Neelsen method

  • Predictive value of a positive test decreases strikingly as prevalence of the disease decreases (Bayes’ s theorem)


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Tuberculin skin test guidelines persons, by year of diagnosis, USA, 1986-2003

  • 5 mm for close contacts; for persons with compatible chest x-rays; and for HIV-infected persons

  • 10 mm for recently-infected persons, persons with high-risk medical conditions, and high-risk patients under 35 years of age

  • 15 mm for low-risk persons under age 35


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Rapid laboratory confirmation persons, by year of diagnosis, USA, 1986-2003

  • Fluorochrome smear on concentrated specimens

  • Rapid methods of detection: Bactec system; polymerase chain reaction

  • Rapid mechanisms of identification: DNA probes; HPLC

  • Rapid methods of susceptibility testing

  • Handle reports as critical laboratory values


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Why was it possible to eradicate smallpox? persons, by year of diagnosis, USA, 1986-2003

  • Visible stigmata of the disease

  • No inapparent reservoir

  • No chronic phase

  • Nearly 100% effective vaccine


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Nontuberculous mycobacteria (NTM) persons, by year of diagnosis, USA, 1986-2003

  • Synonyms: atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), nontuberculous mycobacteria (NTM)

  • Numerous species; widespread

  • Can be difficult to treat

  • “MAC” = M. avium-intracelluare complex


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Pulmonary disease due to NTM in immunocompetent persons persons, by year of diagnosis, USA, 1986-2003

  • Isolation of organism from sputum does not necessarily imply disease

  • M. avium-intracelluare (especially in the Southeast) and M. kansasii (especially in the west) cause disease resembling tuberculosis (clinically milder but more difficult-to-treat)


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Mycobacterium avium-intracelluare persons, by year of diagnosis, USA, 1986-2003(“MAC”) in HIV disease

  • Disseminated “MAC” infection with or without pulmonary involvement

  • Prolonged fever, weight loss, hepatosplenomegaly, diarrhea, abdominal pain

  • Positive blood cultures; AFB also found in bone marrow, liver, and often stool


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Lymphadenitis due to NTM persons, by year of diagnosis, USA, 1986-2003

  • Usually due to M. scrofulaceum or M. avium-intracelluare

  • “Scrofula”: cervical lymphadenitis, usually in children

  • Usual treatment of choice: surgical excision without chemotherapy


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Swimming pool and fish-tank granuloma persons, by year of diagnosis, USA, 1986-2003

  • Caused by Mycobacterium marinum

  • Small violet nodule or pustule at the site of minor trauma may evolve into crusted ulcer or abscess

  • Multiple lesions can resemble lymphocutaneous sporotrichosis


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Infections related to injections or surgery persons, by year of diagnosis, USA, 1986-2003

  • “M. fortuitum complex”: Mycobacterium fortuitum, M. chelonae, M. abscessus (all “rapidly-growing mycobacteria”)

  • Opportunistic pathogens causing wound infections (which can be epidemic) and skin infections


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Leprosy (Hansen’s disease) persons, by year of diagnosis, USA, 1986-2003

  • A chronic granulomatous infection attacking superficial tissues, especially the skin and peripheral nerves

  • M. leprae has not been successfully cultured. It can be propagated in armadillos and in the footpads of mice

  • Phenolic glycolipid I binds to C3 which mediates phagocytosis by macrophages


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Tuberculoid leprosy persons, by year of diagnosis, USA, 1986-2003

  • Delayed hypersensitivity to M. leprae antigens is present (in contrast to lepromatous leprosy)

  • Large, erythematous, anesthetic plaques with flat, dry, hairless centers and raised outer edges

  • Limited but severe involvement of peripheral nerves


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Lepromatous leprosy persons, by year of diagnosis, USA, 1986-2003

  • Anergy to M. leprae antigens

  • B-cell over-activity: polyclonal hyperimmunoglobulinemia with many unusual antibodies (e.g., false-positive VDRL [RPR]; secondary amyloidosis)

  • Massive infiltration of dermis--> leonine facies

  • Nerve involvement is diffuse but less severe than in tuberculoid form


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