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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

Tuberculosis and other Mycobacterial Infections

Charles S. Bryan, M.D.

November 27, 2007

tuberculosis current problems
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
number and percentage of cases of tb among foreign born persons by year of diagnosis usa 1986 2003
Number and percentage of cases of TB among foreign-born persons, by year of diagnosis, USA, 1986-2003
mycobacterium tuberculosis
Mycobacterium tuberculosis
  • 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
tuberculosis the basics
Tuberculosis: the basics
  • 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
tuberculosis the basics 2
Tuberculosis: the basics (2)
  • 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
immunology of tuberculosis
Immunology of tuberculosis
  • 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
immunology of tuberculosis 2
Immunology of tuberculosis (2)
  • 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)
primary tuberculous infection
Primary tuberculous infection
  • 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
reactivation of tuberculosis
Reactivation of tuberculosis
  • 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
residua of primary infection
Residua of primary infection
  • 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”
axioms on simon foci
Axioms on Simon foci
  • “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.”
progression to active tuberculosis
Progression to active tuberculosis
  • 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
insights from genotyping of m tuberculosis isolates n engl j med 2003 349 1149 1155
Insights from genotyping of M. 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.
the cavity 1
The cavity (1)
  • 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.
the cavity 2
The cavity (2)
  • 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.
complications of pulmonary tuberculosis
Complications of pulmonary tuberculosis
  • 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)
major syndromes of extrapulmonary tuberculosis
Major syndromes of extrapulmonary tuberculosis
  • 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
miliary tuberculosis diagnostic aids
Miliary tuberculosis: diagnostic aids
  • 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
cryptic miliary tuberculosis
“Cryptic miliary tuberculosis”
  • An occult illness with gradual decline in general health
  • Often no significant fever
  • Non-reactive tuberculin skin test
  • Normal chest x-ray
frequency order of extrapulmonary sites

Frequency order of extrapulmonary sites

1. Lymph node

2. Pleura

3. Genitourinary tract

4. Bone and joints

5. Meninges

6. Peritoneum

tuberculous pleurisy
Tuberculous pleurisy
  • 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)
tuberculous meningitis
Tuberculous meningitis
  • 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
tuberculous pericarditis
Tuberculous pericarditis
  • 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
tuberculous peritonitis
Tuberculous peritonitis
  • 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
tuberculous arthritis
Tuberculous arthritis
  • 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
genitourinary tuberculosis
Genitourinary tuberculosis
  • 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
tuberculous osteomyelitis
Tuberculous osteomyelitis
  • 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
tuberculosis of the adrenal glands addison s disease
Tuberculosis of the adrenal glands (Addison’s disease)
  • 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
tuberculosis in hiv positive patients
Tuberculosis in HIV-positive patients
  • 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
afb smears
AFB smears
  • 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)
tuberculin skin test guidelines
Tuberculin skin test guidelines
  • 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
rapid laboratory confirmation
Rapid laboratory confirmation
  • 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
why was it possible to eradicate smallpox
Why was it possible to eradicate smallpox?
  • Visible stigmata of the disease
  • No inapparent reservoir
  • No chronic phase
  • Nearly 100% effective vaccine
nontuberculous mycobacteria ntm
Nontuberculous mycobacteria (NTM)
  • Synonyms: atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), nontuberculous mycobacteria (NTM)
  • Numerous species; widespread
  • Can be difficult to treat
  • “MAC” = M. avium-intracelluare complex
pulmonary disease due to ntm in immunocompetent persons
Pulmonary disease due to NTM in immunocompetent persons
  • 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)
mycobacterium avium intracelluare mac in hiv disease
Mycobacterium avium-intracelluare (“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
lymphadenitis due to ntm
Lymphadenitis due to NTM
  • Usually due to M. scrofulaceum or M. avium-intracelluare
  • “Scrofula”: cervical lymphadenitis, usually in children
  • Usual treatment of choice: surgical excision without chemotherapy
swimming pool and fish tank granuloma
Swimming pool and fish-tank granuloma
  • 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
infections related to injections or surgery
Infections related to injections or surgery
  • “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
leprosy hansen s disease
Leprosy (Hansen’s disease)
  • 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
tuberculoid leprosy
Tuberculoid leprosy
  • 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
lepromatous leprosy
Lepromatous leprosy
  • 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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