Return of the White Plague

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Return of the White Plague

• Tuberculosis and Environmental Mycobacteria

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Mycobacteria

• Obligate pathogens
• Mycobacterium tuberculosis
• Mycobacterium bovis
• Mycobacterium leprae
• Saprophytes, opportunistic pathogens
• Mycobacterium avium complex
• others

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Biology of the Mycobacteria
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Bacterial Cell Walls

• Gram Gram -

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Unusual Cell Walls

• Very thick outer lipid layer
• Slow nutrient exchange
• Slow growth

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Ziehl-Neelsen Smear

• Acid-fast stain for Mycobacteria

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TB Culture

• Slow-growing on simple medium enriched with lipids

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Ecology of TB
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TB can infect many organs

• Respiratory lungs
• Skeletal bowed spine
• Scrofula neck swelling, open sores
• Erythema multiformae skin lesions
• Organ lesions

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Symptoms of TB Infection

• Sensation of not feeling well
• Cough, at first with yellow or green mucus and
  occasionally bloody later in the disease.
• Fatigue
• Shortness of breath
• Weight loss
• Slight fever, night sweats
• Pain in the chest, back, or kidneys, and perhaps
  all three

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TB Transmission

• Active pulmonary TB can be transmitted via
  droplets usually requires prolonged contact

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Zoonotic TB

• TB can also be transmitted in meat and milk from
  infected cattle in countries without meat
  inspection programs.

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TB in History

• In the 1700s-1800s, more people in cities
• Consumption was thought to be a sign of
  artistic temperament

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Famous People Who Died of TB

• King Tutankhamen
• John Keats
• Elizabeth Barrett Browning
• Edgar Allan Poe
• Frederic Chopin
• Ralph Waldo Emerson
• Emily Bronte
• Robert Louis Stevenson
• Eleanor Roosevelt
• George Orwell
• Vivien Leigh

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TB in History

• In the 1900s, patients were treated with fresh
  air and sunshine in sanatoria

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20th Century Screening and Antibiotics
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Mycobacteria Evade Immune Elimination

• Mycobacteria are engulfed by macrophages but
  resist fusion of the lysosome with the phagosome

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Activated Macrophages

• Activated Macrophages kill Mycobacteria more
  efficiently and also secrete cytokines to
  attract more macrophages

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TB Pathology

• Formation of granulomas T cells and macrophages

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TB Pathology

• Area inside granuloma fills with dead cells
  caseous necrosis
• May get calcification tubercles

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How is TB Diagnosed?

• Mantoux test memory T cells
• Chest x-ray tubercles
• Identification or isolation of Mycobacterium
  tuberculosis from sputum

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TB Skin Test

• Injected PPD (purified protein derivative
  tuberculin) under skin
• Wait 48-72 hours to read test

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Measure the Diameter

• gt 5mm is positive indicates exposure

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TB Chest X-Ray
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TB Infection vs. Disease
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WHO TB Data 2004
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TB Case Rates US
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US-born vs. Foreign-born
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Countries of Origin
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HIV/TB Co-infection
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TB/HIV Mortality Worldwide
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Risk Factors for TB

• Recent M. tuberculosis infection
• HIV infection
• Immune suppression
• Diabetes or end stage renal disease
• Severe malnutrition
• Substance abuse

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Treatment of Tuberculosis

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol
• Streptomycin
• Combination of drugs (cocktail) for 6-24 months

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TB Drug Resistance

• Mycobacteria develop resistance to antibiotics,
  especially when single drugs are given

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Completion of Therapy
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Direct Observed Therapy
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Mycobacterium bovis

• Infects cattle, wild animal reservoirs (badger in
  UK, possums in New Zealand)
• When transmitted in milk, most common symptoms
  are scrofula, abdominal pain, and skin lesions
• Can be transmitted by cough of cow ?pulmonary TB

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Scrofula (Lymphadenitis)
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M. bovis

• Disease caused by M. bovis indistinguishable from
  that caused by M. tuberculosis
• Relative incidence of each unknown in developing
  countries
• Biggest problem in large (gt 5,000) crowded dairy
  herds

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M. bovis

• Transmission in milk eliminated by pasteurization
• Eliminated from herds by test and slaughter
  policy
• Development of vaccine

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Vaccination with BCG

• Bacillus Calmette Guerin is a Mycobacterium bovis
  strain
• Given to infants, prevents spread of M. tb. in
  body but not infection
• Effectiveness in adults variable
• Causes positive tuberculin skin test
• Not used in US

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BCG and Cancer

• Used as adjuvant therapy for early stage bladder
  cancer
• Infused into bladder
• Thought to attract antigen-presenting cells and T
  cells to kill cancer cells

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Ecology of Leprosy
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Leprosy Hansens Disease

• And the leper in whom the plague is, his
  clothes shall be rent, and the hair of his head
  shall go loose, and he shall cover his upper lip,
  and shall cry, unclean, unclean. And all the days
  wherein the plague is in him he shall be unclean
  he is unclean he shall dwell alone without the
  camp shall his dwelling be. (Leviticus)

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Leprosy in the Middle Ages

• Within the church let a black cloth . . . be set
  upon two trestles at some distance apart before
  the altar, and let the sick man take his place on
  bended knees beneath it between the trestles,
  after the manner of a man dead . . . and in this
  posture let him devoutly hear mass . . . The
  priest then with the spade cast earth on each of
  his feet saying "Be thou dead to the world, but
  live again unto God."

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Leprosy in Hawaii
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Leprosy in Carville LA
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Leprosy in Carville LA

• December 2000 remaining patients protest
  proposed closure of residential facility at
  Carville.

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Leprosy Hansens Disease

• M. leprae infects skin, mucous membranes and
  peripheral nerves
• 12 million cases worldwide
• In US Louisiana, Hawaii, Florida, New York, and
  Puerto Rico

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Leprosy Incidence Worldwide
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Tuberculoid Leprosy

• Few skin lesions
• Severe peripheral nerve damage
• Organisms present at low levels
• Low infectivity
• Strong Th1 response to M. leprae antigens

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Lepromatous Leprosy

• Many skin lesions
• Damage to facial cartilage and bone
• Symmetrical peripheral nerve damage and
  anesthesia
• High infectivity

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Lepromatous Leprosy

• Many Mycobacteria in macrophages
• High serum antibody levels
• Low Th1 response to M. leprae
• Th2 response ? humoral immunity (not protective)

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Th1 and Th2 Cytokines
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Banded Armadillo
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Treatment of Leprosy

• Susceptible to antibiotics (dapsone, rifampin,
  clofazamine)

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Ecology of Environmental Mycobacteria
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Environmental (Atypical, Nontuberculous)
Mycobacterial Infections

• Not obligate pathogens opportunistic
  saprophytes
• Resistant to disinfection, acid, bile salts
• Incidence increased in AIDS and other
  immunosuppressed conditions
• More often diagnosed due to more sensitive
  cultures

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Atypical Mycobacterial Infections

• Mycobacterium avium complex (MAC)
• M. avium-intracellulare
• M. kansasii
• M. marinum
• M. ulcerans
• others

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Environmental Reservoirs

• Water natural, water systems, hot tubs,
  swimming pools
• Soil
• Protozoans
• Animals
• Humans

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Interactions with Protozoans

• M. avium, M. fortuitum, M. marinum survive inside
  Acanthamoeba
• Inhibit lysosomal fusion
• May kill protozoan
• Survive encystment and may use cysts to survive
  starvation and toxic stresses

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M. avium

• M. avium in Acanthamoeba trophozoites

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Human Exposure

• Drinking, swimming, bathing
• Aerosols
• Dust
• Foods

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Human Infections

• Cervical lymphadenitis (children)
• Hypersensitivity pneumonitis (occupational and
  hot tubs)
• Skin abscesses
• Septic arthritis
• Osteomyelitis
• Lung disease
• Mostly transient and asymptomatic

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Other Diseases and Conditions?

• M. avium paratuberculosis associated with Johnes
  disease in ruminants
• Crohns disease (inflammatory bowel disease) in
  humans?

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Other Diseases and Conditions?

• Allergies? Th2 responses
• Reduced exposure to environmental Mycobacteria
  that generate a Th1 response?

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Other Diseases and Conditions?

• Interference with BCG vaccination?
• In mice, M. avium and others shown to block BCG
  replication and prevent immunization

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Other Diseases and Conditions?

• Cross protection in rural Malawi between
  environ-mental Myco-bacteria and TB

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Key Concepts

• Explain how the cell wall structure of
  Mycobacteria contributes to their human
  pathogenicity and virulence.
• Describe the interaction of Mycobacteria with the
  host immune system and how Mycobacteria use the
  macrophage as a survival site.

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Key Concepts

• Describe the connection between the Th immune
  response and the prognosis for TB or leprosy.
• Discuss the origin and problems with MDR TB.
• Discuss the factors that have led to an increased
  incidence of environmental Mycobacterial
  infections.