Case 5: Tuberculosis

1
Case 5 Tuberculosis

• Monica D. Mead
• ITD 5215
• August 18, 2004

2
Case Presentation

• A 68-year old man presented with
• Weight loss over a 4-month period
• Recent onset of fever/chills at night
• Chest x-ray upon admission revealed irregular
  opacity of right lung with pleural effusion
• Thoracocentesis of pleural fluid revealed
  adenocarcinoma
• Hepatomegaly with diffuse lymphadenopathy
• Hyperkalemia and hypocalcemia (ion imbalance)
• Fever did not respond to antibiotics and the
  patient dies four days after admission.

3
Left lung, caseous necrosis

• Histological stain shows hallmarks of TB
  infection
• Granulomas
• Caseous necrosis (most frequently the lung)
• Giant cells

4
Tuberculosis-Acid fast stain of M. tuberculosis

• Direct person-to-person contact via transmission
  of airborne droplets containing Mycobacterium
  tuberculosis (high content of complex lipids)
• More prevalent in developing countries
• Seen in US amongst the elderly and
  immunosuppressed individuals (adenocarcinoma)

5
Tuberculosis-Pathology

• M. tuberculosis infects host alveolar macrophage
  endosome and inhibits microbicidal response
  allowing for uninhibited proliferation ?
  bacteremia ? seeding of multiple sites (patients
  are asymptomatic)
• 3 weeks post-exposure ? cell-mediated immunity
  when processed M. tuberculosis antigens reach
  draining lymph nodes and are presented my
  macrophages to CD4 T cells ? TH1 sub-type
  cytotoxic T cells that kill infected macrophages
  ?Chronic inflammation
• End result Granulomas with hypersensitivity and
  host resistance with caseous necrosis of
  destroyed tissues

6
Characteristics of Chronic Inflammation

• Nature of response
• Mononuclear cell infiltrate
• Macrophages, once activated, secrete acid/neutral
  proteases, complement components, coagulation
  factors, ROS, NO, eicosanoids and cytokines
  (IL-1/TNF)
• Systemic response of patient presented as weight
  loss and fever/chills at night
• Lymphocytes activate additional macrophages which
  secrete IL-1/TNF which activate additional
  lymphocytesvicious cycle
• Plasma cells produce antibodies

7
Characteristics of Inflammation

• Nature of response
• Angiogenesis repair of damaged tissues initiated
  by the release of angiogenesis factors FGF from
  macrophages
• Fibrosis non functional tissue initiated by
  release of growth factors and fibrogenic
  cytokines from macrophages

8
Characteristics of Chronic Inflammation

• Tissue changes
• Regeneration with return to normal function
• Scarring with loss of function
• Granulomatous inflammation TB

9
Granulomatous Inflammation

• Aggregate of activated macrophages assuming a
  squamous cell-like appearance with pink granular
  cytoplasm ?epitheliod cells
• Indistinct cell boundaries with a collar of
  lymphocytes secreting cytokines for ongoing
  macrophage activation
• Giant cells generally found multinucleate fusion
  of gt20 macrophages
• Resulting in hypoxia and free radical injury
  causing a central zone of necrosis caseous
  necrosis (total loss of tissue structure with a
  cheese-like appearance)

10
Granulomatous Inflammation-Lung

• Histochemical stain of patients right lung with
  caseous necrosis
• Pulmonary radiograph confirmation with irregular
  opacity

Caseous necrosis
Giant cell
Epitheliod cells
11
Tuberculosis-Other potential problems

• In immunosuppressed individuals (AIDS, cancer) or
  in the elderly, progressive primary tuberculosis
  or secondary (reactivation) tuberculosis may
  occur.
• Reactivation of viable bacilli that had been
  contained in foci of scarring.
• Due to patients previously acquired
  hypersensitivity, a prompt response occurs
  resulting in cavitations of airways, a large
  source of infectivity because now patient is
  raises sputum containing bacilli.

12
Tuberculosis-Other potential problems cont.

• Organisms can drain through lympatics ? ducts ?
  venous return to right heart ? pulmonary arteries
  ? pleural effusions ? seeds pulmonary return to
  the heart ? systemic arterial system ? seeding of
  multiple organs (Miliary TB)

Testis granulomatous inflammation
13
Granulomatous inflammation of multiple organs-
Disseminated TB

• Disseminated TB caused hepatomegaly/lymphadenopath
  y in my patient
• Destruction of the adrenal cortex accounts for
  patients ion imbalance and resulting
  hyperkalemia/hypocalcemia

Adrenal gland
14
Patients symptoms

• Adenocarcinoma immunosuppression ? Reactivation
  TB
• Opacity of right lung Caseous necrosis
• Lymphadenopathy/hepatomegaly disseminated TB
  (Systemic miliary tuberculosis)
• Granulomatous inflammation of adrenal gland and
  testis disseminated TB

15
Patients symptoms

• Hyperkalemia/hypocalcemia destruction of adrenal
  cortex ? ion imbalance
• Pleural effusion disseminated TB into pulmonary
  arteries
• Weight loss, fever and chills at night systemic
  response to cytokines released by activated
  macrophages
• No response to antibiotic MDR-TB or too severely
  immunocompromised to fight off infection

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Tuberculosis- Diagnostic Tools

• Pulmonary examination
• Pulmonary radiographs
• Skin test
• Fine-needle aspiration (FNA) cytological
  examination Ziehl-Neelsen coloration for
  acid-fast bacilli
• Blood cultures using modified Lowenstein-Jenson
  medium (for patients also infected with HIV)
• Biopsy specimens from lung, liver or bone marrow

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Treatment of Tuberculosis

• Currently includes multiple drugs to be taken for
  6-9 months that include
• 2 months with Rifater (isoniazid, rifampin, and
  pyrazinamide) 4 months of isoniazid and rifampin
  (Rifamate, Rimactane). Ethambutol (Myambutol) or
  streptomycin will be added until your drug
  sensitivity is known.
• Directly Observed Therapy is strongly
  recommended by the CDC to ensure drug regimen
  completion.

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Today in Tuberculosis-Multi-drug Resistant Strains

• Guidelines for use of second-line anti-TB drugs
• Creating evidence-based clinical guidelines for
  MDR-TB treatment
• Start treatment early and use high-end dosing due
  to lower potency
• DOT
• Improper management ? increased drug resistance

• Fighting MDR-TB in developing countries
• Price reduction in second-line drugs
• Global Fund to Fight AIDS, TB and Malaria
• Green Light Committee for Access to Second-line
  anti-TB Drugs

19
Resources

• Adonis-Kofty L, Kouassi F, Timite-Konan AM.
  Analysis of the diagnostic criteria used in
  childhood tuberculosis in a tropical hospital.
  Bull Soc Pathol Exot 2004 May 97 (2) 127-8
• Cotran, Robbins, Kumar. Basic Pathology , 7th
  edition Saunders. Philadelphia, PA.
• David SF, Mukundan U, Brahmadathan KN, John TJ.
  Detecting mycobacteria for diagnosing
  tuberculosis. Ind J. Med Res 2004 June 1199
  259-66
• http//www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.
  htm
• Mukherjee, Joia S., Rich, Michael L. et al.
  Programs and principles in treatment of
  multi-drug-resistant tuberculosis. The Lancet
  2004 Feb 9407(363) 474-81