Chronic Granulomatous Disease

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Chronic Granulomatous Disease

• Genetic disorder with impaired intracellular
  microbial killing by phagocytes
• Recurrent bacterial and fungal infections
• A genetic deficiency in one of the several
  components of the NADPH oxidase responsible for
  generating superoxide. Engulfment of bacteria
  does not result in destruction of bacteria by
  oxygen-dependent mechanisms.

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Pathophysiology

• CGD is a rare inherited immunodeficiency syndrome
• phagocytes' inability to produce sufficient
  reactive oxygen metabolites.
• defect in the NADPH oxidase-is composed of
  several subunits, two of which, gp91phox and
  p22phox, form the membrane-bound cytochrome b558,
  while its three cytosolic components, p47phox,
  p67phox and p40phox, have to translocate to the
  membrane upon activation.
• Encoded on the X-chromosome are several GTP-
  binding proteins-Gp91phox while p47phox, p67phox
  and p40phox are on autosomal chromosomes.
  Deficiency in any of these components causes
  CGD- thus explaining its variable mode of
  inheritance.

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Frequency and Age

• In the U.S the birth rate is between 1/200000 and
  1/250000 in the period 1980-1989
• A registry of United States residents with
  chronic granulomatous disease (CGD) was
  established in 1993, and as of may, 2000, 368
  patients have been registered 259 have the
  X-linked recessive form of CGD, 81 have 1 of the
  autosomal recessive forms, and in 28 the mode of
  inheritance is unknown.
• In the registry, two third of the cases are
  X-linked and 86 are males.
• Over three quarters present the symptoms in the
  first five years of life.

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Common Presentations

• Skin infections
• Pneumonia was the most prevalent infection (79
  of patients) Aspergillus most prevalent cause
• suppurative adenitis (53 of patients) It is
  mostly caused by Staphylococcus subcutaneous
  abscess (42 of patients) Staphylococcus most
  prevalent cause
• liver abscess (27 of patients) It is mostly
  caused by Staphylococcus
• osteomyelitis (25 of patients) Serratia is the
  most prevalent cause
• sepsis (18 of patients) Salmonella most
  prevalent cause
• Fifteen percent of patients had gastric outlet
  obstruction
• 10 urinary tract obstruction
• 17 colitis/enteritis.
• The most common causes of death were pneumonia
  and/or sepsis due to Aspergillus (23 patients) or
  Burkholderia cepacia (12 patients).
• development of granulomas in the skin, GI tract,
  and genitourinary tract. Granulomas are believed
  to occur due to impairment in the feedback
  mechanism after an inflammatory response by toxic
  oxygen radicals

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Extravasation of Leukocytes

• Laminar blood flow and the presence of RBCs push
  leukocytes toward the venular wall and thus
  increasing contact with endothelial cells. The
  expression of ligands and selectins is increased.
• Sequence of events
• Rolling is facilitated by loose selectin binding
  to carbohydrate ligands
• Adhesion to endothelium due to chemokine-induced
  changes in integrin affinity fro endothelial
  ligands
• Transmigration through intercellular junction and
  pierce the basement membrance using PECAM-1
  interactions
• Migrate towards chemoattractants released from a
  source of injury

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Phagocytosis

• Recognition and attachment and binding of
  opsonins (ex Fc portion of IgG molecules)and
  collectins which bind to microbial cell wall
  carbohydrates to receptors on the leukocyte
  surface. The receptors are Fc receptor for IgG.
• Engulfment
• Fusion of the phagocytic vacuole with granules
  and degranulation
• Killing and degradation is accomplished largely
  by reactive oxygen species.
• Fig 2-10A from Basic Path

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Oxidative Burst

• NADPH oxidase2O2 NADPH -----------? 2O2.-
  NADP H
• The superoxide is then converted into hydrogen
  peroxide. 2O2.- ----? H2O2
• H2O2 ---? OCl. In the presence of myeloperoxidase
  and halide such as Cl-
• H2O2 ---? OH. In the presence of Fe

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Diagnosis

• Laboratory findings in these individuals include
  leukocytosis (increased number of white blood
  cells)
• anemia, which is usually microcytic, hypochromic,
  or occasionally normochromic
• abnormal chest X-rays
• hypergammaglobulinemia (increased levels of
  gammaglobulin). IgE levels may be increased.
• Antibody studies are normal
• Specific diagnostic tests for Chronic
  Granulomatous Disease include
• Nitroblue Tetrazolium Reduction
• This is a histochemical study of oxidase activity
  of leukocytes during phagocytosis. It is a useful
  screening test. (An equivalent test is often
  performed using a laboratory instrument called a
  flow cytometer.)
• Superoxide Production
• This is a measure of the amount of the chemical
  reactions produced.
• Analysis of the biochemical components of
  defective neutrophils to identify the specific
  defect present

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Clinical Signs
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Mechanisms of Leukocyte defects

• Defects in leukocyte adhesion
• LAD-1-defective synthesis of CD18 subunit of
  leukocyte integrins LFA-1 and Mac-1 leads to
  impaired adhesion, phagocytosis, spreading, and
  generation of oxidative burst.
• LAD-2 is caused by absence in sialyl- Lewis X,
  that binds to selectins on endothelium.
• Defects in microbicidal activity-CGD
• Defects in phagolysosome formation- Chediak
  higashi syndrome is an autosomal recessive
  disease in which the trafficking of organelles
  resulting in impaired lysosomal degranulation
  into phagosomes.

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Treatment

• Early diagnosis
• Bacterial antibiotics
• Prophylactic oral antibiotics the combination of
  trimethoprim/sulfamethazole (brand names
  Bactrim/Septra)
• Gamma interferon
• Bone marrow transplantation

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Bibliography

• Dohil M, Prendiville JS, Crawford RI Cutaneous
  manifestations of chronic granulomatous disease.
  A report of four cases and review of the
  literature. J Am Acad Dermatol 1997 Jun 36(6 Pt
  1) 899-907
• Kamani. http//www.emedicine.com/ped/topic1590.htm
  sectionintroduction
• Meischl C, Roos D The molecular basis of chronic
  granulomatous disease. Springer Semin
  Immunopathol 1998 19(4) 417-34
• Mouy R, Fischer A, Vilmer E Incidence, severity,
  and prevention of infections in chronic
  granulomatous disease. J Pediatr 1989 Apr 114(4
  Pt 1) 555-60
• Winkelstein JA, Marino MC, Johnston RB Jr
  Chronic granulomatous disease. Report on a
  national registry of 368 patients. Medicine
  (Baltimore) 2000 May 79(3) 155-69
• Imageshttp//cats.med.uvm.edu/cats_teachingmod/ra
  diology/radiology_html/teaching/radio_adult/granul
  omatous20_disease/granulo.htm