Adenosine Deaminase Deficient SevereCombined Immunodeficiency Uncovered After Varicella Vaccination

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Adenosine Deaminase Deficient Severe-Combined
Immunodeficiency Uncovered After Varicella
Vaccination

• Kim George MD
• Virginia Commonwealth University Health Systems
• Richmond, VA

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Case Presentation

• 17 month old black male
• Birth History
• Term
• Wt 3.2 kg (25-50th)
• PMH
• Poor weight gain/ failure to thrive with eating
  problems since 4 mos old currently in
  occupational therapy for difficulty chewing/ diet
  consists of soft, pureed foods.
• ? Gross motor delay (cannot walk independently)
• ? Speech delay (vocabulary 6-8 words)

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Case Presentation

• SH
• Started daycare lt1 mo ago
• Lives with mom and 2 sibs (2 and 5 yrs old)
• FH
• Unremarkable per mom
• Immunizations
• Received 12 mos shots at 12 mos (Hib, Prevnar,
  MMR)
• Received 15 mos shots at age 16 mos (DTaP,
  Varicella)

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Presentation Exam

• General
• Cachetic weight 7.48 kg (lt3rd percentile)
  height 72 cm (lt3rd percentile)
• Fussy but consolable
• CV no murmur
• Resp tachypnea (40s), with mild rales
  bilaterally
• Skin erythematous papules and vesicles in
  various stages of healing throughout body

Admission
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Timeline
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Immune Workup

• CBC severe leukopenia with 1 lymphocytes
• ALC 57/mm3
• Decreased T, B and NK cells
• CD3 27.4 (16/mm3)
• CD4 14.7 (8/mm3)
• CD8 10.3 (6/mm3)
• CD19 6.3 (4/mm3)
• CD56 32.5 (19/mm3)
• Decreased immunoglobulins
• IgG 152, IgM 25, IgA 10 mg/dL

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Immune Workupcontd

• Lymphocyte proliferation
• PHA
• Patient 21,377 CPM, background 189
• Control 188,330 CPM, background 126
• HIV negative
• Bl Cx negative
• Viral EBV, CMV negative

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Diagnosis?

• Severe-combined immunodeficiency
• Which type?

Buckley et. al., Annu Rev Immunol 2004. 22
625-55
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Immune Workupcontd

• Adenosine deaminase (ADA) deficiency labs
• ADA level (hemosylate) 16.8 nmol/h/mg (normal 63)
• RBC nucleotides
• Adenosine nucleotides 0.969 µmol/mL (normal
  1.465)
• Deoxyadenosine nucleotides 0.056 µmol/mL (normal
  lt0.002)

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ADA Deficiency

• ADA
• Enzyme in the purine salvage pathway
• Catalyzes the deamination of adenosine to inosine
  and deoxyadenosine to deoxyinosine
• ADA deficiency causes a significant increase in
  deoxyadenosine levels
• Toxic effects on T and B lymphocytes

ADA
R OH (Ado) or H (dAdo)
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ADA Deficiencycontd

• Usually presents in infancy (80-90) although can
  see delayed or even late (adult)-onset as well as
  partial ADA-deficiency.
• Considered ultimately fatal if untreated.
• Characterized by thymic hypoplasia, profound
  lymphopenia (T, B, and NK lymphocytes), defective
  lymphocyte function, recurrent infections and
  failure to thrive.

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ADA Deficiency

• Also associated to lesser extent with systemic
  metabolic toxicity and alterations in
  non-lymphoid systems
• hepatic
• bone (chondro-osseous dysplasia)
• sclerosis of kidneys/ adrenals/ pituitary
• CNS (mental and motor dysfunction)
• Established by finding low to absent levels of
  ADA in erythrocytes, lymphocytes or fibroblasts
  (carriers may have ½ normal levels).
• Dx can be confirmed via dATP levels and reduced
  S-adenosyl homocysteine hydrolase activity in
  erythrocytes as well as increased d-Ado seen in
  urine.

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Treatment

• ADA replacement
• Pegylated ADA (bovine ADA conjugated with
  polyethylene glycol) at doses of 15-40 u/kg/wk
  IM.
• Maintaining high levels (gt100 fold nl) of ectopic
  ADA in plasma eliminates extracellular Ado and
  dAdo leading to normalization of intracellular
  dATP.
• After initiation of therapy (3 to 16 weeks)
  absolute numbers of T and B lymphocytes as well
  as NK cells have been shown to initially increase
  and protective immune function begins to develop
  (Chan, et al., 2006).
• However, lymphocyte counts usually decrease over
  time as well as a decline of mitogenic
  proliferative responses (Chan, et al., 2006).
• Approximately 50 remain on immunoglobulin
  replacement (Booth et al., 2006).

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Treatment

• Limited by chronic, ongoing therapy that can cost
  200,000-300,000 annually per patient (Chan, et
  al., 2006).
• Other complications may include Coombs ()
  hemolytic anemia, vasculitis, and macrophage
  activation syndrome (Booth et al., 2006).
• Often used as bridge to BMT and considered next
  best treatment option for ADA deficient SCID
  patients lacking HLA-matched bone marrow donors.

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Treatmentcontd

• BONE MARROW TRANSPLANT
• Allogeneic hematopoietic stem cell
  transplantation from an HLA-identical sibling
  donor is preferred method of treatment and can be
  curative with survival rates of 90 .
• Outcomes for patients other than HLA-identical
  sibling donors are generally associated with
  significantly poorer outcomes (matched unrelated
  donor 63 and haplo-identical donor 50).
• Patients still may have neurologic abnormalities
  (mental retardation, motor dysfunction, deafness)
  even after successful transplant and
  reconstitution of immune function.

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Treatmentcontd

• GENE THERAPY
• Correction via autologous hematopoietic stem
  cells (BM, cord blood) and lymphocyte targeted
  gene therapy has been under development since
  1990 ( first clinical gene therapy trial).
• Results often difficult to interpret due to
  concomitant treatment with PEG-ADA but recent
  studies indicate strong selective advantage of
  gene-transfected T cells as measured by T cell
  function and Ab response but incomplete
  correction of metabolic defect.
• Highly encouraging results with gene therapy,
  especially after non-myeloablative conditioning
  with Busulfan or Melphalan, may provide new
  options for patients on PEG-ADA replacement with
  waxing immunity and without related-matched donor
  for BMT.