Mystery Case CIS Summer School Fellow Case Presentation

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Mystery CaseCIS Summer School Fellow Case
Presentation

• Jennifer L. Caicedo, M.D.
• Allergy/Immunology Fellow
• Wake Forest University

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Case Presentation

• 7 year old male
• Presumptive Diagnosis of CVID
• Low IgG, IgA lt15, IgM lt12
• 1 B-cells, low T-cell numbers. Normal T-cell
  mitogens. Absent T-cell antigens.
• Abnormal bacteriophage studies
• Chronic lymphopenia
• Hypothyroidism (Not Autoimmune)
• Partial villous atrophy (TPN-dependent)
• Chronic hepatitis (secondary to chronic TPN
  therapy)
• Chronic lung disease (with pan-lobar
  bronchiectasis)
• On q 3 week IVIG
• Presented to our institution with a three day
  history of cough, congestion, fever, and
  diarrhea.

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Case Presentation

• Admission Labs
• WBC 2200
• 1300 neutrophils
• 400 lymphocytes.
• Hemoglobin 9.4 G/DL and
• Platelet count 42,000.
• serum sodium level of 181 meq/L (normal 136-143)
• total bilirubin 3.1 mg/DL (normal 0.1-1.2),
• AST and ALT were elevated at 545 and 137 U/L
  respectively (normal 15-50).

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Case Presentation

• Hospital admission
• Blood cultures for bacteria and fungus negative.
  
• Stool cultures for bacteria, virus, ova and
  parasites negative.
• PCR for EBV, CMV, HSV 1 2, Parvovirus, HIV 1 and
  2 negative.
• Abdominal ultrasound Increased liver and spleen
  size (2.5cm from baseline)
• Worsening Pancytopenia

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What is the differential diagnosis of the
patients acute medical issues at this point?
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Case Presentation

• Subsequent laboratory studies
• elevated ferritin at 361 ng/mL (normal 30-300),
• elevated triglycerides at 402 (normal lt150).
• WBC 0.6
• Hemoglobin 6.9 G/DL
• platelets 22,000.
• Patient was maintained on IV antibiotics
  throughout his hospitalization for presumptive
  sepsis. He also received a short course of IV
  anti-fungals as well as his regular dose of 1
  gram/kg IVIG. His liver enzymes as well as
  bilirubin levels normalized prior to discharge,
  and all counts on his CBC began to improve,
  although they never returned to his baseline.

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A Bone Marrow Biopsy and Aspirate were performed
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Case Presentation

• Three weeks later
• Patient was readmitted with a similar clinical
  presentation of fever, cough, and diarrhea.
• Laboratory studies Severe pancytopenia, marked
  elevation of liver enzymes and bilirubin, as well
  as elevated triglycerides.
• PCR studies again negative for EBV, Parvovirus,
  HSV 1 and 2, and HIV.
• Soluble IL-2 receptor was elevated at 3,259 U/mL
  (normal 200-1100).
• Treatment
• 2 grams/kilogram IVIG x 3 doses and patient was
  started on Granulocyte-colony stimulating factor
  (G-CSF). He was discharged once again with
  improving counts and clinical picture.

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Case Presentation

• One month later
• Patient re-admitted with fever and respiratory
  distress. He was treated aggressively for sepsis
  and pneumonia with Meropenum, Vancomycin,
  Tobramycin. He showed little improvement with
  therapy. His family signed a DNR order and 24
  hours later, the patient expired.

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What is the Differential Diagnosis of the acute
medical issues at this point?
What is the Differential Diagnosis of the
underlying immunodeficiency?
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Case Presentation

• Studies looking for XLP have revealed normal
  sequencing in the coding region of SH2D1A.
• Although patient labeled as CVID, it is unclear
  as to whether this truly represented his
  underlying immunodeficiency. The family has
  requested an autopsy.
• Our patients multiple admissions with fever and
  pancytopenia prior to his death were thought to
  be secondary to Hemophagocytic lymphohistiocytosis
  (HLH).
• However, it still remains unclear as to whether
  his symptoms represented a manifestation of his
  underlying immunodeficiency.

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Hemophagocytic lymphohistiocytosis (HLH)

• Severe hyperinflammatory condition
• Cardinal symptoms
• Prolonged fever, cytopenias, hepatosplenomegaly,
  and hemophagocytosis
• Genetic forms
• FHL (AR inheritance) (PRF1 (Perforin) UnC13D
  (Munc13-4) mutations)
• Associated primary immunodeficiencies
• Chediak-Higashi Syndrome (LYST (CHS) mutations)
• Griscelli Syndrome (RAB27A (Rab27a) MYO5A
  (Myo5a) mutations)
• X-linked Lymphoproliferative Syndrome (XLP)
• (SH2D1A (SAP) XIAP (XIAP) mutations)
• Acquired forms (leading triggers are infectious)
• EBV, CMV, HSV (most common)
• Parvovirus B-19, Adenovirus, Leishmania
• Identification of infectious agent does not
  discriminate between genetic and acquired forms
  of HLH, since most episodes in genetic HLH are
  triggered by infections.
• Systemic Onset JRA
• Treatment
• Pulse steroids, Cyclosporine, Etoposide.
• Bone marrow transplantation