[CIS PIDD] 5 years old female patient with probable CAEBV

[Mariela Milla]

Dear Colleagues,

I would appreciate any thoughtful input on the following case : probable  CAEBV and/or  PID (     HLH? Itk
deficiency? Mg channels deficiency? CD27 deficiency?

Case: 
Female patient, 5 years old.
Parents are not blood relatives.
No previous medical history before 4 years
of age.
Normal psychomotor development

May 2011: First hospitalization
for probable infection by Epstein Barr Virus (fever; cervical, mesenteric and
mediastinal lymphadenopathy; hepatosplenomegaly; hypergammaglobulinemia). EBVIgG=1.6 (Positive >1.1); EBVIgM 0.7
(Negative< 0.9); Ig A 203 mg/dl (27 –
195 mg/dl), IgG 2408 mg/dl (504 – 1464 mg/dl), IgM 137 mg/dl
(24 – 210 mg/dl).
Bone marrow smear:
·         Lymphocytic marrow
infiltration versus reactive lymphoproliferative syndrome (June 2011)
Bone marrow biopsy:
·         90% cellularity,
presence of all three series, 40% CD8 cytotoxic T lymphocytes of mature
appearance (June 2011)
Liver biopsy:
·         Consistent with extramedullary
hematopoiesis (June 2011)
Lymph node biopsy:
·         Paracortical
hyperplasia with no evidence of malignancy  (June 2011)
 
September 2011:Second
hospitalization: sudden onset of fever, cough and respiratory distress, managed
in ICU for septic shock with respiratory focus, needing oxygen and inotropic
support; oliguria, anemia (received transfusion), hepatosplenomegaly.
The patient received IV acyclovir for 21
days; fluconazole for 10 days; vancomycinandimipenemfor 10 days. Oral aciclovir for 3 months after
discharge.
Discharge diagnosis:Chronic active EBV infection, T cell
lymphoproliferative syndrome associated to EBV infection.
Laboratory:  mild anemia, lymphocytosis, elevated liver enzymes, and
hypergammaglobulinemia
EBV EBNA IgG: positive
EBV EBNA IgM negative
EBV VCA IgG positive
Direct Coombs positive (1+)
LDH 967 (high)
Electrophoretic proteinogram: hyperproteinemia, polyclonal increase of gamma
fraction 
Epstein Barr Virus Viral load (PCR):
1070 copies / ml
Cytomegalovirus viral load <600 copies
Bronchoscopy: thick secretions and fluffy whitish plaques
TCR clonality study: negative
Autoantibodies (ANA, ANCA, ASMA, Anti KLM1, antithyroid): negative

March 2012: Patient continues with hepatoesplenomagalia, lymphocytosis, hypergammaglobulinemia, remaining stable clinical condition.
ALT: 178 (0-41 U/l)
AST: 205 (0-37 U/l)
Alkaline phosphatase: 1764 (0-300 U/l)
Ferritine: 1169 (5-148 ng/mL)
Triglycerides:256  (60-200 mg/dl)
% Perforina /Granzima B (en células NK, T CD8 y NKT)

Perforina + 
% NK Cell (73-91): 56%
NK cells MCF (98-181): 111 MCF
% CD8 cell (0-16): 2%
5 NKT cell: Not reportable
Granzyma B 
% NK Cell (80-98): 56%
NK cells MCF (152-825): 555 MCF
% CD8 cell (0-61): 43%
5 NKT cell: Not reportable
Note: Sample was> 24 hours when it was received in the lab (Cincinnati)

May 2012:Third
hospitalization: fever, cough, dyspnea, marked hepatosplenomegaly, hypergammaglobulinemia.

The patient received IV ceftriaxone for 7
days with good response.
Discharge diagnosis:pneumonia, T cell lymphoproliferative syndrome
associated to EBV infection.
Bone marrow smear:
·         Monocytosis, no
tumoral infiltration (May 2012)
Bone marrow biopsy:
·         Celularity of 60%,
mild hypocellular for age, adequate maturation in 3 series. 15% of CD8+ T cells
positive in relation to a viral infectious process (May 2012).
     Scan: 
      Cervical nodes smaller than 10 mm, Focal consolidation in the posterior segment of right upper lobe and the anterior segment of the left lower lobeI, may correspond to atelectasis. No lymphadenopathy medistinales. Hepatosplenomegaly not associated with focal lesions. Pancreas, adrenals and kidneys showed no abnormalities. No retroperitoneal lymphadenopathy. No free fluid in abdominal and pelvic cavity.

Immunophenotype by
Flow citometry:
  Bone marrow blood   Peripheral blood 
Date Jun-11 September 2011 December 2011 April 2012 
WBC 64,959 16630 14270 9930 
Mature myeloid cells 39% 39% 19% 18% 
Monocytes 3.40% 3.40% 1.40% 4.50% 
Total lymphs 43% 43% 80% 78% 
Normal T lymphs 4% 5% 22% 20% 
Anomalous T lymphs 37% 38% 50% 50% 
B lymphs 3.30% 3.90% 1% 1% 
CD3+CD4+     10% 10% 
CD3+CD8+     12.80% 10% 
Normal T lymphs   5% 22% 20% 
Abnormal T lymphs   38% 50% 50% 
T lymphs Antigen:  
     CD3 Weak positive unavailable Positive Positive 
     CD7 Negative Negative Negative Negative 
     CD2 Strong positive Strong positive Strong positive Strong positive 
     CD8 Positive Positive Strong positive Strong positive 
     CD4 Positive Negative Negative Negative 
     TCRa/b Positive Positive Positive Positive 
     TCRg/d Negative Negative Negative Negative 
     CD5 Weak positive Weak positive Weak positive Weak positive 
     HLA-DR Positive Strong positive Strong positive Strong positive 
     CD24   Negative Negative Negative 
     CD57 Negative Negative Negative Negative 
     CD11c   Negative Negative Negative 
     CD45RA   Negative Negative Negative 
     CD45RO   Positive Positive Positive 
     CD34 Negative Negative Negative   
     TdT Negative Negative Negative   
     CD45 Strong positive Strong positive Strong positive Strong positive 
     CD56 Negative Negative Negative unavailable 
    CD30 unavailable unavailable       unavailable unavailable 
    CD25 Negative Negative Negative unavailable 
    CD28 Positive Positive (74% of cells) Positive (54% of cells)   
 

 
CURRENT DIAGNOSIS:
-        Chronic active
Epstein-Barr virus infection (CAEBV)
-        Primary
immunodeficiency: HLH? Itk deficiency? Mg channels deficiency? CD27 deficiency? leaky SCID?
 
At the hospital where I work, there is no experience of making  bone marrow transplant in patients with CAEVB. I have some questions: 
	* Does this patient with a diagnosis of probable CAEBV would be a candidate for bone marrow transplant? 

	* What are the chances of cure that would offer the bone marrow tranplante? 

	* Does anyone have experience in managing such patients and what suggestions would you recommend?

	* Is it necessary any additional workup to rule out CID?, Do you think it is a leaky SCID? HLH?Itk deficiency? Mg channels deficiency? CD27 deficiency?

	* Did any clinical significance of immunophenotyping?


Thank you in advance for your help. 


Mariela
 
Mariela Milla MD
Clinical Immunologist and allergist
Rebagliati Hospital
Lima
00511-996534597
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