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

[Markus G Seidel, Priv.-Doz.Dr.]

Dear Mariela,
what might be helpful is wether the symptoms responded to steroids or if aciclvir/antibiotics were sufficient. Did the patient not need any chemotherapy e.g. etoposide, cyclosporineA, or rituximab, atg, campath, for intermittent recovery?
FACS of CD27, SAP, XIAP would be interesting, what about NK-cytotoxicity, abDNT cells, vaccine responses? ITK deficiency certainly possible; was the ebv pcr (1e3/mL) done in edta plasma or whole blood? any other virus (or other infectious) problems? how may the response to ceftriaxone be explained under your diagnosis? positive family history of lymphoproliferation? ferritin is not excessively high - not very suggestive of primary HLH... (sIL2R, Fibrinogen..? cytopenias?); how and when were NKT cells (iNKT cells!?) detected- any analyses done during time of clinical remission? IgE? thyroid, other auto-antibodies?
altogether a bit too little information for a discussion of an indication for SCT yet...
Please keep us updated, Kindly yours,
Markus

Markus G. Seidel, M.D. 
Assoc. Professor of Pediatrics │ Consultant Pediatric Hematologist-Oncologist │Focus on Immunology & Stem Cell Transplantation │Coordinator of the Austrian Working Party for Pediatric Immunology of the Austrian Society of Pedatric and Adolescent Medicine│
Medical University Graz │ Univ. Clinics of Pediatrics and Adolescent Medicine │Dept. Ped. Hematolog-Oncology │ Auenbruggerpl. 34/2 A-8036 Graz │M. 0043 316 385 80215 │ T.0043 316 385 13485
│F. 0043 316 385 13717


Am 17.07.2012 um 09:52 schrieb 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). EBV IgG = 1.6 (Positive >1.1); EBV IgM 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; vancomycin and imipenem for 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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