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

[Mariela Milla]

Dear Dr. Markus

Thanks very much for your e-mail. I
will try to answer the questions in the same order that you made.
In the case, the patient received short course of steroids (just 3 days) during the acute event of second hospitalization, along with antibiotics with good response for the acute process that led to hishospitalization, but later in the intermittent periods between hospitalizations, she continued with hepatosplenomegaly, cervical 
micro-lymphadenopathy, lymphocytosis, hypergammaglobulinemia    with no response to acyclovir (received for three months). She
never had a complete remission.  She did not receive other medication such as chemotherapy eg etoposide, cyclosporine A, or rituximab, atg, campath.

NK cytotoxicity study,
sIL2R, is not performed at the hospital.  DNT cells have not been reported in any of the
immunophenotypes but I can get it. Regarding the response to vaccines,
 the patient has not had any adverse reaction, but there is no laboratory
test   to measure response to vaccines in the hospital.


The EBV PCR was made from whole blood.
On the third hospitalization, she was admitted for lower respiratory tract infection (fever, cough and bronchial hyperresponsiveness) and received Ceftriaxone and inhaled bronchodilators with good  response to respiratory episode.
No family history of lymphoproliferation. Fibrinogen: 184 mg/dl (March 2012) and 235 mg/dl (Set 2011) (Normal rate: 200 - 400 mg/dl). IgE normal. 
 
We
do not make the count NKT cells, but was mentioned in the study of Perforin
conducted in January 2012 (period of apparent stable condition but with
hepatosplenomegaly, mild anemia) in Cincinnati Hospital. (Copy
attached). We have no other autoantibodies except those mentioned (ANA, ANCA, ASMA, Anti KLM1, Antithyroid: all negative).

Regarding to cytopenias, the patient  (since June 2011) has had anemia, but over the months has a tendency to leucopenia and
mild thrombocytopenia.
These are some of her blood
count: 
 

  Sept-2011 Dec-2011 March-2012 May-2012 
Leucocytes (10^3/uL) 13.7 14.27 9.56 3.97 
Hemoglobin (g/dl) 11.8 10.2 11 9.7 
MCV (81 fL -2DS:75 fL) 79.2 88.1 77.4 78.5 
MCH (27 pg -2DS: 24 pg) 27.6 27.6 25.1 25.4 
MCHC (34 g/dl -2DS:31 g/dl) 34.9 31.4 32.4 32.3 
Platelets (10^3/uL) 77 140 171 142 
          
RDW-SD (39-46 fL) 57.6 54 52.6 49.8 
RDW-CV (11.6-14.6%) 25.3 17.5 19.3 18.7 
MPV (7.5-9.5 fL)   10.3 10.4 10.5 
IG (10^3/uL)       0.03 (0.8%) 
          
Neutrophils (10^3/uL)-(%) 3.51 (25.6%) 1.61 (11.4%) 2.20 (23%) 1.0 (25.1%) 
Lymphocytes (10^3/uL)-(%) 9.46 (69.1%) 12.19 (85.4%) 6.96 (72.8%) 2.75 (69.3%) 
Monocytes (10^3/uL)-(%) 0.69 (5%) 0.42 (2.9%) 0.36 (3.8%) 0.15 (3.8%) 
Eosinophils (10^3/uL)-(%) 0.01 (0.1%) 0.02 (0.1%) 0.01 (0.1%) 0 
Basophils (10^3/uL)-(%) 0.03 (0.2%) 0.03 (0.2%) 0.03 (0.3%) 0.04 (1%) 
 
Do you think it is necesary to make the study of EBV in  T cells or NK cells for CAEBV diagnosis? 

I appreciate your comments, suggestions that may help the patient. 


Best regards.

Mariela

Mariela Milla MD
Clinical Immunologist and allergist
Rebagliati Hospital
Lima 


________________________________
 De: "Markus G Seidel, Priv.-Doz.Dr." <markus.seidel at medunigraz.at>
Para: Mariela Milla <marielamilla at yahoo.es>; pagid at list.clinimmsoc.org 
Enviado: Martes 17 de julio de 2012 3:34
Asunto: Re: [CIS PIDD] 5 years old female patient with probable CAEBV
 

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). 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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