IJHOSCR
`
`International Journal of Hematology- Oncology and Stem Cell Research
`
`
`
`
`Case Report
`
`Epstein-Barr Virus-Induced Hemophagocytic
`Lymphohistiocytosis
`
`K. Goudarzipour1*, M. kajiyazdi1, A. mahdaviyani2
`1Mofid, Children’s Hospital, shahid beheshti University of Medical Sciences, Tehran, Iran
`2Masih Daneshvari Hospital, shahid beheshti University of Medical Sciences, Tehran, Iran
`
`Corresponding author: K. Goudarzipour, MD
`pediatric congenital hematologic disorders reaserch center, shahid beheshti university of medical science, Tehran, Iran
`E-mail: drkgoudarzipour@yahoo.com
`Tel.: +982122227020
`Fax: +982122220254
`
`Received: 20, Oct, 2012
`Accepted: 16, Nov, 2012
`
`
`
`ABSTRACT
`Hemophagocytic lymphohistiocytosis (HLH) is one of the complications of Epstein-Barr virus (EBV) infection.
`Although the patients who have developed HLH following EBV have normal immune system, there are a few
`patients with EBV-induced immune deficiency who develop HLH as well. Here, we describe the case of a 10-
`year-old girl with neurological complications caused by EBV-induced HLH. The patient received rituximab,
`leading to weakening inflammation associated with EBV infection and suppression of disease through quick
`treatment.
`
`lymphohistiocytosis, Systemic
`lymphoproliferative disease, Hemophagocytic
`KEY WORDS: X-Linked
`inflammatory response syndrome, Infectious mononucleosis, Epstein - Barr virus, Etanercept
`
`
`INTRODUCTION
` The Epstein–Barr virus (EBV) infects B cells. In
`most cases, EBV-positive patients develop a severe
`form of infectious mononucleosis which typically
`manifests
`with
`fever,
`tonsillopharyngitis,
`lymphadenopathy and hepatosplenomegaly. HLH is
`a rare complication of Epstein-Barr virus (EBV)
`infection. Deficiencies may be characterized by
`abnormal activity of lymphocyte function leading to
`hemophagocytosis
`and multi-organ
`failure.
`Although EBV-associated HLH carries a high
`mortality rate, quick diagnosis and appropriate
`treatment can subside the disease.
` We describe here a patient who developed
`hepatosplenomegaly and pancytopenia at 2 years of
`age but achieved automatic recovery. There was no
`neurological manifestation. At age 10, there was a
`clinical suspicion of EBV-induced HLH and the
`patient was given the option of treatment with
`rituximab.
`
`INTRODUCING THE CASE
` A ten-year-old girl diagnosed with pneumonia
`admitted to the hospital. She received antibiotic
`treatment due to fever and chills. During the
`hospitalization period, the patient recovered and
`developed hemophagocytosis with pancytopenia as
`well as sores on the lip. The patient underwent
`BMA and nothing abnormal was found. In spite of
`treatment, the disease did not subside and she
`developed fever, abdominal distention and edema
`in her lower extremities. The patient was then
`transferred to another hospital and was reexamined
`once again. Physical examination showed that the
`patient had decreased deep-tendon reflexes (DTR)
`and was unable to walk. Brain CT scan revealed that
`the cerebral ventricles were surrounded by a
`hypodense area. A chest CT-scan showed the right-
`sided pleural effusion. A CT scan of the abdomen
`showed severe hepatosplenomegaly. The patient
`was positive
`for EBV antibody. Clindamycin,
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`IJHOSCR 7(1) - ijhoscr.tums.ac.ir – January 1, 2013
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`IJHOSCR, 1 January 2013. Volume 7, Number 1
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`Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis
`
`(intravenous
`IVIG
`ceftazidime, dexamethasone,
`immunoglobulin) and G-CSF were administered.
`Since the patient did not achieve full recovery, she
`was transferred to our center. Based on clinical
`symptoms and
`lab tests (Table 1), BMA was
`performed once again and the result raised
`suspicion of EBV-induced secondary HLH. Rituximab
`was injected once and the patient developed a
`blood EBV load of zero within one week. In order to
`control abnormal stimulation of the
`immune
`system, HLH-2004 protocol was used. Full recovery
`was achieved by the patient. EBV PCR was
`immediately checked and rituximab therapy was
`discontinued. Serum Immunoglobulin levels were
`low during the treatment process. The patient was
`investigated for mutations in IL-2-inducible T cell
`kinase (ITK) and negative test results were received.
`(The patient was negative for mutations in IL-2-
`inducible T cell kinase (ITK)). She is now considered
`to be an acceptable candidate for transplantation
`from an HLA matched sibling donor.
`
`
`Table1: Laboratory Values on Admission
`
`WBC
`N
`L
`Mono
`Hb
`HCT
`PLT
`LDH
`BS
`BUN
`Cr
`Na
`K
`Ca
`P
`SGOT
`SGPT
`Bil
`Bilin
`Urea
`Fibrinogen
`Ferritine
`T
`Chol
`Cu
`
`1100/mm2
`387
`-
`-
`8.7/gLbs
`24.2%
`32000
`610
`126
`14
`0.5
`138
`4.3
`9.2
`3.4
`50
`253
`1.3
`0.1
`26
`1
`1159
`200
`180
`117
`
`Ceruloplasmin
`ANA
`ds DNA
`Ig (Before IVIG)
`IgM
`IgG
`IgA
`IgE
`EBV DNA (PBS)
`Ig (Before IVIG)
`IgM
`IgG
`IgA
`IgE
`EBV DNA (PBS)
`LP
`WBC
`RBC
`Pr
`GLo
`PT
`PTT
`Deb Test
`
`
`
`NL
`-
`-
`
`0
`27.1
`25
`7.5
`9850
`
`0
`27.1
`25
`7.5
`9850
`
`0
`0
`NL
`NL
`13
`37
`NL
`
`
`
`
`DISCUSSION
` HLH was first described in 1939. HLH can be
`divided into two subgroups: primary or familial HLH
`and secondary HLH. The primary form
`is an
`inflammatory disease which is similar to secondary
`one on the basis of symptoms.3 Primary HLH usually
`
`arises in young children less than one year old (70%
`cases); however, in rare cases it can also occur in
`adults
`(Perforin gene mutations have been
`identified in patients with primary HLH).4 Five types
`of gene mutations have been identified in patients
`with primary HLH. For example, Type 2 is caused by
`mutations in genes 21-22 and Type 5 is due to
`mutations
`in
`the MUNC18-20
`that may be
`hypogammaglobulinemia.5
`accompanied
`by
`Hypogammaglobulinemia was not confirmed in the
`patient because
`it was not possible to check
`mutation (the related tests were sent to Germany
`to examine the type 5 disease). EBV may also be
`accompanied by hypogammaglobulinemia for a
`certain period
` Secondary HLH is associated with immunologic
`stimulation caused by malignancies and bacterial or
`congenital infections. The most common causes of
`secondary HLH are viral infections by EBV, CMV,
`ProB19 and HIV. EBV-related secondary HLH may
`occur at any age. A secondary form of HLH may also
`occur in patients with normal immune systems.
`However, it may also be seen in patients with
`immune system defects.3, 4 Secondary HLH is a
`known complication of EBV infection, particularly in
`patients with x-linked lymphoproliferative disease.5
`The
`incidence of X-linked
`lymphoproliferative
`syndrome is 1 in 1,000,000 male infants.6, 7
` Diagnostic criteria for HLH disease are listed in
`Table2.
`
`Table2. Diagnostic criteria for HLH disease
`
`* Major Criteria:
`1. Fever of >38.6 Degrees centigrade
`2. Splenomegaly
`3. Cytopenia involving >= 2 cell lines
`4. Hyper Triglyceridemia or Hypofibrinogenemia
`5. Hemophagocytosis demonstrated in bone marrow, spleen or
`lymph node without evidence of malignancy
`* Alternative criteria
`1. Low or absent Nk cell activity
`2. Serum ferritin level of >500
`3. Soluble CD29 (soluble IL-2 receptor) level at >2400
`
`diagnosis of HLH requires the presence of all 5 major criteria. If the
`patient meets only 4criteria but the clinical suspicion for HLH is high,
`one should initiate treatment,
`Because delays may be fatal.
`Alternative criteria 1 or a combination of 2 and 3 may substitute for 1
`major criterion.
`Adapted from Henter JI,Elinder G,Ost A.Semin Oncol. 1991; 18:29-33.
`
` Precise mechanism of EBV-induced HLH has
`recently been found. It means that EBV-infected B
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`K. Goudarzipour, et al.
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`IJHOSCR, 1 January 2013. Volume 7, Number 1
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`cells stimulate cytotoxic T lymphocytes leading to
`hypercytokinemia and stimulation of histolytic
`cells.9, 10 More recently, it has been found that
`chronic stimulation by EBV may cause chronic HLH
`in the patient. On the other hand, EBV causes
`stimulation, generation and uncontrolled secretion
`of T-and NK- cells, as well as generation of IL2, INFa
`and IL6. These materials are said to be responsible
`for Hemophagocytic lymphohistiocytosis. There is
`another mechanism by which EBV stimulates
`membrane protein (LMP-1)
`in cells. The cells
`exceedingly secrete INFa, leading to macrophages.
`Similar to XLP, LMP-1 may cause acquired immune
`deficiency, leading to HLH accordingly.13, 14
` Treatment follows two goals: first, to suppress
`immune response using IVIG, steroid and HLH
`protocol. Second, to inhibit undesirable influence of
`immune response and cytokine-stimulated cell
`activation using immunochemotherapy. In cases
`with
`neurological
`symptoms,
`immunochemotherapy is required. The level of viral
`DNA which is measured by quantitative PCR may be
`useful
`to demonstrate
`treatment
`response
`predicting mortality. The DNA level reached zero in
`our patient. Using IVIG prior to start of protocol
`20042 may be
`regarded as an appropriate
`treatment, raising living hope. It has also been
`recommended in the treatment of EBV-induced
`secondary HLH monthly.2
`for
`treatment
` Rituximab may be a useful
`decreasing mortality. Decrease of B cells, which
`have been contaminated by EBV, actually causes
`decrease of viruses,16 as it may be useful for our
`patient as well. However, it has no significant effect
`on T cells. The effect of anti-INFa has not been
`confirmed
`yet.
`Finally,
`treatment-refractory
`patients,
`transplant candidates, patients with
`familial type of HLH, or recurrent disease undergo
`chemotherapy for 8 weeks. Patients who respond
`favorably
`to
`treatment
`do
`not
`undergo
`transplantation but those who experience relapse
`and exhibit neurological symptoms are considered
`for transplantation.
`
`CONCLUSION
` Severe infection of EBV is not associated with life-
`threatening condition, but our case study needs
`urgent treatment. In patients with long-term EBV
`
`44
`
`and
`coagulopathy
`pancytopenia,
`infection,
`the
`existence of
`hepatosplenomegaly,
`the
`secondary HLH is in doubt. To confirm the diagnosis,
`BMA will be performed and the serum ferritin level
`will be measured as well. For patients with
`secondary HLH, initial therapy with the HLH-2004
`protocol17 approach is appropriate. Rituximab can
`be used when HLH is associated with EBV to inhibit
`the immune response. Thus, the main aim of
`treatment is to reduce the rate of mortality in
`patients with HLH.
`
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