WORKUP	Section 5 of 10
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Lab Studies:

• Heterophil antibodies or Monospot testing is not always positive initially, but EBV generally is detectable by polymerase chain reaction (PCR) in tissues, if this method is available.

• A peripheral blood smear usually shows an atypical lymphocytosis of impressive magnitude.

• Findings consistent with massive hepatonecrosis also are observed, with markedly elevated liver transaminases and liver biopsies that show widespread necrosis.

• Most patients show the presence of immunoglobulin M (IgM) specific for EBV antigens.

• If a laboratory that can perform molecular analysis is available, mutations in the pathognomonic SH2-D1A gene or, alternatively, the absence of the gene transcription product (RNA or protein) in lymphocytes can be demonstrated.

Imaging Studies:

• No specific imaging studies are helpful.

Histologic Findings: Liver biopsy results typically show an intense periportal B-cell lymphoid infiltrate containing EBV, nuclear antigen (EBNA-1) often surrounded by numerous CD8-positive T lymphocytes and natural killer cells. In later stages, periportal necrosis is observed in most patients. Other organs may be involved during the fatal IM syndrome, including the liver, heart, brain, and thymus. Findings in the bone marrow generally are reactive, with hypercellularity and an excess of myeloid cells. Occasionally, a marked increase in the number of macrophages in the marrow can occur, which is associated with aplastic anemia.

	TREATMENT	Section 6 of 10
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Medical Care: A number of treatments have been used with variable success.

• Antiviral therapy: A small number of patients have been treated with either acyclovir or ganciclovir in an effort to halt the proliferative/lytic replication of EBV. Very little success with this therapy has occurred.

• Immunosuppressive therapy

• The use of immunosuppressive agents to decrease the violent immunologic response to EBV and the IM syndrome has been unrewarding.

• The single published trial of steroids with antithymocyte globulin led to a marked increase in the number of lymphomas observed in this group of patients.

• Cytotoxic chemotherapy
  

  • Suggestions exist that treatment with cytotoxic chemotherapy during the acute IM syndrome might be helpful in controlling proliferation of EBV-transformed B cells, as well as potentially activated cytotoxic lymphocytes that may be causing the severe tissue reactions observed in this disorder.

  • In a small number of cases, etoposide has been shown to lead to control of lymphocyte proliferation, at least temporarily. Limited anecdotal data confirm that this or other cytotoxics may be a successful treatment modality; however, further study is needed.

• Bone marrow/stem cell transplantation: Two reports are available of successful bone marrow transplantation in this disease. Both patients initially were treated with high-dose cytotoxic chemotherapy, and both patients received allogeneic bone marrow transplantation. Subsequently, both patients have had resolution of their hypogammaglobulinemia and are healthy at ages 18 months and 3 years, respectively. Further experience is necessary, but this may be an important method of decreasing the high mortality rates of this disease.

	MEDICATION	Section 7 of 10
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No clearly effective medications exist for this disease, although cytotoxic chemotherapy agents may be useful. Further study is needed.

Drug Category: Antineoplastic agents -- Inhibit cell growth and proliferation.

Drug Name	Etoposide (VePesid, VP-16) -- Topoisomerase II inhibitor that leads to single-strand DNA breaks and cell cycle arrest. Has activity in a number of tumors, including small cell lung cancer, germ cell tumors, and lymphoma. One reported case used 200 mg/m2/d IV for 3 d during acute EBV infection in a boy aged 6 years. Led to dramatic, although temporary, improvement. Little data support etoposide therapy in this syndrome.
Adult Dose	Not established
Pediatric Dose	Not established; 200 mg/m2/d IV for 3 d is suggested
Contraindications	Documented hypersensitivity; IT administration may cause death
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Bleeding and severe myelosuppression may occur; decrease dose in hyperbilirubinemia and renal dysfunction; avoid extravasation; should only be administered by trained physician; adverse effects include myelosuppression, nausea, and vomiting (can be controlled with serotonin-antagonist antiemetics such as ondansetron, granisetron, or dolasetron)

Drug Category: Blood products -- For improvement of immunodeficiency.

Drug Name	Immune globulin, intravenous (Gamimune, Gammar-P, Sandoglobulin, Gammagard) -- Limited literature suggests that use of intravenous immunoglobulin may help speed resolution of the acute IM syndrome and prevent some secondary infections due to humoral immunodeficiency. No controlled studies exist, and its use is still speculative.
Adult Dose	Not established; most patients are children
Pediatric Dose	500 mg/kg/d throughout acute course of mononucleosis is suggested; once acute phase has begun to resolve, maintenance therapy can be administered at decreased frequency; one report of a single case added interferon alfa (2 X 106 IU/m2/d) to this regimen with ultimately a good outcome
Contraindications	Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies
Interactions	Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

	FOLLOW-UP	Section 8 of 10
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Complications:

• See Pathophysiology.

Prognosis:

• Except for reported cases of remission due to stem cell transplantation, few children with this syndrome survive to adulthood. Therefore, most patients with available matched donors apparently should be referred for transplantation. However, more data are needed to substantiate the efficacy of this form of therapy.

Patient Education:

• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Mononucleosis.

	MISCELLANEOUS	Section 9 of 10
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Medical/Legal Pitfalls:

• The syndrome should be suspected in the case of an exceptionally severe lymphadenopathic reaction in mononucleosis. Otherwise, the rarity of the disease suggests little likelihood of legal risk.

	BIBLIOGRAPHY	Section 10 of 10
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• Coffey AJ, Brooksbank RA, Brandau O: Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998 Oct; 20(2): 129-35[Medline].
• Harrington DS, Weisenburger DD, Purtilo DT: Malignant lymphoma in the X-linked lymphoproliferative syndrome. Cancer 1987 Apr 15; 59(8): 1419-29[Medline].
• Nichols KE, Harkin DP, Levitz S: Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci U S A 1998 Nov 10; 95(23): 13765-70[Medline].
• Purtilo DT, Cassel CK, Yang JP: X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1975 Apr 26; 1(7913): 935-40[Medline].
• Purtilo DT, Yang JP, Allegra S: Hematopathology and Pathogenesis of the X-linked recessive lymphoproliferative syndrome. Am J Med 1977 Feb; 62(2): 225-33[Medline].
• Purtilo DT, DeFlorio D, Hutt LM: Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome. N Engl J Med 1977 Nov 17; 297(20): 1077-80[Medline].
• Purtilo DT, Grierson HL, Davis JR: The X-linked lymphoproliferative disease: from autopsy toward cloning the gene 1975-1990. Pediatr Pathol 1991 Sep-Oct; 5: 685-710[Medline].
• Sayos J, Wu C, Morra M: The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 1998 Oct 1; 395(6701): 462-9[Medline].
• Sullivan JL: The abnormal gene in X-linked lymphoproliferative syndrome. Curr Opin Immunol 1999 Aug; 11(4): 431-4[Medline].
• Williams LL, Rooney CM, Conley ME: Correction of Duncan's syndrome by allogeneic bone marrow transplantation. Lancet 1993 Sep 4; 342(8871): 587-8[Medline].

Lymphoproliferative Syndrome, X-linked excerpt