Published online April 2, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. e1212-e1218 (doi:10.1542/peds.2006-1534)
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EXPERIENCE & REASON

Epstein-Barr Virus–Induced Hemophagocytic Lymphohistiocytosis and X-Linked Lymphoproliferative Disease: A Mimicker of Sepsis in the Pediatric Intensive Care Unit

Matthew Mischler, MDa, Geoffrey M. Fleming, MDa, Thomas P. Shanley, MDa, Lisa Madden, MDb, John Levine, MDb, Valerie Castle, MDb, Alexandra H. Filipovich, MDc and Timothy T. Cornell, MDa

a Divisions of Critical Care Medicine
b Hematology and Oncology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan
c Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio

ABSTRACT

A rare complication of infection with the Epstein-Barr virus is the development of hemophagocytic lymphohistiocytosis. Although most cases of Epstein-Barr virus–induced hemophagocytic lymphohistiocytosis develop in immunocompetent individuals, the rare immunodeficiency X-linked lymphoproliferative disease is often unmasked by Epstein-Barr virus infection and is clinically indistinguishable from Epstein-Barr virus–induced hemophagocytic lymphohistiocytosis. We describe the clinical course and management of a previously healthy 17-year-old boy who presented with hemodynamic collapse and severe systemic inflammatory response syndrome resulting from overwhelming hemophagocytosis in the setting of X-linked lymphoproliferative disease. A novel therapeutic approach using anti–tumor necrosis factor {alpha} therapy was instituted, aimed at attenuating the viral-induced hyperinflammatory state. Given the similarity to overwhelming sepsis, yet a substantially different therapeutic approach, this case illustrates the importance of early recognition and prompt treatment that are necessary to reduce the high morbidity and mortality associated with Epstein-Barr virus–induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease.

Key Words: X-linked lymphoproliferative disease • hemophagocytic lymphohistiocytosis • systemic inflammatory response syndrome • infectious mononucleosis • sepsis • Epstein-Barr virus • Etanercept

Abbreviations: EBV, Epstein-Barr virus • HLH, hemophagocytic lymphohistiocytosis • XLP, X-linked lymphoproliferative • TNF-{alpha}, tumor necrosis factor {alpha} • IL, interleukin • SAP, signaling lymphocyte activation molecule–associated protein • Th, T helper • LMP-1, latent membrane protein 1 • IVIG, intravenous immunoglobulin

Epstein-Barr virus (EBV), which preferentially infects B cells, has a variety of clinical presentations that range from an asymptomatic carrier state to a fatal overwhelming infection. In the majority of the population, EBV causes acute infectious mononucleosis, a self-limiting illness characterized by fever, lymphadenopathy, tonsillopharyngitis, and hepatosplenomegaly.1 An infrequent complication of EBV infection is the development of hemophagocytic lymphohistiocytosis (HLH), a disorder of unregulated activation of lymphohistiocytic cells that results in hemophagocytosis, hypercytokinemia, and multiorgan system dysfunction. Although associated with substantial morbidity and mortality, early recognition and prompt therapy may result in successful treatment of EBV-induced HLH.

Here we present the case of a previously healthy 17-year-old boy with acute infectious mononucleosis followed by a rapidly deteriorating clinical course resulting from EBV-induced HLH and associated with underlying immunodeficiency X-linked lymphoproliferative (XLP) disease. We also describe our therapeutic approach, which incorporated a novel application of anti–tumor necrosis factor {alpha} (TNF-{alpha}) therapy.

CASE REPORT

Four weeks before admission, a previously healthy 17-year-old boy was diagnosed with infectious mononucleosis on the basis of a 1-week history of fever, malaise, myalgias, headache, abdominal pain, tender splenomegaly, and emesis. EBV antibody titers showed acute infection, with a complete blood cell count showing mild pancytopenia and atypical lymphocytes consistent with acute infectious mononucleosis. In the weeks after diagnosis his symptoms persisted, with recurrent fever to 39°C, nausea, abdominal pain, pharyngitis, intermittent truncal maculopapular rash, fatigue, and poor oral intake. Four weeks after his initial diagnosis, he was readmitted to the hospital for worsening pancytopenia and dehydration. Despite transient response to aggressive intravenous rehydration, his clinical condition rapidly deteriorated on hospital day 2, with refractory hypotension, decreasing urine output, and declining mental status. He was subsequently transferred to the PICU.

On arrival to our PICU, his examination was consistent with low cardiac output including poor distal perfusion and purplish discoloration noted at the distal tips of his fingers, toes, and nose. His admission laboratory values are listed in Table 1. He subsequently went into cardiorespiratory failure and required intubation and mechanical ventilation along with inotropic and vasopressor therapy. Given his clinical presentation of fever, hypotension, and pancytopenia, broad-spectrum antibiotics were empirically started for concern of severe sepsis. Because previous viral infections are commonly associated with subsequent secondary bacterial infections (often termed "superinfections"), this distinct possibility was considered as a principal cause of his acute cardiorespiratory collapse. Blood and urine cultures were performed on presentation and throughout his hospitalization, and results remained negative for the duration of his stay.


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  		TABLE 1 Laboratory Values on Admission to the PICU

 
His prolonged course of EBV, however, led to the inclusion of EBV-related complications such as HLH in the differential diagnosis for the patient's rapid decline. A bone marrow biopsy was performed soon after admission to the PICU, with findings concerning for EBV-induced HLH, namely, pancytopenia, widespread hemophagocytosis, and large granular lymphocytes. Concurrent elevations in lactate dehydrogenase, ferritin, EBV-DNA copy numbers, and soluble interleukin (IL) 2 receptor {alpha} (Table 1) provided additional supportive evidence for EBV-induced HLH. Genetic studies performed at one of the author's (Dr Filipovich's) HLH reference laboratory showed normal perforin activity consistent with secondary HLH.2–4 Additional testing showed decreased natural killer cell function and absent signaling lymphocyte activation molecule–associated protein (SAP),5 both of which are consistent with the underlying immunodeficiency XLP disease. Subsequent genetic testing of the SH2D1A gene,6 which encodes for SAP, revealed no mutations. Furthermore, a detailed family history revealed no XLP disease or immunodeficiency in either the maternal or paternal lineage, which suggested the diagnosis of "sporadic" XLP disease with the specific genetic defect yet undefined versus sporadic HLH with absent SAP and natural killer cell function.6–9

His initial treatment regimen consisted of intravenous immunoglobulin, high-dose methylprednisolone, and rituximab, an anti-CD20 antibody. However, over the next 36 hours, his systemic inflammatory-response syndrome worsened and led to multiple organ dysfunction, as reflected by the need for continuous venovenous hemofiltration therapy for renal failure, increased blood-product replacement for hematologic failure, massive inotropic and vasopressor support for cardiovascular failure, and continued mechanical ventilatory support for respiratory failure.

Given the uncontrolled immune activation unrelated to bacterial infection, etoposide therapy was instituted at 150 mg/m2 in accordance with the HLH-2004 treatment protocol.10 His clinical status continued to show little improvement, and the decision was made to administer an anti–TNF-{alpha} antibody: etanercept 25 mg intravenously. After his dose of etanercept, his clinical status stabilized and improved swiftly over the next 36 hours, with improved liver and kidney function, a decrease in blood-product replacement, and a decrease in inotropic and vasopressor support (Fig 1). On the basis of the favorable clinical response observed after the initial dose but in light of ongoing organ dysfunction, the decision was made by the clinical care team to administer a subsequent course of etanercept. The same dose was administered and was associated with resolution of vasopressor and inotropic requirement, decrease in mechanical ventilatory requirements, and improvement in renal function, which led to eventual withdrawal of continuous renal replacement therapy.


Figure 1
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  		FIGURE 1 Timing of etanercept dose and vasopressor/inotropic requirements.

 
Levels of ferritin and lactate dehydrogenase, which have been suggested to be reliable clinical markers of disease activity in HLH,4 gradually decreased over the subsequent week, with repeat EBV DNA showing 0 copies on intensive care day 7 correlating with his white blood cell count. His fever curve also began to improve and gradually normalized by day 14 of intensive care.

In the 2 weeks after starting etanercept and etoposide, the patient demonstrated steady resolution of his multiple organ failure, affording the discontinuation of renal replacement therapy and continuous infusions of vasoactive and sedative agents. Despite discontinuation of his sedation, the patient showed minimal signs of cognitive function. At this time, initial brain imaging was performed using MRI, which revealed a nonspecific inflammatory pattern with scattered, nonenhancing signal abnormalities in the frontal white matter and cerebellar peduncles, consistent with EBV-induced HLH and XLP disease.2,3,11 Intrathecal chemotherapy was initiated according to the HLH-2004 protocol, and the patient recovered near-normal cognitive function by week 6 of intensive care. Repeat MRI was performed 6 and 12 weeks after initiation of therapy and showed improvement in signal abnormalities corresponding with his improved cognitive status. Aggressive physical and occupational therapy was instituted while he was maintained on the HLH-2004 protocol. He underwent extensive rehabilitation until he eventually had a successful bone marrow transplant.

DISCUSSION

HLH was first described in 1939 and has since been broken down into primary and secondary HLH.4 Primary HLH, also termed familial HLH, is an autosomal recessive disease with an identical phenotype to secondary HLH. More than 70% of patients with familial HLH develop the disease at <1 year of age, although familial forms have been reported into early adulthood.2 It is linked with mutations in the gene coding for perforin, which was evaluated and found to be normal in our patient. Secondary HLH has been associated with immunologic triggers including malignancies, bacterial or parasitic infections, and, most commonly, viral infections including EBV, cytomegalovirus, parvovirus, and HIV. The prototypical and most often reported association is EBV-induced HLH. EBV-induced HLH can affect any age group, ranging from infants to young adults, and tends to occur in apparently immunocompetent individuals.2,4 EBV-induced HLH is a distinct clinical entity with defined diagnostic criteria (Table 2) characterized by evidence of EBV infection, persistent fever, cytopenia, liver dysfunction, coagulopathy, hepatosplenomegaly, and hemophagocytosis in the bone marrow, lymph nodes, liver, and spleen.2–4,11 As the signs and symptoms of EBV-induced HLH imply, the differential diagnosis is extremely broad, particularly in the ICU setting with a critically ill patient. The hematologic and clinical abnormalities often suggest sepsis, leukemia, lymphoma, or systemic autoimmune vasculitis as the underlying cause. The true prevalence of the disease is unknown at this time, because it remains largely underdiagnosed in Western countries. Although the majority of EBV-induced HLH develops in immunocompetent individuals, EBV can unmask an underlying immune disorder, the most common being XLP disease.9 The phenotypic presentation of EBV-induced HLH and XLP disease is largely indistinguishable, and both carry a reported mortality rate of >90%.9,12


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  		TABLE 2 HLH Diagnostic Criteria

 
XLP disease is a congenital immunodeficiency that is estimated to affect 1 in 1000000 males that may present anywhere from childhood to early adulthood. The 3 main phenotypes of XLP disease are (1) inappropriate immune response to EBV with fatal or near-fatal infectious mononucleosis, (2) lymphoproliferative disorders, typically of B-cell origin, and (3) dysgammaglobulinemia. The most common presenting phenotype is fulminant infectious mononucleosis, which is highly fatal and clinically and pathophysiologically identical to EBV-induced HLH. Indeed, the diagnosis of EBV-induced HLH should prompt an investigation for XLP disease, because the clinical presentation of EBV-induced HLH is the most common manifestation of underlying XLP disease.6–9 In addition to fulminant infectious mononucleosis, our patient also exhibited dysgammaglobulinemia after presentation to the PICU, which is consistent with the underlying diagnosis.

The genetic defect in XLP disease was recently mapped to Xq25 in the SH2D1A gene. The SH2D1A gene is responsible for an SAP, found to be deficient or absent in patients with XLP disease.5,13,14 The SH2 domain of SAP binds a phosphorylated tyrosine in the cytoplasmic domain of 2 type 1 transmembrane receptors, physically associating with signaling lymphocyte activation molecule (SLAM) receptors present on T and B lymphocytes and 2B4 receptors present on natural killer cells.15–17 There is some evidence that SAP-deficient cytotoxic T cells are unable to lyse EBV-positive B cells, leading to the rapid proliferation of large granular lymphocytes and enhanced T helper 1 (Th1) cytokine production, which leads to the cytokine storm seen in EBV-induced HLH and XLP disease.18 Other studies suggest deficiency in natural killer cell lytic activity or lack of development of a subset of cytotoxic T lymphocytes known as natural killer T cells.19–21 Regardless of the role of SAP, genetic sequencing of the SH2D1A gene is available to detect known mutations that produce XLP-disease phenotypes and should be sent whenever fulminant infectious mononucleosis and EBV-induced HLH is encountered. The gene testing can detect 97% of known SH2D1A mutations in affected males with the XLP-disease phenotype, but only in those with ≥2 maternal relatives with XLP disease.8,9 Our patient had no family history of XLP disease, and his SH2D1A gene testing revealed none of the known mutations in the coding sequence. Testing of his SAP activity on flow cytometry, however, revealed nearly absent activity and, coupled with his clinical presentation of fulminant infectious mononucleosis and dysgammaglobulinemia, led to the diagnosis of XLP disease rather than sporadic secondary EBV-induced HLH.

The exact mechanism of how EBV induces HLH, with or without XLP disease and producing the characteristic clinical response, has only recently begun to be elucidated. It has been suggested that EBV infection of B cells triggers a polyclonal proliferation of cytotoxic T lymphocytes, which in turn stimulate histiocytes and macrophages, resulting in uncontrolled immune activation and subsequent hypercytokinemia.22,23 Research performed in chronic active EBV infection, a chronic ongoing mononucleosis of unknown etiology but with a somewhat similar presentation as that of EBV-induced HLH and XLP disease, has shown that activated T lymphocytes laden with EBV DNA express both Th1 and Th2 cytokines, which leads to ongoing inflammation and disease activity.1 Other data suggest that EBV targets CD8+ T cells and natural killer cells, which leads to rapid, uncontrolled proliferation and profound release of immense levels of IL-2, interferon {gamma}, TNF-{alpha}, and IL-6, among other inflammatory cytokines, as a result of widespread lymphohistiocytic activation.24–27 More recent studies have focused on characteristics of the virus itself that induce the phenotype of XLP disease and HLH, one of which is latent membrane protein 1 (LMP-1) on the surface of EBV. In EBV-infected cell lines, LMP-1 was shown to upregulate the TNF-{alpha} gene and lead to increased secretion from infected T lymphocytes, corresponding with previous data showing elevations in TNF-{alpha} and macrophage activation in EBV-associated T-cell lymphoproliferative disorders.28,29 There is also evidence that LMP-1 may directly inhibit expression of the SAP gene, which leads to loss of the gene product and increased Th1 cytokine activation. In addition to therapeutic implications, this function of LMP-1 would provide a basis for the similar phenotypic presentation of XLP disease and HLH via gene mutation and suppression of the gene product, respectively.30

Our treatment plan had 2 aspects aimed at reducing the uncontrolled immune response. First, we targeted the sources of immune activation with intravenous immunoglobulin (IVIG) and high-dose corticosteroids followed by the institution of the HLH-2004 treatment protocol. The HLH-2004 protocol, which evolved from the HLH-94 protocol, was devised with the intention of interrupting the inappropriate immune response and cytokine-activation cascade by using immunochemotherapy. After a diagnosis of HLH or a clinical scenario consistent with the diagnosis (see Table 2 for diagnostic criteria), initial therapy involves etoposide at 150 mg/m2 twice weekly and dexamethasone infusion at 10 mg/m2 twice weekly. In the evolution of the HLH protocols, HLH-2004 now includes cyclosporin A, aiming for trough levels of 200 µg/L during the first week, assuming normal renal function.10 The use of cyclosporin is thought to improve patient outcomes by controlling the deregulated release of cytokines and improving neutrophil recovery during disease or therapy-induced neutropenia.4,31 Our patient was in acute renal failure on presentation, precluding the use of cyclosporin until renal function had returned to baseline. Finally, the HLH-2004 protocol also includes intrathecal methotrexate and prednisolone during initiation for patients with central nervous system symptoms that are documented either by irregular lumbar puncture or findings on central nervous system imaging.10 Our patient did indeed show signs of central nervous system involvement, with cognitive impairment noted on presentation to the PICU and continuing after other organ systems had recovered. He did not show full cognitive recovery with intact sensorium until 6 weeks after his initial presentation, corresponding with improvement in the signal abnormality seen on his MRI. During initial immunochemotherapy, disease progression can be assessed with recovery of platelet counts, decrease in ferritin and soluble IL-2 levels, and absence of hemophagocytosis in bone marrow.2–4 In addition, elimination of EBV DNA documented by quantitative polymerase chain reaction has been shown to be useful in documenting response to therapy and predicting mortality.32 Our patient's titers from peripheral whole blood responded well as therapy progressed and corresponded with improvement in his clinical status (Fig 2). The use of IVIG and initial high-dose corticosteroid therapy is well documented and was the standard of care before the initiation of the HLH-2004 protocol.33,34 Later studies have shown that patients who receive etoposide within 4 weeks of diagnosis have a higher rate of survival than those who receive only IVIG and steroids.34,35 However, there is still thought to be a role for IVIG in the initial presentation of EBV-induced HLH and XLP disease; indeed, IVIG is required once every 4 weeks in the HLH-2004 protocol.10 For our patient, IVIG and high-dose corticosteroids were initiated in conjunction with the bone marrow biopsy, when the diagnosis was still not entirely clear but highly suspected, not in lieu of the HLH-2004 protocol. In addition, although not considered standard therapy, the use of Rituxan in our patient was supported by recent data suggesting that B cells may also be targeted in EBV-associated XLP disease, and directed therapy with the anti-CD20 antibody may reduce morbidity and mortality by reducing the circulating B-cell population and, thus, EBV viral load.36 Of note, this approach will not target EBV-infected T lymphocytes that are thought to contribute to widespread immune activation as reviewed above.


Figure 2
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  		FIGURE 2 Association between EBV-genome copies per mL whole blood and white blood cell (WBC) count. The patient received methylprednisolone and IVIG on admission to the PICU. He received etoposide on intensive care days 1, 5, and 23, rituximab on day 1, and etanercept on days 2 and 7.

 
The interruption of the immune activation with the HLH-2004 protocol takes several days to weeks to occur, and because of the rapid clinical deterioration of our patient, our second therapy was aimed at reducing the proinflammatory cytokine levels. The upregulation of the TNF-{alpha} gene leading to widespread macrophage activation has been documented in EBV infection of T cells, which suggests a possible role for the use of an anti–TNF-{alpha} antibody such as etanercept in HLH and XLP disease.28,29 Although etanercept has been suggested as a possible therapeutic intervention, its successful use has not been documented in the literature to date. Our decision to use etanercept was also supported by previous experience with it at our institution for noninfectious cytokine storm37 as well as data suggesting reduction in early mortality with anti–TNF-{alpha} therapy in sepsis.38 After administration of etanercept, our patient had a dramatic improvement in hemodynamics as reflected by a rapid decrease in vasopressor requirements (Fig 1), as well as improvement in renal and liver function and decreased requirement for blood-product replacement. However, we did not measure serum TNF-{alpha} before and after the institution of anti–TNF-{alpha} therapy, which makes it impossible to conclude unequivocally that etanercept specifically afforded control of the severe systemic inflammatory response exclusive of the effects of the additional therapies including etoposide, IVIG, steroids, Rituxan, and/or continuous renal replacement therapy. The clinical response observed after anti–TNF-{alpha} antibody infusion strongly suggests this to be the case, especially in light of the known role of TNF-{alpha} in HLH and XLP disease. Regrettably, TNF-{alpha} levels were not obtained before or after etanercept therapy, so we are unable to precisely show TNF-{alpha} neutralization in this case. Nevertheless, additional studies with etanercept are needed in patients with EBV-induced HLH and XLP disease and other illnesses that result in nonbacterial-induced hypercytokinemia before its routine use in such patients can be universally recommended.

CONCLUSIONS

Acute EBV infection is not life-threatening in the majority of individuals who are infected. Rarely, however, life-threatening complications develop that require immediate recognition and treatment. In the presence of prolonged EBV infection and severe hemodynamic collapse with pancytopenia, coagulopathy, and hepatosplenomegaly, EBV-induced HLH should be suspected and warrant determination of ferritin levels, EBV studies, and a bone marrow aspiration to expedite diagnosis and direct life-saving therapy. Furthermore, any case of EBV-induced HLH in males should prompt an investigation for XLP disease, because the two are clinically indistinguishable. The HLH-2004 protocol provides guidelines for management of these patients in the acute setting, and rapid therapy aimed at attenuating the proinflammatory mediators using etanercept may be warranted given previous research and our experience in this case. As targeted therapy evolves, increased awareness of EBV-induced HLH and XLP disease is necessary to improve and prevent the high associated morbidity and mortality.

FOOTNOTES

Accepted Oct 31, 2006.

Address correspondence to Timothy T. Cornell, MD, Division of Pediatric Critical Care Medicine, C.S. Mott Children's Hospital, University of Michigan, 1500 E Medical Center, Ann Arbor, MI 48109. E-mail: ttcornel{at}med.umich.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

REFERENCES

  1. Ohga S, Nomura A, Takada H, Hara T. Immunological aspects of Epstein-Barr virus infection. Crit Rev Oncol Hematol. 2002;44 :203 –215[Web of Science][Medline]
  2. Henter JI. Hemophagocytic lymphohistiocytosis (HLH): symptoms, signs and diagnosis of a rapidly fatal childhood disease. 2004. Available at: www.histio.org/site/apps/nl/content2.asp?c=kiKTL4PQLvF&b=1850031&ct=2592057. Accessed January 25, 2007
  3. Henter JI, Arico M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH Study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28 :342 –347[CrossRef][Web of Science][Medline]
  4. Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44 :259 –272[Web of Science][Medline]
  5. Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. 1998;395 :462 –469[CrossRef][Medline]
  6. Tabata Y, Villanueva J, Lee SM, et al. Rapid detection of intracellular SH2D1A protein in cytotoxic lymphocytes from patients with X-linked lymphoproliferative disease and their family members. Blood. 2005;105 :3066 –3071[Abstract/Free Full Text]
  7. Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood. 2001;97 :1131 –1133[Abstract/Free Full Text]
  8. Sumegi J, Huang D, Lanyi A, et al. Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. 2000;96 :3118 –3125[Abstract/Free Full Text]
  9. Sumegi J, Johnson J, Filipovich AH, Zhang K. Lymphoproliferative disease, X-linked. 2004. Available at: www.genetests.org/query?gene=SH2D1A. Accessed January 25, 2007
  10. Henter JI, Horne AC, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48 :124 –131[CrossRef][Web of Science][Medline]
  11. Imashuku S, Hlbi S, Todo S. Hemophagocytic lymphohistiocytosis in infancy and childhood. J Pediatr. 1997;130 :352 –357[CrossRef][Web of Science][Medline]
  12. Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol. 1997;66 :135 –151[CrossRef][Web of Science][Medline]
  13. Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998;20 :129 –135[CrossRef][Web of Science][Medline]
  14. Nichols KE, Harkin DP, Levitz S, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci USA. 1998;95 :13765 –13770[Abstract/Free Full Text]
  15. Howie D, Simarro M, Sayos J, Guirado M, Sancho J, Terhorst C. Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation. Blood. 2002;99 :957 –965[Abstract/Free Full Text]
  16. Li C, Iosef C, Jia CY, Gkourasas T, Han VK, Shun-Cheng LS. Disease-causing SAP mutants are defective in ligand binding and protein folding. Biochemistry. 2003;42 :14885 –14892[CrossRef][Medline]
  17. Shlapatska LM, Mikhalap SV, Berdova AG, et al. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J Immunol. 2001;166 :5480 –5487[Abstract/Free Full Text]
  18. Dupre L, Andolfi G, Tangye SG, et al. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood. 2005;105 :4383 –4389[Abstract/Free Full Text]
  19. Pasquier B, Yin L, Fondaneche MC, et al. Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. J Exp Med. 2005;201 :695 –701[Abstract/Free Full Text]
  20. Sullivan JL, Byron KS, Brewster FE, Purtilo DT. Deficient natural killer cell activity in x-linked lymphoproliferative syndrome. Science. 1980;210 :543 –545[Abstract/Free Full Text]
  21. Tangye SG, Phillips JH, Lanier LL, Nichols KE. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J Immunol. 2000;165 :2932 –2936[Abstract/Free Full Text]
  22. Imashuku S, Hibi S, Ohara T, et al. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood. 1999;93 :1869 –1874[Abstract/Free Full Text]
  23. Lee JS, Kang JH, Lee GK, Park HJ. Successful treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol. J Korean Med Sci. 2005;20 :209 –214[Web of Science][Medline]
  24. Imashuku S, Tabata Y, Teramura T, Hibi S. Treatment strategies for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Leuk Lymphoma. 2000;39 :37 –49[Web of Science][Medline]
  25. Kasahara Y, Yachie A. Cell type specific infection of Epstein-Barr virus (EBV) in EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Crit Rev Oncol Hematol. 2002;44 :283 –294[Web of Science][Medline]
  26. Kawaguchi H, Miyashita T, Herbst H, et al. Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virus-associated hemophagocytic syndrome. J Clin Invest. 1993;92 :1444 –1450[Web of Science][Medline]
  27. Larroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun Rev. 2004;3 :69 –75[CrossRef][Medline]
  28. Lay JD, Chuang SE, Rowe M, Su IJ. Epstein-Barr virus latent membrane protein-1 mediates upregulation of tumor necrosis factor-alpha in EBV-infected T cells: implications for the pathogenesis of hemophagocytic syndrome. J Biomed Sci. 2003;10 :146 –155[Web of Science][Medline]
  29. Lay JD, Tsao CJ, Chen JY, Kadin ME, Su IJ. Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest. 1997;100 :1969 –1979[Web of Science][Medline]
  30. Chuang HC, Lay JD, Hsieh WC, et al. Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood. 2005;106 :3090 –3096[Abstract/Free Full Text]
  31. Imashuku S, Hibi S, Kuriyama K, et al. Management of severe neutropenia with cyclosporin during initial treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2000;36 :339 –346[Web of Science][Medline]
  32. Teramura T, Tabata Y, Yagi T, Morimoto A, Hibi S, Imashuku S. Quantitative analysis of cell-free Epstein-Barr virus genome copy number in patients with EBV-associated hemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2002;43 :173 –179[CrossRef][Web of Science][Medline]
  33. Blanche S, Caniglia M, Fischer A, Griscelli C. Epstein-Barr virus-associated hemophagocytic syndrome: clinical presentation and treatment. Pediatr Hematol Oncol. 1989;6 :233 –235[Web of Science][Medline]
  34. Imashuku S, Kuriyama K, Teramura T, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19 :2665 –2673[Abstract/Free Full Text]
  35. Imashuku S, Kuriyama K, Sakai R, et al. Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol. 2003;41 :103 –109[CrossRef][Web of Science][Medline]
  36. Milone MC, Tsai DE, Hodinka RL, et al. Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy. Blood. 2005;105 :994 –996[Abstract/Free Full Text]
  37. Yanik G, Hellerstedt B, Custer J, et al. Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2002;8 :395 –400[CrossRef][Web of Science][Medline]
  38. Abraham E. Why immunomodulatory therapies have not worked in sepsis. Intensive Care Med. 1999;25 :556 –566[CrossRef][Web of Science][Medline]
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M. L. Gulley and W. Tang
Laboratory Assays for Epstein-Barr Virus-Related Disease
J. Mol. Diagn., July 1, 2008; 10(4): 279 - 292.
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