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Epstein-Barr virus–associated hemophagocytic syndrome mimicking severe

Talya Spivack1, Rashmi Chawla1, Paul E Marik1

Department of Internal Medicine, 1Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, PA, USA

ABSTRACT Severe sepsis is amongst the most common reasons for admission to the intensive care unit (ICU) throughout the world and is a common cause of death. The diagnosis of sepsis is usually straightforward, being based on a constellation of clinical and laboratory features. Noninfectious disorders, including pancreatitis, drug reactions, and autoimmune disorders, may cause a systemic inflammatory response that mimics sepsis. We present the case of a 32-year-old male with Epstein-Barr virus–associated hemophagocytic syndrome who presented to the ICU with features of severe sepsis which progressed to multisystem organ failure and death despite aggressive supportive measures.

Key Words: Bile ductopenia, Epstein-Barr virus, erythrophagocytic syndrome, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome, multiorgan failure, sarcoid, sepsis, systemic

INTRODUCTION biopsy performed at another hospital 2 months earlier for presumed alcoholic hepatitis had revealed ‘scattered noncaseating Sepsis is amongst the most common reasons for admission to granulomas within the parenchyma and portal tracts’; culture intensive care units throughout the world and the leading cause and stain for mycobacterium had been negative. These features of death in noncoronary ICUs.[1,2] The diagnoses of sepsis is were considered to be consistent with hepatic sarcoidosis and usually straightforward; patients present variably with tachycardia, treatment with oral prednisone at a dose of 20 mg daily had tachypnea, fever (hypothermia), (or been commenced. and bandemia), together with a hyperdynamic circulation and a presumed source of .[3] These manifestations are On presentation to our hospital, he was markedly jaundiced, largely due to cytokine release triggered by bacterial products. febrile (39.4°C), and hypotensive. He was alert and orientated. Noninfectious disorders, including pancreatitis, drug reactions, Physical examination revealed hepatosplenomegaly and small and autoimmune disorders, may cause a systemic inß ammatory and shotty right axillary lymphadenopathy. He was pancytopenic; response that mimics sepsis. We report a patient with Epstein- hemoglobin (Hb) was 8.7 g/dl, with 1.6% reticulocytes; white Barr virus (EBV)–associated hemophagocytic syndrome (HPS) cell count (WBC) was 1100/μL with 66% neutrophils who presented with the features of severe sepsis. and 18% bands and a platelets count of 104 000/μL. Serum chemistries were normal. Total bilirubin was 33 mg/dl (normal: CASE REPORT 0.2–1.2 mg/dl), direct bilirubin 14 mg/dl (normal: 0.0–0.4 mg/ dl), alanine aminotransferase (ALT) 135 IU/l (normal: 1–45 A 32-year-old male was admitted to our hospital with persistent IU/l), aspartate aminotransferase (AST) 25 IU/l (normal: 7–42 fever, body aches, and rhinorrhea of 2 weeks’ duration. He IU/l), alkaline phosphatase (ALP) 1431 IU/l (normal: 25–120 had recently completed a course of antibiotics for presumed IU/l), lactate dehydrogenase 411 IU/l (normal: 100–200 IU/l), acute sinusitis. He denied having cough, chest pain, abdominal ceruloplasmin 27.2 mg/dl (normal: 22–58 mg/dl), Þ brinogen 138 pain, dysuria, or headaches. He had a history of worsening mg/dl (normal: 201–422 mg/dl), D-dimer 0.68 ug/ml (normal: jaundice and pruritus over the previous 4 months. He gave < 0.68 ug/ml), triglycerides 161 mg/dl, and ferritin 5208 ng/ a history of heavy alcohol abuse in the past. He worked as a ml (normal: 15–280 ng/ml). Immunoglobulin electrophoresis correctional ofÞ cer and enjoyed hunting wild animals. A liver was normal. Portable chest radiograph was reported to be normal. Although there was no obvious source of infection, he was treated with vancomycin and piperacillin/tazobactam for Correspondence: Dr. Paul E Marik, E-mail: [email protected] presumed severe sepsis. His hypotension resolved with ß uid

Journal of Emergencies, Trauma and Shock | 1:2 | Jul - Dec 2008 119 Spivack et al.: EBV-HPS mimicking severe sepsis resuscitation (2 l of 0.9% saline). Blood and urine cultures were negative. HIV; cytomegalovirus; parvovirus; hepatitis A, B, and C; coccidioides; toxoplasmosis; and brucella serologies were negative. Epstein-Barr virus (EBV) IgG was positive, consistent with previous exposure. Autoimmune workup, including ANA, ANCA, rheumatoid factor, and Coomb’s test, were negative. Computerized tomographic scans of his head, chest, and abdomen showed extensive pansinusitis, innumerable scattered bilateral lung nodules measuring up to 1 cm in diameter, mild right axillary lymphadenopathy, and hepatosplenomegaly. A bone marrow biopsy and aspirate revealed a cellular marrow containing all normal hematopoietic elements with left-shifted myelopoiesis and no evidence of malignancy or granulomatous disease; stain for acid fast bacilli was negative.

Figure 1: Hematoxylin-eosin stain of liver sample obtained at The patient’s hospital course was complicated by persistent autopsy showing numerous phagocytic cells with engulfed fever (39.2°C), with progressive pancytopenia (Hb 7.4 g/dl, hematopoietic elements WBC 600/μL, platelets 14/μL) and recurrent episodes of ß uid- responsive hypotension. A 4-drug antituberculous regimen for characterized by prolonged fever; hepatosplenomegaly; cytopenia; possible miliary tuberculosis was started. As there was no clinical coagulopathy; hypertriglyceridemia; and erythrophagocytosis [6,7,10] improvement with treatment over the next few days, a repeat in the bone marrow, liver, spleen, or lymph nodes. Two liver biopsy was performed; this showed ductopenia with no forms of HPS have been deÞ ned; the primary or familial and [6,10] granulomas. At this point, we considered the possibility of the HPS the sporadic or reactive type [Table 1]. The reactive type of and the patient was treated with high-dose methylprednisolone (1 HPS may be associated with , autoimmune disorders, g daily) and polyclonal intravenous immunoglobulin (1 g/kg).[4] or malignancies. Among the infections associated with HPS, [6,10] However, the patient developed volume-refractory hypotension Epstein-Barr virus (EBV) is the most common. requiring escalating doses of vasopressor agents and mechanical ventilation for progressive hypoxemia. His condition rapidly Diagnosis of the HPS syndrome is based upon the clinical, deteriorated and he suffered a cardiac arrest from which he laboratory, and histopathological Þ ndings. Diagnostic guidelines could not be resuscitated. The family agreed to an autopsy were proposed by the Histiocytic Society in 1991 and updated in [11,12] An EBV PCR sent prior to his death demonstrated 692,000 2004 [Table 2]. Our patient had six of the eight diagnostic copies/ml of the virus; PCR for CMV was negative. Autopsy criteria. HPS should be considered in the differential diagnosis conÞ rmed the diagnosis of HPS; there was involvement of liver, in patients presenting with prolonged fever, pancytopenia, and spleen, bone marrow, lymph nodes, maxillary sinuses, and lung a sepsis-like picture which is unresponsive to antibiotics. Since parenchyma, which demonstrated inÞ ltration with hypertrophic therapy can be life saving and some of the clinical criteria occur and erythrophagocytosis [Figure 1]. Electron late in the disease, it is not necessary to wait for fulÞ llment of all microscopy demonstrated hypertrophic macrophages ‘stuffed criteria before initiating therapy. As in our case, hemophagocytosis with phagocytic debris.’ Molecular studies on postmortem bone may be absent on initial bone marrow biopsy and it may have to be [7] marrow, liver, spleen, lung, and liver specimens were positive for repeated. The presence of a high EBV DNA load in the blood [13] EBV. Postmortem cultures for all other viral, fungal, and acid-fast facilitates the diagnosis of EBV-HPS. CD8-positive T/NK cells organisms were negative. Gene mutation analysis for X-linked with positive immunohistochemical staining for EBV-LMP1 and [14] lymphoproliferative disease (BIRC4 and SH2DD1A genes) was EBV-EBNA2 has also been demonstrated. Bile ductopenia was negative. Review of the initial liver biopsy was consistent with lymphocytic hepatitis (primary EBV hepatitis). Table 1: Classification and underlying conditions associated with the hemophagocytic syndrome Genetic HPS DISCUSSION Familial HPS (Farquhar’s disease) Known genetic defects (perforin, munc 13-4, syntaxin 11) HPS, also called hemophagocytic lymphohistiocytosis (HLH), is Unknown gene defects Immune deÞ ciency syndromes a well-deÞ ned clinical disease. It was Þ rst described by Scott and Chediak-Higashi syndrome Robb-Smith in 1939.[5] HPS is a condition in which T cells, natural Griscelli syndrome X-linked lymphoproliferative syndrome killer cells, and macrophages are aberrantly activated, resulting Acquired HPS in hypercytokinemia that causes cellular damage leading to Exogenous agents (toxins) [6,7] mutiorgan failure. Markedly elevated levels of tumor necrosis Infection-associated hemophagocytic syndrome (Herpes virus, adenovirus, factor-alpha (TNF-alpha), soluble interleukin-2 receptor (sIL- parvovirus, inß uenza, hepatitis viruses) activation syndrome (associated with autoimmune diseases) 2R), interferon-gamma (IFN-gamma), IL-6, IL-10, and IL-18 Malignant diseases have been reported in the active phase of the disease.[6,8,9] HPS is HPS: HEMOPHAGOCYTIC SYNDROME

120 Journal of Emergencies, Trauma and Shock | 1:2 | Jul - Dec 2008 Spivack et al.: EBV-HPS mimicking severe sepsis

Table 2: Diagnostic criteria of the hemophagocytic introduction of an etoposide-based regimen has greatly improved [6,19] syndrome (HPS)[12,18] survival times. The diagnosis of HPS is established on fulÞ llment of one of the following criteria A molecular diagnosis consistent with hemophagocytic syndrome (e.g., PRF CONCLUSION mutations, SAP mutations, MUNC13-4 mutations Five out of eight of the following HPS is a rare disorder resulting from the uncontrolled production Fever Splenomegaly of inß ammatory cytokines and a clinical presentation that mimics Cytopenia (two cell lines) sepsis. Delayed diagnosis usually results in a fatal outcome. HPS Hypertriglyceridemia (> 265 mg/dl) and/or hypoÞ brinogenemia (< 150 mg/dl) Hemophagocytosis in the bone marrow, spleen, or lymph nodes, without usually runs an aggressive course and requires a speciÞ c therapeutic evidence of malignancy regimen for cure. Clinicians need to understand the pathophysiology Low or absent natural killer cell cytotoxicity of this disease to facilitate its early recognition and treatment. Hyperferritinemia (> 500 ng/ml) Elevated soluble CD 25 (interleukin-2R alpha chain > 2400 IU/ml) REFERENCES noted on our patient’s second liver biopsy. This Þ nding has been 1. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. reported previously in patients with EBV-associated HPS and it Sepsis in European intensive care units: Results of the SOAP study. Crit [15,16] may be an EBV-associated phenomenon. Care Med 2006;34:344-53. 2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky The epidemiology of EBV-HPS is not well understood. MR. Epidemiology of severe sepsis in the United States: Analysis of Although the disease occurs most commonly in children incidence, outcome and associated costs of care. Crit Care Med 2001;29: and adolescents living in Japan, Taiwan, and other Asian 1303-10. counties, it has also been reported to occur sporadically in 3. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Western countries.[6,13] A highly pathogenic stain of EBV may DeÞ nitions for sepsis and organ failure and guidelines for the use of in- account for the higher incidence in Asian countries. In adults novative therapies in sepsis: The ACCP/SCCM Consensus Conference EBV-HPS is usually a fatal disease in which patients die from Committee; American College of Chest Physicians/Society of Critical progressive multiorgan failure.[10,13–15] Primary EBV infection Care Medicine. Chest 1992;101:1644-55. occurring in early childhood is usually asymptomatic. Primary 4. Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous im- infection in adolescents and young adults may cause infectious munoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: A systematic review and meta-analysis. Crit Care Med mononucleosis, in which EBV infects B cells, with polyclonal 2007;35:2686-92. B cell expansion accompanied by antigen-driven oligoclonal 5. Scott RB, Robb-Smith AH. Histiocytic medullary reticulosis. Lancet on monoclonal proliferation of CD8-positive cytotoxic T cells. 1939;2:194-8. In EBV-HPS, EBV infects CD8-positive T cells, leading to 6. Imashuku S. Clinical features and treatment strategies of Epstein-Barr polyclonal or monoclonal proliferation of EBV-containing T virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol- cells. Although the pathogenesis of EBV-HPS has not yet been Hematol 2002;44:259-72. fully elucidated, inß ammatory cytokines, especially TNF-alpha, 7. Janka GE. Hemophagocytic syndromes. 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Infections associated with haemophagocytic syndrome. Lancet Infect response (cytokine storm) and control of T cell proliferation Dis 2007;7:814-22. using immunosuppressive and cytotoxic drugs. Treatment differs 11. Henter JI, Elinder g, Ost A. Diagnostic guidelines for hemophagocytic in children and adults and depends on the underlying disease, the lymphohistiocytosis. The FHL study Group of the Histiocyte Society. Semin Oncol 1991;18:29-33. presence of a trigger, and the severity of symptoms. EBV-speciÞ c therapy is ineffective in treating EBV-HPS.[10] Chemotherapy 12. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic using dexamethasone, cyclosporin A, and etoposide was adopted lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. by the Histiocyte Society in 1994 (updated 2004) and is used 13. Elazary AS, Wolf DG, Amir G, Avni B, Rund D, Yehuda DB, et al. Severe [12,18] for severe (familial and EBV-HPS) cases. Cyclosporine Epstein-Barr virus-associated hemophagocytic syndrome in six adult A prevents T cell activation. Etoposide inhibits EBV nucleic patients. J Clin Virol 2007;40:156-9. acid synthesis in EBV-infected cells and has cytotoxic activity 14. Kitazawa Y, Saito F, Nomura S, Ishii K, Kadota E. A case of hemophago- in monocytic and histiocytic diseases. EBV-associated HPS cytic lymphohistiocytosis after the primary Epstein-Barr virus infection. was previously thought to be fatal in most cases; however, the Clin Appl Thromb Hemost 2007;13:323-8.

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15. Song KS, Sung HJ. Effect of plasma exchange on the circulating IL-6 cytosis: HLH study Group of the Histiocyte Society. Med Pediatr Oncol levels in a patient with fatal hemophagocytic syndrome associated with 1997;28:342-7. bile ductopenia. Ther Apher Dial 2006;10:87-9. 19. Imashuku S, Kuriyama K, Teramura T, Ishii E, Kinugawa N, Kato M, et al. 16. Kikuchi K, Miyakawa H, Abe K, Fujikawa H, Horiuchi T, Nagai K, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associat- Vanishing bile duct syndrome associated with chronic EBV infection. Dig ed hemophagocytic lymphohistiocytosis. J Clin Oncol 2001;19:2665-73. Dis Sci 2000;45:160-5. 17. Lay JD, Chuang SE, Rowe M, Su IJ. Epstein-barr virus latent membrane protein-1 mediates upregulation of tumor necrosis factor-alpha in EBV- How to cite this article: Spivack T, Chawla R, Marik PE. infected T cells: Implications for the pathogenesis of hemophagocytic Epstein-Barr virus–associated hemophagocytic syndrome mimicking syndrome. J Biomed Sci 2003;10:146-55. severe sepsis. J Emerg Trauma Shock 2008;1:119-22. 18. Henter JI, Arico M, Egeler RM, Elinder G, Favara BE, Filipovich AH, Received: 11.06.08. Accepted: 27.07.08. Source of Support: Nil. Confl ict of Interest: None declared. et al. HLH-94: A treatment protocol for hemophagocytic lymphohistio-

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