<p>A Case of Epstein-Barr Virus Associated Hemophagocytic Lymphohistiocytosis after Scrub Typhus Infection</p>

Clinical Pediatric Hematology-Oncology Volume 19ㆍNumber 1ㆍApril 2012 CASE REPORT

49

쯔쯔가무시병 후 발생한 엡스타인 바이러스 연관 혈구탐식림프조직구증 1예

홍지혜¹ㆍ조현준¹ㆍ김황민¹ㆍ남궁미경¹ㆍ권오건²ㆍ전진경¹

연세대학교 원주의과대학 ¹소아과학교실, ²진단검사의학교실

A Case of Epstein-Barr Virus Associated Hemophagocytic Lymphohistiocytosis after Scrub Typhus Infection

Ji Hye Hong, M.D.¹, Hyun Jun Cho, M.D.¹, Hwang Min Kim, M.D.¹, Mee Kyung Namgoong, M.D.¹, Ohgun Kwon, M.D.² and Jin-Kyong Chun, M.D.¹

Departments of ¹Pediatrics and ²Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju Christian Hospital, Wonju, Korea

A 7-year-old boy with pancytopenia, cervical lymphadenopathy, interstitial pneumonia, and hepatosplenomegaly was diagnosed with Epstein-Barr Virus (EBV)-associated hemo- phagocytic lymphohistiocytosis. His clinical course was characterized by hepatorenal syndrome and myocarditis. Based on his serological markers for EBV and an im- munochromatography test for scrub typhus, this case was inferred as an EBV infection that was reactivated during tsutsugamushi infection. We treated this patient with the HLH-2004 protocol and administered clarithromycin. Normal ferritin level was achieved within 8 weeks after starting chemotherapy and antibiotics.

pISSN 2233-5250 / eISSN 2233-4580 Clin Pediatr Hematol Oncol 2012;19:49∼52

Received on February 15, 2012 Revised on March 5, 2012 Accepted on March 30, 2012

책임저자: 김 황 민

강원도 원주시 일산동 162번지 연세대학교 원주의과대학 원주기독 병원 소아청소년과, 220-701 Tel: 033-741-1284

Fax: 033-732-6229

E-mail: [email protected]

Key Words: Hemophagocytic lymphohistiocytosis, Scrub typhus, Epstein-Barr virus

Introduction

High fever, generalized lymphadenopathy, elevated liver enzymes, hepatosplenomegaly, and pancytopenia can re- mind clinicians of several grave diseases. We encountered a patient who had all of these components. Differential di- agnoses for this case could have included lymphoma, he- mophagocytic lymphohistiocytosis, viral hepatitis with bone marrow suppression, and rickettsial infection. Notably, we diagnosed it as Epstein-Barr virus (EBV)-associated hemo- phagocytic lymphohistiocytosis (HLH) after Orientia tsutsu- gamushi infection.

Few pediatric cases of HLH after scrub typhus have been reported. Chen et al. observed a case of HLH with scrub typhus in a 21-year-old male [1], and Jayakrishnan et al.

[2] noted hemophagocytosis in a 5-year-old patient with scrub typhus. We report a case of HLH that was associated with reactivation of EBV during scrub typhus infection.

Case Report

A 7-year-old male was admitted to Wonju Christian Hospital due to high fever and abdominal pain for 4 days.

He had no skin rash or eschar except mild jaundice but he had had maculopapular rash on whole body two weeks

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Fig. 1. The progressive interstitial pneumonia due to Orientia tsu- tsugamushi. (A) The Chest CT was taken on admission day. (B) It was taken on hospital day 7.

Fig. 2. The smear of bone marrow aspirates. A hemopha- gocytotic macrophage was observed (black arrow). Wright staining ×1,000.

before admission temporarily. He had not experienced weight loss recently or night sweats. He had not taken any special medications for his illness before admission. He was well developed and well nourished. He had no allergy to any drugs or any allergens. There was no remarkable fam- ily history.

On physical examination, the heart rate was 140 beats/min, the respiration rate was 30 breaths/min. He had 3×3-cm right cervical lymphadenopathy, multiple bean-sized inguinal lymphadenopathies, and a hepatomegaly that was approximately 6 cm below the right costal margin on the midclavian line with a splenomegaly that was approx- imately 5 cm below the left costal margin. Myocarditis was suspected due to an enlarged heart and pulmonary edema on the chest X-ray and elevated pro-brain natriuretic pep- tide (pro-BNP) levels (534 pg/mL).

His laboratory tests revealed platelet count: 47,000/μL, white blood cells: 3,760/μL, segmented neutrophils: 60%, and high ferritin levels: ＞1,650 ng/mL. The serum level of lactate dehydrogenase was 1,193 U/L. Aspartate trans- aminase (AST) 157 U/L, alanine transaminase (ALT) 101 U/L, total bilirubin 3.6 mg/dL, direct bilirubin 3.3 mg/dL, and γ-glutamyl transferase 89 U/L, TG 377 mg/dL, PT/aPTT 9.4/24 sec (INR, 0.83%), fibrinogen 158 mg/dL (200-400 mg/dL). Neck and abdomen computerized tomography (CT) showed no abnormal mass but benign reactive cer- vical and mesenteric lymph nodes enlargement and hepatosplenomegaly. Chest CT showed increased interstitial marking on both lower lobes and minimal effusion (Fig.

1A). To exclude bone marrow (BM)-infiltrating diseases,

BM aspiration and biopsy were performed on hospital day (HD) 3. We observed characteristic hemophagocytosis of macrophages on smeared BM aspirates (Fig. 2). EBV was detected in BM aspirates by polymerase chain reaction (PCR). With regard to serological markers for EBV, the re- sults were EBV VCA IgM-positive, EBV VCA IgG-positive, and EB nuclear antigen (EBNA) IgG-positive, The abdomi- nal sonogram detected thickening of the gall bladder wall but no evidence of distension of the gall bladder or ob- struction of the biliary tracts.

Initially cefotaxime and clarithromycin were administered empirically onadmission day. After the results of EBV study were known, corticosteroid and intravenous immunoglobulin (2 g/kg) were added for the treatment of EBV associated

A Case of EBV and Scrub Typhus Associated HLH

Clin Pediatr Hematol Oncol 51

Fig. 3. The changes of liver enzymes during clinical course. The serum levels of aspartate transminase (AST) and alanine transminase (ALT) had been decreased during chemotherapy.

When the antibiotics were discontinued, the serum levels of AST/ALT were increased paradoxically. After administrating clarithromycin, the serum levels of AST/ALT were decreased in spite of chemotherapy. white bar represents the treatment duration of clarithromycin and black bar represents the period of chemotherapy.

HLH. However, the fever was sustained and the anemia, leukopenia, and thrombocytopenia became aggravated to hemoglobin 7.9 g/dL (11.0-16.0 g/dL), WBC 2,520/μL (ANC 2,240/μL), and platelet 17,000/μL. We started chemo- therapy, targeting EBV-associated HLH according to HLH-2004 protocol, on HD 4. Etoposide and dex- amethasone were administered initially. On HD 5, because there was no evidence of bacterial infection and liver en- zymes were rising, cefotaxime and clarithromycin were halted. The findings of CSF study and brain CT were normal.

During chemotherapy, we noticed dramatic improvements in the general lymphadenopathy and hepatosplenomegaly.

However, severe jaundice (direct bilirubin: 18.2 mg/dL) and azotemia (blood urea nitrogen: 53.3 mg/dL) developed. We suspected that these conditions were unusual for HLH or as manifestations of a cytokine storm due to chemotherapy.

Thus, we inferred the other infection such as tsutsugamushi infection which can cause hepatorenal syndrome and pneu- monia because the patient had interstitial pneumonia which was aggravated on follow up chest CT (Fig. 1B). Therefore we performed an immunochromatographic test (ICT) to de- tect the specific IgM and IgG against scrub typhus. On HD 8, the 12^th day after the onset of fever, the IgM antibody against scrub typhus positive was known, we skipped the scheduled cyclosporine treatment and restarted administrat- ing clarithromycin for scrub typhus infection. We used clar- ithromycin instead of doxycycline to avoid tooth dis- coloration in childhood. The liver profiles and kidney func- tion were recovered slowly to normal levels for 1 week with clarithromycin. Etoposide and dexamethasone were administered as scheduled (Fig. 3).

On HD 30, CBC profile recovered fully (WBC 8,470/μL, Hb 9.0 g/dL, platelet 110,000/μL) and elevated levels of liv- er enzymes and total bilirubin declined to near normal level (AST/ALT 48/112 U/L, total bilirubin 0.9 mg/dL). However, ferritin levels remained as high as 1,499 ng/mL. Hence, we resumed cyclosporine therapy as HLH-2004 protocol.

Serum ferritin level was declined to 390 ng/mL on HD 45 and then was 99 ng/mL after 3 months. After the HLH-2004 protocol was finished, the patient is being monitored regu- larly in our outpatient clinic and there is no evidence of

recurrence of HLH.

Discussion

The early diagnosis and treatment of EBV-associated HLH is crucial for good outcomes [3,4]. Imashuku et al.

propose three steps for effecting positive long-term out- comes of EBV-associated HLH: initial 8-week induction therapy, intensification therapy, and in cases of refractory EBV-associated HLH, appropriate application of stem cell transplantation [4]. Most cases with poor outcomes oc- curred in the initial induction period due to fatal hemor- rhages or severe opportunistic infections as a result of neu- tropenia following chemotherapy. Hemophagocytic activity in our case was suppressed within 8 weeks, although we encountered hepatorenal failure, mild congestive heart fail- ure due to myocarditis, and severe thrombocytopenia.

In this case, scrub typhus was a confounding factor in our management of EBV-associated HLH. If scrub ty- phus-associated HLH had been the only issue in this case, the clinical course would have improved when we initially administered clarithromycin and corticosteroid with accom-

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52 Vol. 19, No. 1, April 2012

panying intravenous immunoglobulin [2].

Yet, until we began chemotherapy, the activity of HLH was not suppressed manifesting ongoing fever and pancy- topenia. Therefore, we thought that the scrub typhus might have triggered the reactivation of EBV and HLH. During treatments for HLH, the treatment of scrub typhus also be- came urgent. When we increased the immunosuppression, the liver profile and kidney function exacerbated, in con- trast to the typical clinical course of EBV-associated HLH.

Timely treatment with antibiotics and G-CSF was believed to be a successful key in our management of scrub typhus.

Immunofluorescence assay (IFA) is the gold diagnostic method for scrub typhus infections [5]. Our case was diag- nosed as scrub typhus infection, based on clinical findings and ICT. Blacksell et al. reported that the sensitivity and specificity of the ICT in detecting IgM are 96.8% and 93.3%

when the standard result was based on IFA [6]. We re- peated the ICT, and the result was consistently positive.

ICT is known as a fast and inexpensive method for detect- ing scrub typhus infection [6].

Chen et al. reported a case of scrub typhus associated hemophagocytic syndrome [1], the prognosis of that case was good after treatment with only antibiotics. However, Kim et al. observed a fatal adult case of scrub typhus asso- ciated hemophagocytic syndrome [7].

Our case responded well to etoposide and dex- amethasone with concomitant clarithromycin. The metic- ulous management of myocarditis and liver failure was cru- cial in the clinical course of scrub typhus [8]. Our case had rapidly progressive HLH due to reactivated EBV infection, triggered with the scrub typhus. Therefore, the balance be- tween the intensity of chemotherapy and control of in- fection was considered at each critical step. To confirm the

infection, we also used imaging studies such as chest CT and abdominal sonography, the findings of those studies were compatible with its diagnosis by serology [9].

We experienced an atypical tsutsugamushi infection without eschar that reactivated an EBV infection and caused HLH. This case was successfully treated with the HLH-2004 protocol and clarithromycin. 

References

1. Chen YC, Chao TY, Chin JC. Scrub typhus-associated hemo- phagocytic syndrome. Infection 2000;28:178-9.

2. Jayakrishnan MP, Veny J, Feroze M. Rickettsial infection with hemophagocytosis. Trop Doct 2011;41:111-2.

3. Imashuku S, Hibi S, Ohara T, et al. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Blood 1999;93:1869-74.

4. Imashuku S, Teramura T, Tauchi H, et al. Longitudinal fol- low-up of patients with Epstein-Barr virus-associated hemopha- gocytic lymphohistiocytosis. Haematologica 2004;89:183-8.

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