ORIGINAL ARTICLE pissn 1225-7737/eISSN 2234-8042 Yeungnam Univ J Med 2014;31(2):75-81 http://dx.doi.org/10.12701/yujm.2014.31.2.75 소아에서발생한혈구탐식증후군의예후인자로서혈청빌리루빈의의의 양혜경, 송귀정, 전소은 부산대학교의학전문대학원소아과학교실 Significance of serum total bilirubin as a prognostic factor for hemophagocytic lymphohistiocytosis in childhood Hea Kyoung Yang, Gui Joung Song, So Eun Jun Department of Pediatrics, Pusan National University School of Medicine, Busan, Korea Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. Despite of proper treatment and improving treatment regimens, HLH patients still show a fatal prognosis. Therefore the evaluation of prognostic factor is important and there are many studies about hyperbilirubinemia as a prognostic factor in HLH. So we studied the prognostic value of hyperbilirubinemia in HLH children. Methods: A retrospective analysis was performed about 33 patients who were diagnosed with HLH at Pusan National University Hospital and Yangsan Pusan University Hospital between January 2000 to December 2012. We reviewed the clinical characteristics, laboratory findings, and results of treatment to identify hyperbilirubinemia as a prognostic factor in HLH patients. Results: The median age of patients at diagnosis was 32 months. Most of patients presented with fever, pale appearance, abdominal pain and jaundice. Forty-eight point five percentage of patients showed normal serum bilirubiln level (<2.0 mg/dl) and 51.5% showed hyperbilirubinemia ( 2.0 mg/dl). In normal serum bilirubin group, 1 patient (6.3%) was relapsed and 1 patient (5.9%) was relapsed in hyperbilirubinemia group. In the hyperbilirubinemia group, the mortality was higher than the normal bilirubin group but, there was no statistical significance. Conclusion: As a prognostic factor serum bilirubin at diagnosis in HLH patients, there was no significant correlation between hyperbilirubinemia and poor outcome. But, our study has a limitation that the number of patients is too small and almost showed good prognosis. Keywords: Hemophagocytic lymphohistiocytosis; Serumbilirubin; Prognostic factor 서 론 혈구탐식증후군 (hemophagocytic lymphohistiocytosis, HLH) 은자연살해세포와세포독성 T세포의기능이상에의해발생 Received: May 28, 2014, Revised: August 13, 2014, Accepted: August 20, 2014 Corresponding Author: So Eun Jun, Department of Pediatrics, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 602-739, Korea Tel: +82-51-240-7298, Fax: +82-51-248-6205 E-mail: newwife99@hanmail.net 되는면역질환으로임상증상으로는발열, 간비종대, 범혈구감소증, 고중성지방혈증, 저섬유소원증, 그리고골수나다른장기에서의혈구탐식작용을나타낼수있다 [1]. 또한골수, 간비장, 피부병변등의조직검사에서혈구탐식세포가증가한병리학적특징을찾아볼수있다 [2]. 과거 2차성혈구탐식증후군의생존율에대한후향성연구에따르면증상이나타난이후로부터평균생존율은 1개월미만이며, 진단된이후 1년평균생존율은 5% 밖에되지않는다고보고하였다. 하지만, 최근혈구탐식증후군의효과적인초기치료로항암제와면역억제제의복합치료및면역글로불린, YUJM VOLUME 31, NUMBER 2, DECEMBER 2014 75
Hea Kyoung Yang et al. 스테로이드와사이클로스포린의병합요법과조혈모세포이식 (hematopoietic cell transplantation) 의발달로 5년생존율은 50-70% 에달한다 [3]. 혈구탐식증후군환자들의생존율이이와같이향상되었다고는하지만, 과활성화된혈구탐식세포들은골수뿐만아니라, 비장, 간, 림프절, 폐, 그리고뇌등의여러장기에침투하여범혈구감소증이나간부전, 다발성기관부전증후군등을야기한다 [4-6]. 이와같이혈구탐식증후군을진단받은환자들은다양한병의경과를겪게되고적절한초기치료에도치명적인경과를보일수있기에새롭게혈구탐식증후군을진단받은환아의예후를예측하기위한연구가활발히진행되고있다. Trottestam 등 [7] 은진단시의고빌리루빈혈증, 고페리틴혈증, 중추신경계침범이나쁜예후인자가될수있다고하였다. Trottestam 등 [8] 은고빌리루빈혈증을, Imashuku 등 [9] 은페리틴, 젖산탈수소효소, 염증성사이토카인을, Horne 등 [10] 은뇌척수액검사에서증가된총세포수와단백질을, Lin 등 [11] 은혈청페리틴수치의감소속도를혈구탐식증후군의예후인자로언급하였다. 지금까지의많은연구를살펴보면, 고빌리루빈혈증은혈구탐식증후군의진단기준에는해당하지않지만예후에영향을미치는인자로알려져있기에, 저자들은부산대학교병원소아청소년과에서 2000년 1월부터 2012년 12월까지혈구탐식증후군으로진단받은환자를대상으로진단시및치료중혈청빌리루빈과예후와의상관관계에대해조사하였다. 재료및방법 1. 대상 2000년 1월부터 2012년 12월까지부산대학교병원과양산부산대학교병원소아청소년과에입원하여혈구탐식증후군으로진단받은 56명의환자중최종적으로다른질환으로진단된 23명을제외한 33명환자들의의무기록을후향적으로조사하였다. 혈구탐식증후군의진단은 HLH-2004 에서제시된개정된진단기준에의하여분자생물학적으로혈구탐식증후군과연관된유전자진단이되거나발열, 비장종대, 혈구감소증, 고중성지방혈증또는저섬유소원증, 골수나비장, 림프절에서혈구탐식세포의관찰, 자연살해세포활성도의감소혹은부재, 고페리틴혈증 (>500 μg/l), CD25 의혈중농도증가중에서 5가지이상을만족하는경우진단하였다. 치료는 HLH-2004 프로토콜, 면역글로불린, 스테로이드와사이클로스포린의병합요법, 조혈모세포이식을시행하였고, 조혈모세포이식을시행받은환자는 1명이었다. 2. 방법대상이된환자들의의무기록을후향적으로분석하였으며, 진단시나이, 성별, 내원시발열유무와복통, 안색창백및황달등의임상증상, 신체검진에서간비종대와림프절비대, 피부발진의유무, 혈액검사와골수검사결과, 중추신경계예방의유무를포함한치료방법및치료경과, 재발유무, 합병증에대해조사하였다. 환자들을진단시혈청빌리루빈이 2.0 mg/dl 미만인정상군과 2.0 mg/dl 이상인고빌리루빈혈증군으로나누어비교하였다. 검사소견으로전혈구검사, 혈청아스파르테이트아미노전달효소, 혈청알라닌아미노전달효소, 젖산탈수소효소, 빌리루빈, 간접빌리루빈, 중성지방, 섬유소원, 페리틴, 프로트롬빈시간, 활성화부분트롬보플라스틴시간, soluble IL-2를조사하여두군사이의상관관계를분석하였다. 두군간의치료결과는완치, 재발, 사망, 그리고추적관찰의실패로나누어분석하였다. 3. 통계대상군별, 시점차이를살펴보기위하여평균차이검증인 t-test를이용하여분석을실시하였다. 범주형자료에서비모수기법인경우교차분석 (p) 과 Kaplan-Meier 생존분석을실시하여집단간의차이를살펴보았다. 본연구의실증분석은모두유의수준 p<0.05 에서검증하였으며, 통계처리는 SPSSWIN 21.0 프로그램을사용하여분석하였다. 결과 1. 진단시임상양상혈구탐식증후군을최종적으로진단받은환자는모두 33 명이었다. 진단시나이의중앙값은 32개월이며, 남녀비는 1:1.2였다. 진단시임상증상으로는 33명모두발열을보였으며, 안색창백 10명 (30.3%), 복통 8명 (12.5%), 황달이 5명 (15.1%) 에서관찰되었으며, 그외 11명 (33.3%) 에서는경련, 골수염, 뇌염, 부종, 신부전의증상을보였다. 신체검진에서간비대 25명 (75.6%), 비장비대가 20명 (60.6%) 으로가장많 76 YUJM VOLUME 31, NUMBER 2, DECEMBER 2014
Total bilirubin as a prognostic factor for HLH in childhood 았고, 림프절비대 4명 (12.1%), 피부발진은 7명 (21.2%) 에서관찰되었다. 치료는 HLH-2004 치료가이드라인에따라치료한환자가 23명 (69.7%), 면역글로불린으로치료한환자가 5명 (15.5%), 스테로이드와사이클로스포린의병합요법으로치료한환자가 1명 (3.0%) 이었고, 조혈모세포이식을시행한환자는 1명이었다 (Table 1). 정상군에서는남자 7명 (43.8%), 여자 9명 (56.3%) 으로남녀비는 1:1.28이었고, 고빌리루빈혈증군에서는남자 8명 (47.1%), 여자 9명 (52.9%) 으로남녀비는 1:1.12였다. 두군의진단시나이의중앙값은정상군이 32.5 개월, 고빌리루빈혈증군이 24개월이었다 (Table 2). 2. 진단시검사소견 전혈구검사에서백혈구수는정상군에서 4,125.0±3,544.8/ μl이고, 고빌리루빈혈증군에서는 4,617.6±3,587.2/μL 로고빌리루빈혈증군에서더높았으나, 통계학적으로유의한차이는없었다 (p=0.694). 혈색소는정상군에서 9.6±2.2 g/dl였고, 고빌리루빈혈증군에서 9.4±2.2 g/dl였으며, 혈소판수의평 Table 1. Patient demographics and characteristics (n=33) Characteristic N (%) Sex Male 15 (45.5) Female 18 (54.5) Age at diagnosis (mo) Median (range) 32 (3-192) Symptoms at the diagnosis Fever 33 (100) Abdominal pain 8 (12.5) Pale appearance 10 (30.3) Jaundice 5 (15.1) Others a) 11 (33.3) Physical examination Hepatomegaly 25 (75.6) Splenomegaly 20 (60.6) Lymphadenopathy 4 (12.1) Skin rash 7 (21.2) Treatment regimen HLH-2004 23 (69.7) Steroid+cyclosporin 1 (3.0) Immunoglobulin 5 (15.5) None 4 (12.1) HLH, hemophagocytic lymphohistiocytosis. a) Others are seizure, osteomyelitis, encephalitis, edema, and renal failure. 균값은정상군에서 76,050/μL이고, 고빌리루빈혈증군에서 47,058/μL로정상군에서혈소판이더높았으나통계학적으로유의한차이는보이지않았다 (p=0.07). 혈청총빌리루빈은정상군에서 0.8±0.6 mg/dl이고, 고빌리루빈혈증군에서 5.0±3.0 mg/dl 이다. 간접빌리루빈은정상군에서 0.4±0.4 mg/dl이고, 고빌리루빈혈증군에서 3.4± 2.7 mg/dl를보였고, 혈청페리틴은정상군이 13,195.8± 17,915.1 ng/dl이고, 고빌리루빈혈증군은 9,156.8±8,433.3 ng/dl로통계학적으로유의한차이는보이지않았다 (p=0.4). 정상군의프로트롬빈시간 (international normalized ratio) 은 0.9±0.4, 고빌리루빈혈증군이 1.4±0.5로고빌리루빈혈증군이통계학적으로의미있게높았다 (p<0.05) (Table 3). Table 2. Comparison of demographics between normal and hyperbilirubinemia group Characteristic Normal group Hyperbilirubinemia group p-value Sex Male 7 (43.8) 8 (47.1) Female 9 (56.3) 9 (52.9) Age at diagnosis (mo) Median (range) 32.5(3-192) 24 (3-181) Symptoms at the diagnosis Fever 16 (100.0) 17 (100) Abdominal pain 2 (12.5) 6 (35.3) Pale appearance 4 (25.0) 6 (35.3) 0.72 Jaundice 2 (12.5) 3 (17.6) Others a) 4 (25.0) 7 (41.1) Physical examination Hepatomegaly 11 (68.7) 13 (76.4) Splenomegaly 11 (68.7) 9 (52.9) Lymphadenopathy 3 (18.7) 3 (17.6) 0.90 Skin rash 5 (31.2) 2 (11.7) Treatment HLH-2004 10 (62.5) 13 (76.5) Steroid+cyclosporin 1 (6.3) 0 (0) Immunoglobulin 3 (18.8) 2 (11.8) 0.66 None 2 (12.5) 2 (11.8) CNS prophylaxis Intrathecal b) 0 (0) 3 (17.6) None 16 (100.0) 14 (82.4) HLH, hemophagocytic lymphohistiocytosis; CNS, central nervous system. a) Other symptoms are seizure, osteomyelitis, encephalitis, edema, and renal failure. b) Intrathecal chemotherapy is methotrexate. YUJM VOLUME 31, NUMBER 2, DECEMBER 2014 77
Hea Kyoung Yang et al. Table 3. Comparison of laboratory findings between normal and hyperbilirubinemia group Characteristic Normal n=16 Hyperbilirubinemia n=17 p-value WBC (μl) 4,125.0±3,544.8 4,617.6±3,587.2 0.69 Hb (g/dl) 9.6±2.2 9.4±2.2 0.85 Platelet (μl) 76,050±52,887 47,058±35,294 0.07 Neutrophil count (μl) 1,719.8±2,295.0 952.5±793.0 0.20 AST (IU/L) 443.5±491.4 1,422.5±2,901.8 0.19 ALT (IU/L) 221.1±272.9 3,189.7±2,044.8 0.12 LDH (IU/L) 2,543.1±2,344.6 3,189.7±2,044.8 0.12 Total bilirubin (mg/dl) 0.8±0.6 5.0±3.0 <0.01 Direct bilirubin (mg/dl) 0.4±0.4 3.4±2.7 <0.01 Triglyceride (mg/dl) 191.5±113.2 242.8±142.2 0.26 Fibrinogen (mg/dl) 190.8±71.6 326.3±510.4 0.43 Soluble IL-2 11,532.6±13,803.6 7,888.8±9,666.6 0.38 Ferritin (ng/dl) 13,195.8±17,915.1 9,156.8±8,433.3 0.40 PT (INR) 0.9±0.4 1.4±0.5 0.01 aptt (sec) 73.2±113.7 54.8±15.6 0.52 Values are presented as mean±standard deviation. WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; PT, prothrombin time; INR, international normalized ratio; aptt, activated partial thromboplastin time. 3. 치료및경과정상군 16명의환자중 10명 (62.5%) 을 HLH-2004 치료가이드라인에따라치료하였으며, 3명 (18.8%) 은면역글로불린단독요법, 1명 (4.3%) 은스테로이드와사이클로스포린의병합요법으로치료하였으며, 2명 (12.5%) 은대증적치료를하였다. 고빌리루빈혈증군 17명의환자중 13명 (76.5%) 은 HLH-2004 치료가이드라인에따라치료하였으며, 2명 (11.8%) 은면역글로불린단독요법으로, 2명 (11.8%) 은대증적치료를하였다. 두군간의치료방법의유의한차이는없었다 (p=0.66). 4. 예후 Table 4. Outcomes between normal and hyperbilirubinemia group Characteristic Normal Hyperbilirubinemia Outcome Complete remission 12 (75.0) 11 (64.7) Relapse 1 (6.3) 1 (5.9) Expired 2 (12.5) 4 (23.5) F/U loss 1 (6.3) 1 (5.9) Complications Yes a) 7 (43.7) 11 (64.7) No 9 (56.2) 6 (35.2) a) Complications are oral candidiasis, pneumonia, pulmonary hemorrhage, acute respiratory distress syndrome, viral encephailtis, pleural effusion, brain infarction, and posterior reversible encephalopathy syndrome. F/U, follow up. 치료결과는완치, 재발, 사망, 그리고추적관찰의실패로분류하였다. 정상군에서완치된경우는 12명 (75.0%) 이며, 고빌리루빈혈증군에서는완치된경우는 11명 (64.7%) 이었다. 또한재발된경우는정상군이 1명 (6.3%), 고빌리루빈혈증군이 1명 (5.9%) 이었다. 전체생존율과무합병증생존율을살펴보았을때두군간의의미있는차이는없었다 (Fig. 1). 정상군에서는 7명 (43.7%) 에서폐렴과폐출혈, 뇌염, 급성호흡곤란증후군을보였고, 이중 2명 (6.3%) 이각각급성호흡곤란증후군과뇌염으로사망하였다. 고빌리루빈혈증군에서 는 11명 (64.7%) 이구강캔디다증의감염, 폐렴, 뇌수막염과경련, 가역적후백질뇌병증증후군을보였다. 이중 4명 (23.5%) 이사망하였고, 이가운데폐출혈과패혈증으로 1명, 폐출혈로 1명, 1명은급성신부전과급성호흡곤란증후군, 1 명은뇌출혈이악화되어사망하였다. 두군간의재발을살펴보았을때정상군에서는 1명 (6.3%) 이치료종료후 14일만에재발하였으며, 고빌리루빈혈증군에서는 1명 (5.9%) 이치료종료후 69일만에재발하였다 (Table 4). 78 YUJM VOLUME 31, NUMBER 2, DECEMBER 2014
Total bilirubin as a prognostic factor for HLH in childhood Fig. 1. Kaplan-Meier estimate of overall survival (A) and event free survival (B). 고찰 혈구탐식증후군은크게두범주로분류하는데, 1차성혹은가족성혈구탐식증후군은산발적으로발생하거나가족력을가진다. 가족성혈구탐식증후군 (familial hemophagocytic lymphohistiocytosis) 은 1952년 Farquhar와 Clairequx에의해처음으로기술되었다 [12]. 가족성혈구탐식증후군은특정유전자변이와연관성이있고상염색체열성유전하며, 대개생후 2년이내진단되고 100,000명출생당 1.2명의발병률을보인다고알려져있다 [13-15]. 2차성혈구탐식증후군은감염이나악성질환, 자가면역질환, 그리고약제등에의해발생할수있으며, 특히 Epstein-Barr virus 감염과연관되어발생한다고알려져있다 [16]. 1991년 Histiocyte Society에서제시한혈구탐식증후군의 5가지진단기준은, 1) 7일이상지속되는 38.5 이상의발열, 2) 비장비대, 3) 절대중성구수 1,000/μL 이하, 혈소판수 100 109/L 이하, 혈색소 9.0 g/dl 이하중 2개이상을포함하는혈구감소증, 4) 고중성지방혈증 ( 3.0 mmol/l), 그리고 / 또섬유소원증 ( 1.5 g/dl), 5) 골수, 림프절또는비장에서악성종양의증거없이혈구탐식세포의관찰등이다. 여기에 2004년 6) NK 세포활성도감소또는부재, 7) 고페리틴혈증 (>500 mg/l), 8) soluble IL-2 receptor (CD25) 의혈중농도증가 (>2,400 U/mL) 의 3가지가추가되었고, 이 8가지진단기준중 5가지이상을만족하면혈구탐식증후군으로진단할수있다 [1]. 혈구탐식증후군은임상증상이다양하고검사소견이비특 이적이어서다른질환으로진단하고치료하다가진단이늦어지게되는경우가많다. 또한이유없이지속되는발열을보이는환자들에게서혈구탐식증후군이중요한감별진단으로고려되지않아진단에필요한검사가늦어지게되어치료결과가좋지않은경우가많다 [17,18]. 최근에는항암제와면역억제제의병합요법이나스테로이드를이용한초기치료와조혈모세포이식으로혈구탐식증후군의치료에큰성과를보이고있다. 하지만적절한치료에도불구하고여전히높은사망률을보이고있어나쁜예후를조기에예측하고치료를하는것은임상의에게큰과제로남겨져있다. 이에본연구는혈구탐식증후군을진단받은 33명의환아를대상으로혈구탐식증후군을진단받고치료를시작하기전의임상적정보와혈액학적정보를조사하였다. 진단시혈청빌리루빈의높은수치가예후에영향을미치는인자인지를알아보기위하여혈청총빌리루빈 2.0 mg/dl를기준으로정상군과고빌리루빈혈증군으로나누어두군간의임상증상과혈액검사의특징의차이를비교하였다. 본연구의대상이되었던 33명의환자군분석에서성별, 진단시나이, 발열, 복통, 안색창백이나황달등의내원시임상증상, 그리고간비종대혹은림프절비대나피부발진의신체검진에서는두군간의유의한차이가없었다. 23명의환자는 HLH-2004 치료가이드라인에의해치료하였고, 1명은스테로이드와사이클로스포린의병합요법으로치료하였고, 5명은면역글로불린으로, 나머지 4명은치료없이자연호전되었다. Trottestam 등 [8] 은혈구탐식증후군으로진단받은소아에서조기사망과연관있는예후인자를알아보기위해 232명 YUJM VOLUME 31, NUMBER 2, DECEMBER 2014 79
Hea Kyoung Yang et al. 의환자를대상으로코호트분석을이용하여진단시고빌리루빈혈증, 고페리틴혈증, 뇌척수액세포가나쁜예후인자이며, 치료시작 2주뒤에는혈소판감소증과고페리틴혈증이나쁜예후인자라고언급하였다. 진단시혈청빌리루빈 >50 μmol, 페리틴 >2,000 μg/l, 뇌척수액세포수 >100 10 6 /L인경우나, 치료 2주후혈소판수 <40 10 9 /μl, 페리틴 >2,000 μg/l의수치를보이거나, 지속되는발열과빈혈이있는경우도예후가나빴다. 또한치료에도불구하고조기사망을한환자들의특징적인임상증상으로황달, 전신부종및크레아티닌의증가가있다고하였다. Kogawa 등 [19] 도진단시고빌리루빈혈증 (>1.8 mg/dl) 을의미있는나쁜예후인자라언급하였으나, 본연구에서는혈청빌리루빈이진단시정상군과상승되어있는군간의생존기간과생존율의차이는없었다. Imashuku 등 [9] 은일본의비가족성혈구탐식증후군 82명의환자를대상으로한후향성연구에서페리틴, 젖산탈수소효소그리고염증성사이토카인을치료반응에대한결과를예측가능한값으로언급하였다. 그리고 Horne 등 [10] 은뇌척수액검사에서총세포수와단백질의증가가높은사망률과연관있음을밝혔고, Lin 등 [11] 은페리틴수치의감소와사망률의감소가의미있는상관관계를보인다고하였다. 앞선많은연구에서보고된바에따르면고빌리루빈혈증은혈구탐식증후군의진단기준은아니지만, 치료후결과에대한예후인자로서의의미를가진다고알려져있었다. 그러나본연구에서혈청빌리루빈의정상혹은증가는혈구탐식증후군을진단받은환아들의좋은예후나나쁜예후인자로서의의미있는차이는보이지않았다. 본연구는몇몇연구에서진단시빌리루빈의높은수치가불량한예후인자로작용한다는발표들과달리, 빌리루빈이정상군과상승되어있는군간의치료결과는유의한차이를보이지않아예후를예측하기에는제한이있다는것을보고하는바이다. 하지만단일기관에입원한환자들을대상으로후향적으로의무기록이분석되었으며, 연구대상에포함이되었던환자수가적은점이제한점이라할수있겠다. ACKNOWLEDGEMENT 본연구는 2014년도부산대학병원임상연구비지원으로이루어졌습니다. REFERENCES 1. Henter JI, Horne A, Aricò M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. 2. Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol Oncol 1993;15: 92-8. 3. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009:127-31. 4. Gürgey A, Göğüş S, Ozyürek E, Aslan D, Gümrük F, Cetin M, et al. Primary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Hematol Oncol 2003;20:367-71. 5. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 2012;63:233-46. 6. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29-33. 7. Trottestam H, Horne A, Aricò M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011;118:4577-84. 8. Trottestam H, Berglöf E, Horne A, Onelöv E, Beutel K, Lehmberg K, et al. Risk factors for early death in children with haemophagocytic lymphohistiocytosis. Acta Paediatr 2012;101:313-8. 9. Imashuku S, Hlbi S, Todo S. Hemophagocytic lymphohistiocytosis in infancy and childhood. J Pediatr 1997;130:352-7. 10. Horne A, Trottestam H, Aricò M, Egeler RM, Filipovich AH, Gadner H, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008;140:327-35. 11. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer 2011;56:154-5. 12. Bell RJ, Brafield AJ, Barnes ND, France NE. Familial haemophagocytic reticulosis. Arch Dis Child 1968;43:601-6. 13. Aricò M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996;10:197-203. 14. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991;80:428-35. 15. Allen M, De Fusco C, Legrand F, Clementi R, Conter V, Danesino C, et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica 2001;86: 499-503. 80 YUJM VOLUME 31, NUMBER 2, DECEMBER 2014
Total bilirubin as a prognostic factor for HLH in childhood 16. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:435-44. 17. Seo JY, Seo DD, Jeon TJ, Oh TH, Shin WC, Choi WC, et al. A case of hemophagocytic syndrome complicated by acute viral hepatitis A infection. J Hepatol 2010;16:79-82. Korean. 18. Cho EY, Kim KH, Kim WS, Yoo KH, Koo HH, Ko YH. The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: incidence of disease entities by age groups. J Korean Med Sci 2008;23:185-92. 19. Kogawa K, Sato H, Asano T, Ohga S, Kudo K, Morimoto A, et al. Prognostic factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children: report of the Japan Histiocytosis Study Group. Pediatr Blood Cancer 2014;61:1257-62. YUJM VOLUME 31, NUMBER 2, DECEMBER 2014 81