354
Kasuistik
Fulminant Gastrointestinal Bleeding caused by EBV-triggered Hemophagocytic Lymphohistiocytosis: Report of a Case
Authors
S. Klein1, C. Schmidt1, P. La Rosée2, M. Pletz3, S. Harz4, O. Dirsch4, M. Fritzenwanger5, A. Stallmach1
Affiliations
Affiliation addresses are listed at the end of the article.
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Die hämophagozytische Lymphohistiozytose (HLH) ist ein seltenes, aber häufig letal verlaufendes Hyperinflammationssyndrom mit einer überschießenden Aktivierung des Immunsystems mit Fieber, Zytopenien, deutlich erhöhten Ferritinwerten und Hepatosplenomegalie. Wir beschreiben hier eine 39-jährige schwangere Patientin, die wegen Diarrhoen, intermittierenden gastrointestinalen Blutungen und Fieber hospitalisiert wurde. Nach einer Sektio mit der Geburt von Zwillingen in der 31. Woche verschlechterte sich das Befinden mit schwersten gastrointestinalen Blutungen und einer disseminierten intravaskulären Koagulopathie. Eine Gastro-, Ileokolos- und Kapselendoskopie zeigte multiple, ausgestanzte, teilweise konfluierende Ulzerationen im Magen, Dünndarm und Kolon. Eine Notfalloperation bei unkontrollierbarer Blutung mit intraoperativer Endoskopie ergab heftige Blutungen aus Ulzerationen im Jejunum; nach Resektion kam es zu einer kurzfristigen Stabilisierung. Die Histologie und in situ-Hybridisierung zeigte ausgedehnte Ulzerationen und eine fokale lymphohistiozytäre Infiltration mit EBVpositiven Immunoblasten. Basierend auf den HLH-2004 Diagnosekriterien wurde die Diagnose eines fulminanten HLH bei reaktivierter EBV-Infektion (bis zu 3 × 107 DNA Kopien/mL Blut) gestellt. Trotz aggressiver immunsuppressiver Therapie mit Steroiden, Cyclosporin A und Etoposid in Kombination mit Rituximab verstarb die Patientin an einem sepsisähnlichen, hyperinflammatorischen Syndrom mit Multiorganversagen bei gastrointestinalen Blutungen.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal hyperinflammatory syndrome characterized by fever, cytopenia, dramatically increased ferritin and hepatosplenomegaly. Here, we describe a previously healthy 39 year old pregnant woman in 30th week of her pregnancy with diarrhoea, intermittent gastrointestinal bleeding and fever of unknown focus. After cesarean section of twins in the 31st week she deteriorated with fulminant upper and lower gastrointestinal bleeding and disseminated intravascular coagulation. Gastro-, ileocolonoscopy and capsule endoscopy identified multiple bleeding punched ulcerations in the stomach, the entire small bowel and in parts of the colon. Emergency surgery with intraoperative endoscopy for uncontrolled hemorrhagic shock resulted in the resection of actively bleeding ulcers in the jejunum which temporally stabilized the critically ill patient. Jejunal histology and in situ hybridisation showed extensive ulcerations, focal lymphohistiocytic infiltration and EBV-positive immunoblasts. The diagnosis fulminant EBV-related HLH was confirmed based on the HLH-2004 diagnostic criteria and through detection of a reactivated EBV infection (up to 3 × 107 DNA copies/mL serum). Despite immunosuppressive therapy with steroids, cyclosporine A and etoposide in combination with Rituximab, the patient died from this sepsis-like, hyper-inflammatory syndrome in multiorgan failure with uncontrolled bleeding.
Introduction
rhage has been reported to vary from 40 to 150/ 100,000 annually [1, 2]. Three fundamental clinical principles remain constant in the management of patients with gastrointestinal bleeding. After immediate assessment and stabilization of
● gastrointestinale Blutung ● chronisch entzündliche "
● "
Darmerkrankung infektiöse Kolitis
Key words
● gastrointestinal bleeding ● chronic inflammatory " "
bowel disease
● infectious colitis "
received accepted
1.10.2013 2.2.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366154 Z Gastroenterol 2014; 52: 354–359 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Andreas Stallmach Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinik Jena, Friedrich-Schiller-Universität Erlanger Allee 101 07740 Jena Germany Tel.: ++ 49/36 41/9 32 42 21 Fax: ++ 49/36 41/9 32 42 22 andreas.stallmach@med. uni-jena.de
!
Gastrointestinal bleeding (GI) is a frequently occurring clinical scenario with a potentially serious prognosis. The incidence of non-variceal hemor-
Klein S et al. Fulminant Gastrointestinal Bleeding … Z Gastroenterol 2014; 52: 354–359
Downloaded by: Rutgers University. Copyrighted material.
Fulminante gastrointestinale Blutung bei EBV-induzierter hämophagozytischer Lymphohistiozytose – Ein Fallbericht
Kasuistik
Table 1 Diagnostic criteria for secondary HLH (5 of 8 criteria are necessary for diagnosis). 1.
fever
2.
splenomegaly
3.
cytopenia of at least two cell lines hemoglobin < 9 g/dL neutrophils < 1.0 /µL platelets < 100 000 /µL
4.
hypertriglyceridemia and/or hypofibrinogenemia fasting triglycerides ≥ 3 mmol/L fibrinogen < 1.5 g/L
5.
hemophagocytosis in bone marrow, CSF or lymph nodes
6.
decreased or absent NK-cell activity
7.
ferritin > 500 mg/L
8.
soluble interleukin-2 receptor (> 2400 U/mL)
Case Report !
A previously healthy 39-year-old woman was admitted to hospital in the 30st week of an uncomplicated pregnancy due to watery and bloody diarrhea, intermittent fever and weight loss. Symptomatic treatment with fluid replacement was initiated. A careful diagnostic work-up for the most relevant gastrointestinal infections revealed no pathogen. After one week, healthy twins were delivered via caesarean section. Thereafter, fever and bloody diarrhea deteriorated and the patient developed hepatosplenomegaly with impaired liver function and cholestasis {bilirubin 35 µmol/L (normal value < 21 µmol/L), g-GT: 7.71 µmol/L (< 0.63), ASAT 7.37 µmol/L (< 0.52), prolonged prothrombin time [INR 1.6, Quick 49 % (70 − 130 %)], thrombocytopenia (42 Gpt/L), a marked" Fig. 1), and a very ly rising levels of ferritin (> 90 000 µg/L)} (● high sCD25 serum level (41 562 U/mL; normal range 158 − 623 U/mL). Functional immune assays revealed normal perforin expression and unaffected CD107 expression and unimpaired degranulation of natural killer cells, therefore no evidence for a genetically determined degranulation defect was obvious. PCR showed highly replicative EBV-infection (up to 3.0 × 107 DNA copies/mL) with increasing anti-EBV IgG (130.0 U/mL) despite undetectable IgA. The clinical picture was interpreted as indicative of a hyperinflammatory reaction – an infection-associated HLH. Since intravenous immunoglobulin (IVIG) treatment has emerged as an important immunomodulatory medication at high doses to treat a wide range of autoimmune and inflammatory disorders [17] and has been also shown to effectively decrease hyperinflammatory reaction in HLH [18], we initiated IVIG treatment (30 g/day for five days) in combination with IV steroids (100 mg prednisone/ day). After 5 days ferritin level decreased to 3,154.4 µg/L. However, despite treatment and improvement of inflammatory markers, the patient deteriorated, gastrointestinal bleeding aggravated and she developed neurological symptoms with facial palsy. Endoscopic examinations of the upper gastrointestinal tract and ileocoloscopy revealed small punched ulcers in the stomach and sigmoid without " Fig. 2a, b). active bleeding (● Microscopic findings showed mucosal erosions with focal aggregation of lymphocytes and granulocytes. Adapted chemo-immunotherapy with etoposide (270 mg/weekly × 3), cyclosporin A [5 mg/kg body weight (with plasma level adapted)] and dexamethasone (12 mg/day) according to the HLH-04 protocol in addition to IVIG application was started, and rituximab 375 mg/m2 weekly (four times) was added to control EBV infection [14, 19]. After a transient clinical improvement, the patient deteriorated four days later again with an acute severe hematochezia leading to a decrease in hemoglobin from 6.2 mmol/L to 3.1 mmol/L (normal range: 7.6 – 9.5 mmol/L) in spite of transfusion of 14 red packs and five thrombocyte concentrates. Repeated immediate endoscopic examination of the upper and lower gastrointestinal tract showed no bleeding lesions in the esophagus, stomach and upper part of the duodenum. Ileocolonoscopy revealed multiple, variable sized, irregular shallow ulcerations in the terminal ileum without active bleeding, but old and fresh blood in the proximal part of the ileum. Video capsule endoscopy revealed significant amounts of fresh blood, multiple mucosal erosions and shallow longitudinal ulcers in jejunal and ileal loops. On the same day, an emergency laparotomy with intraoperative peroral endoscopy was performed since computed tomography showed an ectatic vessel in the distal jejunum wall as a possible bleeding source. Deep bleeding ulcers in the middle part of the jejunum were
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the patient, physicians must (a) determine the source of bleeding, (b) stop active bleeding and most importantly (c) treat the underlying disease and prevent recurrent bleeding [3]. Despite suggestive morphological and histological features of endoscopic lesions differential diagnosis must be performed carefully. In 2002, Hsiao et al. reported two cases of patients with bloody diarrhea, fever and weight loss. Endoscopic examinations showed multiple ulcerations in the entire colon. In fact, Epstein-Barr Virus (EBV) induced T-cell lymphoma of the colon was confirmed in these patients and both died of severe hemophagocytic lymphohistiocytosis (HLH) [4]. HLH (ICD-10 code: D76.1 hemophagocytic lymphohistiocytosis) is a rare life-threatening disorder of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages, which can lead to multiple organ failure and death [5, 6]. It can be classified as either hereditary or acquired [7]. Hereditary HLH is an autosomal recessive disorder caused by mutations affecting perforin function and trafficking of natural killer cells [8]. Secondary HLH is associated with a variety of infections with primarily intracellular pathogens, such as EBV and other viral infections, and also with bacterial, fungal, and parasitic infections as well as malignancies, in particular lymphomas [7, 9 – 12]. HLH induced by autoimmune and autoinflammatory disorders is commonly referred to as macrophage activation syndrome (MAS) [13]. At present, the diagnosis of HLH is based on the revised criteria of the pediatric HLH-2004 protocol of the Histiocyte Society, including clinical symptoms (fever and splenomegaly), laboratory tests (cytopenia, hyperferritinaemia, hypertriglyceridemia and/or hypofibrinogenaemia, increased levels of soluble interleukin-2 receptor [sCD25 levels]), immunological examinations (reduced or absent natural killer cell activity) and histopathological evidence of hemophagocytosis in the bone marrow, spleen or lymph nodes " Table 1) [14]. (● Supportive evidence are cerebral symptoms (e. g., peripheral facialis paresis) with moderate pleocytosis and/or elevated protein, elevated transaminases, bilirubin, lactate dehydrogenase levels (modified according [15, 16]). Patients fulfilling at least five of these eight criteria are diagnosed with HLH. Awareness of HLH is of central importance since early diagnosis and rapid initiation of treatment is critical for a successful outcome. We here present a fatal case of an apparently immunocompetent pregnant woman who first presented with signs of inflammatory gastrointestinal disease similar to Crohn’s disease and developed lethal HLH.
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Fig. 1 Kinetics of ferritin levels. HLH-directed treatment is indicated by blue bars.
Fig. 2 a, b Punched ulcerations in the antrum a and terminal ileum b.
" Fig. 3a–d) and a 10 cm resection with end-to-end identified (● anastomosis was performed. Furthermore, a temporary double-barreled jejunal stoma was created to facilitate further enteroscopy in case of any additional bleeding from the small bowel. Histopathological examination of the small bowel segment revealed extensive ulcerations, intramuscular bleeding, a dense lymphohistiocytic jejunal infiltration " Fig. 3) and pronounced fibrinous and purulent peritonitis. In (● situ hybridization for EBV showed EBV-positive immunoblasts " Fig. 4a, b) as well as in the fetal placenin the jejunal resection (● ta and in the bone marrow suggesting viral infection as a probable trigger for the gastrointestinal lesions. After surgery the blood loss persisted overall requiring a total of 54 units of red blood cell concentrates, 72 units of platelet concentrates and 22 units of fresh frozen plasma and 38 g fibrinogen during the next 21 days. Two days after surgery, a hemoperitoneum was suspected and a second explorative laparotomy was performed. Laparatomy revealed diffuse bleeding of the peritoneum and the small intestine. Jejunostomy was re-resected and the small intestine was decompressed but endoscopy showed persistent je" Fig. 1) junal bleeding within the next days. Since ferritin levels (● and EBV replication increased again dramatically, treatment with the immunosuppressive monoclonal anti-CD52 antibody alemtuzumab was initiated (3 mg day 1, 5 mg day 2, 10 mg day 3). Alemtuzumab is a monoclonal antibody that selectively targets CD52, to deplete circulating T and B lymphocytes, the critical mediators inflammatory processes, while having minimal impact on the other immune cells. The decision to use Alemtuzumab was rationalized by the flow-cytometric observation that EBV replication occurred also within the T cell population. Despite maximum immune-sup-
pressive and supportive treatment, pan-cytopenia, coagulopathy and gastrointestinal bleeding persisted. One month after the onset of symptoms, she developed multiorgan failure, massive GI hemorrhage, and died due to intracranial hemorrhage. Autopsy revealed a massive hemorrhagic, ulcerative gastroenteritis and colitis. In situ hybridization established an extensive EBV infection with multiple EBV positive lymphoid cells as the reason, leading to this hemorrhagic, ulcerative gastroenteritis and colitis, as also reported in the literature [20, 21]. Massive hemorrhagic, ulcerative gastroenteritis and colitis clinically resulted in a protracted state of shock. The protracted state of shock was revealed morphologically as multiple organ lesions like centroacinar necrosis of the liver and hyaline thrombi as well as extensive edema of the lungs.
Discussion !
Gastrointestinal bleeding is a common medical condition that may result in high patient morbidity; it frequently presents with hematemesis or melena. In patients with GI bleeding it is important to take a careful patient history, perform a physical examination followed by upper and lower endoscopy to identify the possible source and etiology of the bleeding. Further localization, activity and characterization of etiology of the bleeding source are important in determining an appropriate intervention, as treatment options range from conservative therapies over minimally invasive endoscopic-directed therapy to extensive surgical resection. Diarrhea, gastrointestinal bleeding, fever and endoscopic features such as erosions and ulcerations in rectum, terminal ileum and stomach could be signs of a primary manifestation
Klein S et al. Fulminant Gastrointestinal Bleeding … Z Gastroenterol 2014; 52: 354–359
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357
Fig. 4 A Shallow ulcer of the jejunum, H&E, 30x; B EBV In situ hybridisation, 400x.
of Crohn’s disease. However, highly elevated ferritin levels in association with fever, cytopenia, hypofibrinogenemia, organomegaly – as seen in our patient – are strongly suggestive for a HLH. Allen and coworkers previously reported that ferritin values over 10,000 µg/L in children are highly sensitive and specific for the diagnosis of HLH [22]. The maximal ferritin value in our patient reached 93,419 mg/L and decreased transiently in response to anti-inflammatory treatment. There are only few reports in the literature of patients with HLH which mimics IBD [4, 23 – 25]. However, and more importantly, HLH could be a complication of established IBD. In an excellent recently published review, Fries and coworkers reported 50 patients, mostly patients with Crohn’s disease, who developed HLH. Overall mortality in these cases was 30 %. Virus-related HLH associated with cytomegalovirus or Epstein-Barr virus infections represents the main type of HLH in patients with IBD but in isolated cases bacterial infections precipitated the syndrome. In 8 %, a lymphoma was present at the time of HLH diagnosis or developed shortly thereafter. Thiopurine monotherapy was given before HLH onset in 56 % of the patients, whereas multiple immunosuppressants, including
biologics, were administered to 24 % [26]. Therefore, both scenarios are possible: HLH may mimic IBD and HLH may complicate pre-existing IBD mostly triggered by superinfections. In patients presenting with prolonged fever, cytopenia and hepatosplenomegaly, HLH should be considered as a differential diagnosis. Early recognition of HLH depends on a diagnostic work-up according to the revised criteria [14]. In these patients, bone marrow aspiration and biopsy should be performed. Hemophagocytosis is not a mandatory feature of HLH but may be found in repeat examinations. After establishment of the diagnosis of HLH, immunological work-up (expression of perforin, SAP/XIAP and, NK cell degranulation) and − if indicated by positive hints provided by functional assays, genetic sequencing should be performed to detect late onset hereditary disease [27]. It is of major importance to repeat the work-up (i. e., ferritin, soluble interleukin 2 receptor, fibrinogen, triglycerides) if the symptoms persist but not all required HLH criteria were met initially. It is recommended to involve national HLH-reference centers to guide diagnostics and treatment. The outcome of pediatric patients with HLH has [28] significantly improved from a mortality rate of 95 % to a cure rate of 55 %, since
Klein S et al. Fulminant Gastrointestinal Bleeding … Z Gastroenterol 2014; 52: 354–359
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Fig. 3 a–d Intraoperatively seen bleeding ulcerations in the middle part of the jejunum.
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Affiliations 1
2
3
4
5
Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany Zentrum für Infektionsmedizin und Krankenhaushygiene, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany Institut für Pathologie, Universitätsklinikum Jena, Friedrich-SchillerUniversität Jena, Jena, Germany Klinik für Innere Medizin I mit Schwerpunkt Kardiologie-PneumologieAngiologie-Intensivmedizin, Universitätsklinikum Jena, Friedrich-SchillerUniversität Jena, Jena, Germany
References 01 Gilbert DA. Epidemiology of upper gastrointestinal bleeding. Gastrointestinal endoscopy 1990; 36: S8 – S13 02 Koelz HR, Arn M. New epidemiology of acute gastrointestinal hemorrhage. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 2006; 77: 103 – 110 03 Rockey DC. Gastrointestinal bleeding. In: Feldman MF, Friedman LS, Sleisinger MH eds Gastrointestinal and Liver diseases 211. Philadelphia, London, New York, St. Louis, Sydney, Toronto: Saunders; 2002 04 Hsiao CH, Kao HL, Lin MC et al. Ulcerative colon T-cell lymphoma: an unusual entity mimicking Crohn's disease and may be associated with fulminant hemophagocytosis. Hepato-gastroenterology 2002; 49: 950 – 954 05 Janka G, Imashuku S, Elinder G et al. Infection- and malignancyassociated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol/oncol Clinics North America 1998; 12: 435 – 444 06 Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 2012; 24: 9 – 15 07 Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166: 95 – 109 08 Pachlopnik Schmid J, Cote M, Menager MM et al. Inherited defects in lymphocyte cytotoxic activity. Immunolog Rev 2010; 235: 10 – 23 09 Bohne S, Kentouche K, Petersen I et al. Fulminant Epstein-Barr virusassociated hemophagocytic lymphohistiocytosis. Laryngoscope 2013; 123: 362 – 365 10 Dhote R, Simon J, Papo T et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthr Rheumat 2003; 49: 633 – 639 11 Ellis GR, Gozzard DI, Looker DN et al. Postanginal septicaemia (Lemmiere's disease) complicated by haemophagocytosis. J Infect 1998; 36: 340 – 341 12 Beutel G, Wiesner O, Eder M et al. Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care 2011; 15: R80 13 Ravelli A, Grom AA, Behrens EM et al. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 2012; 13: 289 – 298 14 Henter JI, Horne A, Arico M et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124 – 131 15 Janka GE. Hemophagocytic syndromes. Blood Rev 2007; 21: 245 – 253 16 Switala JR, Hendricks M, Davidson A. Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world. J Pediatr Hematol/Oncol 2012; 34: e89 – e92 17 Kaveri SV, Maddur MS, Hegde P et al. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol 2011; 164 (Suppl 2): 2 – 5 18 Emmenegger U, Frey U, Reimers A et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 2001; 68: 4 – 10 19 Chellapandian D, Das R, Zelley K et al. Treatment of Epstein Barr virusinduced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol 2013; 162: 376 – 382 20 Tashiro Y, Goto M, Takemoto Y et al. Epstein-Barr virus-associated enteritis with multiple ulcers after stem cell transplantation: first histologically confirmed case. Pathol Int 2006; 56: 530 – 537 21 Yanai H, Shimizu N, Nagasaki S et al. Epstein-Barr virus infection of the colon with inflammatory bowel disease. Am J Gastroenterol 1999; 94: 1582 – 1586 22 Allen CE, Yu X, Kozinetz CA et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediat Blood Cancer 2008; 50: 1227 – 1235 23 Galoo E, Potier V, Romand F et al. [Primary chronic ulcerative jejunoileitis complicated by hemophagocytic syndrome]. Gastroenterol clin biol 1999; 23: 783 – 787 24 Ina S, Tani M, Takifuji K et al. Virus-associated hemophagocytic syndrome and hemorrhagic jejunal ulcer caused by cytomegalovirus infection in a non-compromised host; a case report of unusual entity. Hepato-gastroenterology 2004; 51: 491 – 493 25 Moon JH, Hong SP, Park PW et al. A case of hemophagocytic syndrome with terminal ileal ulcerations. KorJ Gastroenterol = Taehan Sohwagi Hakhoe chi 2006; 48: 205 – 209
Klein S et al. Fulminant Gastrointestinal Bleeding … Z Gastroenterol 2014; 52: 354–359
Downloaded by: Rutgers University. Copyrighted material.
diagnostic criteria and treatment regimens have been implemented rapidly [29]. However, HLH as late onset hereditary disease (in particular EBV-induced HLH in males with XLP1 / XLP2-disease) or secondary HLH in response to a variety of infectious, autoimmune, autoinflammatory or neoplastic triggers affects adults in all age groups with about 20 % of patients being > 60 years old [30]. Prognosis in adults is assumed to be worse with a mortality rate of 60 % − 90 % depending on the underlying HLH-trigger disease [28]. Diagnostic criteria have not been validated in larger adult patient cohorts and may have to be adapted as currently being performed in MAS triggered by autoinflammatory Still syndrome [13]. Treatment in adults must be carefully adapted from pediatric protocols according to the wider variety of trigger diseases in adults, and primarly focus on treating the underlying disease [31]. In this regard, our patient was treated with rituximab in order to suppress EBVreplication as the assumed trigger disease. We can only speculate on the cause of severe EBV-reactivation in a pregnant women with secondary HLH, as we did not detect functional defects in immune assays. Post-mortem section did not reveal EBV-associated lymphoma, a condition frequently triggering HLH in adults [32]. When considering the treatment of EBV-HLH, the most important factor is the diagnostic vigilance as time to start of treatment is a major prognostic factor. In hereditary HLH, a poor prognosis has been reported, if treatment is initiated later than 4 weeks after the onset of symptoms (for review see [33]). This indicates that there may be a window for observation or initiation of treatment with rituximab, corticosteroid/cyclosporin A or intravenous immunoglobulin (IVIG) [19]. However, once the disease is defined as "high risk" and/or refractory to such therapy, prompt introduction of etoposide (ideally within 4 weeks) is recommended. Of note, prolonged immunosuppression for HLH in adults should be avoided, as regaining immunocompetence after short-term immunosuppression is a prerequisite for successful eradication of the infectious agent [31]. It is recommended to tailor treatment in cooperation with HLH-reference centers. In Germany, the HLH-in-adults network can be contacted via web. As HLH is a rare and difficult to treat disease, registering patients is encouraged in order to develop guidelines for diagnosis and treatment of adult patients with HLH. In conclusion, our case and the review of the literature indicate that physicians should be aware of the risk of HLH in patients with severe gastrointestinal bleeding, fever and increased ferritin levels. Early diagnosis is essential to start appropriate treatment achieving a better outcome.
Kasuistik
30 Ishii E, Ohga S, Imashuku S et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007; 86: 58 – 65 31 Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 2012; 63: 233 – 246 32 Nawathe PA, Ravindranath TM, Satwani P et al. Severe hemorrhagic coagulopathy with hemophagocytic lymphohistiocytosis secondary to Epstein-Barr virus-associated T-cell lymphoproliferative disorder. Pediatr Crit Care Med 2013; 14: e176 – e181 33 Imashuku S, Kuriyama K, Sakai R et al. Treatment of Epstein-Barr virusassociated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol 2003; 41: 103 – 109
Downloaded by: Rutgers University. Copyrighted material.
26 Fries W, Cottone M, Cascio A. Systematic review: macrophage activation syndrome in inflammatory bowel disease. Alim pharmacol therap 2013; 37: 1033 – 1045 27 Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 2013; 160: 275 – 287 28 Yu JT, Wang CY, Yang Y et al. Lymphoma-associated hemophagocytic lymphohistiocytosis: experience in adults from a single institution. Ann Hematol 2013; DOI: 10.1007/s00277-013-1784-3 29 Jordan MB, Allen CE, Weitzman S et al. How I treat hemophagocytic lymphohistiocytosis. Blood 2011; 118: 4041 – 4052
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Klein S et al. Fulminant Gastrointestinal Bleeding … Z Gastroenterol 2014; 52: 354–359
Kasuistik
Fulminant Gastrointestinal Bleeding caused by EBV-triggered Hemophagocytic Lymphohistiocytosis: Report of a Case
Authors
S. Klein1, C. Schmidt1, P. La Rosée2, M. Pletz3, S. Harz4, O. Dirsch4, M. Fritzenwanger5, A. Stallmach1
Affiliations
Affiliation addresses are listed at the end of the article.
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Die hämophagozytische Lymphohistiozytose (HLH) ist ein seltenes, aber häufig letal verlaufendes Hyperinflammationssyndrom mit einer überschießenden Aktivierung des Immunsystems mit Fieber, Zytopenien, deutlich erhöhten Ferritinwerten und Hepatosplenomegalie. Wir beschreiben hier eine 39-jährige schwangere Patientin, die wegen Diarrhoen, intermittierenden gastrointestinalen Blutungen und Fieber hospitalisiert wurde. Nach einer Sektio mit der Geburt von Zwillingen in der 31. Woche verschlechterte sich das Befinden mit schwersten gastrointestinalen Blutungen und einer disseminierten intravaskulären Koagulopathie. Eine Gastro-, Ileokolos- und Kapselendoskopie zeigte multiple, ausgestanzte, teilweise konfluierende Ulzerationen im Magen, Dünndarm und Kolon. Eine Notfalloperation bei unkontrollierbarer Blutung mit intraoperativer Endoskopie ergab heftige Blutungen aus Ulzerationen im Jejunum; nach Resektion kam es zu einer kurzfristigen Stabilisierung. Die Histologie und in situ-Hybridisierung zeigte ausgedehnte Ulzerationen und eine fokale lymphohistiozytäre Infiltration mit EBVpositiven Immunoblasten. Basierend auf den HLH-2004 Diagnosekriterien wurde die Diagnose eines fulminanten HLH bei reaktivierter EBV-Infektion (bis zu 3 × 107 DNA Kopien/mL Blut) gestellt. Trotz aggressiver immunsuppressiver Therapie mit Steroiden, Cyclosporin A und Etoposid in Kombination mit Rituximab verstarb die Patientin an einem sepsisähnlichen, hyperinflammatorischen Syndrom mit Multiorganversagen bei gastrointestinalen Blutungen.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal hyperinflammatory syndrome characterized by fever, cytopenia, dramatically increased ferritin and hepatosplenomegaly. Here, we describe a previously healthy 39 year old pregnant woman in 30th week of her pregnancy with diarrhoea, intermittent gastrointestinal bleeding and fever of unknown focus. After cesarean section of twins in the 31st week she deteriorated with fulminant upper and lower gastrointestinal bleeding and disseminated intravascular coagulation. Gastro-, ileocolonoscopy and capsule endoscopy identified multiple bleeding punched ulcerations in the stomach, the entire small bowel and in parts of the colon. Emergency surgery with intraoperative endoscopy for uncontrolled hemorrhagic shock resulted in the resection of actively bleeding ulcers in the jejunum which temporally stabilized the critically ill patient. Jejunal histology and in situ hybridisation showed extensive ulcerations, focal lymphohistiocytic infiltration and EBV-positive immunoblasts. The diagnosis fulminant EBV-related HLH was confirmed based on the HLH-2004 diagnostic criteria and through detection of a reactivated EBV infection (up to 3 × 107 DNA copies/mL serum). Despite immunosuppressive therapy with steroids, cyclosporine A and etoposide in combination with Rituximab, the patient died from this sepsis-like, hyper-inflammatory syndrome in multiorgan failure with uncontrolled bleeding.
Introduction
rhage has been reported to vary from 40 to 150/ 100,000 annually [1, 2]. Three fundamental clinical principles remain constant in the management of patients with gastrointestinal bleeding. After immediate assessment and stabilization of
● gastrointestinale Blutung ● chronisch entzündliche "
● "
Darmerkrankung infektiöse Kolitis
Key words
● gastrointestinal bleeding ● chronic inflammatory " "
bowel disease
● infectious colitis "
received accepted
1.10.2013 2.2.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366154 Z Gastroenterol 2014; 52: 354–359 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Andreas Stallmach Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinik Jena, Friedrich-Schiller-Universität Erlanger Allee 101 07740 Jena Germany Tel.: ++ 49/36 41/9 32 42 21 Fax: ++ 49/36 41/9 32 42 22 andreas.stallmach@med. uni-jena.de
!
Gastrointestinal bleeding (GI) is a frequently occurring clinical scenario with a potentially serious prognosis. The incidence of non-variceal hemor-
Klein S et al. Fulminant Gastrointestinal Bleeding … Z Gastroenterol 2014; 52: 354–359
Downloaded by: Rutgers University. Copyrighted material.
Fulminante gastrointestinale Blutung bei EBV-induzierter hämophagozytischer Lymphohistiozytose – Ein Fallbericht
Kasuistik
Table 1 Diagnostic criteria for secondary HLH (5 of 8 criteria are necessary for diagnosis). 1.
fever
2.
splenomegaly
3.
cytopenia of at least two cell lines hemoglobin < 9 g/dL neutrophils < 1.0 /µL platelets < 100 000 /µL
4.
hypertriglyceridemia and/or hypofibrinogenemia fasting triglycerides ≥ 3 mmol/L fibrinogen < 1.5 g/L
5.
hemophagocytosis in bone marrow, CSF or lymph nodes
6.
decreased or absent NK-cell activity
7.
ferritin > 500 mg/L
8.
soluble interleukin-2 receptor (> 2400 U/mL)
Case Report !
A previously healthy 39-year-old woman was admitted to hospital in the 30st week of an uncomplicated pregnancy due to watery and bloody diarrhea, intermittent fever and weight loss. Symptomatic treatment with fluid replacement was initiated. A careful diagnostic work-up for the most relevant gastrointestinal infections revealed no pathogen. After one week, healthy twins were delivered via caesarean section. Thereafter, fever and bloody diarrhea deteriorated and the patient developed hepatosplenomegaly with impaired liver function and cholestasis {bilirubin 35 µmol/L (normal value < 21 µmol/L), g-GT: 7.71 µmol/L (< 0.63), ASAT 7.37 µmol/L (< 0.52), prolonged prothrombin time [INR 1.6, Quick 49 % (70 − 130 %)], thrombocytopenia (42 Gpt/L), a marked" Fig. 1), and a very ly rising levels of ferritin (> 90 000 µg/L)} (● high sCD25 serum level (41 562 U/mL; normal range 158 − 623 U/mL). Functional immune assays revealed normal perforin expression and unaffected CD107 expression and unimpaired degranulation of natural killer cells, therefore no evidence for a genetically determined degranulation defect was obvious. PCR showed highly replicative EBV-infection (up to 3.0 × 107 DNA copies/mL) with increasing anti-EBV IgG (130.0 U/mL) despite undetectable IgA. The clinical picture was interpreted as indicative of a hyperinflammatory reaction – an infection-associated HLH. Since intravenous immunoglobulin (IVIG) treatment has emerged as an important immunomodulatory medication at high doses to treat a wide range of autoimmune and inflammatory disorders [17] and has been also shown to effectively decrease hyperinflammatory reaction in HLH [18], we initiated IVIG treatment (30 g/day for five days) in combination with IV steroids (100 mg prednisone/ day). After 5 days ferritin level decreased to 3,154.4 µg/L. However, despite treatment and improvement of inflammatory markers, the patient deteriorated, gastrointestinal bleeding aggravated and she developed neurological symptoms with facial palsy. Endoscopic examinations of the upper gastrointestinal tract and ileocoloscopy revealed small punched ulcers in the stomach and sigmoid without " Fig. 2a, b). active bleeding (● Microscopic findings showed mucosal erosions with focal aggregation of lymphocytes and granulocytes. Adapted chemo-immunotherapy with etoposide (270 mg/weekly × 3), cyclosporin A [5 mg/kg body weight (with plasma level adapted)] and dexamethasone (12 mg/day) according to the HLH-04 protocol in addition to IVIG application was started, and rituximab 375 mg/m2 weekly (four times) was added to control EBV infection [14, 19]. After a transient clinical improvement, the patient deteriorated four days later again with an acute severe hematochezia leading to a decrease in hemoglobin from 6.2 mmol/L to 3.1 mmol/L (normal range: 7.6 – 9.5 mmol/L) in spite of transfusion of 14 red packs and five thrombocyte concentrates. Repeated immediate endoscopic examination of the upper and lower gastrointestinal tract showed no bleeding lesions in the esophagus, stomach and upper part of the duodenum. Ileocolonoscopy revealed multiple, variable sized, irregular shallow ulcerations in the terminal ileum without active bleeding, but old and fresh blood in the proximal part of the ileum. Video capsule endoscopy revealed significant amounts of fresh blood, multiple mucosal erosions and shallow longitudinal ulcers in jejunal and ileal loops. On the same day, an emergency laparotomy with intraoperative peroral endoscopy was performed since computed tomography showed an ectatic vessel in the distal jejunum wall as a possible bleeding source. Deep bleeding ulcers in the middle part of the jejunum were
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the patient, physicians must (a) determine the source of bleeding, (b) stop active bleeding and most importantly (c) treat the underlying disease and prevent recurrent bleeding [3]. Despite suggestive morphological and histological features of endoscopic lesions differential diagnosis must be performed carefully. In 2002, Hsiao et al. reported two cases of patients with bloody diarrhea, fever and weight loss. Endoscopic examinations showed multiple ulcerations in the entire colon. In fact, Epstein-Barr Virus (EBV) induced T-cell lymphoma of the colon was confirmed in these patients and both died of severe hemophagocytic lymphohistiocytosis (HLH) [4]. HLH (ICD-10 code: D76.1 hemophagocytic lymphohistiocytosis) is a rare life-threatening disorder of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages, which can lead to multiple organ failure and death [5, 6]. It can be classified as either hereditary or acquired [7]. Hereditary HLH is an autosomal recessive disorder caused by mutations affecting perforin function and trafficking of natural killer cells [8]. Secondary HLH is associated with a variety of infections with primarily intracellular pathogens, such as EBV and other viral infections, and also with bacterial, fungal, and parasitic infections as well as malignancies, in particular lymphomas [7, 9 – 12]. HLH induced by autoimmune and autoinflammatory disorders is commonly referred to as macrophage activation syndrome (MAS) [13]. At present, the diagnosis of HLH is based on the revised criteria of the pediatric HLH-2004 protocol of the Histiocyte Society, including clinical symptoms (fever and splenomegaly), laboratory tests (cytopenia, hyperferritinaemia, hypertriglyceridemia and/or hypofibrinogenaemia, increased levels of soluble interleukin-2 receptor [sCD25 levels]), immunological examinations (reduced or absent natural killer cell activity) and histopathological evidence of hemophagocytosis in the bone marrow, spleen or lymph nodes " Table 1) [14]. (● Supportive evidence are cerebral symptoms (e. g., peripheral facialis paresis) with moderate pleocytosis and/or elevated protein, elevated transaminases, bilirubin, lactate dehydrogenase levels (modified according [15, 16]). Patients fulfilling at least five of these eight criteria are diagnosed with HLH. Awareness of HLH is of central importance since early diagnosis and rapid initiation of treatment is critical for a successful outcome. We here present a fatal case of an apparently immunocompetent pregnant woman who first presented with signs of inflammatory gastrointestinal disease similar to Crohn’s disease and developed lethal HLH.
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Fig. 1 Kinetics of ferritin levels. HLH-directed treatment is indicated by blue bars.
Fig. 2 a, b Punched ulcerations in the antrum a and terminal ileum b.
" Fig. 3a–d) and a 10 cm resection with end-to-end identified (● anastomosis was performed. Furthermore, a temporary double-barreled jejunal stoma was created to facilitate further enteroscopy in case of any additional bleeding from the small bowel. Histopathological examination of the small bowel segment revealed extensive ulcerations, intramuscular bleeding, a dense lymphohistiocytic jejunal infiltration " Fig. 3) and pronounced fibrinous and purulent peritonitis. In (● situ hybridization for EBV showed EBV-positive immunoblasts " Fig. 4a, b) as well as in the fetal placenin the jejunal resection (● ta and in the bone marrow suggesting viral infection as a probable trigger for the gastrointestinal lesions. After surgery the blood loss persisted overall requiring a total of 54 units of red blood cell concentrates, 72 units of platelet concentrates and 22 units of fresh frozen plasma and 38 g fibrinogen during the next 21 days. Two days after surgery, a hemoperitoneum was suspected and a second explorative laparotomy was performed. Laparatomy revealed diffuse bleeding of the peritoneum and the small intestine. Jejunostomy was re-resected and the small intestine was decompressed but endoscopy showed persistent je" Fig. 1) junal bleeding within the next days. Since ferritin levels (● and EBV replication increased again dramatically, treatment with the immunosuppressive monoclonal anti-CD52 antibody alemtuzumab was initiated (3 mg day 1, 5 mg day 2, 10 mg day 3). Alemtuzumab is a monoclonal antibody that selectively targets CD52, to deplete circulating T and B lymphocytes, the critical mediators inflammatory processes, while having minimal impact on the other immune cells. The decision to use Alemtuzumab was rationalized by the flow-cytometric observation that EBV replication occurred also within the T cell population. Despite maximum immune-sup-
pressive and supportive treatment, pan-cytopenia, coagulopathy and gastrointestinal bleeding persisted. One month after the onset of symptoms, she developed multiorgan failure, massive GI hemorrhage, and died due to intracranial hemorrhage. Autopsy revealed a massive hemorrhagic, ulcerative gastroenteritis and colitis. In situ hybridization established an extensive EBV infection with multiple EBV positive lymphoid cells as the reason, leading to this hemorrhagic, ulcerative gastroenteritis and colitis, as also reported in the literature [20, 21]. Massive hemorrhagic, ulcerative gastroenteritis and colitis clinically resulted in a protracted state of shock. The protracted state of shock was revealed morphologically as multiple organ lesions like centroacinar necrosis of the liver and hyaline thrombi as well as extensive edema of the lungs.
Discussion !
Gastrointestinal bleeding is a common medical condition that may result in high patient morbidity; it frequently presents with hematemesis or melena. In patients with GI bleeding it is important to take a careful patient history, perform a physical examination followed by upper and lower endoscopy to identify the possible source and etiology of the bleeding. Further localization, activity and characterization of etiology of the bleeding source are important in determining an appropriate intervention, as treatment options range from conservative therapies over minimally invasive endoscopic-directed therapy to extensive surgical resection. Diarrhea, gastrointestinal bleeding, fever and endoscopic features such as erosions and ulcerations in rectum, terminal ileum and stomach could be signs of a primary manifestation
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Fig. 4 A Shallow ulcer of the jejunum, H&E, 30x; B EBV In situ hybridisation, 400x.
of Crohn’s disease. However, highly elevated ferritin levels in association with fever, cytopenia, hypofibrinogenemia, organomegaly – as seen in our patient – are strongly suggestive for a HLH. Allen and coworkers previously reported that ferritin values over 10,000 µg/L in children are highly sensitive and specific for the diagnosis of HLH [22]. The maximal ferritin value in our patient reached 93,419 mg/L and decreased transiently in response to anti-inflammatory treatment. There are only few reports in the literature of patients with HLH which mimics IBD [4, 23 – 25]. However, and more importantly, HLH could be a complication of established IBD. In an excellent recently published review, Fries and coworkers reported 50 patients, mostly patients with Crohn’s disease, who developed HLH. Overall mortality in these cases was 30 %. Virus-related HLH associated with cytomegalovirus or Epstein-Barr virus infections represents the main type of HLH in patients with IBD but in isolated cases bacterial infections precipitated the syndrome. In 8 %, a lymphoma was present at the time of HLH diagnosis or developed shortly thereafter. Thiopurine monotherapy was given before HLH onset in 56 % of the patients, whereas multiple immunosuppressants, including
biologics, were administered to 24 % [26]. Therefore, both scenarios are possible: HLH may mimic IBD and HLH may complicate pre-existing IBD mostly triggered by superinfections. In patients presenting with prolonged fever, cytopenia and hepatosplenomegaly, HLH should be considered as a differential diagnosis. Early recognition of HLH depends on a diagnostic work-up according to the revised criteria [14]. In these patients, bone marrow aspiration and biopsy should be performed. Hemophagocytosis is not a mandatory feature of HLH but may be found in repeat examinations. After establishment of the diagnosis of HLH, immunological work-up (expression of perforin, SAP/XIAP and, NK cell degranulation) and − if indicated by positive hints provided by functional assays, genetic sequencing should be performed to detect late onset hereditary disease [27]. It is of major importance to repeat the work-up (i. e., ferritin, soluble interleukin 2 receptor, fibrinogen, triglycerides) if the symptoms persist but not all required HLH criteria were met initially. It is recommended to involve national HLH-reference centers to guide diagnostics and treatment. The outcome of pediatric patients with HLH has [28] significantly improved from a mortality rate of 95 % to a cure rate of 55 %, since
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Fig. 3 a–d Intraoperatively seen bleeding ulcerations in the middle part of the jejunum.
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Affiliations 1
2
3
4
5
Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany Zentrum für Infektionsmedizin und Krankenhaushygiene, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany Institut für Pathologie, Universitätsklinikum Jena, Friedrich-SchillerUniversität Jena, Jena, Germany Klinik für Innere Medizin I mit Schwerpunkt Kardiologie-PneumologieAngiologie-Intensivmedizin, Universitätsklinikum Jena, Friedrich-SchillerUniversität Jena, Jena, Germany
References 01 Gilbert DA. Epidemiology of upper gastrointestinal bleeding. Gastrointestinal endoscopy 1990; 36: S8 – S13 02 Koelz HR, Arn M. New epidemiology of acute gastrointestinal hemorrhage. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 2006; 77: 103 – 110 03 Rockey DC. Gastrointestinal bleeding. In: Feldman MF, Friedman LS, Sleisinger MH eds Gastrointestinal and Liver diseases 211. Philadelphia, London, New York, St. Louis, Sydney, Toronto: Saunders; 2002 04 Hsiao CH, Kao HL, Lin MC et al. Ulcerative colon T-cell lymphoma: an unusual entity mimicking Crohn's disease and may be associated with fulminant hemophagocytosis. Hepato-gastroenterology 2002; 49: 950 – 954 05 Janka G, Imashuku S, Elinder G et al. Infection- and malignancyassociated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol/oncol Clinics North America 1998; 12: 435 – 444 06 Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 2012; 24: 9 – 15 07 Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166: 95 – 109 08 Pachlopnik Schmid J, Cote M, Menager MM et al. Inherited defects in lymphocyte cytotoxic activity. Immunolog Rev 2010; 235: 10 – 23 09 Bohne S, Kentouche K, Petersen I et al. Fulminant Epstein-Barr virusassociated hemophagocytic lymphohistiocytosis. Laryngoscope 2013; 123: 362 – 365 10 Dhote R, Simon J, Papo T et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthr Rheumat 2003; 49: 633 – 639 11 Ellis GR, Gozzard DI, Looker DN et al. Postanginal septicaemia (Lemmiere's disease) complicated by haemophagocytosis. J Infect 1998; 36: 340 – 341 12 Beutel G, Wiesner O, Eder M et al. Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care 2011; 15: R80 13 Ravelli A, Grom AA, Behrens EM et al. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 2012; 13: 289 – 298 14 Henter JI, Horne A, Arico M et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124 – 131 15 Janka GE. Hemophagocytic syndromes. Blood Rev 2007; 21: 245 – 253 16 Switala JR, Hendricks M, Davidson A. Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world. J Pediatr Hematol/Oncol 2012; 34: e89 – e92 17 Kaveri SV, Maddur MS, Hegde P et al. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol 2011; 164 (Suppl 2): 2 – 5 18 Emmenegger U, Frey U, Reimers A et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 2001; 68: 4 – 10 19 Chellapandian D, Das R, Zelley K et al. Treatment of Epstein Barr virusinduced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol 2013; 162: 376 – 382 20 Tashiro Y, Goto M, Takemoto Y et al. Epstein-Barr virus-associated enteritis with multiple ulcers after stem cell transplantation: first histologically confirmed case. Pathol Int 2006; 56: 530 – 537 21 Yanai H, Shimizu N, Nagasaki S et al. Epstein-Barr virus infection of the colon with inflammatory bowel disease. Am J Gastroenterol 1999; 94: 1582 – 1586 22 Allen CE, Yu X, Kozinetz CA et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediat Blood Cancer 2008; 50: 1227 – 1235 23 Galoo E, Potier V, Romand F et al. [Primary chronic ulcerative jejunoileitis complicated by hemophagocytic syndrome]. Gastroenterol clin biol 1999; 23: 783 – 787 24 Ina S, Tani M, Takifuji K et al. Virus-associated hemophagocytic syndrome and hemorrhagic jejunal ulcer caused by cytomegalovirus infection in a non-compromised host; a case report of unusual entity. Hepato-gastroenterology 2004; 51: 491 – 493 25 Moon JH, Hong SP, Park PW et al. A case of hemophagocytic syndrome with terminal ileal ulcerations. KorJ Gastroenterol = Taehan Sohwagi Hakhoe chi 2006; 48: 205 – 209
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diagnostic criteria and treatment regimens have been implemented rapidly [29]. However, HLH as late onset hereditary disease (in particular EBV-induced HLH in males with XLP1 / XLP2-disease) or secondary HLH in response to a variety of infectious, autoimmune, autoinflammatory or neoplastic triggers affects adults in all age groups with about 20 % of patients being > 60 years old [30]. Prognosis in adults is assumed to be worse with a mortality rate of 60 % − 90 % depending on the underlying HLH-trigger disease [28]. Diagnostic criteria have not been validated in larger adult patient cohorts and may have to be adapted as currently being performed in MAS triggered by autoinflammatory Still syndrome [13]. Treatment in adults must be carefully adapted from pediatric protocols according to the wider variety of trigger diseases in adults, and primarly focus on treating the underlying disease [31]. In this regard, our patient was treated with rituximab in order to suppress EBVreplication as the assumed trigger disease. We can only speculate on the cause of severe EBV-reactivation in a pregnant women with secondary HLH, as we did not detect functional defects in immune assays. Post-mortem section did not reveal EBV-associated lymphoma, a condition frequently triggering HLH in adults [32]. When considering the treatment of EBV-HLH, the most important factor is the diagnostic vigilance as time to start of treatment is a major prognostic factor. In hereditary HLH, a poor prognosis has been reported, if treatment is initiated later than 4 weeks after the onset of symptoms (for review see [33]). This indicates that there may be a window for observation or initiation of treatment with rituximab, corticosteroid/cyclosporin A or intravenous immunoglobulin (IVIG) [19]. However, once the disease is defined as "high risk" and/or refractory to such therapy, prompt introduction of etoposide (ideally within 4 weeks) is recommended. Of note, prolonged immunosuppression for HLH in adults should be avoided, as regaining immunocompetence after short-term immunosuppression is a prerequisite for successful eradication of the infectious agent [31]. It is recommended to tailor treatment in cooperation with HLH-reference centers. In Germany, the HLH-in-adults network can be contacted via web. As HLH is a rare and difficult to treat disease, registering patients is encouraged in order to develop guidelines for diagnosis and treatment of adult patients with HLH. In conclusion, our case and the review of the literature indicate that physicians should be aware of the risk of HLH in patients with severe gastrointestinal bleeding, fever and increased ferritin levels. Early diagnosis is essential to start appropriate treatment achieving a better outcome.
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30 Ishii E, Ohga S, Imashuku S et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007; 86: 58 – 65 31 Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 2012; 63: 233 – 246 32 Nawathe PA, Ravindranath TM, Satwani P et al. Severe hemorrhagic coagulopathy with hemophagocytic lymphohistiocytosis secondary to Epstein-Barr virus-associated T-cell lymphoproliferative disorder. Pediatr Crit Care Med 2013; 14: e176 – e181 33 Imashuku S, Kuriyama K, Sakai R et al. Treatment of Epstein-Barr virusassociated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol 2003; 41: 103 – 109
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26 Fries W, Cottone M, Cascio A. Systematic review: macrophage activation syndrome in inflammatory bowel disease. Alim pharmacol therap 2013; 37: 1033 – 1045 27 Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 2013; 160: 275 – 287 28 Yu JT, Wang CY, Yang Y et al. Lymphoma-associated hemophagocytic lymphohistiocytosis: experience in adults from a single institution. Ann Hematol 2013; DOI: 10.1007/s00277-013-1784-3 29 Jordan MB, Allen CE, Weitzman S et al. How I treat hemophagocytic lymphohistiocytosis. Blood 2011; 118: 4041 – 4052
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