Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents\u2014a single centre experience of 20\xa0years

Volker Strenger,Wolfgang Schwinger,Markus G Seidel,Petra Sovinz,Stephan W Aberle,Martin Benesch,Gerald Merth,Christian Urban,Daniela Sperl,Harald H Kessler,Anna Karastaneva,Herwig Lackner

doi:10.1007/s00277-018-3254-4

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a possibly life-threatening syndrome of immune dysregulation and can be divided into primary (hereditary) and secondary forms (including malignancy-associated HLH (M-HLH)). We retrospectively analysed epidemiological, clinical, virological and laboratory data from patients with M-HLH treated at our department between 1995 and 2014. Out of 1.706 haemato-/oncologic patients treated at our department between 1995 and 2014, we identified 22 (1.29%) patients with secondary HLH (1.3–18.0, median 10.1 years; malignancy induced n = 2; chemotherapy induced n = 20). Patients with acute myeloblastic leukaemia (AML) developed HLH significantly more often than patients with acute lymphoblastic leukaemia (ALL) (10/55, 18.2% vs. 6/148, 4.1%, p = 0.0021). As possible viral triggers, we detected BKV (53.8% of the tested patients), HHV-6 (33.3%), EBV (27.8%), CMV (23.5%), ADV (16.7%) and PVB19 (16.7%) significantly more frequently than in haemato-/oncologic patients without HLH. Despite lacking evidence of concurrent bacterial infection, C-reactive protein (CRP) and procalcitotnin (PCT) were elevated in 94.7 and 77.7% of the patients, respectively. Ferritin and sIL2R were markedly elevated in all patients. HLH-associated mortality significantly (p = 0.0276) decreased from 66.6% (1995–2004) to 6.25% (2005–2014), suggesting improved diagnostic and therapeutic management. Awareness of HLH is important, and fever refractory to antibiotics should prompt to consider this diagnosis. Elevated ferritin and sIL2R seem to be good markers, while inflammatory markers like CRP and PCT are not useful to discriminate viral triggered HLH from severe bacterial infection. Re-/activation of several viruses may play a role as possible trigger.

Highlights

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterised by immunologic dysregulation including activation of macrophages as well as SV and MG contributed to this work.Ann Hematol (2018) 97:989–998 infectious agents triggering HLH are/include Epstein Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), influenza A virus, Mycobacteria spp. and Leishmania [3,4,5]
An important subgroup of secondary HLH is the malignancy-associated HLH (M-HLH) which can be divided into malignancy triggered forms, where the malignancy itself leads to HLH, and the chemotherapy-associated HLH, where the antineoplastic treatment or its side effects serve as a trigger of HLH [2, 8]
Beside commonly described viral triggers of HLH like EBV, CMV and ADV, we found concurrentactivation of BK virus (BKV, 53.8%), human herpesvirus 6 (HHV-6, 33.3%) and parvovirus B19 (PVB19, 16.7%), as well as human herpesvirus 7 (HHV-7), herpes simplex Typ 1 (HSV-1), influenza A, respiratory syncytial virus (RSV), human herpesvirus 8 (HHV-8) and JC virus (JCV) in single patients, each

Summary

Introduction

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterised by immunologic dysregulation including activation of macrophages as well as SV and MG contributed to this work.Ann Hematol (2018) 97:989–998 infectious agents triggering HLH are/include Epstein Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), influenza A virus, Mycobacteria spp. and Leishmania [3,4,5]. Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterised by immunologic dysregulation including activation of macrophages as well as SV and MG contributed to this work. Typical clinical symptoms of HLH may resemble symptoms of malignant diseases as well as severe bacterial infections often occurring during antineoplastic treatment and subsequent immunodeficiency [2, 3, 8, 9]. Chemotherapy-associated HLH is often reported to be triggered by infections and the hyperinflammatory state seems to be the consequence of an inadequate reaction of the dysregulated immune system against common infectious agents. While symptoms may lead to the clinical diagnosis of an infection (with or without identifying the infectious agent), the subsequent immune dysregulation and inadequate immune activation might often remain unidentified leading to a high number of undiagnosed cases of HLH [10]. Systematic data on possible infectious triggers, C-reactive protein (CRP) and procalcitotnin (PCT), two parameters often used as marker for bacterial infections, are scarce or even missing in patients with HLH

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