key: cord-0010199-yskxbzer authors: Heeg, Maximilian; Ammann, Sandra; Klemann, Christian; Panning, Marcus; Falcone, Valeria; Hengel, Harmut; Lehmberg, Kai; zur Stadt, Udo; Wustrau, Katharina; Janka, Gritta; Ehl, Stephan title: Is an infectious trigger always required for primary hemophagocytic lymphohistiocytosis? Lessons from in utero and neonatal disease date: 2018-08-01 journal: Pediatr Blood Cancer DOI: 10.1002/pbc.27344 sha: 5b33034f7b37a76557b4d2db72be64720e73ec15 doc_id: 10199 cord_uid: yskxbzer In this report, we evaluate the hypothesis that hemophagocytic lymphohistiocytosis in patients with defects of lymphocyte cytotoxicity is usually triggered by infections. We show that in the majority of patients, extensive virus PCR panels performed in addition to routine microbiological investigations remain negative and summarize 25 patients with onset of hemophagocytic lymphohistiocytosis in utero or within the first 10 days of life, in none of which an associated bacterial or viral infection was reported. These observations, even though preliminary, invite to consider a key role of lymphocyte cytotoxicity in controlling T‐cell homeostasis also in the absence of apparent infectious stimuli. Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by uncontrolled immune cell activation. 1 Genetic disorders leading to impaired lymphocyte cytoxicity (familial hemophagocytic lymphohistiocytosis, FHL) are the best characterized risk factor for development of HLH. Infants with cytotoxicity defects are usually asymptomatic at birth. The age at onset of inflammatory symptoms varies, even between affected siblings, 2 indicating Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; EBV, Epstein-Barr virus; FHL, familial hemophagocytic lymphohistiocytosis; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GS2, Griscelli syndrome type 2; HLA, human leukocyte antigen; HLH, hemophagocytic lymphohistiocytosis; HHV, human herpesvirus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; RSV, respiratory syncytial virus; TTMV, Torque Teno mini virus; TTV, Torque Teno virus that additional factors are required. Many infections can trigger primary and secondary HLH. [3] [4] [5] The association of FHL manifestation with infections can be interpreted to indicate that in most cases the triggers of HLH are infections, 6 even if they sometimes escape awareness or detection. In a recent analysis of our German HLH registry, we noted that in many FHL patients, no infection had been documented. 7 The PCR panel was validated by 5 patients with 2 • HLH, where the reported trigger could also be found in the stored biomaterial. This report focuses on the question of whether HLH manifestation in FHL patients always requires an infectious trigger. We report on two patient cohorts with primary HLH with a low incidence of infections. Obviously, some limitations require discussion. In the first cohort, the analysis was restricted to viral DNA or RNA isolated from a blood fraction that is not standard for virus detection. Although we could detect EBV, CMV, HSV, TTV, and TTMV in high copy numbers in this material, we could not validate all of the viruses tested in our study, in particular viruses with replication restricted to mucosal sites. Also, viruses may have initiated the immune reaction, but already been eliminated at the time of blood sampling. In addition, unknown viruses or organ- 12 In perforin-deficient mice, at least the large majority of hyperactivated T cells is specific for the triggering virus. 13 The specificity of these T cells in human patients remains an enigma. Understanding their specificity might help to further elucidate the pathogenesis of HLH. The unique amplification of cytotoxic (HLA-DR + CD127 − PD1 + CD57 + perforin + ) CD4 + T cells observed in 1 • , but not in virus-induced 2 • HLH may provide additional clues. 12 From a biological viewpoint, our findings and considerations suggest that in humans lymphocyte cytotoxicity is key to control Tcell activation, also to minor noninfectious stimuli, in a way that prevents an extensive amplification of a dramatic, potentially lethal immune response. This puts lymphocyte cytotoxicity to the center of immune regulation and maintenance of T-cell quiescence, far beyond its activity in virus control. A better understanding of the initiation of immune reactions in HLH and the role of perforin and the secretory pathway in controlling them will therefore be highly relevant for understanding the regulation of human immune responses. Ultimately, it will also provide insights relevant for prophylaxis and intervention in this life-threatening disease. SE has a scientific collaboration with UCB, which is not related to this study. http://orcid.org/0000-0002-9594-1377 Hemophagocytic syndrome: primary forms and predisposing conditions Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Debate around infection-dependent hemophagocytic syndrome in paediatrics the role of infections in primary hemophagocytic lymphohistiocytosis: a case series and review of the literature Familial hemophagocytic lymphohistiocytosis and viral infections An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8 + T cells and interferon gamma are essential for the disorder Effective immunological guidance of genetic analyses including exome sequencing in patients evaluated for hemophagocytic lymphohistiocytosis Human anelloviruses: an update of molecular, epidemiological and clinical aspects Pre-and post-natal treatment of hemophagocytic lymphohistiocytosis Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study Hemophagocytic lymphohistiocytosis Primary and secondary hemophagocytic lymphohistiocytosis have different patterns of T-cell activation, differentiation and repertoire Counting antigenspecific CD8 T cells: a reevaluation of bystander activation during viral infection Additional supporting information may be found online in the Supporting Information section at the end of the article.