Similar but not the same: Differential diagnosis of HLH and sepsis
Introduction
Hemophagocytic lymphohistiocytisis (HLH; hemophagocytic syndrome) is a syndrome of uncontrolled, potentially fatal hyperinflammation. Clinically, HLH is characterized by prolonged fever, splenomegaly, hemophagocytosis in the bone marrow and abnormalities of laboratory parameters: cytopenias, hyperferritinemia, low or absent NK-cell activity, elevated sCD25, hypertriglyceridemia and/or hypofibrinogenemia (Henter et al., 2007). These features form the HLH-2004 criteria. Final diagnosis requires either fulfilling five out of eight of these criteria (Henter et al., 2007) or detection of a mutation in specific genes (Table 1a, Table 1b). Familial HLH (FHL) is in most cases caused by mutations in genes of cytotoxic granule activity pathway (FHLH 2–5, Chédiak–Higashi and Griscelli II syndrome). Any of these defects impairs cytotoxic activity of natural killer cells and cytotoxic T-lymphocytes, while their ability to release cytokines remains intact. Upon activation, being unable to kill the affected cells, the ineffective (yet overstimulated) cytotoxic cells mobilize other parts of immune response (especially macrophages), which in turn try to stimulate them. In this vicious circle communication is mediated via, released in gradually increasing quantities, cytokines—what causes hyperinflammation (Créput et al., 2008, Jędrzejczak, 2008, Ménasché et al., 2005). For the development of symptomatic HLH this pathologic response needs to be activated. There are various known triggering factors—the most common belong to three groups: infection, malignancy and autoimmune disease. Infection-associated hemophagocytic syndrome (IAHS) is caused mostly by viruses with EBV predominance, but occasionally also bacteria, fungi or parasites may trigger this syndrome. Malignancy-associated HS is most frequently induced by lymphoma (LAHS: lymphoma-associated HS), and less frequently by other malignancies of the hematopoietic system or solid tumors (MAHS, malignancy-associated HS). HLH induced by autoimmune or rheumatic diseases is often described as MAS (macrophage activation syndrome) (Machaczka et al., 2011a).
Effective treatment of HLH syndrome is based on HLH-1994 or -2004 protocol and comprises of dexamethasone, etoposide, and cyclosporine A with the necessity of allogeneic hematopoietic stem cell transplantation for cure in patients with familial, persistent or recurrent HLH (Henter et al., 2007). The true incidence of HLH is unknown, as it is largely underdiagnosed. The best data comes from Sweden with 1.2 per million children for primary HLH and 3.6 per million for malignancy-associated HLH in adults (Machaczka et al., 2011b) (infection or autoimmune-associated cases should be added). Among hospitalized children it is estimated in specialized centers from USA and Turkey at 3.3 (Allen et al., 2008) and 7.5 per 10,000 (Gürgey et al., 2003), respectively. The incidence of HLH depends on awareness.
On the other hand, sepsis – a generalized infection caused by various bacteria – is a much more common cause of hyperinflammation than HLH. Sepsis represents a state of infection accompanied by SIRS (severe inflammatory response syndrome). This diagnosis requires fulfillment of at least two of the following criteria: body temperature >38 °C or <36 °C, heart rate >90/min, hyperventilation evidenced by a respiratory rate of >20/min or a PaCO2 of <32 mmHg and a white blood cell count of >12 × 109/l or <4 × 109/l (Levy et al., 2003). SIRS can be caused not only by infection but also by trauma, thermal injury or sterile inflammatory processes. Sepsis with organ dysfunction is described as severe. Septic shock is diagnosed when arterial hypotension is refractory to fluid resuscitation (Levy et al., 2003). From above definitions fever and leucopenia can be present both in HLH and sepsis. Also other HLH features can be present in septic patient: elevated ferritin (acute phase reactant), hypofibrinogenemia and thrombocytopenia caused by DIC (disseminated intravascular coagulation) and especially deteriorating clinical condition.
Treatment of sepsis is essentially based on anti-infectious agents and intensive symptomatic therapy while it does not include key elements of HLH therapy. Although some procedures (like fluid resuscitation) may be beneficial for both patient groups, the main principles differ. Therefore, it is essential to achieve an accurate diagnosis in these critically ill patients—only then the decision about treatment can be optimal and thus save patient's life. The aim of this review is to present features which may help to distinguish HLH from sepsis in pediatric and adult patients.
Section snippets
Studies
We have reviewed 17 studies concerning adult HLH patients, 15 concerning children and 1 analysis of a mixed HLH patient group. Only studies analyzing patients with a diagnosis based on HLH-2004 criteria were considered, that is only patients fulfilling at least 5 of 8 criteria were included. Emphasis was put on providing information about the various factors which triggered HLH. For sepsis 25 studies concerning adult patients and 5 studies with pediatric patients were reviewed. Studies using
Molecular features
Mutations in certain genes (PRF1, UNC13D, STXBP2, RAB27A, STX11, SH2D1A or BIRC4; Jordan et al., 2011) are crucial for the diagnosis of familial HLH; others, not yet described, may predispose to this syndrome. HLH due to genetic predisposition does not only occur in children—in large studies, even 25% (11/44) and 14% (25/175) of adults had typical mutations (Cetica et al., 2016, Zhang et al., 2011). It was 7% (18/252) for patients over 13 years of age (Wang et al., 2014).
Mutations and
Discussion
Differentiating between HLH and sepsis is often challenging and sometimes may be even impossible; therefore, all efforts should be made to identify single HLH patient among hundreds of those with sepsis. Before the introduction of directed therapy, familial HLH was fatal in almost 100% cases, although patients received the best possible care (Aricò et al., 1996). When the possibility of HLH is neglected in the differential diagnosis, prognosis is still very poor. We have faced a great progress
Conclusions
It is crucial to emphasize that HLH is a constellation of at least 5 out of 8 symptoms and that none of them is neither necessary nor sufficient to establish the diagnosis. Despite the name of the syndrome, hemophagocytosis is neither specific nor sensitive for HLH. Although often very similar to sepsis, in many patients HLH has features which allow differentiation between these 2 conditions. Most helpful parameters are: hyperferritinemia, splenomegaly, pronounced cytopenias,
Conflict of interest statement
None of the authors have any conflict of interest.
Funding
RM received a Ph.D. and LPP-Erasmus scholarships.
Rafal Machowicz, M.D., M.Sc., has graduated in Medicine from the Medical University of Warsaw and in Biology from Individual Interfaculty Science Studies from the University of Warsaw. Now he is finishing his Ph.D. studies in the Department of Hematology, Oncology and Internal Diseases at the Medical University of Warsaw, where he works as a physician. He has already published 11 publications (7 as the first and 2 as the second author). He is a member of the “HLH in Adults Working Group” of the
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Rafal Machowicz, M.D., M.Sc., has graduated in Medicine from the Medical University of Warsaw and in Biology from Individual Interfaculty Science Studies from the University of Warsaw. Now he is finishing his Ph.D. studies in the Department of Hematology, Oncology and Internal Diseases at the Medical University of Warsaw, where he works as a physician. He has already published 11 publications (7 as the first and 2 as the second author). He is a member of the “HLH in Adults Working Group” of the Histiocyte Society. He initiated the National Registry for adult HLH patients in Poland.
Prof. Gritta Janka, M.D., Ph.D. is a very renowned specialist in HLH, especially in children. She is a professor emeritus at the Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf. She is the Chair of the HLH Steering Committee of the Histiocyte Society and a member of HLH in Adults Working Group. She has authored over 220 publications with over 8300 citations. Her work has formed the way we perceive HLH. Owing to her efforts to investigate and raise the awareness of HLH (since the late 1970s), it is now diagnosed and treated in pediatric hematology units all over the world. Now she continues this mission also in adult HLH.
Prof. Wieslaw Wiktor-Jedrzejczak, M.D., Ph.D., is the head of the Department of Hematology, Oncology and Internal Diseases at the Medical University of Warsaw. In 1984 he performed the first successful allogeneic hematopoietic stem cell transplantation in Poland. Except of contributions to clinical medicine, he conducted numerous basic science projects. He has published over 200 manuscripts, which were cited over 4300 times. As the National Consultant in Hematology in Poland, he has greatly contributed to the HLH awareness by publications, lectures and most of all by treating adult and adolescent HLH patients as early as the year 2000.