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Hemophagocytic syndromes (HPS) including Hemophagocytic Lymphohistiocytosis (HLH) in Adults: a Systematic… Hayden, Anna; Park, Sujin; Giustini, Dean; Lee, Agnes Y. Y.; Chen, Luke Y. C. Nov 30, 2016

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Hayden et al. age 1 12-Jan-2017HAYDEN et al HLH REVIEW  Hemophagocytic syndromes (HPS) including Hemophagocytic Lymphohistiocytosis (HLH) in Adults: a Systematic Scoping Review  Anna Hayden,1 Sujin Park,1 Dean Giustini,2 Agnes Y.Y. Lee1 and Luke Y.C. Chen1 1Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada; and 2Biomedical Branch Library, University of British Columbia, Vancouver, Canada  Abstract Most knowledge of hemophagocytic syndromes (HPS) including hemophagocytic lymphohistiocytosis (HLH) is derived from pediatric studies; literature on adult HPS/HLH predominantly consists of small retrospective studies with clinical and methodological heterogeneity.  The aims of this systematic scoping review were to provide an overview of existing literature on adult HPS/HLH, describe current practices in diagnosis and treatment, and propose priorities for future research.  Articles from Ovid Medline, Embase and Pubmed (1975-2015) describing 10 or more unique adults (age > 15 years) with HPS/HLH were included.  82 publications were eligible: 10 were prospective and 72 were retrospective.  Of the six distinct diagnostic criteria, the HLH-2004 criteria were by far the most commonly used.  A minority of studies tested for genetic abnormalities (12), soluble interleukin-2 receptor (11), and/or NK function (11) in a subset of patients.  Most centers used steroids and either etoposide based (HLH-94/HLH-2004) or doxorubicin based (CHOP) initial therapy regimens.  Allogeneic hematopoietic cell therapy for treatment of adult HLH has rarely been reported.  Mortality in larger treatment focused studies ranged from 20 to 88%.  Developing adult-specific diagnostic criteria based on widely evaluable features of secondary HPS/HLH and establishing standard initial therapies are priorities for future research.  Hayden et al. HLH REVIEW   2 Keywords Hemophagocytic lymphohistiocytosis, hemophagocytic syndromes, hematophagic histiocytosis, macrophage activation syndromes, hyperferritinemia, adults  Hayden et al. HLH REVIEW   3 1.  Introduction Hemophagocytic syndromes (HPS) are rare, life-threatening conditions characterized by overstimulation of the immune system leading to systemic inflammation, hypercytokinemia and multi-organ failure.1 They are broadly divided into primary hemophagocytic lymphohistiocytosis (HLH) and secondary hemophagocytic syndromes.2 Primary HLH is caused by genetic mutations impairing the cytotoxic function of natural killer (NK) and cytotoxic T cells and typically present in infancy and childhood.  Primary HLH includes familial HLH (fHLH), where patients have autosomal recessive mutations in Perforin (PRF1), MUNC 13-4 (UNC13D), MUNC 19-2 (STXBP2), and Syntaxin 11 (STX11).3-7 Primary HLH also includes other inherited immunodeficiency syndromes such as Chédiak–Higashi syndrome, Griscelli syndrome, and type II Hermansky-Pudlak syndrome.8  Secondary hemophagocytic syndromes generally affect adolescents and adults and are not associated with known genetic defects, although rare cases of fHLH have been reported beyond age 70.9-11    In secondary, or reactive HPS there is often an associated “predisposing condition” causing immune dysregulation, such as malignancy (particularly lymphoma), immunodeficiency, or autoimmune disease, and/or a “trigger”, most commonly infection such as Epstein-Barr virus (EBV).8  In some cases, an associated disease process is not identified.12  HPS may also be referred to as macrophage activation syndrome (MAS) when it occurs in patients with autoimmune disease such as juvenile idiopathic arthritis (JIA), adult onset Still’s disease (AOSD) and systemic lupus erythematosus (SLE).13, 14  The pathologic immune activation that characterizes HPS/HLH can be difficult to distinguish from physiologic macrophage activation.  For example, neither the presence,15, 16 nor amount of hemophagocytosis on bone marrow biopsies is specific for HPS/HLH.17  Historical terms used to describe HPS are summarized in Table 1.    The modern conceptualization of adult HPS/HLH is derived largely from observations of familial HLH in children followed by the discovery of causative Hayden et al. HLH REVIEW   4 genetic abnormalities.  Diagnostic criteria specific for adult HPS have not been established, and diagnosis is largely based on the Histiocyte Society’s HLH-94 or 2004 (Table 2) pediatric diagnostic criteria.12  A number of described manifestations of adult HPS, such as transaminitis, coagulopathy, elevated LDH, rash, hyponatremia, elevated CRP, and neurologic involvement (which is described in one small study), are not included in these criteria.18-22  As with diagnosis, treatment protocols for adult HPS/HLH are often extrapolated from the pediatric HLH-94 and HLH-2004 protocols.  These are etoposide-based regimens containing corticosteroids, cyclosporine A, intravenous immunoglobulins (IVIG), intrathecal therapy, and liberal use of allogeneic stem cell transplant in higher risk patients.23  How well these treatment protocols apply to adults is poorly understood.    To date, the literature on adult HPS/HLH consists largely of retrospective studies, often confined to a single center or geographic region.  Most literature reviews are narrative,24-26 although systematic reviews have been done for specific types of HPS/HLH such as HPS associated with zoonotic infections.27-29 We conducted a systematic search to identify the extent of existing literature on HPS/HLH, an area with considerable clinical and methodological heterogeneity.  We analyzed the findings using scoping review methodology.  Scoping reviews are similar to systematic reviews in terms of searching the literature in a reproducible manner, but the aim of a scoping review is generally to address a broad area or topic (as opposed to a narrowly defined question) and scoping reviews do not emphasize the quality or methodology of included studies (as opposed to the stringent assessment of clinical heterogeneity, methodology and quality in systematic reviews).30-32  The aims of this systematic scoping review were to:  1. Provide an overview of existing adult HPS/HLH literature and publication trends over time   2. Describe established patterns and emerging trends in diagnosis and treatment of adult HPS/HLH 3. Propose priorities for future research   Hayden et al. HLH REVIEW   5  2.  Methods 2.1. Search strategy A comprehensive literature search was performed using the databases Ovid Medline, Embase, and PubMed.  The aim was to maximize sensitivity for finding published, peer-reviewed studies of adult HPS/HLH.  Our search terms and medical subject headings (MeSH) were : h(a)emophagocytic syndrome(s) OR h(a)emophagocytic lymphohistiocytosis OR  h(a)ematophagic histiocytosis OR  macrophage activation syndrome(s) OR cytophagic histiocytic panniculitis AND adult(s) AND English (language) AND humans.  We excluded child(ren) as a search term and limited results to publication years 1975-2015.  As extended search techniques, PubMed and the Web of Science were used to identify more recent articles as well as the most highly cited publications in the field.  Final updated searches were performed on September 3, 2015.  Results were screened based on titles and abstracts to determine suitability for inclusion in this scoping review.  “Grey literature” such as theses were not included; most conference proceedings were excluded except for two abstracts with important information on genetic testing and outcomes after Hematopoetic Cell Transplant (HCT).  Details of the search strategy can be found in Appendix 1, 2 and 3.  2.2. Study selection and data collection  All articles that addressed the topic of HPS/HLH in adults (defined as age >15 years) were screened by full text review.  English language articles with 10 or more original cases were selected for the scoping review.  The minimum of 10 cases was arbitrarily chosen to identify larger studies.  Data abstraction was done by one investigator, checked by two others, and included: first author, journal, year of publication, country of origin, type and design of study, number of patients included, inclusion/exclusion criteria, demographic features, diagnostic criteria, details on genetic testing, associated conditions, clinicopathologic features, treatment, outcomes, and additional notes on the study.   Hayden et al. HLH REVIEW   6   3.  Results  The search strategy gathered 2492 articles and upon manual review and cross-referencing (35) and eliminating duplicates (932), the total number of unique articles on adult HPS/HLH identified was 1590 (Figure 1).  Through the last updated search on Sept 3, 2015, 552 new articles were identified on Web of Science, some of which overlapped with previously identified articles.    82 articles included 10 or more adults with HPS/HLH and were eligible for this review (see Appendix 4 for complete list).  72 articles were retrospective and 10 were prospective.33-42  Two of these prospective studies were clinical trials,33, 34 three examined incidence and natural history of secondary HPS, and five investigated cytokine/biomarker significance.  Figure 2 illustrates the dramatic increase in the number of articles published per year on this subject; 56 of the 82 articles included were published in the past ten years.  44 articles were from Asian institutions (Figure 3).  Three studies that did not strictly meet the inclusion criteria were still included because they were of special interest:   1) A study of 9 patients with HPS because it was one of the few prospective studies.35 2) An abstract of 10 patients who underwent allogeneic HCT in Cincinnati because it was one of the few studies reporting genetic abnormalities adults.43  3) An abstract of 19 patients from Cincinnati, with overlapping patients from the above study, because it reported outcomes after HCT.44  3.1. Studies with overlapping patients:  Hayden et al. HLH REVIEW   7 A recent systematic review combined results from numerous studies to gather information on the clinical presentation and treatment of HLH in adults.24  For example, they reported a mortality rate of 41% in 1109 adults pooled from 13 articles.  However, it is unlikely that these truly represent 1109 unique patients, as many patient series in the literature have been reported numerous times in different publications.  For example, two of the 13 articles cited are from the same French center with overlapping study periods.1, 45 Investigators from this French group have published numerous important articles which describe different aspects of HPS in overlapping cohorts of patients.1, 18, 39, 45-49  A full list of studies with patients that were definitely or potentially described in more than one study is included in Appendix 5.   3.2. Epidemiology  There is limited data on incidence of HPS/HLH, particularly in adult populations.  A nationwide survey in Japan evaluating pediatric and adult cases reported annual incidence at 1 per 800,000.50  Pediatric HLH diagnosis has been approximated to be 1 case per 3000 inpatient admissions, and incidence per live birth has been estimated to be 1-6/300,000.25, 26 A single center retrospective Swedish study reported an incidence of malignancy associated HLH in adults of 0.9% (8 of 887).51  The majority of articles included in this review originated from Asia and particularly Japan (see Figure 3). Whether this suggests a higher incidence of HPS/HLH in this region, geographic variations in EBV-associated HPS/HLH, greater academic interest in HPS/HLH, or some combination thereof, is not clear.  Three single center studies prospectively examined the incidence and natural history of HPS associated with specific conditions in consecutive patients:  32 of 343 pts with AML,38 12 of 20 patients with sepsis and thrombocytopenia on mechanical ventilation35 and 9 of 25 pts with influenza A.37  3.3. Diagnostic Criteria  Hayden et al. HLH REVIEW   8 We reviewed the diagnostic criteria applied by each of the 82 articles in order to understand the consistency of HPS/HLH diagnosis in the literature and how this has changed over time (Table 1).  Six distinct diagnostic criteria have been used, (summarized in Table 3); of these, the Histiocyte Society’s criteria are by far the most commonly used.   3.3.1. Studies using Histiocyte Society diagnostic criteria  The Histiocyte Society published diagnostic criteria in 1991, which were used for the pediatric HLH-94 trial.52  1 survey and 3 other articles used these diagnostic criteria.50, 53-55  Updated criteria, used for the HLH-2004 study, were published in 2007.  36 of the 54 articles (67%) published since 2007 in this review used HLH-2004 and 6 used modified HLH-2004 criteria.  Many investigators have recognized the limitations of applying the pediatric HLH-2004 diagnostic criteria to adults.17, 18, 25, 46  These limitations fall into three categories: 1) Limitations of molecular testing:  Only 12 of 54 studies performed genetic testing on at least one patient (Table 4). 10, 22, 33, 34, 43, 56-62 The largest study of genetic mutations in adults from Cincinnati Children’s Hospital Medical Center (CCHMC) reported that 25 of 175 (15%) adults had a mutation in PRF1, MUNC13-4 or STXBP2.10  Patient samples in this study were referred from all over North America and so the true denominator of adults with HPS/HLH cannot be ascertained.  Moreover, classical familial HLH is caused by homozygous mutations in autosomal recessive genes; heterozygous allele mutations and mutations of unknown functional significance are included in many of these reports, and the significance of these findings is incompletely understood. Hayden et al. HLH REVIEW   9 2) Accessibility of sIL2r and NK function:  Many articles stated that sIL2r and NK function were not readily available at the study center.  Only 11 of 54 studies published since 2007 commented on testing for sIL2r,17, 19, 22, 34, 37, 58, 59, 61-64 and 11 studies commented on NK function testing.10, 17, 19, 22, 43, 57-59, 62, 64, 65 Most of these studies reported testing in a small proportion of patients.  sIL2r was elevated in 148 of 161 patients tested (91.9%) and 41 of 72 (56.9%) patients tested had absent or low NK cell activity.   3) Different presenting features in adults:  A number of studies comment on how hemophagocytic syndromes, particularly reactive hemophagocytic syndromes, may present in adults with manifestations not included in the HLH 2004 criteria, such as elevated aspartate transaminase (AST)18 or lactate dehydrogenase (LDH)66  3.3.2. Studies using other diagnostic criteria  Prior to 2007, all articles in this review required pathologic evidence of hemophagocytosis on bone marrow biopsy, aspirate, lymph node, spleen or liver, in addition to typical clinical features, which often included but did not require fever, cytopenias and splenomegaly.  In total, 14 articles required histologic evidence of hemophagocytosis but no other specific diagnostic criterion.  8 of 11 articles published before 2000 did not use any standardized diagnostic criteria, In 1997, Tsuda et al. and Imashuku et al. each published modified criteria which built on the HLH-94 diagnostic criteria (Table 5).20, 66  These criteria were employed by 11 articles combined (7 and 4 respectively).   One study developed novel diagnostic criteria for diagnosis of HLH in AML patients.38  Emmenegger et al. proposed a ferritin value of  ≥10,000 ug/L and/or morphologic evidence of hemophagocytosis as a screening strategy.14, 67  Takagi et al. created and applied novel criteria for Hematopoeitic Stem Cell Transplantation-related Hemophagocytic Syndrome (HCT-HPS) comprised of 2 Hayden et al. HLH REVIEW   10 major and 4 minor criterion which excluded cytopenias given the post-HCT context.68    Fardet et al. proposed a novel set of diagnostic criteria for reactive HPS, the HScore, which is based on data from 162 patients and the first to be validated in an adult population.18 Nine weighted variables were considered: 3 clinical [known underlying immunosuppression (such as HIV or chronic use of immunosuppressive medications), fever, organomegaly], 5 biologic (triglyceride, ferritin, aspartate transaminase (AST), fibrinogen, cytopenia), and 1 cytologic (HPS features on BM aspirate).  sIL2r levels and NK cell activity were not included due to concerns about accessibility.    Many laboratory tests have been evaluated for adult HLH.  Five studies used a prospective method of patient selection to make comparisons with controls or patients with other diseases in laboratory parameters such as glycosylated ferritin,40, 48 biologically active free interleukin 18 (IL-18)36, adenosine deaminase 41 and comparison of cytokine profiles between B-cell and T/NK-cell lymphocyte associated hemophagocytic syndrome.42  One study reported that the sIL2r/ferritin ration was significantly higher in 11 patients with lymphoma associated HPS compared to 10 patients with benign-disease associated HLH.63  A recent reported a number of abnormalities in the lymphocyte compartment of 21 patients with HLH.  While these abnormalities are too varied and non-specific to assist in diagnosis, they may have prognostic significance.69    3.4. Treatment  Eighteen studies in this review provided detailed descriptions of treatment and outcomes.  Two of these studies were prospective.33, 34  The remainder were retrospective and included a range of ten to 162 patients (table 5).  Unlike diagnosis, where each study applied one set of diagnostic criteria to all study participants, treatment was highly variable both between and within the studies. Among these studies, all except two used an etoposide based regimen for at a Hayden et al. HLH REVIEW   11 proportion of patients. CHOP was used widely for lymphoma associated hemophagocytic syndromes (LAHS), however 2 studies also used CHOP therapy outside of the LAHS context, predominantly for EBV-HLH patients.55, 70 Hematopoietic cell therapy (HCT) was reported in a small number of patients in seven of these 18 studies.34, 44, 55, 62, 65, 70, 71  3.4.1. Initial treatment  Initial glucocorticoids were almost always included in adult treatment regimens.  Beyond this, there was considerable variation in treatment.  The pattern of practice was first and foremost to identify and treat the underlying cause – infection, malignancy, or autoimmune – with disease-appropriate therapy and supportive measures, and if necessary, chemo-immunotherapy.  However, there was significant variation both within and amongst studies in which patients received cytotoxic therapy such as the etoposide-based HLH-94/2004 treatment protocols or CHOP.  In many cases, particularly in treating MAS, patients considered corticosteroid-refractory received only a component of the regimen, such as glucocorticoids and another immunosuppressive drug.13    3.4.2. Etoposide-based Histiocyte Society Protocols (HLH-94 and HLH-2004)    In pediatric HLH, which is rarely associated with an underlying malignancy, use of etoposide has shown significant improvement in survival if initiated within the first 4 weeks of symptoms.72 This finding was replicated in a report of young adults (11 from Kyoto and 9 cases from the literature) with EBV-associated HLH, wherein treatment with etoposide within 4 weeks of presentation was associated with better outcomes (2 of 7 died) than in those who received etoposide after 4 weeks or not at all (12 of 13 died).55 In a retrospective study of 162 adults with HLH, Arca et al. described a trend toward better outcomes when etoposide was employed (85% vs. 74% survival, p = 0.079).46 In contrast, Parikh et al. assessed 62 patients with HLH, of whom 20 received etoposide (9 tumor associated and 11 non-tumor associated), and found that the overall survival was similar between Hayden et al. HLH REVIEW   12 the cohorts receiving etoposide or non-etoposide based regimens.19 In a retrospective study of prognostic factors in adult HLH, Li et al. found that etoposide use was not associated with better outcomes.73    3.4.3. Other initial therapies  Many patients, particularly in Asia, have been treated with doxorubicin-based therapy such as CHOP, often in the context of aggressive lymphoma/LAHS (see table 5).  In a retrospective study examining treatment outcomes with CHOP in 17 adult patients with HLH secondary to lymphoma, EBV or unknown cause, overall response rate was 58.8% (5/7 with lymphoma, 3/5 with EBV, 2/5 with idiopathic HLH) with 2 year overall survival 43.9% suggesting possible benefit of CHOP in adult HLH of multiple etiologies.70    3.4.4. Salvage therapy  The only prospective multicenter study in this review investigated the effects of a salvage therapeutic regimen in 63 adults who had not achieved partial response to standard HLH therapy based on the HLH-94 treatment protocol. The regimen was a hybrid of etoposide and doxorubicin-based regimens, consisting of liposomal doxorubicin, etoposide and pulse methylprednisone (DEP).34  Overall response was 76.2%, however overall mortality was 54% due to either progression of underlying disease or recurrence of HLH.   3.4.5. Special Populations  Allogeneic HCT in adults has rarely been reported.25  Chandrakasan et al. reported on 19 adolescents/adults (age 15-27) with HLH who received alloHCT at CCMHC and reported overall survival 42.1% (8/19).  In the 15 patients > 15 years who received reduced intensity alloHCT, survival was 57% compared to 75% in children < 15 years, p = 0.03.44 Other possible treatment modalities discussed in articles included in this review were IVIG for MAS,67, 74 plasma Hayden et al. HLH REVIEW   13 exchange for patients with serum ferritin ≥ 10 000 ug/L and LDH ≥ 1000 IU/L,75 splenectomy for relapsed HLH of unknown cause,61 and recombinant human thrombopoeitin (rhTPO) which improved thrombocytopenia and decreased platelet transfusion requirements in a small randomized controlled trial of 40 adults with HLH.33   3.5. Prognostic Factors and Outcomes  Outcomes in adult HLH were heterogeneous; among the 18 studies focusing on treatment and outcomes, mortality ranged from 20.4 to 88% depending on population factors and length of follow up (Table 5). Among these studies, the study with the lowest mortality rate only assessed 30-day mortality in order to limit the impact of underlying disease,46 whereas the highest mortality rate was in patients with underlying lymphoma, which was consistently an adverse prognostic factor.71 The largest study, describing 162 patients and all associated HLH conditions, reported overall mortality 42%.47  Mortality was generally lowest in autoimmune disease patients followed by infection-associated and idiopathic HLH patients.  Malignancy, particularly lymphoma-associated HPS/HLH, was a prominent adverse prognostic marker correlating with poorer survival in multiple large studies.19, 46, 47, 58, 73, 76  Patients with T cell lymphoma generally had worse outcomes than those with B cell lymphoma.76-78 Other common adverse prognostic factors included age >30,79 highly elevated ferritin,19, 58, 79 marked thrombocytopenia,1, 46, 79 male sex,73 lack of etoposide therapy46 and low albumin.19     4. Discussion  The number of adult HPS/HLH publications has risen dramatically from less than ten per year in the 1980’s to greater than 100 per year since 2010. Though our inclusion criteria comprises articles from 1975 to current, only one study Hayden et al. HLH REVIEW   14 published prior to 1990 and only 11 articles published between 1990 to 2000 included 10 or more adult patients.  The dramatic rise in larger studies of adult HPS/HLH in recent years likely reflects increased recognition; whether it also indicates a rise in incidence of HPS/HLH is not clear.      4.1. Diagnosis:  Established patterns and emerging trends  The Histiocyte Society’s pediatric HLH-2004 diagnostic criteria has been widely extrapolated for use in adults since their publication in 2007.  However, these criteria have a number of important shortcomings in the adult population.  First, the molecular diagnosis is applicable only to those rare cases of adult-onset fHLH, and testing is available only in specialized centers.  Frequency of genetic mutations is inversely correlated with age of disease onset, with 45% of patients < 1 month found to have an fHLH mutation compared to 6% of those over age 2 years.26 Furthermore, part of the rationale of testing children is to identify patients in whom allogeneic HCT is warranted, but the tolerability and efficacy of HCT in adults, especially older adults is poorly understood.  12 of 82 studies in this review tested a small proportion of patients for genetic mutations, which likely reflects the lack of access, high cost, and ill-defined clinical benefit associated with genetic testing in adults.  Thus, the 8 clinical and laboratory features of HLH 2004 are particularly important in adults, and yet these abnormalities are relatively non-specific to HPS/HLH.  Extreme hyperferritinemia has historically been described as nearly pathognomonic for HLH,8, 26 but recent studies have shown that ferritin > 3000 ug/L and even > 50 0000 ug/L are very non-specific in acutely ill adults.64, 80 Hemophagocytosis on bone marrow sampling lacks both sensitivity and specificity.17, 47, 81  The lack of testing for sIL2r and NK function identified in this review is a major issue in using the HLH 2004 diagnostic criteria in adults.  One approach is to simply exclude sIL2r and NK function from adult diagnostic criteria in favor of other more readily available parameters common to HPS in adults.  For example, in the HScore for reactive HPS, elevated aspartate transaminase (AST) is included but sIL2r and NK function are not.  The exclusion Hayden et al. HLH REVIEW   15 of these two parameters was not on the basis of empiric data.  Rather, in the Delphi study which preceded construction of the HScore, it was judged that sIL2r, NK function, and CD163 were “not frequently enough assessed in routine practice” to be included.18, 21    However, HPS is a syndrome of pathologic immune activation occurring typically in immunocompromised patients and ultimately, sIL2r and NK function are important objective markers of increased T-cell activity and impaired cytoxic function, respectively.  sIL2r is a simple, commercially available biochemistry test and most centers with an interest in HPS/HLH should be able to implement this.  NK function may be useful in some adults, both for diagnosis and confirmation of disease remission, but is more difficult to implement as the flow cytometry assays require specialized technicians and reagents.  4.2. Treatment:  Established patterns and emerging trends  Almost all adult studies describing treatment have been small, retrospective and tend to focus on a component of treatment or a subgroup of HPS/HLH.  Glucocorticoids are standard, and for patients where cytotoxic therapy is thought to be necessary, the etoposide-based HLH-94 and 2004 protocols and CHOP are commonly used. Optimal initial therapies, as well as duration of treatment in adults, require further investigation.  For example, the induction phase of the pediatric HLH-2004 protocol consists of 8 weeks of etoposide-based therapy, and treatment after that, if required, is intended as a bridge to alloHCT.  However, adults treated with CHOP would typically receive CHOP every 3-4 weeks for 6-8 cycles (e.g. 18 to 32 weeks of chemotherapy).  A recent study evaluating liposomal doxorubicin, etoposide and dexamethasone (DEP) represents a true milestone in being the first prospective, multi-center clinical trial in adults.34  Establishing standards for initial therapy remains pressing need; unlike fHLH, a uniform protocol may not be feasible given the heterogeneity of the underlying/triggering conditions.  Rather, treatment strategies tailored to different associated conditions (malignancy, infection or autoimmune) may be needed.  Hayden et al. HLH REVIEW   16  In pediatric HPS/HLH, liberal use of allogeneic HCT is indicated to replace defective cytotoxic T cells in familial HLH, and sometimes to treat the underlying disease process, particularly where in HPS/HLH associated with hematologic malignancy.  However, the liberal use of allogeneic HCT described in the HLH 94 and HLH 2004 protocols may not be as applicable to adults.  In the pediatric HLH 94 study, 124/249 patients (50%) underwent HCT, whereas only 7 of the 18 treatment-focused articles in this review report transplanting a small number of adults.  The low incidence of fHLH, increased morbidity of allogeneic HCT in adults compared to children, relative scarcity of suitable donors, and the poor performance status and organ function of the relapsed and refractory adult patients are likely all factors in the low rate of HCT use in adults.  Moreover, given the high prevalence of secondary HPS/HLH in adults driven by elevated cytokine levels from an underlying trigger, HCT would be unlikely to eradicate the underlying cause.  According to some experts, allogeneic HCT should be considered on a case by case basis in eligible relapsed or refractory patients as well as the rare adults with late onset familial HLH.25    5. Areas for future research and conclusions  5.1. Areas for future research  Currently, the paradigm in children is that a largely genetic disease (fHLH) requires allogeneic HCT in a high proportion of patients.  This review demonstrates that in adults, the vast majority of reported cases have not been associated with a defined inherited molecular defect.  Early diagnosis is essential, as a proportion of these patients will go on to develop critical illness, multi-organ failure, and death, and better diagnostic and prognostic models are needed.  Although the HLH-2004 diagnostic criteria are widely used, molecular testing, sIL2r, and NK function are rarely applied in older patients.  Diagnostic and prognostic models specific to adults, such as the HScore have been Hayden et al. HLH REVIEW   17 developed, but exclude these specialized tests more on the basis of availability than whether they are actually helpful in diagnosis.  The preponderance of secondary/reactive HPS, combined with the lack of specificity of criteria such as cytopenias and hyperferritinemia in adults, begs the question of whether other widely available markers of pathologic immune activation may be useful in diagnosis.  The commercial availability of relatively low cost sIL2r assays implies that further study of this disease marker should be conducted in adult HPS/HLH.  Promising new biomarkers and therapies in children should be promptly evaluated in adults.  For example, interferon gamma has been shown to be a key mediator of the cytopenias in HLH,82and the therapeutic potential of an anti-IFN gamma antibody has shown promise in animal models and a pediatric IFN gamma antibody phase 1 clinical trial is currently underway.83 Another pediatric study of hybrid immunotherapy (anti-thymocyte globulin, dexamethasone and etoposide, the HIT-HLH trial),84 is in progress and the results of this trial, along with the long-awaited HLH-2004 study results, should inform future studies in adult HLH.   5.2. Concluding remarks  Hemophagocytic syndromes in adults have received increasing attention in the literature over the past 30 years.  However, there remains a paucity of prospectively collected, multi-center data and much of the diagnosis and treatment in adults is extrapolated from pediatric data.  In children, the disease paradigm has been based on diagnosis of familial HLH and aggressive treatment thereof with cytotoxic therapy and liberal use of alloHCT.  In adults, the majority of studies describe secondary HPS associated with acquired immune dysregulation, which may present with different clinical and laboratory features, requiring different diagnostic criteria.  The optimal initial therapy and role of alloHCT require further investigation in adults.  Priorities for future research include development of diagnostic criteria and treatment protocols that Hayden et al. HLH REVIEW   18 accommodate those disease aspects unique to adults and also rapidly evaluate and incorporate novel discoveries in pediatric HPS/HLH.  Practice points:  Publications on adult HPS/HLH have increased dramatically in recent years but the majority are retrospective studies.  Most studies apply the pediatric Histiocyte Society diagnostic criteria and treatment protocols, or variants thereof, to adult patients.  Secondary HPS/HLH is much more commonly described than primary HLH, but adults are rarely tested for genetic abnormalities, soluble interleukin-2 receptor, or NK function.    Survival in HLH is heterogeneous and malignancy/lymphoma associated HPS/HLH is associated with poor outcomes.   Research Agenda:  Adult-specific diagnostic criteria based on commonly evaluable clinical and laboratory features of secondary HPS/HLH are needed.  Promising new biomarkers in pediatric HPS/HLH, such as interferon gamma, should be evaluated in adults.    Prospective multicenter trials to evaluate treatment and outcomes of HPS/HLH in adults are needed.   Acknowledgements This study was supported by the Hal Kettleson Hematology Research Fund.    Conflict of interest disclosures The authors state that they have no interests which might be perceived as posing a conflict or bias.   Hayden et al. HLH REVIEW   19 References 1. Buyse S, Teixeira L, Galicier L, Mariotte E, Lemiale V, Seguin A, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med. 2010;36(10):1695-702. 2. Jaffe R. The histiocytoses. Clin Lab Med. 1999;19(1):135-55. 3. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957-9. 4. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol. 2006;6(12):940-52. 5. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. 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Nomenclature and Diagnostic Criteria of Hemophagocytic Syndromes:  Historical Overview   1939 – Histiocytic medullary reticulocytosis85  1952 – Familial hemophagocytic reticulocytosis86  1966 – Malignant histiocytosis described; majority of cases subsequently re-classified as anaplastic large cell lymphoma87  1979 – Virus-associated hemophagocytic syndrome (VAHS)88  1980 – Cytophagic histiocytic panniculitis89  1983 – Familial Hemophagocytic lymphohistiocytosis90  1991 – Histiocyte Society diagnostic criteria for HLH developed52  1993 – Macrophage Activation Syndrome (children with inflammatory joint disease)91  1999 – Perforin gene mutation identified3  2004 – Histiocyte Society diagnostic criteria updated12   Hayden et al. HLH REVIEW   26   Table 2. Histiocyte Society HLH-2004 Diagnostic Criteria.   The diagnosis HLH requires either 1 or 2 below fulfilled: (1) A molecular diagnosis consistent with HLH (2) Diagnostic criteria for HLH fulfilled (5 out of the 8 criteria below) (A) Initial diagnostic criteria     Fever     Splenomegaly     Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood):          Hemoglobin <90 g/L (in infants <4 weeks: hemoglobin <100 g/L)          Platelets <100 x 109/L          Neutrophils <1.0 x 109/L     Hypertriglyceridemia and/or hypofibrinogenemia:          Fasting triglycerides ≥3.0 mmol/L (i.e., ≥265 mg/dl)          Fibrinogen ≥1.5 g/L     Hemophagocytosis in bone marrow or spleen or lymph nodes (B) New diagnostic criteria     Low or absent NK-cell activity      Ferritin ≥500 mg/L     Soluble CD25 (i.e., soluble IL-2 receptor) ≥2,400 U/ml   Hayden et al. HLH REVIEW   27 Table 3. Summary of Main HLH Diagnostic Criteria Used in Literature  HLH Diagnostic Criteria Diagnostic feature HLH 1994 Tsuda 1997 Imashuku 1997 HLH 2004 Takagi 2009 Fardet 2014 Molecular diagnosis -- -- -- X -- -- Fever X X X X X X Splenomegaly  X X X X X X Cytopenia(s) X X X X -- X Hypertriglyceridemia X X -- X -- X Hypofibrinogenemia X X -- X -- X Hemophagocytosis  X X X X X X Coagulopathy -- X -- -- -- X Decreased NK activity -- -- -- X -- -- Serum ferritin  -- -- X X X X Increased LDH  -- -- X -- X -- Increased sIL2r  -- -- -- X -- -- Increased AST  -- -- -- -- -- X Immunosuppression -- -- -- -- -- X Engraftment failure post HCT -- -- -- -- X -- Number of studies using criteria 4 7 4 42 1 1 Notes All required for diagnosis All required for diagnosis All required for diagnosis 5/8 or molecular diagnosis 2 major or 1 major and 4 minor criteria Probability based on HScore *Not all papers are included as some did not specify details of diagnostic criteria applied Hayden et al. HLH REVIEW   28 Table 4. Details of genetic testing done in 12 studies  Ref.  Center Period of study No patients tested No. genetic defects (%) Genetic mutations/variants detected  Zhang 201110 CCHMC ND 175 27 (15%) 18 PRF1, 7 MUNC12-4 and 2 STXBP2  17 monoallelic, 10 biallelic Chandrakasan 2013 43 CCHMC 2004 – 12  10 4 (40) 2 PRF1, 1 MUNC 13-4, 1 XIAP Otrock 201558 WUMC 2003 – 14  7 0 (0) N/A Otrock  201559 WUMC 2003 – 14  1 0 (0) N/A Huasong 201360 Jinan, China 2004 – 13  21 0 (0) N/A Wang 201333 BFH 2010- 11 40 0 (0) N/A Wang 201462 BFH 2006 - 12 195 12 (6.2) 6 PRF1, 2 SH2D1A, 4 STX11, 1 UNCC13D 8 Monoallelic, 4 biallelic or hemizygous Jing-Shi 201561 BFH 2007 – 14 19 0 (0) 2 PRF1, 1 MUNC 13-4, 1 XLP-1 Wang 201534 BFH 2013 – 14 ND 4 ND Sieni 201257 Italian Registry ND (6 years) ND 11 (ND) 6 PRF1, 2 MUNC 13-4, 2 SH2D1A, 1 MUNC 19-9  10/11 biallelic Kuriyama 201256 Kyushu, Japan 2005 – 11  ND 1 (ND) 1 PRF1 Gratton 201522 MGUH/ WRMC  2011 – 11  1 0 (0) N/A ND, not described; N/A, not applicable; CCHMC, Cincinnati Children’s Hospital Medical Center; WUMC, Washington University Medical Center, U.S.A.; BFH, Beijing Friendship Hospital, China; MGUH/WRMC, Medstar Georgetown University Hospital/Walter Reed Medical Center U.S.A. Numbers reported from studies. There may be overlap in cases reported from same centers.  Hayden et al. HLH REVIEW   29 Table 5:  18 Studies with Detailed Description of Treatment and Outcomes Reference HPS patients Country HLH treatments provided Prognostic factors and Outcomes Arca  Br J Haematol 201546 Riviere Am J Med 201447 162  France 42 received HLH-94, 39 etoposide only, 19 glucocorticoids only, 1 IVIG, 61 no HLH specific therapy  Etoposide was associated with a better outcome. Poor prognostic factors included age, thrombocytopenia, lymphoma and no etoposide.   42% overall mortality, 20.4% 30-day morality.  Aulagnon  Am J Kidney Dis 201549 95  France 69 received etoposide, 33 other cytotoxic agent, 56 glucocorticoids, 9 IVIG Early treatment, including etoposide may be associated with improved renal function and survival. Poor prognostic factors included hematologic malignancy and AKI stage ≥ 2.   56% 6 month mortality.  Buyse  Intensive Care Med 20101 56 ICU patients  France 45 received etoposide, 32 other cytotoxic agent, 31 glucocorticoids, 3 IVIG Poor prognostic factors included shock, thrombocytopenia. B cell lymphoma, Castleman’s disease associated with improved survival.   51.8% mortality.  Chandrakasan Biol Blood Marrow Transplant 201343 10 young adult who underwent allogeneic HCT  United States 10 received HLH-04 and HCT Mortality in young adults with HLH is higher than pediatric mortality of 12% at that center.   50% overall mortality (44% with RIC) Chandrakasan ASH abstract 201344 19 young adults who underwent allogeneic HCT United States 19 received HLH-04 and HCT Mortality in young adults with HLH is higher than pediatric mortality of 25% at the same center.   57.9% overall mortality (43% with RIC) Emmenegger Am J Hematol 200167 20 patients with MAS Switzerland 20 received IVIG  IVIG is effective in MAS if given early in disease process.   25% mortality. Hayden et al. HLH REVIEW   30  He International Medical J 201275 21  China 21 received HLH-04; not clear if any patients actually received plasma exchange The authors used to their data to speculate that hemodialysis or plasmapheresis should be for patients with ferritin>1000ng/ml and LDH >1000 IU/L to control hypercytokinemia but did not actually present any data to support this   85.7% mortality.  Imashuku Med Pediatr Onc 200355 11 patients with EBV-HLH Japan 4 received HLH-94, 5 etoposide within 4 weeks of diagnosis, 4 CHOP, 1 other cytotoxic agent, 2 HCT EBV-HLH patients that received etoposide by 4 weeks of diagnosis had a better prognosis than those treated late.  72.7% mortality.  Jing-Shi Ann Hematol 201561 19 patients with relapsed/ refractory HLH China 16 received HLH-94, 3 HLH-04, 19 splenectomies Splenectomy should be considered and may be effective in treating patients with relapsed HLH.   36.8% mortality. Li Medicine 201473 103  China 35 received etoposide, 32/49 LAHS patients received CHOP or other doxorubicin-based regimens, 83 glucocorticoids, 35 IVIG Treating underlying disease, combined with corticosteroids, immunosuppressive therapy and IVIG may improve prognosis. Poor prognostic factors included age, male sex, splenomegaly, thrombocytopenia.   74.8% mortality,  Parikh Ann Hematol 201419 62  United States 15/32 patients with malignancy 4/6 EBV, 1/3 CMV, 3/5 MAS, 1/7 bacterial/fugal infection, 3/4 idiopathic received etoposide 22 LAHS patients received CHOP Survival of patients receiving etoposide-based therapy was similar to cohort receiving non-etoposide based treatment. Worse outcomes in tumour (including lymphoma) associated HLH.   30-day mortality 44%, overall mortality 66%.  Park Anaesthesia 201265 23 patients with non South Korea 2 received HLH-94, 11 received HLH-04, 11 etoposide, 22 glucocorticoids, 5 HCT No difference in patient outcomes between group receiving HLH-94/04 protocol or other Hayden et al. HLH REVIEW   31 LAHS (16 EBV, 6 idiopathic, 1 HAV) immunosuppressive regimen. Earlier initiation of treatment and elevated fibrinogen were positive prognostic factors.   73.9% mortality.  Shin J Korean Med Sci 200870 17 patients with LAHS, EBV-HLH or idiopathic Japan 17 received CHOP, 2 HCT (1 LAHS, 1 EBV-HLH) CHOP regimen appears to be effective in both LAHS and non-LAHS with manageable adverse effects.   52.9% mortality.  Takahashi  Int J Hematol 200171 52  Japan 25/26 LAHS patients received CHOP, 3 VAHS patients received vincristine, 44 glucocorticoids, 21 IVIG. Etoposide/HLH-94 not mentioned.  Underlying disease affects prognosis.   88% LAHS mortality compared to 11.5% mortality of non-LAHS patients (VAHS 6%, BAHS 33%, MAS 0).  Wang Blood 201333 40  China 40 received HLH-94, all LAHS received ECHOP, All MAS treated with fludarabine + methylprednisone. 20/40 received rhTPO.  rhTPO was associated with improved platelet count, less gastrointestinal, pulmonary and urinary tract bleeding but had no effect on survival.   35% mortality.  Wang  PLoS ONE 201462 18/195 HPS patients with genetic mutations China 17/18 with mutations received HLH-94, 5/18 HCT fHLH is more common than expected and should be treated similarly to pediatric HLH.    39% mortality.  Wang Blood 201534 63 patients with relapsed/ refractory HPS China 63 received HLH-94 and DEP, 5 received other cytotoxic. 3 EBV patients received rituximab. 13 HCT, 7 splenectomies DEP is an effective salvage regimen which prolongs survival in refractory HLH.   54% mortality.  HLH-94/04 (a combination of etoposide, dexamethasone with or without cyclosporine A), IVIG, intravenous immunoglobulin; RIC, reduced intensity conditioning; DEP, liposomal doxorubicin, etoposide, methylprednisone; CHOP (a combination of cyclophosphamide, Adriamycin, Hayden et al. HLH REVIEW   32 vincristine, prednisone); LAHS, lymphoma associated hemophagocytosis;; EBV-HLH, EBV associated HLH;  VAHS, virus-associated HLH; BAHS, bacteria-associated HLH; rhTPO, recombinant human thrombopoeitin; HD, hemodialysis; PE, plasma exchange, fHLH, familial HLH; MAS, macrophage activation syndrome    Hayden et al. age 1 12-Jan-2017HAYDEN et al HLH REVIEW  Hemophagocytic syndromes (HPS) including Hemophagocytic Lymphohistiocytosis (HLH) in Adults: a Systematic Scoping Review  Anna Hayden,1 Sujin Park,1 Dean Giustini,2 Agnes Y.Y. Lee1 and Luke Y.C. Chen1 1Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, Canada; and 2Biomedical Branch Library, University of British Columbia, Vancouver, Canada  Abstract Most knowledge of hemophagocytic syndromes (HPS) including hemophagocytic lymphohistiocytosis (HLH) is derived from pediatric studies; literature on adult HPS/HLH predominantly consists of small retrospective studies with clinical and methodological heterogeneity.  The aims of this systematic scoping review were to provide an overview of existing literature on adult HPS/HLH, describe current practices in diagnosis and treatment, and propose priorities for future research.  Articles from Ovid Medline, Embase and Pubmed (1975-2015) describing 10 or more unique adults (age > 15 years) with HPS/HLH were included.  82 publications were eligible: 10 were prospective and 72 were retrospective.  Of the six distinct diagnostic criteria, the HLH-2004 criteria were by far the most commonly used.  A minority of studies tested for genetic abnormalities (12), soluble interleukin-2 receptor (11), and/or NK function (11) in a subset of patients.  Most centers used steroids and either etoposide based (HLH-94/HLH-2004) or doxorubicin based (CHOP) initial therapy regimens.  Allogeneic hematopoietic cell therapy for treatment of adult HLH has rarely been reported.  Mortality in larger treatment focused studies ranged from 20 to 88%.  Developing adult-specific diagnostic criteria based on widely evaluable features of secondary HPS/HLH and establishing standard initial therapies are priorities for future research.  Hayden et al. HLH REVIEW   2 Keywords Hemophagocytic lymphohistiocytosis, hemophagocytic syndromes, hematophagic histiocytosis, macrophage activation syndromes, hyperferritinemia, adults  Hayden et al. HLH REVIEW   3 1.  Introduction Hemophagocytic syndromes (HPS) are rare, life-threatening conditions characterized by overstimulation of the immune system leading to systemic inflammation, hypercytokinemia and multi-organ failure.1 They are broadly divided into primary hemophagocytic lymphohistiocytosis (HLH) and secondary hemophagocytic syndromes.2 Primary HLH is caused by genetic mutations impairing the cytotoxic function of natural killer (NK) and cytotoxic T cells and typically present in infancy and childhood.  Primary HLH includes familial HLH (fHLH), where patients have autosomal recessive mutations in Perforin (PRF1), MUNC 13-4 (UNC13D), MUNC 19-2 (STXBP2), and Syntaxin 11 (STX11).3-7 Primary HLH also includes other inherited immunodeficiency syndromes such as Chédiak–Higashi syndrome, Griscelli syndrome, and type II Hermansky-Pudlak syndrome.8  Secondary hemophagocytic syndromes generally affect adolescents and adults and are not associated with known genetic defects, although rare cases of fHLH have been reported beyond age 70.9-11    In secondary, or reactive HPS there is often an associated “predisposing condition” causing immune dysregulation, such as malignancy (particularly lymphoma), immunodeficiency, or autoimmune disease, and/or a “trigger”, most commonly infection such as Epstein-Barr virus (EBV).8  In some cases, an associated disease process is not identified.12  HPS may also be referred to as macrophage activation syndrome (MAS) when it occurs in patients with autoimmune disease such as juvenile idiopathic arthritis (JIA), adult onset Still’s disease (AOSD) and systemic lupus erythematosus (SLE).13, 14  The pathologic immune activation that characterizes HPS/HLH can be difficult to distinguish from physiologic macrophage activation.  For example, neither the presence,15, 16 nor amount of hemophagocytosis on bone marrow biopsies is specific for HPS/HLH.17  Historical terms used to describe HPS are summarized in Table 1.    The modern conceptualization of adult HPS/HLH is derived largely from observations of familial HLH in children followed by the discovery of causative Hayden et al. HLH REVIEW   4 genetic abnormalities.  Diagnostic criteria specific for adult HPS have not been established, and diagnosis is largely based on the Histiocyte Society’s HLH-94 or 2004 (Table 2) pediatric diagnostic criteria.12  A number of described manifestations of adult HPS, such as transaminitis, coagulopathy, elevated LDH, rash, hyponatremia, elevated CRP, and neurologic involvement (which is described in one small study), are not included in these criteria.18-22  As with diagnosis, treatment protocols for adult HPS/HLH are often extrapolated from the pediatric HLH-94 and HLH-2004 protocols.  These are etoposide-based regimens containing corticosteroids, cyclosporine A, intravenous immunoglobulins (IVIG), intrathecal therapy, and liberal use of allogeneic stem cell transplant in higher risk patients.23  How well these treatment protocols apply to adults is poorly understood.    To date, the literature on adult HPS/HLH consists largely of retrospective studies, often confined to a single center or geographic region.  Most literature reviews are narrative,24-26 although systematic reviews have been done for specific types of HPS/HLH such as HPS associated with zoonotic infections.27-29 We conducted a systematic search to identify the extent of existing literature on HPS/HLH, an area with considerable clinical and methodological heterogeneity.  We analyzed the findings using scoping review methodology.  Scoping reviews are similar to systematic reviews in terms of searching the literature in a reproducible manner, but the aim of a scoping review is generally to address a broad area or topic (as opposed to a narrowly defined question) and scoping reviews do not emphasize the quality or methodology of included studies (as opposed to the stringent assessment of clinical heterogeneity, methodology and quality in systematic reviews).30-32  The aims of this systematic scoping review were to:  1. Provide an overview of existing adult HPS/HLH literature and publication trends over time   2. Describe established patterns and emerging trends in diagnosis and treatment of adult HPS/HLH 3. Propose priorities for future research   Hayden et al. HLH REVIEW   5  2.  Methods 2.1. Search strategy A comprehensive literature search was performed using the databases Ovid Medline, Embase, and PubMed.  The aim was to maximize sensitivity for finding published, peer-reviewed studies of adult HPS/HLH.  Our search terms and medical subject headings (MeSH) were : h(a)emophagocytic syndrome(s) OR h(a)emophagocytic lymphohistiocytosis OR  h(a)ematophagic histiocytosis OR  macrophage activation syndrome(s) OR cytophagic histiocytic panniculitis AND adult(s) AND English (language) AND humans.  We excluded child(ren) as a search term and limited results to publication years 1975-2015.  As extended search techniques, PubMed and the Web of Science were used to identify more recent articles as well as the most highly cited publications in the field.  Final updated searches were performed on September 3, 2015.  Results were screened based on titles and abstracts to determine suitability for inclusion in this scoping review.  “Grey literature” such as theses were not included; most conference proceedings were excluded except for two abstracts with important information on genetic testing and outcomes after Hematopoetic Cell Transplant (HCT).  Details of the search strategy can be found in Appendix 1, 2 and 3.  2.2. Study selection and data collection  All articles that addressed the topic of HPS/HLH in adults (defined as age >15 years) were screened by full text review.  English language articles with 10 or more original cases were selected for the scoping review.  The minimum of 10 cases was arbitrarily chosen to identify larger studies.  Data abstraction was done by one investigator, checked by two others, and included: first author, journal, year of publication, country of origin, type and design of study, number of patients included, inclusion/exclusion criteria, demographic features, diagnostic criteria, details on genetic testing, associated conditions, clinicopathologic features, treatment, outcomes, and additional notes on the study.   Hayden et al. HLH REVIEW   6   3.  Results  The search strategy gathered 2492 articles and upon manual review and cross-referencing (35) and eliminating duplicates (932), the total number of unique articles on adult HPS/HLH identified was 1590 (Figure 1).  Through the last updated search on Sept 3, 2015, 552 new articles were identified on Web of Science, some of which overlapped with previously identified articles.    82 articles included 10 or more adults with HPS/HLH and were eligible for this review (see Appendix 4 for complete list).  72 articles were retrospective and 10 were prospective.33-42  Two of these prospective studies were clinical trials,33, 34 three examined incidence and natural history of secondary HPS, and five investigated cytokine/biomarker significance.  Figure 2 illustrates the dramatic increase in the number of articles published per year on this subject; 56 of the 82 articles included were published in the past ten years.  44 articles were from Asian institutions (Figure 3).  Three studies that did not strictly meet the inclusion criteria were still included because they were of special interest:   1) A study of 9 patients with HPS because it was one of the few prospective studies.35 2) An abstract of 10 patients who underwent allogeneic HCT in Cincinnati because it was one of the few studies reporting genetic abnormalities adults.43  3) An abstract of 19 patients from Cincinnati, with overlapping patients from the above study, because it reported outcomes after HCT.44  3.1. Studies with overlapping patients:  Hayden et al. HLH REVIEW   7 A recent systematic review combined results from numerous studies to gather information on the clinical presentation and treatment of HLH in adults.24  For example, they reported a mortality rate of 41% in 1109 adults pooled from 13 articles.  However, it is unlikely that these truly represent 1109 unique patients, as many patient series in the literature have been reported numerous times in different publications.  For example, two of the 13 articles cited are from the same French center with overlapping study periods.1, 45 Investigators from this French group have published numerous important articles which describe different aspects of HPS in overlapping cohorts of patients.1, 18, 39, 45-49  A full list of studies with patients that were definitely or potentially described in more than one study is included in Appendix 5.   3.2. Epidemiology  There is limited data on incidence of HPS/HLH, particularly in adult populations.  A nationwide survey in Japan evaluating pediatric and adult cases reported annual incidence at 1 per 800,000.50  Pediatric HLH diagnosis has been approximated to be 1 case per 3000 inpatient admissions, and incidence per live birth has been estimated to be 1-6/300,000.25, 26 A single center retrospective Swedish study reported an incidence of malignancy associated HLH in adults of 0.9% (8 of 887).51  The majority of articles included in this review originated from Asia and particularly Japan (see Figure 3). Whether this suggests a higher incidence of HPS/HLH in this region, geographic variations in EBV-associated HPS/HLH, greater academic interest in HPS/HLH, or some combination thereof, is not clear.  Three single center studies prospectively examined the incidence and natural history of HPS associated with specific conditions in consecutive patients:  32 of 343 pts with AML,38 12 of 20 patients with sepsis and thrombocytopenia on mechanical ventilation35 and 9 of 25 pts with influenza A.37  3.3. Diagnostic Criteria  Hayden et al. HLH REVIEW   8 We reviewed the diagnostic criteria applied by each of the 82 articles in order to understand the consistency of HPS/HLH diagnosis in the literature and how this has changed over time (Table 1).  Six distinct diagnostic criteria have been used, (summarized in Table 3); of these, the Histiocyte Society’s criteria are by far the most commonly used.   3.3.1. Studies using Histiocyte Society diagnostic criteria  The Histiocyte Society published diagnostic criteria in 1991, which were used for the pediatric HLH-94 trial.52  1 survey and 3 other articles used these diagnostic criteria.50, 53-55  Updated criteria, used for the HLH-2004 study, were published in 2007.  36 of the 54 articles (67%) published since 2007 in this review used HLH-2004 and 6 used modified HLH-2004 criteria.  Many investigators have recognized the limitations of applying the pediatric HLH-2004 diagnostic criteria to adults.17, 18, 25, 46  These limitations fall into three categories: 1) Limitations of molecular testing:  Only 12 of 54 studies performed genetic testing on at least one patient (Table 4). 10, 22, 33, 34, 43, 56-62 The largest study of genetic mutations in adults from Cincinnati Children’s Hospital Medical Center (CCHMC) reported that 25 of 175 (15%) adults had a mutation in PRF1, MUNC13-4 or STXBP2.10  Patient samples in this study were referred from all over North America and so the true denominator of adults with HPS/HLH cannot be ascertained.  Moreover, classical familial HLH is caused by homozygous mutations in autosomal recessive genes; heterozygous allele mutations and mutations of unknown functional significance are included in many of these reports, and the significance of these findings is incompletely understood. Hayden et al. HLH REVIEW   9 2) Accessibility of sIL2r and NK function:  Many articles stated that sIL2r and NK function were not readily available at the study center.  Only 11 of 54 studies published since 2007 commented on testing for sIL2r,17, 19, 22, 34, 37, 58, 59, 61-64 and 11 studies commented on NK function testing.10, 17, 19, 22, 43, 57-59, 62, 64, 65 Most of these studies reported testing in a small proportion of patients.  sIL2r was elevated in 148 of 161 patients tested (91.9%) and 41 of 72 (56.9%) patients tested had absent or low NK cell activity.   3) Different presenting features in adults:  A number of studies comment on how hemophagocytic syndromes, particularly reactive hemophagocytic syndromes, may present in adults with manifestations not included in the HLH 2004 criteria, such as elevated aspartate transaminase (AST)18 or lactate dehydrogenase (LDH)66  3.3.2. Studies using other diagnostic criteria  Prior to 2007, all articles in this review required pathologic evidence of hemophagocytosis on bone marrow biopsy, aspirate, lymph node, spleen or liver, in addition to typical clinical features, which often included but did not require fever, cytopenias and splenomegaly.  In total, 14 articles required histologic evidence of hemophagocytosis but no other specific diagnostic criterion.  8 of 11 articles published before 2000 did not use any standardized diagnostic criteria, In 1997, Tsuda et al. and Imashuku et al. each published modified criteria which built on the HLH-94 diagnostic criteria (Table 5).20, 66  These criteria were employed by 11 articles combined (7 and 4 respectively).   One study developed novel diagnostic criteria for diagnosis of HLH in AML patients.38  Emmenegger et al. proposed a ferritin value of  ≥10,000 ug/L and/or morphologic evidence of hemophagocytosis as a screening strategy.14, 67  Takagi et al. created and applied novel criteria for Hematopoeitic Stem Cell Transplantation-related Hemophagocytic Syndrome (HCT-HPS) comprised of 2 Hayden et al. HLH REVIEW   10 major and 4 minor criterion which excluded cytopenias given the post-HCT context.68    Fardet et al. proposed a novel set of diagnostic criteria for reactive HPS, the HScore, which is based on data from 162 patients and the first to be validated in an adult population.18 Nine weighted variables were considered: 3 clinical [known underlying immunosuppression (such as HIV or chronic use of immunosuppressive medications), fever, organomegaly], 5 biologic (triglyceride, ferritin, aspartate transaminase (AST), fibrinogen, cytopenia), and 1 cytologic (HPS features on BM aspirate).  sIL2r levels and NK cell activity were not included due to concerns about accessibility.    Many laboratory tests have been evaluated for adult HLH.  Five studies used a prospective method of patient selection to make comparisons with controls or patients with other diseases in laboratory parameters such as glycosylated ferritin,40, 48 biologically active free interleukin 18 (IL-18)36, adenosine deaminase 41 and comparison of cytokine profiles between B-cell and T/NK-cell lymphocyte associated hemophagocytic syndrome.42  One study reported that the sIL2r/ferritin ration was significantly higher in 11 patients with lymphoma associated HPS compared to 10 patients with benign-disease associated HLH.63  A recent reported a number of abnormalities in the lymphocyte compartment of 21 patients with HLH.  While these abnormalities are too varied and non-specific to assist in diagnosis, they may have prognostic significance.69    3.4. Treatment  Eighteen studies in this review provided detailed descriptions of treatment and outcomes.  Two of these studies were prospective.33, 34  The remainder were retrospective and included a range of ten to 162 patients (table 5).  Unlike diagnosis, where each study applied one set of diagnostic criteria to all study participants, treatment was highly variable both between and within the studies. Among these studies, all except two used an etoposide based regimen for at a Hayden et al. HLH REVIEW   11 proportion of patients. CHOP was used widely for lymphoma associated hemophagocytic syndromes (LAHS), however 2 studies also used CHOP therapy outside of the LAHS context, predominantly for EBV-HLH patients.55, 70 Hematopoietic cell therapy (HCT) was reported in a small number of patients in seven of these 18 studies.34, 44, 55, 62, 65, 70, 71  3.4.1. Initial treatment  Initial glucocorticoids were almost always included in adult treatment regimens.  Beyond this, there was considerable variation in treatment.  The pattern of practice was first and foremost to identify and treat the underlying cause – infection, malignancy, or autoimmune – with disease-appropriate therapy and supportive measures, and if necessary, chemo-immunotherapy.  However, there was significant variation both within and amongst studies in which patients received cytotoxic therapy such as the etoposide-based HLH-94/2004 treatment protocols or CHOP.  In many cases, particularly in treating MAS, patients considered corticosteroid-refractory received only a component of the regimen, such as glucocorticoids and another immunosuppressive drug.13    3.4.2. Etoposide-based Histiocyte Society Protocols (HLH-94 and HLH-2004)    In pediatric HLH, which is rarely associated with an underlying malignancy, use of etoposide has shown significant improvement in survival if initiated within the first 4 weeks of symptoms.72 This finding was replicated in a report of young adults (11 from Kyoto and 9 cases from the literature) with EBV-associated HLH, wherein treatment with etoposide within 4 weeks of presentation was associated with better outcomes (2 of 7 died) than in those who received etoposide after 4 weeks or not at all (12 of 13 died).55 In a retrospective study of 162 adults with HLH, Arca et al. described a trend toward better outcomes when etoposide was employed (85% vs. 74% survival, p = 0.079).46 In contrast, Parikh et al. assessed 62 patients with HLH, of whom 20 received etoposide (9 tumor associated and 11 non-tumor associated), and found that the overall survival was similar between Hayden et al. HLH REVIEW   12 the cohorts receiving etoposide or non-etoposide based regimens.19 In a retrospective study of prognostic factors in adult HLH, Li et al. found that etoposide use was not associated with better outcomes.73    3.4.3. Other initial therapies  Many patients, particularly in Asia, have been treated with doxorubicin-based therapy such as CHOP, often in the context of aggressive lymphoma/LAHS (see table 5).  In a retrospective study examining treatment outcomes with CHOP in 17 adult patients with HLH secondary to lymphoma, EBV or unknown cause, overall response rate was 58.8% (5/7 with lymphoma, 3/5 with EBV, 2/5 with idiopathic HLH) with 2 year overall survival 43.9% suggesting possible benefit of CHOP in adult HLH of multiple etiologies.70    3.4.4. Salvage therapy  The only prospective multicenter study in this review investigated the effects of a salvage therapeutic regimen in 63 adults who had not achieved partial response to standard HLH therapy based on the HLH-94 treatment protocol. The regimen was a hybrid of etoposide and doxorubicin-based regimens, consisting of liposomal doxorubicin, etoposide and pulse methylprednisone (DEP).34  Overall response was 76.2%, however overall mortality was 54% due to either progression of underlying disease or recurrence of HLH.   3.4.5. Special Populations  Allogeneic HCT in adults has rarely been reported.25  Chandrakasan et al. reported on 19 adolescents/adults (age 15-27) with HLH who received alloHCT at CCMHC and reported overall survival 42.1% (8/19).  In the 15 patients > 15 years who received reduced intensity alloHCT, survival was 57% compared to 75% in children < 15 years, p = 0.03.44 Other possible treatment modalities discussed in articles included in this review were IVIG for MAS,67, 74 plasma Hayden et al. HLH REVIEW   13 exchange for patients with serum ferritin ≥ 10 000 ug/L and LDH ≥ 1000 IU/L,75 splenectomy for relapsed HLH of unknown cause,61 and recombinant human thrombopoeitin (rhTPO) which improved thrombocytopenia and decreased platelet transfusion requirements in a small randomized controlled trial of 40 adults with HLH.33   3.5. Prognostic Factors and Outcomes  Outcomes in adult HLH were heterogeneous; among the 18 studies focusing on treatment and outcomes, mortality ranged from 20.4 to 88% depending on population factors and length of follow up (Table 5). Among these studies, the study with the lowest mortality rate only assessed 30-day mortality in order to limit the impact of underlying disease,46 whereas the highest mortality rate was in patients with underlying lymphoma, which was consistently an adverse prognostic factor.71 The largest study, describing 162 patients and all associated HLH conditions, reported overall mortality 42%.47  Mortality was generally lowest in autoimmune disease patients followed by infection-associated and idiopathic HLH patients.  Malignancy, particularly lymphoma-associated HPS/HLH, was a prominent adverse prognostic marker correlating with poorer survival in multiple large studies.19, 46, 47, 58, 73, 76  Patients with T cell lymphoma generally had worse outcomes than those with B cell lymphoma.76-78 Other common adverse prognostic factors included age >30,79 highly elevated ferritin,19, 58, 79 marked thrombocytopenia,1, 46, 79 male sex,73 lack of etoposide therapy46 and low albumin.19     4. Discussion  The number of adult HPS/HLH publications has risen dramatically from less than ten per year in the 1980’s to greater than 100 per year since 2010. Though our inclusion criteria comprises articles from 1975 to current, only one study Hayden et al. HLH REVIEW   14 published prior to 1990 and only 11 articles published between 1990 to 2000 included 10 or more adult patients.  The dramatic rise in larger studies of adult HPS/HLH in recent years likely reflects increased recognition; whether it also indicates a rise in incidence of HPS/HLH is not clear.      4.1. Diagnosis:  Established patterns and emerging trends  The Histiocyte Society’s pediatric HLH-2004 diagnostic criteria has been widely extrapolated for use in adults since their publication in 2007.  However, these criteria have a number of important shortcomings in the adult population.  First, the molecular diagnosis is applicable only to those rare cases of adult-onset fHLH, and testing is available only in specialized centers.  Frequency of genetic mutations is inversely correlated with age of disease onset, with 45% of patients < 1 month found to have an fHLH mutation compared to 6% of those over age 2 years.26 Furthermore, part of the rationale of testing children is to identify patients in whom allogeneic HCT is warranted, but the tolerability and efficacy of HCT in adults, especially older adults is poorly understood.  12 of 82 studies in this review tested a small proportion of patients for genetic mutations, which likely reflects the lack of access, high cost, and ill-defined clinical benefit associated with genetic testing in adults.  Thus, the 8 clinical and laboratory features of HLH 2004 are particularly important in adults, and yet these abnormalities are relatively non-specific to HPS/HLH.  Extreme hyperferritinemia has historically been described as nearly pathognomonic for HLH,8, 26 but recent studies have shown that ferritin > 3000 ug/L and even > 50 0000 ug/L are very non-specific in acutely ill adults.64, 80 Hemophagocytosis on bone marrow sampling lacks both sensitivity and specificity.17, 47, 81  The lack of testing for sIL2r and NK function identified in this review is a major issue in using the HLH 2004 diagnostic criteria in adults.  One approach is to simply exclude sIL2r and NK function from adult diagnostic criteria in favor of other more readily available parameters common to HPS in adults.  For example, in the HScore for reactive HPS, elevated aspartate transaminase (AST) is included but sIL2r and NK function are not.  The exclusion Hayden et al. HLH REVIEW   15 of these two parameters was not on the basis of empiric data.  Rather, in the Delphi study which preceded construction of the HScore, it was judged that sIL2r, NK function, and CD163 were “not frequently enough assessed in routine practice” to be included.18, 21    However, HPS is a syndrome of pathologic immune activation occurring typically in immunocompromised patients and ultimately, sIL2r and NK function are important objective markers of increased T-cell activity and impaired cytoxic function, respectively.  sIL2r is a simple, commercially available biochemistry test and most centers with an interest in HPS/HLH should be able to implement this.  NK function may be useful in some adults, both for diagnosis and confirmation of disease remission, but is more difficult to implement as the flow cytometry assays require specialized technicians and reagents.  4.2. Treatment:  Established patterns and emerging trends  Almost all adult studies describing treatment have been small, retrospective and tend to focus on a component of treatment or a subgroup of HPS/HLH.  Glucocorticoids are standard, and for patients where cytotoxic therapy is thought to be necessary, the etoposide-based HLH-94 and 2004 protocols and CHOP are commonly used. Optimal initial therapies, as well as duration of treatment in adults, require further investigation.  For example, the induction phase of the pediatric HLH-2004 protocol consists of 8 weeks of etoposide-based therapy, and treatment after that, if required, is intended as a bridge to alloHCT.  However, adults treated with CHOP would typically receive CHOP every 3-4 weeks for 6-8 cycles (e.g. 18 to 32 weeks of chemotherapy).  A recent study evaluating liposomal doxorubicin, etoposide and dexamethasone (DEP) represents a true milestone in being the first prospective, multi-center clinical trial in adults.34  Establishing standards for initial therapy remains pressing need; unlike fHLH, a uniform protocol may not be feasible given the heterogeneity of the underlying/triggering conditions.  Rather, treatment strategies tailored to different associated conditions (malignancy, infection or autoimmune) may be needed.  Hayden et al. HLH REVIEW   16  In pediatric HPS/HLH, liberal use of allogeneic HCT is indicated to replace defective cytotoxic T cells in familial HLH, and sometimes to treat the underlying disease process, particularly where in HPS/HLH associated with hematologic malignancy.  However, the liberal use of allogeneic HCT described in the HLH 94 and HLH 2004 protocols may not be as applicable to adults.  In the pediatric HLH 94 study, 124/249 patients (50%) underwent HCT, whereas only 7 of the 18 treatment-focused articles in this review report transplanting a small number of adults.  The low incidence of fHLH, increased morbidity of allogeneic HCT in adults compared to children, relative scarcity of suitable donors, and the poor performance status and organ function of the relapsed and refractory adult patients are likely all factors in the low rate of HCT use in adults.  Moreover, given the high prevalence of secondary HPS/HLH in adults driven by elevated cytokine levels from an underlying trigger, HCT would be unlikely to eradicate the underlying cause.  According to some experts, allogeneic HCT should be considered on a case by case basis in eligible relapsed or refractory patients as well as the rare adults with late onset familial HLH.25    5. Areas for future research and conclusions  5.1. Areas for future research  Currently, the paradigm in children is that a largely genetic disease (fHLH) requires allogeneic HCT in a high proportion of patients.  This review demonstrates that in adults, the vast majority of reported cases have not been associated with a defined inherited molecular defect.  Early diagnosis is essential, as a proportion of these patients will go on to develop critical illness, multi-organ failure, and death, and better diagnostic and prognostic models are needed.  Although the HLH-2004 diagnostic criteria are widely used, molecular testing, sIL2r, and NK function are rarely applied in older patients.  Diagnostic and prognostic models specific to adults, such as the HScore have been Hayden et al. HLH REVIEW   17 developed, but exclude these specialized tests more on the basis of availability than whether they are actually helpful in diagnosis.  The preponderance of secondary/reactive HPS, combined with the lack of specificity of criteria such as cytopenias and hyperferritinemia in adults, begs the question of whether other widely available markers of pathologic immune activation may be useful in diagnosis.  The commercial availability of relatively low cost sIL2r assays implies that further study of this disease marker should be conducted in adult HPS/HLH.  Promising new biomarkers and therapies in children should be promptly evaluated in adults.  For example, interferon gamma has been shown to be a key mediator of the cytopenias in HLH,82and the therapeutic potential of an anti-IFN gamma antibody has shown promise in animal models and a pediatric IFN gamma antibody phase 1 clinical trial is currently underway.83 Another pediatric study of hybrid immunotherapy (anti-thymocyte globulin, dexamethasone and etoposide, the HIT-HLH trial),84 is in progress and the results of this trial, along with the long-awaited HLH-2004 study results, should inform future studies in adult HLH.   5.2. Concluding remarks  Hemophagocytic syndromes in adults have received increasing attention in the literature over the past 30 years.  However, there remains a paucity of prospectively collected, multi-center data and much of the diagnosis and treatment in adults is extrapolated from pediatric data.  In children, the disease paradigm has been based on diagnosis of familial HLH and aggressive treatment thereof with cytotoxic therapy and liberal use of alloHCT.  In adults, the majority of studies describe secondary HPS associated with acquired immune dysregulation, which may present with different clinical and laboratory features, requiring different diagnostic criteria.  The optimal initial therapy and role of alloHCT require further investigation in adults.  Priorities for future research include development of diagnostic criteria and treatment protocols that Hayden et al. HLH REVIEW   18 accommodate those disease aspects unique to adults and also rapidly evaluate and incorporate novel discoveries in pediatric HPS/HLH.  Practice points:  Publications on adult HPS/HLH have increased dramatically in recent years but the majority are retrospective studies.  Most studies apply the pediatric Histiocyte Society diagnostic criteria and treatment protocols, or variants thereof, to adult patients.  Secondary HPS/HLH is much more commonly described than primary HLH, but adults are rarely tested for genetic abnormalities, soluble interleukin-2 receptor, or NK function.    Survival in HLH is heterogeneous and malignancy/lymphoma associated HPS/HLH is associated with poor outcomes.   Research Agenda:  Adult-specific diagnostic criteria based on commonly evaluable clinical and laboratory features of secondary HPS/HLH are needed.  Promising new biomarkers in pediatric HPS/HLH, such as interferon gamma, should be evaluated in adults.    Prospective multicenter trials to evaluate treatment and outcomes of HPS/HLH in adults are needed.   Acknowledgements This study was supported by the Hal Kettleson Hematology Research Fund.    Conflict of interest disclosures The authors state that they have no interests which might be perceived as posing a conflict or bias.   Hayden et al. HLH REVIEW   19 References 1. Buyse S, Teixeira L, Galicier L, Mariotte E, Lemiale V, Seguin A, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med. 2010;36(10):1695-702. 2. Jaffe R. The histiocytoses. Clin Lab Med. 1999;19(1):135-55. 3. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957-9. 4. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol. 2006;6(12):940-52. 5. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. 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Nomenclature and Diagnostic Criteria of Hemophagocytic Syndromes:  Historical Overview   1939 – Histiocytic medullary reticulocytosis85  1952 – Familial hemophagocytic reticulocytosis86  1966 – Malignant histiocytosis described; majority of cases subsequently re-classified as anaplastic large cell lymphoma87  1979 – Virus-associated hemophagocytic syndrome (VAHS)88  1980 – Cytophagic histiocytic panniculitis89  1983 – Familial Hemophagocytic lymphohistiocytosis90  1991 – Histiocyte Society diagnostic criteria for HLH developed52  1993 – Macrophage Activation Syndrome (children with inflammatory joint disease)91  1999 – Perforin gene mutation identified3  2004 – Histiocyte Society diagnostic criteria updated12   Hayden et al. HLH REVIEW   26   Table 2. Histiocyte Society HLH-2004 Diagnostic Criteria.   The diagnosis HLH requires either 1 or 2 below fulfilled: (1) A molecular diagnosis consistent with HLH (2) Diagnostic criteria for HLH fulfilled (5 out of the 8 criteria below) (A) Initial diagnostic criteria     Fever     Splenomegaly     Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood):          Hemoglobin <90 g/L (in infants <4 weeks: hemoglobin <100 g/L)          Platelets <100 x 109/L          Neutrophils <1.0 x 109/L     Hypertriglyceridemia and/or hypofibrinogenemia:          Fasting triglycerides ≥3.0 mmol/L (i.e., ≥265 mg/dl)          Fibrinogen ≥1.5 g/L     Hemophagocytosis in bone marrow or spleen or lymph nodes (B) New diagnostic criteria     Low or absent NK-cell activity      Ferritin ≥500 mg/L     Soluble CD25 (i.e., soluble IL-2 receptor) ≥2,400 U/ml   Hayden et al. HLH REVIEW   27 Table 3. Summary of Main HLH Diagnostic Criteria Used in Literature  HLH Diagnostic Criteria Diagnostic feature HLH 1994 Tsuda 1997 Imashuku 1997 HLH 2004 Takagi 2009 Fardet 2014 Molecular diagnosis -- -- -- X -- -- Fever X X X X X X Splenomegaly  X X X X X X Cytopenia(s) X X X X -- X Hypertriglyceridemia X X -- X -- X Hypofibrinogenemia X X -- X -- X Hemophagocytosis  X X X X X X Coagulopathy -- X -- -- -- X Decreased NK activity -- -- -- X -- -- Serum ferritin  -- -- X X X X Increased LDH  -- -- X -- X -- Increased sIL2r  -- -- -- X -- -- Increased AST  -- -- -- -- -- X Immunosuppression -- -- -- -- -- X Engraftment failure post HCT -- -- -- -- X -- Number of studies using criteria 4 7 4 42 1 1 Notes All required for diagnosis All required for diagnosis All required for diagnosis 5/8 or molecular diagnosis 2 major or 1 major and 4 minor criteria Probability based on HScore *Not all papers are included as some did not specify details of diagnostic criteria applied Hayden et al. HLH REVIEW   28 Table 4. Details of genetic testing done in 12 studies  Ref.  Center Period of study No patients tested No. genetic defects (%) Genetic mutations/variants detected  Zhang 201110 CCHMC ND 175 27 (15%) 18 PRF1, 7 MUNC12-4 and 2 STXBP2  17 monoallelic, 10 biallelic Chandrakasan 2013 43 CCHMC 2004 – 12  10 4 (40) 2 PRF1, 1 MUNC 13-4, 1 XIAP Otrock 201558 WUMC 2003 – 14  7 0 (0) N/A Otrock  201559 WUMC 2003 – 14  1 0 (0) N/A Huasong 201360 Jinan, China 2004 – 13  21 0 (0) N/A Wang 201333 BFH 2010- 11 40 0 (0) N/A Wang 201462 BFH 2006 - 12 195 12 (6.2) 6 PRF1, 2 SH2D1A, 4 STX11, 1 UNCC13D 8 Monoallelic, 4 biallelic or hemizygous Jing-Shi 201561 BFH 2007 – 14 19 0 (0) 2 PRF1, 1 MUNC 13-4, 1 XLP-1 Wang 201534 BFH 2013 – 14 ND 4 ND Sieni 201257 Italian Registry ND (6 years) ND 11 (ND) 6 PRF1, 2 MUNC 13-4, 2 SH2D1A, 1 MUNC 19-9  10/11 biallelic Kuriyama 201256 Kyushu, Japan 2005 – 11  ND 1 (ND) 1 PRF1 Gratton 201522 MGUH/ WRMC  2011 – 11  1 0 (0) N/A ND, not described; N/A, not applicable; CCHMC, Cincinnati Children’s Hospital Medical Center; WUMC, Washington University Medical Center, U.S.A.; BFH, Beijing Friendship Hospital, China; MGUH/WRMC, Medstar Georgetown University Hospital/Walter Reed Medical Center U.S.A. Numbers reported from studies. There may be overlap in cases reported from same centers.  Hayden et al. HLH REVIEW   29 Table 5:  18 Studies with Detailed Description of Treatment and Outcomes Reference HPS patients Country HLH treatments provided Prognostic factors and Outcomes Arca  Br J Haematol 201546 Riviere Am J Med 201447 162  France 42 received HLH-94, 39 etoposide only, 19 glucocorticoids only, 1 IVIG, 61 no HLH specific therapy  Etoposide was associated with a better outcome. Poor prognostic factors included age, thrombocytopenia, lymphoma and no etoposide.   42% overall mortality, 20.4% 30-day morality.  Aulagnon  Am J Kidney Dis 201549 95  France 69 received etoposide, 33 other cytotoxic agent, 56 glucocorticoids, 9 IVIG Early treatment, including etoposide may be associated with improved renal function and survival. Poor prognostic factors included hematologic malignancy and AKI stage ≥ 2.   56% 6 month mortality.  Buyse  Intensive Care Med 20101 56 ICU patients  France 45 received etoposide, 32 other cytotoxic agent, 31 glucocorticoids, 3 IVIG Poor prognostic factors included shock, thrombocytopenia. B cell lymphoma, Castleman’s disease associated with improved survival.   51.8% mortality.  Chandrakasan Biol Blood Marrow Transplant 201343 10 young adult who underwent allogeneic HCT  United States 10 received HLH-04 and HCT Mortality in young adults with HLH is higher than pediatric mortality of 12% at that center.   50% overall mortality (44% with RIC) Chandrakasan ASH abstract 201344 19 young adults who underwent allogeneic HCT United States 19 received HLH-04 and HCT Mortality in young adults with HLH is higher than pediatric mortality of 25% at the same center.   57.9% overall mortality (43% with RIC) Emmenegger Am J Hematol 200167 20 patients with MAS Switzerland 20 received IVIG  IVIG is effective in MAS if given early in disease process.   25% mortality. Hayden et al. HLH REVIEW   30  He International Medical J 201275 21  China 21 received HLH-04; not clear if any patients actually received plasma exchange The authors used to their data to speculate that hemodialysis or plasmapheresis should be for patients with ferritin>1000ng/ml and LDH >1000 IU/L to control hypercytokinemia but did not actually present any data to support this   85.7% mortality.  Imashuku Med Pediatr Onc 200355 11 patients with EBV-HLH Japan 4 received HLH-94, 5 etoposide within 4 weeks of diagnosis, 4 CHOP, 1 other cytotoxic agent, 2 HCT EBV-HLH patients that received etoposide by 4 weeks of diagnosis had a better prognosis than those treated late.  72.7% mortality.  Jing-Shi Ann Hematol 201561 19 patients with relapsed/ refractory HLH China 16 received HLH-94, 3 HLH-04, 19 splenectomies Splenectomy should be considered and may be effective in treating patients with relapsed HLH.   36.8% mortality. Li Medicine 201473 103  China 35 received etoposide, 32/49 LAHS patients received CHOP or other doxorubicin-based regimens, 83 glucocorticoids, 35 IVIG Treating underlying disease, combined with corticosteroids, immunosuppressive therapy and IVIG may improve prognosis. Poor prognostic factors included age, male sex, splenomegaly, thrombocytopenia.   74.8% mortality,  Parikh Ann Hematol 201419 62  United States 15/32 patients with malignancy 4/6 EBV, 1/3 CMV, 3/5 MAS, 1/7 bacterial/fugal infection, 3/4 idiopathic received etoposide 22 LAHS patients received CHOP Survival of patients receiving etoposide-based therapy was similar to cohort receiving non-etoposide based treatment. Worse outcomes in tumour (including lymphoma) associated HLH.   30-day mortality 44%, overall mortality 66%.  Park Anaesthesia 201265 23 patients with non South Korea 2 received HLH-94, 11 received HLH-04, 11 etoposide, 22 glucocorticoids, 5 HCT No difference in patient outcomes between group receiving HLH-94/04 protocol or other Hayden et al. HLH REVIEW   31 LAHS (16 EBV, 6 idiopathic, 1 HAV) immunosuppressive regimen. Earlier initiation of treatment and elevated fibrinogen were positive prognostic factors.   73.9% mortality.  Shin J Korean Med Sci 200870 17 patients with LAHS, EBV-HLH or idiopathic Japan 17 received CHOP, 2 HCT (1 LAHS, 1 EBV-HLH) CHOP regimen appears to be effective in both LAHS and non-LAHS with manageable adverse effects.   52.9% mortality.  Takahashi  Int J Hematol 200171 52  Japan 25/26 LAHS patients received CHOP, 3 VAHS patients received vincristine, 44 glucocorticoids, 21 IVIG. Etoposide/HLH-94 not mentioned.  Underlying disease affects prognosis.   88% LAHS mortality compared to 11.5% mortality of non-LAHS patients (VAHS 6%, BAHS 33%, MAS 0).  Wang Blood 201333 40  China 40 received HLH-94, all LAHS received ECHOP, All MAS treated with fludarabine + methylprednisone. 20/40 received rhTPO.  rhTPO was associated with improved platelet count, less gastrointestinal, pulmonary and urinary tract bleeding but had no effect on survival.   35% mortality.  Wang  PLoS ONE 201462 18/195 HPS patients with genetic mutations China 17/18 with mutations received HLH-94, 5/18 HCT fHLH is more common than expected and should be treated similarly to pediatric HLH.    39% mortality.  Wang Blood 201534 63 patients with relapsed/ refractory HPS China 63 received HLH-94 and DEP, 5 received other cytotoxic. 3 EBV patients received rituximab. 13 HCT, 7 splenectomies DEP is an effective salvage regimen which prolongs survival in refractory HLH.   54% mortality.  HLH-94/04 (a combination of etoposide, dexamethasone with or without cyclosporine A), IVIG, intravenous immunoglobulin; RIC, reduced intensity conditioning; DEP, liposomal doxorubicin, etoposide, methylprednisone; CHOP (a combination of cyclophosphamide, Adriamycin, Hayden et al. HLH REVIEW   32 vincristine, prednisone); LAHS, lymphoma associated hemophagocytosis;; EBV-HLH, EBV associated HLH;  VAHS, virus-associated HLH; BAHS, bacteria-associated HLH; rhTPO, recombinant human thrombopoeitin; HD, hemodialysis; PE, plasma exchange, fHLH, familial HLH; MAS, macrophage activation syndrome    Hayden et al. age 1 12-Jan-2017HAYDEN et al HLH REVIEW  Appendix 1: Search strategy Ovid SP  EMBASE, MEDLINE  1     exp hemophagocytic syndrome/  2     exp hemophagocytic lymphohistiocytosis/  3     h*emophagocytic syndrome*.mp.  4     h*emophagocytic lymphohistiocytosis.mp.  5     h*ematophagic histiocytosis.mp.  6     macrophage activation syndrome*.mp.  7     cytophagic histiocytic panniculitis.mp.  8     or/1-7  9     adult*.mp. or exp adult/ [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]  10     child*.mp. or exp child/ [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]  11     8 and 9  12     11 not 10  13     limit 12 to (english language and humans)  14     limit 13 to yr="1975 -Current"    Appendix 2: Search strategy PubMed  (hemophagocytic lymphohistiocytosis) OR (haemophagocytic lymphohistiocytosis) OR (hemophagocytic syndrome*) OR (haemophagocytic syndrome*) OR (cytophagic histiocytic panniculitis) OR (macrophage activation syndrome*) OR (hematophagic histiocytosis) OR (haematophagic histiocytosis) AND adult* NOT child* NOT paediatric* NOT pediatric*  Hayden et al. HLH REVIEW   2 With filters: English language, humans, publication dates from 2014/04/01 to 2015/12/31   Appendix 3: Search strategy Web of Science Core Collection  Query: TOPIC: ("hemophagocytic lymphohistiocytosis") ORTOPIC: ("haemophagocytic lymphohistiocytosis") ORTOPIC: ("hemophagocytic syndrome*") OR TOPIC:("haemophagocytic syndrome*") OR TOPIC: ("macrophage activation syndrome*") OR TOPIC: ("cytophagic histiocytic panniculitis") OR TOPIC: ("hematophagic histiocytosis")OR TOPIC: ("haematophagic histiocytosis") AND TOPIC:(adult*) NOT TOPIC: (child*) NOT TOPIC: (pediatric*) NOTTOPIC: (paediatric*)  Refined By: LANGUAGES: (ENGLISH), timespan 1975-2015  Appendix 4: List of all studies included in review   First author Year Journal 1. Ahn 2010 Am J Hematol 2. Akashi 1994 Br J Haematol 3. Allory 2001 Am J Surg Pathol 4. Arca 2015 Br J Haematol 5. Aulagnon 2015 Am J Kidney Dis 6. Bae 2015 Medicine 7. Beutel 2011 Crit Care 8. Buyse 2010 Intensive Care Med 9. Chandrakasan 2013 Biol Blood Marrow Transplant (abstract) 10. Chandraksan 2013 Blood (ASH abstract) 11. Chang 1994 J Formos Med Assoc 12. Chen  2015 Int J Lab Hem 13. Dalal 2015 Ann Hematol 14. De Kerguenec 2001 Am J Gastroenterol 15. Delavigne 2014 Haematologica Hayden et al. HLH REVIEW   3 16. Dhote 2003 Arthritis Rheum 17. Egues 2015 Reumatol Clin 18. Emmenegger 2001 Am J Hematol 19. Emmenegger 2002 Swiss Med Wkly 20. Falini 1990 Blood 21. Fardet 2008 AIDS 22. Fardet 2010 Arthritis Rheum 23. Florena 2002 Virchows Arch 24. Fukaya 2008 Rheumatology 25. Gratton 2015 J Neurosciences 26. Han 1999 Korean J Intern Med 27. Han 2014 Leuk Lymphoma 28. He  2012 International Med J 29. Ho 2014 Am J Clin Pathol 30. Huasong 2013 J Rheumatol 31. Imashuku 2003 Med Pediatr Onc 32. Ishii 2007 Int J Hematol 33. Jing-Shi 2015 Ann Hematol 34. Kaito 1997 Eur J Haematol 35. Kim 2012 Ann Hematol 36. Kim 2014 J Rheumatol 37. Kojima 2002 Br J Haematol 38. Kumakura 2003 Intern Med 39. Kuriyama 2012 Blood 40. Li 2014 Med Oncol 41. Li 2014 Medicine 42. Majluf-Cruz 1998 Leuk Res 43. Maruoka 2014 Ann Hematol 44. Mazodier 2005 Blood 45. McCall 2012 Am J Clin Pathol 46. Menard 2008 Clin Infect Dis 47. Nair 2012 Postgrad Med J 48. Ohno 2003 Int J Hematol 49. Ohshima 1999 Pathol Int 50. Okamoto 2009 Intern Med Hayden et al. HLH REVIEW   4 51. Otrock 2014 Am J Hematol  52. Otrock 2015 Blood cells Mol Dis 53. Parikh 2014 Ann Hematol 54. Park 2012 Anaesthesia 55. Prendki 2011 Am J Surg Pathol 56. Rajagopala 2012 Indian J Crit Care Med 57. Reiner 1988 Medicine 58. Riviere 2014 Am J Med 59. Ruscitti 2015 Autoimmun Rev 60. Schaer 2005 Eur J Haematol 61. Schram 2015 Blood 62. Shabbir 2011 Hematol Oncol 63. Shimazaki 2001 Intern Med 64. Shin 2008 J Korean Med Sci 65. Shirono 1995 Eur J Haematol 66. Sieni 2012 PLoS ONE 67. Stephan 1997 Clin Infect Dis 68. Takagi 2009 Br J Haematol 69. Takahashi 2001 Int J Hematol 70. Takahashi 2001 Int J Hematol 71. Tseng 2011 J Microbiol Immunol Infect 72. Tsuda 1999 Acta Haematol 73. Tsuji 2014 Ann Hematol 74. Wang 2009 Int J Hematol 75. Wang 2013 Ann Hematol 76. Wang 2014 PLoS ONE 77. Wang  2015 Blood 78. Wong 1992 Am J Med 79. Xie 2013 Ann Hematol 80. Yao 1994 Br J Haematol 81. Yu 2013 Ann Hematol 82. Zhang 2011 Blood  Appendix 5:  Summary of studies with definite or potentially overlapping patients  Hayden et al. HLH REVIEW   5 Country Institution(s) Reference Patients Dates of inclusion Emphasis of study/Key messages China  35 centers in China Wang Y PLoS One 2014 195 adults with HPS, 10 with fHLH.  Jan 2006 – June 2012 Late onset fHLH more common than previously suspected. China Beijing Friendship Hospital Wang Z Int J Hematol 2009 29 patients with reactive HPS Oct 2007 – Oct 2008  Value of glycosylated ferritin in diagnosis of reactive HPS China Beijing Friendship Hospital  Wang Y Ann Hematol 2013 40 patients with reactive HPS Mar 2010 – Dec 2011 Effect of recombinant human thrombopoietin on platelet count in HLH.   China 6 centers in China  Wang Y Blood 2015 59 patients with reactive HPS, 4 with primary HLH June 2013 – June 2014 Prospective treatment trial assessing a salvage regimen of DEP for patients refractory or relapsed after HLH-94 treatment.   France Hôpital St. Louis Hôpital St. Antoine Hôpital de Bicêtre Fardet Arth Rheum 2014 162 patients with reactive HPS  (out of 312 adults  with suspected HPS) Jan 2006-Dec 2011 Construction and Validation of the HScore, a diagnostic model for adult reactive HPS France Hôpital St. Louis Hôpital St. Antoine Hôpital de Bicêtre Riviere Am J Med 2014 162 adults with reactive HPS  (out of 312 adults with suspected HPS) Jan 2006-Dec 2011 General description of adult reactive HPS France Hôpital St. Louis Hôpital St. Antoine Hôpital de Bicêtre Arca Br J Haematol 2014 162 adults with reactive HPS  (out of 312 adults with suspected HPS) Jan 2006-Dec 2011 Prognostic factors in adult reactive HPS France Hôpital St. Louis Hôpital St. Antoine Fardet AIDS 2010 58 adults with reactive HPS Jan 2006-Dec 2007 Description of reactive HPS in HIV positive patients Hayden et al. HLH REVIEW   6 Hôpital de Bicêtre France Hôpital St. Louis Hôpital St. Antoine Hôpital de Bicêtre Fardet Arth Rheum 2008 14 adults with reactive HPS, 7 with suspected HPS, 21 controls Oct 2006-Sep 2007 Value of glycosylated ferritin in diagnosis of reactive HPS France Hôpital St. Louis Buyse Int Care Med 2010 56 adults with HPS in intensive care Jan 1998-Jan 2009 Diagnosis, treatment and outcomes in critically ill patients with HPS France Hôpital St. Louis Aulagnon Am J Kid Dis 2015 95 adults with HPS in intensive care Feb 2007-Jan 2013 59 adults (62%) had acute kidney injury, and of these 27 required renal replacement therapy Switzerland Geneva University Hospital and 10 other Swiss centers Emmeneger Am J Hematol 2001 20 adults with reactive MAS Oct 1993-May 2000 Rapid decrease in ferritin with IVIg therapy Switzerland Geneva University Hospital and 24 other Swiss centers Emmeneger Swiss Med Wkly 2002 57 adults with reactive MAS Oct 1993-Jun 2001 Use of ferritin ≥ 10 000 μg/L and systemic inflammatory response as a screen for HPS U.S. CCHMC* Zhang Blood 2011 175 adults with fHLH out of 1531 patients (adults and children) with HLH referred for genetic testing.  Patients were referred from N. America and tested at CCHMC Unspecified 5 year period before 2011 25 of 175 adults had genetic mutations in PRF1, MUNC13-4, and STXBP2 U.S. CCHMC* Chandrakasan Blood 2013** 19 adolescents and young adults with HLH Jan 2000- Jun 2013 Outcomes in allogeneic hemotopoietic transplantation Hayden et al. HLH REVIEW   7 U.S. CCHMC* Chandrakasan Biol BMT 2013** 10 adults with fHLH Jan 2004-Sep 2012 Genetic mutations in adults with fHLH Japan Akita University Hospital Takahashi Int J Hematol 2001 20 adults with T/NK lymphoma assoc HPS Jan 1990-Dec 1999 Comparison 13 adults who presented with HPS at diagnosis on lymphoma and 7 adults with HPS later in the course of lymphoma treatment Japan Akita University Hospital Takahashi Int J Hematol 2001 52 adults with HPS Jan 1990-Oct 2000 8% survival in LAHS vs 83% survival in other HPS Japan Survey of 292 Institutions in Japan Ishii Int J Hematol 2007 247 adults with HLH 2001-2005 National Survey of Japanese Centers  * Cincinnati Children’s Hospital Medical Center ** abstract only   

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