Best Practice & Research Clinical Rheumatology: Georgia Grif Fin, Susan Shenoi, Grant C. Hughes

Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
Hemophagocytic lymphohistiocytosis: An
update on pathogenesis, diagnosis, and therapy
Georgia Griffin a, *, Susan Shenoi a, 1, Grant C. Hughes b, 2
a
Division of Rheumatology, Seattle Children's Hospital, Seattle, WA, USA
b
Division of Rheumatology, University of Washington, Seattle, WA, USA
a b s t r a c t
Keywords:
Hemophagocytic lymphohistiocytosis (HLH) Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening
Macrophage activation syndrome (MAS) state of immune hyperactivation that arises in the setting of genetic
mutations and infectious, inflammatory, or neoplastic triggers. Sus-
tained, aberrant activation of cytotoxic CD8þ T cells and resultant in-
flammatory cytokine release are core pathogenic mechanisms. Key
clinical features include high persistent fever, hepatosplenomegaly,
blood cytopenia, elevated aminotransferase and ferritin levels, and
coagulopathy. HLH is likely under-recognized, and mortality remains
high, especially in adults; thus, prompt diagnosis and treatment are
essential. Familial forms of HLH are currently treated with chemo-
therapy as a bridge to hematopoietic stem cell transplantation. HLH
occurring in rheumatic disease (macrophage activation syndrome) is
treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other
forms of HLH, addressing the underlying trigger is essential. There re-
mains a pressing need for more sensitive, context-specific diagnostic
tools. Safer, more effective therapies will arise with improved under-
standing of the cellular and molecular mechanisms of HLH.
© 2020 Elsevier Ltd. All rights reserved.
* Corresponding author. University of Washington, School of Medicine, Department of Pediatrics; M/S OC.7.830, PO Box 5371,
Seattle, WA, 98145-5005, USA.
E-mail address: georgia.griffin@seattlechildrens.org (G. Griffin).
1
Susan Shenoi: Seattle Children’s Hospital and Research Center, University of Washington, School of Medicine, Department
of Pediatric Rheumatology; M/S MA.7.110, PO Box 5371, Seattle, WA, 98145-5005; Email: susan.shenoi@seattlechildrens.org
2
Grant C. Hughes: University of Washington, School of Medicine, Division of Rheumatology; 1959 NE Pacific St., Box 356428,
Seattle, WA 98195-6428; Email: hughesg@uw.edu
https://doi.org/10.1016/j.berh.2020.101515
1521-6942/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Griffin G et al., Hemophagocytic lymphohistiocytosis: An update on patho-
genesis, diagnosis, and therapy, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/
j.berh.2020.101515
2 G. Griffin et al. / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Summary and overview
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening immunological syndrome

characterized by the uncontrolled activation of cytotoxic lymphocytes and macrophages, resulting in
cytokine-mediated tissue injury and multiorgan dysfunction. Interferon-gamma (IFN-g), interleukin
(IL)-1b, and IL-18 appear to be key soluble mediators of HLH immunopathology [1e3]. Historically, HLH
has been divided into a primary/familial form (F-HLH) and secondary/sporadic/reactive forms. F-HLH is
a heritable disease conferred by highly penetrant genetic mutations/variations impacting cytolytic
functions, lymphocyte survival, or inflammasome activation. In contrast, secondary HLH is driven
primarily by acquired factors, such as chronic inflammation, infection, or malignancy. When HLH oc-
curs in the context of rheumatological diseases, such as systemic juvenile idiopathic arthritis (sJIA),
adult onset Still's disease (ASD), or systemic lupus erythematosus (SLE), it is often referred to as
macrophage activation syndrome (MAS). It is now known that heterozygous or low-penetrance mu-
tations in F-HLH-associated genes are involved in the pathogenesis of some forms of secondary HLH
and MAS. If untreated, HLH is fatal; so early recognition and prompt treatment is critical for patient
survival. Patients present with rapid clinical deterioration, fever, hepato-splenomegaly, coagulopathy,
hepatic injury, blood cytopenia, hyperferritinemia, and diminished/absent NK cytolytic activity. While
diagnostic criteria for F-HLH are well established, similarly effective criteria for secondary HLH are
being developed based on epidemiological and mechanistic studies [4]. F-HLH patients are treated with
cytotoxic and immunosuppressive agents as a bridge to life-saving hematopoietic stem cell trans-
plantation (HSCT) [5]. MAS is treated with high-dose intravenous (IV), corticosteroids (CS), and tar-
geted IL-1 blockade. In other secondary forms of HLH, identifying and addressing disease triggers
(infection, drugs, and malignancy) is a critical component of therapy. Despite major advances in the last
two decades, mortality in HLH remains unacceptably high, especially in adult forms of the disease.
Thus, there remains a pressing need for improved classification systems, more accurate diagnostic
tools, and more effective, less toxic therapies. These advances will come with improved understanding
of the cellular and molecular bases of HLH. This review article provides an overview of HLH syndromes
with updates on pathogenesis, classification, diagnosis, and therapy.
History and classification systems
History
The first published report of HLH was by Scott and Robb-Smith in 1939 [6] who described four
adults with fever, lymphadenopathy, splenomegaly, and hepatomegaly followed by jaundice, purpura,
anemia, and leukopenia. Post-mortem microscopic examination of tissues revealed numerous histio-
cytes that had engulfed erythrocytes (erythrophagocytosis). The syndrome was thought to be an
atypical form of Hodgkin's disease and was called “histiocyte medullary reticulosis.” In 1952, Farquhar
and Claireaux [7] reported F-HLH in two siblings who within the first of months of life each succumbed
to a syndrome of fever, hepatosplenomegaly, cytopenia, and proliferation of erythrophagocytic his-
tiocytes in solid organs. Secondary HLH was first described in 1979 by Risdall et al., who proposed that
viral infections in immunocompromised hosts induced immune dysregulation and features of HLH [8].
In 1985, Hadchouel et al. [9] coined the term MAS to describe patients with sJIA who became acutely ill
with a life-threatening hyperinflammatory syndrome.
Classification systems
HLH constitutes one group in a family of conditions that includes the histiocytoses and neoplasms of
macrophage-dendritic lineage cells [10]. As mentioned above, HLH historically has been classified into
F-HLH and secondary/sporadic/reactive forms. However, this classification system fails to inform the
prognosis and therapy of secondary HLH, which, as will be discussed, has many different causes. For
this and other reasons,-the North American Consortium for Histiocytosis (NACHO) recommends a new
j.berh.2020.101515
G. Griffin et al. / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx 3
classification system, which includes all syndromes that meet consensus diagnostic criteria (discussed
below), but designates those likely benefiting from HLH-directed immunosuppressive therapies as
“HLH disease” and those unlikely to benefit from these therapies (or require entirely different thera-
peutic strategies) as “HLH mimics” [4]. In this construct, HLH disease is further broken down into
clinically recognizable categories with potential for overlap between HLH disease and HLH mimics: F-
HLH, HLH associated with malignancy (M-HLH), HLH associated with rheumatic conditions (Rh-HLH,
also called MAS), HLH occurring after certain immune-activating therapies or with drug hypersensi-
tivity (Rx-HLH), HLH occurring with immune compromise, either primary or acquired (IC-HLH), and
HLH not associated with other specific conditions (HLH-NOS). In addition, NACHO recognizes syn-
dromes that resemble HLH but do not meet classification criteria, i.e., mild HLH/MAS or forme fruste
HLH. This new construct, rooted in human biology, provides a helpful framework for understanding
pathogenesis, diagnosis, and therapy. With some exceptions, we will use this framework throughout
the article.
Pathogenesis
Overview
The cellular and molecular mechanisms underlying HLH are incompletely understood. HLH is not
one disease, but rather a distinct state of sustained immune system activation that may be engaged
through a number of different pathways, depending on an individual's predispositions and environ-
mental triggers. Three major observations can be distilled from decades of clinical observation, genetic
analysis, and basic science research [4]: 1) Disease in HLH is driven primarily by the aberrant immune
response, not underlying triggers; 2) immune responses in HLH do not appear to target self-antigens,
as seen in autoimmune diseases; and 3) uncontrolled activation of T cells (especially CD8þ cytotoxic T
cells), not macrophages, is the root abnormality in most forms of HLH. Genetic susceptibility to HLH
clusters around genes whose products are involved in cell-mediated cytotoxicity and lymphocyte
activation/survival. Immunosuppression and chronic inflammation also predispose to HLH; in these
settings, HLH is often triggered by infection, most often viruses, but also other intracellular pathogens.
Certain hematological malignancies and cancer-related therapies may trigger and drive HLH in the
absence of identifiable genetic or infectious factors. Clinical and laboratory features of HLH reflect
tissue infiltration by activated immune cells (especially T cells, macrophages, and neutrophils) and the
local and systemic effects of inflammatory cytokines such as IFN-g, tumor necrosis factor (TNF)-a, IL-
1b, IL-6, IL-10, and IL-18 (2, 3). Perpetuation of HLH immunopathology appears to involve feed-forward
amplification loops whereby activated CD8þ T cells and macrophages stimulate each other in a so-
called “cytokine storm.” Key pathogenic factors and a proposed mechanistic model are shown in Fig. 1.
Lessons from familial HLH
F-HLH is subclassified based on the underlying genetic mutation (Table 1). Identified causative mu-
tations in F-HLH result in impaired CD8þ T cell and NK cell cytotoxicity or altered lymphocyte activation
and survival [11]. Around 70% of F-HLH is caused by the loss of function mutations in PRF1, the gene
encoding perforin, a key cargo of cytolytic vesicles, or in UNC13D, encoding Munc13-4, which is critical for
the release of cytolytic vesicles from T and NK cells [12]. Mutations in other genes involved in cytolysis,
such as STX11 and STXP2, are associated with F-HLH as well [13]. Cytolytic dysfunction caused by
abnormal granule exocytosis causes certain primary immunodeficiency (PID) syndromes associated with
HLH, such as Che diak-Higashi syndrome (CHS), Griscelli syndrome type 2 (GS2), and Hermansky-Pudlak
syndrome type 2 (HPS2). These genetic mutations are highly penetrant, and in F-HLH types 1e5, disease
develops within the first year of life [2]. Because F-HLH manifests shortly after birth (usually in the first
few weeks to months), and varies between siblings with identical mutations, it is thought that an
j.berh.2020.101515
infectious trigger is required for disease expression, even though an infectious trigger is usually not
identified. Interestingly, F-HLH may develop in utero [14], suggesting HLH-related mutations may be
important in maintaining immune homeostasis in the absence of infection (see Table 2).
In 2004, Jordan et al. reported [15] on mice deficient in perforin that developed a syndrome similar
to human HLH when infected with lymphocytic choriomeningitis virus (LCMV), a model for F-HLH 2. In
this model, CD8þ T cells (but not NK cells) and IFN-g were essential for disease expression. A similar
phenotype is observed in LCMV-infected Unc13d-mutant mice, a model for F-HLH 3 [16]. Subsequent
studies with these models established critical roles for Toll-like receptor (TLR)/IL-1R signaling adapter
molecules [17] as well as IL-33, a molecule released by damaged cells [18]. These studies helped form
the basis of a working model of F-HLH, wherein the context of viral infection and tissue inflammation/
damage, CD8þ T cells and macrophages provide mutual stimulation, driving an amplification loop of
inflammatory cytokine production (Fig. 1). In this virus-dependent model, CD8þ T cells (and perhaps
NK cells), unable to kill target cells owing to defective cytolysis, are subject to sustained cell-cell
contact, antigen presentation, and stimulation [19]. Moreover, excessive CD8þ T cell stimulation in F-
HLH appears to involve their reduced susceptibility to activation-induced apoptosis in addition to their
inability to kill antigen-presenting dendritic cells [3] (Fig. 1, amplification loop #1). Sustained activation
of CD8þ T cells results in the release of large amounts of IFN-g, a potent activator of macrophages. In
response, macrophages produce high levels of IL-1b, IL-6, IL-18, and TNF-a, which may account for
many clinical features of HLH [20]. TNF-a induces further macrophage activation in an autocrine and
paracrine manner [3]. Subsequent tissue injury, through the release of IL-33 and IL-1b, may contribute
to additional macrophage activation, worsening HLH disease [3,18]. Many of these inflammatory cy-
tokines are also produced by monocytes, neutrophils, and non-hematopoietic cells such as epithelial
cells [3]. Indeed, recent observations [21] in models of familial and secondary HLH indicate an
important role for neutrophil activation in end-organ damage. IL-18, in conjunction with IL-12, is
believed to drive the further activation of CD8þ T cells and their production of IFN-g (Fig. 1, amplifi-
cation loop #2) [22,23]. In addition, IFN-g upregulates the major histocompatibility complex (MHC) I
protein expression on infected cells, further enhancing amplification loop #1 (Fig. 1). This interde-
pendent activation of T cells and macrophages in HLH is strongly supported by kinetic analysis of the
soluble IL-2 receptor (sIL-2R), a T cell activation marker, and soluble hemoglobin-haptoglobin scav-
enger receptor (CD163), a macrophage activation marker that rises and falls together [24]. It is unclear
if these amplification loops occur systemically or primarily in virally infected tissues, where antigen-
presenting cells, CD8þ T cells, and macrophages are found in close proximity. Together, these obser-
vations have generated interest in IFN-g, IL-1b, IL-33, and IL-18 as therapeutic targets in HLH. Finally, it
appears that IFN-g is not required for the development of HLH, as indicated by HLH in individuals with
genetic IFN-g receptor deficiency [25].
In all forms of HLH, inflammatory cytokines appear to mediate key clinical features, and higher
cytokine levels are associated with poorer prognosis [2]. IFN-g contributes to fever, lymphadenopathy
(e.g., through sequestration of lymphocytes in lymphoid tissues), and cytopenia (through sequestration
and myelosuppression). Mouse models of HLH suggest that anemia is driven by IFN-g through the
suppression of erythropoiesis and stimulation of hemophagocytosis [3,26]. A larger pathogenic role for
hemophagocytosis in HLH disease has not been established. Data from other mouse models suggest
that IFN-g production also mediates weight loss, splenomegaly, hyperferritinemia, cytopenia, and liver
inflammation [27]. Ferritin released by activated macrophages increases plasminogen activator,
resulting in enhanced lysis of fibrinogen/hypofibrinogenemia [28,29]. IL-1b, TNF-a, and IL-6 are
believed to play important roles in key clinical features of HLH, such as fever, endothelial activation,
disseminated intravascular coagulation (DIC), and organ dysfunction.
Rheumatic-HLH
Susceptibility to HLH in chronic rheumatic diseases appears to involve a combination of inherited

genetic factors, chronic inflammation, and immunosuppression [1]. Strikingly, heterozygous mutations
in F-HLH associated genes occur in up to 40% of sJIA patients who develop MAS (sJIA-MAS/HLH)
[3,30,31]. These mutations, through the subtle impairment of cytolytic functions, may lower the
threshold for HLH disease, particularly in the setting of chronic inflammation, tissue damage, and/or
j.berh.2020.101515
Fig. 1. HLH pathogenesis: HLH is not one disease but rather a highly distinct state of immunological hyperactivation that has many
different causes. A sustained and uncontrolled activation of CD8þ T cells is a core immunological feature of HLH; and in most forms
of HLH, this activation is sustained by amplification loops involving antigen-presenting cells (APCs) and macrophages/monocytes.
Depending on the individual, the development of HLH involves genetic and/or acquired risk factors. In familial HLH (F-HLH), genetic
defects in cytolysis are the primary determinants of risk. In HLH associated with systemic juvenile idiopathic arthritis (sJIA), risk is
determined by genetic and acquired factors, particularly chronic inflammation. In adults, HLH most often occurs in the settings of
untreated hematological malignancy, chronic rheumatic disease, or immunosuppression. In many patients with HLH, a proximate
inciting event or agent (trigger) is identified, most often an infection (particularly viral), occult hematological malignancy (partic-
ularly T or NK lymphoma), recent/ongoing immune-activating therapy (e.g., CAR-T therapy), or certain drugs associated with drug-
induced hypersensitivity syndromes (DIHS). In F-HLH and certain forms of HLH associated with primary EBV infection, genetic
defects in the killing of virally infected cells (e.g., PERF1 deficiency) results in sustained antigen presentation to, and activation of,
CD8þ T cells, which is amplified by IFN-g release and subsequent MHC-I upregulation (Loop #1). Sustained IFN-g release from
activated CD8þ T cells is believed to drive the activation of tissue macrophages/monocytes, which results in the release of in-
flammatory mediators such as IL-1b, IL-6, IL-18, and IL-12. IL-18 and IL-12 may serve to enhance IFN-g production by CD8þ T cells
(Loop #2). Macrophages/monocytes are further activated by chronic inflammation, tissue injury (through Il-1b and IL-33), and TLR
stimulation from infection. In malignancy-associated HLH, transformed cells may drive HLH through autonomous cytokine release
and/or sustained presentation of EBV antigen. HLH after CAR-T therapy likely reflects exuberant activation of therapeutic CD8þ CAR-
T cells. In HLH associated with DIHS, drug-MHC-I complexes may drive CD8þ T cell hyperactivation. Important clinical and laboratory
abnormalities appear to be driven by macrophage/monocyte- and T-cell-derived molecules, several of which serve as important
disease biomarkers (*). Abbreviations: ASD, adult onset Stills disease; CAR-T, chimeric antigen receptor T cell; CHS, Che diak-Higashi
syndrome; DIHS, drug-induced hypersensitivity syndrome; EBV, Epstein-Barr virus; ICI, immune checkpoint inhibitor; MHC-I, major
histocompatibility complex I; PERF-1, perforin-1; sIL-2 R, soluble Il-2 receptor; sJIA, systemic juvenile idiopathic arthritis; TCR, T cell
antigen receptor; TLR, toll-like receptor; XLP1, and X-linked lymphoproliferative disorder type 1.
infection. In sJIA, cytolysis is suppressed when it is associated with disease activity, perhaps through
direct effects of IL-6 on cytotoxic lymphocytes [32]. Chronic stimulation of TLR 9, along with increased
IL-1b and IL-18 signaling, may play important roles in the development of HLH in sJIA, SLE, and with
Epstein-Barr virus (EBV) infection [3,33]. The importance of IL-1b and IL-18 in HLH is illustrated by the
discovery of the NLRC4 gain-of-function mutations in F-HLH [34] (Table 1). In sJIA-MAS/HLH, endog-
enous anti-inflammatory molecules IL-1 receptor antagonist (IL-1RA), IL-18 binding protein (IL-18BP),
and IL-10 are upregulated, but not enough to control and/or break the amplification loops described
above [1e3]. However, treatment with high levels of recombinant IL-18BP, especially in conjunction
with IL-1 blockade, may be effective in sJIA-MAS/HLH [35,36]. While TNF-a and IL-6 are important
drivers of sJIA and are involved in the cytokine storm of sJIA-MAS/HLH [37], targeted blockade of TNF-a
[38] or IL-6 [1,39,40] does not appear to prevent or consistently ameliorate MAS disease. Indeed, MAS
may develop in children with sJIA shortly after starting targeted blockers of IL-6, IL-1b, or TNF-a [41],
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Table 1
Genetic causes of HLH.
HLH type/association Gene or locus (protein) HLH-related dysfunction Unique clinical features
Familial HLH [13]

Type 1 (F-HLH 1) 9q21.3-q22 (unknown) Unknown N/A
Type 2 (F-HLH 2) PRF1 (perforin) Cytolytic pore formation None
Type 3 (F-HLH 3) UNC13D (Unc-13 homolog Cytolytic vesicle priming Increased incidence of CNS
D) disease
Type 4 (F-HLH 4) STX11 (Syntaxin 11) Cytolytic vesicle fusion Mild, recurrent HLH, colitis
Type 5 (F-HLH 5) STXBP2 (Syntaxin binding Cytolytic vesicle fusion Colitis;
protein 2) hypogammaglobulinemia, and
sensorineural hearing loss
Primary Immunodeficiency Syndromes [13]
diak-Higashi syndrome
Che LYST (Lysosomal trafficking Cytolytic vesicle trafficking Partial oculocutaneous
regulator) albinism, recurrent pyogenic
infections, and bleeding
tendency
Hermansky-Pudlak AP3B1 (Adaptor Related Cytolytic vesicle trafficking Partial albinism;
syndrome type 2 Protein Complex 3 Subunit immunodeficiency, bleeding
Beta 1) tendency, and platelet storage
pool deficiency
Griscelli syndrome type 2 RAB27A (Rab-27A protein) Cytolytic vesicle docking Partial albinism and silvery grey
hair
EBV-triggered [49]
X-linked SH2D1A (SH2 Domain Defective killing of EBV- Severe HLH;
lymphoproliferative Containing 1A) infected B cells Hypogammaglobulinemia, and
disorder type 1 (XLP1) lymphoma
X-linked XIAP (X-linked inhibitor of Increased inhibition of Mild, recurrent HLH (may be
lymphoproliferative apoptosis protein) apoptosis in EBV-infected triggered by non-EBV viruses)
disorder type 2 (XLP2) cells (gain of function)
IL-2-inducible T cell kinase ITK (IL2 inducible T cell Impaired proliferation of Hodgkin lymphoma
deficiency kinase) EBV-specific T cells
CD27 deficiency CD27 Impaired proliferation of Combined immunodeficiency
EBV-specific T cells
X-linked MAGT1 (Magnesium Impaired proliferation of Combined immunodeficiency,
immunodeficiency with transporter 1) EBV-specific T cells chronic viral infections, and
magnesium defect lymphoma
(XMEM)
Inflammasome activation [34,105]
Autoinflammatory disease NLRC4 (NLR Family CARD Increased inflammasome Mild and recurrent HLH
Domain Containing 4) activation (gain of function)
Abbreviations: CNS, central nervous system; EBV, Epstein-Barr virus.
suggesting that sudden changes to inflammatory milieu, not just inflammation itself, is an important
factor in disease development. The role of IFN-g in sJIA-MAS/HLH pathogenesis is not as clear as it is for
F-HLH. Some studies have found significant elevations of IFN-g, whereas others have not [42e45]. In
this latter group, macrophage activation may rely on TLR stimulation, or IFN-g production may be
limited to certain tissues or undetectable in plasma due to its short half-life (46).
Immune compromise, infection, and HLH
IC-HLH occurs in patients with PID syndromes and those with acquired immune compromise. PID
syndromes strongly associated with HLH are listed in Table 1. HLH may also occur with severe com-
bined immunodeficiency, chronic granulomatous disease, Wiskott-Aldrich syndrome, DiGeorge syn-
drome, X-linked agammaglobulinemia, and autoimmune lymphoproliferative syndrome (4). The
association between PID and HLH appears to reflect both host susceptibility to triggering infections and
abnormal immune responses to the pathogen. For example, children with CHS, HPS2, or GS2 are
susceptible to a wide range of pathogens, but HLH is likely triggered by defective cytolysis in the face of
viral infections, similar to F-HLH [2]. Accordingly, HLH in these children often follows a severe and
refractory course, as is seen in children with F-HLH [4].
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Table 2
Categorization of HLH [4].
G. Griffin et al. / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Familial-HLH (F-HLH) Rheumatological HLH with immune HLH with malignancy (M-HLH) Iatrogenic HLH (Rx-HLH)
HLH (Rh-HLH) compromise (IC-HLH)
Demographics Children < 1 year - Children: sJIA*, - Immunosuppressed - Older adults (most common) Children or adults treated with
KD, SLE children or adults - Children (rare) - CAR-T therapy
- Adults: ASD*, SLE - Children with - ICI therapy
select PID syndromes - drugs assoc. with DIHS
*High risk (see Table 1)
Susceptibility Genetic defects in Chronic inflammation - Immunosuppression Hematologic malignancy (esp. Specific HLA-A or HLA-B alleles (DIHS only)
cytotoxicity (esp. IL-18) - Defective T, NK lymphoma)
cytotoxicity (genetic
or acquired)
Triggers Viral infection Unknown Infection with viruses Hematologic malignancy (esp. Exposure to drug/therapy
(presumed) (TLR stimulation?) (esp. EBV and CMV), T, NK lymphoma)
M. tuberculosis, fungi,
parasites
Unique clinical or - Prominent CNS - Falling WBC and/or Children with PID: Smoldering or chronic HLH-like - DIHS: prominent rash, eosinophilia
laboratory features involvement platelet counts partial albinism, disease - CAR-T: HLH occurs in setting of CRS
- Severe/fulminant - Transformation of recurrent infections,
disease quotidian to bleeding
- Family history persistent fever
- Consanguinity
Specific diagnostic HLH-2004 H-score H-score None None
tools MS score (sJIA)
Abbreviations: ASD, adult Still's disease; CAR-T, chimeric antigen receptor T cell; CMV, cytomegalovirus; CRS, cytokine-release syndrome; DIHS, drug-induced hypersensitivity syndrome;
EBV, Epstein-Barr virus; HLA, human leukocyte antigen; ICI, immune checkpoint inhibitor; Kawasaki disease; PID, primary immunodeficiency; sJIA, systemic juvenile idiopathic arthritis;
SLE, systemic lupus erythematosus; TLR, toll-like receptor.
7
HLH also occurs in adults undergoing chemotherapy for cancer or immunosuppressive therapy for
inflammatory disease such as inflammatory bowel disease [4]. Aside from increased susceptibility to
triggering infections, the pathogenesis of HLH in this setting is poorly understood. However, it is
believed that drug-induced suppression of cytolytic activity plays an important role. Consistent with
this idea, the majority of identified infections triggering IC-HLH are intracellular pathogens, especially
viruses. In adults, viral infection (primary or reactivation in the setting of immunosuppression) is the
most common identified trigger of IC-HLH; herpes viruses, EBV and cytomegalovirus (CMV), are the
most commonly identified viral pathogens, but other viruses such as disseminated adenovirus, herpes
simplex virus (HSV), respiratory syncytial virus, rotavirus, parvovirus B19, and influenza have been
reported [47]. Chronic viral infections such as human immunodeficiency virus (HIV) and hepatitis virus
(B or C) can trigger HLH during the acute or chronic phase of infection. In HIV, some of these cases may
be triggered by opportunistic infections, neoplasms, or initiation of antiretroviral therapy [47]. Un-
commonly, HLH can be triggered by bacterial, parasitic, and fungal triggers; intracellular pathogens
such as Mycobacterium tuberculosis, Pneumocystis jiroveci, and Plasmodium species are most widely
reported [2,47]. Together, these observations suggest that the inability to suppress or clear intracellular
infections contributes to the development of HLH, perhaps through persistent antigenic stimulation of
T cells.
EBV is the most commonly identified infectious trigger of HLH. HLH driven by primary EBV infection
(EBV-HLH) occurs mostly in children and adolescents [48], often in the context of F-HLH and PID [49];
in adults, HLH is more often triggered by EBV reactivation in the setting of immune compromise [47]. A
unifying process in EBV-HLH appears to be the failure to control viral replication in B cells [48,49]. This
is most clearly illustrated by HLH occurring in children and adolescents with genetically determined
selective vulnerability to severe primary EBV infection (Table 1). Children with X-linked lymphopro-
liferative disorders type 1 or 2 (XLP1 and XLP2) frequently develop HLH with primary EBV infection,
which appears to reflect the inability of CD8þ T cells and NK cells to kill EBV-infected B cells (XLP1), or
the resistance of infected B cells to cytolysis (XLP2). Other genetic susceptibility to EBV-HLH involves
the impaired expansion (but not stimulation) of EBV-specific T cell clones. In all of these scenarios,
uncontrolled viral replication and sustained antigenic stimulation of T cells appear to drive HLH [49]. In
industrialized countries, where primary EBV infection is delayed, genetically susceptible individuals
may not develop HLH until adolescence. Interestingly, mouse models of Rh-HLH suggest that unbridled
EBV replication may help drive HLH disease through sustained activation of TLR9 by viral DNA [1,33].
These mechanisms may also be involved in HLH driven by EBV-associated hematological malignancies
and EBV reactivation with immunosuppression. Because defective killing of EBV-infected B cells ap-
pears to drive EBV-HLH, B cell depleting therapies (e.g., rituximab) may be particularly effective.
Malignancy-associated HLH
Malignancy plays a causative role in approximately half of all adult HLH; and HLH may complicate
up to 1% of malignancies occurring in adults [47,50]. Hematological malignancy, particularly T, NK, and
B-cell lymphoma, account for most cases of M-HLH. M-HLH may occur before cancer treatment or
during therapy, likely due to immunosuppression and associated infections [50,51]. One possible
explanation is that unregulated production of IFN-g and TNF-a by transformed cells, particularly in the
presence of malignancy-associated EBV replication, drives HLH disease or that it markedly lowers the
threshold of disease after infection.
Therapy-induced HLH
Rx-HLH is reported to occur in settings of immune-activating therapies for cancer and with certain
drugs associated with drug-induced hypersensitivity syndrome (DIHS). Like other forms of HLH, Rx-
HLH is believed to be driven by the aberrant and sustained activation of CD8þ T cells. Immune
checkpoint inhibitor (ICI) therapies exert their therapeutic effects by activating and inducing anti-
tumor CD8þ T cell responses (see Immunologic adverse events from immune checkpoint therapy, this
edition. Immunologic adverse events from immune checkpoint therapy Immune Checkpoint chapter of
this edition). Off-target CD8þ T cell activation appears to play important roles in commonly reported
j.berh.2020.101515
immune-related adverse events and rarer inflammatory syndromes resembling HLH [52]. Genetically
engineered autologous CD8þ cytotoxic T cells expressing chimeric antigen receptors (CAR-T) are a
highly effective approach for treating patients with hematological and solid malignancies. However,
CAR-T therapy is frequently complicated by the cytokine release syndrome (CRS), which can evolve into
HLH [53]. Finally, HLH occasionally occurs in the setting of DIHS [54,55], which appears to involve
hyperstimulation of CD8þ T cells and highly specific molecular interactions between the offending drug
and human leukocyte antigen (HLA) proteins encoded by DIHS-associated risk alleles (e.g., lamotrigine
and HLA-B*1502).
Epidemiology of HLH
HLH is a rare but likely under-recognized syndrome that occurs in both children and adults. It is
estimated that up to 1 in 3000 cases admitted to tertiary pediatric hospitals could have HLH [56]. HLH
is associated with high mortality rates in children (8e22%) and adults (~40%) [47,57,58]. A retrospective
study estimated the cross-sectional prevalence of HLH in Texas to be 1 in 100,000 children, with a 1:1
male: female ratio [59]. The incidence and prevalence of HLH in adults is unclear, but a recent review of
775 cases indicated a mean age of onset of 49 years and a 1.7:1 male: female predominance [47].
F-HLH
Up to 25% of reported cases of HLH are F-HLH, which typically presents in children under one year of
age. Prevalence and incidence vary by geographic region with increased rates in populations with
higher rates of consanguinity [60]. The Swedish national registry reports the incidence of F-HLH to be
up to 0.15 per 100,000 children/year [61]. HLH is estimated to occur in the neonatal period at a rate of 1
in 50,000 to 150,000 births [62]. Ethnic variations in causative mutations have also been reported, with
47% of white F-HLH patients having mutations in UNC13D, 22% in STXBP2, and 20% in PRF1. In contrast,
Hispanics and blacks were more likely to have PRF1 mutations (71% and 98%, respectively), versus
Arabs, who had a 36% PRF1 mutation rate [56].
Non familial HLH
In contrast, nonfamilial or sporadic F-HLH usually presents in children >1 year and in adults; it is
often associated with an identifiable predisposition and/or trigger. Adults with HLH are most likely to
have an underlying hematological malignancy or infection [47,51]. In children and young adults, EBV is by
far the most commonly identified trigger, followed by CMV [63]. EBV-HLH is particularly prevalent in
Japan, with 40% of all HLH cases having associated EBV infection, according to a nationwide survey [64].
Bacterial infections are reported in 9% of adult HLH cases, including M. tuberculosis (accounting for 38% of
bacterial HLH cases) and less commonly Ehrlichia, Bartonella, and Brucella [4,47,61]. Parasites (e.g.,
Leishmania, Plasmodium, and Toxoplasma) and fungi (Histoplasma) are less frequently identified triggers.
Rh-HLH
HLH occurs in approximately 10% of children with sJIA (sJIA-MAS/HLH) [58] with subclinical or
partial presentations in 30e40% of children [65]. An international multicenter study of 362 patients
with sJIA-MAS/HLH found that 22% of patients had HLH at the onset of sJIA. The median time between
onset of sJIA and HLH was approximately 4 months, strongly supporting the idea that HLH occurs in
earlier stages of sJIA. In approximately half of these individuals, HLH occurred in the context of active
sJIA without an identified trigger; infection was identified as a trigger in one third, and drugs in <4%
[58].
In other rheumatic diseases, HLH is seen with following frequencies: up to 20% in ASD [66],
0.9e4.6% in SLE [67], and 1.1e1.9% of Kawasaki disease (KD) [68,69]. Estimates for other rheumatic
diseases including juvenile dermatomyositis, rheumatoid arthritis, ankylosing spondylitis, mixed
€gren's syndrome, and periodic fever syndromes are
connective tissue disease, vasculitis, sarcoidosis, Sjo
not known [70,71].
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M-HLH
Lymphoma is the most common malignancy associated with HLH, and this contributes to the
relatively older mean age of M-HLH and adult HLH in general. A systematic review of M-HLH found the
most common tumor types triggering HLH to be hematological neoplasms (93.7%), with T- or NK-cell
lymphoma or leukemia (35.2%), followed by B-cell lymphoma (31.8%), other nonspecified hemato-
logical neoplasms (14.4%), other leukemias (6.4%), and Hodgkin's lymphoma (5.8%) [47].
Clinical and laboratory features
Clinical features
Early recognition of HLH is critical, because patients can decompensate rapidly and progress to
multiorgan failure and death. HLH usually presents with high, persistent fevers, organomegaly,
lymphadenopathy, central nervous system dysfunction, liver dysfunction, and coagulopathy. Patients
may present insidiously or with rapid-onset critical illness that progresses to a shock-like clinical
scenario [2,47,72]. High, persistent fever is a near universal feature of HLH and is often a presenting
sign. In patients with sJIA or ASD, transformation of the typical quotidian fever to an unremitting fever
can signal onset of HLH. Splenomegaly is present in most patients, and hepatomegaly is expected in
children with HLH [2]. While lymphadenopathy may be seen in HLH, extensive or bulky lymphade-
nopathy should clue the physician as to the possibility of underlying lymphoma. Liver injury and
dysfunction is common, which with severe disease is associated with coagulopathy (hemorrhage,
petechiae, ecchymosis, purpura, and DIC). Coagulopathy in HLH likely reflects the combined effects of
hepatic synthetic dysfunction, endothelial activation, and DIC. In the sickest patients, involvement of
the lungs, heart, and kidney occurs [47,58]. Nonspecific gastrointestinal symptoms are common,
including diarrhea, nausea, vomiting, jaundice, and abdominal pain. Rarely, gastrointestinal hemor-
rhage and pancreatitis are observed [47]. Central nervous system (CNS) involvement appears to be
more common in pediatric HLH (especially F-HLH); it is seen in about one quarter to one third of cases
and can present as seizures, meningismus, cranial nerve involvement, ataxia, dysarthria, lethargy, and
encephalopathy [2,47,73]. Posterior reversible encephalopathy syndrome (PRES) may complicate HLH,
particularly F-HLH [74]. Cardiopulmonary involvement can lead to hypotension and respiratory failure
requiring vasopressor and ventilator support, respectively. Similarly, renal involvement may be severe
enough to require hemodialysis.
Laboratory features
Most patients with HLH present with or develop a combination of blood cytopenia, evidence of
hepatocellular injury, coagulopathy, and in severe cases, biochemical evidence of organ failure. It is
important to recognize the full spectrum of abnormalities, because some appear earlier in the disease
than others, and none alone is specific to the diagnosis of HLH. Combinations of leukopenia (including
neutropenia), anemia, and thrombocytopenia are extremely common in children presenting with HLH,
but may be less pronounced in adults (2). In patients with sJIA or ASD, falling leukocyte and/or platelet
counts through the normal range can herald impending HLH. Because HLH is driven by the effects of
inflammatory cytokines, high C-reactive protein (CRP) levels are usually observed. Early on, this is
accompanied by elevated erythrocyte sedimentation rates (ESR), but as disease progresses and
fibrinogen is consumed, ESR levels fall. Elevated (liver) aminotransferase levels can appear early and
often track with disease activity. Hepatic injury is thought to be driven in part by periportal lym-
phocytic infiltration [75]. Coagulation abnormalities including hypofibrinogenemia, elevated D-dimer
and prolonged prothrombin and partial thromboplastin time are seen as disease progresses. Other
important laboratory abnormalities include hypertriglyceridemia and marked hyperferrritinemia,
often 10e100 times the upper limit of normal (discussed in more detail below). With CNS involvement,
cerebrospinal fluid analysis demonstrates pleocytosis and elevated protein levels. MRI findings include
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wide areas of increased T2-weighted signal, with symmetric periventricular white matter hyper-
intensity, meningeal enhancement, diffusion restriction; necrosis is seen in advanced disease [4].
HLH derives its name from the observation of hemophagocytic macrophages (with benign
morphology) on the biopsy of bone marrow, lymph nodes, liver, or spleen. However, depending on the
tissue, hemophagocytic macrophages are demonstrated in only 43e95% of biopsies in patients fulfilling
HLH diagnostic criteria [2]. Minoia et al. [58] reported that of 362 children with sJIA-MAS/HLH un-
dergoing bone marrow biopsy, only 60% had the evidence of hemophagocytosis. Furthermore, tissue
hemophagocytosis is commonly observed in the absence of HLH, e.g., with infections, blood trans-
fusions, autoimmune disease, and bone marrow failure [76]. Thus, the presence of tissue hemophago-
cytosis is neither necessary nor sufficient for diagnosing of HLH.
Consistent with the current model of immunopathology (Fig. 1), HLH is almost always associated
with high blood levels of sIL-2R (a.k.a. sCD25), a marker of T cell activation [1,2]. sCD163 is also elevated
and parallels sIL-2R levels [24]. Reduced cytotoxic CD8þ T cell and NK cell activity is frequently re-
ported, which, depending on the form of HLH, can reflect genetic deficiency or the effects of inflam-
mation and immunosuppression [41,47,77]. However, because assays for these biomarkers are not
available at most medical centers, their utility in real-time diagnosis and monitoring remains limited.
Hyperferritinemia, often pronounced, is observed in essentially all cases of pediatric HLH and the
vast majority of cases of adult-onset HLH [1,2,4]. Depending on the cutoff value used, hyperferritinemia
has good negative predictive value [78]. Very high ferritin levels (e.g., greater than 100 x upper limit of
normal) may be highly specific in pediatric HLH (esp. sJIA-MAS/HLH), but in adults this finding has
relatively low specificity. Ferritin levels above 10,000 ng/mL have been reported in nonHLH patients
with hematological malignancy, ASD, infection, and hepatocellular injury [79]. Low percentages of
ferritin glycosylation (which indicates macrophage origin) may be a unique finding of HLH, but this
assay is not available in most medical centers [80]. If neither ferritin nor sIL-2R is elevated (key in-
dicators of macrophage and T cell activation, respectively), the diagnosis of HLH should be called into
question [4].
Unique clinical and laboratory features
Certain clinical and laboratory features provide important clues as to the underlying drivers of HLH
for individual patients. In adults, partial or mild HLH with a smoldering course often indicates an
underlying occult malignancy [51]. Moreover, patients with occult lymphoma have particularly high
levels of sIL-2R, disproportionate to ferritin elevation [81]. Other features and presentations are unique
to the underlying genetic defect or disease. For example, patients with STXBP2 mutations (Table 1)
have hypogammaglobulinemia, severe diarrhea, bleeding, and sensorineural hearing loss [82]. GS2
patients have partial albinism and silvery grey hair. CHS patients have light-colored eyes and hair,
hypopigmented skin, and a history of frequent pyogenic infections. Children with HPS2 can have
oculocutaneous albinism with a platelet storage pool deficiency. HLH in children accompanied by the
presence of severe or unusual or atypical infection should provide a clue as to an undiagnosed un-
derlying PID syndrome.
SJIA or ASD can have the typical salmon pink evanescent macular erythematous rash that then
evolves to a more fixed or erythroderma like rash with onset of HLH. Recently, sJIA has been associated
with a newly recognized form of lung disease [83,84]. Characteristic findings include diffuse ground-
glass opacities, septal thickening, lymphadenopathy on chest CT, and lymphoplasmacytic infiltrates
with pulmonary alveolar proteinosis and endogenous lipoid pneumonia on histopathology. Risk factors
for developing this type of lung disease include Trisomy 21, young age of sJIA onset, history of
anaphylactic reactions to the IL-6 inhibitor, tocilizumab, higher IL-18 levels, and more frequent epi-
sodes of MAS. Interestingly, De Jesus A. et al. described a cohort of undifferentiated systemic auto-
inflammatory diseases with elevated interferon signaling (n ¼ 36/66) and identified a subset of 8
patients with elevated IL-18 levels, clubbing, pulmonary alveolar proteinosis, and recurrent MAS that
they categorized as a distinct previously unrecognized disease called IL-18 associated PAP and MAS
syndrome [85].
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Diagnosing HLH
One of the main obstacles clinicians face in diagnosing HLH is awareness. As mentioned above,
pediatric HLH is probably under-recognized. Moreover, certain forms of adult HLH can smolder for
weeks before accelerating to a full-blown disease. Even when HLH is suspected, diagnosis remains a
challenge because there are no pathognomonic, clinical, laboratory, or histopathological findings, and
current diagnostic tools lack sufficient sensitivity to be relied upon in the clinical setting, especially in
early disease.
HLH diagnostic criteria (i.e., HLH 94 and HLH 2004) were developed to recognize children with F-
HLH for inclusion into clinical trials. For the lack of better tools, clinicians have relied on these criteria
for diagnosing other forms of HLH. According to the updated HLH 2004 criteria, diagnosis of F-HLH
requires five of the following eight features [1]: fever [2], splenomegaly [3] cytopenias affecting 2 of
3 cell lineages (hemoglobin <9 g/dL or <10 g/dL in infants younger than 4 weeks; platelets <100 103/
mcL; and neutrophils <1 103/mcL) [4], hypertriglyceridemia and/or hypofibrinogenemia (fasting
triglyceride 3 mmol/L; fibrinogen (1.5 g/L) [5], hemophagocytosis [6], hyperferritinemia (500
mcg/L) [7], high sIL-2R levels (2400 U/mL), and [8] low/absent NK cell activity [86]. Alternatively,
diagnosis can be made based on genetic testing; however, these results are not expedient or imme-
diately available [86]. While the HLH 2004 criteria remain the most widely used to define and diagnose
HLH, they have some limitations, particularly for HLH in adult patients with early disease. Clinicians
should not wait for patients to meet HLH 2004 criteria before initiating presumptive therapy for HLH.
The HLH 2004 criteria also require NK cell activity and sIL-2R assays, which are not immediately
available to most clinicians. Hemophagocytosis may not always be present or captured in biopsies of
patients with HLH, as discussed above. Lastly, while ferritin 500 mcg/L may be sensitive, it is not
specific for HLH and can be seen in many other inflammatory and noninflammatory conditions [79].
The H-score was recently developed using the Delphi survey and logistic regression modeling to
help identify patients with nonfamilial forms of HLH [87] [http://saintantoine.aphp.fr/score/]. The H-
Score uses the following weighted variables [1]: known immunosuppressive state [2], maximum
temperature [3], hepatomegaly and/or splenomegaly [4], extent of cytopenia [5], degree of hyper-
ferritinemia [6], degree of hypertriglyceridemia [7], hypofibrinogenemia [8], elevation in serum glu-
tamic oxaloacetic transaminase, and [9] the presence of hemophagocytic features on bone marrow
aspirate. The H-Score has been validated in adults and children, with some variation in cutoff values
[87e89]. In their multicenter cohort study, Debaugnies et al. found the H-score to be more sensitive
than HLH-2004 criteria, with lower, but still adequate, specificity. They noted that H-score was
particularly appropriate for children and that its performance is best at initial presentation, before
nadir values are reached [88].
In 2016, a multinational collaborative effort presented classification criteria specifically designed for
clinical trials in sJIA-MAS/HLH, after it was recognized that subclinical forms of HLH in rheumatological
disease were frequently being missed [90]. A multistep process was employed combining expert
opinion and patient data, which consisted of the following parts [1]: a survey aimed at identifying MAS
features potentially suitable for inclusion in classification criteria [2], data collection from 428 patient
cases with sJIA-MAS/HLH, acute phase sJIA, and sJIA with acute infection, which were classified by a
panel of 28 experts [3], web-based procedure for attaining >80% consensus on the classification of 391
of 428 patients [4], selection of candidate criteria through statistical analysis [5], selection of final
classification criteria through a consensus conference, and [6] cross-sectional validation of final clas-
sification criteria. The final criteria focused on laboratory values as opposed to clinical features with the
exception of fever, which was ranked as the highest clinical clue. This is consistent with the view that
clinical symptoms of MAS may be delayed or easily confused with other conditions. For sJIA presenting
with fever, diagnosis of MAS requires hyperferritinemia (>684 ng/mL) plus any two of the following
laboratory criteria [1]: thrombocytopenia (181 109/L) [2], elevated aspartate aminotransferase (>48
U/L) [3], elevated triglycerides (>156 mg/dL), and [4] hypofibrinogenemia (360 mg/dL) [90]. Vali-
dation analysis yielded a very high specificity of 99% with moderate sensitivity of 73%. The effectiveness
of this classification criteria for capturing only patients with sJIA-MAS/HLH is consistent with its pri-
mary purpose to be used in clinical trials and research studies. However, it is important to recognize
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that it does not capture all patients with MAS and is not meant to be used for clinical diagnosis of
patients [90].
For sJIA-MAS/HLH, it has been argued that relative change over time may be more valuable in early
diagnosis rather than absolute threshold values. Minoia et al. [58] found that platelet count, liver
transaminases, ferritin, lactate dehydrogenase, triglyceride, and D-dimer levels were the only bio-
markers that showed >50% change between pre-MAS and MAS onset. One of the objectives of the
international collaborative effort mentioned above was to identify laboratory tests that could be used
to identify early or emerging sJIA-MAS/HLH [91]. Using a data-driven, consensus formation approach,
platelet count, ferritin, and AST were identified as tests in which early changes were the most
important predictors of developing HLH. However, because of study limitations, changes in these
parameters were not included in the new sJIA-MAS/HLH classification criteria.
Using the data collected for the 2016 sJIA-MAS/HLH criteria, a diagnostic scoring tool was developed
and validated to allow the distinction of sJIA with MAS from active sJIA without MAS (called the MS
Score) [92]. Fever is a mandatory criterion for diagnosis and it was excluded. The MS score is weighted
and includes seven variables: CNS involvement (lethargy, seizures, irritability, confusion, headache,
mood changes, or coma) [score 1 for present, 0 for absent x 2.44], hemorrhagic involvement (petechiae,
ecchymosis, purpura, mucosal, or GI bleed, DIC) [score 1 for present, 0 for absent x 1.54], arthritis [score
1 for present, 0 for absent x 1.30], platelet count [x 109/L x 0.003], lactic dehydrogenase [units/L x
0.001], fibrinogen [mg/dL x 0.004], and ferritin [ng/mL x 0.0001]. The score can range from 8.4 to
41.8, and a score 2.1 is considered positive with the sensitivity of 85% and specificity of 95% [92]. A
simpler and more practical measure to distinguish sJIA-MAS/HLH and active sJIA is the ferritin: ESR
ratio, with a cutoff of 21.5 known to have a sensitivity of 82% and specificity of 78% [93].
Minoia et al. also developed and validated a diagnostic scoring tool to help distinguish F-HLH and
sJIA-MAS/HLH, called the MAS-HLH or MH score [94]. The MH score comprises of six variables: age at
onset, neutrophil count, fibrinogen level, splenomegaly, platelet count, and hemoglobin. The MH score
can range from 0 to 123. For MH score <11, the likelihood of F-HLH was <1% and the best cutoff value
for discriminating F-HLH was a score of 60 (sensitivity of 91% and specificity of 93%). Unsurprisingly,
an age at onset of 1.6 years and neutrophil count 1.4 109/L were the most important factors fa-
voring the diagnosis of F-HLH [94]. Future diagnostic and monitoring tools for diagnosis, HLH will need
to factor in the effects of IL-6 and IL-1 blockers, which can obscure early MAS diagnosis by blunting
fever and other indicators of disease.
Biopsy of affected tissues can help clarify the diagnosis and identify/exclude possible infectious and
malignant triggers. The majority (60e90%) of patients with HLH demonstrate hemophagocytosis in the
bone marrow, liver, spleen, or lymph nodes, but as discussed above, this finding is neither necessary
nor sufficient for diagnosis, and its absence should not delay or prevent therapy.
In the majority of HLH cases (particularly adult HLH), an infectious, malignant, or iatrogenic trigger
is identified. Addressing these triggers is an integral part of management for most patients with HLH.
Therefore, when HLH is considered, particularly in adult patients, it is mandatory for clinicians to
conduct an appropriately thorough search for triggers, guided by individual patient characteristics. For
example, most older children (>1 year of age) who develop HLH outside the context of sJIA have an
identifiable infectious trigger, usually primary EBV or CMV infection [4]. Similarly, when immuno-
compromised adults present with HLH, the reactivation of EBV, CMV, M. tuberculosis, or other
opportunistic infections must be considered. A high ratio of ferritin to sIL-2R can be a clue to infection-
driven HLH [81,95]. In the older adult presenting with HLH, particularly when disease is low grade or
smoldering, the underlying cause is often an occult hematological malignancy, particularly T or NK cell
lymphoma. Here, the ferritin to sIL-2R ratio is relatively low compared to infection-related HLH.
Because HLH can be driven by small populations of malignant cells, the identification of occult ma-
lignancy may require repeat imaging and tissue biopsies, best directed by an oncologist [4,47].
Therapy, monitoring, and prognosis
Treatment of HLH depends on the underlying cause/trigger(s) and severity of disease. The imme-
diate goals are to control inflammation and address/control any triggers identified [29]. Central to the
care of HLH patients is a multidisciplinary team. Depending on the patient, care teams involve oncology
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Fig. 2. Management algorithm for adults with HLH or suspected HLH. Adapted from La Rose e et al., 2019. For the treatment of
children with sJIA-MAS/HLH and other pediatric forms of Rh-HLH; see text, the HLH-94 treatment protocol is consensus therapy for
F-HLH. Medical treatment of adults with HLH is not standardized and should be adapted to severity of illness and underlying triggers
(infection, rheumatic disease, drugs, and malignancy). Hematologists/oncologists should be involved early in care, because the
treatment of severe, refractory, or relapsed disease involves chemotherapy (dashed lines) and case-by-case consideration of allo-
genic stem cell transplant or highly experimental therapies (question marks). Shown here are frequently encountered clinical
scenarios (shaded boxes), major assessment nodes (dashed line boxes), and treatment options (solid line boxes). Abbreviations: aIL-
1, anti-IL-1 (e.g., anakinra); aIL-6, anti-IL-6 (e.g., tocilizumab); Allo-HSCT, allogeneic hematopoietic stem cell transplant; Auto-HSCT,
autologous hematopoietic stem cell transplant; CNS, central nervous system; CRS, cytokine release syndrome; CS, corticosteroids;
CsA, cyclosporine A; CYC, cyclophosphamide; DIHS, drug-induced hypersensitivity syndrome; EBV, Epstein-Barr virus; IVIg, intra-
venous immunoglobulin; MP, methylprednisolone; and TB, Mycobacterium tuberculosis.
(M-HLH), hematology, and genetics (F-HLH), rheumatology (Rh-HLH), infectious diseases (IC-HLH),
and intensive care specialists. In patients with coagulopathy and DIC, supportive care with blood
products can be lifesaving, and blood pressure and ventilator support is often needed for the sickest
patients.
The HLH-94 protocol is consensus treatment for children with F-HLH. Treatment of HLH occurring
in the setting of sJIA and ASD is guided by extensive case series data. In contrast, medical treatment for
adults with HLH not standardized; rather, it must be customized to the severity of disease and iden-
tified triggers. A useful algorithm for medical managements of adults with HLH is presented in Fig. 2.
Below, we discuss in more detail treatment approaches based on the type of HLH.
F-HLH
At most institutions, the treatment of children with F-HLH is managed by hematologists. The
Histiocyte Society first published international treatment protocol for HLH in 1994 (HLH-94), which
combined chemotherapy and immunotherapy (etoposide, CS, cyclosporine A [CsA], and intrathecal
methotrexate in select patients) to control the inflammatory response as a bridge to HSCT. The protocol
was reserved for patients with familial, relapsing, or severe/persistent HLH [96]. HLH-94 dramatically
improved survival in F-HLH from an estimated 5-year rate of 22% to an estimated 3-year rate of 51% ±20
[96]. The protocol (minus HSCT) was also found to be beneficial in secondary forms of HLH [77]. For this
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reason, HLH-94 is often recommended by oncologists for the treatment of nonfamilial forms of HLH
that are severe or relapsing (Fig. 2).
Based on experience with HLH-94, the Histiocyte Society in 2004 modified the protocol (HLH-2004)
in several ways, most notably by adding early and continuous CsA therapy [86]. During therapy with
either protocol, patients should be monitored closely for clinical and laboratory response, and relapses
should be expected as steroids are weaned (around week 6 in HLH-94) [4]. HSCT remains the only long-
term curative treatment, and achieving disease remission of HLH prior to transplant is essential for
good prognosis, because HSCT complications (infection, hemorrhage, organ failure, graft rejection, and
graft versus host disease) and mortality are associated with HLH disease activity [97].
For disease refractory to HLH-94/2004, an anti-CD52 monoclonal antibody called alemtuzumab
(which depletes T and B cells) has shown effectiveness as a salvage therapy [4,98]. Salvage therapy
should be directed by oncologists and hematologists (Fig. 2). Other experimental and emerging ther-
apies for HLH are discussed in detail below.
Rh-HLH
There are no controlled trials to guide the treatment of Rh-HLH, and treatment is based on pub-
lished case series and expert opinion [99]. SJIA- and ASD-associated HLH are typically treated with
high-dose pulse IV methylprednisolone (30 mg/kg/day for 3 consecutive days, maximum 1000 mg/
day) followed by lower doses of daily CS therapy (methylprednisolone IV 1e10 mg/kg/d) [41] or
additional pulse methylprednisolone as indicated. CsA IV or PO (3e5 mg/kg/day) has also been a
principal therapy as it preferentially targets T lymphocyte proliferation and cytokine secretion (by
inhibiting NFAT family of transcription factors), dampening a key component of the HLH amplification
loop (Fig. 1) [100e102]. Identification of key soluble mediators in HLH and a need for less toxic
treatments has led to the increased use of recombinant anticytokine therapies in Rh-HLH. IL-1 blockade
appears to hold more promise for treating Rh-HLH than does IL-6 blockade [1], which is not surprising
given the importance of IL-1 (and IL-18) in the development and perpetuation of sJIA-MAS/HLH.
Increasing evidence indicates that sJIA-MAS/HLH refractory to CS and CsA therapy can respond
dramatically to high-dose recombinant IL-1 antagonist, and may be similarly effective for refractory
HLH in ASD [66]. Anakinra appears to be most effective for sJIA-MAS/HLH at high doses (e.g., 4e15 mg/
kg/day) [1,37], and can be administered intravenously or subcutaneously, with a short half-life and few
reported side effects. Anakinra for Rh-HLH is being studied in recent and ongoing clinical trials
(NCT03265132 and NCT02780583). The use of the anti-IL-6-receptor monoclonal antibody, tocilizu-
mab, and other IL-1 antagonists (canakinumab and rilonacept) in Rh-HLH has not been established
[37,103]. In children with sJIA, tocilizumab therapy is effective for controlling arthritis and systemic
symptoms, yet it does not seem to provide commensurate protection against developing HLH
[1,58,103]. Moreover, tocilizumab may delay the recognition of HLH by dampeaning CRP and fever
responses. Interestingly, in sJIA patients under tocilizumab therapy, high IL-18 - IL-6 ratios are asso-
ciated with an increased risk of developing HLH [104], suggesting that IL-6, while central to sJIA dis-
ease, is not a key cytokine in sJIA-MAS/HLH.
The inflammatory cytokines, IL-1b and IL-18, may be important in other forms of pediatric HLH.
Barsalou et al. [105] recently reported a patient with a NLRC4 gain-of-function mutation (see Table 1)
who presented with neonatal HLH and was successfully treated with a combination of anakinra and
rapamycin (an inhibitor of mTOR). Rapamycin was found to reduce the secretion of both IL-18 and IL-1b
by phagocytic cells through the reduction of caspase-1 activation, suggesting that patients with
inherited autoinflammatory disorders may benefit from mTOR inhibition [105]. Indeed, as IL-18 also
contributes to T cell activation and IFN-g secretion (Fig. 1), it may prove to be an important therapeutic
target in sJIA-MAS/HLH as well as other forms of HLH. Further investigation into mTOR inhibitors and
targeted IL-18 blockade is warranted.
When recombinant IL-1 blockers are not available, intravenous immunoglobulin (IVIg) should be
considered for the treatment of sJIA-MAS/HLH [106,107]. Other medications that have been used
include tacrolimus, rituximab, and plasma exchange [58].
Rh-HLH in KD and SLE has also been treated with high-dose IV methylprednisolone and/or anakinra
[108,109]. Rituximab, a B-cell depleting anti-CD20 antibody, has been used in refractory HLH associated
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with SLE [110], even though its use has also been identified as a trigger of HLH in SLE [111]. In one case
series, cyclophosphamide IV proved effective in cases of SLE- and ASD-associated HLH refractory to CS,
CsA, and IVIg [112]. Adults receiving biological therapy for rheumatic/inflammatory disease who
develop HLH frequently have an infectious trigger. One study of 30 cases [113] identified M. tubercu-
losis, CMV, and EBV as the most commonly identified pathogens. Thus, it is imperative that patients
receiving immunosuppressive therapy who develop HLH (IC-HLH) be evaluated for infection, as dis-
cussed below.
M-HLH
The treatment of M-HLH aims to control the overactive immune system and to treat underlying
malignancy [50,51]. Because prospective, randomized, and controlled trials for managing M-HLH are
lacking, there are no generally accepted guidelines for balancing HLH-directed with malignancy-
directed therapies [5]. It is important to differentiate between malignancy-triggered HLH (as a pre-
senting feature of the malignancy at diagnosis or relapse) versus HLH during chemotherapy [51].
Malignancy-triggered HLH has the worst prognosis of all HLH types. In adults, management typi-
cally includes CS with or without IVIg as first line to suppress inflammation prior to initiating cancer-
specific treatment (Fig. 2) [51]. In highly active HLH, or when there are signs of severe organ damage, a
disease-adapted version of HLH-94 with etoposide IV (50e100 mg/m2) is used prior to cancer-specific
treatment. In patients with aggressive lymphoma, CNS involvement should be evaluated with MRI and
lumbar puncture [51]. Methylprednisolone is the most common CS used; however, dexamethasone is
preferred if there is CNS involvement as it more easily crosses the blood-brain barrier [5]. Methotrexate
may be considered to prevent CNS relapse [51]. Rituximab has had success treating HLH associated
with diffuse large B-cell lymphoma [114]. Autologous HSCT should be considered in patients who
achieve the remission of HLH disease. Primary allogenic HSCT should be considered in patients with
HLH and lymphoma, particularly EBV-driven lymphoma [51].
HLH during chemotherapy is often triggered by infection in the setting of intense immunosup-
pression (IC-HLH), or because of the recurrence of underlying malignancy [51]. While investigation for
these triggers is underway, HLH disease should be controlled with IV CS (methylprednisolone 1e2 mg/
kg/day or dexamethasone 5e10 mg/m2); IVIg (1.6 g/kg over 2e3 days) is a useful adjunct if HLH is
triggered by infection. Etoposide and maintenance chemotherapy should be used only sparingly,
particularly in the setting of active infection [51,115].
Rx-HLH
HLH or HLH-like disease has been reported in patients receiving immune-activating therapies
including T-cell engaging antibodies, CAR-T cells, ICI, and certain chemical drugs known to trigger DIHS.
Rarely, patients treated with CAR-T cells will develop HLH in the context of the well-described CRS. A
severity-based treatment algorithm for CRS and associated HLH has been developed, which involves IV
dexamethasone and IL-6 blockade with tocilizumab or siltuximab [53]. For HLH triggered by ICI
therapy, optimal treatment is unclear, but the addition of high-dose CS therapy alone has been suffi-
cient in some cases [116]. Finally, HLH-like disease can be triggered by drugs associated with DIHS. In a
series of eight probable cases of HLH triggered by lamotrigine, seven patients improved with the
cessation of drug and only minimal/brief immunosuppression [117], consistent with a role for drug-
dependent activation of CD8þ T cells (discussed above).
IC-HLH and HLH mimics
Infection is a common trigger of HLH in immunocompromised individuals. When a triggering

infection is identified (or highly suspected), HLH-targeted immunosuppressive therapy (e.g., HLH-94)
is usually not warranted and may even be harmful. In the setting of infection, inflammation may be
controlled with CS and IVIg [118,119], provided the infection is addressed. In a review [120] of nearly
forty cases of M. tuberculosis-associated HLH, the decision to provide antimycobacterial therapy (with
or without CS) appeared to be a critical determinant of survival. In cases of EBV-HLH (primary infection
j.berh.2020.101515
or reactivation), the depletion of B cells, an important site of EBV replication, may be a useful adjunct
therapy. Rituximab IV 375 mg/m2 weekly for up to four weeks has been reported to be successful
[121,122]. Other therapies that have been used in EBV-HLH include CHOP (cyclophosphamide, doxo-
rubicin, vincristine, and prednisolone [123], DEP (liposomal doxorubicin, etoposide, and methyl-
prednisolone) in refractory cases [124], and ruxolitinib [125] IVIg [56]. Patients with PID syndromes
(see Table 1) who develop HLH typically experience refractory disease (4), and treatment follows the
HLH-94/2004 protocol as a bridge to HSCT [86]. For CMV and EBV reactivation in the setting of chronic
immunosuppression, patients often benefit from the cessation of immunosuppressive agent, CS
therapy, and targeted treatment to inhibit viral replication [126].
Severe, treatment-refractory HLH and HLH-like disease have been reported in children with metabolic
disorders such as Wolman's disease, Gaucher's disease type 2, Niemann-Pick disease, and type Ia glycogen
storage disease [127e130]. In these cases, no discrete trigger was identified. One patient with HLH
occurring in the setting of lysinuric protein intolerance was successfully treated with CS and CsA [131].
Monitoring and prognosis
Monitoring response to therapy
Fever, aminotransferase levels, ferritin, and coagulation parameters are practical, sensitive, and dy-
namic measures useful in the day-to-day monitoring of HLH patients. Blood counts must be interpreted
with the consideration of effects of myelosuppressive therapies (i.e., etoposide). As mentioned, sIL-2R and
sCD163 appear to be useful indicators of active disease, but the restricted availability of these assays limits
their utility in day-to-day management. Monitoring coagulation parameters is essential, but they may not
show marked abnormalities until late in the disease course. In general, persistent or progressive disease in
the face of standard initial therapy, should prompt continued investigation for an underlying infectious or
malignant trigger (especially in adults). At the same time, HLH-targeted therapies should be intensified
under the guidance of an experienced oncologist and/or hematologist (see Fig. 2).
Prognosis
The advent of HLH-94 and HLH-2004 treatment protocols markedly improved the survival of
children with F-HLH. Nevertheless, F-HLH survivors may suffer long-term side effects such as cognitive
and growth delay, hearing impairment, and obstructive lung disease [96]. Prognosis for adults with
HLH remains poor. Overall mortality rates ranged between 42 and 88% [132]. In a series of 68 adult
patients with HLH from multiple tertiary care centers, half of whom had an underlying malignancy,
only 31% of patients were alive at a median follow up of 32 months [133]. Predictors of mortality in
adult HLH include older age and underlying lymphoma [134]. These data illustrate a pressing need for
better diagnostics and therapies for HLH, particularly in the adult population.
Future directions
Emerging biomarkers in sJIA-MAS/HLH
Currently, there are no definitive biomarkers for establishing the diagnosis of sJIA-MAS/HLH. As
mentioned, elevated sCD163 levels correspond to macrophage activation and have been used to trend
disease activity and response to treatment in some centers [135]. Sakumura et al. [136] found that
serum sCD163 levels in sJIA patients with MAS were significantly higher than in patients with sJIA
disease flares. Moreover, sCD163 levels were not suppressed after IL-6 blockade with tocilizumab, in
contrast to other cytokines and inflammatory markers [136], consistent with a redundant/subordinate
role for IL-6 sJIA-MAS/HLH. Shimizu et al. [137] recently compared serum biomarkers in a large cohort
of patients with sJIA, sJIA-MAS/HLH, EBV-HLH, KD, and healthy controls (n ¼ 117, 29, 15, 15, and 28,
j.berh.2020.101515
respectively). Consistent with prior observations, IL-18 was significantly elevated in sJIA-MAS/HLH
patients when compared to EBV-HLH patients. They found that the ratio of blood soluble TNF-a re-
ceptor (sTNF-R) type II to type I significantly increased in EBV-HLH and the sJIA-MAS. They found that
using a cutoff of sTNFRII >12,250 pg/ml was 90% sensitive and that a cutoff sTNF-RII/I ratio of >4562 pg/
ml was 92% specific for the diagnosis of MAS/HLH. sTNF-RI and sTNF-RII mediate the biological effects
of TNF-a [138]. sTNFR-II may be a useful marker of transition to MAS in patients with sJIA, SLE, and KD
as well [45,137,139]. Mizuta et al. studied blood cytokine levels in 15 sJIA patients who developed MAS
and identified significant increases in CXCL9, sTNF-RI, sTNF-RII, Axl, and MIP-1S during the MAS phase
compared with active phase sJIA, with CXCL9 showing the most significant increase and correlating
positively with disease severity [138]. Interestingly, levels of CXCL9 were significantly lower in patients
receiving tocilizumab, suggesting that IL-6 inhibition may suppress CXCL9 expression. The expression
of many inflammatory cytokines was suppressed in patients on tocilizumab, consistent with the idea
that IL-6 signaling contributes to disease manifestations in MAS, even though it may not be necessary
for MAS [138].
Shimizu et al. reported higher levels of serum neopterin in patients with EBV-HLH compared to KD,
sJIA-MAS/HLH, or active sJIA without MAS [140]. Neopterin is a catabolite produced by macrophages
upon IFN-g stimulation and appears to reflect the degree of tissue lymphohistiocytosis in HLH [45].
This implies that IFN-g may be more important in EBV-HLH pathogenesis than in sJIA-MAS/HLH, where
proinflammatory cytokines like IL-18 and IL-1b dominate.
IFN-g appears to be a key pathogenic molecule in many forms of HLH, so it is not surprising that HLH
biomarkers would include molecules whose expression is induced by IFN-g, either directly at the gene
expression level (e.g., CXCL9) [141] or indirectly, through the activation of macrophages (e.g., ferritin,
sCD163, and neopterin) (see Fig. 1). However, because of its very short in vivo half-life (~30 min) [46],
IFN-g itself is not easily detected in blood samples. Instead, assessing the expression of IFN-g-inducible
mRNA and proteins may prove to be a feasible way to assess INF-g activity as a biomarker in HLH.
Interestingly, a recent study [142] suggests that the TB INF-g release assay, which measures blood IFN-g
release ex vivo, may be a novel and readily available tool for diagnosing HLH.
Adenosine deaminase 2 (ADA2), a protein released by monocytes and macrophages, has been
explored as a biomarker of MAS in sJIA. However, ADA2's role in distinguishing MAS and infection still
needs to be determined, as it can be elevated in chronic infections such as HIV or tuberculosis [143].
Cytokine patterns
There is growing appreciation that cytokine profiles differ considerably depending on the under-
lying cause of HLH; clarifying these differences should result in improved diagnostics, predictive tools,
and therapies. For example, there appears to be two distinct subsets of patients with sJIA or ASD: an IL-
6 dominant subset that is associated with arthritis-related manifestations, and an IL-18 dominant
subset that is more likely to develop MAS [104,140,144,145]. These observations suggest that sJIA pa-
tients, up to 40% of whom will develop some form of MAS, should be risk-stratified upon initial
diagnosis. Those showing an IL-18 dominant phenotype should not be treated with IL-6 blockade but
should instead be treated with IL-1 or IL-18 blockade.
IL-18 can pass from mother to fetus, leading to significantly elevated serum IL-18 levels in the
newborn [146]. Shimizu et al. recently reported three neonates born to mothers with ASD who
developed MAS and had extremely high levels of circulating IL-18, supporting the idea that excessive
IL-1 and/or IL-8 production predisposes to HLH as well as suggesting that children born to mothers
with active ASD and high IL-18 levels should be monitored for HLH [146].
Cytokine profiles appear to vary between various forms of Rh-HLH in children. For example, Jinkawa
et al. found that patients with KD-MAS had elevated TNF-a and IFN-g levels, which were associated
with a greater degree of coronary artery lesions and MAS activity [147]. Patients with KD were found to
have higher levels of IL-6 than those with EBV-HLH or sJIA-MAS/HLH [140]. Jinkawa et al. (Jinkawa
2019) analyzed 78 patients with KD, including 5 with MAS. They found that serum neopterin, IL-18,
sTNFR-II levels, and sTNFR-II/I ratio were significantly elevated in KD patients with MAS compared
to acute KD without MAS. They concluded that the overproduction of IFN-g and TNF-a reflected by
j.berh.2020.101515
increased serum levels of neopterin and sTNFR-II are closely associated with the pathogenesis of MAS
in KD [147]. Like KD-MAS, SLE-MAS is associated with striking increases in TNF-a levels [148].
Taken together, these results indicate that further study and the classification of various forms of
Rh-HLH based on circulating cytokine profiles will yield more sensitive and specific diagnostic tests,
accurate predictive tools, and ultimately, highly targeted and effective therapies.
Emerging therapeutic strategies
Despite their success, the HLH-94 and HLH-2004 protocols involve the use of etoposide, CsA, and
sustained high-dose glucocorticoids e broadly immunosuppressive therapies that carry significant risk
of toxicity, infection, and long term adverse effects. Therefore, more targeted and less toxic treatments
are needed, particularly for nongenetic forms of HLH where controlling aberrant inflammation and
addressing underlying triggers can be curative. One approach is the targeted blockade of cytokines that
drive the amplification loops of HLH, e.g., IFN-g and IL-18. A recently published Phase II/III trial
(reviewed in Vallurupalli 2019 [149]) of the IFN-g-blocking antibody, emapalumab, plus IV dexa-
methasone for the treatment of young children with presumed F-HLH (some resistant to HLH-94
protocol) showed remarkable efficacy (26% complete response, 30% partial response, and 7.4% some
improvement); this led to the US FDA's approval of emapalumab for the treatment of F-HLH in late
2018. Trials of emapalumab are being planned or underway in adult HLH (NCT03985423) and sJIA-
MAS/HLH (NCT03311854). There is increasing interest in the use of recombinant IL-18 binding pro-
tein (IL-18BP) in the treatment of HLH driven by IL-18, e.g., sJIA-MAS/HLH and HLH associated with
NLRC4 mutations [3]. Similarly, IL-33, a member of the IL-1 family of cytokines, may be an important
therapeutic target [3]. Combination cytokine blockade has not been well studied in humans, but this
strategy is likely to prove highly effective based on what is known about HLH amplification loops
(Fig. 1). As mentioned above, blockade of IL-1 with high-dose anakinra is often used when treating
children with sJIA-MAS/HLH, and related clinical trials are being planned or underway (e.g.,
NCT02780583).
Small molecule inhibitors of Janus kinases (JAKs), which transduce signals through various cytokine
receptors, offer the ability to inhibit simultaneously multiple cytokine pathways with limited toxicity.
Consistent with this concept, in a study [21] of mouse models of both primary and secondary HLH,
treatment with ruxolitinib, a small molecule JAK1/2 inhibitor (which inhibits IFN-g and IL-6 signals),
provided efficacy and broader effects than did treatment with IFN-g-neutralizing antibodies. Wang
et al. conducted a study of ruxolitinib for salvage therapy, treating 34 patients with refractory/relapsed
HLH (in addition to low-dose methylprednisolone in patients who were already on long-term high-
dose CS). Complete remission was achieved in 15% of patients, and partial remission in 59% of patients
(Wang 2019). Currently, a prospective multicenter large-scale clinical trial is underway in China to
evaluate combined ruxolitinib and doxorubicin for refractory/relapsed HLH (NCT03533790). JAK in-
hibition was also noted to be beneficial in the treatment of IL-18 PAP-MAS patients [85].
Antibody-mediated ablation of lymphocytes, especially B cells, T cells, and NK cells, can be helpful in
cases of severe or relapsed HLH, particularly EBV-HLH and M-HLH (reviewed in La Rosee 2019). Other
salvage therapies include plasma exchange, splenectomy, and cytokine adsorption. Prescription and
management of these highly experimental approaches should be directed by an oncologist or
hematologist.
Summary
First described in 1939, HLH is now known to be a highly distinct state of immune hyperactivation
that may result from a variety of disparate causes. Genetic analysis of children with F-HLH (and related
animal models) helped identify aberrant activation of cytotoxic CD8þ T cells and macrophages as core
pathogenic mechanisms. Subsequent investigations into secondary/sporadic forms of HLH in children
and adults underscored the importance of chronic inflammation, immunosuppression, and malignancy
in triggering and sustaining HLH disease. Even with the development of HLH-specific treatment pro-
tocols, mortality remains unacceptably high, especially for adults with HLH. Thus, there remains a
pressing need for more accurate predictive tools, more sensitive diagnostic algorithms, and therapies
j.berh.2020.101515
that are both more effective and less toxic than current approaches. Progress in the diagnosis and
management of HLH disease will require sustained support of basic science and observational inves-
tigation into the cellular and molecular mechanisms of HLH in all its forms.
Funding statement
The work of G.C.H. was supported by the Robert F. Willkens, M.D. e Lucile T. Henderson Endowed
Professorship in Rheumatology, University of Washington, School of Medicine.
Declaration of Competing Interest
Susan Shenoi is on MAS adjudication committee for Pfizer. Grant Hughes has received institutional
support from Pfizer and Janssen Biotech.
Practice Points
Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease that affects infants,

children, and adults; early recognition and prompt treatment is critical for patient survival.
Uncontrolled activation of CD8þ cytotoxic T cells is the root abnormality in most forms of
HLH.
HLH is a distinct state of immunological amplification that is comprised of several different
forms: primary/familial forms (F-HLH) that arise in early childhood and secondary/reactive
forms including that are associated with rheumatic disease (often called macrophage acti-
vation syndrome [MAS]), malignancy, infections, and certain drugs/therapies.
o Primary forms of HLH, including F-HLH and HLH arising in the setting of primary immune
deficiency (PID) is caused by discrete mutations in genes related to cytotoxicity, lympho-
cyte survival, and inflammasome activation
o HLH-2004 is an important diagnostic tool for F-HLH, but it lacks sensitivity in diagnosing
other forms of HLH
o Systemic juvenile idiopathic arthritis (sJIA) and adult onset Still’s disease (ASD) are the
most common rheumatic diseases that present with HLH
o HLH in older adults is usually caused by infection or hematological malignancy
HLH should be suspected in clinically deteriorating patients presenting with high, sustained
fever, declining cell lines (cytopenias), rising transaminases and ferritin, and evolving coa-
gulopathy. Elevated soluble IL-2 receptor (sIL-2R) and decreased/absent natural killer cells
are frequently observed features of HLH.
The presence of tissue hemophagocytosis is neither necessary nor sufficient for diagnosing
of HLH.
HLH protocols using combination chemotherapy are consensus treatment for children with
F-HLH, typically followed by hematopoietic stem cell transplantation, but the optimal treat-
ment of other forms of HLH is not well-defined.
In HLH occurring in the setting of sJIA, immediate high-dose pulsed intravenous methyl-
prednisolone with IL-1 blockade (high-dose anakinra) or cyclosporine A can be lifesaving.
In secondary HLH, identifying and addressing disease triggers (e.g., infection, malignancy,
and drugs) is essential.
Emerging therapies target key cytokines in HLH amplification loops (e.g., IFN-g, IL-18, and IL-
1b).
j.berh.2020.101515
Research Agenda
Intensified basic and translational research is needed to clarify the cellular and molecular
mechanisms of HLH types.
This research is expected to inform the development of highly sensitive, context-specific
diagnostic tools in secondary HLH, new biomarkers, and safer, more effective therapies.
Future clinical trials should focus on combinatorial cytokine blockade, use of small molecule
inhibitors of cytokine signaling, and cell ablation therapy.
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Best Practice & Research Clinical

Summary and overview

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening immunological syndrome

History and classiﬁcation systems

Lessons from familial HLH

Susceptibility to HLH in chronic rheumatic diseases appears to involve a combination of inherited

Familial HLH [13]

Abbreviations: CNS, central nervous system; EBV, Epstein-Barr virus.

Immune compromise, infection, and HLH

Non familial HLH

Clinical and laboratory features

Unique clinical and laboratory features

Therapy, monitoring, and prognosis

IC-HLH and HLH mimics

Infection is a common trigger of HLH in immunocompromised individuals. When a triggering

Monitoring and prognosis

Monitoring response to therapy

Emerging biomarkers in sJIA-MAS/HLH

Emerging therapeutic strategies

Declaration of Competing Interest

 Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease that affects infants,

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