Clinical Features and Diagnosis of Hemophagocytic Lymphohistiocytosis - UpToDate

15/5/2021 Clinical features and diagnosis of hemophagocytic lymphohistiocytosis - UpToDate
Authors: Kenneth L McClain, MD, PhD, Olive Eckstein, MD

Section Editor: Peter Newburger, MD
Deputy Editor: Alan G Rosmarin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2021. | This topic last updated: Apr 06, 2020.
INTRODUCTION
Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of

excessive immune activation. It most frequently affects infants from birth to 18 months of age, but
the disease is also observed in children and adults of all ages. HLH can occur as a familial or
sporadic disorder, and it can be triggered by a variety of events that disrupt immune homeostasis.
Infection is a common trigger both in those with a genetic predisposition and in sporadic cases.
Prompt treatment is critical, but the greatest barrier to a successful outcome is often a delay in
diagnosis due to the rarity of this syndrome, variable clinical presentation, and lack of specificity of
the clinical and laboratory findings.
The clinical features and diagnosis of HLH and a related disorder, the macrophage activation
syndrome (MAS), will be discussed here. The management of patients with these disorders is
discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
TERMINOLOGY
Our approach to describing HLH is consistent with the recommendations from the North American
Consortium for Histiocytosis (NACHO) [1]. We favor not using of the terms "primary HLH" and
"secondary HLH," which have been used in an attempt to distinguish between an underlying genetic
cause versus an alternative source of pathologic immune activation, respectively. These terms have
caused a great deal of confusion because both primary and secondary HLH can be triggered by
infections or other immune activating events, and gene mutations can be found in individuals of any
age and with any family history.
We use the following terminology:
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● HLH syndrome – A condition of pathologic immune activation that is often associated with
genetic defects of lymphocyte cytotoxicity. The clinical presentation is described below. (See
'Clinical features' below and 'Laboratory and radiographic abnormalities' below.)
● HLH disease – HLH syndrome in which the distinctive immune activation is the core problem;
HLH disease may be associated with a specific genetic and/or environmental causes, as
described below. (See 'Genetics' below and 'Associated illnesses' below.)
● HLH disease mimics – Other disorders that resemble HLH syndrome but are caused by other
conditions. (See 'Differential diagnosis' below.)
The term, macrophage activation syndrome (MAS) refers to a form of HLH that occurs primarily
in patients with juvenile idiopathic arthritis or other rheumatologic diseases. Some authors call
this "reactive hemophagocytic syndrome." (See 'Rheumatologic disorders/MAS' below.)
PATHOPHYSIOLOGY
Immunologic abnormalities — HLH is a syndrome of excessive inflammation and tissue

destruction due to abnormal immune activation. The hyperinflammatory/dysregulated immune state
is thought to be caused by the absence of normal downregulation by activated macrophages and
lymphocytes [2].
The cell types involved in the pathogenesis of HLH include the following:
● Macrophages – Macrophages are professional antigen presenting cells derived from

circulating monocytes; they present foreign antigens to lymphocytes. In HLH, macrophages
become activated and secrete excessive amounts of cytokines, ultimately causing severe
tissue damage that can lead to organ failure. (See "An overview of the innate immune system",
section on 'Monocytes and macrophages'.)
● Natural killer cells and cytotoxic lymphocytes – Natural killer (NK) cells constitute 10 to 15
percent of lymphocytes. NK cells eliminate damaged, stressed, or infected host cells such as
macrophages, typically in response to viral infection or malignancy, in an MHC-unrestricted
manner. (See "An overview of the innate immune system", section on 'Natural killer (NK) cells'.)
Cytotoxic lymphocytes (CTLs) are activated T lymphocytes that lyse autologous cells such as
macrophages bearing foreign antigen in association with class I histocompatibility proteins.
Most CTLs express CD8. (See "The adaptive cellular immune response: T cells and cytokines",
section on 'CD8+ T cell activation'.)

In HLH, NK cells and/or CTLs fail to eliminate activated macrophages. This lack of normal
feedback regulation results in excessive macrophage activity and highly elevated levels of
interferon gamma and other cytokines.
Other lymphocyte abnormalities include altered numbers of CD4 and CD8 lymphocyte subsets
[3]. In a series of adult patients, those with increased CD8 numbers and decreased CD4/CD8
ratios had the best survival. Decreased total CD3 numbers portended a bad outcome. (See
"Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Prognosis'.)
Consistent with this mechanism, most patients with HLH have impaired cytotoxic function of NK
cells and CTLs, coupled with excessive activation of macrophages [4-9]. Excessive cytokine
production by macrophages, NK cells, and CTLs is thought to be a primary mediator of tissue
damage [2]. (See 'Immunologic profile' below and 'Cytokine storm' below.)
The normal elimination of activated macrophages by NK cells and CTLs occurs through perforin-
dependent cytotoxicity. NK cells and CTLs lyse target cells in a series of steps that include
formation of an immunologic synapse; creation of a pore in the macrophage membrane; and
delivery of cytolytic granules into the macrophage. The granules contain a variety of proteases such
as granzyme B that can initiate cell death, often through apoptosis. Most of the genetic defects in
patients with familial HLH encode proteins involved in this process. (See "The adaptive cellular
immune response: T cells and cytokines" and "NK cell deficiency syndromes: Clinical
manifestations and diagnosis", section on 'Mechanisms of killing' and 'Genetics' below.)
Toll-like receptor (TLR) activation of the immune system can be another cause of HLH [10]. TLRs
are non-antigen-specific receptors on the surface of NK cells that are activated by components of
bacteria, fungi, viruses, or mycoplasma. Normal mice with repeated TLR9 stimulation develop an
illness similar to macrophage activation syndrome (MAS) [11]. Genes associated with
TLR/interleukin 1 receptor (IL-1R) signaling are upregulated in patients with juvenile idiopathic
arthritis and MAS [12].
Hemophagocytosis — In addition to antigen presentation and cytokine production, macrophages

can also phagocytize host cells. Hemophagocytosis refers to the engulfment (literally "eating") of
host blood cells by macrophages. Hemophagocytosis is characterized by the presence of red blood
cells, platelets, or white blood cells (or fragments of these cells) within the cytoplasm of
macrophages ( picture 1 and picture 2). Hemophagocytosis can be observed in biopsies of
immune tissues (lymph nodes, spleen, liver) or bone marrow aspirates/biopsies. Although it can be
a marker of excessive macrophage activation and supports the diagnosis of HLH,
hemophagocytosis alone is neither pathognomonic of, nor required for, the diagnosis of HLH. (See
'Bone marrow evaluation' below and 'Diagnosis' below.)

Cytokine storm — The persistent activation of macrophages, NK cells, and CTLs in patients with
HLH leads to excessive cytokine production (cytokine storm) by all of these cell types, and is
thought to be responsible for multiorgan failure and the high mortality of this syndrome [2,13,14].
Cytokines found at extremely high levels in the plasma of patients with HLH include interferon
gamma (IFN gamma); tumor necrosis factor alpha (TNF alpha); interleukins (IL) such as IL-6, IL-10,
and IL-12; and the soluble IL-2 receptor (CD25) [15-17]. Elevated IL-16 levels may be important for
a TH1-type response that recruits macrophages and other cells implicated in HLH [18]. In a study of
adults with secondary HLH, markedly elevated levels of IL-18 and its binding protein were found
[19]. Some of these cytokines can be measured in serum and are useful in distinguishing HLH from
other conditions. A study of IFN gamma, IL-6, and IL-18 in patients with systemic JIA (sJIA) versus
HLH showed higher levels of IFN gamma and IFN gamma-induced proteins in HLH compared with
sJIA, but the ratio of IL-18/IFN gamma was higher in sJIA [20]. (See 'Specialized testing' below.)
An extensive study on the role of IL-18 in MAS and other rheumatologic conditions has shed light on
the differences in pathophysiology of HLH and MAS [21]. Unbound (free) IL-18 levels >24,000
pg/mL could distinguish MAS from familial HLH with an 83 percent sensitivity and 94 percent
specificity. Many patients with MAS had IL-18 levels >100,000 pg/mL, which helped distinguish
MAS from other autoinflammatory conditions. A mouse model of MAS revealed that IL-18 was
primarily produced by intestinal epithelium, which provides an intriguing biologic model for a
syndrome of infantile enterocolitis and MAS caused by NLRC4 inflammasome hyperactivity [22].
Triggers — Patients with HLH can have a single episode of the disease or relapsing episodes, with
relapses occurring most often in patients with familial HLH. The instigating trigger for an acute
episode is often an infection or an alteration in immune homeostasis. The two broad categories of
triggers include those that cause immune activation and those that lead to immune deficiency.
Immune activation from an infection is a common trigger both in patients with a genetic
predisposition and in sporadic cases with no underlying genetic cause identified. The most common
infectious trigger is a viral infection, especially Epstein-Barr virus (EBV) [2]. Primary EBV infection
can trigger HLH in individuals with a defect in perforin-dependent cytotoxicity, as well as in those
without a known predisposition; patients with X-linked lymphoproliferative disease (XLP) are at
particularly high risk [23]. Many other infectious organisms are also implicated. Kawasaki disease, a
common vasculitis of childhood, can also trigger HLH and can often be misdiagnosed initially. The
immune checkpoint inhibitors, nivolumab and ipilimumab, may be linked to development of HLH, but
the incidence has not been defined [24]. (See 'Immunodeficiency syndromes' below and 'Infections'
below and "Kawasaki disease: Clinical features and diagnosis".)

Excessive cytokine release in patients with chronic granulomatous disease (CGD) may also lead to
HLH. In one institution, 3 of 17 patients with CGD developed HLH [25]. Common causes of
immunodeficiency triggers include inherited syndromes, malignancy, rheumatologic disorders, or
HIV infection. (See 'Genetics' below and 'Malignancy' below and 'Rheumatologic disorders/MAS'
below and 'Immunodeficiency' below.)
The coexistence of immune dysregulation with unchecked inflammation distinguishes HLH from
other syndromes of immune activation, immunodeficiencies, and inflammatory states [23].
GENETICS
Genetic defects play a major role in childhood HLH and are increasingly found in adult cases [9,26-
30]. Genetic information can be helpful in determining the likelihood of recurrence, the need for
hematopoietic cell transplant, and the risk of HLH in family members. (See 'Diagnosis' below and
"Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
Most of the implicated genes encode components of the machinery for perforin-dependent
cytotoxicity ( figure 1) [31] (see 'Pathophysiology' above). These genes act in an autosomal
recessive fashion (ie, inheritance of a mutation at both alleles of a gene is required to manifest the
disease) and many cases are related to consanguinity; however, heterozygosity for an HLH
mutation is occasionally found in an individual (typically an adult) with HLH associated with another
condition [32]. (See 'Associated illnesses' below.)
In addition to homozygous mutation in a single HLH gene, individuals with HLH may be compound
heterozygotes (ie, they may have a different mutation in each allele of the same gene) or they may
show digenic inheritance (ie, they may have separate mutations in two different genes). A review of
2701 patients referred for genetic testing revealed that 225 (8 percent) were homozygous or
compound heterozygous for mutations, and 28 (1 percent) showed digenic inheritance [30]. Another
study reported similar findings, with monoallelic mutations of known familial HLH genes found in 43
of 281 patients classified as having "sporadic" disease, suggesting that this disorder is not a simple
recessive one [33].
In a study that used whole exome sequencing, heterozygous variants in LYST, MUNC13-4, and
STXBP2 were discovered in 5 of 14 patients with juvenile idiopathic arthritis (JIA) who had
macrophage activation syndrome (MAS), but in only 4 of 29 patients with JIA who did not have MAS
[34]. Several other recessive pairs and compound heterozygotes were found.
The likelihood of identifying a gene mutation is highest in the youngest patients. In a review of 476
North American children, a gene mutation was identified in 45 percent of those less than one month
of age [23]. In those aged between two months to one year, one to two years, and greater than two
years, the frequencies of identifying a gene mutation were 39, 20, and 6 percent, respectively. In
another study of 175 adults (age range, 18 to 75 years), 14 percent had gene mutations; these
tended to cause partial defects in protein function rather than complete loss of the protein; this
partial loss of function may explain the later age of HLH onset in some adults [35]. (See 'Features in
adults' below.)
In a study of 101 patients who met the HLH-2004 criteria for diagnosis of HLH, only 19 percent had
biallelic mutations in the six primary genes associated with HLH [36]. Heterozygous variants in
patients with potentially two HLH-associated gene mutations were not statistically different from the
general population, suggesting these "digenic" cases were not disease causing. Of 47 patients with
none of the expected HLH-associated gene mutations, 28 (58 percent) had potential disease-
causing genetic defects. These defects were in genes associated with primary immunodeficiency
disease or dysregulated immune activation or proliferation associated genes such as NLRC4 and
NLRP12 as well as biallelic variants in NLRP4, NLRC3, and NLRP13.
Mutations at FHL loci — Several HLH gene mutations map to loci that code for elements of the
cytotoxic granule formation and release pathway, and have been labeled familial hemophagocytic
lymphohistiocytosis (FHL) loci. (See 'Terminology' above.)
● PRF1/Perforin – FHL2 results from mutations of PRF1, which encodes perforin. Perforin is
delivered in cytolytic granules and forms pores in the membrane of target cells. Mutations in
other genes that affect perforin expression have also been reported [27,37-39].
● UNC13D/Munc13-4 – FHL3 results from mutations of UNC13D, which encodes Munc13-4

[28,40]. Proteins of the Unc (uncoordinated) family regulate cytolytic granule maturation.
● STX11/Syntaxin 11 – FHL4 results from mutations of STX11, which encodes syntaxin 11.
Syntaxins control granule exocytosis. Several syntaxin mutations were reported in a group of
Kurdish families with HLH [29,41].
● STXBP2/Munc18-2 – FHL5 results from mutations of STXBP2, which encodes Munc18-2 (also
called syntaxin binding protein 2) [32,42]. This protein binds to syntaxin 11 and promotes the
release of cytotoxic granules.
The gene defect responsible for FHL1 remains uncharacterized.
Immunodeficiency syndromes — Several mutations that cause congenital immunodeficiency

syndromes are also associated with an increased incidence of HLH. These include the following:

● Griscelli syndrome (GS) – GS type 2 is caused by mutations of RAB27A, which encodes a

GTP-binding protein [43]. GS2 is characterized by hypopigmentation, immune deficiency,
thrombocytopenia, and/or neurologic defects. (See "Syndromic immunodeficiencies", section
on 'Griscelli syndrome'.)
● Chediak-Higashi syndrome (CHS) – CHS is caused by mutations of CHS1/LYST, which

encodes a lysosomal trafficking regulatory protein [44]. CHS is characterized by partial
oculocutaneous albinism, neutrophil defects, neutropenia, and neurologic abnormalities. (See
"Chediak-Higashi syndrome".)
● X-linked lymphoproliferative disease – X-linked lymphoproliferative disease type 1 (XLP1) is

caused by mutations in SH2 domain protein 1A (SH2D1A), also called signaling lymphocyte
activation molecule (SLAM)-associated protein (SAP), which encodes an activator of NK and T
cells [45]. XLP2 is caused by mutations in X-linked inhibitor of apoptosis (XIAP), also called
baculoviral IAP-repeat-containing protein 4 (BIRC4); the encoded protein protects cells from
apoptosis [46]. XLP (also called Duncan disease) is characterized by an abnormal response to
Epstein-Barr virus (EBV) infection. (See "X-linked lymphoproliferative disease", section on
'Genetics'.)
● XMEN disease – X-linked immunodeficiency with magnesium defect, EBV infection, and
neoplasia (XMEN) disease is another immunodeficiency syndrome with EBV-associated
malignancies and rarely HLH [47]. A loss-of-function mutation in a gene encoding magnesium
transporter 1 (MAGT1) leads to CD4 lymphopenia, chronic, high-level EBV infection, normal
levels of NK-T cells, and dysregulated immune responses to EBV. (See "Malignancy in primary
immunodeficiency", section on 'XMEN disease'.)
● Interleukin-2-inducible T cell kinase (ITK) deficiency – Patients with ITK deficiency, like
those with XLP and XMEN deficiencies, are unable to control EBV infections. They have a
variety of lymphoproliferative diseases, lymphomatoid granulomatosis, HLH, and
dysgammaglobulinemia.
● CD27 (TNFRSF7) deficiency – Missense mutations that reduce expression of CD27 have
been associated with a syndrome of severe EBV infections associated with HLH, Hodgkin
lymphoma, uveitis, and recurrent infections [48].
● Hermansky-Pudlak syndrome (HPS) – HPS is a rare disorder characterized by

oculocutaneous albinism and platelet storage pool deficiency [49,50]. Several responsible gene
mutations have been identified: HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1
(HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN). (See "Hermansky-Pudlak syndrome".)

● Lysinuric protein intolerance – Lysinuric protein intolerance (LPI; MIM 222700) is a recessive
aminoaciduria caused by defective cationic amino acid transport in epithelial cells of the
intestine and kidney. SLC7A7 (also called y+LAT1), the gene mutated in LPI, encodes the light
subunit of a cationic amino acid transporter. Patients with LPI frequently display severe
complications such as pulmonary disease, hematologic abnormalities, and disorders of the
immune response [51].
● Chronic granulomatous disease (CGD) – CGD is a genetically heterogeneous condition

associated with recurrent, life-threatening bacterial and fungal infections. (See "Chronic
granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)
Genotype-phenotype correlations — Patients with HLH gene mutations tend to present at a

younger age than those without mutations. The affected gene and specific type and site of mutation
may affect the age of presentation and clinical features, but there is controversy regarding the
contribution of hypomorphic mutations to development of HLH [35,36]. Informative studies that
evaluated genotype-phenotype correlations with HLH include:
● Patients with PRF1 null mutations typically present within the first year of life, whereas those
with missense mutations and variable degrees of perforin expression have a more variable age
of presentation, even into adulthood [52-59].
● In a series of 76 patients with HLH, those with PRF1 mutations had a significantly higher risk of
early disease onset (ie, <6 months) than those with STX11 mutations (adjusted odds ratio 8.2;
95% CI 1.2-56) [60].
● In another study, the most common PRF1 mutation in African Blacks (50delT-PRF1) was found
to be associated with an earlier age of disease onset compared with that reported for other
PRF1 mutations (median age at diagnosis, three months for 50delT-PRF1 versus 36 months for
others) [55,61].
● In a series of patients with digenic inheritance (inheritance of mutations at two separate FHL
loci), PRF1 mutation in combination with a mutation affecting degranulation (eg, UNC13D,
STX11, STXBP2) predicted disease onset at age two years or greater, whereas two mutations
affecting degranulation predicted disease onset at <2 years of age [30].
● Adult patients with hypomorphic mutations of PRF1, MUNC13-4, and STXBP2 often have a
more indolent course than younger patients [35].
● Individuals with STXBP2/Munc18-2 mutations (FHL-5) have defective erythropoiesis with

aberrant cell morphology and decreased CD235a expression resulting in hemolysis [62].

EPIDEMIOLOGY
HLH is primarily a pediatric syndrome. Infants are most commonly affected, with the highest
incidence in those <3 months [63]. The male-to-female ratio is close to 1:1 [63]. In adults, there may
be a slight male predisposition [64].
It is estimated that approximately 1 child in 3000 admitted to a tertiary care pediatric hospital will
have HLH, which corresponds to several cases per center per year [23]. Earlier reviews reported
much lower rates of incidence, likely reflecting underdiagnosis of the condition. As an example, in a
series from the 1970s that reported an incidence of 1.2 children per million per year, the diagnosis
of HLH was made antemortem in only 11 of 32 patients [63]. A review of HLH cases from the largest
pediatric hospitals in Texas revealed an incidence of 1 in 100,000 children [65].
Although HLH is primarily a pediatric disease, it is diagnosed in patients of all ages, including adults
as old as 70 years of age [52,53,66]. A review of 2197 adult cases worldwide found that
approximately half of reported patients were from Japan [64]. A nationwide survey in Japan from
2001 to 2005 identified 799 patients with HLH; of the 470 with sufficient data for analysis, 192 (41
percent) were older than 14 years [67]. In addition, there seems to be an ethnic predisposition for
development of malignancy-associated HLH, with one large study demonstrating a much higher risk
in Japanese and East Asian patients with malignancy compared with Western patients [68].
Up to one-quarter of HLH cases are thought to be familial. The frequency of specific HLH mutations
was evaluated in a multi-ethnic cohort of 76 patients with familial HLH originating from 65 unrelated
families [60]. In this cohort, mutations in STX11, PRF1, and UNC13D were found in 20, 18, and 10
percent of affected individuals, respectively.
A review of 224 North American patients with HLH mutations found the following distribution of
specific mutations according to ethnicity [23]:
● Whites were most likely to have mutations in UNC13D (47 percent), STXBP2 (22 percent), and
PRF1 (20 percent)
● Hispanics were most likely to have mutations in PRF1 (71 percent) and UNC13D (17 percent)
● Blacks were most likely to have mutations in PRF1 (98 percent)
● Arabs were most likely to have mutations in PRF1 (36 percent), UNC13D (27 percent), and
STXBP2 (18 percent)
Other studies of specific ethnic groups have found the following distributions:

● Individuals of Turkish origin had a high incidence of mutations in PRF1, UNC13D, or STX11
[69]
● Individuals from Saudi Arabia, the United Arab Emirates, and Turkey had a high incidence of
STXBP2 mutations [54,70,71]
● Japanese individuals had a high incidence of PRF1 mutations [72]
Genetic causes of HLH are discussed above. (See 'Genetics' above.)
CLINICAL FEATURES
Initial presentation — HLH presents as a febrile illness associated with multiple organ
involvement. Thus, initial signs and symptoms of HLH can mimic common infections, fever of
unknown origin, hepatitis, or encephalitis. With few exceptions, the clinical features are similar
regardless of whether an underlying genetic defect has been identified. (See 'Genotype-phenotype
correlations' above.)
The HLH-2004 study, which included 369 patients, reported the following clinical findings [73]:
● Fever – 95 percent
● Splenomegaly – 89 percent
● Bicytopenia – 92 percent
● Hypertriglyceridemia or hypofibrinogenemia – 90 percent
● Hemophagocytosis – 82 percent
● Ferritin >500 mcg/L – 94 percent
● Low/absent NK cell activity – 71 percent
● Soluble CD25 elevation – 97 percent
In addition to the typical presenting signs and symptoms, some HLH gene mutations are associated
with distinct clinical features. As an example, a review of 37 patients with STXBP2 mutations
reported hypogammaglobulinemia, severe diarrhea, bleeding, and sensorineural hearing loss in 59,
38, 22, and 16 percent, respectively [54]. Defective granule mobilization by neutrophils has also
been identified in these patients [74]. This leads to inadequate bacterial killing, especially of gram
negative bacteria, and is hypothesized to lead to the association of chronic diarrhea in this subset of
HLH patients.
Some clinical findings are observed less frequently in affected patients from different ethnic groups.
This was illustrated in a case series of 20 neonates from Japan, in which the incidence of fever was
extremely low in the eight preterm infants (12 percent); hypertriglyceridemia and neutropenia were
uncommon; and familial mutations were undetectable in most patients (65 percent) [75].
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Laboratory and radiographic abnormalities
Cytopenias — Cytopenias, especially anemia and thrombocytopenia, are seen in >80 percent of
patients on presentation [65,73,76,77]. Platelet counts range from 3000 to 292,000 (median
69,000)/microL, and hemoglobin levels of 3.0 to 13.6 (median 7.2) g/dL are typical [65].
Cytopenias may occur later in the disease course in patients with macrophage activation syndrome
(MAS; ie, HLH in the setting of a rheumatologic disorder), especially those with juvenile idiopathic
arthritis (JIA), because patients with JIA often have elevated blood counts prior to developing MAS.
Serum ferritin levels — A very high serum ferritin level is common in HLH and, especially in
children, has high sensitivity and specificity. In the HLH-94 study, ferritin levels greater than 500,
5000, and 10,000 ng/mL were seen in 93, 42, and 25 percent, respectively; the median ferritin level
was 2950 ng/mL [76]. Serum ferritin in this range is seen in very few other inflammatory disorders in
children, and when it does occur in other syndromes, it is often in the setting of iron overload
syndromes (eg, in multiply transfused patients). This was illustrated in a series of 330 children with
high serum ferritin levels (320 controls and 10 HLH patients), in which a ferritin level >10,000 ng/mL
was 90 percent sensitive and 96 percent specific for HLH, with very minimal overlap with sepsis,
infections, and liver failure [78]. When the control group was re-analyzed with a comparison cohort
of 120 patients with HLH, a ferritin level ≥2000 mcg/L had a 70 percent sensitivity and 68 percent
specificity for diagnosing HLH [79]. There was no difference when primary and secondary HLH
cases were analyzed separately.
In adults and neonates, other potential causes of extremely high ferritin levels should also be
evaluated. As an example, ferritin levels over 10,000 ng/mL can be seen in neonatal
hemochromatosis or fulminant liver failure; however, the presence of cytopenias and fevers, as well
as elevated soluble IL-2 receptor alpha (sIL-2R) and sCD163 in patients with HLH may help to
exclude these other possible diagnoses [80]. (See 'Other diagnostic considerations' below and
'Differential diagnosis' below.)
While a very high ferritin level is helpful in suggesting the possibility of HLH, a low ferritin (eg, ferritin
<500 ng/mL) does not exclude the possibility of HLH. A relatively normal ferritin can occasionally be
seen in HLH genetic syndromes, even during a disease flare, and disease activity in some patients
may correlate more closely with elevated sIL-2R or sCD25 than with ferritin.
Macrophages are a primary source of ferritin, which may account for the association between HLH
and very high ferritin levels [81]. A protein responsible for modulation of iron homeostasis, growth
differentiation factor 15, is dramatically upregulated in patients with HLH and is responsible for
increased serum ferritin by enhancing the ferroportin-mediated iron efflux [82].
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Liver function and coagulation abnormalities — Nearly all patients with HLH will have
hepatitis, manifested by elevated liver function tests (LFTs), including liver enzymes (AST, ALT,
GGT), lactate dehydrogenase (LDH), and bilirubin. Increased triglycerides and abnormal
coagulation parameters (especially elevated D-dimer) caused by hepatic dysfunction and
disseminated intravascular coagulopathy are also frequently seen. The degree of abnormality
ranges from mild to hepatic failure; hydrops fetalis has been reported in neonates [83].
● Liver enzyme levels greater than three times the upper limit have been reported in 50 to 90
percent of patients with HLH [65,77,83]; LDH is elevated in 85 percent [77]. Bilirubin levels
between 3 and 25 mg/dL are seen in greater than 80 percent. The GGT level is an especially
sensitive number to follow because of biliary tract infiltration by lymphocytes and macrophages
[23].
● Hypertriglyceridemia can be due to severe liver involvement, but may not be elevated until the
liver has been affected for some time. In a review of patients with HLH associated with a variety
of triggers, 68 percent had elevated triglycerides at diagnosis or during the course of the
disease [84].
● Coagulation abnormalities due to impaired hepatic synthetic function and/or disseminated

intravascular coagulation are common [85].
● Liver biopsy, if done, is likely to show lymphocytic infiltrates in patients with HLH. On autopsy,
the livers of patients who have died from HLH show chronic persistent hepatitis with periportal
lymphocytic infiltration [86].
Neurologic findings — Neurologic abnormalities have been observed in one-third of patients

with HLH, are highly variable, and may include seizures, mental status changes (including severe
changes consistent with encephalitis), and ataxia [2,23,87]. These findings may dominate the
clinical picture or develop prior to the appearance of other signs and symptoms [88,89]. As an
example, two patients with familial HLH due to a PRF1 mutation presented with isolated HLH of the
central nervous system; one patient presented with severe encephalitis, while the other presented
with a demyelinating peripheral neuropathy caused by diffuse macrophage infiltration of the nerve
sheath [90,91].
Patients with HLH are at risk of developing posterior reversible encephalopathy syndrome (PRES),
which presents with headache, altered consciousness, visual disturbances, and/or seizures. On
examination, patients may have retinal hemorrhages and optic nerve edema. PRES is associated
with characteristic findings on brain magnetic resonance imaging (MRI), including vasogenic
cerebral edema predominantly in the posterior cerebral hemispheres. (See "Reversible posterior
leukoencephalopathy syndrome".)
MRI of the brain in patients with HLH also may show hypodense or necrotic areas [92].
Approximately 50 percent of patients have abnormalities of the cerebrospinal fluid, which may carry
an increased risk for mortality and neurologic sequelae [93]. In a series of 10 adults with HLH,
seven had neurological impairment, which included encephalopathy and seizures. Basal ganglia
abnormalities were found in four patients [94]. (See 'Initial evaluation' below and "Treatment and
prognosis of hemophagocytic lymphohistiocytosis", section on 'Prognosis'.)
Other findings — HLH can affect other organ systems, including the respiratory system, heart,
and skin.
● Respiratory abnormalities may lead to an urgent need for ventilatory support and death from
acute respiratory distress syndrome. Deteriorating respiratory function may be due to
worsening of the HLH (causing an acute respiratory distress syndrome [ARDS]-like syndrome),
or due to an infection. Pulmonary involvement was reported in 42 percent of a series of 775
adults with HLH [64].
● Severe hypotension may require administration of one or more vasopressors.
● Renal dysfunction occurs in many patients and may present with hyponatremia, perhaps
caused by a syndrome of inappropriate ADH (SIADH) mechanism. Many patients develop renal
failure and require dialysis. Renal involvement was reported in 16 percent of a series of 775
adults with HLH [64].
● Skin manifestations can be quite varied. These include generalized rashes, erythroderma,
edema, petechiae, and purpura. Skin rash was reported in one-quarter of a series of 775 adults
with HLH [64].
● Bleeding is also a common manifestation of HLH. It may be due to altered coagulation from
liver failure, thrombocytopenia from bone marrow failure, or platelet function defects associated
with an underlying genetic defect in platelet granule processing. (See 'Genetics' above.)
● Patients with underlying immunodeficiency syndromes may also have syndrome-specific

findings (eg, albinism). (See 'Immunodeficiency syndromes' above.)
● Some have clinical features of Kawasaki disease, including conjunctivitis, red lips, and cervical
lymphadenopathy. (See "Kawasaki disease: Clinical features and diagnosis", section on
'Clinical manifestations'.)
Associated illnesses — Infection, malignancy, rheumatologic, and immunodeficiency syndromes

are common in patients with HLH, especially adults. (See 'Features in adults' below.)

It is important to identify these conditions because effective treatment may lead to clinical
improvement of the HLH and allow the patient to avoid more toxic therapy (eg, hematopoietic cell
transplant). However, evaluation for these associated syndromes should not delay diagnostic testing
or initiation of HLH-specific treatment in those who are acutely ill.
Infections — HLH is often associated with viral infections, including Epstein-Barr virus (EBV),
cytomegalovirus (CMV), parvovirus, herpes simplex virus, varicella-zoster virus, measles virus,
human herpes virus 8, H1N1 influenza virus, parechovirus, and HIV, alone or in combination [64,95-
103]. An HLH-like syndrome has been reported in association with SARS-CoV-2 (the novel
coronavirus that causes COVID-19) [104,105]. The development of HLH shortly after the initiation of
antiretroviral therapy (ART) for the treatment of HIV infection has also been reported [106]. Patients
with rheumatologic diseases who are treated with anti-TNF agents and develop HLH may be
infected with mycobacterium tuberculosis, CMV, EBV, Histoplasma capsulatum, and other bacteria
[107].
Although less common, HLH may also occur in the setting of infections due to bacteria (eg,
Brucella, gram negative bacteria, tuberculosis), parasites (eg, Leishmaniasis, malaria), and fungi
[64,103,108,109].
Malignancy — HLH has been reported in association with malignancies, most commonly
lymphoid cancers (including B, T, and NK cell) and leukemias, but also solid tumors [23,103,110-
122]. Rarely, the diagnosis of HLH may precede the identification of the malignancy [123]. A review
of malignancy-associated HLH from a single institution revealed an 18 percent incidence of HLH in
patients with acute myeloid leukemia and a 4 percent incidence in patients with acute lymphocytic
leukemia [124].
Many patients with a malignancy who develop secondary HLH seem to have an acute infectious
trigger. A retrospective review of 22 patients with hematologic malignancies and secondary HLH at
one center reported BK virus in 54 percent, HHV-6 in 33 percent, EBV in 28 percent, CMV in 24
percent, adenovirus in 17 percent, and parvovirus-type B in 17 percent [124]. When it is associated
with a malignancy, HLH is often more immediately life-threatening than the malignancy itself. (See
"Causes of anemia in patients with cancer" and "Clinical manifestations, pathologic features, and
diagnosis of subcutaneous panniculitis-like T cell lymphoma" and "Clinical manifestations,
pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)
Overall prognosis is quite poor for any malignancy-associated HLH, regardless of the patient's age
at presentation, as discussed separately. (See "Treatment and prognosis of hemophagocytic
lymphohistiocytosis", section on 'Prognosis'.)

Rheumatologic disorders/MAS — HLH can occur in the setting of rheumatologic disorders.

The most common association is in children with systemic juvenile idiopathic arthritis (sJIA, formerly
called Still's disease, systemic onset JIA, or systemic onset juvenile rheumatoid arthritis). The term
macrophage activation syndrome (MAS) is used when a hemophagocytic syndrome develops in
children with JIA and other rheumatologic conditions. MAS should be thought of as HLH in the
setting of a rheumatologic disorder rather than as a separate syndrome. Performance guidelines for
the diagnosis of MAS have been published [125]. (See "Systemic juvenile idiopathic arthritis:
Course, prognosis, and complications", section on 'Macrophage activation syndrome' and
"Kawasaki disease: Complications", section on 'Macrophage activation syndrome'.)
HLH may develop any time during the course of a rheumatologic disorder (eg, on presentation,
during therapy, in association with a concurrent infection). In patients with sJIA treated with
tocilizumab, 23 of 394 developed confirmed or probable MAS [126]. When MAS occurs as a
presenting manifestation of lupus and systemic juvenile or adult rheumatoid arthritis, the diagnosis
of both conditions may be challenging. Other autoimmune diseases associated with HLH include
dermatomyositis, systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome,
Sjögren's syndrome, ankylosing spondylitis, vasculitis, and sarcoidosis [85]. Some patients with
MAS have also been found to have heterozygosity for mutations in HLH genes (eg, PRF1,
UNC13D) [34]. (See 'Genetics' above.)
Immunodeficiency — HLH has been found in patients with inherited immunodeficiency

disorders, including those due to mutations that are associated with HLH as well as others [25,43-
45,127-130]. (See 'Immunodeficiency syndromes' above.)
Acquired immunodeficiencies have also been associated with HLH, including HIV/AIDS,
hematopoietic cell transplantation, or kidney or liver transplant [103,131,132]. Sometimes HLH
occurs in the setting of a concurrent infection or a lymphoproliferative syndrome [133-135]. In one
small series, the development of HLH in kidney transplant patients appeared to be associated with
the combination of splenectomy and the administration of anti-thymocyte globulin [136].
Features in adults — HLH presenting in adulthood is increasingly recognized [64,137-141]. Adults

can have similar clinical features of HLH as children. As an example, a series of 775 adults with
HLH reported similar predominance of fever (96 percent), splenomegaly (69 percent), and
hepatomegaly (67 percent) [64].
However, emerging diagnostic criteria for adults with HLH indicate several differences from those
used in pediatric patients. A Delphi analysis (a method for finding consensus using iterative
anonymous questionnaires) from an expert panel determined the following clinical features to be
important in adults [142]:

● Underlying predisposing disease

● Fever
● Organomegaly
● Cytopenias
● Elevated ferritin
● Elevated LDH
● Hemophagocytosis on the bone marrow aspirate
A 2015 review noted that HLH in adults is more likely to be associated with a hematologic
malignancy, and an elevated ferritin level is less specific in adults due to the higher incidence of
other inflammatory conditions [137].
The frequency of underlying conditions such as hematologic malignancies, infections, and

rheumatologic conditions in adults with HLH have been illustrated in various case series:
● In a series of 162 adults with HLH, hematologic malignancies (especially non-Hodgkin

lymphoma) were the most common trigger, seen in 92 (57 percent) [143]. An additional 40
patients (25 percent) had infections, which were caused by bacterial, viral, parasitic, or fungal
organisms; six (4 percent) had both hematologic malignancy and infection. Additional analysis
of this cohort identified a source of immunosuppression in 73 (45 percent) [144]. For 61, the
source of immunosuppression was HIV infection; for the remainder, it was an
immunosuppressive medication.
● Several single-institution studies focusing on HLH in adults have documented infection in 23 to

41 percent of patients and rheumatologic/autoimmune disease in 8 to 20 percent [145-147]. In
a series of 30 patients who had testing for EBV DNA, 10 were found to be positive [148]. Adults
with EBV-associated HLH have higher ferritin, LDH, AST, and ALT levels than those without
EBV infection [149].
● Reports of coexisting autoimmune and rheumatologic diseases in adults include systemic lupus
erythematosus, rheumatoid arthritis, Still's disease, polyarteritis nodosa, mixed connective
tissue disease, pulmonary sarcoidosis, systemic sclerosis, and Sjögren's syndrome
[85,103,136,150-155].
The reduced specificity of an extremely high ferritin in adults was illustrated in a series of 113 adults
with a serum ferritin level >50,000 ng/mL (median age, 58) [156]. Of these, only 19 (17 percent)
were ultimately diagnosed with HLH; 9 of the 19 had secondary HLH due to a malignancy and 6 of
the 19 had secondary HLH due to infection. More common diagnoses than HLH included renal
failure (65 percent), hepatocellular injury (54 percent), infection (46 percent), and hematologic

malignancy (32 percent). Other diagnoses associated with extremely high ferritin levels in adults are
discussed separately. (See 'Differential diagnosis' below.)
The later age of onset in some adults may be explained by the presence of a mutation with partial
residual protein function, which may be able to compensate in the setting of some immune triggers.
(See 'Genetics' above.)
EVALUATION AND DIAGNOSTIC TESTING
Initial evaluation — Most patients with HLH are acutely ill with multiorgan involvement, cytopenias,
liver function abnormalities, and neurologic symptoms. Patients may have already experienced a
prolonged hospitalization or clinical deterioration without a clear diagnosis before the possibility of
HLH is raised. A priority should be placed on rapid evaluation for organ involvement including
testing for signs of bone marrow insufficiency, liver abnormalities, neurologic involvement, and
immune activation, with the goal of starting treatment as rapidly as possible once the diagnosis (or a
high likelihood) of HLH is established. The diagnostic approach is similar in infants, children, and
adults [23].
Patients with suspected HLH (or their families) should be asked about parental consanguinity,
familial disorders, antecedent infections, recurrent fevers, and pre-existing immunologic defects (eg,
HIV infection, rheumatologic disorders, immunosuppressive medications). (See 'Genetics' above
and 'Associated illnesses' above.)
The physical examination should focus on identifying rashes, bleeding, lymphadenopathy,

hepatosplenomegaly, and neurologic abnormalities. A thorough examination for signs of other organ
involvement (eg, cardiac, respiratory) is also necessary.
Many of the initial tests that are helpful in evaluating HLH will have already been done as part of the
evaluation of an unexplained febrile illness that involves multiple organs. Others, including serum
ferritin, triglycerides, and screening immunologic studies, should be done immediately.
We suggest the following tests in all patients:
● Complete blood count with differential
● Coagulation studies, including PT, aPTT, fibrinogen, D-dimer
● Liver function tests, including ALT, AST, GGT, total bilirubin, albumin, and lactate
dehydrogenase (LDH)

● Serum triglycerides (fasting)
● Serum ferritin
● Soluble IL-2 receptor alpha (sCD25 or sIL-2R), and/or CXCL9
Identifying signs of infection and specific organ injury is helpful in making the diagnosis of HLH, as
well as for management of organ-specific complications. Based on the symptoms and signs of
specific organ involvement and/or the degree of suspicion for the presence of HLH, we perform the
following studies in all patients:
● Cultures of blood, bone marrow, urine, cerebrospinal fluid, and other potentially infected body
fluids; and viral titers and quantitative polymerase chain reaction (PCR) testing for Epstein-Barr
virus (EBV), cytomegalovirus (CMV), adenovirus, and other suspected viruses. It is critical to
follow the levels of any identified virus during treatment with the appropriate anti-viral therapy.
● Bone marrow evaluation. (See 'Bone marrow evaluation' below.)
● Electrocardiograph, chest radiography, and an echocardiogram.
● Lumbar puncture with cerebrospinal fluid (CSF) analysis should be performed for all patients,
including cultures and testing for viruses (eg, by PCR), as indicated by clinical findings and
epidemiology. CSF is abnormal in over half of patients with HLH, with findings of cellular
pleocytosis, rarely hemophagocytosis, and elevated protein. (See "Viral encephalitis in adults"
and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)
● Brain magnetic resonance imaging (MRI) scan, with and without contrast (unless contrast is
contraindicated). Imaging of the central nervous system may show parameningeal infiltrations,
subdural effusions, necrosis, and other abnormalities.
● Computed tomography (CT) scans of neck, chest, abdomen, and pelvis or a positron emission
tomography (PET) scan to evaluate for occult malignancy.
● Abdominal ultrasound, if the physical examination for splenomegaly is inconclusive.
We do a rapid immunologic evaluation in those with a high clinical suspicion of HLH. (See
'Immunologic profile' below.)
Bone marrow evaluation — All patients should have a bone marrow aspirate and biopsy to
evaluate the cause of cytopenias and/or detect hemophagocytosis. Bone marrow specimens should
also be cultured, and examined for infectious organisms and evidence of malignancy. Bone marrow

cellularity can be high, low, or normal in HLH [23]. Hemophagocytosis on bone marrow examination
is reported in 25 to 100 percent of cases of HLH [143].
Hemophagocytosis is not pathognomonic for HLH. A review of 78 bone marrow aspirates that
showed hemophagocytosis included 40 that were associated with diagnosis of HLH and 38 without
an associated diagnosis of HLH; however phagocytosis of nucleated cells or multiple nucleated
cells was strongly correlated with a diagnosis of HLH [157]. Some patients may only show
hemophagocytosis later in the disease course, even as they are clinically improving [23]. A review
of adult patients exhibiting hemophagocytosis in bone marrow aspirates revealed that 170 (64
percent) had lymphoma, especially T/NK and B cell lymphoma. Of 182 patients with sufficient
clinical data to judge HLH-2004 diagnostic criteria for HLH, only 77 (29 percent) fulfilled 5 of 8
criteria (see 'Diagnostic criteria' below). Of those who had a malignancy, survival was a median of 9
months, versus 71.8 months in those with non-malignant disorders [158].
Infiltration of the bone marrow by activated macrophages is consistent with HLH. The macrophages
in HLH do not have the cellular atypia associated with malignant histiocytes, and they are clearly
different from the CD1a-staining Langerhans cells of Langerhans cell histiocytosis (formerly called
histiocytosis-X). It is helpful to stain the bone marrow for the hemoglobin-haptoglobin scavenger
receptor CD163 to highlight the macrophages (both hemophagocytosing and not). (See 'Diagnosis'
below.)
Specialized testing
Immunologic profile — Immunologic and cytokine studies are appropriate for those suspected
of having HLH based on the results of the initial evaluation. (See 'Initial evaluation' above.)
We typically perform the following immunologic testing:
● Soluble IL-2 receptor alpha (sCD25 or sIL-2R)
● Tests of NK cell function/degranulation (eg, by flow cytometry for surface expression of

CD107alpha, also called LAMP-1 [lysosomal-associated membrane protein 1])
● Flow cytometry for cell surface expression of perforin and granzyme B proteins
● Flow cytometry for cell surface expression of SAP and XIAP proteins in males
● Soluble levels of the hemoglobin-haptoglobin scavenger receptor (sCD163)
● Immunoglobulin levels (eg, IgG, IgA, IgM)
● Lymphocyte subsets (underlying immune deficiency diseases are sometimes found)

The first five are only available in specialized centers [159].
Findings consistent with HLH include elevated sIL-2R; reduced NK function or cell surface
expression of CD107alpha; elevated sCD163; and reduced perforin, SAP, or XIAP [6,160-165].
Immunoglobulin levels are variable [6]. Peripheral blood lymphocyte subsets generally show normal
T cell numbers and helper/suppressor ratio, and may show decreased numbers of B cells or NK
cells [6,166]. Elevation of granzyme B has been found and is thought to be part of the immune
signature of lymphocyte activation [167].
Of all the immunologic studies, we find sIL-2R to correlate most closely with disease activity [23].
The ratio of sIL-2R to serum ferritin may be useful in patients with lymphoma. A review of patients
with lymphoma-associated HLH versus non-lymphoma-associated cases found that the former had
a much higher ratio of sIL-2R to ferritin than the latter (ratio 8.56 versus 0.66) [168].
Levels of the sIL-2R will be available in one to two days, while the other tests take longer. Thus,
therapy should not be delayed while awaiting results of this immunologic testing.
The NK cytotoxicity assay is not widely available, is labor-intensive, and has limited utility in cases
of low circulating NK cells. Flow cytometry for reduced/absent NK cell perforin and CD107alpha is
more sensitive and has equivalent specificity in screening patients for HLH, and may be an
acceptable surrogate [169].
HLH associated with lymphoma can be challenging to differentiate from clinical presentations of
sepsis. A study in 15 adults with lymphoma-associated HLH showed potential for the use of assays
of the cytokines CXCL9 and CXCL10; elevated levels had a high sensitivity and specificity for
lymphoma-associated HLH compared to sepsis [170].
Genetic testing — Genetic testing (ie, identification of an HLH gene mutation) is indicated in all
patients who meet the diagnostic criteria for HLH, and in those with a high likelihood of HLH based
on the initial evaluation.
For patients whose relatives have a known familial syndrome, selective genetic testing may be used
to confirm the genetic disorder.
For patients without an identified familial syndrome, we favor genetic testing with either a next
generation sequencing panel of HLH-associated genes or whole exome sequencing; for some
cases, it may be necessary to request intronic sequencing to find rare variants [36]. These
approaches offer efficiency of testing, the possibility of identifying biallelic or hypomorphic
mutations, and/or the possibility of identifying novel HLH-associated gene defects [36]. Moreover, if
allogeneic hematopoietic cell transplant (HCT) is being considered, the patient and any matched

related donor should have expedited whole exome sequencing performed to mitigate the risk of an
unsuccessful transplant due to transplantation with a similar genetic defect.
An acceptable alternative for evaluating patients without a known familial syndrome is selective
testing guided by the immunophenotype:
● If cellular perforin protein levels are low, we do PRF mutation analysis.
● If CD107alpha mobilization is low, we do UNC13D, STX11, STXBP2, and RAB27A mutation

analysis.
● If SAP expression is low, we do SH2D1A mutation analysis.
● If XIAP expression is low, we do BIRC4 mutation analysis.
Laboratories that can perform genetic testing can be found in the Genetic Testing Registry
(http://www.ncbi.nlm.nih.gov/gtr/tests/). (See "Next-generation DNA sequencing (NGS): Principles
and clinical applications", section on 'Whole genome, exome, or gene panel'.)
HLA testing — Human leukocyte antigen (HLA) typing is indicated during the initial evaluation in
preparation for identifying a donor for allogeneic HCT. Performing this testing at the time of initial
presentation avoids delays in identifying donors should they be needed. (See "Treatment and
prognosis of hemophagocytic lymphohistiocytosis".)
DIAGNOSIS
HLH should be suspected in an infant, child, or adult with unexplained cytopenias, hepatitis, or
inflammatory central nervous system findings who has unexplained fever, hepatosplenomegaly,
prior HLH-like episodes, a family history of HLH, or a known genetic disorder associated with HLH.
The natural history of untreated HLH syndrome is almost uniformly fatal. A high degree of suspicion
is required because of the clinical complexity, rarity, and diversity of causes. Prompt recognition of
the HLH syndrome and diagnosis of the underlying cause of HLH disease is critical to enable urgent
and appropriate treatment.
Diagnostic criteria — The diagnosis of HLH syndrome is based on a compatible clinical

presentation in the setting of elevated inflammatory markers (eg, ferritin, sCD25, and/or CXCL9).
(See 'Clinical features' above.)
If neither sCD25 nor CXCL9 is elevated, the diagnosis of HLH is unlikely and other disorders in the
differential diagnosis should be strongly considered. (See 'Differential diagnosis' below.)
Ideally, the diagnosis of HLH is based on fulfilling the published diagnostic criteria used in the HLH-
2004 trial [23]. Not infrequently, however, a diagnosis of HLH is made in the patient who only partly
meets the most stringent criteria because definitive HLH therapy must be initiated due to an
inadequate response to general supportive care. A presumptive diagnosis depends on a careful
consideration of the presence or absence of the specific elements of the diagnostic criteria, the
results of additional laboratory tests (eg, D-dimer and liver function tests), and a nuanced view of
the overall clinical status.
We recommend that the diagnosis of HLH be based on the following criteria, which were used in the
HLH-2004 trial [23,73]:
In children, homozygosity or compound heterozygosity for verified HLH-associated mutations (eg,

PRF1, UNC13D, STX11, STXBP2, Rab27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS) or
gene defects of other immune regulatory genes (identified by whole exome sequencing [WES]),
described above. (See 'Terminology' above.)
In adults, heterozygosity of one of the above genes together with clinical findings associated with
HLH [35,36].
OR
Five of the following eight findings:
● Fever ≥38.5°C
● Splenomegaly
● Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL (for infants <4
weeks, hemoglobin <10 g/dL); platelets <100,000/microL; absolute neutrophil count
<1000/microL
● Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen

<150 mg/dL)
● Hemophagocytosis in bone marrow, spleen, lymph node, or liver
● Low or absent NK cell activity
● Ferritin >500 ng/mL (the author prefers to consider a ferritin >3000 ng/mL as more indicative of
HLH [78])

● Elevated soluble CD25 (soluble IL-2 receptor alpha [sIL-2R]) two standard deviations above
age-adjusted laboratory-specific norms
It should be noted that these diagnostic criteria were devised for use in clinical trials and are
therefore unlikely to capture every case of HLH. Because of the high mortality of HLH in the
absence of appropriate treatment, we do not always require these diagnostic criteria to be met in
order to initiate treatment. Specifically, we do not delay treatment while awaiting the results of
genetic or specialized immunologic testing.
Diagnostic criteria are essentially the same in adults, with the caveat that adults are more likely to
have a secondary form of HLH than children, and adults with secondary HLH are more likely to
have an underlying malignancy as the cause.
We consider flow cytometry for reduced/absent NK cell perforin and/or CD107alpha a satisfactory
alternative to the NK cytotoxicity assay.
We consider the following modified criteria sufficient to diagnose HLH: three of four clinical findings
(fever, splenomegaly, cytopenias, hepatitis) plus abnormality of one of four immune markers
(hemophagocytosis, increased ferritin, hypofibrinogenemia, absent or very decreased NK cell
function) [23,171]. These criteria are useful because it is common for a patient with HLH to exhibit
only three or four of the eight diagnostic criteria, but also have central nervous system (CNS)
symptoms, hypotension, and renal or respiratory failure.
Examples of others we would be likely to treat include the following:
● A patient with CNS symptoms, cytopenias, fever, and

ferritin over 3000 ng/mL or rapidly rising ferritin or elevated sCD25
● A patient with CNS symptoms, hepatitis, coagulopathy, and

● A patient with hypotension, fever, no response to broad spectrum antibiotics, and

In contrast, we would not give HLH-specific therapy to a patient with fever, hepatitis,
hypofibrinogenemia, and cytopenias, with a ferritin <3000 ng/mL and sCD25 only slightly above the
age-related norm, because of the possibility that this could represent bacterial or viral infections.
Other diagnostic considerations — Although hemophagocytosis and a very high serum ferritin
are quite helpful in the diagnosis of HLH (see 'Serum ferritin levels' above), the following caveats
are important to keep in mind:

● Hemophagocytosis is neither pathognomonic of, nor required for, the diagnosis of HLH. For
patients with multiorgan failure and an immunologic profile typical of HLH who are acutely ill,
serial bone marrow evaluations for hemophagocytosis can be conducted concurrently with
initiation of treatment.
● Results from the HLH-94 study indicated that a ferritin level >500 ng/mL was only 80 percent
specific for the diagnosis of HLH.
• Based on our experience, in children we consider serum ferritin levels >2000 to 3000
ng/mL in the proper clinical setting as concerning for HLH, and ferritin >10,000 ng/mL as
highly suggestive of the disease. Support for our approach comes from a retrospective
review of all patients admitted to Texas Children's Hospital, in Houston, Texas, with ferritin
levels >500 mcg/L over a two-year period [78]. In this cohort, a ferritin level >500 mcg/L
was 100 percent sensitive for HLH, but less specific. A ferritin level >10,000 mcg/L in
children was 90 percent sensitive and 96 percent specific for HLH, with very minimal
overlap with sepsis, infections, and liver failure. (See 'Serum ferritin levels' above.)
• In adults, we rely less heavily on an isolated serum ferritin elevation, because serum
ferritin is less specific for HLH in adults. (See 'Features in adults' above.)
A scoring system has been developed to generate a diagnostic score referred to as an "Hscore"
that estimates the probability of HLH [172]; this incorporates points for immunosuppression; fever;
organomegaly; levels of triglycerides, ferritin, alanine aminotransferase, and fibrinogen; degree of
cytopenias; and presence of hemophagocytosis on the bone marrow aspirate. An Hscore ≥250
confers a 99 percent probability of HLH, whereas a score of ≤90 confers a <1 percent probability of
HLH.
DIFFERENTIAL DIAGNOSIS
HLH may simulate a number of common conditions that cause fever, pancytopenia, hepatic
abnormalities, or neurologic findings. We find cytopenias, a very high ferritin level, and liver function
abnormalities to be especially helpful in distinguishing HLH from these other conditions. The
frequency of liver function test (LFT) abnormalities is so high in HLH that we believe the absence of
LFT abnormalities should prompt a thorough search for an alternative diagnosis. (See 'Cytopenias'
above and 'Serum ferritin levels' above and 'Liver function and coagulation abnormalities' above.)
It is also important to remember that HLH can develop in association with many of the conditions in
its differential diagnosis.

● Macrophage activation syndrome (MAS) – MAS should be thought of as a form of HLH

associated with a rheumatologic disease, rather than as a separate clinical entity. (See
'Rheumatologic disorders/MAS' above.)
● Infection/sepsis – Systemic infections and/or sepsis share many features with HLH, including
fever, cytopenias, and hepatic involvement. Both sepsis and HLH can have findings of
disseminated intravascular coagulation and widespread inflammation with cytokine
abnormalities. Unlike HLH, which is often triggered by a viral infection, sepsis is typically
caused by a bacterial or fungal micro-organism, and sepsis is typically not characterized by
ongoing lymphocyte activation. While there is no ideal test to distinguish between sepsis and
HLH, an extremely high ferritin and elevated lactate dehydrogenase level were highly predictive
of a subsequent diagnosis of HLH in a series of 19 children with an initial diagnosis of fever of
unknown origin [77]. Ferritin levels tend to be static in patients with infections, but are prone to
dramatic increases in those with HLH. (See "Sepsis syndromes in adults: Epidemiology,
definitions, clinical presentation, diagnosis, and prognosis".)
● Liver disease/liver failure – Primary liver disease and HLH can both present with
hepatomegaly and elevated LFTs. Both can cause a coagulopathy with prolonged PT and
aPTT, low fibrinogen, and elevated D-dimer, and both can cause encephalopathy. Unlike liver
disease, HLH is a multisystem disorder. Those with HLH typically have more extensive organ
involvement, cytopenias, extremely high ferritin, and neurologic findings. Cytokine profiles seen
in HLH are not typically seen in primary liver disease. (See "Acute liver failure in adults:
Etiology, clinical manifestations, and diagnosis".)
● Multiple organ dysfunction syndrome – Multiple organ dysfunction syndrome (MODS) refers
to progressive organ dysfunction in an acutely ill patient. Like HLH, MODS can affect any organ
system, and there may be some overlap between these diagnoses [173]. It is possible that a
subset of patients who have been diagnosed with MODS have in fact had HLH. An extremely
high ferritin or dramatically increasing ferritin is more consistent with HLH than with MODS.
(See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis,
and prognosis", section on 'Multiple organ dysfunction syndrome' and 'Evaluation and
diagnostic testing' above.)
● Encephalitis – Encephalitis can result from infection, autoimmunity, and a number of viral
infections; and the clinical manifestations can range from subtle neurologic deficits to complete
unresponsiveness. The neurologic presentation of those with encephalitis can thus be identical
to those with HLH. However, those with HLH typically have more extensive organ involvement,
cytopenias, liver abnormalities, and high ferritin, whereas findings in encephalitis are typically

confined to the central nervous system. (See "Acute viral encephalitis in children: Clinical
manifestations and diagnosis" and "Viral encephalitis in adults".)
● Autoimmune lymphoproliferative syndrome (ALPS) – ALPS is an immune dysregulation

syndrome caused by genetic defects in the machinery for FAS-mediated apoptosis, which leads
to expansion of some autoreactive lymphocyte populations. Patients present with
hepatosplenomegaly, rash, and autoimmune cytopenias, along with other autoimmune
manifestations that could mimic findings of HLH (eg, autoimmune hepatitis, Guillain Barré
syndrome). Unlike those with HLH, patients with ALPS typically do not manifest multiorgan
failure and signs of excessive inflammation such as extremely high ferritin levels and severe
liver failure. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and
diagnosis".)
● Drug reaction with eosinophilia and systemic symptoms (DRESS) – DRESS is a severe
drug-induced hypersensitivity reaction possibly initiated by viral reactivation. Like HLH, DRESS
is characterized by fever and liver function test abnormalities. DRESS can also be associated
with hemophagocytosis, although this is rare [174]. Unlike HLH, DRESS is characterized by
temporal relationship to a drug, eosinophilia and skin rash. DRESS is unlikely to cause an
extremely high ferritin or cytopenias, which are found in most patients with HLH. (See "Drug
eruptions", section on 'Drug reaction with eosinophilia and systemic symptoms'.)
● Child abuse – Child abuse and HLH may present with similar features involving the central
nervous system [175,176]. The majority of child abuse victims with brain injury also have some
laboratory abnormalities such as a prolonged aPTT [177]. However, cytopenias, abnormal
LFTs, and high serum ferritin typical of HLH are not features of child abuse. (See "Differential
diagnosis of suspected child physical abuse".)
● Kawasaki disease – Kawasaki disease (KD), a vasculitis that predominantly affects children, is
characterized by widespread inflammation that include fever, rash, lymphadenopathy, elevated
triglycerides, and abnormal cerebrospinal fluid. KD typically causes bilateral conjunctivitis and
mucositis, as well as cardiac findings (eg, coronary artery aneurysms), which are much less
common in HLH; conversely, HLH is more likely to be associated with cytopenias and liver
abnormalities. KD can act as a trigger for HLH, so its diagnosis does not eliminate the
possibility of HLH. Compared with patients with KD, those with HLH associated with KD have a
longer history of fever and higher levels of the N-terminal pro-brain natriuretic peptide (NT-
proBNP; 889 pg/mL versus 233 pg/mL, respectively) [178]. A patient with the diagnosis of KD,
especially if "atypical", whose symptoms do not respond to intravenous immune globulin (IVIG)
therapy, should be evaluated for HLH. (See "Kawasaki disease: Clinical features and
diagnosis" and "Kawasaki disease: Complications", section on 'Cardiac complications'.)
● Cytophagic histiocytic panniculitis – Cytophagic histiocytic panniculitis is a rare systemic

disorder consisting of lobular panniculitis (ie, inflammation of the subcutaneous fat), fever,
hepatosplenomegaly, and liver failure. This panniculitis can be associated with a form of T cell
lymphoma [179,180]. A subset of patients diagnosed with this condition may have had HLH.
These patients with panniculitis, who primarily present with subcutaneous nodules, are less
likely to have the severe multiorgan involvement seen in HLH. (See "Clinical manifestations,
pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma" and
"Panniculitis: Recognition and diagnosis", section on 'Malignancy'.)
● Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or

drug-induced thrombotic microangiopathy (DITMA) – TTP, HUS, and DITMA (also called
drug-induced TTP) are characterized by endothelial damage, microvascular thrombosis, and
anemia; fever, neurologic findings, or renal failure may be present. Unlike the anemia of HLH,
the anemia in these syndromes is microangiopathic (ie, Coombs negative, characterized by
schistocytes). Patients with TTP, HUS, or DITMA generally do not have rising ferritin or liver
function abnormalities, although a DITMA syndrome associated with quinine may have
multiorgan failure. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic
microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy".)
● Transfusion-associated graft-versus-host disease (ta-GVHD) – Ta-GVHD is a rare

complication of transfusion of any non-irradiated blood component. It occurs when viable donor
lymphocytes in the transfusion attack the recipient's tissues (skin, bone marrow, gastrointestinal
tract), often fatally. It is most common after hematopoietic cell transplantation but can also
occur in immunocompetent individuals who have a partial human leukocyte antigen (HLA)
match with the donor (eg, in ethnically homogenous populations or after directed donation). The
typical presentation includes fever, rash, pancytopenia, and elevated liver enzymes, 4 to 30
days after transfusion. High ferritin levels and hemophagocytosis in the bone marrow can also
be seen. Unlike HLH, skin biopsy in ta-GVHD shows vacuolization of the basal layer and a
histiocytic infiltrate, and sometimes the pathognomonic finding of satellite dyskeratosis. In
cases where the two diagnoses cannot be distinguished, a trial of dexamethasone, and, if not
sufficient, etoposide, can be used. (See "Transfusion-associated graft-versus-host disease".)
SUMMARY
● Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of

excessive immune activation. It is most common in infants and young children but can affect
patients of any age, with or without a predisposing familial condition. (See 'Introduction' above
and 'Epidemiology' above.)
● Most patients with HLH are acutely ill with multiorgan involvement. Common findings include
fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high
serum ferritin, and liver function abnormalities. (See 'Initial presentation' above.)
● Patients may have already experienced a prolonged hospitalization or clinical deterioration

without a clear diagnosis before the possibility of HLH is raised. A priority should be placed on
rapid evaluation, with the goal of starting treatment as soon as possible. (See 'Initial evaluation'
above.)
● Many patients with HLH have a predisposing genetic defect, and/or an immunologic trigger,
which can include infection, malignancy, rheumatologic disorder such as juvenile idiopathic
arthritis, or another disorder associated with immune dysregulation. These genetic defects and
immunologic triggers should be identified in all patients. (See 'Genetics' above and 'Associated
illnesses' above.)
● The initial evaluation includes a complete blood count with differential, coagulation studies,
serum ferritin, liver function tests, triglycerides, blood cultures, and viral testing. The bone
marrow should be examined for the cause of cytopenias, infectious organisms,
hemophagocytosis, and macrophage infiltration; and sent for cultures. All patients should have
a lumbar puncture with cerebrospinal fluid (CSF) analysis and magnetic resonance imaging
(MRI) of the brain. Computed tomography (CT) scans of the neck, chest, abdomen, and pelvis
or positron emission tomography (PET) scan should be done to evaluate for possible
malignancy. (See 'Initial evaluation' above and 'Bone marrow evaluation' above.)
● For those with a high clinical suspicion, specialized testing of immunologic parameters and
genetic testing are also indicated. HLA typing is done in preparation for possible allogeneic
hematopoietic cell transplantation. (See 'Specialized testing' above.)
● The diagnosis of HLH is made by identifying a mutation in an HLH gene, or by fulfilling five of
eight diagnostic criteria. Many patients fit only three or four of the eight criteria, yet have clinical
evidence of HLH and require HLH-specific treatment. Modified diagnostic criteria may also be
used. Hemophagocytosis, while often seen, is neither necessary nor sufficient for the diagnosis
of HLH. (See 'Diagnosis' above.)
● The differential diagnosis of HLH includes several multisystem illnesses characterized by fever,
hepatic failure, and neurologic symptoms. Many of the conditions in the differential diagnosis of
HLH can also cause HLH. We consider macrophage activation syndrome to be a form of HLH
associated with a rheumatologic condition rather than a distinct entity. (See 'Differential
diagnosis' above and 'Rheumatologic disorders/MAS' above.)

ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge the late Laurence A Boxer, MD, for his
previous role as a section editor for this topic.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Jordan MB, Allen CE, Greenberg J, et al. Challenges in the diagnosis of hemophagocytic
lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis
(NACHO). Pediatr Blood Cancer 2019; 66:e27929.
2. Filipovich A, McClain K, Grom A. Histiocytic disorders: recent insights into pathophysiology

and practical guidelines. Biol Blood Marrow Transplant 2010; 16:S82.
3. Dalal BI, Vakil AP, Khare NS, et al. Abnormalities of the lymphocyte subsets and their
immunophenotype, and their prognostic significance in adult patients with hemophagocytic
lymphohistiocytosis. Ann Hematol 2015; 94:1111.
4. Pachlopnik Schmid J, Côte M, Ménager MM, et al. Inherited defects in lymphocyte cytotoxic
activity. Immunol Rev 2010; 235:10.
5. Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts.

Curr Opin Pediatr 2012; 24:9.
6. Egeler RM, Shapiro R, Loechelt B, Filipovich A. Characteristic immune abnormalities in

hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 1996; 18:340.
7. Eife R, Janka GE, Belohradsky BH, Holtmann H. Natural killer cell function and interferon
production in familial hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol 1989;
6:265.
8. Ishii E, Ueda I, Shirakawa R, et al. Genetic subtypes of familial hemophagocytic

lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer
cell functions. Blood 2005; 105:3442.
9. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial

hemophagocytic lymphohistiocytosis. Science 1999; 286:1957.

10. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805.
11. Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation results in macrophage
activation syndrome-like disease in mice. J Clin Invest 2011; 121:2264.
12. Fall N, Barnes M, Thornton S, et al. Gene expression profiling of peripheral blood from
patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular
heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum 2007;
56:3793.
13. Henter JI, Elinder G, Söder O, et al. Hypercytokinemia in familial hemophagocytic

lymphohistiocytosis. Blood 1991; 78:2918.
14. Osugi Y, Hara J, Tagawa S, et al. Cytokine production regulating Th1 and Th2 cytokines in
hemophagocytic lymphohistiocytosis. Blood 1997; 89:4100.
15. Aricò M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic

lymphohistiocytosis. Br J Haematol 2001; 114:761.
16. Komp DM, McNamara J, Buckley P. Elevated soluble interleukin-2 receptor in childhood
hemophagocytic histiocytic syndromes. Blood 1989; 73:2128.
17. Tang Y, Xu X, Song H, et al. Early diagnostic and prognostic significance of a specific Th1/Th2
cytokine pattern in children with haemophagocytic syndrome. Br J Haematol 2008; 143:84.
18. Takada H, Ohga S, Mizuno Y, et al. Increased IL-16 levels in hemophagocytic

lymphohistiocytosis. J Pediatr Hematol Oncol 2004; 26:567.
19. Mazodier K, Marin V, Novick D, et al. Severe imbalance of IL-18/IL-18BP in patients with
secondary hemophagocytic syndrome. Blood 2005; 106:3483.
20. Put K, Avau A, Brisse E, et al. Cytokines in systemic juvenile idiopathic arthritis and
haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and
interferon-γ. Rheumatology (Oxford) 2015; 54:1507.
21. Weiss ES, Girard-Guyonvarc'h C, Holzinger D, et al. Interleukin-18 diagnostically distinguishes

and pathogenically promotes human and murine macrophage activation syndrome. Blood
2018; 131:1442.
22. Girard-Guyonvarc'h C, Palomo J, Martin P, et al. Unopposed IL-18 signaling leads to severe
TLR9-induced macrophage activation syndrome in mice. Blood 2018; 131:1430.

23. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis.
Blood 2011; 118:4041.
24. Summary safety review: Nivolumab and ipilimumab used alone, or in combination. Health Can
ada. Government of Canada. https://hpr-rps.hres.ca/reg-content/summary-safety-review-detai
l.php?lang=en&linkID=SSR00225 (Accessed on July 11, 2019).
25. Parekh C, Hofstra T, Church JA, Coates TD. Hemophagocytic lymphohistiocytosis in children
with chronic granulomatous disease. Pediatr Blood Cancer 2011; 56:460.
26. Ohadi M, Lalloz MR, Sham P, et al. Localization of a gene for familial hemophagocytic
lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet
1999; 64:165.
27. Göransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. Spectrum of perforin gene

mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet 2001; 68:590.
28. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion
and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;
115:461.
29. zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic

lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in
syntaxin 11. Hum Mol Genet 2005; 14:827.
30. Zhang K, Chandrakasan S, Chapman H, et al. Synergistic defects of different molecules in the
cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood 2014;
124:1331.
31. Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child
2011; 96:688.
32. Spessott WA, Sanmillan ML, McCormick ME, et al. Hemophagocytic lymphohistiocytosis
caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane
fusion. Blood 2015; 125:1566.
33. Cetica V, Sieni E, Pende D, et al. Genetic predisposition to hemophagocytic

lymphohistiocytosis: Report on 500 patients from the Italian registry. J Allergy Clin Immunol
2016; 137:188.

34. Kaufman KM, Linghu B, Szustakowski JD, et al. Whole-exome sequencing reveals overlap
between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial
hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014; 66:3486.
35. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and
STXBP2 are associated with adult-onset familial HLH. Blood 2011; 118:5794.
36. Chinn IK, Eckstein OS, Peckham-Gregory EC, et al. Genetic and mechanistic diversity in
pediatric hemophagocytic lymphohistiocytosis. Blood 2018; 132:89.
37. Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V
and N252S and 22 missense perforin mutations associated with familial hemophagocytic
lymphohistiocytosis. Blood 2005; 105:4700.
38. Trambas C, Gallo F, Pende D, et al. A single amino acid change, A91V, leads to
conformational changes that can impair processing to the active form of perforin. Blood 2005;
106:932.
39. Voskoboinik I, Thia MC, De Bono A, et al. The functional basis for hemophagocytic
lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1)
gene. J Exp Med 2004; 200:811.
40. Meeths M, Chiang SC, Wood SM, et al. Familial hemophagocytic lymphohistiocytosis type 3
(FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 2011; 118:5783.
41. Rudd E, Göransdotter Ericson K, Zheng C, et al. Spectrum and clinical implications of syntaxin
11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-
free remissions and haematopoietic malignancies. J Med Genet 2006; 43:e14.
42. Côte M, Ménager MM, Burgess A, et al. Munc18-2 deficiency causes familial hemophagocytic
lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin
Invest 2009; 119:3765.
43. Ménasché G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome
associated with haemophagocytic syndrome. Nat Genet 2000; 25:173.
44. Rubin CM, Burke BA, McKenna RW, et al. The accelerated phase of Chediak-Higashi
syndrome. An expression of the virus-associated hemophagocytic syndrome? Cancer 1985;
56:524.

45. Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistiocytosis due to germline

mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 2001; 97:1131.
46. Marsh RA, Madden L, Kitchen BJ, et al. XIAP deficiency: a unique primary immunodeficiency
best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked
lymphoproliferative disease. Blood 2010; 116:1079.
47. Li FY, Chaigne-Delalande B, Su H, et al. XMEN disease: a new primary immunodeficiency

affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 2014; 123:2148.
48. Alkhairy OK, Perez-Becker R, Driessen GJ, et al. Novel mutations in TNFRSF7/CD27:
Clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin
Immunol 2015; 136:703.
49. Jessen B, Bode SF, Ammann S, et al. The risk of hemophagocytic lymphohistiocytosis in
Hermansky-Pudlak syndrome type 2. Blood 2013; 121:2943.
50. Dell'Acqua F, Saettini F, Castelli I, et al. Hermansky-Pudlak syndrome type II and lethal
hemophagocytic lymphohistiocytosis: Case description and review of the literature. J Allergy
Clin Immunol Pract 2019; 7:2476.
51. Barilli A, Rotoli BM, Visigalli R, et al. Impaired phagocytosis in macrophages from patients
affected by lysinuric protein intolerance. Mol Genet Metab 2012; 105:585.
52. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of
hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 2002;
100:2266.
53. Nagafuji K, Nonami A, Kumano T, et al. Perforin gene mutations in adult-onset

hemophagocytic lymphohistiocytosis. Haematologica 2007; 92:978.
54. Pagel J, Beutel K, Lehmberg K, et al. Distinct mutations in STXBP2 are associated with
variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis
type 5 (FHL5). Blood 2012; 119:6016.
55. Lee SM, Sumegi J, Villanueva J, et al. Patients of African ancestry with hemophagocytic
lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr
2006; 149:134.
56. Feldmann J, Le Deist F, Ouachée-Chardin M, et al. Functional consequences of perforin gene

mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol

2002; 117:965.
57. Ueda I, Ishii E, Morimoto A, et al. Correlation between phenotypic heterogeneity and gene
mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Pediatr Blood
Cancer 2006; 46:482.
58. Ueda I, Kurokawa Y, Koike K, et al. Late-onset cases of familial hemophagocytic

lymphohistiocytosis with missense perforin gene mutations. Am J Hematol 2007; 82:427.
59. Muralitharan S, Al Lamki Z, Dennison D, et al. An inframe perforin gene deletion in familial
hemophagocytic lymphohistiocytosis is associated with perforin expression. Am J Hematol
2005; 78:59.
60. Horne A, Ramme KG, Rudd E, et al. Characterization of PRF1, STX11 and UNC13D
genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J
Haematol 2008; 143:75.
61. Molleran Lee S, Villanueva J, Sumegi J, et al. Characterisation of diverse PRF1 mutations
leading to decreased natural killer cell activity in North American families with
haemophagocytic lymphohistiocytosis. J Med Genet 2004; 41:137.
62. Kostova EB, Beuger BM, Veldthuis M, et al. Intrinsic defects in erythroid cells from familial
hemophagocytic lymphohistiocytosis type 5 patients identify a role for STXBP2/Munc18-2 in
erythropoiesis and phospholipid scrambling. Exp Hematol 2015; 43:1072.
63. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial
hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.
64. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, et al. Adult haemophagocytic syndrome.

Lancet 2014; 383:1503.
65. Niece JA, Rogers ZR, Ahmad N, et al. Hemophagocytic lymphohistiocytosis in Texas:
observations on ethnicity and race. Pediatr Blood Cancer 2010; 54:424.
66. Shin HJ, Chung JS, Lee JJ, et al. Treatment outcomes with CHOP chemotherapy in adult
patients with hemophagocytic lymphohistiocytosis. J Korean Med Sci 2008; 23:439.
67. Ishii E, Ohga S, Imashuku S, et al. Nationwide survey of hemophagocytic lymphohistiocytosis

in Japan. Int J Hematol 2007; 86:58.
68. Ferreri AJ, Dognini GP, Campo E, et al. Variations in clinical presentation, frequency of
hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different
geographical regions. Haematologica 2007; 92:486.
69. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary
hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D,
STX11, and RAB27A. Hum Mutat 2006; 27:62.
70. Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial

hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 2010;
116:2635.
71. Sandrock K, Nakamura L, Vraetz T, et al. Platelet secretion defect in patients with familial
hemophagocytic lymphohistiocytosis type 5 (FHL-5). Blood 2010; 116:6148.
72. Ueda I, Morimoto A, Inaba T, et al. Characteristic perforin gene mutations of haemophagocytic
lymphohistiocytosis patients in Japan. Br J Haematol 2003; 121:503.
73. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in
HLH treatment: long-term results of the cooperative HLH-2004 study. Blood 2017; 130:2728.
74. Zhao XW, Gazendam RP, Drewniak A, et al. Defects in neutrophil granule mobilization and
bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome
caused by STXBP2/Munc18-2 mutations. Blood 2013; 122:109.
75. Suzuki N, Morimoto A, Ohga S, et al. Characteristics of hemophagocytic lymphohistiocytosis

in neonates: a nationwide survey in Japan. J Pediatr 2009; 155:235.
76. Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic

lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011;
118:4577.
77. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important
diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003; 36:306.
78. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of
hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:1227.
79. Lehmberg K, McClain KL, Janka GE, Allen CE. Determination of an appropriate cut-off value
for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer
2014; 61:2101.
80. Lee WS, McKiernan PJ, Kelly DA. Serum ferritin level in neonatal fulminant liver failure. Arch
Dis Child Fetal Neonatal Ed 2001; 85:F226.
81. Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages
through a nonclassical secretory pathway. Blood 2010; 116:1574.
82. Wu JR, Yuan LX, Ma ZG, et al. GDF15-mediated upregulation of ferroportin plays a key role in
the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis.
Pediatr Blood Cancer 2013; 60:940.
83. Stapp J, Wilkerson S, Stewart D, et al. Fulminant neonatal liver failure in siblings: probable
congenital hemophagocytic lymphohistiocytosis. Pediatr Dev Pathol 2006; 9:239.
84. Okamoto M, Yamaguchi H, Isobe Y, et al. Analysis of triglyceride value in the diagnosis and
treatment response of secondary hemophagocytic syndrome. Intern Med 2009; 48:775.
85. Fukaya S, Yasuda S, Hashimoto T, et al. Clinical features of haemophagocytic syndrome in

patients with systemic autoimmune diseases: analysis of 30 cases. Rheumatology (Oxford)
2008; 47:1686.
86. Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic
lymphohistiocytosis. Histopathology 1998; 32:310.
87. Jovanovic A, Kuzmanovic M, Kravljanac R, et al. Central nervous system involvement in

hemophagocytic lymphohistiocytosis: a single-center experience. Pediatr Neurol 2014;
50:233.
88. Haddad E, Sulis ML, Jabado N, et al. Frequency and severity of central nervous system
lesions in hemophagocytic lymphohistiocytosis. Blood 1997; 89:794.
89. Deiva K, Mahlaoui N, Beaudonnet F, et al. CNS involvement at the onset of primary
hemophagocytic lymphohistiocytosis. Neurology 2012; 78:1150.
90. Feldmann J, Ménasché G, Callebaut I, et al. Severe and progressive encephalitis as a

presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity.
Blood 2005; 105:2658.
91. De Armas R, Sindou P, Gelot A, et al. Demyelinating peripheral neuropathy associated with
hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study. Acta
Neuropathol 2004; 108:341.
92. Henter JI, Nennesmo I. Neuropathologic findings and neurologic symptoms in twenty-three
children with hemophagocytic lymphohistiocytosis. J Pediatr 1997; 130:358.

93. Horne A, Trottestam H, Aricò M, et al. Frequency and spectrum of central nervous system
involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008;
140:327.
94. Gratton SM, Powell TR, Theeler BJ, et al. Neurological involvement and characterization in
acquired hemophagocytic lymphohistiocytosis in adulthood. J Neurol Sci 2015; 357:136.
95. McClain K, Gehrz R, Grierson H, et al. Virus-associated histiocytic proliferations in children.

Frequent association with Epstein-Barr virus and congenital or acquired immunodeficiencies.
Am J Pediatr Hematol Oncol 1988; 10:196.
96. Mou SS, Nakagawa TA, Riemer EC, et al. Hemophagocytic lymphohistiocytosis complicating
influenza A infection. Pediatrics 2006; 118:e216.
97. Harms PW, Schmidt LA, Smith LB, et al. Autopsy findings in eight patients with fatal H1N1
influenza. Am J Clin Pathol 2010; 134:27.
98. Yuzurihara SS, Ao K, Hara T, et al. Human parechovirus-3 infection in nine neonates and
infants presenting symptoms of hemophagocytic lymphohistiocytosis. J Infect Chemother
2013; 19:144.
99. Chen TL, Wong WW, Chiou TJ. Hemophagocytic syndrome: an unusual manifestation of
acute human immunodeficiency virus infection. Int J Hematol 2003; 78:450.
100. Fardet L, Blum L, Kerob D, et al. Human herpesvirus 8-associated hemophagocytic

lymphohistiocytosis in human immunodeficiency virus-infected patients. Clin Infect Dis 2003;
37:285.
101. Grossman WJ, Radhi M, Schauer D, et al. Development of hemophagocytic

lymphohistiocytosis in triplets infected with HHV-8. Blood 2005; 106:1203.
102. Hegerova LT, Lin Y. Disseminated histoplasmosis: a cause of hemophagocytic syndrome.

Mayo Clin Proc 2013; 88:e123.
103. Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients
with hemophagocytic lymphohistiocytosis. Am J Hematol 2015; 90:220.
104. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of
immunomodulatory therapy. Cell Mol Immunol 2016; 13:3.
105. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and
immunosuppression. Lancet 2020; 395:1033.
106. Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of
highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis 2004;
36:516.
107. Brito-Zerón P, Bosch X, Pérez-de-Lis M, et al. Infection is the major trigger of hemophagocytic
syndrome in adult patients treated with biological therapies. Semin Arthritis Rheum 2016;
45:391.
108. Risdall RJ, Brunning RD, Hernandez JI, Gordon DH. Bacteria-associated hemophagocytic
syndrome. Cancer 1984; 54:2968.
109. Sung PS, Kim IH, Lee JH, Park JW. Hemophagocytic Lymphohistiocytosis (HLH) Associated
with Plasmodium vivax Infection: Case Report and Review of the Literature. Chonnam Med J
2011; 47:173.
110. Falini B, Pileri S, De Solas I, et al. Peripheral T-cell lymphoma associated with
hemophagocytic syndrome. Blood 1990; 75:434.
111. Okuda T, Sakamoto S, Deguchi T, et al. Hemophagocytic syndrome associated with

aggressive natural killer cell leukemia. Am J Hematol 1991; 38:321.
112. Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated hemophagocytic

syndrome: clinicopathological characteristics. Ann Hematol 2000; 79:378.
113. Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome.

Leuk Lymphoma 2000; 38:121.
114. Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic
syndrome with Kaposi's sarcoma-associated herpesvirus-related primary effusion lymphoma.
Br J Haematol 2000; 111:1112.
115. Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic

syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008; 47:531.
116. O'Brien MM, Lee-Kim Y, George TI, et al. Precursor B-cell acute lymphoblastic leukemia
presenting with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:381.
117. Fox CP, Shannon-Lowe C, Gothard P, et al. Epstein-Barr virus-associated hemophagocytic

lymphohistiocytosis in adults characterized by high viral genome load within circulating natural
killer cells. Clin Infect Dis 2010; 51:66.

118. Su IJ, Hsu YH, Lin MT, et al. Epstein-Barr virus-containing T-cell lymphoma presents with
hemophagocytic syndrome mimicking malignant histiocytosis. Cancer 1993; 72:2019.
119. Pasqualini C, Minard-Colin V, Saada V, et al. Clinical analysis and prognostic significance of
haemophagocytic lymphohistiocytosis-associated anaplastic large cell lymphoma in children.
Br J Haematol 2014.
120. Allory Y, Challine D, Haioun C, et al. Bone marrow involvement in lymphomas with
hemophagocytic syndrome at presentation: a clinicopathologic study of 11 patients in a
Western institution. Am J Surg Pathol 2001; 25:865.
121. Shimizu Y, Tanae K, Takahashi N, et al. Primary cutaneous anaplastic large-cell lymphoma
presenting with hemophagocytic syndrome: a case report and review of the literature. Leuk
Res 2010; 34:263.
122. Lehmberg K, Sprekels B, Nichols KE, et al. Malignancy-associated haemophagocytic

lymphohistiocytosis in children and adolescents. Br J Haematol 2015; 170:539.
123. Chang TY, Jaffray J, Woda B, et al. Hemophagocytic lymphohistiocytosis with MUNC13-4
gene mutation or reduced natural killer cell function prior to onset of childhood leukemia.
Pediatr Blood Cancer 2011; 56:856.
124. Strenger V, Merth G, Lackner H, et al. Malignancy and chemotherapy induced

haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience
of 20 years. Ann Hematol 2018; 97:989.
125. Davì S, Minoia F, Pistorio A, et al. Performance of current guidelines for diagnosis of
macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis
Rheumatol 2014; 66:2871.
126. Yokota S, Itoh Y, Morio T, et al. Macrophage Activation Syndrome in Patients with Systemic
Juvenile Idiopathic Arthritis under Treatment with Tocilizumab. J Rheumatol 2015; 42:712.
127. Ezdinli EZ, Kucuk O, Chedid A, et al. Hypogammaglobulinemia and hemophagocytic

syndrome associated with lymphoproliferative disorders. Cancer 1986; 57:1024.
128. Rohr J, Beutel K, Maul-Pavicic A, et al. Atypical familial hemophagocytic lymphohistiocytosis

due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases.
Haematologica 2010; 95:2080.

129. Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistiocytosis in

Hermansky-Pudlak syndrome type II. Blood 2006; 108:81.
130. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome after Kawasaki disease.
Pediatr Infect Dis J 2003; 22:663.
131. Abe Y, Choi I, Hara K, et al. Hemophagocytic syndrome: a rare complication of allogeneic
nonmyeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant 2002;
29:799.
132. Ferreira RA, Vastert SJ, Abinun M, et al. Hemophagocytosis during fludarabine-based SCT for
systemic juvenile idiopathic arthritis. Bone Marrow Transplant 2006; 38:249.
133. Karras A, Thervet E, Legendre C, Groupe Coopératif de transplantation d'Ile de France.

Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of
literature. Transplantation 2004; 77:238.
134. Lladó L, Figueras J, Comí S, et al. Haemophagocytic syndrome after liver transplantation in
adults. Transpl Int 2004; 17:221.
135. George TI, Jeng M, Berquist W, et al. Epstein-Barr virus-associated peripheral T-cell
lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and
review of the literature. Pediatr Blood Cancer 2005; 44:270.
136. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a
benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979; 44:993.
137. Nikiforow S, Berliner N. The unique aspects of presentation and diagnosis of hemophagocytic
lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program 2015; 2015:183.
138. Hayden A, Park S, Giustini D, et al. Hemophagocytic syndromes (HPSs) including

hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev
2016; 30:411.
139. Rosado FG, Rinker EB, Plummer WD, et al. The diagnosis of adult-onset haemophagocytic
lymphohistiocytosis: lessons learned from a review of 29 cases of bone marrow
haemophagocytosis in two large academic institutions. J Clin Pathol 2016; 69:805.
140. La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc

Hematol Educ Program 2015; 2015:190.

141. Campo M, Berliner N. Hemophagocytic Lymphohistiocytosis in Adults. Hematol Oncol Clin

North Am 2015; 29:915.
142. Hejblum G, Lambotte O, Galicier L, et al. A web-based delphi study for eliciting helpful criteria
in the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS One 2014;
9:e94024.
143. Rivière S, Galicier L, Coppo P, et al. Reactive hemophagocytic syndrome in adults: a

retrospective analysis of 162 patients. Am J Med 2014; 127:1118.
144. Arca M, Fardet L, Galicier L, et al. Prognostic factors of early death in a cohort of 162 adult
haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide.
Br J Haematol 2015; 168:63.
145. Parikh SA, Kapoor P, Letendre L, et al. Prognostic factors and outcomes of adults with
hemophagocytic lymphohistiocytosis. Mayo Clin Proc 2014; 89:484.
146. Li J, Wang Q, Zheng W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103

adult patients. Medicine (Baltimore) 2014; 93:100.
147. Schram AM, Mullally A, Fogerty AE, et al. Hemophagocytic lymphohistiocytosis: The Partners
Healthcare experience over the past 8 years. Blood 2014; 124:4104.
148. Ahn JS, Rew SY, Shin MG, et al. Clinical significance of clonality and Epstein-Barr virus
infection in adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2010;
85:719.
149. Chen J, Wang X, He P, et al. Viral etiology, clinical and laboratory features of adult
hemophagocytic lymphohistiocytosis. J Med Virol 2016; 88:541.
150. Wong KF, Hui PK, Chan JK, et al. The acute lupus hemophagocytic syndrome. Ann Intern
Med 1991; 114:387.
151. Morris JA, Adamson AR, Holt PJ, Davson J. Still's disease and the virus-associated
haemophagocytic syndrome. Ann Rheum Dis 1985; 44:349.
152. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic
disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.
153. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic
disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.

154. Hot A, Toh ML, Coppéré B, et al. Reactive hemophagocytic syndrome in adult-onset Still
disease: clinical features and long-term outcome: a case-control study of 8 patients. Medicine
(Baltimore) 2010; 89:37.
155. Tabata R, Tabata C, Terada M, Nagai T. Hemophagocytic syndrome in elderly patients with
underlying autoimmune diseases. Clin Rheumatol 2009; 28:461.
156. Schram AM, Campigotto F, Mullally A, et al. Marked hyperferritinemia does not predict for HLH
in the adult population. Blood 2015; 125:1548.
157. Gars E, Purington N, Scott G, et al. Bone marrow histomorphological criteria can accurately
diagnose hemophagocytic lymphohistiocytosis. Haematologica 2018; 103:1635.
158. Lim SH, Park S, Jang JH, et al. Clinical significance of bone marrow hemophagocytosis in
adult patients with malignancy and non-malignancy-induced hemophagocytic
lymphohistiocytosis. Ann Hematol 2016; 95:325.
159. https://www.cincinnatichildrens.org/service/c/cancer-blood/hcp/clinical-laboratories/diagnostic-l
ab (Accessed on June 19, 2017).
160. Schaer DJ, Schleiffenbaum B, Kurrer M, et al. Soluble hemoglobin-haptoglobin scavenger

receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J
Haematol 2005; 74:6.
161. Bleesing J, Prada A, Siegel DM, et al. The diagnostic significance of soluble CD163 and
soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated
new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum 2007; 56:965.
162. Wang LL, Hu YX, Chen WF, et al. [Significance of soluble interleukin-2 receptor and NK cell
activity in patients with hemophagocytic lymphohistiocytosis]. Zhongguo Shi Yan Xue Ye Xue
Za Zhi 2012; 20:401.
163. Wang Z, Wang YN, Feng CC, et al. [Diagnostic significance of NK cell activity and soluble
CD25 level in serum from patients with secondary hemophagocytic lymphohistiocytosis].
Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008; 16:1154.
164. Imashuku S, Hibi S, Tabata Y, et al. Biomarker and morphological characteristics of Epstein-
Barr virus-related hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 1998; 31:131.
165. Bryceson YT, Pende D, Maul-Pavicic A, et al. A prospective evaluation of degranulation

assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 2012; 119:2754.

166. Lee WI, Chen SH, Hung IJ, et al. Clinical aspects, immunologic assessment, and genetic
analysis in Taiwanese children with hemophagocytic lymphohistiocytosis. Pediatr Infect Dis J
2009; 28:30.
167. Mellor-Heineke S, Villanueva J, Jordan MB, et al. Elevated Granzyme B in Cytotoxic

Lymphocytes is a Signature of Immune Activation in Hemophagocytic Lymphohistiocytosis.
Front Immunol 2013; 4:72.
168. Tsuji T, Hirano T, Yamasaki H, et al. A high sIL-2R/ferritin ratio is a useful marker for the
diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 2014; 93:821.
169. Rubin TS, Zhang K, Gifford C, et al. Perforin and CD107a testing is superior to NK cell
function testing for screening patients for genetic HLH. Blood 2017; 129:2993.
170. Maruoka H, Inoue D, Takiuchi Y, et al. IP-10/CXCL10 and MIG/CXCL9 as novel markers for
the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 2014;
93:393.
171. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology
Am Soc Hematol Educ Program 2009; :127.
172. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for
the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014; 66:2613.
173. Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome:

Unrecognized cause of multiple organ failure. Pediatr Crit Care Med 2000; 1:51.
174. Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome:

clinical and biologic disease patterns in 24 patients. Medicine (Baltimore) 2009; 88:131.
175. Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as

child abuse: presentation of three cases and review of central nervous system findings in
hemophagocytic lymphohistiocytosis. Pediatrics 2003; 111:e636.
176. Rostasy K, Kolb R, Pohl D, et al. CNS disease as the main manifestation of hemophagocytic
lymphohistiocytosis in two children. Neuropediatrics 2004; 35:45.
177. Hymel KP, Abshire TC, Luckey DW, Jenny C. Coagulopathy in pediatric abusive head trauma.
Pediatrics 1997; 99:371.
178. Choi JE, Kwak Y, Huh JW, et al. Differentiation between incomplete Kawasaki disease and
secondary hemophagocytic lymphohistiocytosis following Kawasaki disease using N-terminal
pro-brain natriuretic peptide. Korean J Pediatr 2018; 61:167.
179. Marzano AV, Berti E, Paulli M, Caputo R. Cytophagic histiocytic panniculitis and subcutaneous
panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol 2000; 136:889.
180. Craig AJ, Cualing H, Thomas G, et al. Cytophagic histiocytic panniculitis--a syndrome
associated with benign and malignant panniculitis: case comparison and review of the
literature. J Am Acad Dermatol 1998; 39:721.
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15/5/2021 Clinical features and diagnosis of hemophagocytic lymphohistiocytosis - UpToDate

Authors: Kenneth L McClain, MD, PhD, Olive Eckstein, MD

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of

We use the following terminology:

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Immunologic abnormalities — HLH is a syndrome of excessive inflammation and tissue

● Macrophages – Macrophages are professional antigen presenting cells derived from

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Hemophagocytosis — In addition to antigen presentation and cytokine production, macrophages

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● UNC13D/Munc13-4 – FHL3 results from mutations of UNC13D, which encodes Munc13-4

The gene defect responsible for FHL1 remains uncharacterized.

Immunodeficiency syndromes — Several mutations that cause congenital immunodeficiency

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● Griscelli syndrome (GS) – GS type 2 is caused by mutations of RAB27A, which encodes a

● Chediak-Higashi syndrome (CHS) – CHS is caused by mutations of CHS1/LYST, which

● X-linked lymphoproliferative disease – X-linked lymphoproliferative disease type 1 (XLP1) is

● Hermansky-Pudlak syndrome (HPS) – HPS is a rare disorder characterized by

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● Chronic granulomatous disease (CGD) – CGD is a genetically heterogeneous condition

Genotype-phenotype correlations — Patients with HLH gene mutations tend to present at a

● Individuals with STXBP2/Munc18-2 mutations (FHL-5) have defective erythropoiesis with

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Genetic causes of HLH are discussed above. (See 'Genetics' above.)

Laboratory and radiographic abnormalities

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● Coagulation abnormalities due to impaired hepatic synthetic function and/or disseminated

Neurologic findings — Neurologic abnormalities have been observed in one-third of patients

● Severe hypotension may require administration of one or more vasopressors.

● Patients with underlying immunodeficiency syndromes may also have syndrome-specific

Associated illnesses — Infection, malignancy, rheumatologic, and immunodeficiency syndromes

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Rheumatologic disorders/MAS — HLH can occur in the setting of rheumatologic disorders.

Immunodeficiency — HLH has been found in patients with inherited immunodeficiency

Features in adults — HLH presenting in adulthood is increasingly recognized [64,137-141]. Adults

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● Underlying predisposing disease

The frequency of underlying conditions such as hematologic malignancies, infections, and

● In a series of 162 adults with HLH, hematologic malignancies (especially non-Hodgkin

● Several single-institution studies focusing on HLH in adults have documented infection in 23 to

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EVALUATION AND DIAGNOSTIC TESTING

The physical examination should focus on identifying rashes, bleeding, lymphadenopathy,

We suggest the following tests in all patients:

● Complete blood count with differential

● Coagulation studies, including PT, aPTT, fibrinogen, D-dimer

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● Serum triglycerides (fasting)

● Soluble IL-2 receptor alpha (sCD25 or sIL-2R), and/or CXCL9

● Bone marrow evaluation. (See 'Bone marrow evaluation' below.)

● Electrocardiograph, chest radiography, and an echocardiogram.

● Abdominal ultrasound, if the physical examination for splenomegaly is inconclusive.

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We typically perform the following immunologic testing:

● Soluble IL-2 receptor alpha (sCD25 or sIL-2R)

● Tests of NK cell function/degranulation (eg, by flow cytometry for surface expression of

● Soluble levels of the hemoglobin-haptoglobin scavenger receptor (sCD163)

● Immunoglobulin levels (eg, IgG, IgA, IgM)

● Lymphocyte subsets (underlying immune deficiency diseases are sometimes found)

The first five are only available in specialized centers [159].

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