Med Oncol (2013) 30:740
DOI 10.1007/s12032-013-0740-3
REVIEW ARTICLE
Hemophagocytic lymphohistiocytosis (HLH): a review
of literature
Rohtesh S. Mehta • Roy E. Smith
Received: 28 August 2013 / Accepted: 25 September 2013 / Published online: 9 October 2013
Ó Springer Science+Business Media New York 2013
Abstract Hemophagocytic lymphohistiocytosis (HLH) is
a rare disease in children and an exceptionally rare
occurrence in adults. It is categorized broadly into primary
(familial) or the secondary types; the latter being associated
most commonly with an underlying malignancy. HLH
carries a high rate of mortality, and the treatment itself is
associated with significant morbidity and risk of mortality.
A high degree of suspicion for the diagnosis, early treat-
ment and aggressive supportive care is critical for man-
agement. We present a comprehensive review of literature
describing the clinical features, diagnosis, management and
outcome of HLH.
Keywords Hemophagocytic lymphohistiocytosis
(HLH)
Fever of unknown origin (FUO)
Cytopenia

Hyperferritinemia
Soluble CD25

Hypofibrinogenemia
Abbreviations
HLH Hemophagocytic lymphohistiocytosis
F-HLH Familial hemophagocytic lymphohistiocytosis
HSCT Hematopoietic stem cell transplant
MAS Macrophage activation syndrome
R. S. Mehta (&)
R. E. Smith
Division of Hematology-Oncology, University of Pittsburgh
Medical Center, UPMC Cancer Pavilion, Room 463,
5150 Centre Avenue, Pittsburgh, PA 15232, USA
e-mail: mehtars@upmc.edu
Background
Hemophagocytic lymphohistiocytosis (HLH) is an inap-
propriate immune activation syndrome manifesting as
hematological disorder encompassed by an array of patho-
logical findings and various physical and laboratory abnor-
malities. It is broadly classified as either primary or
secondary form. Primary HLH is autosomal recessive/
familial (F-HLH), which is usually diagnosed within the first
2 years of life [1], although adult onset primary HLH has also
been reported rarely. On paper described two siblings in their
20 s diagnosed with HLH with perforin (PRF1) mutations
[2], while another case reported HLH with PRF1 mutation in
a 62-year-old Japanese male [3]. Secondary HLH may
develop anytime during life as a consequence of a ‘‘strong
activation of the immune system,’’ which may occur with
various malignancies (malignancy-associated hemophago-
cytic syndrome, MAHS), infections (infection-associated
hemophagocytic syndrome, IAHS)—most commonly with
viruses such as Epstein-Barr virus (EBV), respiratory syn-
cytial virus (RSV), rotavirus, adenovirus (VAHS), ‘‘fol-
lowing prolonged intravenous nutrition including
administration of soluble lipids (fat overload syndrome)’’ or
autoimmune disorders such as systemic lupus erythematosus
(SLE) [4], adult onset Still’s disease, mixed connective tis-
sue diseases and other rheumatic disease [1, 5, 6]. In the
setting of rheumatological diseases, this disorder is often
referred to as macrophage activation syndrome (MAS). HLH
has also been reported after kidney [7], liver [8] and hema-
topoietic stem cell transplants [9].
With the identification of several molecular defects
associated with the primary HLH, this category is now
subdivided into F-HLH types 1–5, associated respectively
with (a) an unidentified defect on chromosome 9q21.3-22,
(b) perforin gene (PRF1) mutation on 10q22, found in
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6–58 % of patients with F-HLH2, (c) UNC13D gene muta-
tion on 17q25.1, which encodes for the Munc13-4 protein,
found in 8–13 % of patients with F-HLH3, (d) syntaxin 11
(STX11) gene mutation on 6q24, found in about 20 % of
F-HLH4 cases and (e) syntaxin-binding protein-2 (STXBP2)
gene mutation, which encodes for syntaxin-binding protein-
2 or Munc18-2 protein [10].
Certain rare hereditary disorders are closely related to
HLH. These include X-linked lymphoproliferative (XLP)
syndromes types 1 (XLP1) and 2 (XLP2), Griscelli syndrome
type 2, Chédiak–Higashi syndrome and Hermansky-Pudlak
syndrome type 2 caused by mutations in SH2D1A, XIAP
[11], RAB27A [12], LYST [13] and AP3B1 [14], respec-
tively. XLP is associated with an unusual susceptibility to
Epstein-Barr virus (EBV) infection. HLH can occur in both
XLP-1 (55 %) and XLP-2 (76 %), but recurrent spleno-
megaly, cytopenias and fever are more common in XLP-2
(87 %) than XLP-1 (7 %) [15]. Chédiak–Higashi syndrome
is an autosomal recessive disorder that presents in children
with hair and skin hypopigmentation, recurrent pyogenic
infections, mild coagulation defects and varying degree of
neurological problems [16]. It may mimic HLH in its
accelerated phase [17]. Griscelli syndrome is also an auto-
somal recessive disorder that presents in children with partial
albinism, neutropenia, thrombocytopenia, neurological
involvement, immunodeficiency and may also mimic HLH
in its accelerated phase [18, 19]. Hermansky-Pudlak syn-
drome type II primarily presents as a platelet defect-related
bleeding disorder, neutropenia, recurrent respiratory ill-
nesses and oculocutaneous albinism [20], but may progress
to fulminant HLH [21].
Epidemiology
HLH is a rare disease. The incidence of the familial type is
estimated to be 1.2 per 1,000,000 children per year [22]. A
retrospective review of 2306 bone marrow biopsies con-
ducted between 1987 and 1990 found 23 cases of sec-
ondary HLH. Of these, 17 (73 %) had lymphoma-
associated hemophagocytic syndrome (LAHS). The
remaining cases were associated with acute myelomono-
cytic leukemia (AMML), myelodysplastic syndrome—
refractory anemia with excess blasts (MDS-RAEB), dia-
betes mellitus and SLE, and a few were of unknown eti-
ology [23]. Of all the LAHS cases, HLH was the presenting
feature of lymphoma in approximately 40 % (9/23), while
30 % (7/23) had a preexisting diagnosis of lymphoma,
which was diagnosed within the previous 6 months to
6 years. Further, there was only a single case of HLH
diagnosed with PTCL-cd type found on splenectomy.
Another retrospective study of 52 children with sec-
ondary HLH found that almost half of the cases were due to
123
Med Oncol (2013) 30:740
an underlying malignancy (MAHS), 28 % were due to an
infection and the rest were idiopathic. Of all the MAHS
cases, 60 % were associated with non-Hodgkin’s lym-
phoma—primarily T-cell type, followed by other malig-
nancies such as acute leukemias, MDS, Langerhans cell
histiocytosis and histiocytic sarcoma [24]. Similarly, in
adults, 55 % of the cases of secondary HLH are associated
with an underlying lymphoma (LAHS). Most of them are
due to an aggressive NK/T-cell leukemia (38 %), periph-
eral T-cell lymphoma (28 %), diffuse large B-cell lym-
phoma (18 %), extranodal NK/T-cell lymphoma (10 %)
and anaplastic large cell lymphoma (7 %) [25]. Other
malignancies associated with HLH include ALL, AML,
rhabdomyosarcoma, neuroblastoma, Hodgkin disease and
Langerhans cell histiocytosis [26].
Pathophysiology
The basic pathophysiological mechanism underlying HLH
is an inappropriate activation of T-lymphocytes and mac-
rophages resulting in phagocytosis of other blood cells,
excessive cytokine production (interferon-c, TNF-a, IL-2,
IL-6, IL-8, IL-10, IL-12 and IL-4), resulting in fever and
other clinical manifestations [27–30].
Clinical features
In cases of primary HLH, fever (91 %), hepatomegaly
(90–95 %) and splenomegaly (84 %) are common occur-
rences, while neurological symptoms (47 %), rash (43 %)
and lymphadenopathy (42 %) are seen less frequently.
Common laboratory abnormalities include thrombocyto-
penia (97 %), anemia (88 %), neutropenia (69 %) [31],
hypertriglyceridemia (68 %) [32], hyperferritin-
emia [ 10,000 lg/L (60 %) [31], hypofibrinogenemia,
transaminitis, hyperbilirubinemia and hypoalbuminemia
[22]. Neurological symptoms (33 %) [31] with or without
CSF abnormalities such as spinal fluid mononuclear pleo-
cytosis and/or elevated spinal fluid protein may also be
present. Conversely, CSF abnormalities may be present in
the absence of neurological symptoms. Among children
enrolled in the HLH-94 trial who had CSF analysis done at
the time of diagnosis, 52 % (101/193) had CSF abnor-
mality and 37 % had neurological symptoms (72/193).
Seizure was the most common symptom (11 %) [33], fol-
lowed by a diverse variety of neurological symptoms
ranging from irritability to coma [34, 35].
In secondary HLH, fever, anemia and hypertriglyceri-
demia are seen almost universally, while neutropenia
(55–100 %), thrombocytopenia (70–80 %), hepatomegaly
(60–90 %), splenomegaly (13–90 %), hyperferritinemia
Med Oncol (2013) 30:740
Table 1 Diagnostic criteria for HLH
The diagnosis HLH can be established if either I or II is fulfilled
(I) A molecular diagnosis consistent with HLH
(II) Diagnostic criteria for HLH fulfilled (five out of the eight
criteria below)
(A) Initial diagnostic criteria (to be evaluated in all patients with
HLH)
1. Fever
2. Splenomegaly
3. Cytopenias (affectingC 2 of 3 lineages in the peripheral
blood):
Hemoglobin \90 g/L (in infants \4 weeks:
hemoglobin \100 g/L)
Platelets \100 9 109/L
Neutrophils \1.0 9 109/L
4. Hypertriglyceridemia and/or hypofibrinogenemia:
Fasting triglycerides C3.0 mmol/L (i.e., C265 mg/dL)
Fibrinogen B1.5 g/L
5. Hemophagocytosis in bone marrow or spleen or lymph
nodes
No evidence of malignancy
(B) New diagnostic criteria
6. Low or absent NK-cell activity (according to local
laboratory reference)
7. Ferritin C500 lg/L
8. Soluble CD25 (i.e., soluble IL-2 receptor) C2,400 U/mL
Comments:
(1) If hemophagocytic activity is not proven at the time of
presentation, further search for hemophagocytic activity is
encouraged. If the bone marrow specimen is not conclusive,
material may be obtained from other organs. Serial marrow
aspirates overtime may also be helpful
(2) The following findings may provide strong supportive
evidence for the diagnosis: (a) spinal fluid pleocytosis
(mononuclear cells) and/or elevated spinal fluid protein,
(b) histological picture in the liver resembling chronic persistent
hepatitis (biopsy)
(3) Other abnormal clinical and laboratory findings consistent
with the diagnosis are as follows: cerebromeningeal symptoms,
lymph node enlargement, jaundice, edema, skin rash. Hepatic
enzyme abnormalities, hypoproteinemia, hyponatremia, VLDL
:, HDL ;
Reproduced with written permission from Henter et al. [1, 6]
(55–100 %), hypofibrinogenemia (14–100 %), hypertri-
glyceridemia (43–79 %) and elevated LDH (50–100 %)
occur variably depending upon the underlying etiology [4,
36–39].
Radiographic abnormalities
Over two-third of patients may have nonspecific abnor-
malities detected on a chest X-ray or a CT scan. These
include atelectasis (25 %), interstitial opacities (28 %),
Page 3 of 7
consolidation, pleural effusions, pulmonary edema with
airspace disease, pneumothorax or mediastinal lymphade-
nopathy. Abdominal imaging (ultrasound or CT) may
reveal hepatosplenomegaly, lymphadenopathy or ascites.
Brain CT or MRI in patients with neurological symptoms
may show nonspecific white-matter signal abnormalities,
cerebral volume loss, hydrocephalus, enhancing hemi-
spheric lesions, edema, parenchymal hemorrhage, hemor-
rhagic infarct, sinus thrombosis or parenchymal
calcifications [40].
Diagnosis (Table 1) [1, 6]
In the absence of family history or above-mentioned
molecular defects consistent with F-HLH, five out of the
eight criteria must be met to make a diagnosis of HLH.
These include (a) fever, (b) splenomegaly, (c) cytopenias
affecting at least two of three lineages, (d) hypertriglyceri-
demia and/or hypofibrinogenemia, (e) hemophagocytosis,
(f) low/absent NK-cell activity, (g) hyperferritinemia and
(h) high-soluble interleukin-2-receptor (soluble CD25)
levels. Once the diagnosis of F-HLH is established, genetic
counseling to all siblings should be offered [41].
Treatment
In general, the treatment backbone for the primary HLH is
constituted by chemotherapy combined with immunother-
apy. The most common chemotherapy class of drugs used
includes vinca alkaloids—primarily etoposide (VP-16) [42,
43] and rarely teniposide [44]—and the immunotherapy
agents include cyclosporin A, antithymocyte globulin
(ATG) and steroids [45]. This framework of chemo-
immunotherapy was laid by a landmark trial—HLH-94 [1],
which was later modified to the HLH-2004 [6] regimen. It
should, however, be noted that both these trials included
only children; HLH-94 enrolled patients aged 15 or
younger; and the HLH-2004 enrolled patients aged 18 or
younger.
Both these trials included two treatment phases—(a) an
induction phase and (b) continuation phase—which was
continued until a suitable donor was available for HSCT,
which is the only curative treatment for F-HLH. All
patients received induction therapy for the first 8 weeks,
starting with dexamethasone 10 mg/m2 daily, tapered over
8 weeks (5 mg/m2 for 2 weeks, 2.5 mg/m2 for 2 weeks,
1.25 mg/m2 for 1 week, and 1 week of tapering) and eto-
poside 150 mg/m2 twice weekly for 2 weeks and then
weekly.
The use of continuation therapy beyond 8 weeks was
limited to those with F-HLH, genetically proven HLH,
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persistent secondary HLH or those who relapse after the
discontinuation of induction therapy. Continuation therapy
included dexamethasone 10 mg/m2 for 3 days at two
weekly intervals alternating every week with VP-16
150 mg/m2 at two weekly intervals. In HLH-94, daily oral
cyclosporine (target trough levels of 200 lg/L) was also
used in the continuation phase. In HLH-2004, on the other
hand, cyclosporine was used upfront and continued in both
the phases to intensify the induction regimen. Intrathecal
chemotherapy is used in selected patients. In one study,
posterior reversible encephalopathy syndrome (PRES)
developed in 5 out of 17 patients during the course of
treatment, which was presumed to be related to cyclo-
sporine and other potential contributors such as the ele-
vated blood pressure, liver dysfunction and inflammation.
Of note, cyclosporine levels in all of them were greater
than 200 ng/mL (range 204–532) [46].
Intrathecal therapy
HLH-2004 recommends CSF analysis at every 4 weeks in
all children or CSF analysis along with brain MRI at the
time of new onset of CNS symptoms or re-activation of
systemic or CNS disease. CSF analysis should include at
least proteins and cell count. Cytological analysis should be
conducted using cytocentrifugation method (‘‘Cytospin’’) if
pleocytosis is noted.
Both the HLH protocols used intrathecal treatment
weekly during the induction phase from weeks 3–6 in
patients who had an evidence of CNS disease progression
after 2 weeks of systemic treatment, or in those with
worsening or unimproved CSF pleocytosis. The rationale
of not using upfront intrathecal chemotherapy in everybody
who had CNS involvement was that the CNS symptoms
improved with systemic therapy alone in most of the cases.
HLH-94 protocol used intrathecal methotrexate alone,
while HLH-2004 used intrathecal prednisone in addition.
Other treatment options
Chemotherapy regimens
In a Korean study [39], seventeen HLH adults were treated
with standard CHOP regimen, which included cyclophos-
phamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine
1.4 mg/m2 (maximum dose 2 mg) intravenously on day 1
and prednisone 40 mg/m2 orally for 5 days, repeated
3–4 weeks for a total of 6–8 cycles. Seventy percent of the
patients were younger than 60 years of age and approxi-
mately 40 % had an underlying lymphoma. At any point
during the treatment, patients with available HLA-matched
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Med Oncol (2013) 30:740
sibling donor were offered hematopoietic stem cell trans-
plantation (HSCT). Response was evaluated after every
two cycles. Complete response (CR) was defined as
‘‘unequivocal resolution of clinical signs and symptoms, as
well as normalization of the laboratory findings, particu-
larly the serum level of ferritin.’’ Partial response (PR) was
defined as ‘‘a persistent fever and other symptoms of HLH
or an abnormally high level of serum ferritin in the absence
of definitive symptoms.’’ The rest of the cases were clas-
sified as non-responders. After two cycles, CR and PR were
attained in 41 and 18 %, respectively. The overall response
rate was 70 % in LAHS, 60 % in EBV–HLH and 40 % in
idiopathic cases. The median follow-up was 100 weeks,
median overall survival (OS) was 18 weeks (95 % CI
6–30 weeks) and the 2-year OS rate was roughly 44 %.
Salvage treatment with DHAP (dexamethasone, highdose
cytarabine and cisplatin) was used in 2/17; one patient
received ESHAP (etoposide, methylprednisolone, highdose
cytarabine and cisplatin), and two patients underwent
allogeneic SCT. All of the patients who received salvage
chemotherapy or HSCT died.
Anti-CD52 monoclonal antibody
One retrospective review [47] explored the outcome with
alemtuzumab as a salvage therapy in patients refractory to
prior treatment, including a variety of agents such as dexa-
methasone, etoposide, cyclosporine, intrathecal hydrocorti-
sone, intrathecal methotrexate, methylprednisolone and
rituximab. Although nobody achieved a CR, 14/22 (63 %)
did achieve a PR, defined as ‘‘at least a 25 % improvement in
two or more quantifiable symptoms or laboratory markers of
HLH 2 weeks following alemtuzumab.’’ Long-term outcome
is unknown.
One case report described the use of alemtuzumab as a
bridge to allogeneic-matched unrelated donor HSCT,
which resulted in a complete remission with a normal bone
marrow biopsy at 1 year with full donor chimerism [48].
Immunotherapy
In a case series, six children with F-HLH [45], with an age
range from 3 weeks to 4.5 years, were treated with intra-
venous methylprednisolone starting at 2–5 mg/kg/day,
along with rabbit ATG (10 mg/kg/day) for 5 days, after
which steroids were tapered and patients were started on
continuous infusion of cyclosporine A (CSA) (3–5 mg/kg/
day) with a target trough level between 150 and 200 ng/
mL, followed by oral CSA (8–10 mg/kg/day). Intrathecal
methotrexate and corticosteroids were also administered.
One patient had received chemotherapy with etoposide,
highdose intravenous methotrexate and cyclophosphamide
about 3 weeks prior to receiving ATG and steroids. All
Med Oncol (2013) 30:740
other children received ATG and steroids as the initial
therapy. Two children underwent T-cell-depleted HSCT,
conditioned with VP-16, busulfan and cyclophosphamide.
One of them died at around day 100, while the other one
was alive 2 years after the diagnosis with full donor
engraftment. Three out of other four children who did not
undergo transplant were well and alive, on maintenance
treatment with CSA (with or without prednisone) at the
follow-up period ranging from 3 to 22 months. One died
within 30 days from sepsis.
Another retrospective review [49] from the same insti-
tute presented the outcome of the same regimen in 38
patients with F-HLH. Seventy-three percent (28/38)
received ATG as the first line treatment—82 % (23/28) of
those attained CR and 18 % (5/28) achieved PR. The
remaining ten patients received ATG as the second line,
resulting in CR in 50 % (5/10) and PR in 40 % (4/10).
Overall, the toxicity profile was ‘‘acceptable.’’
Other immune modulators
Some of the immune modulating drugs such as anti-TNF-a
(Infliximab, 10 mg/kg once per week) and IL-1 receptor
antagonist anakinra [50] have also been used to treat HLH/
MAS with ‘‘marked clinical and laboratory improvements.’’
Hematopoietic stem cell transplant (HSCT)
HSCT is the only curative treatment for F-HLH. However,
even after the transplant, mortality remains high, which is
primarily treatment related (TRM).This is reflected by a
majority (50–100 %) of deaths occurring within the first
100 days of HSCT [51]. Some of the most common
treatment-related complications include acute infections
(bacterial and fungal), infections caused by CMV re-acti-
vation, veno-occlusive disease, graft-versus-host disease
and hemorrhage [51]. In addition to these, progression of
HLH is one of the causes of deaths occurring beyond
100 days of HSCT, which accounts for as high as 50 % of
the late deaths in some series [51] to as little as 0–10 % in
others [52–54]. Reduced intensity conditioning (RIC) reg-
imens are proposed to be associated with lower TRM as
compared to the myeloablative conditioning regimens
(MAC), perhaps at the expense of mixed donor chimerism
[55]. On the other hand, a few non-comparative studies
using MAC and RIC in selected patients with EBV–HLH
did not show any statistically significant difference in
overall survival [53].
The role of HSCT in secondary HLH is not clearly
defined, as most of the trials involved patients primarily
with F-HLH. A few studies that included EBV-associated
cases either alone [56] or along with F-HLH cases [53, 57]
Page 5 of 7
suggest that the overall survival may be better in EBV–
HLH compared to the F-HLH case (median 10-year OS
85.7 ± 9.4 vs. 65 ± 7.9 %). However, caution is war-
ranted while interpreting these results as the patient pop-
ulations were not directly comparable. Few isolated reports
have suggested the potential role of HSCT in LAHS, based
on the underlying type of lymphoma [39, 58].
Survival
Untreated HLH is universally fatal with a median survival
of about 2 months [22]. With treatment and HSCT, the
5-year survival probability ranges from 45 to 75 % based
on the study. For instance, in the HLH-94 trial, with a
median follow-up of 6.2 years, the cumulative 5-year sur-
vival was 54 % (95 % CI ± 6 %); 66 ± 14 % after HSCT
and 0 % without HSCT [31]. There was no survival dif-
ference between matched related (74 ± 16 %) and mat-
ched unrelated donor transplantations (76 ± 12 %).
Patients with neurological symptoms and CSF abnormality
at the time of diagnosis had poorer outcome (40 ± 14 %).
Supportive care
As most patients have fever, broad spectrum antimicrobials
should be used presumptively until the culture results are
available. Prophylactic use of cotrimoxazole three times a
week, oral antimycotic therapy during initial dexametha-
sone phase and IVIG (0.5 g/kg) every 4 weeks are also
recommended [1, 6]. Gastrointestinal prophylaxis with a
proton pump inhibitor or an H-2 blocker should be used
with steroids. Granulocyte colony-stimulating factor (G-
CSF) and blood transfusions should be used as needed.
However, the use of GM-CSF (granulocyte–macrophage
colony-stimulating factor) is associated with worse out-
come manifested by worsening of thrombocytopenia,
splenomegaly and even death [59]. Early involvement of
multidisciplinary care teams including a nutritionist, social
worker, psychologist or a palliative care specialist may be
helpful in providing psychological and symptomatic sup-
port to the patient as well as family.
Conclusion
HLH is a rare disease in children and an extremely rare
occurrence in adults, which is universally fatal without
treatment. A majority (50-75 %) of the cases of secondary
HLH may have an underlying malignancy—most com-
monly lymphoma. For familial HLH, steroids and etopo-
side-based regimens constitute the induction phase of
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treatment, and HSCT is the only curative treatment, which
itself is associated with high morbidity and mortality.
Reduced intensity conditioning regimens may be better
than the traditional myeloablative regimens in terms of
toxicity as well as overall survival, although comparative
trials are lacking. Some cases of secondary HLH may
respond to the treatment for the underlying disease, but
there is a paucity of data, suggesting that the risk of
recurrence is poorly defined. Most patients with secondary
HLH require treatment with chemo-immunotherapy (same
as for F-HLH). Some authors suggest using chemo-
immunotherapy as an initial treatment for LAHS followed
by the specific treatment for the lymphoma, with a goal of
pacifying the heightened inflammatory response first [60].
The role of HSCT in secondary forms is less clearly
defined. A high degree of clinical suspicion for diagnosis is
required; immediate referral to a tertiary care center and
early treatment are of paramount importance.
Conflict of interest None.
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