Hemophagocytic Lymphohistiocytosis
Tarun
Kumar Dutta, B Hitha
Tarun
Kumar Dutta, B Hitha, Department of Clinical Hematology, Jawaharlal Institute
of Postgraduate Medical Education & Research (JIPMER), Puducherry 605006,
India
Correspondence to: Tarun Kumar Dutta, Professoer, Head,
Department of Clinical Hematology, Jawaharlal Institute of Postgraduate Medical
Education & Research (JIPMER), Puducherry 605006, India.
Email: tkduttajipmer@yahoo.co.uk
Telephone: +91-9443602330
Received: January 4,
2015
Revised: March 16, 2015
Accepted: March 21, 2015
Published online: April 30, 2015
ABSTRACT
Hemophagocytic
lymphohistiocytosis (HLH) is a disease characterised by pathological immune
activation, fatal hyperinflammation, tissue injury and death if left untreated.
It may be primary (genetic or familial) due to mutation in the genes involved
in granule dependent cytolytic secretory pathway or sporadic, associated with a
variety of triggers. The disease is characterized by fever, cytopenias,
splenomegaly, hypertriglyceridemia and/or hypofibrinogenemia and
hemophagocytosis. The clinical picture may be mimicked by many conditions like
infections, systemic inflammatory response syndrome, rheumatological diseases,
malignancies etc, causing the timely diagnosis a challenge. Early recognition
and institution of chemoimmunotherapy improves the chance of survival in this
potentially fatal disease.
© 2015 ACT. All
rights reserved.
Key words: Targeted therapy; Personalized medicine
Dutta TK, Hitha B.
Hemophagocytic Lymphohistiocytosis. International
Journal of Hematology Research 2015; 1(1): 7-11 Available from: URL:
http://www.ghrnet.org/index.php/ijhr/article/view/1009
INTRODUCTION
Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disorder characterised by uncontrolled
activation of immune system resulting in a pathological systemic inflammatory state
with multiorgan involvement, tissue destruction and high mortality rate if left
untreated. The incidence of HLH is estimated to be 1.2/1000000 individuals[1].
The first description of HLH dates back to 1952 when it was called “ familial
hemophagocytic reticulosis” in a case report published by Farquhar JW and
Claireaux AE[2]. The identification of perforin mutation in 1999 by
Stepp et al as the first genetic mutation associated with HLH was a
major leap in understanding the genetic basis of the disease[3].
Since then, major advances have occurred in the diagnostic and therapeutic
aspects of HLH. Even so, our understanding of the disease is still incomplete.
HLH is a rare disease. The estimated prevalence in various parts of the world
is as – 1/100000 cases in USA; 1.2/1000000 cases in Sweden; 0.342 in Japan and
7.5/1000 in Turkey[4]. The disease occurs in all age groups and all
ethnic groups.
PATHOGENESIS
The clinical features of HLH arise due to three basic defects: (1)
Abnormal stimulation and uncontrolled activation of cytotoxic CD8 T lymphocytes
and macrophages and depressed NK cell activity, following an immune trigger;
(2) Hypercytokinemia with markedly elevated proinflammatory cytokines leading
to systemic inflammatory response and organ dysfunction; (3) Proliferation and
tissue infiltration by macrophages and hemophagocytes with uncontrolled tissue
destruction.
Tissues of
haematopoietic and lymphoid function are directly involved; other organs are
secondarily damaged by circulating cytokines and chemokines[5].
Cytopenias result mainly from suppression of hematopoiesis by elevated
inflammatory cytokines such as TNF-α and IFN-γ and from engulfment of
hematopoietic cells by bone marrow macrophages[6]. The serum
concentrations of these cytokine levels in HLH are markedly elevated. HLH
patients have low numbers of hematopoetic stem cells (HSCs), and hematopoetic
stem cells from HLH patients down-regulate CD47 and are prone to be engulfed by
macrophages more actively than normal HSCs. Inflammatory cytokines can
down-regulate the expression of CD47 selectively in HSCs[7].
Types of HLH
HLH is broadly divided into primary and secondary forms (Table 1).
Primary form
occurs in children who have genetic defects leading to abnormalities in
proteins that play important role in cytolytic secretory pathway causing
abnormal cytotoxic function of T cells and NK cells. Examples are Familial
HLH1, FHLH2 (perforin 1 gene mutation), FHLH3 (MUNC13.4), FHLH4 (STX11), FHLH5
(STXBP2), Chediak Higashi, Griscelli2, Hermansky Pudlak2, XLP syndrome (X
linked lymphoproliferative syndrome)[4] (Table 1).
Secondary form
occurs in adolescents, adults or elderly in the context of an underlying
disorder which may be an infection (bacterial, viral, protozoal),
rheumatological disorder (systemic onset juvenile idiopathic arthritis, adult
onset still’s disease, systemic lupus erythematosus (SLE) and malignancies
(lymphoma, leukemia and solid tumors)[8].
Macrophage
activation syndrome (MAS) is the type of HLH arising in the context of
rheumatological disorders.
In a series of
eight cases from our institute, various diseases associated with HLH were
tuberculosis, EBV infection, lymphoma, scrub typhus and dengue fever. Scrub
typhus and dengue fever are exclusively uncommon causes in the West. Three
patients died including one with scrub typhus and overall mortality was 38% at
a median follow up of 13 months (unpublished report).
Clinical
Features (Table 2)
The important clinical features are fever, hepatosplenomegaly,
cytopenias, coagulopathy and bleeding manifestations, liver dysfunction (acute
hepatitis and liver failure), neurological
abnormalities (seizure, altered sensorium, cranial nerve palsy), skin
rash and pulmonary dysfunction.
In patients
with FUO, the presence of cytopenias and highly elevated ferritin should prompt
physicians to suspect HLH. Cytopenia occurs in more than 80% of patients at
disease presentation[6]. HLH should also be considered in the
differential diagnosis of hepatitis and acute liver failure. Nearly 95% of HLH
patients have features of disseminated intravascular coagulation (DIC)[5].
Prevalence of haemophagocytosis in association with HLH diagnosis ranges from
25 to 100%, with 1-10 haemophagocytes per 500 cells in cases reported as
positive[9]. Skin manifestations include generalized maculopapular
erythematous rashes, generalized erythroderma, oedema, panniculitis,
morbilliform erythema, petechiae, and purpura[10]. Neurological symptoms, including seizures, meningismus, decreased
level of consciousness, cranial nerve palsy, psychomotor retardation, ataxia,
irritability and hypotonia; and are encountered in more than one third of the
patients[5].
The importance
of recognising this rare disorder cannot be underestimated considering a
reported mortality of 95% if left untreated[1]. Early diagnosis and
institution of treatment brings down the mortality to 8-24 %[4].
Hence HLH should be considered as a medical emergency. The crucial challenge as
far as HLH is concerned is establishing a timely diagnosis. HLH is a syndromic
diagnosis made when a constellation of clinical features and laboratory
abnormalities coexist; since most of the signs and symptoms of HLH are
nonspecific and they can occur in any systemic inflammatory state.
Differential
Diagnosis
The disease itself is a great mimicker. Following conditions may be
considered in differential diagnosis (Table 3).
In adults HLH
may be mistaken for infection with sepsis syndrome, hepatitis, leishmania
donovani infection, haematological malignancy etc. In pediatric age group, HLH
like clinical presentation may be misinterpreted as a metabolic disorder with
organomegaly and hypertriglyceridemia, Kawasaki syndrome[11],
Langerhans cell histiocytosis and neonatal hemochromatosis[4]. These
factors along with the rarity of the disease, lack of specificity of the
diagnostic criteria and absence of a single gold standard test which clinches
the diagnosis result in substantial delay in diagnosing HLH in most instances.
This delay is detrimental, as early initiation of treatment before significant
organ damage is mandatory for adequate recovery. Maintaining a high index of
suspicion is the only solution for this dilemma. HLH should be suspected in any
patient with prolonged and unexplained fever, hepatosplenomegaly, unexplained
liver dysfunction, cytopenias, coagulopathy and central nervous system (CNS)
dysfunction, in the background of any disease which can trigger HLH.
Occasionally features of severe sepsis and SLE may be totally indistinguishable
from HLH, when absence of hyperfibrinogenemia, extreme hyperferritinemia and
hypertriglyceridemia distinguish sepsis from HLH. Extreme hyperferritenemia
(level>30000 µg/mL) is almost diagnostic of HLH[1].
Diagnostic
Criteria
To overcome these difficulties, the Histiocytic Society proposed
standard diagnostic criteria based on the common clinical findings, laboratory
and histopathological findings in 1991. The HLH-1994 criteria included: (1)
Fever; (2) Splenomegaly; (3) Cytopenias affecting at least two out of three
lineages in peripheral blood; (4) Hypertriglyceridemia and/or
hypofibrinogenemia; (5) Hemophagocytosis in bone marrow, spleen or lymph nodes
(Table 4).
The major
drawback of this diagnostic criteria was the lack of specificity. Liver
dysfunction and CNS dysfunction which often give us clue to diagnosis are not
included in this criteria. The criteria was updated by the Histiocytic Society
in 2004 to include three more criteria: (1) Hyperferritenemia; (2) Low/absent
NK cell activity; (3) Elevated soluble CD25 level. The presence of severe
abnormality in any of these is particularly helpful in diagnosis. Serum
Ferritin level>10000 µg/mL has 93% specificity; >30000 µg/mL has 100%
specificity in making the diagnosis[1]. Similarly, sCD25 level
(sIL2r) reflects the degree of activation of T cells and is useful in diagnosis
as well as follow up. Very high levels are never seen outside the setting of
HLH. The HLH-2004 diagnostic criteria is given in table 4[12].
Criticism to
this diagnostic criteria
The major drawback of these diagnostic criteria was the lack of
specificity. Liver dysfunction and CNS dysfunction which often give us clue to
diagnosis are not included in these criteria[9].
Newer
Tests
The new laboratory tests evolving are CD163 (marker for activation of
scavenger macrophages), decreased intensity of CD107a signalling on peripheral
blood mononuclear cell surface (suggestive of a genetic cause for failure of
degranulation), perforin protein expression by flow cytometry, gene sequencing
of FHLH and XLP genes[1]. Mutation analysis should be requested for
all suspected familial HLH[5]. Needless to say, the diagnosis of HLH
can be made without need to fulfil 5/8 criteria if the characteristic genetic
defect can be demonstrated. It should include analysis of known HLH mutations -
PRF 1, UNC 13 D, STX 11and UNC 18 B.
Treatment
The mainstay of treatment of HLH is a combination of immunotherapy and
chemotherapy (Table 5).
HLH 1994
Protocol (Figure 1)
The first international treatment protocol for HLH was organized by
International Histiocytic Society in 1994. This included 8 week induction
therapy with corticosteroids, dexamethasone, etoposide, cyclosporine and
intrathecal methotrexate. Corticosteroids are used to suppress
hypercytokinemia, and chemotherapy with etoposide blocks cell division and
proliferation[5]. This was combined with intrathecal methotrexate
for patients in whom CNS HLH did not remit with two weeks of dexamethasone[12].
Cyclosporine inhibits T cell activation (IL-2 inhibition) (Figure 2)[13].
In HLH 94 trial, mortality was reduced from 95% to 30-35 % and reported 3 year
survival was 55 %[14].
HLH 2004
Protocol (Figure 3)
In HLH-2004, the 1994 protocol was revised. It consists of 1-8 week
therapy with etoposide, cyclosporine and dexamethasone. At the end of 8 weeks,
if the disease is resolved and is nongenetic, the therapy is stopped. However,
if a reactivation occurs, they have to be initiated on continuation treatment
followed by hematopoetic stem cell transplant (HSCT). Those patients with
familial HLH and those with persistent disease (even if nongenetic) would
receive continuation treatment followed by HSCT[9].
Familial HLH
Patients with familial HLH have high chance of recurrence and long term
survival is not possible without hematopoetic stem cell transplant[1,12].
All primary HLH patients treated with stem cell transplant after myeloablative
conditioning are likely to have survival of 70% with family donor stem cell
transplant and 50 % with
haploidentical transplant[1]. Alternative immunosuppressive
drugs used are antithymocyte globulin (ATG) and intravenous gamma globulin (IV
Ig). Supportive care with antibiotics, antifungals and antiviral agents may be
needed[9].
All patients
of HLH need not be started on full protocol. Corticosteroids alone may be tried
for the initial treatment of secondary HLH, with the intention to proceed to
the full protocol if there is no resolution within first 48 hours or if there
is rapid progression[1,12]. Macrophage activation syndrome, HLH
associated with systemic onset juvenile idiopathic arthritis (SoJIA), may be
treated with corticosteroid monotherapy or in combination with cyclosporine.
Other agents used are anakinra, etanercept, IV Ig etc. Therapy may be stopped
on complete resolution of clinical and laboratory findings.
conclusion
HLH is a rare and underdiagnosed disease. High mortality in the absence
of timely treatment makes an early diagnosis mandatory. The disease is a big
masquerader, hence high index of suspicion has to be maintained to recognize
the situation early. Because of the low specificity of the diagnostic criteria,
the significance of newer molecular markers like sCD25, sCD163, CD107a and
genetic testing is great. Mortality has improved significantly over the past
few decades due to the institution of chemo-immunotherapy and stem cell
transplant. Trials are underway which include the hybrid immunotherapy with ATG
and etoposide; and these are likely to improve the treatment outcomes in
future.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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