Hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis

Apollo Medicine 2011 DecemberReview Article

Volume 8, Number 4; pp. 302–304

© 2011, Indraprastha Medical Corporation Ltd

Hemophagocytic lymphohistiocytosis

Vibha Bafna**Consultant Paediatrician and Paediatric Hematologist and Oncologist, Jehangir Apollo Hospital, Pune – 411001, Assistant Professor, Bharati Vidyapeeth Deemed University Medical College, Pune – 411043, India.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is not an uncommon disorder. It should be actively considered when we have an acutely ill child with fever, organomegaly, rapidly evolving cytopenias and deranged liver functions. It is a life-threatening disease characterized by uncontrolled hyperinflammation on the basis of a variety of inherited or acquired immune deficiency. Paediatricians, especially in the tertiary care setting, need to be sensitized about its clinical symptoms and diagnostic criteria so that we can offer timely treatment. This article characterizes this condition in detail and outlines its treatment.

Keywords: Coagulopathy, cytopenia, deranged LFT, hemophagocytic lymphohistiocytosis, inflammation

Correspondence: Dr. Vibha Bafna, E-mail: [email protected]: 10.1016/S0976-0016(11)60012-4

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition and not an uncommon disorder. Its frequency is about 1:50,000 live births. It is characterized by an overreaction of the immune system leading to uncon-trolled hyperinflammation due to a cytokine storm. Various acquired and inherited disorders can manifest as HLH.

It is classified by the World Health Organization as type II histiocytosis and further classified as primary HLH, sec-ondary HLH (infection-associated hemophagocytic syn-drome [IAHS] and macrophage activation syndrome [MAS]).

CLASSIFICATION OF HEMOPHAGOCYTIC

LYMPHOHISTIOCYTOSIS1

A Primary Hemophagocytic

Lymphohistiocytosis

1. Familial HLH • Known gene defects—Perforin, Munc 13–4, Syntaxin 11 • Unknown gene defects

2. Immune deficiency syndromes • Chédiak–Higashi syndrome (CHS) • Griscelli syndrome (GS)

• Hermansky–Pudlak syndrome (HPS) • X-linked lymphoproliferative syndrome (XLP)

B Secondary Hemophagocytic

Lymphohistiocytosis

1. Infection-associated—bacteria, viruses, parasites and fungi.

2. Macrophage activation syndrome—juvenile rheumatoid arthritis (JRA) and systemic lupus erythematosus (SLE).

3. Malignancy associated—non-Hodgkin’s lymphoma (NHL; especially, B-cell NHL), anaplastic large cell lymphoma (ALCL), Hodgkin’s lymphoma (HL) and leukemia.Familial or acquired causes share the common feature

of a highly stimulated and an ineffective immune response.Familial HLH is due to congenital defects, mediated

by an autosomal-recessive inheritance, in various proteins that are involved in the killing of the infected antigen-presenting cells (APCs) by the natural killer (NK) cells or the cytotoxic T-lymphocyte (CTL). These proteins are involved in granule exocytosis or in the perforin granzyme pathway. Hemo phagocytic lymphohistiocytosis is predominantly seen in XLP disorder which is primarily an immune defi-ciency disorder. It is also seen in pigmentary disorders such as CHS, GS and HPS. The genes involved are listed in Tables 1 and 2.

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Hemophagocytic lymphohistiocytosis Review Article 303


Acquired HLH is more commonly seen with infections (IAHSs).1. Infections

• Bacterial—Tubercle bacillus (TB), Salmonella, pyo-genic infections

• Viruses—Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), avian influenza (H5N1)

• Parasites—malaria and kala azar • Fungal infections

2. Rheumatic diseases like JRA and SLE can trigger HLH; it is better known as MAS.

3. Malignancies like NHL (B-cell NHL), HL, acute lym-phoblastic leukemia (ALL), congenital leukemia.

PATHOPHYSIOLOGY2

The hallmark of HLH is defective NK cell and cytotoxic T-cell activity. These cells are responsible for eliminating virally or otherwise infected target cells via granules contain-ing apoptosis-inducing machinery, i.e., the perforin protein and granzyme B. Perforin perforates the target cell mem-brane forming a channel allowing granzyme B to enter the cells and induce its apoptosis.

If there are defects in this apoptotic pathways, NK cells and cytotoxic T cells are unable to kill the target cells. This

leads to overstimulation of the immune system and excess proliferation of T-cells and NK cells which infiltrate various organs such as the liver, spleen, central nervous system (CNS) and lymph nodes. Cytokines namely interferon gamma, TNF and interleukin are released. These activate macrophages leading to hemophagocytosis which is mediated through the CD163 heme scavenging receptor. These activated mac-rophages or histiocytes are the hallmark finding in HLH after which it is named. Since the infection is not elimi-nated, the effector immune cells are not culled resulting in the massive expansion of effector T cell leading to organ infiltration, tissue necrosis and multi-organ failure. The diverse clinical manifestation of HLH correlates with the hypercytokinemia.

CLINICAL MANIFESTATIONS

Hemophagocytic lymphohistiocytosis should be suspected in a child with fever, hepatosplenomegaly and cytopenias, especially in the intensive care setting. The laboratory param-eters would be raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, deranged liver function tests (LFT), hypertriglyceridemia, hyponatremia, coagu-lopathy, and hypofibrinogenemia. Hemophagocytosis can be seen in bone marrow and sometimes in liver and lymph nodes. Soluble CD25 levels are markedly raised and are specific for HLH. However, this may not be available in routine practice. Central nervous system involvement mani-fest as seizures, encephalopathy, focal neurological deficits and cerebrospinal fluid (CSF) may show macrophages on cytospin. We must try to identify the triggering infective agents by ordering for relevant cultures, serology and poly-merase chain reaction (PCR) tests as indicated.

Test for genetic defects such as perforin levels or Munc protein levels must be carried out if available. Evaluation of the basic genetic mutations will help in genetic counseling and prenatal diagnosis.

Filipovich has suggested a diagnostic criteria in 2009 for HLH.2

DIAGNOSTIC CRITERIA 2009

1. Molecular diagnosis of HLH or XLP2. At least three of four:

• Fever• Splenomegaly• Hepatitis• Cytopenias

Table 1 Genetic etiology of hemophagocytic lymphohistio-cytosis.2

FHL Defective gene Familial HLH cases (%)

FHL 1 Chromosome-9 –FHL 2 Perforin 20–25FHL 3 Munc 13–4 15–20FHL 4 Syntaxin 10FHL 5 Munc 18–2 20–25XLP1 SH2D1A-SAP –XLP2 BIRC4 (XIAP) –

FHL: familial hemophagocytic lymphohistiocytosis; XLP: X-linked lympho-proliferative syndrome; SAP: SLAM associated protein; XIAP: X-linked inhibitor of apoptosis protein; HLH: hemophagocytic lymphohistiocytes.

Table 2 Pigmentary disorders associated with hemophago-cytic lymphohistiocytes.

Pigmentary syndrome Gene involved Comment

Chédiak–Higashi syndrome Lyst Accelerated phase of CHSGriscelli syndrome type 2 RAB 27 alfa –Hermansky–Pudlak type 2 AP3B1 –

CHS: Chédiak–Higashi syndrome.

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304 Apollo Medicine 2011 December; Vol. 8, No. 4 Bafna


3. At least one of four:• Hemophagocytosis• Hyperferritinemia• Increased soluble IL2R alfa/sCD25• Absent or very decreased NK cell function

4. Supportive of HLH:• Hypertriglyceridemia• Hypofibrinogenemia• HyponatremiaUntreated patients progress rapidly and deteriorate very

quickly leading to death. It is very important to suspect and diagnose HLH in a critically ill child because it is a poten-tially treatable condition.

MANAGEMENT

The primary trigger if identified such as TB, malaria, kala azar, malignancy and JRA should be treated. Hemophago-cytic lymphohistiocytosis is treated with the HLH 2004 protocol of the histiocytic society.4,5

The drugs used are as follows:1. Dexamethasone: Lympholytic, inhibits cytokines, has a

good CNS penetration and suppresses maturation of APC.2. Cyclosporine: Prevents T-cell activation.3. Etoposide: Inhibits monocytes, macrophages and EBV-

infected cells.4. Intravenous immunoglobulins: Provide pathogen-specific

antibodies and immunomodulation.5. Intrathecal methotrexate: Given for CNS HLH.

As soon as the inflammation is controlled, the patient should be offered bone marrow transplant to achieve a cure.

In secondary HLH, the treatment is given for 8 weeks and he is re-evaluated for HLH, and if well is followed up to detect recurrence. In case of recurrent disease, he should be offered transplant.

CONCLUSION

Hemophagocytic lymphohistiocytosis is not an uncommon disease and a practicing paediatrician needs to be aware of it especially in a tertiary care setup. It should be actively considered in the differential diagnosis when we have an acutely ill child with fever, organomegaly, cytopenias, LFT derangements and coagulopathy. To evaluate further, we should order serum ferritin, serum triglycerides and serum fibrinogen. A bone marrow aspiration may help to confirm if hemophagocytes are reported.

The patient should be treated aggressively or he may deteriorate very rapidly. Secondary HLH also needs to be treated on the HLH 2004 protocol, as hyperinflammation cannot be controlled on infection-directed therapy alone.

Paediatrician needs to be more aware and sensitized toward this condition as we may save patients. Bone mar-row transplant facilities should be available more freely to offer a cure.

REFERENCES

1. Janka G, zur Stadt U. Familial and acquired hemophagocytic

lymphohistiocytosis. Hematology Am Soc Hematol Educ

Program 2005:82–8.

2. Filipovich AH. Hemophagocytic lymphohistiocytosis and

related disorders. American Society of Hematology, 2021L,

St NW, Suite 900, Washington DC 20036. Hematology Am Soc

Hematol Educ Program 2009:127–31.

3. Histiocytic Society web site Disease Information on

Hemophagocytic Syndrome.

4. HLH protocol available on www.histio.org/soceity/protocols.

5. Currimbhoy Z, Desai MM, Madkaikar M. Primary Immuno-

deficiency Diseases Booklet, 2010.

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