Hemophagocytic Syndromes and Infection

, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Disclosures

Emerging Infectious Diseases. 2000;6(6) 

In This Article

Abstract and Introduction

Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, splenomegaly, jaundice, and the pathologic finding of hemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors) in bone marrow and other tissues. HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection. Hyperproduction of cytokines, including interferon-gamma and tumor necrosis factor-alpha, by EBV-infected T lymphocytes may play a role in the pathogenesis of HLH. EBV-associated HLH may mimic T-cell lymphoma and is treated with cytotoxic chemotherapy, while hemophagocytic syndromes associated with nonviral pathogens often respond to treatment of the underlying infection.

The term hemophagocytosis describes the pathologic finding of activated macrophages, engulfing erythrocytes, leukocytes, platelets, and their precursor cells (Figure 1)[1]. This phenomenon is an important finding in patients with hemophagocytic syndrome, more properly referred to as hemophagocytic lymphohistiocytosis (HLH)[2]. HLH is a distinct clinical entity characterized by fever, pancytopenia, splenomegaly, and hemophagocytosis in bone marrow, liver, or lymph nodes. The syndrome, which has also been referred to as histiocytic medullary reticulosis, was first described in 1939[3]. HLH was initially thought to be a sporadic disease caused by neoplastic proliferation of histiocytes. Subsequently, a familial form of the disease[4] (now referred to as familial hemophagocytic lymphohistiocytosis[5]) was described. However, the nearly simultaneous development of fatal HLH by a father and son in 1965 indicated that infection might play a role[6].

Figure 1.

Hemophagocytosis in the bone marrow of an 18-year-old woman with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. The patient visited her physician in September 1997 with pharyngitis and an elevated heterophile agglutinin titer. She was diagnosed with infectious mononucleosis, and her symptoms resolved in 2 weeks. Approximately 2 months later, she had persistent, spiking fevers and became jaundiced; her immunoglobulin (Ig) M to EBV capsid antigen was positive; and EBV capsid IgG and nuclear IgG were negative. She had pancytopenia and was hospitalized. Bone marrow evaluation revealed a hypocellular marrow, with active hemophagocytosis. The macrophage in the center of this image appears "stuffed" with phagocytosed erythrocytes. Phagocytosis of platelets and leukocytes by macrophages was also seen (not shown). The patient was treated with intravenous immunoglobulin, steroids, and cyclosporine A, but not etoposide. Her condition worsened; she had respiratory, renal, and hepatic failure; and she died of an intracerebral hemmorhage on hospital day 34, 3 1/2 months after her initial illness. Original photomicrograph 100 X magnification with oil immersion, courtesy of Frank Evangelista, Beth Israel Deaconess Medical Center. Photomicrograph published in Blood 1999;63:1991 and reproduced by permission of the publisher.

HLH has since been associated with a variety of viral, bacterial, fungal, and parasitic infections, as well as collagen-vascular diseases[7,8,9,10,11] and malignancies, particularly T-cell lymphomas[12,13,14]. This diversity has prompted the suggestion that HLH secondary to an underlying medical illness should be designated reactive hemophagocytic syndrome. The association between HLH and infection is important because 1) both sporadic and familial cases of HLH are often precipitated by acute infections; 2) HLH may mimic infectious illnesses, such as overwhelming bacterial sepsis and leptospirosis[15]; 3) HLH may obscure the diagnosis of a precipitating, treatable infectious illness (as reported for visceral leishmaniasis [[16]); and 4) a better understanding of the pathophysiology of HLH may clarify the interactions between the immune system and infectious agents.

This article describes the clinical features and epidemiology of HLH and summarizes its association with infection; reviews evidence that this syndrome results from disordered cellular immunity; outlines options for treatment of patients with infection-associated HLH; and discusses issues related to hemophagocytosis in genetic, malignant, and autoimmune disease. The genetic basis of hemophagocytic syndromes has been reviewed in detail[17].

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