Secondary Hemophagocytic Lymphohistiocytosis in Adults: An Update on Diagnosis and Therapy Roman Leonid Kleynberg, MD, and Gary J. Schiller, MD Dr. Kleynberg is a Resident in the Abstract: Hemophagocytic lymphohistiocytosis (HLH), also known Department of Internal Medicine, David as hemophagocytic syndrome (HPS), is a rare, life-threatening, Geffen School of Medicine at UCLA, hematologic disorder manifested by clinical findings of extreme Olive View-UCLA Medical Center, inflammation and unregulated immune activation. In both its in Sylmar, California. Dr. Schiller is a Professor of Medicine in the Division congenital (primary) and adult (secondary) forms, it is most often of Hematology/Oncology, David Geffen characterized by fevers, hepatomegaly or splenomegaly, and bi- or School of Medicine at UCLA, University trilineage cytopenias. In addition, elevated liver enzymes, hyper- of California, in Los Angeles, California. ferritinemia, hypertriglyceridemia, and hypofibrinogenemia are commonly seen in HLH patients. A high index of suspicion is neces- Address correspondence to: sary for early diagnosis. Furthermore, a thorough diagnostic evalua- Roman Leonid Kleynberg, MD David Geffen School of Medicine at tion is necessary, and prompt treatment of the underlying causes is UCLA key in order to prevent irreversible tissue damage. Here we discuss Olive View-UCLA Medical Center the clinical signs, diagnosis, and treatments associated with this rare Department of Internal Medicine and potentially lethal disorder as manifested in adults. 14445 Olive View Drive Sylmar, CA 91342 Phone: 818-694-1690 Fax: 818-783-3268 Introduction E-mail: [email protected] Hemophagocytic lymphohistiocytosis (HLH) was first described in 1952 by the Scottish pediatricians James Farquhar and Albert Clar- ieaux, who encountered 2 infants with an unrecognized complex of cytopenias, hepatosplenomegaly, and unremitting fevers. Both infants died a few weeks after initial presentation. Upon autopsy, there was evidence of widespread infiltration in the lymph nodes, spleen, liver, and bone marrow with lymphocytes and benign- appearing histiocytes with hemophagocytosis. They identified this syndrome as familial hemophagocytic reticulosis,1 which is now known as HLH. Its incidence is estimated to be approximately 1.2 cases per 1,000,000 individuals per year.2 It is useful to think of HLH as the severe end of a spectrum of hyperinflammatory diseases in which the immune system causes damage to host tissues. Classification: Primary Versus Secondary HLH HLH can be classified according to the underlying etiology into either primary (genetic) or secondary (acquired) HLH, both of Keywords Adult hemophagocytic syndrome, hemophagocytic which are clinically characterized by hepatosplenomegaly, cytope- lymphohistiocytosis (HLH), hemophagocytosis nias, and prolonged fevers (often hectic and persistent). Primary 726 Clinical Advances in Hematology & Oncology Volume 10, Issue 11 November 2012 S e con d A r y H e m O p ha g oc y t I C Ly m p hohis t ioc y t O S I S I N A d u Lt S Table 1. Classification of Hemophagocytic Lymphohistiocytosis Genetic HLH Gene Protein Chromosome Location Familial HLH FHL-1 HPLH1 Unknown 9q21.3–q22 FHL-2 PRF-1 Perforin 10q22 FHL-3 UNC13D Munc13–4 17q25.3 FHL-4 STX11 Syntaxin 11 6q24.1 FHL-5 STXBP2(UNC18B) MUNC18–2 19p13.3-p13.2 Acquired HLH Infectious agents Autoinflammatory and autoimmune diseases (macrophage activation syndrome) Malignant diseases Immunosuppression, hematopoietic stem cell and organ transplantation, AIDS Metabolic factors AIDS=acquired immunodeficiency syndrome; FHL=familial hemophagocytic lymphohistiocytosis; HLH=hemophagocytic lymphohistiocytosis. HLH occurs due to various genetic abnormalities and Thus, a careful search for underlying disease triggers often presents during infancy and early childhood, but should be performed in all patients and, most impor- can occur into the seventh decade of life. It is associated tantly, initial treatment should not be delayed or altered with an autosomal recessive inheritance pattern, and in based on these categories. It is helpful to think of HLH a majority of cases, the gene mutations are responsible along a spectrum of disease, where distinction between for fixed defects in cytotoxic cell function (Table 1). primary and secondary HLH has become more blurred, Secondary HLH is less age-restricted, and although it as patients who develop the disease after childhood are can occur in young children, it is more common in older often found to share some of the same genetic defects as children and adults who present with no known genetic those who present with primary HLH. cause or family history of HLH. It is a very heterogeneous disorder and is often associated with various infections Pathophysiology and malignant, metabolic, and rheumatologic condi- tions. The list of potential etiologies is long and includes Both familial and secondary forms of HLH share the infections (eg, Epstein-Barr virus [EBV], herpes simplex histologic feature of hemophagocytosis, which results virus, cytomegalovirus, avian influenza),3-5 rheumatologic from dysregulation of the immune system. The ensu- diseases (eg, rheumatoid arthritis, systemic lupus ery- ing molecular pathway ultimately leads to organ failure, thematosus, Kawasaki syndrome, adult-onset Still’s dis- unless appropriate treatment is instituted. More recent ease),6,7 malignancy (eg, natural killer [NK]-cell leukemia, work with whole-gene analysis expression has shown peripheral T-cell lymphoma, EBV in T-cell lymphoma, downregulation of proapoptotic signals and genes related B-cell lymphoma, and a variety of other lymphomas),8,9 to innate and adaptive immune responses, along with acquired immune deficiency states (eg, after organ trans- the upregulation of genes coding for proinflammatory plantation), and drugs.10 cytokines and antiapoptotic factors.11 Primary HLH In patients who present with secondary HLH, treat- occurs secondary to genetic defects in genes important in ment of the underlying cause can lead to control and the cytolytic secretory pathway that cause perforin and resolution of HLH. Nevertheless, the process of reso- granzymes to induce apoptosis in target cells (Table 1). lution is not well understood or thoroughly defined. If These preformed proteins are delivered to the synaptic HLH recurs in the absence of any underlying causes, it is junction between cytolytic cells (NK-cells and cytotoxic T most likely that the patient has primary HLH. However, lymphocytes [CTLs]) and their targets.12 Thus, dysfunc- labeling patients as having either primary or secondary tion of these proteins causes dysregulation and depression HLH is often not possible (eg, cases without a known of CTL and NK-cell function, which are responsible for genetic defect or family history) and does not appear to the homeostatic removal of cells that are superfluous or add much value with respect to patient management. dangerous to the organism. Clinical Advances in Hematology & Oncology Volume 10, Issue 11 November 2012 727 K L e y N b e r g A N d S chill e r Despite recent advances, the pathogenesis of HLH These cellular mechanisms lead to a polysyndromic requires further investigation. Pathogenesis of secondary presentation of HLH, including the findings of fevers, HLH remains unclear, although patients with this form cytopenias, hepatosplenomegaly, liver abnormalities, are increasingly found to have heterozygous changes or coagulation disorders, encephalopathy, hypertriglyc- polymorphisms in the familial proteins. The current eridemia, hyperferritinemia, coagulation disorders, and understanding of HLH on a molecular level is based on hyponatremia. The symptomatic presentations of both specific key cellular processes, including cytokine storm primary and secondary HLH are often overlapping, and with elevations of IL-2, IL-6, TNF-α, and IFN-γ second- many patients presenting with secondary HLH are at risk ary to an inflammatory cytokine release,13 and mediator of dying from disease sequelae. A retrospective analysis molecules, such as prostaglandins,14 which lead to the found that the presence of fever was the only factor that overactivation of antigen-presenting cells (histiocytes, was statistically significant in determining prognosis.15 macrophages) and CD8+ T cells. This uninhibited pro- cess thereby leads to activated CTLs and the migration Diagnosis of T-helper cells, resulting in end-organ damage.15 It is believed that this phagocytic, non-neoplastic activation In 1994, the Histiocyte Society formed a standard defini- leads to marked histiocytic proliferation, hypercyto- tion of HLH as part of the HLH-94 clinical trial. It has kinemia, and T-cell immunosuppression.16,17 Thus, the since been revised as part of the HLH-2004 trial and is pathways that lead to impaired immune activation in the definition most commonly employed for diagnostic acquired forms of HLH require further study. Most purposes (Table 2). Five out of 8 criteria are necessary to likely, the mechanisms underlying secondary forms of make a diagnosis of HLH. The utility of this approach HLH are multifactorial. They may involve an imbal- has been questioned due to the lack of specificity of the ance between infected cells and immune effector cells, various criteria. However, it is the presence of multiple immune dysfunction from immunosuppressive medica- criteria, along with the progression and magnitude of the tions, or low populations of NK cells, and, additionally, abnormalities, which reflects