Hemophagocytic Lymphohistiocytosis.

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of extreme, systemic immune activation characterized by prolonged fever, hepatosplenomegaly, cytopenias, and elevated markers of inflammation. This constellation of clinical and laboratory findings results from dysregulation of the pathways that govern the immune system’s inflammatory response, leading to persistent activation of lymphocytes and macrophages. The mortality rate is high, and prompt recognition and treatment initiation are essential for survival. However, diagnosis can be challenging because HLH is rare and can present with nonspecific clinical findings that overlap with other disease states, such as sepsis or malignancy.HLH has been historically classified as primary/familial HLH, caused by a genetic mutation, or secondary, caused by an environmental or acquired trigger, such as infection, malignancy, or an autoimmune disorder. Today there is a growing understanding that this dichotomy does not fully capture the complex interactions between genetic predisposition and environmental factors that can lead to HLH or clearly identify the patients who require prompt treatment with immunosuppressive medications. New descriptive categories have been proposed to capture this spectrum more fully. Most broadly, the umbrella term HLH syndrome includes all conditions characterized by the typical HLH pattern of symptoms and laboratory findings. This term encompasses both HLH disease, for conditions in which pathologic immune activation is the driving factor and requires HLH-directed therapies, as well as HLH disease mimics, for conditions in which another pathology, such as infection or a newly diagnosed malignancy, results in the HLH signature but may require combination or entirely different treatments, such as antibiotics or antineoplastic treatment.HLH results from pathologic immune activation and hyperinflammation. The immune system protects against viruses or tumor cells through macrophages, cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. The presence of foreign antigens sets off an inflammatory cascade with the release of cytokines, which stimulate these immune cells to proliferate and release cytotoxic proteins that mediate apoptosis of target cells. The success of this process depends on the proper packaging, trafficking, docking, and membrane fusion of these proteins with the target cell. Once the target is destroyed, the stimulus for this process is eliminated and the immune system’s inflammatory response dies down. However, when this process is disrupted, as it is in HLH, the immune stimulus persists and intensifies, leading to hypercytokinemia and the prolonged activation and proliferation of lymphocytes and macrophages. Activated immune cells can demonstrate organ infiltration, resulting in phagocytosis of hematologic cells by histiocytes seen on biopsy, including bone marrow, liver, central nervous system (CNS), and lymph nodes. This organ invasion results in tissue damage and multiorgan failure. Because the natural history of HLH is generally fatal, timely diagnosis is imperative to minimize severe consequences.Genetic mutations, isolated and as part of a syndrome, can interfere with this process, resulting in ineffective lymphocyte cytotoxicity. For example, in primary/familial HLH type 2, there is a mutation in the PRF1 gene, which encodes perforin, a key protein necessary for the elimination of target cells by the immune system, resulting in perforin deficiency. The known genetic defects that cause HLH are generally null mutations and are inherited in either a homozygous or compound heterozygous manner. The incidence of primary/familial HLH is low and has been shown to be 1 in 50,000 live births in a population-based study.HLH can also be precipitated by infection, malignancy, or autoimmunity, with or without a genetic predisposition. Acute viral infections are closely linked to HLH, especially DNA viruses such as Epstein-Barr virus, parvovirus, herpes simplex virus, and adenovirus. Epstein-Barr virus is the most common virus associated with HLH, and it has been shown to ignite immune dysregulation by infecting CD8+ CTLs instead of B cells. Malignancy is another well-established cause of HLH, either at the time of diagnosis or during treatment. Lymphoma in particular can initiate HLH by producing proinflammatory cytokines that drive persistent CTLs and NK cell activation. When HLH occurs in the setting of a known rheumatologic disorder, such as juvenile idiopathic arthritis, it takes the name macrophage activating syndrome. In these cases, identification of the underlying trigger is crucial to guide multimodal treatment of HLH and the precipitating infection, malignancy, or autoimmunity.The clinical presentation of HLH is highly variable and can include fever, splenomegaly, liver dysfunction, cytopenias, coagulopathy, CNS dysfunction, colitis, rash, and lymphadenopathy. Patients are generally critically ill with a systemic inflammatory response picture and organ failure but can also present with a more subacute course with nonspecific symptoms, including failure to thrive, diarrhea, and liver dysfunction, that can be seen in other infectious, inflammatory, or hematologic disorders. HLH can, in rare cases, also present atypically with isolated CNS symptoms, such as encephalopathy and seizures; is important to consider in the differential diagnosis of CNS symptoms; and can be diagnosed using imaging and specialized laboratory testing of cerebrospinal fluid and HLH-associated genetic mutations.The laboratory signature of HLH reflects the underlying immune dysregulation and activation: cytopenias (usually 2 or 3 cell lines), hypertriglyceridemia, hypofibrinogenemia, elevated ferritin level, decreased NK cell function, and elevated soluble interleukin-2 receptor levels (Table 1). Serum ferritin levels are usually significantly elevated, and a level greater than 10,000 ug/L is highly specific for HLH, although not as sensitive. In addition, given the role that CTLs play in disease pathogenesis, elevated soluble interleukin-2 receptor levels are both supportive of an HLH diagnosis and useful in tracking response to therapy. Bone marrow biopsy may reveal hemophagocytosis, but it is not specific to HLH or required for the diagnosis.The Histiocyte Society created a standard set of 8 criteria for diagnosing HLH to use as the basis for clinical trials, which has now been adopted as the accepted diagnostic criteria (Table 1). These criteria encompass the underlying immunodeficiency (eg, a known genetic defect or low NK cell function), the excessive immune activation and inflammation (eg, fever or elevated ferritin level), and the abnormal immune response (eg, cytopenias or decreased fibrinogen level) that together result in HLH. The diagnosis of HLH can be made either by the fulfillment of 5 of 8 criteria or by the identification of a known HLH-related mutation. It is important for clinicians to note that these criteria are best understood as a guide and do not rule out the possibility of simultaneous disease processes.Thinking about and considering HLH is key to facilitating rapid diagnosis and management, which includes ruling out infection, malignancy, and storage and metabolic disorders, which can mimic HLH and delay diagnosis and the initiation of treatment, especially in the critically ill patient. In addition, once HLH is considered on the differential diagnosis it is crucial to initiate the diagnostic evaluation because some of the specialized immunologic assays may need to be sent out to specific laboratories. Therefore, it is essential that all health-care team members who may come in contact with these patients, such as primary care physicians, emergency medicine physicians, intensivists, hematologists, neurologists, immunologists, and others, be able to recognize early clinical signs of HLH and initiate the appropriate diagnostic evaluation.The mainstay of treatment for HLH is composed of immunosuppressive and chemotherapeutic agents that control and reverse the uncontrolled immune response. Simultaneous initiation of trigger-directed therapy is essential for this multimodal approach. The current standard regimen to treat this immune activation and inflammatory response consists of etoposide and dexamethasone based on protocols developed by the Histiocyte Society. There are also several biological agents under investigation for the treatment of HLH, including alemtuzumab (anti-CD52 antibody) anakinra (recombinant IL-1 receptor antagonist), and emapalumab (monoclonal antibody against interferon-γ), that are effective in dampening the immune response. Finally, allogeneic stem cell transplant is used to treat patients with a demonstrated family history or genetic mutations, patients with CNS involvement, or patients with recurrent disease.The first report of familial HLH was published in 1952, and the first genetic cause was discovered by Stepp et al in 1999. The HLH trial in 2004 led to the current HLH diagnostic criteria, and this time frame demonstrates another miracle of medical science to identify a previously unknown entity and work collaboratively to better define and treat a life-threatening disease process. I find the diagnosis of HLH fascinating and also so very challenging. The diagnosis remains syndromic by considering a constellation of diverse clinical findings and the need to recognize the diagnosis of HLH as quickly as possible to initiate treatment and minimize resulting organ damage. The clinical conundrum is to recognize the correct diagnosis of HLH to initiate and provide timely treatment to those who will benefit from immunosuppressive treatments but avoid inappropriate treatment (to those with an alternative diagnosis) for whom the treatment could be harmful. Hence, it is imperative for primary care providers to partner with specialists, including hematologists and immunologists, who have expertise with the diagnosis and treatment of this rare yet fascinating disease.–Janet R. Serwint, MDAssociate Editor, In Brief