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Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by excessive immune activation, leading to tissue damage, multiorgan failure, and often death if untreated. HLH is classified into primary (familial) and secondary (acquired) forms. Primary HLH typically manifests in early childhood and is caused by inherited genetic mutations affecting immune regulation, sometimes in association with syndromes like Chediak-Higashi or Griscelli. Secondary HLH occurs more often in adults and is usually triggered by infections, malignancies, autoimmune diseases, or certain therapies and transplants. Clinically, HLH presents with nonspecific signs of systemic inflammation, including prolonged fever, cytopenias, hepatosplenomegaly, and elevated inflammatory markers like ferritin. Neurological symptoms, liver dysfunction, and respiratory distress may also occur. This course explores the complexities surrounding this syndrome, including the current diagnostic criteria and treatment protocols. Newer therapies are being investigated, particularly in refractory cases. This activity for healthcare professionals is designed to enhance the learner's competence in identifying HLH, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition, which is critical to improving survival outcomes. Objectives: Identify the etiology of hemophagocytic lymphohistiocytosis. Assess the laboratory findings consistent with a diagnosis of hemophagocytic lymphohistiocytosis. Differentiate the management options available for hemophagocytic lymphohistiocytosis. Apply interprofessional team strategies to improve care coordination and outcomes in patients with hemophagocytic lymphohistiocytosis. Access free multiple choice questions on this topic.

Hemophagocytic lymphohistiocytosis (HLH) is a devastating, hyperinflammatory condition that results in increasing phagocytic activity with tissue damage, multiorgan failure, and death. The disease is characterized by systemic inflammation resulting from the inappropriate, deregulated activation and proliferation of natural killer (NK) cells, CD8+ cytotoxic T-cells, and macrophages. The disease is classified as either primary, resulting from inherited genetic mutations, or secondary, an inappropriate host response to infection, malignancy, or autoimmune disease. Patients with primary disease present early in childhood, whereas those with secondary disease present as adults with an associated acute illness, most commonly sepsis or a hematologic malignancy. Treatment is focused on immunosuppression coupled with cytotoxic chemotherapy, without which large proportions of patients inevitably die.[1][2][3][4]

HLH can be divided into distinct primary or secondary clinical manifestations based on the underlying etiology. Primary Hemophagocytic Lymphohistiocytosis Primary HLH presents in early childhood due to genetic mutations impairing the interaction between NK cells, CD8+ cytotoxic T-cells, and antigen-presenting cells. As a result, these ineffective and deregulated cells increase their production of proinflammatory cytokines, leading to systemic activation of macrophages and the subsequent cellular destruction. Primary HLH is further subdivided by the hereditability of the genetic mutations involved (X-linked versus recessive versus dominant) or the clinical syndromes with which it can be associated (ie, Chediak Higashi syndrome, Griscelli syndrome, and X-linked lymphoproliferative disorder). Forms without an associated genetic syndrome are typically referred to as familial HLH.[2][5][6] HLH has been associated with a TERC variant of teleomere biology disorders (TBD).[7] Secondary Hemophagocytic Lymphohistiocytosis Secondary HLH presents in adults with a mean age of 50 in response to an acute illness trigger rather than an underlying genetic mutation. The most common triggers that involve secondary HLH include infections (eg, tuberculosis, fungal, and histoplasma both with and without HIV) and malignancy. The most prevalent malignancies are T-cell (anaplastic large cell lymphoma and lymphoblastic lymphoma) or natural killer (NK) cell lymphomas, B-cell lymphomas (commonly diffuse large B-cell lymphoma), and autoimmune disorders.[8][9][10][11][12][13][14] HLH is a consequence of some monoclonal antibody therapies.[15][16][17] HLH also can occur as a sequela of transplantation.[18] Classically, HLH, when occurring in the context of an autoimmune disorder, is referred to as macrophage activation syndrome. This is more a historical relic than an indication of a separate disease process. Around 14% of adult patients have allelic abnormalities in primary HLH genes. The significance of these allelic polymorphisms is not fully understood; however, experts hypothesize that they serve as predisposing factors in the face of specific triggers.[1][6][19][20] HLH can occur as a complication of pregnancy, and its presentation can be quite variable with the signs, symptoms, and issues of the overlying pregnancy compounding the situation.[21]

Accurate estimates of the prevalence and distribution of HLH within the population are difficult to obtain due to various factors, the most apparent of which is imprecise diagnostic criteria and the presence of multiple confounding medical illnesses at the time of diagnosis. The most comprehensive data regarding primary HLH comes from a Swedish national registry that collected data from 1987 to 2006 and demonstrated a yearly incidence of roughly 1.5 per million.[22] For children admitted to the intensive care unit, a retrospective review of 30,000 pediatric admissions at Texas Children’s Hospital estimated the incidence as high as 1 in 3,000.[23] In adults with secondary HLH, accurate estimates are even more difficult. Not only is the presentation often indistinguishable from the underlying trigger (eg, sepsis, uncontrolled malignancy, and autoimmune flare), but laboratory investigations to confirm HLH are infrequently undertaken. Some estimates place it at 1 in 2000 for adult critical care admissions.[24] Suspicion and institutional culture significantly affect the diagnostic workup and, therefore, the recorded incidence of the disease.[6] No clear racial or ethnic predilection has been observed in the literature; rather, these categories tend to distribute in a fashion that approximates the surrounding geographic location of the study.[23] In the 2 largest epidemiologic studies in children, the gender distribution was approximately 1 to 1.[22][25] However, in adults, there may be a slightly increased ratio of HLH in males compared to females of slightly less than 2 to 1.[4][24] Consanguineous marriage was also felt to play a role.[26]

HLH is characterized by a deregulated innate immune system, specifically NK cells and CD 8+ cytotoxic T-cells. In a healthy immune system, NK cells and CD 8+ cytotoxic T-cells produce 2 cytolytic enzymes: perforin and granzyme. These proteins are packaged into granules and discharged into the immunologic synapse between the effector and target cells. Perforin forms destabilizing pores in the target cell's membrane, allowing for the entrance of the strongly proteolytic granzyme and osmotic shifts, resulting in target cell degradation. In patients with HLH, this process is disrupted through specific genetic mutations or acquired through some highly immunogenic stimulus (a viral infected or malignant cell). CD*+T-cells (manifesting CD38 and HLA-DR) undergo cytotoxic activation.[27] The ineffective interaction between NK cells, CD8+ cytotoxic T-cells, and their targets leads to a vicious cycle of inflammation. More and more cytotoxic cells are recruited but remain unable to rid the body of the pathologic antigen, and a massive increase in circulating cytokines occurs. This hypercytokinemia leads to the widespread activation of macrophages, resulting in hemophagocytosis and excessive, organ-damaging inflammation, which characterizes the disease.[1] The first genetic mutations identified in primary or familial HLH were in the PRF1 gene, which encodes for perforin.[28] Subsequently, several genetic mutations and associated syndromes have been identified with varying heritability patterns.[13] The familial form carries an autosomal recessive status, while the other genetic maladies associated with HLH, eg, Chediak-Higashi syndrome (also autosomal recessive) and X-linked lymphoproliferative disease (X-linked recessive), carry similar formats. Although secondary HLH is classically understood as a purely acquired disorder, a large institutional series found genetic polymorphisms in primary HLH genes in 14% of adults, including in patients older than 70.[29]

The first genetic mutations identified in primary or familial HLH were in the PRF1 gene, which encodes for perforin.[28] Subsequently, several genetic mutations and associated syndromes have been identified with varying heritability patterns.[13] The familial form carries an autosomal recessive status, while the other genetic maladies associated with HLH, eg, Chediak-Higashi syndrome (also autosomal recessive) and X-linked lymphoproliferative disease (X-linked recessive), carry similar formats. Although secondary HLH is classically understood as a purely acquired disorder, a large institutional series found genetic polymorphisms in primary HLH genes in 14% of adults, including in patients older than 70.[29] Early research into HLH demonstrated high serum-soluble interleukin 2 receptor (sIL-2R) levels in affected children. Additionally, levels correlated well with disease activity.[30] Since the discovery of sIL-2R, many other cytokines have been implicated in the pathophysiology of the disease, including interferon-gamma (INF-y), tumor necrosis factor (TNF), and IL-2. Limited success has been demonstrated in experiential studies of their related inhibitor antibodies.[31][32] COVID-19 patients found to test positive for HLH had an increased mortality.[33] Present opinion favors an overlap of the "cytokine storm" of COVID-19 with the "hyperinflammation" of HLH.[34] Their concurrent existence may be sequential; however, the presence of one does not obviate the need to check for the other.[35]

Suspected cases of HLH typically undergo a biopsy of either lymph nodes, bone marrow, or spleen. The historical histopathologic finding is hemophagocytosis, in which macrophages are captured engulfing bone marrow cells. Although pathognomonic, this finding is not required for diagnosis. In fact, in patients who otherwise meet diagnostic criteria, pathologic review demonstrates hemophagocytosis present in only 67% of pediatric and 85% of adult cases.[19][22]

Given the sizeable clinical overlap between HLH and other systemic inflammatory conditions (eg, severe infection, malignancy, and autoimmune disease), presenting symptoms are often nonspecific signs of inflammation, eg, fever, malaise, and fatigue. Furthermore, blurring the distinction between HLH and other multiorgan inflammatory diseases is the fact that such disease processes often serve as the trigger for developing HLH. While children can have spontaneous HLH driven by genetic mutations, they can also develop HLH as the result of an antigenic stimulus or trigger, much in the same way it typically presents in adults. The most common trigger in children with primary HLH is an infection, particularly the herpes virus family infections, and even more specifically, the Epstein Barr virus.[36] In adults, the most common trigger is malignancy, accounting for about 45% of adult cases.[6] Because of a relic of history rather than distinct pathophysiology, HLH associated with autoimmune diseases continues to be referred to as macrophage activation syndrome. The physical exam is similarly protean. Many exam findings can be anticipated by remembering that HLH is a disease of hyperreactive immune cells, with particular attention paid to the reticuloendothelial system. To varying degrees, patients can present with cytopenias with associated bleeding, infection, or stressors related to extreme anemia (myocardial infarction, stroke, and syncope) and with hepatosplenomegaly and/or diffuse adenopathy. Additionally, the severe systemic inflammation can present as altered mental status, including life-threatening meningoencephalitis, adult respiratory distress syndrome, acute liver failure, and acute renal failure.[1]

HLH has had 2 significant shifts in classification in its lifetime. The first major classification system was defined in the seminal trial known as HLH-94 (representing the year participants began enrolling), and the more recent definition is referred to as HLH-2004 (again representing the year participants were enrolled in the most recent therapeutic trial). In the last 5 years, attempts to redefine the diagnostic criteria have occurred but are not as validated as their predecessors. The original HLH-94 criteria included the following features, of which 5 out of 5 must be met to establish a diagnosis: Fever Cytopenias (at a minimal 2 lineages) Splenomegaly Hypertriglyceridemia +/- hypofibrinogenemia Biopsy-proven hemophagocytosis [37] In the HLH-2004 criteria, the following 3 additional laboratory findings were added, and the diagnosis is established by the presence of at least 5 of the now combined 8 total criteria: Ferritin >500 ng/ml Low or absent NK-cell activity Elevated sIL2Ra levels ≥2400 U/mL [38] Notably, a diagnosis no longer requires the presence of biopsy-proven hemophagocytosis, as it reportedly has a favorable sensitivity but a less favorable specificity.[10] The bone marrow may initially be hypocellular or hypercellular but eventually will become hypoplastic.[13] Other parameters noted during the diagnosis and monitoring of disease activity include the following: Elevated soluble IL2 receptor alpha (sCD25) [39][13] Hypofibrinogenemia [10] Abnormal liver function tests [10] Low C3 [40] Decreased MATR3 in the bone marrow (Matrix 3, a genetic regulatory protein) [40] CD163, macrophage-specific scavenger receptor [13] Mutational analysis has revealed the association of HLH with MUNC13-4, PRF1, STAT1, CARD9, UNC130, STX11, and STXBP2. Flow cytometry is felt to be useful in identifying some mutations in HLH, though it is believed to be of dubious sensitivity.[13] The main drawbacks of this test remain its availability, costs, and complexity for the staff.

The mainstay of treatment focuses on immunosuppression and cytotoxic therapy. Both are contraindicated in patients with severe infections and underline the importance of arriving at a clear diagnosis before initiation. The landmark HLH-94 protocol was first developed and tested in an international collaborative study that enrolled and gathered data from 113 children.[37] This protocol included a combination of dexamethasone, etoposide, cyclosporine A, and intrathecal methotrexate (IT-MTX) in select patients followed by a preplanned bone marrow transplant (BMT). Outcomes of this trial demonstrated a 3-year survival rate of 55% and a 5-year survival rate of 22%, both of which were quite favorable compared to the otherwise invariably rapid death in affected children.[3][41] The HLH-2004 protocol enrolled patients with both primary and secondary HLH. It changed the previous protocol slightly by adding cyclosporine to the initial therapy cocktail, as well as adding intrathecal steroids to IT-MTX for those with underlying neurologic dysfunction.[42] Study analysis demonstrated no improvement in outcomes with the addition of upfront cyclosporine or intrathecal steroid therapy.[38][43] Both regimens' conditioning before BMT is achieved with reduced-intensity conditioning similar to that achieved with fludarabine/busulfan.[44] Recent literature appears to favor the use of steroids with etoposide for refractory or severe cases and anakinra (IL1 receptor antagonist).[15] Emapalumab, a monoclonal antibody against IFN-gamma, has some activity through its inhibition of this compound.[39][31][32] Ruxolitinib, a medication currently approved for treating myelofibrosis and polycythemia vera, has shown promise in murine models of HLH. Perforin-deleted mice were treated with 1 mg/kg for 10 days and demonstrated improved survival, cytopenias, and serum levels of TNF-a and IL-6. The results of studies show promise in terms of salvage therapy.[45]

Presenting symptoms are often nonspecific or are thought to be accounted for in the context of known sepsis or malignancy. A higher degree of suspicion should be maintained in children who present with symptoms suggestive of Kawasaki disease or toxic shock syndrome. In adults, in which the disease is rarer, presentation is often obscured by another confirmed multiorgan system process, eg, malignancy, sepsis, or an autoimmune process. A high index of suspicion should be maintained in any patient who presents with multiorgan failure with associated cytopenias, coagulopathy, and failure to improve with standard treatment.

Children affected by HLH invariably die if left untreated, whereas adults can have spontaneous remission without recurrence. Admittedly, obtaining accurate estimates of adult fatality rates is difficult, since whether deaths are the direct results of HLH or the underlying trigger (eg, infection or malignancy) is unclear. Retrospective studies have demonstrated a 3-year survival rate of 55% in children who received treatment with HLH-94. In children who survived to undergo BMT, 3-year survival rates were significant (60% to 70%).[3][37][46] Experts believe that early hematopoietic stem cell transplant (HSCT) represents the only curative measure (after successful bridging chemo-immunotherapy).[26] Although adults can have a spontaneous remission of HLH, the overall mortality rate remains quite high at roughly 41%.[19] A recent multicenter case series in the United States demonstrated the poorest survival rates in patients with malignancy-associated HLH. The median survival time was only 2.8 months versus 10.7 months in those with nonmalignancy-associated disease.[4]

HLH is, in essence, a complication as HLH is, by definition, a multiorgan pathology with disease occurring indiscriminately due to widespread, deregulated immune system activity. Lungs can develop acute respiratory distress syndrome, hearts can be affected by myocarditis with its myriad of complications, and kidneys can suffer microangiopathies; brains can succumb to fatal meningoencephalitis, and livers can acutely fail. Not a single major organ system is spared the devastating effects of this disease. The majority of patients who die from the disease die as a result of hemodynamic collapse.

Patient education for HLH focuses on increasing awareness of early symptoms and the importance of timely medical attention. While HLH itself cannot always be prevented, especially in cases with genetic predisposition, educating patients and caregivers—particularly those with a family history or underlying immune conditions—about warning signs, eg, persistent high fever, fatigue, or organ dysfunction, can lead to earlier evaluation and intervention. Close monitoring and proactive communication with healthcare practitioners are essential for patients with known triggers, eg, autoimmune diseases or certain infections. Empowering patients with knowledge can support earlier diagnosis and potentially life-saving treatment.

Managing HLH requires a highly coordinated, interprofessional approach to ensure timely diagnosis, effective treatment, and optimal patient outcomes. Physicians must lead the diagnostic process by maintaining a high index of suspicion for HLH in critically ill patients, particularly when standard treatments for sepsis, malignancy, or autoimmune conditions fail. Advanced practitioners, such as nurse practitioners and physician assistants, play a vital role in clinical assessments, early recognition of HLH signs, and ongoing monitoring of response to therapy. Nurses provide essential bedside care, ensuring accurate monitoring of vital signs, laboratory trends, and adverse effects from immunosuppressive or cytotoxic therapy. Their frequent patient contact also positions them to detect subtle clinical changes that may signify disease progression or complications. Pharmacists contribute their expertise by ensuring appropriate dosing of complex treatment regimens, monitoring for drug interactions, and supporting medication safety—especially in patients receiving therapies like etoposide, corticosteroids, or newer agents such as anakinra or ruxolitinib. Effective interprofessional communication is essential to aligning care goals, minimizing errors, and responding swiftly to the patient’s changing condition. Clear, consistent communication among all members of the care team—through structured rounds, shared documentation, and timely consults—facilitates collaborative decision-making. Social workers and case managers are instrumental in coordinating care transitions, arranging follow-up, and supporting families during what is often a critical illness with complex emotional and logistical needs. Together, this team-based strategy promotes patient-centered care, enhances safety, and improves outcomes for patients facing this life-threatening syndrome.