Tools
Hemophagocytic Lymphohistiocytosis
Introduction
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]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
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]
Epidemiology
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]
Pathophysiology
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]
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]
Histopathology
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]
History and Physical
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]
Evaluation
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.
Treatment / Management
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] (B2)
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](B2)
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](B2)
Differential Diagnosis
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.
Prognosis
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]
Complications
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.
Deterrence and Patient Education
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.
Enhancing Healthcare Team Outcomes
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.
References
Al-Samkari H, Berliner N. Hemophagocytic Lymphohistiocytosis. Annual review of pathology. 2018 Jan 24:13():27-49. doi: 10.1146/annurev-pathol-020117-043625. Epub 2017 Sep 13 [PubMed PMID: 28934563]
Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatrics international : official journal of the Japan Pediatric Society. 2016 Sep:58(9):817-25. doi: 10.1111/ped.13064. Epub [PubMed PMID: 27289085]
Janka GE. Familial hemophagocytic lymphohistiocytosis. European journal of pediatrics. 1983 Jun-Jul:140(3):221-30 [PubMed PMID: 6354720]
Schram AM, Comstock P, Campo M, Gorovets D, Mullally A, Bodio K, Arnason J, Berliner N. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. British journal of haematology. 2016 Feb:172(3):412-9. doi: 10.1111/bjh.13837. Epub 2015 Nov 5 [PubMed PMID: 26537747]
Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, Requena-Caballero L, Jordan MB, Abdel-Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Rodriguez-Galindo C, Rollins BJ, Tazi A, Vassallo R, Weiss LM, Histiocyte Society. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2:127(22):2672-81. doi: 10.1182/blood-2016-01-690636. Epub 2016 Mar 10 [PubMed PMID: 26966089]
Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology. American Society of Hematology. Education Program. 2015:2015():177-82. doi: 10.1182/asheducation-2015.1.177. Epub [PubMed PMID: 26637718]
Marathe CS, Torpy DJ. A role for corticosteroid-binding globulin variants in stress-related disorders. Expert review of endocrinology & metabolism. 2012 May:7(3):301-308. doi: 10.1586/eem.12.20. Epub [PubMed PMID: 30780848]
Jacobs MW, Rocco JM, Andersen LK, Robertson TE. Babesiosis with low parasitemia as a cause of secondary hemophagocytic lymphohistiocytosis in a previously healthy adult. IDCases. 2025:39():e02172. doi: 10.1016/j.idcr.2025.e02172. Epub 2025 Jan 28 [PubMed PMID: 39980845]
Level 3 (low-level) evidenceSeog WJ, Steinberg J, Ghafary I, Clores M, Aroniadis O. Severe Acute Liver Injury From Hemophagocytic Lymphohistiocytosis Related to Disseminated Herpes Simplex Virus Type 1 in a Young Immunocompetent Man. ACG case reports journal. 2025 Jan:12(1):e01581. doi: 10.14309/crj.0000000000001581. Epub 2025 Jan 4 [PubMed PMID: 39764152]
Level 3 (low-level) evidenceChiu CY, Hicklen RS, Kontoyiannis DP. Fungal-Induced Hemophagocytic Lymphohistiocytosis: A Literature Review in Non-HIV Populations. Journal of fungi (Basel, Switzerland). 2025 Feb 18:11(2):. doi: 10.3390/jof11020158. Epub 2025 Feb 18 [PubMed PMID: 39997452]
Kurver L, Seers T, van Dorp S, van Crevel R, Pollara G, van Laarhoven A. Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome. Open forum infectious diseases. 2024 Apr:11(4):ofad697. doi: 10.1093/ofid/ofad697. Epub 2024 Jan 11 [PubMed PMID: 38560612]
Angrand RC, Telesca L, Aslam M. Disseminated histoplasmosis and hemophagocytic lymphohistiocytosis: A case report. IDCases. 2025:39():e02175. doi: 10.1016/j.idcr.2025.e02175. Epub 2025 Feb 1 [PubMed PMID: 39995816]
Level 3 (low-level) evidencePonnatt TS, Lilley CM, Mirza KM. Hemophagocytic Lymphohistiocytosis. Archives of pathology & laboratory medicine. 2022 Apr 1:146(4):507-519. doi: 10.5858/arpa.2020-0802-RA. Epub [PubMed PMID: 34347856]
Castro Vieira J, Madeira R, Santos MM, Vieira Afonso J, Teotónio AC. Hemophagocytic Lymphohistiocytosis Secondary to Non-Hodgkin Lymphoma: A Case Report. Cureus. 2025 Jan:17(1):e77492. doi: 10.7759/cureus.77492. Epub 2025 Jan 15 [PubMed PMID: 39958137]
Level 3 (low-level) evidenceGajagowni S, Wang E, Wang J, Campbell MT, Siddiqui BA. Hemophagocytic Lymphohistiocytosis (HLH) Following Immune Checkpoint Therapy (ICT). Case reports in oncological medicine. 2025:2025():5582848. doi: 10.1155/crom/5582848. Epub 2025 Jan 6 [PubMed PMID: 39816730]
Level 3 (low-level) evidenceWalmsley CS, Schoepflin Z, De Brabandt C, Rangachari D, Berwick S, Patell R. Hemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitor use: A review of the current knowledge and future directions. Blood cells, molecules & diseases. 2025 Feb:110():102896. doi: 10.1016/j.bcmd.2024.102896. Epub 2024 Sep 30 [PubMed PMID: 39366077]
Level 3 (low-level) evidenceSun J, Luo P, Guo Y, He Y, Wang C. Clinical Features, Treatment, and Outcomes of Nivolumab-Induced Hemophagocytic Lymphohistiocytosis. Journal of immunotherapy (Hagerstown, Md. : 1997). 2025 Feb-Mar 01:48(2):58-62. doi: 10.1097/CJI.0000000000000540. Epub 2024 Aug 26 [PubMed PMID: 39183530]
Povedano Medina MA, Arnau Prieto Á, Parra Zurutuza A, Martínez Amunarriz C, Bustinduy Odriozola MJ, Camino Ortiz de Barrón X, Pérez Santaolalla E, Maíz Alonso O, Benavente Claveras I, Rodrigo de Tomas MT. Hemophagocytic Lymphohistiocytosis in a Kidney Transplant Recipient: Case Report. Transplantation proceedings. 2025 Jan-Feb:57(1):90-92. doi: 10.1016/j.transproceed.2024.12.012. Epub 2025 Jan 2 [PubMed PMID: 39753491]
Level 3 (low-level) evidenceRamos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet (London, England). 2014 Apr 26:383(9927):1503-1516. doi: 10.1016/S0140-6736(13)61048-X. Epub 2013 Nov 27 [PubMed PMID: 24290661]
Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. The Journal of pediatrics. 1985 Apr:106(4):561-6 [PubMed PMID: 3981309]
Rojas-Suarez J, Ramos M, Lazarte I, Cifuentes S, Leon J, Castañeda W, Morales K, Pajaro Y, Dueñas-Castell C. Hemophagocytic lymphohistiocytosis in early pregnancy: A rare and fatal diagnostic challenge. Obstetric medicine. 2025 Jan 24:():1753495X251314168. doi: 10.1177/1753495X251314168. Epub 2025 Jan 24 [PubMed PMID: 39867859]
Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatric blood & cancer. 2015 Feb:62(2):346-352. doi: 10.1002/pbc.25308. Epub 2014 Nov 8 [PubMed PMID: 25382070]
Niece JA, Rogers ZR, Ahmad N, Langevin AM, McClain KL. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatric blood & cancer. 2010 Mar:54(3):424-8. doi: 10.1002/pbc.22359. Epub [PubMed PMID: 19953651]
Level 2 (mid-level) evidenceParikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clinic proceedings. 2014 Apr:89(4):484-92. doi: 10.1016/j.mayocp.2013.12.012. Epub 2014 Feb 26 [PubMed PMID: 24581757]
Level 2 (mid-level) evidenceHenter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta paediatrica Scandinavica. 1991 Apr:80(4):428-35 [PubMed PMID: 2058392]
Level 2 (mid-level) evidenceAkyol Ş, Yılmaz E, Tokgöz H, Karaman K, Pekpak E, Özcan A, Şi Mşek A, Arslan B, Ören AC, Gökçeli HS, Acıpayam C, Güzel T, Tuncel DA, Gök V, Arslan K, Eken A, Canatan H, Akbayram S, Karakükcü M, Aycan N, Çalışkan Ü, Patıroğlu T, Özdemi R MA, Chiang SCC, Bryceson YT, Ünal E. Clinical spectrum of primary hemophagocytic lymphohistiocytosis: experience of reference centers in Central and Southeast Anatolia. Annals of hematology. 2025 Jan:104(1):123-130. doi: 10.1007/s00277-024-06087-y. Epub 2024 Nov 23 [PubMed PMID: 39579250]
Sun S, Liu Y, Zhao H, Miu Y, Huang X, Shen S, Ren H, Zhang J. Cytotoxic T-cell activation profile in critically ill children with malignancies and hemophagocytic lymphohistiocytosis. Pediatric research. 2025 Mar 5:():. doi: 10.1038/s41390-025-03962-w. Epub 2025 Mar 5 [PubMed PMID: 40044884]
Dufourcq-Lagelouse R, Jabado N, Le Deist F, Stéphan JL, Souillet G, Bruin M, Vilmer E, Schneider M, Janka G, Fischer A, de Saint Basile G. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. American journal of human genetics. 1999 Jan:64(1):172-9 [PubMed PMID: 9915956]
Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, Villanueva J, Risma KA, Wei Q, Klein PS, Filipovich AH. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011 Nov 24:118(22):5794-8. doi: 10.1182/blood-2011-07-370148. Epub 2011 Aug 31 [PubMed PMID: 21881043]
Komp DM, McNamara J, Buckley P. Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood. 1989 Jun:73(8):2128-32 [PubMed PMID: 2786434]
Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood. 2016 Jul 7:128(1):60-71. doi: 10.1182/blood-2016-02-700013. Epub 2016 May 24 [PubMed PMID: 27222478]
Daver N, McClain K, Allen CE, Parikh SA, Otrock Z, Rojas-Hernandez C, Blechacz B, Wang S, Minkov M, Jordan MB, La Rosée P, Kantarjian HM. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017 Sep 1:123(17):3229-3240. doi: 10.1002/cncr.30826. Epub 2017 Jun 16 [PubMed PMID: 28621800]
Oppenauer J, Clodi-Seitz T, Kornfehl A, Wenisch C, Eibensteiner F, Brock R, Neymayer M, Oppenauer A, Pilz A, Veigl C, Tihanyi D, Strassl R, Agis H, Schnaubelt S. Secondary Hemophagocytic Lymphohistiocytosis in severe COVID-19 - a retrospective cohort study. Scientific reports. 2025 Feb 20:15(1):6137. doi: 10.1038/s41598-025-90766-x. Epub 2025 Feb 20 [PubMed PMID: 39979496]
Level 2 (mid-level) evidenceCanny SP, Stanaway IB, Holton SE, Mitchem M, O'Rourke AR, Pribitzer S, Baxter SK, Wurfel MM, Malhotra U, Buckner JH, Bhatraju PK, Morrell ED, Speake C, Mikacenic C, Hamerman JA. Proteomic Analyses in COVID-19-Associated Secondary Hemophagocytic Lymphohistiocytosis. Critical care explorations. 2025 Feb 1:7(2):e1203. doi: 10.1097/CCE.0000000000001203. Epub 2025 Jan 31 [PubMed PMID: 39888602]
Fadlallah MM, Salman SM, Fadlallah MM, Rahal H. Hemophagocytic Syndrome and COVID-19: A Comprehensive Review. Cureus. 2023 Mar:15(3):e36140. doi: 10.7759/cureus.36140. Epub 2023 Mar 14 [PubMed PMID: 37065291]
Smith MC, Cohen DN, Greig B, Yenamandra A, Vnencak-Jones C, Thompson MA, Kim AS. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. International journal of clinical and experimental pathology. 2014:7(9):5738-49 [PubMed PMID: 25337215]
Level 3 (low-level) evidenceHenter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G, Histocyte Society. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002 Oct 1:100(7):2367-73 [PubMed PMID: 12239144]
Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, Ishii E, Janka G, Ladisch S, Lehmberg K, McClain KL, Minkov M, Montgomery S, Nanduri V, Rosso D, Henter JI. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017 Dec 21:130(25):2728-2738. doi: 10.1182/blood-2017-06-788349. Epub 2017 Sep 21 [PubMed PMID: 28935695]
Chandrakasan S, Allen CE, Bhatla D, Carter J, Chien M, Cooper R, Draper L, Eckstein OS, Hanna R, Hays JA, Hermiston ML, Hinson AP, Hobday PM, Isakoff MS, Jordan MB, Leiding JW, Modica R, Nakano TA, Oladapo A, Patel SA, Pednekar P, Riskalla M, Sarangi SN, Satwani P, Tandra A, Walkovich KJ, Yee JD, Zoref-Lorenz A, Behrens EM, REAL‐HLH investigators. Emapalumab Treatment in Patients With Rheumatologic Disease-Associated Hemophagocytic Lymphohistiocytosis in the United States: A Retrospective Medical Chart Review Study. Arthritis & rheumatology (Hoboken, N.J.). 2025 Feb:77(2):226-238. doi: 10.1002/art.42985. Epub 2024 Nov 5 [PubMed PMID: 39245963]
Level 2 (mid-level) evidenceShu X, Gao X, Dai Y, Wang Y, Liu Y, Wang D, Guo T. C3 as a predictive and prognostic biomarker in adult hemophagocytic lymphohistiocytosis: a large cohort study in China. Blood advances. 2025 Apr 22:9(8):1836-1846. doi: 10.1182/bloodadvances.2024014715. Epub [PubMed PMID: 39913689]
Level 3 (low-level) evidenceAricò M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, Martinetti M, Rusca MP. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996 Feb:10(2):197-203 [PubMed PMID: 8637226]
Level 2 (mid-level) evidenceBishwakarma K, Bishwakarma K, Bogati S, Jha S. Macrophage Activation Syndrome/Secondary Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease: An Uncommon Initial Presentation in a Young Nepalese Female: A Case Report. Clinical case reports. 2025 Jan:13(1):e70128. doi: 10.1002/ccr3.70128. Epub 2025 Jan 12 [PubMed PMID: 39807223]
Level 3 (low-level) evidenceHenter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer. 2007 Feb:48(2):124-31 [PubMed PMID: 16937360]
Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, Mehta PA, Davies SM, Jordan MB, Bleesing JJ, Filipovich AH. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 23:116(26):5824-31. doi: 10.1182/blood-2010-04-282392. Epub 2010 Sep 20 [PubMed PMID: 20855862]
Level 2 (mid-level) evidenceWang J, Wang Y, Wu L, Wang X, Jin Z, Gao Z, Wang Z. Ruxolitinib for refractory/relapsed hemophagocytic lymphohistiocytosis. Haematologica. 2020 May:105(5):e210-e212. doi: 10.3324/haematol.2019.222471. Epub 2019 Sep 12 [PubMed PMID: 31515353]
Xiao J, Yang X, Wu N, Fan S, Liu Z, Jiang F, Chen J, Wei J, Sun Y. Modified G-CSF/ATG-Based Haploidentical Transplantation Protocol in Pediatric Primary Hemophagocytic Lymphohistiocytosis: A Long-Term Follow-Up Single-Center Experience. Pediatric blood & cancer. 2025 Mar:72(3):e31495. doi: 10.1002/pbc.31495. Epub 2024 Dec 20 [PubMed PMID: 39704507]