Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages. HLH can occur as a familial or sporadic disorder, and it can be triggered by a variety of events that disrupt immune homeostasis. Infection is a common trigger both in those with a genetic predisposition and in sporadic cases.
Prompt initiation of treatment is essential for the survival of affected patients. Often the greatest barrier to a successful outcome is a delay in diagnosis, which is difficult because of the rarity of this syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings.
The clinical features and diagnosis of HLH and a related disorder, the macrophage activation syndrome (MAS), will be discussed here. The management of patients with these disorders is discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
TERMINOLOGY — Terms used to describe HLH and related syndromes have evolved since the original patient was described as having "familial hemophagocytic reticulosis" in 1952.
Use of the term "primary HLH" to denote the presence of an underlying genetic disorder and "secondary HLH" to denote presence of the HLH phenomenon occurring secondary to another condition has caused a great deal of confusion among clinicians. Both primary and secondary HLH can be triggered by infections or other immunologically activating events, and gene mutations can be found in individuals of any age and with any family history. In practice, distinction between primary and secondary HLH is not essential for the initial diagnosis and management. However, identification of a gene mutation may be useful for subsequent management. (See 'Evaluation and diagnostic testing' below.)
The following terms have been found in the literature:
●Primary HLH, also called familial hemophagocytic lymphohistiocytosis (FHL), refers to HLH caused by gene mutation, either at one of the FLH loci or in a gene responsible for one of several immunodeficiency syndromes. The FHL loci include FHL1 (OMIM 267700); FHL2 (OMIM 603553); FHL3 (OMIM 608898); FHL4 (OMIM 603552); and FHL5 (OMIM 613101). Additional genetic loci for HLH include GS2 (RAB27A) (OMIM 603868); HPS2 (OMIM 608233); XLP1 (OMIM 308240); XLP2 (OMIM 300635); BLOC1S6 (OMIM 604310); CD27 (OMIM186711); ITK (OMIM186973); LYST (OMIM606897); MAGT1 (XMEN) (OMIM300853); SLC7A7 (OMIM 603593); and XIAP (BIRC4) (OMIM 300079) . (See 'Genetics' below.)
●Secondary (sporadic, acquired) HLH has generally been used to describe those without a known familial mutation; adults; and those for whom a clear trigger of the HLH episode has been identified (eg, viral illness, autoimmune disease, lymphoma). However, this term can create confusion because many patients with "secondary HLH" do in fact have a genetic defect associated with the syndrome (eg, heterozygous defect, mutation resulting in partial protein expression), and many patients with primary HLH experience symptoms in response to one of these triggers. (See 'Triggers' below.)
●Macrophage activation syndrome – Macrophage activation syndrome (MAS) is a form of HLH that occurs primarily in patient with juvenile idiopathic arthritis or other rheumatologic diseases. Some authors call this "reactive hemophagocytic syndrome." (See 'Rheumatologic disorders/MAS' below.)
Less commonly used terms for HLH include virus-associated hemophagocytic syndrome, hemophagic histiocytosis, familial erythrophagocytic lymphohistiocytosis (FEL), and viral-associated hemophagocytic syndrome (VAHS) [1-6].
Immunologic abnormalities — HLH is not a malignancy; it is a syndrome of excessive inflammation and tissue destruction due to abnormal immune activation and excessive inflammation. In general, the excessive inflammation is thought to be caused by a lack of normal downregulation of activated macrophages and lymphocytes .
The cell types involved in the pathogenesis of HLH include the following:
●Macrophages – Macrophages are professional antigen presenting cells derived from circulating monocytes; they present foreign antigens to lymphocytes. In HLH, macrophages become activated and secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure. (See "An overview of the innate immune system", section on 'Monocytes and macrophages'.)
●Natural killer cells and cytotoxic lymphocytes – Natural killer (NK) cells constitute 10 to 15 percent of lymphocytes. NK cells eliminate damaged, stressed, or infected host cells such as macrophages, typically in response to viral infection or malignancy, in an MHC-unrestricted manner. (See "An overview of the innate immune system", section on 'Natural killer cells' and "The development of immune cells in the fetus and neonate".)
Cytotoxic lymphocytes (CTLs) are activated T lymphocytes that lyse autologous cells such as macrophages bearing foreign antigen associated with Class I histocompatibility proteins. Most CTLs express CD8. (See "The adaptive cellular immune response", section on 'T cell cytotoxicity'.)
In HLH, NK cells and/or CTLs fail to eliminate activated macrophages. This lack of normal feedback regulation results in excessive macrophage activity and highly elevated levels of interferon gamma plus other cytokines.
Other lymphocyte abnormalities include altered numbers of CD4 and CD8 lymphocyte subsets . In a series of adult patients, those with increased CD8 numbers and decreased CD4/CD8 ratios had the best survival. Decreased total CD3 numbers portended a bad outcome. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Prognosis'.)
Consistent with this mechanism, most patients with HLH exhibit impaired cytotoxic function of NK cells and CTLs, coupled with excessive activation of macrophages [9-14]. Excessive cytokine production by macrophages, NK cells, and CTLs is thought to be a primary mediator of tissue damage . (See 'Immunologic profile' below and 'Cytokine storm' below.)
The normal elimination of activated macrophages by NK cells and CTLs occurs through the process of perforin-dependent cytotoxicity. NK cells and CTLs lyse target cells in a series of steps that include formation of an immunologic synapse; creation of a pore in the macrophage membrane; and delivery of cytolytic granules into the macrophage. The granules contain a variety of proteases such as granzyme B that can initiate cell death, often through apoptosis. Most of the genetic defects in patients with familial HLH encode proteins involved in this process. (See "The adaptive cellular immune response", section on 'T cell cytotoxicity' and "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Mechanisms of killing' and 'Genetics' below.)
Toll-like receptor (TLR) activation of the immune system can be another cause of HLH . TLRs are non-antigen-specific receptors on the surface of NK cells that are activated by components of bacteria, fungi, viruses, or mycoplasma. Normal mice with repeated TLR9 stimulation develop an illness similar to MAS . Genes associated with TLR/interleukin 1 receptor (IL-1R) signaling are upregulated in patients with juvenile idiopathic arthritis and MAS .
Hemophagocytosis — In addition to antigen presentation and cytokine production, macrophages can also phagocytize host cells. Hemophagocytosis refers to the engulfment (literally "eating") of host blood cells by macrophages. Hemophagocytosis is characterized by the presence of red blood cells, platelets, or white blood cells (or fragments of these cells) within the cytoplasm of macrophages (picture 1 and picture 2). It can be seen on biopsies of immune tissues (lymph nodes, spleen, liver) or bone marrow aspirates/biopsies. Although it can be a marker of excessive macrophage activation and supports the diagnosis of HLH, hemophagocytosis alone is neither pathognomonic of, nor required for, an HLH diagnosis. (See 'Bone marrow evaluation' below and 'Diagnosis' below.)
Cytokine storm — The persistent activation of macrophages and NK cells and CTLs that occurs in patients with HLH leads to excessive cytokine production (cytokine storm) by all of these cells. It is thought that the excessive cytokines are ultimately responsible for multiorgan failure and the high mortality of the syndrome [7,18,19].
Cytokines found at extremely high levels in the plasma of patients with HLH include interferon gamma (Ifn-γ); tumor necrosis factor alpha (TNF-α); interleukins (IL) such as IL-6, IL-10, and IL-12; and the soluble IL-2 receptor (CD25) [20-22]. Elevated IL-16 levels may be important for a TH1-type response that recruits macrophages and other cells implicated in HLH . In a study of adults with secondary HLH, markedly elevated levels of IL-18 and its binding protein were found . Some of these cytokines can be measured in serum and are useful in distinguishing HLH from other conditions. A study of IFN-γ, IL-6, and IL-18 in patients with systemic JIA (sJIA) versus HLH showed higher levels of IFN-γ and IFN-γ-induced proteins in HLH compared with sJIA, but the ratio of IL-18/IFN-γ was higher in sJIA . (See 'Specialized testing' below.)
Triggers — Patients with HLH can have a single episode of the disease or relapsing episodes. The initiating trigger for an acute episode is often an infection or an alteration in immune homeostasis. The two broad categories of triggers include those that cause immune activation, and those that lead to immune deficiency.
Immune activation is typically initiated by an infection. Infection is a common trigger both in those with a genetic predisposition and in sporadic cases. The most common infectious trigger for HLH is viral infection, especially with Epstein-Barr virus (EBV) . Primary EBV infection can trigger HLH in individuals with a defect in perforin-dependent cytotoxicity as well as those without a known predisposition; patients with X-linked lymphoproliferative disease (XLP) are at particularly high risk . Kawasaki disease, a common vasculitis of childhood, can also trigger HLH. Many other infectious organisms are also implicated. (See 'Immunodeficiency syndromes' below and 'Infections' below and "Kawasaki disease: Clinical features and diagnosis".)
The excessive cytokine release in patients with chronic granulomatous disease (CGD) may also lead to HLH, as 3 of 17 patients with CGD at one institution developed HLH . The HLH in these patients was controlled with antimicrobials, steroids, and intravenous immune globulin (IVIG).
Common causes of immunodeficiency triggers include inherited syndromes, malignancy, rheumatologic disorders, or HIV infection. (See 'Genetics' below and 'Malignancy' below and 'Rheumatologic disorders/MAS' below and 'Immunodeficiency' below.)
The coexistence of immune dysregulation with unchecked inflammation distinguishes HLH from other syndromes of immune activation, immunodeficiencies, and inflammatory states .
GENETICS — Genetic defects play a major role in childhood HLH and are increasingly found in adult cases [14,28-32]. Most of the implicated genes encode components of the machinery for perforin-dependent cytotoxicity (figure 1) . (See 'Pathophysiology' above.)
These genes act in an autosomal recessive fashion (ie, inheritance of a mutation at both alleles of a gene is required to manifest the disease); however, heterozygosity for an HLH mutation is occasionally found in an individual (typically an adult) with HLH associated with another condition . (See 'Associated illnesses' below.)
In addition to homozygous mutation in a single HLH gene, individuals with HLH may be compound heterozygotes (ie, they may have a different mutation in each allele of the same gene) or they may show digenic inheritance (ie, they may have separate mutations in two different genes). A review of 2701 patients referred for genetic testing revealed that 225 (8 percent) were homozygous or compound heterozygous for mutations, and 28 (1 percent) showed digenic inheritance . Another study reported similar findings, with monoallelic mutations of known familial HLH genes found in 43 of 281 patients classified as having "sporadic" disease, suggesting that this disorder is not a simple recessive one .
In a study that used whole exome sequencing, heterozygous variants in LYST, MUNC13-4, and STXBP2 were discovered in 5 of 14 patients with juvenile idiopathic arthritis (JIA) who had macrophage activation syndrome (MAS), but in only 4 of 29 patients with JIA who did not have MAS . Several other recessive pairs and compound heterozygotes were found.
The presence of homozygous, compound heterozygous, or digenic mutations in a patient with suspected HLH (or a heterozygous mutation in an adult) is sufficient for diagnosis. Genetic information can also be helpful in determining the likelihood of recurrence, the need for hematopoietic cell transplant, and the risk of HLH in family members. (See 'Diagnosis' below and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
The likelihood of identifying a gene mutation is highest in the youngest patients. In a review of 476 North American children, a gene mutation was identified in 45 percent of those less than one month of age . In those aged between two months to one year, one to two years, and greater than two years, the frequencies of identifying a gene mutation were 39, 20, and 6 percent, respectively.
In another study of 175 adults (age range, 18 to 75 years), 14 percent had gene mutations; these tended to cause partial defects in protein function rather than complete loss of the protein . This partial loss of function may explain the later age of HLH onset in some adults. (See 'Features in adults' below.)
Mutations at FLH loci — Several of the gene mutations in HLH map to familial hemophagocytic lymphohistiocytosis (FLH) loci. (See 'Terminology' above.)
●PRF1/Perforin – FHL2 results from mutations in the PRF1 gene, which encodes perforin. Perforin is delivered in cytolytic granules and forms pores in the membrane of target cells. Mutations in other genes that affect perforin expression have also been reported [29,38-40].
●UNC13D/Munc13-4 – FHL3 results from mutations in the UNC13D gene, which encodes Munc13-4 [30,41]. Proteins of the Unc (uncoordinated) family regulate cytolytic granule maturation.
●STX11/Syntaxin 11 – FHL4 results from mutations in the STX11 gene, which encodes Syntaxin 11. Syntaxins control granule exocytosis. Several Syntaxin mutations were reported in a group of Kurdish families with HLH [31,42].
●STXBP2/Munc18-2 – FHL5 results from mutations in the STXBP2 gene, which encodes Munc18-2 (also called Syntaxin binding protein 2) [34,43]. This protein binds to Syntaxin 11 and promotes the release of cytotoxic granules.
The gene defect responsible for FLH1 remains uncharacterized.
Immunodeficiency syndromes — Several mutations that cause congenital immunodeficiency syndromes are also associated with an increased incidence of HLH. These include the following:
●Griscelli syndrome – Griscelli syndrome (GS) type 2 is caused by mutations in RAB27A, which encodes a GTP binding protein . GS2 is characterized by hypopigmentation, immune deficiency, thrombocytopenia, and/or neurologic defects. (See "Syndromic immunodeficiencies", section on 'Griscelli syndrome'.)
●Chediak-Higashi syndrome – Chediak-Higashi syndrome (CHS) is caused by mutations in CHS1/LYST, which encodes a lysosomal trafficking regulatory protein . CHS is characterized by partial oculocutaneous albinism, neutrophil defects, neutropenia, and neurologic abnormalities. (See "Chediak-Higashi syndrome".)
●X-linked lymphoproliferative disease – X-linked lymphoproliferative disease type 1 (XLP1) is caused by mutations in SH2 domain protein 1A (SH2D1A), also called signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which encodes an activator of NK and T cells . XLP2 is caused by mutations in X-linked inhibitor of apoptosis (XIAP), also called baculoviral IAP-repeat-containing protein 4 (BIRC4); the encoded protein protects cells from apoptosis . XLP (also called Duncan disease) is characterized by an abnormal response to Epstein-Barr virus infection. (See "X-linked lymphoproliferative disease", section on 'Genetics'.)
●XMEN disease – X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease is another immunodeficiency syndrome with EBV-associated malignancies and rarely HLH . A loss of function mutation in a gene encoding magnesium transporter 1 (MAGT1) leads to CD4 lymphopenia, chronic, high-level EBV infection, normal levels of NK T cells, and lack of fatal dysregulated immune responses to EBV. (See "Malignancy in primary immunodeficiency", section on 'XMEN disease'.)
●Interleukin-2-inducible T cell kinase (ITK) deficiency – These patients, like those with XLP and XMEN deficiencies, are unable to control EBV infections. They have a variety of lymphoproliferative diseases, lymphomatoid granulomatosis, HLH, and dysgammaglobulinemia.
●CD27 (TNFRSF7) deficiency – Missense mutations that reduce expression of CD27 have been associated with a syndrome of severe EBV infections associated with HLH, Hodgkin lymphoma, uveitis, and recurrent infections .
●Hermanski-Pudlak syndrome – Hermansky-Pudlak syndrome (HPS) is a rare disorder characterized by oculocutaneous albinism and platelet storage pool deficiency. Several responsible gene mutations have been identified: HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN). Patients with HPS type 2 have a lower risk of developing HLH than those with type 1 because of a milder defect in cytotoxicity . (See "Congenital and acquired disorders of platelet function", section on 'Storage pool disorders'.)
●Lysinuric protein intolerance – Lysinuric protein intolerance (LPI; MIM 222700) is a recessive aminoaciduria caused by defective cationic amino acid transport in epithelial cells of the intestine and kidney. SLC7A7 (also called y+LAT1), the gene mutated in LPI, encodes the light subunit of a cationic amino acid transporter. Patients with LPI frequently display severe complications such as pulmonary disease, hematologic abnormalities, and disorders of the immune response .
●Chronic granulomatous disease – Chronic granulomatous disease (CGD) is a genetically heterogenous condition associated with recurrent, life-threatening bacterial and fungal infections. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)
Genotype-phenotype correlations — Patients with HLH gene mutations tend to present at a younger age than those without mutations. In addition, the specific gene mutated and the mutation site may affect the age of presentation. These observations are supported by the following reports:
●Patients with PRF1 null mutations typically present within the first year of life, whereas those with missense mutations and variable degrees of perforin expression have a more variable age of presentation, even into adulthood [5,52-58].
●In a series of 76 patients with HLH, those with PRF1 mutations had a significantly higher risk of early disease onset (ie, <6 months) than those with STX11 mutations (adjusted odds ratio 8.2; 95% CI 1.2-56) .
●In another study, the most common PRF1 mutation in African blacks (50delT-PRF1) was found to be associated with an earlier age of disease onset compared with that reported for other PRF1 mutations (median age at diagnosis, three months for 50delT-PRF1 verus 36 months for others) [54,60].
●In a series of patients with digenic inheritance (inheritance of mutations at two separate FLH loci), PRF1 mutation in combination with a mutation affecting degranulation (eg, UNC13D, STX11, STXBP2) predicted disease onset at age two years or greater, whereas two mutations affecting degranulation predicted disease onset at <2 years of age .
●Adult patients with hypomorphic mutations of PRF1, MUNC13-4, and STXBP2 often have a more indolent course than younger patients .
●Individuals with STXBP2/Munc18-2 mutations (FLH-5) have defective erythropoiesis with aberrant cell morphology and decreased CD235a expression resulting in hemolysis .
EPIDEMIOLOGY — HLH is primarily a pediatric syndrome. Infants are most commonly affected, with the highest incidence in those <3 months . The male-to-female ratio is close to 1:1 . In adults, there may be a slight male predisposition .
Based on the incidence at several tertiary care pediatric hospitals, we estimate that approximately 1 child in 3000 admitted to the hospital will have HLH, translating to several cases per year . Earlier reviews of the epidemiology of HLH reported incidences that were much lower, likely reflecting underdiagnosis of the condition. As an example, in a series from the 1970s that reported an incidence of 1.2 children per million per year, the diagnosis of HLH was made antemortem in only 11 of 32 patients . A review of HLH cases from the largest pediatric hospitals in Texas revealed an incidence of 1 in 100,000 children .
Although HLH is primarily a pediatric disease, it is diagnosed in patients of all ages, including adults as old as 70 years of age [5,52,65]. A review of 2197 adult cases worldwide found that approximately half of reported patients were from Japan . A nationwide survey in Japan from 2001 to 2005 identified 799 patients with HLH; of the 470 with sufficient data for analysis, 192 (41 percent) were older than 14 years . In addition, there seems to be an ethnic predisposition for development of malignancy-associated HLH, with one large study demonstrating a much higher risk in Japanese and East Asian patients with malignancy compared with Western patients .
Up to 25 percent of HLH cases are familial. As previously noted, the transmission of HLH is autosomal recessive, and parental consanguinity is common. (See 'Genetics' above.)
The frequency of specific HLH mutations was evaluated in a multi-ethnic cohort of 76 patients with familial HLH originating from 65 unrelated families . In this cohort, mutations in STX11, PRF1, and UNC13D were found in 20, 18, and 10 percent of affected individuals, respectively.
A review of 224 North American patients with HLH mutations found the following distribution of specific mutations according to ethnicity :
●Whites were most likely to have mutations in UNC13D (47 percent), STXBP2 (22 percent), and PRF1 (20 percent)
●Hispanics were most likely to have mutations in PRF1 (71 percent) and UNC13D (17 percent)
●Blacks were most likely to have mutations in PRF1 (98 percent)
●Arabs were most likely to have mutations in PRF1 (36 percent), UNC13D (27 percent), and STXBP2 (18 percent)
Other studies of specific ethnic groups have found the following distributions:
●Individuals of Turkish origin had a high incidence of mutations in PRF1, UNC13D, or STX11 .
●Individuals from Saudi Arabia, the United Arab Emirates, and Turkey had a high incidence of STXBP2 mutations [53,69,70].
●Japanese individuals had a high incidence of PRF1 mutations .
Initial presentation — HLH presents as a febrile illness associated with multiple organ involvement. Thus, initial signs and symptoms of HLH can mimic common infections, fever of unknown origin, hepatitis, or encephalitis. With few exceptions, the clinical features are similar regardless of whether an underlying genetic defect has been identified. (See 'Genotype-phenotype correlations' above.)
In the HLH-94 study of 249 patients, which is one of the largest cohorts described, prominent clinical signs included the following :
●Hepatomegaly – 95 percent
●Lymphadenopathy – 33 percent
●Neurologic symptoms – 33 percent
●Rash – 31 percent
In a European registry that included 122 patients, splenomegaly was seen in 97 percent, and fever in 93 percent .
Some HLH gene mutations are associated with distinct clinical features in addition to the typical presenting signs and symptoms. As an example, a review of 37 patients with STXBP2 mutations reported hypogammaglobulinemia, severe diarrhea, bleeding, and sensorineural hearing loss in 59, 38, 22, and 16 percent, respectively . Defective granule mobilization of neutrophils has also been identified in these patients . This leads to inadequate bacterial killing, especially of gram negative bacteria, and is hypothesized to lead to the association of chronic diarrhea in this subset of HLH patients.
Some clinical findings are observed less frequently in affected patients from different ethnic groups. This was illustrated in a case series of 20 neonates from Japan, in which the incidence of fever was extremely low in the eight preterm infants (12 percent); hypertriglyceridemia and neutropenia were uncommon; and familial mutations were undetectable in most patients (65 percent) .
Laboratory and radiographic abnormalities
Cytopenias — Cytopenias, especially anemia and thrombocytopenia, are seen in greater than 80 percent of patients on presentation [64,72,75]. Platelet counts range from 3000 to 292,000 (median 69,000)/microL, and hemoglobin levels of 3.0 to 13.6 (median 7.2) g/dL are typical .
Cytopenias may occur later in the disease course in those with macrophage activation syndrome (MAS; ie, HLH in the setting of a rheumatologic disorder), especially those with juvenile idiopathic arthritis (JIA), because patients with JIA often have elevated blood counts prior to developing MAS.
Serum ferritin levels — A very high serum ferritin level is common in HLH. In the HLH-94 study, ferritin levels greater than 500, 5000, and 10,000 ng/mL were seen in 93, 42, and 25 percent, respectively; the median ferritin level was 2950 ng/mL . Serum ferritin in this range is seen in very few other inflammatory disorders in children, and when it does occur in other syndromes, it is often in the setting of iron overload syndromes (eg, in multiply transfused patients). This was illustrated in a series of 330 children with high serum ferritin levels (320 controls and 10 HLH patients), in which a ferritin level >10,000 mcg/L was 90 percent sensitive and 96 percent specific for HLH, with very minimal overlap with sepsis, infections, and liver failure . When the control group was re-analyzed with a comparison cohort of 120 patients with HLH, a ferritin level ≥2000 mcg/L had a 70 percent sensitivity and 68 percent specificity for diagnosing HLH . There was no difference when primary and secondary HLH cases were analyzed separately.
Thus, the high specificity of ferritin levels is useful diagnostically, especially in children; whereas in adults, other potential causes of extremely high ferritin levels should also be evaluated. (See 'Other diagnostic considerations' below and 'Differential diagnosis' below.)
While a very high ferritin level is helpful in suggesting the possibility of HLH, a low ferritin (eg, ferritin <500 ng/mL) does not exclude the possibility of HLH. A relatively normal ferritin can occasionally be seen in HLH genetic syndromes, even during a disease flare, and disease activity in some patients may correlate more closely with elevated soluble IL-2 receptor alpha (sIL-2R or sCD25) than with ferritin.
Interestingly, macrophages are a primary source of ferritin, which may explain the association between HLH and very high ferritin levels . A protein responsible for modulation of iron homeostasis, growth differentiation factor 15, is dramatically upregulated in patients with HLH and is responsible for increased serum ferritin by enhancing the ferroportin-mediated iron efflux .
Liver function and coagulation abnormalities — Nearly all patients with HLH will have hepatitis, manifested by elevated liver function tests (LFTs), including liver enzymes (AST, ALT, GGT), LDH, and bilirubin. Increased triglycerides and abnormal coagulation parameters (especially elevated D-dimer) caused by hepatic dysfunction and disseminated intravascular coagulopathy are also frequently seen. The degree of abnormality ranges from mild to hepatic failure; hydrops fetalis has been reported in neonates .
●Liver enzyme levels greater than three times the upper limit have been reported in 50 to 90 percent of patients with HLH [64,75,80]; LDH is elevated in 85 percent . Bilirubin levels between 3 and 25 mg/dL are seen in greater than 80 percent. The GGT level is an especially sensitive number to follow because of biliary tract infiltration by lymphocytes and macrophages .
●Hypertriglyceridemia may be due to severe liver involvement, and triglycerides may not be elevated until the liver has been affected for some time. In a review of patients with HLH associated with a variety of triggers, 68 percent had elevated triglycerides at diagnosis or during the course of the disease .
●Coagulation abnormalities due to impaired hepatic synthetic function and/or disseminated intravascular coagulation are common .
●Liver biopsy, if done, is likely to show lymphocytic infiltrates in patients with HLH. On autopsy, the livers of patients who have died from HLH show chronic persistent hepatitis with periportal lymphocytic infiltration .
Neurologic findings — Neurologic abnormalities have been observed in one-third of patients with HLH. The types of abnormalities may be highly variable, and include seizures, mental status changes (including severe changes consistent with encephalitis), and ataxia [7,26,84]. Sometimes these findings dominate the clinical picture or develop prior to the appearance of other signs and symptoms [85,86]. As examples, two patients with familial HLH due to a mutation in the PRF1 gene presented with only severe encephalitis, while another child presented with a demyelinating peripheral neuropathy caused by diffuse macrophage infiltration of the nerve sheath [87,88].
Patients with HLH are at risk of developing posterior reversible encephalopathy syndrome (PRES), which presents with headache, altered consciousness, visual disturbances, and/or seizures. On examination, patients may have retinal hemorrhages and optic nerve edema. PRES is associated with characteristic findings on brain MRI, including vasogenic cerebral edema predominantly in the posterior cerebral hemispheres. (See "Reversible posterior leukoencephalopathy syndrome".)
Magnetic resonance imaging (MRI) of the brain in patients with HLH also may show hypodense or necrotic areas . Approximately 50 percent of patients have abnormalities of the cerebrospinal fluid, which may carry an increased risk for mortality and neurologic sequelae . In a series of 10 adults with HLH, seven had neurological impairment, which included encephalopathy and seizures. Basal ganglia abnormalities were found in four patients . (See 'Initial evaluation' below and "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Prognosis'.)
Other findings — HLH can affect other organ systems, including the respiratory system, heart, and skin.
●Respiratory abnormalities may lead to an urgent need for ventilatory support and death from acute respiratory distress syndrome. Deteriorating respiratory function may be due to worsening of the HLH (causing an acute respiratory distress syndrome [ARDS]-like syndrome), or due to an infection. Pulmonary involvement was reported in 42 percent of a series of 775 adults with HLH .
●Severe hypotension may require administration of one or more vasopressors.
●Renal dysfunction occurs in many patients and may present with hyponatremia, perhaps caused by a SIADH mechanism. Many patients develop renal failure and require dialysis. Renal involvement was reported in 16 percent of a series of 775 adults with HLH .
●Skin manifestations can be quite varied. These include generalized rashes, erythroderma, edema, petechiae, and purpura. Skin rash was reported in one-quarter of a series of 775 adults with HLH .
●Bleeding is also a common manifestation of HLH. It may be due to altered coagulation from liver failure, thrombocytopenia from bone marrow failure, or platelet function defects associated with an underlying genetic defect in platelet granule processing. (See 'Genetics' above.)
●Patients with underlying immunodeficiency syndromes may also have syndrome-specific findings (eg, albinism). (See 'Immunodeficiency syndromes' above.)
●Some have clinical features of Kawasaki disease, including conjunctivitis, red lips, and cervical lymphadenopathy. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations'.)
Associated illnesses — Infection, malignancy, rheumatologic, and immunodeficiency syndromes are common in patients with HLH, especially adults. (See 'Features in adults' below.)
It is important to identify these conditions because effective treatment may lead to clinical improvement of the HLH and allow the patient to avoid more toxic therapy (eg, hematopoietic cell transplant). However, evaluation for these associated syndromes should not delay diagnostic testing or initiation of HLH-specific treatment in those who are acutely ill.
Infections — HLH is often associated with infections, especially viral. Common viruses include Epstein-Barr virus, cytomegalovirus, parvovirus, herpes simplex virus, varicella-zoster virus, measles virus, human herpes virus-8, H1N1 influenza virus, parechovirus, and HIV, alone or in combination [63,92-100]. The development of HLH shortly after the initiation of antiretroviral therapy (ART) for the treatment of HIV infection has also been reported . Patients with rheumatologic diseases who are treated with anti-TNF agents and develop HLH may be infected with mycobacterium tuberculosis, cytomegalovirus, EBV, Histoplasma capsulatum, and other bacteria .
Although less common, HLH may also occur in the setting of infections due to bacteria (eg, Brucella, gram negative bacteria, tuberculosis), parasites (eg, Leishmaniasis, malaria), and fungi [63,100,103,104].
Malignancy — HLH has been reported in association with malignancies, most commonly lymphoid cancers, including T, NK, and anaplastic large cell lymphomas, and leukemias [100,105-114]. B cell lymphoblastic leukemia, myeloid malignancies, and solid tumors occurring in association with HLH have also been noted [26,107,115-117]. Rarely, the diagnosis of HLH may precede the identification of the malignancy .
Many patients with malignancy who develop HLH appear to have an acute infectious trigger. When associated with a malignancy, the HLH is often more immediately life-threatening than the malignancy. (See "Hematologic complications of malignancy: Anemia and bleeding" and "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)
Overall prognosis is quite poor for any malignancy-associated HLH, regardless of the patient's age at presentation, as discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Prognosis'.)
Rheumatologic disorders/MAS — HLH can occur in the setting of rheumatologic disorders. The most common association is in children with systemic juvenile idiopathic arthritis (sJIA, formerly called Still's disease, systemic onset JIA, or systemic onset juvenile rheumatoid arthritis). The term macrophage activation syndrome (MAS) is used when a hemophagocytic syndrome develops in children with JIA and other rheumatologic conditions. MAS should be thought of as HLH in the setting of a rheumatologic disorder rather than as a separate syndrome. Performance guidelines for the diagnosis of MAS have been published . (See "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome' and "Kawasaki disease: Complications", section on 'Macrophage activation syndrome'.)
HLH may develop any time during the course of a rheumatologic disorder (eg, upon presentation, during therapy, in association with a concurrent infection). In patients with sJIA treated with tocilizumab, 23 of 394 developed confirmed or probable MAS . When MAS occurs as a presenting manifestation of lupus and systemic juvenile or adult rheumatoid arthritis, the diagnosis of both conditions may be challenging. Other autoimmune diseases associated with HLH include dermatomyositis, systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome, Sjögren's syndrome, ankylosing spondylitis, vasculitis, and sarcoidosis . Some patients with MAS have also been found to have heterozygosity for mutations in HLH genes (eg, PRF1, UNC13D) . (See 'Genetics' above.)
Immunodeficiency — HLH has been found in patients with inherited immunodeficiency disorders, including those due to mutations that are associated with HLH as well as others [27,44-46,121-124]. (See 'Immunodeficiency syndromes' above.)
Acquired immunodeficiencies have also been associated with HLH, including HIV/AIDS, hematopoietic cell transplantation, or kidney or liver transplant [100,125,126]. Sometimes HLH occurs in the setting of a concurrent infection or a lymphoproliferative syndrome [127-129]. In one small series, the development of HLH in kidney transplant patients appeared to be associated with the combination of splenectomy and the administration of anti-thymocyte globulin .
Features in adults — HLH presenting in adulthood is increasingly recognized [63,131-135]. Adults can have similar clinical features of HLH as children. As an example, a series of 775 adults with HLH reported similar predominance of fever (96 percent), splenomegaly (69 percent), and hepatomegaly (67 percent) .
However, emerging diagnostic criteria for adults with HLH indicate several differences from those used in pediatric patients. A Delphi analysis (a method for finding consensus using iterative anonymous questionnaires) from an expert panel determined the following clinical features to be important in adults :
●Underlying predisposing disease
●Hemophagocytosis on the bone marrow aspirate
A 2015 review noted that HLH in adults is more likely to be associated with a hematologic malignancy, and an elevated ferritin level is less specific in adults due to the higher incidence of other inflammatory conditions .
The frequency of underlying conditions such as hematologic malignancies, infections, and rheumatologic conditions in adults with HLH have been illustrated in various case series:
●In a series of 162 adults with HLH, hematologic malignancies (especially non-Hodgkin lymphoma) were the most common trigger, seen in 92 (57 percent) . An additional 40 patients (25 percent) had infections, which were caused by bacterial, viral, parasitic, or fungal organisms; six (4 percent) had both hematologic malignancy and infection. Additional analysis of this cohort identified a source of immunosuppression in 73 (45 percent) . For 61, the source of immunosuppression was HIV infection; for the remainder, it was an immunosuppressive medication.
●Several single-institution studies focusing on HLH in adults have documented infection in 23 to 41 percent of patients and rheumatologic/autoimmune disease in 8 to 20 percent [139-141]. In a series of 30 patients who had testing for Epstein-Barr virus (EBV) DNA, 10 were found to be positive . Adults with EBV-associated HLH have higher ferritin, LDH, AST, and ALT levels than those without EBV infection .
●Reports of coexisting autoimmune and rheumatologic diseases in adults include systemic lupus erythematosus, rheumatoid arthritis, Still's disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, and Sjögren's syndrome [82,100,130,144-149].
The reduced specificity of an extremely high ferritin in adults was illustrated in a series of 113 adults with a serum ferritin level >50,000 ng/mL (median age, 58) . Of these, only 19 (17 percent) were ultimately diagnosed with HLH; 9 of the 17 had secondary HLH due to a malignancy and 6 of the 17 had secondary HLH due to infection. More common diagnoses than HLH included renal failure (65 percent), hepatocellular injury (54 percent), infection (46 percent), and hematologic malignancy (32 percent). Other diagnoses associated with extremely high ferritin levels in adults are discussed separately. (See 'Differential diagnosis' below and "Iron overload syndromes other than hereditary hemochromatosis", section on 'Extremely high ferritin levels'.)
The later age of onset in some adults may be explained by the presence of a mutation with partial residual protein function, which may be able to compensate in the setting of some immune triggers. (See 'Genetics' above.)
EVALUATION AND DIAGNOSTIC TESTING
Initial evaluation — Most patients with HLH are acutely ill with multiorgan involvement, cytopenias, liver function abnormalities, and neurologic symptoms. Patients may have already experienced a prolonged hospitalization or clinical deterioration without a clear diagnosis before the possibility of HLH is raised. A priority should be placed on rapid evaluation for organ involvement including testing for signs of bone marrow insufficiency, liver abnormalities, neurologic involvement, and immune activation, with the goal of starting treatment as rapidly as possible once the diagnosis (or a high likelihood) of HLH is established. The diagnostic approach is similar in infants, children, and adults .
Patients with suspected HLH (or their families) should be asked about parental consanguinity, familial disorders, antecedent infections, recurrent fevers, and preexisting immunologic defects (eg, HIV infection, rheumatologic disorders, immunosuppressive medications). (See 'Genetics' above and 'Associated illnesses' above.)
The physical examination should focus on identifying rashes, bleeding, lymphadenopathy, hepatosplenomegaly, and neurologic abnormalities. A thorough examination for signs of other organ involvement (eg, cardiac, respiratory) is also necessary.
Many of the initial tests that are helpful in evaluating HLH will have already been done as part of the evaluation of an unexplained febrile illness that involves multiple organs. Others, including serum ferritin, triglycerides, and screening immunologic studies, should be done immediately.
We do the following tests in all patients:
●Complete blood count with differential
●Coagulation studies, including PT, aPTT, fibrinogen, D-dimer
●Liver function tests, including ALT, AST, GGT, total bilirubin, albumin, and LDH
Identifying signs of infection and specific organ injury is helpful in making the diagnosis of HLH, as well as for management of organ-specific complications. Based upon the symptoms and signs of specific organ involvement and/or the degree of suspicion for the presence of HLH, we perform the following studies in all patients:
●Cultures of blood, bone marrow, urine, cerebrospinal fluid, and other potentially infected body fluids; and viral titers and quantitative polymerase chain reaction testing for EBV, CMV, adenovirus, and other suspected viruses. It is critical to follow the levels of any identified virus during treatment with the appropriate anti-viral therapy.
●Bone marrow evaluation (see 'Bone marrow evaluation' below)
●Electrocardiograph, chest radiography, and an echocardiogram.
●Cerebrospinal fluid analysis. The cerebrospinal fluid is abnormal in over half of patients with HLH, with findings of cellular pleocytosis, rarely hemophagocytosis, and elevated protein. Cultures and testing for viruses (eg, by polymerase chain reaction) should be done as indicated by clinical findings and epidemiology. (See "Viral encephalitis in adults" and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)
Brain MRI scan with and without contrast (if contrast is not contraindicated). Imaging of the CNS may show parameningeal infiltrations, subdural effusions, necrosis, and other abnormalities.
●Computed tomography scans of neck, chest, abdomen, and pelvis to evaluate for possible malignancy.
●Abdominal ultrasound, if the physical examination for splenomegaly is inconclusive.
We do a rapid immunologic evaluation in those with a high clinical suspicion of HLH. (See 'Immunologic profile' below.)
Bone marrow evaluation — All patients should have examination of a bone marrow aspirate and biopsy to evaluate the cause of cytopenias and/or to detect hemophagocytosis. The bone marrow specimens should also be cultured and examined for infectious organisms and evidence of malignancy. Bone marrow cellularity can be high, low, or normal in HLH .
The reported incidence of hemophagocytosis on bone marrow examination ranges from 25 to 100 percent . Some patients may only show hemophagocytosis later in the disease course, even as they are clinically improving . A review of adult patients exhibiting hemophagocytosis in bone marrow aspirates revealed that 170 (64 percent) had lymphoma, especially T/NK and B cell lymphoma. Of 182 patients with sufficient clinical data to judge HLH-2004 diagnostic criteria for HLH, only 77 (29 percent) fulfilled 5 of 8 criteria (see 'Diagnostic criteria' below). Of those who had a malignancy, survival was a median of 9 months, versus 71.8 months in those with non-malignant disorders .
Infiltration of the bone marrow by activated macrophages is consistent with HLH. The macrophages in HLH do not have the cellular atypia associated with malignant histiocytes, and they are clearly a different cell from the CD1a-staining Langerhans cell of Langerhans cell histiocytosis (formerly called histiocytosis-X). It is helpful to stain the bone marrow for the hemoglobin-haptoglobin scavenger receptor CD163 to highlight the macrophages. This is often how many macrophages (hemophagocytosing and not) are seen in the bone marrow specimens of patients with HLH. (See 'Diagnosis' below.)
Immunologic profile — Immunologic and cytokine studies are appropriate for those suspected of having HLH based on the results of the initial evaluation. (See 'Initial evaluation' above.)
We typically perform the following immunologic testing:
●Soluble IL-2 receptor alpha (sCD25 or sIL-2R)
●Tests of NK cell function/degranulation (eg, by flow cytometry for surface expression of the lysosomal-associated membrane protein 1 [LAMP-1, also called CD107alpha])
●Flow cytometry for cell surface expression of perforin and granzyme B proteins
●Flow cytometry for cell surface expression of SAP and XIAP proteins in males
●Soluble levels of the hemoglobin-haptoglobin scavenger receptor (sCD163)
●Immunoglobulin levels (eg, IgG, IgA, IgM)
●Lymphocyte subsets (underlying immune deficiency diseases are sometimes found)
The first five are only available in specialized centers .
Findings consistent with HLH include elevated soluble IL-2 receptor alpha; reduced NK function or cell surface expression of CD107alpha; elevated sCD163; and reduced perforin, SAP, or XIAP. Peripheral blood T cell subsets show a normal helper/suppressor ratio, with low numbers of B cells and variable immunoglobulin levels [11,153-159]. Elevation of granzyme B has been found and is thought to be part of the immune signature of lymphocyte activation .
Of all the immunologic studies, we find soluble IL-2 receptor alpha (sIL-2R) to correlate most closely with disease activity . The ratio of sIL-2R to serum ferritin may be useful in patients with lymphoma. A review of patients with lymphoma-associated HLH versus non-lymphoma-associated cases found that the former had a much higher ratio of sIL-2R to ferritin than the latter (ratio 8.56 versus 0.66) .
Levels of the soluble IL-2 receptor alpha will be available in one to two days, while the other tests take longer. Thus, therapy should not be delayed while awaiting results of this immunologic testing.
HLH associated with lymphoma can be challenging to differentiate from clinical presentations of sepsis. A study in 15 adults with lymphoma-associated HLH showed potential for the use of assays the cytokines CXCL9 and CXCL10; elevated levels had a high sensitivity and specificity for lymphoma-associated HLH compared to sepsis .
Genetic and HLA testing — Genetic testing (ie, identification of an HLH gene mutation) is indicated in all patients that meet the HLH diagnostic criteria, and those with a high likelihood of HLH based on the initial evaluation. For those with a known familial mutation or immunodeficiency syndrome, directed genetic analysis for the known mutation should be performed. For those without a known family mutation, one could base genetic testing on protein levels obtained during the initial evaluation:
●If cellular perforin protein levels are low, we do PRF mutation analysis.
●If CD107a mobilization is low, we do UNC13D, STX11, STXBP2, and RAB27A mutation analysis.
●If SAP expression is low, we do SH2D1A mutation analysis.
●If XIAP expression is low, we do BIRC4 mutation analysis.
However, we find it most efficient to send blood for a next generation sequencing of a panel of HLH-associated genes because of the possibility of bi-allelic or hypomorphic mutations. Also, it is sometimes necessary to request intronic sequencing to find rare variants. (See "Principles and clinical applications of next-generation DNA sequencing", section on 'Whole genome, exome, or gene panel'.)
Laboratories that can perform genetic testing can be found in the Genetic Testing Registry (http://www.ncbi.nlm.nih.gov/gtr/tests/).
Human leukocyte antigen (HLA) typing is indicated during the initial evaluation in preparation for identifying a donor for allogeneic hematopoietic cell transplantation. Performing this testing at the time of initial presentation avoids delays in identifying donors should they be needed. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
DIAGNOSIS — Ideally, the diagnosis of HLH is based upon fulfilling the published diagnostic criteria used in the HLH-2004 trial . Not infrequently, however, a diagnosis of HLH is made in the patient who only partly meets the most stringent criteria because definitive HLH therapy must be initiated due to an inadequate response to general supportive care. A presumptive diagnosis depends upon a careful consideration of the presence or absence of the specific elements of the diagnostic criteria, the results of additional laboratory tests (eg, D-dimer and liver function tests), and a nuanced view of the overall clinical status.
Diagnostic criteria — We recommend that the diagnosis of HLH be based upon the following criteria, which were used in the HLH-2004 trial :
Molecular identification of an HLH-associated gene mutation (eg, PRF1, UNC13D, STX11, STXBP2, Rab27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS). Children require documentation of homozygosity or compound heterozygosity for HLH-associated gene mutations. By comparison, heterozygosity may be sufficient for adults if they have clinical findings associated with HLH.
Five of the following eight findings:
●Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL (for infants <4 weeks, hemoglobin <10 g/dL); platelets <100,000/microL; absolute neutrophil count <1000/microL
●Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 mg/dL)
●Hemophagocytosis in bone marrow, spleen, lymph node, or liver
●Low or absent NK cell activity
●Ferritin >500 ng/mL (the author prefers to consider a ferritin >3000 ng/mL as more indicative of HLH )
●Elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms
It should be noted that these diagnostic criteria were devised for use in clinical trials and are therefore unlikely to capture every case of HLH. Because of the high mortality of HLH in the absence of appropriate treatment, we do not always require these diagnostic criteria to be met in order to initiate treatment. Specifically, we do not delay treatment while awaiting the results of genetic or specialized immunologic testing.
Diagnostic criteria are essentially the same in adults, with the caveat that adults are more likely to have a secondary form of HLH than children, and adults with secondary HLH are more likely to have an underlying malignancy as the cause.
It is common for a patient to only exhibit three or four of the eight diagnostic criteria, but also have CNS symptoms, hypotension, and renal or respiratory failure. To address this issue, a modification of the diagnostic criteria has been proposed . In this approach, diagnosis requires three of four clinical findings (fever, splenomegaly, cytopenias, hepatitis) plus one of four immune markers (hemophagocytosis, increased ferritin, hypofibrinogenemia, absent or very decreased NK cell function) . We also consider such criteria sufficient for diagnosis .
Examples of others we would be likely to treat include the following:
●A patient with CNS symptoms, cytopenias, fever, and
ferritin over 3000 ng/mL or rapidly rising ferritin or elevated sCD25
●A patient with CNS symptoms, hepatitis, coagulopathy, and
ferritin over 3000 ng/mL or rapidly rising ferritin or elevated sCD25
●A patient with hypotension, fever, no response to broad spectrum antibiotics, and
ferritin over 3000 ng/mL or rapidly rising ferritin or elevated sCD25
In contrast, we would not give HLH-specific therapy to a patient with fever, hepatitis, hypofibrinogenemia, and cytopenias, with a ferritin less than 3000 ng/mL and sCD25 only slightly above the age-related norm, because of the possibility that this could represent bacterial sepsis.
Other diagnostic considerations — Although hemophagocytosis and a very high serum ferritin are quite helpful in the diagnosis of HLH (see 'Serum ferritin levels' above), the following caveats are important to keep in mind:
●Hemophagocytosis is neither pathognomonic of, nor required for, the diagnosis of HLH. For patients with multiorgan failure and an immunologic profile typical of HLH who are acutely ill, serial bone marrow evaluations for hemophagocytosis can be conducted concurrently with initiation of treatment.
●Results from the HLH-94 study indicated that a ferritin level >500 ng/mL was only 80 percent specific for the diagnosis of HLH.
•Based on our experience, in children we generally view serum ferritin levels greater than 2000 to 3000 ng/mL in the proper clinical setting as concerning for HLH, and ferritin >10,000 ng/mL as highly suggestive of the disease. Support for our approach comes from a retrospective review of all patients admitted to Texas Children’s Hospital, Houston, TX with ferritin levels >500 mcg/L over a two-year period . In this cohort, a ferritin level >500 mcg/L was 100 percent sensitive for HLH, but less specific. A ferritin level >10,000 mcg/L in children was 90 percent sensitive and 96 percent specific for HLH, with very minimal overlap with sepsis, infections, and liver failure. (See 'Serum ferritin levels' above.)
•In adults, we rely less heavily on an isolated serum ferritin elevation, as serum ferritin is less specific for HLH in adults. (See 'Features in adults' above.)
A scoring system has been developed to generate a diagnostic score referred to as an "Hscore" that estimates the probability of HLH ; this incorporates points for immunosuppression; fever; organomegaly; levels of triglycerides, ferritin, alanine aminotransferase, and fibrinogen; degree of cytopenias; and presence of hemophagocytosis on the bone marrow aspirate. An Hscore ≥250 confers a 99 percent probability of HLH, whereas a score of ≤90 confers a <1 percent probability of HLH.
DIFFERENTIAL DIAGNOSIS — HLH may simulate a number of common conditions that cause fever, pancytopenia, hepatic abnormalities, or neurologic findings. We find cytopenias, a very high ferritin level, and liver function abnormalities to be especially helpful in distinguishing HLH from these other conditions. The frequency of LFT abnormalities is so high in HLH that we believe the absence of LFT abnormalities should prompt a thorough search for an alternative diagnosis. (See 'Cytopenias' above and 'Serum ferritin levels' above and 'Liver function and coagulation abnormalities' above.)
It is also important to remember that HLH can develop in association with many of the conditions in its differential diagnosis.
●Macrophage activation syndrome (MAS) – MAS should be thought of as a form of HLH associated with a rheumatologic disease, rather than as a separate clinical entity. (See 'Rheumatologic disorders/MAS' above.)
●Infection/sepsis – Systemic infections and/or sepsis share many features with HLH, including fever, cytopenias, and hepatic involvement. Both sepsis and HLH can have findings of disseminated intravascular coagulation and widespread inflammation with cytokine abnormalities. Unlike HLH, which is often triggered by a viral infection, sepsis is typically caused by a bacterial or fungal microorganism, and sepsis is typically not characterized by ongoing lymphocyte activation. While there is no ideal test to distinguish between sepsis and HLH, an extremely high ferritin and elevated lactate dehydrogenase level were highly predictive of a subsequent diagnosis of HLH in a series of 19 children with an initial diagnosis of fever of unknown origin . Ferritin levels tend to be static in patients with infections, but are prone to dramatic increases in those with HLH. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)
●Liver disease/liver failure – Primary liver disease and HLH can both present with hepatomegaly and elevated liver function tests. Both can cause a coagulopathy with prolonged PT and aPTT, low fibrinogen, and elevated D-dimer and both can cause encephalopathy. Unlike liver disease, HLH is a multisystem disorder. Those with HLH typically have more extensive organ involvement, cytopenias, extremely high ferritin, and neurologic findings. Cytokine profiles seen in HLH are not typically seen in primary liver disease. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
●Multiple organ dysfunction syndrome – Multiple organ dysfunction syndrome (MODS) refers to progressive organ dysfunction in an acutely ill patient. Like HLH, MODS can affect any organ system, and there may be some overlap between these diagnoses . It is possible that a subset of patients who have been diagnosed with MODS have in fact had HLH. An extremely high ferritin or dramatically increasing ferritin is more consistent with HLH than with MODS. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Multiple organ dysfunction syndrome' and 'Evaluation and diagnostic testing' above.)
●Encephalitis – Encephalitis can result from infection, autoimmunity, and a number of viral infections; and the clinical manifestations can range from subtle neurologic deficits to complete unresponsiveness. The neurologic presentation of those with encephalitis can thus be identical to those with HLH. However, those with HLH typically have more extensive organ involvement, cytopenias, liver abnormalities, and high ferritin, whereas findings in encephalitis are typically confined to the central nervous system. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis" and "Viral encephalitis in adults".)
●Autoimmune lymphoproliferative syndrome (ALPS) – ALPS is an immune dysregulation syndrome caused by genetic defects in the machinery for FAS-mediated apoptosis, which leads to expansion of some autoreactive lymphocyte populations. Patients present with hepatosplenomegaly, rash, and autoimmune cytopenias, along with other autoimmune manifestations that could mimic findings of HLH (eg, autoimmune hepatitis, Guillain Barré syndrome). Unlike those with HLH, patients with ALPS typically do not manifest multiorgan failure and signs of excessive inflammation such as extremely high ferritin levels and severe liver failure. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)
●Drug reaction with eosinophilia and systemic symptoms (DRESS) – DRESS is a severe drug-induced hypersensitivity reaction possibly initiated by viral reactivation. Like HLH, DRESS is characterized by fever and liver function test abnormalities. DRESS can also be associated with hemophagocytosis, although this is rare . Unlike HLH, DRESS is characterized by temporal relationship to a drug, eosinophilia and skin rash. DRESS is unlikely to cause an extremely high ferritin or cytopenias, which are found in most patients with HLH. (See "Drug eruptions", section on 'Drug reaction with eosinophilia and systemic symptoms (DRESS)'.)
●Child abuse – Child abuse and HLH may present with similar features involving the central nervous system [167,168]. The majority of child abuse victims with brain injury also have some laboratory abnormalities such as a prolonged aPTT . However, cytopenias, abnormal liver function tests, and high serum ferritin typical of HLH are not features of child abuse. (See "Differential diagnosis of suspected child physical abuse".)
●Kawasaki disease – Kawasaki disease, a vasculitis that predominantly affects children, is characterized by signs of widespread inflammation that include fever, rash, and lymphadenopathy as well as elevated triglycerides and abnormal cerebrospinal fluid findings. Kawasaki disease typically causes bilateral conjunctivitis and mucositis, as well as cardiac findings (eg, coronary artery aneurysms), findings that are much less common in HLH. Additional features that help distinguish Kawasaki disease from HLH include the more likely presence of cytopenias and liver abnormalities with HLH. A patient with the diagnosis of Kawasaki disease, especially if "atypical", whose symptoms do not respond to intravenous immune globulin (IVIG) therapy, should be evaluated for HLH. Kawasaki disease can act as a trigger for HLH, so its diagnosis does not eliminate the possibility of HLH. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Complications", section on 'Cardiac complications'.)
●Cytophagic histiocytic panniculitis – Cytophagic histiocytic panniculitis is a rare systemic disorder consisting of lobular panniculitis (ie, inflammation of the subcutaneous fat), fever, hepatosplenomegaly, and liver failure. This panniculitis can be associated with a form of T cell lymphoma [170,171]. A subset of patients diagnosed with this condition may have had HLH. These patients with panniculitis, who primarily present with subcutaneous nodules, are less likely to have the severe multiorgan involvement seen in HLH. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma" and "Panniculitis: Recognition and diagnosis", section on 'Malignancy'.)
●Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced thrombotic microangiopathy (DITMA) – TTP, HUS, and DITMA (also called drug-induced TTP) are characterized by endothelial damage, microvascular thrombosis, and anemia; fever, neurologic findings, or renal failure may be present. Unlike the anemia of HLH, the anemia in these syndromes is microangiopathic (ie, Coombs negative, characterized by schistocytes). Patients with TTP, HUS, or DITMA generally do not have rising ferritin or liver function abnormalities, although a DITMA syndrome associated with quinine may have multiorgan failure. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy".)
●Transfusion-associated graft-versus-host disease (ta-GVHD) – Ta-GVHD is a rare complication of transfusion of any non-irradiated blood component. It occurs when viable donor lymphocytes in the transfusion attack the recipient's tissues (skin, bone marrow, gastrointestinal tract), often fatally. It is most common after hematopoietic cell transplantation but can also occur in immunocompetent individuals who have a partial human leukocyte antigen (HLA) match with the donor (eg, in ethnically homogenous populations or after directed donation). The typical presentation includes fever, rash, pancytopenia, and elevated liver enzymes, 4 to 30 days after transfusion. High ferritin levels and hemophagocytosis in the bone marrow can also be seen. Unlike HLH, skin biopsy in ta-GVHD shows vacuolization of the basal layer and a histiocytic infiltrate, and sometimes the pathognomonic finding of satellite dyskeratosis. In cases where the two diagnoses cannot be distinguished, a trial of dexamethasone, and, if not sufficient, etoposide, can be used. (See "Transfusion-associated graft-versus-host disease".)
●Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It is most common in infants and young children but can affect patients of any age, with or without a predisposing familial condition. (See 'Introduction' above and 'Epidemiology' above.)
●Most patients with HLH are acutely ill with multiorgan involvement. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, and liver function abnormalities. (See 'Initial presentation' above.)
●Patients may have already experienced a prolonged hospitalization or clinical deterioration without a clear diagnosis before the possibility of HLH is raised. A priority should be placed on rapid evaluation, with the goal of starting treatment as soon as possible. (See 'Initial evaluation' above.)
●Many patients with HLH have a predisposing genetic defect, and/or an immunologic trigger, which can include infection, malignancy, rheumatologic disorder such as juvenile idiopathic arthritis, or another disorder associated with immune dysregulation. These genetic defects and immunologic triggers should be identified in all patients. (See 'Genetics' above and 'Associated illnesses' above.)
●The initial evaluation includes a complete blood count with differential, coagulation studies, serum ferritin, liver function tests, triglycerides, blood cultures, and viral testing. The bone marrow should be examined for the cause of cytopenias, infectious organisms, hemophagocytosis, and macrophage infiltration; and sent for cultures. All patients should have cerebrospinal fluid analysis and magnetic resonance imaging of the brain. Computed tomography scans of the neck, chest, abdomen and pelvis should be done to evaluate for possible malignancy. (See 'Initial evaluation' above and 'Bone marrow evaluation' above.)
●For those with a high clinical suspicion, specialized testing of immunologic parameters and genetic testing are also indicated. HLA typing is done in preparation for possible allogeneic hematopoietic cell transplantation. (See 'Specialized testing' above.)
●The diagnosis of HLH is made by identifying a mutation in an HLH gene, or by fulfilling five of eight diagnostic criteria. Many patients fit only three or four of the eight criteria, yet have clinical evidence of HLH and require HLH-specific treatment. Modified diagnostic criteria may also be used. Hemophagocytosis, while often seen, is neither necessary nor sufficient for the diagnosis of HLH. (See 'Diagnosis' above.)
●The differential diagnosis of HLH includes several multisystem illnesses characterized by fever, hepatic failure, and neurologic symptoms. Many of the conditions in the differential diagnosis of HLH can also cause HLH. We consider macrophage activation syndrome to be a form of HLH associated with a rheumatologic condition rather than a distinct entity. (See 'Differential diagnosis' above and 'Rheumatologic disorders/MAS' above.)
- Larroche C. Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment. Joint Bone Spine 2012; 79:356.
- Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
- Aricò M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996; 10:197.
- Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine (Baltimore) 1988; 67:369.
- Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 2002; 100:2266.
- Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol 2004; 124:4.
- Filipovich A, McClain K, Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines. Biol Blood Marrow Transplant 2010; 16:S82.
- Dalal BI, Vakil AP, Khare NS, et al. Abnormalities of the lymphocyte subsets and their immunophenotype, and their prognostic significance in adult patients with hemophagocytic lymphohistiocytosis. Ann Hematol 2015; 94:1111.
- Pachlopnik Schmid J, Côte M, Ménager MM, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 2010; 235:10.
- Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 2012; 24:9.
- Egeler RM, Shapiro R, Loechelt B, Filipovich A. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 1996; 18:340.
- Eife R, Janka GE, Belohradsky BH, Holtmann H. Natural killer cell function and interferon production in familial hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol 1989; 6:265.
- Ishii E, Ueda I, Shirakawa R, et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 2005; 105:3442.
- Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999; 286:1957.
- Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805.
- Fall N, Barnes M, Thornton S, et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum 2007; 56:3793.
- Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011; 121:2264.
- Henter JI, Elinder G, Söder O, et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991; 78:2918.
- Osugi Y, Hara J, Tagawa S, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood 1997; 89:4100.
- Aricò M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol 2001; 114:761.
- Komp DM, McNamara J, Buckley P. Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood 1989; 73:2128.
- Tang Y, Xu X, Song H, et al. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol 2008; 143:84.
- Takada H, Ohga S, Mizuno Y, et al. Increased IL-16 levels in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 2004; 26:567.
- Mazodier K, Marin V, Novick D, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood 2005; 106:3483.
- Put K, Avau A, Brisse E, et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ. Rheumatology (Oxford) 2015; 54:1507.
- Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis. Blood 2011; 118:4041.
- Parekh C, Hofstra T, Church JA, Coates TD. Hemophagocytic lymphohistiocytosis in children with chronic granulomatous disease. Pediatr Blood Cancer 2011; 56:460.
- Ohadi M, Lalloz MR, Sham P, et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 1999; 64:165.
- Göransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet 2001; 68:590.
- Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003; 115:461.
- zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 2005; 14:827.
- Zhang K, Chandrakasan S, Chapman H, et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood 2014; 124:1331.
- Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011; 96:688.
- Spessott WA, Sanmillan ML, McCormick ME, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood 2015; 125:1566.
- Cetica V, Sieni E, Pende D, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry. J Allergy Clin Immunol 2016; 137:188.
- Kaufman KM, Linghu B, Szustakowski JD, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014; 66:3486.
- Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 2011; 118:5794.
- Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood 2005; 105:4700.
- Trambas C, Gallo F, Pende D, et al. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood 2005; 106:932.
- Voskoboinik I, Thia MC, De Bono A, et al. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med 2004; 200:811.
- Meeths M, Chiang SC, Wood SM, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 2011; 118:5783.
- Rudd E, Göransdotter Ericson K, Zheng C, et al. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J Med Genet 2006; 43:e14.
- Côte M, Ménager MM, Burgess A, et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest 2009; 119:3765.
- Ménasché G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 2000; 25:173.
- Rubin CM, Burke BA, McKenna RW, et al. The accelerated phase of Chediak-Higashi syndrome. An expression of the virus-associated hemophagocytic syndrome? Cancer 1985; 56:524.
- Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 2001; 97:1131.
- Marsh RA, Madden L, Kitchen BJ, et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood 2010; 116:1079.
- Li FY, Chaigne-Delalande B, Su H, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 2014; 123:2148.
- Alkhairy OK, Perez-Becker R, Driessen GJ, et al. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol 2015; 136:703.
- Jessen B, Bode SF, Ammann S, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Blood 2013; 121:2943.
- Barilli A, Rotoli BM, Visigalli R, et al. Impaired phagocytosis in macrophages from patients affected by lysinuric protein intolerance. Mol Genet Metab 2012; 105:585.
- Nagafuji K, Nonami A, Kumano T, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica 2007; 92:978.
- Pagel J, Beutel K, Lehmberg K, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood 2012; 119:6016.
- Lee SM, Sumegi J, Villanueva J, et al. Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr 2006; 149:134.
- Feldmann J, Le Deist F, Ouachée-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol 2002; 117:965.
- Ueda I, Ishii E, Morimoto A, et al. Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Pediatr Blood Cancer 2006; 46:482.
- Ueda I, Kurokawa Y, Koike K, et al. Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. Am J Hematol 2007; 82:427.
- Muralitharan S, Al Lamki Z, Dennison D, et al. An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression. Am J Hematol 2005; 78:59.
- Horne A, Ramme KG, Rudd E, et al. Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol 2008; 143:75.
- Molleran Lee S, Villanueva J, Sumegi J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 2004; 41:137.
- Kostova EB, Beuger BM, Veldthuis M, et al. Intrinsic defects in erythroid cells from familial hemophagocytic lymphohistiocytosis type 5 patients identify a role for STXBP2/Munc18-2 in erythropoiesis and phospholipid scrambling. Exp Hematol 2015; 43:1072.
- Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.
- Ramos-Casals M, Brito-Zerón P, López-Guillermo A, et al. Adult haemophagocytic syndrome. Lancet 2014; 383:1503.
- Niece JA, Rogers ZR, Ahmad N, et al. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer 2010; 54:424.
- Shin HJ, Chung JS, Lee JJ, et al. Treatment outcomes with CHOP chemotherapy in adult patients with hemophagocytic lymphohistiocytosis. J Korean Med Sci 2008; 23:439.
- Ishii E, Ohga S, Imashuku S, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007; 86:58.
- Ferreri AJ, Dognini GP, Campo E, et al. Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions. Haematologica 2007; 92:486.
- Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat 2006; 27:62.
- Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 2010; 116:2635.
- Sandrock K, Nakamura L, Vraetz T, et al. Platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL-5). Blood 2010; 116:6148.
- Ueda I, Morimoto A, Inaba T, et al. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol 2003; 121:503.
- Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011; 118:4577.
- Zhao XW, Gazendam RP, Drewniak A, et al. Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations. Blood 2013; 122:109.
- Suzuki N, Morimoto A, Ohga S, et al. Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan. J Pediatr 2009; 155:235.
- Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003; 36:306.
- Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:1227.
- Lehmberg K, McClain KL, Janka GE, Allen CE. Determination of an appropriate cut-off value for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2014; 61:2101.
- Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 2010; 116:1574.
- Wu JR, Yuan LX, Ma ZG, et al. GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2013; 60:940.
- Stapp J, Wilkerson S, Stewart D, et al. Fulminant neonatal liver failure in siblings: probable congenital hemophagocytic lymphohistiocytosis. Pediatr Dev Pathol 2006; 9:239.
- Okamoto M, Yamaguchi H, Isobe Y, et al. Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. Intern Med 2009; 48:775.
- Fukaya S, Yasuda S, Hashimoto T, et al. Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases: analysis of 30 cases. Rheumatology (Oxford) 2008; 47:1686.
- Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology 1998; 32:310.
- Jovanovic A, Kuzmanovic M, Kravljanac R, et al. Central nervous system involvement in hemophagocytic lymphohistiocytosis: a single-center experience. Pediatr Neurol 2014; 50:233.
- Haddad E, Sulis ML, Jabado N, et al. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood 1997; 89:794.
- Deiva K, Mahlaoui N, Beaudonnet F, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology 2012; 78:1150.
- Feldmann J, Ménasché G, Callebaut I, et al. Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity. Blood 2005; 105:2658.
- De Armas R, Sindou P, Gelot A, et al. Demyelinating peripheral neuropathy associated with hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study. Acta Neuropathol 2004; 108:341.
- Henter JI, Nennesmo I. Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis. J Pediatr 1997; 130:358.
- Horne A, Trottestam H, Aricò M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008; 140:327.
- Gratton SM, Powell TR, Theeler BJ, et al. Neurological involvement and characterization in acquired hemophagocytic lymphohistiocytosis in adulthood. J Neurol Sci 2015; 357:136.
- McClain K, Gehrz R, Grierson H, et al. Virus-associated histiocytic proliferations in children. Frequent association with Epstein-Barr virus and congenital or acquired immunodeficiencies. Am J Pediatr Hematol Oncol 1988; 10:196.
- Mou SS, Nakagawa TA, Riemer EC, et al. Hemophagocytic lymphohistiocytosis complicating influenza A infection. Pediatrics 2006; 118:e216.
- Harms PW, Schmidt LA, Smith LB, et al. Autopsy findings in eight patients with fatal H1N1 influenza. Am J Clin Pathol 2010; 134:27.
- Yuzurihara SS, Ao K, Hara T, et al. Human parechovirus-3 infection in nine neonates and infants presenting symptoms of hemophagocytic lymphohistiocytosis. J Infect Chemother 2013; 19:144.
- Chen TL, Wong WW, Chiou TJ. Hemophagocytic syndrome: an unusual manifestation of acute human immunodeficiency virus infection. Int J Hematol 2003; 78:450.
- Fardet L, Blum L, Kerob D, et al. Human herpesvirus 8-associated hemophagocytic lymphohistiocytosis in human immunodeficiency virus-infected patients. Clin Infect Dis 2003; 37:285.
- Grossman WJ, Radhi M, Schauer D, et al. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8. Blood 2005; 106:1203.
- Hegerova LT, Lin Y. Disseminated histoplasmosis: a cause of hemophagocytic syndrome. Mayo Clin Proc 2013; 88:e123.
- Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2015; 90:220.
- Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis 2004; 36:516.
- Brito-Zerón P, Bosch X, Pérez-de-Lis M, et al. Infection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies. Semin Arthritis Rheum 2016; 45:391.
- Risdall RJ, Brunning RD, Hernandez JI, Gordon DH. Bacteria-associated hemophagocytic syndrome. Cancer 1984; 54:2968.
- Sung PS, Kim IH, Lee JH, Park JW. Hemophagocytic Lymphohistiocytosis (HLH) Associated with Plasmodium vivax Infection: Case Report and Review of the Literature. Chonnam Med J 2011; 47:173.
- Falini B, Pileri S, De Solas I, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood 1990; 75:434.
- Okuda T, Sakamoto S, Deguchi T, et al. Hemophagocytic syndrome associated with aggressive natural killer cell leukemia. Am J Hematol 1991; 38:321.
- Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol 2000; 79:378.
- Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma 2000; 38:121.
- Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic syndrome with Kaposi's sarcoma-associated herpesvirus-related primary effusion lymphoma. Br J Haematol 2000; 111:1112.
- Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008; 47:531.
- O'Brien MM, Lee-Kim Y, George TI, et al. Precursor B-cell acute lymphoblastic leukemia presenting with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:381.
- Fox CP, Shannon-Lowe C, Gothard P, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis 2010; 51:66.
- Su IJ, Hsu YH, Lin MT, et al. Epstein-Barr virus-containing T-cell lymphoma presents with hemophagocytic syndrome mimicking malignant histiocytosis. Cancer 1993; 72:2019.
- Pasqualini C, Minard-Colin V, Saada V, et al. Clinical analysis and prognostic significance of haemophagocytic lymphohistiocytosis-associated anaplastic large cell lymphoma in children. Br J Haematol 2014.
- Allory Y, Challine D, Haioun C, et al. Bone marrow involvement in lymphomas with hemophagocytic syndrome at presentation: a clinicopathologic study of 11 patients in a Western institution. Am J Surg Pathol 2001; 25:865.
- Shimizu Y, Tanae K, Takahashi N, et al. Primary cutaneous anaplastic large-cell lymphoma presenting with hemophagocytic syndrome: a case report and review of the literature. Leuk Res 2010; 34:263.
- Lehmberg K, Sprekels B, Nichols KE, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol 2015; 170:539.
- Chang TY, Jaffray J, Woda B, et al. Hemophagocytic lymphohistiocytosis with MUNC13-4 gene mutation or reduced natural killer cell function prior to onset of childhood leukemia. Pediatr Blood Cancer 2011; 56:856.
- Davì S, Minoia F, Pistorio A, et al. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol 2014; 66:2871.
- Yokota S, Itoh Y, Morio T, et al. Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis under Treatment with Tocilizumab. J Rheumatol 2015; 42:712.
- Ezdinli EZ, Kucuk O, Chedid A, et al. Hypogammaglobulinemia and hemophagocytic syndrome associated with lymphoproliferative disorders. Cancer 1986; 57:1024.
- Rohr J, Beutel K, Maul-Pavicic A, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica 2010; 95:2080.
- Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood 2006; 108:81.
- Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome after Kawasaki disease. Pediatr Infect Dis J 2003; 22:663.
- Abe Y, Choi I, Hara K, et al. Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29:799.
- Ferreira RA, Vastert SJ, Abinun M, et al. Hemophagocytosis during fludarabine-based SCT for systemic juvenile idiopathic arthritis. Bone Marrow Transplant 2006; 38:249.
- Karras A, Thervet E, Legendre C, Groupe Coopératif de transplantation d'Ile de France. Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation 2004; 77:238.
- Lladó L, Figueras J, Comí S, et al. Haemophagocytic syndrome after liver transplantation in adults. Transpl Int 2004; 17:221.
- George TI, Jeng M, Berquist W, et al. Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature. Pediatr Blood Cancer 2005; 44:270.
- Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979; 44:993.
- Nikiforow S, Berliner N. The unique aspects of presentation and diagnosis of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program 2015; 2015:183.
- Hayden A, Park S, Giustini D, et al. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev 2016.
- Rosado FG, Rinker EB, Plummer WD, et al. The diagnosis of adult-onset haemophagocytic lymphohistiocytosis: lessons learned from a review of 29 cases of bone marrow haemophagocytosis in two large academic institutions. J Clin Pathol 2016; 69:805.
- La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program 2015; 2015:190.
- Campo M, Berliner N. Hemophagocytic Lymphohistiocytosis in Adults. Hematol Oncol Clin North Am 2015; 29:915.
- Hejblum G, Lambotte O, Galicier L, et al. A web-based delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS One 2014; 9:e94024.
- Rivière S, Galicier L, Coppo P, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med 2014; 127:1118.
- Arca M, Fardet L, Galicier L, et al. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol 2015; 168:63.
- Parikh SA, Kapoor P, Letendre L, et al. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc 2014; 89:484.
- Li J, Wang Q, Zheng W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine (Baltimore) 2014; 93:100.
- Schram AM, Mullally A, Fogerty AE, et al. Hemophagocytic lymphohistiocytosis: The Partners Healthcare experience over the past 8 years. Blood 2014; 124:4104.
- Ahn JS, Rew SY, Shin MG, et al. Clinical significance of clonality and Epstein-Barr virus infection in adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2010; 85:719.
- Chen J, Wang X, He P, et al. Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis. J Med Virol 2016; 88:541.
- Wong KF, Hui PK, Chan JK, et al. The acute lupus hemophagocytic syndrome. Ann Intern Med 1991; 114:387.
- Morris JA, Adamson AR, Holt PJ, Davson J. Still's disease and the virus-associated haemophagocytic syndrome. Ann Rheum Dis 1985; 44:349.
- Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.
- Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.
- Hot A, Toh ML, Coppéré B, et al. Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features and long-term outcome: a case-control study of 8 patients. Medicine (Baltimore) 2010; 89:37.
- Tabata R, Tabata C, Terada M, Nagai T. Hemophagocytic syndrome in elderly patients with underlying autoimmune diseases. Clin Rheumatol 2009; 28:461.
- Schram AM, Campigotto F, Mullally A, et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood 2015; 125:1548.
- Lim SH, Park S, Jang JH, et al. Clinical significance of bone marrow hemophagocytosis in adult patients with malignancy and non-malignancy-induced hemophagocytic lymphohistiocytosis. Ann Hematol 2016; 95:325.
- http://www.cincinnatichildrens.org/service/i/immune-deficiency/diagnostic-lab/ (Accessed on June 17, 2013).
- Schaer DJ, Schleiffenbaum B, Kurrer M, et al. Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol 2005; 74:6.
- Bleesing J, Prada A, Siegel DM, et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum 2007; 56:965.
- Wang LL, Hu YX, Chen WF, et al. [Significance of soluble interleukin-2 receptor and NK cell activity in patients with hemophagocytic lymphohistiocytosis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012; 20:401.
- Wang Z, Wang YN, Feng CC, et al. [Diagnostic significance of NK cell activity and soluble CD25 level in serum from patients with secondary hemophagocytic lymphohistiocytosis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008; 16:1154.
- Imashuku S, Hibi S, Tabata Y, et al. Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 1998; 31:131.
- Lee WI, Chen SH, Hung IJ, et al. Clinical aspects, immunologic assessment, and genetic analysis in Taiwanese children with hemophagocytic lymphohistiocytosis. Pediatr Infect Dis J 2009; 28:30.
- Bryceson YT, Pende D, Maul-Pavicic A, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 2012; 119:2754.
- Mellor-Heineke S, Villanueva J, Jordan MB, et al. Elevated Granzyme B in Cytotoxic Lymphocytes is a Signature of Immune Activation in Hemophagocytic Lymphohistiocytosis. Front Immunol 2013; 4:72.
- Tsuji T, Hirano T, Yamasaki H, et al. A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 2014; 93:821.
- Maruoka H, Inoue D, Takiuchi Y, et al. IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 2014; 93:393.
- Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009; :127.
- Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014; 66:2613.
- Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome: Unrecognized cause of multiple organ failure. Pediatr Crit Care Med 2000; 1:51.
- Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore) 2009; 88:131.
- Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics 2003; 111:e636.
- Rostasy K, Kolb R, Pohl D, et al. CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children. Neuropediatrics 2004; 35:45.
- Hymel KP, Abshire TC, Luckey DW, Jenny C. Coagulopathy in pediatric abusive head trauma. Pediatrics 1997; 99:371.
- Marzano AV, Berti E, Paulli M, Caputo R. Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol 2000; 136:889.
- Craig AJ, Cualing H, Thomas G, et al. Cytophagic histiocytic panniculitis--a syndrome associated with benign and malignant panniculitis: case comparison and review of the literature. J Am Acad Dermatol 1998; 39:721.