Hemophagocytic lymphohistiocytosis (hemophagocytic syndrome)

What every physician needs to know:

Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome characterized by uncontrolled hyper-activation of the immune response, leading to a severe systemic illness with organ dysfunction. HLH may be a primary, that is, familial disorder, or it may develop secondary to another disorder such as an infection, cancer or rheumatologic disease.

Are you sure your patient has hemophagocytic lymphohistiocytosis (hemophagocytic syndrome)? What should you expect to find?

HLH is defined by a set of clinical and laboratory criteria that are still relatively unrefined. In 2004, The Histiocyte Society proposed diagnostic criteria (see below). Keep in mind that these clinical and laboratory characteristics are each non-specific, and may not be evaluable or simultaneously present, at the time of diagnosis.

The diagnosis of HLH can be established if one of the two main items (in bold) below is fulfilled.

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Molecular diagnosis consistent with HLH

Diagnostic criteria for HLH fulfilled (five out of the eight criteria below):

  • Fever

  • Splenomegaly

  • Cytopenias (affecting >2 of 3 lineages in the peripheral blood):

    Hemoglobin < 90g/L

    Platelets < 100 x 109/L

    Neutrophils < 1.0 x 109/L

  • Hypertriglyceridemia and/or hypofibrinogenemia

    Fasting triglycerides >3.0mmol/L (> 265mg/dL)

    Fibrinogen < 1.5g/L

  • Hemophagocytosis in bone marrow or spleen or lymph nodes

– No evidence of malignancy.

  • Low or absent natural killer (NK) cell activity assayed by chromium release assay

  • Ferritin >500ug/L

  • Soluble CD25 (that is, soluble IL-2 receptor) >2,400U/mL

In addition, rash, hyponatremia, liver dysfunction (hepatomegaly, hyperbilirubinemia, elevated transaminases) and central nervous system (CNS) manifestations (lethargy, irritability, seizures, cerebrospinal fluid pleocytosis) are frequent associated findings.

Beware of other conditions that can mimic hemophagocytic lymphohistiocytosis (hemophagocytic syndrome):

Many of the diagnostic features of HLH are non-specific, including fever, cytopenias, and splenomegaly. Patients with HLH, especially adult acquired forms, are often thought to have an acute overwhelming infection, because they present with the features of cytokine release. In addition, it is important to remember that both familial and acquired HLH can be triggered by infection, especially Epstein-Barr virus (EBV) infection. Therefore, the diagnostic features of HLH may appear, after what originally appeared to be an uncomplicated infectious process.

Which individuals are most at risk for developing hemophagocytic lymphohistiocytosis (hemophagocytic syndrome):

Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare, heritable, genetically heterogeneous immune disorder. Although most cases of FHLH present in infancy, occasional cases present later in childhood or in adulthood. Defects in any of several genes involved in the lymphocyte cytolytic pathway lead to the disease.

There are both autosomal recessive and X-linked recessive forms of FHLH. Parental consanguinity and/or a positive family history of HLH may be elicited in some cases.

In addition, there are several immune deficiency syndromes that have a terminal phase of HLH. These include Chédiak-Higashi syndrome, Griscelli syndrome, and the X-linked lymphoproliferative syndrome. These are also heritable syndromes, and present the risk of other affected siblings.

Secondary HLH shares clinical and laboratory features with FHLH, but the fundamental nature of the disease is different. Hemophagocytic syndrome is an acquired process that may be triggered by any intense immune stimulation or modulation including infection (especially EBV infection), cancer (especially hematologic malignancies), and rheumatologic conditions (especially systemic onset juvenile idiopathic arthritis [SoJIA]). In adults, approximately half of patients with HLH have underlying malignancy, usually lymphoma.

When HLH develops in patients with a systemic autoimmune disorder it is termed the macrophage-activation syndrome. Individuals of any age are at risk for secondary HLH. It has been reported to occur with increased frequency in the setting of immune suppression for inflammatory bowel disease, where it is usually triggered by EBV or Cytomegalovirus (CMV) infection.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The following laboratory studies are indicated in the work-up of any patient with suspected HLH. The tests should be interpreted in light of the HLH-2004 diagnostic criteria:

  • Routine blood tests

Complete blood count, electrolyte panel, liver panel, coagulation studies, fibrinogen, d-dimer, fasting triglycerides, and ferritin.

  • Specialized blood tests to be performed if available

CD25 (soluble IL-2 receptor), NK functional activity, CD107a mobilization assay. In the appropriate clinical context and if available: flow cytometry for perforin, and assay for mutations in the genes causing X-linked lymphoproliferative disease, SH2D1A/SAP and BIRC/XIAP.

  • Infectious disease studies

Depending on clinical setting, consider testing for EBV, CMV, herpes simplex virus (HSV), varicella zoster virus (VZV), influenza, Leishmania, and brucellosis.

  • Invasive procedures

Bone marrow aspiration/biopsy. Consider diagnostic lumbar puncture. Consider biopsy of liver, lymph node, and spleen in some cases.

The laboratory tests outlined above are appropriate for making the diagnosis of HLH. A few aspects of the laboratory evaluation should be emphasized:

  • The finding of hemophagocytosis is not a sensitive or specific marker of HLH

Even in FHLH, it may require multiple samplings of the bone marrow to see definitive histologic evidence of hemophagocytosis. The cytopenias associated with HLH are a reflection primarily of cytokine-induced marrow suppression and not the result of hemophagocytosis. Furthermore, other syndromes associated with macrophage activation (active hemolytic anemia and acute viral infection) can also give rise to hemophagocytosis. Consequently, although a diagnostic feature of HLH, it remains only one of the clinical criteria and is not necessary or sufficient to make the diagnosis.

  • Hyperferritinemia, though not specific, is an extremely helpful finding in making the diagnosis of HLH

In children, an extremely high ferritin (greater than 8,000-10,000) is an uncommon laboratory finding that occurs in very few settings, and should raise the suspicion for HLH. Even in the setting of Still’s disease (systemic juvenile inflammatory arthritis, sJIA), which is characteristically associated with an elevated ferritin, extreme elevations are often a sign of associated macrophage activation syndrome (MAS). In pediatric patients, a ferritin >10,000 is over 90% sensitive and specific for HLH. In adults, the finding of elevated ferritin is much less diagnostic of HLH. In one study reviewing the records of ferritin measurements within the Partners hospitals, over 100 patients were identified with ferritin levels over 50,000. and less than 20% of these patients had HLH. Conversely, ferritin levels in patients with diagnosed HLH ranged widely, from just over 500 to over 50,000. Thus, while the negative predictive value of a normal ferritin is excellent for ruling out HLH, there is no level of ferritin elevation in adult patients that is diagnostic of the disease.

  • Functional studies of NK cells are extremely helpful in making a diagnosis of FHLH

They are much less helpful in diagnosing acquired HLH in adults.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of hemophagocytic lymphohistiocytosis (hemophagocytic syndrome)?

N/A

If you decide the patient has hemophagocytic lymphohistiocytosis (hemophagocytic syndrome), what therapies should you initiate immediately?

Patients with HLH typically present with rapidly progressive systemic illness, requiring urgent intervention and intensive supportive care. When there is clinical suspicion for HLH, it may be necessary to initiate therapy before absolute diagnostic certainty is achieved. Moreover, distinguishing familial from secondary HLH at the time of initial presentation is sometimes impossible. Prompt, effective suppression of the immune system is the main goal of initial treatment and should be initiated using the provider’s best clinical judgement.

Standard therapy for children with suspected FHLH or EBV associated HLH, consists of combination of high dose corticosteroid, etoposide and cyclosporin A, according to the HLH 94 regimen.

Management of secondary hemophagocytic syndrome and MAS in children and adults is not standardized. Hematologists/oncologists and rheumatologists take distinct approaches to therapy.

  • In the setting of MAS

Immunoglobulin infusion plus high dose glucocorticoids and cyclosporine can often be efficacious, and this approach is favored in that setting.

  • Most patients with infection-associated or idiopathic HLH in the absence of underlying rheumatologic disease, require more potent immunosuppression

Because the disease is rare in adults, there is no established approach to therapy. However, given the extremely poor prognosis of these patients, aggressive therapy is warranted. Given the absence of an established protocol tailored to adults, the standard therapy is with the HLH94 protocol that has been established in pediatric patients. Other immunosuppressive agents that have been tried with anecdotal success include tumor necrosis factor (TNF) inhibitors, anakinra, and Campath. Novel therapies in clinical trials include interferon gamma (INFγ) inhibitors and JAK1-2 inhibition with ruxolitinib.

  • When active malignancy is found to be triggering hemophagocytic syndrome

Treatment directed at the underlying cancer should be initiated.

More definitive therapies?

Familial hemophagocytic lymphohistiocytosis

Chemoimmunotherapy for HLH according the HLH 94 regimen effectively suppresses the hyper-immunity seen in HLH in most cases. Clinical and laboratory manifestations of the disease usually improve rapidly. However, signs and symptoms may not abate, or they may recrudesce as immune suppression is tapered. Re-escalation of steroid dosing, more frequent etoposide administration, and early initiation of cyclosporin may help in this situation. The CNS is a potential site of treatment failure and control of CNS disease sometimes requires administration of intrathecal therapy (methotrexate +/- hydrocortisone). Second line agents include anti-thymocyte globulin (ATG), anakinra, and etanercept.

In patients with an established genetic diagnosis of FHLH, or in whom immunosuppressive therapy cannot be discontinued because of disease reactivation, allogeneic hematopoietic cell transplantation represents the only treatment with curative potential.

Acquired hemophagocytic lymphohistiocytosis

Patients with MAS usually respond to steroids, intravenous immunoglobulin (IVIG), and cyclosporine A, although recurrent episodes can occur. These episodes occur with flares of the underlying autoimmune disease and often respond to repeated therapy with the same agents.

Patients with infection-associated HLH or idiopathic acquired HLH have a disease that is often extremely difficult to control. In the setting of an acute viral infection, treatment of the underlying infection with the addition of steroids and IVIG may be sufficient until the infection resolves, However, in many patients, the manifestations of HLH persist well beyond the period of active infection and become self-sustaining. Early intervention with etoposide-containing regimens may offer the best opportunity to control the disease.

Although supportive literature is limited, patients with persistent and resistant disease may be best treated with hematopoietic stem cell transplantation. Transplantation in patients with actively symptomatic disease is not advised, as this may lead to high transplant-related mortality, especially from GVHD. Use of alemtuzumab to control active disease, or as part of the preparative regimen in patients who are in remission reduces GVHD.

What other therapies are helpful for reducing complications?

Patients undergoing treatment for HLH are at high risk of infectious complications related to the myelo- and immuno-suppressive effects of the disease and the treatment. Prophylactic antibiotics to prevent pneumocystis pneumonia and fungal infections are recommended.

What should you tell the patient and the family about prognosis?

FHLH is a fatal condition unless allogeneic hematopoietic stem cell transplant is successfully performed.

Outcomes after treatment for secondary HLH depend on the underlying disease and are not well defined. However, increasing evidence suggests that allogeneic hematopoietic stem cell transplantation offers the best chance of definitive cure.

EBV associated HLH in children responds extremely well to the HLH 94 protocol, with 100% survival reported in one study.

The responsiveness in adults remains undefined, again reflecting the rarity of the syndrome.

MAS tends to respond better to standard immunosuppressive therapy than other forms of HLH, although patients may experience recurrent episodes that follow the waxing and waning course of their underlying rheumatologic disease.

Idiopathic HLH in adults has a very poor prognosis, with a mortality rate of over 50%. Because it is rare, prompt recognition of the disease and early administration of aggressive therapy may improve outcomes.

What if scenarios.

Is it safe to give etoposide-containing regimen if the patient is neutropenic?

The cytopenias in HLH are a reflection of the underlying hypercytokinemia and macrophage activation. Therefore, appropriate therapy should not be held for neutropenia. Counts should improve with appropriate response to therapy.

Is it safe to give etoposide-containing regimen if the patient has abnormal liver function tests?

Although not a defining clinical criterion for HLH, transaminitis and hyperbilirubinemia are often prominent in patients with HLH. Some patients may even present with fulminant hepatic failure. In the face of severe hepatic dysfunction, etoposide is relatively contraindicated, although this must be balanced against the pressing necessity to administer appropriate therapy.

There are no clear guidelines for how to modify therapy for liver dysfunction in HLH. It is probably reasonable to give etoposide in the setting of isolated hyperbilirubinemia and/or with mild transaminitis. In the setting of moderate liver dysfunction, dose reduction by 25-75% may allow the introduction of therapy that can be increased as liver function improves.

Pathophysiology

HLH is the consequence of a generalized, extreme hyper-inflammatory state. All of the features of HLH result from activation of macrophages and T cells and the cytokines these cells produce.

Normal immune cell effector function depends on the orderly mobilization and degranulation of cytolytic granules, leading to targeted killing of virally infected and tumor cells. Normally, this process is potentiated by the elaboration of various inflammatory cytokines. When this process does not efficiently lead to target eradication, extreme hypercytokinemia results, leading to the manifestations of HLH.

Familial hemophagocytic lymphohistiocytosis

Inherited defects of the proteins that participate in cytolytic function are responsible for FHLH. There are at least five types of FHLH. The molecular basis of HLH is unknown in many cases that are presumed to be familial. Inheritance of mutated perforin, mammalian uncoordinated 13-2 (MUNC 13-2), Syntaxin 11 or Syntaxin 11-BP (also called MUNC 18-2) account for approximately one half of familial cases. Two X-linked forms, XLP1 and XLP2, occur in males with abnormalities of SH2D1a and BIRC-4 respectively. Additionally, HLH may occur in association with the Griscelli Syndrome and Chédiak-Higashi syndrome.

Acquired hemophagocytic lymphohistiocytosis

  • Infection-associated HLH

Infection-associated HLH is seen most commonly in association with herpesvirus infections, most notably, EBV. Interestingly, HLH in the setting of EBV is primarily caused by EBV infection of T lymphocytes. Normal NK or T-Cell cytotoxicity results in feedback that controls the immune reaction, termed activation-induced T-cell death (AICD). HLH reflects a failure of successful targeted killing of infected cells, with a secondary failure of AICD, stimulation of macrophages, and marked cytokine release. The basis for the failure of cytotoxicity in the absence of identifiable defects in the cytolytic pathway is unknown. It has been noted that immunosuppression may contribute to the failure of cytotoxicity. For example, patients with inflammatory bowel disease treated with thiopurines are at increased risk of developing HLH in association with herpesvirus infection.

  • Macrophage activation syndrome

Macrophage activation syndrome frequently presents in the setting of an acute exacerbation of underlying hematologic disease, and may be difficult to distinguish from many of the features of the underlying illness.

It is attractive to consider that the macrophage activation is merely an exaggerated manifestation of the underlying disease and not a separate entity. This is supported by the observation that the disease, unlike other forms of acquired HLH, tends to respond well to steroids, cyclosporine and IVIG, which also may control the underlying autoimmune diathesis. However, provocative studies have linked the appearance of MAS in patients with sJIA to specific polymorphisms in the MUNC13-4 gene, one of the genes that is mutated in FHLH. Indeed, two patients with sJIA and MAS were found to have diagnostic FHLH mutations in the MUNC 13-4 gene.

The prevalence of the polymorphism in patients with sJIA with MAS was over 50%, while its presence in normal individuals and sJIA patients without MAS was 12% and 8% respectively. This suggests the intriguing possibility of a novel genetic link between autoimmune disease and regulators of the adaptive immune response, and may also yield important insights into immune polymorphisms that predict for the development of acquired HLH.

  • Malignancy associated HLH

HLH may complicate malignancy, most commonly lymphoproliferative diseases of T and NK cells, although it has been reported with myeloid malignancy, and more rarely, germ cell tumors and solid tumors. Recommendations include treating to control the inflammation, but the cornerstone is primary treatment directed at the underlying malignancy.

What other clinical manifestations may help me to diagnose hemophagocytic lymphohistiocytosis (hemophagocytic syndrome)?

HLH is a clinical diagnosis based on the criteria outlined above.

What other additional laboratory studies may be ordered?

The laboratory tests outlined above are appropriate for making the diagnosis of HLH.

What’s the Evidence?

Blank, VF, Sheth, MK, Talano, J. J Pediat.. vol. 159. 2011. pp. 808-812. [Documentation of high rate of HLH complicating thiopurine therapy of inflammatory bowel disease, and association to EBV infection.]

Filipovich, AH.. “The expanding spectrum of hemophagocytic lymphohistiocytosis”. Curr Opin Allergy Clinic Immunol.. vol. 11. 2011. pp. 512-516. [Recent review of pathophysiology of HLH, with particular attention to the growing list of pathogenetic mutations in FHLH.]

Grom, A, Mellins, ED.. “Macrophage activation syndrome: advances towards understanding pathogenesis”. Curr Opin Rheumatol.. vol. 22. 2010. pp. 561-566. [Review of understanding of MAS and the relationship of its pathophysiology to that of FHLH.]

Henter, J, Horne, A, Arico, M. “HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis”. Pediat Blood Cancer.. vol. 48. 2007. pp. 124-131. [Report of the first prospective international study of cytotoxic regimen for the treatment of pediatric HLH.]

Henter, J, Chow, C, Leung, C, Lau, Y.. “Cytotoxic therapy for severe avian influenza A (H5N1) infection”. Lance.. vol. 367. 2006. pp. 870-873. [Hypothesis that cytotoxic therapy is treatment of choice for viral-associated HLH seen with avian influenza.]

James, DG, Stone, CD, Wang, LH, Stenson, WF.. “Reactive hemophagocytic syndrome complicating the treatment of inflammatory bowel disease”. Inflamm Bowel Dis.. vol. 12. 2006. pp. 573-580. [Study of HLH in adult patients with IBD associated primarily with herpesvirus infections.]

Janka, GE.. “Familial and acquired hemophagocytic lymphohistiocytosis”. Eur J Pediatr.. vol. 166. 2007. pp. 95-109. [Review of diagnosis, pathogenesis, and treatment of HLH.]

Jordan, MB, Allen, CE, Weitzman, S, Filipovich, AH, McClain, KL.. “How I treat hemophagocytic lymphohistiocytosis”. Blood.. vol. 118. 2011. pp. 4041-4052. [Treatment algorithm for both FHLH and acquired HLH.]

Li, J, Wang, Q, Zheng, W. “Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients”. Medicine. vol. 93. 2014. pp. 100-5. [One of several new reviews of adult HLH.]

Maakaroun, NR, Moanna, A, Jacob, JT, Albrecht, H.. “Viral infections associate with haemophagocytic syndrome”. Rev Med Virol.. vol. 20. 2010. pp. 93-105. [Review of viral associated HLH, diagnosis and therapy.]

Marsh, RA, Allen, CE, McClain, KL. “Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab”. Pediatric blood & cancer. vol. 60. 2013. pp. 101-9. [Use of alemtuzumab for salvage of refractory HLH.]

Otrock, ZK, Eby, CS.. “Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis”. American journal of hematology. vol. 90. 2015. pp. 220-4. [Review of patients with adult HLH.]

Nikiforow, S.. “The Role of Hematopoietic Stem Cell Transplantation in Treatment of Hemophagocytic Lymphohistiocytosis”. Hematol Oncol Clin North Am.. vol. 29. 2015. pp. 943-959. [Review of the role of hematopoietic stem cell transplantation for HLHL.]

Parikh, SA, Kapoor, P, Letendre, L, Kumar, S, Wolanskyj, AP.. “Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis”. Mayo Clinic proceedings. vol. 89. 2014. pp. 484-92. [First large case series of adult HLH.]

Schram, AM, Berliner, N.. “How I treat hemophagocytic lymphohistiocytosis in the adult patient”. Blood. vol. 125. 2015. pp. 2908-14. [Diagnostic and therapeutic approach to adult HLH.]

Schram, AM, Campigotto, F, Mullally, A. “Marked hyperferritinemia does not predict for HLH in the adult population”. Blood.. vol. 125. 2015. pp. 1548-1552. [Study of the diagnostic value of hyperferritinemia for adult HLH.]

Zhang, K, Biroschak, J, Glass, DN, Thomson, SD. “Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms”. Arthritis and Theumatism.. vol. 58. 2008. pp. 2892-2896. [Demonstration that MUNC13-4 polymorphisms are linked to development of HLH in patients with sJIA. Suggests a link to FHLH.]

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