Hemophagocytic lymphohistiocytosis


Hemophagocytic lymphohistiocytosis, also known as haemophagocytic lymphohistiocytosis, and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages, characterised by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes. There are inherited and non-inherited causes of hemophagocytic lymphohistiocytosis.

Signs and symptoms

The onset of HLH occurs under the age of one year in approximately 70 percent of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with familial HLH has a twenty-five–percent chance of developing the disease, a fifty-percent chance of carrying the defective gene, and a twenty-five–percent chance of not being affected and not carrying the gene defect.
Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of intensive care unit patients with cytopenia and hyperferritinemia. Patients in the earlier stages of HLH are frequently hospitalized at internal medicine wards.
HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash. Laboratory findings may include elevated triglyceride levels, low fibrinogen levels, transaminitis, and elevated ferritin levels.

Causes

Primary HLH is caused by loss of function, mutations in genes that code for proteins cytotoxic T cells and NK cells use to kill targeted cells, such as those infected with pathogens like the Epstein-Barr virus or the Dengue virus. These mutations include those in the following genes: UNC13D, STX11, RAB27A, STXBP2, LYST, PRF1 1, SH2D1A, BIRC4, ITK, CD27, and MAGT1.
Secondary HLH ; and infections caused by EBV, cytomegalovirus, HIV/AIDS, bacteria, protozoa, fungi and possibly SARS-CoV-2. Secondary HLH may also result from iatrogenic causes such as bone marrow or other organ transplantations; chemotherapy; or therapy with immunosuppressing agents;
About 33% of all HLH cases, ~75% of Asian HLH cases, and nearly 100% of HLH cases caused by mutations in SH2D1A are associated with, and thought triggered or promoted by, EBV infection. These cases of HLH are classified as belonging to the class of Epstein–Barr virus-associated lymphoproliferative diseases and termed EBV+ HLH.

Pathophysiology

The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers. Impaired NK-cell cytotoxicity is the hallmark of HLH. All genetic defects for familial HLH are related to granule-dependent cytotoxicity. This inability to remove infected and antigen-presenting cells and terminate the immune response leads to uncontrolled proliferation and activation of the immune system with release of excessive cytokines. These cells then infiltrate organs, releasing more cytokines, which gives the clinical picture. The fever is caused by IL-1, IL-6 and TNF-alpha; the cytopenia is due to the suppressive effect on hematopoiesis by TNF-alpha and TNF-gamma. TNF-alpha and TNF-gamma may also lead to inhibition of lipoprotein lipase or stimulate triglyceride synthesis. Activated macrophages secrete ferritin and plasminogen activator leading to hyperfibrinolysis.

Genetics

Five genetic subtypes are described, with an estimated overall prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1, UNC13D, STX11, and STXBP2, is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop in utero. However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases.
The five subtypes of FHL are each associated with a specific gene:
Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations.

Diagnosis

The blood count typically shows decreased numbers of blood cells—including a decreased number of circulating red blood cells, white blood cells, and platelets.The bone marrow may show hemophagocytosis.The liver function tests are usually elevated. A low level of the protein albumin in the blood is common.
The serum C reactive protein, erythrocyte sedimentation rate, and ferritin level are markedly elevated. In children, a ferritin above 10000 is very sensitive and specific for the diagnosis of HLH, however, the diagnostic utility for ferritin is less for adult HLH patients.
The serum fibrinogen level is usually low and the D-dimer level is elevated.
The sphingomyelinase is elevated.
Bone marrow biopsy shows histiocytosis.

Classification

Primary HLH, also known as familial haemophagocytic lymphohistiocytosis or familial erythrophagocytic lymphohistiocytosis, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity.
Secondary haemophagocytic lymphohistiocytosis occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy.
Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in the absence of treatment.
A subtype of primary HLH where the inflammation is limited to the central nervous system has been described.

Diagnostic criteria

The current diagnostic criteria for HLH are
1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D, or STX11.
OR
2. Fulfillment of five out of the eight criteria below:
In addition, in the case of familial HLH, no evidence of malignancy should be apparent.
Not all five out of eight criteria are required for diagnosis of HLH in adults, and a high index of suspicion is required for diagnosis as delays results in increased mortality. The diagnostic criteria were developed in pediatric populations and have not been validated for adult HLH patients. Attempts to improve diagnosis of HLH have included use of the , which can be used to estimate an individual's risk of HLH. In adults, soluble IL-2 has been found to be a very sensitive marker for HLH, demonstrating 100% sensitivity for ruling out HLH below a cutoff of 2400 U/mL and optimal cutoff for ruling in at 2515 U/mL, with 93% specificity at >10 000 U/mL..

Differential diagnosis

The differential diagnosis of HLH includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.
Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome. As a syndrome of intense inflammation it needs to be differentiated from sepsis, what may be extremely challenging.
The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.

Griscelli syndrome

A major differential diagnosis of HLH is Griscelli syndrome. This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and lymphohistiocytosis. Most cases have been diagnosed between 4 months and 7 years of age, with a mean age of about 17 months.
Three types of Griscelli syndrome are recognised: type 1 has neurologic symptoms and mutations in MYO5A. Prognosis depends on the severity of neurologic manifestations. Type 2 has mutations in RAB27A and haemophagocytic syndrome, with abnormal T-cell and macrophage activation. This type has a grave prognosis if untreated. Type 3 has mutations in melanophilin and is characterized by partial albinism. This type does not pose a threat to those so affected.

Treatment

In secondary cases, treatment of the cause, where possible, is indicated. Additionally, treatment for HLH itself is usually required.
While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids, etoposide and cyclosporin. Intravenous immunoglobulin is also used. Methotrexate and vincristine have also been used. Other medications include cytokine targeted therapy.
On 20 November 2018, the FDA approved the anti-IFN-gamma monoclonal antibody emapalumab for the treatment of pediatric and adult primary HLH.

Prognosis

The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.
Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment. However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system.

History

The first case report of HLH was published in 1952.

Research

A systematic review recently reported the pooled proportion are fever 97.2%, hepatomegaly 70.2%, splenomegaly 78.4%, thrombocytopenia 90.1%, anemia 76.0%, and serum ferritin ≥500 μg/L 97.1%. The case fatality rate is 14.6% among dengue hemophagocytic lymphohistiocytosis patients.