Hemophagocytic lymphohistiocytosis

Classification according to ICD-10
D76.1	Hemophagocytic lymphohistiocytosis
ICD-10 online (WHO version 2019)

The hemophagocytic lymphohistiocytosis , abbreviated HLH , English Synonyms hemophagocytic syndrome ( HPS ), reactive hemophagocytic syndrome ( RHS ), macrophage activation syndrome ( MAS , German macrophage activation syndrome) or lymphohistiocytic syndrome ( LHS ) is a rare, extremely difficult running hyperinflammatory disease of the immune system , which is characterized by high fever , enlargement of the liver and spleen ( hepatosplenomegaly ), more rarely also the lymph nodes , rashes and effusions in the abdomen ( ascites ) or the chest ( pleural effusion ). The mortality rate is very high at 30–50%.

Classification

HLH is divided into a primary and a secondary form. The primary form ( Farquhar's disease ) is a rare, fatal, heterogeneous group of genetic diseases. It usually occurs in families, rarely also sporadically. It usually begins in early infancy. The secondary form, also known as reactive, is considered to be associated with infection or disease. It can affect all age groups and is not hereditary.

root cause

For the primary, hereditary familial form, various changes in the genetic material were found, thereby dividing familial hemophagocytic lymphohystiocytosis (FHL) into several types. FHL1 is linked to changes in the 9q21.3-q22 gene location . In FHL2, there is a mutation in the PRF1 gene, which codes for perforin and is located on chromosome 10q22 . FHL3 is caused by a mutation in the UNC13D gene on chromosome 17q25.1 and FHL4 by a mutation in the syntaxin 11 gene on chromosome 6q24 .

In the secondary forms, either an infection with viruses , bacteria or parasites, a malignant degeneration of the blood-forming cells ( leukemia ) or an autoimmune disease ( rheumatoid arthritis , systemic lupus erythematosus and others) lead to activation of T cells and macrophages . The result is an extraordinary increase in the production of messenger substances ( cytokines ), for which the term cytokine storm was coined. This stimulates T-helper cells and releases more inflammatory substances, especially interferon-γ (IFN-γ), which in turn activates and multiplies macrophages in the bone marrow , liver and lymph nodes. This is accompanied by a considerable overproduction of macrophage-typical messenger substances ( tumor necrosis factor-α (TNF-α), interleukin-6 and ferritin ). As a result of the massive activation, the macrophages tend to phagocytize the body's own white blood cells . How exactly this phenomenon is caused is not yet known in detail. IFN-γ alone does not lead to such pronounced phagocytosis in vitro . In 1985 a phagocytosis-inducing-factor ( PIF ) was described, which is produced by a subgroup of T helper cells.

Symptoms and diagnosis

Diagnostic criteria ^†

1	fever
2	Splenomegaly
3	Peripheral blood cytopenia
4th	Hypertriglyceridemia and / or hypofibrinogenemia
5	Serum ferritin > 500 ng / ml
6th	Soluble CD25 > 2,500 U / ml
7th	Decreased or absent NK cell activity
8th	Hemophagocytosis in the bone marrow, CNS, or lymph nodes
† At least 5 of the 8 criteria must be met

The main symptom of hemophagocytic lymphohistiocytosis is a fever above 38.5 ° C which lasts for more than seven days in connection with an enlarged spleen ( splenomegaly ). Various changes that can only be detected by laboratory tests are also required as the main diagnostic criteria : a reduction in the number of cells in at least two of the three cell lines in the blood ( anemia , neutropenia , thrombopenia ), an increase in blood lipid levels, a reduction in the coagulation factor fibrinogen in the blood and evidence of haemophagocytosis (absorption and digestion) blood cells by macrophages) in the bone marrow, spleen or lymph nodes. Concomitant clinical symptoms such as enlarged lymph nodes, jaundice ( jaundice ), edema and rashes are considered secondary criteria . The secondary criteria also include an increase in liver enzyme levels, an increase in the iron storage protein ferritin, a decrease in the total amount of protein in the blood ( hypoproteinemia ) and a decrease in the sodium concentration in the blood ( hyponatremia ). In children, involvement of the central nervous system with neck stiffness ( meningism ), seizures, signs of increased intracranial pressure (increased intracranial pressure) and an increase in the protein content in the cerebrospinal fluid ( cerebrospinal fluid ) has also been described. Such changes have not yet been found in adults.

therapy

The primary form is to be cured by a stem cell transplant . As a result, healthy progenitor cells of the immune system are transferred without the genetic defect causing them and the fatal macrophage activation does not occur.

In November 2018, the Food and Drug Administration (FDA) approved emapalumab (trade name: Gamifant , manufacturer: Novimmune or, since July 2019, Swedish Orphan Biovitrum AB / Sobi) for the treatment of pediatric (newborn and older) and adult patients with primary HLH approved who have a refractory, relapsing, or progressive disease or intolerance to conventional HLH therapy. This approval is the first specific for HLH. Approval for the EU is still pending.

The treatment of secondary HLH consists first and foremost of treating the underlying disease (infection, degeneration of blood formation, autoimmune disease). A standardized therapy protocol was introduced for the first time in 1994 for both symptomatic treatment and treatment of the primary form. This includes an initial treatment with a highly effective cortisone preparation ( dexamethasone ) and the cell growth-inhibiting substance etoposide , a cytostatic , for an initial eight weeks. If the hemophagocytosis remains active, maintenance therapy with dexamethasone pulses, etoposide and an immunosuppressant, cyclosporine A , follows . Various other successful treatment methods have also been published. High doses of immunoglobulin , alone or in combination with steroids, were also effective in various cases . A combination of cyclosporin A with granulocyte colony stimulating factor (G-CSF) was also found to be effective.

forecast

The prognosis of patients with secondary hemophagocytic lymphohistiocytosis depends crucially on the underlying disease. In a Japanese study, the mortality rate in patients with virus-associated HLH was 75%, significantly higher than in patients with malignant underlying disease, with a mortality rate of around 31%.

Individual evidence

1. ↑ Gritta Janka, Karin Beutel, Maximilian Christopeit, Stephan Ehl, Paul Graf La Rosée, Kai Lehmberg, Georg Maschmeyer, Jens Panse, Olaf Penack, Thomas Schenk, Thomas Weber: Haemophagocytic Lymphohistiocytosis (HLH). In: Onkopedia. March 2014, accessed August 9, 2016 . 
2. ↑ Hemophagocytic lymphohistiocytosis.  In: Online Mendelian Inheritance in Man . (English).
3. ↑ N. Berlin, C. Kurra, D. Chou: CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 1-2016. An 18-Year-Old Man with Fever, Abdominal Pain, and Thrombocytopenia. In: N Engl J Med. 374 (2), 2016, pp. 165-173. doi: 10.1056 / NEJMcpc1501306 PMID 26760088
4. ↑ H. Tsuda: Hemophagocytic syndrome (HPS) in children and adults. In: Int J Hematol. 65, 1996, pp. 212-226.
5. ↑ FDA approves first treatment specifically for patients with rare and life-threatening type of immune disease , PM FDA, November 20, 2018, accessed November 6, 2019
6. ↑ J. Hermann et al.: Haemophagocytic lymphohistiocytosis in 3 children - case report and literature review. In: Monthly Pediatrics. 150, 2002, pp. 748-755.
7. ↑ S. Imashuku et al.: Hemophagocytic lymphohistiocytosis in infancy and childhood. In: J Pediatr. 130, 1997, pp. 352-357.

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