Hemophagocytic lymphohistiocytosis is a group of congenital and acquired diseases resulting from disorders of the regulation of the immune response and characterized by hyperproduction of histiocytes, as well as cytotoxic T-lymphocytes. Clinical symptoms are manifested by febrile fever, enlargement of the liver and spleen, peripheral lymph nodes, damage to the nervous system, bone marrow and other organs. Diagnosis is based on clinical, laboratory (cytopenia, coagulopathy, bilirubinemia, etc.) and instrumental examination data. Treatment: immunosuppressive therapy, corticosteroids, effects on causal factors.
76.1 Hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (hemophagocytic syndrome) is a congenital or acquired violation of the regulation of the immune response, in which abnormal activation of cytotoxic T–lymphocytes, monocytes and macrophages occurs with accumulation in target organs and the development of a pronounced pathological process in them (inflammation, tissue damage, phagocytosis of shaped blood elements). With a congenital, genetically determined form of the disease, mainly young children suffer and in 60-80% of cases – in the first year of life.
Secondary (acquired) hemophagocytic lymphohistiocytosis occurs in all age categories, develops against the background of a prolonged course of various infectious diseases, autoimmune processes and neoplasms. For the first time, signs of hemophagocytic syndrome were described back in 1939, and the disease was then called histiocytic medullary reticulosis. The familial hereditary form of lymphohistiocytosis was first described in 1959. The prevalence of the disease ranges from 1 case per 50 thousand newborns to 1-2 cases per 1 million children under the age of 15.
Congenital hemophagocytic lymphohistiocytosis occurs due to a genetic defect in the mechanisms of cellular cytotoxicity due to mutations of the perforin gene. Normally, the regulation of the immune response is ensured by timely restriction of the activity of immune system effectors in the process of eliminating the threat to the body from infiltrated infectious agents and other negative influences. Mechanisms of cellular cytotoxicity play an important role in this regulation.
In primary hemophagocytic lymphohistiocytosis, the regulatory role of cytotoxic cell granules and cytotoxic T-lymphocytes in relation to target cells is disrupted, excessive activation of immune cells occurs, pro-inflammatory cytokines (interferons, tumor necrosis factor, etc.) are produced in excess. Activated due to the “cytokine storm” T-lymphocytes and macrophages infiltrate, and then damage organs and fabrics. An important factor in the pathogenesis of the disease is the development of pathological hemophagocytosis of mature shaped blood elements. Such phagocytosis also occurs normally, helping the body to get rid of old cells. In this case, macrophages begin to phagocytize full-fledged, normally functioning shaped blood elements, leading to pronounced cytopenia, coagulopathy and other manifestations of the disease.
Acquired (secondary) hemophagocytic lymphohistiocytosis develops against the background of certain infectious diseases, tumors, autoimmune processes, during organ and tissue transplantation, and characteristic violations of the regulation of the immune response can be both a consequence of the underlying disease and a complication associated with immunosuppressive therapy and the occurrence of secondary infection.
Hemophagocytic lymphohistiocytosis symptoms
Clinical manifestations of hemophagocytic lymphohistiocytosis are extremely variable. The most common is a prolonged fever, refractory to antibacterial and antiviral therapy. Chills, signs of general intoxication (weakness, sweating, sleep disorders, refusal to eat, nausea and vomiting, muscle pain) continue for a long time, acquiring a wave-like course with periodic temporary improvements in well-being.
A characteristic manifestation of the disease is an increase in the liver and spleen, which has a progressive character. The early symptoms of primary hemophagocytic lymphohistiocytosis include the appearance of a skin rash, an increase in peripheral lymph nodes, as well as the development of neurological disorders in the form of increased excitability, motor disorders and sensitivity disorders, convulsive syndrome, signs of increased intracranial pressure in young children. There are also symptoms with hemophagocytic lymphohistiocytosis that indicate the presence of anemia, coagulopathy – pallor and jaundice of the skin, peripheral edema, signs of bleeding from the digestive tract (black feces, blood admixture in feces, etc.).
With secondary hemophagocytic syndrome, clinical signs of damage to the immune system and manifestations of the underlying disease (viral infection, malignant neoplasms, autoimmune diseases).
The diagnosis is established as a result of a thorough study of the anamnesis, the clinical picture of the disease, the results of laboratory and instrumental studies. Examinations of a hematologist, an allergist-immunologist, an oncologist, an infectious disease specialist, a rheumatologist and other specialists are necessary. International diagnostic criteria for hemophagocytic lymphohistiocytosis have been developed, which include:
- fever with a temperature rise above 38.5 degrees, lasting more than a week;
- enlargement of the liver and spleen;
- cytopenia with a decrease in hemoglobin below 90 g/l, platelets – less than 100,000 cells /ml, neutrophils – less than 1000/ ml;
- signs of coagulopathy;
- the increase in ferritin is more than 500 ng/ml;
- increasing the level of soluble sCD25 in the blood;
- low or complete absence of NK cell activity.
The presence of at least five of these signs indicates hemophagocytic lymphohistiocytosis. To establish the hereditary form of the disease, a genetic study is necessary, as a result of which mutations of the PRF1, UNC13D, Munc18-2, STX11 genes are detected.
Acquired forms of hemophagocytic syndrome are diagnosed on the basis of the above-described international criteria and an updated diagnosis of the underlying disease, for which it is often necessary to perform complex laboratory and instrumental studies (endoscopic, ultrasound, CT, MRI, PET).
Differential diagnosis of hemophagocytic lymphohistiocytosis is performed with:
- various congenital and acquired immune diseases,
- blood diseases,
- acute and chronic viral infections,
- malignant neoplasms (acute lymphoblastic leukemia, non-Hodgkin’s lymphomas, other malignant tumors after chemotherapy),
- systemic connective tissue diseases: systemic lupus erythematosus, juvenile dermatomyositis, nodular periarteritis, juvenile rheumatoid arthritis.
Hemophagocytic lymphohistiocytosis treatment
Modern tactics of treatment of the hereditary form of hemophagocytic lymphohistiocytosis include chemotherapy using immunosuppressive agents (dexamethasone, etoposide, cyclosporine A), as well as stem cell transplantation. The prognosis of the disease is significantly improved with timely transplantation from a histocompatible related donor.
In viral, bacterial and parasitic infections that have caused the appearance of hemophagocytic syndrome, etiotropic antimicrobial therapy, infusions of high-dose immunoglobulin, as well as immunosuppressive therapy with the introduction of cyclosporine A and corticosteroids are performed. Sometimes bone marrow transplantation is indicated. In case of tumors, along with the treatment of the underlying disease, immunosuppressive agents in individually selected doses are included in the therapeutic regimen. In autoimmune processes, treatment includes a combination of immunoglobulin, pulse therapy using corticosteroids, as well as cyclosporine A.