Hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a group of diseases developing from ordinary macrophages characterized by a rapid, fatal course; the main clinical symptoms of which are fever, massive splenomegaly, bi- or pancytopenia, hypofibrinogenemia, hypertriglyceridemia, symptoms of CNS damage. There are two groups of lymphogystyocytosis - primary (family and sporadic) with autosomal recessive type of inheritance and secondary, associated with various infections, immunodeficiencies, autoimmune and other diseases. The International Society for the Study of Histiocyte Society (Histiocyte Society) classifies primary hemophagocytic lymphohistiocytosis as a group of histiocytosis from macrophage cells.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Epidemiology

Primary (familial and sporadic) hemophagocytic lymphogystyocytosis occurs in various ethnic groups and is spread throughout the world. The incidence of primary hemophagocytic lymphogystyocytosis, according to J.Henter, is approximately 1.2 per 1,000,000 children under 15 years old or 1 per 50,000 newborns. These indicators are comparable with the prevalence in newborns of phenylketonuria or galactosemia.

The ratio of diseased boys and girls suffering from primary hemophagocytic lymphogystyocytosis is approximately equal. In 56-80% of children, the disease develops in the first year of life, and in some of them is diagnosed at birth, in about 20% of children the first clinical signs of the disease appear after 3 years of life. There are data on the debut of the disease at a later age: 6, 8, 12, 25 years. It is important to note that the age of the affected siblings is very often the same. Approximately half of the cases have a positive family history - sick siblings or a closely related marriage.

[10], [11], [12], [13], [14], [15]

Causes of the hemophagocytic lymphogystyocytosis

For the first time the symptom complex of lypho-histiocytosis was described in 1952 by JWFarquhar and AEClaireaux. The authors reported a rapidly progressive, fatal disease in two newborn siblings. In the clinical picture of both patients, in the absence of infection, fever, vomiting, diarrhea, increased excitability and expressed splenomegaly dominated, laboratory changes were represented by normochromic anemia, granulocytopenia and thrombocytopenia. In both cases, the disease ended lethal. Autopsy revealed significant histiocytic proliferation in the lymph nodes, liver and kidneys (bone marrow was not studied) with active phagocytosis mainly of erythrocytes, as well as lymphocytes and granulocytes. Later, a similar disease was diagnosed in the fourth child of this family. The authors attributed this syndrome to a group of histiocytoses called "family hemophagocytic reticulosis, highlighting its difference from Letterer-Siwe in several respects: family character, absence of bone defects and presence of hemophagocytosis in the affected tissues. The following stages of studying clinical and diagnostic manifestations of lymphogystyocytosis in children were reviewed by G. Janka, published in 1983, (123 cases of the disease) and the creation in 1996 of the International Registry of Hemophagocytic Lymphogystiocytosis in Children, which initially included 122 children. Detailed study of the disease on a large group of patients allowed to formulate diagnostic criteria and propose a protocol for the treatment of this syndrome. By now, the genetic nature of hemophagocytic lymphogystyocytosis has been partially deciphered, but some aspects of pathogenesis have not been sufficiently studied today.

[16], [17], [18], [19]

Pathogenesis

The hereditary nature of primary hemophagocytic lymphogystyocytosis was postulated already in early studies. The high incidence of familial marriages in families with hemophagocytic lymphogystyocytosis, multiple cases of waterborne disease in healthy parents, and pointed to the autosomal recessive nature of inheritance, but only with the development of modern methods of genetic analysis has it been possible to partially decipher the genesis of familial hemophagocytic lymphogystyocytosis (HDVH).

The first attempts to localize the genetic defect were undertaken in the early 90's on the basis of an analysis of the linkage of polymorphic markers associated with genes involved in the regulation of T-lymphocyte and macrophage activation. Data from these studies made it possible to exclude from the list of candidates such genes as STLA-4, interleukin (IL) -10, CD80 / 86. In 1999, as a result of the analysis of the cohesion of hundreds of polymorphic markers in more than twenty families with familial hemophagocytic lymphogystyocytosis, two significant loci were identified: 9q21.3-22 and 10qHl-22. Locus 9q21.3-22 was mapped in the analysis of four Pakistani families, however, in the study of patients of another ethnicity, the involvement of this locus was not recorded, indicating a possible "founder effect"; candidate genes located in this area have not been identified to date.

Pathogenesis of lymphogystyocytosis

[20], [21], [22], [23], [24], [25], [26]

Symptoms of the hemophagocytic lymphogystyocytosis

The initial symptoms of lymphohistiocytosis are numerous and nonspecific: fever accompanied by symptoms of gastrointestinal pathology or viral infection, progressive hepatosplenomegaly, lymphadenopathy, nonspecific rash, jaundice, edema, symptoms of CNS involvement, rarely hemorrhagic syndrome.

Thus, symptoms such as: prolonged hectic fever with spontaneous regression in some patients, refractory to antibacterial therapy; rapidly enlarges the size of the spleen, often in combination with increased liver size. All other manifestations are detected significantly less frequently, on average in a third of patients. Among them: a transient maculopapular rash, a widespread lymphoacinopathy of moderate severity, in the absence of conglomerates and adhesion of lymph nodes between themselves and surrounding tissues; neurologic symptoms in the form of increased excitability, vomiting, seizures, signs of intracranial hypertension and delayed psychomotor development.

Symptoms of lymphogystyocytosis

[27], [28], [29], [30], [31]

Diagnostics of the hemophagocytic lymphogystyocytosis

Of the laboratory characteristics of lymphohistiocytosis, the most important are: changes in the pattern of peripheral blood, certain biochemical indices and moderate pleocytosis of the lymphocyte monocyte-like liquor. The most common are anemia and thrombocytopenia. Anemia is usually normocytic, with inadequate reticulocytosis due to intramedullary destruction of red cells and inhibitory action of TNF. Thrombocytopenia is a diagnostic more significant element, allowing to estimate the degree of activity of the syndrome and the activity of treatment. The number of leukocytes may be different, but more often leucopenia is detected with a neutrophil count of less than 1 thousand in μl. In the leukocyte formula, atypical lymphocytes with a hyperbasophilic cytoplasm are often found.

Cytopenia of peripheral blood is usually not associated with hypocellularity or bone marrow dysplasia. On the contrary, the bone marrow is rich in cells, with the exception of late stages of the disease. According to G.Janka, 2/3 of 65 patients do not have any changes in the bone marrow or there are specific changes without disturbance of maturation and hypo-cellulence. The phenomenon of hemophagocytosis is not found in all patients, and often only repeated studies of the bone marrow and other affected organs can detect hemophagocytic cells.

Diagnosis of lymphogystyocytosis

[32], [33]

Treatment of the hemophagocytic lymphogystyocytosis

In the vast majority of cases, the disease is fatal. In one of the first reviews on hemophagocytic lymphogystyocytosis, it was reported that the average life expectancy from the onset of the first signs of the disease is approximately 6-8 weeks. Before the introduction of modern protocols of chemo- and immunosuppressive therapy and TCM / TSCA, the average life expectancy was 2-3 months.

According to G. Janka, presented in a literature review in 1983, 40 of 101 patients died during the first month of the disease, another 20 in the second month of the disease, only 12% of patients lived more than six months, only 3 children survived.

The first real therapeutic success in hemophagocytic lymphogystyocytosis was the use of epipodophyllotoxin VP16-213 (VP-16) in 2 children, which allowed complete remission (1980). However, in the future, both children developed a relapse with CNS damage, which ended in a lethal outcome after 6 months and 2 years after the diagnosis. Proceeding from the fact that VP-16 does not penetrate the hemato-zvecephalic barrier. A. Fischeretal. In 1985, combined treatment of four children VP-16, steroids in combination with intrathecal administration of methotrexate, or cranial irradiation. All four children at the time of publication were in remission with a catamnesis of 13-27 months.

Treatment of lymphogystyocytosis