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 lymphohistiocytosis - primary (familial and sporadic) with an autosomal recessive type of inheritance and secondary, associated with various infections, immunodeficiencies, autoimmune and other diseases. The Histiocyte Society classifies primary hemophagocytic lymphohistiocytosis as a group of histiocytoses from macrophage cells.

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Epidemiology

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

The ratio of sick boys and girls suffering from primary hemophagocytic lymphohistiocytosis is approximately equal. In 56-80% of children, the disease develops in the first year of life, and in some of them it 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 sick siblings very often coincides. In about half of the cases there is a positive family history - sick siblings or consanguineous marriage.

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Causes hemophagocytic lymphohistiocytosis.

The symptom complex of lymphohistiocytosis was first described in 1952 by JWFarquhar and AEClaireaux. The authors reported a rapidly progressive, fatal disease in two newborn siblings. The clinical picture of both patients, in the absence of infection, was dominated by fever, vomiting, diarrhea, increased excitability and pronounced splenomegaly, laboratory changes were represented by normochromic anemia, granulocytopenia and thrombocytopenia. In both cases, the disease ended fatally. At autopsy, significant histiocytic proliferation was revealed in the lymph nodes, liver and kidneys (bone marrow was not examined) with active phagocytosis mainly of erythrocytes, as well as lymphocytes and granulocytes. Subsequently, a similar disease was diagnosed in the fourth child of this family. The authors classified this syndrome in a group of histiocytoses called "familial hemophagocytic reticulosis", emphasizing its difference from Letterer-Siwe disease in several aspects: familial nature, absence of bone defects and presence of hemophagocytosis in the affected tissues. The next stages of studying the clinical and diagnostic manifestations of lymphohistiocytosis in children were the review by G. Janka, published in 1983 (123 cases of the disease) and the creation in 1996 of the International Registry of Hemophagocytic Lymphohistiocytosis in Children, which initially included 122 children. A detailed study of the disease in a large group of patients made it possible to formulate diagnostic criteria and propose a treatment protocol for this syndrome. To date, the genetic nature of hemophagocytic lymphohistiocytosis has been partially deciphered, but some aspects of pathogenesis have not been sufficiently studied even today.

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Pathogenesis

The hereditary nature of primary hemophagocytic lymphohistiocytosis was postulated already in early studies. The high frequency of consanguineous marriages in families with hemophagocytic lymphohistiocytosis, multiple cases of the disease in one generation with healthy parents, indicated an autosomal recessive nature of inheritance, but only with the development of modern methods of genetic analysis was it possible to partially decipher the genesis of familial hemophagocytic lymphohistiocytosis (FHLH).

The first attempts to localize the genetic defect were made in the early 1990s based on linkage analysis of polymorphic markers associated with genes involved in the regulation of T-lymphocyte and macrophage activation. The data from these studies allowed excluding such genes as CTLA-4, interleukin (IL)-10, and CD80/86 from the list of candidates. In 1999, linkage analysis of hundreds of polymorphic markers in more than twenty families with familial hemophagocytic lymphohistiocytosis identified two significant loci: 9q21.3-22 and 10qHl-22. Locus 9q21.3-22 was mapped in four Pakistani families, but no involvement of this locus was detected in patients of other ethnicities, indicating a possible “founder effect”; candidate genes located in this region have not been identified to date.

Pathogenesis of lymphohistiocytosis

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Symptoms hemophagocytic lymphohistiocytosis.

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 damage, and rarely hemorrhagic syndrome.

Thus, the following symptoms are practically obligatory: prolonged hectic fever with spontaneous regression in some patients, refractory to antibacterial therapy; rapidly increasing spleen, often in combination with an enlarged liver. All other manifestations are detected much less frequently, on average in a third of patients. Among them: transient maculopapular rash, widespread lymphacinopathy of moderate severity, in the absence of conglomerates and adhesion of lymph nodes to each other and surrounding tissues; neurological symptoms in the form of increased excitability, vomiting, convulsions, signs of intracranial hypertension and delayed psychomotor development.

Symptoms of lymphohistiocytosis

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Diagnostics hemophagocytic lymphohistiocytosis.

The most important laboratory characteristics of lymphohistiocytosis are: changes in the peripheral blood picture, some biochemical parameters and moderate pleocytosis of the cerebrospinal fluid of a lymphocytic-monocytic nature. Anemia and thrombocytopenia are most often detected. Anemia is usually normocytic, with inadequate reticulocytosis, caused by intramedullary destruction of red cells and the inhibitory effect of TNF. Thrombocytopenia is a more diagnostically significant element, allowing us to assess the degree of activity of the syndrome and the activity of treatment. The number of leukocytes may vary, but leukopenia with a neutrophil level of less than 1 thousand per μl is most often detected; atypical lymphocytes with hyperbasophilic cytoplasm are often detected in the leukocyte formula.

Peripheral blood cytopenia is usually not associated with hypocellularity or dysplasia of the bone marrow. On the contrary, the bone marrow is rich in cellular elements, excluding late stages of the disease. According to G. Janka, 2/3 of 65 patients show no changes in the bone marrow or specific changes without disruption of maturation and hypocellularity. The phenomenon of hemophagocytosis is not detected in all patients, and often only repeated studies of the bone marrow and other affected organs allow detecting hemophagocytic cells.

Diagnosis of lymphohistiocytosis

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Treatment hemophagocytic lymphohistiocytosis.

In the vast majority of cases, the disease is fatal. One of the first reviews on hemophagocytic lymphohistiocytosis reported that the median survival from the onset of disease symptoms was approximately 6-8 weeks. Before the introduction of modern chemo- and immunosuppressive therapy protocols and BMT/HSCT, the median survival was 2-3 months.

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

The first real therapeutic success in hemophagocytic lymphohistiocytosis was the use of epipodophyllotoxin VP16-213 (VP-16) in 2 children, which allowed to achieve complete remission (1980). However, later both children developed a relapse with CNS damage, which ended in death 6 months and 2 years after diagnosis. Based on the fact that VP-16 does not penetrate the hemato-encephalic barrier. A. Fischer et al. in 1985 conducted a combined treatment of four children with VP-16, steroids in combination with intrathecal methotrexate, or cranial irradiation. All four children were in remission at the time of publication with a follow-up of 13-27 months.

Treatment of lymphohistiocytosis