Diagnosis of lymphohistiocytosis

Of the laboratory characteristics of lymphohistiocytosis, the most important are: changes in the pattern of peripheral blood, some biochemical parameters and moderate pleocytosis of the lymphocyte-monocytic liquor. The most frequently detected anemia and thrombocytopenia. Anemia is usually normocytic, with inadequate reticulocytosis, due to the intramedullary destruction of red cells and the inhibitory effect of TNF. Thrombocytopenia is a more diagnostically significant element, allowing to evaluate the degree of activity of the syndrome and the activity of treatment. The number of leukocytes can be different, but leukopenia with a neutrophil level of less than 1 thousand per μL is more often found. Atypical lymphocytes with hyperbasophilic cytoplasm are often found in leukocyte formula.

Peripheral blood cytopenia is usually not associated with hypocellularity or bone marrow dysplasia. In contrast, the bone marrow is rich in cell elements, excluding the late stages of the disease. According to G.Janka, 2/3 of 65 patients do not show any changes in the bone marrow or there are 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 can detect hemophagocytic cells.

Changes in the biochemical composition of blood are more diverse. The dominant among them are the indicators characterizing disorders of fat metabolism and liver function. Thus, lipid metabolism detected in 90-100% of patients is evidenced by hyperlipidemia due to an increase in triglyceride levels, an increase in the fraction of prelipoproteins of very low IV or V type density and a decrease in high-density lipoproteins is probably due to the suppression of TMF synthesis of lipoprotein lipase necessary for the implementation of lipid hydrolysis of triglycerides. Elevated triglyceride levels are a reliable measure of disease activity.

The frequency of hypertransaminasemia (5-10 times the excess of the norm) and hyperbilirubinemia (up to 20 norms), increasing as the disease progresses, are detected in 30-90% of children. Often there are such common changes characteristic of various inflammatory processes, such as increased levels of ferritin, lactate dehydrogenase (LDH), hyponagremia and hypoproteinemia / hypoalbuminemia.

Of the indicators of the hemostasis system, a decrease in the level of fibrinogen detected in the early stages of the disease in 74-83% of children is diagnostically significant. Presumably hypofibrinogenemia is associated with increased production of plaminogen activators by macrophages. At the same time, violations in the parameters of the coagulogram, which allow suspecting DIC, or deficiency of factors of the prothrombin complex, are usually not detected. Hemorrhagic syndrome in hemophagocytic lymphohistiocytosis is caused by thrombocytopenia and hypofibrinogenemia.

Immunological disorders are represented by a decrease in the activity of cellular cytotoxicity, primarily due to a decrease in the activity of NK cells. During remission, their function can be partially normalized, but is fully restored only after TKM. In the active phase of the disease, an increased number of activated lymphocytes (CD25 + HLA-DR +) and cytokines (IFNy, TNF, soluble IL-2 receptors, 1L-J, C-6) are determined.

Pathological changes

The morphological substrate of lymphohistiocytosis is diffuse lymphohistiocytic infiltration with hemophagocytosis, mainly in the bone marrow, spleen, lymph nodes, CNS, liver, thymus.

Histiocytes carry the markers of mature ordinary macrophages and do not have cytological signs of malignancy and increased mitotic activity. Hemophagocytosis is a major, but non-specific, pathological morphological symptom of hemophagocytic lymphohistiocytosis. Histopathological assessment is difficult in 30-50% of patients due to the absence of hemophagocytosis in the early stages of the disease or its disappearance under the influence of therapy. Some authors associate the degree of lymphohistiocytic infiltration and the presence of hemophagocytosis with the growth of the patient and the duration of the disease.

As a rule, given the presence of cytopenia and splenomegaly, which are mandatory signs of hemophagocytic lymphohistiocytosis, the bone marrow is examined in a timely manner. During the initial examination of the bone marrow, hemophagocytosis is found only in 30-50% of patients. Carrying out trephine biopsy with negative results of bone marrow puncture is mandatory, but its diagnostic capabilities are also limited. At the “advanced” stages of the disease, the bone marrow cellularity is markedly reduced, which can be mistakenly interpreted in favor of regenerative blood diseases or taken as a side effect of chemotherapy.

Hemophagocytosis is rarely found in the lymph nodes, with the exception of the later stages of the disease. The diagnostic capabilities of the morphological study of the liver are rather limited: hemophagocytosis is rarely detected, Kupffer cell proliferation is moderate, but the overall histological picture resembling chronic persistent hepatitis, with other manifestations of the disease, may become an important additional criterion for hemophagocytic lymphohistiocytosis. Hemophagocytic activity is almost always detected in the spleen, but due to technical difficulties the biopsy of the spleen is performed extremely rarely.

With a fairly bright and frequent neurological symptoms, its morphological basis is usually represented by lymphohistiocytic infiltration of the meninges and brain substance. By itself, it is devoid of any specific signs. Hemophagocytosis is not always pronounced; in severe cases, multiple foci of necrosis of the brain substance are found without pronounced vascular occlusion.

In other organs, the picture of hemophagocytosis is rarely detected.

[1], [2], [3], [4]

Diagnostics

As was shown above, it is extremely difficult to objectify the alleged diagnosis of hemophagocytic lymphohistiocytosis. The difficulty of diagnosis is associated with a deficit of specific clinical and laboratory symptoms. Establishing a diagnosis requires meticulous, comprehensive assessment of all anamnestic, clinical, laboratory, and morphological data.

Given the absence of pathognomonic signs of the disease, the International Society for the Study of Histiocytic Diseases proposed the following diagnostic criteria (1991).

Diagnostic criteria for hemophagocytic lymphohistiocytosis, 1991.

Clinical criteria:

1. Fever over 7 days over> 38.5 degrees.
2. Splenomegaly 3 and more, see from the edge of the costal arch.

Laboratory criteria:

1. 1. Cytopenia of peripheral blood with a lesion of at least 2 sprouts in the absence of hypocellularity or myelodysplastic changes in the bone marrow: (hemoglobin less than 90 g / l, platelets less than 100 x 10 ⁹ / l, neutrophils less than 1.0 x 10 ⁹ / l).
2. 2. Hypertriglebiriaemia and / or hypofibrinogenemia (triglyceridemia> 2.0 mmol / l; fibrinogen <1.5 g / l).

Histopathological criteria:

1. Hemophagocytosis in the bone marrow, spleen or lymph nodes.
2. No signs of malignancy.

Note: The diagnosis of familial hemophagocytic lymphohistiocytosis is established only with a family history or with related marriages.

Comments: the presence of pleocytosis of mononuclear character in the cerebrospinal fluid, a histological picture in the liver by the type of chronic persistent hepatitis and reduced activity of natural killers can be used as additional criteria. Other clinical and laboratory signs that, together with the rest of the symptoms, may indicate the diagnosis of hemophagocytic lymphohistiocytosis, include the following: neurological symptoms of meningoencephalitis, lymphadenopathy, jaundice, rash, elevated liver enzymes, hyperferritinemia, hypoproteinemia, and hypoproteinemia, jaundice, rash, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and jaundice, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and jaundice, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and jaundice, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and jaundice, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and jaundice, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and jaundice, elevation of hepatic enzymes, hyperferritinemia, hypoproteinemia, and hypoproteinemia, as well as neurological symptomatology. If manifestations of hemophagocytosis are not found, it is necessary to continue the search for morphological confirmation. Accumulated experience shows that if bone marrow puncture and / or trepanobiolysis are not diagnostic, it is necessary to perform a puncture biopsy of another organ (spleen or lymph node), and repeated tests of the bone marrow are justified to confirm the diagnosis.

According to these diagnostic criteria, it is necessary to have 5 criteria for making a diagnosis of primary hemophagocytic lymphohistiocytosis: fever, cytopenia (in 2 of 3 lines), splenomegaly, hypertriglyceridemia, and / or hypofibrinogenemia, and hemophagocytosis. To confirm the familial form of the disease, a positive family history or a related marriage is required.

[5], [6], [7], [8], [9], [10], [11], [12], [13]

Differential diagnostics

The range of diseases differentiated with hemophagocytic lymphohistiocytosis is quite large. These are viral infections, bacterial infections, leishmaniasis; blood diseases - hemolytic and aplastic anemia, myelodysplastic syndrome, combined immunodeficiency. Hemophagocytic lymphohistiocytosis may also occur under the guise of severe CNS lesions.

When conducting a differential diagnosis with histiocytosis of other passages, the histiocytosis from Langerhans cells, which occurs with multisystem lesions, deserves the most attention. Both in hemophagocytic lymphohistiocytosis and in the multisystem variant of hemophagocytic lymphohistiocytosis, infants and children of early age are sick, but in hemophagocytic lymphohistiocytosis, there is always no family history. Of the clinical differences, the most characteristic are bone lesions in hemophagocytic lymphohistiocytosis, which never occur in hemophagocytic lymphohistiocytosis and a characteristic rash (similar to seborrhea), which also does not occur in lymphohistiocytosis. Damage to the central nervous system, which is found in 80% of cases in hemophagocytic lymphohistiocytosis, is extremely rare in hemophagocytic lymphohistiocytosis. One of the most significant differences in PGLG and GCR is morphological and immunohistochemical characteristics. In hemophagocytic lymphohistiocytosis infiltration there is monoclonal proliferation of CL, there is no admixture of lymphocytes and histiocytes, as well as signs of lymphoid atrophy and hemophagocytosis. Cells contain CDla antigen, S-100 protein, Bnrbek granules.

[14], [15],