Hemophagocytic syndrome in children: primary, secondary

A rare and complex disease - hemophagocytic syndrome, is called hemophagocytic lymphogystyocytosis. This serious illness is associated with the emergence of a deficiency of many organs as a result of uncontrolled activation of the effector component of cellular immune defense.

With hemophagocytic syndrome there is a strong increase in the functionality of toxic T-lymphocytes and macrophages, which leads to the development of numerous anti-inflammatory cytokines. In turn, this process entails an intense systemic inflammatory reaction and a large-scale disruption of the function of many organs.

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

Causes of the hemophagocytic syndrome

Hemophagocytic syndrome is more often primary - that is, hereditary type as a result of genetic disturbance in the work of macrophages.

Secondary hemophagocytic syndrome is also called acquired: it is associated with various infectious pathologies, tumor processes, autoimmune diseases, congenital metabolic disorders.

In the classical version of the hereditary type of hemophagocytic syndrome, children are often placed for treatment in the intensive care unit or ICU in infectious hospitals, diagnosing septic complications or intrauterine generalized infection. Direct diagnosis of hemophagocytic syndrome is often established after a fatal outcome.

However, common at first glance, infectious diseases of viral or microbial origin can cause such a complication as a life-threatening hemophagocytic syndrome.

Hemophagocytic syndrome in adults is almost always secondary in most cases: most often pathology develops against the background of lymphoproliferative diseases and chronic VEB infections.

Hemophagocytic syndrome in children can be both primary and secondary - due to the transferred infectious diseases (chicken pox, meningoencephalitis, etc.).

[5], [6], [7], [8], [9]

Symptoms of the hemophagocytic syndrome

Signs of the syndrome were first described in the middle of the last century. The following characteristic symptoms were identified:

• stable fever;
• a decrease in the level of hematopoietic substances;
• an increase in the size of the liver and spleen;
• expressive hemorrhagic syndrome.

Patients can observe the phenomena of hepatic insufficiency, high content of ferritin and transaminazine, a clear neurological picture with a disturbance of the functionality of the central nervous system, high serum triglycerides, accelerated blood coagulation and coagulopathy.

Often, the diseased find enlarged lymph nodes, skin rashes, yellowing of the sclera, skin and mucous membranes, as well as puffiness.

Parenchyma of the spleen, sinusoidal hepatic capillaries, sinuses of the lymph nodes, bone marrow and central nervous system are distinguished by diffuse infiltration of active macrophages against the background of hemophagocytic symptoms. Lymphoid tissue is depleted. In the study of the liver, there are lesions typical of the chronic form of persistent inflammation.

[10], [11], [12], [13]

Forms

There are two clinical forms that are difficult to differentiate at first.

1. Primary hemophagocytic lymphohistiocytosis, which is an autosomal recessive pathology, in the development of which the mutation of the perforin gene is of primary importance.
2. Secondary form of hemophagocytic lymphohistiocytosis, which develops as a result of excessive immune activity of the chain of mononuclear phagocytes.

[14], [15]

Complications and consequences

• Accession of infection with subsequent intoxication. This complication is characterized by a gradual loss of function of the main organs and systems, fever, exhaustion of the patient.
• Malignant degeneration of cells. Usually, malignancy is the development of lymphoma, leukemia and other malignant diseases.
• Autoimmune pathologies - a kind of aggressive reaction of the patient's own immune defense.
• Persistent decrease in immunity with the development of immunodeficiency state.
• Lack of kidney and liver function.
• Internal bleeding, hemorrhage.
• The death of the patient from total organ dysfunction or from septic complications.

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

Diagnostics of the hemophagocytic syndrome

If the family history is not burdened, then determine the primary or secondary hemophagocytic syndrome is very difficult. In order to make an accurate diagnosis, it is necessary to carry out a histological differentiation of hemophagocytosis.

Many diseases are difficult to determine using only the information obtained from tissue biopsies: lymph nodes, liver and bone marrow.

Conducting immunological studies that allow us to see the inhibited function of NK-cell structures and increase the content of the interleukin-2 receptor can not serve as a basis for the diagnosis. Additionally, the features of the clinical picture, damage and disruption of the central nervous system and changes in the blood composition of the patient are taken into account.

The final point in the diagnosis is the data of molecular genetic analysis.

[20], [21]

Differential diagnosis

Differentiation of the disease is extremely difficult, with the approach to be determined depending on the age of the patient. In pediatrics it is important to detect the genetic forms of hemophagocytic syndrome as early as possible, analyzing all possible factors that may indicate a hereditary variety of pathology.

So, the rapid development of the syndrome during the first 12 months of life with an uncomplicated family history is typical for the primary form of hemophagocytic syndrome. The observed expression of perforin on NK-cell structures using flow cytofluorometry and molecular genetic studies of perforin helps to establish a correct diagnosis in about 30% of cases of hereditary hemophagocytic syndrome. Simultaneous appearance of the disease against the background of albinism is detected with such syndromes:

• Chediak-Higashi syndrome;
• Griessely's syndrome.

If inheritance has an X-linked type, that is, when the disease develops in related males along the mother's line, then the most likely is the presence of an autoimmune lymphoproliferative syndrome.

In secondary hemophagocytic syndrome, the main thing is to timely detect malignant tumors, which are often the causes of the syndrome in adulthood.

Treatment of the hemophagocytic syndrome

Treatment for hemophagocytic syndrome is quite complicated: the success of such treatment largely depends on the patient's age and on how timely the disease was discovered.

Therapeutic regimens for hemophagocytic syndrome involve the use of glucocorticosteroid drugs (Dexamethasone), cytostatics (Etoposide, Ciclosporin A). Cytotoxic drugs are prescribed to suppress the pro-inflammatory effect of phagocytes with further alogenic transplantation of stem cells.

A single treatment regimen used for hemophagocytic syndrome has not yet been determined. Etiotropic treatment is considered insufficient to combat the syndrome, and the use of immunosuppressors can adversely affect the course of the viral-bacterial process.

It is recommended to inject high doses of immunoglobulin, based on the amount of 1-2 mg per kilogram of the patient's weight per day.

Plasmaphoresis can be prescribed as part of a pathogenetic treatment to monitor hypercytokinemia.

The basis of treatment is splenectomy and transplantation of the donor bone marrow.

Prevention

Experts at the moment do not have clear information about methods of preventing primary hemophagocytic syndrome, as the causes of this pathology are not fully understood.

As for secondary hemophagocytic syndrome, preventive measures can be as follows:

• competent and timely treatment of viral and microbial infections;
• qualified treatment of autoimmune pathologies under the supervision of a medical specialist of the rheumatological profile.

[22], [23], [24], [25], [26], [27], [28], [29]

Forecast

The prognosis of hemophagocytic syndrome is considered extremely unfavorable, which can be seen from the statistical information: six deaths among seven cases. The maximum duration of survival at the moment is two years.

Hemophagocyte syndrome is considered a very complex and insidious disease, which today "competes" except with infection of the immunodeficiency virus, and the frequency of the consequences even surpasses HIV.

[30], [31]