Over the past decades, significant progress has been made in studying the biological characteristics of the macrophage system, which is regarded as a biological filter of blood and lymph, helps to remove microorganisms, cells affected by tumor and infected viruses, toxins, metabolites, and drug residues.
Hemophagocytic syndrome as a nosological form includes a group of acquired and congenital pathological conditions, which are based on impaired regulation of the immune response to abnormalities in the activation of cytotoxic T-lymphocytes and macrophages and the occurrence of damage to inflammatory organs mediated by them.
Basic concept
The term “hemophagocytosis” means the pathomorphological phenomenon of phagocytosis of mature mature blood elements by macrophages of tissues. This phenomenon is quite common and is not considered synonymous with lymphohistiocytosis of the hemophagocytic species as a nosological form.
Attention to this pathology in the clinical practice of infectious disease specialists is due to the fact that at the diagnostic stage, patients with traditional hereditary forms of hemophagocytic lymphohistiocytosis, due to the peculiarities of medical presentation, are often observed in infectious hospitals with identical diagnoses, such as, for example, an intrauterine infection or a process associated with sepsis and often a true diagnosis is made with a dangerous long delay.
On the other hand, the course of many commonplace infections can be complicated by the development of a life-threatening secondary hemophagocytic syndrome. In addition to the standard etiotropic treatment, it requires immunosuppressive and immunomodulating therapy, which should be aimed at controlling the pathological activation of the immune response. In accordance with the classification adopted by the Society for the Study of Histiocytosis in hemophagocytic lymphohistiocytosis is classified as a disease with a variable clinical picture.
Primary, that is, hereditarily determined hemophagocytic syndromes include familial lymphohistiocytosis and some rare primary immunodeficiencies. Secondary forms include those that develop in the context of tumor, infectious, and autoimmune pathological phenomena.
It must be emphasized that as the molecular mechanisms of pathology are investigated, the line between genetically determined and secondary lymphohistiocytoses substantially loses its clarity.
How is hemophagocytic syndrome manifested in adults and children?
Symptomatology
The clinical picture of the disease is characterized by prolonged fever, refractory to antibacterial medications, splenic megalia, hemorrhagic syndrome, edematous syndrome, hepatomegaly, signs of central nervous system damage. The pathological process in most cases begins extremely sharply. Trigger of clinical manifestation of pathology is a banal infection.
The psychomotor and physical development of the patient until the onset of hemophagocytic syndrome in most cases does not suffer. At the initial stage of the examination, an intrauterine infection is often diagnosed, or (in the later stages of the development of the disease) meningoencephalitis or sepsis. Non-stopping fever and intoxication manifestations become the main reason for hospitalization in the hospital of an infectious diseases hospital, where during a diagnostic examination it is often possible to confirm infection with the most common pathogen using laboratory methods. The administration of etiotropic treatment does not lead to a significant improvement in the patient's condition.
Temporary normalization of the condition can be noted with the appointment of corticosteroids in accordance with the severity of the condition. However, the fever most often persists, hepatosplenomegaly progresses, hemorrhagic syndrome begins to appear, neurological symptoms significantly increase and include severe irritability, vomiting, refusal to eat, the occurrence of seizures, meningeal symptoms.
In some cases, the onset of the pathological process is disguised as isolated encephalomyelitis, encephalitis, and recurrent seizures lead to the formation of a stable neurological deficit. As a rule, the clinical manifestations of hemophagocytic syndrome in children and adults are supplemented by characteristic changes in laboratory parameters, which necessarily include peripheral blood cytopenia, involving two or more hematopoiesis branches.
Anemia and thrombocytopenia
In most cases, anemia and thrombocytopenia are detected in the early stages of the development of the disease, and neutropenia and leukopenia develop as it progresses. The occurrence of coagulopathy is also characteristic, which is most often manifested by hypofibrinogenemia, somewhat less often in the form of total hypocoagulation.
Among the values of a biochemical blood test, hypoalbuminemia, hypertriglyceridemia, hyponatremia, and an increase in the level of lactate dehydrogenase and bilirubin are most characteristic.
Increased ferritin
The increase in serum ferritin content, in some cases to an extreme level (more than 10,000 μg / l), is also quite characteristic. In a laboratory study of cerebrospinal fluid, moderate monocytic and lymphocytic pleocytosis, an increase in protein level, are detected.
When conducting a myelogram using standard staining, a polymorphic picture is observed in the bone marrow with activated macrophages or monocytes, as well as phagocytosis in the cellular elements (red blood cells, less often platelets and white blood cells). The most specific manifestation in a laboratory study of hemophagocytic syndrome is a decrease in NK cell cytotoxicity.
Classification
Hemophagocytic lymphohistiocytosis belongs to the category “H” in the modern classification of histiocytosis. Primary forms of this disease, due to known genetic defects, and secondary, which are not associated with an inherited genetic anomaly, are distinguished.
A complete classification of this pathology:
- primary syndrome: hereditary pathologies leading to the development of GLH;
- HLH associated with a defect in the cytotoxicity of lymphocytes;
- GLH associated with activation defects of the inflammasome;
- GLH associated with hereditary diseases that affect the development of the inflammatory process;
- familial forms of HLH with undetermined genetic defects;
- secondary hemophagocytic syndrome associated with infection;
- virus-associated GLH;
- GLH associated with bacterial infections;
- HLH associated with fungal infections;
- HLH associated with parasitic infections;
- GLH, which is associated with malignant neoplasms;
- HLH associated with chemotherapy behavior (not associated with the primary occurrence of a malignant tumor);
- GLH associated with the development of rheumatological diseases;
- HLH associated with transplantation;
- GLH, which is associated with iatrogenic activation of the immune system;
- a syndrome associated with the development of iatrogenic immunosuppression;
- hemophagocytic syndrome associated with sepsis.
Procalcitonin
Procalcitonin is a compound that belongs to the glycoproteins of their protein-carbohydrate complex, which contains 116 amino acids. It is a precursor of calcitonin, a hormonal compound produced mainly in the thyroid gland by C cells.
During metabolic processes, procalcitonin breaks down into calcitonin, catacalcin, and the terminal peptide. An increase in the level of this compound is often observed in small cell lung carcinoma, which indicates its formation not only in the thyroid gland. In addition, most interestingly, a particularly pronounced change in the concentration of procalcitonin in hemophagocytic syndrome in children.
This is a presumably fatal complication, which is based on impaired regulation of the immune response as a result of mutations in genes that control cytolytic functions, leading to defective activation of cytotoxic monocytes, T-lymphocytes, macrophages and a systemic inflammatory response in a child. This disease belongs to the category of histiocytic cells that develop from macrophage cells. It is extremely important to carry out laboratory diagnostics to identify the level of procalcitonin and other specific compounds in the blood.
Secondary syndrome how does it develop?
Secondary hemophagocytic syndrome in children occurs, as a rule, with infections, rheumatic pathologies, malignant tumors and in the oncohematological category of diseases. An association of secondary HFS with a number of pathogens has been proved, which includes both viruses (herpes virus, HIV, influenza A, parvovirus B19, adenovirus), bacteria (mycobacteria, salmonella, mycoplasmas, rickettsia, pneumococcus), fungi and protozoa.
Herpes viruses
Among the viruses most often associated with secondary hemophagocytic syndrome, herpes viruses are in the first place. At the same time, this ailment is able to imitate a number of infectious diseases, for example, visceral leishmaniasis, leptospirosis and sepsis.
The HFS complex includes splenomegaly, fever, central nervous system damage, hepatitis, coagulation disorders, cytopenia, many biochemical markers. The above signs are rather nonspecific, which significantly complicates the diagnosis of such a pathological condition, especially in the early stages, leading to an ambiguous prognosis of life, especially in immunocompromised patients.
How is secondary and primary hemophagocytic syndrome detected?
Diagnostics
Initial diagnosis of the disease includes collecting a medical history and complaints of the patient, as well as conducting a physical examination. Next, the necessary laboratory diagnostics is carried out, in which it is necessary to determine the level of the following substances in the blood:
- direct and common bilirubin;
- ALT / AST;
- LDH;
- albumen;
- sodium;
- triglycerides;
- ferritin;
- urea;
- creatinine.
In addition, coagulograms, studies of cerebrospinal fluid, cytometry, etc. are necessary.
Instrumental diagnostics
Instrumental diagnostics include:
- MRI of the brain with contrasting gadolinium;
- CT of the lungs;
- Ultrasound of the abdomen;
- Chest x-ray.
Find out what are the prospects for hemophagocytic syndrome in children and adults?
Treatment
The goal of conservative treatment is to suppress the inflammatory response, restore the functioning of organs and perform transplantation of stem hematopoietic cells. HSCT is the only curative treatment technique. Next, immunosuppressive chemotherapy is carried out, combined with the use of medications: "Dexamethasone", "Methotrexate", "Prednisolone", "Cyclospogrin A", etc.
The duration of treatment for hemophagocytic syndrome and the establishment of dosages is carried out by a doctor.
Transplantation
Modern tactics for treating hereditary forms of lymphohistiocytosis include not only the above methods. The prognosis of the disease is significantly improved with timely transplantation from a compatible related donor. In bacterial, viral and parasitic infections that provoked the appearance of this syndrome, etiotropic antimicrobial therapy, high-dose immunoglobulin infusion, and immunosuppressive treatment are implemented. Bone marrow transplantation is sometimes indicated.
The prognosis of hemophagocytic syndrome
This is directly related to the neglect of the pathological process and its form. Primary syndrome is treated much more difficult, and the chances of recovery are relatively few. Extremely negative prognosis in children with congenital forms of the disease - with untimely treatment and complex forms of pathology, the mortality rate is very high.