Over the past decades, significant progress has been made in studying the biological characteristics of the macrophage system, which is considered as a biological filter of blood and lymph, helps to remove microorganisms, cells affected by tumor and infected viruses, toxins, metabolites, drug residues.
Hemophagocytic syndrome as a nosological form includes a group of acquired and congenital pathological conditions, which are based on dysregulation of the immune response to anomalies in the activation of cytotoxic T-lymphocytes and macrophages and the occurrence of damage to the affected inflammatory organs mediated by them.
Basic concept
The concept of "hemophagocytosis" means the pathomorphological phenomenon of phagocytosis of shaped mature blood elements by tissue macrophages. This phenomenon is quite common and is not considered a synonym for lymphohistiocytosis of the hemophagocytic type 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 their medical presentation, are often noted in infectious diseases hospitals with identical diagnoses, such as, for example, intrauterine infection or a process associated with sepsis and often a dangerously long delay in the true diagnosis.
On the other hand, the course of many banal infections can be complicated by the development of a life-threatening secondary hemophagocytic syndrome. It requires, in addition to the standard etiotropic treatment, immunosuppressive and immunomodulatory 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, 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. The secondary ones include forms that develop in the context of tumor, infectious and autoimmune pathological phenomena.
It should be emphasized that as the molecular mechanisms of the occurrence of pathology are studied, the line between genetically determined andsecondary lymphohistiocytosis significantly loses clarity.
How does hemophagocytic syndrome manifest itself in adults and children?
Symptomatics
The clinical picture of the disease is characterized by prolonged fever, refractory to antibacterial drugs, splenomegaly, hemorrhagic syndrome, edematous syndrome, hepatomegaly, signs of CNS damage. The pathological process in most cases begins extremely acutely. The trigger for the 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, intrauterine infection is often diagnosed, or (in the later stages of the development of the disease) meningoencephalitis or sepsis. Intractable fever and manifestations of intoxication are the main reason for hospitalization in the hospital of the infectious diseases hospital, where diagnostic examinations can often confirm infection with the most common pathogen using laboratory methods. The appointment 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, fever most often persists, hepatosplenomegaly progresses, hemorrhagic syndrome begins to appear, neurological symptoms increase significantly and include severe irritability, vomiting, refusal toeating, seizures, meningeal symptoms.
In some cases, the beginning of the pathological process passes under the guise of isolated encephalomyelitis, encephalitis, and recurrent attacks lead to the formation of a stable neurological deficit. As a rule, the clinical manifestations of hemophagocytic syndrome in children and adults are complemented by characteristic changes in laboratory parameters, which necessarily include peripheral blood cytopenia, involving two or more branches of hematopoiesis.
Anemia and thrombocytopenia
In most cases, anemia and thrombocytopenia are detected in the early stages of the disease, and as it progresses, neutropenia and leukopenia develop. 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, increased levels of lactate dehydrogenase and bilirubin are most characteristic.
Increased ferritin
It is also quite characteristic to increase the content of ferritin in serum, in some cases to extreme levels (more than 10,000 mcg/l). Laboratory examination of the cerebrospinal fluid revealed moderate monocytic and lymphocytic pleocytosis, an increase in protein levels.
When conducting a myelogram using standard staining, a polymorphic picture is observed in the bone marrow with activatedmacrophages or monocytes, as well as the phenomena of phagocytosis in cellular elements (erythrocytes, less often platelets and leukocytes). The most specific manifestation in the laboratory study of hemophagocytic syndrome is a decrease in NK cell cytotoxicity.
Classification
Hemophagocytic lymphohistiocytosis is classified as “H” in the modern classification of histiocytosis. Primary forms of this disease are distinguished, due to known genetic defects, and secondary, which are not associated with an inherited genetic anomaly.
Full classification of this pathology:
- primary syndrome: hereditary pathologies leading to the development of HLH;
- HLH associated with a defect in lymphocyte cytotoxicity;
- HLH associated with inflammasome activation defects;
- HLH associated with hereditary diseases that affect the development of the inflammatory process;
- familial forms of HF with unidentified genetic defects;
- secondary hemophagocytic syndrome associated with infection;
- HLH-associated virus;
- HLH associated with bacterial infections;
- HFH associated with fungal infections;
- HLH associated with parasitic infections;
- HLH, which is associated with malignant neoplasms;
- CHLH associated with chemotherapy behavior (not associated with primary onset of malignancy);
- HLH associated with the development of rheumatic diseases;
- GLG,associated with transplant;
- HLH, which is associated with iatrogenic activation of the immune system;
- 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 to calcitonin, a hormonal compound produced primarily by C-cells in the thyroid gland.
Procalcitonin during metabolic processes decomposes into calcitonin, katacalcin and 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, what is most interesting, the change in the concentration of procalcitonin in hemophagocytic syndrome in children is especially pronounced.
This is a presumably fatal complication, which is based on dysregulation 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 the emergence of a systemic inflammatory response in the child. This disease belongs to the category of histiocytic, which develop from cells of the macrophage series. It is extremely important to carry out laboratory diagnostics to detect the level of procalcitonin andother 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 oncohematological diseases. The association of HPS of a secondary nature with a number of pathogens has been proven, which includes both viruses (herpesvirus, HIV, influenza A, parvovirus B19, adenovirus), bacteria (mycobacteria, salmonella, mycoplasma, rickettsia, pneumococcus), fungi and protozoa.
Herperviruses
Among the viruses most often associated with secondary hemophagocytic syndrome, herpesviruses are in the first place. At the same time, this disease is able to mimic a number of infectious diseases, such as visceral leishmaniasis, leptospirosis and sepsis.
HFS complex includes splenomegaly, fever, CNS damage, hepatitis, coagulation disorders, cytopenias, many biochemical markers. The above signs are rather non-specific, which significantly complicates the diagnosis of such a pathological condition, especially in the early stages, leading to an ambiguous life prognosis, especially in immunocompromised patients.
How are secondary and primary hemophagocytic syndrome diagnosed?
Diagnosis
Primary diagnosis of the disease includes the collection of anamnesis and patient complaints, as well as a physical examination. Further, the necessary laboratory diagnostics is carried out, in which it is necessary to clarifyblood levels of the following substances:
- bilirubin direct and total;
- ALT/ACT;
- LDG;
- albumin;
- sodium;
- triglycerides;
- ferritin;
- urea;
- creatinine.
In addition, a coagulogram, cerebrospinal fluid studies, cytometry, etc. are needed.
Instrumental diagnostics
Instrumental diagnostics includes:
- MRI of the brain with gadolinium contrast;
- CT lungs;
- Ultrasound of the abdominal cavity;
- 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 organ function, and perform hematopoietic stem cell transplantation. HSCT is the only curative therapy method. Next, immunosuppressive chemotherapy is carried out, combined with the use of medications: Dexamethasone, Methotrexate, Prednisolone, Cyclospogrin A, etc.
The duration of the treatment of hemophagocytic syndrome and the establishment of dosages is carried out by a doctor.
Transplantation
Modern tactics for the treatment of hereditary forms of lymphohistiocytosis include not only the above methods. The prognosis of the disease is significantly improved with the timely implementation of transplantation from a compatiblerelated donor. In case of bacterial, viral and parasitic infections that provoked the appearance of this syndrome, etiotropic antimicrobial therapy, high-dose immunoglobulin infusions, and immunosuppressive treatment are implemented. Sometimes a bone marrow transplant is indicated.
Prognosis for hemophagocytic syndrome
This is directly related to the neglect of the pathological process and its form. The primary syndrome is much more difficult to treat, and the chances of recovery are relatively few. An 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.
