Neutropenia is a reduced level of neutrophilic granulocytes in the total cellular composition of the blood to a level of less than 1500 / μL. The severity of the patient's condition and the risk of serious complications of infectious and bacterial origin directly depends of the severity of neutropenia.
To select effective treatment, it is necessary not only to establish the fact of neutrophil reduction under normal cell indices of other hematopoiesis, but also to establish reliably the etiopathogenetic mechanism of the occurrence of this dangerous state for the patient's health.
The incidence of severe neutropenia is no more than one episode per 150,000 population. The level of mortality from neutropenia of varying severity is in the range of 10-60%.
Severe forms of neutropenia, in which the level of neutrophilic granulocytes in the peripheral blood does not exceed 500 / μl, are extremely rare, but in the management of a patient with agranulocytosis, one should bear in mind the extremely high risk of inflammatory diseases caused by the patient's own endogenous flora.
Causes of neutropenia
In order to understand the pathogenetic mechanisms of neutropenia, it is necessary to consider the physiological processes of normal hematopoiesis and the proliferation of these vital blood cells. The entire life span of neutrophil granulocytes takes 15 days and is divided into three phases: proliferation in the main hematopoietic organ, free circulation in the peripheral blood stream, and if necessary in organs and tissues, and their physiological destruction.
Violation of each of these periods of vital activity of neutrophilic granulocytes can become a provocateur for the development of a particular form of neutropenia. So, the violation of proliferation and differentiation of granulocytes in the structure of the bone marrow can occur as a result of both a congenital defect, and with various autoimmune diseases, oncopathologies of different localization.
Due to the fact that a larger percentage of neutrophils are not in a free state in the flow of circulating blood, but in an adhesive wall to the vascular wall (the so-called marginal fraction of neutrophilic granulocytes), conditions for the development of pseudoneutropenia are created. This condition is characterized by a decrease in neutrophils in the circulating blood, although the overall level of neutrophilic granulocytes remains unchanged due to the large number of adherent neutrophils.
Isolated destruction of a large number of neutrophils occurs only when exposed to antileukocyte antibodies.
Neutropenia belongs to the category of polyethiologic syndromes, so it can act both as a primary condition and as a complication of other diseases. Congenital diseases accompanied by neutropenic syndrome are: cyclic neutropenia, congenital immunodeficiency, genetically conditioned agranulocytosis , accumulation diseases (acidemia, glycogenosis), myelocaecia, phenotypic anomalies (metaphyseal chondrodysplasia, congenital dyskeratosis ).
The acquired diseases accompanied by neutropenic syndrome include: autoimmune diseases (benign anemia in children , systemic lupus erythematosus , Vegera granulomatosis), bone marrow pathology ( aplastic anemia , metastasis with localization in the medullary canal, prolonged exposure to ionized radiation), diseases of the infectious nature (bacterial generalized sepsis, HIV and AIDS, cytomegalovirus lesion, tuberculosis of various localization).
A separate group of neutropenia is the so-called "dosage forms", which are provoked by the toxic effects of certain groups of medications (mercury diuretics, nonsteroidal anti-inflammatory drugs, antidepressants, antithyroid and antihistamines).
Symptoms of neutropenia
A typical clinical symptomatology with a neutropenic syndrome develops with a marked decrease in the neutrophilic granulocyte count in the peripheral blood and is manifested by symptoms similar to hypoplastic anemia.
The first characteristic symptom of neutropenia is necrotizing-ulcerous changes with localization in the oral cavity ( tonsillitis , stomatitis and gingivitis ), chest cavity (pneumonia with a tendency to abscess and pleural empyema), skin (subcutaneous abscesses, nail felon and intermuscular phlegmon), soft tissues pararectal localization (purulent paraproctitis in fistulous form).
In a situation where necrotic ulceration processes affect the small intestine, a clinic of necrotic enteropathy develops, which manifests itself by the appearance of acute pain in the abdominal cavity without clear localization, nausea and vomiting unrelated to food intake, and atony of the intestine with the patient's tendency to constipation . The danger of necrotic enteropathy lies in its propensity to develop complications that threaten the patient's life (intestinal perforation and peritonitis).
With the development of severe neutropenia, which provokes long-term use of anticonvulsant, sulfanilamide, hypensensibilizing and analgesic drugs, a bright clinical symptom complex with a sharp debut and a high degree of lethality is formed. This form of neutropenia refers to the immune agranulocytosis caused by the reaction of anti-leukocyte antibodies to its own neutrophilic granulocytes and manifests itself in acute fever, headache, aching pain in large joints and severe weakness. In various organs and tissues, ulceration with an inflammatory component (oral cavity, esophagus, vagina and intestine) appears up to the development of generalized septicemia. The duration of the acute period is 3-4 days and in 30% of cases ends in a lethal outcome.
Thus, in each patient who has frequent infectious diseases, especially those taking place in severe form, neutropenia should be suspected, especially in patients receiving radiotherapy or cytotoxic treatment.
At initial manifestations of neutropenia, there are no characteristic complaints of the patient, in this connection, it is necessary to pay special attention to an objective examination of the patient with mandatory examination of the oral cavity, skin, anus, catheterization and venipuncture of the central vessels, as well as palpation of the abdomen.
In addition to the characteristic clinical symptoms for establishing a reliable diagnosis of "neutropenia", it is very important to identify laboratory changes.
Special attention should be given to laboratory examination of patients with febrile fever, which implies not only a general blood count with granulocyte counting, but, if necessary, double blood culture for the presence of pathogenic bacteria and fungal attack. In postoperative patients it is necessary to examine the sowing of the contents from the drainage graduate, and in the presence of relaxation of the stool, it is recommended that the feces be tested for clostridial infection.
Of great importance in the diagnosis of neutropenia is the study of the hematopoietic function of the bone marrow, in which it is possible not only to assess the inhibition of one or another germ of the hematopoiesis, but also to determine the cause of its occurrence.
Neutropenia in children
Neutropenia in childhood appears as a manifestation of hypothyroidism in the bone marrow and in different ages the criteria for neutropenic syndrome differ. Thus, neutropenia in the infant occurs with a quantitative content of neutrophilic granulocytes in the blood of less than 1000 / μL of peripheral blood. In older age, the main sign of neutropenia is a decrease in the quantitative content of neutrophils less than 1500 / μl.
At the age of up to one year, neutropenia is most often acute or chronic (the clinical picture develops within a few months). Primary neutropenic syndromes are represented by three main forms: immune neutropenia, chronic benign neutropenia and genetically determined form.
If the neutropenic syndrome is poorly expressed, that is, the child has a slight decrease in the number of neutrophilic granulocytes in the peripheral blood, most often the asymptomatic course of the disease is noted. In some cases, there are frequent recurring episodes of acute respiratory viral diseases with a tendency to prolonged course and attachment of bacterial complications. As a rule, neutropenia data do not need specific treatment and are well suited for therapy with standard antiviral and antibacterial drugs.
Children's neutropenia of moderate severity is characterized by a tendency to recurrent purulent-septic diseases, up to the appearance of signs of infectious-toxic shock.
Severe neutropenia in childhood is always accompanied by severe intoxication syndrome, a hectic type of fever and severe purulent-destructive complications with localization in the thoracic, oral and abdominal cavities. Under the condition of improper treatment, this condition is quickly complicated by the development of signs of generalized sepsis, often resulting in a fatal outcome.
When establishing the diagnosis, the mandatory criteria are:
- determination of the fact of burdened heredity in this pathology;
- evaluation of clinical symptoms present in the child, as well as thorough primary objective examination;
- weekly evaluation of the hemogram with mandatory counting of all types of blood cells (in case of cyclic neutropenia, the hemogram is evaluated at least twice a week for two months);
- in the determination of moderate neutropenia it is advisable to perform the myelogram;
- In case of virus-associated neutropenia, a serum blood test is necessary to increase the titer of anti-granulocyte antibodies;
- in the presence of purulent necrotic foci, bacterial culture of the blood should be performed to determine the specific flora that provokes the neutropenic condition.
In childhood, not only secondary neutropenic conditions can be observed, but also primary hereditary neutropenia, each of which has its own flow characteristics and general features.
The general criteria characteristic of all hereditary neutropenia are: the fact of burdened heredity, the debut of clinical and laboratory manifestations during the first months of the child's life, genetic defects are revealed by molecular biological methods of diagnosis.
Severe forms of hereditary neutropenia include Costman's syndrome, which is characterized by autosomal recessive transmission of a defective gene, but sporadic morbidity may also occur. With this pathology, during the newborn period, the child has frequent episodes of bacterial and infectious diseases with a tendency to recurrent course.
With Costman's syndrome, there is a marked decrease in neutrophil granulocyte counts in the blood, up to the development of agranulocytosis (in 1 μl less than 300 neutrophils). Children with Costman's syndrome are at risk for acute myeloblastic leukemia and myeloplastic syndrome. The disease of Costman's syndrome is the rationale for the appointment of lifelong specific therapy with the use of colony-stimulating factors (filgrastim subcutaneously at a daily dose of 6 mcg / kg of the child's weight). In the case of ineffectiveness of colony-stimulating therapy, an allogeneic bone marrow transplantation is recommended for a sick child.
Another form of hereditary neutropenia, accompanied by a violation of the small activity of the release of neutrophilic granulocytes from the medullary canal, is the so-called "mielocaeca". This type of neutropenia is caused by associated changes, manifested in the accelerated apoptosis of granulocytes in the bone marrow and reduced chemotaxis. During the first year of life, the child has a relative neutropenia associated with severe eosinophilia and elevated levels of monocytes in the peripheral blood. When the bacterial infection is attached, a marked neutrophilic leukocytosis is observed, which is rapidly transformed into leukopenia .
A rare form of hereditary neutropenic syndrome, observed in childhood, is cyclic neutropenia, which is inherited exclusively recessively. The principal difference of this neutropenic syndrome from other forms of neutropenia is the intermittent flow with the presence of crises. This neutropenia is called "cyclical" because it has a clear timeframe for the debut of the next crisis (an average of 3-8 days) and a clear interictal period (2 weeks-3 months). Since the onset of the crisis, the child has bright clinical and laboratory signs in the form of a sharp drop in the number of neutrophilic granulocytes and simultaneous monocytosis and eosinophilia, the emergence of foci of infection of various locations with purulent contents. After the end of the neutropenic crisis, the child's general health and the parameters of the leukocyte blood formula are normalized.
The principal approaches to the treatment of cyclic neutropenia are the appointment of colony-stimulating factors two days before the anticipated onset of the crisis. The duration of a specific treatment depends on the rate of normalization of the granulocyte counts in the peripheral blood.
Febrile neutropenia or "neutropenic fever" is an acute severe condition for the patient, which develops in the case of a marked decrease in neutrophilic granulocytes in the peripheral blood.
Typical symptoms of febrile neutropenic syndrome are: febrile fever, severe chills, followed by increased sweating, increased heart rate and a simultaneous sharp decrease in arterial systolic pressure until signs of hypotensive shock develop.
In connection with the fact that in the human body there is a marked decrease in neutrophilic leukocytes responsible for the formation of an immune response and the formation of an inflammatory reaction, often the patient can not diagnose the primary focus of infection. And only with prolonged course of the disease, in conditions of pronounced immunosuppression, purulent-septic foci of different localization appear.
Febrile neutropenia is most often observed in patients who repeatedly underwent massive cytotoxic and radiation therapy used in malignant tumors and is regarded as a hyperergic reaction in response to the toxic effects of medications.
In patients suffering from febrile neutropenia, there is a severe course of infectious diseases that a healthy person does not cause a prolonged health disorder. In connection with the sharp suppression of immunity, in patients with febrile neutropenia there is a rapid spread of infection from the primary focus to all tissues and organs, thereby causing generalized sepsis.
The main pathogens of infection in febrile neutropenia are anaerobic microorganisms, clostridia and pathogenic Gram-positive cocci, as well as reinfection with herpes and cytomegalovirus viruses.
After determining the fact of a decrease in the level of neutrophilic granulocytes in combination with a pronounced intoxication syndrome, it is mandatory to take blood and biological fluids to determine the sensitivity to antibacterial drugs of various groups in order to select an appropriate and appropriate treatment regimen.
Antibacterial treatment of febrile neutropenia should adhere to combined treatment regimens based on the combined use of antibacterial agents that affect both the positive and gram-negative flora (Augmentin 375 mg 2 times per day orally, Medaxone 1 g 1 r / day intramuscularly, Gentamicin in daily dose of 2.4 mg / kg intravenously). Due to the fact that these antibacterial agents adversely affect both the pathogenic flora and its own useful intestinal microflora, thereby causing the spread of fungal infection, it is mandatory to use antifungal medicines (Fluconazole at a daily dose of 400 mg intravenously or orally).
The effectiveness of antibiotic empirical therapy is assessed, as a rule, within the first two days, and in the absence of positive dynamics of clinical and laboratory indicators, massive antifungal treatment should be prescribed (Amphotericin B in a daily dose of 0.25 mg / kg intravenously-drip).
The non-specific symptomatic treatment methods, which are used according to strict indications to alleviate the patient's condition and prevent possible complications, include granulocyte mass transfusion and injection of hyperimmune plasma by intravenous infusion.
Chronic benign neutropenia is a pathology of the blood that is observed exclusively in childhood with a duration of no more than two years and does not require the use of specific therapy.
Registration of changes in the blood test confirming neutropenia in the child is the justification for clinical monitoring by doctors of various profiles (hematologist, allergologist-immunologist, neonatologist, pediatrician). This pathology of blood does not cause severe health disorders and psychomotor development of the child.
There is no specific etiopathogenetic factor of the occurrence of benign neutropenia in childhood and the appearance of signs of changes in the white blood picture is usually associated with imperfection of the blood system due to insufficient maturity of the hematopoietic tissue.
In addition to the reduced quantitative content of neutrophilic granulocytes, no other changes are seen in the blood. Benign neutropenia is characterized not by a severe course and has a favorable prognosis for life in almost 100% of cases.
From medical methods of treatment of benign neutropenia, only antibacterial and antiviral regimens for medical use are used, the doses of which do not differ from the usual regimens used for bacterial and viral infections in young children.
Treatment of neutropenia
The choice of an appropriate method of treatment depends not only on the severity of the patient's condition, but also on the presence or absence of the alleged complications, and also on the individual characteristics of the organism. In determining the tactics of patient treatment, it is advisable to monitor the course of the disease around the clock, therefore, severe forms of neutropenia should be treated only in a hospital setting of the hematologic profile.
In a situation where there is a suspicion of a disease of an infectious nature, it is necessary to begin immediately etiopathogenetic treatment with antibacterial drugs in higher doses than with the same pathology without neutropenia. When choosing a suitable antibacterial drug should take into account the antimicrobial sensitivity of the most common pathogens of infectious diseases and their potential toxicity.
Most often, antibacterial agents are administered by the method of intravenous infusion through central venous access, but confirmation of bacteraemia provoked by golden staphylococcus a patient is an indication for removal of the venous catheter.
The duration of antibiotic therapy may be different, depending on the form of neutropenia, the causative agent of infection and the severity of neutropenia. The generally accepted criteria for the effectiveness of antibacterial treatment is the improvement of the patient's condition within the first 72 hours, and the absence of positive dynamics is the justification for changing the antibiotic or increasing the dose of the previously used antibacterial drug.
The transient form of neutropenia observed after the use of immunosuppressive therapy in cancer patients also requires antibacterial empirical treatment, the duration up to an increase in the neutrophilic granulocyte count of more than 500/1 μl.
Absence of positive dynamics of the patient's condition with antibacterial therapy can be caused by infections with resistant microorganisms, superinfection caused by two or more kinds of bacteria, insufficient serum and tissue levels of antibiotics or an infectious focus of limited localization (abscess).
Associated with antibiotic therapy, a long-term fever patient with neutropenia recommended the appointment of an antifungal treatment regimen (Amphotericin intravenously-drip 0.25 mg / kg per day). The use of antifungal drugs for prophylactic purposes is unreasonable and not justified in the treatment of neutropenia. Trimethoprim-sulfamethoxazole is used as an antibacterial agent used for prophylactic purposes for patients with mild neutropenia at a maximum daily dose of 100 mg, taking into account the possible manifestation of its side effects (candidiasis of the mucous membranes of the intestine and oral cavity, provocation of the resistance of microorganisms to antibacterial agents, myelosuppressive effect).
Recently, medical treatment of a severe form of neutropenia with the use of colony-stimulating factors has become widespread, especially with the febrile type of neutropenic syndrome. Also, the area of application of these drugs is the prevention of possible infectious complications in patients who have recently undergone bone marrow transplantation. The drugs of choice in this situation are colony-stimulating factors with proven efficacy (Filgrastim 5 mg / 1 kg of body weight per day intravenously, Molgrimostin in a daily dose of 5 μg / kg subcutaneously) that are used before the normalization of neutrophilic granulocyte counts in the blood.
Also in the complex treatment of neutropenia is the use of symptomatic drugs that do not themselves affect the process of improving the proliferation and maturation of neutrophils, but which affect the process of their distribution and decay. Drugs of this group include glucocorticoid hormones (hydrocortisone in a daily dose of 250 mg), drugs that improve metabolic processes in the body (Pentoxyl at a daily dose of 600 mg orally, Leucogen 0,02 g 3 r / day, Methyluracil 2 g / day ), as well as Folic acid with the calculation of a daily dose of 1 mg / 1 kg of body weight.
From operational therapies for neutropenia due to increased destruction of neutrophilic granulocytes in the spleen, a splenectomy is indicated. Absolute contraindications to the product of this operation is a severe degree of neutropenic syndrome and a generalized infectious process.