Neutropenia (agranulocytosis, granulocytopenia)

Neutropenia (agranulocytosis, granulocytopenia) is a decrease in the number of blood neutrophils (granulocytes). In severe neutropenia, the risk and severity of bacterial and fungal infections increase. Symptoms of infection may be implicit, but fever manifests itself in most serious infections. The diagnosis is determined by counting the number of leukocytes, but it is also necessary to determine the cause of neutropenia. The presence of fever suggests the presence of infection and the need for the empirical administration of broad-spectrum antibiotics. Treatment with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor is effective in most cases.

Neutrophils are the main protective factor of the body against bacterial and fungal infections. In neutropenia, the body’s inflammatory response to this type of infection is ineffective. The lower limit of the normal level of neutrophils (the total number of segmented and rod neutrophils) in people of the white race is 1500 / μl, slightly lower in people of the black race (about 1200 / μl).

The severity of neutropenia is associated with the relative risk of developing an infection and is distributed as follows: mild (1000–1500 / μl), moderate (500–1000 / μl), and severe (<500 / μl). By reducing the number of neutrophils less than 500 / μl, the endogenous microbial flora (for example, the oral cavity or gastrointestinal tract) can cause the development of infection. If neitrophils decrease to less than 200 / μl, there may be no inflammatory response. Acute severe neutropenia, especially in the presence of concomitant factors (for example, cancer), also adversely affects the immune system, predisposes to the development of a transient fatal infection. The integrity of the skin and mucous membranes, the blood supply to the tissues and the energy status of the patient affect the risk of developing infectious complications. The most common infectious complications in patients with deep neutropenia are inflammation of the subcutaneous tissue, liver abscess, furunculosis and septicemia. The presence of catheters in the vessels, puncture sites are an additional risk factor for the development of infections, among which the most frequent pathogens are coagulase-negative staphylococci and Staphylococcus aureus. Often there are stomatitis, gingivitis, paraproctitis, colitis, sinusitis, paronychia, otitis media. Patients with prolonged neutropenia after bone marrow transplantation or chemotherapy, as well as receiving large doses of glucocorticoids are predisposed to the development of fungal infections.

[1]

Causes of Neutropenia

Acute neutropenia (formed over several hours or days) can develop as a result of rapid consumption, destruction or impairment of the production of nitrophils. Chronic neutropenia (lasting for months and years) is usually due to a decrease in cell production or excessive sequestration in the spleen. Neutropenia can be classified as primary in the presence of an internal deficiency of myeloid cells in the bone marrow or as secondary (due to the influence of external factors on bone marrow myeloid cells).

[2], [3]

Neutropenia due to an internal defect of bone marrow maturation of myeloid cells or their precursors

This type of neutropenia occurs infrequently. Cyclic neutropenia is a rare congenital granulocytopoietic disease transmitted in an autosomal dominant manner. It is characterized by regular, periodic fluctuations in the number of peripheral nitrophils. On average, the oscillation period is 21 + 3 days.

Severe congenital neutropenia (Kostmann syndrome) is a rare disease, sporadically manifested and characterized by impaired myeloid maturation in the bone marrow at the promyelocyte stage, which leads to a decrease in the absolute number of nitrophils less than 200 / μl.

Chronic idiopathic neutropenia is a group of rare and currently incomprehensible diseases involving stem cells committed in the myeloid direction of development; erythrocyte and platelet sprouts are not affected. The spleen is not enlarged. Chronic benign neutropenia is one of the subtypes of chronic idiopathic neutropenia, in which the remaining functions of the immune system remain undisturbed, even if the number of nitrophils is less than 200 / μl, serious infections usually do not occur, probably because an adequate number of nitrophils is sometimes produced in response to infection.

Neutropenia can also be the result of bone marrow failure in rare syndromes (for example, congenital dyskeratosis, type I glycogenosis, Shwachman-Diamond syndrome, Chediak-Higashi syndrome). Neutropenia is a characteristic feature of myelodysplasia (in which it can be accompanied by megaloblastoid changes in the bone marrow), aplastic anemia, and can occur with dysgammaglobulinemia and paroxysmal nocturnal hemoglobinuria.

[4], [5], [6], [7]

Symptoms of agranulocytosis

Neutropenia does not appear until the infection joins. Fever is often the only sign of infection. Local symptoms may develop, but are often subtle. In patients with drug-induced neutropenia, caused by hypersensitivity, fever, rash, lymphadenopathy can be detected.

Some patients with chronic benign neutropenia and a neutrophil count of less than 200 / µL may not have serious infections. Patients with cyclic neutropenia or severe congenital neutropenia often have oral ulcerations, stomatitis, pharyngitis, and lymph node enlargement during a period of severe chronic neutropenia. Often there are pneumonia and septicemia.

[8], [9], [10]

Neutropenia classification

Classification category	Etiology
Neutropenia due to internal deficiency of bone marrow maturation of myeloid cells or their precursors	Aplastic anemia. Chronic idiopathic neuropropenia, including benign neutropenia. Cyclic neutropenia. Myelodysplasia. Neutropenia associated with dysgammaglobulinemia. Paroxysmal night hemoglobinuria. Severe congenital neitropenia (Kostmann syndrome). Syndrome-associated neutropenia. (for example, congenital dyskeratosis, type 1B glycogenosis, Schwachman-Diamond syndrome)
Secondary Neutropenia	Alcoholism. Autoimmune neutropenia, including chronic secondary neutropenia in AIDS. Bone marrow replacement in cancer, myelofibrosis (for example, due to granuloma), Gaucher disease. Cytotoxic chemotherapy or radiation. Drug-induced neutropenia. Vitamin B 12 or folic acid deficiency. Hypersplenism. Infections. T-lymphoproliferative disease

Secondary neutropenia

Secondary neuropenia can result from the use of certain medications, bone marrow infiltration or replacement, infections or immune responses.

Drug-induced neutropenia is the most common cause of neutropenia, in which neutrophil production may decrease as a result of toxicity, idiosyncrasy, hypersensitivity, or increased destruction of neutrophils in peripheral blood through immune mechanisms. With the toxic mechanism of neutropenia, there is a dose-dependent effect in response to taking medications (for example, when using phenothiazines). The reaction of idiosyncrasy occurs unpredictably and is possible with the use of a wide range of drugs, including alternative medications, as well as extracts and toxins. A hypersensitivity reaction is a rare event, and sometimes occurs when using anticonvulsants (for example, phenytoin, phenobarbital). These reactions can last several days, months or years. Often, hepatitis, nephritis, pneumonia, or aplastic anemia are accompanied by neutropenia induced by a hypersensitivity reaction. Immune drug-induced neurotropia occurs when drugs are used that have hapten properties and stimulate the formation of antibodies, and usually lasts about 1 week after the end of medication. Such drugs as aminopyrin, propylthiouracil, penicillins or other antibiotics cause immune neutropenia. Severe dose-dependent neitropia is predictably manifested after the use of cytotoxic anticancer drugs or radiation therapy, which inhibit bone marrow hematopoiesis. Neutropenia due to ineffective hematopoiesis can occur with megaloblastic anemia caused by a deficiency of vitamin B ₁₂ and folic acid. Macrocytic anemia and sometimes thrombocytopenia usually develop simultaneously.

Bone marrow infiltration in leukemia, multiple myeloma, lymphoma, or metastases of solid tumors (for example, breast cancer, prostate cancer) can interfere with neutrophil production. Tumor-induced myelofibrosis may further enhance neutropenia. Myelofibrosis can also occur in granulomatous infections, Gaucher disease and radiation therapy. Any cause of hypersplenism can lead to moderate neutropenia, thrombocytopenia and anemia.

Infections can cause neutropenia, damaging the production of neutrophils or inducing immune destruction or rapid consumption of neutrophils. Sepsis is the most serious cause of neutropenia. Neutropenia, which occurs with typical childhood viral infections, develops during the first 1-2 days and can last from 3 to 8 days. Transient neutropenia can result from viral or endotoxin-induced redistribution of neutrophils from circulation to the local pool. Alcohol can contribute to the development of neutropenia by inhibiting the neutrophilic response of the bone marrow during infections (for example, pneumococcal pneumonia).

Chronic secondary neutropenia often accompanies HIV, as there is damage to the production and an increase in the destruction of neutrophils by antibodies. Autoimmune neutropenia can be acute, chronic or episodic. Antibodies can be directed against neutrophils themselves or their bone marrow progenitors. Most patients with autoimmune neutropenia have autoimmune or lymphoproliferative diseases (for example, SLE, Felty syndrome).

[11], [12], [13]

Diagnosis of neutropenia

Neutropenia is suspected in patients with frequent, severe, or unusual infections, or in patients with risk factors for developing neutropenia (for example, receiving cytotoxic or radiation therapy). The diagnosis is confirmed after performing a complete blood count.

The priority is to confirm the presence of infection. Since the infection can have subtle signs, a systematic examination of the most frequently affected areas is needed: mucous membranes of the digestive tract (mouth, pharynx, anus), lungs, stomach, urethra, skin and fingernails, venipuncture sites and vascular catheterization.

In acute neutropenia, rapid laboratory evaluation is required. In patients with febrile temperature, blood cultures should be performed for bacterial and fungal cultures at least 2 times; in the presence of a venous catheter, blood for seeding is taken from the catheter and separately from the peripheral vein. In the presence of permanent or chronic drainage, a material is also required for the microbiological cultivation of atypical mycobacteria and fungi. Material for cytological and microbiological examination is taken from skin lesions. Urinalysis, urine culture, lung radiography is performed in all patients. In the presence of diarrhea, feces should be examined for pathogenic enterobacteria and Clostridium difficile toxins .

If there are symptoms or signs of sinusitis (for example, positional headache, pain in the upper jaw or upper teeth, swelling in the face, nasal discharge), radiography or computed tomography may be useful.

The next step is to determine the cause of neutropenia. Anamnesis is being studied: what drugs or other drugs, and possibly poisons, was taken by the patient. A patient is examined for splenomegaly or signs of other diseases (for example, arthritis, lymphadenopathy).

Detection of antineutrophil antibodies suggests the presence of immune neutropenia. Patients at risk of developing vitamin B ₁₂ deficiency and folic acid determine their blood levels. The most important is the study of the bone marrow, which determines whether neutropenia is due to a decrease in neutrophil production or is secondary in nature and is caused by increased destruction or consumption of cells (establish a normal or elevated level of neutrophil formation). A bone marrow examination may also indicate a specific cause of neutropenia (for example, aplastic anemia, myelofibrosis, leukemia). Additional bone marrow studies are being conducted (for example, cytogenetic analysis, special staining and flow cytometry for the diagnosis of leukemia, other oncological diseases and infections). In the presence of chronic neutropenia from childhood, recurrent episodes of fever and chronic gingivitis in history, leukocyte count with leukocyte formula 3 times a week for 6 weeks is necessary to determine the possible presence of cyclic neutropenia. At the same time the number of platelets and reticulocytes is determined. The levels of eosinophils, reticulocytes and platelets often change synchronously with the level of neutrophils, while monocytes and lymphocytes may have a different cycle. Conducting other studies to determine the cause of neutropenia depends on what the expected diagnosis. Differential diagnosis between neutropenia caused by the use of certain antibiotics and infection can be quite difficult. The level of white blood cells before the start of antibiotic therapy usually reflects changes in the blood caused by infection. If neutropenia develops during treatment with a drug capable of inducing neutropenia (for example, chloramphenicol), switching to an alternative antibiotic is often helpful.

[14],

Treatment of agranulocytosis

Treatment of acute neutropenia

If an infection is suspected, treatment should begin immediately. In cases of detection of fever or hypotension suggest the presence of a serious infection and prescribe large doses of broad-spectrum antibiotics according to the empirical scheme. The selection of antibiotics is based on the presence of the most likely infectious microorganisms, antimicrobial sensitivity and potential toxicity of the regimen. Because of the risk of developing resistance, vancomycin is used only with the supposed resistance of gram-positive microorganisms to other drugs. In the presence of a permanent venous catheter, it is usually not removed, even if there is suspicion or proven bacteremia, but the expediency of its extraction should be considered in the presence of such pathogens as S. aureus, Bacillus, Corynebacterium, Candida sp, or in constantly positive blood cultures, despite adequate antibiotic therapy. Coagulase-negative staphylococcal infections are usually well treated with antimicrobial therapy.

If there is a positive bacterial culture, antibiotic therapy is selected in accordance with the sensitivity tests of microorganisms. If a patient has a positive trend within 72 hours, antibiotic therapy is continued for at least 7 days, until complaints and symptoms of infection disappear. With transient neutropenia (for example, after myelosuppressive therapy), antibiotic therapy is usually continued until the number of neutrophils exceeds 500 μl; however, discontinuation of antimicrobial therapy may be discussed in individual patients with persistent neutropenia, especially when resolving the symptoms and signs of inflammation and with negative results of bacterial culture.

If the fever persists for more than 72 hours, despite antibiotic therapy, a non-bacterial cause of fever, infection with a resistant type of microorganisms, superinfection with two bacterial types, inadequate serum or tissue levels of antibiotics, or localized infection, such as abscess, are suggested. Patients with neutropenia and persistent fever should be examined every 2–4 days with an external examination, bacterial culture and chest X-ray. With the improvement of the patient's condition, with the exception of fever, the initial mode of antibiotics can be continued. When the patient's condition deteriorates, an alternative antibacterial regimen is considered.

The presence of a fungal infection is the most likely cause of the preservation of the fever and the deterioration of the patient. Antifungal therapy (for example, itraconazole, voriconazole, amphotericin, fluconazole) is added empirically, with inexplicable persistence of fever after 4 days of broad-spectrum antibiotic therapy. When fever persists after 3 weeks of empirical therapy (including 2 weeks of antifungal therapy) and when neutropenia is resolved, the question of discontinuing all antibacterial drugs and revising the cause of fever is considered.

The prophylactic administration of antibiotics in patients with neurotropia and without fever remains controversial. Trimethoprim-sulfamethoxazole (TMP-SMX) provides prophylaxis of pneumonia caused by Pneumcystis jiroveci (formerly P. Carinii) in patients with nitropenia and with impaired cellular immunity. In addition, TMP-SMX prevents the development of bacterial infections in patients who are expected to develop deep neutropenia for more than 1 week. The disadvantage of TMP-SMX is the development of side effects, potentially myelosuppressive action, the development of resistant bacteria, oral candidiasis. Antifungal routine prophylaxis is not recommended for patients during neutropenia, but for patients who are at high risk of developing a fungal infection (for example, after bone marrow transplantation and after taking high doses of glucocorticoids), it may be useful.

Myeloid growth factors [granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)] are now widely used to increase the level of neutrophils and prevent infections in patients with severe neutropenia (for example, after bone marrow transplantation and intensive chemotherapy). These are expensive drugs. However, if the risk of developing febrile neutropenia is> 30%, the prescription of growth factors is indicated (estimated when the number of neutrophils is <500 / μl, the presence of infections during previous chemotherapy courses, the presence of concomitant diseases, or age> 75 years). In general, the greatest clinical effect is achieved when prescribing growth factors within 24 hours after completion of chemotherapy. Myeloid growth factors are shown to patients with neurophenia, caused by the development of idiosyncrasy on drugs, especially if a delay in recovery is expected. The dose of G-CSF is 5 μg / kg subcutaneously 1 time per day; for GM-CSF 250 µg / m ² subcutaneously 1 time per day.

Glucocorticoids, anabolic steroids and vitamins do not stimulate the production of neutrophils, but can affect their distribution and destruction. If you suspect the development of acute neutropenia in response to a drug or toxin, all potential allergens are canceled.

Rinsing with saline or hydrogen peroxide every few hours, pain pills (benzocaine 15 mg after 3 or 4 hours) or rinsing with chlorhexidine (1% solution) 3 or 4 times a day alleviate the discomfort caused by stomatitis or ulceration in the mouth and throat. Candidiasis of the oral cavity or esophagus is treated with nystatin (400 000-600 000 IU oral irrigation or ingestion with esophagitis) or systemic use of antifungal agents (for example, fluconazole). During stomatitis or esophagitis, a gentle, liquid diet is needed to minimize discomfort.

Treatment of chronic neutropenia

Production of neutrophils with congenital cyclic or idiopathic neutropenia can be enhanced by prescribing G-CSF at a dose of 1 to 10 µg / kg sc daily. The effect can be supported by prescribing daily or every other day for G-CSF for several months or years. Patients with inflammation in the mouth and pharynx (even a small degree), fever, other bacterial infections need to receive appropriate antibiotics. Long-term administration of G-CSF can be used in other patients with chronic neutropenia, including myelodysplasia, HIV and autoimmune diseases. In general, neutrophil levels increase, although clinical efficacy is not clear enough, especially in patients who do not have severe neutropenia. In patients with autoimmune neutropenia or after organ transplantation, cyclosporine administration can be effective.

In some patients with increased neutrophil destruction caused by autoimmune diseases, glucocorticoids (usually prednisolone at a dose of 0.5-1.0 mg / kg orally once a day) increase the level of blood neutrophils. This increase can often be supported by the appointment of G-CSF every other day.

Splenectomy increases the level of neutrophils in some patients with splenomegaly and sequestration of neutrophils in the spleen (for example, Felty's syndrome, hairy cell leukemia). However, splenectomy is not recommended for patients with severe neutropenia (<500 / µl) and serious inflammatory processes, since this procedure leads to the development of infectious complications with encapsulated microorganisms.