Neutropenia (agranulocytosis, granulocytopenia)

Neutropenia (agranulocytosis, granulocytopenia) is a decrease in the number of neutrophils (granulocytes) in the blood. With severe neutropenia, the risk and severity of bacterial and fungal infections are increased. Symptoms of infection may be subtle, but fever is present with most serious infections. The diagnosis is made by counting the white blood cell count, but the cause of neutropenia must also be determined. The presence of fever suggests infection and the need for empirical broad-spectrum antibiotics. Treatment with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor is effective in most cases.

Neutrophils are the body's main defense 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 neutrophil level (the total number of segmented and band neutrophils) in white people is 1500/μl, slightly lower in black people (about 1200/μl).

The severity of neutropenia is associated with the relative risk of infection and is classified as mild (1000-1500/μl), moderate (500-1000/μl), and severe (< 500/μl). When the neutrophil count drops below 500/μl, endogenous microbial flora (e.g., oral or gastrointestinal) may cause infection. When the neutrophil count drops below 200/μl, the inflammatory response may be absent. Acute severe neutropenia, especially in the presence of concomitant factors (e.g., cancer), also has a negative effect on the immune system and predisposes to the development of a rapidly fatal infection. The integrity of the skin and mucous membranes, tissue blood supply, and the patient's energy status affect the risk of infectious complications. The most common infectious complications in patients with deep neutropenia are subcutaneous tissue inflammation, 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 common pathogens are coagulase-negative staphylococci and Staphylococcus aureus. Stomatitis, gingivitis, paraproctitis, colitis, sinusitis, paronychia, and otitis media are common. Patients with prolonged neutropenia after bone marrow transplantation or chemotherapy, as well as those receiving high doses of glucocorticoids are predisposed to the development of fungal infections.

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Causes of Neutropenia

Acute neutropenia (developing over hours or days) may result from rapid consumption, destruction, or impaired production of neutrophils. Chronic neutropenia (lasting months to years) is usually due to decreased cell production or excess sequestration in the spleen. Neutropenia may be classified as primary, due to an intrinsic deficiency of myeloid cells in the bone marrow, or secondary, due to external factors affecting bone marrow myeloid cells.

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

This type of neutropenia is uncommon. Cyclic neutropenia is a rare congenital granulocytopoietic disorder transmitted in an autosomal dominant manner. It is characterized by regular, periodic fluctuations in the number of peripheral neutrophils. The average period of fluctuations is 21+3 days.

Severe congenital neutropenia (Kostmann syndrome) is a rare disease that occurs sporadically and is characterized by a disruption of myeloid maturation in the bone marrow at the promyelocyte stage, resulting in an absolute neutrophil count of less than 200/μl.

Chronic idiopathic neutropenia is a group of rare and poorly understood disorders involving stem cells committed to the myeloid lineage; the red blood cell and platelet lineages are spared. The spleen is not enlarged. Chronic benign neutropenia is a subtype of chronic idiopathic neutropenia in which other immune functions remain intact, even with neutrophil counts below 200/μL; serious infections are usually uncommon, probably because adequate neutrophils are sometimes produced in response to infection.

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

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Symptoms of agranulocytosis

Neutropenia does not manifest until infection occurs. Fever is often the only sign of infection. Local symptoms may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may present with fever, rash, and lymphadenopathy.

Some patients with chronic benign neutropenia and neutrophil counts less than 200/μL may not have serious infections. Patients with cyclic neutropenia or severe congenital neutropenia often have oral ulcers, stomatitis, pharyngitis, and lymphadenopathy during the period of severe chronic neutropenia. Pneumonia and septicemia are common.

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Classification of neutropenia

Classification category	Etiology
Neutropenia due to intrinsic deficiency of bone marrow maturation of myeloid cells or their precursors	Aplastic anemia. Chronic idiopathic neutropenia, including benign neutropenia. Cyclic neutropenia. Myelodysplasia. Neutropenia associated with dysgammaglobulinemia. Paroxysmal nocturnal hemoglobinuria. Severe congenital neutropenia (Kostmann syndrome). Syndrome-associated neutropenia (eg, dyskeratosis congenita, glycogen storage disease type 1B, Shwachman-Diamond syndrome)
Secondary neutropenia	Alcoholism. Autoimmune neutropenia, including chronic secondary neutropenia in AIDS. Bone marrow replacement in cancer, myelofibrosis (eg, due to granuloma), Gaucher disease. Cytotoxic chemotherapy or radiation. Drug-induced neutropenia. Vitamin B12 or folate deficiency. Hypersplenism. Infections. T-lymphoproliferative disorder

Secondary neutropenia

Secondary neutropenia may result from the use of certain medications, bone marrow infiltration or replacement, infections, or immune reactions.

Drug-induced neutropenia is the most common cause of neutropenia, which may involve decreased neutrophil production due to toxicity, idiosyncrasy, hypersensitivity, or increased destruction of neutrophils in the peripheral blood by immune mechanisms. In toxic neutropenia, there is a dose-dependent effect in response to medication (eg, phenothiazines). Idiosyncratic reactions occur unpredictably and can occur with a wide range of drugs, including alternative medicines, extracts, and toxins. Hypersensitivity reactions are rare events and sometimes occur with anticonvulsants (eg, phenytoin, phenobarbital). These reactions may last for days, months, or years. Hepatitis, nephritis, pneumonia, or aplastic anemia are often accompanied by neutropenia induced by a hypersensitivity reaction. Immune drug-induced neutropenia occurs with drugs that have haptenic properties and stimulate antibody formation and usually lasts about 1 week after stopping the medication. Immune neutropenia is caused by drugs such as aminopyrine, propylthiouracil, penicillins, or other antibiotics. Severe dose-dependent neutropenia predictably occurs after the use of cytotoxic antineoplastic drugs or radiation therapy that suppress bone marrow hematopoiesis. Neutropenia due to ineffective hematopoiesis may occur in megaloblastic anemia caused by vitamin B12 and folate deficiency _. Macrocytic anemia and sometimes thrombocytopenia usually develop simultaneously.

Bone marrow infiltration from leukemia, multiple myeloma, lymphoma, or metastasis from solid tumors (eg, breast cancer, prostate cancer) may impair neutrophil production. Tumor-induced myelofibrosis may further exacerbate neutropenia. Myelofibrosis may also occur with granulomatous infections, Gaucher disease, and radiation therapy. Hypersplenism from any cause may result in mild neutropenia, thrombocytopenia, and anemia.

Infections may cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid consumption of neutrophils. Sepsis is the most serious cause of neutropenia. The neutropenia that occurs with typical childhood viral infections develops within the first 1 to 2 days and may last 3 to 8 days. Transient neutropenia may result from viral or endotoxin-induced redistribution of neutrophils from the circulation to a local pool. Alcohol may contribute to neutropenia by inhibiting the bone marrow neutrophil response during infections (eg, pneumococcal pneumonia).

Chronic secondary neutropenia often accompanies HIV, as there is damage to production and increased destruction of neutrophils by antibodies. Autoimmune neutropenia may be acute, chronic, or episodic. Antibodies may be directed against the neutrophils themselves or their bone marrow precursors. Most patients with autoimmune neutropenia have autoimmune or lymphoproliferative diseases (eg, SLE, Felty's syndrome).

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Diagnosis of neutropenia

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

The priority task is to confirm the presence of infection. Since the infection may have subtle signs, a systematic examination of the most frequently affected areas is necessary: the mucous membranes of the digestive tract (oral cavity, pharynx, anus), lungs, abdomen, urinary tract, skin and fingernails, sites of venipuncture and vascular catheterization.

In acute neutropenia, rapid laboratory evaluation is necessary. In patients with fever, blood cultures for bacterial and fungal cultures should be performed at least twice; if a venous catheter is present, blood for culture is taken from the catheter and separately from a peripheral vein. In the presence of permanent or chronic drainage, material for microbiological cultivation of atypical mycobacteria and fungi is also necessary. Material for cytological and microbiological examination is taken from skin lesions. Urinalysis, urine culture, and chest radiography are performed in all patients. In the presence of diarrhea, stool examination for pathogenic enterobacteria and Clostridium difficile toxins is necessary.

If you have symptoms or signs of sinusitis (eg, positional headache, pain in the upper jaw or upper teeth, swelling in the facial area, nasal discharge), an x-ray or CT scan may be helpful.

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

The detection of antineutrophil antibodies suggests the presence of immune neutropenia. In patients at risk of developing vitamin B12 and folate deficiency, _their blood levels are determined. The most important is the bone marrow examination, which determines whether the neutropenia is due to decreased neutrophil production or is secondary to increased cell destruction or consumption (normal or increased neutrophil production). Bone marrow examination may also indicate a specific cause of neutropenia (eg, aplastic anemia, myelofibrosis, leukemia). Additional bone marrow studies are performed (eg, cytogenetic analysis, special stains, and flow cytometry for the diagnosis of leukemia, other cancers, and infections). In patients with chronic neutropenia since childhood, recurrent fever, and a history of chronic gingivitis, a white blood cell count with differential should be obtained 3 times weekly for 6 weeks to determine whether cyclic neutropenia is present. Platelet and reticulocyte counts should be obtained at the same time. Eosinophil, reticulocyte, and platelet levels often cycle synchronously with neutrophil levels, whereas monocytes and lymphocytes may cycle differently. Other tests to determine the cause of neutropenia depend on the suspected diagnosis. Differentiating between neutropenia caused by certain antibiotics and infection can be difficult. The white blood cell count before starting antibiotic therapy usually reflects changes in the blood caused by the infection. If neutropenia develops during treatment with a drug known to induce neutropenia (eg, chloramphenicol), switching to an alternative antibiotic is often helpful.

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Treatment of agranulocytosis

Treatment of acute neutropenia

If infection is suspected, treatment should be started promptly. If fever or hypotension is detected, serious infection is assumed and high-dose broad-spectrum antibiotics are given empirically. Antibiotic selection is based on the presence of the most likely infecting organisms, antimicrobial susceptibility, and toxicity potential of the regimen. Because of the risk of resistance, vancomycin is used only when gram-positive organisms are suspected of being resistant to other drugs. If an indwelling venous catheter is present, it is usually left in place even if bacteremia is suspected or proven, but removal should be considered if organisms such as S. aureus, Bacillus, Corynebacterium, Candida sp are present or if blood cultures are persistently positive despite adequate antibiotic therapy. Infections due to coagulase-negative staphylococci usually respond well to antimicrobial therapy.

If a positive bacterial culture is present, antibiotic therapy is adjusted according to susceptibility testing. If the patient shows positive dynamics within 72 hours, antibiotic therapy is continued for at least 7 days, until complaints and symptoms of infection disappear. In transient neutropenia (eg, after myelosuppressive therapy), antibiotic therapy is usually continued until the neutrophil count exceeds 500 μL; however, discontinuation of antimicrobial therapy may be considered in selected patients with persistent neutropenia, especially when symptoms and signs of inflammation resolve and bacterial cultures are negative.

If fever persists for more than 72 hours despite antibiotic therapy, a nonbacterial cause of fever, infection with a resistant species, superinfection with two bacterial species, inadequate serum or tissue antibiotic levels, or a localized infection such as an abscess are considered. Neutropenic patients with persistent fever should be evaluated every 2 to 4 days with physical examination, bacterial culture, and chest radiography. If the patient's condition improves except for fever, the original antibiotic regimen can be continued. If the patient's condition worsens, an alternative antibiotic regimen is considered.

A fungal infection is the most likely cause of persistent fever and deterioration in the patient's condition. Antifungal therapy (eg, itraconazole, voriconazole, amphotericin, fluconazole) is added empirically if fever persists unexplained after 4 days of broad-spectrum antibiotic therapy. If fever persists after 3 weeks of empirical therapy (including 2 weeks of antifungal therapy) and neutropenia resolves, discontinuation of all antibacterial agents and reassessment of the cause of fever are considered.

Prophylactic antibiotic administration in afebrile patients with neutropenia remains controversial. Trimethoprim-sulfamethoxazole (TMP-SMX) provides prophylaxis against Pneumcystis jiroveci (formerly P. carinii) pneumonia in patients with neutropenia and impaired cell-mediated immunity. In addition, TMP-SMX prevents bacterial infections in patients expected to have profound neutropenia for more than 1 week. The disadvantages of TMP-SMX include adverse effects, potential myelosuppressive effects, development of resistant bacteria, and oral candidiasis. Routine antifungal prophylaxis is not recommended in patients with neutropenia, but may be useful in patients at high risk for fungal infections (eg, after bone marrow transplantation and after high-dose glucocorticoid therapy).

Myeloid growth factors [granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)] are now widely used to increase neutrophil counts and prevent infections in patients with severe neutropenia (eg, after bone marrow transplantation and intensive chemotherapy). They are expensive. However, if the risk of developing febrile neutropenia is >30%, growth factors are indicated (assessed by neutrophil count <500/μL, presence of infections during previous chemotherapy courses, presence of comorbidities, or age >75 years). In general, the greatest clinical benefit is achieved when growth factors are administered within 24 hours after completion of chemotherapy. Myeloid growth factors are indicated in patients with neutropenia due to an idiosyncratic drug reaction, especially if a delay in recovery is expected. The dose of G-CSF is 5 mcg/kg subcutaneously once a day; for GM-CSF 250 mcg/m2 ^{subcutaneously} once a day.

Glucocorticoids, anabolic steroids and vitamins do not stimulate neutrophil production, but may affect their distribution and destruction. If there is a suspicion of acute neutropenia in response to a drug or toxin, all potential allergens are discontinued.

Rinsing with saline or hydrogen peroxide every few hours, pain-relieving tablets (benzocaine 15 mg every 3 or 4 hours), or rinsing with chlorhexidine (1% solution) 3 or 4 times daily may relieve discomfort caused by stomatitis or ulcers in the mouth and pharynx. Oral or esophageal candidiasis is treated with nystatin (400,000-600,000 IU by mouth irrigation or by swallowing for esophagitis) or systemic antifungals (eg, fluconazole). During stomatitis or esophagitis, a soft, liquid diet is necessary to minimize discomfort.

Treatment of chronic neutropenia

Neutrophil production in congenital cyclic or idiopathic neutropenia can be enhanced by G-CSF at a dose of 1 to 10 mcg/kg subcutaneously daily. The effect can be maintained by daily or every other day administration of G-CSF for months or years. Patients with inflammation of the mouth and pharynx (even mild), fever, or other bacterial infections require appropriate antibiotics. Long-term administration of G-CSF may be used in other patients with chronic neutropenia, including myelodysplasia, HIV, and autoimmune diseases. In general, neutrophil levels are increased, although the clinical benefit is unclear, particularly in patients without severe neutropenia. Cyclosporine may be effective in patients with autoimmune neutropenia or after organ transplantation.

In some patients with increased neutrophil destruction due to autoimmune diseases, glucocorticoids (usually prednisolone at 0.5-1.0 mg/kg orally once daily) increase blood neutrophil levels. This increase can often be maintained by alternate-day administration of G-CSF.

Splenectomy increases neutrophil levels in some patients with splenomegaly and neutrophil sequestration in the spleen (eg, Felty syndrome, hairy cell leukemia). However, splenectomy is not recommended in patients with severe neutropenia (< 500/μL) and severe inflammatory processes, as this procedure leads to the development of infectious complications with encapsulated microorganisms.