Neutropenia

Neutropenia is defined as ANC less than 1800 cells^L, approximately 2 SD below the mean, and includes both mature PMN and band forms. Some ethnic populations, such as those of African descent or Yemenite Jews, may have a lower total WBC count and ANC that can be normal at 1000 neutrophils/^. The primary concern with neutropenia is the risk of infection. Severe infection does not usually occur unless ANC is less than 500 cells^L (Table 39-5). When severe neutropenia occurs, patients are at risk for serious infection from breaks in cutaneous or mucosal barriers in areas such as the GI tract or oropharynx. If they are taking corticosteroids, the risk of infection in the presence of neu-tropenia is greatly enhanced because of the steroidal effect on immune responsiveness.

As with RBC disorders, neutropenia can be classified as production disorders, maturation disorders, and increased destruction disorders (Box 39-4). Production disorders may be congenital or caused by genetic abnormalities, such as cyclic neutropenia, characterized by recurrent mouth infec-

Table 39-5 Relation of Absolute Neutrophil Count (ANC) to Risk of Infection

ANC (cells/^L)

Risk/Management

>1500

None.

1000-1500

No significant risk of infection; fever can be managed on outpatient basis

500-1000

Some risk of infection; fever can occasionally be managed on outpatient basis.

<500

Significant risk of infection; fever should always be managed on inpatient basis with parenteral antibiotics; clinical signs of infection present.

<200

Very significant risk of infection; fever should always be managed on inpatient basis with parenteral antibiotics; clinical signs of infection may be late phenomena.

From Neutrophilia. http://www.uptodate.com. November 2009.

Box 39-4 Classification of Neutropenia

Production disorders

Congenital neutropenia Cyclic neutropenia Chédiak-Higashi syndrome

Cancer drugs (cyclophosphamide, methotrexate, azathioprine)

Maturation disorders

Vitamin B12, folate deficiencies Myelodysplastic syndromes Viral infections

Disorders of Increased destruction

Immune induction agents

Postinfection disorders (HBV, EBV, HIV/AIDS, bacteria)

Autoimmune disorders

Felty's syndrome Systemic lupus erythematosus Acute respiratory disease Hypersplenism Rheumatoid arthritis Transfusion reaction tions and 21-day fluctuations in the neutrophil count. Congenital neutropenia, also known as infantile genetic agranulocytosis, is a chromosomal abnormality possibly related to a G-CSF receptor defect. Chédiak-Higashi syndrome is an autosomal recessive chromosomal abnormality characterized by recurrent infections, partial albinism, and lymphoproliferative features caused by defective neutrophil migration and bactericidal properties. Cancer chemothera-peutic agents (e.g., cyclophosphamide, methotrexate, azathioprine) also directly suppress neutrophil production, in a dose-dependent manner.

Maturation disorders include vitamin B12 and folic acid deficiencies, myelodysplastic syndromes, and viral infections. Disorders of increased neutrophil destruction include those caused by antibodies to neutrophils induced by drugs such as antibiotics, antithyroid medications, and sulfa-containing compounds. Infections caused by hepatitis B, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), rickett-siae, and parasites may induce the production of antibodies that adversely effect the sequestration and destruction of neutrophils.

Autoimmune causes of neutropenia may also have an associated thrombocytopenia and hemolytic anemia. Felty's syndrome is the combination of rheumatoid arthritis, splenomegaly, and neutropenia, which is caused by antineutrophil antibodies. Similar antibodies can also be found in systemic lupus erythematous and Sjögren's syndrome. Antineutrophil antibodies can occasionally be found in hyperthyroidism and Wegener's granulomatosis as well. Antibodies to G-CSF also play a role in some of these autoimmune disorders. Isoimmune neonatal neutropenia is a disorder in infants secondary to transplacental transfer of IgG antibodies that react with neutrophilic antigens. These antigens are inherited from the father of the infant, and the disease process is similar to that of Rh-hemolytic disease of the newborn. This disorder resolves spontaneously, but occasionally the administration of G-CSF is necessary.

Treatment

Treatment of neutropenia depends on its cause and relative severity. Chronic neutropenia will necessitate a careful family history, a chronology of the types and severity of infections, and recurrent findings, such as oral ulcers, cellulitis, and sepsis. A medication history is extremely important in determining the cause of recent-onset neutropenia. Bone marrow aspiration is indicated if a production deficit is suspected or if there is any question of a myelodysplastic or malignant cause. If a viral infection is suspected, serologic testing for infectious mononucleosis, hepatitis, HIV, EBV, and parvo-virus may be indicated. When an autoimmune disorder is implicated, testing for antinuclear antibodies and rheumatoid factor is necessary. When neutropenia is found, a direct review of the peripheral blood smear using Wright-Giemsa stain not only confirms the relative absence or decreased number of neutrophils, but also can provide clues if there are toxic granulations, Döhle bodies, or changes seen in the maturation of the available neutrophils. If anemia or thrombo-cytopenia (or both) is found along with neutropenia, bone marrow aspiration and biopsy should be performed to determine the cause of this deficit in bone marrow production.

The Infectious Disease Society of America (IDSA; www.idsociety.org) and the American Society of Clinical

Oncology (www.asco.org) have developed evidence-based guidelines for the treatment of neutropenia associated with acute febrile episodes and those associated with cancer chemotherapy. These websites are kept current for use in clinical practice. Box 39-5 provides guidelines for the management of febrile neutropenia.

Mild neutropenia in the absence of a recurrent or protracted infection is most likely benign and can be observed. The history of a recent viral infection or new medication is often associated with mild neutropenia. The patient should be examined carefully and ANC monitored until it returns to normal. Once the neutropenia resolves, CBC should be determined whenever a fever occurs. If the neutropenia continues for 8 weeks or longer, a bone marrow aspiration and biopsy may help determine the cause and prognosis.

In patients with moderate to severe neutropenia with recurrent infection, a more vigorous approach should be undertaken to determine the cause. Bone marrow aspiration and biopsy, appropriate serologic tests, and blood cultures are necessary. Determination of antinuclear antibodies, complement levels, and antineutrophil antibodies and serologic studies for entities such as HIV infection are needed. An acute episode of febrile neutropenia requires a careful history and examination for potential sites of infection; blood and body fluid samples should be tested, and immediate implementation of IV antibiotic therapy is required. If indicated, antibiotics should be adjusted after 3 days, depending on culture results. Low-risk patients and patients responding quickly may be switched to oral antibiotic therapy. If the patient is severely

Box 39-5 Guidelines for Management and Prevention of Febrile Neutropenia

Management

Take careful history and conduct thorough physical examination of the patient.

Examine patient carefully for portal for bacterial or fungal infections. Culture blood and other appropriate body fluids. Start antibiotics immediately.

Treat with monotherapy (e.g., ceftazidime or imipenem) or duo-therapy (e.g., aminoglycoside such as gentamicin, with |-lactam drug effective against Pseudomonas, such as piperacillin). Add vancomycin if there is a significant risk of gram-positive sepsis. Adjust antibiotic therapy after 3 days, depending on the results of cultures and the patient's clinical status. Switch low-risk patients to oral therapy. Continue broad-spectrum therapy for severely ill patients. Consider antifungal treatments.

Consider colony-stimulating factors as an adjunct to antibiotics for febrile neutropenia in severely ill, high-risk patients.

Prevention

Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the incidence of febrile neutropenia by about 50% when risk of febrile neutropenia is about 40%.

Use G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) as a preventive strategy for patients who have had their cancer treatment reduced or experience a delay in treatment because of an episode of febrile neutropenia or a prolonged period of neutropenia. Consider reducing the intensity of chemotherapy.

ill and is not responding, treatment with antifungal agents and G-CSF should be considered.

Chronic neutropenia in Felt/ s syndrome may respond to splenectomy and regular doses of methotrexate. The long-term use of corticosteroids, gamma globulin injections, and splenectomy are generally not indicated in patients who have chronic neutropenia. Long-term antibiotics have no proven benefit in preventing infections in patients with chronic or recurrent neutropenia. Patients with fever and ANC higher than 1000 cells^L can generally be managed on an outpatient basis with oral antibiotics.

The use of myeloid growth factors (G-CSF, GM-CSF) may be helpful for some neutropenic patients. These recombi-nant-manufactured products can correct neutropenia and reduce infectious morbidity, particularly in patients subject to recurrent infections, such as those with severe congenital neutropenia, cyclic neutropenia, HIV infection, and long-term bone marrow suppression from cancer chemotherapy. In controlled studies in patients with severe chronic neutro-penia or HIV disease with low CD4+ cell count and ANC less than 1000/^, administration of G-CSF reduced the incidence of infection by 30% to 40% (Jadersten et al., 2005). G-CSF is now recommended to be given in the first cycle of chemotherapy, when the incidence of febrile neutropenia is likely to be higher than 20%. Patients receiving G-CSF may have more intensive chemotherapy and better survival but a greater risk of leukemia (Dale, 2009). Patients older than 55 with neutropenia or with acute myeloid leukemia may benefit from the administration of CSFs after completion of induction therapy. These agents can be started 24 to 72 hours after chemotherapy and are continued until ANC reaches or exceeds 1000^L.

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