eMedicine Specialties > Hematology > Immune System and Disorders

Neutropenia

John E Godwin, MD, MS, Professor of Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine
Christopher D Braden, DO, Attending Physician, Department of Hematology and Oncology, St. Francis Cancer Center, Indianapolis, Indiana.

Updated: Oct 4, 2009

Introduction

Background

Neutropenia is a decrease in circulating neutrophils in the peripheral blood.¹ The absolute neutrophil count (ANC) number defines neutropenia. An abnormal ANC value contains fewer than 1500 cells per mm³. Blacks may have a lower but normal ANC value of 1000 cells per mm^3, with a normal total white blood cell (WBC) count. The ANC is calculated by multiplying the percentage of bands and neutrophils (segmented neutrophils or granulocytes) on a complete blood cell (CBC) count differential times the total WBC count.

Note that many modern automated instruments actually calculate and provide the ACN number in their reports. These instruments usually do not separate bands from segmented neutrophils, and so the combined number is termed the granulocyte number. Thus, in such an instrument report, the ANC is equivalent to the absolute segmented neutrophil or granulocyte number. If a band number is reported separately, then add it to the granulocyte number.

The severity of neutropenia is categorized as mild when the ANC is 1000-1500 cells per mm³, moderate when the ANC is 500-1000 cells per mm³, and severe when the ANC is less than 500 cells per mm³. The risk of bacterial infection is related to both the severity and duration of the neutropenia.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Immune System Center. Also, see eMedicine's patient education articles Anemia, Sepsis (Blood Infection), Leukemia, and Lymphoma.

Pathophysiology

Mature neutrophils are produced by precursors in the bone marrow. The total body neutrophil content can be divided conceptually into the following 3 compartments: the bone marrow, the blood, and the tissues. In the marrow, the neutrophils exist in 2 divisions—the proliferative, or mitotic, compartment (myeloblasts, promyelocytes, myelocytes) and the maturation-storage compartment (metamyelocytes, bands, polymorphonuclear leukocytes ["polys"]).

Neutrophils leave the marrow storage compartment and enter the blood without reentry into the marrow. In the blood, 2 compartments are also present, the marginal compartment and the circulating compartment. Some neutrophils do not circulate freely (marginal compartment), but are adherent to the vascular surface, and these constitute approximately half of the total neutrophils in the blood compartment.

Neutrophils leave the blood pool in a random manner after 6-8 hours and enter the tissues, where they are destined for cellular action or death. Thus, if the process producing neutropenia is unknown, measurements of the blood neutrophil number, ANC, must often be supplemented by bone marrow examination to determine whether adequate production of neutrophils or increased destruction of neutrophils exists.

Sites and mechanisms of injury that cause neutropenia can be restricted to the mitotic or mature-storage pools in the marrow or the mature circulating pools (sequestration). Benign congenital neutropenias are associated with a decrease in circulating neutrophils but entirely normal marrow pools, marginal blood pools, and tissue neutrophils. The clinical sequelae of neutropenia manifest as infections, most commonly of the mucous membranes. Skin is the second most common infection site, manifesting as ulcers, abscesses, rashes, and delays in wound healing. The genitalia and perirectum are also affected. Signs of infection, including warmth and swelling, may be absent.

In prolonged severe neutropenia, life-threatening gastrointestinal and pulmonary infections occur, as does sepsis. However, patients with neutropenia are not at increased risk for parasitic and viral infections.

Frequency

International

The incidence of agranulocytosis is 3.4 cases per million persons per year. The incidence of drug-induced neutropenia is 1 case per million persons per year.

Mortality/Morbidity

Morbidity in those with neutropenia usually involves infections during severe, prolonged episodes of neutropenia. Serious medical complications occur in 21% of patients with cancer and neutropenic fever. Mortality correlates with the duration and severity of the neutropenia and the time elapsed until the first dose of antibiotics is administered for neutropenic fever.^2,3,4

• The 3 identified high-risk groups among cancer patients with neutropenic fever (many of whom have received aggressive chemotherapy) are inpatients with fever while developing neutropenia, outpatients requiring acute hospital care for problems beyond neutropenia and fever, and stable outpatients with uncontrolled cancer.
• Drug-induced agranulocytosis carries a mortality rate of 6-10%. Neutropenic fever in cancer patients carries an overall mortality rate of 4-30%.

Sex

Neutropenia occurs more commonly in females than in males.

Age

Elderly individuals have a higher incidence rate of neutropenia than younger individuals.

Clinical

History

Patients with neutropenia often present with infection. Other sequelae may reflect concurrent pancytopenia (which may increase the patient's risk for spontaneous bleeding), with anemic symptoms (eg, fatigue, weakness, dyspnea on exertion) and symptoms of thrombocytopenia (eg, petechiae, purpura, epistaxis). This article focuses on neutropenia as the primary disorder. For further information on pancytopenia, refer to the eMedicine article Bone Marrow Failure.

The patient history should focus on the following areas:

• Determine if a fever is present, because the physician must be aware of a possible life-threatening infection.
• Obtaining a history of infections may aid in the current diagnostic workup.
• Obtaining a careful drug history may reveal the offending agent and spare the patient from an extensive diagnostic workup.
• A family history of infections or sudden death may be an indication of inherited disorders.
• The maternal medical history (in neonatal neutropenia) may indicate inherited disorders or adverse effects of maternal medications.
• Records of past CBC counts establish the chronicity of the neutropenia.
• Determining the age at onset aids in the differential diagnosis.

Physical

During the physical examination of a patient with neutropenia, focus on finding signs of an infection.

• The skin examination focuses on rashes, ulcers, or abscesses.
• The oral mucosa examination assesses for aphthous ulcers, thrush, or periodontal disease.
• Lymphadenopathy is a possible indication of a disseminated infection or, possibly, malignancy.
• For perirectal infections, look for abscesses or mucous membrane abnormalities.
• For perineal infections, look for rashes, abscesses, or lymphadenopathy.
• Lung infections are usually bacterial or fungal pneumonias.

Causes

The list for all the potential causes of neutropenia is not short. Neutropenia can conceptually be viewed in 2 broad ways, by mechanism or etiologic category. Because the mechanisms for neutropenia are varied and not completely understood, the etiologic category is simplest to retain. Therefore, the etiology of neutropenia can be classified as congenital (hereditary) or acquired. In the setting of hereditary neutropenias, these disorders can be further described as associated with isolated neutropenia or with other defects, whether immune or phenotypic.

Causes of acquired neutropenia are also complex, but most are related to 3 major categories: infection, drugs, or immune. Chronic benign neutropenia, or chronic idiopathic neutropenia, appears to be an overlap disorder with hereditary and acquired forms, and is sometimes indistinguishable. Some patients with neutropenia give a clear history and familial pattern, whereas other patients with neutropenia have no familial history, few blood test determinations, and an unknown duration of neutropenia. This group of patients could have hereditary or acquired neutropenia. The following list briefly summarizes the congenital and acquired forms of neutropenia, as well as various therapies.^1,5,6,7,8

• Congenital neutropenia with associated immune defects⁹
  • Neutropenia with abnormal immunoglobulins: This disorder is observed in individuals with X-linked agammaglobulinemia, isolated immunoglobulin A (IgA) deficiency, X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I. In XHIGM, which is due to mutations in the CD40 ligand, patients can actually have normal or elevated levels of IgM but markedly decreased serum IgG levels. In all these disorders, the infection risk is high, and the treatment is intravenous immunoglobulin (IVIG).
  • Reticular dysgenesis: Patients demonstrate severe neutropenia, no cell-mediated immunity, agammaglobulinemia, and lymphopenia. Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF).^10,11,2 Bone marrow transplantation is the treatment of choice.
• Congenital or chronic neutropenias
  • Severe congenital neutropenia (SCN) or Kostmann syndrome
    • This disorder was described by Rolf Kostmann in 1956 as an autosomal recessive disorder in a large family from Sweden.¹²
    • Patients present by age 3 months with recurrent bacterial infections. The mouth and perirectum are the most common sites of infection. This type of neutropenia is severe, and the treatment is G-CSF.
    • No uniform genetic defect exists in Kostmann syndrome. Mutations in the neutrophil elastase gene (ELA-2), which are causative for cyclic neutropenia (see below) are not sufficient to explain the phenotype of Kostmann-like severe congenital neutropenia. Some patients with other forms of severe congenital neutropenia appear to have mutations in GFI1, a zinc-finger transcriptional repressor gene. It is involved in hematopoietic stem cell function and lineage commitment decisions. In patients with severe congenital neutropenia, risk of conversion to myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) with monosomy 7 after G-CSF treatments is associated with additional acquired mutations. Most of these cases are caused by a mutation in the G-CSF receptor. Patients whose condition responds clinically to G-CSF are treated for life.
  • Cyclic neutropenia (CN): Cyclic neutropenia is characterized by a 21-day cycle of oscillating neutrophil numbers. Discoveries have been reported showing autosomal dominant forms of cyclic neutropenia, and some sporadic cases of cyclic neutropenia have mutations in ELA2. People with cyclic neutropenia experience periodic neutropenia with subsequent infections, followed by peripheral neutrophil count recovery. They present as infants or children, but acquired forms of cyclic neutropenia in adulthood exist. The prognosis is good with a benign course; however, 10% of patients will experience life-threatening infections. The treatment for cyclic neutropenia is daily G-CSF.
• Chronic benign neutropenia: Affected individuals with chronic benign neutropenia have an overall low risk of infection.
  • Familial chronic benign neutropenia: This is a disorder with an autosomal dominant pattern of inheritance observed in western Europeans, Africans, and Jewish Yemenites. Patients are typically asymptomatic, and the infections are mild. No specific therapy is required.
  • Nonfamilial chronic benign neutropenias: Mild infections with a benign course typify this disorder. The ANC, however, does respond to stress, such as infection, corticosteroids, and catecholamines.
• Idiopathic chronic severe neutropenia: This disorder is a diagnosis of exclusion. Affected patients exhibit infections and severe neutropenia.
• Neutropenia associated with phenotypic abnormalities
  • Shwachman syndrome (Shwachman-Diamond): This disorder has an autosomal recessive inheritance pattern. The neutropenia is moderate to severe, with a mortality rate of 15-25%, and the syndrome presents in infancy, with recurrent infections, diarrhea, and difficulty in feeding. Dwarfism, chondrodysplasia, and pancreatic exocrine insufficiency can occur. Shwachman-Diamond syndrome and X-linked dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), and Diamond-Blackfan anemia (DBA) all appear to share common gene defects involved in ribosome synthesis. Most cases of Shwachman-Diamond syndrome are caused by mutations in the SBDS gene.¹³ The precise function of this gene is still being elucidated; however, it is involved in ribosome synthesis and RNA processing reactions. The treatment is G-CSF.
  • Cartilage-hair hypoplasia: The inheritance pattern is autosomal recessive on chromosome 9, and it is observed in Amish and Finnish families. The neutropenia is moderate to severe. Cartilage-hair hypoplasia presents with cell-mediated immunity defects, macrocytic anemia, gastrointestinal disease, and dwarfism. It also shows a predisposition to cancer, especially lymphoma. Cartilage-hair hypoplasia is caused by mutations in the RMRP gene. This RMRP gene encodes the RNA component of the ribonuclease mitochondrial RNA processing (RNase MRP) complex. The treatment is bone marrow transplantation.
  • Dyskeratosis congenita (Zinsser-Cole-Engman syndrome): This disorder presents with mental retardation, pancytopenia, and defective cell-mediated immunity. Dyskeratosis congenita is more common in men than in women and is hematologically similar to Fanconi anemia. Dyskeratosis congenita is usually X-linked recessive, although autosomal dominant and autosomal recessive forms of this disorder exist. The X-linked recessive form of the disorder has been linked to mutations in DKC1. DKC1 encodes dyskerin, a nucleolar protein associated with ribonucleoprotein particles. The autosomal dominant form of dyskeratosis congenital is associated with mutations in another gene, TERC, which is part of telomerase. Telomerase has both a protein and RNA component, and TERC codes the telomerase RNA component. Patients with this disorder have shorter telomeres than normal. The treatment is G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), and bone marrow transplantation.
  • Barth syndrome: This is an X-linked recessive disorder presenting with cardiomyopathy in infancy, skeletal myopathy, recurrent infections, dwarfism, and moderate to severe neutropenia.
  • Chediak-Higashi syndrome: This is an autosomal recessive disorder with recurrent infections, mental slowing, photophobia, nystagmus, oculocutaneous albinism, neuropathy, bleeding disorders, gingivitis, and lysosomal granules in various cells. The neutropenia is moderate to severe, and the treatment is bone marrow transplantation.
• Myelokathexis: This disorder presents in infancy with moderate neutropenia. An abnormal nuclear appearance is observed, with hypersegmentation with nuclear strands, pyknosis, and cytoplasmic vacuolization. The treatment is G-CSF and GM-CSF.
• Lazy leukocyte syndrome: This is a severe neutropenia with associated abnormal neutrophil motility. The etiology is unknown, and the treatment is supportive in nature.
• Metabolic diseases: These are chronic neutropenias with variable ANCs. They include glycogen storage disease type 1b and various acidemias, such as isovaleric, propionic, and methylmalonic. In glycogen storage disease type 1b, the treatment is G-CSF and GM-CSF.
• Immune-mediated neutropenia
  • Isoimmune neonatal neutropenia: The mother produces IgG antineutrophil antibodies to fetal neutrophil antigens that are recognized as nonself. This occurs in 3% of live births. The disorder manifests as neonatal fever, urinary tract infection, cellulitis, pneumonia, and sepsis. The duration of the neutropenia is typically 7 weeks.
  • Chronic autoimmune neutropenia: This disorder is observed in adults and has no age predilection. As many as 36% of patients will exhibit serum antineutrophil antibodies, and the clinical course is usually less severe. Patients can have this disorder in association with systemic lupus erythematosus, rheumatoid arthritis, Wegener granulomatosis, and chronic hepatitis. If chronic autoimmune neutropenia is associated with these diseases, corticosteroids are indicated as treatment. In neonates and children, this disorder is associated with a lower risk of infection and milder infections involving the middle ear, gastrointestinal tract, and skin.
  • T-gamma lymphocytosis: This is a clonal disorder of T lymphocytes that infiltrate the bone marrow. Also known as leukemia of large granular lymphocytes, T-gamma lymphocytosis can be associated with rheumatoid arthritis and is associated with high-titer antineutrophil antibodies. The neutropenia is persistent and severe. The treatment is supportive in nature, but it is also directed at eliminating the clonal population.
• Infections are the most common form of acquired neutropenia.
• Nutritional deficiencies include vitamin B-12, folate, and copper deficiency.
• Acquired neutropenia caused by drugs and chemicals, excluding cytotoxic chemotherapy
  • The highest risk categories are antithyroid medications, macrolides, and procainamides.
  • Antimicrobials include penicillin, cephalosporins, vancomycin, chloramphenicol, gentamicin, clindamycin, doxycycline, flucytosine, nitrofurantoin, novobiocin, minocycline, griseofulvin, lincomycin, metronidazole, rifampin, isoniazid, streptomycin, thiacetazone, mebendazole, pyrimethamine, levamisole, ristocetin, sulfonamides, chloroquine, hydroxychloroquine, quinacrine, ethambutol, dapsone, ciprofloxacin, trimethoprim, imipenem/cilastatin, zidovudine, fludarabine, acyclovir, and terbinafine.
  • Analgesics and anti-inflammatory agents include aminopyrine, dipyrone, phenylbutazone, indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine.
  • Antipsychotics, antidepressants, and neuropharmacologic agents include phenothiazines (chlorpromazine, methylpromazine, mepazine, promazine, thioridazine, prochlorperazine, trifluoperazine, trimeprazine), clozapine, risperidone, imipramine, desipramine, diazepam, chlordiazepoxide, amoxapine, meprobamate, thiothixene, and haloperidol.
  • Anticonvulsants include valproic acid, phenytoin, trimethadione, mephenytoin(Mesantoin), ethosuximide, and carbamazepine.
  • Antithyroid drugs include thiouracil, propylthiouracil, methimazole, carbimazole, potassium perchlorate, and thiocyanate.
  • Cardiovascular drugs include procainamide, captopril, aprindine, propranolol, hydralazine, methyldopa, quinidine, diazoxide, nifedipine, propafenone, ticlopidine, and vesnarinone.
  • Antihistamines include cimetidine, ranitidine, tripelennamine (Pyribenzamine), methaphenilene, thenalidine, brompheniramine, and mianserin.
  • Miscellaneous drugs include allopurinol, colchicine, aminoglutethimide, famotidine, bezafibrate, flutamide, tamoxifen, penicillamine, retinoic acid, metoclopramide, phenindione, dinitrophenol, ethacrynic acid, dichlorodiphenyltrichloroethane (DDT), cinchophen, antimony, pyrithyldione, rauwolfia, ethanol, chlorpropamide, tolbutamide, thiazides, spironolactone, methazolamide, acetazolamide, IVIG, and levodopa.
  • Heavy metals include gold, arsenic, and mercury.
• Miscellaneous immunologic neutropenias
  • Immunologic neutropenias may occur after bone marrow transplantation and blood product transfusions.
  • Felty syndrome: This is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenectomy shows an initial response, but neutropenia may recur in 10-20% of patients. Treatment is directed toward rheumatoid arthritis.
  • Complement activation–mediated neutropenia: Hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO) expose blood to artificial membranes and can cause complement activation with subsequent neutropenia.
  • Splenic sequestration: The degree of neutropenia resulting from this process is proportional to the severity of the splenomegaly and the bone marrow's ability to compensate for the reduction in circulating bands and neutrophils.

Differential Diagnoses

Other Problems to Be Considered

Acquired immunodeficiency syndrome (AIDS)
Chronic myelomonocytic leukemia

Workup

Laboratory Studies

• CBC count with manual differential is indicated.
• In patients with neutropenic fever, the following tests should be obtained, although their yield is low:
  • Two sets of blood cultures
  • Urinalysis and urine culture
  • Sputum Gram stain and culture
• Obtain serum vitamin B-12 and RBC folate levels.
• Perform HIV testing if clinical risk factors are present.

Imaging Studies

• If the neutropenic patient is febrile, obtain a posterior-anterior and lateral chest radiograph to assess for signs of pneumonia.

Procedures

• If anemia and thrombocytopenia are present, performing a bone marrow aspiration and biopsy is indicated.
• Obtaining a bone marrow biopsy to assess for an intrinsic marrow defect, maturation arrest, congenital neutropenia, fungal infection, and a vitamin B-12 or folate deficiency.

Treatment

Medical Care

Care for patients with neutropenia is mostly supportive and based on the etiology, severity, and duration of the neutropenia.

• Remove any offending drugs or agents.
• Use careful oral hygiene to prevent infections of the mucosa and teeth.
• Avoid rectal temperature measurements and rectal examinations.
• Administer stool softeners for constipation.
• Use good skin care for wounds and abrasions.

Consultations

• Request a hematology consultation for guidance on the management of patients with neutropenia and for diagnostic bone marrow aspiration and biopsy.
• Request an infectious disease consultation in patients with complicated infections or prolonged neutropenic fever that is not responding to standard therapy.

Diet

During severe neutropenia, advise patients to avoid fresh fruits, vegetables, and flowers to eliminate possible sources of infection.

Medication

Medications are used to treat fevers or possible infections and to stimulate bone marrow in order to increase the production of neutrophils. The 1997 guidelines of the Infectious Diseases Society of America for treating neutropenic fever recommended empiric broad-spectrum antibiotics be started immediately.¹⁴
 
The guidelines of the US Centers for Disease Control and Prevention (CDC) suggested adding vancomycin if Staphylococcus aureus infections are suspected. Delays in administering the first dose are associated with higher mortality. No single or double antibiotic regimen has been found to be superior over another.

Antibiotics

Antibiotic therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.¹⁵

Imipenem and cilastatin (Primaxin)

Broad-spectrum antibiotics for the treatment of serious infections and neutropenic fever.

Dosing

Adult

500 mg IV q6h

Pediatric

Avoid use in children <12 y whenever possible; however, if absolutely necessary, use the suggested dose as follows:

<1 week: 25 mg/kg q12h

1-4 weeks: 25 mg/kg q8h

4 weeks to 3 months: 25 mg/kg q6h

>3 months: 15-25 mg/kg/dose IV q6h

Interactions

Coadministration with cyclosporine may increase the adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizure.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust the dose in the presence of renal insufficiency; avoid use in children <12 y; confusion, myoclonus, and seizures can occur in CNS disorders or when the total daily doses are exceeded; long-term use can lead to microbial resistance: reevaluate in long-term use.

Ceftazidime (Fortaz)

Third-generation cephalosporin shown in randomized trial to be a safe alternative to double antibiotic regimens when treating neutropenic fever in patients with cancer. Has broad-spectrum, gram-negative activity. Lower efficacy against gram-positive organisms. Higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Dosing

Adult

1 g IV q8h

Pediatric

Not established

Interactions

Nephrotoxicity may increase with aminoglycosides, furosemide, and ethacrynic acid; probenecid may increase ceftazidime levels; concomitant use of chloramphenicol can be antagonistic to bactericidal activity.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in the presence of renal impairment; vitamin K–dependent clotting factors can be depleted; supplement vitamin K if the PT is elevated.

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms disappear.

Two prospective randomized clinical trials showed PO antibiotics could be safely substituted for IV antibiotics in low-risk patients with neutropenic fever. Until validated in large randomized trials, routine outpatient treatment is not recommended. Chemoprophylactic use has shown decreased mortality resulting from aerobic gram-negative bacteria.

Dosing

Adult

500 mg PO q12h

400 mg IV q12h

Pediatric

<18 years: Not recommended

Interactions

Antacids, iron salts, and zinc salts may reduce the serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with the metabolism of fluoroquinolones; ciprofloxacin reduces the therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase he toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase the effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Infuse slowly over 1 h to prevent local reactions; in prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust the dose in the presence of renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy.

Amphotericin B (Amphocin, Fungizone)

Empirically indicated in persistent neutropenic fever after a minimum of 4 d of broad-spectrum antibiotics (eg, imipenem or ceftazidime). For empirical therapy for fungal infections or for documented fungal infections. Produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.

Dosing

Adult

0.25-1.5 mg/kg/d IV; infuse over 4-6 h

Pediatric

0.25-1 mg/kg/d IV; infuse over 2-6 h

Interactions

Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine; increases flucytosine and skeletal muscle toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at the lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who receive leukocyte transfusions (separate the time of amphotericin infusion from the time of leukocyte transfusion).

Liposomal amphotericin B (AmBisome)

Liposomal preparation of amphotericin B. Large, multicenter, randomized, double-blind trial found liposomal amphotericin B to be as effective as standard amphotericin B for empiric treatment of neutropenic fever and showed less breakthrough fungal infections and toxicity.¹⁶

Dosing

Adult

Empiric therapy: 3 mg/kg/d IV

Systemic fungal infections: 3-5 mg/kg/d IV

Pediatric

Administer as in adults.

Interactions

Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine; increases flucytosine and skeletal muscle toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at the lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who receive leukocyte transfusions (separate the time of amphotericin infusion from the time of leukocyte transfusion).

Amoxicillin/clavulanate (Augmentin)

Beta-lactam antibiotic and beta-lactamase inhibitor, clavulanic acid, is the combination used to treat bacteria resistant to beta-lactam antibiotics. Two prospective randomized clinical trials showed PO antibiotics were safely substituted for IV antibiotics in low-risk patients with neutropenic fever. Until validated in large randomized trials, routine outpatient treatment for these patients is not recommended.

Dosing

Adult

500 mg PO q12h

Pediatric

<40 kilograms ( <12 wk): 30 mg/kg/d PO q12h

<40 kilograms (>12 wk): 45 mg/kg/d PO q12h; alternatively, 40 mg/kg/d PO q8h

>40 kilograms: Administer as in adults.

Dosing is based on the amoxicillin component.

Interactions

Coadministration with warfarin or heparin increases the risk of bleeding.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in the presence of renal impairment: modify the dose and/or frequency

Hematopoietic Growth Factors

Hematopoietic growth factors are administered to accelerate neutrophil recovery and shorten the duration of neutropenic fever. These agents are also indicated to treat patients with chronic neutropenia. However, although many benefits exist with using hematopoietic growth factors in acute neutropenic fever after chemotherapy, a survival benefit has not been shown.

Filgrastim (Neupogen)

G-CSF that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils. Shown to accelerate neutrophil recovery and shorten duration of neutropenic fever. Antibiotic treatment duration, amphotericin B use, hospital stay duration, and mortality, however, are unchanged. Most efficacious in severe neutropenia and documented infections.

Dosing

Adult

5 mcg/kg/d IV/SC

Pediatric

Administer as in adults.

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use 12-24 h before or 24 h after administering cytotoxic chemotherapy, because the sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy will increase; obtain CBC count before therapy, and monitor twice weekly during therapy to avoid excessive leukocytosis; rarely, cutaneous vasculitis is reported with long-term use in severe chronic neutropenia.

Sargramostim (Leukine)

GM-CSF indicated in the acceleration of neutrophil recovery after chemotherapy, mobilization of autologous peripheral blood progenitor cells, bone marrow transplantation, and in the delay or failure of bone marrow transplant engraftment.

Dosing

Adult

250 mcg/m²/d IV/SC

Pediatric

Administer as in adults.

Interactions

Lithium and corticosteroids may potentiate the myeloproliferative effects.

Contraindications

Documented hypersensitivity; concomitant radiation or chemotherapy; radiation or chemotherapy (administer 24 h before or following radiation or chemotherapy); <10% leukemic myeloid blasts in peripheral blood or bone marrow

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in the presence of any myeloid malignancy resulting from unknown growth factor effects on a tumor; check the CBC count twice weekly for excessive leukocytosis; monitor renal and hepatic function

Pegfilgrastim (Neulasta)

A long-acting filgrastim created by the covalent conjugate of recombinant G-CSF (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, it thereby activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.

Dosing

Adult

6 mg SC once per chemotherapy cycle

Pediatric

<45 kg: Not established

>45 kg: Administer as in adults.

Interactions

Do not administer in the period between 14 d before and 24 h after the administration of cytotoxic chemotherapy or radiation, because it increases the sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy; lithium may potentiate the release of neutrophils.

Contraindications

Documented hypersensitivity to E. coli; derived proteins‚ PEG, or filgrastim

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Splenic rupture has been reported rarely; ARDS secondary to an influx of neutrophils to sites of inflammation in the lungs may occur; may precipitate sickle cell crisis; may cause bone pain; there is a risk of developing myelodysplastic syndrome or acute myeloid leukemia in certain patients; leukocytosis; possible tumor growth

Follow-up

Further Inpatient Care

• Obtain daily CBC counts with manual differential to monitor the neutropenic patient's recovery from an etiologic agent or to monitor the neutropenia's response to G-CSF or GM-CSF.

Complications

• Most commonly, complications of neutropenia include fever and infections.

Prognosis

• The prognosis depends on the primary etiology, duration, and severity of the neutropenia.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize neutropenia by performing a CBC count may lead to medicolegal pitfalls.
• Failure to consider the presence of neutropenic fever, a medical emergency that usually requires hospital admission: Hospital protocols indicate expediting the first dose of antibiotics in patients with neutropenic fever, which helps to minimize medicolegal problems and improves the prognosis for the patient.

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Keywords

neutropenia, Schultz disease, agranulocytosis, granulocytopenia, leukopenia, neutropenic fever, circulating neutrophils, granulocyte colony-stimulating factor, G-CSF, bone marrow transplantation, Kostmann syndrome, Shwachman-Diamond syndrome, Zinsser-Cole-Engman syndrome

Contributor Information and Disclosures

Author

John E Godwin, MD, MS, Professor of Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine
John E Godwin, MD, MS is a member of the following medical societies: American Association for the Advancement of Science, American Heart Association, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Christopher D Braden, DO, Attending Physician, Department of Hematology and Oncology, St. Francis Cancer Center, Indianapolis, Indiana.
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Related eMedicine Topics

• Agranulocytosis
• Autoimmune and Chronic Benign Neutropenia [in the Pediatrics: General Medicine section]
• Granulocytopenia
• Kostmann Disease [in the Pediatrics: General Medicine section]

• Fatigue and Symptom Burden in Febrile Neutropenia
• Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)

• ACR Appropriateness Criteria® fever without source - child. American College of Radiology - Medical Specialty Society. 1999 (revised 2008). 8 pages. NGC:007009
• 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. American Society of Clinical Oncology - Medical Specialty Society. 1994 Nov (revised 2006 Jul 1). 19 pages. NGC:005040

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