AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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

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, polys). Neutrophils leave the marrow storage compartment and enter the blood without reentry into the marrow. In the blood, 2 compartments also are 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 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, often must 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 also are 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 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 neutropenia and the time elapsed until the first dose of antibiotics is administered for neutropenic fever.

• 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 than younger individuals.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients often present with infection. Other sequelae may reflect concurrent pancytopenia, with anemic symptoms (eg, fatigue, weakness, dyspnea on exertion) and symptoms of thrombocytopenia (eg, petechiae, purpura, epistaxis). This chapter focuses on neutropenia as the primary disorder. For further information on pancytopenia, refer to 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.
• 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 CBCs establish the chronicity of the neutropenia.
• Determining the age at onset aids in the differential diagnosis.

Physical

During the examination, focus on finding signs of an infection.

• Skin examination focuses on rashes, ulcers, or abscesses.
• Oral mucosa examination looks for aphthous ulcers, thrush, or periodontal disease.
• Lymphadenopathy is a possible indication of 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 usually are 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. Since 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, sometimes indistinguishable. Some patients with neutropenia give a clear history and familial pattern, while 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.

• Congenital with associated immune defects
• • 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 actually can 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). 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.
    • 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 SCN. Some patients with other forms of SCN 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 SCN, 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 who respond clinically to G-CSF are treated for life.
  • Cyclic neutropenia: Cyclic neutropenia (CN) is characterized by a 21-day cycle of oscillating neutrophil numbers. Recent discoveries show that autosomal dominant forms of CN and some sporadic cases of CN have mutations in ELA2. People with CN experience periodic neutropenia with subsequent infections, followed by peripheral neutrophil count recovery. They present as infants or children, but acquired forms in adulthood exist. Prognosis is good with a benign course; however, 10% of patients will experience life-threatening infections. The treatment is daily G-CSF.
• Chronic benign neutropenia: This group of people has 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 typically are 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. These patients exhibit infections and severe neutropenia.
• Neutropenia associated with phenotypic abnormalities
• • Shwachman syndrome (Shwachman-Diamond): This disorder has an autosomal recessive inheritance pattern. This neutropenia is moderate to severe, with a mortality rate of 15-25%. The syndrome presents in infancy, with recurrent infections, diarrhea, and difficulty in feeding. Dwarfism, chondrodysplasia, and pancreatic exocrine insufficiency can occur. This disorder 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. 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. It presents with cell-mediated immunity defects, macrocytic anemia, gastrointestinal disease, and dwarfism. It also shows a predisposition to cancer, especially lymphoma. This disorder 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): It presents with mental retardation, pancytopenia, and defective cell-mediated immunity. This disorder 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: It 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 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 immunoglobulin G (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 neutropenia typically is 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 usually is less severe. Patients can have this disorder in association with systemic lupus erythematosus, rheumatoid arthritis, Wegener granulomatosis, and chronic hepatitis. If 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, it can be associated with rheumatoid arthritis. This disorder is associated with high-titer antineutrophil antibodies, and the neutropenia is persistent and severe. Treatment is supportive in nature but also is 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, 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 transplant 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 splenomegaly and the bone marrow's ability to compensate for the reduction in circulating bands and neutrophils.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acquired Immunodeficiency Syndrome (AIDS)
Chronic myelomonocytic leukemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC 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 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 will assess for an intrinsic marrow defect, maturation arrest, congenital neutropenia, fungal infection, and a vitamin B-12 or folate deficiency.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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

• Removal of any offending drugs or agents
• Careful oral hygiene to prevent infections of the mucosa and teeth
• Avoidance of rectal temperature measurements and rectal examinations
• Administration of stool softeners for constipation
• Good skin care for wounds and abrasions

Consultations

• Hematology consultation for guidance on management and for diagnostic bone marrow aspiration and biopsy
• Infectious disease consultation in 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications are used to treat fevers or possible infections and to stimulate bone marrow in order to increase the production of neutrophils. According to the 1997 guidelines of the Infectious Diseases Society of America for treating neutropenic fever, empiric broad-spectrum antibiotics should be started immediately. The guidelines of the US Centers for Disease Control and Prevention (CDC) suggest 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.

Drug Category: Antibiotics

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

Drug Category: Hematopoietic growth factors

To accelerate neutrophil recovery and shorten duration of neutropenic fever. Also indicated to treat patients with chronic neutropenia.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Obtain daily CBCs with manual differential to monitor recovery from an etiologic agent or to monitor the response to G-CSF or GM-CSF.

Complications

• Most commonly, complications include fever and infections.

Prognosis

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

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize neutropenia by performing a CBC.
• 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 minimize medical/legal problems and improves the prognosis for the patient.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Pizzo PA, Hathorn JW, Hiemenz J, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med. Aug 28 1986;315(9):552-8. [Medline].
• Schimpff SC, Gaya H, Klastersky J, et al. Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. The EORTC international antimicrobial therapy project group. J Infect Dis. Jan 1978;137(1):14-29.
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• Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. Mar 11 1999;340(10):764-71. [Medline].
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Article Last Updated: Aug 9, 2006