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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 mm3, 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.
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.
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.
• 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.
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