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996 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 65: Neutropenia and Neutrophilia 997

at any time, but tends to occur relatively early in the course of treatment should include a careful history with particular attention to drugs. The
with drugs to which the patient has been previously exposed. physical examination should give careful attention to the oropharynx,
Our basic understanding of drug-induced neutropenia is limited, sinuses, chest, abdomen, bones for evidence of tenderness, and size of
partly because of the unpredictable occurrence of cases, the myriad the lymph nodes and spleen. Prompt blood counts and microbial cul-
agents involved, and the lack of good animal models for research. Clin- tures, institution of intravenous fluids, antibiotics, and other supportive
ical studies suggest the rate of recovery can be roughly predicted from measures may be lifesaving. In this situation, fever and infections usu-
the degree of marrow hypoplasia present when neutropenia is discov- ally result from surface bacteria sensitive to numerous broad-spectrum
ered. In patients with sparse marrow neutrophils but normal-appearing agents, unless the patient has been treated recently with antibiotics. A
precursor cells (promyelocytes and myelocytes), neutrophils reappear in complete blood count should be obtained and a marrow examination
the blood approximately 4 to 7 days after the offending drug is stopped. considered, particularly if the cause of acute neutropenia is not known.
Often an increase in the blood monocyte count heralds marrow recov- The marrow may reveal fibrosis, selective or nonselective hypoplasia of
ery, and an “overshoot” with marked neutrophilia follows. When early marrow precursors, excessive blasts, or atypical cells. With this infor-
precursor cells are severely depleted, recovery may require considerably mation in hand and supportive care started, further diagnostic tests can
more time. be considered.
Symptomatic patients with drug-induced neutropenia usually Chronic neutropenia often is discovered as a chance finding at a
present with fever, myalgia, and sore throat, but usually no rash or evi- routine examination or during the course of investigation of a patient
127
dence of allergy elsewhere. Blood examination shows few or absent with recurrent fevers and infections. Determining if the neutropenia
neutrophils. Mild lymphopenia may be observed, but other cell counts is chronic or cyclic and the mean level of blood cell counts when the
usually are normal. A high level of suspicion and careful clinical his- patient is afebrile and relatively well is useful. Other important hema-
tory are critical to identifying the offending drug. Differential diagnosis tologic and immunologic data include the absolute monocyte, lym-
includes acute viral infections, particularly infectious mononucleosis phocyte, eosinophil, and platelet counts; hematocrit or hemoglobin
and infectious hepatitis, and acute bacterial sepsis. If other hemato- determination; and immunoglobulin levels. Patients with hypergam-
logic abnormalities also are present, acute leukemia and aplastic anemia maglobulinemia usually have chronic and recurrent inflammation;
should be considered. Treatment usually consists of supportive care, patients with hypogammaglobulinemia and neutropenia usually are
including broad-spectrum antibiotics for febrile patients. Hematopoi- very susceptible to recurrent infections. Morphologic examination of
etic growth factors such as G-CSF or GM-CSF may be beneficial, but the blood and marrow can identify some causes of benign neutrope-
their use in this setting has not been established in randomized trials. nia in children, the Chédiak-Higashi syndrome, and myelokathexis.
130
An alternative to discontinuing drugs such as clozapine is the addition The marrow examination is most useful for ruling out leukemia and
of G-CSF treatment, 127–129 although it is usually preferable to discontinue myelodysplastic disorders and assessing the severity of the marrow
the suspected offending agent. defect.
Table 65–1 lists some of the drugs frequently implicated in neu- In patients with chronic neutropenia, measurement of antinuclear
tropenia. Given the rapidity of introduction of new agents, consult the antibodies (ANA) and rheumatoid factor titers and other serologic tests
manufacturer, a drug information center, or a poison control center for autoimmune diseases may be useful. Usually, neutropenia associated
when questions arise to learn if a drug can cause neutropenia. with these disorders occurs in patients with obvious and severe disease,
but occasionally patients are seen with occult splenomegaly, high ANA
and rheumatoid factor titers, and a few other symptoms. Examination
NEUTROPENIA WITH INFECTIOUS DISEASES of the blood and marrow for large granular lymphocytes may be helpful.
Neutropenia can result from acute or chronic bacterial, viral, para- Infectious and nutritional causes of chronic neutropenia are rare and
usually are evident at the time of patient evaluation. In adults, differen-
sitic, or rickettsial diseases. Several mechanisms are involved. Certain tiation between chronic idiopathic neutropenia and the myelodysplastic
viral infections, such as infectious mononucleosis, infectious hepatitis, syndromes may be the most difficult. Abnormalities in other cell lines
Kawasaki disease, and HIV infection, may cause severe or protracted (e.g., anemia with poikilocytosis, anisocytosis, basophilic stippling, and
neutropenia and pancytopenia resulting from infection of hematopoi- thrombocytopenia, pseudo–Pelger-Huët cells), low proportions of blast
etic precursor cells. Other agents, such as Rickettsia and Bartonella, can cells in the marrow, dysmorphic granulocyte and erythroid precursors,
infect endothelial cells. These agents may cause leukopenia, neutrope- and clonal chromosomal abnormalities indicate myelodysplasia, partic-
nia, thrombocytopenia, and anemia as part of a generalized vasculitic ularly in older patients. Investigations of the mechanism of neutropenia
process. Increased neutrophil adherence to altered endothelial cells with marrow and blood kinetic studies, in vitro marrow cultures, mea-
may occur in dengue, measles, and other viral infections. With severe surements of marrow granulocyte reserves, and indirect measurements
Gram-negative bacterial infections, neutropenia probably results from of marrow proliferative activity may be useful in defining mechanisms
increased adherence to the endothelium and increased utilization at the of neutropenia, but are not widely available.
site of infection. Some chronic infections causing splenomegaly, such as
tuberculosis, brucellosis, typhoid fever, malaria, and kala azar, probably
cause neutropenia because of splenic sequestration and marrow inva- NEUTROPHILIA
sion and suppression.
Neutrophilia is defined as an increase in the absolute blood neutrophil
count to a level greater than 2 SD above the mean value for normal
CLINICAL APPROACH TO THE PATIENT individuals. For children age 1 month or older and adults of all ages,
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PRESENTING WITH NEUTROPENIA this level is approximately 7.5 × 10 /L, combining bands and mature
neutrophils (Chap. 2). At birth the mean neutrophil count is 12 × 10 /L,
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Ordinarily, patients with acute onset of severe neutropenia present with and counts as high as 26 × 10 /L are regarded as normal (Chap. 7).
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fever, sore throat, and evidence of inflammation beneath the skin or Several terms are used almost synonymously with neutrophilia,
mucous membranes. New respiratory or abdominal symptoms should including neutrophilic leukocytosis, polymorphonuclear leukocytosis,
heighten concern of an urgent clinical situation. Immediate investigation and granulocytosis. Leukocytosis is used because an elevated number of

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