Ni Hms 490811

NIH Public Access
Author Manuscript
Semin Hematol. Author manuscript; available in PMC 2014 July 01.
Published in final edited form as:
NIH-PA Author Manuscript
Semin Hematol. 2013 July ; 50(3): 198–206. doi:10.1053/j.seminhematol.2013.06.010.
Evaluation and Management of Patients with Isolated

Neutropenia
Peter E. Newburgera and David C. Daleb
aDepartments of Pediatrics and Cancer Biology, University of Massachusetts Medical School,
Worcester, MA
bDepartment of Medicine, University of Washington, Seattle WA
Abstract
Neutropenia, defined as an absolute neutrophil count below 1.5 × 109/L, encompasses a wide
range of diagnoses, from normal variants to life-threatening acquired and congenital disorders.
This review addresses the diagnosis and management of isolated neutropenia, not multiple
cytopenias due to splenomegaly, bone marrow replacement, or myelosuppression by

chemotherapy or radiation. Laboratory evaluation generally includes repeat complete blood counts
with differentials and bone marrow examination with cytogenetics. Neutrophil antibody testing
may be useful, but only in the context of clinical and bone marrow findings. The discovery of
genes responsible for congenital neutropenias now permits genetic diagnosis in many cases.
Management of severe chronic neutropenia includes common-sense precautions to avoid
infection; aggressive treatment of bacterial or fungal infections; and administration of granulocyte
colony-stimulating factor (G-CSF). Patients with severe congenital neutropenia, particularly those
who respond poorly to G-CSF, have a risk of eventually developing myelodysplastic syndromes
(MDS) or acute myeloid leukemia (AML) and require monitoring for this complication, which can
also occur without G-CSF therapy. Patients with cyclic, idiopathic and autoimmune neutropenia
have virtually no risk of evolving to MDS or AML. Hematopoietic stem cell transplantation is a
curative therapy for congenital neutropenia with MDS/AML or with cytogenetic abnormalities
indicating impending conversion.
Introduction
Neutropenia, usually defined as an absolute neutrophil count (ANC) below 1.5 × 109/L
(1500/mm3), encompasses a wide range of diagnoses, from normal variants to life-

threatening acquired and congenital disorders. The functional consequences depend largely,
but not exclusively, on the severity of neutropenia: ANC of 1.0–1.5 × 109/L does not impair
host defense, but may warrant investigation of the underlying cause; ANC of 0.5–1.0 × 109/
L may slightly increase the risk of infections, but only if other arms of the immune system
are impaired; ANC of 0.2–0.5 × 109/L is associated with an increased risk of infections in
most patients. ANC of 0.2 × 109/L or less (often referred to as “agranulocytosis”) carries a
risk of severe, life-threatening infections with susceptibility to opportunistic organisms.
© 2013 Elsevier Inc. All rights reserved.

Address correspondence to Peter E. Newburger, MD, Department of Pediatrics, University of Massachusetts Medical School, 55 Lake
Avenue North, Worcester, MA 01655. Tel. 508-856-4225. Fax 508-856-4282. peter.newburger@umassmed.edu.
Financial disclosures: PEN: none. DCD: consultant and receives research support from Amgen, Thousand Oaks CA
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Newburger and Dale Page 2
These oft-quoted criteria were derived from clinical experience with neutropenia secondary
to cancer chemotherapy, so patients with isolated neutropenia and otherwise normal immune
systems would be expected to have lower risks of infection at any ANC.
Healthy Caucasian and Asian populations generally have ANCs of 1.5 to 7.0 × 109/L.
Persons of African descent, however, often have lower normal neutrophil counts, with ANC
<1.5 × 109/L occurring in about 4.5% of black participants in one U.S. survey,1 and
associated with the Duffy negative blood group.2 It was once thought that neutrophil levels
fluctuate cyclically in the normal person, but best evidence now indicates that levels
fluctuate considerably but do not normally cycle in a mathematically regular fashion.3
This review will address the diagnosis and management of isolated neutropenia, not multiple
cytopenias due to splenomegaly, bone marrow replacement, or myelosuppression by
chemotherapy or radiation. Other reviews summarize these disorders and their
management.4;5
Classification of Neutropenia
Neutropenia can be described as transient (or “acute”) or chronic (or “persistent”); extrinsic
or intrinsic; by descriptive names (e.g., neonatal isoimmune neutropenia of infancy, cyclic
neutropenia, severe congenital neutropenia) and as syndromes (e.g., Kostmann,
Shwachman-Diamond, and Barth syndromes). The discovery of the diverse causes for the
congenital neutropenias now permits genetic diagnosis in many cases.
Transient and Chronic Neutropenia

Transient neutropenia is most commonly associated with viral infections.6–8 Table 1
identifies some of the most important viral agents, but almost any viral infection can be
associated with transient neutropenia. Infectious mononucleosis due to Epstein-Barr virus
infection is a relatively common viral infection causing neutropenia.4 Overwhelming
bacterial infections, particularly in patients with alcoholism or underlying hematological
diseases, may deplete bone marrow reserves and cause neutropenia, a dire sign in this
setting. In acute malaria, neutropenia occurs due to a rapidly enlarging spleen.9;10 Chronic
bacterial infections and some inflammatory and autoimmune diseases (e.g., rheumatoid
arthritis and sarcoidosis) are also associated with splenomegaly and neutropenia. (Table 1)
Chemotherapy agents and a wide variety of other medications cause transient isolated
neutropenia; the drugs listed in Table 1 are the most common agents associated with
isolated, idiosyncratic, drug-induced neutropenia.
Chronic neutropenia is usually defined as an ANC less than 1.5 × 109/L lasting for more
than 3 months.11 It is quite common for healthy individuals to have an occasional ANC
value in the range of 1.5–2.0 × 109/L, especially with the counts performed early in the day.
Some individuals in good health can have isolated counts even lower, i.e., 1.0–1.5 ×109/L.
In these individuals, periodic complete blood cell counts are usually all that is needed for
their initial evaluation. The primary purpose of serial counts and follow-up is to see if the
ANC is chronically reduced and if, over time, other hematological abnormalities or evidence
of an underlying infectious, inflammatory or malignant disease will appear. Discovery of
lower neutrophils for any reason, i.e. ANC 0.5–1.0 × 109/L, is cause for an in-depth
evaluation. In both children and adults, the most common diagnosis for counts in this range
is autoimmune or idiopathic neutropenia. However, there are a number of other acquired and
inherited causes (Table 2). Severe chronic neutropenia is a term for a category of diseases in
which the ANC is consistently or regularly reduced to less than 0.5 × 10 9/L. The major sub-
types are congenital, cyclic, idiopathic and autoimmune.11 Patients with severe chronic

neutropenia need careful diagnostic testing because of the severity of infectious

complications associated with this hematological abnormality.
It is important to note that blood neutrophil counts are not as stable as other blood cell
counts or many other physiological measurements. Counts may vary considerably over short
periods of time, associated with activity, exercise, eating or just the time of day. Counts vary
even more with serious infections, inflammatory disorders, corticosteroid therapy or extreme
anxiety. It is always important in the evaluation of blood neutrophil counts to consider the
conditions when the blood sample was obtained and to have several measurements when
defining the severity of acute or chronic neutropenia.11
Extrinsic and Acquired Causes of Chronic Neutropenia

Nutritional Neutropenias
Nutritional deficiencies of vitamin B12, folic acid or copper, or severe protein-calorie
malnutrition can cause neutropenia. These deficiencies almost always cause multiple
cytopenias rather than isolated neutropenia and are usually diagnosed based on medical
history, physical examination and laboratory measurements of specific vitamin levels.
Immune and autoimmune neutropenias

Neonatal isoimmune neutropenia occurs in newborns with fetal/maternal neutrophil antigen
incompatibility, leading to transplacental transfer of antibodies to specific epitopes

expressed on the newborn’s neutrophils. These most commonly involve alleles of the
HNA-1a, HNA-lb and HNA-1c antigens (formerly termed NA1, NA2, and SH) that
represent polymorphisms of Fc gamma receptor IIIb (FcγRIIIb; CD16b);12;13 the disorder
can also occur with maternal FcγRIIIb deficiency.13 Neutropenia can be profound and lead
to omphalitis, cellulitis, or sepsis. As with other isoimmune cytopenias, the process resolves
spontaneously in about six weeks, with decay of the maternal antibody, but neutropenia can
last as long as 6 months11 Parental neutrophil antigen typing and infant neutrophil antibody
testing can be useful to establish the diagnosis and predict the risk in future pregnancies.
Autoimmune neutropenia in mothers may also cause neonatal neutropenia due to trans-
placental transfer of IgG antibodies that are reactive with both the mother’s and the child’s
neutrophils. This is an unusual condition, but it may be devastating because of the risk of
severe infections in the newborn.
Chronic autoimmune neutropenia of infancy and early childhood is a relatively common

disorder and virtually always runs a benign course, despite very low ANCs. It usually
resolves spontaneously by age 3–5 years, with a mean duration of 17 months.14;15 In most
cases, neutropenia is detected during the occurrence of an acute febrile illness. With follow-
up, the neutropenia persists after resolution of the illness that led to testing. Systematic
studies indicate that many, but not all, of these children have autoantibodies directed against
surface antigens of neutrophils.14 From a clinical perspective the value of testing for
autoantibodies in patients with moderate to severe neutropenia without evidence of recurrent
fevers or infections is debatable. Testing is not widely available and, if done, it is best
performed by a reference laboratory performing these assays frequently. Serial testing may
give inconsistent results and patients with genetic as well as acquired neutropenia may have
false positive test results.
In older children, chronic autoimmune neutropenia or multiple immune cytopenias should

raise suspicion of a congenital immunological disorder such as autoimmune
lymphoproliferative syndrome or common variable immunodeficiency.16;17 Screening for
these disorders can be performed by measurement of circulating T cell receptor alpha/beta

positive, CD4/CD8 double negative T cells or of serum immunoglobulins, respectively.

Definitive diagnosis of these conditions requires specialized immunological testing.
In adult women, autoimmune and idiopathic neutropenia are relatively common,

overlapping diagnoses, with a female to male ratio of about 5:1. Because of the lack of any
definitive tests, the diagnoses “autoimmune neutropenia” and “idiopathic neutropenia” are
used nearly synonymously. Ordinarily the neutropenia is recognized on a routine complete
blood cell count, often without any history of recurrent fevers or infections. Often there is a
mild reduction in the blood lymphocyte count with symmetrical, not selective, reduction in
blood lymphocyte subtypes. The neutropenia may be mild, moderate or severe. Patients with
more severe neutropenia are prone to recurrent fevers, upper respiratory infections and skin
infections, but the infections are readily treated with antibiotics in most cases. With
infections, the ANC may rise to a normal level. In typical cases, the diagnosis can be made
from the history, physical examination and a series of complete blood cell counts. If a bone
marrow examination is performed it may show a mild reduction in mature neutrophils and
clusters of polyclonal lymphocytes. It is uncommon for patients presenting with this type of
isolated neutropenia to have arthralgias, stiffness, fatigue or weight loss or laboratory test
results suggesting a systemic autoimmune disease. It is also uncommon for these patients to
progress to develop systemic lupus erythematosus, rheumatoid arthritis, Sjögren or Felty
syndrome, or other systemic autoimmune diseases.11
Neutropenia also occurs as an integral part of systemic autoimmune diseases such as lupus
erythematosus and rheumatoid arthritis. These diseases are diagnosed based on systemic
symptoms and a constellation of disease-associated physical findings and specific
immunological tests, e.g., antinuclear antibodies, rheumatoid factor, other autoantibodies.
Typically, with the exception of Felty syndrome, neutropenia associated with the systemic
autoimmune diseases is mild and best managed as part of treatment of the underlying
disease. Transient (<24 hr) neutropenia often accompanies transfusion-related acute lung
injury (“TRALI”) due to pulmonary trapping of recipient neutrophils opsonized by
transfused alloantibodies or activated by soluble mediators.18
Neutropenia commonly accompanies, or can be a presenting feature of, large granular

lymphocytic (LGL) leukemia,19 in which cytokine-mediated inhibition of granulopoiesis
combines with neutrophil destruction by both cell-mediated and humoral immune
mechanisms. Other typical characteristics of the disease include lymphocytosis and
splenomegaly. LGL leukemia diagnosis is based on the finding of clonal expansion (>0.5 ×
109/L) of peripheral blood LGL with markers of activated T cells (e.g. CD3+/CD8+/CD57+
and/or CD16+ with clonal T cell receptor gene rearrangement) or NK cells (e.g. CD3−/
CD8+/CD16+ and/or CD16+/CD56+).20
Intrinsic neutropenias
The intrinsic neutropenias are due to genetic or acquired abnormalities in hematopoietic
progenitor cells resulting in the failure of the bone marrow to produce mature neutrophils.
They are either acquired or congenital (Table 2). Myelodysplastic syndromes (MDS) and
acute myeloid leukemia (AML) are acquired disorders and rarely present as isolated
neutropenia. However, patients with severe congenital neutropenia, as well as patients with
other inherited marrow failure disorders, may develop MDS and AML; these cases are
classified as secondary MDS/AML.
Congenital neutropenia has many causes and may occur either as an isolated manifestation
of a single lineage disorder or in the setting of a multi-system syndrome. The congenital
neutropenias are categorized by clinical/classical names or based on the name of the mutated
gene known to cause the disease (Table 2).5;21;22

Severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) are examples of well
understood causes of severe chronic neutropenia that are usually still called by their original/
classic names. Both diseases derive from excessive apoptosis of myeloid precursors early in
development. In SCN, apoptosis at the promyelocyte stage of development leads to apparent

“maturation arrest” in the bone marrow. The loss of cells early in their development results
in “ineffective production” and severe neutropenia with ANCs usually below 0.5 × 109/L,
and often lower. In CyN, bone marrow maturation, and hence peripheral blood neutrophil
counts, follow a regular oscillating pattern with consistent, usually 21-day, periodicity. Most
commonly, SCN is inherited as an autosomal dominant disorder and attributed to mutations
in ELANE (formerly ELA2). This gene encodes neutrophil elastase, an abundant protein
first expressed at high levels in promyelocytes.23;24 Most mutations are missense or splicing
defects that produce an abnormal protein product, resulting in apoptosis through the
unfolded protein response.25;26 Most cases of CyN are also attributable to ELANE
mutations. Because the same gene is responsible for both diseases – with some mutations
associated with both phenotypes,24 even in the same kindred27 – the combined entity has
also recently been called “ELANE associated neutropenia.”
Autosomal recessive SCN can be caused by defects in several genes, including HAX1, an
anti-apoptotic gene that is responsible for the classic “Kostmann syndrome,” and G6PC3,
which encodes a neutrophil-specific catalytic subunit of glucose-6-phosphatase.28;29 By
contrast with ELANE, which is expressed selectively in myeloid cells, these genes are
broadly expressed in many tissues and organs. As a result, some patients with HAX1 protein
defects have associated neurological deficits, and G6PC3 defects were originally described
in a cohort of patients with cardiac anomalies, urogenital abnormalities, and venous
angiectasias. Both HAX1 and G6PC3 mutations can also be responsible for isolated
neutropenia without an extended phenotype.30;31 Very rare forms of SCN result from
mutations in GFI1 (autosomal dominant) and WAS (X-linked, gain of function
mutations).21;32;33 Approximately 60% of patients with a diagnosis of severe congenital
neutropenia can now be given a precise genetic diagnosis.
Clinical Evaluation
Careful medical history and family history are the initial steps in evaluating patients with
neutropenia or recurrent infections suggesting isolated neutropenia. It is important to know
the frequency of illness, the severity of fever and other constitutional symptoms, the
presence or absence of oral inflammation (mouth ulcers, gingivitis, periodontitis, tooth loss
and replacement), and the presence or absence of other common infectious problems of
patients with neutropenia (cellulitis, sinusitis, otitis, pharyngitis, pneumonia, gastrointestinal
symptoms, perirectal infections and sepsis or evidence of deep tissue infections). It is also
important to know how these problems have been previously managed and the patient’s
antibiotic exposures. A history of viral infections, other symptoms suggesting

immunodeficiency, and general health, growth and development are also very important.
Because many defects in host defenses including neutropenia are heritable, family history is
also important beginning with an understanding of the medical history of the patient’s
immediate family, and extending as far as possible, especially if there are clues that other
family members may have similar symptoms, laboratory findings or may have died from
infections or hematological malignancies. It is important to note that the severity of illness
may vary within families with the same genetic cause for neutropenia. Relatives of patients
with very severe neutropenia may have ANC levels of 0.5–1.5 × 109/L and relative few
symptoms and still have the same underlying genetic disease. Unexplained infant deaths
may also indicate an inherited form of neutropenia.

The physical examination may reveal mouth ulcers, abnormal teeth and gums, and evidence
of acute or chronic sinusitis, pharyngitis, or otitis. Careful examination of the chest and
abdomen is very important. Acute abdominal pain and fever in neutropenic patients should
raise concerns about neutropenic colitis and sepsis from an abdominal source. The perirectal
and anal area should also be examined carefully because patients with severe neutropenia
often develop cellulitis, including necrotizing cellulitis due to infection with Clostridial
species and other anaerobic organisms, in this area. Because neutropenia is associated with a
reduced inflammatory response with less than typical pain and redness, it is important to
examine and reexamine the patient carefully.
Laboratory Evaluation
CBC—Neutropenia is usually discovered with a complete blood cell count (CBC) and
leukocyte differential count (Diff), done either as a part of evaluation of a patient for acute
or recurrent fever and infection, or as part of a general health examination. In a patient with
mild neutropenia and no other health or hematological problems, a follow-up CBC and Diff
may be all that is necessary. The medical history and the severity of neutropenia with the
initial counts generally direct further evaluation. Every opportunity should be made to
capture information from previous CBCs and Diffs, generally by asking the patient to
request this information from all previous providers. It is particularly important to retrieve
counts from very early in life, if possible.
To determine the severity and duration of neutropenia, at least three determinations over
three months are a minimum. If CyN is part of the differential diagnosis – due to family
history, highly variable past neutrophil counts, or regularly recurrent fever or mouth ulcers –
then a CBC and differential count should be obtained at least three times per week for four
to six weeks (i.e. more than one, preferably two, 21 day cycles). In CyN, reciprocal
oscillations of monocytes often occur; reticulocyte, lymphocyte, eosinophil, and platelet
numbers may also show cyclical variation.34
Bone marrow examination—A bone marrow examination is valuable to identify

abnormalities in myelopoiesis in neutropenic patients. Initially it may be critical to look for
excess myeloblasts and other markers of MDS and AML. If there is concern about MDS or
AML, cytogenetic examination of the marrow specimen is also useful. A marrow smear is
particularly useful to identify the stage of the defect in myelopoiesis causing neutropenia.
For example, patients with severe congenital neutropenia due to ELANE or HAX1
mutations usually have “maturation arrest” with a generous number of promyelocytes but
only a few mature myeloid cells.23;28 At the other extreme, patients with myelokathexis
have abundant “hypermature” neutrophils in the bone marrow, because the cells had
difficulty exiting the marrow and entering the blood. In patients with cyclic neutropenia, the
cellularity of the marrow and the marrow differential count depend on the timing in the
neutrophil cycle when the sample is obtained. In fact, serial sampling shows the proliferative
response and the accumulation of mature neutrophils in the marrow that precedes the
recovery phase for neutrophils in the blood.34 Careful examination of both bone marrow and
peripheral blood smears, plus bone marrow cytogenetics, are essential before a patient is
treated with hematopoietic growth factors, in order to have a patient-specific reference for
subsequent comparisons.
As a part of their long-term care, it is recommended that patients with SCN, but not other
groups, have annual bone marrow examinations with chromosome analysis to recognize
evolution to MDS/AML as early as possible. One established marker of transition is the
development of mutations in the receptor for G-CSF, but time from the first appearance of
such a mutation to clinical signs of MDS/AML can be very long even many years.35

Chromosomal changes such as monosomy 7 are a more specific finding. Ongoing research
suggests that other markers, i.e. RUNX1 mutations, may occur later and be a better predictor
of developing AML.36
In patients with mild or asymptomatic neutropenia, the bone marrow reserve pool of mature
neutrophils can be assessed less invasively by a glucocorticoid stimulation test.37 After a
baseline CBC with differential count, prednisone 1–2 mg/kg is administered as a single oral
dose and the CBC/differential repeated 4–6 hours later. A more than two-fold rise indicates
the presence of an adequate bone marrow reserve pool that can be mobilized at times of
stress or infection. This condition is sometimes termed, nonspecifically, “chronic benign
neutropenia.”
Neutrophil antibodies and antigens—Testing for anti-neutrophil antibodies, by

immunofluorescence, agglutination, or flow cytometric assays, may help support the
diagnosis of autoimmune neutropenia, but must be interpreted in the context of clinical and
bone marrow findings, as the tests are fraught with false positive and false negative
results.14;38;39 Testing should only be performed by a laboratory with considerable
experience in performing and interpreting the assay. Determination of parental neutrophil
antigens may be helpful for the diagnosis of neonatal alloimmune neutropenia.40
Genetic testing—Identification of the specific gene and mutation responsible for

congenital neutropenia may help support the diagnosis, indicate a relative risk for late
complications such as MDS/AML or aplasia (e.g. in SCN or dyskeratosis congenita), guide
screening for non-hematological phenotypes (e.g. in Shwachman-Diamond syndrome or
G6PC3 defects), and provide a basis for genetic counseling of the family. However, genetic
testing may be expensive and have unanticipated psychological and social consequences,
and may fail to identify a mutation in many patients.
Other laboratory tests that may aid in the diagnosis of chronic neutropenia include
evaluations for nutritional deficiencies (e.g. vitamin B12, folate, copper), immune
deficiencies (e.g. quantitative immunoglobulins), and rheumatologic disorders (e.g. anti-
nuclear antibody and other tests). Based on clinical findings and family history, testing for
phenotypic or genotypic findings of specific neutropenic syndromes (Table 2) may be
indicated, often in consultation with a geneticist.
Laboratory testing in transient neutropenia should be directed at underlying diseases,

particularly treatable infectious agents such as bacteria, protozoa, and HIV.
Management of Isolated Neutropenia

Acute infections
Fever in the setting of profound neutropenia is a medical emergency requiring immediate
treatment with broad spectrum antibiotics. Patients with ANC of 0.2 × 109/L or less almost
invariably require hospital admission for IV antibiotics, with the choice of drugs depending
upon local community and/or hospital flora and antibiotic sensitivities. Importantly,
antibiotic therapy should include anaerobic coverage when fever is accompanied by
abdominal pain, as may recur frequently in cyclic neutropenia. Patients with an ANC 0.2 ×
109/L usually require admission, but culturing and out-patient antibiotics may be used for
some with more benign forms of neutropenia, such as chronic autoimmune neutropenia of
infancy, with relatively good delivery of neutrophils to tissues sites of infection.

Chronic Neutropenia
Individuals with the diagnosis of chronic neutropenia who maintain ANC>1.0 × 109/L on G-
CSF therapy may be evaluated and treated as would any non-neutropenic patients. Those in
the intermediate range of ANC 0.5–1.0 × 109/L need evaluation on a case-by-case basis.
Precautions to Avoid infections

Although many families try to sterilize their living quarters with disinfectants, simple soap-
and-water hygiene and hand-washing, plus a few common-sense precautions are sufficient.
In fact, most measures are not only inconvenient but ineffective, because the source of most
infections in neutropenic patients are their own skin and gut flora. Although neutropenia
does not impair defense against viral infections, avoidance of very crowded areas or close
contact with infected individuals may decrease the likelihood of a precautionary admission
for febrile neutropenia or for virus-induced mucosal breach to provide entry for a secondary
bacterial infection. To avoid invasive fungal infection, neutropenic patients should also
avoid highly contaminated sources such as mulch, dusty construction or demolition sites,
and bird or animal waste. Good dental hygiene is also important, to minimize chronic
gingivitis and tooth loss.
Myeloid Growth Factor Therapy

Hematopoiesis is regulated by a family of hematopoietic growth factors; the myeloid-
specific cytokine granulocyte colony-stimulating factor (G-CSF) is the principal regulator of

the blood neutrophil count. Recombinant human G-CSF (filgrastim; Neupogen®, Amgen,
Inc., Thousand Oaks, CA) is now widely used to stimulate neutrophil production in patients
with chemotherapy-induced neutropenia. It is also very useful for management of severe
chronic neutropenia, with slightly different principles governing its administration.
Randomized controlled trials established that patients with congenital, cyclic and idiopathic
neutropenia have fewer mouth ulcers, febrile events and infections when treated with daily,
subcutaneous G-CSF.11;41 In the original trials G-CSF was given with careful adjustment of
the daily dose to increase counts to the low-normal range, i.e., to raise counts to
approximately 2 × 109/L. Subsequently, in work overseen by the Severe Chronic
Neutropenia International Registry (SCNIR), it has been learned that a G-CSF dose
sufficient to maintain blood neutrophils greater than approximately 1.0 × 109/L is sufficient
for many patients. G-CSF can be administered every other day or three days per week for
many patients, particularly those with idiopathic, autoimmune, or cyclic neutropenia. In
contrast to patients receiving G-CSF after chemotherapy, is very important to give the
lowest effective dose of G-CSF. Ordinarily it is easier to start with a very low dose, 0.5 to 3
mcg per kilogram per day given on a daily basis, going up gradually to find the lowest
effective dose and then giving the injections less often. Both children and adults respond
well to G-CSF and adverse events are relatively infrequent. The most common acute adverse
events associated with G-CSF therapy are bone pain and headache. Less frequent
administration of larger doses can intensify bone pain, so weekly or twice weekly injections
are seldom tolerated, and increasing the frequency of administration may ameliorate pain in
some patients. Injection site reactions, fever, chills and other acute inflammatory responses
are quite uncommon. G-CSF has now been administered to many patients with severe
chronic neutropenia on a daily or alternate day basis for more than 10 years. Treatment
responses tend to be quite stable once an effective dose for the individual patient is found.
The dose should be gradually adjusted for body weight in growing children, with monitoring
of the response.
From the beginning of long-term use of G-CSF to treat chronic neutropenia, there have been
concerns that this growth factor might stimulate development of leukemia. Before G-CSF

was available it was known that patients with SCN are at risk of developing AML. For this
reason the SCNIR was established to determine the risk of AML during long-term G-CSF
therapy. This observational study has established that patients with severe congenital
neutropenia who respond poorly, i.e., requiring more than the median dose of 8 mcg/kg/day,
have a greater risk of AML than patients responding to lower doses.42;43 Patients with
cyclic, idiopathic and autoimmune neutropenia, appeared to have virtually no risk of
evolving to develop MDS or AML on long-term G-CSF treatment.42 Recent studies also
suggest that some ELANE mutations are associated with a higher development of MDS/
AML than others.23;44 Currently most experts believe that the risk of MDS/AML is largely
intrinsic and related to the underlying specific genetic cause of neutropenia, but it is
difficult, if not impossible, to rule out G-CSF as a contributing risk factor for development
of AML in these patients.
It is important to keep in mind that the major objective of G-CSF therapy is to provide a
normal life style, and patients with corrected ANCs on G-CSF therapy do not need to pursue
any precautions beyond those practiced by their normal peers. It is also important to treat
only patients with a clinical history of infections and problems with oral health sufficient to
justify regular and expensive, long-term injection therapy. An individual patient can be
evaluated by a brief clinical trial to determine the response to G-CSF and the benefits of
treatment; ordinarily only about 4 to 6 weeks are sufficient to make this assessment. In
patients with neutropenia responding to G-CSF, discontinuation of this therapy leads to
return of neutrophil levels to their baseline, usually within a few days
Alternatives to G-CSF Treatment

There are no other hematopoietic growth factors, including GM-CSF, which are of proven
efficacy for long-term treatment of chronic neutropenia. For many years corticosteroids
were used. These agents may increase counts modestly but do not stimulate neutrophil
production and carry the added risk of increasing the patient’s susceptibility to infection, as
well as multiple additional toxicities. Lithium salts, androgens and vitamin therapies are also
not of proven benefit. Pegylated G-CSF has now been used in many patients; most respond
but some respond excessively with marked leukocytosis, bone pain, and even, rarely,
infiltration of the tissues by neutrophils.45;46 Neutrophil transfusions are a potential therapy
for acute neutropenia but are not suitable as a long term approach to management because of
the likelihood of allo-immunization and severe transfusion reactions.
Hematopoietic stem cell transplantation is an alternate therapy which can be used in patients
failing to respond to G-CSF (i.e., requiring > 20 mcg/kg/day, an inconvenient dose to try to
administer on a long term basis) or with high risk of evolving into MDS/AML (e.g.
requirement for high doses of G-CSF or presence of abnormal cytogenetic clones in the
bone marrow). Transplantation, with or without pre-transplant chemotherapy, also is used as

part of the treatment strategy for patients with frank MDS or AML. At present there is no
clear consensus about the frequency and specific markers to use as indicators for
hematopoietic transplantation. Success of a transplant also depends upon the availability and
quality of the match of the potential donor and the recipient. Consultation with an expert in
hematopoietic stem cell transplantation is highly recommended for patients not responding
well to G-CSF, developing cytopenias while on G-CSF, or developing chromosomal
changes or increasing myeloblasts in the marrow.
Supportive care
Chronic periodontal disease is a hallmark of untreated or refractory neutropenia. Good
dental hygiene and regular professional treatment are necessary to forestall or prevent tooth
loss, and far outweigh any theoretical risk of bacteremia from local trauma. Psychosocial

support can help alleviate the psychological and financial burdens of a chronic illness, and
can be provided both by health professionals and by patient/parent groups such as the
National Neutropenia Network in the U.S. (http://www.neutropenianet.org/) and the
Neutropenia Support Association, Inc., in Canada (http://www.neutropenia.ca/).
Acknowledgments
Supported in part by NIH grants R01DK054369 and R24AI049393
Abbreviations
AML acute myeloid leukemia

ANC absolute neutrophil count
CyN cyclic neutropenia
G-CSF granulocyte colony-stimulating factor
LGL large granular lymphocyte
MDS myelodysplastic syndrome
SCN severe congenital neutropenia
References
1. Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the
U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007; 146:486–
492. [PubMed: 17404350]
2. Reich D, Nalls MA, Kao WH, et al. Reduced neutrophil count in people of African descent is due to
a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 2009;
5:e1000360. [PubMed: 19180233]
3. Dale DC, Alling DW, Wolff SM. Application of time series analysis to serial blood neutrophil
counts in normal individuals and patients receiving cyclophosphamide. Br J Haematol. 1973;
24:57–644. [PubMed: 4715138]
4. Dale, DC. Neutropenia and neutrophilia. In: Lichtman, MA.; Kipps, TJ.; Kaushansky, K.; Beutler,
B.; Seligsohn, U.; Prchal, JT., editors. Williams Hematology. New York: Mcgraw-Hill; 2010. p.
939-950.
5. Dinauer, MC.; Newburger, PE. The phagocyte system and disorders of granulopoiesis and
granulocyte function. In: Orkin, SH.; Ginsburg, D.; Nathan, DG.; Look, AT.; Fisher, DA.; Lux, SE.,
editors. Nathan & Oski’s Hematology of Infancy and Childhood. Philadelphia: Saunders Elsevier;
2009. p. 1109-1217.
6. Husain EH, Mullah-Ali A, Al-Sharidah S, Azab AF, Adekile A. Infectious etiologies of transient
neutropenia in previously healthy children. Pediatr Infect Dis J. 2012; 31:575–577. [PubMed:
22414904]
7. Savard M, Gosselin J. Epstein-Barr virus immunossuppression of innate immunity mediated by
phagocytes. Virus Res. 2006; 119:134–145. [PubMed: 16545476]
8. Sloand E. Hematologic complications of HIV infection. AIDS Rev. 2005; 7:187–196. [PubMed:
16425959]
9. Dale DC, Wolff SM. Studies of the neutropenia of acute malaria. Blood. 1973; 41:197–206.
[PubMed: 4575057]
10. Olliaro P, Djimde A, Dorsey G, et al. Hematologic parameters in pediatric uncomplicated
Plasmodium falciparum malaria in sub-Saharan Africa. Am J Trop Med Hyg. 2011; 85:619–625.
[PubMed: 21976561]
11. Dale DC, Bolyard AA, Schwinzer BG, et al. The Severe Chronic Neutropenia International
Registry: 10-Year follow-up report. Support Cancer Ther. 2006; 3:220–231. [PubMed: 18632498]

12. Bux J. Human neutrophil alloantigens. Vox Sang. 2008; 94:277–285. [PubMed: 18208407]
13. Clay ME, Schuller RM, Bachowski GJ. Granulocyte serology: current concepts and clinical
signifcance. Immunohematology. 2010; 26:11–21. [PubMed: 20795313]
14. Bruin M, Dassen A, Pajkrt D, et al. Primary autoimmune neutropenia in children: a study of
neutrophil antibodies and clinical course. Vox Sang. 2005; 88:52–59. [PubMed: 15663723]
15. Bux J, Behre G, Jaeger G, Welte K. Diagnosis and clinical course of autoimmune neutropenia in
infancy: Analysis of 240 cases. Blood. 1998; 91:181–186. [PubMed: 9414283]
16. Kwon SW, Procter J, Dale JK, Straus SE, Stroncek DF. Neutrophil and platelet antibodies in
autoimmune lymphoproliferative syndrome. Vox Sang. 2003; 85:307–312. [PubMed: 14633257]
17. Podjasek JC, Abraham RS. Autoimmune cytopenias in common variable immunodeficiency. Front
Immunol. 2012; 3:189. [PubMed: 22837758]
18. Fung YL, Silliman CC. The role of neutrophils in the pathogenesis of transfusion-related acute
lung injury. Transfus Med Rev. 2009; 23:266–283. [PubMed: 19765516]
19. Mohan SR, Maciejewski JP. Diagnosis and therapy of neutropenia in large granular lymphocyte
leukemia. Curr Opin Hematol. 2009; 16:27–34. [PubMed: 19057202]
20. Lamy T, Loughran TP Jr. How I treat LGL leukemia. Blood. 2011; 117:2764–2774. [PubMed:
21190991]
21. Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of
human neutrophil granulocytes. Annu Rev Immunol. 2011; 29:399–413. [PubMed: 21219176]
22. Boxer LA, Newburger PE. A molecular classification of congenital neutropenia syndromes. Pediatr
Blood Cancer. 2007; 49:609–614. [PubMed: 17584878]
23. Dale, DC. Pagon, RA.; Bird, TD.; Dolan, CR.; Stephens, K.; Adams, MP., editors. [Accessed
11-24-2012] ELANE-Related Neutropenia. GeneReviews. http://www.ncbi.nlm.nih.gov/books/
NBK1533/
24. Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in
congenital and cyclic neutropenia. Blood. 2000; 96:2317–2322. [PubMed: 11001877]
25. Grenda DS, Murakami M, Ghatak J, et al. Mutations of the ELA2 gene found in patients with
severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood.
2007; 110:4179–4187. [PubMed: 17761833]
26. Kollner I, Sodeik B, Schreek S, et al. Mutations in neutrophil elastase causing congenital
neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein
response. Blood. 2006; 108:493–500. [PubMed: 16551967]
27. Newburger PE, Pindyck TN, Zhu Z, et al. Cyclic neutropenia and severe congenital neutropenia in
patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype
determination by modifying genes. Pediatr Blood Cancer. 2010; 55:314–317. [PubMed:
20582973]
28. Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causes autosomal recessive severe
congenital neutropenia (Kostmann disease). Nat Genet. 2006; 39:86–92. [PubMed: 17187068]
29. Boztug K, Appaswamy G, Ashikov A, et al. A syndrome with congenital neutropenia and
mutations in G6PC3. N Engl J Med. 2009; 360:32–43. [PubMed: 19118303]

30. Boztug K, Rosenberg PS, Dorda M, et al. Extended spectrum of human glucose-6-phosphatase
catalytic subunit 3 deficiency: novel genotypes and phenotypic variability in severe congenital
neutropenia. J Pediatr. 2012; 160:679–683. [PubMed: 22050868]
31. Germeshausen M, Grudzien M, Zeidler C, et al. Novel HAX1 mutations in patients with severe
congenital neutropenia reveal isoform-dependent genotype-phenotype associations. Blood. 2008;
111:4954–4957. [PubMed: 18337561]
32. Ancliff PJ, Blundell MP, Cory GO, et al. Two novel activating mutations in the Wiskott-Aldrich
syndrome protein result in congenital neutropenia. Blood. 2006; 108:2182–2189. [PubMed:
16804117]
33. Xia J, Bolyard AA, Rodger E, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS,
WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009; 147:535–
542. [PubMed: 19775295]

34. Guerry D, Dale DC, Omine M, Perry S, Wolff SM. Periodic hematopoiesis in human cyclic
neutropenia. J Clin Invest. 1973; 52:3220–3230. [PubMed: 4750451]
35. Beekman R, Valkhof MG, Sanders MA, et al. Sequential gain of mutations in severe congenital
neutropenia progressing to acute myeloid leukemia. Blood. 2012; 119:5071–5077. [PubMed:

22371884]
36. Skokowa J, Steinemann D, Makaryan V, et al. RUNX1 Mutations Are the Most Frequent
Leukemia Associated Mutations in Congenital Neutropenia Patients. ASH Annual Meeting
Abstracts. 2012; 120:7.
37. de Alarcon PA, Goldberg J, Nelson DA, Stockman JA III. Chronic neutropenia: diagnostic
approach and prognosis. Am J Pediatr Hematol Oncol. 1983; 5:3–9. [PubMed: 6602565]
38. Boxer LA, Bolyard AA, Schwinzer B, et al. Antineutrophil antibodies lead to mistaken identity in
severe congenital neutropenia [abstract]. Blood (ASH Annual Meeting Abstracts). 2005; 106:385.
39. Riera NE, Rosso SM, Galan V, et al. Anti-polymorphonuclear neutrophil antibodies in patients
with leukopenia or neutropenia. Int J Lab Hematol. 2010; 32:e96–105. [PubMed: 19594833]
40. Muschter S, Berthold T, Greinacher A. Developments in the definition and clinical impact of
human neutrophil antigens. Curr Opin Hematol. 2011; 18:452–460. [PubMed: 21912255]
41. Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant
human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic
neutropenia. Blood. 1993; 81:2496–2502. [PubMed: 8490166]
42. Rosenberg PS, Zeidler C, Bolyard AA, et al. Stable long-term risk of leukaemia in patients with
severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol. 2010; 150:196–199.
[PubMed: 20456363]
43. Rosenberg PS, Alter BP, Bolyard AA, et al. The incidence of leukemia and mortality from sepsis
in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood. 2006;
107:4628–4635. [PubMed: 16497969]
44. Makaryan V, Zeidler C, Bolyard AA, et al. Clinical Outcomes for Patients with Severe Chronic
Neutropenia Due to Mutations in the Gene for Neutrophil Elastase, ELANE. ASH Annual Meeting
Abstracts. 2012; 120:3275.
45. Beaupain B, Leblanc T, Reman O, et al. Is pegfilgrastim safe and effective in congenital
neutropenia? An analysis of the French Severe Chronic Neutropenia registry. Pediatr Blood
Cancer. 2009; 53:1068–1073. [PubMed: 19618456]
46. Fioredda F, Calvillo M, Lanciotti M, et al. Pegfilgrastim in children with severe congenital
neutropenia. Pediatr Blood Cancer. 2010; 54:465–467. [PubMed: 19927291]

Table 1
Causes of transient neutropenia
INFECTION
Viral Cytomegalovirus, Epstein-Barr virus, HIV, influenza, parvovirus B19
Bacterial Brucella, paratyphoid, tuberculosis, tularemia, typhoid; Anaplasma phagocytophilum and other rickettsia
Protozoan Plasmodium vivax, P. falciparum

DRUGS
Anticonvulsant Carbamazepine, valproate
Antimicrobial Sulfonamides, penicillins, trimethoprim/sulfamethoxazole
Antipsychotic Clozapine, olanzapine, phenothiazines
Antirheumatic Gold, levamisole, penicillamine
Antithyroid Methimazole, propylthiouracil
Other Aminopyrine, deferiprone, rituximab, levamisole-adulterated cocaine
IMMUNE
Neonatal isoimmune
Autoimmune

Table 2
Causes of chronic neutropenia
EXTRINSIC
Nutritional Vitamin B12, folate, copper, protein-calorie
Immune Autoimmune
Congenital immunological disorder
Systemic autoimmune disorder
INTRINSIC
Myelodysplasia
Acquired bone marrow failure Aplastic anemia
Congenital bone marrow failure
Isolated neutropenia Severe congenital neutropenia

Cyclic neutropenia
Neutropenic syndromes Disorders of granule sorting: Chédiak-Higashi syndrome, Cohen syndrome, Griscelli syndrome type 2,
Hermansky-Pudlak syndrome type 2, and p14 deficiency
Disorders of metabolism: Glycogen storage disease type 1b, Barth syndrome, Pearson syndrome
Disorders of immune function: Hyper-IgM syndrome, WHIM syndrome, cartilage-hair hypoplasia,

Schimke immuno-osseous dysplasia
Disorders of molecular homeostasis: Dyskeratosis congenita, Fanconi anemia, Shwachman- Diamond

syndrome
Idiopathic

Ni Hms 490811

Uploaded by

Copyright:

Available Formats

Ni Hms 490811

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Ni Hms 490811

Uploaded by

Copyright:

Available Formats

NIH Public Access

Semin Hematol. 2013 July ; 50(3): 198–206. doi:10.1053/j.seminhematol.2013.06.010.

Evaluation and Management of Patients with Isolated

cytopenias due to splenomegaly, bone marrow replacement, or myelosuppression by

(1500/mm3), encompasses a wide range of diagnoses, from normal variants to life-

© 2013 Elsevier Inc. All rights reserved.

congenital neutropenias now permits genetic diagnosis in many cases.

Transient and Chronic Neutropenia

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

neutropenia need careful diagnostic testing because of the severity of infectious

Extrinsic and Acquired Causes of Chronic Neutropenia

Immune and autoimmune neutropenias

incompatibility, leading to transplacental transfer of antibodies to specific epitopes

Chronic autoimmune neutropenia of infancy and early childhood is a relatively common

In older children, chronic autoimmune neutropenia or multiple immune cytopenias should

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

positive, CD4/CD8 double negative T cells or of serum immunoglobulins, respectively.

In adult women, autoimmune and idiopathic neutropenia are relatively common,

Neutropenia commonly accompanies, or can be a presenting feature of, large granular

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

development. In SCN, apoptosis at the promyelocyte stage of development leads to apparent

antibiotic exposures. A history of viral infections, other symptoms suggesting

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

Bone marrow examination—A bone marrow examination is valuable to identify

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

Neutrophil antibodies and antigens—Testing for anti-neutrophil antibodies, by

Genetic testing—Identification of the specific gene and mutation responsible for

Laboratory testing in transient neutropenia should be directed at underlying diseases,

Management of Isolated Neutropenia

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

Precautions to Avoid infections

Myeloid Growth Factor Therapy

specific cytokine granulocyte colony-stimulating factor (G-CSF) is the principal regulator of

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

return of neutrophil levels to their baseline, usually within a few days

Alternatives to G-CSF Treatment

bone marrow). Transplantation, with or without pre-transplant chemotherapy, also is used as

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

Neutropenia Support Association, Inc., in Canada (http://www.neutropenia.ca/).

AML acute myeloid leukemia

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

mutations in G6PC3. N Engl J Med. 2009; 360:32–43. [PubMed: 19118303]

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

neutropenia progressing to acute myeloid leukemia. Blood. 2012; 119:5071–5077. [PubMed:

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

Protozoan Plasmodium vivax, P. falciparum

Anticonvulsant Carbamazepine, valproate

Antimicrobial Sulfonamides, penicillins, trimethoprim/sulfamethoxazole

Antipsychotic Clozapine, olanzapine, phenothiazines

Antirheumatic Gold, levamisole, penicillamine

Antithyroid Methimazole, propylthiouracil

Other Aminopyrine, deferiprone, rituximab, levamisole-adulterated cocaine

Semin Hematol. Author manuscript; available in PMC 2014 July 01.

Congenital immunological disorder

Systemic autoimmune disorder

Acquired bone marrow failure Aplastic anemia

Congenital bone marrow failure

Isolated neutropenia Severe congenital neutropenia

Disorders of immune function: Hyper-IgM syndrome, WHIM syndrome, cartilage-hair hypoplasia,

Schimke immuno-osseous dysplasia