The Continually Updated Clinical Reference
[This extracts parts of the original paper that pertain to a specific case
treating cancer patient]
Article Last Updated: Aug 9, 2006
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 is a member of the following medical societies: American
Association for the Advancement of Science, American Heart Association, and
American Society of Hematology
Coauthor(s): Christopher D Braden, DO, Fellow in Hematology/Oncology, Division
of Hematology/Oncology, Loyola University Medical Center
Editors: Karen Seiter, MD, Professor, Department of Internal Medicine,
Division of Oncology/Hematology, New York Medical College; Francisco Talavera,
PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD,
Director of Cancer Institute, Baptist Medical Center; Rajalaxmi McKenna, MD,
FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants,
SC, Good Samaritan Hospital, Advocate Health Systems; Emmanuel C Besa, MD,
Professor, Department of Medicine, Division of Hematologic Malignancies,
Kimmel Cancer Center, Thomas Jefferson University
Synonyms and related keywords: neutropenia, Schultz disease, agranulocytosis,
granulocytopenia, leukopenia, neutropenic fever, circulating neutrophils,
granulocyte colony-stimulating factor, G-CSF, bone marrow transplantation
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.
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.
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
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
Neutropenia occurs more commonly in females than in males.
Elderly individuals have a higher incidence rate than younger individuals
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
- 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
- Records of past CBCs establish the chronicity of the
- Determining the age at onset aids in the differential diagnosis.
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
- Lymphadenopathy is a possible indication of disseminated infection
or, possibly, malignancy.
- For perirectal infections, look for abscesses or mucous membrane
- For perineal infections, look for rashes, abscesses, or
- Lung infections usually are bacterial or fungal pneumonias.
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
- 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
1) This disorder was described by Rolf Kostmann in 1956 as
an autosomal recessive disorder in a large family from Sweden.
2) 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.
3) 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
- 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
- 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
- Idiopathic chronic severe neutropenia: This disorder is a
diagnosis of exclusion. These patients exhibit infections and severe
- 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
- 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
- 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
- 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
- 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
- Acquired neutropenia caused by drugs and chemicals, excluding
- 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
- 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.
G-CSF that activates and stimulates 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
5 mcg/kg/d IV/SC
Administer as in adults
C - Safety for use during pregnancy has not been established.
Do not use 12-24 h before or 24 h after administering cytotoxic
chemotherapy because will increase sensitivity of rapidly dividing myeloid
cells to cytotoxic chemotherapy; obtain CBC 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