Benign Disorders of WBC:

Neutrophilia and Neutropenia

Elizabeth Quinlan-Bohn, MS, PA-C
Clinical Assistant Professor
DYouville College PA Program
October 23, 2014

What does the term benign WBC

disorders mean?
The term benign WBC disorders refers to
non-malignant causes of either decreased
or elevated WBCs.
Therefore, for the purpose of this
discussion, we will not include any
malignant disorders (e.g., leukemia) or
HIV-related illness which directly result in
WBCs or WBCs.

Blood Cell Maturation

Important Definitions
Granulocyte:
This term refers to a category white blood cells which have granules
in the cytoplasm, and includes: neutrophils, basophils, and
eosinophils.
Granulocytopenia:
This term refers to a reduced granulocyte count.
Neutropenia:
This term refers to a reduced neutrophil count, and typically is
used when the absolute neutrophil count (ANC) < 1,500. The risk
for infection increases once the ANC < 1,000, and the risk for severe
life-threatening infection increases significantly if the ANC < 500.
Neutrophilia:
This term refers to an increase in the absolute neutrophil count
(ANC) > 7,500

More Important Definitions

Agranulocytosis:
This term refers to a complete absence of blood granulocytes, and is
often used to indicate very severe neutropenia when the ANC < 500.
Absolute Neutrophil Count (ANC):
[Total WBC x (% segmented neutrophils + % bands)] = ANC
Leukopenia:
This term refers to a total WBC below the normal range, and generally
that is defined as a total WBC < 4,300. For many institutions, the normal
WBC range = 4.5K-11K.

Pancytopenia:
This term refers to a decrease in the number of blood cells from all
three cell lines: WBCs, RBCs, and platelets.

More Important Definitions

Left shift or shift to the left: The

concept of a left shift or shift to the left
originated in 1904, when German scientist
Josef Arneth published a monograph,
Neutrophile Leucocytes in Infectious
Diseases, based on a study of blood
smears from many types of acute and
chronic infections. He divided the
neutrophils into five classes, based on the
number of lobes in the nucleus.

More Important Definitions

Class I: horseshoe shape; one lobe (band)

Class II: two nuclear lobes
Class III: three nuclear lobes
Class IV: four nuclear lobes
Class V: five or more nuclear lobes
Arneth determined that younger neutrophils
had one or two nuclear lobes, and older
neutrophils had increasing number of lobes.

More Important Definitions

Arneth found that when infection was present,
there was an increase in Class I and Class II
cells, representing an influx of less mature
neutrophils being released by the body in
response to the toxic state.
Hence, this was termed a shift to the left.
The Arneth count determined the percentage of
each type of neutrophil in Class I Class V.
While the Arneth count is no longer used today,
the term left shift has endured.

Lets try to calculate the absolute

neutrophil count (ANC)
Mrs. S. is a 42-year-old female with recent onset leukopenia.
On recent CBC, she was noted to have:
Total WBC: 1,800 and Differential: [38S 2B 54L 2M 1E 1BAS]
[38% segs, 2% bands, 54% lymphs, 2% monos, 1% eos,
1% basos]
ANC = [Total WBC x (% segmented neutrophils + % bands)]
ANC = [1,800 x (38% + 2%)] = [1,800 x 0.40] = 720
Based on this information, is Mrs. S. neutropenic?

Life Cycle of the Neutrophil

Phase I: Bone Marrow

10-14 days

Phase II: Peripheral Blood

life of peripheral blood neutrophils is 6-10 hours

Phase III: Tissue Phase

2-4 days

Neutrophils not actively involved in an inflammatory

response in the tissue will die (apoptosis).

Life Cycle of the Neutrophil

Phase One: Bone Marrow Phase
Takes approximate 10-14 days
Most of the bodys neutrophil pool exists in the bone marrow
As neutrophils mature, they develop the capacity to enter the
bloodstream due to increased deformability and changes in
adhesion proteins on surface membranes
Stimulation of neutrophil release from the bone marrow with GCSF*, GM-CSF**, corticosteroids, or endotoxin administration can
result in doubling or tripling of the blood neutrophil count within
3-5 hours.
Ref: Scientific American Web MD 2002

*Granulocyte colony stimulating factor

**Granulocyte monocyte colony stimulating factor

Life Cycle of the Neutrophil

Phase Two: Peripheral Blood Phase

Blood half-life of neutrophils is approximately 6-10 hours

In a healthy individual, ~ 5% of the bodys total neutrophils are in the
peripheral blood at any given time. The remaining neutrophils (~ 95% of the
total body neutrophils) reside in the bone marrow, ready to be released in
the event of bacterial infection or other trigger (e.g., G-CSF)
Within the peripheral blood compartment, the neutrophils are equally
divided between the circulating pool and the marginating pool
Cells in the marginating pool can be swept into the circulation within
minutes by:
a) endogenous or exogenous epinephrine
b) as a result of exercise
c) any cause of cardiac output
This response is known as demargination, and is also quickly reversible.
The process whereby cells in the circulating pool enter the marginating
pool is known as margination.

Ref: Scientific American Web MD 2002

Equilibrium between circulating pool and

marginating pool neutrophils

Peripheral Blood Neutrophils

Circulating pool Marginating pool
At any given time, the number of neutrophils
in the circulating pool is approximately
equal to the number of neutrophils in the
marginating pool.

http://www.ndsu.nodak.edu/instruct/tcolvill/435/hematopoiesis.htm

Life Cycle of the Neutrophil

Phase Three: Tissue phase
Neutrophils in the marginating pool leave the blood and enter the
tissues by migrating between endothelial cells and penetrating the
capillary basement membrane. They remain in the tissues for 2-4
days.
It is believed that neutrophils that are not actively engaged in an
extravascular inflammatory process will die by a process known as
apoptosis, in the blood or bone marrow. This is a process where
cell death occurs by a predetermined sequence of events, resulting
in elimination of the cell without releasing harmful substances into
the surrounding area.
Ref: Scientific American Web MD 2002
Ref: http://www.medterms.com/script/main/art.asp?articlekey=11287

Endothelial cells

Almost all tissues depend on a blood supply, and the blood supply depends
on endothelial cells, which form the linings of the blood vessels.

The largest blood vessels are arteries and veins, which have a thick, tough
wall of connective tissue and many layers of smooth muscle cells.

The wall is lined by an exceedingly thin single sheet of endothelial cells,

the endothelium, separated from the surrounding outer layers by a basal
lamina.

Endothelial cells line the entire vascular system, from the heart to the
smallest capillary, and control the passage of materialsand the transit of
white blood cellsinto and out of the bloodstream.

Ref: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.section.4126

http://home.ccr.cancer.gov/connections/features3.asp

Causes of Neutropenia
Increased Neutrophil Destruction
Primary autoimmune neutropenia
Secondary autoimmune neutropenia
Drug induced neutropenia

Decreased or Ineffective Neutrophil Production

Megaloblastic Anemia
Drug-induced decreased or ineffective neutrophil production
Infections
Congenital defects
Chronic idiopathic neutropenia (CIN)
Cyclic neutropenia
T-cell lymphocyte induced

Causes of Neutropenia
Abnormal Distribution
Sequestration of Neutrophils
Margination of Neutrophils

Miscellaneous or Combination Causes

Pseudoneutropenia
Benign chronic neutropenia (including ethnic neutropenia
variant)
Complement-activated neutropenia

Quick Review: Causes of Neutropenia

Increased neutrophil destruction

Decreased or ineffective neutrophil
production
Abnormal distribution
Miscellaneous or combination causes

Causes of Neutropenia: Increased

Neutrophil Destruction
Autoimmune neutropenia:
In autoimmune neutropenia, the body develops
antibodies to white blood cells (WBCs). This can be due
to either a primary or secondary disorder.
Primary autoimmune neutropenia (AIN) is a rare
disorder, and most often is diagnosed in early childhood,
with the average age of onset of 6-12 months. Infections
are typically mild or moderate; serious infections are
uncommon. Spontaneous remission occurs in 95% of
cases of childhood AIN within 2 years.

Causes of Neutropenia: Increased

Neutrophil Destruction
Secondary autoimmune neutropenia:
Antineutrophil antibodies have been reported in conjunction with
other autoimmune disorders including systemic lupus
erythemotosus (SLE), and rheumatoid arthritis (RA).
Approximately 50% of patients with SLE will develop neutropenia,
although less than 5% of patients with SLE develop severe
neutropenia.
Only ~ 1% of patients with RA will develop Feltys syndrome, and
these patients may be at increased risk for non-Hodgkins
lymphoma.
Feltys syndrome = triad of RA + splenomegaly + neutropenia.

Causes of Neutropenia: Increased

Neutrophil Destruction
Drug-induced increased neutrophil
destruction:
Many different drugs can cause this type of
neutropenia, but antibiotics are most commonly
implicated. Examples include: sulfa-containing
medications, cephalosporins, and penicillins.
Ref: http://www.harrisonpractice.com/practice/ub/view/Harrisons_Practice/Neutropenia/141535

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
Megaloblastic anemia:
Megaloblastic anemia is a type of macrocytic anemia caused by
either vitamin B12 or folic acid deficiency.
Recall that vitamin B12 and folate are needed for DNA synthesis.
Folic acid or vitamin B12 deficiency may result in ineffective
neutrophil production:
Lack of these essential cofactors interferes with nucleic acid
synthesis of myeloid precursors in the bone marrow and
results in ineffective graunulopoiesis.
Ref: Wintrobes Clinical Hematology, by Maxwell Myer Wintrobe & John P. Greer (2004)

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
Drug-induced Decreased or Ineffective Neutrophil Production:
Many drugs can cause decreased neutrophil production by
directly suppressing the bone marrow. For example,
chemotherapy drugs induce a very predictable neutropenic period
related to both the dose of the drug and the frequency of the
chemotherapy regimen being used. Other examples include:
antiretroviral drugs (e.g., zidovudine), chloramphenicol, and
trimethoprim-sulfamethoxazole (Bactrim).
Drugs may selectively cause a decreased production of
neutrophils, without causing either anemia or thrombocytopenia.
Multiple mechanisms for drug-induced decreased neutrophil
production exist, and the list of potential offending agents is quite
extensive.

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
Infection-associated neutropenia:
Infection is one of the most common causes of neutropenia.
There are multiple types of infections that can result in decreased
neutrophil production. For example:
a) Chronic infections such as tuberculosis, brucellosis, malaria,
and typhoid fever can result in decreased neutrophil production due
to bone marrow suppression by the infection.
b) Viral infections commonly cause neutropenia in the pediatric
setting. Examples include: respiratory syncytial virus (RSV),
influenza, measles, rubella, and varicella.

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
Infection-associated neutropenia (contd):
c) Some viral agents such as those causing infectious
hepatitis and infectious mononucleosis can cause
neutropenia and pancytopenia by infecting the
hematologic progenitor cells in the bone marrow. This
may result in severe neutropenia.
d) Infection-related neutropenia may occur with acute and
chronic bacterial, viral, parasitic, and rickettsial
diseases.

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
Congenital defects:
There are a number of congenital disorders that cause
neutropenia, including, but not limited to the following:
a) Severe congenital neutropenia syndrome (also known as
Kostmann syndrome)
b) Shwachman-Diamond syndrome (neutropenia, short stature,
pancreatic insufficiency, skeletal abnormalities, developmental
retardation)
c) Chdiak-Higashi syndrome (neutropenia, oculocutaneous
albinism)
d) Cartilage-Hair Hypoplasia syndrome (neutropenia, short-limbed
dwarfism, fine hair)

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production

Chronic idiopathic neutropenia (CIN): There are a number of

factors that help to distinguish CIN from other chronic neutropenic
states:
Acquired disorder that typically follows a benign and uncomplicated
course.
Median age at diagnosis is 50 years; female:male ratio of 3-6:1
May occur during childhood; with only slight female predominance in
patients < 18 years old
ANC < 1500 for more than three months
No clinical evidence of underlying disease that could be associated
with neutropenia
No history of exposure to radiation, use of chemical compounds, or
intake of drugs that could potentially cause neutropenia
Normal bone marrow karyotype analysis
Absence of antineutrophil antibodies

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
. Cyclic neutropenia:
This is an autosomal dominant trait with variable degrees of
expression. While it may often present during childhood, it can also
present during adulthood.
Typically, this disorder is manifested by predictable periods of
neutropenia approximately every 21 days, lasting 3-4 days.
The patient may complain of mouth sores, malaise, and fatigue.
The patient may also develop bacterial infection and fever during
these periods of neutropenia.

Autosomal Dominant Inheritance

wikis.lib.ncsu.edu

Example of Neutropenia-Related Oral

Ulcers

Causes of Neutropenia: Decreased or

Ineffective Neutrophil Production
T-cell lymphocyte induced neutropenia:
Studies of rheumatoid arthritis patients who are
neutropenic, have demonstrated clonal expansion of
large granular lymphocytes (T-cell lymphocytes) that
may impair neutrophil production, suggesting a
multifactorial basis for the neutropenia associated with
Feltys syndrome. This lymphocytosis may gradually
evolve into a lymphoid malignancy.
Recall that patients with Feltys syndrome are at
increased risk for non-Hodgkins lymphoma.

Causes of Benign Neutropenia: Abnormal

Neutrophil Distribution
Sequestration of neutrophils: Portal HTN
When the spleen becomes congested due to portal hypertension,
the blood flow is preferentially shunted toward the spleen resulting in
splenic sequestration of the blood cells with resultant cytopenias.
Examples of disorders that may cause portal HTN include:
a) Hepatic cirrhosis
b) Budd-Chiari syndrome
(results from hepatic venous outflow obstruction due to thrombosis and can be
caused by infections, myeloproliferative disorders, liver cancer, oral
contraceptive use, among others)

c) Splenic vein thrombosis

d) Hepatitis
e) Portal vein thrombosis
f) Splenic A-V fistula

Hepatic Vascular System

Anatomy of Various Conditions Causing

Portal HTN

http://clinicalexamprep.wordpress.com/tag/gastro/
http://clinicalexamprep.wordpress.com/tag/gastro/

Budd-Chiari Syndrome

Causes of Benign Neutropenia: Abnormal

Neutrophil Distribution
Sequestration of neutrophils: Splenic trapping of neutrophils due
to infection:
In cases of parasitic infections causing splenomegaly, such as acute
malaria, splenic sequestration and accelerated destruction of
neutrophils can cause a resultant neutropenia.
Sequestration of neutrophils: Feltys syndrome:
Recall that splenomegaly is associated with Feltys syndrome. As a
result of the splenomegaly, there can be splenic trapping of
neutrophils and accelerated destruction. These factors contribute to
the multi-factorial neutropenia seen in Feltys syndrome.

Causes of Neutropenia: Abnormal

Neutrophil Distribution
Margination of neutrophils:
Severe bacterial infections release endotoxin into the
bloodstream causing margination, which results in the
neutrophils remaining in the infected tissues and not
returning to the bloodstream, especially in patients with
already depleted bone marrow reserve due to prior
chemotherapy, other drugs, or alcohol. If a patient with
a severe bacterial infection has a low neutrophil
count, this is a grave prognostic sign.

Causes of Neutropenia: Miscellaneous and

Combination Causes
Pseudoneutropenia:

Interestingly, in situations where a patient suffers from chronic anxiety or

other underlying emotional disorder, such as anorexia nervosa, a significant
chronic neutropenia may occur. However, despite the low neutrophil count,
there is no history of recurrent infection. The total body neutrophil pool is
normal, however, a larger portion of their neutrophils are in the marginating
pool rather than the circulating pool. This type of neutropenia is termed
pseudoneutropenia.

In these patients, there may be a dramatic response to epinephrine. Recall

that epinephrine is one of the stiumuli than can cause demargination,
resulting in the movement of neutrophils from the marginating pool to the
circulating pool. Therefore, there is no indication for further evaluation
and treatment of this condition.

Causes of Neutropenia: Miscellaneous and

Combination Causes
Benign chronic neutropenia (BCN):
This condition often begins within the first two years of life (also
known as pediatric benign chronic neutropenia). Most children
are asymptomatic.
A variant of BCN involves persons who are of African, Yemenite
Jewish, or of Western European descent. This is sometimes termed
ethnic neutropenia.
Both the total WBC and ANC may be as low as 50% of normal
levels. In stimulation tests, there is normal granulocyte reserve,
suggesting that the low neutrophil count is related to the degree of
neutrophil marrow release.
Life expectancy is normal, and these patients do not generally
experience recurrent infections.

Causes of Neutropenia: Miscellaneous and

Combination Causes
Complement-activated neutropenia:

The complement system plays an integral role in the bodys defense

against infection and in response to tissue injury. When the system is
working correctly, the complement fragments play a pivotal role in the acute
inflammatory response.

In certain situations, if there is excessive local or systemic complement

activation, the result may be to stimulate the formation of neutrophil
aggregates that are transiently sequestered in the pulmonary capillary
bed, which can result in respiratory distress.

Dialysis patients may experience this type of neutropenia, which is

thought to be stimulated by certain types of dialysis membrane.

Septic patients or patients undergoing cardiopulmonary bypass surgery

may also experience complement-activated neutropenia.

Clinical Evaluation of New-Onset

Neutropenia of Unknown Cause:
Workup of new-onset neutropenia of unknown cause may include:
CBC with differential
Examination of peripheral blood smear
Antinuclear antibody (ANA), Rheumatoid factor (RF), and antineutrophil
antibody testing (to rule out underlying autoimmune disease)
Serum B12 and folate levels (to rule out meglaoblastic anemia)
Serial CBC with differential (ANC calculated serially in cyclic neutropenia)
Assess spleen size (liver/spleen scan, CT scan, or ultrasound to rule out
splenic sequestration)
Obtain bone marrow aspirate and biopsy (to rule out underlying bone
marrow disorders or malignancy)
Epinephrine and prednisone mobilization tests (if suspect benign chronic
neutropenia or pseudoneutropenia) though in clinical practice, these
tests are not routinely done
Complete medication history is required (to rule out drug-induced
neutropenia)

Clinical Evaluation of New-Onset

Neutropenia of Unknown Cause:
Important Questions to Consider:
Is the patient of African American or Yemenite Jewish descent?
Has the patient had recent surgery (CABG) or hemodialysis?
Is the patient septic?
Has the patient had a recent acute illness or infection?
Is there a family history of cyclic neutropenia?
Is there a family history of congenital syndromes associated
with neutropenia?
Does the patient have an underlying emotional disorder (e.g.,
anorexia nervosa or chronic anxiety)?

Treatment of the Afebrile Neutropenic

Patient:
The most appropriate treatment is to address the
underlying condition:
In cases of hypersplenism (enlarged spleen
accompanied by decrease in one or more blood cell
lines), if it can be determined with a significant degree of
clinical certainty that the enlarged spleen is the likely
cause of the neutropenia, splenectomy may be helpful.
In Feltys syndrome, 80-90% of patients will respond to
splenectomy, though the result is generally transient. At
least 30% of the patients relapse, and even among those
with normalization of the neutrophil count, recurrent
infections still may occur in 1/3 of these patients.
Recall Check: What is the clinical triad in Feltys
syndrome?

Treatment of the Afebrile Neutropenic

Patient:
Antibody-mediated neutropenia or lymphocyte induced
neutropenia may respond to corticosteroids.
Corticosteroids cause an increase in neutrophil count
within 4-6 hours, due to release of neutrophils from the
bone marrow storage pool, and a decrease in the
movement of neutrophils from the marginating pool into
tissues.
Helpful hint: Corticosteroids will cause an elevated
WBC with an associated lymphopenia (decrease in
number of lymphocytes) and no left shift (i.e., bands
should remain within normal range in absence of
infection).

Treatment of the Afebrile Neutropenic

Patient:
In cases of complement-activated neutropenia, treatment with
corticosteroid (e.g., methylprednisolone) may help decrease the
neutrophil aggregates and improve respiratory function.
Granulocyte-Colony Stimulating Factor (G-CSF) has been used
successfully (1-5 g/kg/day) in treatment of congenital, idiopathic,
and cyclic neutropenia, and may hasten bone marrow recovery
following chemotherapy.
If neutropenia is mild, treatment of any underlying infection and
discontinuation of any possible offending drugs may be all that is
needed.
However, repeat CBC with differential must be done within 1-2
weeks, since in some patients, the neutrophil count may then be
normalized. If, however, the patient appears very ill, even if the ANC
is approaching adequate levels, more frequent and intensive followup may be indicated.

How does G-CSF Work?

Granulocyte colony stimulating factors (CSFs), which
are also known as myeloid growth factors, have been
evaluated for prophylactic use following the
administration of chemotherapy when neutropenia is
anticipated ("primary prophylaxis"), during retreatment
after a previous cycle of chemotherapy that caused
neutropenic fever ("secondary prophylaxis"), and to
shorten the duration of severe chemotherapy-induced
neutropenia in patients who have neutropenia without
fever ("afebrile neutropenia). They are generally not
recommended for routine use in patients with
established fever and neutropenia.

http://www.uptodate.com/contents/use-of-granulocyte-colony-stimulating-factors-in-patients-with-chemotherapyinduced-neutropenia

How does G-CSF Work?

Because of the potential sensitivity of rapidly dividing
myeloid cells to cytotoxic chemotherapy, growth factors
should be discontinued several days before the next
chemotherapy treatment and they should not be given
on the same day as chemotherapy. Experience from
clinical trials indicates that myelosuppression is
more profound if the myeloid growth factors were
given immediately prior to or on the same day as the
chemotherapy. For the same reason, growth factors
should not be given concurrently with radiation therapy
directed at portals containing active marrow.

http://www.uptodate.com/contents/use-of-granulocyte-colony-stimulating-factors-in-patients-with-chemotherapyinduced-neutropenia

How does G-CSF Work?

G-CSF is generally started 24-72 hours
after cessation of chemotherapy, and often
continued with twice weekly CBC
monitoring until after the WBC nadir has
been reached, and recovery of neutrophil
counts has begun.
It is important not to prematurely
discontinue G-CSF before the WBC nadir
has been reached.

Clinical Presentation of the Febrile

Neutropenic Patient:
Signs/symptoms:
Regardless of the underlying mechanism for neutropenia, the
presenting signs and symptoms may be similar.
Recall that since there is a very diminished number of neutrophils in
the peripheral blood, the patient may not have sufficient neutrophils
to make an inflammatory response such as an infiltrate on CXR, or
pus in an abscess.
The only presenting symptoms may be fever and malaise.
In a neutropenic patient, any fever exceeding 100.4F (38C) is
significant.
There may be other signs and symptoms of underlying infections
such as shaking chills, skin breakdown (indicating a possible
portal of entry for infection), hypotension, productive cough,
urinary symptoms, among others.

Clinical History of the Febrile

Neutropenic Patient:
Important Questions to Consider:

Has the patient undergone any recent invasive procedure (e.g., Foley
catheter placement, peripheral or central venous catheter placement)?

Has the patient undergone any recent chemotherapy? When was Day 1
of treatment? (The WBC nadir is typically 10-14 days after the start of the
chemotherapy cycle, depending on the agents that are used).

Has the patient been receiving any recent antibiotic treatment that could
affect culture results? When was the most recent dose of the antibiotic?

Has the patient recently started on any new non-chemotherapy drugs

that may be causing neutropenia? If so, any potential offending agent
should be discontinued if possible.

Diagnostic Evaluation of the Febrile

Neutropenic Patient:
Complete physical examination with close attention to
any indwelling catheter sites, areas of skin
breakdown/cellulitis, oral exam to assess for oral ulcers
or abscesses, and perianal exam to visually inspect for
any evidence of a perirectal abscess.
Note that the perirectal examination must be done very
carefully. A digital rectal exam should NEVER be
performed in a neutropenic patient, due to the concern
that bacteria from the area could enter the bloodstream if
any localized trauma to the area occurred as a result of
the exam, or if skin breakdown was already present.

Diagnostic Evaluation of the Febrile

Neutropenic Patient:
As noted above, since findings suggesting a source of infection may
be lacking due to the neutropenic state, you must obtain cultures
from any possible source of infection. Typically, this would
include:
a) Two sets of blood cultures [Note: If patient has an
indwelling venous catheter, it is often helpful to obtain one
set from the peripheral blood and one set from any
indwelling venous catheter]
b) Urine for urinalysis and culture
c) Sputum (if patient has productive cough): for gram stain and
culture
d) CXR
e) Stool (if patient presents with abdominal pain and diarrhea):
for ova and parasites (O & P), stool culture for enteric
pathogens, and C. diff toxin testing.

Empiric Antibiotic Treatment of the

Febrile Neutropenic Patient:
Empiric broad-spectrum antibiotic treatment should
be initiated immediately after obtaining all necessary
cultures. Delay in starting appropriate antibiotic
coverage can be life-threatening for the febrile
patient with significant neutropenia.
In absence of a known source, it is suggested that
coverage include broad gram-negative coverage (to
include Pseudomonas aeuriginosa) and grampositive cocci (to include alpha-hemolytic
streptococcus). Vancomycin is also often added initially,
if there is suspicion of a skin source of infection (such as
an indwelling catheter site), particularly if the patient is
clinically unstable.

Empiric Antibiotic Treatment of the

Febrile Neutropenic Patient:
Examples of empiric antibiotic regimens for neutropenic fever:
Monotherapy:
Ceftazadime OR Cefepime [+ Vancomycin (if clinically indicated)]
Combination therapy:
Aminoglycoside + [antipseudomonal PCN or cefepime or
ceftazadime or carbapenem]
--------------------------------------------------------------------------------Aminoglycoside commonly used: Gentamicin
Antipseudomonal PCNs include: Ticarcillin, Piperacillin, Carbenicillin
Carbapenems include: Imipenem, Meropenem

Neutropenic Precuations and Treatment

of the Neutropenic Febrile Patient:
Neutropenic precautions should be initiated at the time of admission:
Private room for the patient
Reverse isolation for all caregivers of the patient, particularly if ill
Avoid use of humidifiers or humidified oxygen, due to risk of bacterial
contamination with standing water source
Use sterile technique with venous access devices
Avoid or minimize invasive techniques when possible
No fresh flowers in patient room (due to risk of fungal contamination)
No fresh fruits or raw vegetables (due to risk of exposure to gram-negative
bacteria in these foods)
Meticulous handwashing immediately before entering room and immediately
after exiting from room
Use soft swabs for oral care; avoid toothbrushing while neutropenic
Stool softener (to prevent perirectal skin trauma during bowel movement)

Causes of Benign Neutrophilia

Increased production of neutrophils
Accelerated release of neutrophils from the bone marrow
storage pool into the peripheral blood, in response to
infection, inflammation, corticosteroids, or colony
stimulating factors (e.g., G-CSF, GM-CSF)
Shift from the marginating pool to the circulating pool
of neutrophils (demarginiation); rarely more than a twofold increase
Reduced movement of neutrophils from the peripheral
blood to the tissues
A combination of these mechanisms

Causes of Benign Neutrophilia:

Increased Production of Neutrophils
Increased bone marrow production of neutrophils may be due to:
Cigarette smoking (due to underlying inflammation of the
ariways/lungs); the average neutrophil count of people who smoke 2
packs of cigarettes/day is twice normal.
Even after cessation of smoking, the total WBC may remain
elevated for up to several years, possibly due to underlying
smoking-related inflammation.
Infections- may occur with localized and systemic acute bacterial,
mycotic, rickettsial, spirochetal, and certain viral infections.
Inflammatory conditions (e.g., vasculitis, gout)
Tissue necrosis (e.g., burns, following acute myocardial infarction,
pulmonary infarction, or renal infarction)
Trauma (includes surgery)
Drug-induced (e.g., lithium)

Causes of Benign Neutrophilia: Increased

Peripheral Distribution of Neutrophils
Impaired movement of neutrophils from peripheral blood into tissues:
Glucocorticoids*
*multifactorial process also includes release of neutrophils from bone marrow
storage pool and demargination

Reduction in marginating pool with increase in circulating pool:

Exercise-induced neutrophilia (causes demargination; as endogenous
epinephrine shifts cells from marginating pool into circulating pool)
Emotional stress
Seizures
Increased peripheral distribution post-splenectomy:
Since the spleen is no longer available as a reservoir for blood cells, there
will be an increase in the number of circulating neutrophils in patients after
the spleen has been removed.

Causes of Benign Neutrophilia:

Leukemoid Reactions
Leukemoid reactions may occur due to:
Sepsis
Hemorrhagic shock
Severe tissue injury
Secondary to congenital abnormalities (e.g., Down
syndrome [trisomy 21])
Leukemoid reaction:
Total WBC may exceed 30K-50K, mimicking leukemia;
hence the name leukemoid
Leukocyte alkaline phosphatase (LAP) score is normal
or high in leukemoid reaction, and low or zero in
chronic myelogenous leukemia (CML)

How Is the LAP Score Determined?

The test detects the activity of alkaline

phosphatase in the cytoplasm of
neutrophils (segs + bands)
100 neutrophils are evaluated and graded
on a scale of 0-4+, based on the quantity
and intensity of the alkaline phosphatase
activity in each cell. The total is
determined based on the sum of the grade
for each of these cells.

Example of Leukocyte Alkaline Phosphatase

(LAP) Score in Leukemoid Reaction and CML

LAP SCORE IN CLINICAL PRACTICE

While LAP Score has previously been used to
differentiate between leukemoid reaction and
Chronic Myelogenous Leukemia (CML), the test
is subject to interpretation and test results are
difficult to reproduce, based on technical
variability.
Currently, although this test remains available in
some clinical laboratories, most facilities are
relying on additional molecular and cytogenetic
testing for the presence of CML, thus eliminating
the possibility of leukemoid reaction.

Causes of Benign Neutrophilia:

Miscellaneous Other Causes
Miscellaneous other causes of benign neutrophilia:
Hereditary neutrophilia (rare)
Idiopathic neutrophilia (rare)
Leukocyte adhesion deficiency (rare)
Familial cold urticaria and leukocytosis (rare)

Approach to Patients with Benign

Neutrophilia:
Signs and symptoms:
May be immediately apparent what underlying process is causing the
neutrophilia and specific signs and symptoms would be associated with that
condition.
Findings on exam that may be helpful include splenomegaly (consider
myeloproliferative process)
Diagnostic tests:
Peripheral blood smear: look for evidence of immature WBCs circulating in
the peripheral blood, which may suggest leukemia. Toxic granulations or
Dohle bodies suggest serious underlying bacterial infection
Leukocyte alkaline phosphatase (LAP) score: should typically be elevated
with a leukemoid reaction and low or absent in the setting of CML
Treatment of neutrophilia:
Except for the presence of an underlying myeloproliferative process,
treatment of benign neutrophilia is generally not indicated. The neutrophilia
will generally resolve once the underlying inflammatory process resolves.
Hereditary and idiopathic neutrophilia are quite rare and follow a benign
course.

Now, lets put it all together.

Case #1: 56 year-old with fever

Case #2: 42-year-old for routine exam
Case #3: 72-year-old with low WBC
Case #4: 34-year-old follow up HTN

Case #1:
A 56-year-old male currently undergoing chemotherapy for
non-small cell lung cancer, presents for evaluation of newonset fever. He is currently on Day #10 of his chemotherapy
cycle. He reports that his temperature was 101F at home
earlier today. What important questions should you ask him
when taking the history, while you are waiting for his CBC
results?
The CBC results are as follows:
WBC: 1, 200
Hgb: 10.8 g/dL
HCT: 34%
MCV: 90
Plt: 140,000
Diff: 42% segs, 4% bands, 46% lymphs, 4% monos, 2% eos, 2%
baso
Calculate the absolute neutrophil count (ANC): ________
Is this patient neutropenic?

Case #2:
A 42-year-old female with no significant PMH, presents for a routine
physical when changing medical providers. She reports that she has
not been to her primary care doctor in the past 5 years, so baseline
laboratory testing is done. CBC with diff is ordered and the results
reveal an elevated neutrophil count of 11,400. She denies recent acute
illness and is currently without complaints. The patient denies PMH of
cigarette smoking, frequent vigorous exercise, or increased stress.
She is currently not taking any prescription medications or over-thecounter herbal remedies or supplements. She states that she was
involved in a motor vehicle accident several years ago and required
hospitalization.
What do you suspect is the most likely cause of the neutrophilia in
this patient?

Case #3:
Patient is a 72-year-old male who presents for evaluation of
new-onset neutropenia. He was noted to have a total WBC
2,800 (ANC = 1,200). The patients PMH is significant for
rheumatoid arthritis for the past 12 years. The patient denies
any recent acute viral or bacterial illness and denies fever.
Based on this information, what important diagnostic clues
would you look for on physical examination? What initial
laboratory tests would you order?

Case #4:
Patient is a 34-year-old male who presents to a new medical provider
for follow-up of his HTN and review of his recent blood work. He
reports feeling entirely well, and is afebrile on exam. His CBC results
are as follows:
WBC: 3,000
Hgb: 14.8 g/dL
HCT: 45%
MCV: 84
Plt: 180,000
Diff: 44% segs, 3% bands, 45% lymphs, 4% monos, 2% eos, 2% baso
Based on this information, calculate the absolute neutrophil count
(ANC): __________
What are some possible underlying causes of this patients
neutropenia? What initial tests would you order? How would you
treat this patient?