I. Problem/Condition.

Neutrophils usually make up 50-70% of circulating white blood cells and serve as the first defense against bacterial infections. Neutropenia is a reduction in the number of white blood cells, specifically neutrophils, resulting in immunosuppression and thereby putting patients at risk for infection. Neutropenia is defined as an absolute neutrophil count of less than or equal to 1500 cells/microliter (ul).

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The causes of neutropenia can be divided into the following groups based on the production of neutrophils by the bone marrow:

Decreased production or Ineffective granulopoiesis:

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Aplastic anemia

Acute and chronic leukemia





-viral (Epstein Barr, Hepatitis, human immunodeficiency virus [HIV], hepatitis C virus)

Medication effects:





Arsenic Poisoning

Hereditary disorders (e.g., congenital neutropenia and cyclic neutropenia)


Vitamin B12 deficiency

Folate Deficiency

Copper deficiency

Transfusion Reactions

Increased Destruction:

Autoimmune neutropenia



Sequestration or Shift of PMNs into Vascular Endothelium:



B. Describe a diagnostic approach/method to the patient with this problem.

The absolute neutrophil count or ANC is calculated using the following formula:

Absolute Neutrophil Count (ANC) = 10 × WBC count in 1000s X (% polymorphonuclear (PMN) + % Bands)

Guidelines to classify the severity of neutropenia is based on the ANC or the absolute neutrophil count in a microliter of blood:

Mild neutropenia ANC = 1000-1500/ul
Moderate neutropenia ANC = 500-1000/ul
Severe neutropenia ANC < 500/ul

An ANC <1500/ul is the generally accepted definition of neutropenia, as well as the threshold for neutrophil toxicity and infectious risk following chemotherapy.

1. Historical information important in the diagnosis of this problem.

One must ascertain from the patient if there has been a recent history of a viral infection or recent chemotherapy treatment. A complete review of systems is important in order to illicit information from the history in order to identify localizing symptoms of infection such as a cough, sinus symptoms, dysuria, etc. or frequent and recurrent infections greater than three or more a year.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

In the absence of an inflammatory response because of the lack of neutrophils, the great majority of patients with neutropenia will have a normal physical examination.

However, signs of immunosuppression such as thrush, mucositis, rashes such as vesicular lesions or an abnormal pulmonary examination may be suggestive of a localizing site of infection in neutropenia.

It is also important to examine the insertion site and surrounding area of any indwelling line such as a peripherally inserted central catheter (PICC) line or a port-a-catheter in all patients with neutropenia for erythema or pus suggestive of a line infection. Of note, depending on the degree of neutropenia, some patients may show no signs of infection, such as in profound neutropenia <500/ul.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

One must first confirm the presence of neutropenia. If the complete blood count (CBC with differential) is generated using an automated counter, it should be repeated manually and a Wright-Giemsa stained peripheral blood smear to confirm the number of neutrophils.

As explained above, neutropenia results from the three basic mechanisms including: decreased production or ineffective granulopoiesis, increased destruction or sequestration.

Confirmation of any of these mechanisms necessitates leukokinetic studies employing bone marrow cultures, radionuclide tagging of blood PMNs and other techniques which are not available outside of a research laboratory.

Thus, it is practical to classify neutropenia as being is acquired or congenital, or by using the associations of neutropenia with various disease states as outlined in Section A above.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Neutropenia in infants and young children is limited to hereditary or congenital disorders such as Isoimmune neonatal neutropenia, severe congenital neutropenia, Shwachman Diamkond-Oski syndrome, autoimmune neutropenia and cyclic neutropenia.

Isoimmune neonatal neutropenia presents as a moderate to severe neutropenia with and without sepsis in newborns. Diagnosis is dependent upon detection of antineutrophil antibodies in the serum of the infant and mother.

Severe congenital neutropenia (SCN) is characterized by severe infections in the first months of life and maturation arrest of myelopoiesis at the promyelocytic stage.

Shwachman Diamond-Oski Syndrome is characterized by pancreatic insufficiency, metaphyseal dysostosis, neutropenia with or without thrombocytopenia and/or anemia.

Autoimmune neutropenia is usually not associated with recurrent infections and typically occurs later (between 5-15 months of age). A small number of patients can present with characteristics of patients with SCN and the diagnosis is ultimately made by the detection of granulocyte-specific antibodies in the serum.

Cyclic neutropenia usually occurs as neutropenic periods lasting 3-6 days and occur approximately every 21 days. This condition is diagnosed by monitoring the ANC three times a week every 6 to 8 weeks.

Mild neutropenia in the absence of infections or recurrent infections are benign and usually a period of observation is indicated if the patient is asymptomatic and may have had a history of a recent viral illness.

An ultrasound can be used to confirm the presence of splenomegaly in those neutropenic patients where hypersplenism may be the cause of sequestration of polymorphonuclear neutrophils, which may be the cause of neutropenia.

Neutropenia associated with other abnormalities of the CBC such as normocytic or microcytic anemia, thrombocytopenia or even eosinophilia should lead to further investigation including a bone marrow biopsy.

The severity of the clinical presentation should determine the diagnostic approach. For example, if a patient has a sore throat, a respiratory viral panel might be ordered. If on the other hand, a patient presents with sinus congestion, a computed tomography (CT) scan of the sinuses would be in order.

However, all patients with neutropenia and fever should have an investigation for serious bacterial infection including two sets of peripheral blood cultures, urinalysis with culture and chest x-ray. Viral and parasitic cultures may be deemed appropriate depending on the patient’s history prior to the administration of antibiotics if the situation allows thereby increasing the odds of isolating the causative agent.

In addition, if a patient has an indwelling line such as a PICC line or port-a-catheter used for chemotherapy, a set of cultures should be drawn from that line.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

It should be noted that upwards of 70% of patients with neutropenia and fever will have never have positive blood or urine cultures given the absence of an inflammatory response as discussed above. So, although some may argue that obtaining several cultures from a patient may rarely lead to the actual bacterial or viral source, the possibility of identifying the pathogen causing an infection so that appropriate antibiotics are administered make such measures appropriate.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Neutropenia.

The management of neutropenic states depends upon the cause and degree of neutropenia as well as the presence of fever usually suggested to be a temperature greater than or equal to 101.0- 101.5°F or a temperature of 100.4°F persistent for greater than one hour.

Sepsis poses the greatest risk in patients with severe neutropenia. The source of the bacterial pathogen is usually from the gastrointestinal tract or skin. Thus, patients with neutropenia and fever are a medical emergency and require treatment with broad spectrum antibiotics immediately. For those patients with prolonged neutropenia, particularly those with hematological malignancies, fungal pathogens are more of a concern.

Specific bacterial pathogens of concern are endogenous bacteria including Staphylococcus aureus from the skin and Gram negative organisms from the gastrointestinal and urinary tract. Isolated neutropenia does not increase the susceptibility to viral or parasitic infection.

Patients who receive broad spectrum antibiotics for 2 weeks or longer and remain neutropenic are more prone to infection with enteric bacteria and fungal pathogens. Those with indwelling lines or catheters are more likely to become infected with coagulase-negative staphylococci.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Antibiotic resistance is a common concern in the approach to treating the neutropenic patient with fever. Individual hospitals, particularly large cancer centers, sometimes employ neutropenic fever protocols with different antibiotic regimens to cover Gram positive and Gram negative organisms depending on the month or time of year and alternate their use depending upon the resistance patterns at their particular institution.

Rectal examinations should not be performed on neutropenic patients given concern for translocation of bacteria into bloodstream.

Myeloid growth factors can be administered to correct the neutropenia that is commonly associated with chemotherapeutic regimens such as granulocyte colony stimulating factor (G-CSF or filgastrim). Congenital neutropenia, cyclic neutropenia and acquired immunodeficiency syndrome (AIDS) can also be treated with G-CSF, although it does appear to be less effective in those with cyclic neutropenia.

It should be noted, however, that G-CSF is not indicated for the treatment of all etiologies of neutropenia. It should be reserved for those patients with myeloid suppression/arrest and for whom infection is of major concern. For those patients with late marrow arrest, HIV disease and/or normocellular marrow, it is not as effective. The latter would include children in whom the diagnosis of chronic benign neutropenia of infancy has been confirmed.

Common side effects of G-CSF include bone pain, headache, edema, constipation and severe allergic reactions.

Neupogen® (Filgastim): 300 micrograms/milliliter (mcg/mL) (1 mL, 1.6 mL) [contains sodium (0.035 milligrams/milliliter [mg/mL]) and sorbitol]

Neulasta® (Pegfilgrastim): 10mg/ml (0.6mL)