Hematology / Oncology

Fever & Neutropenia in the Non-Chemotherapy Patient


Laboratory errors may occur in the initial diagnosis of neutropenia, and as such significant neutropenia must be confirmed by repeating the CBC with differential & platelets in order to avoid an extensive evaluation due a laboratory error.

Once confirmed, neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/microL. The ANC is calculated using the following formula:




Normal values for the ANC vary by age, particularly during the first weeks after birth.  See Reference number 1 by Segel et al or click here for a reference table of normal leukocyte counts by age.

In general, for patients older than 1 year of age, neutropenia is defined as:

  • Mild - ANC 1,000 to 1,500/mcL
  • Moderate -  ANC 500 to 1,000/mcL
  • Severe  -  ANC less than 500/mcL

In general, there is little or no heightened infectious risk if the ANC is greater than 1,000/mcL.


There are various acquired and inherited etiologies that can account for fever and non-chemotherapy-induced neutropenia in children.  In general, the acquired neutropenias are considered first because they are most common.  

The most common underlying etiology for mild-to-moderate neutropenia is transient marrow suppression due to a variety of viral infections.

The table below is from Segel et al and it highlights the causes of aquired neutropenia in children:



Inherited neutropenias are less common that those that are acquired, and include the following etiologies:

  • Severe congenital neutropenias such as Kostmann syndrome
  • Cyclic neutropenia
  • Familial benign neutropenia
  • Shwachman-Diamond Syndrome
  • Bone marrow failure syndromes such as Fanconi Anemia and Blackfan Diamond Syndrome
  • Various Syndromes associated With neutropenia and immunodeficiency such as Chediak-Higashi Syndrome

It is very important to determine whether the child has an isolated 
neutropenia as opposed to having other affected cell lines, as this may alter both the work up, differential and potential treatment plans. 



Presenting infections due to neutropenia commonly include:

  • Oropharyngeal issues such as stomatitis, gingivitis, pharyngitis & periodontal infection
  • Acute otitis media
  • Upper respiratory tract infections
  • Skin infections (most commonly due to Staphylococci or Streptococci) including cellulitis, particularly labial cellulitis or abscess in girls

Children with fever and neutropenia need medical evaluation due to the risk of developing life-threatening infection.

The level of urgency and degree of this medical evaluation is going to vary however based on several factors including:

  • The severity of neutropenia as defined above
  • Worrisome findings on physical exam including the child's overall appearance
  • Clues in the history as to the etiology or cause.
  • Longer durations of neutropenia
  • Low neutrophil count without recovery
  • Prolonged or extreme fever (103 degree F or 39.5 degrees C) 
  • Spreading of a localized bacterial infection

As such, perhaps one of the most important assessment steps in managing a patient with fever and neutropenia, aside from the physical exam and history, is the assessment of their individual level of risk as below:

  • Low risk – Otherwise healthy, well-appearing child with transient, isolated neutropenia
  • Low to moderate risk – Well-appearing child with chronic benign neutropenia or cyclic neutropenia
  • High risk – Ill-appearing child with neutropenia (of any etiology); well- or ill-appearing child with severe congenital neutropenia (Kostmann syndrome) or aplastic anemia; children with a previous episode of complicated febrile illness or life-threatening infection



There are a variety of points during the historical assessment of a patient with neutropenia and fever that are important to assess.  These include:

  • New site-specific symptoms
  • History of recurrent infections (number and type), response to antibiotics, and etiology if known
  • Antimicrobial prophylaxis
  • Infection exposures, including illness (e.g., cough, influenza, etc.) in family members
  • History of documented previous infections or colonization
  • Concomitant noninfectious cause of fever (e.g., received blood products)
  • Underlying comorbid conditions (eg, diabetes, recent surgery)
  • Congenital anomalies suggestive of an inherited syndrome
  • Presence of intravascular catheters or other devices
  • Immunization history (deficient immunizations or questionable immunization history)
  • Family history of recurrent bacterial infections or neutropenia 


Physical Examination:

A thorough, and periodically repeated physical exam is necessary for these patients, with particular attention to:

  • Skin:  especially folds, areas surrounding nail beds, and central venous catheter sites including the subcutaneous tunnel, if present
  • Sinuses: sinus tenderness should be evaluated
  • Oropharynx: especially the gingival line and buccal mucosa
  • Lungs
  • Abdomen
  • Perineum: especially examining the perianal and labial regions looking for signs of infection, or abscess is important.  Note, in cases of severe neutropenia, manipulation of the rectal area (rectal temperatures, digital rectal examinations, or rectal medications) are to be avoided because of the risk of generating a perianal or perirectal infection.


Evaluation & Management

Although guidelines have been formulated for patients who have chemotherapyinduced neutropenia, relatively few data are available for patients who have neutropenia not associated with cancer treatment.

As such, this makes evaluation of these patients somewhat difficult.

When in doubt, discussion, consultation and collaboration with a experienced pediatric hematologist can prove invaluable, not only for the primary care provider but for the patient and their families as well.  Their guidance can help aid in timely treatment and diagnosis, as well as reassurance and avoidance of extensive and unnecessary diagnostic testing.

Segel's Pediatrics In Review article (see references) is a good guide in terms of what interventions and workup may be needed:

The decision surrounding treatment and potential hospitalization depends on the likelihood of bacterial infection, the location and severity of the infection, the severity of the neutropenia, and the likelihood and timeframe of neutrophil recovery. Furthermore, the age of the patient, the proximity of specialized medical care, and the reliability of the guardians should be considered in the management decision.

The following table, also taken from Segel's paper, is a good starting point in terms of management:


In general, hospitalization is required for patients who have severe neutropenia (ANC less than 500/mcL), moderate neutropenia and severe infection, or any level of neutropenia combined with ill appearance.


The decision to start antibiotics is a difficult one as well, and again should be based on the likelihood of bacterial infection, the location and severity of the infection, severity of the neutropenia, and likelihood and timeframe of neutrophil recovery.

Antimicrobial coverage should strive to cover the most likely organisms involved with consideration for their prevalence and susceptibility patterns in each community and hospital.  As such, common initial broad spectrum antibiotic choices include ceftazidime or cefepime.

Consultation with a pediatric infectious disease specialist is key, particularly with hopspitalized paitents, as the decision point when to stop antibiotics can be difficult.  

In general if the blood cultures are negative and the child becomes afebrile and clinically improves, antibiotics can be stopped, even if the neutropenia persists.  However, if this is not the case, other etiologies for the fever must be explored.  Treatments such as G-CSF can be considered if the neutropenia is profound or if there are frequent infections.


Anticipatory Guidance

Care takers of children with neutropenia need to know how to contact a health-care practitioner at the onset of any febrile illness to assure prompt, appropriate care.

Immunization guidelines should be followed to ensure protection from preventable diseases.  Note however, children who have impaired T- or B-lymphocyte function should not receive live or attenuated-live vaccines.  Refer to the current American Academy of Pediatrics Red Book for further information.

A common concern for families of children with neutropenia is child care.  Child care and school attendance are reasonable for most children who have mild-to-moderate neutropenia, although contact with obviously ill children should be avoided. Children who have severe neutropenia or a history of serious infections with neutropenia require greater isolation to avoid exposure to infectious agents.



  1. Segel GB et al.  Neutropenia in Pediatric Practice.  Peds in Review.  2008;29;12-24
  2. Boxer AL et al.  Molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer. 2007; 49(5):609.
  3. Freifeld AG et al.  Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011; 52(4):e56.
  4. Jonsson OG et al.  Chronic neutropenia during childhood. A 13-year experience in a single institution. Am J Dis Child. 1991; 145(2):232.