11/14/2016

Risk of infection in children with fever and non-chemotherapy-induced neutropenia - UpToDate

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www.uptodate.com 2016 UpToDate

Risk of infection in children with fever and non-chemotherapy-induced neutropenia

Authors: Nabil M Ahmed, MD, MPH, Debra L Palazzi, MD, MEd
Section Editors: Morven S Edwards, MD, Donald H Mahoney, Jr, MD
Deputy Editor: Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2016. | This topic last updated: May 04, 2016.
INTRODUCTION Fever may be the first manifestation of a life-threatening infection in the neutropenic
child, particularly one with a primary hematologic disease such as severe aplastic anemia or congenital
neutropenia. Because of important differences between hematology and oncology patients with
neutropenia, the risk of infection in hematology patients with different types of non-chemotherapy-induced
neutropenia and fever are reviewed here. The management of fever and neutropenia in these patients and
in children with chemotherapy-induced neutropenia are discussed separately. (See "Evaluation and
management of fever in children with non-chemotherapy-induced neutropenia" and "Fever in children with
chemotherapy-induced neutropenia", section on 'Definitions'.)
DEFINITIONS Generally, neutropenia is defined as an absolute neutrophil count (ANC) <1500
cells/microL. The ANC is calculated using the following formula:
ANC = total white blood cell count (cells/microL) x (percent neutrophils + percent bands) 100
Recognizing that the definition of a normal ANC varies with age and race is important. The lower limit of
normal for the ANC in infants between two weeks and six months of age is lower than that for the older child
(1000/microL versus 1500/microL) [1]. Also, normal neutrophil values for people of African descent are
lower than those for Caucasians [2].
The degree of neutropenia is classified as follows:
Mild ANC 1000 to 1500/microL
Moderate ANC 500 to 1000/microL
Severe ANC <500/microL
Most studies evaluating the significance of the degree of neutropenia on the risk of infection have been in
cancer patients, in whom an increased risk of infection becomes apparent at an ANC <1000/microL, is
greater at <500/microL, and greatest at <100/microL [3].
In addition to the ANC, factors that influence a patient's susceptibility to infection include:
Duration of neutropenia
Function of the neutrophils
Ability of the bone marrow to respond to an infectious insult
Function of other components of the immune system
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These factors contribute to the differences in infectious complications that are observed between
hematology patients with neutropenia and cancer patients with therapy-induced neutropenia. For example,
neutropenia in the oncology patient is related to cytotoxic therapy and generally is self-limited, whereas in
the patient with severe aplastic anemia, neutropenia may be prolonged for months to years. However, the
neutropenic oncology patient often has defects in several arms of the immune system because of the
underlying disease and/or chemotherapeutic agents used, and these defects may not exist in the
hematology patient.
FEVER AND NEUTROPENIA IN THE OTHERWISE HEALTHY CHILD The afebrile child with the finding
of isolated neutropenia may be followed with serial blood counts and examinations since, in most cases,
the neutropenia arises in association with a viral infection and is transient, resolving in one to two weeks [47]. Drugs, such as antibiotics and anticonvulsants, also can cause neutropenia that most often resolves
after cessation of the drug. However, if such a child develops fever, or if a previously healthy child is found
to have isolated neutropenia during a febrile illness, appropriate management requires consideration of
the risk of serious bacterial infection. Such scenarios are not uncommon. In contrast to the wealth of
studies in oncology patients with fever and neutropenia, only a few have been conducted in patients with
non-chemotherapy-induced neutropenia.
One retrospective study to establish the risk of infection was performed in 119 well-appearing children
without underlying co-morbid illnesses who were found to be neutropenic, nine severely so, during minor
acute illnesses, routine preoperative screening, or treatment for common childhood conditions [8]. No
patients with neutropenia lasting less than 30 days developed infectious complications. Of the 36 patients
found to be neutropenic for more than 30 days, only four (11 percent) developed infectious complications.
The four infections were stomatitis (2), cellulitis (1), and pneumonia (1).
Another retrospective study examined the outcomes of patients presumed to be immunocompetent who
presented to a pediatric primary care clinic or pediatric emergency department with fever and newly
identified moderate to severe neutropenia, leukopenia, or both [9]. This study found that leukopenia and
neutropenia did not necessarily occur together. The prevalence of bacteremia was 5.5 percent, and while
neither the degree of neutropenia nor leukopenia predicted bacteremia, nearly all bacteremic children
were toxic-appearing at presentation. The prevalence of other infections was 14 percent, and the most
common of these was pneumonia.
A retrospective case-control study examined 71 children aged 3 months to 18 years presenting with fever
of at least 38C (100.4F) and neutropenia with an absolute neutrophil count (ANC) of 1000/microL or less
who had not received antibiotics in the 48 hours before presentation and 71 age-matched controls
(consecutive febrile patients who underwent complete blood count and blood culture) [10]. Serious
bacterial infections (eg, bacteremia, pneumonia, urinary tract infection, dysentery) were more common in
the control group (27 versus 8 percent). Of 14 children with severe neutropenia (ANC <500/microL), two
had bacterial pneumonia. Rash was more common in neutropenic children (23 versus 6 percent), which the
authors speculate may have been consistent with viral exanthems in the neutropenic children. More
children in the control group received antibiotics (55 versus 28 percent), and there was a nonsignificant
trend toward increased admission rates in the control group (66 versus 49 percent; p = 0.06).
A prospective study of 161 previously healthy children aged 3 months to 14 years (mean age 3 years) with
febrile neutropenia sought to determine the clinical course, complications, and outcomes [5]. The majority
of patients had mild to moderate transient neutropenia (most resolved in <30 days) associated with viral
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infections. Twenty-five (15.5 percent) of 161 patients had chronic neutropenia (>180 days); an infectious
agent was associated with the initial diagnosis in only five children. Two years after the diagnosis of febrile
neutropenia, 6 of 143 children (4.2 percent) available for evaluation remained neutropenic without a cause
identified. Three of these patients suffered infectious complications: periorbital cellulitis, Pseudomonas
sepsis with labial abscess, and a severe bacterial infection in a patient diagnosed with myelodysplastic
syndrome.
These, albeit limited, observations suggest that the otherwise well-appearing child with isolated
neutropenia and fever can be managed safely with age-appropriate treatment of any minor acute illness
and frequent follow-up. However, any ill-appearing child with fever and neutropenia must be considered at
risk for a serious bacterial infection and should receive empiric intravenous antibiotic therapy. (See
"Evaluation and management of fever in children with non-chemotherapy-induced neutropenia", section on
'Treatment'.)
INFECTION IN PATIENTS WITH SEVERE CHRONIC NEUTROPENIA Chronic neutropenia is defined as
neutropenia lasting longer than eight weeks. The patient with severe chronic neutropenia presents a
different problem from that of the well-appearing patient with transient neutropenia. Severe chronic
neutropenia has multiple causes. Among the primary hematologic diagnoses are:
Chronic benign neutropenia (autoimmune or idiopathic) (see "Immune neutropenia")
Cyclic neutropenia (see "Cyclic neutropenia")
Severe congenital neutropenia (infantile agranulocytosis or Kostmann syndrome) (see "Congenital
neutropenia")
Aplastic anemia (see "Inherited aplastic anemia in children and adolescents" and "Acquired aplastic
anemia in children and adolescents")
The types and risk of infection vary among the conditions, as does the management in response to fever
(table 1).
Chronic autoimmune and idiopathic neutropenia The most common cause of chronic neutropenia
in children is chronic benign neutropenia, which can be autoimmune or idiopathic. Autoimmune
neutropenia typically occurs in infants 5 to 15 months of age; antineutrophil antibodies are characteristic,
and spontaneous recovery occurs [11]. By contrast, chronic idiopathic neutropenia is seen more often in
older children or adolescents and is less frequently associated with recovery [12]. (See "Immune
neutropenia", section on 'Autoimmune neutropenia' and "Immune neutropenia", section on 'Chronic
idiopathic neutropenia'.)
Most patients with autoimmune or idiopathic chronic neutropenia have a benign course and do not require
hospitalization and parenteral antibiotics for uncomplicated febrile illnesses. Patients with adequate marrow
reserves usually can be treated appropriately with oral antibiotics and close outpatient management. (See
"Evaluation and management of fever in children with non-chemotherapy-induced neutropenia", section on
'Treatment'.)
The relatively benign course for children with autoimmune or idiopathic chronic neutropenia is illustrated by
several case series:
Among 38 children with autoimmune neutropenia included in the Italian Neutropenia Registry between
2000 and 2009, there were only 25 infectious episodes (<1 episode per patient per year), 10 of which
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required hospitalization [13]. Most of the infections were of the skin and soft tissues (18 of 25
episodes), but there were four cases of pneumonia, and one bloodstream infection.
Among 23 children with idiopathic neutropenia included in the Italian Neutropenia Registry between
2000 and 2009, there were only 14 infectious episodes (<1 episode per patient per year), five of which
required hospitalization [13]. Most of the infections were of the skin and soft tissues (6 of 14), but
there were two cases of pneumonia and two bloodstream infections.
In a natural history study conducted over a 13-year period, only 2 of 45 patients with chronic
neutropenia of both idiopathic and autoimmune types had severe and recurrent infections [4]. Upper
respiratory tract infections, otitis media, and skin infections were relatively frequent in all of the
patients. Among the 43 patients without severe and recurrent infections, 11 nevertheless had
significant infections, including six girls with cellulitis or abscess of the labia (three of these infections
were caused by Pseudomonas aeruginosa), three with recurrent gingivitis or mouth ulcers, and one
each with periorbital cellulitis and pneumonia.
Thirty-four patients (76 percent) experienced ANCs <200/microL, with occasional fluctuations into the
normal range. All patients were treated with antibiotics during febrile episodes, usually by mouth.
Hospitalizations other than for the initial evaluation were infrequent. Bone marrow was evaluated in 28
patients and demonstrated either normal or decreased numbers of neutrophils. Only three patients
had maturation arrest at an early stage in myeloid maturation, and two of these were among the
patients who suffered severe infectious complications.
Similar rates of infection were observed in a separate study of 240 infants with autoimmune chronic
neutropenia [11]. Minor infections developed in 90 percent of the patients despite severe neutropenia,
whereas severe infections such as pneumonia, meningitis and sepsis developed in 12 percent. Most
patients were followed for up to six years.
Cyclic neutropenia Patients with cyclic neutropenia experience bouts of severe neutropenia, which
last for three to six days, at approximately 21-day intervals. During these episodes they often have fevers,
oral ulcers, gingivitis, periodontitis, pharyngitis, adenopathy, and malaise. Significant infections such as
bacteremia, cellulitis, acute otitis media, sinusitis, pneumonia, or appendicitis occur less frequently [14].
Life-threatening illnesses, particularly necrotizing enterocolitis caused by Clostridium septicum [15,16], may
occur, although they are uncommon. (See "Cyclic neutropenia", section on 'Clinical manifestations'.)
To minimize oral complications, meticulous oral hygiene is important. Patients generally do not require
antibiotics for the fevers or mucocutaneous inflammatory lesions that are typical during their neutrophil
nadirs [14]. However, antibiotics should be administered if patients develop:
Uncharacteristic fever patterns
Atypical oral lesions
Significant infections such as acute otitis media, sinusitis, or lower respiratory tract infection.
Complaints of abdominal pain should raise the possibility of Clostridium necrotizing enterocolitis. If this
entity is suspected, the patient should be hospitalized and receive broad-spectrum antibiotics that include
anaerobic coverage [17].
The prophylactic use of granulocyte colony-stimulating factor (G-CSF) can reduce the risk and severity of
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infection in patients with cyclic neutropenia. The use of G-CSF and the management of fever in these
patients are discussed separately. (See "Cyclic neutropenia", section on 'Granulocyte colony-stimulating
factor'.)
Severe congenital neutropenia Severe congenital neutropenia (infantile agranulocytosis or
Kostmann syndrome) presents shortly after birth with frequent and severe infections. Among 12 children
with severe congenital neutropenia included in the Italian Neutropenia Registry between 2000 and 2009,
there were a total of 69 infectious episodes (an average of 5.75 episodes per patient per year),
approximately one-half of which required hospitalization [13].
Omphalitis, cellulitis, and perirectal abscesses are common during the first few months of life [18]. The
most frequent types of infection among children with severe congenital neutropenia who were included in
the Italian Neutropenia Registry were skin and soft tissue infection (28 of 69); pneumonia (13 of 69); ear,
nose, or throat infection (9 of 69), and bloodstream infection (8 of 69) [13]. Disseminated infections, which
may be life-threatening, are frequently caused by Staphylococcus aureus, Escherichia coli, and
Pseudomonas spp. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)
Because of the risk of serious infection, patients with severe congenital neutropenia should be evaluated
and treated aggressively when febrile. Prophylactic use of G-CSF can reduce the risk and severity of
infection. (See "Congenital neutropenia", section on 'Treatment'.)
Aplastic anemia With the availability of platelet transfusions, infection has replaced bleeding as the
major cause of death in patients with severe aplastic anemia. (See "Inherited aplastic anemia in children
and adolescents" and "Acquired aplastic anemia in children and adolescents".)
A sentinel retrospective study reviewed the types of infections in 150 patients, including children, with
aplastic anemia treated at the Clinical Hematology Branch of the National Heart, Lung and Blood Institute
(NHLBI) between 1978 and 1990 [19]. By the end of the study period, 24 percent of patients died of
infectious complications.
Infection was documented microbiologically in 47 percent and clinically in another 22 percent of febrile
episodes in this study [19]. The infected sites included the respiratory tract (32 percent), soft tissues (24
percent), blood (22 percent), gastrointestinal tract (17 percent), and urinary tract (6 percent).
Among the pathogens identified, the vast majority were bacterial (67 percent), with fungal, viral, and
parasitic accounting for 23, 7, and 3 percent, respectively. Gram-positive and gram-negative bacteria
accounted for equal numbers of bacteremic episodes, with S. epidermidis, Klebsiella pneumoniae, P.
aeruginosa, S. aureus, and E. coli isolated most frequently. The majority of invasive fungal disease was
caused by Aspergillus spp, followed by Candida spp. Ten of 11 Aspergillus infections were pulmonary.
Although fungal organisms caused only 5 percent of primary infections, these pathogens accounted for 30
percent of secondary infections that arose during antibiotic therapy.
The spectrum of pathogens isolated from these patients with aplastic anemia was similar to that observed
in cancer patients with therapy-induced neutropenia. The major exception was the finding that Aspergillus
spp were the dominant fungi, which likely is due to the prolonged duration of neutropenia observed in
many patients with aplastic anemia; Candida spp are most common in cancer patients. These data indicate
that patients with severe aplastic anemia and fever are at very high risk of serious infectious complications
and must receive urgent evaluation and empiric antimicrobial therapy. (See "Evaluation and management
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of fever in children with non-chemotherapy-induced neutropenia".)

Similar findings were reported in a retrospective analysis of the types of infections and outcomes in
patients with aplastic anemia treated in a five-year interval between 1994 and 2000 [20]. One hundred four
infectious events were documented in 42 patients (81 percent of the sample that ranged in age from 3 to
82 years). The number of severe infectious episodes was significantly higher in patients who were
neutropenic. Fungal infections occurred only in neutropenic patients. Five patients in the study population
died of infection. All of these patients had prolonged pancytopenia and invasive fungal infections, most of
which were caused by molds. Four of the five patients who died also had bacterial coinfections.
An Italian, multicenter retrospective analysis of children (0 to 18 years) diagnosed with acquired aplastic
anemia between 1996 and 2007 documented 111 episodes of infection in 42 patients (54 percent) [21].
When disease severity was stratified according to international criteria [22], no episodes of infection
occurred in nonsevere aplastic anemia while 67 percent occurred in patients with very severe aplastic
anemia. Documented infection episodes included bacteremia (38 percent), microbiologically documented
infection without bacteremia (12 percent), clinically documented infection (42 percent), and invasive fungal
disease (8 percent). S. aureus was the most frequently isolated pathogen. Bacteremia, pneumonia,
sinusitis, severe stomatitis, skin and soft tissue infection, and catheter-related infection occurred. Risk of
infection was associated with the degree of aplasia. The mortality rate due to infection was 9 percent.
Other bone marrow failure syndromes Many syndromes, including Shwachman-Diamond syndrome,
Fanconi anemia, dyskeratosis congenita, cartilage-hair hypoplasia and reticular dysgenesis, are
associated with isolated neutropenia or bone marrow failure. The risk of infection caused by chronic
profound neutropenia appears to be similar to that in patients with non-constitutional causes of severe
aplastic anemia. (See appropriate topic reviews).
SUMMARY AND RECOMMENDATIONS
Neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/microL, with mild, moderate,
and severe neutropenia defined as an ANC of 1000 to 1500/microL, 500 to 1000/microL, and
<500/microL, respectively. (See 'Definitions' above.)
The risk of serious infection in otherwise healthy children with isolated transient neutropenia (eg, in
the setting of a viral illness or in association with drugs such as antibiotics or anticonvulsants) is
reflected in the general appearance of the child. Ill-appearing children are at greater risk for serious
infection.
The well-appearing child can be managed safely with age-appropriate treatment of any minor
acute illness and frequent follow-up. (See 'Fever and neutropenia in the otherwise healthy child'
above.)
The ill-appearing child should receive empiric intravenous antibiotic therapy. (See "Evaluation
and management of fever in children with non-chemotherapy-induced neutropenia".)
The risk and types of infection in children with fever and severe chronic neutropenia vary according to
the underlying hematologic disorder (table 1). The appropriate evaluation and specific management of
these patients is discussed separately. (See "Evaluation and management of fever in children with
non-chemotherapy-induced neutropenia".)
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Children with idiopathic or autoimmune chronic neutropenia have a low to moderate risk of
infection. They often can be managed with appropriate oral antibiotic therapy and close
outpatient follow-up. (See "Immune neutropenia".)
Children with cyclic neutropenia generally have a low to moderate risk of infection, but should
receive antibiotics if they develop uncharacteristic fever patterns, atypical oral lesions, or
recurrent or significant infections (eg, acute otitis media, sinusitis, or lower respiratory tract
infection). Complaints of abdominal pain in addition to fever should prompt consideration of
Clostridium necrotizing enterocolitis and may warrant hospitalization and broad-spectrum
antibiotics, including coverage for anaerobic organisms. (See "Cyclic neutropenia".)
Children with severe congenital neutropenia and aplastic anemia are at high risk for infection.
They should undergo aggressive evaluation, hospitalization, and initiation of broad-spectrum
antibiotics. (See "Congenital neutropenia", section on 'Severe congenital neutropenia' and
"Acquired aplastic anemia in children and adolescents" and "Inherited aplastic anemia in children
and adolescents" and "Evaluation and management of fever in children with non-chemotherapyinduced neutropenia".)
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GRAPHICS
Risk and types of infections in pediatric hematology patients with neutropenia
Predominant
causes of fever

Category

Condition

Low risk

Otherwise
healthy child
with
transient,
isolated
neutropenia

Viral infection

Appropriate treatment for age or site of localized

infection; careful follow-up

Lowmoderate
risk

C hronic
benign
neutropenia

C ommon Upper
respiratory tract
infections, acute otitis
media, skin infections,
gingivitis, mouth
ulcers, labial cellulitis
or abscess in girls

Oral antibiotics and close outpatient management

for patients with adequate marrow reserves

Less common
Pneumonia, periorbital
cellulitis, meningitis,
sepsis

Hospitalization and parenteral antibiotics for

complicated febrile illnesses (eg, hemodynamic
instability, skin or soft-tissue infection, pneumonia,
concern for catheter-related infection);
hospitalization also may be warranted in patients
with prior complicated febrile illness

Frequent Oral
ulcers, gingivitis,
periodontitis,
pharyngitis,
adenopathy

Generally do not require antibiotics for fevers or

mucocutaneous inflammatory lesions that are
typical during neutrophil nadirs

Less frequent
Bacteremia, cellulitis,
acute otitis media,
sinusitis, pneumonia,
appendicitis

C areful assessment of the need for hospitalization

as well as administration of antibiotics for atypical
fevers or lesions, or infections such as acute otitis
media, sinusitis, and lower respiratory tract
disease; hospitalization also may be warranted in
patients with prior complicated febrile illness

Uncommon
Clostridium-associated
necrotizing
enterocolitis

Hospitalization and broad-spectrum parenteral

antibiotics for complaints of abdominal pain,
significant localized infection, or signs of sepsis

Severe
congenital
neutropenia
(Kostmann
syndrome)

Omphalitis, cellulitis,
perirectal abscess,
sepsis

Hospitalization and initiation of broad-spectrum

antibiotics

Aplastic
anemia

Respiratory tract
infections, soft tissue
infections, bacteremia,
invasive fungal
disease, especially due
to Aspergillus spp.

Hospitalization and initiation of broad-spectrum

antibiotics; antifungal agents may be warranted

(chronic
autoimmune
and
idiopathic
neutropenia)

C yclic
neutropenia

High risk

Ill-appearing

Initial management

Hospitalization and initiation of broad-spectrum

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child with
neutropenia

antibiotics

Graphic 65091 Version 11.0

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