Download Outcomes of Febrile Children Presumed to be

Outcomes of Febrile Children Presumed
to be Immunocompetent Who Present
with Leukopenia or Neutropenia
to an Ambulatory Setting
J. R. Serwint, MD1
M. M. Dias, MD3
H. Chang4
M. Sharkey, MD5
A. R. Walker, MD2
Summary: To determine significant medical outcomes in febrile children presenting to an
ambulatory setting with neutropenia and/or leukopenia. Methods: Retrospective medical record review conducted on febrile patients who had a blood culture drawn, with white blood cell counts less
than 5,000/mm3 and/or an absolute neutrophil count less than 1000/mm3. Ninety-one patients
were identified; 5 with positive blood culture results, 13 with significant non-oncologic disease, and
3 patients with leukemia who had involvement of 2 or more cell lines. Conclusions: In the majority
of patients, clinical judgment, physical findings, and review of all cell lines of the complete blood
cell count identified those with significant disease. Clin Pediatr. 2005;44:593-600
Introduction
P
ediatricians use the total
and the differential white
blood cell (WBC) counts to
aid in identifying children at increased risk of serious bacterial
infections.1,2 WBC counts greater
than 15,000/mm3, absolute neutrophil counts of greater than
10,000/mm3 and absolute band
counts of greater than 1500/mm3
are associated with increased risk
of bacterial infections, while WBC
Department of Pediatrics, 1Division of General Pediatrics, 2Division of Emergency Medicine,
Johns Hopkins Children’s Center, Baltimore, MD; 3CHOP Connection at Shore Memorial
Hospital, Somers Point, NJ; 4Tender Care Pediatrics, Northfield NJ; 5University of Arkansas Area
Health Education Center, Northwest Arkansas Pediatric Clinic, Fayettesville, AR.
Presented in part at the Pediatric Academic Society meeting, San Francisco, CA, 1999.
Reprint requests and correspondence to: Janet R. Serwint, MD, Division of General Pediatrics,
Johns Hopkins Hospital, Park 389, 600 N. Wolfe St., Baltimore, MD 21287.
© 2005 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.
counts of 5000 to 15,000/mm 3
place a child at baseline risk.3 Few
studies have examined the morbidity of febrile children presumed to be immunocompetent
with leukopenia (WBC <5000/
mm3) or moderate to severe neutropenia (absolute neutrophil
counts [ANC] <1000/mm3). Clinicians are often concerned that
children with WBC counts less
than 5000/mm3 or ANC less than
1000/mm3 may present because
of marrow depletion from overwhelming sepsis, 1,2,4 while concern has been raised that patients
with neutropenia may have difficulty fighting infections as has
been the experience with patients
with malignancies where guide-
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lines suggest prompt initiation of
empiric antibiotics.5 Other possible etiologies for leukopenia or
neutropenia include bone marrow suppression from viral infections, medication side effects
from antibiotics or anticonvulsants, or the inadvertent discovery
of leukemia or cyclic neutropenia
when a complete blood cell
(CBC) count is obtained during a
febrile illness. The ability to distinguish between these possibilities is
essential to the clinician, who
must make emergent decisions at
the time of presentation based on
the results of the WBC counts and
the clinical appearance of the
child. A febrile child with leukopenia or neutropenia may present a
treatment challenge for a clinician
in trying to decide whether to initiate antibiotics on an outpatient
basis, hospitalize the patient, or
pursue a further investigation for
a hematologic abnormality or a
malignancy.
No studies, to our knowledge,
have examined leukopenia and
fever solely in febrile children
who are presumed to be immunocompetent at the time of first contact to medical care. While Alario
and colleagues examined neutropenia in well-appearing children, they included children
from both inpatient and outpatient settings in addition to children who had received a complete blood cell count as part of a
preoperative evaluation.6 Bowden
and colleagues examined neutropenia in the pediatric population but included both hospitalized and ambulator y patients
regardless of the cause for the
visit.7 Eighty percent of patients in
their study had no signs of infection. Bonadio and colleagues examined febrile children who had
a CBC and blood culture performed as part of their evaluation,
but their inclusion of both hospi-
594
talized and ambulatory patients
biased the results toward a potentially more severely ill group.4 No
one, to our knowledge, has studied febrile children with leukopenia or neutropenia from an ambulator y standpoint to obtain
more accurate prevalence rates
and determine the medical outcomes of these children. The aim
of this study was to assist clinicians
in their initial treatment decision
for febrile children who present
with leukopenia or neutropenia.
The objectives were to: 1) determine the prevalence of positive
blood culture results and hematologic conditions in febrile children presumed to be immunocompetent, found to be leukopenic
or neutropenic on presentation
for medical care; and 2) describe
the medical outcomes for these
children.
Methods
The study was a retrospective
medical records review of patients
who presented to a pediatric primar y care clinic or pediatric
emergency department (ED) at a
large, academic, urban hospital.
Case identification took place using an Excel © database file of
hospital laboratory results. Cases
were identif ied by searching
through the identification numbers of the pediatric primary care
clinic or the pediatric emergency
department from March 1, 1995
to January 1, 1998.
Patients were included if they
had 1) a temperature of 38°C or
greater at the time of presentation or had a documented history
of fever, 2) had a CBC count and
a blood culture drawn during the
visit, and 3) were found to have either leukopenia (defined as a
WBC count <5000/mm3) or moderate to severe neutropenia, (de-
fined as an ANC <1000/mm3), or
both. The ANC was calculated by
multiplying the total WBC by the
percentage of segmented and
band forms.1 Because this study
was retrospective, all laboratory
studies were done at the discretion of the treating physician.
Other studies such as urine, cerebrospinal fluid, stool cultures, radiographs, etc. were performed
when clinically indicated. All laboratory analyses were done at a
single laboratory. Patients were
excluded if chart review revealed
a known disease entity to explain
their neutropenia or leukopenia
such as a malignancy (leukemia,
lymphoma, solid tumors, brain tumors), receipt of immunosuppressive therapy, hematologic disease
such as chronic or cyclic neutropenia or sickle cell disease, or
if they were infected with human
immunodeficiency virus (HIV).
Patients were included if the chart
review revealed that they were on
anticonvulsants or antibiotics.
The dependent variables, obtained by review of the chart and
the electronic patient record, included age, gender, ethnicity, type
of insurance, site where patient
presented (clinic or pediatric
emergency department), and
whether the patient was taking antibiotics or anticonvulsants. Outcome variables included a positive
blood culture result for a true
pathogen, significant diagnoses,
antibiotic administration after the
evaluation of the patient, hospitalization, or death. Patients who
were admitted to the hospital
and/or seen in the outpatient settings were tracked for the next
month via chart review at the parent institution to determine any
additional diagnoses or outcomes. The study was approved by
the Institutional Review Board at
Johns Hopkins University School
of Medicine.
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Immunocompetent Children with Leukopenia or Neutropenia
Data analysis was performed
using the Statistical Program for
Social Sciences (SPSS) version
10.0 (Chicago, IL). Chi-square
analysis, Fisher’s exact test, and
student t test were performed.
Results
Ninety-one febrile patients
were identified during this period
with leukopenia and/or neutropenia. This included 10 patients (11%) who were younger
than 3 months of age, 55 (60%) 3
to 35 months of age, and 26
(29%) who were 36 months of age
or older. The demographics of
the patient population are presented in Table 1. The majority of
patients had leukopenia while
13% exhibited both leukopenia
and neutropenia (Figure 1). Figures 2 and 3 demonstrate the distribution of the degree of
leukopenia and neutropenia in
this study population. The medical outcomes of the patients included 5 patients (5.5%) with a
positive blood culture result
(Table 2), 6 (7%) with oncologic/hematologic disease (Table
Table 1
DEMOGRAPHICS (n=91)
Characteristic
n (%)
Male gender
55 (60%)
African American
68 (75%)
Medical assistance or self-pay
41 (45%)
Site of visit
Primary care clinic
32 (35%)
Emergency department
59 (65%)
Age
< 3 mo
10 (11%)
3–35 mo
55 (60%)
≥36 mo
25 (29%)
Antecedent medications associated
with leukopenia/neutropenia
Antibiotics
13 (14%)
Anticonvulsants
3), one of whom had a positive
blood culture result for Staphylococcus aureus, 12 (13%) with other
significant diagnoses (Table 4),
and 1 (1%) death while the re-
3 ( 3%)
maining 68 patients (75%) experienced no significant morbidity.
The one death occurred in a 6month-old female patient who
presented to the ED with fever,
Figure 1. Distribution of patients with leukopenia, neutropenia, or both.
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Figure 2. Distribution of patients by total white blood cell count.
Figure 3. Distribution of patients by absolute neutrophil count.
596
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Immunocompetent Children with Leukopenia or Neutropenia
petechiae, and a toxic appearance. Purpura fulminans, septic
shock, and disseminated intravascular coagulopathy developed
rapidly. Her CBC parameters on
admission included a WBC of
4700/mm3, ANC of 1683/mm3,
hemoglobin of 8.0 g/dL, and
platelet count of 67,000/mm 3.
She was admitted to the pediatric
intensive care unit and treated
with antibiotics and aggressive
supportive therapy, but died
within 12 hours of admission. Her
blood and urine culture results
were negative and she had been
too unstable to undergo a lumbar
puncture.
Of the 17 patients (19%) who
under went lumbar puncture,
only one had a positive culture result that grew a pathogen, in this
case group B streptococcus. This
patient is the same 1-month-old in-
fant who was also found to have a
positive blood culture result for
the same organism. Thirty patients
(33%) had a urine culture obtained and 5 patients (6%) had a
stool culture obtained; all of these
culture results were negative.
Medical outcomes are presented by age in Figure 4. Children
younger than 3 months of age were
more likely to have been admitted
and treated with antibiotics. When
Table 2
PATIENTS WITH POSITIVE BLOOD CULTURE RESULTS (n=5)
Age
(mo) Pathogen
WBC/mm3 ANC/mm3 Hgb (g/dL)
Platelets
Toxic
Appearance Hospitalized Comments
1
Group B Streptococcus
1900
992
9.3
82,000
Yes
Yes
Confirmed with
CSF culture results
9
Neisseria meningitidis
3300
2300
13.3
270,000
No
No
Admitted when
aware + culture;
no sequelae
88
Streptococcus pneumoniae
3000
Not done
11.6
157,000
Yes
Yes
Diagnosed with
pneumonia
156
Staphylococcus aureus
25,000
0
0
36,000
Yes
Yes
Diagnosed with
leukemia during
admission
193
Escherichia coli
4100
3649
10.1
69,000
Yes
Yes
Septic at
admission
Table 3
PATIENTS FOUND TO HAVE ONCOLOGIC/HEMATOLOGIC DISEASE (n=6)
Age (mo)
Diagnosis
WBC/mm3
ANC/mm3
Hgb (g/dL)
Platelets
27
Leukemia
2400
24
5.3
309,000
39
Leukemia
2400
30
8.1
119,000
156
Leukemia
25,000
0
6.0
36,000
Presented with S. aureus bacteremia
Comments
6
Chronic neutropenia
6000
726
11.5
359,000
Confirmed by hematology service
11
Chronic neutropenia
8100
405
10.5
391,000
Confirmed by hematology service
51
Chronic neutropenia
6700
268
12.8
512,000
Confirmed by hematology service
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Table 4
OTHER SPECIFIC DIAGNOSES (n=12)
Diagnosis
Mean Age (mo)
(Range)
Mean WBC/mm3
(Range)
Mean ANC/mm3
(Range)
7
Pneumonia
68 (10–202)
4930 (3700–8400)
1855 (777–3044)
1
Intussusception
7
3800
1700
1
Cellulitis
14
4106
600
1
Labial abscess
39
3500
35
1
Osteomyelitis
88
400
2488
1
Rocky Mountain spotted fever
106
4400
2790
No. of
Patients
Figure 4. Medical outcomes by age.
considering medical outcomes by
degrees of neutropenia and
leukopenia, patients diagnosed
with oncologic/hematologic disorders 5/6 (83%) were more
likely to have an ANC less than
500, compared to those without
598
6/74 (9%), OR 61, (95% CI 5.3,
1662, p <0.001). In comparing patients with a WBC count of less
than 3000/mm3, those 2/4 (33%)
of patients with oncologic/hematologic disorders had this degree
of leukopenia, compared to 4/85
(5%) of patients without these
disorders. This approached statistical significance with OR 10,
(95% CI 0.94, 105, p = 0.05. Neither the degree of neutropenia
nor leukopenia was predictive in
identifying those with bacteremia.
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Immunocompetent Children with Leukopenia or Neutropenia
Discussion
This study examined the outcomes of febrile children thought
to be immunocompetent who
presented with leukopenia
and/or neutropenia. No serious
outcomes occurred in the majority of patients, presumably experiencing a transient leukopenia
and/or neutropenia as a result of
a viral infection. Boxer has commented that patients with neutropenia in conjunction with a
malignancy are more likely to develop serious bacterial infections
because their entire cellular immune system is compromised
while those with transient neutropenia have an intact cellular
immune system.1 The prevalence
of bacteremia in this study, including all age groups, was 5.5%.
However, only 1 patient younger
than 3 months and 1 patient in
the 3- to 36-month age groups had
a positive blood culture result.
Our results are similar to those of
Bonadio and colleagues, who
found that febrile infants younger
than 8 weeks of age with neutropenia were not at higher risk of
serious bacterial infections.4 In
the 3- to 36-month age group, this
would have led to a prevalence of
1/55 or 1.8%. This is comparable
to present prevalence rates of bacteremia.8 The one positive blood
culture result in this age group
was due to Neisseria meningitidis,
an organism that is regularly difficult to diagnose and this child
had not received antibiotics at
presentation. Twenty-five percent
to 50% of children who presented
with meningococcal disesase reported in retrospective series have
been evaluated as outpatients in
the 2 to 3 days before diagnosis,9-12
and these children do not commonly have leukocytosis.9,11,13 In a
study by Fleischer, 3 of the 43 patients in the 2 series of meningo-
coccal bacteremia had WBC
counts less than 5000/mm 3, as
was the case in our study.14
The higher rate of positive
blood culture results in the patients older than 36 months may
represent a bias arising from the
fact that patients who appeared
more ill in this age group would
have been more likely to have had
blood cultures obtained. Four of
the five patients with bacteremia
were hospitalized at the time of
presentation because of a toxic
appearance at admission as was
the patient who died of purpura
fulminans.
As would be expected when
looking at the distribution of
leukopenia and neutropenia, the
more severe either is, the less frequently either occurs. In looking
at the helpfulness of these parameters, an ANC less than
500/mm3 was more predictive of
oncologic/hematologic disease
and a WBC count less than
3000/mm3 approached statistical
significance as being more likely
associated with oncologic/hematologic disease. Although these
findings are important, the small
sample size does not allow firm
conclusions to be drawn.
The utility of obtaining a differential WBC count is highlighted by the obser vation that
leukopenia and neutropenia do
not always track together. The patients diagnosed with leukemia
were all significantly neutropenic,
all with ANCs of 30 or less, and
two thirds were leukopenic. The
patients diagnosed with chronic
neutropenia had ANCs between
268 and 726; none were
leukopenic. All 3 of the patients
diagnosed with leukemia had
other evidence of bone marrow
suppression with at least one
other cell line affected.
Our study results cor responded with those of other au-
thors that the most common infections in patients with neutropenia include infections of the
skin, mucous membranes, lungs,
labia, gingivitis, and bacteremia
with S. aureus and gram-negative
organisms.1,15 Neither leukopenia
nor neutropenia in and of itself
was associated with sepsis in our
study. All patients with bacteremia
except one presented with toxicity and were hospitalized. The exception was the child with N.
meningitidis bacteremia who suffered no significant morbidity after admission.
Limitations
Several limitations of this
study must be addressed. The
computerized data set used for
the laborator y values may not
have included all possible patients. The number of patients
with initial neutropenia or
chronic neutopenia may have
been underestimated because not
all patients in this sample had an
initial ANC performed (n=11).
There is also the possibility that
the number of patients with
chronic neutropenia may have
been underestimated because
only 58% had documentation of a
repeat CBC and differential in the
following month. Because medical follow-up was limited to our
institution, the potential morbidity within the following month
may have underestimated the potential longer term morbidity if
patients had presented to another
institution. We are not aware of
any cases in which this occurred.
Conclusions
The prevalence of positive
blood culture results in this study
population was comparable to the
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prevalence reported in studies of
populations not selected for low
WBC count. A number of patients
with significant disease were recognized on clinical grounds of
toxicity or physical findings. All
patients eventually diagnosed
with leukemia had involvement of
at least one additional cell line besides their WBC count. Although
our sample size was small, oncologic/hematologic disease was associated with more severe
leukopenia and /or neutropenia,
but infectious disease and bacteremia was not.
Implications
In the majority of cases of
febrile patients with leukopenia
and/or neutropenia, clinical
judgment, physical findings, and
review of all cell lines of the CBC
will identify patients with significant disease. We recommend
close follow-up with repeat CBC
and differential in patients who
do not have obvious significant
disease at the time leukopenia
and/or neutropenia is first documented. These recommendations, from this study of febrile
children presenting to an ambulatory setting, are consonant with
the recommendations from other
authors.16,17
Suggested Approach
to Neutropenia
If a patient has an ANC less
than 1000/mm3, a manual differential should be obtained to determine whether blasts or immature neutrophils are present. If
the neutropenia occurs shortly
after a presumed viral infection,
a repeat CBC with differential
600
should be repeated 3 to 4 weeks
later to allow assessment of recovery of the ANC. If recovery has not
occurred, further evaluation is required. If a patient is noted to have
leukopenia and/or neutropenia
and signs of a serious infection,
toxicity, gingivitis, or a skin infection, then a more aggressive
workup may be warranted.
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