Download Fever and Neutropenia

Fever and Neutropenia
Pediatric Resident
Education Series
Normal Body Defenses
Barriers – skin, mucosa, etc.
 Phagocytes – PMN, monocytes,
eosinophils
 Lymphocytes

– Antibodies
– Cell mediated immunity
Reticulo-endothelial system (RES)
 Complement
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Infection Questions
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Sites
Frequency
Organisms
Treatments
Outcomes
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Co-morbities
Exposures
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School
Home
Food
Water
Pets
Immunizations
Family History
Recent chemotherapy
– i.e., immune suppression?
Primary work-up
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Barriers:
– History, Physical exam

Phagocytes:
– CBC/diff
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Lymphocytes:
– CBC/diff, Quantitative Ig
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RES:
– blood smear (Howell-Jolly bodies?)
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Complement:
– rare
Secondary work-up
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Barriers:
– Biopsy with EM
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Phagocytes:
– tests for mobilization, chemothaxis,
opsonization, ingestion, killing (NBT test)
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Lymphocytes:
– subsets (T, B, NK, others), antibody titers,
skin tests, isohemaggluinins, function tests
(mixing T, B cells)
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RES:
– Tc Scan
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Complement:
– Factor titers
Neutropenia
Neutrophil
Risk for
count (cells/uL) infection
> 1500
No increased risk
1000-1499
Slight increased risk
500-900
Moderate increased
risk
High increased risk
<499
Pneumonia in a neutropenic patient
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Empiric antibiotics
– Bacteria: cefepime,
tobramycin, vancomycin
– Mycoplasma: azithromycin
– Pneumocystis: Bactrim
– Viral: acyclovir
– Fungal: Ambisome, other
Pneumonia in a neutropenic patient..

Lavage: if done well, gives 75% of
pathogens found on biopsy
– Frequently worsens lung scans
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Biopsy:
– usually worsens lung status
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Empiric antibiotic therapy:
– if wrong drugs, then lavage/biopsy needed in
sicker patients
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In one small trial, outcome of empiric
therapy was equivalent to that of biopsy
(Pizzo et al).
Fever, neutropenia pearls
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Limited ability to mount cellular
response means signs/symptoms of
infection may be subtle
Treat the rectum with respect
(limit exams, no medications)
Pneumonia without tachypnea is rare
UTI without dysuria must be considered
in a female
Fever in Neutropenia: Definitions

Fever
– Single oral temp of > 38.3

Neutropenia
– Severe: ANC < 200
(rising septicemia risk)
– Moderate: 200-500
(rising serious infection risk)
– Mild: 500-1000
– Duration: 7-day cut-off
Evaluation
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Careful physical, (including perineal/perianal
palpation)
CBC; UA; cultures from all lines/ports and
infected-appearing exit sites
Imaging as indicated by exam
Repeat exam daily; culture daily for fever
spikes > 38.3oC or chills (the ideal time to
culture is just before the fever rises!)
Site specific cultures
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Diarrhea
– (C diff, rotavirus, Stool culture, O and P)
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Skin- if wound present-culture
CVL site
– (bacterial, fungal, mycobacteria)
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Viral cultures
– Mucosal or cutaneous vesicular/ulcerated
lesions
– Respiratory viral PCR
Management – 1

Broad spectrum single antibiotic
(cefepime)
– Add tobramycin if strong suspicion of gram
negative organism
– Add vancomycin if sick or skin involvement

Still febrile after 72 hours?
– Add or change antibiotics

Still febrile after 5-7 days?
– Consider anti-fungal therapy
Management - 2

No pathogen
– Continue antibiotics until afebrile x 24 hours
AND evidence of marrow recovery
– If afebrile, but NO evidence of marrow
recovery, continue antibiotics for 10-14 days
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Pathogen
– Treat until afebrile with negative cultures
AND ANC > 500 for 7-10 days.
Management:
fever without neutropenia
Exam; blood cultures
 other w/u as suggested by H&P
 If NO line and no obvious pathogen:
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– No antibiotic unless left shift, or
unexpected upswing in ANC
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If line:
– Consider observation vs. ceftriaxone
with reassessment in 24 hours (or less)
ISDA/ASCO guidelines
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Fever is defined as a single oral temperature of
> 38.3C (101F) or a temperature of > 38.0C
(100.4F) for 1hour.
Neutropenia is defined as an ANC < 500 or
< 1000 with a predicted decrease to < 500.
Oral therapy allowed (Amox/Clav) for low-risk
patients: no bacterial focus, no systemic sxs
(hypotension, rigors) other than fever, good
access. Preferably also recovering monocytes.
See table and chart
General comments
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The incidence of bacteremia in febrile neutropenic
pediatric patients is estimated at 4 to 36%
Many studies document bacteremia in patients
who lack concerning exam findings
At least one study suggests many parents do NOT
want outpatient Rx, even for low-risk children
[JCO 22(19):3922-6, 2004 Oct. 1]

In adult studies from Japan and South America,
outpatient management (typically with oral
antibiotics) is referenced as a “standard;”
meta-analysis supports the safety of that approach
[J Antimicrob Chemo 54(1):29-37, 2004 Jul]

Most bacteremia in F&N patients is gm(+)
[Clin Infx Dz 39Suppl S25-31, 2004 Jul 15]
Indiana U. – F/N Rx factors
JCO 14(3);919-24, 1996 March
115 consecutive episodes of F&N in 72 pediatric
oncology patients.
Analysis showed the only predictive factors to be the
absolute monocyte count, AMoC and admission
temperature, but NOT remission status, mucositis,
ill appearance, GI symptoms, cellulitis, use of GCSF,
or ANC at admission.
Patients then grouped
% positive cultures
• low (AMoC > 100, any temp)
0
• intermediate (AMoC < 100, T < 39)19
• high risk (AMoC < 100, T > 39)
48
UC Davis – F/N Rx factors
Pediatric Emergency Care. 20(2):79-84, 2004 Feb
303 events in 143 patients, of which 36 (11.9%)
received a critical care therapy
Higher temperature at presentation and capillary filling
time (CFT) of >3 seconds retained significance in the
multivariable analysis
Positive and negative predictive values
of the presence of either
T ≥ 39.5oC or CFT of >3 seconds
were 35% and 91%, respectively.
Sloan-Kettering – F/N Rx factors
Cancer 77(4):791-8, 1996 Feb. 15
161 patients pediatric oncology patients with 509
episodes of fever studied retrospectively for risk of
bacteremia
Clinical features correlating with increased risk of +
cultures: chills, hypotension, requirement for fluid
resuscitation, diagnosis of leukemia or lymphoma
NOT whether or not leukemia pt’s were in remission.
ICU admit and/or death predicted ONLY by ANC < 100
after 48 hours and persistent fever (both; not an and/or)
Children’s Hosp of Eastern Ontario:
early diagnosis, PO antibiotics?
J Pediatr Hematol Oncol. 2000 Sep-Oct;22(5):405-11
Randomized, double-blind, placebo-controlled study design:
73 patients at low-risk with episodes of F&N were Discharged
while still neutropenic: 37 with oral cloxacillin and cefixime
vs. 36 with placebos.
Low-risk criteria included: afebrile for more than 24 hours,
negative blood culture results at 48 hours, absence of clinical
sepsis, cancer in bone marrow remission, and absence of
comorbid conditions.
5 patients re-admitted with fever; no difference between groups;
1 patient (placebo) re-admitted with + cultures; no fatalities.
See also: JCO 22(18):3784-9, 2004 Sept 15
UT SW and Children’s Med Ctrs.
Early diagnosis, PO antibiotics?
Clin Infx Dz 25:74-8,1997 July
580 episodes of F&N in 253 peds onc patients; 333 d/c’d prior to
reaching an ANC of 500. [N.B. here “fever” = > 38.5 x 1 or > 38.0 x 2 in 24h]
25% were d/c’d on oral Abx, for specific (focal) infections
Lower risk: (-)blood cultures x > 24h, afeb x 24 hrs, appeared well,
some evidence of marrow recovery.
The groups (discharge early or not) differed: those going early were less
likely to be on GCSF and had fewer mean days of fever; also had a more
likely final diagnosis of FUO.
6% re-admit rate for recurrent fever (NOT different from re-admit rate
in those discharged at ANC > 500), 15 of which had no evidence of
marrow recovery retrospectively.
No cases of bacteremia in discharged cohort.
Similar studies (same centers) Cancer 74(1):189-96, 1994 July 1, JCO
8(12):1998-2004, 1990 Dec., J Peds 128(6):847-9, 1996 June
NCI and participants (run out of U of
Nebraska): PO vs. IV antibiotics
Randomized, double-blind, placebo-controlled study of
patients (age 5 to 74 years) w/ F&N during
chemotherapy.
Neutropenia < 10 days, no other underlying conditions.
Assigned to PO ciprofloxacin plus amoxicillin–
clavulanate or IV ceftazidime. All hospitalized.
116 episodes in each group (84 patients in the PO group
and 79 patients in the IV group).
Treatment was successful without the need for
modifications in 71 percent of episodes in the PO group
and 67 percent of episodes in the IV group (difference
between groups, 3%; 95% CI: –8% to 15%; p=0.48).
There were no deaths.
NEJM 341(5):305-311
MASCC risk-index score [for adults]
Multinational Association (for) Supportive Care in Cancer
 Predictive factors for risk of serious complications of
F&N, weighted
 Absence of sxs/mild sxs (x5)
 Absence of hypotension (x4)
 Absence of COPD (x4)
 Presence of solid tumor or,
if liquid tumor, absence of prior fungal infx (x4)
 Outpatient at the time (x3)
 Absence of dehydration (x3)
 Age < 60 yrs (x2)
 < 21 = “low risk”
Validation study @ CHOP: Uys et al, Supportive care
in Cancer 12(8):555-60, 2004 Aug.
Temp conversions
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38.0
38.3
38.4
38.5
39
39.1
38.0556
38.3333
38.6111
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100.4
100.94
101.12
101.3
102.2
102.38
100.5
101
101.5
Low-risk status (for ANC 200-500)
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Fever < 39
Well-appearing
No chills
No hypotension
No dehydration
If bone marrow disease, in
remission
If solid tumor, not
progressive dz
No serious bacterial focus
No co-morbidities or endorgan dysfunction
No severe mucositis
APC, monocytes, platelets
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No peri-rectal sxs
– Consider other GI sxs
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No diffuse cellulitis
Expected count recovery
in < 7 days
> 12 mos old
Reliable social situation
Not on high-risk Rx
–
–
–
–
–
No BMT pt’s
No AML pt’s
No induction pt’s
No Burkitt pt’s
Consider if intensification
phase
Purpura in DIC
Purpura in DIC
HSV
Infections
Invasive Aspergillosis
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CT scan of chest
– may diagnose aspergillosis
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A halo sign
– characteristic of angioinvasive organisms
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Galactomannan assay
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–
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detects aspergillus fungal wall (PCR test)
81% sensitivity, 89% specificity
Serial monitoring
Order as ‘miscellaneous microbiology test’
SEPTIC SHOCK
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Fever or hypothermia
Tachycardia
Vasodilation
Change in mental status
• Inconsolable, Irritability
• Lack of interaction with parents
• Inability to be aroused
Clinical diagnosis
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Fever, hypothermia
Decreased perfusion
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Prolonged capillary refill > 2 seconds-cold shock
Flash capillary refill- warm shock
Diminished (cold) or bounding (warm) pulses
Mottled extremities
Decreased urine output (< 1cc/kg/hour)
Hypotension
Monitoring and Testing
Pulse oximeter
 Continuous cardiac monitor
 Blood pressure
 Temperature
 Urine output
 Glucose and ionized calcium
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Fluid Resuscitation
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Rapid fluid boluses of 20 mL/kg (isotonic saline
or colloid) by push while watching for new
onset of rales, gallop rhythm, hepatomegaly,
and/or increased work of breathing.
In the absence of these clinical findings, fluid
can be administered to as much as 200 mL/kg in
the first hour.
The average requirement is 40-60 mL/kg in the
first hour.
Fluid should be pushed with the goal of
attaining normal perfusion and blood pressure.
Transfuse PRBCs, Platelets, FFP if needed
From ABP
Certifying Exam Content Outline
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Recognize the need for immediate evaluation of a
febrile child who is neutropenic as a result of
chemotherapy
Recognize recurrent bacterial infections as a
manifestation of quantitative or qualitative leukocyte
disorders
Know that a total leukocyte count and a leukocyte
differential count are needed to diagnose
neutropenia
Know that neutropenia is usually defined as a
neutrophil count <1000/mm3
Know that children with severe neutropenia may
become infected with their own skin and bowel flora
Recognize mucosal ulcerations as a sign of
neutropenia
From ABP
Certifying Exam Content Outline, continued
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infections in the compromised host
Know the major opportunistic infections seen in the
immunocompromised host, eg, cancer and neutropenia,
AIDS, nephrotic syndrome, asplenia, sickle cell
disease
Know that an accepted antibiotic regimen for an
immunocompromised child with fever should be
effective against Pseudomonas aeruginosa and
staphylococci
Recognize that aspergillosis is a fungal infection
usually of the lungs, and occurs almost exclusively in
patients with impaired host responses
From ABP
Certifying Exam Content Outline, continued
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Identify varicella as a life-threatening illness in a
patient receiving chemotherapy, and know that
varicella-zoster immune globulin should be given
immediately after exposure to varicella
Know the indications for the use of varicellazoster immune globulin after exposure to varicella
in immunocompromised patients and in certain
high-risk infants
Know that varicella-zoster immune globulin should
be given within 96 hours after exposure to
varicella
From ABP
Certifying Exam Content Outline, continued

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Understand that live-virus vaccines should not be
given during chemotherapy
Understand which immune-deficient patients
should not receive a live-virus vaccine
Plan an immunization schedule for an
immunedeficient patient
Credits
…as listed
 Meghen Browning MD
