02 fever with neutropenia v2
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8/4/2019 02 Fever With Neutropenia v2
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Fever and Neutropenia
Pediatric Resident
Education Series
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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
Sites
Frequency
Organisms
Treatments
Outcomes
Co-morbities
Exposures – School
– Home
– Food
– Water
– Pets
Immunizations Family History
Recent chemotherapy
– i.e., immune suppression?
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Primary work-up
Barriers:
– History, Physical exam
Phagocytes:
– CBC/diff
Lymphocytes:
– CBC/diff, Quantitative Ig
RES: – blood smear (Howell-Jolly bodies?)
Complement:
– rare
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Secondary work-up Barriers:
– Biopsy with EM
Phagocytes: – tests for mobilization, chemothaxis,
opsonization, ingestion, killing (NBT test)
Lymphocytes: – subsets (T, B, NK, others), antibody titers,
skin tests, isohemaggluinins, function tests(mixing T, B cells)
RES: – Tc Scan
Complement: – Factor titers
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Neutropenia
Neutrophil
count (cells/uL)
Risk for
infection
> 1500 No increased risk
1000-1499 Slight increased risk
500-900 Moderate increasedrisk
<499 High increased risk
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Pneumonia in a neutropenic patient
Empiric antibiotics
– Bacteria: cefepime,
tobramycin, vancomycin
– Mycoplasma: azithromycin
– Pneumocystis: Bactrim
– Viral: acyclovir – Fungal: Ambisome, other
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Pneumonia in a neutropenic patient..
Lavage: if done well, gives 75% of pathogens found on biopsy – Frequently worsens lung scans
Biopsy: – usually worsens lung status
Empiric antibiotic therapy: – if wrong drugs, then lavage/biopsy needed in
sicker patients
In one small trial, outcome of empirictherapy was equivalent to that of biopsy(Pizzo et al).
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Fever, neutropenia pearls
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
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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
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Evaluation
Careful physical, (including perineal/perianal
palpation)
CBC; UA; cultures from all lines/ports andinfected-appearing exit sites
Imaging as indicated by exam
Repeat exam daily; culture daily for feverspikes > 38.3oC or chills (the ideal time to
culture is just before the fever rises!)
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Site specific cultures
Diarrhea
– (C diff, rotavirus, Stool culture, O and P)
Skin- if wound present-culture CVL site
– (bacterial, fungal, mycobacteria)
Viral cultures
– Mucosal or cutaneous vesicular/ulceratedlesions
– Respiratory viral PCR
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Management – 1
Broad spectrum single antibiotic
(cefepime)
– Add tobramycin if strong suspicion of gramnegative 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
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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
Pathogen
– Treat until afebrile with negative culturesAND ANC > 500 for 7-10 days.
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Management:
fever without neutropenia
Exam; blood cultures
other w/u as suggested by H&P
If NO line and no obvious pathogen:
– No antibiotic unless left shift, or
unexpected upswing in ANC
If line:
– Consider observation vs. ceftriaxone
with reassessment in 24 hours (or less)
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ISDA/ASCO guidelines
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, goodaccess. Preferably also recovering monocytes.
See table and chart
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General comments 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 NOTwant 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]
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Indiana U. – F/N Rx factors
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 admissiontemperature, 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
JCO 14(3);919-24, 1996 March
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UC Davis – F/N Rx factors
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 themultivariable analysis
Positive and negative predictive values
of the presence of eitherT ≥ 39.5oC or CFT of >3 seconds
were 35% and 91%, respectively.
Pediatric Emergency Care. 20(2):79-84, 2004 Feb
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Sloan-Kettering – F/N Rx factors
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)
Cancer 77(4):791-8, 1996 Feb. 15
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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
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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 ratein 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
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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 formodifications 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
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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.
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Temp conversions
38.0
38.3
38.4
38.5 39
39.1
38.0556
38.3333
38.6111
100.4
100.94
101.12
101.3 102.2
102.38
100.5
101
101.5
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Low-risk status (for ANC 200-500)
Fever < 39
Well-appearing
No chills
No hypotension
No dehydration
If bone marrow disease, inremission
If solid tumor, notprogressive dz
No serious bacterial focus No co-morbidities or end-
organ dysfunction
No severe mucositis
APC, monocytes, platelets
No peri-rectal sxs
– Consider other GI sxs
No diffuse cellulitis
Expected count recoveryin < 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 intensificationphase
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Purpura in DIC
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Purpura in DIC
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HSV
Infections
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Invasive Aspergillosis
CT scan of chest
– may diagnose aspergillosis
A halo sign – characteristic of angioinvasive organisms
Galactomannan assay
– detects aspergillus fungal wall (PCR test)
– 81% sensitivity, 89% specificity – Serial monitoring
– Order as „miscellaneous microbiology test‟
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SEPTIC SHOCK
– Fever or hypothermia
– Tachycardia
– Vasodilation – Change in mental status
• Inconsolable, Irritability
• Lack of interaction with parents
• Inability to be aroused
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Clinical diagnosis
Fever, hypothermia
Decreased perfusion
– 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
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Monitoring and Testing
Pulse oximeter
Continuous cardiac monitor
Blood pressure
Temperature
Urine output
Glucose and ionized calcium
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Fluid Resuscitation Rapid fluid boluses of 20 mL/kg (isotonic saline
or colloid) by push while watching for newonset of rales, gallop rhythm, hepatomegaly,and/or increased work of breathing.
In the absence of these clinical findings, fluidcan be administered to as much as 200 mL/kg inthe first hour.The average requirement is 40-60 mL/kg in thefirst hour.
Fluid should be pushed with the goal of attaining normal perfusion and blood pressure.
Transfuse PRBCs, Platelets, FFP if needed
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From ABP
Certifying Exam Content Outline
Recognize the need for immediate evaluation of afebrile child who is neutropenic as a result ofchemotherapy
Recognize recurrent bacterial infections as a
manifestation of quantitative or qualitative leukocytedisorders
Know that a total leukocyte count and a leukocytedifferential count are needed to diagnoseneutropenia
Know that neutropenia is usually defined as aneutrophil count <1000/mm3
Know that children with severe neutropenia maybecome infected with their own skin and bowel flora
Recognize mucosal ulcerations as a sign ofneutropenia
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From ABP
Certifying Exam Content Outline, continued
infections in the compromised host
Know the major opportunistic infections seen in theimmunocompromised host, eg, cancer and neutropenia,
AIDS, nephrotic syndrome, asplenia, sickle celldisease
Know that an accepted antibiotic regimen for animmunocompromised child with fever should beeffective against Pseudomonas aeruginosa and
staphylococci Recognize that aspergillosis is a fungal infection
usually of the lungs, and occurs almost exclusively inpatients with impaired host responses
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From ABP
Certifying Exam Content Outline, continued
Identify varicella as a life-threatening illness in apatient receiving chemotherapy, and know thatvaricella-zoster immune globulin should be givenimmediately after exposure to varicella
Know the indications for the use of varicella-zoster immune globulin after exposure to varicellain immunocompromised patients and in certainhigh-risk infants
Know that varicella-zoster immune globulin shouldbe given within 96 hours after exposure tovaricella
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From ABP
Certifying Exam Content Outline, continued
Understand that live-virus vaccines should not begiven during chemotherapy
Understand which immune-deficient patients
should not receive a live-virus vaccine Plan an immunization schedule for an
immunedeficient patient
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Credits
…as listed
Meghen Browning MD
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