02 Fever With Neutropenia v2

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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



Infection Questions

Sites

Frequency

Organisms

Treatments

Outcomes

Co-morbities

Exposures – School

– Home

– Food

– Water

– Pets

Immunizations Family History

Recent chemotherapy

– i.e., immune suppression?



Primary work-up

Barriers:

– History, Physical exam

Phagocytes:

– CBC/diff

Lymphocytes:

– CBC/diff, Quantitative Ig

RES: – blood smear (Howell-Jolly bodies?)

Complement:

– rare



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



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



Pneumonia in a neutropenic patient

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

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).



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



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

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!)



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



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



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.



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)



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







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]



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



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



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



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 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



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



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

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



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



Purpura in DIC



Purpura in DIC



HSV

Infections





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‟





SEPTIC SHOCK

– Fever or hypothermia

– Tachycardia

– Vasodilation – Change in mental status

• Inconsolable, Irritability

• Lack of interaction with parents

• Inability to be aroused



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



Monitoring and Testing

Pulse oximeter

Continuous cardiac monitor

Blood pressure

Temperature

Urine output

Glucose and ionized calcium



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





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



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



From ABP


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



From ABP


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



Credits

…as listed

Meghen Browning MD

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02 Fever With Neutropenia v2

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