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 Risk for count (cells/uL) infection
> 1500 1000-1499 500-900 <499
No increased risk Slight increased risk Moderate increased risk 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 empiric therapy 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 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

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/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

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:

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, good access. 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 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 pts were in remission. ICU admit and/or death predicted ONLY by ANC < 100 after 48 hours and persistent fever (both; not an and/or)

Childrens 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 Childrens 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/cd 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/cd 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

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, in remission If solid tumor, not progressive dz No serious bacterial focus No co-morbidities or endorgan dysfunction No severe mucositis APC, monocytes, platelets

No peri-rectal sxs
Consider other GI sxs

No diffuse cellulitis Expected count recovery in < 7 days > 12 mos old Reliable social situation Not on high-risk Rx
No BMT pts No AML pts No induction pts No Burkitt pts Consider if intensification phase

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 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

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

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

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

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