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

NeutropeniaNeutrophil count (cells/uL)

Risk for infection

> 1500 No increased risk

1000-1499 Slight increased risk

500-900 Moderate increased risk

<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 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 factors115 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

JCO 14(3);919-24, 1996 March

UC Davis – F/N Rx factors303 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.

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 lymphomaNOT 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 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 end-

organ 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 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 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 varicella-zoster 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