Inpatient / Hematology and Oncology

Neutropenic Fever

Last Updated: 2/16/23

# Neutropenic Fever 2/2 ***

-- ABC's: does the patient have severe sepsis requiring pressors and ICU care?
-- Chart Check: outpatient oncologist, cancer type, last treatment and date, last known WBC and ANC, previous micro data including susceptibilities and MDROs, recent abx use (including prophylaxis), recent healthcare exposures, indwelling lines
-- Admission Criteria: calculate MASCC Score for risk stratification
-- HPI Intake: timing of fevers at home and Tmax, sick contacts, indwelling lines, localizing symptoms (SOB, cough, rhinorrhea, congestion, abd pain, diarrhea, dysuria, urinary frequency, CVA tenderness, wounds, rashes, ulcers, headaches), travel, animal exposure
-- Can't Miss: severe sepsis, bacteremia
-- Admission Orders: CBC with diff daily (ANC), BCx at 2+ sites (always include central line if there is one), UA/UCx, sputum Cx if appropriate, RVP, procalcitonin, ABG/VBG if c/f pulm source, lactate if concered about sepsis, EKG, CMV PCR if BMT transplant, CXR and CT chest if pulm sxs, stool cultures, O+P,  CDiff if diarrhea; consider PJP - LDH, beta-D-glucan
-- Initial Treatment to Consider: fluids and abx - cefepime in most, meropenem if h/o MDRO, vancomycin if septic, c/f line infection, or severe mucositis

-- Last Treatment:
 *** drug(s) and dates
Timing: *** first fever, last fever, and Tmax
-- Sick Contacts: ***
-- Localizing Symptoms: 
*** SOB, cough, rhinorrhea, congestion, abd pain, diarrhea, dysuria, urinary frequency, CVA tenderness, wounds, rashes, ulcers
-- Indwelling Lines: ***
foleys, PICC, chemo port, drains
-- Recent Abx Use: ***
-- Previous infections: ***
 bug, resistance patterns
-- Other: *** travel, animal exposure, occupation, TB risk factors

-- History: *** previous infection, fever timing, sick contacts, travel,
-- Clinical: *** general sick vs not sick, SOB, cough, rhinorrhea, congestion, abd pain, diarrhea, dysuria, urinary frequency
-- Exam: *** pulm  source (crackles, rhonchi), adominal source (pain, distention), urinary source (AMS, cloudy urine, CVA tenderness), SSTI (edema, erythema, warmth), indwelling lines (erythema, tenderness), mucositis, c/f endocarditis (murmurs, Janeway lesions, splinter hemorrhages)
-- Data: *** ANC, CXR, UA, UCx, procal
-- Etiology/DDx: *** bacterial infection, viral infection, fungal infection, transfusion reaction, engraftment, differentiation, GVHD, TLS, drug fevers, thromboplebitis, hematoma

The patient's HPI is notable for ***. Exam showed ***. Labwork and data were notable for ***. Taken together, the patient's presentation is most concerning for ***, with a differential including ***.

-- f/u BCx, UA/UCx, Sputum Cx, RVP, procalcitonin if c/f bacterial pneumonia
-- send fungal markers (LDH, beta-D-glucan, galactomannan) if imaging with nodules c/f aspergillus or ground glass c/f PJP
-- stool cultures, O+P,  CDiff if diarrhea
-- if imaging showing c/f atypical infection, may also benefit from BAL for better samples
-- Daily CBC with diff for ANC

-- Fluids:  ***, s/p ***
-- Oxygen: currently ***, continuous pulse ox with goal >92%
-- Abx: *** empiric cefepime 2g q8h, zosyn 4.5g q6h, meropenem 1g q8 if c/f ESBL; PO options include cipro/levo + amox/clav; GPC coverage with vancomycin if severe sepsis, c/f blood-stream infection associated with catheter, or patient has mucositis, obvious SSTI; can also consider going to linezolid or daptomycin if history of VRE; can add metronidazole if history of intra-abdominal infections, or patient has severe oral ulcers
-- Add fungal coverage with voriconazole or posaconazole if fevering despite treatment for 4-7 days, or evidence of positive fungal markers; use fluconazole if you have grown susceptible candida in cultures (does not cover endemic mycoses or aspergillus)
-- culture positive - treat for usual course, then fluoroquinolone ppx; culture neg - empiric abx until no fevers for ~4 days, then daily fluoroquinolone ppx
-- Supportive Care: *** tylenol PRN, analgesia, anti-emetics; neutropenic precautions
-- Pull indwelling line if BCx grows staph aureus, PsA, fungi, or there is c/f endocarditis

If You Remember Nothing Else

If patient fevers with ANC <500 or high likelihood that they will have ANC <500 within 48 hours they should receive antibiotics. Most patients will be treated inpatient, but the MASCC Risk Index Score can help identify healthy patients who can be treated at home.

Most patients never have an identifiable source of infection as cause of fevers; though we treat empirically with cefepime to cover GNRs, in patients who do have an identifiable bacterial infection, they are more likely to have a GPC. Consider fungal infections or MDROs in those with severe sepsis, CT imaging with GGOs or nodules, and those who fevers 4-7 days despite adequate abx therapy.

Treating prolonged neutropenic fevers can be puzzling. Remember the general differential for persistent fevers - wrong bug (viral, fungal, atypical), wrong drug, wrong process (not infection), no source control (abscess, endocarditis, indwelling line), not enough time.

Most patients with neutropenic fever fully recover. However, due to immunosuppressed state, some patients go on to develop severe sepsis and the mortality in these populations is extremely high.

Clinical Pearls

  • Neutropenic Fever is defined as T >100.4 with ANC <500 or expectation that ANC will be <500 within 48 hours
  • Calculate ANC by multiplying WBC by the % neutrophils on the diff
  • Functional neutropenia is when ANC >500, but PMNs are defective, often in leukemia, though this is controversial
  • Only 30% of cases identify an infectious source - 40% GNR, 60% GPC (commonly from lines and mucositis) - need to treat for possible PsA empirically since GNRs can make patients sick very quickly, but overall more likely to be a GPC if bacterial (Clin Microbiol Infect 2013), (Clin Infect Dis 2014)
  • Fungal infections are more likely with prolonged ANC <500, previous abx use, TPN use
  • MASCC Risk Index Score - use to identify low-risk patients (Score >21) who may be able to go home on PO abx, or who can be treated in the outpatient setting - criteria include symtpom severity, hypotension, active COPD, solid vs liquid tumor, prior fungal infection, dehydration requiring IV fluid, and whether the fever started inpatient or outpatient
  • Differential for fevers despite antibiotics includes: wrong bug (viral, fungal, atypical), wrong drug, wrong process (not infection), no source control (abscess, endocarditis, indwelling line), not enough time
  • Never do a DRE on patients with neutropenic fevers - translocation of intestinal bacteria
  • If worried about MRSA pneumonia, daptomycin is inactivated by surfactant, not useful for pulmonary infection - best saved if concern for VRE
  • Patients at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs)
  • Prophylaxis with fluoroquinolone after finish inpatient antibiotic course until ANC >500, especially in high-risk heme malignancy patients
  • Fluconazole does not cover endemic fungi and aspergillus, thus voriconazole or posaconazole is preferred for empiric coverage for possible disseminated fungal infection, especially in immunocompromised patients
  • CT chest has high NPV for PJP - if no characteristic GGOs, very unlikely to be due to PJP
  • CD4 <200 or steroids of ~ pred 20mg/day for 2-4 weeks is usually enough to be at risk for PJP - someone chronically on steroids is at risk up to 3-6 months after being tapered
  • 1,3-BDG is a cell wall polysaccharide unique to fungi - seen in PJP, aspergillus, candida, Histoplasma, coccicdioides, rhizopus; notable exceptions include Blastomyces, cryptococcus; is sensitive but not specific for PJP - should raise concern for fungal infection in general
  • Antifungal ppx with an -azole or echinocandin during neutropenia and 75 days after receiving HSCT
  • Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended treatment for patients receiving chemotherapy regimens associated with greater than 3.5% risk for pneumonia from Pneumocystis jirovecii

Trials and Literature

  • Review for Optimal Management of Neutropenic Fever in Patients with Cancer (J Oncol Pract 2019) 
  • Neutropenic Diet does not prevent infections, improve mortality, or change stool microbiota in patients who receiving inpatient induction therapy for acute leukemia; Major infections occurred in 32 (32%) patients in the regular diet arm and 26 (25%) patients in the neutropenic diet arm (p=0.26) (BMJ 2022)

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