Febrile neutropenia , low neutrophil with fever

1. Febrile Neutropenia

2. Table of contents
01 Introduction
02 Definition
03 Pathogenesis
04 History and Physical
05 Diagnosis testing
06 Management

3. Introduction
01
Febrile neutropenia is a medical emergency defined as fever in a
patient with an abnormally low number of circulating neutrophils,
commonly associated with cytotoxic chemotherapy.

4. Definition
• fever defined as either
• single oral temperature ≥ 38.3 degrees C (101 degrees F)
• oral temperature ≥ 38 degrees C (100.4 degrees F) sustained for ≥
1 hour
• neutropenia graded according to severity, which determines risk of
infection
• mild 1-1.5 × 109/L (1,000-1,500 cells/mm3); does not impair host
defense
• moderate 0.5-1 × 109/L (500-1,000 cells/mm3); slight increased risk
of infection if other arms of immune system also impaired
• severe < 0.5 × 109/L (< 500 cells/mm3); increased risk of infection
in most patients
• most severe/agranulocytosis ≤ 0.2 × 109/L (≤ 200 cells/mm3); risk
of severe, life-threatening infections
• profound neutropenia < 100 cells/mm3 confirmed by manual blood
smear

5. Differential diagnosis
bacterial pathogens commonly identified in neutropenic patients with
bloodstream infections include

6. • invasive fungal infections may be responsible for febrile neutropenia that
persists after empiric antibiotic treatment,
including Candida and Aspergillus species
• viral infections may also cause fever, including
• herpesviruses
• respiratory viruses, such as influenza, parainfluenza, adenovirus,
respiratory syncytial virus, and human metapneumovirus
• noninfectious sources of fever may include
• drug-related fever
• thrombophlebitis
• underlying cancer
• resorption of blood from large hematoma

7. Pathogenesis
• pathogenesis varies with cause but often involves toxicities related to
chemotherapy and subsequent altered response to potential pathogenscytotoxic
chemotherapy may impair host immunity in multiple ways that predispose a patient
to infection
• development of neutropenia compromises a critical part of the innate immune
response
• delivery of chemotherapy often requires indwelling catheter placement, breaching
the skin, and providing systemic access to skin flora
• addition of B- or T-cell-depleting monoclonal antibodies may compound risk of
infection and broaden the spectrum of infections that occur.

8. History and Physical
History
• consider
• type and timing of chemotherapy regimen received
• other iatrogenic immunosuppression including corticosteroids
• expected absolute neutrophil count (ANC) nadir and count recovery
• ask about
• localized symptoms
• prior infections or colonization, particularly
• latent infections known to reactivate (such as tuberculosis)
• multidrug-resistant organisms
• HIV

9. •recent antibiotic use
•exposures, such as
• recent sick contacts
• pets
• travel
• tuberculosis
• blood product administration
•ask about risk factors for other infections that may be clinically unapparent, such as
• hepatitis B
• hepatitis C
• syphilis
•possible noninfectious causes of fever, such as
• blood product administration
• new medications
•underlying comorbid conditions, including
• diabetes
• chronic obstructive lung disease
• allergies
• recent surgical procedures
• chronic kidney disease

10. Physical
• assess for signs of systemic inflammatory response syndrome (SIRS) or sepsis including
• look for
• fever (> 38 degrees C [100.4 degrees F]) or hypothermia (< 36 degrees C [96.8
degrees F])
• tachycardia (> 90 beats per minute [BPM])
• tachypnea (> 20 BPM)
• hypotension
• note that inflammatory response may be blunted in neutropenic patients
• standard criteria for SIRS or sepsis may not be fulfilled
• general deterioration, mental status change, or other nonspecific signs may be only
indication of sepsis

11. •remainder of physical examination should include a careful search for potential sources of
infection3
• particular attention should be paid to commonly infected sites, including
• skin
• prior or present vascular access sites
• oropharynx, including periodontium
• alimentary tract
• lungs
• perineum
• other sites that warrant close examination may include
• sinuses, assessing for
• facial anesthesia
• alterations in nasal mucosa, such as discoloration or ulceration
• palpation of frontal and maxillary sinuses
• abdomen
• distention
• pain (right lower quadrant pain may suggest neutropenic enterocolitis [typhlitis])
• rebound or guarding
• inspection for perirectal abscess should be performed but digital rectal examination is
contraindicated

12. Diagnosis Testing
Initial testing
Recommendations
•American Society of Clinical Oncology/Infectious Diseases Society of America (ASCO/IDSA) recommendations
for initial testing in patients with fever within 6 weeks of chemotherapy
general blood tests
• complete blood count (CBC) with differential leukocyte count, hemoglobin, and platelet count
• serum creatinine
• serum electrolytes
• serum lactate
• blood urea nitrogen
• Liver function testing including transaminases, total bilirubin, and alkaline phosphatase
• ≥ 2 sets of blood cultures from different anatomical sites, including cultures from peripheral vein and
indwelling IV catheter, if present cultures from other sites as clinically indicated, including urine, lower
respiratory tract, cerebrospinal fluid, or wounds chest imaging for patients with signs or symptoms of
lower respiratory tract infection for patients with influenza-like illness.
• obtain nasopharyngeal swab for detection of influenza
• consider expanded viral panels for detection of other respiratory viruses (parainfluenza virus,
adenovirus, coronavirus, respiratory syncytial virus, human metapneumovirus, enteroviruses, and
rhinovirus), particularly in patients with hematologic malignancy and hematopoietic stem cell
transplantation

13. Imaging studies
•computed tomography (CT) may have higher sensitivity for detection of pulmonary
abnormalities compared to x-ray in children with febrile neutropenia
Additional testing
Cerebrospinal fluid (CSF) analysis
•meningitis may present without pleocytosis in patients with febrile neutropenia
Biomarkers for detection of infection
Galactomannan testing
General principles of galactomannan testing
• galactomannan may serve as diagnostic biomarker of fungal infections

14. Procalcitonin
•procalcitonin may have moderate diagnostic accuracy for detection of
bacteremia in patients with suspected infection or sepsis
Bronchoalveolar lavage (BAL)
•culture of BAL fluid may be considered for patients with unknown infiltrate on chest
imaging

15. Management
Assess the risk of complications and death using the Multinational
Association of Supportive Care in Cancer (MASCC) score or a simplified
classification:
1) High risk: Expected long-term (>7 days) and profound
neutropenia (ANC ≤0.1×109/L) and/or clinically significant complications.
2) Low risk: All other patients.

16. J Clin Oncol. 2000;18(16):3038-51

17. Immediately start empiric febrile neutropenia therapy using an
escalation strategy. This strategy, avoiding initial combination therapies
and carbapenems, could be used in patients with no previous infections
or colonization with resistant bacteria and in centers where infections
due to resistant pathogens are rarely seen

18. Clin Infect Dis. 2011;52(4):e56-93.

19. With the escalation strategy being the standard of care, in some
cases a de-escalation strategy may be employed. Examples
include initial therapy involving carbapenems as the first-line
regimens (in seriously ill patients, eg, with septic shock; known
previous colonization with extended-spectrum beta-
lactamase (ESBL)-producing Enterobacteriaceae or gram-negative
bacteria resistant to narrow-spectrum beta-lactam antibiotics or
centers with high prevalence of such strains) or combinations with
aminoglycosides (septic shock,
resistant Pseudomonas or Acinetobacter strains likely due to
colonization or local epidemiology, or use of carbapenems within
the previous month). Subsequent management is directed to treat
the identified infection (even if it is culture-negative) and to narrow
the coverage

20. Haematologica. 2013;98(12):1826-35.

21. Clin Infect Dis. 2011;52(4):e56-93.

22. Patients with persistent neutropenia who have completed a course of
antibiotics should stay in the hospital for an observation lasting ≥24 to
48 hours. Management of high-risk patients with fever persisting for
>4 days of empiric antibiotic therapy should include either the addition
of empiric antifungal therapy or preemptive therapy (therapy as
directed by testing indicating the possibility of fungal infection
[bronchoalveolar lavage, galactomannan, high-resolution computed
tomography]) in selected patients

23. Clin Infect Dis. 2011;52(4):e56-93.

24. References
https://empendium.com/mcmtextbook/chapter/B31.II.22.2.5.
Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient Management of Fever and
Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology
and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin
Oncol. 2018 May 10;36(14):1443-1453.
Wang XJ, Chan A. Optimizing Symptoms and Management of Febrile Neutropenia
among Cancer Patients: Current Status and Future Directions. Curr Oncol Rep. 2017
Mar;19(3):20.
J Clin Oncol. 2000;18(16):3038-51
Haematologica. 2013;98(12):1826-35
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of
antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious
Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
Clin Infect Dis. 2011;52(4):e56-93