Pathophysiology of Neutropenic Fever: Impact on Diagnosis and Treatment

Part 1 of the febrile neutropenia miniseries

Febrile neutropenia is an emergency, although often not an obvious one from the bedside

Febrile neutropenia is an emergency, although often not an obvious one from the bedside. I still remember myself arguing in the emergency department that such patients should have priority from the nurses as they should have antibiotics within an hour. In essence, the workup consists of taking blood cultures and then starting an anti-pseudomonal beta-lactam, mainly cefepime, piperacillin-tazobactam or a carbapenem (8). However, during my residency, I saw a lot of heterogeneity in treating these patients, which made me wonder how to best manage febrile neutropenia. The following miniseries is a deep dive into some of my questions.

In this post, I want to take a closer look at the pathophysiology of febrile neutropenia and what it means for its diagnostic workup.

1. What is the pathophysiology of febrile neutropenia?

Febrile neutropenia is defined by the presence of fever in people with a neutrophil count of less than 500 cells/microliter (or expected to decrease below this level in the coming days) (1). Most often, this condition emerges a week to 10 days after the administration cyto-reductive therapy and therefore the following factors contribute to its pathophysiology:

(a) Absence of neutrophils

This of course makes patients vulnerable for bacterial and fungal infections. For instance, the risk of invasive fungal infections is inversely related to the absolute neutrophil count (1).

(b) Presence of febrile mucositisAlthough often forgotten, there is strong evidence that mucosal barrier injury plays a central role in the pathophysiology of febrile neutropenia:

• Most microorganisms that cause febrile neutropenia are colonizers of the skin and mucosa (3) whereas common disease pathogens, for instance S. pneumoniae are rare in these patients. By contrast, S. pneumoniae is a common pathogen in chronic idiopathic neutropenia and untreated hematologic malignancies, indicating that the pathophysiology of these conditions is different (2).

• In up to 70% of the people with febrile neutropenia no clinical or microbiological source of infection can be identified (4). This so-called fever of unknown/unexplained origin is often caused by a mucositis-associated inflammation (5). Some of the underlying mechanisms are the following (2):

  • The release of cytokines by tissue macrophages, dendritic cells and epithelial cells provoked by cell damage            

  • The disruption of the mucosal barrier with translocation of microbes and pathogen-associated molecular patterns             

  • The disturbances to the normal innate immune system at the mucosal barrier

• In a prospective, observational study, citrulline, a marker of intestinal mucosal integrity, was found to be severely low in almost 63% of patients with febrile neutropenia (5), corresponding to severe mucositis. This was considered as the main source of fever in the majority of patients. However, the same study couldn’t demonstrate a clear link between mucositis and onset of bloodstream infections.

• The role of mucositis was also emphasized by CDC in 2013 with the introduction of the term mucosal barrier injury laboratory-confirmed bloodstream infection. This is considered a non-preventable infection in oncology and hematology patients, in contrast to central line-associated bloodstream infection (6).

2. What are the implications of the pathophysiology of febrile neutropenia for its diagnosis and treatment?

(a) Risk of fungal infections

Long-term neutropenia predisposes for fungal infections. Apart from considering antifungal prophylaxis in high-risk individuals (7), this also implicates that if fever persists for several days despite negative cultures and adequate empirical antibiotic therapy, invasive fungal infections become much more likely (7).

(b) Persistent fever does not necessarily mean antibiotic failure

Ongoing fever for days is common in febrile neutropenia. Although clinicians commonly escalate antimicrobial treatment as a response, this is often not needed for the following reasons:

1. Defervescence in febrile neutropenia takes time. In a large database of 2500 episodes, for instance, the median time for the fever to abate was 3 and 4 days, respectively if no infection and an infection was documented (7).

2. As mentioned before, in up to 70% of patients, no cause is found for the fever. In these cases, mucositis and its associated inflammation are thought to be responsible for the raised temperature (5).

3. A few studies have shown that antibiotic therapy can be stopped after 3 days, even in case of persisting fevers (17, 18, 19)

(c) Additional workup is needed in case of persistent fever

Although persistent fever is common in febrile neutropenia, it doesn’t always require escalating antibiotic treatment (or even treatment in certain situations). By contrast, further diagnostic vigilance remains important.

Diagnostic workup to exclude fungal infections:

1. Serum galactomannan

Bi-to tri-weekly screening of serum galactomannan aids in early detection of fungal infections (7). However, this test loses a lot of its positive predictive value if patients are receiving anti-fungal prophylaxis (8).

2. 1-3-beta-D-Glucan

This can help in the diagnosis of invasive candidiasis but also in fusariosis and pneumocystis. A meta-analysis showed a moderate sensitivity and a good specificity (8).

3. CT Chest and sinuses.

In case of ongoing fever after 4 to 5 days, this is a necessary test to exclude invasive fungal infections. If suspicious signs are present, a bronchoalveolar lavage (for culture, PCR and galactomannan) or biopsy of the sinus need to be considered (7).

Diagnostic workup to exclude bacterial infections:

As most bacterial infections in febrile neutropenia can easily be cultured by blood cultures (3), the main question is if blood cultures (usually drawn before starting antibiotics) should be repeated if the fever persists. The IDSA recommends against daily blood cultures as long as the patient remains stable (15).

• In one study, 7 of 134 episodes of febrile neutropenia had positive blood cultures after 3 days. Only in three times the microorganism wasn’t yet known (20). Good predictors for negative cultures were absence of shivering and low-grade fever. Another study found similar findings (20).

• By contrast, in a study by de Jonge et al, 4 of the 281 patients most likely died because of candidemia and E. faecium sepsis (17). The authors of this study concluded that “caregivers should be vigilant in patients with persistent fever”.

My view: Blood cultures can really steer antibiotic therapy. I would still suggest repeating them every few days if the febrile neutropenia persists, especially if ongoing chills or subtle changes in the clinical presentation.

To exclude other causes of fever:

Apart from mucositis-associated inflammation, many other disorders can cause persistent fever in neutropenic patients such as drug-fever, engraftment syndrome, cytokine release syndrome, tumor lysis syndrome and hemophagocytic lymphohistiocytosis (21). After all, a broad differential diagnosis remains important in these patients.

References:

1. Stern A, Carrara E, Bitterman R, et al. Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution in people with cancer. Cochrane Database Syst Rev. 2019 Jan 3;1(1):CD012184.

2. van der Velden WJ, Herbers AH, Netea MG, Blijlevens NM. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol. 2014 Nov;167(4):441-52. 

3. Alves J, Abreu B, Palma P, et al. Antimicrobial Stewardship on Patients with Neutropenia: A Narrative Review Commissioned by Microorganisms. Microorganisms. 2023 Apr 26;11(5):1127. 

4. Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia. [Updated 2023 Mar 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541102/. 

5. de Jonge NA, Janssen JJWM, Ypma P, et al. Mucositis-associated bloodstream infections in adult haematology patients with fever during neutropenia: risk factors and the impact of mucositis severity. Support Care Cancer. 2024 Aug 8;32(9):579. 

6. Dandoy CE, Alonso PB. MBI-LCBI and CLABSI: more than scrubbing the line. Bone Marrow Transplant. 2019 Dec;54(12):1932-1939. 

7. Nucci M. How I Treat Febrile Neutropenia. Mediterr J Hematol Infect Dis. 2021 Mar 1;13(1):e2021025. 

8. Keck JM, Wingler MJB, Cretella DA, et al. Approach to fever in patients with neutropenia: a review of diagnosis and management. Ther Adv Infect Dis. 2022 Nov 26;9:20499361221138346. 

9. Beyar-Katz O, Dickstein Y, Borok S, et al. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2017 Jun 3;6(6):CD003914. 

10. Yalçın C, Özkalemkaş F, Özkocaman V, et al. Evaluation of Using Empiric Glycopeptides in Accordance with the IDSA Guidelines in Hematologic Malignancy Patients with Febrile Neutropenia. Mediterr J Hematol Infect Dis. 2022 May 1;14(1):e2022039. 

11. Mayer K, Hegge N, Molitor E, et al. Comparison of Empiric Antibiotic Escalation Therapy with Vancomycin (VAN) versus Linezolid (LIN) in Patients with Febrile Neutropenia. Mediterr J Hematol Infect Dis. 2022 May 1;14(1):e2022032. 

12. Schmidt-Hieber M, Teschner D, Maschmeyer G, et al. Management of febrile neutropenia in the perspective of antimicrobial de-escalation and discontinuation. Expert Rev Anti Infect Ther. 2019 Dec;17(12):983-995. 

13. Martinez-Nadal G, Puerta-Alcalde P, Gudiol C, et al. Inappropriate Empirical Antibiotic Treatment in High-risk Neutropenic Patients With Bacteremia in the Era of Multidrug Resistance. Clin Infect Dis. 2020 Mar 3;70(6):1068-1074. 

14. Rosa RG, Dos Santos RP, Goldani LZ. Mortality related to coagulase-negative staphylococcal bacteremia in febrile neutropenia: A cohort study. Can J Infect Dis Med Microbiol. 2014 Spring;25(1):e14-7. 

15. 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. 

16. From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel. J Infect Dis. 1990 Mar;161(3):397-401. 

17. de Jonge NA, Sikkens JJ, Zweegman S, et al. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial. Lancet Haematol. 2022 Aug;9(8):e563-e572. 

18. Niessen FA, van Mourik MSM, Bruns AHW, et al. Early discontinuation of empirical antibiotic treatment in neutropenic patients with acute myeloid leukaemia and high-risk myelodysplastic syndrome. Antimicrob Resist Infect Control. 2020 May 27;9(1):74. 

19. Schauwvlieghe A, Dunbar A, Storme E, et al. Stopping antibiotic therapy after 72 h in patients with febrile neutropenia following intensive chemotherapy for AML/MDS (safe study): A retrospective comparative cohort study. EClinicalMedicine. 2021 Apr 25;35:100855. 

20. Kimura SI, Gomyo A, Hayakawa J, et al. Clinical significance of repeat blood cultures during febrile neutropenia in adult acute myeloid leukaemia patients undergoing intensive chemotherapy. Infect Dis (Lond). 2017 Oct;49(10):748-757. 

21. Aslan AT, Akova M, Kontoyiannis DP. The Heterogeneous Syndrome of Noninfectious Causes of Persistent Fever in Neutropenic Patients With Hematologic Malignancy: Another Opportunity for Stewardship? Clinical Infectious Diseases. 2024 Dec 15;79(6):1333-1337