Febrile neutropenia (FN) is defined as an elevated oral temperature > 38.5°C or a temperature > 38.0°C measured on 2 consecutive occasions over 2 hours, along with an absolute neutrophil count (ANC) < 0.5 × 109/L or an expected < 0.5 × 109/L.
Incidence of FN, complication rates and mortality
Despite advances in preventive and therapeutic measures, FN remains the complication of highest concern in cancer treatment and is a major cause of complications, increased health resource investment, and diminished treatment effectiveness due to chemotherapy delays and dose reductions. Although the mortality rate of FN has steadily decreased year by year, it is still relatively significant, with an overall mortality rate of approximately 5% in patients with solid tumors and up to 11% in some hematologic malignancies.
Patients with confirmed bacteraemia have a poorer prognosis, with mortality rates of 18% and 5% for Gram-negative and positive organisms, respectively. Mortality correlates with MASSC prognostic score: only 3% with MASCC score >21, but up to 36% if MASCC score <15. Elderly patients are more likely to develop febrile neutropenia after chemotherapy and have higher complications and mortality. However, due to the inclusion criteria, there is a lack of prospective trials in the elderly and therefore a lack of relatively specific treatment recommendations.
The detection rate of positive microorganisms in standard blood cultures is dependent on whether the patient is on prophylactic antimicrobial use and has central venous cannulation (CVC). In one solid tumor trial, only a small proportion of patients with CVCs were given antimicrobial prophylaxis, and most did not receive antimicrobial prophylaxis. A higher proportion of patients in the hematologic tumor trial had CVCs, 17% to 31%.
Pathogenic infections vary by treatment center, and over the past few decades, there has been a shift from predominantly Gram-negative to Gram-positive infections in FN, with 70% of positive FN blood cultures being Gram-positive. Drug-resistant strains such as ESBL gram-negative, vancomycin-resistant enterococci (VRE), and MRSA are on the rise, as are fluconazole-resistant Candida infections (Pseudomonas graminearum and Pseudomonas smoothus).
Patient education and appropriate policies
Successful treatment of FN presupposes rapid recognition and rapid response to potential infection, so it is important to educate out-of-hospital patients, such as monitoring temperature and instructing patients when and how to contact health care providers. In addition, local policies for rapid response to suspected FN are critical, as some patients may be seen in the emergency room for FN, when a clear plan would allow for proper management of the patient.
Initial assessment
Take a detailed history, including chemotherapy, prophylactic antimicrobials, concomitant use of glucocorticoids, history of recent surgery, and any history of allergies. It is important to identify a history of previous positive microbial infections by reviewing the clinical record, especially if there has been a previous antimicrobial resistant microbial or bacterial infection, to further guide treatment.
It is important to initially assess circulatory and respiratory function and to resuscitate if necessary, and subsequently to check for the presence of underlying foci of infection, as the antimicrobial agents empirically selected to treat FN sometimes do not cover certain infections (e.g., community-acquired pneumonia).
Signs and symptoms of infection in neutrophil deficient patients are not obvious, especially in patients who have received glucocorticoids. Any patient at risk for FN who presents with discomfort, hypotension, and hypothermia should be alerted to the possibility of developing Gram-negative bacterial sepsis, which requires prompt treatment.
Emergency blood tests to clarify neutrophil levels and other tests needed, which are critical to guide early treatment. Secondary blood cultures of peripheral venous blood, indwelling venous catheters, in addition to sputum, urine, skin swabs, and stool specimens are obtained prior to empiric broad-spectrum antimicrobial therapy when appropriate clinical signs are present.
High-risk patients
Patients with FN who have a high risk MASCC score or who are judged by their physician to have high risk features should be admitted immediately and started on broad-spectrum intravenous antimicrobial therapy.
1. Choice of intravenous antimicrobial agents
Regional bacterial prevalence and resistance are critical to empirical treatment selection, as coverage of MRSA or gram-negative resistant organisms may be required. A meta-analysis comparing monotherapy (anti-Pseudomonas cephalosporins such as ceftazidime or carbapenems) with combination therapy found equal effectiveness, but it remains unclear whether prolonged neutrophil deficiency or bacteraemia is indicated, when a combination of antimicrobials with ß-lactamase bactericidal action and aminoglycosides is preferred.
2. Treatment of specific changes
In addition to the standard broad-spectrum antimicrobial therapy, many institutions need some special treatment plans in practice. The duration of treatment varies widely, and local antimicrobial treatment guidelines should be followed at this time.
(1) Central venous placement: If catheter-associated infection is suspected, blood cultures must be obtained from the catheter and periphery to measure the difference in time to positive alarm (DTTP), as the time to positive culture in the catheter differs from that of a positive peripheral blood culture. If ≥ 2 hours is highly suggestive of catheter-associated bacteremia.
All FN catheter-associated infections (CRIs) require determination of the type of intravenous antimicrobial and the duration of treatment, as well as removal of the catheter. Suspected CRI
If the patient is stable and there is no evidence of microbial infection, the catheter should not be removed and a glycoside such as vancomycin should be used to cover gram-positive organisms. Instead of vancomycin, ticoranib, which is given once a day near the end of the infusion, may be used. Successful treatment of CRI and the need to remove catheters is related to the pathogens isolated by blood culture.
With coagulase-negative staphylococcal (CNS) CRI, an attempt should be made to retain the catheter if the patient is stable. A prospective cohort study of neonates with CVC treated with antimicrobials for CNS bacteremia showed successful catheter retention in 46% of cases. A recent retrospective study in adults reported a 93% success rate for antimicrobial treatment of CRIs due to CNS, with a 4-month follow-up reinfection rate of only 8%. Catheter retention does not affect CNS bacteremia, but is an important factor in recurrence.
Indications for catheter removal include luminal infections, port of implantation infections, persistent bacteraemia despite adequate treatment, atypical mycobacterial infections, and Candida bacteraemia. The treatment of S. aureus infection is currently divided, with Germany recommending essential catheter removal, but Korean studies showing a 50% success rate of catheter retention with appropriate anti-S. aureus therapy.
Whether or not to retain the catheter needs to be balanced against the risk of bloodstream implant transmission, so it is recommended that the catheter should be removed if possible, but may be retained for a short period of time with treatment. Persistent fever and bacteremia despite proper antimicrobial therapy are indications for catheter removal.
(2) Pneumonia If pneumonia is diagnosed clinically or on imaging, antimicrobials must cover atypical pathogens such as Legionella and mycoplasma, primarily macrolides in combination with endocannabinoid antimicrobials. Pneumocystis infection should be considered if the patient has a rapid respiratory rate, is off oxygen or has a rapid decrease in oxygen satiation at low oxygen concentrations. Susceptibility factors include history of glucocorticoid application, immunosuppressant use after organ transplantation, and previous use of purine analogs. High-dose compounded sulfamethoxazole for suspected Pneumocystis infection.
(3) Cellulitis: add vancomycin to cover skin pathogens.
(4) Intra-abdominal or pelvic sepsis: Treatment with metronidazole is required if there is clinical or microbiological evidence of intra-abdominal or pelvic sepsis.
(5) Diarrhea to assess for Clostridium difficile infection, if suspected metronidazole should be given.
(6) A risk factor for the development of systemic Candida infection in patients with candidiasis is prolonged neutrophil deficiency, and most of these patients have undergone debulking therapy for hematologic malignancies. The diagnosis of Candida bacteremia should be confirmed by blood culture, but blood culture often takes several days to get the result, so the treatment is usually transmissible. Anti-Candida therapy should be considered when a patient presents with fever and broad-spectrum antimicrobial therapy is ineffective for 3-7 days, and a chest CT should be performed to look for any typical imaging changes before starting treatment.
First-line empiric therapy is patient-dependent, and if the patient has been exposed to azoles or has a clear non-Candida albicans infection, then liposomal disulfiramycin B or an echinocandin-based antimicrobial such as caspofungin are the correct first-line treatment options. Fluconazole can be used as first-line therapy if the patient is at low risk of developing invasive Aspergillus infection, local epidemiologic data show a low incidence of azole-resistant Candida, and the patient has not received prophylactic treatment with azole antifungals.
Once antifungal therapy is initiated, it needs to be continued until neutrophil recovery, or at least 14 days if the patient has a proven fungal infection.
(7) Patients with pulmonary infiltrative acute myeloid leukemia during induction chemotherapy or who have undergone allogeneic hematopoietic stem cell transplantation are at risk for invasive Aspergillus infections. Repeated assessment of response to antimicrobial therapy is necessary, and in the absence of a therapeutic response, further clarification of the nature of the infection is required. If Aspergillus infection is suspected, a high-resolution CT examination should be performed to look for typical features of Aspergillus infection such as nodules with a halo or hairy glass-like changes. If infiltration is found, bronchoalveolar lavage should be performed if possible.
Appropriate treatment of fungal and pneumocystis infections should be performed with the advice of an infectious disease (ID) specialist. The choice of antifungal medication depends on the provider, the individual patient, and the history of previous prophylactic use. voriconazole or liposomal disulfiramycin B should be used for suspected Aspergillus infections. when there is no response to treatment, the above antifungal agents may be used in combination with echinocandins.
(8) Suspected viral infection: Acyclovir treatment is initiated after obtaining the specimen. Ganciclovir is required only when there is a high suspicion of invasive cytomegalovirus infection.
(9) Suspected meningitis or encephalitis.
Lumbar puncture is mandatory and ceftazidime combined with amoxicillin or meropenem should be given for bacterial meningitis. Viral encephalitis should be treated with high-dose acyclovir.
Follow-up, assessment of treatment response
The frequency of clinical follow-up depends on the severity of the disease and may be every 2 to 4 hours for patients requiring resuscitation. Fever trends and, if indicated, bone marrow and renal function should be assessed daily until the patient is no longer febrile and neutrophils exceed 0.5 × 109/L (Figure 2), and imaging review should be performed in patients with persistent fever.
Assessment of response to therapy and follow-up treatment
If fever is no longer present and neutrophils exceed 0.5×109/L, consider switching to oral antimicrobials for low-risk patients with no identified etiology; for high-risk patients with no identified etiology, consider discontinuing aminoglycosides if ongoing therapy is required; continue specific therapy if the etiology is clear.
If fever is still present at 48 hours, continue initial antimicrobial therapy if the disease is stable; if the disease is unstable, change antimicrobial therapy coverage, or increase antimicrobial coverage if the disease progresses with symptoms that support the use of certain types of antimicrobials.
Some blood centers are willing to add aminoglycosides to existing therapy, while others will change the regimen to a combination of carbapenems and aminoglycosides. ID specialists should be consulted to adjust treatment regimens when patients are at high risk for serious complications. Attention must be paid to uncommon infections, especially if CRP is increasing and imaging of the chest and upper abdomen shows progressive changes to exclude fungal or yeast infections or abscesses, and fever lasting more than 4 to 6 days requires antifungal therapy.
Duration of treatment
If the neutrophil count exceeds 0.5 x 109/L, the patient is asymptomatic, the fever has stopped for 48 hours, and the blood culture is negative, the antimicrobial agent may be discontinued. If the neutrophil count is less than 0.5×109/L, but the patient has no complications and has been fever-free for 5-7 days, the antimicrobial agent may be discontinued unless high-dose chemotherapy is used for high-risk patients such as acute leukemia, at which point the antimicrobial agent may be continued for 10 days or until the neutrophil count exceeds 0.5×109/L.
Patients with recovered granulocyte counts but persistent fever need to be evaluated by an ID specialist and considered for antifungal therapy.