C-Reactive Protein Monitoring and Clinical Presentation of Fever as Predictive Factors of Prolonged Febrile Neutropenia and Blood Culture Positivity after Autologous Hematopoietic Stem Cell Transplantation—Single-Center Real-Life Experience

Background: Febrile neutropenia (FN) is a medical emergency that requires urgent evaluation, timely administration of empiric broad-spectrum antibiotics and careful monitoring in order to optimize the patient’s outcome, especially in the setting of both allogeneic and autologous hematopoietic stem cell transplant (ASCT). Methods: In this real-life retrospective study, a total of 49 consecutive episodes of FN were evaluated in 40 adult patients affected by either multiple myeloma (thirty-eight) or lymphoma (eleven), following ASCT, with nine patients having fever in both of the tandem transplantations. Results: Febrile neutropenia occurred a median of 7 days from ASCT. Median duration of FN was 2 days, with 25% of population that had fever for at least four days. Ten patients had at least one fever spike superior to 39 °C, while the median number of daily fever spikes was two. Twenty patients had positive blood cultures with XDR germs, namely Pseudomonas aeruginosa and Klebsiella pneumoniae, present in seven cases. ROC analysis of peak C-reactive protein (CRP) values was conducted based on blood culture positivity and a value of 12 mg/dL resulted significant. Onset of prolonged fever with a duration greater than 3 days was associated with the presence of both a peak number of three or more daily fever spikes (p = 0.02) and a body temperature greater than 39 °C (p = 0.04) based on odds ratio (OR). Blood culture positivity and peak CRP values greater than 12 mg/dL were also associated with prolonged fever duration, p = 0.04, and p = 0.03, respectively. The probability of blood culture positivity was also greater in association with fever greater than 39 °C (p = 0.04). Furthermore, peak CRP values below the cut-off showed less probability of positive blood culture (p = 0.02). Conclusions: In our study, clinical characteristics of fever along with peak CRP levels were associated with a higher probability of both prolonged fever duration and positive blood culture, needing extended antibiotic therapy.

Decreased Incidence of Michigan Emergency Department Visits for Febrile Neutropenia Observed After Public Health Measures for the COVID-19 Pandemic

Importance: Masking and social distancing appear to decrease the of febrile neutropenia in susceptible populations, especially among patients with hematologic malignancies.Objective: To determine whether COVID-19 infection mitigation efforts, namely masking and social distancing, results in a reduction in the incidence of febrile neutropenia.Design: This was a retrospective cohort study comparing the incidence of FN in the 13 months prior to (Year 0) and 13 months following (Year 1) the public health executive orders (PHEO) in Michigan. Data voluntarily submitted by Michigan emergency departments to the National Syndromic Surveillance Program (NSSP) was queried for all ED visits from April 1st, 2019 to March 31st, 2021.Setting: Population based study.Participants: A population-based sample of patients who reported to a Michigan emergency department and on whom data was captured.Intervention(s): Population based masking and social distancing.Main Outcome(s) and Measure(s): The primary study outcome was the incidence of FN as a proportion of emergency visits in the 13-months before and after COVID-19 mitigations efforts, namely masking and social distancing. We hypothesized that there would be a significant decrease in the incidence of FN in the period following the public health executive orders aimed at reducing the spread of the COVID-19 virus.Results: There was a total of 8,979,221 total ED visits captured during the study period. In Year 0 there were 5,073,081 recorded ED visits and 3,906,140 in Year 1, a decrease of 23%. There was a significant reduction in the proportion of total ED visits with a diagnosis of FN, decreasing 13.3% across periods (0.15% vs. 0.13%, p=0.036). In patients with a hematologic malignancy the incidence of FN was significantly lower in the period following PHEO (22% vs 17%, p=0.02, Table 2).Conclusions and Relevance: Our study found a significant association between social distancing and mask guidelines implemented on a large public scale with decreased rates of FN, particularly in those with a hematologic malignancy. These findings may be useful in the design of clinical trials as well as informing future recommendations for the prevention of FN.

Safety & efficacy of antibiotic de-escalation and discontinuation in high-risk haematological patients with febrile neutropenia: a single-centre experience

Background There is currently no consensus on optimal duration of antibiotic treatment in febrile neutropenia. We report on the clinical impact of implementation of antibiotic de-escalation and discontinuation strategies based on the 4th European Conference on Infections in Leukaemia (ECIL-4) recommendations in high-risk haematological patients. Methods We studied 446 admissions after introduction of an ECIL-4 based protocol (= ECIL-4 group) in comparison to a historic cohort of 512 admissions. Primary clinical endpoints were the incidence of infectious complications including septic shock, infection-related intensive care unit (ICU) admission and overall mortality. Secondary endpoints included the incidence of recurrent fever, bacteraemia and antibiotic consumption. Results Bacteraemia occurred more frequently in the ECIL-4 group [46.9% (209/446) vs 30.5% (156/512); p<0.001], without an associated increase in septic shock [4.7% (21/446) vs 4.5% (23/512); p=0.878] or infection-related ICU admission [4.9% (22/446) vs 4.1% (21/512); p=0.424]. Overall mortality was significantly lower in the ECIL-4 group [0.7% (3/446) vs 2.7% (14/512); p=0.016], resulting mainly from a decrease in infection-related mortality [0.4% (2/446) vs 1.8% (9/512); p=0.058]. Antibiotic consumption was significantly reduced by a median of 2 days on antibiotic therapy (12 versus 14; p=0.001) and 7 daily antibiotic doses (17 versus 24; p<0.001) per admission period. Conclusions Our results support implementation of ECIL-4 recommendations to be both safe and effective based on real world data in a large high-risk patient population. We found no increase in infectious complications and total antibiotic exposure was significantly reduced.

Evaluation of early de-escalation of empiric antimicrobial therapy in acute leukemia patients with febrile neutropenia at a large academic medical center

Introduction Recent trials have shown early de-escalation of empiric antimicrobial therapy (EAT) in febrile neutropenia has led to less adverse effects with no difference in patient mortality. In 2019, our institution adjusted internal guidelines to de-escalate EAT after 7 days of intravenous anti-pseudomonal therapy in patients with signs of clinical recovery from febrile neutropenia and no evidence of infection. Methods This was a retrospective, single-center, observational, cohort study. Eligible patients were adults with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received induction chemotherapy and developed febrile neutropenia without documented infection. Patients were separated based on EAT duration: ≤ 9 days and > 9 days. Empiric antimicrobial therapy was defined as the initiation of an anti-pseudomonal beta-lactam. The primary outcome was the difference in number of EAT-free days. Secondary outcomes included fever recurrence, ICU admissions, fever duration, infections post de-escalation, and Clostridioides difficile infection (CDI). Results Forty-four encounters met inclusion. The EAT ≤ 9 days group had 7 more EAT-free days compared to the EAT > 9 days group (p < 0.001). No between-group differences were identified in terms of fever after EAT discontinuation (p = 0.335), ICU admission (p = 0.498), or CDI (p = 0.498). The EAT > 9 days group experienced longer initial fever (p < 0.001) and received addition of resistant Gram-positive coverage (p = 0.014). More patients receiving EAT > 9 days had a diagnosis of AML (p = 0.001). Conclusions Shorter EAT duration did not lead to worse outcomes in patients with AML or ALL who received induction chemotherapy and developed febrile neutropenia without a documented infection source.