INSIGHTS INTO THE PATHOGENESIS OF POST-CHEMOTERAPY SEPSIS FROM THE TRAJECTORY OF NEUTROPHIL: PLATELET RATIO IN THE EARLY STAGES OF SEVERE FEBRILE NEUTROPENIA

Abstract

Sepsis is the most feared complications of chemotherapy-induced cytopenias and the main cause of early mortality in patients with hematological malignancies. Neutrophils and platelets play critical roles in the host response to sepsis: on the one hand, they contribute to pathogen removal; on the other hand, they contribute to tissue damage ascellular players of immunothrombosis. The association of neutropenia with mortality in critically-ill cancer patients is not a consistent finding, andremainscontroversial in the literature. In addition, given the critical role of neutrophils and platelets for sepsis-associated organ damage, the mechanisms that mediate sepsis-related tissue damage in post-chemotherapy severe febrile neutropenia (FN) have not been elucidated. Here we explored the association of neutrophil and platelet counts, and of the neutrophil:platelet ratio (NPR) in the first 48 hs after FN, with sepsis complications. Patients were retrospectively identified using the database of CBC results from an academic hospital. Selection criteria was an absolute neutrophil count (ANC) < 500/mL at any time during admission, from 2018 to 2021. The study population was then filtered using administrative and clinical data, to obtain a cohort of patients with hematological malignancies who developed chemotherapy-associated FN. Clinical and laboratory data were obtained from the electronic health records. The study population consisted of 111 consecutive in-patients with severe neutropenia and fever. Median age was 50.1, and 46.9% had a diagnosis of acute leukemia. Mean neutrophil and platelet counts at the time of FN onset were 129 ± 175/mL and 51.2 ± 78.2 *109/mL, respectively. Mean variation (D) in cell counts in the first 48 hs after FN onset was -14 ± 183 neutrophils/mL and 0.7 ± 104.9*109 platelets/mL. Sepsis-related 30-day mortality (primary outcome) occurred in 19/111 patients (17.1%), with 30/111 (27.0%) and 26/111 (23.4.5%) developing septic shock or requiring mechanical ventilation, respectively. ANC at fever onset was lower in patients who later died from sepsis (p = 0.005), while platelet counts were lower in the same group, 48 hours after fever onset (p = 0.027). Median NPR followed different trajectories according to mortality, oscillating from 1.32 to 1.12 among survivors (p = 0.39), and increasing from 0.62 to 3.3 among non-survivors (p = 0.012). This increase was mainly due to a significant rise in ANC from 23/mL at FN onset to 99/mL 48h thereafter (p = 0.008), compared to an oscillation from 152/mL to 120/mL in surviving patients in the same period. Platelet counts remained stable in this time window in both subroups. In multivariate analysis, qSOFA and D ANC in the first 48h were independently associated with 30-day sepsis-related mortality. D ANC was also independently associated with the need for mechanical ventilation. Our results suggest that despite a marked reduction of ANC in patients with hematological malignancies and chemotherapy-induced FN, higher neutrophil counts in the immediate hours after fever is associated with a worse prognosis. Additional studies are warranted to address whether neutrophils and platelets contribute to sepsis-related tissue damage in these patients, as shown in non-neutropenic sepsis.