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. 2024 Aug 26;16(17):2974.
doi: 10.3390/cancers16172974.

The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease

Elia Seguí  1   2 , Juan Manuel Torres  3 , Edouard Auclin  4 , David Casadevall  5 , Sara Peiro Carmona  3 , Juan Aguilar-Company  6 , Marta García de Herreros  1   2 , Teresa Gorría  2 , Juan Carlos Laguna  1   2 , Marta Rodríguez  6   7 , Azucena González  3 , Nicolas Epaillard  4 , Javier Gavira  8 , Victor Bolaño  3 , Jose C Tapia  8 , Marco Tagliamento  9   10 , Cristina Teixidó  1   11   12 , Hugo Arasanz  13 , Sara Pilotto  14 , Rafael Lopez-Castro  15 , Xabier Mielgo-Rubio  16 , Cristina Urbano  17 , Gonzalo Recondo  18 , Mar Diaz Pavon  3 , Maria Virginia Bluthgen  19 , José Nicolas Minatta  20 , Lorena Lupinacci  20 , Fara Brasó-Maristany  1 , Aleix Prat  1   2   12   21   22 , Alexandru Vlagea  3 , Laura Mezquita  1   2   12
Affiliations

The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease

Elia Seguí et al. Cancers (Basel). .

Abstract

Purpose: Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations.

Methods: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease.

Results: Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection.

Conclusions: A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.

Keywords: COVID-19; IL-6; cancer; dNLR; neutrophils.

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Conflict of interest statement

E.S. declares personal fees for educational events and/or material from Novartis, Pfizer, Eisai, and Daiichi Sankyo; advisory fees from Pfizer and Seagen; and travel/accommodation expenses from Gilead, Daiichi Sankyo, Novartis, and Lilly. M.G.H reports personal fees (invited speaker) from Ipsen and travel/accommodation expenses from Novartis. T.G declares personal fees (invited speaker) from GSK and travel/accommodation expenses from Bristol Myers Squibb, Reddy’s, Pfizer, and MSD. J.G declares personal fees (invited speaker) from LEO Pharma and Astellas Pharma, and travel/accommodation expenses from Lilly, Bristol Myers Squibb/Roche, Ipsen, Novartis, and Roche. J.C.T reports travel/accommodation expenses from: Merck, Pfizer, Roche, and Lily/Genentech. M.T declares travel/accommodation expenses from ElI−Lilly. C.T declares no competing non-financial interests but reports advisory and consulting fees from Novartis and AstraZeneca, lecture fees from Roche, Pfizer, Biocartis, MSD, and Janssen Oncology, and research fees from Novartis. H.A declares consulting fees from AstraZeneca, lecture fees from Takeda, and travel/accommodation expenses from Angelini Pharma, BMS, MSD, Roche, and Takeda. S.P reports personal fees (invited speaker, advisory board) from AstraZeneca, ElI−Lilly, Novartis, AMGEN, Takeda, Sanofi, Bristol Myers Squibb, MSD, and Roche, and research grants from AstraZeneca, Bristol Myers Squibb, and Roche outside the submitted work. X.M.-R. declares research grants from Bristol Myers Squibb; fees for educational activities from Novartis, Bristol Myers Squibb, AstraZeneca, Roche, Pfizer, MSD, Takeda, Ferrer, and Esteve; advisory fees from Takeda, Pfizer, MSD, Boehringer, and AstraZeneca; travel/accommodation expenses from Lilly, Boehringer, Roche, and Bristol Myers Squibb. F.B-M. has filed the HER2DX patent (PCT/EP2022/086493), the DNADX patent (EP22382387.3), and the TNBCDX patent (EP23382703.9). A.P. reports advisory and consulting fees from Roche, DaiichI−Sankyo, AstraZeneca, Pfizer, Novartis, Guardant Health, and Peptomyc; lecture fees from Roche, Novartis, AstraZeneca, and Daiichi Sankyo; institutional financial interests from Boehringer, Novartis, Roche, AstraZeneca, DaiichI−Sankyo, MedSIR, SL, Celgene, Astellas, and Pfizer; stockholder and consultant fees from Reveal Genomics, SL; the filing of the patent PCT/EP2016/080056, the HER2DX patent (PCT/EP2022/086493), the DNADX patent (EP22382387.3), and the TNBCDX patent (EP23382703.9). L.M. declares research grants from Amgen, Inivata, AstraZeneca, and Gilead; fees for educational activities from Bristol Myers Squibb, AstraZeneca, Roche, Takeda, Janssen, Pfizer, MSD, DaiichI−Sankyo, and Radonova; advisory fees from Roche, Takeda, AstraZeneca, Jannsen, and MSD; and travel/accommodation expenses from Bristol Myers Squibb, Roche, Takeda, AstraZeneca, and Janssen. The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(A) dNLR in patients with cancer and COVID-19 infection; (B) building of the FLARE score. Legend: dNLR: derived neutrophil-to-lymphocyte ratio; COVID-19 dx: COVID-19 diagnosis; ΔdNLR: delta dNLR.
Figure 2
Figure 2
(A) Kaplan–Meier curves demonstrating survival across FLARE groups; (B) multivariate logistic Regression analysis for 30-Day mortality. Legend: T+/I+: concurrent tumor and infection-related inflammation (poor FLARE group); T+/I−: tumor-related inflammation only (T−only FLARE group); T/I+: COVID-related inflammation only (I−only FLARE group); T−/I−: no inflammation (favorable FLARE group); OR: odds ratio; CI: confidence interval; PS: performance status.
Figure 3
Figure 3
Circulating neutrophils in patients with cancer and COVID-19 infection. Legend: (A) Median circulating neutrophils in healthy volunteers (HV), patients with cancer (CC), and patients with cancer and COVID-19 disease (Cancer + COVID); (B) principal component analysis (PCA) of circulating neutrophils in HV, CC, and Cancer + COVID; (C) heatmap displaying distinct subpopulations of circulating neutrophils in Cancer + COVID patients; (D) circulating immature neutrophils based on COVID-19 severity; (E) circulating IL-6 levels in HV, CC, and Cancer + COVID; IL-6 levels (F) based on COVID-19 disease severity and (G) based on circulating immature neutrophils (low vs. high).
Figure 4
Figure 4
Monitoring of circulating immature neutrophils and IL-6 across COVID-19 infection. Legend: (A) Circulating immature neutrophils and (B) circulating IL-6 levels across different timepoints during COVID-19 infection. (C) Illustration demonstrating the acquisition of immature neutrophils during the course of COVID-19 evolution in FLARE#15 and its association with the development of severe disease. Toci: tocilizumab; DXM: dexamethasone; ICU: intensive care unit; O2; oxygen; NIV; noninvasive ventilation.
See this image and copyright information in PMC

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