Soluble CD137 as a potential biomarker for severe COVID-19.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly pathogenic infection responsible for the world pandemic in 2020. COVID-19 is characterized by an increased number of critically ill patients with a high risk of health care system collapse. Therefore, the search for severity biomarkers and potential therapies is crucial. In this study, we evaluated SARS-CoV-2 -induced cytokines, cytokines receptors and growth factors profile, in critical COVID-19 patients admitted in intensive care unit (ICU) aiming to identify potential biomarkers and therapeutic targets. We designed a prospective study enrolling 62 adults with severe COVID-19 during the first two Brazilian COVID-19 waves (from May to July 2020 and December 2020 to May 2021), convenience samples recruitment in first 24 hours and then, every 4 days until day 20 of ICU admission from a tertiary hospital in São Paulo, Brazil. Controls were healthy blood donors. Whole blood was used to evaluate 17 cytokines, cytokines receptors and growth factors. Due to low mortality rate, we used the need of mechanical ventilation as primary endpoint. In our analysis, we found a different pattern in soluble CD137 (sCD137) in critically ill patients with COVID-19, with a direct relationship between increased levels and worse clinical outcome. sCD137 was related with increased risk of mechanical ventilation and World Health Organization (WHO) clinical score for disease severity. CD137 is a tumor necrosis factor receptor (TNF) family member, mainly responsible for T-cell activation. Soluble isoforms of immune checkpoints competitively regulate function of their membrane-bound counterparts. Our study demonstrated the onward increase in sCD137 levels during severe SARS-CoV-2 infection and its correlation with worse outcomes, suggesting sCD137 as a potential reliable severity biomarker.

Imbalance of Pro- and Anti-Inflammatory Cytokines in Patients With cHL Persists Despite Treatment Compared With Control Subjects.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a malignant lymphoma that most commonly affects young adults. The lymphomagenesis of cHL depends largely on immune alterations that contribute to proliferation and maintenance of the Hodgkin-Reed-Sternberg (HRS) neoplastic cells. A combination of different immune processes is responsible for the escape of HRS cells, the imbalance between pro- and anti-inflammatory cytokines being one of them. In this study, we aimed to measure serum levels of pro- and anti-inflammatory cytokines in cHL patients before and after treatment compared with a healthy controls group, and to investigate associations with clinical and pathologic characteristics. PATIENTS AND METHODS: We prospectively studied all cases of cHL diagnosed between March 2009 to March 2013 at the Universidade Federal de São Paulo and Hospital Santa Marcelina, in Sao Paulo, Brazil. Twenty-nine cases with sufficient clinical data were included in this study. Additionally, 18 healthy control subjects were included and recruited from our University Blood Bank. Serum cytokine levels of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, soluble IL-2 receptor (sCD25), vascular endothelial growth factor (VEGF), and interferon (IFN)-γ were determined in serum of patients and controls using a multiplexed immunoassay system. RESULTS: Higher International Prognostic Score was positively correlated with increased levels of IL-6 (P = .003); sCD25 levels were higher in patients with low serum albumin (P = .04), and IFN-γ seemed to correlate with B symptoms, although did not reach statistical significance (P = .057). Pretreatment levels of IL-10, IL-6, TNF-α, and sCD25 were increased in cHL patients compared with in healthy control subjects (P < .001), with median values of 7 pg/mL (range, 0.3-230.9), 5.3 pg/mL (range, 0.4-72.7), 14.6 (range, 4.0-60.4), and 575.9 pg/mL (range, 7.5-1813.3), respectively. Treatment significantly reduced levels of IL-10 (7.0 to 0.3; P < .001), IL-6 (5.3 to 0.4; P = .014), and sCD25 (575.9 to 93.5; P < .001), however, levels of IL-4 increased (0.6 to 2.2; P = .002). Compared with normal control subjects, increased levels of IL-6 (0.4 to 0.4; P = .027), sCD25 (93.5 to 7.5; P = .002), and TNF-α (12 to 8.7; P = .003) persisted after treatment. CONCLUSION: In this study we showed higher levels of IL-6, IL-10, TNF-α, and sCD25 in cHL patients at diagnosis than in healthy control subjects. After treatment, levels of IL-6, IL-10, and sCD25 decreased gradually but did not normalize. Understanding the cytokine pattern is extremely important in the development of future therapies that target interactions between neoplastic cells and the inflammatory microenvironment.