Effect of Exercise on Acute Senescent Lymphocyte Counts: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Highly differentiated, senescent lymphocytes are pro-inflammatory and contribute to age-related systemic inflammation, called inflammageing. There are several reports of acute changes in senescent lymphocyte counts post exercise, which potentially have consequences for systemic inflammation. However, there is little consensus since the studies differ with respect to participants, exercise protocols, cellular markers assessed, and the time point of assessment post exercise. <b><i>Objective:</i></b> We performed a systematic review and meta-analysis to assess the impact of exercise on senescent lymphocyte counts in blood immediately, 1 h and 2 h post exercise. <b><i>Methods:</i></b> The search was performed in PubMed (MEDLINE), Web of Science, Embase, Scopus, and Cochrane, on January 11, 2021. The 13 studies selected tested aerobic exercise effects, mainly in young men. They assessed the counts of lymphocytes (CD4 T cells, CD8 T cells, and NK cells), with the following immune cell marker combinations: KLRG1+, CD57+ (only NK cells), EMRA T cells (CD45RA+CCR7−CD28−CD27−), CD28−CD27−, KLRG1+CD28−, and CD28−. Independent extraction of articles was done by 2 researchers. <b><i>Results:</i></b> Standardized mean difference (SMD) and 95% confidence interval between baseline and post exercise showed significant increase (SMD &#x3e;0.9, <i>p</i> &#x3c; 0.003) in all types of senescent lymphocytes counts immediately post exercise. At 1 h post exercise, senescent CD4 T cells returned to baseline values (<i>p</i> = 0.74), CD8 T cells were reduced (−0.26 [−0.41; −0.11], <i>p</i> = 0.001), and senescent NK cells were raised (0.62 [0.14; 1.10], <i>p</i> = 0.01) above baseline. By 2 h post exercise, senescent CD4 T cells were reduced (−0.94 [−1.40; −0.48], <i>p</i> &#x3c; 0.001), CD8 T cells remained below baseline (−0.53 [−1.04; −0.009], <i>p</i> = 0.04), and NK cells had returned to baseline values (−0.29 [−0.64; 0.07], <i>p</i> = 0.11). The main determinants of heterogeneity between studies were cytomegalovirus (CMV) serostatus and the characteristics of exercise protocols. CMV+ individuals had a higher immediate lymphocytosis and 1 h post lymphopenia than CMV− individuals. Exercise performed at higher intensities and shorter durations led to higher magnitude of change in senescent lymphocyte counts at all time-points. <b><i>Conclusion:</i></b> The differing effects of exercise on senescent NK cells and CD4 and CD8 T cells suggest differing susceptibility to factors modulating lymphocyte extravasation such as adrenaline and exercise intensity.

Combination of Tertiary Lymphoid Structure and Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients With Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) is the most common pathological type of primary liver cancer. The lack of prognosis indicators is one of the challenges in HCC. In this study, we investigated the combination of tertiary lymphoid structure (TLS) and several systemic inflammation parameters as a prognosis indicator for HCC.Materials and MethodsWe retrospectively recruited 126 postoperative patients with primary HCC. The paraffin section was collected for TLS density assessment. In addition, we collected the systemic inflammation parameters from peripheral blood samples. We evaluated the prognostic values of those parameters on overall survival (OS) using Kaplan-Meier curves, univariate and multivariate Cox regression. Last, we plotted a nomogram to predict the survival of HCC patients.ResultsWe first found TLS density was positively correlated with HCC patients’ survival (HR=0.16, 95% CI: 0.06 − 0.39, p &lt; 0.0001), but the power of TLS density for survival prediction was found to be limited (AUC=0.776, 95% CI:0.772 − 0.806). Thus, we further introduced several systemic inflammation parameters for survival analysis, we found neutrophil-to-lymphocyte ratio (NLR) was positively associated with OS in univariate Cox regression analysis. However, the combination of TLS density and NLR better predicts patient’s survival (AUC=0.800, 95% CI: 0.698-0.902, p &lt; 0.001) compared with using any single indicator alone. Last, we incorporated TLS density, NLR, and other parameters into the nomogram to provide a reproducible approach for survival prediction in HCC clinical practice.ConclusionThe combination of TLS density and NLR was shown to be a good predictor of HCC patient survival. It also provides a novel direction for the evaluation of immunotherapies in HCC.

Uveitis as a Risk Factor for Developing Acute Myocardial Infarction in Ankylosing Spondylitis: A National Population-Based Longitudinal Cohort Study

BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease. Excess cardiovascular risks were well recognized in patients with AS and were attributed to prolonged systemic inflammation. Uveitis is one of the most common extra-articular symptoms of AS and is also considered an indicator of systemic inflammation. This study aimed to investigate whether uveitis was a risk factor for developing acute myocardial infarction (AMI) in patients with AS using the National Health Insurance Research Database (NHIRD).MethodsData were collected from the NHIRD over a fifteen-year period. Variables were analyzed using the Pearson chi-square test and Fisher’s exact test. Risk factors for the occurrence of AMI were examined by calculating hazard ratio. Kaplan-Meier analysis was performed to compare the cumulative incidence of AMI in the uveitis and non-uveitis cohorts.ResultsA total of 5905 patients with AS were enrolled, including 1181 patients with uveitis (20%) and 4724 patients without uveitis (80%). The Kaplan–Meier method with the log-rank test showed that the uveitis group had a significantly higher cumulative hazard for patients with AMI than the non-uveitis group (p &lt; 0.001). The adjusted hazard ratio (aHR) of AMI was higher in the uveitis group than in the non-uveitis group (aHR = 1.653, p &lt; 0.001). Stratified analysis revealed that patients with uveitis had an increased risk of developing AMI regardless of their sex (male/female aHR = 1.688/1.608, p &lt; 0.001). Patients with uveitis in all age groups were independently associated with an increased risk of developing AMI compared to those without uveitis (20–39 years/40–59 years/≥ 60 years, aHR = 1.550, 1.579, 3.240, p &lt; 0.001). Patients with uveitis had a higher probability of developing AMI regardless of comorbidities. Uveitis patients with comorbidities had a higher risk of developing AMI compared to uveitis patients without comorbidities.ConclusionUveitis is a significant risk factor for developing AMI in patients with AS. Physicians should be aware of the potential cardiovascular risk in AS patients with uveitis, especially simultaneously with other traditional risk factors of AMI. Further prospective studies are needed to elucidate the underlying mechanism between uveitis and AMI in patients with AS.

Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

Fatigue Is Common in Immunoglobulin G Subclass Deficiency and Correlates With Inflammatory Response and Need for Immunoglobulin Replacement Therapy

PurposeIndividuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT.MethodThirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion.ResultsQoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1.ConclusionFatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.

Systemic Inflammation Index and Tumor Glycolytic Heterogeneity Help Risk Stratify Patients with Advanced Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma Treated with Tyrosine Kinase Inhibitor Therapy

Tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Over half of patients failed to achieve prolonged survival benefits from TKI therapy. Awareness of a reliable prognostic tool may provide a valuable direction for tailoring individual treatments. We explored the prognostic power of the combination of systemic inflammation markers and tumor glycolytic heterogeneity to stratify patients in this clinical setting. One hundred and five patients with advanced EGFR-mutated lung adenocarcinoma treated with TKIs were retrospectively analyzed. Hematological variables as inflammation-induced biomarkers were collected, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII). First-order entropy, as a marker of heterogeneity within the primary lung tumor, was obtained by analyzing 18F-fluorodeoxyglucose positron emission tomography images. In a univariate Cox regression analysis, sex, smoking status, NLR, LMR, PLR, SII, and entropy were associated with progression-free survival (PFS) and overall survival (OS). After adjusting for confounders in the multivariate analysis, smoking status, SII, and entropy, remained independent prognostic factors for PFS and OS. Integrating SII and entropy with smoking status represented a valuable prognostic scoring tool for improving the risk stratification of patients. The integrative model achieved a Harrell’s C-index of 0.687 and 0.721 in predicting PFS and OS, respectively, outperforming the traditional TNM staging system (0.527 for PFS and 0.539 for OS, both p < 0.001). This risk-scoring model may be clinically helpful in tailoring treatment strategies for patients with advanced EGFR-mutated lung adenocarcinoma.