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BACKGROUND Increases in cardiac troponin (cTn) in coronavirus disease 2019 (COVID-19) have been associated with worse prognosis. Nonetheless, data about the significance of cTn in elderly subjects with COVID-19 are lacking. METHODS From a registry of consecutive patients with COVID-19 admitted to a hub hospital in Italy from 25/02/2020 to 03/07/2020, we selected those ≥ 60 year-old and with cTnI measured within three days from the molecular diagnosis of SARS-CoV-2 infection. When available, a second cTnI value within 48 h was also extracted. The relationship between increased cTnI and all-cause in-hospital mortality was evaluated by a Cox regression model and restricted cubic spline functions with three knots. RESULTS Of 343 included patients (median age: 75.0 (68.0−83.0) years, 34.7% men), 88 (25.7%) had cTnI above the upper-reference limit (0.046 µg/L). Patients with increased cTnI had more comorbidities, greater impaired respiratory exchange and higher inflammatory markers on admission than those with normal cTnI. Furthermore, they died more (73.9%vs. 37.3%, P < 0.001) over 15 (6−25) days of hospitalization. The association of elevated cTnI with mortality was confirmed by the adjusted Cox regression model (HR = 1.61, 95%CI: 1.06−2.52, P = 0.039) and was linear until 0.3 µg/L, with a subsequent plateau. Of 191 (55.7%) patients with a second cTnI measurement, 49 (25.7%) had an increasing trend, which was not associated with mortality (univariate HR = 1.39, 95%CI: 0.87−2.22, P = 0.265). CONCLUSIONS In elderly COVID-19 patients, an initial increase in cTn is common and predicts a higher risk of death. Serial cTn testing may not confer additional prognostic information.

The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches., Author summary This is a detailed study of activating and inhibitory receptors in NK cells of COVID-19 patients when first admitted to the hospital for respiratory insufficiency. NK cells are known to be the first line of defense against invading viruses, and regulate downstream B and T cell responses, including antibody production. We observed intense NK cell activation with decreased functional activity, as well as intense circulation of putative tissue resident CD69+CD103+CXCR6+ NK cells, with a related surge in inflammatory CD34+ precursors from the bone marrow. The findings suggest that there is unprecedented trafficking of NK cells from peripheral tissues, their increased death with recruitment of emergency precursors from the bone marrow, and a relationship with the subsequent course of the disease of the patients. This in turn suggests possible areas of treatment and prevention.

Bone tissue has remarkable repair capacity, and generally heals by regeneration. This unique potential, expressed during remodeling and bone fracture healing, is tuned by a complex interplay of active factors and responding cells, which resides on an informative extracellular matrix and acts under a strict genetic control and different mechanical stimuli. The coordinated interaction of these elements is increasingly understood thanks to the progress in cellular and molecular biology. This chapter deals with the sequential events leading to bone repair, with special attention to the role of mesenchymal stem cells in regenerating bone. The genetic control of bone healing, the pathways underlying such process, and the regulation by a variety of growth factors and cytokines are outlined according to the recent literature. The understanding of the key elements of bone regeneration and their cross-talk is not merely a theoretical advancement in the knowledge of the physiological turnover of bone tissue, but offers practical tools to increase the efficacy of orthopaedic procedures, such as the delivery of pro-osteogenic growth factors or mesenchymal stem cells.

Bone is a common site of osteolytic and richly vascularized metastases of renal cell carcinoma (RCC) and Interferon (IFN)-alpha based therapies have been considered for the treatment of patients affected by this disease. The effects of IFN-alpha on metastatic RCC patients have been related to its immunomodulatory, and cytotoxic activity on tumor cells, but there could be an effect also on tumor induced osteoclast differentiation and bone angiogenesis. When osteoclasts obtained from human peripheral blood mononuclear cells, cultured in the presence of receptor activator of nuclear factor-kappaB (RANKL) and macrophage-colony stimulating factor (M-CSF), were treated with IFN-alpha, the expression of bone tartrate resistant acid phosphatase (TRACP) type 5b was reduced, as well as calcium-phosphate resorption activity and expression of pro-osteoclatic transcription factor c-Fos. IFN-alpha modulation of angiogenesis was studied by analysis of proliferation, survival, and migration of a bone endothelial cell line (BBE), and by the analysis of pro-angiogenic factor expression in RCC cell lines. IFN-alpha inhibited bone endothelial cell proliferation and the expression of FGF-2, while the vascular endothelial growth (VEGF) did not show any significant variation. Moreover, IFN-alpha inhibited the migration induced by the RCC through the impairment of fibroblast growth factor-2 (FGF-2) secretion. These data demonstrate multiple activities of IFN-alpha on renal cancer-induced bone disease, in addition to its recognized role as a cytotoxic and immunomodulatory agent, because they indicate its ability to reduce bone resorption and to impair tumor-associated angiogenesis, and they also suggest the use of IFN-alpha to treat skeletal metastases of other carcinomas.