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      Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics

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          Abstract

          Background

          SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper—Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells—DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts—OBs and osteoclasts—OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002–2004 revealed the long-term negative impact (decreased bone mineral density—BMDs) of these infections on bone health.

          Methodology

          We used the keywords “immunopathogenesis of SARS-CoV-2,” “SARS-CoV-2 and bone cells,” “factors influencing bone health and COVID-19,” “GUT microbiota,” and “COVID-19 and Bone health” to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus.

          Conclusion

          Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota—GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.

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          Most cited references59

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          An inflammatory cytokine signature predicts COVID-19 severity and survival

          Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < 0.0001, P = 0.0205 and P = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients (n = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.
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            Gender Differences in Patients With COVID-19: Focus on Severity and Mortality

            Objective: The recent outbreak of Novel Coronavirus Disease (COVID-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS. Study Design and Setting: We extracted the data from: (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases of patients who died of COVID-19 and 1,019 patients who survived in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003. Results: Older age and a high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men's cases tended to be more serious than women's (P = 0.035). In the public data set, the number of men who died from COVID-19 is 2.4 times that of women (70.3 vs. 29.7%, P = 0.016). In SARS patients, the gender role in mortality was also observed. The percentage of males were higher in the deceased group than in the survived group (P = 0.015). Conclusion: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.
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              SARS-CoV-2: A Storm is Raging

              The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunological characteristics between moderate and severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-γ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.
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                Author and article information

                Contributors
                rupesh_srivastava13@yahoo.co.in , rupeshk@aiims.edu
                Journal
                Inflamm Res
                Inflamm Res
                Inflammation Research
                Springer International Publishing (Cham )
                1023-3830
                1420-908X
                28 July 2022
                : 1-16
                Affiliations
                [1 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Translational Immunology, Osteoimmunology and Immunoporosis Lab (TIOIL), Department of Biotechnology, , All India Institute of Medical Sciences (AIIMS), ; New Delhi, 110029 India
                [2 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Department of Orthopaedics, , All India Institute of Medical Sciences (AIIMS), ; New Delhi, 110029 India
                [3 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Department of Rheumatology, , All India Institute of Medical Sciences (AIIMS), ; New Delhi, 110029 India
                [4 ]Department of Molecular Biology, ICMR-NIREH, Bhopal, MP-462001 India
                Article
                1616
                10.1007/s00011-022-01616-9
                9330992
                35900380
                d58f665f-7928-4ea5-94a8-09de8c986606
                © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022

                This work was financially supported by the Intramural project (A-COVID-98) from the All India Institute of Medical Sciences (AIIMS), New Delhi-India sanctioned to RKS. LS, CS, BV, and RKS acknowledge the Department of Biotechnology, AIIMS, New Delhi—India for providing infrastructural facilities. LS thanks UGC for the research fellowship. Figures are created with the help of Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license ( https://smart.servier.com).

                History
                : 31 March 2022
                : 9 July 2022
                : 18 July 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100007338, All-India Institute of Medical Sciences;
                Award ID: A-COVID-98
                Award Recipient :
                Categories
                Review

                Immunology
                sars-cov-2,covid-19,bone health,inflammation,probiotics,gut microbiota
                Immunology
                sars-cov-2, covid-19, bone health, inflammation, probiotics, gut microbiota

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