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Respiratory viral infections in the elderly: From the perspective of the aging immune system

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    1. The elderly have a worse prognosis after respiratory viral infections.

      Aging immune system with low efficacy leads to ineffective viral clearance.

      Individualized assessment of immune status is necessary for appropriate treatment.

      Modulating the aging immune system is a crucial treatment strategy.

  • The susceptibility of the elderly to respiratory viral infections and the challenges posed by an aging population necessitate imperative development of advanced preventive and therapeutic strategies for elderly individuals. The clinical outcome of such infections is intricately determined by the complex interplay among viruses, host tissues, and immune cells. Elderly individuals exhibit a diminished efficacy of their immune system to clear viruses, consequently leading to prolonged viral insults, tissue damage, and an excessive activation of inflammatory cells. These ultimately result in worse clinical outcomes. Targeting the dysregulated antiviral immune responses has emerged as a potential approach to improve the prognosis of geriatric patients. It is noteworthy that the impacts of aging on antiviral immune responses are highly heterogenous. Thus, individualized patient assessment and management assume paramount importance. This review aims to summarize the current evidence elucidating the effects of aging on immune responses to respiratory viruses, with the ultimate goal of identifying knowledge gaps that can inform future research and enhance the management of elderly individuals.
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  • [1] WHO. (2020). Leading causes of death and disability 2000-2019: A visual summary. https://www.who.int/data/stories/leading-causes-of-death-and-disability-2000-2019-a-visual-summary.

    View in Article Google Scholar

    [2] Ruuskanen, O., Lahti, E., Jennings, L.C., et al. (2011). Viral pneumonia. Lancet 377: 1264−1275. DOI: 10.1016/S0140-6736(10)61459-6.

    View in Article CrossRef Google Scholar Scopus

    [3] Jain, S. (2017). Epidemiology of viral pneumonia. Clin. Chest Med. 38: 1−9. DOI: 10.1016/j.ccm.2016.11.012.

    View in Article CrossRef Google Scholar

    [4] Jain, S., Self, W.H., Wunderink, R.G., et al. (2015). Community-acquired pneumonia requiring hospitalization among US. adults. N. Engl. J. Med. 373: 415−427. DOI: 10.1056/NEJMoa1500245.

    View in Article CrossRef Google Scholar

    [5] Zhou, F., Wang, Y., Liu, Y., et al. (2019). Disease severity and clinical outcomes of community-acquired pneumonia caused by non-influenza respiratory viruses in adults: A multicentre prospective registry study from the CAP-China Network. Eur. Respir. J. 54 : 1802406. DOI: 10.1183/13993003.02406-2018.

    View in Article Google Scholar

    [6] WHO. (2023). WHO coronavirus (COVID-19) dashboard. https://covid19.who.int (accessed on June 23rd, 2023).

    View in Article Google Scholar

    [7] Hansen, C.L., Chaves, S.S., Demont, C., et al. (2022). Mortality associated with influenza and respiratory syncytial virus in the US, 1999-2018. JAMA Netw. Open 5: e220527. DOI: 10.1001/jamanetworkopen.2022.0527.

    View in Article CrossRef Google Scholar

    [8] Cohen, C., Walaza, S., Treurnicht, F.K., et al. (2018). In- and out-of-hospital mortality associated with seasonal and pandemic influenza and respiratory syncytial virus South Africa, 2009-2013. Clin. Infect. Dis. 66: 95−103. DOI: 10.1093/cid/cix740.

    View in Article CrossRef Google Scholar

    [9] Matias, G., Taylor, R., Haguinet, F., et al. (2014). Estimates of mortality attributable to influenza and RSV in the United States during 1997-2009 by influenza type or subtype, age, cause of death, and risk status. Influenza Other Respir. Viruses 8: 507−515. DOI: 10.1111/irv.12258.

    View in Article CrossRef Google Scholar Scopus

    [10] Fleming, D.M., Taylor, R.J., Lustig, R.L., et al. (2015). Modelling estimates of the burden of Respiratory Syncytial virus infection in adults and the elderly in the United Kingdom. BMC Infect. Dis. 15: 443. DOI: 10.1186/s12879-015-1218-z.

    View in Article CrossRef Google Scholar Scopus

    [11] Heppe-Montero, M., Gil-Prieto, R., Del Diego Salas, J., et al. (2022). Impact of respiratory syncytial virus and influenza virus infection in the adult population in Spain between 2012 and 2020. Int. J. Environ. Res. Public Health 19 : 14680. DOI: 10.3390/ijerph192214680.

    View in Article Google Scholar

    [12] Nazareno, A.L., Muscatello, D.J., Turner, R.M., et al. (2022). Modelled estimates of hospitalisations attributable to respiratory syncytial virus and influenza in Australia, 2009-2017. Influenza Other Respir. Viruses 16: 1082−1090. DOI: 10.1111/irv.13003.

    View in Article CrossRef Google Scholar

    [13] Kyeyagalire, R., Tempia, S., Cohen, A.L., et al. (2014). Hospitalizations associated with influenza and respiratory syncytial virus among patients attending a network of private hospitals in South Africa, 2007-2012. BMC Infect. Dis. 14: 694. DOI: 10.1186/s12879-014-0694-x.

    View in Article CrossRef Google Scholar Scopus

    [14] Qi, L., Li, Q., Ding, X.B., et al. (2020). Mortality burden from seasonal influenza in Chongqing, China, 2012-2018. Hum. Vaccin. Immunother. 16: 1668−1674. DOI: 10.1080/21645515.2019.1693721.

    View in Article CrossRef Google Scholar

    [15] Park, M., Wu, P., Goldstein, E., et al. (2016). Influenza-associated excess mortality in South Korea. Am. J. Prev. Med. 50: e111−e119. DOI: 10.1016/j.amepre.2015.09.028.

    View in Article CrossRef Google Scholar

    [16] Murray, C.J., Lopez, A.D., Chin, B., et al. (2006). Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918-20 pandemic: A quantitative analysis. Lancet 368: 2211−2218. DOI: 10.1016/S0140-6736(06)69895-4.

    View in Article CrossRef Google Scholar

    [17] Louie, J.K., Jean, C., Acosta, M., et al. (2011). A review of adult mortality due to 2009 pandemic (H1N1) influenza A in California. PLoS One 6: e18221. DOI: 10.1371/journal.pone.0018221.

    View in Article CrossRef Google Scholar

    [18] Shaw, E.R., and Su, H.C. (2021). The influence of immune immaturity on outcome after virus infections. J. Allergy Clin. Immunol. Pract. 9: 641−650. DOI: 10.1016/j.jaip.2020.11.016.

    View in Article CrossRef Google Scholar

    [19] Centers for Disease Control and Prevention. (2022). Risk for COVID-19 infection, hospitalization, and death by age group. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (accessed on June 26th, 2023).

    View in Article Google Scholar

    [20] COVID-19 Forecasting Team. (2022). Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: A systematic analysis. Lancet 399: 1469−1488. DOI: 10.1016/S0140-6736(21)02867-1.

    View in Article CrossRef Google Scholar

    [21] Dzau, V.J., Inouye, S.K., Rowe, J.W., et al. (2019). Enabling healthful aging for all - the national academy of medicine grand challenge in healthy longevity. N. Engl. J. Med. 381: 1699−1701. DOI: 10.1056/NEJMp1912298.

    View in Article CrossRef Google Scholar

    [22] Berbudi, A., Rahmadika, N., Tjahjadi, A.I., et al. (2020). Type 2 diabetes and its impact on the immune system. Curr. Diabetes Rev. 16: 442−449. DOI: 10.2174/1573399815666191024085838.

    View in Article CrossRef Google Scholar Scopus

    [23] Syed-Ahmed, M., and Narayanan, M. (2019). Immune dysfunction and risk of infection in chronic kidney disease. Adv. Chronic Kidney Dis. 26: 8−15. DOI: 10.1053/j.ackd.2019.01.004.

    View in Article CrossRef Google Scholar

    [24] Bhat, T.A., Panzica, L., Kalathil, S.G., et al. (2015). Immune dysfunction in patients with chronic obstructive pulmonary disease. Ann. Am. Thorac. Soc. 12 Suppl 2 : S169-175. DOI: 10.1513/AnnalsATS.201503-126AW.

    View in Article Google Scholar

    [25] Kuek, L.E., and Lee, R.J. (2020). First contact: The role of respiratory cilia in host-pathogen interactions in the airways. Am. J. Physiol. Lung Cell Mol. Physiol. 319: L603−l619. DOI: 10.1152/ajplung.00283.2020.

    View in Article CrossRef Google Scholar Scopus

    [26] Ho, J.C., Chan, K.N., Hu, W.H., et al. (2001). The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia. Am. J. Respir. Crit. Care Med. 163: 983−988. DOI: 10.1164/ajrccm.163.4.9909121.

    View in Article CrossRef Google Scholar Scopus

    [27] Proença de Oliveira-Maul, J., Barbosa de Carvalho, H., Goto, D.M., et al. (2013). Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 143: 1091-1097. DOI: 10.1378/chest.12-1183.

    View in Article CrossRef Google Scholar Scopus

    [28] Svartengren, M., Falk, R., and Philipson, K. (2005). Long-term clearance from small airways decreases with age. Eur. Respir. J. 26: 609−615. DOI: 10.1183/09031936.05.00002105.

    View in Article CrossRef Google Scholar Scopus

    [29] Moliva, J.I., Rajaram, M.V., Sidiki, S., et al. (2014). Molecular composition of the alveolar lining fluid in the aging lung. Age (Dordr) 36: 9633. DOI: 10.1007/s11357-014-9633-4.

    View in Article CrossRef Google Scholar Scopus

    [30] Lehmann, R., Müller, M.M., Klassert, T.E., et al. (2018). Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells. Mucosal Immunol. 11: 627−642. DOI: 10.1038/mi.2017.100.

    View in Article CrossRef Google Scholar Scopus

    [31] Wosen, J.E., Mukhopadhyay, D., Macaubas, C., et al. (2018). Epithelial MHC class II expression and its role in antigen presentation in the gastrointestinal and respiratory tracts. Front. Immunol. 9: 2144. DOI: 10.3389/fimmu.2018.02144.

    View in Article CrossRef Google Scholar Scopus

    [32] Chason, K.D., Jaspers, I., Parker, J., et al. (2018). Age-associated changes in the respiratory epithelial response to influenza infection. J. Gerontol. A Biol. Sci. Med. Sci. 73: 1643−1650. DOI: 10.1093/gerona/gly126.

    View in Article CrossRef Google Scholar Scopus

    [33] Chen, J., Deng, J.C., Zemans, R.L., et al. (2022). Age-induced prostaglandin E(2) impairs mitochondrial fitness and increases mortality to influenza infection. Nat. Commun. 13: 6759. DOI: 10.1038/s41467-022-34593-y.

    View in Article CrossRef Google Scholar

    [34] Yin, L., Zheng, D., Limmon, G.V., et al. (2014). Aging exacerbates damage and delays repair of alveolar epithelia following influenza viral pneumonia. Respir. Res. 15: 116. DOI: 10.1186/s12931-014-0116-z.

    View in Article CrossRef Google Scholar Scopus

    [35] Lambrecht, B.N. (2006). Alveolar macrophage in the driver's seat. Immunity 24: 366-368. DOI: 10.1016/j.immuni.2006.03.008.

    View in Article CrossRef Google Scholar

    [36] Morales-Nebreda, L., Misharin, A.V., Perlman, H., et al. (2015). The heterogeneity of lung macrophages in the susceptibility to disease. Eur. Respir. Rev. 24: 505−509. DOI: 10.1183/16000617.0031-2015.

    View in Article CrossRef Google Scholar Scopus

    [37] Mould, K.J., Barthel, L., Mohning, M.P., et al. (2017). Cell origin dictates programming of resident versus recruited macrophages during acute lung injury. Am. J. Respir. Cell Mol. Biol. 57: 294−306. DOI: 10.1165/rcmb.2017-0061OC.

    View in Article CrossRef Google Scholar Scopus

    [38] Shi, C., and Pamer, E.G. (2011). Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11: 762−774. DOI: 10.1038/nri3070.

    View in Article CrossRef Google Scholar Scopus

    [39] Iwasaki, A., Foxman, E.F., and Molony, R.D. (2017). Early local immune defences in the respiratory tract. Nat. Rev. Immunol. 17: 7−20. DOI: 10.1038/nri.2016.117.

    View in Article CrossRef Google Scholar Scopus

    [40] Metcalf, T.U., Cubas, R.A., Ghneim, K., et al. (2015). Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 14: 421-432. DOI: 10.1111/acel.12320.

    View in Article CrossRef Google Scholar Scopus

    [41] Metcalf, T.U., Wilkinson, P.A., Cameron, M.J., et al. (2017). Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists. J. Immunol. 199: 1405−1417. DOI: 10.4049/jimmunol.1700148.

    View in Article CrossRef Google Scholar Scopus

    [42] Molony, R.D., Nguyen, J.T., Kong, Y., et al. (2017). Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. Sci. Signal 10 : eaan2392. DOI: 10.1126/scisignal.aan2392.

    View in Article Google Scholar

    [43] Johansson, C., and Kirsebom, F.C.M. (2021). Neutrophils in respiratory viral infections. Mucosal Immunol. 14: 815−827. DOI: 10.1038/s41385-021-00397-4.

    View in Article CrossRef Google Scholar Scopus

    [44] Lim, K., Hyun, Y.M., Lambert-Emo, K., et al. (2015). Neutrophil trails guide influenza-specific CD8+ T cells in the airways. Science 349: aaa4352. DOI: 10.1126/science.aaa4352.

    View in Article CrossRef Google Scholar

    [45] Kulkarni, U., Zemans, R.L., Smith, C.A., et al. (2019). Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality. Mucosal Immunol. 12: 545−554. DOI: 10.1038/s41385-018-0115-3.

    View in Article CrossRef Google Scholar Scopus

    [46] Wong, C.K., Smith, C.A., Sakamoto, K., et al. (2017). Aging impairs alveolar macrophage phagocytosis and increases influenza-induced mortality in mice. J. Immunol. 199: 1060−1068. DOI: 10.4049/jimmunol.1700397.

    View in Article CrossRef Google Scholar Scopus

    [47] Fu, B., Tian, Z., and Wei, H. (2014). Subsets of human natural killer cells and their regulatory effects. Immunology 141: 483-489. DOI: 10.1111/imm.12224.

    View in Article CrossRef Google Scholar Scopus

    [48] Björkström, N.K., Strunz, B., and Ljunggren, H.G. (2022). Natural killer cells in antiviral immunity. Nat. Rev. Immunol. 22: 112−123. DOI: 10.1038/s41577-021-00558-3.

    View in Article CrossRef Google Scholar Scopus

    [49] Luczo, J.M., Ronzulli, S.L., and Tompkins, S.M. (2021). Influenza A virus hemagglutinin and other pathogen glycoprotein interactions with NK cell natural cytotoxicity receptors NKp46, NKp44, and NKp30. Viruses 13 : 156. DOI: 10.3390/v13020156.

    View in Article Google Scholar

    [50] Zhou, G., Juang, S.W., and Kane, K.P. (2013). NK cells exacerbate the pathology of influenza virus infection in mice. Eur. J. Immunol. 43: 929−938. DOI: 10.1002/eji.201242620.

    View in Article CrossRef Google Scholar Scopus

    [51] Nogusa, S., Ritz, B.W., Kassim, S.H., et al. (2008). Characterization of age-related changes in natural killer cells during primary influenza infection in mice. Mech. Ageing Dev. 129: 223−230. DOI: 10.1016/j.mad.2008.01.003.

    View in Article CrossRef Google Scholar Scopus

    [52] Beli, E., Clinthorne, J.F., Duriancik, D.M., et al. (2011). Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mech. Ageing Dev. 132: 503−510. DOI: 10.1016/j.mad.2011.08.005.

    View in Article CrossRef Google Scholar Scopus

    [53] Kopf, M., Schneider, C., and Nobs, S.P. (2015). The development and function of lung-resident macrophages and dendritic cells. Nat. Immunol. 16: 36−44. DOI: 10.1038/ni.3052.

    View in Article CrossRef Google Scholar Scopus

    [54] Jakubzick, C., Helft, J., Kaplan, T.J., et al. (2008). Optimization of methods to study pulmonary dendritic cell migration reveals distinct capacities of DC subsets to acquire soluble versus particulate antigen. J. Immunol. Methods 337: 121−131. DOI: 10.1016/j.jim.2008.07.005.

    View in Article CrossRef Google Scholar Scopus

    [55] Kim, T.S., and Braciale, T.J. (2009). Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses. PLoS One 4: e4204. DOI: 10.1371/journal.pone.0004204.

    View in Article CrossRef Google Scholar Scopus

    [56] Lin, K.L., Suzuki, Y., Nakano, H., et al. (2008). CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J. Immunol. 180: 2562−2572. DOI: 10.4049/jimmunol.180.4.2562.

    View in Article CrossRef Google Scholar Scopus

    [57] Toapanta, F.R., and Ross, T.M. (2009). Impaired immune responses in the lungs of aged mice following influenza infection. Respir. Res. 10: 112. DOI: 10.1186/1465-9921-10-112.

    View in Article CrossRef Google Scholar Scopus

    [58] Zhao, J., Zhao, J., Legge, K., et al. (2011). Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121: 4921−4930. DOI: 10.1172/JCI59777.

    View in Article CrossRef Google Scholar

    [59] Liu, W.M., Nahar, T.E., Jacobi, R.H., et al. (2012). Impaired production of TNF-α by dendritic cells of older adults leads to a lower CD8+ T cell response against influenza. Vaccine 30: 1659-1666. DOI: 10.1016/j.vaccine.2011.12.105.

    View in Article CrossRef Google Scholar Scopus

    [60] Langlois, R.A., and Legge, K.L. (2010). Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T cells. J. Immunol. 184: 4440−4446. DOI: 10.4049/jimmunol.0902984.

    View in Article CrossRef Google Scholar Scopus

    [61] Sridharan, A., Esposo, M., Kaushal, K., et al. (2011). Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr) 33: 363-376. DOI: 10.1007/s11357-010-9191-3.

    View in Article CrossRef Google Scholar Scopus

    [62] Prakash, S., Agrawal, S., Cao, J.N., et al. (2013). Impaired secretion of interferons by dendritic cells from aged subjects to influenza : Role of histone modifications. Age (Dordr) 35: 1785−1797. DOI: 10.1007/s11357-012-9477-8.

    View in Article CrossRef Google Scholar Scopus

    [63] Levavi, H., Lancman, G., and Gabrilove, J. (2021). Impact of rituximab on COVID-19 outcomes. Ann. Hematol. 100: 2805−2812. DOI: 10.1007/s00277-021-04662-1.

    View in Article CrossRef Google Scholar Scopus

    [64] Carr, E.J., Dooley, J., Garcia-Perez, J.E., et al. (2016). The cellular composition of the human immune system is shaped by age and cohabitation. Nat. Immunol. 17: 461−468. DOI: 10.1038/s41590-020-00839-4.

    View in Article CrossRef Google Scholar Scopus

    [65] Alpert, A., Pickman, Y., Leipold, M., et al. (2019). A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25: 487−495. DOI: 10.1038/s41591-019-0381-y.

    View in Article CrossRef Google Scholar Scopus

    [66] Yahata, T., Takanashi, T., Muguruma, Y., et al. (2011). Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 118: 2941−2950. DOI: 10.1182/blood-2011-01-330050.

    View in Article CrossRef Google Scholar Scopus

    [67] Pang, W.W., Price, E.A., Sahoo, D., et al. (2011). Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl. Acad. Sci. U. S. A. 108 : 20012-20017. DOI: 10.1073/pnas.1116110108.

    View in Article Google Scholar

    [68] Tuljapurkar, S.R., McGuire, T.R., Brusnahan, S.K., et al. (2011). Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging. J. Anat. 219: 574−581. DOI: 10.1111/j.1469-7580.2011.01423.x.

    View in Article CrossRef Google Scholar Scopus

    [69] Sempowski, G.D., Hale, L.P., Sundy, J.S., et al. (2000). Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J. Immunol. 164: 2180−2187. DOI: 10.4049/jimmunol.164.4.2180.

    View in Article CrossRef Google Scholar Scopus

    [70] Britanova, O.V., Putintseva, E.V., Shugay, M., et al. (2014). Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192: 2689−2698. DOI: 10.4049/jimmunol.1302064.

    View in Article CrossRef Google Scholar

    [71] Yoshida, K., Cologne, J.B., Cordova, K., et al. (2017). Aging-related changes in human T-cell repertoire over 20years delineated by deep sequencing of peripheral T-cell receptors. Exp. Gerontol. 96: 29−37. DOI: 10.1016/j.exger.2017.05.015.

    View in Article CrossRef Google Scholar

    [72] Qi, Q., Liu, Y., Cheng, Y., et al. (2014). Diversity and clonal selection in the human T-cell repertoire. Proc. Natl. Acad. Sci. U. S. A. 111: 13139−13144. DOI: 10.1073/pnas.1409155111.

    View in Article CrossRef Google Scholar Scopus

    [73] Gibson, K.L., Wu, Y.C., Barnett, Y., et al. (2009). B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8: 18-25. DOI: 10.1111/j.1474-9726.2008.00443.x.

    View in Article CrossRef Google Scholar Scopus

    [74] de Bourcy, C.F., Angel, C.J., Vollmers, C., et al. (2017). Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging. Proc. Natl. Acad. Sci. U. S. A. 114: 1105−1110. DOI: 10.1073/pnas.1617959114.

    View in Article CrossRef Google Scholar Scopus

    [75] Yager, E.J., Ahmed, M., Lanzer, K., et al. (2008). Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J. Exp. Med. 205: 711−723. DOI: 10.1084/jem.20071140.

    View in Article CrossRef Google Scholar Scopus

    [76] Gil, A., Yassai, M.B., Naumov, Y.N., et al. (2015). Narrowing of human influenza A virus-specific T cell receptor α and β repertoires with increasing age. J. Virol. 89: 4102−4116. DOI: 10.1128/JVI.03020-14.

    View in Article CrossRef Google Scholar Scopus

    [77] Gallerani, E., Proietto, D., Dallan, B., et al. (2021). Impaired priming of SARS-CoV-2-specific naive CD8(+) T cells in older subjects. Front. Immunol. 12: 693054. DOI: 10.3389/fimmu.2021.693054.

    View in Article CrossRef Google Scholar

    [78] Zheng, Y., Liu, X., Le, W., et al. (2020). A human circulating immune cell landscape in aging and COVID-19. Protein Cell 11: 740-770. DOI: 10.1007/s13238-020-00762-2.

    View in Article CrossRef Google Scholar Scopus

    [79] Bahadoran, A., Lee, S.H., Wang, S.M., et al. (2016). Immune responses to influenza virus and its correlation to age and inherited factors. Front. Microbiol. 7: 1841. DOI: 10.3389/fmicb.2016.01841.

    View in Article CrossRef Google Scholar Scopus

    [80] Rydyznski Moderbacher, C., Ramirez, S.I., Dan, J.M., et al. (2020). Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 183: 996-1012.e1019. DOI: 10.1016/j.cell.2020.09.038.

    View in Article CrossRef Google Scholar

    [81] Lefebvre, J.S., Masters, A.R., Hopkins, J.W., et al. (2016). Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Sci. Rep. 6: 25051. DOI: 10.1038/srep25051.

    View in Article CrossRef Google Scholar Scopus

    [82] Lu, L., Yu, S., Liu, M., et al. (2022). SARS-CoV-2-specific antibody response characteristics in COVID-19 patients of different ages. Acta Biochim. Biophys. Sin. (Shanghai) 54: 556−564. DOI: 10.3724/abbs.2022014.

    View in Article CrossRef Google Scholar Scopus

    [83] Selva, K.J., van de Sandt, C.E., Lemke, M.M., et al. (2021). Systems serology detects functionally distinct coronavirus antibody features in children and elderly. Nat. Commun. 12: 2037. DOI: 10.1038/s41467-021-22236-7.

    View in Article CrossRef Google Scholar Scopus

    [84] Garcia-Beltran, W.F., Lam, E.C., Astudillo, M.G., et al. (2021). COVID-19-neutralizing antibodies predict disease severity and survival. Cell 184: 476-488.e411. DOI: 10.1016/j.cell.2020.12.015.

    View in Article CrossRef Google Scholar Scopus

    [85] Po, J.L., Gardner, E.M., Anaraki, F., et al. (2002). Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech. Ageing Dev. 123 : 1167-1181. DOI: 10.1016/s0047-6374(02)00010-6.

    View in Article Google Scholar

    [86] Williams-Bey, Y., Jiang, J., and Murasko, D.M. (2011). Expansion of regulatory T cells in aged mice following influenza infection. Mech. Ageing Dev. 132: 163−170. DOI: 10.1016/j.mad.2011.03.001.

    View in Article CrossRef Google Scholar Scopus

    [87] Westmeier, J., Paniskaki, K., Karaköse, Z., et al. (2020). Impaired cytotoxic CD8(+) T cell response in elderly COVID-19 patients. mBio 11 : e02243-20. DOI: 10.1128/mBio.02243-20.

    View in Article Google Scholar

    [88] Goplen, N.P., Wu, Y., Son, Y.M., et al. (2020). Tissue-resident CD8(+) T cells drive age-associated chronic lung sequelae after viral pneumonia. Sci. Immunol. 5 : eabc4557. DOI: 10.1126/sciimmunol.abc4557.

    View in Article Google Scholar

    [89] Morales-Nebreda, L., Helmin, K.A., Torres Acosta, M.A., et al. (2021). Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia. JCI Insight 6 : e141690. DOI: 10.1172/jci.insight.141690.

    View in Article Google Scholar

    [90] Humbert, M., Olofsson, A., Wullimann, D., et al. (2023). Functional SARS-CoV-2 cross-reactive CD4(+) T cells established in early childhood decline with age. Proc. Natl. Acad. Sci. U. S. A. 120: e2220320120. DOI: 10.1073/pnas.2220320120.

    View in Article CrossRef Google Scholar

    [91] Zhao, M., Chen, J., Tan, S., et al. (2018). Prolonged evolution of virus-specific memory t cell immunity after severe avian influenza A (H7N9) virus infection. J. Virol. 92 : e01024-18. DOI: 10.1128/JVI.01024-18.

    View in Article Google Scholar

    [92] Ho, F.K., Petermann-Rocha, F., Gray, S.R., et al. (2020). Is older age associated with COVID-19 mortality in the absence of other risk factors? General population cohort study of 470,034 participants. PLoS One 15 : e0241824. DOI: 10.1371/journal.pone.0241824.

    View in Article Google Scholar

    [93] Fajnzylber, J., Regan, J., Coxen, K., et al. (2020). SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat. Commun. 11: 5493. DOI: 10.1038/s41467-020-19057-5.

    View in Article CrossRef Google Scholar Scopus

    [94] Kawasuji, H., Morinaga, Y., Tani, H., et al. (2022). SARS-CoV-2 RNAemia with a higher nasopharyngeal viral load is strongly associated with disease severity and mortality in patients with COVID-19. J. Med. Virol. 94: 147−153. DOI: 10.1002/jmv.27282.

    View in Article CrossRef Google Scholar Scopus

    [95] Bermejo-Martin, J.F., González-Rivera, M., Almansa, R., et al. (2020). Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19. Crit. Care 24: 691. DOI: 10.1186/s13054-020-03398-0.

    View in Article CrossRef Google Scholar Scopus

    [96] Vasquez, C.R., Gupta, S., Miano, T.A., et al. (2021). Identification of distinct clinical subphenotypes in critically ill patients with COVID-19. Chest 160: 929-943. DOI: 10.1016/j.chest.2021.04.062.

    View in Article CrossRef Google Scholar

    [97] López-Martínez, C., Martín-Vicente, P., Gómez de Oña, J., et al. (2023). Transcriptomic clustering of critically ill COVID-19 patients. Eur. Respir. J. 61 : 2200592. DOI: 10.1183/13993003.00592-2022.

    View in Article Google Scholar

    [98] Nguyen, Q.D., Moodie, E.M., Forget, M.F., et al. (2021). Health heterogeneity in older adults: Exploration in the canadian longitudinal study on aging. J. Am. Geriatr. Soc. 69: 678−687. DOI: 10.1111/jgs.16919.

    View in Article CrossRef Google Scholar

    [99] Del Valle, D.M., Kim-Schulze, S., Huang, H.H., et al. (2020). An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 26: 1636−1643. DOI: 10.1038/s41591-020-1051-9.

    View in Article CrossRef Google Scholar Scopus

    [100] McElvaney, O.J., McEvoy, N.L., McElvaney, O.F., et al. (2020). Characterization of the inflammatory response to severe COVID-19 illness. Am. J. Respir. Crit. Care Med. 202: 812−821. DOI: 10.1164/rccm.202005-1583OC.

    View in Article CrossRef Google Scholar

    [101] Mogilenko, D.A., Shchukina, I., and Artyomov, M.N. (2022). Immune ageing at single-cell resolution. Nat. Rev. Immunol. 22: 484−498. DOI: 10.1038/s41577-021-00646-4.

    View in Article CrossRef Google Scholar Scopus

    [102] Keenan, C.R., and Allan, R.S. (2019). Epigenomic drivers of immune dysfunction in aging. Aging Cell 18: e12878. DOI: 10.1111/acel.12878.

    View in Article CrossRef Google Scholar Scopus

    [103] Reis, G., Moreira Silva, E.A.S., Medeiros Silva, D.C., et al. (2023). Early treatment with pegylated interferon lambda for COVID-19. N. Engl. J. Med. 388: 518−528. DOI: 10.1056/NEJMoa2209760.

    View in Article CrossRef Google Scholar

    [104] Pan, H., Peto, R., Henao-Restrepo, A.M., et al. (2021). Repurposed antiviral drugs for COVID-19 - interim WHO Solidarity trial results. N. Engl. J. Med. 384: 497−511. DOI: 10.1056/NEJMoa2023184.

    View in Article CrossRef Google Scholar

    [105] Shankar-Hari, M., Vale, C.L., Godolphin, P.J., et al. (2021). Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA 326: 499−518. DOI: 10.1001/jama.2021.11330.

    View in Article CrossRef Google Scholar

    [106] Zhang, X., Shang, L., Fan, G., et al. (2021). The efficacy and safety of Janus kinase inhibitors for patients with COVID-19: A living systematic review and meta-analysis. Front. Med. (Lausanne) 8: 800492. DOI: 10.3389/fmed.2021.800492.

    View in Article CrossRef Google Scholar

    [107] Netea, M.G., Joosten, L.A., Latz, E., et al. (2016). Trained immunity: A program of innate immune memory in health and disease. Science 352: aaf1098. DOI: 10.1126/science.aaf1098.

    View in Article CrossRef Google Scholar Scopus

    [108] Netea, M.G., Domínguez-Andrés, J., Barreiro, L.B., et al. (2020). Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20: 375−388. DOI: 10.1038/s41577-020-0285-6.

    View in Article CrossRef Google Scholar Scopus

    [109] Bekkering, S., Domínguez-Andrés, J., Joosten, L.A.B., et al. (2021). Trained immunity: Reprogramming innate immunity in health and disease. Annu. Rev. Immunol. 39: 667−693. DOI: 10.1146/annurev-immunol-102119-073855.

    View in Article CrossRef Google Scholar

    [110] Giamarellos-Bourboulis, E.J., Tsilika, M., Moorlag, S., et al. (2020). Activate: Randomized clinical trial of BCG vaccination against infection in the elderly. Cell 183: 315−323.e319. DOI: 10.1016/j.cell.2020.08.051.

    View in Article CrossRef Google Scholar

    [111] Tsilika, M., Taks, E., Dolianitis, K., et al. (2022). ACTIVATE-2: A double-blind randomized trial of BCG vaccination against COVID-19 in individuals at risk. Front. Immunol. 13: 873067. DOI: 10.3389/fimmu.2022.873067.

    View in Article CrossRef Google Scholar

    [112] Debisarun, P.A., Gössling, K.L., Bulut, O., et al. (2021). Induction of trained immunity by influenza vaccination - impact on COVID-19. PLoS Pathog 17: e1009928. DOI: 10.1371/journal.ppat.1009928.

    View in Article CrossRef Google Scholar

    [113] Pittet, L.F., Messina, N.L., Orsini, F., et al. (2023). Randomized trial of BCG vaccine to protect against COVID-19 in health care workers. N. Engl. J. Med. 388: 1582−1596. DOI: 10.1056/NEJMoa2212616.

    View in Article CrossRef Google Scholar

    [114] Weinberger, B., Herndler-Brandstetter, D., Schwanninger, A., et al. (2008). Biology of immune responses to vaccines in elderly persons. Clin. Infect. Dis. 46: 1078−1084. DOI: 10.1086/529197.

    View in Article CrossRef Google Scholar Scopus

    [115] Schwarz, T., Tober-Lau, P., Hillus, D., et al. (2021). Delayed antibody and T-cell response to BNT162b2 vaccination in the elderly, Germany. Emerg. Infect. Dis. 27: 2174−2178. DOI: 10.3201/eid2708.211145.

    View in Article CrossRef Google Scholar Scopus

    [116] Wei, J., Stoesser, N., Matthews, P.C., et al. (2021). Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom. Nat. Microbiol. 6: 1140−1149. DOI: 10.1038/s41564-021-00947-3.

    View in Article CrossRef Google Scholar Scopus

    [117] Meng, Z., Zhang, J., Shi, J., et al. (2020). Immunogenicity of influenza vaccine in elderly people: A systematic review and meta-analysis of randomized controlled trials, and its association with real-world effectiveness. Hum. Vaccin. Immunother. 16: 2680−2689. DOI: 10.1080/21645515.2020.1747375.

    View in Article CrossRef Google Scholar

    [118] Collier, D.A., Ferreira, I., Kotagiri, P., et al. (2021). Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature 596: 417-422. DOI: 10.1038/s41586-021-03739-1.

    View in Article CrossRef Google Scholar Scopus

    [119] Gilbert, P.B., Montefiori, D.C., McDermott, A.B., et al. (2022). Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial. Science 375: 43-50. DOI: 10.1126/science.abm3425.

    View in Article CrossRef Google Scholar Scopus

    [120] Khoury, D.S., Cromer, D., Reynaldi, A., et al. (2021). Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 27: 1205−1211. DOI: 10.1038/s41591-021-01377-8.

    View in Article CrossRef Google Scholar Scopus

    [121] Bell, M.R., and Kutzler, M.A. (2022). An old problem with new solutions: Strategies to improve vaccine efficacy in the elderly. Adv. Drug Deliv. Rev. 183: 114175. DOI: 10.1016/j.addr.2022.114175.

    View in Article CrossRef Google Scholar Scopus

    [122] Wilkinson, K., Wei, Y., Szwajcer, A., et al. (2017). Efficacy and safety of high-dose influenza vaccine in elderly adults: A systematic review and meta-analysis. Vaccine 35: 2775-2780. DOI: 10.1016/j.vaccine.2017.03.092.

    View in Article CrossRef Google Scholar Scopus

    [123] Coleman, B.L., Sanderson, R., Haag, M.D.M., et al. (2021). Effectiveness of the MF59-adjuvanted trivalent or quadrivalent seasonal influenza vaccine among adults 65 years of age or older, a systematic review and meta-analysis. Influenza Other Respir. Viruses 15: 813−823. DOI: 10.1111/irv.12871.

    View in Article CrossRef Google Scholar Scopus

    [124] McElhaney, J.E., Beran, J., Devaster, J.M., et al. (2013). AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: A phase 3 randomised trial. Lancet Infect. Dis. 13: 485−496. DOI: 10.1016/S1473-3099(13)70046-X.

    View in Article CrossRef Google Scholar Scopus

    [125] Pereira, B., Xu, X.N., and Akbar, A.N. (2020). Targeting inflammation and immunosenescence to improve vaccine responses in the elderly. Front. Immunol. 11: 583019. DOI: 10.3389/fimmu.2020.583019.

    View in Article CrossRef Google Scholar

    [126] López-Otín, C., Blasco, M.A., Partridge, L., et al. (2013). The hallmarks of aging. Cell 153: 1194-1217. DOI: 10.1016/j.cell.2013.05.039.

    View in Article CrossRef Google Scholar Scopus

    [127] Cao, X., Li, W., Wang, T., et al. (2022). Accelerated biological aging in COVID-19 patients. Nat. Commun. 13: 2135. DOI: 10.1038/s41467-022-29801-8.

    View in Article CrossRef Google Scholar Scopus

    [128] Di Micco, R., Krizhanovsky, V., Baker, D., et al. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22: 75−95. DOI: 10.1038/s41580-020-00314-w.

    View in Article CrossRef Google Scholar Scopus

    [129] Debacq-Chainiaux, F., Erusalimsky, J.D., Campisi, J., et al. (2009). Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat. Protoc. 4: 1798−1806. DOI: 10.1038/nprot.2009.191.

    View in Article CrossRef Google Scholar

    [130] Herranz, N., and Gil, J. (2018). Mechanisms and functions of cellular senescence. J. Clin. Invest. 128: 1238−1246. DOI: 10.1172/JCI95148.

    View in Article CrossRef Google Scholar Scopus

    [131] Hao, X., Wang, C., and Zhang, R. (2022). Chromatin basis of the senescence-associated secretory phenotype. Trends Cell Biol. 32: 513−526. DOI: 10.1016/j.tcb.2021.12.003.

    View in Article CrossRef Google Scholar Scopus

    [132] Schafer, M.J., Zhang, X., Kumar, A., et al. (2020). The senescence-associated secretome as an indicator of age and medical risk. JCI Insight 5 : e133668. DOI: 10.1172/jci.insight.133668.

    View in Article Google Scholar

    [133] Kirkland, J.L., and Tchkonia, T. (2020). Senolytic drugs: From discovery to translation. J. Intern. Med. 288: 518−536. DOI: 10.1111/joim.13141.

    View in Article CrossRef Google Scholar

    [134] Niedernhofer, L.J., and Robbins, P.D. (2018). Senotherapeutics for healthy ageing. Nat. Rev. Drug Discov. 17: 377. DOI: 10.1038/nrd.2018.44.

    View in Article CrossRef Google Scholar Scopus

    [135] Gasek, N.S., Kuchel, G.A., Kirkland, J.L., et al. (2021). Strategies for targeting senescent cells in human disease. Nat. Aging 1: 870−879. DOI: 10.1038/s43587-021-00121-8.

    View in Article CrossRef Google Scholar Scopus

    [136] Kelley, W.J., Zemans, R.L., and Goldstein, D.R. (2020). Cellular senescence: Friend or foe to respiratory viral infections? Eur. Respir. J. 56 : 2002708. DOI: 10.1183/13993003.02708-2020.

    View in Article Google Scholar

    [137] Camell, C.D., Yousefzadeh, M.J., Zhu, Y., et al. (2021). Senolytics reduce coronavirus-related mortality in old mice. Science 373 : eabe4832. DOI: 10.1126/science.abe4832.

    View in Article Google Scholar

    [138] Evangelou, K., Veroutis, D., Paschalaki, K., et al. (2022). Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: Possible implications for viral mutagenesis. Eur. Respir. J. 60 : 2102951. DOI: 10.1183/13993003.02951-2021.

    View in Article Google Scholar

    [139] Lee, S., Yu, Y., Trimpert, J., et al. (2021). Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature 599: 283-289. DOI: 10.1038/s41586-021-03995-1.

    View in Article CrossRef Google Scholar Scopus

    [140] Di Pierro, F., Derosa, G., Maffioli, P., et al. (2021). Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: A prospective, randomized, controlled, and open-label study. Int. J. Gen. Med. 14: 2359−2366. DOI: 10.2147/IJGM.S318720.

    View in Article CrossRef Google Scholar

    [141] Di Pierro, F., Iqtadar, S., Khan, A., et al. (2021). Potential clinical benefits of quercetin in the early stage of COVID-19: Results of a second, pilot, randomized, controlled and open-label clinical trial. Int. J. Gen. Med. 14: 2807−2816. DOI: 10.2147/IJGM.S318949.

    View in Article CrossRef Google Scholar Scopus

    [142] Johnson, S.C., Rabinovitch, P.S., and Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature 493: 338-345. DOI: 10.1038/nature11861.

    View in Article CrossRef Google Scholar

    [143] Powell, J.D., Pollizzi, K.N., Heikamp, E.B., et al. (2012). Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30: 39−68. DOI: 10.1146/annurev-immunol-020711-075024.

    View in Article CrossRef Google Scholar Scopus

    [144] Quinn, K.M., Palchaudhuri, R., Palmer, C.S., et al. (2019). The clock is ticking: the impact of ageing on T cell metabolism. Clin. Transl. Immunol. 8: e01091. DOI: 10.1002/cti2.1091.

    View in Article CrossRef Google Scholar Scopus

    [145] Mannick, J.B., Del Giudice, G., Lattanzi, M., et al. (2014). mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6: 268ra179. DOI: 10.1126/scitranslmed.3009892.

    View in Article CrossRef Google Scholar Scopus

    [146] Mannick, J.B., Morris, M., Hockey, H.P., et al. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10 : eaaq1564. DOI: 10.1126/scitranslmed.aaq1564.

    View in Article Google Scholar

    [147] Mannick, J.B., Teo, G., Bernardo, P., et al. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: Phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2: e250−e262. DOI: 10.1016/S2666-7568(21)00062-3.

    View in Article CrossRef Google Scholar

    [148] Cao, S., Zhang, Q., Song, L., et al. (2022). Dysregulation of innate and adaptive immune responses in asymptomatic SARS-CoV-2 infection with delayed viral clearance. Int. J. Biol. Sci. 18: 4648−4657. DOI: 10.7150/ijbs.72963.

    View in Article CrossRef Google Scholar

    [149] Bjornson-Hooper, Z.B., Fragiadakis, G.K., Spitzer, M.H., et al. (2022). A comprehensive atlas of immunological differences between humans, mice, and non-human primates. Front. Immunol. 13: 867015. DOI: 10.3389/fimmu.2022.867015.

    View in Article CrossRef Google Scholar

    [150] Lu, J., Duan, X., Zhao, W., et al. (2018). Aged mice are more resistant to influenza virus infection due to reduced inflammation and lung pathology. Aging Dis. 9: 358−373. DOI: 10.14336/AD.2017.0701.

    View in Article CrossRef Google Scholar Scopus

    [151] Sun, S., Zhao, G., Xiao, W., et al. (2011). Age-related sensitivity and pathological differences in infections by 2009 pandemic influenza A (H1N1) virus. Virol. J. 8: 52. DOI: 10.1186/1743-422X-8-52.

    View in Article CrossRef Google Scholar

    [152] Smith, C.A., Kulkarni, U., Chen, J., et al. (2019). Influenza virus inoculum volume is critical to elucidate age-dependent mortality in mice. Aging Cell 18: e12893. DOI: 10.1111/acel.12893.

    View in Article CrossRef Google Scholar Scopus

    [153] Califano, D., Furuya, Y., and Metzger, D.W. (2018). Effects of influenza on alveolar macrophage viability are dependent on mouse genetic strain. J. Immunol. 201: 134−144. DOI: 10.4049/jimmunol.1701406.

    View in Article CrossRef Google Scholar Scopus

    [154] Wang, J., Li, F., Sun, R., et al. (2013). Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages. Nat. Commun. 4: 2106. DOI: 10.1038/ncomms3106.

    View in Article CrossRef Google Scholar Scopus

    [155] Salahudeen, A.A., Choi, S.S., Rustagi, A., et al. (2020). Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature 588: 670-675. DOI: 10.1038/s41586-020-3014-1.

    View in Article CrossRef Google Scholar Scopus

    [156] Francis, I., Shrestha, J., Paudel, K.R., et al. (2022). Recent advances in lung-on-a-chip models. Drug Discov. Today 27: 2593-−2602. DOI: 10.1016/j.drudis.2022.06.004.

    View in Article CrossRef Google Scholar Scopus

    [157] McClain, M.T., Constantine, F.J., Nicholson, B.P., et al. (2021). A blood-based host gene expression assay for early detection of respiratory viral infection: an index-cluster prospective cohort study. Lancet Infect Dis 21: 396-404. DOI: 10.1016/S1473-3099(20)30486-2.

    View in Article CrossRef Google Scholar Scopus

    [158] Lydon, E.C., Henao, R., Burke, T.W., et al. (2019). Validation of a host response test to distinguish bacterial and viral respiratory infection. EBioMedicine 48: 453-461. DOI: 10.1016/j.ebiom.2019.09.040.

    View in Article CrossRef Google Scholar Scopus

  • Cite this article:

    Zhang X., Xu J., Wang Y., et al., (2023). Respiratory viral infections in the elderly: From the perspective of the aging immune system. The Innovation Medicine 1(2), 100022. https://doi.org/10.59717/j.xinn-med.2023.100022
    Zhang X., Xu J., Wang Y., et al., (2023). Respiratory viral infections in the elderly: From the perspective of the aging immune system. The Innovation Medicine 1(2), 100022. https://doi.org/10.59717/j.xinn-med.2023.100022

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