Age-Related Differences in Immunological Responses to SARS-CoV-2

Abstract

There is a striking age-related disparity in the prevalence and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 infections, which might be explained by age-dependent immunological mechanisms. These include age-related physiological differences in immunological responses, cross-neutralizing antibodies, and differences in levels and binding affinity of angiotensin-converting enzyme 2, the SARS-CoV-2 target receptor; antibody-dependent enhancement in adults manifesting with an overexuberant systemic inflammation in response to infection; and the increased likelihood of comorbidities in adults and the elderly. Emerging immunological phenomena such as Pediatric Multi-System Inflammatory Disorder Temporally associated with SARS-CoV-2 or Multisystem Inflammatory Syndrome in Children are now being observed, though the underlying mechanisms are still unclear. Understanding the mechanisms through which pediatric patients are protected from severe novel coronaviruses infections will provide critical clues to the pathophysiology of coronavirus disease 2019 infection and inform future therapeutic and prophylactic interventions. Asymptomatic carriage in children may have major public health implications, which will have an impact on social and health care policies on screening and isolation practices, school reopening, and safe distancing requirements in the community.

Keywords: COVID-19; Pediatric Multi-System Inflammatory Disorder; SARS-CoV-2.

Figure 1

Differences in physiological responses of children, adults, and elderly to SARS-CoV-2. Children generally experience infrequent, mild, and self-limiting infections, which may be due to (a) higher levels of cross-neutralizing antibodies, (b) lower levels of ACE-2 receptors in nasal epithelium, which lowers susceptibility to infection, (c) immature B and T cells and higher regulatory T-cell response, and (d) lower IL-6 and TNF-α production, limiting inflammatory response. Moreover, adults may experience ADE where the S protein enhances entry into cells via Fc receptors, resulting in cytokine storms, which cause severe lung injury. Elderly may be even more susceptible to ADE because they have more afucosylated IgG, which has a higher affinity with Fc receptors. Existing comorbidities in elderly also result in upregulation of CD147, increasing viral entry as well as exacerbation of proinflammatory responses, which increase mortality risk.