Biological mechanisms underpinning the development of long COVID.

As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-CoV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences. Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available. To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.

Long COVID: a review and proposed visualization of the complexity of long COVID.

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition. Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.

T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults.

In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.

The aging of the immune system and its implications for transplantation.

By the last third of life, most mammals, including humans, exhibit a decline in immune cell numbers, immune organ structure, and immune defense of the organism, commonly known as immunosenescence. This decline leads to clinical manifestations of increased susceptibility to infections, particularly those caused by emerging and reemerging microorganisms, which can reach staggering levels-infection with SARS-CoV-2 has been 270-fold more lethal to older adults over 80 years of age, compared to their 18-39-year-old counterparts. However, while this would be expected to be beneficial to situations where hyporeactivity of the immune system may be desirable, this is not always the case. Here, we discuss the cellular and molecular underpinnings of immunosenescence as they pertain to outcomes of solid organ and hematopoietic transplantation.