SARS-CoV-2 Viral Load is Associated with Increased Disease Severity and Mortality

Fajnzylber, Jesse; Regan, James; Coxen, Kendyll; Corry, Heather; Wong, Colline; Rosenthal, Alexandra; Worrall, Daniel; Giguel, Françoise; Piechocka-Trocha, Alicja; Atyeo, Caroline; Fischinger, Stephanie; Chan, Andrew T.; Flaherty, Keith T.; Hall, Kathryn; Dougan, Michael; Ryan, Edward A.; Gillespie, Elizabeth; Chishti, Rida; Li, Yijia; Jilg, Nikolaus; Hanidziar, Dusan; Baron, Rebecca M.; Baden, Lindsey R.; Tsibris, Athe; Armstrong, Katrina; Alter, Galit; Kuritzkes, Daniel R.; Walker, Bruce D.; Yu, Xu G.; Li, Jonathan

doi:10.21203/rs.3.rs-43878/v1

Cited by 194 publications

(249 citation statements)

References 19 publications

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“…One of the potential determinants of the severity of SARS-CoV2 infection is the degree of activation and multiplication of this new emergent virus in human cells [8,9]. The spike protein of SARS-CoV-2 is used by the virus to engage and bind its target cell receptor, the angiotensin converting enzyme 2 (ACE2) [10].…”

mentioning

confidence: 99%

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

et al. 2021

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Background Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells. Methods We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels. Results ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes. Conclusion Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.

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confidence: 99%

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

et al. 2021

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“…Adipose tissues also serve as an endocrine organs and secrete hormones like leptin, adiponectin, and inflammatory cytokines such as IL-6 and TNF ( Banerjee et al, 2020 ). ACE2 expression levels are higher in visceral adipose tissue compared to subcutaneous fat ( Zhang et al, 2018 ), and since obese and diabetic patients have more adipose tissue, they have increased numbers of ACE2 expressing adipocytes, potentially increasing their susceptibility to an elevated viral load in the adipose tissue ( Banerjee et al, 2020 ), which could lead to increased severity of SARS-CoV-2 infection ( Fajnzylber et al, 2020 ). Aging is also associated with metabolic dysfunction in correlation with dysfunction of adipose tissue, as evidenced by correlation between mitochondrial and arterial dysfunction in epididymal white adipose tissue and metabolic dysfunction in aged B6D2F1 mice ( Donato et al, 2014 ).…”

Section: Innate Immunitymentioning

confidence: 99%

Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections?

et al. 2021

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The novel coronavirus severe acute respiratory syndrome coronavirus 2 causing the Coronavirus disease (COVID-19) pandemic has ravaged the world with over 72 million total cases and over 1.6 million deaths worldwide as of early December 2020. An overwhelming preponderance of cases and deaths is observed within the elderly population, and especially in those with pre-existing conditions and comorbidities. Aging causes numerous biological changes in the immune system, which are linked to age-related illnesses and susceptibility to infectious diseases. Age-related changes influence the host immune response and therefore not only weaken the ability to fight respiratory infections but also to mount effective responses to vaccines. Immunosenescence and inflamm-aging are considered key features of the aging immune system wherein accumulation of senescent immune cells contribute to its decline and simultaneously increased inflammatory phenotypes cause immune dysfunction. Age-related quantitative and qualitative changes in the immune system affect cells and soluble mediators of both the innate and adaptive immune responses within lymphoid and non-lymphoid peripheral tissues. These changes determine not only the susceptibility to infections, but also disease progression and clinical outcomes thereafter. Furthermore, the response to therapeutics and the immune response to vaccines are influenced by age-related changes within the immune system. Therefore, better understanding of the pathophysiology of aging and the immune response will not only help understand age-related diseases but also guide targeted management strategies for deadly infectious diseases like COVID-19.

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“…Viral loads in the lower respiratory tract (LRT) are positively associated with disease outcomes 81,82 .…”

Section: Accepted Articlementioning

confidence: 99%

Mechanistic Modeling of SARS‐CoV‐2 and Other Infectious Diseases and the Effects of Therapeutics

Perelson

2021

Clin Pharma and Therapeutics

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Modern viral kinetic modeling and its application to therapeutics is a field that attracted the attention of the medical, pharmaceutical, and modeling communities during the early days of the AIDS epidemic. Its successes led to applications of modeling methods not only to HIV but a plethora of other viruses, such as hepatitis C virus (HCV), hepatitis B virus and cytomegalovirus, which along with HIV cause chronic diseases, and viruses such as influenza, respiratory syncytial virus, West Nile virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which generally cause acute infections. Here we first review the historical development of mathematical models to understand HIV and HCV infections and the effects of treatment by fitting the models to clinical data. We then focus on recent efforts and contributions of applying these models towards understanding SARS‐CoV‐2 infection and highlight outstanding questions where modeling can provide crucial insights and help to optimize nonpharmaceutical and pharmaceutical interventions of the coronavirus disease 2019 (COVID‐19) pandemic. The review is written from our personal perspective emphasizing the power of simple target cell limited models that provided important insights and then their evolution into more complex models that captured more of the virology and immunology. To quote Albert Einstein, “Everything should be made as simple as possible, but not simpler,” and this idea underlies the modeling we describe below.

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SARS-CoV-2 Viral Load is Associated with Increased Disease Severity and Mortality

Cited by 194 publications

References 19 publications

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections?

Mechanistic Modeling of SARS‐CoV‐2 and Other Infectious Diseases and the Effects of Therapeutics

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