New Evidence for Key Factors that Drive COVID-19 Severity

key factors COVID-19 Severity
Key Factors – COVID-19 Severity

The COVID-19 outbreak was first identified in Wuhan, China. Despite the causal agent being closely related to a bat coronavirus (RaTG13), several questions remain regarding the origin, evolution and host interaction of COVID-19. Although the Seafood Market in Wuhan is suggested as the origin of the outbreak, some initial cases occurred in patients without contact with the market.

In their Nature study Xiaonan Zhang et al. from the Shanghai Public Health Clinical Center, Fudan University, Shanghai, China, analyzed the clinical, molecular and immunological characteristics of 326 confirmed COVID-19 patients in Shanghai between January 20th to February 25th, 2020. Patients were divided into 4 groups according to their presentation of infection; asymptomatic, mild (fever and pneumonia), critical (+dyspnea and lung opacity) or severe (+acute respiratory distress with oxygen support). Their clinical features were correlated with virus genome variation and host factors associated with disease severity.

The authors compared the genome of the virus isolated in Shanghai with the first-release genomes from Wuhan (Wuhan-Hu-1) and reported a similar viral genome between these two cities. Further analysis of COVID-19 genomic phylogeny indicated that the two major viral lineages share a common ancestor.

These viral lineages showed stable and predictable genome evolution and differed by only two nucleotides out of the approximately 30,000 nucleotides in the SARS-CoV-2 genome. Importantly, the authors found no difference in disease manifestation, mutation or infection rate between the two SARS-CoV-2 lineages.

As Marios Koutsakos and Katherine Kedzierska commented, these data suggest that the two viral lineages originated from a common viral ancestor and spread independently at the same time: clade I through the Wuhan market, and clade II outside it.

In addition, Zhang et al. showed progressive decline of CD3+, CD4+, and CD8+ T cells counts in COVID-19 infected patients. The lymphocytopenia observed in these patients was inversely correlated to serum IL-6 and IL-8 levels, and a significant high level of IL-6 was found in critical patients. These results indicate that loss of blood T lymphocytes and increased levels of serum IL-6 in COVID-19-infected patients can anticipate disease severity and mortality.

The authors discuss that the loss of CD3+ T lymphocytes may represent an underlying mechanism for disease progression, most likely caused by lymphocyte infiltration, induced by pro-inflammatory cytokines.

It is a matter of debate whether the increase of IL-6 and IL-8 levels should be considered a ‘cytokine storm’, a term often used recently in COVID-19 research, as they are lower than the median values typically reported in other forms of acute respiratory distress syndrome (ARDS). Thus, in COVID-19, the list of major pathogenicity factors should also include vascular injury, including alveolar microthrombi or endothelial cell damage and thromboinflammation.

In summary, the study of Zhang et al. found evidence that COVID-19 severity is associated with depletion of CD3+ T lymphocytes, particularly the CD4+ and CD8+ fractions, and associated with high levels of IL-6 and IL-8. The study provides new insights into viral and host factors contributing to disease mechanisms and outcome that may help in designing new treatment strategies for COVID-19.

Source: Nature, 2020: 583, 437–440. Doi: 10.1038/s41586-020-2355-0

Read more: Nature


On: Viral and host factors related to the clinical outcome of COVID-19, by Zhang et al., Nature, 2020 Jul;583(7816):437-440., doi: 10.1038/s41586-020-2355-0.

Author’s Affiliation

Gabriel Bassi, PhD – Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA

Cover Image Credit: According to the severity of the disease, the clinical course of COVID-19 can be classified into three stages, namely “early infection”, “pulmonary phase”, and “hyperinflammation phase”, each one characterised by specific biochemical alterations. From: Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19), by Marcello Ciaccio and Luisa Agnello: De Gruyter | 2020; DOI:,

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