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Low CD4s and CD8s-But Not Viral
Genetics-Predict COVID-19 Progression
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Mark Mascolini
Low CD4 and CD8 T-cell counts and other host factors predicted COVID-19 progression in 326 people in Shanghai early in the epidemic's course [1]. SARS-CoV-2, the virus that causes COVID-19, stayed genetically stable over time and did not affect disease outcomes.
Researchers from Shanghai's Fudan University and collaborators from other centers conducted this study to identify progression predictors in 326 people with PCR-confirmed COVID-19 seen between January 20 and February 25, 2020 in Shanghai. Five people had no symptoms, 293 had mild disease (fever and radiologic manifestations of pneumonia), 12 people had severe disease (dyspnea and early expanding ground-glass opacity on lung x-ray), and 16 people had critical disease (acute respiratory distress syndrome that required mechanical ventilation or oxygen support). Through April 1, 6 people had died and 315 had been discharged from the hospital.
The researchers sequenced 112 SARS-CoV-2 samples collected from sputum or oropharyngeal swabs. Using viral genomes from 94 study participants plus 221 sequences from the database of the Global Initiative on Sharing All Influenza Data (GISAID), the researchers identified two major clades (viral groups), and both clades included people diagnosed in early December 2019. The Shanghai study population had sequences throughout these two major clades. Neither the two major clades nor subclades expanded in the Shanghai population. Study participants with clade I or clade II virus did not differ in viral mutation rate or transmissibility.
Clinical manifestations of COVID-19 did not differ much between people with clade I or clade II virus, including disease severity (P = 0.88), T-cell count (P = 0.79), CD3 T-cell count (P = 0.21), C-reactive protein (an inflammation marker) (P = 0.83), D-dimer (a coagulation marker) (P = 0.19), or duration of viral shedding after onset (P = 0.79). Neither did the researchers find differences in disease severity among the 13 most frequent viral sequence variations.
The Shanghai team did find clinical markers of progression. Lymphocyte counts dropped progressively, particularly in people with severe or critical COVID-19, whether measured as CD3 T cells (P < 10[-6]), CD4 T cells (P < 10[-6]), or CD8 T cells (P = 1 x 10[-5]). Yet T-cell counts fell significantly not only in people with severe or critical disease, but also in those with asymptomatic or mild disease. Although CD19 B cells dropped significantly in people with critical disease (P = 1 x 10[-5]), they did not fall significantly in those with asymptomatic, mild, or severe disease.
During follow-up, COVID-19 progression proved significantly more likely in people with coexisting conditions (P = 0.01). Univariate analysis identified four predictors of disease progression: older age (P < 0.0001), lower lymphocyte count upon admission (P < 0.00001), comorbidities (P = 0.01), and male gender (P = 0.014). Multivariate analysis singled out two independent predictors of progression: lower lymphocyte count (P = 0.002) and older age (P = 0.002).
Among 11 cytokines measured at admission and during treatment, IL-6 (P < 10[-6]) and IL-8 (P = 1 x 10[-5]) rose the most and correlated inversely with lymphocytes (the higher the cytokine level, the lower the lymphocyte count). IL-6 levels (P = 0.001) and IL-8 levels (P = 0.006) were significantly higher in the critical COVID-19 group than in the other groups.
The researchers conclude that their analysis of recently treated people in Shanghai "provides further evidence that the viral genome is largely stable." They write that reasons for the relationships they found between virologic activity, cytokine release, and low lymphocytes remain unclear. They "hypothesize that the immunopathological response against SARS-CoV-2 involving 'cytokine storm' and loss of CD3+ T lymphocytes could constitute, at least in part, an underlying mechanism for disease progression and fatality."
Reference
1. Zhang X, Tan Y, Ling Y, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature. 2020 May 20. doi: 10.1038/s41586-020-2355-0. https://pubmed.ncbi.nlm.nih.gov/32434211
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