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Authors:Ana Marcos-Jiménez et al. 

Journal/ Pre-Print: MedRXiv 

Tags: Clinical, Immunology/Immunity, Inflammation, Cell biology 

Research Highlights

  1. In sever COVID-19 cases, frequencies of circulating CD4 follicular helper T cells in blood were increased, and the level of expression of CCR7 on these cells was higher. 

  1. In contrast, increased severity of disease correlated with reduced serum levels of IgG and C4 complement and decline in plasma cells levels over time. 

  1. Significant increase in frequencies of NK cells and reduced expression levels of CD16 were observed in severe cases, possibly indicating enhanced ADCC activity. 


PBMCs and serum samples from 276 COVID-19 patients were compared to 19 healthy controls. COVID-19 patients exhibited an increase in plasma cell numbers, frequencies of circulating Tfh cells and serum levels of C3 and C4. However, of those patients that went on to develop severe symptoms and that required prolonged hospitalization gradual and significant reduction in C4, IgG and plasma cell levels was observed over time. In contrast, sever cases showed increase in the frequency of CD56-CD16+ NK cells. The authors propose the possibility that enhanced ADCC responses may correlate with severity of diseases.   

Impact for SARS-CoV2/COVID19 research efforts  

  • Provides descriptive information correlating the cellular and humoral immune response to SARS-CoV2/COVID19 with severity of disease. 

  • Indicate gradual reduction in IgG, plasma cells and serum C4 levels in patients that develop severe symptoms. 

  • Suggests a higher activation complement as well as NK-mediated cytotoxicity in severe COVDI-19 cases.  

Study Type 

  • Clinical Cohort study 

Strengths and limitations of the paper 

Novelty: The study correlates COVID-19 severity with dysregulated humoral immune responses characterized by an increase of IgG and complement protein C4 consumption, identifying new targets for therapeutic approaches. They also observed increased CCR7 expression on cTFH cells which could be relevant to the humoral response. 

Standing in the field: The results were not controversial. The increase in cTfh frequencies and decrease in lymphocyte numbers supports previous findings  

Appropriate statistics: Yes 

Viral model used: SARS-CoV-2 strain, nCoV2019 

Translatability: Limited translatability. This study argues in favour of the use of complement inhibitors for severe COVID-19 cases 

Main limitations:  

  1. The author suggests that expansion of CD56- NK cells could be related to IgG consumption and ADCC response. However, no direct correlation was reported between the two parameters.CD56- NK cells are known to expand in other viral infections and associated with NK dysregulation/dysfunction. Would be useful to show direct correlation between IgG levels and NK cell frequencies. 

  1.  Would be useful to have a longer longitudinal analysis of level of serum IgG, IgA and IgM after 10 days of admission. Previous studies have shown that the peak humoral responses are after 16 days of viral detection.  

  1. Unsupervised FlowSom analysis shows a decrease in the CD56+ NK cluster in patients compared with healthy, however no significant differences were detected in the percentage of CD56bright and CD56dim populations. Reporting the absolute number of NK subsets may help in clearing confusion between the two types of analysis.    

  1. Minimal information is given regarding the median days of hospitalisation for the severe group “>15 days”. 

  1. Some of the data appears to be inconsistent (e.g. there is no difference in IgG between severe and non-severe in fig. 4, contradicting data in figure 3). These discrepancies are likely due to lower sample numbers.