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Authors:Fanelli V., et. al 

Journal/ Pre-Print:Cell press Sneak peek  

TagsCell Biology, Clinical, Immunology/Immunity, Inflammation 

Research Highlights

  1. In critical COVID-19 patients undergoing extracorporeal membrane oxygenation (ECMO), there is no significant change in the abundance of lymphoid populations over the course of 3 weeks. 

  1. Levels of C-reactive protein, procalcitonin and ferritin are reduced 3 weeks after beginning ECMO. 

  1. Treatment of ECMO with  tocilizumab (anti-IL-6) and steroids may reduce lymphocyte counts, ferritin and inflammatory markers.   Caution is advised in the interpretation until the authors clarify the size and sample acquisition of the treatment subgroups.  

Summary

  • The study analysed circulating immune cell counts, as well as inflammatory and fibrinolytic biomarkers levels in 13 critical COVID-19 patients over 3 weeks after beginning ECMO. The patient cohort is heterogenous for underlying comorbidities and treatment, including antiviralstocilizumab or steroid therapies. No clinical outcomes are reported, moreover 11/13 patients acquired bacterial superinfections most likely nosocomial.  It is not clear how this impacted the immunological findings. While ECMO is known to reduce lymphocyte counts, no further reduction was observed in these presumably already lymphopenic patients. While C-reactive protein, procalcitonin and ferritin were reduced by day 28, but not D-Dimers.  The patient samples are stratified according to treatment course, but it is unclear when samples are taken.  The data suggests that patients receiving tocilizumab and steroids had lower lymphocyte counts and lower CRP PCT, ferritin and D-dimer levels. 

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19  

Treat of SARS-CoV2/COVID19 positive individuals 

Study Type  

  • Clinical Cohort study   

Strengths and limitations of the paper 

Novelty: Profiling of COVID-19 patients specifically undergoing ECMOOnly a small portion of critical patients will receive ECMO, but data is valuable to understand the impact of this approach.    

Standing in the field:The authors explore the use of tocilizumab and steroids as a way to reduce inflammation in COVID-19 patients, but the reduction in lymphocyte counts (showed in this study) is usually associated with worst COVID-19 prognosis. Immunosuppression might be particularly bad for patients in ECMO that are extremely prone to superinfections. 

Appropriate statistics: Yes, although weak considering all the comparisons done.  The group sizes should be made clear in the figures, particularly when comparing treatments (Fig 3 and 4).  For transparency, it would be beneficial to see the individual data points in addition to the descriptive statistics. 

Viral model used:SARS-CoV-2 infected patients in Turin, Italy from 1st March to 30th April 2020. 

Translatability:Tocilizumab and steroids are being used in the clinic and investigated by clinical trialsECMO can be used as a last resort in suitable patients.  

Main limitations:  

  • The study is too small to draw any significant conclusionsThe cohort is also heterogeneous for comorbidities, bacterial infection and medical treatments.    

  • The study does not well describe the impact/onset/severity/treatment of bacterial infection and sepsis, which would impact the inflammatory and immunological data.  Did the clinicians withdraw steroids and anti-IL-6 during sepsis?  Authors observed low PCT despite the occurrence of sepsis and this is not commented on. 

  • It is not clear for how long the patients had undergone tocilizumab or steroid therapy before the analysis was done.  It is not clear how patients were allocated into treatment groups or no treatment.  It is also implied that patient treatments changed over the course of the study, but it is not specified how these samples were allocated in the analysis of treatment subgroups (figure 3 and 4). The number of samples in each group should be stated. 

  • It is not clear how the immune cells were counted (missing from the methods). Possibly as routine bloods were withdrawn. 

  • It is not stated which antivirals were used. 

  • There is no comparison with the alternate standard of care (mechanical ventilation) or reference to baseline healthy values for the measurements taken.  Neither is there a measurement taken before ECMO, so it is unclear if any changes observed are inflicted by ECMO. 

  • No clinical outcomes or changes in viral load are stated, so there is no context on the benefit vs risk of ECMO, steroids, antivirals or tocilizumab.  This removes value from the research.