Corticosteroid for COVID-19: How to tackle the storm?

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Comprehensive data on the COVID-19 epidemic1,2 emphasizing the biology, epidemiology and public health implications and clinical characteristics3 and posit where things may be headed. Some key issues identified are defining susceptible population(s), transmissibility4, the threshold for seeking medical attention and discovery, treatment approach and case-fatality rate.

Living in one world, medical providers and scientists working in the midst of the battle have, appropriately, effected a comprehensive approach on many levels ranging from basic science, virology to public health measures and initiate trials of remdesivir inspired by its success to individual case through compassionate use principle.  However, when concerning the long waiting of evaluation and availability of novel drug worldwide, the current emergent need calls for more practical solutions in the real world practice. One important area of research, which has received little attention and potentially help with management, is host-related co-variates: why do only a fraction of exposed persons become infected5 and what host co-variates modulate infection severity?

The potential host immunity state, so far unstudied, may be one key answer to help understand and control COVID-19. Empiric treatment with corticosteroid on COVID-19, which was learned from SRAS-CoV management with two-sided effect, indicated some clinical benefit but lack of consensus guideline.  The genetic homology difference between SARS-CoV and COVID-19 may explain the different clinical features and make it not reasonable by simply repeating the usage of corticosteroid from SARS-CoV to COVID-19. Strikingly, one of the interesting disease feature of COVID-19 is that the respiratory symptom of patient usually present fairly mild at first, then at certain point it will suddenly get worse, which can happens in a few hours and leads to a relative high fatality rate.

This seems mediated by sudden and severe cytokine release syndrome (CRS) like occurs in some persons with leukaemias receiving chimeric antigen receptor (CAR) T-cells. Corticosteroids are mostly ineffective in this setting but tocilizumab are safe and appear beneficial, if given early before there is irreversible end-organ damage. Limited trials of this approach for COVID-19 are in progress. Should corticosteroids be given, when and for how long? Should our focus instead be on preventing or reversing CRS?  Theoretically, too early intervention of corticosteroid will suppress the T cell function and deteriorate virus impairment to organs.  Nor can it be too late because the patient could miss the chance from corticosteroid to survive from the acute respiratory distress syndrome (ARDS).

In order to understand the real world experience about the use of corticosteroid in coronavirus infection, we performed this systematic review and meta-analysis.  Corticosteroid use in subjects with SARS-CoV-2, SARS-CoV, MERS-CoV infections delayed virus clearing and did not convincingly improve survival reduce hospitalization duration or ICU admission rate and/or use of mechanical ventilation. However, because of a preponderance of observational studies in the dataset and selection and publication biases our conclusions, especially regarding SARS-CoV-2, need confirmation in randomized clinical trials.  In the interim we suggest caution using corticosteroids in persons with COVID-19. Our finding further consolidate the recommendations from National Institute of Health (NIH) COVID-19 treatment guideline regarding corticosteroid interventions.

To elucidate this, a model construction might be able to provide the foundation for the corticosteroid related clinical trial design.  It should include the analysis of the parameters of virus load, IgM and IgG titer, kurtosis of TCR, cytokine level, and flow test for observing T cell exhaustion, chest CT scan and CBC to correlate with clinical vital signs. Accordingly, a RCT of yes/no corticosteroids can be designed.

Written by Yang Liang(1), Huan Li(1,2), Chongxiang Chen(2,3), Fang Hu(1), Robert Peter Gale(4)

1Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China

2Department of ICU, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, 510060, China

3Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong Province, 510120, China;

4Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK

References

1.         Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med 2020.

2.         Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020.

3.         Chan JF-W, Yuan S, Kok K-H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. The Lancet 2020.

4.         Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 2020.

5.         Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020.


Yang Liang

Professor, Sun Yat-sen University Cancer Center

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