key: cord-0996828-tsqni28d
authors: Hu, Zhigang; Li, Sijia; Song, Xinyu
title: Cytokine storm with rapidly elevated interleukin-6 indicates sudden death in patients with critical COVID-19
date: 2020-08-25
journal: Cytokine Growth Factor Rev
DOI: 10.1016/j.cytogfr.2020.08.001
sha: 09fef79bcc4d9ad7cb61d59531412f3f8303c745
doc_id: 996828
cord_uid: tsqni28d

nan

Few mild patients with coronavirus disease 2019(COVID-19) have the potential to suddenly deteriorate in the early stages of diseases and the process of recovery, meanwhile some critical patients may rapidly develop acute respiratory distress syndrome (ARDS), multiple-organ failure (MOF) or even death [1] . This phenomenon may be attributed to excessive immune response induced by cytokine storm manifested by elevated interleukin-6 (IL-6). In the current edition of Cytokine & Growth Factor Reviews, Sun and his colleagues detailed review the role of cytokine storm in the pathogenesis and progression of COVID-19 pneumonia and the current understanding of cytokine storm intervention in the early stages of COVID-19 pneumonia [2] . As an addition, we estimate its association between cytokine storm and sudden death in patients with critical COVID-19 in the hope that this will help clinicians better manage critical patients. Because case 14 rejected all examinations and treatments after hospital admission, we did not speculate his death cause. After light activity, case 4 suddenly occurred cardiopulmonary arrest and was speculated to be pulmonary embolism. In the remaining 17 patients, the major death cause was attributed to MOF (6) and respiratory failure (6), followed by cardiac arrest (3), septic shock (2). We found 11 patients with two tests of IL-6 during three days before death (Table 1 ). All 8 patients with rapid elevated IL-6 were associated with sudden death at 24 hours. Among the remaining 3 patients without significantly elevated IL-6, case 15 and case 16 were attributed to cardiac arrest secondary to refractory heart failure and case 8 was MOF.

In addition, case 12 with one test occurred high level of IL-6 before death (176ng ml).

In this retrospective study about fatal patients with critical COVID-19, we found significantly higher prevalence of lymphocytopenia and eosinophilopenia than mild patients. Persistent immunodepression manifested by lymphocytopenia and eosinophilopenia were identified to have a poor prognosis of COVID-19 [4] . More complications occurred in critical patients, including bacterial infection, myocardial damage, liver damage, and renal damage. In addition, the risk of thromboembolism secondary to SARS-CoV-2 infection also deserves our full attention. As above mentioned, death cause of case 4 was attributed to pulmonary embolism and 11 patients had elevated D-dimer. High prevalence (69%) of thromboembolic events still was presented in critical COVID-19 patients even though therapeutic anticoagulation [5] . Cardiac damage was another main concern in patients with critical COVID-19 [6] .

Our study harbored ten patients with abnormal manifestations of myocardial enzyme spectrum and three patients with cardiac arrest. Our study observed that cytokine storm manifested by rapidly elevated IL-6 in a short time maybe the main cause of sudden death. All 8 patients with cytokine storm died at 24 hours. SARS-CoV-2 infection seemingly have the ability to induce long-term cytokine storm. We performed corticosteroid, plasma exchange, COVID-19 convalescent plasma and tocilizumab to manage persistent cytokine storm of Case 17. Unfortunately, his death still was attributed to cytokine storm with rapidly elevated IL-6 (from 1824 pg/ml to 3276 pg/ml) at 37 days after admission. Case 18 died at 72 days after admission, who J o u r n a l P r e -p r o o f 6 also was associated with cytokine storm before death(IL-6 from 80.92 pg/ml to 936.5 pg/ml) . A recent study showed that SARS-CoV-2 infection not only impaired innate immune response [7] , but also induced persistently strong expression of chemokines and interleukins [8] . Even after the reduction of viral load and viral shedding, this strong cytokine storm still was presented [8] . Our study observed that case 17 still occurred cytokine storm after viral shedding (three negative SARS-CoV-2 testings and normal SARS-CoV-2 IgM and IgG). Tocilizumab, as anti-human IL-6 receptor monoclonal antibody, was observed to have the ability to immediately improve the clinical outcome in patients with severe and critical COVID-19 [9] .

In conclusion, our study showed that SARS-CoV-2 infection can induce long-term immunodepression and cytokine storm. Cytokine storm manifested by rapidly 

The pathogenesis and treatment of the `Cytokine Storm' in COVID-19

Cytokine storm intervention in the early stages of COVID-19 pneumonia

National Health Commission of the People's Republic of China. The notice of launching guideline on diagnosis and treatment of the novel coronavirus pneumonia (NCP)

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study

High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients

Antariksa, B. meta-analysis

COVID-19: immunopathology and its implications for therapy

Imbalanced host response to SARS-CoV-2 drives development of COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

We thank all our colleagues and expert groups from Fujian who helped us during the current study. We are also grateful to the many front-line medical staff for their dedication in the face of this outbreak, despite the potential threat to their own lives and the lives of their families.

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.