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Cited by 498COVID-19 Clinical Research StudiesSARS-CoV-2 and COVID-19 ResearchLong-Term Effects of COVID-19

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The role of interleukin‐6 in monitoring severe case of coronavirus disease 2019

Open access
Liu, Tao, Zhang, Jieying, Yang, Yuhui, Ma, Hong, Li, Zhenyu, Zhang, Jiaoyue, Cheng, Ji, Zhang, Xiaoyun, Zhao, Yanxia, Xia, Zihan, Zhang, Liling, Wu, Gang, Yi, Jianhua·2020·EMBO Molecular Medicine
DOI 10.15252/emmm.202012421PMC PMC7280589

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Abstract

Progression to severe disease is a difficult problem in treating coronavirus disease 2019 (COVID‐19). The purpose of this study is to explore changes in markers of severe disease in COVID‐19 patients. Sixty‐nine severe COVID‐19 patients were included. Patients with severe disease showed significant lymphocytopenia. Elevated level of lactate dehydrogenase (LDH), C‐reactive protein (CRP), ferritin, and D‐dimer was found in most severe cases. Baseline interleukin‐6 (IL‐6) was found to be associated with COVID‐19 severity. Indeed, the significant increase of baseline IL‐6 was positively correlated with the maximal body temperature during hospitalization and with the increased baseline of CRP, LDH, ferritin, and D‐dimer. High baseline IL‐6 was also associated with more progressed chest computed tomography (CT) findings. Significant decrease in IL‐6 and improved CT assessment was found in patients during recovery, while IL‐6 was further increased in exacerbated patients. Collectively, our results suggest that the dynamic change in IL‐6 can be used as a marker for disease monitoring in patients with severe COVID‐19.

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Figure 1 Laboratory findings in severe versus non‐severe COVID‐19 patients ANeutrophils and lymphocytes count.BLevels of creatine kinase (CK) and creatinine.CLevels of procalcitonin (PCT) and C‐reactive protein (CRP).DLevels of erythrocyte sedimentation rate (ESR) and ferritin.ELevels of d‐dimer and lactate dehydrogenase (LDH).FProportion of total CD3+ and CD4+ T cells.GProportion of CD8+ T cells and CD4+/CD8+ T cell ratio.HProportion of B and natural killer (NK) cells.I–KCytokine profile of COVID‐19 patients for IL‐2, IL‐4 (I), IL‐6, IL‐10 (J), and TNF‐α and IFN‐γ (K).Data information: Statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test (A–D). Blue dotted lines denote normal value or normal range. Error bars, SEM.
Figure 1 Laboratory findings in severe versus non‐severe COVID‐19 patients ANeutrophils and lymphocytes count.BLevels of creatine kinase (CK) and creatinine.CLevels of procalcitonin (PCT) and C‐reactive protein (CRP).DLevels of erythrocyte sedimentation rate (ESR) and ferritin.ELevels of d‐dimer and lactate dehydrogenase (LDH).FProportion of total CD3+ and CD4+ T cells.GProportion of CD8+ T cells and CD4+/CD8+ T cell ratio.HProportion of B and natural killer (NK) cells.I–KCytokine profile of COVID‐19 patients for IL‐2, IL‐4 (I), IL‐6, IL‐10 (J), and TNF‐α and IFN‐γ (K).Data information: Statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test (A–D). Blue dotted lines denote normal value or normal range. Error bars, SEM.CC BY · PubMed Central
Figure 2 Time to different type of events in severe versus non‐severe COVID‐19 patients ATime from symptom onset to initial diagnosis (TFSD).BTime from symptom onset to development of pneumonia (TFSP).CTime from symptom onset to treatment (TFST).DTime from development of pneumonia to recovery (TFPR).Data information: Statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test (A–D). Error bars, SEM.Source data are available online for this figure.
Figure 2 Time to different type of events in severe versus non‐severe COVID‐19 patients ATime from symptom onset to initial diagnosis (TFSD).BTime from symptom onset to development of pneumonia (TFSP).CTime from symptom onset to treatment (TFST).DTime from development of pneumonia to recovery (TFPR).Data information: Statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test (A–D). Error bars, SEM.Source data are available online for this figure.CC BY · PubMed Central
Figure 3 Correlation between baseline IL‐6 level and clinical and laboratory characteristics of severe COVID‐19 patients ACorrelation between IL‐6 and maximal body temperature during hospitalization.BCorrelation between IL‐6 and C‐reactive protein (CRP).CCorrelation between IL‐6 and lactate dehydrogenase (LDH).DCorrelation between IL‐6 and d‐dimer.ECorrelation between IL‐6 and ferritin.FLevels of baseline IL‐6 in patients who received glucocorticoids, human immunoglobulin, high‐flow oxygen inhalation, or mechanical ventilation during hospitalization versus patients who did not. Error bars, SEM.Data information: In (A–E), data were not normally distributed, and correlation was tested by Spearman correlation. In (F), statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test.
Figure 3 Correlation between baseline IL‐6 level and clinical and laboratory characteristics of severe COVID‐19 patients ACorrelation between IL‐6 and maximal body temperature during hospitalization.BCorrelation between IL‐6 and C‐reactive protein (CRP).CCorrelation between IL‐6 and lactate dehydrogenase (LDH).DCorrelation between IL‐6 and d‐dimer.ECorrelation between IL‐6 and ferritin.FLevels of baseline IL‐6 in patients who received glucocorticoids, human immunoglobulin, high‐flow oxygen inhalation, or mechanical ventilation during hospitalization versus patients who did not. Error bars, SEM.Data information: In (A–E), data were not normally distributed, and correlation was tested by Spearman correlation. In (F), statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test.CC BY · PubMed Central
Figure 4 Variation in IL‐6 level and radiological findings in severe COVID‐19 patients during disease course AIL‐6 levels before and after treatment in three patient groups classified according to baseline IL‐6 levels of ≥ 40 pg/ml (n = 11), ≥ 20 pg/ml (n = 6), or < 20 pg/ml (n = 9; left). Two representative chest computed tomography (CT) scans before and after treatment from each group (right).BIL‐6 levels at diagnosis and after disease progression in three exacerbated patients (left). Progressed radiological findings were recorded in two patients (right), while radiological assessment after treatment was not performed in the third patient due to poor general condition.CThe baseline IL‐6 level was 197.39 pg/ml in a 69‐year‐old female patient who showed high fever and dyspnea. IL‐6 decreased to 9.47 pg/ml after treatment (day 8), while the symptoms were not relieved. The C‐reactive protein (CRP) rebounded and procalcitonin (PCT) increased together with disease exacerbation. Follow‐up chest computed tomography (CT) assessment was not performed due to poor general condition, whereas chest X‐ray showed aggravated pneumonia. Follow‐up sputum culture confirmed the exacerbation was caused by bacterial infection.Data information: In (A), statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test. Blue dotted lines denote normal value or normal range.
Figure 4 Variation in IL‐6 level and radiological findings in severe COVID‐19 patients during disease course AIL‐6 levels before and after treatment in three patient groups classified according to baseline IL‐6 levels of ≥ 40 pg/ml (n = 11), ≥ 20 pg/ml (n = 6), or < 20 pg/ml (n = 9; left). Two representative chest computed tomography (CT) scans before and after treatment from each group (right).BIL‐6 levels at diagnosis and after disease progression in three exacerbated patients (left). Progressed radiological findings were recorded in two patients (right), while radiological assessment after treatment was not performed in the third patient due to poor general condition.CThe baseline IL‐6 level was 197.39 pg/ml in a 69‐year‐old female patient who showed high fever and dyspnea. IL‐6 decreased to 9.47 pg/ml after treatment (day 8), while the symptoms were not relieved. The C‐reactive protein (CRP) rebounded and procalcitonin (PCT) increased together with disease exacerbation. Follow‐up chest computed tomography (CT) assessment was not performed due to poor general condition, whereas chest X‐ray showed aggravated pneumonia. Follow‐up sputum culture confirmed the exacerbation was caused by bacterial infection.Data information: In (A), statistical analysis was performed by paired two‐tailed Mann–Whitney U‐test. Blue dotted lines denote normal value or normal range.CC BY · PubMed Central
Figure 5 A case of a 59‐year‐old male patient diagnosed as severe COVID‐19 on the fifth day from the onset of fever AThe chest computed tomography (CT) was normal 5 days after symptom onset. Disease aggravation was evidenced by progressed chest CT images 10 days after symptom onset displaying bilateral multiple patchy ground glass opacities. Disease alleviation was evidenced by improved chest CT images 25 days after symptom onset.BProcalcitonin (PCT) levels stayed within normal range throughout the course of disease.CLymphocyte count was normal 5 days after symptom onset, while firstly decreasing and then returning to normal range during the course of disease.D, EBoth abnormal C‐reactive protein (CRP) (D) and IL‐6 (E) were detected 5 days after symptom onset when the chest CT and lymphocyte count were still normal. In association with changes in chest CT scans, both CRP and IL‐6 further increased 10 days after symptom onset and returned to normal range 25 days after symptom onset.FThe body temperature was elevated when CRP and IL‐6 levels were rising, but returned to normal when CRP and IL‐6. Levels were declining.Data information: Blue dotted lines denote normal value or normal range.
Figure 5 A case of a 59‐year‐old male patient diagnosed as severe COVID‐19 on the fifth day from the onset of fever AThe chest computed tomography (CT) was normal 5 days after symptom onset. Disease aggravation was evidenced by progressed chest CT images 10 days after symptom onset displaying bilateral multiple patchy ground glass opacities. Disease alleviation was evidenced by improved chest CT images 25 days after symptom onset.BProcalcitonin (PCT) levels stayed within normal range throughout the course of disease.CLymphocyte count was normal 5 days after symptom onset, while firstly decreasing and then returning to normal range during the course of disease.D, EBoth abnormal C‐reactive protein (CRP) (D) and IL‐6 (E) were detected 5 days after symptom onset when the chest CT and lymphocyte count were still normal. In association with changes in chest CT scans, both CRP and IL‐6 further increased 10 days after symptom onset and returned to normal range 25 days after symptom onset.FThe body temperature was elevated when CRP and IL‐6 levels were rising, but returned to normal when CRP and IL‐6. Levels were declining.Data information: Blue dotted lines denote normal value or normal range.CC BY · PubMed Central

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Metadata

Authors
Liu, T., Zhang, J., Yang, Y., Ma, H., Li, Z., Zhang, J., Cheng, J., Zhang, X., Zhao, Y., Xia, Z., Zhang, L., Wu, G., & Yi, J.
Affiliations
  • Wuhan Union Hospital (CN)
  • Fudan University (CN)
Corresponding author
  • Zhang, Liling
  • Wu, Gang
  • Yi, Jianhua
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-06-05
Volume
12
Issue
7
Pages
e12421-e12421
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.202012421
PMC
PMC7280589
OpenAlex
W3025830962
Cited by
498
References
27
Citations by year
2026: 13 · 2025: 27 · 2024: 38 · 2023: 83 · 2022: 87 · 2021: 118 · 2020: 130
FWCI
13.69
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • The National Natural Science Foundation of China (81602696)
  • Fundamental Research Funds for Central Universities of the Central South University (2015QN190)
  • The National Science and Technology Major Project of China (2018ZX10302204‐002‐003)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Clinical Neurology › Long-Term Effects of COVID-19
Keywords
interleukin-6, severe COVID-19, disease severity markers, lymphopenia, lactate dehydrogenase, C-reactive protein, ferritin, D-dimer, chest CT findings, fever, disease surveillance, cytokine dynamics
MeSH terms
Betacoronavirus, COVID-19, SARS-CoV-2, Adult, Aged, Aged, 80 and over, Antiviral Agents, C-Reactive Protein, Female, Humans, Lymphopenia, Male, Middle Aged, Pneumonia, Viral, Severity of Illness Index, Tomography, X-Ray Computed, Biomarkers, Interleukin-6, Coronavirus Infections, Pandemics

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