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

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.

Keywords: biomarker; coronavirus disease 2019; cytokine storm; disease monitoring; interleukin-6.

Conflict of interest statement

The authors declare that they have no conflict of interest.

© 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Figures

Figure 1. Laboratory findings in severe versus non‐severe COVID‐19 patients

1. A

   Neutrophils and lymphocytes count.

2. B

   Levels of creatine kinase (CK) and creatinine.

3. C

   Levels of procalcitonin (PCT) and C‐reactive protein (CRP).

4. D

   Levels of erythrocyte sedimentation rate (ESR) and ferritin.

5. E

   Levels of d‐dimer and lactate dehydrogenase (LDH).

6. F

   Proportion of total CD3+ and CD4+ T cells.

7. G

   Proportion of CD8+ T cells and CD4+/CD8+ T cell ratio.

8. H

   Proportion of B and natural killer (NK) cells.

9. I–K

   Cytokine 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 2. Time to different type of events in severe versus non‐severe COVID‐19 patients

1. A

   Time from symptom onset to initial diagnosis (TFSD).

2. B

   Time from symptom onset to development of pneumonia (TFSP).

3. C

   Time from symptom onset to treatment (TFST).

4. D

   Time 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 3. Correlation between baseline IL‐6 level and clinical and laboratory characteristics of severe COVID‐19 patients

1. A

   Correlation between IL‐6 and maximal body temperature during hospitalization.

2. B

   Correlation between IL‐6 and C‐reactive protein (CRP).

3. C

   Correlation between IL‐6 and lactate dehydrogenase (LDH).

4. D

   Correlation between IL‐6 and d‐dimer.

5. E

   Correlation between IL‐6 and ferritin.

6. F

   Levels 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 4. Variation in IL‐6 level and radiological findings in severe COVID‐19 patients during disease course

1. A

   IL‐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).

2. B

   IL‐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.

3. C

   The 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 5. A case of a 59‐year‐old male patient diagnosed as severe COVID‐19 on the fifth day from the onset of fever

1. A

   The 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.

2. B

   Procalcitonin (PCT) levels stayed within normal range throughout the course of disease.

3. C

   Lymphocyte count was normal 5 days after symptom onset, while firstly decreasing and then returning to normal range during the course of disease.

4. D, E

   Both 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.

5. F

   The 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.