The Value of Interleukin-6 among Several Inflammatory Markers as a Predictor of Respiratory Failure in COVID-19 Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Study Design
2.2. Laboratory Analysis of Blood Specimens
2.3. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Laboratory Markers in COVID-19 Patients with Respiratory Failure
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
- Poggiali, E.; Zaino, D.; Immovilli, P.; Rovero, L.; Losi, G.; Dacrema, A.; Nuccetelli, M.; Vadacca, G.B.; Guidetti, D.; Vercelli, A.; et al. Lactate dehydrogenase and C-reactive protein as predictors of respiratory failure in COVID-19 patients. Clin. Chim. Acta 2020, 509, 135–138. [Google Scholar] [CrossRef] [PubMed]
- Ponti, G.; Maccaferri, M.; Ruini, C.; Tomasi, A.; Ozben, T. Biomarkers associated with COVID-19 disease progression. Crit. Rev. Clin. Lab. Sci. 2020, 398–399. [Google Scholar] [CrossRef]
- Han, H.; Ma, Q.; Li, C.; Liu, R.; Zhao, L.; Wang, W.; Zhang, P.; Liu, X.; Gao, G.; Liu, F.; et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microbes Infect. 2020, 9, 1123–1130. [Google Scholar] [CrossRef] [PubMed]
- Terpos, E.; Ntanasis-Stathopoulos, I.; Elalamy, I.; Kastritis, E.; Sergentanis, T.N.; Politou, M.; Psaltopoulou, T.; Gerotziafas, G.; Dimopoulos, M.A. Hematological findings and complications of COVID-19. Am. J. Hematol. 2020, 95, 834–847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sharma, A. Inferring molecular mechanisms of dexamethasone therapy in severe COVID-19 from existing transcriptomic data. Gene 2021, 788, 145665. [Google Scholar] [CrossRef] [PubMed]
- Luo, P.; Liu, Y.; Qiu, L.; Liu, X.; Liu, D.; Li, J. Tocilizumab treatment in COVID-19: A single center experience. J. Med. Virol. 2020, 92, 814–818. [Google Scholar] [CrossRef] [PubMed]
- Herold, T.; Jurinovic, V.; Arnreich, C.; Lipworth, B.J.; Hellmuth, J.C.; von Bergwelt-Baildon, M.; Klein, M.; Weinberger, T. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J. Allergy Clin. Immunol. 2020, 146, 128–136.e4. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Z.; Cai, T.; Fan, L.; Lou, K.; Hua, X.; Huang, Z.; Gao, G. Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int. J. Infect. Dis. 2020, 95, 332–339. [Google Scholar] [CrossRef] [PubMed]
- Liu, F.; Li, L.; Xu, M.; Wu, J.; Luo, D.; Zhu, Y.; Li, B.; Song, X. Prognostic value of IL-6, CRP, and PCT in patients with COVID-19. J Clin Virol. 2020, 127, 104370. [Google Scholar] [CrossRef] [PubMed]
- Hu, B.; Huang, S.; Yin, L. The cytokine storm and COVID-19. J. Med. Virol. 2021, 93, 250–256. [Google Scholar] [CrossRef] [PubMed]
- Paces, J.; Strizova, Z.; Smrz, D.; Cerny, J. COVID-19 and the Immune System. Physiol. Res. 2020, 9973, 379–388. [Google Scholar] [CrossRef] [PubMed]
- Jamilloux, Y.; Henry, T.; Belot, A.; Viel, S.; Fauter, M.; El, T.; Walzer, T.; François, B.; Sève, P. Should we suppress or stimulate immune responses for COVID-19. Autoimmun. Rev. 2020, 19, 102567. [Google Scholar] [CrossRef] [PubMed]
- Pasin, L.; Navalesi, P.; Zangrillo, A.; Kuzovlev, A.; Fresilli, S. Corticosteroids for Patients With Coronavirus Disease 2019 (COVID-19) With Different Disease Severity: A Meta-Analysis of Randomized Clinical Trials. J. Cardiothorac. Vasc. Anesth. 2020, 35, 578–584. [Google Scholar] [CrossRef] [PubMed]
- Mcgonagle, D.; Sharif, K.; Regan, A.O.; Bridgewood, C. The role of cytokines including IL-6 in COVID-19 induced pneumonia and MAS-like disease. Autoimmun. Rev. 2020, 19, 102537. [Google Scholar] [CrossRef] [PubMed]
- Nakamura, M.; Hitosugi, M. Emerging COVID-19-related deaths during home recuperation in Japan. Geriatr. Gerontol. Int. 2021, 3–4. [Google Scholar] [CrossRef]
Baseline Characteristics | Total (n = 81) | Maximum FiO2 ≥ 0.4 | p-Value | |
---|---|---|---|---|
Yes (n = 16) | No (n = 65) | |||
Mean age, y (±SD) | 62.0 ± 16.3 | 68.1 ± 13.9 | 60.6 ± 16.5 | 0.090 |
Male sex, n (%) | 50 (61.7%) | 12 (75.0%) | 38 (58.5%) | 0.260 |
Mean BMI, kg/m2 (±SD) | 25.0 ± 4.5 | 25.7 ± 4.4 | 24.9 ± 4.5 | 0.500 |
Any comorbidities, n (%) | 52 (64.2%) | 15 (93.8%) | 37 (56.9%) | 0.007 |
Hypertension, n (%) | 35 (43.2%) | 10 (62.5%) | 25 (38.5%) | 0.100 |
Coronary artery disease, n (%) | 8 (9.9%) | 2 (12.5%) | 6 (9.2%) | 0.650 |
Diabetes mellitus, n (%) | 18 (22.2%) | 5 (31.2%) | 13 (20.0%) | 0.330 |
Chronic obstructive pulmonary disease, n (%) | 7 (8.6%) | 2 (12.5%) | 5 (7.7%) | 0.620 |
Bronchial asthma, n (%) | 6 (7.4%) | 0 (0%) | 6 (9.2%) | 0.590 |
Sleep apnea syndrome, n (%) | 8 (9.9%) | 2 (12.5%) | 6 (9.2%) | 0.650 |
Chronic kidney disease, n (%) | 6 (7.4%) | 3 (18.8%) | 3 (4.6%) | 0.088 |
Bacterial superinfection, n (%) | 2 (2.5%) | 1 (6.2%) | 1 (1.5%) | 0.360 |
Laboratory parameters | ||||
Median IL-6 level, pg/mL (IQR) | 24.5 (13.3–51.9) | 93.8 (52.4–121.5) | 18.0 (9.6–37.3) | <0.001 |
Median CRP level, mg/dL (IQR) | 3.0 (1.1–7.9) | 8.7 (7.0–12.1) | 2.3 (0.9–5.7) | <0.001 |
Median LDH level, IU/L (IQR) | 249 (203–329) | 335 (285–484) | 236 (193–300) | <0.001 |
Median WBC count, ×103/mm3 (IQR) | 5.6 (4.2–7.8) | 8.3 (5.3–11.2) | 5.1 (3.9–7.3) | 0.003 |
Median D-dimer level, μg/mL (IQR) | 0.7 (0.2–1.4) | 0.9 (0.8–2.0) | 0.5 (0.2–1.4) | 0.048 |
Median Cr level, mg/dL (IQR) | 0.8 (0.7–1.1) | 1.1 (0.9–1.1) | 0.8 (0.7–1.1) | 0.027 |
Treatments | ||||
Invasive mechanical ventilation, n (%) | 14 (17.3%) | 13 (81.2%) | 1 (1.5%) | <0.001 |
Supplemental oxygen, n (%) | 25 (30.9%) | 3 (18.8%) | 22 (33.8%) | 0.370 |
Dexamethasone, n (%) | 63 (77.8%) | 16 (100%) | 47 (72.3%) | 0.017 |
Favipiravir, n (%) | 53 (65.4%) | 9 (56.2%) | 44 (67.7%) | 0.400 |
Median time from symptom onset to admission, days (IQR) | 4 (2–7) | 7 (5–7) | 4 (2–6) | 0.020 |
Median time from symptom onset to the first measurement of blood samples, days (IQR) | 6 (4–9) | 7 (6–10) | 5 (3–9) | 0.030 |
Prognosis | ||||
Survivors, n (%) | 76 (93.8%) | 13 (81.2%) | 63 (96.9%) | 0.050 |
Non-survivors, n (%) | 5 (6.2%) | 3 (18.8%) | 2 (3.1%) |
Preceding Dexamethasone Maximum FiO2 ≥ 0.4 | p-Value | Following Dexamethasone Maximum FiO2 ≥ 0.4 | p-Value | |||
---|---|---|---|---|---|---|
Yes (n = 10) | No (n = 18) | Yes (n = 6) | No (n = 29) | |||
Median IL-6 level, pg/mL (IQR) | 97.3 (58.1–144.0) | 13.6 (4.9–27.3) | <0.001 | 79.2 (48.5–106.5) | 31.7 (17.2–45.0) | 0.054 |
Median CRP level, mg/dL (IQR) | 7.4 (6.8–12.5) | 2.7 (1.6–7.4) | 0.018 | 9.9 (8.3–11.4) | 3.0 (1.1–5.7) | 0.023 |
Median LDH level, IU/L (IQR) | 325 (263–455) | 267 (210–349) | 0.084 | 408 (301–585) | 234 (199–270) | 0.003 |
Median WBC count, ×103/mm3 (IQR) | 10.5 (6.1–12.6) | 7.5 (6.4–9.9) | 0.204 | 6.2 (4.7–8.3) | 4.9 (4.0–6.3) | 0.220 |
Median D-dimer level, μg/mL (IQR) | 1.0 (0.8–2.9) | 1.1 (0.4–1.8) | 0.360 | 0.8 (0.4–1.0) | 0.3 (0.1–1.2) | 0.342 |
Median Cr level, mg/dL (IQR) | 1.0 (0.8–1.1) | 0.8 (0.8–1.1) | 0.401 | 1.1 (1.1–1.2) | 0.9 (0.7–1.1) | 0.069 |
Invasive mechanical ventilation, n (%) | 7 (70.0%) | 0 (0.0%) | <0.001 | 6 (100%) | 1 (3.4%) | <0.001 |
Supplemental oxygen, n (%) | 3 (30.0%) | 11 (61.1%) | 0.236 | 0 (0.0%) | 10 (34.5%) | 0.152 |
Median time from onset to dexamethasone, days (IQR) | 3.5 (2.0–5.0) | 5.5 (3.0–10.0) | 0.111 | 6.5 (6.0–8.5) | 7.0 (5.0–8.0) | 0.581 |
Variable | AUC (CI) | p-Value | Cutoff | Sensitivity (%) (CI) | Specificity (%) (CI) | PPV (%) (CI) | NPV (%) (CI) |
---|---|---|---|---|---|---|---|
IL-6 level (pg/mL) | 0.85 (0.74–0.97) | <0.001 | 43.9 | 87.5 (61.7–98.4) | 81.5 (70.0–90.1) | 53.8 (33.4–73.4) | 96.4 (87.5–99.6) |
CRP level (mg/dL) | 0.82 (0.71–0.92) | <0.001 | 5.7 | 87.5 (61.7–98.4) | 73.8 (61.5–84.0) | 45.2 (27.3–64.0) | 96.0 (86.3–99.5) |
LDH level (IU/L) | 0.81 (0.70–0.92) | <0.001 | 268 | 81.2 (54.4–96.0) | 69.2 (56.6–80.1) | 39.4 (22.9–57.9) | 93.8 (82.8–98.7) |
WBC count (×103/mm3) | 0.74 (0.61–0.87) | <0.001 | 7.8 | 56.2 (29.9–80.2) | 81.5 (70.0–90.1) | 42.9 (21.8–66.0) | 88.3 (77.4–95.2) |
D-dimer level (μg/mL) | 0.66 (0.52–0.80) | 0.023 | 0.7 | 81.2 (54.4–96.0) | 58.5 (45.6–70.6) | 32.5 (18.6–49.1) | 92.7 (80.1–98.5) |
Cr level (mg/dL) | 0.68 (0.54–0.82) | 0.012 | 0.9 | 66.7 (41.0–86.7) | 58.5 (45.6–70.6) | 30.8 (17.0–47.6) | 86.4 (72.6–94.8) |
Whole | Preceding Dexamethasone | Followed Dexamethasone | ||||
---|---|---|---|---|---|---|
Variable | Crude OR (CI) | p-Value | Adjusted OR (CI) | p-Value | Adjusted OR (CI) | p-Value |
IL-6 | 29.1 (5.6–295.6) | <0.001 | 53.9 (4.5–3242.8) | <0.001 | 12.1 (1.1–646.6) | 0.019 |
CRP | 18.9 (3.8–188.4) | <0.001 | 16.1 (1.6–847.9) | 0.006 | 12.1 (1.1–646.6) | 0.019 |
LDH | 9.5 (2.3–57.4) | <0.001 | 2.3 (0.4–18.0) | 0.434 | ∞ (2.3–∞) | <0.001 |
WBC | 5.5 (1.5–21.5) | 0.004 | 2.8 (0.4–22.5) | 0.254 | 4.1 (0.3–50.0) | 0.195 |
D-dimer | 6.0 (1.5–35.8) | 0.005 | 5.4 (0.5–285.8) | 0.194 | 3.6 (0.4–47.0) | 0.191 |
Cr | 2.8 (0.8–10.2) | 0.068 | 4.4 (0.7–36.5) | 0.114 | 3.4 (0.32–180.4) | 0.377 |
Variable | Cutoff | Sensitivity (%) (CI) | Specificity (%) (CI) | PPV (%) (CI) | NPV (%) (CI) |
---|---|---|---|---|---|
IL-6 level (pg/mL) | 91.5 | 56.2 (29.9–80.2) | 95.4 (87.1–99.0) | 75.0 (42.8–94.5) | 89.9 (80.2–95.8) |
CRP level (mg/dL) | 6.7 | 81.2 (54.4–96.0) | 80.0 (68.2–88.9) | 50.0 (29.9–70.1) | 94.5 (84.9–98.9) |
LDH level (IU/L) | 305 | 68.8 (41.3–89.0) | 76.9 (64.8–86.5) | 42.3 (23.4–63.1) | 90.0 (80.0–97.0) |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Fujino, M.; Ishii, M.; Taniguchi, T.; Chiba, H.; Kimata, M.; Hitosugi, M. The Value of Interleukin-6 among Several Inflammatory Markers as a Predictor of Respiratory Failure in COVID-19 Patients. Diagnostics 2021, 11, 1327. https://doi.org/10.3390/diagnostics11081327
Fujino M, Ishii M, Taniguchi T, Chiba H, Kimata M, Hitosugi M. The Value of Interleukin-6 among Several Inflammatory Markers as a Predictor of Respiratory Failure in COVID-19 Patients. Diagnostics. 2021; 11(8):1327. https://doi.org/10.3390/diagnostics11081327
Chicago/Turabian StyleFujino, Mitsuhiro, Michiyo Ishii, Takuya Taniguchi, Hiroya Chiba, Masaki Kimata, and Masahito Hitosugi. 2021. "The Value of Interleukin-6 among Several Inflammatory Markers as a Predictor of Respiratory Failure in COVID-19 Patients" Diagnostics 11, no. 8: 1327. https://doi.org/10.3390/diagnostics11081327