Dear editor,
We recently read the article by Grifoni et al. with great interest, which reported the diagnostic value of serum interleukin-6 (IL-6) level at admission for predicting severe COVID-19 progression and/or in-hospital mortality.1 The pathophysiology of COVID-19 is characterized by early direct viral invasion of lung alveolar epithelial cells and a late hyperinflammatory period caused by cytokine cascades, such as IL-6.2 In addition, Krebs von den Lungen-6 (KL-6) is a representative serum marker for alveolar damage.3 Therefore, we conducted a retrospective Cohort study evaluating the diagnostic value of serum KL-6 and IL-6 levels for predicting patient in-hospital mortality among critically ill patients with COVID-19-associated pneumonia.
Adult patients (≥ 18 years) with respiratory organ support, who were admitted to Samsung Changwon Hospital - a 760-bed tertiary teaching hospital, between January 2021 and March 2022 were included. Respiratory organ support was defined as mechanical ventilation or high-flow nasal cannula (FiO2 ≥ 0.3 with a flow rate ≥ 30 L/min). KL-6 and IL-6 measurements were recommended for COVID-19 patients; these biomarkers were measured at admission and weekly thereafter (Methods for tests were described in supplementary material). The objective of this study was to evaluate the association between mortality and serum KL-6/IL-6 in critically ill patients with COVID-19. In addition, subgroup analysis was performed for patients with ≥ 2 serial KL-6 and/or IL-6 measurements to analyze and compare trend changes in KL-6 or IL-6 levels measured at admission and one week after admission in deceased and survived patients. The study was approved by the Samsung Changwon Hospital Institutional Review Board (IRB number: SCMC 2022–06–016).
A total of 102 critically ill patients were included in this study (Supplementary Fig. 1). In-hospital mortality was 28.4% (29/102). In the deceased and survived groups, initial KL-6 level (median 345.1 U/mL (interquartile range 252.3–477.1) vs. 276.4 (211.4–435.2), P = 0.064)) and initial IL-6 level (106.0 pg/mL (24.9–340.8) vs. 50.1 (11.2–196.0)) tended to be higher in the deceased group without statistical significance. Meanwhile, peak KL-6 level (499.9 U/mL (344.3–1317.8) vs. 353.6 (248.1–577.4), P = 0.008)) and peak IL-6 level (178.5 pg/mL (75.6–457.5) vs. 67.4 (21.1–352)) were significantly higher in the deceased group. In addition, lower platelet count, higher serum lactate, and presence of AKI were more frequently observed in the deceased group (Supplementary Table 1). Before performing multivariable analysis, the following cut-off values for age and laboratory results were defined based on Youden index: 68 years, 1019.2 U/mL for peak KL-6, 101.5 pg/mL for peak IL-6, 222 K/µL for platelet count, and 2.2 mmol/L for serum lactate. In multivariate analysis, peak KL-6 ≥ 1019.2 U/mL was associated with mortality and showed the highest odds ratio (OR 14.19, 95% confidence interval (CI) 2.33–86.34, P = 0.004) (Table 1 ).
Table 1.
Predictors of mortality in critically ill COVID-19 patients.
| Univariate analysis |
Multivariate analysis |
|||
|---|---|---|---|---|
| OR (95% CI) | P-value | OR (95% CI) | P-value | |
| Age ≥ 68 years | 6.08 (1.92–19.22) | 0.002 | 31.85 (3.48–291.10) | 0.002 |
| Modified CCI per point | 1.15 (0.94–1.41) | 0.174 | ||
| Inotrope /vasopressor use | 9.63 (3.52–26.19) | < 0.001 | 8.88 (2.35–33.49) | 0.001 |
| Peak KL-6 ≥ 1019.2 (U/mL) | 9.07 (2.99–27.54) | < 0.001 | 14.19 (2.33–86.34) | 0.004 |
| Peak IL-6 ≥ 101.5 (pg/mL) | 5.01 (1.81–13.87) | 0.002 | ||
| Initial Platelet ≤ 222 (K/µL | 3.73 (1.36–10.23) | 0.011 | ||
| Initial Lactate ≥ 2.2 (mmol/L) | 4.78 (1.86–12.29) | 0.001 | 4.31 (1.07–17.44) | 0.040 |
| AKI | 3.08 (1.24–7.63) | 0.015 | ||
COVID-19, coronavirus disease-19; ECMO, extracorporeal membrane oxygenation; CCI, Charlson Comorbidity Index; KL-6, Krebs von den Lungen-6; IL-6, interleukin-6; AKI, acute kidney injury.
*Data from 97 patients with complete laboratory data (70 and 27 for survived and deceased patients, respectively).
In subgroup analysis, serum KL-6 level tended to be higher in the deceased group (345.1 U/mL (274.8–454.3) than in the survived group (276.4 (213.5–465.3)) at admission and was significantly higher one week after admission (763.1 U/mL (323.6–1154.1) and 353.0 (243.2–599.2), respectively). However, the magnitude of increase was higher in the deceased group than in the survived group (P = 0.001; Fig. 2A). When serum IL-6 level was compared in the deceased group (136.5 pg/mL (37.9–368.0)) and the survived group (52.7 (17.8–274.0)) at admission and one week after admission (33.8 pg/mL (12.6–232.3) and 17.5 (4.4–48.4), respectively), a decrease in IL-6 level was observed in the survived group. No tendency was observed in the deceased group. In addition, statistical difference was not found in increased or decreased tendency between the deceased and survived groups (P = 0.937) (Fig. 1 ).
Fig. 1.
Difference between serum KL-6 and IL-6 levels measured at admission and one week after admission.
(a) KL-6
KL‐6, Krebs von den Lungen‐6
*Serial data of KL-6 measurements from 25 to 65 deceased and survived patients, respectively.
(b) IL-6
IL-6, interleukin-6
*Serial data of IL-6 measurements from 24 to 59 deceased and survived patients, respectively.
Critically ill COVID-19 patients were described as experiencing sequential disease progression to three stages: early infection, pulmonary phase, and hyperinflammation phase.2 The hyperinflammation phase results from dysregulated host inflammatory response, and IL-6 is the representative disease marker during this period.4 In a meta-analysis, the diagnostic role of IL-6 in COVID-19 also showed that patients admitted to the intensive care unit had a higher IL-6 level (ratio of means = 3.24; 95% CI 2.54–4.14).4 The results in the present study are in agreement with the previous studies.
KL-6 is a specific marker in ILD for disease activity, prediction for progression, and mortality.5 This high-molecular-weight glycoprotein is mainly expressed on the surface of type II alveolar epithelial cells, and air-blood barrier disruption by inflammation enhances permeability to elevate KL-6 influx into the bloodstream.6 Therefore, elevated serum KL-6 level can be observed in all causes of inflammatory lung damage.7 In the present study, peak serum KL-6 level was higher in the deceased group compared with the survived group among critically ill patients. The serum KL-6 level cut-off value of 1019.2 U/mL for predicting mortality in this study was similar to other studies predicting poor outcomes among COVID-19 patients.8 Therefore, 1000 IU/mL might be an important level of serum KL-6 for predicting mortality in COVID-19 patients.
In the present study, both serum peak KL-6 and IL-6 levels were higher in the deceased group than the survived group. However, the kinetics of these biomarkers differed. IL-6, an important biomarker for hyperinflammation, was frequently elevated at admission, and a decrease was not observed. KL-6, an important biomarker for inflammatory lung injury, was increased one week after admission. Therefore, this finding appeared to reflect the pathophysiology of critically ill patients with COVID-19.9 Therefore, serial measurement of these serum biomarkers is important to predict poor outcomes of critically-ill patients with COVID-19-associated pneumonia.
In conclusion, peak serum KL-6 and IL-6 levels were associated with mortality. In particular, KL-6 level of 1000 IU/mL could be an important cut-off value for predicting mortality in COVID-19 patients. Although KL-6, reflecting lung injury resulting from hyperinflammation, was more highly increased during serial measurement in the deceased group compared with the survived group, IL-6, reflecting hyperinflammation, was higher in the deceased group and often increased at admission but did not show significant change during serial measurements.
CRediT authorship contribution statement
Si-Ho Kim: Methodology, Visualization, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing. Hyun Kyu Cho: Data curation, Formal analysis, Investigation, Data curation, Writing – review & editing. Chun-Hoo Jeon: Data curation, Writing – review & editing. Hye Sung Ock: Methodology, Writing – review & editing. Beomsu Shin: Conceptualization, Methodology, Supervision, Writing – review & editing. Yu Mi Wi: Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgment
The authors thank Yi-Rang Jeong, who supported the image visualization of our study data.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jinf.2022.08.016.
Appendix. Supplementary materials
References
- 1.Grifoni E., Valoriani A., Cei F., Lamanna R., Gelli A.M.G., Ciambotti B., et al. Interleukin-6 as prognosticator in patients with COVID-19. J Infect. 2020;81:452–482. doi: 10.1016/j.jinf.2020.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Siddiqi H.K., Mehra M.R. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39:405–407. doi: 10.1016/j.healun.2020.03.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Choi M.G., Choi S.M., Lee J.H., Yoon J.K., Song J.W. Changes in blood Krebs von den Lungen-6 predict the mortality of patients with acute exacerbation of interstitial lung disease. Sci Rep. 2022;12:4916. doi: 10.1038/s41598-022-08965-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Coomes E.A., Haghbayan H. Interleukin-6 in Covid-19: a systematic review and meta-analysis. Rev Med Virol. 2020;30:1–9. doi: 10.1002/rmv.2141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kobayashi J., Kitamura S. KL-6: a serum marker for interstitial pneumonia. Chest. 1995;108:311–315. doi: 10.1378/chest.108.2.311. [DOI] [PubMed] [Google Scholar]
- 6.Zhang T., Shen P., Duan C., Gao L. KL-6 as an immunological biomarker predicts the severity, progression, acute exacerbation, and poor outcomes of interstitial lung disease: a systematic review and meta-analysis. Front Immunol. 2021;12 doi: 10.3389/fimmu.2021.745233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sato H., Callister M.E.J., Mumby S., Quinlan G.J., Welsh K.I., duBois R.M., et al. KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome. Eur Respir J. 2004;23:142–145. doi: 10.1183/09031936.03.00070303. [DOI] [PubMed] [Google Scholar]
- 8.Maruyama S., Nakamori Y., Nakano H., Tsuyumu K., Kanayama S., Iwamura H., et al. Peak value of serum KL-6 may be useful for predicting poor prognosis of severe COVID-19 patients. Eur J Med Res. 2022;27:69. doi: 10.1186/s40001-022-00690-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Datta S.D., Talwar A., Lee J.T. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324:2251–2252. doi: 10.1001/jama.2020.22717. [DOI] [PubMed] [Google Scholar]
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