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. 2023 Mar 30;18(3):e0279897.
doi: 10.1371/journal.pone.0279897. eCollection 2023.

Validation of the severe COVID-19 prognostic value of serum IL-6, IFN-λ3, CCL17, and calprotectin considering the timing of clinical need for prediction

Kei Yamamoto  1 , Yusuke Ohsiro  2 , Tetsuya Suzuki  1 , Michiyo Suzuki  1 , Sayaka Miura  1 , Maki Nagashima  1 , Noriko Iwamoto  1 , Junko S Takeuchi  3 , Moto Kimura  3 , Wataru Sugiura  3 , Satoru Nebuya  4 , Masato Kurokawa  4 , Norio Ohmagari  1
Affiliations

Validation of the severe COVID-19 prognostic value of serum IL-6, IFN-λ3, CCL17, and calprotectin considering the timing of clinical need for prediction

Kei Yamamoto et al. PLoS One. .

Abstract

Although biomarkers to predict coronavirus disease 2019 (COVID-19) severity have been studied since the early pandemic, no clear guidelines on using them in clinical practice are available. Here, we examined the ability of four biomarkers to predict disease severity using conserved sera from COVID-19 patients who received inpatient care between January 1, 2020 and September 21, 2021 at the National Center for Global Health and Medicine, collected at the appropriate time for prediction. We predicted illness severity in two situations: 1) prediction of future oxygen administration for patients without oxygen support within 8 days of onset (Study 1) and 2) prediction of future mechanical ventilation support (excluding non-invasive positive pressure ventilation) or death of patients within 4 days of the start of oxygen administration (Study 2). Interleukin-6, IFN-λ3, thymus and activation-regulated chemokine, and calprotectin were measured retrospectively. Other laboratory and clinical information were collected from medical records. AUCs were calculated from ROC curves and compared for the predictive ability of the four biomarkers. Study 1 included 18 patients, five of whom had developed oxygen needs. Study 2 included 45 patients, 13 of whom required ventilator management or died. In Study 1, IFN-λ3 showed a good predictive ability with an AUC of 0.92 (95% CI 0.76-1.00). In Study 2, the AUC of each biomarker was 0.70-0.74. The number of biomarkers above the cutoff showed the possibility of good prediction with an AUC of 0.86 (95% CI 0.75-0.97). When two or more biomarkers were positive, sensitivity and specificity were 0.92 and 0.63, respectively. In terms of biomarker testing at times when prognostication may be clinically useful, IFN-λ3 was predictive of oxygenation demand and a combination of the four biomarkers was predictive of mechanical ventilator requirement.

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Conflict of interest statement

K.Y. received research grants from Sanyo Chemical Industries, Ltd. [no grant number] for the submitted work. S. N. and M. Kurokawa. are employees of Sanyo Chemical Industries, Ltd. K.Y. received research grants from Fujirebio, Inc., Mizuho Medy, Co., Ltd., VisGene, Co., Ltd., Canon medical systems Co., and CarbGeM Inc., and M. Kimura received research grants from SB Coronavirus Inspection Center Corp., Canon medical systems Co., and Ezaki Glico Co., Ltd., and W. S received research grants from SB Coronavirus Inspection Center Corp. and Nippon genetics Co., Ltd. outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. K. Y. and Sanyo Chemical Industries have a patent pending on the calprotectin assay. There are no additional patents, products in development or marketed products associated with this research to declare.

Figures

Fig 1
Fig 1. Natural history of COVID-19 and the point at which prediction is needed.
Fig 2
Fig 2. Clinical outcomes of eligible patients.
NC: nasal canula, NHFC: Nasal high-flow cannula, NPPV: Non-invasive positive pressure ventilation, ECMO: Extracorporeal membrane oxygenation.
Fig 3
Fig 3. Comparison of the predictive ability of biomarkers for disease severity in hospitalized individuals with a COVID-19 diagnosis.
A: Predictive ability for future oxygen administration in patients within 8 days after symptom onset, who did not require oxygen supply at the time of serum collection (Study 1). B: Predictive ability for future mechanical ventilation administration or death in patients with oxygen support except mechanical ventilation within 4 days after starting the oxygen supply (Study 2). C: Predictive ability for future oxygen support by a nasal high-flow cannula, non-invasive positive pressure ventilation, or mechanical ventilation in patients with oxygen support by a nasal canula or mask within 4 days after starting the oxygen supply (Study 2).
Fig 4
Fig 4. Predictive ability for mechanical ventilation administration or death in patients with oxygen support except mechanical ventilation within 4 days after starting the oxygen supply by the number of positive results of the four biomarkers (Study 2).
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Grants and funding

K.Y. received research grants from Sanyo Chemical Industries, Ltd. [no grant number] for the submitted work. S. N. and M. Kurokawa. are employees of Sanyo Chemical Industries, Ltd. K.Y. received research grants from Fujirebio, Inc., Mizuho Medy, Co., Ltd., VisGene, Co., Ltd., Canon medical systems Co., and CarbGeM Inc., and M. Kimura received research grants from SB Coronavirus Inspection Center Corp., Canon medical systems Co., and Ezaki Glico Co., Ltd., and W. S received research grants from SB Coronavirus Inspection Center Corp. and Nippon genetics Co., Ltd. outside the submitted work. Sanyo Chemical Industries, Ltd. had a role in the conduct of the research and preparation of the manuscript. The funders had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.