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Diagnostic Value of Nucleocapsid Protein in Blood for SARS-CoV-2 Infection

Updated: Sep 9, 2022

Editor: Jieli Shirley Li, MD, PhD, DABCC, NRCC, FCACB, Assistant Professor, Department of Pathology, The Ohio State University, Columbus, OH

Author: Jada (Yu) Zhang, MD, PhD, DABCC, NRCC, Assistant professor, University of Massachusetts Chan Medical School

Laboratory diagnostics play paramount roles in managing the ongoing COVID pandemic, including detecting infection, evaluating transmission risk, immune response, disease severity, and prognosis. Different biomarkers, including viral RNA, proteins, and antibodies, have been widely explored and implemented into clinical practice, which reveal different aspects and serve for different clinical indications. Dr. Zhang et al. has investigated blood nucleocapsid protein (N-Ag) for COVID diagnosis by evaluating its diagnostic sensitivity and specificity for active infection, its correlation with disease severity, and the kinetics of N-Ag and antibodies (Abs) during disease progression.

Compared to viral RNA tests in swabs, the diagnostic sensitivity and specificity of serum N-Ag reached 90.9% (95%CI, 85.1%-94.6%) and 98.3% (95%, 91.1-99.9%) within the first week of symptom onset. It became detectable as early as day two from symptom onset with a sensitivity of ~81.5%. Moreover, serum N-Ag concentration closely correlated with disease severity, reflected by the highest level of care, medical interventions, chest imaging, and the length of hospital stays. Longitudinal analysis revealed the simultaneous increase of Abs and decline of N-Ag.

Serum N-Ag may offer extra diagnostic value compared to viral RNA or Ag in the respiratory system. Although molecular tests were well accepted as the gold standard, the correlation of viral RNA with disease severity remains debated. Furthermore, viral RNA can be detected for weeks after recovery. With the correlation with disease severity and quick recovery, serum N-Ag facilitates us to use medical resources efficiently by avoiding unnecessary caution and treatment.

Additionally, serum N-Ag detected by immunoassays offers technical and practical advantages over molecular testing. It can be implemented on automated platforms in clinical laboratories and transformed into Point-of-care testing. Blood specimen collection circumvents viral RNA collection issues, such as uneven viral distribution in the respiratory system, inadequate sampling, or RNA instability. We can collect both Ag and Ab info from one specimen.

Dr. Zhang’s work was recently published in a special issue of Clinical Chemistry, which focused on "Controversies and Emerging Applications for the Diagnosis and Management of Infectious Diseases"[1]. In the same issue, Dr. Benjamin A Pinsky from Stanford University reported that plasma N-Ag exhibited comparable diagnostic performance to upper respiratory nucleic acid amplification testing, and the concentration of plasma N-Ag at diagnosis was associated with ICU admission[2]. These two independent works testified the diagnostic value of blood N-Ag for COVID. With the wide spread of SARS-CoV-2 in the last three years of pandemic, COVID severity becomes more concerned than infection, for which blood N-Ag has more diagnostic potential.


在当前的新冠大流行中, 实验室诊断起到了至关重要的作用,从检测感染,到评估传播风险、免疫反应、病情严重和预后。不同的标志物,包括病毒RNA、蛋白和抗体, 已经被充分的研发利用到临床实践中。 它们揭示了疾病的不同方面,有着不同的临床应用。 张博士对核衣壳蛋白在新型冠状病毒感染中的诊断价值做了深入研究,包括诊断的灵敏度和特异性,与病情严重程度的相关性,以及病程中抗原抗体的动态变化。

以拭子病毒RNA检测作为参照,血清中核衣壳蛋白 (N-Ag) 在出现症状的第一周内 对新冠的诊断灵敏度达到90.9% (95% 置信区间, 85.1%-94.6%) ,特异性达到98.3% (95% 置信区间, 91.1-99.9%)。 在出现症状的第二天,其灵敏度约81.5%。 而且,血清N-Ag 与疾病严重性呈现紧密的相关性。这种相关性在不同的评估方法中均有所体现,包括照护级别(无症状,有症状居家,住院,ICU治疗), 吸氧/呼吸机治疗,胸片/CT异常,住院时长。 对病人的长期跟踪研究表明抗原的减少伴随抗体的增加同时发生。

跟呼吸系统的病毒RNA和抗原相比,血液系统中的N-Ag提供了额外的诊断价值。 尽管分子检测病毒RNA作为金标准被广为接受,病毒RNA载量跟疾病严重性相关度仍很大争议。而且,病毒RNA在病情恢复数周后仍可检测到。 血清N-Ag跟病情严重紧密相关而且恢复期可快速下降, 这些可以辅助我们避免不必要的防范和治疗从而更有效地利用医疗资源。

在技术上和实践上,免疫方法检测血清N-Ag与RNA分子诊断相比也有着一定优势。 免疫方法可以应用到临检实验室的自动化平台,也可以被转化到POCT。 血样的采集避免了呼吸系统病毒RNA采集的一些问题,包括病毒分布不均,采样不充分,以及RNA的不稳定性。此外,一份血样可以同时检测血液中抗原抗体的浓度。

张博士的这项工作近期发表在Clinical Chemistry 一期题为 “感染性疾病诊断管理中的争议和新应用”的专刊中。在该专刊中,来自斯坦福大学的Pinsky博士也报道了血浆N-Ag跟上呼吸系统核酸扩增实验有相当的诊断表现,而且其浓度跟ICU收治呈相关性。 这两项独立工作验证了血液系统中N-Ag对COVID的诊断价值。 随着SARS-CoV-2在过去近三年内的广泛传播,跟感染与否相比,如何评估COVID病情的严重性吸引了更多关注,对此血液N-Ag具有更多诊断潜力。


1. Zhang, Y., et al., Diagnostic Value of Nucleocapsid Protein in Blood for SARS-CoV-2 Infection. Clin Chem, 2021. 68(1): p. 240-248.

2. Wang, H., et al., SARS-CoV-2 Nucleocapsid Plasma Antigen for Diagnosis and Monitoring of COVID-19. Clin Chem, 2021. 68(1): p. 204-213.`

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