Discussion
The present study investigated the role of circulating SARS-CoV-2 NCP in COVID-19 with relation to antibody status, disease severity, time post diagnosis and inflammation markers. We show that high systemic concentrations of NCP antigen are a consistent feature of the early phase of hospitalized COVID-19 patients, independent of disease severity. Remarkably, NCP antigen clearance to levels below the detection threshold was impaired after the 8th day of disease in COVID-19 patients needing intensive care compared to non-ICU patients, suggesting a reduced systemic antigen clearance in severe disease.
Circulating NCP antigen is detected at higher concentrations in severely ill COVID19 patients [7, 9-11]. Our study identified a moderate but significant correlation between NCP antigenemia and CRP / IL-6 in ICU patients. Earlier investigations had observed an association of higher NCP antigenemia with CRP [6], IL-10, IP-10 and RAGE [10]. As a prognostic marker, NCP concentrations of >1000 pg/mL upon hospitalization were associated with later ICU admission and delayed hospital discharge [10, 12]. Our study now adds that clearance of NCP antigenemia is delayed in >40% of severely ill COVID19 patients who required intensive care. Thus, if NCP is detectable after 1 week of illness, a potentially severe course of disease is likely, emphasizing its role as a prognostic biomarker.
The biological basis of NCP antigenemia is still ill-defined. Plasma NCP antigenemia was found not to correlate with mucosal Ct values [8]. However, it is unresolved whether NCP antigen in plasma reflects ongoing systemic viral replication [12], or rather dissemination from the respiratory tract [10]. Our study is the first to show that prolonged antigenemia in ICU patients is associated with lower S1- but not NCP-specific IgG after 8 days post diagnosis. Reduced S1-specific antibodies could thus result in less efficient neutralization and permit systemic dissemination of virions.
Of note, the present study found that PCR results from nasopharyngeal swabs did not differ significantly between ICU and non-ICU patients, as also described by Yilmaz et al. [13]. In contrast, systemic NCP antigenemia could differentiate both groups, suggesting independent regulation of viral clearance from the mucosa and systemic clearance of viral antigen. Consequently, detection of systemic NCP antigen after 8 days post COVID-19 diagnosis identifies patients that progress to clinical deterioration requiring intensive care, while those who clear antigenemia after this time are likely to recover. Thus, prolonged antigenemia can serve as a novel biomarker to recognize severe courses of COVID-19 infection.