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. 2021 Aug 23:11:709893.
doi: 10.3389/fcimb.2021.709893. eCollection 2021.

Elevated Neopterin Levels Predict Fatal Outcome in SARS-CoV-2-Infected Patients

Manon Chauvin  1 , Martin Larsen  1 , Bibiana Quirant  2   3 , Paul Quentric  1 , Karim Dorgham  1 , Luca Royer  1 , Hélène Vallet  1   4 , Amelie Guihot  1   5 , Béhazine Combadière  1 , Christophe Combadière  1 , Jaume Barallat  6 , Julien Mayaux  7 , Charles-Edouard Luyt  8 , Alexis Mathian  1   9 , Zahir Amoura  1   9 , Jacques Boddaert  1   10 , Fernando Armestar  11   12 , Guy Gorochov  1   5 , Eva Martinez-Caceres  2   3 , Delphine Sauce  1
Affiliations

Elevated Neopterin Levels Predict Fatal Outcome in SARS-CoV-2-Infected Patients

Manon Chauvin et al. Front Cell Infect Microbiol. .

Abstract

Highlights: Innate immune activation during Covid-19 infection is associated with pernicious clinical outcome.

Background: Coronavirus disease 2019 (Covid-19) is a worldwide threat that has already caused more than 3 000 000 deaths. It is characterized by different patterns of disease evolution depending on host factors among which old-age and pre-existing comorbidities play a detrimental role. Previous coronavirus epidemics, notably SARS-CoV, were associated with increased serum neopterin levels, which can be interpreted as a sign of acute innate immunity in response to viral infection. Here we hypothesize that neopterin may serve as a biomarker of SARS-CoV-2 viral infection and Covid-19 disease severity.

Methods: We measured neopterin blood levels by ELISA. Seric concentration was quantified from 256 healthy donors and 374 Covid-19 patients at hospital admission. Enrolled Covid-19 patients were all symptomatic and displayed a large spectrum of comorbidities. Patients were followed until disease resolution or death.

Results: Severe and critically ill SARS-CoV-2 infected patients were characterized by a profound exacerbation of immune activation characterized by elevated neopterin blood levels. Systemic neopterin levels above 19nM stratified healthy individuals from Covid-19 patients with 87% specificity and 100% sensitivity. Moreover, systemic neopterin levels above 53nM differentiated non-survivors from survivors with 64% specificity and 100% sensitivity.

Conclusion: We propose that neopterin concentration measured at arrival to hospital is a hallmark of severe Covid-19 and identifies a high-risk population of pernicious clinical outcome with a need for special medical care.

Keywords: SARS-CoV-2; biomarker; clinical outcome; death; neopterin.

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Conflict of interest statement

ML and DS are inventors of patent EP20305794.8. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Discriminating parameters to segregate Covid-19 suffering patents from healthy individuals. (A) Principal component analysis (PCA) using serum neopterin and clinical variables on hospitalized patients. Red symbols represent deceased patients. Blue symbols represent patients who recovered within one month-follow-up (survivors). (B) Histograms depicting the contribution of individual PCA parameters with regards to the variance of principal component 1 (PC1).
Figure 2
Figure 2
Higher serum level of neopterin is associated with Covid-19 infection and fatal outcome. (A) Violin plot representing serum neopterin levels (in nM) stratified according to infectious status (CTRL (uninfected healthy donors, uninfected, in green); Covid-19 (SARS-CoV-2 infected individuals, in purple). Shape of dots represents country of inclusion of infected patients (Circles for France; Triangles for Spain). Dotted line shows the threshold (19nM) enabling the stratification of healthy vs infected patients. (B) Receiver Operating Characteristics (ROC) curve depicting sensitivity and specificity of prediction model for SARS-CoV-2 infection based on neopterin level. Grey zone represents confidence interval. AUC= 0.963; Specificity = 100%; Sensitivity= 87%; threshold = 19nM. (C) Violin plot representing serum neopterin levels (in nM) stratified according to clinical outcome (RECOVERY (survivors) or DEAD (non-survivors). Colors of dots represent country of inclusion of infected patients (Black circles for France; Orange circles for Spain). Dotted line shows the threshold (53nM) enabling the stratification of deceased vs survivors. (D) Receiver Operating Characteristics (ROC) curve depicting sensitivity and specificity of prediction model for fatal outcome based on neopterin level. Grey zone represents confidence interval. AUC = 0.94; Specificity = 100%; Sensitivity = 64%; threshold = 53nM.
Figure 3
Figure 3
Neopterin is a biomarker of fatal outcome in SARS-CoV-2 infected patients. (A) Time from symptoms onset to discharge (or death) was examined in this multi-centric study. Survival curves for Covid-19 patients with high (>53nm) or low (<53nM) serum concentration of neopterin at hospital admission. Kaplan-Meier estimator graph with log-rank based statistics. (B) Cox proportional hazard model was used to analyze the effect of confounders, such as age, sex, country, diabetes, obesity, hypertension, respiratory disease and cardiovascular disease. Proportional hazard ratios are indicated along with their 95% confidence intervals.
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