A PTX3/LDH/CRP signature correlates with lung injury CTs scan severity and disease progression in paucisymptomatic COVID-19
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Abstract
Background
Quantitative CT (QCT) analysis is an invaluable diagnostic tool to assess lung injury and predict prognosis of patients affected by COVID-19 pneumonia. PTX3 was recently described as one of the most reliable serological predictors of clinical deterioration and short-term mortality. The present study was designed to evaluate a correlation between serological biomarkers of inflammation and lung injury measured by QCT.
Methods
This retrospective monocentric study analysed a cohort of patients diagnosed with COVID-19 and admitted because of respiratory failure, or significant radiological involvement on chest CT scan. All patients, males and non-pregnant females older than 18 years, underwent chest CT scan and laboratory testing at admission. Exclusion criteria were defined by concurrent acute pathological processes and ongoing specific treatments which could interfere with immune activity. The cohort was stratified based on severity in mild and severe forms. Compromised lung at QCT was then correlated to serological biomarkers representative of SARS-CoV-2. We further developed a multivariable logistic model to predict CT data and clinical deterioration based on a specific molecular signature. Internal cross-validation led to evaluate discrimination, calibration, and clinical utility of the tool that was provided by a score to simplify its application.
Findings
592 patients were recruited between March 19th and December 1st, 2020. Applying exclusion criteria which consider confounders, the cohort resulted in 366 individuals characterized by 177 mild and 189 severe forms. In our predictive model, blood levels of PTX3, CRP and LDH were found to correlate with QCT values in mild COVID-19 disease. A signature of these three biomarkers had a high predictive accuracy in detecting compromised lungs as assessed by QCT. The score was elaborated and resulted representative of lung CT damage leading to clinical deterioration and oxygen need in mild disease.
Interpretation
The LDH, PTX3, CRP blood signature can serve as a strong correlate of compromised lung in COVID-19, possibly integrating cellular damage, systemic inflammation, myeloid and endothelial cell activation.
Funding
This work was supported by a philanthropic donation by Dolce & Gabbana fashion house (to A.M., C.G.) and by a grant from Italian Ministry of Health for COVID-19 (to A.M. and C.G.).
Research in context
Evidence before this study
Besides nasopharyngeal swab and serological test, chest CT scan represents one of the most useful tools to confirm COVID-19 diagnosis; moreover, QCT has been demonstrated to foresee oxygen need as well as deterioration of health status. Several clinical and serological parameters have been studied alone or combined in scores to be applied as prognostic tools of SARS-CoV-2 pneumonia; however, no one has yet reached the everyday practice. Recently, our group has investigated the expression and clinical significance of PTX3 in COVID-19 demonstrating the correlation with short-term mortality independently of confounders. The result was confirmed by other studies in different settings increasing evidence of PTX3 as a strong biomarker of severity; noteworthy, a recent report analysed proteomic data with a machine learning approach identifying age with PTX3 or SARS-CoV-2 RNAemia as the best binary signatures associated to 28-days mortality.
Added value of this study
The present study was designed to investigate associations between markers of damage and the CT extension of SARS-CoV-2 pneumonia in order to provide a biological footprint of radiological results in paucisymptomatic patients. QCT data were considered in a binary form identifying a threshold relevant for clinical deterioration, as already proved by literature. Our findings demonstrate a significant correlation with three peripheral blood proteins (PTX3, LDH and CRP) which result representative of COVID-19 severity. The study presents a predictive model of radiological lung involvement which performs with a high level of accuracy (cvAUC of 0·794±0·107; CI 95%: 0·74–0·87) and a simple score was provided to simplify the interpretation of the three biomarkers. Besides additional finding on PTX3 role in SARS-CoV2 pathology, its prognostic value was confirmed by data on clinical deterioration; indeed, paucisymptomatic subjects showed a 11·9% deaths. The model offers the possibility to quickly assess patients resulted positive for SARS-CoV-2 and estimate people at risk of deterioration despite normal clinical and blood gases analysis, with potential to identify those who need better clinical monitoring and interventions.
Implications of all the available evidence
Predicting the extension, severity, and clinical deterioration in COVID-19 patients its pivotal to allocate enough resources in emergency and to avoid health system burden. Despite the urgent clinical need of biomarkers, SARS-CoV-2 pneumonia still lacks something able to provide an easy measure of its severity. Some multiparametric scores have been proposed for severe COVID-19 and rely on deep assessment of patients status (clinical, serological, and radiological data). Our model represents an unprecedented effort to provide a tool which could predict CT pneumonia extension, oxygen requirement and clinical deterioration in mild COVID-19. Based on the measurement of three proteins on peripheral blood, this score could improve early assessment of asymptomatic patients tested positive by SARS-CoV2 specifically in first level hospitals as well in developing countries.
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SciScore for 10.1101/2021.09.29.21264061: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was evaluated by the Ethics Committee of the IRCCS Istituto Clinico Humanitas (independent organization with registered office in Rozzano, Milan-Italy).
Consent: The Independent Ethics Committee approved the study (authorization 233/20) and the requirement for informed consent was waived.Sex as a biological variable We included all males and non-pregnant females, 18 years of age or older, admitted to Humanitas Clinical and Research Center (Rozzano, Milan, Italy) between March 19th and December 1st, 2020 with a laboratory-confirmed diagnosis of COVID-19. Randomization not detected. Blinding PTX3 plasma levels were measured, as previously described, by a sandwich ELISA (detection … SciScore for 10.1101/2021.09.29.21264061: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was evaluated by the Ethics Committee of the IRCCS Istituto Clinico Humanitas (independent organization with registered office in Rozzano, Milan-Italy).
Consent: The Independent Ethics Committee approved the study (authorization 233/20) and the requirement for informed consent was waived.Sex as a biological variable We included all males and non-pregnant females, 18 years of age or older, admitted to Humanitas Clinical and Research Center (Rozzano, Milan, Italy) between March 19th and December 1st, 2020 with a laboratory-confirmed diagnosis of COVID-19. Randomization not detected. Blinding PTX3 plasma levels were measured, as previously described, by a sandwich ELISA (detection limit 0·1 ng/mL, inter-assay variability from 8 to 10%) developed in-house, by personnel blind to patients’ characteristics.18 In each analytical session a sample obtained from a pool of plasma from healthy donors was used as internal control. Power Analysis We compute the cvAUC with its 95% CI to measure the predictive power of our prognostic index. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The present study has limitations. It is retrospective and single-centre and needs to be extended on a large scale to be validated. Moreover, the significant association was defined in a selected population of paucisymptomatic patients at admission, but we missed the follow up during the hospitalization because of the lack of standardized time in lung CT. It will therefore be important to confirm the value with external cohorts of patients considering time and data for the radiologic follow-up. The rapid dissemination of SARS-CoV-2 globally and the outbreak of new viral variants compels the evolution of new tools to approach evolving clinical and social needs. Even though the start of vaccination, the spread of the virus remains high as demonstrated by the growing pandemic which counts more than 200 million of people infected worldwide with 4 million of deaths (WHO report 6 August 2021). With these assumptions, it becomes crucial to develop innovative instruments to manage every clinical condition the virus determines with the aim to be applied on a large scale. Nowadays, a major part of the studies on COVID-19 are focused on a better definition of severe and critically ill patients to define new strategies of clustering and discover additional biomarkers. The most diffuse approach is based on complex multiparametric scores which rely on clinical and laboratory variables leading to esteem deterioration of health status and mortality.39,40 Other methods focus on the identifica...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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Results from scite Reference Check: We found no unreliable references.
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