ABSTRACT
Background. Accurately identifying COVID-19 patients at-risk to deteriorate remains challenging. Dysregulated immune responses impact disease progression and development of life-threatening complications. Tools integrating host immune-protein expression have proven useful in determining infection etiology and hold potential for prognosticating disease severity. Methods. Adults with COVID-19 were enrolled at medical centers in Israel, Germany, and the United States (Figure 1). Severe outcome was defined as intensive care unit admission, non-invasive or invasive ventilation, or death. Tumor necrosis factor related apoptosis inducing ligand (TRAIL), interferon gamma inducible protein-10 (IP-10) and C-reactive protein (CRP) were measured using an analyzer providing values within 15 minutes (MeMed Key®). A signature indicating the likelihood of severe outcome was derived generating a score (0-100). Description of derivation cohort RT-PCR, reverse transcription polymerase chain reaction. Results. Between March and November 2020, 518 COVID-19 patients were enrolled, of whom 394 were eligible, 29% meeting a severe outcome. Age ranged between 19-98 (median 61.5), with 59.1% male. Patients meeting severe outcomes exhibited higher levels of CRP and IP-10 and lower levels of TRAIL (Figure 2;p < 0.001). Likelihood of severe outcome increased significantly (p < 0.001) with higher scores. The signature's area under the receiver operating characteristic curve (AUC) was 0.86 (95% confidence interval: 0.81-0.91). Performance was not confounded by age, sex, or comorbidities and was superior to IL-6 (AUC 0.77;p = 0.033) and CRP (AUC 0.78;p < 0.001). Clinical deterioration proximal to blood draw was associated with higher signature score. Scores of patients meeting a first outcome over 3 days after blood draw were significantly (p < 0.001) higher than scores of non-severe patients (Figure 3). Moreover, the signature differentiated patients who further deteriorated after meeting a severe outcome from those who improved (p = 0.004) and projected 14-day survival probabilities (p < 0.001;Figure 4). TRAIL, IP-10, CRP and the severity signature score are differentially expressed in severe and non-severe COVID-19 infection Dots represent patients and boxes denote median and interquartile range (IQR) The signature score of patients meeting a severe outcome on or after the day of blood draw is significantly (p < 0.001) higher than the signature score of non-severe patients. Dots represents patients and boxes denote median and IQR Kaplan-Meier survival estimates for signature score bins Conclusion. The derived signature combined with a rapid measurement platform has potential to serve as an accurate predictive tool for early detection of COVID-19 patients at risk for severe outcome, facilitating timely care escalation and de-escalation and appropriate resource allocation.
ABSTRACT
Background: It is estimated that up to 10% of SARS-CoV-2 patients progress from early and pulmonary stages to the most severe stage of illness, which manifests as an extra-pulmonary systemic hyperinflammatory syndrome. Interferon gamma-induced protein 10 (IP-10) is an inflammatory marker that plays a role in the dysregulated host response of COVID-19 infected patients. Clinical monitoring of IP-10 has been restricted in the absence of a rapid diagnostic test. MeMed KeyTM is a novel platform recently cleared to provide IP-10 measurements in 15 minutes. We hypothesized that providing physicians with real time IP-10 measurements would support detection and continuous monitoring of patients with a dysregulated immune response and potentially allow personalized immunomodulation to improve patient outcome. IP-10 levels reflect corticosteroid treatment Methods: From 7th April 2020 to 10th May 2020 blood was routinely collected serially from 52 SARS-CoV-2 positive patients hospitalized at a COVID-19 dedicated medical center. A clinical decision support protocol was in place focused on managing viral response, oxygenation and inflammatory state (NCT04389645). Results: The median age of the 52 patients was 69, 69% were male, 21% were ventilated, 4 died, 2 due to non-COVID-19 related complications. The most common comorbidities were Diabetes 40% and Hypertension 46%. IP-10 >1000 pg/ml correlated with ICU admission (p< 0.05) and increased COVID-19 severity score (p< 0.01). 19 of the 52 patients had IP-10 >1000 pg/ml, of these 12 were treated with corticosteroids. Monitoring IP-10 within the clinical decision support protocol assisted with personalized corticosteroid regimens with the aim of reducing IP-10 < 1000 pg/ml. The 10 patients that survived exhibited IP-10 levels >1000 pg/ml for 2.6 days on average. In contrast, the 2 patients that died of COVID-19 related complications displayed an average of 7.5 days with IP-10 >1000 pg/ml (p< 0.05). Conclusion: Providing physicians with real time measurements of IP-10 in COVID-19 patients proved a useful tool as part of the clinical decision support protocol. Timely identification, monitoring and personalized treatment of COVID-19 patients exhibiting a dysregulated immune response may aid in improving patient outcome. Further studies are warranted.