IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study

Abstract

BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness.MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients.FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients.InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.Research in contextEvidence before this studyWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms “IFI27”, “COVID-19, “gene expression” and “outcome prediction”. We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of “gene expression” and “COVID-19”, IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic.Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic.Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.

Prediction of COVID-19 Based on Genomic Biomarkers of Metagenomic Next-Generation Sequencing Data Using Artificial Intelligence Technology

“…Analysis of the dataset using the Boruta feature selection method resulted in the genes IFI27, TPT1, FAM83A, SCGB3A1, TBCE, DCUN1D3, PCSK5, PDGFRB, METRNL, MTRNR2LI2, LGR6, PCDHBD9, DUSP6, SIX5, and RTN2 as biomarker candidate genes for COVID-19. Shojaei et al (26) found that IFI27 transcription was an early predictor for COVID-19 outcomes. They reported that IFI27 was expressed in the respiratory tract of COVID-19 patients and that high IFI27 expression was associated with the presence of a high viral load.…”

Molecular and Clinical Prognostic Biomarkers of COVID-19 Severity and Persistence

“…Regarding the novel biomarker IFI27, it is known to reflect active influenza virus infection, as it appears to be co-expressed with many genes with anti-viral functions and its TLR7-driven expression is observed in DCs and NK cells [ 93 ]. In contrast to the above, others report that there is no difference in the expression of IFI27 and IFITM3 between severe and mild samples [ 38 ] and a study that is currently under peer review supports that the alterations in gene expression reflect only local activity of IFI27 in the lower respiratory tract, as in the lung tissue of deceased individuals suffering COVID-19, IFI27 was upregulated and the overexpression is correlated with high viral load [ 94 ]. On the other hand, a significant association between IFI27 levels in the upper respiratory tract (nasopharyngeal IFI27) and the severity of the disease was reported [ 94 ].…”

“…In contrast to the above, others report that there is no difference in the expression of IFI27 and IFITM3 between severe and mild samples [ 38 ] and a study that is currently under peer review supports that the alterations in gene expression reflect only local activity of IFI27 in the lower respiratory tract, as in the lung tissue of deceased individuals suffering COVID-19, IFI27 was upregulated and the overexpression is correlated with high viral load [ 94 ]. On the other hand, a significant association between IFI27 levels in the upper respiratory tract (nasopharyngeal IFI27) and the severity of the disease was reported [ 94 ]. This IFN-I related gene is strongly upregulated in COVID-19 patients too and in fact is more elevated in those with severe disease, compared to the mid- and moderate ones, whereas its levels are far lower in critical patients [ 69 ].…”

Implications of Using Host Response-Based Molecular Diagnostics on the Management of Bacterial and Viral Infections: A Review

“…Moreover, in another multi-cohort observational study, IFI27 was shown to be expressed in COVID-19 infected patients, and its level of expression was associated with the presence of a high viral load (36). These results are promising although further validation is required to achieve high specificity of this gene marker to a particular disease.…”