Precision medicine for pandemics: stratification of COVID-19 molecular phenotypes defined by topological analysis of global blood gene expression. (preprint)

Precision medicine offers a promising avenue for better therapeutic responses to pandemics such as COVID-19. This study leverages independent patient cohorts in Florence and Liege gathered under the umbrella of the DRAGON consortium for the stratification of molecular phenotypes associated with COVID-19 using topological analysis of global blood gene expression. Whole blood from 173 patients was collected and RNA was sequenced on the Novaseq platform. Molecular phenotypes were defined through topological analysis of gene expression relative to the biological network using the TopMD algorithm. The two cohorts from Florence and Liege allowed for independent validation of the findings in this study. Clustering of the topological maps of differential pathway activation revealed three distinct molecular phenotypes of COVID-19 in the Florence patient cohort, which were also observed in the Liege cohort. Cluster 1, was characterised by high activation of pathways associated with ESC pluripotency, NRF2, and TGF-B; receptor signalling. Cluster 2 displayed high activation of pathways including focal adhesion-PI3K-Akt-mTOR signalling and type I interferon induction and signalling, while Cluster 3 exhibited low IRF7-related pathway activation. TopMD was also used with the Drug-Gene Interaction Database (DGIdb), revealing pharmaceutical interventions targeting mechanisms across multiple phenotypes and individuals. The data illustrates the utility of molecular phenotyping from topological analysis of blood gene expression, and holds promise for informing personalised therapeutic strategies not only for COVID-19 but also for Disease X. Its potential transferability across multiple diseases highlights the value in pandemic response efforts, offering insights before large-scale clinical studies are initiated.

Utility of bronchoalveolar lavage for COVID-19: a perspective from the Dragon consortium. (preprint)

Diagnosing COVID-19 and treating its complications remains a challenge. This review reflects the perspective of some of the Dragon (IMI 2-call 21, #101005122) research consortium collaborators on the utility of bronchoalveolar lavage (BAL) in COVID-19. BAL has been proposed as a potentially useful diagnostic tool to increase COVID-19 diagnosis sensitivity. In both critically ill and non-critically ill COVID-19 patients, BAL has a relevant role in detecting other infections or in supporting alternative diagnosis, and can change management decisions in up to two-third of patients. BAL is used to guide steroid and immunosuppressive treatment and to narrow or discontinue antibiotic treatment reducing the use of unnecessary broad antibiotics. Moreover, cellular analysis and novel multi-omics techniques on BAL are of critical importance for the understanding of the microenvironment and interaction between epithelial cells and immunity revealing novel potential prognostic and therapeutic targets. The BAL technique has been described as safe for both patients and health care workers in more than a thousand procedures reported to date in the literature. Based on these preliminary studies, we recognize that BAL is a feasible procedure in COVID-19 known or suspected cases, useful to properly guide patient management and with great potential for research.

The Role of Chest CT in Deciphering Interstitial Lung Involvement: Systemic Sclerosis Versus COVID-19 (preprint)

Background: In clinical practice, the striking similarities observed at computed tomography (CT) between the diseases make it difficult to distinguish a COVID-19 pneumonia from a progression of interstitial lung disease (ILD) secondary to Systemic sclerosis (SSc). The aim of the present study was to identify the main CT features that may help distinguishing SSc-ILD from COVID-19 pneumonia. Methods: This multicentric study included 22 international readers divided in the radiologist group (RAD) and non-radiologist group (nRAD). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.Findings: Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p <0.0001) and signs of fibrosis in GGO in the lower lobes (p <0.0001) remained independently associated with COVID-19 pneumonia or SSc-ILD, respectively. A predictive score weas created which resulted positively associated with the COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity).Interpretation: The CT differential diagnosis between COVID-19 pneumonia and SSc-ILD is possible through the combination our score and the radiologic expertise. If an overlap of both diseases is suspected, the presence of consolidation in the lower lobes may suggest a COVID-19 pneumonia while the presence of fibrosis inside GGO may indicate a SSc-ILD.Funding: No Funding were received for this study.Declaration of Interests: SC reports personal fees from NOVARTIS-SANOFI-LILLY-CELTHER-PFIZER-JANSSEN; MK reports grants and personal fees from Boehringer-Ingelheim, personal fees from Corbus, grants and personal fees from Chugai, grants and personal fees from Ono Pharmeceuticals, personal fees from Tanabe-Mitsubishi, personal fees from Astellas, personal fees from Gilead, personal fees from Mochida; ST reports personal fees from Boehringer Ingelheim, personal fees from Roche, outside the submitted work; GS reports personal fees from Boehringer Ingelheim; CB reports personal fees from Actelion, personal fees from Eli Lilly, grants from European Scleroderma Trial and Research (EUSTAR) group, grants from New Horizon Fellowship, grants from Foundation for Research in Rheumatology (FOREUM), grants from Fondazione Italiana per la Ricerca sull'Artrite (FIRA); CV reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from F. Hoffmann-La Roche Ltd.; FL reports lectures fee from Roche and from Boehringer- Ingelheim; CPD reports grants and personal fees from GSK, personal fees from Boerhinger Ingelheim, grants from Servier, grants and personal fees from Inventiva, grants and personal fees from Arxx Therapeutics, personal fees from Corbus, personal fees from Sanofi, personal fees from Roche; FL reports grants and personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from Orion Pharma, personal fees from AstraZeneca, grants from MSD, personal fees from HIKMA, personal fees from Trudell International, grants and personal fees from Chiesi Farmaceutici, personal fees from Novartis Pharma; MH reports personal fees from Speaking fees from Actelion, Eli lilly and Pfizer; D K reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from Boehringer Ingelhem, personal fees from CSL Behring, grants and personal fees from Horizon, grants from Pfizer, personal fees from Corbus, grants and personal fees from BMS, outside the submitted work; and Dr Khanna is the Chief Medical officer of Eicos Sciences Inc and has stock options. All the mentioned authors declared previous feed outside the submitted work. All other authors declare no competing interests.Ethics Approval Statement: This retrospective, observational, multicentric, international study was approved by the Institutional Ethics Committee of Florence Careggi hospital (protocol number 17104_oss).