ABSTRACT
Background: Advances in computational methodologies have enabled processing of large datasets originating from imaging studies. However, most imaging biomarkers suffer from a lack of direct links with underlying biology, as they are only observationally correlated with pathophysiology. Purpose(s): To develop and validate a novel AI-assisted image analysis platform, by applying quantitative radiotranscriptomics that quantifies cytokinedriven vascular inflammation from routine CT angiograms (CTA) performed as part of clinical care in COVID-19. Method(s): We used this platform to train the radiotranscriptomic signature C19-RS, derived from the perivascular space around the aorta and the internal mammary artery in routine chest CTAs, to best describe cytokinedriven vascular inflammation, defined using transcriptomic profiles from RNA sequencing data from human arterial biopsies (A). This signature was validated externally in 358 clinically indicated CT pulmonary angiograms from patients with or without COVID-19 from 3 different geographical regions. Result(s): First, 22 patients who had a CTA before the pandemic underwent repeat CTA <6 months post COVID-19 infection (B). Compared with 22 controls (matched for age, gender, and BMI) C19-RS was increased only in the COVID-19 group (C). Next, C19-RS was calculated in a cohort of 331 patients hospitalised during the pandemic, and was higher in COVID-19 positives (adjusted OR=2.97 [95% CI: 1.43-6.27], p=0.004, D). C19-RS had prognostic value for in-hospital mortality in COVID-19, with HR=3.31 ([95% CI: 1.49-7.33], p=0.003) and 2.58 ([95% CI: 1.10-6.05], p=0.028) in two testing cohorts respectively (E, F), adjusted for clinical factors and biochemical biomarkers of inflammation and myocardial injury. The corrected HR for in-hospital mortality was 8.24 [95% CI: 2.16-31.36], p=0.002 for those who received no treatment with dexamethasone, but only 2.27 [95% CI: 0.69-7.55], p=0.18 in those who received dexamethasone subsequently to the C19-RS based image analysis, suggesting that vascular inflammation may have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0.61, p=0.0003) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. Conclusion(s): We present the first proof of concept study that combines transcriptomics with radiomics to provide a platform for the development of machine learning derived radiotranscriptomics analysis of routine clinical CT scans for the development of non-invasive imaging biomarkers. Application in COVID-19 produced C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation, that predicts inhospital mortality and identifies people who will have better response to anti-inflammatory treatments, allowing targeted therapy. This AI-assisted image analysis platform may have applications across a wide range of vascular diseases, from infections to autoimmune diseases.
ABSTRACT
Background: COVID-19 has documented multisystem effects. Whether clinically significant cardiac involvement is related to severity of disease in a working age military population remains unknown, but has implications for occupational grading and ability to deploy. Aims: To determine in the military population 1) whether prior SARS-CoV-2 infection causes clinically significant cardiac disease and 2) whether changes are related to disease severity. Methods: 105 military personnel were recruited, 85 with prior SARS-CoV-2 infection (39±10 years, 87% male;50 mild (community), 35 severe (hospitalized) and 20 healthy volunteers (mean age 39 ±8.4 years, 90% male) underwent comprehensive cardiopulmonary investigations including;cardiopulmonary exercise test, exercise echocardiography, cardiac31MRI and P-MR spectroscopy (rest and dobutamine stress). Results: Prior SARS-CoV-2 infection was related to lower VO2max (110±18.2 vs 133±6.7% predicted, p<0.05), anaerobic threshold (45±10 vs 56±14% of peak VO2, p<0.05), VO2/HR (102±21 vs 128±24% predicted, p<0.05) and VE/VCO2 slope (28.3±5.0 vs 25.8±2.7, p<0.05) and an increase in average E/e' change from rest to exercise stress (+1.49±2.4 vs-0.16±3.6, p<0.05). Whilst resting myocardial energetics were similar, prior SARS-CoV-2 infection was associated with a fall in PCr/ATP during stress (by 8%, p=<0.01) which was not seen in healthy controls. When groups were ordered normal> mild> severe disease, RVEDVi, RV stroke volume, VO2peak, VO2pulse and VE/VCO slope were reduced (Jonckheere-Terpstra, all p<0.05). Conclusion: In a young military population, prior SARS-CoV-2 infection is associated with subclinical cardiovascular changes including;lower right ventricular volumes, reduced markers of exercise capacity and reduced myocardial energetics during stress.
ABSTRACT
Background: Cardiac magnetic resonance (CMR) and cardiopulmonary exercise testing (CPET) have provided important insights into the prevalence of early cardiopulmonary abnormalities in COVID-19 patients. It is currently unknown whether such abnormalities persist over time and relate to ongoing symptoms. Purpose: To describe the longitudinal trajectory of cardiopulmonary abnormalities on CMR and CPET in moderate to severe COVID-19 patients and assess their relationship with ongoing symptoms. Methods: Fifty-eight previously hospitalised COVID-19 patients and 30 age, sex, body mass index, comorbidity-matched controls underwent CMR, CPET and a symptom-based questionnaire at 2-3 months (2-3m). Repeat assessments (including gas transfer) were performed in 46 patients at 6 months (6m). Results: During admission, 1/3rd of patients needed ventilation or intensive care (Table 1) and three (5%) had a raised troponin. On CMR, patients had preserved left (LV) and right ventricular (RV) volumes and function at 2-3m from infection. By 6m, LV function did not change but RV end diastolic volume decreased (mean difference -4.3 mls/m2, p=0.005) and RV function increased (mean difference +3.2%, p<0.001, Fig. 1A). Patients had higher native T1 (a marker of fibroinflammation) at 2-3m compared to controls (Table 1, Fig. 1B), which normalised by 6m. Extracellular volume was normal and improved by 6m. Native T2, a marker of myocardial oedema, did not differ between patients and controls on serial CMR. At 2- 3m, late gadolinium enhancement (LGE) was higher in patients (p=0.023) but became comparable to controls by 6m (p=0.62). Six (12%) patients had LGE in a myocarditis pattern and one (2%) had myocardial infarction. None had active myocarditis using the Modified Lake Louise Criteria. Lung imaging (T2-weighted) revealed parenchymal abnormalities in 2/3rds of patients at 2-3 and 6 months. The extent of abnormalities improved on serial imaging (Table 1). Gas transfer (DLco) was worse in those with lung abnormalities (77% vs 91% of predicted, p=0.009). CPET revealed reduced peak oxygen consumption (pVO2) in patients at 2-3m, which normalised by 6m (80.5% to 93.3% of predicted, p=0.001) (Table 1, Fig. 1C). At 2-3m, 49% of patients had submaximal tests (respiratory exchange ratio <1.1), reducing to 25% by 6m (p=0.057). VE/VCO2 slope, a marker of lung efficiency, was abnormal in patients but improved on serial CPET (Table 1, Fig. 1D). Cardiac symptoms (chest pain, dyspnoea, palpitations, dizziness or syncope) were present in 83% of patients at 2-3m, reducing to 52% by 6m (p<0.001). There was no significant association between CMR or CPET parameters and persistent cardiac symptoms at 6m (Fig. 1E). Conclusions: Cardiopulmonary parameters (on CMR and CPET) improved in moderate-severe COVID-19 patients from 2-3 to 6 months post infection. Despite this, patients continued to experience cardiac symptoms which had no relationship with measured parameters. (Figure Presented).
ABSTRACT
Background Evidence suggests that adverse outcomes in COVID-19 may be driven by a cytokine-induced vascular inflammatory response, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Aim We aimed to develop a non-invasive method for quantifying cytokine-driven vascular inflammation in patients with acute COVID-19 infection that could allow risk stratification. Methods We developed a platform for rapid development of novel imaging biomarkers of vascular inflammation, by applying quantitative radiotranscriptomics to images from standard Computed Tomography Angiography (CTA). We used this platform to train a radiotranscriptomic signature (C19-RS) from the perivascular space around the aorta and the internal mammary artery, visualized in routine chest CTAs, to best describe cytokine-driven vascular inflammation, defined using transcriptomic profiles from RNA sequencing data from human arterial biopsies. This signature was tested externally in 435 clinically indicated CT pulmonary angiograms (CTPAs) from patients with or without COVID-19 from 3 different geographical regions. Results COVID-19 patients were characterised by significantly higher C19-RS values (adjusted odds ratio of 2.97 [95%CI: 1.43-6.27], p=0.004), while patients infected with the new B.1.1.7 variant (“UK variant”) were also found to have higher C19-RS values compared to those with the original variant, evidence suggestive of higher degrees of vascular inflammation. C19-RS had prognostic value for in-hospital mortality in COVID-19, with hazard ratios of 3.31 ([95%CI: 1.49-7.33], p=0.003) and 2.58 ([95%CI: 1.10-6.05], p=0.028) in two external testing cohorts respectively, after correction for clinical factors and biochemical biomarkers of inflammation (WBC, CRP) and myocardial injury (troponin). Importantly, the corrected HR for in-hospital mortality was 8.24[95%CI: 2.16- 31.36], P=0.002 for those who received no treatment with dexamethasone, but only 2.27[95%CI: 0.69-7.55], p=0.18 in those who received dexamethasone after the test, suggesting that anti-inflammatory treatment may be modifying the natural history of COVID-19 infection by improving outcomes specifically in those patients with high vascular inflammation. Conclusions Our study introduces a new radiotranscriptomic signature, C19-RS, extracted from routine CTPAs, trained to detect cytokine-driven arterial inflammation, and demonstrates that vascular inflammation determined in this way has prognostic value in patients with COVID-19. The “UK variant” leads to higher vascular inflammation measured in this way, and the risk associated with COVID-19 arteritis is modifiable by dexamethasone.