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Monocytopenia, morphological anomalies and hyperinflammation characterise severe COVID-19 in type 2 diabetes

ABSTRACT: Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk-factor for severe disease. Inflammation is central to the aetiology of both conditions where immune responses influence disease course. Identifying at-risk groups through immuno-inflammatory signatures can direct personalised care and help develop potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leukocyte populations in circulation from a cohort of 45 hospitalised COVID-19 patients with and without T2D. Lymphocytopenia, of CD8+ lymphocytes, was associated with severe COVID-19 and intensive care admission in non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia of classical monocytes were specifically associated with severe COVID-19 in patients with T2D requiring intensive care. Over-expression of inflammatory markers reminiscent of the type-1 interferon pathway underlaid the immunophenotype associated with T2D. These changes may contribute to severity of COVID-19 in T2D. These findings show characteristics of severe COVID-19 in T2D as well as provide evidence that type-1 interferons may be actionable targets for future studies.

SUBMITTER: Fawaz Alzaid

PROVIDER: S-SCDT-EMM-2020-13038 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:(1) Background: Cirrhotic patients have an increased risk for severe COVID-19. We investigated the renin-angiotensin-aldosterone system (RAS), parameters of endothelial dysfunction, inflammation, and coagulation/fibrinolysis in cirrhotic patients and in COVID-19 patients. (2) Methods: 127 prospectively characterized cirrhotic patients (CIRR), along with nine patients with mild COVID-19 (mild-COVID), 11 patients with COVID-19 acute respiratory distress syndrome (ARDS; ARDS-COVID), and 10 healthy subjects (HS) were included in the study. Portal hypertension (PH) in cirrhotic patients was characterized by hepatic venous pressure gradient (HVPG). (3) Results: With increased liver disease severity (Child-Pugh stage A vs. B vs. C) and compared to HS, CIRR patients exhibited higher RAS activity (angiotensin-converting enzyme (ACE), renin, aldosterone), endothelial dysfunction (von Willebrand-factor (VWF) antigen), inflammation (C-reactive protein (CRP), interleukin-6 (IL-6)), and a disturbed coagulation/fibrinolysis profile (prothrombin fragment F1,2, D-dimer, plasminogen activity, antiplasmin activity). Increased RAS activity (renin), endothelial dysfunction (vWF), coagulation parameters (D-dimer, prothrombin fragment F1,2) and inflammation (CRP, IL-6) were significantly altered in COVID patients and followed similar trends from mild-COVID to ARDS-COVID. In CIRR patients, ACE activity was linked to IL-6 (ρ = 0.26; p = 0.003), independently correlated with VWF antigen (aB: 0.10; p = 0.001), and was inversely associated with prothrombin fragment F1,2 (aB: -0.03; p = 0.023) and antiplasmin activity (aB: -0.58; p = 0.006), after adjusting for liver disease severity. (4) Conclusions: The considerable upregulation of the RAS in Child-Pugh B/C cirrhosis is linked to systemic inflammation, endothelial dysfunction, and abnormal coagulation profile. The cirrhosis-associated abnormalities of ACE, IL-6, VWF antigen, and antiplasmin parallel those observed in severe COVID-19.

Project description:BackgroundWhether infection with SARS-CoV-2 leads to excess risk of requiring hospitalization or intensive care in persons with diabetes has not been reported, nor have risk factors in diabetes associated with increased risk for these outcomes.MethodsWe included 44,639 and 411,976 adult patients with type 1 and type 2 diabetes alive on Jan 1, 2020, and compared them to controls matched for age, sex, and county of residence (n=204,919 and 1,948,900). Age- and sex-standardized rates for COVID-19 related hospitalizations, admissions to intensive care and death, were estimated and hazard ratios were calculated using Cox regression analyses.FindingsThere were 10,486 hospitalizations and 1,416 admissions into intensive care. A total of 1,175 patients with diabetes and 1,820 matched controls died from COVID-19, of these 53•2% had been hospitalized and 10•7% had been in intensive care. Patients with type 2 diabetes, compared to controls, displayed an age- and sex-adjusted hazard ratio (HR) of 2•22, 95%CI 2•13-2•32) of being hospitalized for COVID-19, which decreased to HR 1•40, 95%CI 1•34-1•47) after further adjustment for sociodemographic factors, pharmacological treatment and comorbidities, had higher risk for admission to ICU due to COVID-19 (age- and sex-adjusted HR 2•49, 95%CI 2•22-2•79, decreasing to 1•42, 95%CI 1•25-1•62 after adjustment, and increased risk for death due to COVID-19 (age- and sex-adjusted HR 2•19, 95%CI 2•03-2•36, complete adjustment 1•50, 95%CI 1•39-1•63). Age- and sex-adjusted HR for COVID-19 hospitalization for type 1 diabetes was 2•10, 95%CI 1•72-2•57), decreasing to 1•25, 95%CI 0•3097-1•62) after adjustment• Patients with diabetes type 1 were twice as likely to require intensive care for COVID-19, however, not after adjustment (HR 1•49, 95%CI 0•75-2•92), and more likely to die (HR 2•90, 95% CI 1•6554-5•47) from COVID-19, but not independently of other factors (HR 1•38, 95% CI 0•64-2•99). Among patients with diabetes, elevated glycated hemoglobin levels were associated with higher risk for most outcomes.InterpretationIn this nationwide study, type 2 diabetes was independently associated with increased risk of hospitalization, admission to intensive care and death for COVID-19. There were few admissions into intensive care and deaths in type 1 diabetes, and although hazards were significantly raised for all three outcomes, there was no independent risk persisting after adjustment for confounding factors.

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Monocytopenia, morphological anomalies and hyperinflammation characterise severe COVID-19 in type 2 diabetes

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