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Research Article: Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS)

Date Published: 2023-11-30

Abstract:
SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes. These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin system, leading to accumulation of bradykinin and its derivatives, which act on receptors B1R and B2R. Receptor activation causes cough, hypotension, oedema and release of the cytokine interleukin-6 (IL-6) which recruits lymphocytes. These effects are core features seen in early SARS CoV-2 infection. Methods and analysis In this study, hypoxic patients with COVID-19 with symptom onset ?7?days will be randomised to either a bradykinin inhibitor (icatibant) or placebo. Patients and investigators will be blinded. The primary outcome will be blood oxygenation, measured by arterial blood sampling. The secondary outcome will be cardiovascular status. Retinal imaging will be performed to assess vessel size. Blood samples will be taken for measurement of inflammatory analyses including IL-6. As a separate substudy, we will also take comparator blood inflammatory samples from a COVID-19-negative cohort. Ethics and dissemination The study has received the following approvals: West Midlands–Edgbaston Research Ethics Committee. Medicines and Healthcare products Regulatory Agency has issued a clinical trial authorisation. Belfast Health and Social Care Trust is the study sponsor. Results will be made available to participants upon request and findings will be presented and published. Trial registration number NCT05407597

Introduction:
SARS-CoV-2 causes a spectrum from asymptomatic infection to severe respiratory failure and death. SARS-CoV-2 enters cells by binding to the ACE2 receptor, which is expressed in many tissues including the upper airway, kidneys, adipose tissue, small intestine, heart and lungs. 1 2 The principal effects of the resultant infection are cough, breathlessness, loss of taste/smell and infiltrates on the chest radiograph or CT. These infiltrates are alveolar filling defects caused by oedema. Patients may also develop…

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