Angioedema in COVID-19.

A 62-year-old man with a history of hypertension presented with 12 h of lip and facial swelling. Twelve days prior to presentation, he developed fevers (up to 39°C), chills, fatigue, myalgias, anorexia, anosmia, ageusia, and a dry cough. These symptoms were improving aside from a lingering dry cough. He noticed upper lip swelling the night prior to presentation, which progressed to include swelling of his cheeks and lower face. He did not experience concomitant rash, pruritus, or shortness of breath. Medications prior to admission included amlodipine and lisinopril, without recent dosing changes and which he had tolerated for 10 years. He had no personal or family history of angioedema.

On examination, he was normotensive with a room air oxygen saturation of 99%. He was breathing comfortably without stridor. Compared with his usual state (Panel A), he had slightly asymmetric, non-pitting oedema of his cheeks and lips (Panel B). He had no other sites of swelling and had no rash. Reverse transcription–PCR was positive for SARS-CoV-2. Other laboratory findings included leukocytosis with relative lymphopenia and elevated high-sensitivity C-reactive protein and D-dimer. Functional C1 inhibitor levels (59.7 mg/dL), C3 levels (206 mg/dL), and C4 levels (46 mg/dL) were all elevated (Supplementary material online, ). Computed tomography imaging of his chest showed patchy ground-glass opacities with subpleural and bronchovascular distribution. On presentation, he received intravenous methylprednisolone, famotidine, and diphenhydramine. His lisinopril was held. By hospital day 2, the patient’s swelling markedly improved (Panel C) and he was discharged home in stable condition.

Vascular permeability is a proposed pathological feature of COVID-19, and the dry cough has been remarked to resemble the idiopathic cough seen in 10–15% of patients who receive angiotensin-converting enzyme (ACE) inhibitors. Both ACE inhibitor-induced cough and certain forms of angioedema are thought to be bradykinin dependent. Bradykinin and its metabolites are cleaved by a series of enzymes, including ACE and its homologue ACE2. After SARS-CoV-2 gains cellular entry by binding to ACE2, it results in down-regulation of surface ACE2, impairing its role in the breakdown of several substrates, including bradykinin metabolites. While late-onset angioedema during chronic ACE inhibition is rarely observed, SARS-CoV-2-mediated dysregulation of ACE2 may represent a ‘second hit’ that contributed to angioedema in this case. As preclinical models have suggested that bradykinin receptor signalling may be a factor in facilitating pulmonary injury and inflammation, modulation of this pathway should be explored as a potential therapeutic option in COVID-19.

Conflict of interest: S.D.S. has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos, and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos. M.V. is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541), serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa, and participates on clinical endpoint committees for studies sponsored by Novartis and the NIH. All other authors report no disclosures.

Supplementary material is available at European Heart Journal online.

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