Reply to Chan and Majluf-Cruz: Is the Angioedema Associated with COVID-19 a Real Entity, a Mimic, or Both?

From the Authors:

We wish to reply to the letter by Chan and colleagues that comments on our previous report regarding angioedema and coronavirus disease (COVID-19) (1).

Risk Factors for Angioedema

Multiple risk factors are believed to increase the incidence of ACE (angiotensin-converting enzyme) inhibitor (ACEI)–induced angioedema through various pathways, including polymorphisms in the genes encoding NEP and APP, medications that inhibit DPP4, and autoantibodies against C1-INH.

Onset of Angioedema

Although we hypothesize similarities between ACEI-induced angioedema and COVID-19–associated angioedema, there is a wide window for the development of angioedema after the onset of COVID-19 symptoms and it can still be related to the kallikrein–kinin system for the following reasons:

First, the timeline for COVID-19 phases and clinical manifestations continues to evolve because of complex multisystem activities. Studies have noted that the onset of the COVID-19 hyperinflammatory state has ranged between 2 and 5 weeks (2).

Second, the presentation of ACEI-induced angioedema can range between weeks and months after starting and discontinuing the medication. Thus, we can anticipate a similar variability in angioedema onset in patients hospitalized for COVID-19 (3).

Third, ACE2 does not inhibit BK but mainly inhibits DABK and Lys-DABK, which are downstream in the systemic and tissue kallikrein pathway, leading to a later onset in their signaling activity.

Fourth, BK binds primarily to β2R, which is expressed on endothelial cells and does not rely on the inflammatory cascade to induce angioedema. In contrast, DABK and Lys-DABK bind primarily to β1R, which is only upregulated in the setting of inflammation. Therefore, accumulation of DABK and Lys-DABK would not induce angioedema until the establishment of the inflammatory state.

Proning and Angioedema

Regarding proning the patients, patients 1, 2, and 3 developed angioedema 6–7 days after the last time they were proned. Patient 4 was never proned. The swelling involved the whole face, tongue, lips, upper airway edema, and laryngeal edema. For those patients who were proned, they were positioned in reverse Trendelenburg position when proned. Therefore, proning was not believed to be related to angioedema.

Role of C1-INH in Angioedema Associated with ACE2 Dysregulation

Although the patient with angioedema described by Cohen, referenced in our original letter, had an elevated functional concentration of C1-INH, it may not necessarily prevent angioedema. This is evidenced by data showing that many patients with ACEI angioedema do not respond to C1-INH concentrate. Also, C1-INH is a potent inhibitor of BK release from HMWK (high‐molecular‐weight kininogen) but it does not directly affect the metabolism of LMWK (low-molecular-weight kininogen) to Lys-BK and subsequently to Lys-DABK, which can precipitate angioedema in the setting of dysfunctional ACE2. However, it is important to note that the rapid improvement in the patient’s angioedema may be related to the inactivation of BK by the elevated C1-INH concentration

Regarding the issue of LMWH enhancing C1-INH activity, Chan and colleagues raise an interesting point. All of our patients were on deep venous thrombosis prophylaxis; two were receiving heparin and two were receiving LMWH. Current literature suggests that autoimmune phenomena may be increased during COVID-19 and in the post–COVID-19 syndrome (4). Consequently, one can speculate that autoantibodies to C1-INH can develop during COVID-19, increasing the risk of angioedema. Thus, the suggestion by Chan and colleagues to use LMWH to augment the activity of C1-INH bears consideration and could become a potential treatment for COVID-19–associated angioedema in combination with β1R and β2R blockade. Furthermore, LMWH might become the preferred anticoagulant in patients with COVID-19 with angioedema and hypercoagulability concerns.

Recently Published Similar Cases

At this time, we have noted several publications associating facial, tongue, eye, and lips swelling with COVID-19; however, none of them made a definitive association with race (5–8).

Conclusions

With the second wave of increase in cases of COVID-19, we can anticipate additional reports of angioedema in patients with COVID-19.