key: cord-0927155-i0hdf2ks
authors: Azmy, Veronica; Benson, Jemma; Love, Keith; Steele, Ryan
title: Idiopathic Nonhistaminergic Acquired Angioedema in a Patient with COVID-19
date: 2020-07-01
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2020.06.039
sha: cd87baf99cb9c9cb2a93f4e4ef361e3574770e1f
doc_id: 927155
cord_uid: i0hdf2ks

nan

corticosteroids. 1 Compared with other forms of hereditary and acquired angioedema, InH-AAE 3 seems to have a predilection for facial and tongue swelling, and is often difficult to diagnose as 4 patients have normal laboratory values and no family history. 1 To our knowledge, there have 5 been no publications to date describing idiopathic nonhistaminergic angioedema as a 6 complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 7

although nonhistaminergic angioedema has been seen in the setting of other viral infections. 2,3 8

We describe a case of suspected InH-AAE in an intubated patient with coronavirus disease 2019 9

(COVID-19). We review post-intubation macroglossia as a potential differential diagnosis and 10 why this etiology is unlikely in our patient. Finally, we briefly discuss the hyperinflammatory 11 response to SARS-CoV-2 and its potential role in the development of InH-AAE. 12

A 29-year-old African American female with past medical history of poorly controlled type 2 14 diabetes mellitus, class 3 obesity, and hyperlipidemia was admitted for hypoxemic respiratory 15 failure secondary to PCR confirmed SARS-CoV-2 infection seven days after symptom onset. 16

Initial therapy included hydroxychloroquine 400 mg twice per day (BID), followed by 200 mg 17 BID the following day. On day four of admission, she developed acute respiratory distress 18 syndrome (ARDS) necessitating intubation and was given hydromorphone and midazolam for 19 sedation and pain management. One day later, she was found to have enterococcal bacteremia 20 and was started on piperacillin/tazobactam and vancomycin, which was then narrowed to 21 ampicillin. On the day she was intubated, she was enrolled in a clinical trial for remdesivir and received four total doses of 100 mg daily; it was discontinued on day four of intubation due to a 23 rise in transaminases. 24

On day seven of intubation, she developed severe tongue angioedema without urticaria ( Figure  26 1). A bedside exam did not reveal any laryngeal swelling, evidence of traumatic intubation, or 27 self-inflicted trauma such as bite marks on her tongue or buccal mucosa. The patient had no 28 known drug allergies or personal history of angioedema; however, she did have a maternal aunt 29 with a history of angiotensin converting enzyme (ACE) inhibitor induced angioedema. The inhibitor function 100%, C2 2.9 mg/dL, CH50 >95.0 units/mL, C1q 6.2 mg/dL, and tryptase 7.1 mg/dL, all normal values. Given the lack of improvement in her tongue swelling, the primary 46 barrier to her extubation, the patient received C1 esterase inhibitor (Berinert) at 20 units/kg 47 dosing as empiric treatment for a bradykinin mediated angioedema on day ten of intubation. 48

Diphenhydramine, methylprednisolone, and hydromorphone were discontinued and she was 49 started on loratadine 10 mg BID. One day after receiving C1 esterase inhibitor, she demonstrated 50 mild improvement in her tongue swelling, which fully abated two days later. She remained 51 intubated for several more days due to severe agitation, thought to be secondary to intensive care 52 unit (ICU) delirium, and was ultimately extubated without complication on hospital day 53 eighteen. She was discharged home eight days later, after a 27-day hospital stay. Switzerland. 9 In our patient, it is difficult to know whether the C1 inhibitor had an effect, given 81 that the time course of her tongue swelling is consistent with the natural course of untreated 82 nonhistaminergic angioedema. 2 Furthermore, cytokines which are commonly elevated in 83 COVID-19, including interleukin (IL)-6, IL-1β, and IFNγ, are also potent mediators of 84 inflammation and may theoretically predispose to the development of angioedema. 10 It is 85 possible that InH-AAE is another manifestation of the hyperimmune response to SARS-CoV-2, 86 and should be considered in patients who have angioedema without urticaria which is 87 nonresponsive to antihistamines or corticosteroids.

Tongue angioedema in an intubated patient with COVID-19. Photo was taken one day after onset of tongue swelling. Dry, cracked blistering lesions on tongue noted. A bedside exam did not reveal laryngeal swelling, evidence of traumatic intubation, or self-inflicted trauma such as bite marks. No lip or periorbital swelling were present.

Idiopathic nonhistaminergic acquired angioedema versus hereditary angioedema

Angioedema without urticaria: a large clinical survey

Tongue swelling complicating management of a ventilated patient with acute respiratory distress syndrome secondary to novel influenza A (H1N1)

Hydroxychloroquine desensitization, an effective method to overcome hypersensitivity-a multicenter experience

Apparent massive tongue swelling a complication of orotracheal intubation on the intensive care unit

Massive macroglossia developing fast and immediately after endotracheal extubation

Macroglossia in neurosurgery

Acute urticaria with angioedema in the setting of coronavirus disease

Encouraging results from use of Ruconest in COVID-19 patients

COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet