Idiopathic Nonhistaminergic Acquired Angioedema in a Patient with COVID-19.

Idiopathic nonhistaminergic acquired angioedema (InH-AAE) is a rare disease characterized by submucosal swelling without concomitant urticaria and poor response to antihistamines and corticosteroids. Compared with other forms of hereditary and acquired angioedema, InH-AAE seems to have a predilection for facial and tongue swelling and is often difficult to diagnose because patients have normal laboratory values and no family history. To the best of our knowledge, there have been no publications to date describing idiopathic nonhistaminergic angioedema as a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although nonhistaminergic angioedema has been seen in the setting of other viral infections. , Here, we describe a case of suspected InH-AAE in an intubated patient with coronavirus disease 2019 (COVID-19). We review postintubation macroglossia as a potential differential diagnosis and why this etiology is unlikely in our patient. Finally, we briefly discuss the hyperinflammatory response to SARS-CoV-2 and its potential role in the development of InH-AAE.

A 29-year-old African American woman with a past medical history of poorly controlled type 2 diabetes mellitus, class 3 obesity, and hyperlipidemia was admitted for hypoxemic respiratory failure secondary to polymerase chain reaction–confirmed diagnosis of SARS-CoV-2 infection 7 days after symptom onset. Initial therapy included a dose of hydroxychloroquine 400 mg twice per day, followed by 200 mg twice per day on the next day. On day 4 of admission, she experienced acute respiratory distress syndrome necessitating intubation and was given hydromorphone and midazolam for sedation and pain management. The next day, she was diagnosed as having enterococcal bacteremia and was started on a combination of piperacillin-tazobactam and vancomycin, which was then narrowed to ampicillin. On the day she was intubated, she was enrolled in a clinical trial for remdesivir and received 4 total doses of 100 mg daily; it was discontinued on day 4 of intubation owing to a rise in transaminases.

On day 7 of intubation, she experienced severe tongue angioedema without urticaria (Fig 1 ). A bedside examination did not reveal any laryngeal swelling, evidence of traumatic intubation, or self-inflicted trauma, such as bite marks on her tongue or buccal mucosa. The patient had no known drug allergies or a personal history of angioedema; however, she had maternal aunt with a history of angiotensin converting enzyme inhibitor–induced angioedema. The patient was not on angiotensin converting enzyme inhibitors or other renin-angiotensin-aldosterone system–inhibiting agents. On the day of angioedema onset, her absolute lymphocyte count was 2.1 × 1000/μL, creatinine was 1.14 mg/dL (from a baseline of 0.8 mg/dL), aspartate aminotransferase was 196 U/L, alanine aminotransferase was 198 U/L, and alkaline phosphatase was 73 U/L. In addition, her D-dimer level was 0.69 mg/L, which was down from 1.44 mg/L measured 3 days before. The patient did not undergo any imaging studies of the tongue or posterior pharynx to look for anatomic abnormalities, such as thrombosis, which could explain her tongue swelling. She had been on an intermediate-dose of prophylactic anticoagulation with lovenox 40 mg every 12 hours for the duration of her hospital stay.

Figure 1

Tongue angioedema in an intubated patient with COVID-19. The photograph was taken one day after the onset of tongue swelling. Dry, cracked blistering lesions on the tongue were noted. A bedside examination did not reveal any laryngeal swelling, evidence of traumatic intubation, or self-inflicted trauma, such as bite marks. No lip or periorbital swelling was present. COVID-19, coronavirus disease 2019.

She was treated with a dose of diphenhydramine 50 mg intravenously every 6 hours and received 2 doses of methylprednisolone 60 mg daily. Ampicillin was stopped given the concern for a new immediate hypersensitivity reaction without noted clinical improvement. Complement component 4 (C4) returned at 30 mg/dL, C1 esterase inhibitor protein was 48 mg/dL, C1 esterase inhibitor function was at 100%, C2 was 2.9 mg/dL, CH50 was more than 95.0 U/mL, C1q was 6.2 mg/dL, and tryptase was 7.1 mg/dL, these were all normal values. Given the lack of improvement in her tongue swelling, the primary barrier to her extubation, the patient received C1 esterase inhibitor (Berinert) at 20 U/kg dosing as empirical treatment for a bradykinin-mediated angioedema on day 10 of intubation. Diphenhydramine, methylprednisolone, and hydromorphone were discontinued, and she was started on a dose of loratadine 10 mg twice per day. On the next day after receiving C1 esterase inhibitor, she had mild improvement in her tongue swelling, which fully abated after 2 days. She remained intubated for several more days owing to severe agitation, thought to be secondary to intensive care unit delirium, and was ultimately extubated without complication on hospital day 18. She was discharged home 8 days later, after a 27-day hospital stay.

We present a case of suspected InH-AAE in a young woman with COVID-19. She had normal C4, C1 esterase inhibitor protein level and function, C1q, and no response to antihistamines or corticosteroids. With normal laboratory results and lack of family history, hereditary angioedema was effectively ruled out. Regarding the possibility of a hypersensitivity reaction, she did not have urticaria or other features of immediate hypersensitivity reactions, such as an elevated tryptase. Considering possible drug reactions, delayed hypersensitivity reactions to hydroxychloroquine involving urticaria and angioedema are quite rare and would likely improve with antihistamines and corticosteroids. Furthermore, there are previous reports of idiopathic acquired angioedema in the setting of oseltamivir given for H1N1 infection, but to date, there are no published cases of remdesivir-associated angioedema.

Postintubation macroglossia has been described in the setting of difficult intubations, in which the anatomic position of the tongue obstructs the route of the endotracheal tube. In these cases, tongue swelling occurs typically within 36 hours after intubation and usually improves with corticosteroids. , It is less likely to have occurred in our patient because she did not have a technically difficult intubation and her tongue swelling presented 7 days later. In addition, macroglossia can be caused by impaired lymphatic drainage, but this is most often associated with prolonged neurosurgical procedures that utilize prone positioning.

There is currently one case report of histaminergic urticaria with angioedema in the setting of SARS-CoV-2 infection; however, our patient had nonhistaminergic angioedema without wheals, which likely suggests a different underlying pathophysiology. It has been proposed that extreme complement activation is an important component in the hyperinflammatory syndrome seen in severe COVID-19 infection, and which leads to the development of acute respiratory distress syndrome. Hence, Ruconest, a recombinant human C1 inhibitor, is being investigated in a clinical trial, after indicating positive results in 5 patients who received it as part of a compassionate use program in Switzerland. In our patient, it is difficult to know whether the C1 inhibitor had an effect, given that the time course of her tongue swelling is consistent with the natural course of untreated nonhistaminergic angioedema. Furthermore, cytokines that are often elevated in COVID-19, including interleukin (IL)-6, IL-1β, and interferon gamma, are also potent mediators of inflammation and may theoretically predispose to the development of angioedema. It is possible that InH-AAE is another manifestation of the hyperimmune response to SARS-CoV-2 and should be considered in patients who receive a diagnosis of angioedema without urticaria, which is nonresponsive to antihistamines or corticosteroids.