In Cureus, Cobb and Bernabe presented the rare case of a patient with hereditary angioedema (HAE) who continued to experience severe, frequent angioedema attacks despite being on prophylaxis treatment. 

A 38-year-old woman received her first SARS-CoV-2 vaccine and experienced an anaphylactic reaction that required intensive care. After she recovered, she began to experience an increased frequency of angioedema attacks, which resulted in a referral to an outpatient allergy clinic. 

Since the age of 16, the patient has had episodes of angioedema flares that she says are brought on by lidocaine injections, angiotensin receptor blockers, and eating mango. Her family history includes her mother and her grandmother both suffering from idiopathic angioedema. The patient’s physicians operated under a working diagnosis of HAE with normal C1 esterase inhibitor (HAE nCI-INH), given her corroborating laboratory findings.

Continue Reading

When the patient was seen in the allergy clinic, she presented with hoarseness, tongue swelling, and right upper lid swelling accompanied by visual impairment. Her physicians administered Ruconest—an intravenous recombinant C1 esterase inhibitor—and her symptoms drastically improved within 1 hour. 

Read more about HAE etiology 

Refractory Angioedema Despite Therapy 

Her physicians decided to administer her long-term prophylaxis; her cocktail of drugs included Ruconest and Firazyr, a subcutaneous bradykinin B2 receptor antagonist that was administered on-demand. She was also prescribed Orladeyo, an oral kallikrein inhibitor. However, just a few days later, she was readmitted into intensive care due to severe laryngeal swelling. 

“Due to a lack of on-demand HAE medication availability, she was intubated and given glucocorticoids, Pepcid (an H2 antagonist), Benadryl (an H1 antagonist), Berinert (an intravenous plasma-derived C1 esterase inhibitor), and fresh frozen plasma,” the authors wrote. 

Upon discharge, her physicians added on Haegarda, a subcutaneous plasma-derived C1 esterase inhibitor, for long-term prophylaxis. Nevertheless, her angioedema episodes continued, leading to more hospitalizations. Her physicians decided to discontinue the Orladeyo and Firazyr and replace them with Takhzyro, a subcutaneous kallikrein inhibitor, and Sajazir, a subcutaneous bradykinin B2 receptor antagonist as on-demand therapy. 

The switch in medications led to some improvements in the severity of her angioedema episodes; nonetheless, they persisted, with 1 case requiring hospitalization. Her physicians began to explore other avenues to help alleviate her symptoms. Given that estrogen has been implicated in HAE nCI-INH exacerbations, she was prescribed Danazol, an anabolic androgen, and had discussions with her obstetrician-gynecologist about a possible oophorectomy. 

“The patient’s quality of life has been severely affected, and a short-term disability has been obtained,” Cobb and Bernabe concluded. 

When Things Go From Bad to Worse

The rare disease course of HAE in this patient deserves further exploration. A few important points of note: first, she was diagnosed with HAE nC1-INH, a rare subtype of an already rare disease, which means that much about the condition remains unknown. Scientists have proposed that this disorder may be bradykinin-mediated, similar to HAE C1-INH; however, this remains an unconfirmed theory. 

Second, the patient’s bout of severe angioedema began with an initial dose of Spikevax, the name of the COVID-19 vaccine she received. Although rare, there have been reports of patients with HAE clinically deteriorating postvaccination. Once again, the exact link between the 2 is unknown and remains largely speculative. 

The most perplexing part of this case study is the patient’s worsening condition despite being on long-term prophylaxis. If anything, this case report illustrates the large gaps in our understanding of the disease: what drives it and how best to treat it. 

Read more about HAE treatments 

In the Journal of Investigational Allergology and Clinical Immunology, Teresa Caballero from the Center for Biomedical Research Network on Rare Diseases in Spain wrote, “Long term prophylaxis, also called routine prophylaxis, is continued on maintenance treatment aimed at decreasing the frequency, severity, and duration of angioedema attacks. It should be considered in symptomatic patients whose condition is not adequately controlled exclusively with optimal on-demand treatment, taking into account disease severity and health-related quality of life.” 

This was precisely the reason that the patient’s physicians started her on long-term prophylaxis. But just how strong is the evidence regarding this form of pre-emptive treatment? Well, the indications for the start of long-term prophylaxis have changed continuously over the last 2 decades. Efficacy outcomes have not been defined. Experts remain in disagreement over the merits of some of the drugs used as long-term prophylaxis in HAE. Furthermore, the theory that angioedema attacks may be estrogen-linked is still under investigation; because of potentially serious adverse effects, physicians tend to shy away from prescribing therapies that can cause hormonal interference. 

It is always difficult for physicians to tell their patients that they have done all they can medically to help them, and that their worsening symptoms are now beyond their control. This may be true in the short- to medium-term, but new therapies under investigation may yet revolutionize HAE care. Scientists are studying drugs that target the kallikrein-kinin system in a more refined way; other drugs block the activation of factor XII. 

“New treatments under development point to a very promising future for affected patients,” Caballero concluded. 


Caballero T. Treatment of hereditary angioedemaJ Investig Allergol Clin Immunol. 2021;31(1):1-16. doi:10.18176/jiaci.0653

Cobb G, Bernabe CC. Hereditary angioedema with normal C1 esterase inhibitor refractory to long-term prophylaxis: a case reportCureus. 2023;15(1):e33800. doi:10.7759/cureus.33800