Persistent angioedema of the tongue
I have been following a 41 year-old male with a history of recurrent tongue angioedema for the last three years. At the start of his presentation, he apparently had an episode of genital swelling as well as lip swelling, but since I have been following him it has been only tongue swelling. At the start of his presentation, his episodes of swelling occurred once every few months, but his episodes subsequently began to occur monthly, and now are occurring two to three times weekly. Episodes begin suddenly, without apparent trigger, and then when untreated last about two to three days before resolving. He has never had urticaria and allergy workup, including tryptase values both at baseline and during an episode, has been unremarkable.
His lab evaluation for HAE/AAE has been normal on several occasions: normal C1 inhibitor level and function, normal C4, normal C1q, normal SPEP, in addition to a negative factor XII mutational analysis. He has been trialed on high dose antihistamines, steroids, and epinephrine without effect. Ecallantide was tried and seemed to be highly effective at relieving his symptoms the first few times it was used; however, this seemed to be less effective after about a year, he would receive the appropriate dose with transient improvement followed by a recurrence of swelling. He was also trialed on several other treatments for HAE, including danazol, icatibant, c1 esterase replacement therapy, and finally, lanadelumab. None of these treatments have subsequently been effective, and his frequency of episodes has remained at 2-3 times per week. FFP seems to help his swelling reduce partially but then he typically will have a recurrence of symptoms. Ultimately he underwent a prophylactic tracheostomy due to recurrent intubations. At this point he seems to have tongue swelling more often than not.
I have read some case reports of using omalizumab in idiopathic nonhistaminergic angioedema, but I don’t see how that would be effective in a patient who initially responded to an agent such as ecallantide. Would it be worth trying? I am wondering if there is any other workup or treatment I should be considering, too.
This is clearly a very challenging patient and worsening despite very aggressive management.
You have effectively ruled out HAE 1 & 2, as well as AAE. HAE 3 remains somewhat of a mystery, although the fact that your patient is male and response to anti-bradykinin and C-1-esterase replacement therapy has been marginal at best, makes this very unlikely. You did not state it, but I assume he is not taking an ACE-Inh. While mast cell and bradykinin-mediated angioedema are relatively well defined in terms of diagnostic and therapeutic approach, angioedema with unknown mechanisms represents a challenge for patients and physicians.
A trial of Omalizumab 300mg every 4 weeks is certainly worthwhile. However, I feel at this point, you should consider less common conditions such as Melkersson Rosenthal syndrome, sarcoidosis, superior cava syndrome, and head and neck, lymphoma, or pulmonary tumors can induce persistent, progressive, localized edema. In short, I feel a biopsy may be your next step to consider.
We had two similar cases, ultimately diagnosed with biopsy. One was confirmed to have sarcoidosis, the other angiosarcoma. I have seen cases of superior cava syndrome, though it would be unusual for the edema to be limited to the tongue. If superior cava syndrome is a consideration, then chest CT would be warranted.
I found a very nice review article in Experimental and Therapeutic Medicine, which you may find helpful.
Irena Nedelea, Diana Deleanu. Isolated angioedema: An overview of clinical features and etiology. 2019, Exp Ther Med. 2019 Feb; 17(2): 1068–1072.
Jeffrey Demain, MD, FAAAAI