The characteristics of upper airway edema in hereditary and acquired angioedema with C1‐inhibitor deficiency

Abstract Background Angioedemas localized in the upper airway are potentially life threatening, and without proper treatment, they may lead to death by suffocation. Upper airway edemas (UAE) in bradykinin‐mediated angioedemas can even be the first symptoms of the disease. Methods Our survey was performed with a retrospective long‐term follow‐up method from the medical history of 197 hereditary (C1‐INH‐HAE) and 20 acquired C1‐inhibitor deficiency (C1‐INH‐AAE), 3 factor XII and 3 plasminogen gene mutation (FXII‐HAE, PLG‐HAE) patients treated at our center between 1990 and 2020. The UAE group included edemas localized to the mesopharynx, hypopharynx, and larynx, as narrowing of these anatomical regions can lead to suffocation. Results 98/197 C1‐INH‐HAE (47 families) and 13/20 C1‐INH‐AAE, 1/3 PLG‐HAE, 1/3 FXII‐HAE patients had experienced UAE at least once according to their medical history. In case of C1‐INH‐HAE patients, in 6/47 families who had undiagnosed ancestors had 13 members who died of suffocation. After the diagnosis, 1‐1 member of two families died of UAE. 44/64 C1‐INH‐HAE patients did not smoke, 20/64 did. The occurrence of UAE was significantly higher in smoker patients. We analyzed 7607 HAE attacks of 56/98 patients. Out of all attacks, the incidence of UAE in the C1‐INH‐HAE group was 4%, and 9.5% in the C1‐INH‐AAE group, respectively. Conclusion Early diagnosis is key in bradykinin‐mediated angioedemas cases, since the patient must be provided with adequate treatment; and also it is essential to inform patients about the importance of avoiding the trigger factors and the early symptoms of UAE, as these measures could significantly decrease the incidence of lethal UAEs.


| INTRODUCTION
The upper respiratory tract is the anatomical structure connecting  [9][10][11][12][13][14] There are acquired types of bradykinin-mediated angioedemas as well, for example, acquired angioedema with C1-inhibitor deficiency (C1-INH-AAE), acquired angioedema related to angiotensin-converting enzyme inhibitors (ACEI-AAE), and idiopathic nonhistaminergic acquired angioedema (InH-AAE). In case of C1-INH-AAE, the classical pathway of the complement system is activated and the C1-INH consumption is increased, which can be attributed to lymphoproliferative, tumorous, autoimmune, or infectious diseases, but autoantibodies against C1-INH may also lead to inadequate C1-INH function. 15 The disease occurs later than the hereditary form and the family history is negative to AE. AE is a rare side effect of ACEI therapy, which could occur either separately or as a provoking factor of C1-INH deficient forms. In the Caucasian population, the incidence of AE in patients taking ACEI is approximately between 0.1% and 0.7%, but it is more common in Black people. 16,17 For 30% of patients presenting with angioedematous symptoms at the emergency care department, the possibility of the provoking role of ACEIs arises. 18  Bradykinin-mediated forms of AE generally develop more slowly than other AEs, but UAE can show a fulminant course. 25 The purpose of the study was to analyze the clinical expression of UA angioedematous attacks in HAE and C1-INH-AAE patients treated in our center during the long-term follow-up.  F I G U R E 1 Death due to airway obstruction in C1-INH-HAE patients and their relatives. Group A gathers those patients who and/or whose families member(s) experienced upper airway edemas (UAE). Patients in group "B" their families members have never experienced UAE. After we analyzed the incidence of deaths due by suffocation in the families of both groups, which partially included those patients who were not treated at the Center. In group "A1", 13 patients; in group "B1", 2 patients; and in group "A2" another 2 patients died of suffocation. UAE attacks were more frequent in smokers, which was statistically significant. The Fisher exact test statistic value is 0.0119. The result is significant at p < 0.05 (Figure 3).

| C1-INH-HAE patients followed up between 2010 and 2020
We wanted to get a clear picture about the distribution of the attacks, so those patients were included in the group whose 2010-2020 data was available for the complete 10 years. We analyzed the data of 56 patients and 7607 attacks of these patients:

| DISCUSSION
Currently, the first appearance and the frequency of UAE cannot be predicted, it occurred in all four examined patient groups (C1-INH-HAE, C1-INH-AAE, PLG-HAE and FXII- They found that their life expectancy did not differ significantly from that of the general population; suffocation was preceded by death by malignant and cerebrovascular diseases, which could be explained by the availability of on-demand treatment. 27 The first UAE occurs at a young age, mostly in the second or third decade; however, it can also occur in children. In the literature the youngest age when UAE occurred was 3 years. UAE in children could rapidly cause suffocation since the diameter of the airways is way smaller than the airways of an adult; therefore a mild mucosa edema can cause an airway obstruction. In earlier studies, a connection was found between the early appearance of symptoms and the severity of the manifestation of HAE attacks. 28 Since the area of the larynx is highly exposed to pathogens and irritative agents, it is presumed that the larynx has an important immunological function in the airways; this is also supported by the mucosa-associated lymphoid tissue specific to the larynx found on the laryngeal surface of the epiglottis, the false vocal cords. 38 They showed that the chemical agents in tobacco smoke help neutrophil granulocytes produce superoxides and reactive oxygens; the necrosis of the mucosa could lead to the edema of the distal airways. 41

ACKNOWLEDGMENTS
We would like to thank the medical professionals working in the day-to-day care of these patients, without whose help this study could

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from Semmelweis University, Hungarian Angioedema Center of Reference and Excellence.