Beyond Skin Deep: Olfactory Dysfunction as a Common Problem Among Chinese Hereditary Angioedema Patients

Abstract

Hereditary angioedema (HAE) is a rare genetic condition characterised by recurrent, unpredictable episodes of skin, laryngeal and abdominal swelling [1]. In 2011, Perricone et al. reported the issue of olfactory dysfunction (OD), such as hyposmia (reduced sense of smell) and even functional anosmia (loss of sense of smell), in Italian patients with HAE [2]. We believe this is a significant finding, which remains largely neglected and under-investigated by the HAE community and requires validation in non-Western cohorts [2-4]. We therefore conducted this study to address this gap from an Asian perspective.

We recruited all HAE patients from Queen Mary Hospital, an Angioedema Center of Reference and Excellence (ACARE) in Hong Kong [5, 6]. Healthy individuals, matched by age and sex who reported normal olfaction and no history of smelling or OD-related disorders, were recruited as controls. All participants underwent the locally validated ‘Sniffin' Sticks’ test (SST; Burghart Messtechnik, Wedel, Germany) with previously described protocols [7]. They were classified as ‘supersmellers’ (score ≥ 41.5), ‘normosmia’ (30.5 < score < 41.5), ‘hyposmia’ (≤ 30.5) or ‘anosmia’ (≤ 16) [8]. For HAE patients, data on their lowest C4, C1-inhibitor (C1-INH) levels and function, and SERPING1 mutations were collected. The Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster granted approval for this study. All participants provided informed consent. Statistical analysis was performed using IBM SPSS Statistics version 28.0 (IBM Corp, Armonk, NY). Chi-squared test and independent t-test were utilised to compare categorical and continuous variables, respectively. Logistic regression was performed to control for age and sex. Among HAE patients, we examined the Spearman correlations among continuous variables. Additionally, a subgroup analysis was conducted between patients with HAE type I and II. A p-value of < 0.05 was considered statistically significant.

Our study included 21 HAE patients (16 [76.2%] type I and 5 [23.8%] type II) and 21 healthy controls, all of Han Chinese ethnicity. Their demographics, SST results and pathogenic mutations are available in the Online Repository (https://osf.io/7fz8u/). As shown in Figure 1, HAE patients had significantly lower SST scores compared to healthy controls (30.8 ± 7.5 vs. 34.7 ± 3.5, p = 0.040). Among HAE patients, 38.1% (8/21) had OD (hyposmia [33.3%, 7/21] or anosmia [4.8%, 1/21]), which was significantly more than the control group (hyposmia [9.5%, 2/21], p = 0.030). After controlling for age and sex, HAE was still significantly associated with OD, with an odds ratio of 9.946 (95% confidence interval = 1.161–85.235, p = 0.036).

Overall, we found no significant correlations between the C4, C1-INH, and SST scores among HAE patients (see the Online Repository). In our subgroup analysis, C1-INH levels were significantly correlated to SST scores in both type I and II HAE patients, but in opposite directions (type I: ρ = −0.536, p = 0.032; type II: ρ = 0.900, p = 0.037). There were no significant differences in SST scores between type I and II HAE (30.2 ± 8.3 in type I vs. 32.8 ± 4.2 in type II, p = 0.523), nor in the proportion of patients with OD (37.5% [6/16] in type I vs. 40.0% [2/5] in type II, p = 1.000). Patients with gross or structural deletions tended to have lower SST scores than those with missense or nonsense mutations (28.4 ± 11.6 vs. 32.0 ± 4.5), though this difference did not reach statistical significance (p = 0.459).

To the best of our knowledge, this is the first study to report impaired olfaction in Asian HAE patients. In line with past reports, roughly one-third of HAE patients displayed OD. Even after adjusting for age (a well-recognised factor associated with OD) and sex, HAE patients continued to exhibit a significantly higher, 10-fold risk of OD than healthy individuals. The underlying mechanism of OD in HAE remains elusive. Some postulate that OD is associated with complement depletion, which is similarly observed in multiple other autoimmune conditions despite unclear pathways [2, 9]. Another possible contributing factor is the proximity of the SERPING1 gene and the olfactory receptor genes on chromosome 11q13, where a high frequency of recombination and linkage disequilibrium between the two may lead to abnormalities in gene expression [3]. However, interestingly, in agreement with Forster-Ruhrmann et al., we found that the size or nature of SERPING1 mutations did not predict olfactory outcomes, suggesting that the underlying pathophysiology of OD in HAE may be complex and multifactorial [3].

This study's limitations include its small sample size, which only included type I and II HAE patients. It would be interesting to investigate its effect on quality of life and if this phenomenon exists in HAE with normal C1-INH. Besides, no specific investigations such as nasoendoscopy were employed to definitively exclude comorbid nasal pathologies.

In conclusion, our study indicates that approximately 1 in 3 Chinese patients with HAE suffers from OD, which underscores the need for further large-scale and mechanistic studies.

H.W.F.M. researched the data and drafted the manuscript. V.C., J.S.H.Y., E.L. and D.L.Y.L. researched the data. P.H.L. conceptualised and supervised the study. All authors contributed to and approved the final version of the manuscript before submission.

The authors declare no conflicts of interest.