Discussion
The significant progress that has been made in the past decade in elucidating the pathophysiological mechanisms of HAE has led to discoveries of novel therapies providing patients with better on-demand and prophylactic treatment options. As a result, patient care and their quality of life has significantly improved.22 The majority of participants enrolled in the current study were working full- or part-time and they frequently engaged in physical activities. At the same time, there was a very high level of satisfaction among the HAE patients (>90%) regarding the medical care they receive from physicians. Additionally, the majority of participants (70%) felt they manage their disease well. These findings are encouraging and show the significant progress made. However, HAE patients are still profoundly burdened with disease, experiencing frequent and unpredictable attacks and thus, their ability to live their life the way they want remains heavily impacted. Despite the progress made in HAE management, only 5% of participants said the disease has no impact on their everyday life. Thus, improvement in the care of individuals suffering from HAE is still needed.
The perception of prodromal signs and symptoms is unique to each individual patient. However, there is a pattern of early signs and symptoms experienced by majority of patients. These might include malaise, fatigue, changes in mood or emotions, such as sadness and irritability, as well as a tingling sensation and skin rash (i.e. erythema marginatum), abdominal pain or nausea.11,16,23,24 Data from our study revealed a similar pattern, with fatigue, followed by pressure or tightness in the skin, pressure and widespread pain in the abdomen being most commonly noted. Given the fact that there is a wide spectrum of prodromal symptoms, the majority of them subjective, the most important question is whether the patients themselves can recognize their symptoms and predict a forthcoming attack, and thus “treat early” prior to a swelling occurring.
We believe that early signs and symptoms that precede episodes of swelling are potentially helpful and important to further improving the management of HAE. Previously, the information about HAE prodromes has been published in the form of short case reports or series.25–30 Recently, the awareness of the clinical value of prodromes increased the number of more purposeful clinical research studies involving larger cohorts of patients.24,31–34In 2013, Reshef et al. gathered the results from 3 independent surveys (totalling 113 patients) conducted in Israel and the USA, thus providing the largest source of data at that time.16 The study showed that the majority of patients (83–96%) reported experiencing prodromes and 2/3 indicated that prodromes preceded > 50% of their attacks. Furthermore, prodromes are experienced in 42–58% of paediatric HAE patients.28,35 More recently, in a survey conducted in 2019, 84% of patients declared ever experiencing a prodrome and 64.3% confirmed that they could predict an oncoming attack.21,31 All this data is in agreement with the results delivered by our study. We conducted one of the largest surveys of its kind by simultaneously collecting data from 208 HAE patients from the UK and Spain. The results demonstrated that 56% of patients who had ever experienced a prodrome were usually aware of prodromal symptoms before the swelling occurred.
Previous studies by Leibovich et al. indicated there was a significant correlation between the perception of prodrome and the ability of patients to predict an oncoming attack.21 Our survey confirmed that for most patients, the early signs have a predictive nature, allowing them to be aware that an attack is underway and that swelling may be imminent, and to prepare for it. Interestingly, the actions taken by patients when they experienced prodromal signs differed between the UK and Spain. While the majority of patients in the UK (56%) reported taking some form of medication, most patients in Spain (65%) chose to relax or wait to see how the situation would develop. These differences in approach may be related to the easier access to on-demand treatment for patients in the UK, where the vast majority have their medication delivered, making them more likely to act and “treat early”. Of those participants who took medication when they had prodromal symptoms before the swelling started, two-thirds felt that they had avoided an attack by treating early. Importantly, the percentage of patients who only needed one injection to treat the attack increased when patients took their medication early in the prodromal stage (from 55 to 66%). Although the medication injected by the patients was not specified, we suspect that it was most likely icatibant, given the known half-lives of the various products. These findings suggest that early self-treatment does improve treatment response. This is consistent with the evidence in the literature showing that early treatment is associated with a shorter time to symptom resolution and shorter total HAE attack duration, regardless of attack severity.20,36 However, the specificity of prodromes is still unknown and treating early may lead to overuse of on-demand therapy.21,24,31,37
Of note, the 2021 international World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) HAE guidelines advocate treating all attacks as early as possible.37 The recommendations are based on studies showing that early on-demand treatment of HAE attacks with intravenous-C1-INH, ecallantide, or icatibant provides a better treatment response than late treatment.20,38–40 Most significantly, the guidelines acknowledge that in many patients, a significant number of attacks are preceded by prodromal symptoms, and in some, this may be an opportunity to treat before an attack occurs.37 Our survey data does indicate that a considerable proportion of patients do already use treatment in the prodromal phase.
Although almost three-quarters of respondents said that their HCP had advised them to ’treat early’, the understanding of what is meant by ’treat early’ is variable, with some patients believing that this means taking the medication as soon as the swelling starts. 39% of participants take their medication at the prodromal signs, but 50% wait for the swelling to start. Given the pain associated with the attacks, the aim would be to treat as soon as prodromes occur, not only to reduce the duration and severity of the attacks but, more crucially, to prevent swelling altogether. Further studies are therefore needed to determine the percentage of attacks that are preceded by prodromes and to show the relationship between prodromes and attacks. This is of paramount importance, especially in light of recent evidence showing that pathophysiological changes begin as early as the onset of EM, suggesting that the prodrome is not a separate entity but actually a first phase of an attack itself.17
Our study has several limitations related to survey methodology, such as population bias (patients who accepted the invitation were self-selected), recall bias, and potential misclassification of responses. In addition, the survey excluded patients under the age of 16 years and therefore does not reflect the paediatric population. Response to the study was voluntary and the validity of the results is limited to the population that completed the survey. These limitations restricted our analysis to a descriptive presentation of the findings. However, the fact that the results were generally consistent with published literature indicates that these limitations did not overly bias the results.