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.