DISCUSSION
Pre-attack perceptions has been reported by HAE patient’s from the early descriptions of this rare genetic disorder, but are still loosely defined and therefore pose a clinical condundrum.7-12Some prodromes are charchterized by objective physical signs, even at the same location of the attack, which helps to fortell its development (i.e. Erythema Marginatum rash on the abdomen), but some are manifested by subjective sensations reflecting high variability in individual perceptions.8 At the present time, a large body of evidence supports the observation that prodromes are an intergral part of the edematous attacks, and may even represent a continuity of pathophysiologic events invlovling the bradykinin-forming cascade as well as the vascular endothelium. 14-17
HAE is a life-long illness and prodromes with its recurring nature are having a profound effect on the patient’s perception of their illness-trajectory and burden of disease.5,8 The present study indicates that personal variables such as age, gender, and experience in illness, can affect patient’s perception of prodromes and their ability to predict oncoming attacks. So far the main obstacle to the investigation of prodromes’ clinical significance has been the lack of reliable scientific methods that can capture the essential elements of the prodromes and their association with consequent attacks.9-12 Clearly, there is an unmet need for a unified definition of prodromes, its temporal relations to attacks, its predictive power as an early warning sign, and its use in mitigating cosequences of attacks.
A newly developed disease-specific evaluation instrument (HAE Evaluarion of Prodromes and Attacks, HAE-EPA), was chosen for this study.13 This investigational tool is based on the principles of patient-reported outcome measures (PRO) that have already shown its effectiveness in clinical research and medical practice.18-19 HAE-EPA is the first tool to measure both prodromes and attacks, while other HAE instruments are focusing on either attack attributes, or disease-related quality of life (HRQoL) or both (reviewed in ref. 13). The dimensions and domains selected for evaluation of the attacks and prodromes in our study are meant to authentically reflect the patients’ perception of disease severity and its effect on their daily routine, and therefore represent their real-life illness prespective.
The present study is an exploratory pilot which applied the HAE-EPA instrument to a cohort of 66 patients who were willing to share their experience on both prodromes and attacks, out of a total of 197 HAE patients surveyed in Israel.20
The statistical analysis presented in this study demonstrates significant differences in the dimensions of prodromes and attacks (i.e. pain, severity, limitation, functionality) across all pre-defined body domains (”clusters”). This means that patients could clearly distinguish between these two events. The positive correlations support our basic assumption that prodromes could predict attack location, severity and degree of impairment and functionality. These correlations indicate that high intensity prodromes can predict high severity of the subsequent attacks, which was particulary emphasized in the abdominal location. Moreover, the relationships seems not to be based on compensatory response during the attack (i.e. intense prodrome results in mild attack), but on a predictive principle (i.e intense prodrome predicts intense attack). As expected, prodromes were far less intense than attacks on all dimensions.
In this study we tried to comprehend how personal characteristics affect the interactions between prodromes and attacks in individual patients. Personal experience seems to be an essential asset when it comes to coping with chronic illness.21 Even though prodromes and attacks are unpredictable and vary in their manifestations, experienced patients are more attentive to their body cues and capable of finding some consistency and repetitiveness in the prodromes, enabling them better coping skills than the less experienced patients (i.e. newly diagnosed or with fewer attacks) who, according to our study, perceive more intense prodromes and attacks. Experience in illness is strongly associated with the patients’ ability of to predict attacks, distinguish them from the prodromes and employ these insights as a coping strategy. Experienced patients are expected to better endure the challenges of the disease by using the prodromes as an early warning sign and prepare to take preventative actions to mitigate the attacks. These finding are in-line with the observation that experienced patients are coping better with chronic disease and able to utilize their individual resources more efficiently21. In chronic diseases, patients develop their own perception of illness as a limitation and cultivate their own individual coping strategies. 22-23 More experienced and trained patients can recognize the early warning signs and use them as an efficient strategy in the management of attacks (i.e. timing of self-administration of rescue medication). 24