Prodromes predict attacks of Hereditary Angioedema: results of a prospective Study

To the Editor,

Hereditary Angioedema (HAE) is a lifetime disease characterized by repetitive bouts of tissue edema.¹ Early signs, symptoms and perceptions (prodromes) are manifested by subjective and objective signals, preceding attacks by several hours.^2-3 Using an new HAE-specific instrument, we have recently shown that patients can identify prodromes and able to predict oncoming attacks.⁴ However, that study was retrospective, which might have been affected by recall bias.

In the present study a cohort of 48 HAE patients prospectively reported four events of prodromes followed by attack, attacks not preceded by a prodrome and incidents with only a prodrome. Pre-defined domains (clusters of body locations) and scalable dimensions (pain, severity, impairment and functionality), time of onset and termination were assessed in each episode.^3-4 (Statistical methods are described in the supplementary data ). The study was approved by the ethics committees of Tel-Aviv University, Sheba Medical Center and Barzilai Medical center. All patients signed an informed-consent form. Mean age was 35.25 years (SD ±16.4), Median 30.0 (age range 10-70) and 27 (56.25%) were females. Mean age of onset was 8.3 years and age at diagnosis 10.9 years (2.7 years diagnostic gap) (Table S1 ).

We received reports on 119 prodromes and 192 attacks. The majority experienced a prodrome before at least one of their attacks, and 64% affirmed that they can predict an oncoming attack by having a prodrome.(Table S1) .

Significant differences were found between prodromes and attacks across all dimensions of the predefined clusters of body locations. Statistical analysis verified that prodromes could be discriminated from attacks for all parameters. (Table 1) Positive correlations were found between the same attributes of prodromes and attacks, most notably in the abdominal and extremity clusters (Table S2, Fig S1A-E) . Mean duration of prodromes was significantly shorter than attacks, and prodromes overlapped the attack in 24.3% of cases. The predictive power analysis indicates that individuals who experience a prodrome had higher risk for having an attack in the same region. Sensitivity of the prodrome as a predictor of attack was 95% to 99%, and specificity 18% to 64%. (Table 2).

HAE prodromes represents a continuity of pathophysiologic events, initiated by the activation of the bradykinin-forming cascade and ending with a breach in vascular endothelial integrity.^{2, 5}(Fig S2 ) In this study we aimed to capture the critical elements of prodromes and their association with consequent attacks and evaluate their predictive power as an early warning sign.^2-4 The HAE-EPA instrument reliably captures patient’s experience by using the same metrics, and the prospective design better reflects patients’ experience in real-time, which may have been missed in our previous study.

The study shades light on the predictive value of prodromes as forecasters of attacks.^2-4 It affirms that patients can clearly distinguish prodromes from attacks. The positive correlations support our basic assumption that prodromes could predict attack location and severity, which is particularly germane in the abdomen. In most cases a high intensity attack was predated by a high intensity prodrome. This substantiate our observation on inter-personal differences between subjects⁴ Mean disease duration of the cohort (27 years) may surmise that the study subjects were experienced patients, who could recognize early pre-attack cues.

Treating oncoming attack at the prodromal stage may enhance resolution of attacks.^{6, 7} Therefore; experienced patients can use prodromes as an efficient strategy in managing attacks by employing early interventions. Such approach can apply in other diseases with relapsing-remitting pattern and advance the concept of prodrome-triggered intervention.⁸

In conclusion , the study ascertained that HAE patients can distinguish prodromes from attacks and a prodrome may predict attack in the same location. Having a prodrome increase the likelihood of subsequent attack, alerting the patients and assisting in early initiation of therapy.