The Enigma of Prodromes in Hereditary Angioedema (HAE)


A prodrome is a premonitory set of signs and symptoms indicating the onset of a disease. Prodromes are frequently reported by hereditary angioedema (HAE) patients, antedating attacks by a few hours or even longer. In some studies, high incidence of prodromes was reported by patients, with considerable number being able to predict oncoming attacks. Regrettably, prodromes have never received a consensual definition and have not been properly investigated in a systematic fashion. Therefore, their nature remains elusive and their contribution to the diagnosis and treatment of disorders is uncertain. The term “prodrome,” as used in various pathologies, denotes different meanings, timing, and duration, so it may not be equally suitable for all clinical situations. Perception of a prodrome is unique for each individual patient depending on self-experience. As modern drugs delegate the administration decision to the patients, early detection of a developing attack may help mitigate its severity and allow deployment of appropriate therapy. New diagnostic instruments were recently developed that can assist in defining the attributes of prodromes and their association with attacks. We will review the prodrome phenomenon as exhibited in certain clinical situations, with an emphasis on prodromes of HAE.

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Data Availability

Iris Leibovich Nassi RN, PhD thesis (Tel Aviv University).







Bradykinin receptor


C1 Inhibitor


Calcitonin gene-related peptide


Complement component 4


Erythema marginatum


Familial Mediterranean fever




Hereditary angioedema


Herpes zoster virus


Kallikrein-kinin system


Neurokinin A


Nitrous oxide species


Phospholipid A


Patient reported outcome


Substance P


Transient receptor potential


Vascular endothelial growth factor


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ILN received educational grants from the Stanley Steyer Foundation (Tel Aviv University, Israel) and CSL-Behring (Germany).

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Correspondence to Avner Reshef.

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The study was approved and supervised by the Ethics and Helsinki IRB committees of Tel Aviv University, Sheba Medical Center and Barzilai Medical Center, Israel.

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Leibovich-Nassi, I., Reshef, A. The Enigma of Prodromes in Hereditary Angioedema (HAE). Clinic Rev Allerg Immunol (2021).

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  • Angioedema
  • Attacks
  • Bradykinin
  • Prodromes
  • PRO