New Instrument for the Evaluation of Prodromes and Attacks of Hereditary Angioedema (HAE-EPA)


A disease-specific, patient-reported outcome instrument suitable for evaluation of prodromes and attacks of hereditary angioedema (HAE) is a clinical unmet need. We constructed such instrument and examined its validity, acceptability, and discriminative ability. Sixty-six patients participated in a survey addressing their demographics, social, and medical status. Discriminant content validity involved: (1) construct definition by in-depth cognitive debriefing interviews, (2) item selection identifying relevant categories, and (3) judgment of the format whereby questionnaires were tested on experienced patients and its content/reliability was validated. Prodromes and attacks affecting certain body systems (domains) were organized in “clusters”. Internal consistency, content, and convergent validities were analyzed. Analyses of variance and regression models were used to evaluate the discriminative ability of the instrument to differentiate between attacks and prodromes. The study demonstrates very high internal consistency (Cronbach’s α: attacks 0.88–0.98, prodromes 0.78–0.98). Analysis of variance confirmed significant differences between all dimensions and in pre-defined clusters (F (4, 61) = 45.74, p < 0.001, Eta2 = 0.77). Significant correlations were found between dimensions of prodromes and attacks. Prodromes are associated but differentiated from attacks. Correlations in severity were high for all domains. Interactions were found between prodromes and patients' experience in illness. In conclusion, the new Prodrome-Attack Evaluation questionnaire (HAE-EPA) is capable of distinguishing attacks and prodromes of HAE, as well as determining associations between the two interrelated phenomena. The new instrument achieves the required discriminative ability, acceptability, and content validity/reliability and therefore can be used as a reliable tool for the investigation of prodromes, attacks, and their relationships.

This is a preview of subscription content, access via your institution.

Fig. 1

Data Availability

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





Complement 1-esterase Inhibitor




Hereditary angioedema


Patient-reported outcome


HAE Evaluation of Prodromes and Attacks


Health-related quality of Life


  1. 1.

    Busse PJ, Christiansen SC (2020) Hereditary angioedema. N Engl J Med 382:1136–1148.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Reshef A, Kidon M, Leibovich I (2016) The story of angioedema: from Quincke to bradykinin. Clin Rev Allergy Immunol 51(2):121–139.

    Article  PubMed  Google Scholar 

  3. 3.

    Zuraw BL, Christiansen SC (2016) HAE: pathophysiology and underlying mechanisms. Clin Rev Allergy Immunol 51(2):216–229.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kaplan AP, Joseph K (2017) Pathogenesis of hereditary angioedema: the role of the bradykinin-forming cascade. Immunol Allergy Clin N Am 37(3):513–525.

    Article  Google Scholar 

  5. 5.

    Lumry WR, Castaldo AJ, Vernon MK et al (2010) The humanistic burden of hereditary angioedema: impact on health-related quality of life, productivity, and depression. Allergy Ast Proc 31(5):407–414

    Article  Google Scholar 

  6. 6.

    Wilson D, Bork K, Shea EP et al (2010) Economic costs associated with acute attacks and long-term management of hereditary angioedema. Ann Allergy, Ast and Immunol 104(4):314–320.

    Article  Google Scholar 

  7. 7.

    Lumry WR (2018) Hereditary angioedema: the economics of treatment of an orphan disease. Front Med 5:22.

    Article  Google Scholar 

  8. 8.

    Kemp JG, Craig TJ (2009) Variability of prodromal signs and symptoms associated with hereditary angioedema attacks: a literature review. Allergy Ast Proc 30:493–499

    Article  Google Scholar 

  9. 9.

    Prematta MJ, Kemp JG, Gibbs JG, Craig TJ (2009) Frequency, timing, and type of prodromal symptoms associated with hereditary angioedema attacks. Allergy Ast Proc 30:506–511

    Article  Google Scholar 

  10. 10.

    Prematta MJ, Bewtra AK, Levy RJ et al (2012) Per-attack reporting of prodromal symptoms concurrent with C1-inhibitor treatment of hereditary angioedema attacks. Adv Ther 29(10):913–922.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Reshef A, Prematta M, Craig TJ (2013) Signs and symptoms preceding acute attacks of hereditary angioedema: results of three recent surveys. Allergy Ast Proc 34(3):261–266

    Article  Google Scholar 

  12. 12.

    Leibovich-Nassi I, Golander H, Somech R, Har-Even D, Reshef A (2019) Are HAE patients able to distinguish prodromes from attacks, and are they correlated? Allergy, Ast Clin Immunol 15(Suppl 4):P10

    Google Scholar 

  13. 13.

    Santana MJ, Feeny D (2014) Framework to assess the effects of using patient-reported outcome measures in chronic care management. Qual Life Res 23:1505–1513

    Article  Google Scholar 

  14. 14.

    Nelson EC, Eftimovska E, Lind C et al (2015) Patient reported outcome measures in practice. BMJ 350:g7818.

    Article  PubMed  Google Scholar 

  15. 15.

    Kelman L (2004) The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs. Headache 44(9):865–872

    Article  Google Scholar 

  16. 16.

    Schoonman GG, Evers DJ, Terwindt GM, van Dijk JG, Ferrari MD (2006) The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients. Cephalalgia 26:1209–1213

    CAS  Article  Google Scholar 

  17. 17.

    Houtveen JH, Sorbi MJ (2013) Prodromal functioning of migraine patients relative to their interictal state—an ecological momentary assessment study. PLoS ONE 8(8):e72827.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lidar M, Yaqubov M, Zaks N et al (2006) The prodrome: a prominent yet overlooked pre-attack manifestation of familial Mediterranean fever. J Rheumatol 33(6):1089–1092

    PubMed  Google Scholar 

  19. 19.

    Babaoglu H, Varan O, Kucuk H et al (2019) On demand use of anakinra for attacks of familial Mediterranean fever (FMF). Clin Rheumatol 38(2):577–581

    Article  Google Scholar 

  20. 20.

    Vernon MK, Rentz AM, Wyrwich KW, White MV, Grienenberger A (2009) Psychometric validation of two patient-reported outcome measures to assess symptom severity and changes in symptoms in hereditary angioedema. Qual Life Res 18:929–939.

    Article  PubMed  Google Scholar 

  21. 21.

    McMillan CV, Speight J, Relan A et al (2012) Content validity of visual analog scales to assess symptom severity of acute angioedema attacks in adults with hereditary angioedema: an interview study. Patient 5(2):113–126.

    Article  PubMed  Google Scholar 

  22. 22.

    Weller K, Groffik A, Magerl M et al (2013) Development, validation, and initial results of the Angioedema Activity Score. Allergy 68:1185–1192

    CAS  PubMed  Google Scholar 

  23. 23.

    Bonner N, Abetz-Webb L, Renault L et al (2015) Development and content validity testing of a patient-reported outcomes questionnaire for the assessment of hereditary angioedema in observational studies. Health Qual Life Outcomes 3:92.

    Article  Google Scholar 

  24. 24.

    Bygum A, Busse P, Caballero T et al (2017) Disease severity, activity, impact and control and how to assess them in patients with hereditary angioedema. Front Med 4:212

    Article  Google Scholar 

  25. 25.

    Weller K, Donoso T, Magerl M et al (2020a) Development of the Angioedema Control Test—a patient-reported outcome measure that assesses disease control in patients with recurrent angioedema. Allergy 75:1165–1177

    Article  Google Scholar 

  26. 26.

    Weller K, Donoso T, Magerl M et al (2020b) Validation of the Angioedema Control Test (AECT)—a patient reported outcome instrument for assessing angioedema control. J Allergy Clin Immunol Pract 8(6):2050–2057

    Article  Google Scholar 

  27. 27.

    João Forjaz M, Ayala A, Caminoa M et al (2020) HAE-AS, a specific disease activity scale for hereditary angioedema with C1-inhibitor deficiency. J Investig Allergol Clin Immunol 10. Online ahead of print.

  28. 28.

    Weller K, Groffik A, Magerl M et al (2012) Development and construct validation of the angioedema quality of life questionnaire. Allergy 67:1289–1298

    CAS  Article  Google Scholar 

  29. 29.

    Prior N, Remor E, Gomez-Traseira C et al (2012) Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project. Health Qual Life Outcomes 10:82

    Article  Google Scholar 

  30. 30.

    Weller K, Magerl M, Peveling-Oberhag A et al (2016) The Angioedema Quality of Life Questionnaire (AE-QoL)—assessment of sensitivity to change and minimal clinically important difference. Allergy 71:1203–1209

    CAS  Article  Google Scholar 

  31. 31.

    Prior N, Remor E, Pérez-Fernández E et al (2016) Psychometric field study of Hereditary Angioedema Quality of Life Questionnaire for adults: HAE-QoL. J Allergy Clin Immunol Pract 4:464–473

    Article  Google Scholar 

  32. 32.

    Strauss AL, Glaser BG (1975) Chronic illness and the quality of life (2nd Edition). Saint-Louis MO: CV Mosby pp160. ISBN-10: 0801648378

  33. 33.

    Leibovich-Nassi I, Golander H, Somech R, Har-Even D, Reshef A (2019) A new instrument for the evaluation of premonitory signs and symptoms (prodromes) of Hereditary Angioedema. Allergy 74: S106 (P. 215)

  34. 34.

    Farrar JT, Portenoy RK, Berlin JA, Kinman JL, Strom BL (2000) Defining the clinically important difference in pain outcome measures. Pain 88:287–294.

    Article  PubMed  Google Scholar 

  35. 35.

    Cronbach L (1951) Coefficient alpha and the internal structure of tests. Psychometrika 16:297–334

    Article  Google Scholar 

  36. 36.

    Baiardini I, Bousquet PJ, Brzoza Z et al (2010) Recommendations for assessing patient reported outcomes and health-related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper. Allergy 65(3):290–295.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Baiardini I, Braido F, Bindslev-Jensen C et al (2011) Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA(2) LEN taskforce position paper. Allergy 66(7):840–844.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Leibovich-Nassi I, Reshef A, Somech R, Golander H (2017) A survey of hereditary angioedema in Israel. Allergy, Ast Clin Immunol 13(Suppl 2):34

    Google Scholar 

  39. 39.

    Barlow JH, Cullen A, Rowe IF (1999) Comparison of knowledge and psychological well-being between patients with a short disease duration and patients with more established rheumatoid arthritis. Pat Edu Counsel 38:195–203

    CAS  Article  Google Scholar 

  40. 40.

    Scully JL (2004) What is a disease? Disease, disability and their definitions. Europ Moll Biology Organ Rep 5(7):650–653

    CAS  Google Scholar 

  41. 41.

    Folkman S, Lazarus R (1980) An analysis of coping in a middle-aged community sample. J Health Soc Behav 21:219–239

    CAS  Article  Google Scholar 

  42. 42.

    Lazarus R, Folkman S (1984) Stress. Appraisal and Coping, New York, Springer

    Google Scholar 

  43. 43.

    Maurer M, Aberer W, Bouillet L et al (2013) Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS ONE 8(2):e53773.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Betschel S, Badiou J, Binkley K et al (2019) The International/Canadian Hereditary Angioedema Guideline. Allergy Ast Clin Immunol 15:72.

    Article  Google Scholar 

  45. 45.

    Kreiberg KB, Bygum A (2019) Reporting through smartphone application results in detailed data on acquired and hereditary angioedema attacks. Allergy 74:1800–1802

    Article  Google Scholar 

Download references


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

Author information




Concept and design:ILN, HG, AR.

Acquisition of data:ILN.

Analysis and interpretation of data:ILN, DH-E, HG.

Drafting of the manuscript:ILN, AR.

Critical revision for intellectual content: ILN, AR, HG, RS, DH-E.

Statistical analysis:ILN, DH-E.

Supervision:AR, HG, RS.

Corresponding authors

Correspondence to Iris Leibovich-Nassi or Avner Reshef.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Leibovich-Nassi, I., Golander, H., Somech, R. et al. New Instrument for the Evaluation of Prodromes and Attacks of Hereditary Angioedema (HAE-EPA). Clinic Rev Allerg Immunol (2021).

Download citation


  • Attacks
  • Dimensions
  • Hereditary angioedema
  • Prodromes
  • PRO
  • Validity