Content Validity of Visual Analog Scales to Assess Symptom Severity of Acute Angioedema Attacks in Adults with Hereditary Angioedema

An Interview Study
  • Carolyn Vivienne McMillan
  • Jane Speight
  • Anurag Relan
  • Luca Bellizzi
  • Gerald Haase
  • Marco Cicardi
Original Research Article


Background: Hereditary angioedema (HAE) is a rare, debilitating, potentially life-threatening condition characterized by recurrent acute attacks of edema of the skin, face/upper airway, and gastrointestinal and urogenital tracts. During a laryngeal attack, people with HAE may be at risk of suffocation, while other attacks are often associated with intense pain, disfigurement, disability, and/or vomiting. The intensity of some symptoms is known only to the person experiencing them. Thus, interview studies are needed to explore such experience and patient-reported outcome measures (PROMs) are required for systematic assessment of symptoms in the clinical setting and in clinical trials of treatments for acute HAE attacks.

Objective: The aim of this interview study was to assess the content validity and suitability of four visual analog scale (VAS) instruments for use in clinical studies. The VAS instruments were designed to assess symptoms at abdominal, oro-facial-pharyngeal-laryngeal, peripheral, and urogenital attack locations. This is the first known study to report qualitative data about the patient’s experience of the rare disorder, HAE.

Methods: Semi-structured exploratory and cognitive debriefing interviews were conducted with 27 adults with a confirmed clinical/laboratory diagnosis of HAE (baseline plasma level of functional plasma protein C1 esterase inhibitor [C1INH] <50% of normal without evidence for acquired angioedema). There were 17 participants from the US and 10 from Italy, with mean age 42.5 (SD 14.5) years, range 18–72 years, mean HAE duration 21.3 (SD 14.1) years, range 1–45 years, 67% female, and 44% VAS-naïve. Experience of acute angioedema attacks was first explored, noting spontaneous mentions by participants of HAE symptomatology. Cognitive debriefing of the VAS instruments was undertaken to assess the suitability, comprehensibility, and relevance of the VAS items. Asymptomatic participants completed the VAS instruments relevant to their angioedema experience, reporting as if they were experiencing an acute angioedema attack at the time. Interviews were conducted in the clinic setting in the US and Italy over an 8-month period.

Results: Participants mentioned spontaneously almost all aspects of acute angioedema attacks covered by the four VAS instruments, thus providing strong support for inclusion of nearly all VAS items, with no important symptoms missing. Predominant symptoms found to be associated with acute angioedema attacks were edema and pain, and there was evidence of varying degrees of disruption to everyday activities supporting the inclusion of an overall severity item reflecting the disabling effects of HAE symptoms. VAS item wording was understood by participants.

Conclusion: This interview study explored and reported the patient experience of HAE attacks. It demonstrated the content validity of the four anatomical location HAE VAS instruments and their suitability for use in clinical trials of recombinant human C1INH (rhC1INH) treatment for ascertaining trial participants’ assessments of the severity of acute angioedema symptoms.


Visual Analog Scale Angioedema Hereditary Angioedema Attack Location Cognitive Debriefing 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study and manuscript preparation were funded by Pharming Technologies BV who were involved in the design and conduct of the study, and the review and approval of the manuscript.

CVM is a Consultant Health Psychologist at AHP Research and JS is Director of Research at AHP Research, an independent research company that received funding from Pharming to conduct this study and received consultancy fees related to contributions to other aspects of Pharming’s clinical studies. AR is a Medical Director at Pharming Technologies BV and has also received stock options in the company. GH is an independent consultant who was engaged by Pharming and received fees and expenses from the study sponsor throughout the conduct and reporting of the study. MC has or has had consultancy agreements with Pharming, Jerini, and Dyax and is on the advisory board for Jerini/Shire, CSL Behring, Pharming, Viro Pharma, and Dyax. Università degli Studi di Milano (= The University of Milan) received a payment from Pharming for performing the study. LB has a consultancy agreement with Pharming for running research and development activities.

The authors acknowledge valuable assistance from staff at all clinics (Family Allergy & Asthma Center P.C., Atlanta, GA, USA; Asthma, Allergy & Immunology Clinical Research Unit, Tampa, FL, USA; Allergy, Asthma & Immunology Clinic P.A., Irving, TX, USA; and Dipartimento di Scienze Cliniche “Luigi Sacco,” Ospedale Luigi Sacco, Milan, Italy) where people with HAE were recruited and interviews carried out. The authors thank Adele Succetti for conducting the interviews in Italy and all 27 participants for sharing their experiences and insights into HAE and contributing their time to aid our understanding of this condition.

GH and AR conceived the need for the interview study, which was designed by JS, CVM, AR, and GH and coordinated by CVM. MC reviewed the study protocol. JS and CVM conducted the interviews in the US and LB coordinated the interviews in Italy. CVM and JS analyzed the data and wrote the report upon which this manuscript is based. CVM drafted the manuscript, JS and AR contributed to the manuscript development, and all authors read and approved the final manuscript. CVM is the guarantor of the overall content of this article.


  1. 1.
    Agostoni A, Ygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress — proceedings of the Third C1 Esterase Inhibitor Deficiency Workshop and beyond. J Allergy Clin Immunol 2004 Sep; 114Suppl. 3: S51–131PubMedCrossRefGoogle Scholar
  2. 2.
    Davis III AE. The pathogenesis of hereditary angioedema. Transfus Apher Sci 2003 Dec; 29(3): 195–203PubMedCrossRefGoogle Scholar
  3. 3.
    Zuraw BL. Clinical practice: hereditary angioedema. N Engl J Med 2008 Sep 4; 359(10): 1027–36PubMedCrossRefGoogle Scholar
  4. 4.
    Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005 Mar; 139(3): 379–94PubMedCrossRefGoogle Scholar
  5. 5.
    Lumry WR, Castaldo AJ, Vernon MK, et al. The humanistic burden of hereditary angioedema: impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc 2010 Sep; 31(5): 407–14PubMedCrossRefGoogle Scholar
  6. 6.
    Myles PS, Urquhart N. The linearity of the visual analogue scale in patients with severe acute pain. Anaesth Intensive Care 2005 Feb; 33(1): 54–8PubMedGoogle Scholar
  7. 7.
    Stadler M, Schlander M, Braeckman M, et al. A cost-utility and cost-effectiveness analysis of an acute pain service. J Clin Anesth 2004 May; 16(3): 159–67PubMedCrossRefGoogle Scholar
  8. 8.
    Gerlinger C, Schumacher U, Faustmann T, et al. Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyses of two placebo-controlled, randomized trials. Health Qual Life Outcomes 2010 Nov 24; 8(1): 138PubMedCrossRefGoogle Scholar
  9. 9.
    Kelly AM. The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain. Emerg Med J 2001 May; 18(3): 205–7PubMedCrossRefGoogle Scholar
  10. 10.
    Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010 Aug 5; 363(6): 532–41PubMedCrossRefGoogle Scholar
  11. 11.
    U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health. Guidance for industry. Patient-reported outcome measures — use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes 2006; 4: 79CrossRefGoogle Scholar
  12. 12.
    Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol 2010 Oct; 126(4): 821–7PubMedCrossRefGoogle Scholar
  13. 13.
    Vernon MK, Rentz AM, Wyrwich KW, et al. Psychometric validation of two patient-reported outcome measures to assess symptom severity and changes in symptoms in hereditary angioedema. Qual Life Res 2009 Sep; 18(7): 929–39PubMedCrossRefGoogle Scholar
  14. 14.
    Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993; 118: 622–9PubMedGoogle Scholar
  15. 15.
    Bowling A. Measuring health: a review of quality of life measurement scales. 3rd ed. New York (NY): Open University Press, 2005Google Scholar
  16. 16.
    Willis G. Cognitive interviewing: a tool for improving questionnaire design. Thousand Oaks (CA): Sage Publications, 2005Google Scholar
  17. 17.
    Rothman M, Burke L, Erickson P, et al. Use of existing patient-reported outcome (PRO) instruments and their modification: the ISPOR Good Research Practices for Evaluating and Documenting Content Validity for the Use of Existing Instruments and Their Modification PRO Task Force Report. Value in Health 2010; 12(8): 1075–83CrossRefGoogle Scholar
  18. 18.
    Joffe H, Yardley L. Content and thematic analysis. In: Marks DF, Yardley L, editors. Research methods for clinical and health psychology. London: Sage, 2004: 56–68Google Scholar
  19. 19.
    Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009 Oct; 124(4): 801–8PubMedCrossRefGoogle Scholar
  20. 20.
    Bouillet L, Longhurst H, Boccon-Gibod I, et al. Disease expression in women with hereditary angioedema. Am J Obstet Gynecol 2008 Nov; 199(5): 484PubMedCrossRefGoogle Scholar
  21. 21.
    Bork K, Meng G, Staubach P, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006 Mar; 119(3): 267–74PubMedCrossRefGoogle Scholar
  22. 22.
    Speight J, Reaney M, Barnard KD. The use of hypothetical scenarios and importance weightings when measuring the impact of diabetes on quality of life: a response to Brose et al. Diabet Med 2010; 26(10): 1077–9CrossRefGoogle Scholar
  23. 23.
    Pramming S, Thorsteinsson B, Bendtson I, et al. Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabet Med 1991 Apr; 8(3): 217–22PubMedCrossRefGoogle Scholar
  24. 24.
    Gallagher EJ, Bijur PE, Latimer C, et al. Reliability and validity of a visual analog scale for acute abdominal pain in the ED. Am J Emerg Med 2002 Jul; 20(4): 287–90PubMedCrossRefGoogle Scholar
  25. 25.
    Todd KH, Funk KG, Funk JP, et al. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996 Apr; 27(4): 485–9PubMedCrossRefGoogle Scholar
  26. 26.
    Food and Drug Administration. Firazyr (icatibant) injection for the treatment of acute attacks of hereditary angioedema (HAE) in patients 18 years of age and older: briefing document [report no. NDA 022-150]. 2011 [online]. Available from URL: loads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM 260020.pdf [Accessed 2011 Jul 5]Google Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  • Carolyn Vivienne McMillan
    • 1
  • Jane Speight
    • 1
    • 2
    • 3
  • Anurag Relan
    • 4
  • Luca Bellizzi
    • 5
  • Gerald Haase
    • 6
  • Marco Cicardi
    • 7
  1. 1.AHP ResearchHornchurchUK
  2. 2.The Australian Centre for Behavioural Research in DiabetesMelbourneAustralia
  3. 3.The Centre for Mental Health and Wellbeing ResearchDeakin UniversityBurwoodAustralia
  4. 4.Pharming Group NVJersey CityUSA
  5. 5.Sintesi Research S.r.l.MilanItaly
  6. 6.Gordon & Levine Consultancy Services Ltd, Kingston upon ThamesUK
  7. 7.Dipartimento di Scienze Cliniche “Luigi Sacco,”Università degli Studi di Milano Ospedale Luigi SaccoMilanItaly

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