Introduction & Methods

Second International HHT Guidelines

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of approximately 1 per 5,000(1). It is characterized by clinically significant vascular malformations (VMs) of skin and mucous membranes of the nose and gastrointestinal tract as well as the brain, lung and liver. HHT is under-diagnosed and there is often a long diagnostic delay (2). Making the diagnosis of HHT in a patient allows appropriate screening and preventive treatment to be undertaken in the patient and their affected family members. The most common symptom of HHT, epistaxis, has an age-related expression, as does the appearance of the typical telangiectasia (3). In 2000, consensus clinical diagnostic criteria known as the Curaçao Criteria were published(4) (Supplement Table 1), and upheld in the first International HHT Guidelines(5). Genetic testing for HHT diagnosis was also recommended in the first International HHT Guidelines, primarily for asymptomatic people from a family with known HHT, as detailed in Table. In 97% of patients with a definite clinical HHT diagnosis, a causative mutation is identified in one of these genes: Endoglin (ENG, HHT1), Activin-Receptor Like kinase-1 (ACVRL1, HHT2), and Mothers Against Decapentaplegic homolog 4 (SMAD4, JP-HHT) (6).

The goal of this Second International HHT Guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT, the prevention of HHT-related complications and treatment of symptomatic disease in areas not previously addressed by guidelines and areas where significant new literature had been published. Several other recommendations from the first International HHT Guidelines were not re-assessed during this current process and remain currently recommended (Table)

Methods

The Second International HHT Guidelines were developed using the AGREE-II framework and GRADE methodology. The international HHT community provided priority topics to be included or updated based on new evidence or topics not previously addressed. Recommendations not revisited, but still considered currently recommended, are detailed in Table. Topic groups were appointed for each of the six areas selected for update or new review. Topic groups identified key questions to guide the systematic search strategy of the literature. Six sets of search strategies were developed and executed between May and June 2019 in Ovid MEDLINE by a medical librarian (KLR) with input from the Chair, and through a series of pre-determined steps illustrated in Appendix 1, including double review of both abstracts and full text articles; 221 articles were summarized into evidence tables. The quality of included RCTs was assessed (Appendix 2) using the structured framework of the Cochrane Risk of Bias Tool(7). In the months preceding the conference, the six topic groups generated draft recommendations based on key questions and the evidence tables and consistent with GRADE(8) formatting for levels of evidence and strength of recommendation. Draft recommendations were distributed to all panel members 2 weeks before the consensus meeting. 

The Guidelines Working Group (GWG) convened at the Guidelines Conference in November 2019 in Toronto Canada to partake in a structured consensus process. The GWG included clinical and genetic experts in all aspects of HHT from fifteen countries, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives, and patients with HHT.  

The GWG completed individual conflict of interest disclosures and potential conflicts were reviewed by the chair. 

The GWG was presented draft recommendations with supporting quality of evidence, voted anonymously on the wording/quality of evidence, was presented the draft strength of recommendation with justification by GRADE methodology, and then voted on the strength of recommendation. Consensus of 80% was required for the recommendation to be included in the Guidelines. 

A structured process was used to identify sources of disagreement for votes of less than 80% (see below). 

The recommendations were sent for external review to HHT experts and organizations; their comments were collated and addressed (Appendix 3). 

The funding sources had no role in the design, conduct or reporting of the Guidelines or in the decision to submit for publication.

The Table includes Clinical Recommendations from the:

  • Second International HHT Guidelines (with >=80% consensus)
  •  First International HHT Guidelines (with >=80% consensus AND which were not re-assessed by the 2019 International Guidelines Working Group. 

The expert panel is aware of new evidence and insights regarding some of these existing guidelines and they have been prioritized for updating at the next Guidelines process (Appendix 4).  

Consensus Process:

At the beginning of the conference, recommendation development methods were reviewed and discussed with the attendees(panel). For each topic area, topic groups met and refined draft recommendations. For each topic group, the topic leader presented the draft recommendation and quality of evidence to the entire panel, with supporting details for clinical considerations, after which time was allowed for discussion. The panel then voted anonymously on the wording of the recommendation and quality of evidence, using a standard format for wording and the evidence levels HIGH-MODERATE-LOW-VERY LOW (consensus). The topic leader then presented the draft strength of recommendation with justification by GRADE methodology (quality of evidence, balance of benefits and harms, values and preferences, cost - not considered explicitly but discussed as relevant). The panel then voted on the strength of recommendation. Consensus of 80% had to be achieved to allow the recommendation to be included in the guideline. If the initial vote was less than 80% consensus, the recommendation was deferred to the second day of the conference for further discussion and revision. Subsequent voting had also to achieve 80% consensus for the recommendation to be included. In the event that the panel did not achieve 80% consensus for strength of recommendation, the alternate strength was voted upon (STRONG/WEAK). If consensus was still not achieved, discussion continued to clarify the panel’s views on which factors (quality of evidence, balance of benefits and harms, values and preferences, cost) were driving dissent. In this way, the panel made every effort to make explicit non-evidentiary factors influencing recommendation strength. After all recommendations were discussed and voted upon, the chair reviewed next steps, surveyed the panel regarding future research and guidelines priorities Appendix 4) and the conference was adjourned.

Patient Involvement:

Patient representatives (patients with HHT, caregivers as well as representatives from Cure HHT and other patient advocacy organizations) were included at every step of the development process. Patient values were incorporated into the recommendations, during discussion and voting. Patients voted anonymously on recommendations and participated as manuscript authors.  Patients and patient advocacy groups also were involved in the External Review of the guidelines.

Funding Sources and Competing Interests

Funding Sources: The Christopher McMahon Family and Cure HHT.

Financial support for MEF: Nelson Arthur Hyland Foundation, Li Ka Shing Knowledge Institute of St Michael’s Hospital.

Role of Funding Sources: The funding sources had no role in the design, conduct or reporting of the study or in the decision to submit the results for publication. Although the funding sources were not directly involved in the generation of the recommendations, some of the participants in the guidelines process were also board members of Cure HHT, officers of Cure HHT or members of various Cure HHT committees.                                      

Competing interests: VAP received an honorarium for moderating the HHT Guidelines Conference, DC received an honorarium for conference participation and KLR was compensated for conducting the literature search and evidence review; neither participated in voting.

Potential conflicts of interest were reported prior to the Guidelines Conference: All were classified as “no significant conflict”, as per process detailed in the methods.

Contributors: All of the authors contributed to the Guidelines development and the resulting manuscript.

Authors and Author Affiliations

Authors:

Marie E. Faughnan MDMSc1,2, Johannes J. Mager MD PhD3, Steven Hetts MD4, Valerie A. Palda MD MSc5, Kelly Lang-Robertson6, Elisabetta Buscarini MD7, Erik Deslandres MD8,Raj S. Kasthuri MD9, Andrea Lausman MD10, David Poetker MD MA11, Felix Ratjen, MD12, Mark S. Chesnutt MD13, Marianne Clancy RDH MPA14, Kevin J. Whitehead MD15, Hanny Al-Samkari MD16, Murali Chakinala MD17, Miles Conrad MD18, Daniel Cortes BscPhm19, Claudia Crocione20, Jama Darling MD21, Els de Gussem MD22, Carol Derksen23, Sophie Dupuis-Girod MD PhD24, Patrick Foy MD25, Urban Geisthoff MD26, James R. Gossage MD27, Adrienne Hammill MD28, Ketil Heimdal, MD29, Katharine Henderson MS, CGC30, Vivek N. Iyer MD MPH31, Anette D. Kjeldsen, MD32, Masaki Komiyama MD33, Kevin Korenblatt MD34, Jamie McDonald MS CGC35, J. McMahon36, J. McWilliams MD37, Mary E. Meek MD38, Meir Mei-Zahav MD39, Scott Olitsky, MD MBA14, Sara Palmer, PhD40, Rose Pantalone RN1, Jay F. Piccirillo MD41, Beth Plahn RN MHA42, Mary E.M. Porteous MD43, Marco C. Post MD PhD44, Ivan Radovanovic MD45, Paul J. Rochon, MD46, Josanna Rodriguez-Lopez MD47, Carlo Sabba MD48, Marcelo Serra MD49, Claire Shovlin PhD MA50, Dennis Sprecher, MD51, Andrew J. White MD52, Ingrid Winship MBChB MD53, Roberto Zarrabeitia MD54.

Author affiliations:

  1. Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada 
  2. Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada 
  3. St. Antonius Hospital, Nieuwegein/Utrecht, The Netherlands
  4. Department of Neurointerventional Radiology, University of California San Francisco USA 
  5. Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada 
  6. Centre for Effective Practice, Toronto, ON, Canada 
  7. UOC Gastroenterologia ed Endoscopia Digestiva, HHT Reference Center ERN,  Ospedale Maggiore, ASST Crema, Italy
  8. Department of Gastroenterology, CHUM, Hotel Dieu, Montreal, QC Canada
  9. Division of Hematology/Oncology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA
  10. Department of Obstetrics and Gynecology, University of Toronto, St. Michael’s Hospital, Toronto, ON, Canada
  11. Department of Otolaryngology, Froedtert and Medical College of Wisconsin, Milwaukee, WI, USA
  12. Division of Respiratory Medicine, Department of Pediatrics, Translational Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON Canada
  13. VA Portland Health Care System, HHT Center of Excellence, Dotter Department of Interventional Radiology, Oregon Health & Science University, USA
  14. Cure HHT, Monkton, Maryland, USA 
  15. Department of Cardiovascular Medicine and Pediatric Cardiology, University of Utah Medical l Center, Salt Lake City, Utah, USA
  16. Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  17. Department of Pulmonology and Critical Care, Washington University School of Medicine, St. Louis, MO, USA 
  18. Department of Interventional Radiology University of California San Francisco USA 
  19. Pharmacy Department, St. Michaels Hospital, Unity Health Toronto, Toronto, Canada
  20. HHT Europe, Rome, Italy
  21. Department of Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA
  22. Department of Medicine, Section of Respirology, Grace Hospital, Winnipeg, MB Canada 
  23. HHT Canada, Spruce Grove, Alberta, Canada
  24. Hospices Civils de Lyon, Femme-Mère-Enfant, Hospital 69677 BRON, France
  25. Department of Hematology, Froedtert and Medical College of Wisconsin, Milwaukee, WI USA
  26. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Marburg, Phillips University Marburg, Marburg Germany
  27. Augusta University, Augusta, GA, USA
  28. Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital, and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
  29. Department of Genetics, Oslo University Hospital, RIkshopitalet, Oslo, Norway, 
  30. Yale University School of Medicine, New Haven, CT, USA
  31. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
  32. Department of Otorhinolaryngology Head and Neck Surgery,HHT-center OUH, Vascern member Odense University Hospital, Odense, Denmark
  33. Department of Neurointervention, Osaka City General Hospital, Osaka, Japan
  34. Department of Hepatology, Washington University School of Medicine, St. Louis, MO, USA
  35. Department of Pathology and Radiology, University of Utah Medical Center, Salt Lake City, Utah, USA
  36. Chester, New Jersey, USA 
  37. Department of Interventional Radiology, University of California Los Angeles, California, USA
  38. Department of Interventional Radiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
  39. Pulmonology Institute, Schneider Children’s Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Israel
  40. Baltimore, Maryland, USA
  41. Department of Otolaryngology-Head & Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA
  42. Sioux Falls, South Dakota, USA  
  43. Department of Genetics University of Edinburgh, Center of Molecular Medicine, Edinburgh, Scotland 
  44. Department of Cardiology, St. Antonius Hospital, Nieuwegein/Utrecht and University Medical Center Utrecht, The Netherlands
  45. Department of Neurosurgery, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Canada 
  46. Department of Interventional Radiology, University of Colorado Hospital, Aurora, CO, 
  47. Department of Pulmonology, Massachusetts General Hospital, Boston, Massachusetts, USA
  48. Department of Internal Medicine, University of Bari, Bari, Italy
  49. Department of Internal Medicine, Hospital Italiano de Buenos Aires, Burenos Aires, Argentina
  50. Department of Pulmonology, Hammersmith Hospital, London, England
  51. Blue Bell, PA, USA
  52. Division of Pediatric Immunology and Rheumatology, Washington University School of Medicine, St. Louis, MO, USA
  53. Genomic Medicine, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia
  54. Servicio de Medicina Interna, Unidad HHT, Hospital Sierrallana (Servicio Cántabro de Salud), Torrelavega (Cantabria), Spain

Correspondence to: Dr. M.E. Faughnan, St. Michael’s Hospital, University of Toronto, St. Michael’s Hospital, 30 Bond St, Toronto, M5B-1W8, Canada; [email protected]