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    Workshop on Dengue Clinical Case Classification for Clinical Research

April 27-28, 2015 - Washington DC, USA

Case definitions for dengue were first developed using clinical experiences from dengue outbreaks involving children in Southeast Asia. The case definitions were published in the World Health Organization (WHO) technical guide in 1975 and updated in 1997. The WHO 1997 classification offers the possibility of grading of the severity of dengue cases. In November 2009, a new dengue case classification using a set of clinical and/or laboratory parameters was released by WHO to improve clinical management and surveillance across the globe in all settings, regardless of resources.

The value of a standardized dengue clinical case classification system

The workshop’s main objective was to reach consensus on a dengue clinical case classification (DCCC) system for moderate and severe dengue to be used in pathogenesis studies and/or intervention trials. Standardized definitions are very important to help ensure complete, accurate and harmonized classification of cases to monitor the long-term safety and effectiveness of dengue vaccines and to compare interventions. Currently, manufacturers use their own endpoints for severity.

Contributing to more targeted clinical research on dengue

The WHO case definitions established in 2009 are widely applied in endemic countries for case detection, patient triage and clinical management. However, they are of limited use in clinical research, especially as regards criteria for severe disease.

The workshop addressed this challenge by developing a refined clinical case classification for moderate and severe dengue that can be applied in interventional trials and pathogenesis studies as secondary endpoints. Case definitions are to be used to classify study subjects who are being monitored as part of an interventional trial or pathogenesis study and who meet the primary efficacy endpoint (i.e., two days of fever plus laboratory-confirmed DENV infection).

Workshop outcomes

Although the final definition of a proposed clinical case classification for clinical trials was not reached, workshop participants made progress in the identification of clinical and laboratory parameters to clearly approach a consensus about the definition of severe dengue. After the April workshop, a follow-up meeting was planned to coincide with the 64th Annual Meeting of the American Society of Tropical Medicine and Hygiene, October 25-29 2015.

At this follow-up workshop, held in Philadelphia on October 29, participants continued to move forward to reach consensus about clinical trial endpoints for the purpose of measuring the efficacy of dengue interventions on disease severity.

Assessing the impact of PDC’s holistic approach

Improving the comparability of data obtained from interventional trials and pathogenesis studies is particularly useful for the purpose of measuring the impact of PDC’s integrated vaccine intervention and vector control approach and to accurately assess the clinical benefit of a vaccine or drug. Standardization was requested during the Mexico meeting on surveillance. Comparability between interventions is a key step for assessing public health strategies.

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Speakers & Participants

  • Ana Carvalho, Sabin Vaccine Institute
  • Danilo Casimiro, Merck
  • Cristina Cassetti, NIAID
  • Beth-Ann Coller, Merck and Co.
  • Norma De Bosch, Universidad Central de Venezuela
  • Walla Dempsey, NIAID
  • Benjamin D’Hont, PDC
  • Anna Durbin, Johns Hopkins University
  • Catherine Dutel, PDC
  • Robert Edelman, University of Maryland
  • Michael Fay, NIAID
  • Duane Gubler, PDC / Duke University
  • Adrienne Guignard, GSK
  • Scott Halstead, Dengue Vaccine Initiative
  • Eva Harris, University of Berkeley
  • Katharina Hartmann, Takeda Vaccines Inc.
  • Joachim Hombach, WHO
  • Elizabeth Hunsperger, CDC
  • Thomas Jänisch, University Heidelberg
  • Denny Kim, Takeda Vaccines
  • Andrew Lane, LANE medical writing services
  • Catherine Laughlin, NIAID
  • Maïna L’Azou, Sanofi Pasteur
  • Lucy Lum, Univ Malaya Medical Center
  • Harold Margolis, CDC
  • Morgan Marks, Merck and Co. Inc
  • Federico Narvaez, Hospital Infantil Manuel de Jesus Rivera
  • Van Vinh Chau Nguyen, Hospital for Tropical Diseases
  • Fernando Noriega, Sanofi Pasteur
  • Alexander Precioso, Instituto Butantan
  • Elsa Rojas, Universidad Industrial de Santander
  • Alan Rothman, University of Rhode Island
  • Mitra Saadatian, PDC
  • Alexander Schmidt, GSK
  • Thomas W. Scott, University of California
  • João Bosco Siqueira, Federal University of Goias
  • Daniel Stoughton, DMID/NIAID/NIH
  • Piyarat Suntarattiwong, Queen sirikit Nat’l Inst of Child Health
  • Rémy Teyssou, PDC
  • Stephen Thomas, WRAIR
  • Laurent Thomas, Emergency Department / University Hospital
  • Hasitha Tissera, Ministry of Health Sri Lanka
  • Kay Tomashek, NIAID
  • Harshini Turner, Takeda Vaccines Inc.
  • Kirsten Vannice, WHO
  • Frank Von Sonnenburg, Department Infectious Diseases and Tropical Medicine, University of Munich, LMU
  • Derek Wallace, Takeda
  • Stephen Whitehead, Laboratory of Infectious Diseases, NIAID
  • Annelies Wilder-Smith, IVI
  • Bridget Wills, Oxford University Clinical Research Unit
  • Dana Yancey, Emmes Corporation
  • Yee Sin Leo, National University of Singapore
  • In-Kyu Yoon, AFRIMS

Program – Day 1

08h00 – 10h00

Concomitant Scientific Working Group Meetings

10h00 – 10h30

Welcome and Introduction

10h30 – 12h00

Session I: Framing the issue: the challenges of measuring dengue disease severity in pathogenesis studies and interventional research

  • Observational/pathogenesis studies in international clinical settings (Thomas Jänisch)
  • Sanofi’s experience on disease classification from Phase II/Phase III vaccine trials (Fernando Noriega)
  • Takeda’s experience on disease classification from Phase II vaccine trials (Derek Wallace)
  • Oxford University’s experience from Phase II therapeutic trials (Bridget Wills)
  • Status of rapid dengue diagnostics for use in interventional trials (Elizabeth Hunsperger)

13h00 – 13h50

Session II: Defining dengue severity markers: acute febrile illness (Bob Edelman and Stephen Thomas)

13h50 – 15h00

Session III: Defining dengue severity markers: severe bleeding Lucy Lum and Norma de Bosch)

15h30 – 17h30

Session IV: Defining dengue severity markers: plasma leakage (Bridget Wills and Elsa Rojas)

Program – Day 2

08h00 – 12h00

Session V: Defining dengue severity markers: organ involvement

  • Liver and gastrointestinal tract (Kay Tomashek)
  • Central nervous system and lung (Lucy Lum and Laurent Thomas)
  • Muscle, heart, and kidney (Laurent Thomas and Anna Durbin)

13h00 – 14h00

Session VI: Plans to evaluate a refined dengue clinical case definition (Thomas Jänisch and João Bosco Siqueira)

14h30 – 16h30

Session VII: Summary and next steps (Walla Dempsey and Stephen Thomas)