title: Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries.
abstract: BACKGROUND
  The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course.
  
  
  METHODS
  This is a prospective multi-centre observational study aiming to enrol 7-8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later.
  
  
  CONCLUSIONS
  Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for "Integrated Management of Childhood Illness" used in dengue-endemic countries.
  
  
  BACKGROUND
  NCT01550016. Registration Date: March 7, 2012.
authors.affiliation: Section Clinical Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jaenisch
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.|University of Medicine and Pharmacy of Ho Chi Minh City, Ho Chi Minh City, Vietnam.
authors.forename: Dong Thi Hoai
authors.initials: DT
authors.lastname: Tam
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Tan Thanh
authors.initials: NT
authors.lastname: Kieu
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tran
authors.initials: T
authors.lastname: Van Ngoc
authors.affiliation: Children's Hospital Number 2, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Tran
authors.initials: NT
authors.lastname: Nam
authors.affiliation: National Hospital for Tropical Diseases, Hanoi, Vietnam.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Van Kinh
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.|Department of Medicine, Imperial College, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Yacoub
authors.affiliation: Angkor Hospital for Children, Siem Reap, Cambodia.
authors.forename: Ngoun
authors.initials: N
authors.lastname: Chanpheaktra
authors.affiliation: Angkor Hospital for Children, Siem Reap, Cambodia.|Present address: Rwanda Military Hospital and the University of Rwanda in Kigali, Kigali, Rwanda.
authors.forename: Varun
authors.initials: V
authors.lastname: Kumar
authors.affiliation: University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
authors.forename: Lucy Lum Chai
authors.initials: LL
authors.lastname: See
authors.affiliation: Ampang Hospital, Kuala Lumpur, Malaysia.
authors.forename: Jameela
authors.initials: J
authors.lastname: Sathar
authors.affiliation: Hospital Nacional de Niños Benjamin Bloom, San Salvador, El Salvador.
authors.forename: Ernesto Pleités
authors.initials: EP
authors.lastname: Sandoval
authors.affiliation: Hospital Nacional de Niños Benjamin Bloom, San Salvador, El Salvador.|Present address: St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Gabriela Maria Marón
authors.initials: GM
authors.lastname: Alfaro
authors.affiliation: Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Ida Safitri
authors.initials: IS
authors.lastname: Laksono
authors.affiliation: Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Yodi
authors.initials: Y
authors.lastname: Mahendradhata
authors.affiliation: James P Grant School of Public Health, BRAC University, Dhaka, Bangladesh.
authors.forename: Malabika
authors.initials: M
authors.lastname: Sarker
authors.affiliation: International Center for Diarrhoeal Diseases Research, Dhaka, Bangladesh.
authors.forename: Firoz
authors.initials: F
authors.lastname: Ahmed
authors.affiliation: Universidade Estadual Do Ceará, Fortaleza, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caprara
authors.affiliation: Universidade Estadual Do Ceará, Fortaleza, Brazil.
authors.forename: Bruno Souza
authors.initials: BS
authors.lastname: Benevides
authors.affiliation: Centro de Pesquisas Aggeu Magalhaes, Fundacao Oswaldo Cruz, Recife, Pernambuco, Brazil.
authors.forename: Ernesto T A
authors.initials: ET
authors.lastname: Marques
authors.affiliation: Centro de Pesquisas Aggeu Magalhaes, Fundacao Oswaldo Cruz, Recife, Pernambuco, Brazil.
authors.forename: Tereza
authors.initials: T
authors.lastname: Magalhaes
authors.affiliation: Instituto Nacional de Infectologia Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Brasil
authors.affiliation: Secretaria Municipal de Saúde de Resende, Rio de Janeiro, Brazil.
authors.forename: Marco
authors.initials: M
authors.lastname: Netto
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia, Venezuela.
authors.forename: Adriana
authors.initials: A
authors.lastname: Tami
authors.affiliation: Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia, Venezuela.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bethencourt
authors.affiliation: Institute Pedro Kouri, Havana, Cuba.
authors.forename: Maria
authors.initials: M
authors.lastname: Guzman
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.|Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Cameron
authors.initials: C
authors.lastname: Simmons
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thanh Ha
authors.initials: NT
authors.lastname: Quyen
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Merson
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thi Phuong
authors.initials: NT
authors.lastname: Dung
authors.affiliation: Section Clinical Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Beck
authors.affiliation: Section Clinical Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Wirths
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.
authors.forename: Phung Khanh
authors.initials: PK
authors.lastname: Lam
authors.affiliation: Section Clinical Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Rosenberger
authors.affiliation: Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam. bwills@oucru.org.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK. bwills@oucru.org.
authors.forename: Bridget
authors.initials: B
authors.lastname: Wills
mesh_terms: D000293:Adolescent; D000328:Adult; D001208:Asia / Q000453:epidemiology; D002648:Child; D003715:Dengue / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D003716:Dengue Virus / Q000302:isolation & purification; D003937:Diagnosis, Differential; D019468:Disease Management; D005260:Female; D006801:Humans; D007843:Latin America / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult
keywords: Asia; Dengue; Diagnosis; Latin America; Pathogenesis; Risk prediction