Respiratory Virus Hospitalization Study (FLU 003 Plus)

An International Observational Study to Characterize Adults Who Are Hospitalized With Influenza or Other Targeted Respiratory Viruses

Following the sudden and unexpected emergence of influenza A(H1N1)pdm09 (2009 H1N1) virus, this observational study was initiated to estimate rates of morbidity and mortality and to examine predictors of severity among participants with 2009 H1N1 infection. In 2011, as surveillance indicated that 2009 H1N1 virus was co-circulating with other seasonal influenza A and B viruses worldwide, the protocol was expanded to include other influenza A subtypes and influenza B viruses. The current version of the protocol (released in August 2013) further broadens the scope of this observational study. With the recognition that novel respiratory viruses other than novel influenza A viruses, e.g., Middle East Respiratory Syndrome Coronavirus (MERS-CoV), could become prevalent and of major public health importance, the objectives of this protocol have been expanded.

Study Overview

• Status: Completed
• Conditions: Influenza; Novel Respiratory Virus-1 Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV); Novel Respiratory Virus-2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)

Detailed Description

The purpose of this observational study is to describe the characteristics and outcomes over a 60-day follow-up period of participants with influenza virus infection (including influenza A subtypes such as H3N2 and 2009 H1N1, or influenza B), or a targeted non-influenza respiratory virus, who are hospitalized with severe illness and/or complications in geographically diverse locations.

Specific objectives related to influenza virus infection are to estimate the percentage of participants who go on to develop severe disease or complications that require hospitalization; to obtain information on risk factors for disease severity; and to establish a central repository of specimens for use in virus characterization, including subtyping, antigenic and genetic analyses, identification of signature mutations associated with antiviral drug resistance, mutational evolution, and additional reassortment.

Specific objectives related to novel non-influenza respiratory viruses of potential major public health importance are to characterize initial cases and their outcomes in order to develop more specific protocols that could inform the prevention and treatment of these new infections.

The information used from this study on participants with influenza and novel respiratory virus infections will be rapidly analyzed and shared broadly in order to guide policymakers and to design future studies.

Approximately 500 patients with influenza will be enrolled each year at an estimated 75 sites which are in geographically diverse locations across several continents.

Study Plan:

• Participants who meet the eligibility criteria will be enrolled at participating clinical sites.
• Patients with a diagnosis of influenza (confirmed or suspected), who are hospitalized with complications or severe disease, will be enrolled.
• At enrollment, consent is signed and information (demographics, medical history (including prior influenza and pneumococcal vaccination), medications (including antivirals) and treatments prescribed) will be recorded. A blood sample for serum and plasma will be obtained at enrollment, as well as an upper respiratory tract sample and lower respiratory tract sample, if appropriate. The respiratory specimens will be sent for central reverse transcriptase polymerase chain reaction (RT-PCR) testing for influenza.
• For participants who are still hospitalized, and not intubated, 5 to 7 days after enrollment an additional upper respiratory sample is obtained.
• Status will be re-assessed at approximately 28 days and 60 days after enrollment and another blood sample for serum and plasma will obtained at both time points.
• For participants who are mechanically ventilated additional upper and lower respiratory tract specimens will be obtained at specific timepoints.

In February 2012, the FLU 004 Genomics protocol v 1.0 was released to the field. In August 2013, v 2.0 of the protocol was released as INSIGHT Genomics. The protocol was expanded beyond the FLU 002 and FLU 003 studies to include all qualifying INSIGHT studies (list of qualifying studies is posted on the INSIGHT website, www.insight-trials.org). The purpose of this substudy is to obtain a whole blood sample from which DNA will be extracted to study polymorphisms in immune response genes and other genetic variants that may be associated with an increased risk of severe influenza.

Participating FLU 003 Plus sites are given the option to also participate in INSIGHT Genomics which requires a separate protocol registration. Participants, once consented to FLU 003 Plus, will be offered the option to also consent to INSIGHT Genomics which includes a single whole blood sample collection. Participation in FLU 003 Plus will not be compromised if a participant opts not to participate in INSIGHT Genomics.

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires
  • Buenos Aires, Argentina
    • CEMIC
  • Buenos Aires, Argentina
    • Hospital General de Agudos JM Ramos Mejia
  • Buenos Aires, Argentina
    • Hospital Interzonal General de Agudos Dr. Diego Paroissien
  • Cordoba, Argentina
    • Hospital Rawson
  • Cordoba, Argentina
    • Hospital Privado Centro Medico de Cordoba
  • Buenos Aires
    • El Palomar, Buenos Aires, Argentina
      • Hospital Nacional Profesor Alejandro Posadas
    • La Plata, Buenos Aires, Argentina
      • Instituto Medico Platense
    • Pilar, Buenos Aires, Argentina
      • Hospital Universitario Austral
    • Vicente Lopez, Buenos Aires, Argentina
      • Hospital Profesor Bernardo Houssay
  • Santa Fe
    • Rosario, Santa Fe, Argentina
      • Sanatorio Británico
• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
• Belgium
  • Brussels, Belgium
    • Centre Hospitalier Universitaire St. Pierre (C.H.U. St. Pierre)
• Chile
  • Santiago, Chile
    • Clinica Alemana
  • Santiago, Chile
    • Fundacion Arriaran
• Denmark
  • Aarhus, Denmark
    • Arhus Universitetshospital, Skejby
  • Copenhagen, Denmark
    • CHIP
  • Hvidovre, Denmark
    • Hvidovre University Hospital, Department of Infectious Diseases
  • Odense, Denmark
    • Odense University Hospital
• Germany
  • Bonn, Germany
    • Medizinische Universitatsklinik - Bonn, Immunologische Ambulanz CRS
  • Cologne, Germany
    • Klinik I fur Innere Medizin der Universitat zu Koln, Studienburo fur Infektiologie u. HIV
  • Frankfurt, Germany
    • Johann Wolfgang Goethe - University Hospital, Infektionsambulanz CRS
• Greece
  • Athens, Greece
    • Evangelismos General Hospital
  • Athens, Greece
    • Hippokration University General Hospital of Athens
  • Athens, Greece
    • 1st Dept of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital
  • Athens, Greece
    • 1st Respiratory Medicine Dept, Athens Hosp for Diseases of the Chest "Sotiria Hospital"
• Peru
  • Lima, Peru, 01
    • Hospital Nacional Arzobispo Loayza
  • Lima, Peru, 13
    • Hospital Nacional Guillermo Almenara Irigoyen
• Spain
  • Madrid, Spain
    • Hospital La Paz
  • Madrid, Spain
    • Hospital Clinico San Carlos
  • Madrid, Spain
    • Hospital Universitario Infanta Leonor
  • Madrid, Spain
    • Hospital Universitario Gregorio Mara�on
  • Vitoria-Gasteiz, Spain
    • Hospital Txagorritxu
• Thailand
  • Bangkok, Thailand, 10330
    • Chulalongkorn University Hospital
  • Khon Kaen, Thailand, 40002
    • Khon Kaen University, Srinagarind Hospital
  • Nonthaburi, Thailand, 11000
    • Bamrasnaradura Institute
• United Kingdom
  • Newcastle upon Tyne, United Kingdom, NE4 6BE
    • Newcastle General Hospital
  • Berkshire
    • Slough, Berkshire, United Kingdom
      • Heatherwood and Wexham Park Hospitals NHS Foundation Trust
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN2 1ES
      • Brighton and Sussex University Hospitals NHS Trust
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 9LJ
      • Churchill Hospital
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Sheffield teaching hospital NHS foundation trust
  • West Yorkshire
    • Bradford, West Yorkshire, United Kingdom, BD9 6RJ
      • Bradford Teaching Hospitals NHS Foundation Trust
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • St James's University Hospital
• United States
  • California
    • San Diego, California, United States, 92103-8208
      • UCSD Antiviral Research Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington DC VA Medical Center
    • Washington, District of Columbia, United States, 20037
      • George Washington Medical Faculty Associates
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Springfield, Massachusetts, United States, 01199
      • Baystate Infectious Diseases Clinical Research
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School Adult Clinical Research Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10010
      • Cornell ID-CRU
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Medical Center
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • University of Tennessee College of Medicine
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients who are hospitalized with a diagnosis (confirmed or suspected) of influenza or a targeted non-influenza viral respiratory infection, as soon as possible after the suspected diagnosis is made. Participants may have already been admitted to the hospital at the study site or may have been previously seen at another hospital where the diagnosis of influenza or infection with a targeted respiratory virus was made.

Description

Inclusion Criteria:

• Be ≥ 18 years of age
• Have been admitted to hospital
• Have a signed informed consent by participant or surrogate/representative

• Have a local diagnosis (confirmed or suspected) of influenza, or of a targeted non-influenza viral respiratory infection*, resulting in (or extending a previous) hospitalization

  • A list of targeted non-influenza respiratory viruses is maintained on the INSIGHT website.

Exclusion Criteria:

• Current imprisonment, or compulsory detention (involuntary incarceration) for treat of a psychiatric or physical illness.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Influenza; Influenza A and subtypes such as H3N2 and 2009 H1N1 or influenza B
Novel Respiratory Virus-1; MERS-CoV (Middle East Respiratory Syndrome Coronavirus
Novel Respiratory Virus-2; SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Death	60-day period following enrollment

Secondary Outcome Measures

Outcome Measure	Time Frame
Recovery from influenza illness (including days lost from normal activities) duration of hospitalization, days in intensive care, days of mechanical ventilation, days of dialysis, pregnancy outcome	approximately 60 days

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Clinical & Translational Science Institute, University of Minnesota
• Investigators: Principal Investigator: Cavan Reilly, PhD, University of Minnesota - Dept Biostatistics

Publications and helpful links

General Publications

• World Health Organization (WHO), www.who.int/, accessed 26 August 2013
• Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Guggemos W, Kallies R, Muth D, Junglen S, Muller MA, Haas W, Guberina H, Rohnisch T, Schmid-Wendtner M, Aldabbagh S, Dittmer U, Gold H, Graf P, Bonin F, Rambaut A, Wendtner CM. Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis. 2013 Sep;13(9):745-51. doi: 10.1016/S1473-3099(13)70154-3. Epub 2013 Jun 17.
• World Health Organization (WHO), Severe Acute Respiratory Syndrome (SARS), www.who.int/csr/sars/, accessed 26 August 2013
• Wendt CH, Castro-Pearson S, Proper J, Pett S, Griffin TJ, Kan V, Carbone J, Koulouris N, Reilly C, Neaton JD; INSIGHT FLU003 Plus Study Group. Metabolite profiles associated with disease progression in influenza infection. PLoS One. 2021 Apr 2;16(4):e0247493. doi: 10.1371/journal.pone.0247493. eCollection 2021.
• Simonsen L, Higgs E, Taylor RJ, Wentworth D, Cozzi-Lepri A, Pett S, Dwyer DE, Davey R, Lynfield R, Losso M, Morales K, Glesby MJ, Weckx J, Carey D, Lane C, Lundgren J; INSIGHT FLU002 and FLU003 Study Groups. Using Clinical Research Networks to Assess Severity of an Emerging Influenza Pandemic. Clin Infect Dis. 2018 Jul 18;67(3):341-349. doi: 10.1093/cid/ciy088.
• Pett SL, Kunisaki KM, Wentworth D, Griffin TJ, Kalomenidis I, Nahra R, Montejano Sanchez R, Hodgson SW, Ruxrungtham K, Dwyer D, Davey RT, Wendt CH; INSIGHT FLU003 Plus Study Group. Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study. Open Forum Infect Dis. 2017 Oct 25;5(1):ofx228. doi: 10.1093/ofid/ofx228. eCollection 2018 Jan.
• Lynfield R, Davey R, Dwyer DE, Losso MH, Wentworth D, Cozzi-Lepri A, Herman-Lamin K, Cholewinska G, David D, Kuetter S, Ternesgen Z, Uyeki TM, Lane HC, Lundgren J, Neaton JD; INSIGHT Influenza Study Group. Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies. PLoS One. 2014 Jul 8;9(7):e101785. doi: 10.1371/journal.pone.0101785. eCollection 2014.
• Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-2615.
• Guery B, Poissy J, el Mansouf L, et al. Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet 2013;381(9885):2265-2272.

Helpful Links

• INSIGHT website

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2009
• Primary Completion (Actual): August 30, 2024
• Study Completion (Actual): August 30, 2024

Study Registration Dates

• First Submitted: January 25, 2010
• First Submitted That Met QC Criteria: January 25, 2010
• First Posted (Estimated): January 26, 2010

Study Record Updates

• Last Update Posted (Actual): October 21, 2024
• Last Update Submitted That Met QC Criteria: October 17, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: influenza; hospitalization; MERS-CoV; flu; swine flu; respiratory virus; SARS-CoV
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Disease; Orthomyxoviridae Infections; Severe Acute Respiratory Syndrome; Coronavirus Infections; Syndrome; Virus Diseases; Influenza, Human
• Other Study ID Numbers: 0603M83587 FLU 003