Mark G Thompson1, Min Z Levine2, Silvia Bino3, Danielle R Hunt4, Tareq M Al-Sanouri5, Eric A F Simões6, Rachael M Porter2, Holly M Biggs7, Lionel Gresh8, Artan Simaku3, Illham Abu Khader5, Veronica L Tallo9, Jennifer K Meece10, Meredith McMorrow2, Edelwisa S Mercado9, Sneha Joshi2, Nicholas P DeGroote7, Iris Hatibi3, Felix Sanchez11, Marilla G Lucero9, Samir Faouri12, Stacie N Jefferson2, Numila Maliqari13, Angel Balmaseda14, Diozele Sanvictores9, Crystal Holiday2, Cristina Sciuto4, Zachary Owens2, Eduardo Azziz-Baumgartner2, Aubree Gordon15. 1. Influenza Division, National Center for Immunization and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: isq8@cdc.gov. 2. Influenza Division, National Center for Immunization and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, GA, USA. 3. Department of Epidemiology and Control of Infectious Diseases, Institute of Public Health, Tirana, Albania. 4. Abt Associates, Atlanta, GA, USA. 5. The Eastern Mediterranean Public Health Network (EMPHNET), Amman, Jordan. 6. Center for Global Health, Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA. 7. Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. 8. Sustainable Sciences Institute, Managua, Nicaragua. 9. Research Institute for Tropical Medicine, Department of Health, Muntinlupa, Philippines. 10. Marshfield Clinic Research Foundation, Marshfield, WI, USA. 11. Hospital Infantil Manuel de Jesus Rivera, Ministry of Health, Managua, Nicaragua. 12. Al Bashir Hospital, Ministry of Health, Amman, Jordan. 13. General Pediatrics Unit, University Hospital Center "Mother Teresa", Tirana, Albania. 14. Laboratorio Nacional de Virologia, Centro Nacional de Diagnostico y Referencia, Ministry of Health, Managua, Nicaragua. 15. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Abstract
BACKGROUND: Since influenza often presents non-specifically in infancy, we aimed to assess the extent to which existing respiratory surveillance platforms might underestimate the frequency of severe influenza disease among infants. METHODS: The Influenza and Respiratory Syncytial Virus in Infants (IRIS) study was a prospective observational study done at four hospitals in Albania, Jordan, Nicaragua, and the Philippines. We included acutely ill infants aged younger than 1 year admitted to hospital within 10 days or less of illness onset during two influenza seasons (2015-16 and 2016-17) in Albania, Jordan, and Nicaragua, and over a continuous 34 week period (2015-16) in the Philippines. We assessed the frequency of influenza virus infections by real-time RT-PCR (rRT-PCR) and serology. The main study outcome was seroconversion, defined as convalescent antibody titres more than or equal to four-fold higher than acute sera antibody titres, and convalescent antibody titres of 40 or higher. Seroconverison was confirmed by haemagglutination inhibition assay for influenza A viruses, and by hemagglutination inhibition assay and microneutralisation for influenza B viruses. FINDINGS: Between June 27, 2015, and April 21, 2017, 3634 acutely ill infants were enrolled, of whom 1943 were enrolled during influenza seasons and had complete acute-convalescent pairs and thus were included in the final analytical sample. Of the 1943 infants, 94 (5%) were influenza-positive by both rRT-PCR and serology, 58 (3%) were positive by rRT-PCR-only, and 102 (5%) were positive by serology only. Seroconversion to at least one of the influenza A or B viruses was observed among 196 (77%) of 254 influenza-positive infants. Of the 254 infants with influenza virus, 84 (33%) only had non-respiratory clinical discharge diagnoses (eg, sepsis, febrile seizures, dehydration, or other non-respiratory viral illness). A focus on respiratory diagnoses and rRT-PCR-confirmed influenza underdetects influenza-associated hospital admissions among infants by a factor of 2·6 (95% CI 2·0-3·6). Findings were unchanged when syndromic severe acute respiratory infection criteria were applied instead of clinical diagnosis. INTERPRETATION: If the true incidence of laboratory-confirmed influenza-associated hospital admissions among infants is at least twice that of previous estimates, this substantially increases the global burden of severe influenza and expands our estimates of the preventive value of maternal and infant influenza vaccination programmes. FUNDING: US Centers for Disease Control and Prevention.
BACKGROUND: Since influenza often presents non-specifically in infancy, we aimed to assess the extent to which existing respiratory surveillance platforms might underestimate the frequency of severe influenza disease among infants. METHODS: The Influenza and Respiratory Syncytial Virus in Infants (IRIS) study was a prospective observational study done at four hospitals in Albania, Jordan, Nicaragua, and the Philippines. We included acutely ill infants aged younger than 1 year admitted to hospital within 10 days or less of illness onset during two influenza seasons (2015-16 and 2016-17) in Albania, Jordan, and Nicaragua, and over a continuous 34 week period (2015-16) in the Philippines. We assessed the frequency of influenza virus infections by real-time RT-PCR (rRT-PCR) and serology. The main study outcome was seroconversion, defined as convalescent antibody titres more than or equal to four-fold higher than acute sera antibody titres, and convalescent antibody titres of 40 or higher. Seroconverison was confirmed by haemagglutination inhibition assay for influenza A viruses, and by hemagglutination inhibition assay and microneutralisation for influenza B viruses. FINDINGS: Between June 27, 2015, and April 21, 2017, 3634 acutely ill infants were enrolled, of whom 1943 were enrolled during influenza seasons and had complete acute-convalescent pairs and thus were included in the final analytical sample. Of the 1943 infants, 94 (5%) were influenza-positive by both rRT-PCR and serology, 58 (3%) were positive by rRT-PCR-only, and 102 (5%) were positive by serology only. Seroconversion to at least one of the influenza A or B viruses was observed among 196 (77%) of 254 influenza-positive infants. Of the 254 infants with influenza virus, 84 (33%) only had non-respiratory clinical discharge diagnoses (eg, sepsis, febrile seizures, dehydration, or other non-respiratoryviral illness). A focus on respiratory diagnoses and rRT-PCR-confirmed influenza underdetects influenza-associated hospital admissions among infants by a factor of 2·6 (95% CI 2·0-3·6). Findings were unchanged when syndromic severe acute respiratory infection criteria were applied instead of clinical diagnosis. INTERPRETATION: If the true incidence of laboratory-confirmed influenza-associated hospital admissions among infants is at least twice that of previous estimates, this substantially increases the global burden of severe influenza and expands our estimates of the preventive value of maternal and infantinfluenza vaccination programmes. FUNDING: US Centers for Disease Control and Prevention.
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