Diana Marangu1, Stephanie Kovacs2, Judd Walson3, Jan Bonhoeffer4, Justin R Ortiz5, Grace John-Stewart6, David J Horne7. 1. Department of Pediatrics and Child Health, University of Nairobi, Nairobi, Kenya. Electronic address: marangud@gmail.com. 2. Department of Epidemiology, University of Washington, Seattle, WA, United States. 3. Department of Epidemiology, University of Washington, Seattle, WA, United States; Department of Medicine, University of Washington, Seattle, WA, United States; Department of Global Health, University of Washington, Seattle, WA, United States; Department of Pediatrics, University of Washington, Seattle, WA, United States. 4. Brighton Collaboration Foundation, Basel, Switzerland; University of Basel Children's Hospital, Basel, Switzerland. 5. Initiative for Vaccine Research (IVR), World Health Organization, Geneva, Switzerland. 6. Department of Epidemiology, University of Washington, Seattle, WA, United States; Department of Medicine, University of Washington, Seattle, WA, United States; Department of Global Health, University of Washington, Seattle, WA, United States. 7. Department of Medicine, University of Washington, Seattle, WA, United States; Department of Global Health, University of Washington, Seattle, WA, United States.
Abstract
INTRODUCTION: Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). OBJECTIVE: To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. METHODS: We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. RESULTS: Of 1205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. CONCLUSION: Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.
INTRODUCTION: Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). OBJECTIVE: To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. METHODS: We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. RESULTS: Of 1205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. CONCLUSION: Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.
Authors: R B Belshe; W C Gruber; P M Mendelman; I Cho; K Reisinger; S L Block; J Wittes; D Iacuzio; P Piedra; J Treanor; J King; K Kotloff; D I Bernstein; F G Hayden; K Zangwill; L Yan; M Wolff Journal: J Pediatr Date: 2000-02 Impact factor: 4.406
Authors: H S Izurieta; W W Thompson; P Kramarz; D K Shay; R L Davis; F DeStefano; S Black; H Shinefield; K Fukuda Journal: N Engl J Med Date: 2000-01-27 Impact factor: 91.245
Authors: Flor M Munoz; Nanette H Bond; Maurizio Maccato; Phillip Pinell; Hunter A Hammill; Geeta K Swamy; Emmanuel B Walter; Lisa A Jackson; Janet A Englund; Morven S Edwards; C Mary Healy; Carey R Petrie; Jennifer Ferreira; Johannes B Goll; Carol J Baker Journal: JAMA Date: 2014-05-07 Impact factor: 56.272
Authors: Varsha K Jain; Luis Rivera; Khalequ Zaman; Roberto A Espos; Chukiat Sirivichayakul; Beatriz P Quiambao; Doris M Rivera-Medina; Pirunghul Kerdpanich; Mehmet Ceyhan; Ener C Dinleyici; Alejandro Cravioto; Mohammed Yunus; Pornthep Chanthavanich; Kriengsak Limkittikul; Zafer Kurugol; Emre Alhan; Adrian Caplanusi; Serge Durviaux; Philippe Boutet; Opokua Ofori-Anyinam; Vijayalakshmi Chandrasekaran; Ghassan Dbaibo; Bruce L Innis Journal: N Engl J Med Date: 2013-12-11 Impact factor: 91.245
Authors: Arto A Palmu; Jukka Jokinen; Heta Nieminen; Hanna Rinta-Kokko; Esa Ruokokoski; Taneli Puumalainen; Dorota Borys; Patricia Lommel; Magali Traskine; Marta Moreira; Lode Schuerman; Terhi M Kilpi Journal: Lancet Infect Dis Date: 2013-11-26 Impact factor: 25.071
Authors: Justin R Ortiz; Doli Goswami; Kristen D C Lewis; Amina Tahia Sharmeen; Moshtaq Ahmed; Mustafizur Rahman; Mohammed Z Rahman; Jodi Feser; Kathleen M Neuzil; W Abdullah Brooks Journal: Vaccine Date: 2015-04-24 Impact factor: 3.641