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Wheeze as an adverse event in pediatric vaccine and drug randomized controlled trials: A systematic review
Diana Marangu1, Stephanie Kovacs2, Judd Walson3
1Department of Pediatrics and Child Health, University of Nairobi, Nairobi, Kenya.
Insights
Standardized definitions for wheeze, a key adverse event in pediatric vaccine and drug trials, are lacking. This systematic review highlights the urgent need for consistent criteria to accurately assess safety in clinical research.
Area of Science:
- Pediatric clinical research
- Vaccinology
- Pharmacovigilance
Background:
- Wheeze is a critical indicator of potential severe adverse events in pediatric vaccine and drug trials.
- Current randomized controlled trials (RCTs) lack consensus on wheeze definitions and associated respiratory compromise.
- This ambiguity hinders accurate safety assessments in pediatric populations.
Purpose of the Study:
- To systematically identify and evaluate definitions and severity grading scales for wheeze as an adverse event in pediatric vaccine and drug RCTs (children <5 years).
- To determine the diagnostic performance (sensitivity, specificity, inter-observer agreement) of identified wheeze assessment methods.
Main Methods:
- Systematic review of electronic databases and reference lists, restricted to trials published from 1970 onwards.
- Abstraction and ranking of wheeze definitions and severity grading scales using a diagnostic certainty score.
- Analysis focused on sensitivity, specificity, and inter-observer agreement.
Main Results:
- 58 eligible trials across 38 countries were identified, predominantly involving vaccines (90%), especially influenza vaccines.
- Only 15 trials provided explicit wheeze definitions; 24 described severity, often linked to broader respiratory illness.
- Combined caregiver reports and healthcare worker assessments demonstrated the highest sensitivity and specificity for wheeze detection.
Conclusions:
- A significant lack of standardized wheeze definitions and severity grading scales exists for pediatric vaccine and drug trials.
- Standardized definitions are crucial for reliable assessment of adverse events during the evaluation of new pediatric vaccines and drugs.
- Implementing consistent criteria will improve the accuracy and comparability of safety data in pediatric clinical research.
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.
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