Need for developing a case definition and guidelines for data collection, analysis, and presentation of wheeze as an adverse event following immunization
Wheeze is a common presenting symptom of respiratory disease in children [1]. It is a high pitched, whistling, adventitious breath sound lasting, indicating limitation of airflow [2]. Limitation of airflow in a compliant airway is accompanied by flutter of the walls at the site of flow limitation [3], [4]. In the presence of airway narrowing, this flutter may include the airway walls and become large enough to generate sound, heard as wheezing [5]. The lung volume, the air flow rate, the mechanical properties of the airway wall and adjacent tissues that are set into oscillation determine the intensity, pitch, composition (monophonic or polyphonic notes), duration (long or short), and timing (inspiratory or expiratory, early or late) of this dynamic process [5], [6]. Processes including mucosal swelling, mucus deposition in the airway, bronchoconstriction, and airway narrowing by foreign body or tumor may result in airflow limitation.
Wheeze generated by the obstruction of larger airways has a constant acoustical character throughout the lung, but varies in loudness depending upon the distance from the site of obstruction. It is referred to as monophonic (or homophonous) wheezing. In contrast, in small airway obstruction, the degree of narrowing varies from place to place within the lung. As a result, the sounds generated also vary in acoustical character and are described as polyphonic (or heterophonous) wheezes [1], [7].
Bronchiolitis, bronchitis, and asthma are common clinical conditions which may present with multiple respiratory signs and symptoms including wheeze. For clinical purposes wheeze has been used synonymously with some of these conditions, e.g. a first episode of wheezing in infants is commonly called bronchiolitis [8]. In turn, wheeze definitions vary and range from transient audible breath sounds with no associated respiratory symptoms to the presence of severe respiratory distress accompanying the breath sound. Rhonchi are similar to wheeze in that they are also musical sounds common in airway narrowing. However, they are low in pitch and not considered wheeze equivalents [9].
Wheeze may have multiple etiologies, including viral and allergic causes, particularly in infants and young children, and wheeze may reflect the immune response to immunization. Thus, it is an important clinical sign of a potential adverse respiratory event in pediatric drug and vaccine studies [10], [11], [12], [13]. Reports of wheeze in children participating in live attenuated influenza vaccine trials have raised particular concern of adverse respiratory events associated with the trials [12], [14], [15], [16]. A systematic review of definitions and severity gradings of wheeze as an adverse event in vaccine and drug randomized controlled trials (RCTs) enrolling children < 5 years old recently identified 51 eligible vaccine trials mainly conducted in high-income settings, 33 of which involved influenza vaccines [12]. Wheeze has also been used as a primary outcome of RCTs [17], highlighting the importance and challenge of objective wheeze assessment.
