To improve comparability of vaccine safety data, the Persistent Crying Working Group has developed a case definition and guidelines for persistent crying, applicable in study settings with different availability of resources, in health care settings that differ by availability of and access to health care, and in different geographic regions.
The definition and guidelines were developed through group consensus. They are grounded on both expert opinion and a systematic literature review related to the assessment of persistent crying as an adverse event following immunization and to the determination of persistent crying in infants and children. To our knowledge no structured work, put into the development of a case definition of any type of crying as an adverse event following immunization is available.
1.1. Background on persistent crying
Crying in children is a common reaction to painful stimuli. Following injected vaccines, various patterns of crying have been described. Most often, crying with immediate onset after an immunization is short-lived, lasting 0.5–2 min on average, has typical acoustic characteristics, and is viewed by parents and medical staff as normal [1], [2]. However, studies over the last 20 years suggest that other types of crying elicit concern in parents and medical staff. This crying has been described as prolonged, persistent, unusual, increased as well as high-pitched, protracted uncontrollable, and inconsolable. The event likely is also referred to by the terms “severe irritability”, “weeping”, and “fierce screaming” [3], [4], [5], [6], [7], [8], [9]. The concerned reactions evoked in the observer are indicated by expressions like “never heard the child cry like this before” and interpretations like “cerebral cry”. However, little is known about the pathophysiology of these types of crying [10], [11], [12].
In studies of prolonged, persistent, unusual and increased crying incidences range between 0 and 17.5%, 2 and 42%, 7 and 72%, and 12 and 39%, respectively [4], [5], [6], [13], [14], [15], [16], [17]. The wide range of incidences are probably a result of the different case definitions used rather than differences in study population or vaccines used. Nevertheless, the incidence seems to continuously decrease with subsequent immunizations [4], [7], [16], [17]. Given the different case descriptions used, the wide range of data on onset (2–8 h) and duration (30 min to 21 h) of the various cries might be an expression of different etiologies, pathophsiological mechanisms, the severity of the event, or a result of the various time cut-offs used [3], [11].
1.2. Rationale for decisions about case definition
A time frame for onset of crying was not included in the definition for two reasons. First, there is not sufficient evidence to assume that all types of crying are caused by the same event eliciting persistent crying. A heterogeneous group of causes including pain caused by local reactions or the discomfort caused by fever is likely to determine the onset of crying. Second, because the definition itself defines a clinical entity without inference of a causal relation to a given exposure, the time interval between immunization and onset of the event cannot be part of the definition itself, but should be assessed as described in the guidelines.
