To improve comparability of vaccine safety data the Brighton Collaboration Local Reactions Working Group has developed a case definition and guidelines for the clinical diagnosis of nodule at injection site, 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 case definition and guidelines were developed through group consensus. They are grounded on both expert opinion and a review of the literature related to the assessment of nodule at injection site as an adverse event following immunization and to the diagnosis of nodule at injection site in humans. In general, published studies are scarce; most articles reviewed (MEDLINE 1966 to September 2002; search terms vaccination OR immunization, AND cold abscess OR sterile abscess, OR granuloma OR subcutaneous nodule OR antigen cyst) were case reports of relatively few subjects or mentioned formation of a nodule at the injection site briefly as part of a broader discussion of local reactions to immunization. A systematic review of the incidence and clinical symptoms of nodules at injection site was not found in the literature reviewed, and neither was a publication of a vaccine study aiming to define or to evaluate a definition of a nodule at injection site. Published clinical characteristics of nodules at injection site include firmness [1], tenderness or pain [1], [2], [3], [4], [5], and pruritus [2], [6]. Nodules at injection site have also been described as being asymptomatic [1], [2], [7]. There have been several review papers about the role of aluminum salts in vaccines and the development of nodules at injection sites [8], [9], [10], especially when the vaccine is administered subcutaneously [11].
1.1. Rationale for decisions about case definition
The Working Group agreed that the discrete (i.e., well-demarcated) clinical feature of a nodule at injection site sufficiently differentiates it from the more common clinical picture of acute induration and swelling, which are more diffuse and of shorter duration. Moreover, no clear cut-off time based on duration and onset of a nodule at injection site versus acute induration and swelling could be identified on the basis of the current understanding of these reactions [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Onset and duration for these reactions can be overlapping and any cut-off can lead to decreased sensitivity and specificity of either event (i.e., false inclusion or exclusion based on such time considerations). Although a period of observation may be needed before a diagnosis of nodule at injection site can be made, it is expected that the inclusion and exclusion criteria listed in the definition will be met at the time of diagnosis.
