Discussion
itch, lymphadenopathy, swelling, erythema, non-suppurative lymphadenopathy, regional lymphadenopathy, Crohn’s disease, abscess, osteitis/osteomyelitis, urticarial reaction, ulcer
SCAR, LYMPHADENOPATHY, BCG VACCINE, ADVERSE EVENTS, EVENT, ERYTHEMA, BCG INFECTION, ABSCESS, REGIONAL LYMPHADENOPATHY, INJECTION SITE REACTION, ABSCESSES, HAND SWELLING, ULCER, COMPLICATIONS
Using active safety surveillance, we evaluated the safety of BCG vaccination and revaccination in over 5000 healthcare workers within a large international trial. The majority of BCG recipients experienced the expected normal well-described local injection site reactions characterized by the appearance of a small, red papule or swelling at the injection site within 2–3 weeks. Usually, the papule softens, resulting in a small ulcer, healing over several weeks to months into a small flat scar.In a study of BCG-vaccinated infants in Guinea-Bissau, those who developed a BCG skin reaction by age 2 months had associated better survival, correlating with reaction size.Itch at the BCG injection site was reported by half of BCG recipients with a median duration of 10 days following vaccination. This symptom has not been previously reported in relation to the BCG vaccine,Revaccination has been associated with an increased risk of common local injection site reactions, as well as adverse events, such as injection site abscess and lymphadenopathy.Our study is the first to compare injection site reactions between BCG-naïve and BCG-revaccinated adults. Two previous smaller studies have reported similar proportions of injection site reactions (93%–98%) in BCG-revaccinated adults; one study was in 500 HCW in South Africa revaccinated with BCG-Denmark,The most common adverse events of special interest in our study were abscess (incidence 1.6%) and regional lymphadenopathy (incidence 3.0%). The incidence of injection site abscess is consistent with studies of BCG-Denmark (1.3%–2.5%) in infantsCharacteristics of BCG injection site abscesses in both trial stages were similar and most (80%) healed within 1 month without medical intervention. Various treatment strategies (antibiotics with and without fine needle aspiration or surgery) were used in the minority of participants who sought external medical advice, reflective of the paucity of robust evidence for the best management approach.The incidence of BCG-associated lymphadenopathy in our study was also consistent with large studies of BCG-Denmark reporting incidence of non-suppurative lymphadenopathy in children and adolescents (range <1% to 4.8%).The incidence of urticarial reaction (0.03% (1/3379)) is within range of the reported rate of this rare event (≥1/10000 to <1/1000).All SAE were hospital presentations deemed unrelated to vaccination, except for one SUSAR (causal relationship assigned as ‘probable’) and one participant hospitalized with Crohn’s disease (causal relationship assigned as ‘unlikely’). Importantly, there were no disseminated BCG infection or BCG osteitis/osteomyelitis cases (rare severe complications, seen in infants with undiagnosed immunodeficiency).BCG vaccination during pregnancy is generally not recommended.Our study has several limitations. First, prior BCG vaccination classification relied on participant self-report without vaccination record confirmation and no information on BCG strain (most participants had their primary BCG vaccination in childhood). However, the majority who reported having received prior BCG also had scar evidence (data not shown). Second, even though the same BCG strain was used for all sites in this study, the vaccinators differed. Vaccine administration technique has been previously shown to influence the incidence of AEFI.Strengths of our study include the active safety surveillance of over 5000 healthcare workers across three continents comprising both high and low TB-prevalence settings, using standard case definitions for adverse events, with safety data available for 99% participants. Safety medical doctors met regularly to discuss AE as they occurred, reaching consensus decisions on classification.In conclusion, BCG revaccination was found to be safe and well tolerated in adults. Although local injection site reactions were more common in BCG-revaccinated than in BCG-naïve adults, these were usually self-limited and the duration of erythema and swelling was shorter. We found itch at the BCG injection site to be a common initial symptom and recommend its addition to the list of expected BCG reactions. Injection site abscess and regional lymphadenopathy, the most common significant adverse events, had a benign course and self-resolved within a month in most participants. This study shows that BCG vaccination and revaccination has an acceptable safety profile in adults at a time when BCG is being increasingly considered for its novel indications.