Bacillus Calmette-Guerín (BCG) is a live attenuated vaccine to prevent tuberculosis, routinely administered at birth as part of the World Health Organization global expanded immunisation programme. Given intradermally, it can cause adverse reactions, including local, regional, distant and disseminated manifestations that may cause parental distress. Rarely, it can cause serious illness and even death. Among those patients with immunocompromised conditions, such as the human immunodeficiency virus (HIV) infection, the complication rate is even higher.
To assess the effects of different interventions for treating BCG-induced disease in children.
The following databases were searched: the Cochrane Infectious Diseases Group Specialized Register and Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (The Cochrane Library 2012, Issue 4); MEDLINE (1966 to November 2012); EMBASE (1947 to November 2012); and LILACS (1980 to November 2012). The metaRegister of Controlled Trials (mRCT) and the WHO trials search portal. Conference proceedings for relevant abstracts and experts were also contacted to identify studies. No language restrictions were applied.
Randomized controlled trials (RCTs) comparing any medical or surgical treatment modality for BCG-induced disease in children.
Data collection and analysis
Two authors independently evaluated titles, applied inclusion criteria, and assessed the risk of bias of studies. The primary outcomes were the failure rate of therapies for all types of BCG vaccine-induced complications and the time to resolution of illness measured in months. The secondary outcomes were death from BCG vaccine-induced disease and the all-cause mortality. Risk ratios (RRs) were used as measure of effect for dichotomous outcomes and mean differences for continuous outcomes.
Five RCTs analysing 341 children addressed the primary outcomes and were included. Four arms compared oral antibiotics to no intervention or placebo, one arm evaluated needle aspiration compared to no intervention, and another evaluated the use of locally instilled isoniazid versus oral erythromycin.
Two small studies evaluated oral isoniazid; we are uncertain of whether this intervention has an effect on clinical failure (RR 1.48; 95% Confidence Interval (CI) 0.79 to 2.78; 54 participants, two studies, very low quality evidence). Similarly, for oral erythromycin, we are uncertain if there is an effect (clinical failure RR 1.03; 95% CI 0.70 to 1.53; 148 participants, three studies, very low quality evidence), and for oral isoniazid plus rifampicin (clinical failure, RR 1.20; 95% CI 0.51 to 2.83; 35 participants, one study, very low quality evidence).
In patients with lymphadenitis abscess, needle aspiration may reduce clinically persistent BCG-induced disease at 6 to 9 months of follow-up (RR 0.13; 95% CI 0.03 to 0.55; 77 participants, one study, low quality evidence). In another study of patients with the same condition, aspiration plus local instillation of isoniazid reduces time to clinical cure compared to aspiration plus oral erythromycin (mean difference 1.49 months less; 95% CI 0.82 to 2.15 less; 27 participants, one study).
No RCTs of HIV-infected infants with a BCG-induced disease evaluated the use of antibiotics or other therapies for reducing the rate of clinical failure or the time to clinical resolution. No data on mortality secondary to the interventions for treating BCG-induced disease were reported.
It is unclear if oral antibiotics (isoniazid, erythromycin, or a combination of isoniazid plus rifampicin) are effective for the resolution of BCG-induced disease. Most non-suppurated lymphadenitis will resolve without treatment in 4 to 6 months. Patients with lymphadenitis abscess might benefit from needle aspiration and possibly local instillation of isoniazid could shorten recovery time. Included studies were generally small and could be better conducted. Further research should evaluate the use of needle aspiration and local instillation of isoniazid in fluctuant nodes. Therapeutic and preventive measures in HIV-infected infants could be important given the higher risk of negative outcomes in this group.
Plain Language Summary
Bacillus Calmette-Guérin (BCG) is a widely used tuberculosis vaccine derived from a non-infectious strain of the bovine tuberculosis bacillus (Mycobacterium bovis) and mainly given to young children. Usually, the only adverse reaction to the vaccine is an ulcer at the site of injection, which may leave a small scar.
Very occasionally, however, especially in children with weakened immune systems, the vaccine can cause more serious side effects. These can include local infections at the injection site, which may spread to the lymph nodes, causing lymphadenopathy, and the bones, and can even prove life-threatening. These adverse reactions to the BCG vaccine are a particular risk for children infected with the Human Immunodeficiency Virus (HIV), where the condition is known as BCG immune reconstitution inflammatory syndrome (BCG-IRIS).
In many cases, the infections resolve without any intervention, but treatments can include oral antibiotics, needle aspiration, draining abscesses, and surgically removing infected lymph nodes. This review was conducted to try to determine the effectiveness of these different treatments.
The review found no evidence of any benefit of using oral antibiotics to treat local or regional BCG-induced disease. In patients with abscess-forming lymphadenopathy, the only intervention with proven benefit was needle aspiration of the abscesses with or without local injection of the antibiotic isoniazid.
Based on these findings, the review authors recommend a 'wait and see' approach with follow-up visits for minor reactions and lymphadenopathy without abscesses. For abscess-forming lymphadenopathy, which can cause distress and discomfort, they advise needle aspiration. However, this review is based on only five studies, all of which were assessed as having a low or very low quality of evidence. As a consequence, the authors conclude there is an urgent need for more and better studies on ways to prevent and treat BCG-induced disease, especially BCG-IRIS.
Cuello-García, C.A.; Pérez-Gaxiola, G.; Jiménez Gutiérrez, C. Treating BCG-induced disease in children. Cochrane Database of Systematic Reviews (2013) (Issue 1) Art. No.: CD008300. [DOI: 10.1002/14651858.CD008300.pub2]