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Management of Bacille Calmette-Guérin Lymphadenitis and Abscess in Immunocompetent Children

A Systematic Review

Villanueva, Paola MBBS, BMedSci*,†,‡; Pittet, Laure F. MD, PhD*,†,§; Curtis, Nigel FRCPCH, PhD*,†,§

Author Information
The Pediatric Infectious Disease Journal: November 2021 - Volume 40 - Issue 11 - p 1037-1045
doi: 10.1097/INF.0000000000003237

Abstract

A century since the first use of Bacille Calmette-Guérin (BCG) in humans, there is still no consensus for the management of common adverse reactions to the vaccine. BCG is one of the most extensively used vaccines and is given in infancy to protect against tuberculosis in over 150 countries.1 More recently, there has been growing interest in broader applications of BCG vaccine for its beneficial immunomodulatory effects.2 A number of randomized controlled trials (RCTs) of BCG vaccine’s “off-target” effects are in progress, including its ability to reduce the impact of coronavirus disease 2019.3

BCG is a live-attenuated vaccine with a well-established intradermal vaccination safety profile in immunocompetent individuals, although sometimes associated with a strong local reaction.4 The most common adverse reactions include regional lymphadenitis and injection site abscess.

BCG-associated regional lymphadenitis, defined as the development of ipsilateral regional lymph node enlargement, can be nonsuppurative (simple) or suppurative. The most common site for regional lymphadenitis is the ipsilateral axilla. Supraclavicular or cervical lymph nodes may also be involved in combination or separately.5 The onset is usually within 6 months of vaccination and the incidence ranges from 0.1 to 38 per 1000 vaccinated.6

Nonsuppurative lymphadenitis is considered a normal reaction to BCG vaccination and usually has a benign course (especially when infracentimetric) with regression over time.7,8 However, this may sometimes progress to become suppurative lymphadenitis, identified by the presence of fluctuation in the lymph node with erythema and edema of the overlying skin.7,9 This can spontaneously perforate and form a sinus tract, with prolonged drainage, which can lead to ulcerative lesions, causing significant discomfort.10

An injection site abscess is a fluctuant or draining fluid-filled lesion at the site of injection.11 It may occur any time up to 2 months after BCG vaccination, with an incidence of 2.5 per 100 vaccinated.12

The frequency of adverse reactions is influenced by vaccine and host factors, including dosage, BCG strain, administration technique, age at vaccination and host immune status.6,13,14 Treatment approaches for BCG complications remain highly variable; the literature describes the use of antibiotics, antimycobacterial medications, needle aspiration, surgery, a combination of these, or a conservative “watch and wait” strategy.

A previous systematic review of BCG-induced complications did not include studies that evaluated surgical treatment modalities or management of BCG injection site abscess.15 Here we review strategies for the management of BCG-associated lymphadenitis and BCG injection site abscess in immunocompetent children.

MATERIALS AND METHODS

The systematic review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.16 Medline (1946 to present) and Embase (1947 to present) were searched using the Ovid interface. A PubMed search was also done to retrieve articles not indexed in Medline. Search terms included multiple variants of the terms BCG, lymphadenitis and abscess, in addition to MeSH Headings (Supplemental Digital Content 1, https://links.lww.com/INF/E454). The references of relevant identified articles were hand-searched for further studies. The search was last updated on November 7, 2020.

Predefined inclusion criteria were RCTs or cohort studies published in English that aimed to compare management strategies for BCG-associated lymphadenitis or BCG injection site abscess following intradermal BCG vaccination in immunocompetent children. Studies without outcome data were excluded. The following variables were extracted from the included studies using a data extraction sheet: country of study, design, sample size, age at BCG vaccination and at onset of lymphadenitis/abscess, BCG vaccine strain, management strategies and outcomes measured.

The included studies were assessed for risk of bias by 2 reviewers (P.V. and L.F.P.) using tools from the Cochrane Collaboration. The recovery outcome was assessed using the RoB-2 tool for randomized trials, and the ROBINS-I tool for cohort studies.17–19 A third assessor (N.C.) arbitrated any disagreement.

RESULTS

The search identified 1338 unique articles of which 15 met the inclusion criteria and were included (Fig. 1). Management strategies for 1022 children with BCG-associated lymphadenitis were compared in 6 RCTs, 4 prospective studies and 4 retrospective studies (Tables 1 and 2). Management strategies for up to 36 cases of BCG injection site abscess were compared in 1 prospective and 1 retrospective study (Table 1). Participants were all children, predominantly infants vaccinated with BCG in the neonatal period (mostly BCG-Pasteur and BCG-Denmark). One study included 8 school-age children with lymphadenitis after BCG revaccination. Most participants were screened for active tuberculosis and other health conditions before inclusion.

TABLE 1. - Summary of Studies on Management of BCG-Associated Lymphadenitis and Injection Site Abscess (Details in Supplementary Tables 2–4, Supplemental Digital Content 2, Http://Links.Lww.Com/INF/E455; Supplemental Digital Content 3, Http://Links.Lww.Com/INF/E456; Supplemental Digital Content 4, Http://Links.Lww.Com/INF/E457; Supplemental Digital Content 5, Http://Links.Lww.Com/INF/E458)
Study Type Management No. of Studies No. of Patients (n = 1022) References
Nonsuppurative lymphadenitis
  Randomized controlled trials Total 4 274 10, 20–22
No treatment/placebo* 4 111 10, 20–22
INH 1 21 21
INH + RIF 1 21 21
ERY* 3 86 10, 21, 22
LEX 1 20 20
STR instillation 1 15 10
  Prospective cohort studies Total 2 76 23, 24
No treatment/placebo 2 38 23, 24
INH 2 24 23, 24
ERY 1 11 24
STR + INH 1 3 24
  Retrospective cohort studies Total 2 61 25, 26
No treatment 2 57 25, 26
INH ± RIF 1 1 26
FNA 1 2 26
FNA + INH ± RIF 1 1 26
Suppurative lymphadenitis
  Randomized controlled trials Total 2 104 22, 27
No treatment 1 34 27
FNA 1 43 27
FNA + ERY 1 14 22
FNA + INH instillation 1 13 22
  Prospective cohort studies Total 2 64 24, 28
No treatment/placebo 2 19 24, 28
FNA 1 23 28
FNA + ERY 1 5 24
Surgery 1 10 28
Surgery + ERY 1 3 24
Surgery + STR + INH 1 4 24
  Retrospective cohort studies Total 4 167 25, 26, 29, 30
No treatment 1 3 26
Topical therapy 1 6 29
INH 1 21 29
INH ± RIF 1 7 26
INH + RIF + EMB 1 27 25
FNA 1 7 26
FNA + INH ± RIF 1 2 26
Incision and drainage 1 4 30
Surgery ± INH ± RIF 1 90 26, 30
Mixed suppurative and nonsuppurative lymphadenitis,† or type not specified
  Randomized controlled trials Total 1 18 31
No treatment 1 10 31
INH 1 8 31
  Prospective cohort studies Total 2 225 23, 32
No treatment 1 54 32
INH 1 75 32
Surgery 1 29 32
Surgery + INH 2 67 23, 32
  Retrospective cohort studies Total 2 33 25, 30
No treatment 1 2 30
INH 1 6 30
FNA 1 20 25
Surgery + INH 1 5 30
Injection site abscess
 Prospective cohort studies Total 1 18 33
ERY 1 9 33
INH 1 9 33
 Retrospective cohort studies Total 1 18 26
No treatment 1 16 26
INH ± RIF 1 1 26
FNA 1 1 26
Some studies included multiple reaction type groups. The number of patients describes number per respective reaction type group.
*±Fine needle aspiration during follow-up.
Within 1 comparator group.

TABLE 2. - Summary of BCG-Associated Lymphadenitis Management Strategies in Children
Management n Study Design Rx Duration Time to Recovery (Mean) Recovery Rate (%) Complication Type and Rate (%) Ref
Nonsuppurative lymphadenitis
 No treatment 42 RCT 67%* (28/42) at 6 months Spontaneous drainage 33% (14/42) 21
15 RCT 11.9 ± 1.5 days Abscess 80% (12/15) 10
Sinus tract 40% (6/15)
33 Prosp 29.1 weeks Spontaneous drainage and sinus tract 18% (6/33) 23
15 RetroCS 93% (14/15) at 6 months 26
42 RetroCS 100% (42/42) at 1 year Sinus tract 9% (6/69) 25
 No treatment§ 20 RCT 15.8 ± 5.7 weeks Fluctuance, indication for FNA 15% (3/20) 20
 Placebo 5 Prosp 3.6 months 24
 Placebo§ 34 RCT 1 month 3.5 ± 1.4 months Abscess, indication for FNA (subsequently had 1 dose INH instillation) 59% (20/34) 22
 INH 21 RCT 2 months 52%* (11/21) at 6 months Spontaneous drainage 48% (10/21) 21
17 Prosp 6 months 28.2 weeks Spontaneous drainage and sinus tract 0% (0/17) 23
7 Prosp 6 months 3.8 months 24
 INH + RIF 21 RCT 2 months 62%* (13/21) at 6 months Spontaneous drainage 38% (8/21) 21
 INH ± RIF 1 RetroCS 100% (1/1) at 6 months 26
 ERY 36 RCT 1 month 67%* (24/36) at 6 months Spontaneous drainage 33% (12/36) 21
11 Prosp 10 days 3.1 months 24
 ERY§ 35 RCT 1 month 4.1 ± 1.5 months Abscess, indication for FNA 46% (16/35) 22
15 RCT 1 month 9.4 ± 0.5 weeks Abscess, indication for FNA 100% (15/15) 10
Sinus tract 0% (0/15)
 LEX 20 RCT 10 days 16.1 ± 6.5 weeks Fluctuance, indication for FNA 10% (2/20) 20
 STR + INH 3 Prosp 2 months; 12 months 3.0 months 24
 STR instillation.§ 15 RCT 7.1 ± 0.5 weeks Abscess, indication for FNA 100% (15/15) 10
Sinus tract 0% (0/15)
 FNA 2 RetroCS 100% (2/2) at 6 months 26
 FNA + INH ± RIF 1 RetroCS 0% (0/1) at 6 months 26
Suppurative lymphadenitis
 No treatment 34 RCT 65% (22/34) at 6 months Sinus tract at 6 months 44% (15/34) 27
3 RetroCS 33% (1/3) at 6 months Sinus tract 33% (1/3) 26
 No treatment (prev drainage) 17 Prosp 8 weeks 28
 Placebo 2 Prosp 3.5 months 24
 INH ± RIF 7 RetroCS 29% (2/7) at 6 months Sinus tract 14% (1/7) 26
 INH + RIF + EMB 27 RetroCS 3 months 100% (27/27) at 1 year Sinus tract 9% (6/69) 25
 FNA 43 RCT 95% (41/43) at 6 months Sinus tract 7% (3/43) 27
23 Prosp 87% (20/23) at 1 month Spontaneous drainage after FNA 13% (3/23) 28
7 RetroCS 29% (2/7) at 6 months Sinus tract 0% (0/7) 26
 FNA + INH ± RIF 2 RetroCS 50% (1/2) at 6 months Sinus tract 50% (1/2) 26
 FNA + ERY 14 RCT 1 month 5.2 ± 1.3 months 22
5 Prosp 10 days 2.4 months 24
 FNA + INH instil. + po placebo 13 RCT 1 month 3.9 ± 1.1 months 22
 Incisional drainage 4 RetroCS 100% (4/4) at post-op FU 30
 Surgery 10 Prosp 100% (10/10) Discharge during post-op FU 0% (0/10) 28
 Surgery + ERY 3 Prosp 10 days 1.3 months 24
 Surgery + STR + INH 4 Prosp 2 months; 12 months 3.5 months 24
 Surgery + INH ± RIF 1 RetroCS 0% (0/1) at 6 months Sinus tract 100% (1/1) 26
Mixed suppurative and nonsuppurative lymphadenitis, or type not specified
 No treatment 10 RCT 2–7 months Abscess 40% (4/10) 31
54 Prosp 53% (21/40) at 3 months Spontaneous or surgical drainage 43% (17/40) 32
2 RetroCS 0% (0/2) at 12 months Supp or unresolved after 4–11 months 100% (2/2) 30
 INH 8 RCT 2–7 months Abscess 63% (5/8) 31
75 Prosp 3 months 39% (19/49) at 3 months Spontaneous or surgical drainage 61% (30/49) 32
6 RetroCS ≤12 months 17% (1/6) at 12 months Supp or unresolved after 4–11 months 83% (5/6) 30
 FNA 20 RetroCS 95% (19/20) at 12 months Sinus tract 50% (10/20) 25
 Surgery 29 Prosp 100% (19/19) improvement at 3 months 32
26 Prosp 4.4 weeks Spontaneous drainage and sinus tract 0% (0/26) 23
 Surgery + INH 16 Prosp 6 months 4.0 weeks Spontaneous drainage and sinus tract 0% (0/16) 23
25 Prosp 3 months 100% (20/20) improvement at 3 months 32
5 RetroCS ≤3 months 100% (5/5) at post-op FU 30
Only management groups with reported recovery outcomes were included in the table.
*Rate of improvement (decrease in lymph node size with no complication) or stabilization.
Standard error.
Individual group complication rate not reported.
§FNA is also done for subsequent lymphadenitis fluctuance during follow-up period for some or all participants.
Not reported.
Standard deviation.
Abbreviations: EMB indicates ethambutol; ERY, erythromycin; FNA, fine needle aspiration; FU, follow-up; INH, isoniazid; LEX, cephalexin; n, number of participants per comparator group; NR, not reported; Prosp, prospective cohort study; RetroCS, retrospective cohort study; RIF, rifampicin; Rx, treatment; STR, streptomycin; supp, suppurative; Surgery, total surgical excision

FIGURE 1.
FIGURE 1.:
PRISMA flow diagram. *One retrospective study included both BCG-associated lymphadenitis and BCG injection site abscess cohorts. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

The majority of BCG-associated lymphadenitis was ipsilateral axillary (n = 779), supraclavicular (n = 69) or cervical (n = 27) lymphadenitis. The size of lymphadenitis at presentation varied between trials, ranging from 0.5 to 8 cm in diameter. Some studies did not separate participants into nonsuppurative and suppurative lymphadenitis groups. Management strategies included antibiotics, antimycobacterial medications, needle aspiration, total surgical excision, a combination of these or no intervention (Fig. 2).

FIGURE 2.
FIGURE 2.:
BCG-associated lymphadenitis management strategies and time to recovery. Only studies reporting time to recovery are included in the figure. ERY indicates erythromycin; FNA, fine needle aspiration; INH, isoniazid; STR, streptomycin.

For BCG injection site abscess present beyond 10–12 weeks postvaccination, management strategies described were medical treatment with antibiotics, needle aspiration or no treatment.

Outcome measures reported varied between studies. For regional lymphadenitis, these were rate of and time to: recovery, complication, treatment failure and adverse event (Table, Supplemental Digital Content 2, https://links.lww.com/INF/E455 and Table, Supplemental Digital Content 3, https://links.lww.com/INF/E456). Some studies defined lymphadenitis recovery as a decrease in lymph node size to <0.5 cm or when nonpalpable, and absence of sinus formation or residual ulceration. The follow-up period ranged from 3 to 12 months, or until lymphadenitis recovery. For BCG injection site abscess (Table, Supplemental Digital Content 4, https://links.lww.com/INF/E457), in one study outcome was assessed by measuring diameter and evaluating for fluctuance, by an investigator blind to treatment.33 Serial photographs of injection sites were also compared by another blinded assessor. The follow-up period was 1 month. In the second study, recovery of abscess was defined as presence of small scar at injection site, with a follow-up period of 6 months.26

In the risk of bias assessment, all the RCTs were assessed as either “high-risk” or “some concerns.” The most common cause was bias arising from the randomization process; allocation sequence concealment was often inadequately described (Table, Supplemental Digital Content 5, https://links.lww.com/INF/E458). Most cohort studies were assessed to be at “serious risk” of bias, mainly due to potential confounding (Table, Supplemental Digital Content 6, https://links.lww.com/INF/E459 and Table, Supplemental Digital Content 7, https://links.lww.com/INF/E460).

BCG-associated Lymphadenitis

Medical Treatment

Medical treatment strategies were studied mostly in infants with nonsuppurative lymphadenitis.

Antimicrobials used comprised isoniazid (duration 2–12 months), isoniazid plus rifampicin (2 months), isoniazid plus streptomycin injection (12 and 2 months, respectively), erythromycin (10 days to 1 month), cephalexin (10 days) or streptomycin instillation (1 dose). These were compared with each other, no treatment or oral placebo.

Isoniazid (Including Combination Treatment)

Managing nonsuppurative lymphadenitis with isoniazid was compared with placebo or no intervention in 2 RCTs21,31 and 3 prospective cohort studies23,24,32 that reported similar outcomes. Treatment with isoniazid had a resolution rate of 39%–62% in 2–7.1 months with a complication rate of 0%–63% (compared with a resolution rate of 53%–67% in 2–7.3 months with a complication rate of 18%–43% in controls).

Managing suppurative lymphadenitis with isoniazid was assessed in 2 retrospective studies. In 1 small study,26 only 2/7 cases had complete resolution by 6 months, with a course of isoniazid ± rifampicin, and 5/7 had residual complications beyond 6 months (sinus formation, significant scarring, keloid formation, ulceration). In contrast, in another retrospective study,25 27 cases treated with 3-months of isoniazid, rifampicin and ethambutol all had complete healing, although this was assessed at 1-year follow up.

Erythromycin

Three RCTs10,21,22 and 1 prospective cohort study24 assessed erythromycin for the treatment of lymphadenitis. All 4 studies showed no significant difference between erythromycin and control group, in the proportion of patients with improvement21 or time to recovery.10,22,24 One of the RCTs10 reported that all 15 participants who received erythromycin developed suppuration and subsequently had needle aspiration. There was no significant difference in mean time to recovery between the erythromycin plus subsequent aspiration group and the no treatment group (9.4 weeks vs. 11.9 weeks, respectively).

Cephalexin

One RCT compared oral cephalexin (10 days) with no treatment.20 The time to recovery was similar between the 2 groups (mean 16.1 weeks vs. 15.8 weeks, respectively), as was the development of suppuration (2/20 vs. 3/20).

Streptomycin Instillation

One RCT assessed local streptomycin instillation.10 Infants with nonsuppurative lymphadenitis at recruitment were randomized to receive 1 dose of streptomycin directly into the affected lymph node, oral erythromycin or no treatment. All infants in the streptomycin and erythromycin groups developed suppuration and subsequently had needle aspiration. The mean time to healing was significantly shorter in infants receiving streptomycin plus subsequent aspiration compared with no treatment (7.1 weeks vs. 11.9 weeks; P = 0.009).

Needle Aspiration

In children with suppurative lymphadenitis, 2 RCTs22,27 and 2 prospective cohort studies24,28 evaluated the role of needle aspiration at presentation, with or without antimicrobials.

One RCT27 reported that more patients (41/43) in the needle aspiration group had lymph node regression by 6 months compared with no treatment group (22/34; P < 0.002). Also, the proportion of patients with spontaneous drainage and sinus tract formation was significantly less in the needle aspiration group (3/43) compared with no treatment (15/34; P < 0.003) at 6 months post needle aspiration. Six patients had a repeat needle aspiration. Two of these had matted lymph nodes with multilocular collections; 1 patient subsequently had surgical excision of affected lymph nodes.

Two studies assessed the combination of needle aspiration plus antimicrobials. One RCT22 had a subgroup of 27 infants presenting with lymphadenitis complicated by abscess formation; they had needle aspiration, followed by randomization to oral erythromycin plus saline placebo instillation, or oral placebo plus local isoniazid instillation. Those in the latter group had a significantly earlier time to resolution of lymphadenitis (mean 5.2 months vs. 3.9 months, P < 0.001). A prospective cohort study24 divided children with suppurative lymphadenitis into 4 treatment groups, with 5 or less patients per group. The mean time to recovery for those who had needle aspiration plus erythromycin was 2.4 months, shorter than 3.5 months for the 2 patients in the placebo group.

Two retrospective studies assessed needle aspiration.25,26 One study26 showed that none of 7 cases of suppurative lymphadenitis who had needle aspiration alone developed sinus formation, although one had significant scarring. Other treatment groups in the same study had only 1 or 2 cases each, which precluded statistical comparisons between groups. This contrasts with the study described above,25 which reported 10 of 20 cases developed sinus formation following needle aspiration and subsequently had surgical excision. However, it was not specified whether these cases were suppurative or not at presentation.

Surgical Excision

Surgical excision was investigated in 4 prospective cohort studies assessing patients with suppurative lymphadenitis. In 1 study, investigating a subgroup of children with discharging lymph nodes,28 recovery was better in the 10 of 27 children whose parents accepted surgical excision compared with the 17 that did not. No surgical patients had discharge during the postoperative follow-up period. In those who did not have surgery, it took a mean of 8 weeks for cessation of drainage and wound healing.

Two further studies23,32 found no significant difference in outcomes between total surgical excision alone or combined with oral isoniazid. In another study,24 which included 4 treatment groups with only 5 or less children in each, the mean time to recovery was shorter in those who had surgical excision plus erythromycin, compared with surgical excision plus streptomycin injection and isoniazid. No group had surgery alone.

Two retrospective studies reported surgical procedures for children referred to pediatric surgery departments.29,30 One study30 reported surgical excision plus isoniazid (up to 3 months) for lymphadenitis without abscess, and surgical drainage for lymphadenitis with abscess in 9 children. All had complete resolution by end of postoperative follow-up. A different group of 8 children in the same study was managed nonsurgically initially (type of Nonsuppurative lymphadenitis: 7/8 subsequently had surgical excision due to progression of lymphadenitis or lack of resolution after 4–11 months.

BCG Injection Site Abscess

Two cohort studies assessed management strategies for BCG injection site reactions (including abscesses) present beyond 10–12 weeks postvaccination.26,33 One prospective study found no difference in outcome in school-age children treated with oral erythromycin compared with isoniazid for 1 month.33 The maximum reduction in diameter of erythema or induration at 1-month was 55%, although the initial abscess sizes were not reported. A macular rash was noted in 1 patient in the erythromycin group. A retrospective study26 of 18 children reported complete resolution in 16/16 cases with no treatment within 6 months of presentation, as did the 1 case that had needle aspiration. One case received antimycobacterial therapy and had persistent scarring at the injection site referred to plastic surgery.

DISCUSSION

This comprehensive systematic review assesses a range of medical and surgical strategies for the management of BCG-associated lymphadenitis and injection site abscess.

For BCG-associated lymphadenitis, the role of medical antimicrobial therapy was evaluated mainly in infants with nonsuppurative lymphadenitis at presentation. Nonsuppurative lymphadenitis has been described to commonly regress over several months without intervention,7,34 even when >2 cm diameter.25 However, some continue to enlarge and develop suppuration.34 No antibiotic was found to significantly impact on time to resolution or prevention of suppuration. Side effects occurred in 7% of infants in 1 study, leading to early discontinuation of treatment.21 One RCT suggests that oral erythromycin or streptomycin instillation for nonsuppurative lymphadenitis may lead to earlier progression to suppuration, increasing the need for needle aspiration and subsequent shorter time to recovery. The potential recovery time saved (2–4 weeks) needs to be balanced against the burden of intervention. Overall, a watch and wait conservative approach appears reasonable for nonsuppurative BCG lymphadenitis.

For suppurative lymphadenitis, needle aspiration has been the most commonly assessed intervention. Prospective studies demonstrate that needle aspiration may shorten the time to resolution and prevent spontaneous drainage and sinus tract formation. The development of sinus tracts can cause significant morbidity with prolonged purulent discharge for many months. There is possible additional benefit following needle aspiration with local isoniazid instillation. However, there is no evidence to support the addition of an oral antimicrobial compared with needle aspiration alone. Needle aspiration may need to be repeated in cases of reaccumulation. Size of needle appears to be important, as 1 study reported that needles with bores larger than 20-gauge lead to development of persistent drainage requiring subsequent total surgical excision. Conversely, a needle with a bore that is too narrow may inhibit evacuation of thick inflammatory material.35 A 21- or 22-gauge needle has been recommended.8,36 Needle aspiration technique may also matter, as some specify a subcutaneous approach 2–3 cm from periphery of affected lymph node, to avoid iatrogenic sinus formation. Aspirated pus often reveals no growth.35 Secondary bacterial infection of BCG-associated lymphadenitis has been reported to occur.28

Criteria for surgical excision varied between studies. Most were for suppurative lymphadenitis, such as discharging lymph nodes or lymphadenitis remaining unresolved after several months (4–11 months). Some studies also specified size, reserving surgical excision for fluctuating lymph nodes >1.5 cm diameter, or those at least 2 cm diameter with induration and edema. Reported outcomes were generally favorable with complete healing. Addition of oral isoniazid did not influence postoperative recovery time. This is in contrast to surgical incision and drainage, which has been discouraged for BCG-associated lymphadenitis management, due to resulting persistently discharging wounds for many months and significant irregular scarring.28,35,37 Surgical excision also requires general anesthesia, which carries inherent risks. Therefore, surgical excision should generally be reserved for cases of suppurative lymphadenitis in which repeat needle aspiration has been unsuccessful, or when sinus tract formation has already occurred.

Management guidelines for BCG injection site abscess vary worldwide, with some countries (such as Brazil) recommending medical therapy38 and others a conservative approach (Finland, Canada).39,40 A prospective cohort study comparing oral erythromycin with isoniazid for 1 month in school-age children showed no difference in outcome between the groups, but did not include a control group. Another retrospective study described complete resolution without treatment in all 16 cases with BCG injection site reactions (including abscesses) within 6 months of presentation. Similarly, an Australian surveillance study reported 16 of 23 injection site abscesses resolving spontaneously.12 Seven had various interventions including surgical excision and antibiotics. However, the size of the abscesses was not provided in any of these studies. This is important, as the expected evolution involves formation of a pustule at the injection site with discharge (normal reaction), which can sometimes be challenging to differentiate from a small injection site abscess (adverse reaction). A case definition using a minimum 1 cm diameter for a BCG injection site abscess has been proposed in children to assist with more accurate classification of adverse reactions.8,41–43

Limitations of this review include a lack of consistent case definitions for BCG-associated lymphadenitis (including distinguish suppurative and nonsuppurative cases) and BCG injection site abscess. An inherent weakness of cohort studies is the potential imbalance of prognostic factors between groups, introducing selection bias. Some studies assessed heterogeneous BCG-associated lymphadenitis cohorts and interventions, including a mix of nonsuppurative and suppurative cases within the same group. Nonsuppurative and suppurative lymphadenitis have different natural courses7 and therefore should be evaluated separately. A few studies had no control group or had small sample size, with incomplete outcome data, making it difficult to interpret results and draw firm conclusions.

Most of the included studies were done before 2000 and reported complications following the use of BCG-Pasteur, which is no longer used.44 A large number of studies did not specify the BCG strain used, precluding the ability to discern the influence of strain. BCG strains differ genetically,45–47 induce different immune responses,48 and are associated with a different frequency of adverse reactions.49,50 Many countries have reported an increase in frequency of BCG-associated lymphadenitis and BCG injection site abscess following a change of strain used for vaccination.41,51–53 BCG vaccine strains have also been shown to differ in their susceptibility to antimycobacterial agents, an important consideration when planning management in immunocompromised children with BCG-associated adverse reactions.54

Immunocompromised children, such as those with human immunodeficiency virus infection who develop BCG-related complications due to immune reconstitution inflammatory syndrome, are a distinct population which warrants separate consideration.43,55

In conclusion, in immunocompetent children, the studies in this review do not support a role for antimicrobial therapy in the management of localized reactions to BCG vaccination. For suppurative lymphadenitis, needle aspiration may help shorten the recovery period, reserving surgical excision for persistent cases where this fails. BCG injection site abscess usually heals without intervention, however, studies evaluating interventions are limited. Future studies should incorporate clear case definitions for adverse reactions and specify the BCG strain used. The growing numbers of research trials into novel BCG applications provide opportunities to investigate optimal management strategies for adverse reactions, in a prospective manner using active safety surveillance.

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Keywords:

Bacille Calmette-Guérin; Mycobacterium bovis; lymphadenitis; abscess; adverse events following immunization

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