Vaccine 33 (2015) 4391–4397

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Review

Management of Bacillus Calmette-Guérin osteomyelitis/osteitis in

immunocompetent children—A systematic review
Wen-Li Lin a , Nan-Chang Chiu a,b , Pin-Hui Lee c , Angela Song-En Huang c , Fu-Yuan Huang a ,
Hsin Chi a,b,d , Daniel Tsung-Ning Huang a,d , Pei-Chun Chan c,e,f,∗
a
Department of Pediatrics, MacKay Children’s Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan
b
MacKay Junior College of Medicine, Nursing and Management, No. 42, Sec. 3, Zhongzheng Rd., Sanzhi Dist., 252, New Taipei City, Taiwan
c
Centers for Disease Control, No. 6, Linsen S. Rd., Jhongjheng District, Taipei 10050, Taiwan
d
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren Ai Rd, Taipei 10051, Taiwan
e
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, No. 17, Xuzhou Rd., Taipei 10055, Taiwan
f
Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, College of Medicine, No. 8, Zhongshan S. Rd., Taipei 10041,
Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Bacillus Calmette-Guérin (BCG) osteomyelitis/osteitis in immunocompetent children is a

Received 1 February 2015 rare but serious complication of BCG immunization. Rationale for its treatment is unclear.
Received in revised form 10 July 2015 Methods: Due to the rarity of this complication, no randomized control trials has ever been conducted to
Accepted 13 July 2015
evaluate methods of intervention. As such, we searched the literature for any reported BCG vaccination-
Available online 26 July 2015
related osteomyelitis/osteitis among immunecompetent children published before April 15, 2014. We
summarized the data from different affected regions of the body by recording the number of reported
Keywords:
cases, while noting outcomes and their medical and/or surgical interventions.
BCG vaccine
Osteomyelitis
Results: From 34 eligible studies gleaned from a screening of 804 articles, a total of 331 cases were enrolled.
Osteitis Involvement of the lower limbs was present in 55.6%, followed by the axial skeleton (26.0%), the upper
Disease management limbs (15.4%), and multiple bones (3.0%). Of the 64 patients having records of detailed chemotherapy
Review regimens, 45 patients (70%) received two or fewer drugs. Among the 80 patients with detailed surgical
records, 50 (62.5%) received surgical procedures for diagnostic purposes. While there were uneventful
outcomes for those receiving diagnostic procedures, 7 of the 30 (23.3%) patients receiving surgical inter-
ventions had major complications (p = 0.002, Fisher’s exact test). The overall prognosis was good with a
97.6% cure rate. Nevertheless, eight patients (2.4%) suffered major complications.
Conclusions: The rationale for treatment of BCG osteomyelitis/osteitis in immunocompetent children is
highly subjective. However, patients receiving diagnostic procedures instead of surgical interventions
may avoid major complications. Because only a few of the publications had detailed treatment infor-
mation, further studies are needed to identify proper treatments, while infant BCG vaccination is still in
use.
© 2015 Elsevier Ltd. All rights reserved.

1. Introduction promising results in human trials so far [5], understanding how to

Bacillus Calmette-Guérin (BCG) is a live-attenuated vaccine,
which mainly prevents severe disseminated tuberculosis (TB) in
young children. Osteomyelitis/osteitis is a rare but serious compli-
cation of BCG immunization, even in immunocompetent children
[1–4]. Because new TB vaccines in the pipeline have not shown
∗ Corresponding author at: No. 6, Linshen S. Rd., Taipei 10050, Taiwan.
Tel.: +886 2 23959825x4008; fax: +886 2 33936149.
E-mail address: pcanita.tw@cdc.gov.twg (P.-C. Chan).
best treat BCG complications is extremely important.
BCG osteomyelitis/osteitis, typically presents in children 1–2
years after BCG inoculation who develop insidious clinical symp-
toms/signs despite massive radiologic findings. These lesions
usually show as osteolytic lesions on radiology, as cold lesion
on bone scan, and the clinical progress of these lesions is slow
with poor response to traditional antibiotics [6]. Histology of
biopsy shows granulomatous reaction with caseous necrosis. The
diagnosis is challenging but prognosis for immunocompetent chil-
dren is generally good with adequate antituberculous treatment
[7,8].

http://dx.doi.org/10.1016/j.vaccine.2015.07.039
0264-410X/© 2015 Elsevier Ltd. All rights reserved.
4392 W.-L. Lin et al. / Vaccine 33 (2015) 4391–4397
# 804 records idenfied through
database searching & screened
# 59 full-text arcles
assessed for eligibility
# 34 studies (331 cases)
# 25 full-text arcles
included in qualitave excluded
synthesis
#7 case series (300 cases)
# 27 case report (31 cases)
Review arcle lack of individual detail (n=10)
Paents with immune-deficiencies (n=2)
BCG disseminated disease (n=2)
Lack of treatment protocol, prognosis and without clear diagnosis (n=7)
Same case presented in 2 different papers (n=1)
Other languages (n=2)
BCG not osteomyelis (n=1)
Fig. 1. Flowchart of identification of eligible patients.
Because of the low incidence [3], there are currently no avail-
able randomized controlled trials (RCTs) or case-control studies
that discuss management strategies. Therefore, we reviewed the
literature that suggested medical and surgical intervention for
treating BCG osteomyelitis/osteitis, and compared their outcome
and prognosis. The objective of this study is to describe and summa-
rize the clinical course and prognosis of BCG osteomyelitis/osteitis
in children and to suggest a proper treatment plan for clinical
practice.
2. Materials and methods
2.1. Types of studies
We included observational studies (i.e., cohort studies),
case-control studies, and case reports related to BCG osteomyeli-
tis/osteitis among children aged 18 years and younger.
2.2. Inclusion and exclusion criteria
Studies were enrolled if they had BCG inoculation records and
developed osteomyelitis/osteitis with well-defined lesion sites.
The definitions of diagnosis of BCG were: culture and biochem-
ical methods or polymerase chain reaction (PCR) confirming
Mycobacterium bovis or histology showing granulation tissue with
caseous necrosis without a history of contact with TB. Studies
were excluded, if BCG vaccine was inadvertently given to patients
with immunodeficiencies or used for the treatment of urogeni-
tal cancers. Studies were also excluded, if the information was
not available either for types of exposures or types of outcome
measures mentioned above. We also excluded non-original publi-
cations and abstracts of conferences, for which the details of study
could not be obtained.
#745 records excluded
Irrelevant arcles (n=343)
Mycobacterium not BCG strain (n=161)
BCG used for urogenital cancers (n=78)
BCG adverse effect without osteomyelis/osteis (n=26)
Paents with immune-deficiencies (n=62)
Other languages (n=62)
Paper published before 1971 and
Informaon not available (n=5)
Paper published in 1971 or aer but
abstracts or full arcle not available (n=8)
2.3. Types of outcome measures
Poor outcome was defined as scoliosis, limb deformity, residual
disability, such as motor weakness, paralysis, chronic pain, limited
range of motion, or mortality. Good outcome was defined as sur-
vival and disappearance of apparent signs and symptoms with no
residual disability.
2.4. Electronic searches and selection of studies
We searched PubMed (to April, 15, 2014) and EMBASE (1947
to April, 15, 2014) for primary studies. Searches were restricted to
English, Chinese, and Japanese. The search strategies for PubMed
were: (“Bacillus Calmette-Guérin” OR “BCG Vaccine” [Mesh]) AND
(“osteomyelitis” [Mesh] OR “osteitis” [Mesh] OR “bone infection”).
The search strategies for EMBASE were: (“BCG” AND “osteomyeli-
tis”) OR (“BCG” AND “osteitis”) OR (“BCG” AND “bone infection”).
Studies identified by the search strategy were reviewed for eligibil-
ity based on title and abstract by the investigator (Fig. 1). Full text
of the papers identified through screening was reviewed for con-
sideration based on the inclusion and exclusion criteria. If a study
was reported in more than one paper, we only included the one
with the most detailed study information. The investigator resolved
uncertainties by consensus with a second investigator.
2.5. Data extraction and management
Full articles were reviewed by two investigators; if reach-
ing a consensus was necessary, a third, independent investigator
was enrolled. For every eligible study, detailed information on
important study characteristics and results using a standard data
collection form was collected. The data extracted included the
following information: age of diagnosis and vaccination, site of
diagnosis, definitions for BCG identification, antimicrobial ther-
apy regimen and duration, surgery and outcome. For the studies
 W.-L. Lin et al. / Vaccine 33 (2015) 4391–4397 4393

Table 1
Summary of studies included in this review on BCG osteomyelitis/osteitis.

Reference Year Country Type Case no. Age Definitions for BCG Antimicrobial Surgery Outcome
identification therapy

[7] 1995 Finland S 222 – Culture (51%), Not included Not included (5) Poor
histology (49%)
[8] 2009 Japan S 20 + PCRb (60%), culture + + +
(10%), histology
(30%)
[9] 1990 France R 1 + Culture + + +
[10] 1983 Sweden R 1 + Culture + + +
[11] 1978 Denmark R 1 + Culture + + +
[12] 2012 Korea R 1 + PCRb + + +
[13] 2011 Japan R 1 + PCRc + + (1)Poor
[14] 1976 Sweden S 18 – Culture (39%), Not included + (1) Poor
histology (61%)
[15] 1988 Czechoslovakia S 26 – Culture (35%), Not included Not included (1) Poor
histology (65%)
[16] 2012 Korea R 1 + PCRb + + +
[17] 1997 Chile S 10 – Culture (10%), + Not included +
histology (90%)
[18] 2004 Taiwan S 4 – Histology (100%) + Not included +
[19] 1981 Switzerland R 1 + Culture + + +
[20] 2013 Japan R 1 + PCRb , c + + +
[21]a 1984 Finland S 10 – Culture (40%), Not included + (4) Poor
histology 6(60%)
[26] 1992 Austria R 1 + Histology + + +
[28] 1992 Germany R 1 + Histology + + +
[29] 1977 United R 1 + Histology + + +
Kingdom
[30] 1984 Saudi Arabia R 1 + Histology + + +
[31] 2012 Saudi Arabia R 3 + PCRb + + +
[32] 2002 Turkey R 1 + Histology + + +
[33] 1997 Japan R 1 + PCRb + + +
[34] 2010 Hong Kong R 1 + PCRc + + +
[35] 2010 Taiwan R 1 + PCRb + + +
[36] 1996 Japan R 1 + PCRc + + +
[37] 2008 Japan R 1 + PCRb + + +
[38] 1999 Turkey R 2 + Histology + + +
[39] 2006 Iran R 1 + Culture + + +
[40] 2008 Korea R 2 + PCRb + + +
[41] 1986 India R 1 + Culture + + +
[42] 1999 Taiwan R 1 + PCRb + + +
[43] 2012 Brazil R 1 + PCRb + + +
[44] 2008 India R 1 + Culture + + +
[45] 2008 Brazil R 1 + Histology + + +

BCG: Bacillus Calmette-Guérin, R: case report, S: case series, +: information available, −: information not available and stands for “excluded”, PCR: polymerase chain reaction.
a
Ten patients in reference 18 had been also mentioned in reference 7. Reference 18 was not deleted because it provided extra data for the sub-group analysis of reference
7.
b
PCR based on gene analysis or M. bovis BCG specific primers.
c
PCR may only allow differentiation to the level of M tuberculosis complex or M. bovis, but not M. bovis BCG.

provided only tabular data for certain characteristics, we used the
total case number in that particular study times the proportion of
the characteristics given to calculate the attributable case number.
In regards to further investigation of regimen, duration of treatment
and surgical intervention, only studies that could provide detailed
information were enrolled for subgroup analysis. Two by two tables
were compared using chi-square tests (Fisher’s exact test was used
when sample sizes were small).
3. Results
From 34 eligible studies gleaned from a screening of 804
database identified articles, 331 cases were reviewed and iden-
tified as BCG osteomyelitis/osteitis for analysis (Table 1). The
diagnosis was confirmed by PCR in 28 cases (8.5%), while M.
bovis was identified by culture in 138 cases (41.7%). The other
165 cases (49.8%) were confirmed by histopathology and ful-
filled the following criteria: they received BCG vaccination, denied
tuberculosis contact history, and had histopathology reports with
either a positive acid-fast bacilli stain or typical caseous necrosis
change. A high proportion of cases were confirmed by culture or
histopathology without molecular diagnosis because in the past
(specifically in the 1960s–1980s), methods such as PCR were not
available. As to the locations of lesions, 184 cases (55.6%) involved
lower limbs including the femur, tibia, fibula, calcaneus, and talus,
while 51 cases (15.4%) involved upper limbs. A total of 86 cases
(26.0%) involved lesions of the axial skeletons: the sternum, ribs,
clavicle, scapula, ilium, hip, and the spine. Ten cases (3.0%) involved
multiple bones. Among the 224 patients immunized in the left
gluteal or deltoid regions, 119 developed left-sided lesions, while
two patients immunized in the right deltoid region developed
right-sided lesions. The site of BCG administration was not sig-
nificantly related to the side of the bones affected (p = 0.223 with
Fisher’s exact test). Bones under inoculation sites did not bear a
higher risk of developing osteitis (data not shown).
3.1. Outcome
The overall prognosis was good and healing without sequela
was reported in 323 cases (97.6%). Eight patients (2.4%) experi-
enced sequelae (Table 2), including disturbance of growth in leg (5),
arm deformity (1), scoliosis (1), and disability with multiple bone
4394 W.-L. Lin et al. / Vaccine 33 (2015) 4391–4397

Table 2
Clinical data of patients with sequelae and complications.

No. Ref. Exact site Diagnosis Surgery Sequelae and complications

11 [13] Left tibial PCR Yes, curettage twice. He started Leg shorten 1.4 cm at a 2-year
growth plate treatment with Cefazolin 2 weeks after follow-up
involved onset of symptoms, then shifted to
panipenem and ceftriaxone for 4
weeks. The firsts urgery, curettage of
proximal tibia, was done 6 weeks after
initial symptoms. Knee pain recurred 1
month later and the second surgery,
curettage of epiphysis and one-third of
the growth plate, was performed.
46 [14] Bilateral elbow, Culture Yes, curettage. Repeated incision for Disability with multiple lesions around
multiple bone abscess and Penicillin for 6 months the elbow joint, spread to adjacent
before the definite diagnosis was made. joint under treatment
81 [7] Humerus Culturea Unknown surgical history Arm deformity
86 [7,21] right femur Culture Yes, trephination Coxa valga required osteotomy
88 [7,21] Head of right Culture Yes, trephination Coxa magna and subluxation
femur
90 [7,21] left femur Histology Yes, trephination Femur shorten 1 cm
91 [7,21] Left femur Histology Yes, sequestrectomy after knee pain for Knee arthritis, sequestration, femur
4 weeks lengthen 0.5 cm
328 [27] Spine Histology Yes, costotranversotomy for Scoliosis
paravertebral abscess
13 [11] Left calcaneus Culture Yes, twice. Initial incision and Secondary infection with abscess and
debridement, followed by incision and fistula formation. After the second
debridement 4 months later for fistula. surgery, Streptomycin and Ethambutol
were added. Gradual improvement
after 3 months. No sequel
48 [15] Proximal Histology Open biopsy or drainageb Relapse in the fourth month of
metaphysis of treatment featuring fistula and abscess
tibia formation. Resolved without sequela at
1-year follow-up.
49 [15] Proximal Histology Open biopsy or drainageb Fistula and abscess formation, resolved
metaphysis of without sequela at 1-year follow-up
tibia
84 [21] Left fifth rib Histology Yes, rib resection Abscess development 6 months after
treatment, resolved without sequela
85 [21] Neck of left Histology Yes, trephination Hip arthritis, resolved without sequela
femur
87 [21] Left fifth rib Culture Yes, rib resection Abscess development 6 years later,
resolved without sequela
a
Diagnostic method mentioned in the case series; no special result mentioned for individual patients.
b
Surgical intervention mentioned in the case series; no specific procedure mentioned for individual patients.

involvement (1). Among five cases with leg growth disturbance, the
growth plate was involved in two cases, one of which resulted in a
leg being shortened by more than 1 cm. The other case involving the
growth plate had severe coxa valga and required osteotomy. There
were another six patients summarized in Table 2 who suffered from
complications, which resolved during the follow-up. The complica-
tions include a slow-healing fistula or spreading of an abscess into
adjacent tissues with a risk of recurrence.
Among 86 cases involving the axial skeleton, seven (8.1%) had
vertebral lesions (Table 3). None of these seven patients were con-
firmed by PCR and only one case was identified by culture as the
Mycobacterium bovis. This was a 15-year-old boy who received BCG
vaccination twice, once during the neonatal period and then again
at age 14 as a booster [9]. Only two patients (29%) received surgical
intervention and both of them needed orthopedic casts. Six of these
seven patients recovered without sequela; only one developed gib-
bus and mild scoliosis. All 79 axial skeleton cases not involving the
vertebrae completely recovered.
3.2. Age of vaccination and disease onset
A total of 303 cases from 32 of the articles mentioned the age
of vaccination. Excluding the one case inoculated twice [9] and
another case vaccinated at age 8 years, 260 cases (86.4%) were inoc-
ulated before the age of 1 month, and 41 cases (13.6%) between 2
and 12 months. A total of 55 cases from the 29 articles mentioned
the age of disease onset. A total of 52 cases (95%) had an onset of
disease before the age of 5 years. Three patients—all diagnosed by
culture—developed disease at the ages of 8 years, 13 years and 15
years (these patients were vaccinated at age 8 years, as a newborn,
and as a newborn and at age 14 years, respectively) [9–11]. BCG
osteitis can also afflict those vaccinated after the age of 5 years,
though this is rare. Excluding the aforementioned patient whose
osteitis was diagnosed at age 13 years [10], the mean duration
between vaccination and disease onset of the 54 patients was 13.9
months (2–46 months).
3.3. Chemotherapy regimen
A total of 64 patients from 30 articles recorded chemother-
apy regimens (Table 4). A total of 37 cases (57%) started with a
2-drug regimen (isoniazid plus rifampicin with or without pyraz-
inamide). After escalation, de-escalation, or discontinuation of
treatment, 45 patients (70%) ultimately received therapy consist-
ing of two or fewer drugs. A total of 41 cases (64%) ended up
with a 2-drug regimen (isoniazid plus rifampicin with or with-
out pyrazinamide). Among the 37 cases that were started on a
2-drug regimen, one patient’s therapy was escalated to a 4-drug
regimen. It was a 9-month-old girl with a lesion of the elbow.
She showed no improvement after being treated with isoniazid,
rifampicin, and pyrazinamide for 2 months following an initial sur-
gical intervention [12]. Subsequent PCR confirmed BCG strain and
 W.-L. Lin et al. / Vaccine 33 (2015) 4391–4397 4395

Table 3
Clinical data of patients with BCG vertebral lesions.

Reference Year Country Site of Definitions for Antimicrobial Duration (m) Surgery Outcome
diagnosis BCG identification therapy/orthopedic cast

[7,21] 1995 Finland Lumbar spine, Histology 2HRS + 4HR + ?Ha /plaster 10–24 No, biopsy only Good
L4-5 bed
[9] 1990 France Thoracic spine, Culture, M. bovis HERZ/Stagnara brace 6 No, paravertebral Goodb
T11 BCG abscess, biopsy
only
[14] 1976 Sweden Thoracic spine Histology HRSa /plaster bed 6 No, curettage Good
T7-9
[26] 1992 Austria Thoracic spine, Histology HER/plaster-cast jacket 6 Yes, scraped off Good
T2-3 prevertebral
tumor with
raspatory
[15] 1988 Czechoslovakia Spine Clinical 3HRS + 3HRa /plaster bed 6 No Good
[15] 1988 Czechoslovakia Spine Clinical 3HRS + 3HRa /plaster bed 6 No Good
[15] 1988 Czechoslovakia Thoracic spine, Histology 3HRS + 3HRa /plaster bed 6 Yes, paravertebral Developed a
T3-6 abscess, costo- gibbus with
tranversotomy scoliosis

BCG: Bacillus Calmette-Guérin, H: isoniazid, E: ethambutol, R: rifampicin, Z: pyrazinamide, S: streptomycin.

a
Preferred medications prescribed in the case series; no specific regimen mentioned for individual patients.
b
This was a 15-year-old boy who received BCG vaccination twice, once during the neonatal period and then again at age 14 as a booster. Ten months after the booster,
he experienced lower back pain and was subsequently diagnosed with 11th thoracic vertebra osteitis. He was put in a brace for 6 months, treated with four drugs and then
recovered.

Table 4 course of diagnosis and treatment before definite diagnosis was

Chemotherapy regimens and escalation for BCG osteomyelitis/osteitis.
made. Though he experienced an increased dosage of chemother-
Chemotherapy regimens Case no. % apy prescribed after the second operation, the growth of his left leg
2-drug combination (with or without 37 57% was stunted by 14 mm due to involvement and disruption of his
Z) growth plate.
Escalate to HERS 1
Remain 2-drug combination 36
HR(Z) → HR(16), HR → HR(Z)(2) a , 3.4. Chemotherapy duration
remain HR(Z)(6) remain HR(12)
3-drug combination (with or without 21 33% A total of 50 patients from 30 articles had reviewable courses of
Z)
chemotherapy. A total of 31 cases (62%) received a treatment course
De-escalate to 1 drug 2
HER → H(1), HRS(Z) → H(Z)(1) of 6 months or less; 15 cases (30%) were treated for over 6 months
De-escalate to HR 5 but less than 12 months; two cases (4%) were treated for over 12
HRS(Z) → HR(3), HER(Z) → HR(1), months but for less than 18 months; and two cases (4%) terminated
HRS → HR(3), HER(Z) → HR(1),
treatment within the first 2 months due to side effects. The duration
HRS → HR(1)
Liver enzyme elevated & 1
of chemotherapy had no bearing on outcomes relative to the age of
rash → discontinuedb the children nor in relation to lesion sites. Among 33 patients who
Remain 3-drug combination 13 received chemotherapy for no more than 6 months, one of them had
HER(Z) (1), HER(6), HRS(2), a poor outcome. He was the aforementioned patient with stunted
HRS → HRS(Z) (1) remain HR + PAS(3)
left leg [13]. Among the 17 patients who received chemotherapy
4-drug combination 3 5%
Remain 4-drug combination (HERS) 3 for more than 6 months, all of them had a good outcome.
Others (non-HR-based regimen) 3 5% Though the number of patients who received no antitubercu-
H → HSE 1 losis treatment is not known, nearly all of the patients lacking
HS + PASc (1) 1
detailed chemotherapy regimens received chemotherapy of some
remain HS(Z)(1) 1
Total 64 100%
kind [7,14,15]. A majority of these had backbone regimens, includ-
ing isoniazid and rifampicin. In the intensive phase, streptomycin
H: isoniazid, E: ethambutol, R: rifampicin, Z: pyrazinamide, S: streptomycin PAS: N
was added from 1 to 3 months; occasionally, ethambutol was used
para-aminosalicyclic acid
a
One of the two patients had poor outcome [13]. as an alternative to streptomycin. The continuation phase usually
b
A 9-month-old infant who suffered from both elevated liver enzymes and rash lasted from 3 to 6 months with backbone regimens. Up to 40%
[28]. of the cases in the studies from Finland received the Copenhagen
c
A 3-year-old boy with a lesion of the right femur. He was put on a course of para- strain [7], isoniazid was used alone in the continuation phase after
aminosalicyclic acid, isoniazid and streptomycin for 2 months, after which his limp
disappeared. No recurrence was observed in either of these patients in 3.5 years of
4 months of backbone treatment regimens to complete a median
follow-up [29]. 12-month treatment course. Only 15 of the remaining cases men-
tioned the BCG strain used [16–20]. None of the reported patients
mentioned resistance to isoniazid, nor was isoniazid discontinued
isoniazid, ethambutol, rifampicin, and streptomycin were admin-
for any of the patients mentioned above.
istered. She received a second operation 4 months after the first for
debridement and curettage. Her elbow regained full function after
12 months of chemotherapy and there were no signs of disturbed 3.5. Surgery
growth in the afflicted limb.
Among the 64 patients with detailed chemotherapy regimens, Surgical intervention was mentioned in less than 25% of these
only one had a poor outcome. It was a 1-year-old boy with a lesion children. Among 80 patients from 30 articles with mention of
on the growth plate of the left tibia, who eventually had a poor out- type of surgical intervention, 50 cases (62.5%) received proce-
come due to delayed diagnosis [13]. Table 2 shows his protracted dures for diagnostic purposes, including aspiration biopsy (10),
4396 W.-L. Lin et al. / Vaccine 33 (2015) 4391–4397
curettage (28), and open bone biopsy (12). The other 30 cases
received surgical interventions, including total (3) or partial
bone excision (5), incision & drainage (7), trephination (7), and
multiple surgeries (8). While the 50 patients receiving diagnos-
tic procedures had uneventful outcomes, 7 of the 30 (23.3%)
patients receiving surgical interventions had major complications
(p = 0.002, Fisher’s exact test). Though only 34 of the patients
with records of surgery had a detailed treatment duration record,
the duration of treatment between patients receiving diagnostic
procedures and those receiving surgical intervention did not dif-
fer significantly (treatment duration ≤ 6 months: 10/17 vs. 8/17,
p = 0.732).
4. Discussion
Our study shows that BCG osteomyelitis/osteitis among
immunocompetent children generally has a good outcome. Based
on the limited data found in this systematic review on chemother-
apy it seems as if a regimen of isoniazid and rifampicin for 6 months
may be sufficient for treating BCG-related osteomyelitis/osteitis
in immunocompetent children. Surgical interventions for diag-
nostic purposes were helpful; however, a significant proportion
of patients receiving interventional surgery as part of treatment
for BCG osteomyelitis/osteitis had permanent complications post-
surgery, therefore, the latter is not recommended. Involvement
of weight bearing joints, growth plates, or the vertebrae increase
the risk of sequelae. Vertebral involvement is rare, but happens
on occasion. BCG osteomyelitis/osteitis among those vaccinated
after the age of 5 years is rare, but does happen. BCG osteomyeli-
tis/osteitis should be considered in the differential diagnosis of
chronic osteomyelitis/osteitis with cold lesions and a poor response
to antibiotics treatment in children.
The most promising new TB vaccine trial—the MVA-85 A prime
booster—failed to demonstrate protective effect for infants, forcing
us to reexamine BCG [5]. The incidence of osteomyelitis/osteitis
after BCG vaccination varies from 0.01 per million in Japan to 300
per million in Finland [7,8]. It is associated with several factors:
route of delivery, strain of the vaccine, dosage, age at the time
of vaccination, the status of the patient’s immune system, and
surveillance strategies [4]. In our review, inoculation with the BCG
vaccine later in infancy even childhood does not seem to prevent
all BCG osteomyelitis/osteitis. The nonspecific initial symptoms
and laboratory findings of BCG osteomyelitis/osteitis delayed diag-
nosis (Table 2). Typical X-rays will show osteolytic lesions with
mild periosteal reaction and negative bone scan [21]. Misdiagno-
sis often hampers treatment until poor response to conventional
antibiotics forces the physician to consider the possibility of
BCG.
There are no available treatment guidelines for BCG-related
adverse events for immunocompetent children. For HIV-infected or
immunocompromised children, BCG-related diseases spread more
easily from local to distant sites and have higher rates of mortal-
ity. Hesseling et al. suggest a 4-drug regimen for at least 9 months
in order to limit the spread and achieve better outcome [22]. Until
now, there have been no RCTs for BCG osteomyelitis/osteitis com-
pared to a Cochrane review of RCTs for BCG lymphadenitis [23]. We
found a generally good outcome after chemotherapy. Less than 20%
of the publications we reviewed had information detailed enough
to allow for a conclusive rationale regimen. Nevertheless, nearly
all of the patients lacking detailed chemotherapy regimens data
received some kind of chemotherapy. A 6 to 12 months isoni-
azid plus rifampicin combination therapy could be suggested as
an initial treatment option for BCG osteomyelitis/osteitis. Differ-
ent from M. tuberculosis, M. bovis BCG is less virulent and resistant
to pyrazinamide [24]. The Copenhagen strain is noted to have a
low-level resistance to isoniazid [25]. There was a prolonged use of
isoniazid observed in Finland, a country in which the Copenhagen
strain accounted for 40% of BCG vaccinations. Meanwhile, 3-drug
regimens including streptomycin were favored in Finland and
Sweden [7,14]. Therefore, it is hard to conclude that BCG-related
isoniazid resistance has an influence on the choice of treatment
regimens.
Surgical approaches may be useful for diagnosis; however,
removal of bony lesions may be harmful. Patients at a higher
risk for complications usually have lesions on weight bearing
joints, growth plates, or vertebrae. Our subgroup analysis revealed
that patients receiving diagnostic procedures only, compared to
patients receiving surgical interventions, significantly avoided
major complications and patients in the latter group did not benefit
shorter course. Since those with severe manifestations were more
likely to receive operations, we would suggest operations should be
carried out as minimally as possible for BCG osteomyelitis/osteitis.
Contrary to the long-held assumption that BCG-related osteomyeli-
tis/osteitis never involves the vertebrae, seven cases involving the
spine (including one with multi-focal lesions) have been reported
[7,9,14,15,21,26]. BCG used for intravesical therapy among patients
with bladder carcinoma also showed that M. bovis spondylodiscitis
did occur [27].
Our main limitation is publication bias. Due to the rarity of this
disease, it is difficult to conduct an RCT. Therefore, the articles
enrolled in our study were all case reports and case series. Cases
with successful treatments and good outcomes are more likely to
be published than those with poor outcomes. The small number
of cases available for subgroup analysis of regimen and treat-
ment duration might limit accuracy. A 222 case series, contributed
from the National Registry of both the vaccine compensatory and
laboratory in Finland, had no individual information in regards
to regimens, duration of treatment or surgical intervention [7].
The median duration of treatment was 12 months in that study,
whereas 62% of the cases in our subgroup analysis that received
treatment for 6 months only. However, because no similar analysis
exists, our review can encourage further reporting and analysis.
Diagnostic methods for BCG osteomyelitis/osteitis pose another
major limitation. An exact diagnosis of BCG disease is hardly ever
found to be reported. Earlier reports often lacked definite diagnoses
and many articles only reported inadequate details (especially in
regards to clinical follow-up) [14,15,17]. Constraints on health-
care resources differ around the world. For places in which BCG
vaccination rates are still high, BCG-related diseases are underes-
timated because of the difficulty in distinguishing BCG from M.
bovis or even M. tuberculosis complex. In places where a definite
diagnosis of BCG can be made, the rarity of BCG osteomyelitis
leads to case reports only [12,13]. Further research on M. bovis
osteitis/osteomyelitis could help us understand more about the
true rate of BCG osteitis/osteomyelitis and also the possibility of
acquiring M. bovis from the environment or through milk consump-
tion among children.
In conclusion, the rationale for treatment of BCG osteomyeli-
tis/osteitis in immunocompetent children is highly subjective.
However, patients receiving diagnostic procedures instead of sur-
gical interventions may avoid major complications. Because only a
few of the publications had detailed treatment information, further
studies are needed to identify proper treatments while infant BCG
vaccination is still in use.
Conflicts of interest statement and source of funding
All authors have no conflicts of interest or financial relationships
relevant to this article to disclose. No external funding was secured
for this study.
 W.-L. Lin et al. / Vaccine 33 (2015) 4391–4397
Acknowledgments
We thank Hsien-Ho Lin for comments and Geoff Hughes for
English language support.
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