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osteitis in immunocompetent children—A systematic review
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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 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 b
a r t i c l e
i n f o
Article history: Received 1 February 2015 Received in revised form 10 July 2015 Accepted 13 July 2015 Available online xxx Keywords: BCG vaccine Osteomyelitis Osteitis Disease management Review
a b s t r a c t Background: Bacillus Calmette-Guérin (BCG) osteomyelitis/osteitis in immunocompetent children is a rare but serious complication of BCG immunization. Rationale for its treatment is unclear. Methods: Due to the rarity of this complication, no randomized control trials has ever been conducted to evaluate methods of intervention. As such, we searched the literature for any reported BCG vaccinationrelated 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 cases, while noting outcomes and their medical and/or surgical interventions. Results: From 34 eligible studies gleaned from a screening of 804 articles, a total of 331 cases were enrolled. Involvement of the lower limbs was present in 55.6%, followed by the axial skeleton (26.0%), the upper limbs (15.4%), and multiple bones (3.0%). Of the 64 patients having records of detailed chemotherapy 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 interventions 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 information, further studies are needed to identify proper treatments, while infant BCG vaccination is still in use. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction 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 complication 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: [email protected] (P.-C. Chan).
promising results in human trials so far [5], understanding how to best treat BCG complications is extremely important. BCG osteomyelitis/osteitis, typically presents in children 1–2 years after BCG inoculation who develop insidious clinical symptoms/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 children 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.
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# 804 records idenfied through database searching & screened
#745 records excluded
# 59 full-text arcles assessed for eligibility
# 34 studies (331 cases) included in qualitave synthesis
# 25 full-text arcles excluded
#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)
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)
BCG not osteomyelis (n=1)
Fig. 1. Flowchart of identification of eligible patients.
Because of the low incidence [3], there are currently no available 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 summarize 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 osteomyelitis/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 biochemical 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 urogenital 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 publications and abstracts of conferences, for which the details of study could not be obtained.
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 survival 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 “osteomyelitis”) OR (“BCG” AND “osteitis”) OR (“BCG” AND “bone infection”). Studies identified by the search strategy were reviewed for eligibility based on title and abstract by the investigator (Fig. 1). Full text of the papers identified through screening was reviewed for consideration 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 reaching 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 therapy regimen and duration, surgery and outcome. For the studies
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Table 1 Summary of studies included in this review on BCG osteomyelitis/osteitis. Reference
Year
Country
Type
Case no.
Age
Definitions for BCG identification
Antimicrobial therapy
Surgery
Outcome
[7]
1995
Finland
S
222
–
Not included
Not included
(5) Poor
[8]
2009
Japan
S
20
+
+
+
+
[9] [10] [11] [12] [13] [14]
1990 1983 1978 2012 2011 1976
France Sweden Denmark Korea Japan Sweden
R R R R R S
1 1 1 1 1 18
+ + + + + –
+ + + + + Not included
+ + + + + +
+ + + + (1)Poor (1) Poor
[15]
1988
Czechoslovakia
S
26
–
Not included
Not included
(1) Poor
[16] [17]
2012 1997
Korea Chile
R S
1 10
+ –
+ +
+ Not included
+ +
[18] [19] [20] [21]a
2004 1981 2013 1984
Taiwan Switzerland Japan Finland
S R R S
4 1 1 10
– + + –
+ + + Not included
Not included + + +
+ + + (4) Poor
[26] [28] [29]
1992 1992 1977
R R R
1 1 1
+ + +
+ + +
+ + +
+ + +
[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
1984 2012 2002 1997 2010 2010 1996 2008 1999 2006 2008 1986 1999 2012 2008 2008
Austria Germany United Kingdom Saudi Arabia Saudi Arabia Turkey Japan Hong Kong Taiwan Japan Japan Turkey Iran Korea India Taiwan Brazil India Brazil
Culture (51%), histology (49%) PCRb (60%), culture (10%), histology (30%) Culture Culture Culture PCRb PCRc Culture (39%), histology (61%) Culture (35%), histology (65%) PCRb Culture (10%), histology (90%) Histology (100%) Culture PCRb , c Culture (40%), histology 6(60%) Histology Histology Histology
R R R R R R R R R R R R R R R R
1 3 1 1 1 1 1 1 2 1 2 1 1 1 1 1
+ + + + + + + + + + + + + + + +
Histology PCRb Histology PCRb PCRc PCRb PCRc PCRb Histology Culture PCRb Culture PCRb PCRb Culture 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 identified 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 fulfilled 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 significantly 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%) experienced sequelae (Table 2), including disturbance of growth in leg (5), arm deformity (1), scoliosis (1), and disability with multiple bone
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4 Table 2 Clinical data of patients with sequelae and complications. No.
Ref.
Exact site
Diagnosis
Surgery
Sequelae and complications
11
[13]
Left tibial growth plate involved
PCR
Leg shorten 1.4 cm at a 2-year follow-up
46
[14]
Bilateral elbow, multiple bone
Culture
81 86 88
[7] [7,21] [7,21]
Culturea Culture Culture
90 91
[7,21] [7,21]
Humerus right femur Head of right femur left femur Left femur
Yes, curettage twice. He started treatment with Cefazolin 2 weeks after 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. Yes, curettage. Repeated incision for abscess and Penicillin for 6 months before the definite diagnosis was made. Unknown surgical history Yes, trephination Yes, trephination
328
[27]
Spine
Histology
13
[11]
Left calcaneus
Culture
48
[15]
Proximal metaphysis of tibia
Histology
Open biopsy or drainageb
49
[15]
Histology
Open biopsy or drainageb
84
[21]
Proximal metaphysis of tibia Left fifth rib
Histology
Yes, rib resection
85
[21]
Histology
Yes, trephination
87
[21]
Culture
Yes, rib resection
a b
Neck of left femur Left fifth rib
Histology Histology
Yes, trephination Yes, sequestrectomy after knee pain for 4 weeks Yes, costotranversotomy for paravertebral abscess Yes, twice. Initial incision and debridement, followed by incision and debridement 4 months later for fistula.
Disability with multiple lesions around the elbow joint, spread to adjacent joint under treatment Arm deformity Coxa valga required osteotomy Coxa magna and subluxation Femur shorten 1 cm Knee arthritis, sequestration, femur lengthen 0.5 cm Scoliosis Secondary infection with abscess and fistula formation. After the second surgery, Streptomycin and Ethambutol were added. Gradual improvement after 3 months. No sequel Relapse in the fourth month of treatment featuring fistula and abscess formation. Resolved without sequela at 1-year follow-up. Fistula and abscess formation, resolved without sequela at 1-year follow-up Abscess development 6 months after treatment, resolved without sequela Hip arthritis, resolved without sequela Abscess development 6 years later, resolved without sequela
Diagnostic method mentioned in the case series; no special result mentioned for individual patients. 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 complications 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 confirmed 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 gibbus 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 inoculated 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 chemotherapy regimens (Table 4). A total of 37 cases (57%) started with a 2-drug regimen (isoniazid plus rifampicin with or without pyrazinamide). After escalation, de-escalation, or discontinuation of treatment, 45 patients (70%) ultimately received therapy consisting of two or fewer drugs. A total of 41 cases (64%) ended up with a 2-drug regimen (isoniazid plus rifampicin with or without 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 surgical intervention [12]. Subsequent PCR confirmed BCG strain and
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Table 3 Clinical data of patients with BCG vertebral lesions. Reference
Year
Country
Site of diagnosis
Definitions for BCG identification
Antimicrobial therapy/orthopedic cast
Duration (m)
Surgery
Outcome
[7,21]
1995
Finland
Histology
No, biopsy only
Good
1990
France
2HRS + 4HR + ?Ha /plaster bed HERZ/Stagnara brace
10–24
[9]
Lumbar spine, L4-5 Thoracic spine, T11
6
Goodb
[14]
1976
Sweden
No, paravertebral abscess, biopsy only No, curettage
[26]
1992
Austria
Good
[15] [15] [15]
1988 1988 1988
Czechoslovakia Czechoslovakia Czechoslovakia
Yes, scraped off prevertebral tumor with raspatory No No Yes, paravertebral abscess, costotranversotomy
Culture, M. bovis BCG
Thoracic spine T7-9 Thoracic spine, T2-3
Histology
HRSa /plaster bed
6
Histology
HER/plaster-cast jacket
6
Spine Spine Thoracic spine, T3-6
Clinical Clinical Histology
3HRS + 3HRa /plaster bed 3HRS + 3HRa /plaster bed 3HRS + 3HRa /plaster bed
6 6 6
Good
Good Good Developed a gibbus with 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 Chemotherapy regimens and escalation for BCG osteomyelitis/osteitis. Chemotherapy regimens
Case no.
2-drug combination (with or without Z) Escalate to HERS Remain 2-drug combination HR(Z) → HR(16), HR → HR(Z)(2) a , remain HR(Z)(6) remain HR(12) 3-drug combination (with or without Z) De-escalate to 1 drug HER → H(1), HRS(Z) → H(Z)(1) De-escalate to HR HRS(Z) → HR(3), HER(Z) → HR(1), HRS → HR(3), HER(Z) → HR(1), HRS → HR(1) Liver enzyme elevated & rash → discontinuedb Remain 3-drug combination HER(Z) (1), HER(6), HRS(2), HRS → HRS(Z) (1) remain HR + PAS(3) 4-drug combination Remain 4-drug combination (HERS) Others (non-HR-based regimen) H → HSE HS + PASc (1) remain HS(Z)(1) Total
37
% 57%
1 36
21
3.4. Chemotherapy duration 33%
2 5
1 13
3 3 3 1 1 1 64
course of diagnosis and treatment before definite diagnosis was made. Though he experienced an increased dosage of chemotherapy prescribed after the second operation, the growth of his left leg was stunted by 14 mm due to involvement and disruption of his growth plate.
5% 5%
100%
H: isoniazid, E: ethambutol, R: rifampicin, Z: pyrazinamide, S: streptomycin PAS: N para-aminosalicyclic acid a One of the two patients had poor outcome [13]. b A 9-month-old infant who suffered from both elevated liver enzymes and rash [28]. c A 3-year-old boy with a lesion of the right femur. He was put on a course of paraaminosalicyclic 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 follow-up [29].
isoniazid, ethambutol, rifampicin, and streptomycin were administered. 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 growth in the afflicted limb. Among the 64 patients with detailed chemotherapy regimens, only one had a poor outcome. It was a 1-year-old boy with a lesion on the growth plate of the left tibia, who eventually had a poor outcome due to delayed diagnosis [13]. Table 2 shows his protracted
A total of 50 patients from 30 articles had reviewable courses of chemotherapy. A total of 31 cases (62%) received a treatment course of 6 months or less; 15 cases (30%) were treated for over 6 months but less than 12 months; two cases (4%) were treated for over 12 months but for less than 18 months; and two cases (4%) terminated treatment within the first 2 months due to side effects. The duration of chemotherapy had no bearing on outcomes relative to the age of the children nor in relation to lesion sites. Among 33 patients who received chemotherapy for no more than 6 months, one of them had a poor outcome. He was the aforementioned patient with stunted left leg [13]. Among the 17 patients who received chemotherapy for more than 6 months, all of them had a good outcome. Though the number of patients who received no antituberculosis treatment is not known, nearly all of the patients lacking detailed chemotherapy regimens received chemotherapy of some kind [7,14,15]. A majority of these had backbone regimens, including isoniazid and rifampicin. In the intensive phase, streptomycin was added from 1 to 3 months; occasionally, ethambutol was used as an alternative to streptomycin. The continuation phase usually lasted from 3 to 6 months with backbone regimens. Up to 40% of the cases in the studies from Finland received the Copenhagen strain [7], isoniazid was used alone in the continuation phase after 4 months of backbone treatment regimens to complete a median 12-month treatment course. Only 15 of the remaining cases mentioned the BCG strain used [16–20]. None of the reported patients mentioned resistance to isoniazid, nor was isoniazid discontinued for any of the patients mentioned above. 3.5. Surgery Surgical intervention was mentioned in less than 25% of these children. Among 80 patients from 30 articles with mention of type of surgical intervention, 50 cases (62.5%) received procedures for diagnostic purposes, including aspiration biopsy (10),
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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 diagnostic 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 differ 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 chemotherapy 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 diagnostic purposes were helpful; however, a significant proportion of patients receiving interventional surgery as part of treatment for BCG osteomyelitis/osteitis had permanent complications postsurgery, 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 osteomyelitis/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 diagnosis (Table 2). Typical X-rays will show osteolytic lesions with mild periosteal reaction and negative bone scan [21]. Misdiagnosis 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 mortality. 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 compared 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 isoniazid plus rifampicin combination therapy could be suggested as an initial treatment option for BCG osteomyelitis/osteitis. Different 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 osteomyelitis/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 treatment 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 healthcare resources differ around the world. For places in which BCG vaccination rates are still high, BCG-related diseases are underestimated 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 consumption among children. In conclusion, 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 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.
Please cite this article in press as: Lin W-L, et al. Management of Bacillus Calmette-Guérin osteomyelitis/osteitis in immunocompetent children—A systematic review. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.039
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Acknowledgments We thank Hsien-Ho Lin for comments and Geoff Hughes for English language support. References [1] Murphy D, Corner LA, Gormley E. Adverse reactions to Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination against tuberculosis in humans, veterinary animals and wildlife species. Tuberculosis 2008;88:344–57. [2] Clavel G, Grados F, Lefauveau P, Fardellone P. Osteoarticular side effects of BCG 303 therapy. Joint, bone, spine: revue du rhumatisme.73:24-8. [3] Kroger L, Brander E, Korppi M, Wasz-Hockert O, Backman A, Kroger H, et al. Osteitis after newborn vaccination with three different Bacillus CalmetteGuérin vaccines: twenty-nine years of experience. Pediatr Infect Dis J 1994;13:113–6. [4] Yamamoto S, Yamamoto T. Historical review of BCG vaccine in Japan. Jpn J Infect Dis 2007;60:331–6. [5] Dye C, Fine PE. A major event for new tuberculosis vaccines. Lancet 2013;381:972–4. [6] Mortensson W, Eklof O, Jorulf H. Radiologic aspects of BCG-osteomyelitis in infants and children. Acta Radiol Diagn (Stockh) 1976;17:845–55. [7] Kroger L, Korppi M, Brander E, Kroger H, Wasz-Hockert O, Backman A, et al. Osteitis caused by bacille Calmette-Guérin vaccination: a retrospective analysis of 222 cases. J Infect Dis 1995;172:574–6. [8] Koyama A, Toida I, Nakata S. [Osteitis as a complication of BCG vaccination]. Kekkaku 2009;84:125–32. [9] Moreno L, Gottrand F, Herbaux B, Savage C, Farriaux JP. Vertebral osteitis following BCG vaccination in a previously healthy child. Eur J Pediatr 1990;149:668. [10] Sandstrom S. Multifocal sclerotic BCG spondylitis in a 13-year-old girl. Pediatr Radiol 1983;13:239–40. [11] Kallesoe O, Jespersen A. Metastatic osteomyelitis following BCG vaccination. Acta Orthop Scand 1978;49:134–7. [12] Kwon HJ, Chung BH, Choi BM, Park KU, Kim YK. Severe osteomyelitis as a complication of Tokyo-172 BCG vaccination. J Korean Med Sci 2012;27:221–4. [13] Ishimaru D, Ogawa H, Ito Y, Shimizu K. Surgical treatment of an infant with Bacille Calmette-Guérin osteomyelitis extending across the growth plate. Orthopedics 2011;34:55. [14] Bergdahl S, Fellander M, Robertson B. BCG osteomyelitis: experience in the Stockholm region over the years 1961–1974. J Bone Joint Surg Br 1976;58:212–6. [15] Marik I, Kubat R, Filipsky J, Galliova J. Osteitis caused by BCG vaccination. J Pediatr Orthop 1988;8:333–7. [16] Ahn HY, Kim YD, Jeon SE, Park SS, Park SE, Lee IS, et al. Parasternal mass revealing as a postvaccinal Bacillus Calmette-Guérin (BCG)-elicited sternal osteomyelitis. Thorac Cardiovasc Surg 2014;62:258–60. [17] Castro-Rodriguez JA, Gonzalez R, Girardi G. Osteitis caused by bacille CalmetteGuérin vaccination: an emergent problem in Chile? Int J Tuberc Lung Dis 1997;1:417–21. [18] Lin WJ, Lu JJ, Chu CC, Chang TY, Wang CC. Calmette-Guérin bacillus sternal osteomyelitis diagnosed by DNA sequencing analysis of PNC A. Pediatr Infect Dis J 2004;23:784–6. [19] Schopfer K, Matter L, Brunner C, Pagon S, Stanisic M, Baerlocher K. BCG osteomyelitis. Case report and review. Helv Paediatr Acta 1982;37:73–81. [20] Oyachi N, Obana K, Suzuki T, Kimura S, Chino K, Oyama T, et al. Costal BCG osteomyelitis developing 1 year after BCG vaccination. Pediatr Int 2013;55:641. [21] Peltola H, Salmi I, Vahvanen V, Ahlqvist J. BCG vaccination as a cause of osteomyelitis and subcutaneous abscess. Arch Dis Child 1984;59:157–61.
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[22] Hesseling AC, Rabie H, Marais BJ, Manders M, Lips M, Schaaf HS, et al. Bacille Calmette-Guérin vaccine-induced disease in HIV-infected and HIV-uninfected children. Clin Infect Dis 2006;15(42):548–58. [23] Cuello-Garcia CA, Perez-Gaxiola G, Jimenez Gutierrez C. Treating BCG-induced disease in children. Cochrane Database Syst Rev 2013;1:CD008300. [24] Hannan MM, Desmond EP, Morlock GP, Mazurek GH, Crawford JT. Pyrazinamide-monoresistant Mycobacterium tuberculosis in the United States. J Clin Microbiol 2001;39:647–50. [25] Ritz N, Tebruegge M, Connell TG, Sievers A, Robins-Browne R, Curtis N. Susceptibility of Mycobacterium bovis BCG vaccine strains to antituberculous antibiotics. Antimicrob Agents Chemother 2009;53:316–8. [26] Geissler W, Pumberger W, Wurnig P, Stuhr O. BCG osteomyelitis as a rare cause of mediastinal tumor in a one-year-old child. Eur J Pediatr Surg 1992;2:118–21. [27] Obaid S, Weil AG, Rahme R, Gendron C, Shedid D. Mycobacterium bovis spondylodiscitis after intravesical Bacillus Calmette-Guérin therapy. Surg Neurol Int 2011:2011. [28] Hoppe JE, Orlikowsky T, Klingebiel T, Niethammer D. Costal BCG osteomyelitis presenting as a tumor. Infection 1992;20:94–6. [29] Pauker M, Seelefreund M, Morain G. Conservative treatment of a BCG osteomyelitis of the femur. Arch Dis Child 1977;52:330–1. [30] Al-Arabi KM, Al-Khider ME, Sadiq S. Osteitis of the humerus following BCG vaccination. Tubercle 1984;65:305–7. [31] Al-Jassir FF, Aldeeri RA, Alsiddiky AM, Zamzam MM. Osteomyelitis following Bacille Calmette-Guérin vaccination. Saudi Med J 2012;33:87–90. [32] Aribas OK, Kanat F, Gormus N, Turk E. Cold abscess of the chest wall as an unusual complication of BCG vaccination. Eur J Cardiothorac Surg 2002;21:352–4. [33] Nishi J, Kamenosono A, Sarker KP, Yoshino S, Ikei J, Matsuda Y. Bacille CalmetteGuérin osteomyelitis. Pediatr Infect Dis J 1997;16:332–3. [34] Chan PK, Ng BK, Wong CY. Bacille Calmette-Guérin osteomyelitis of the proximal femur. Hong Kong Med J 2010;16:223–6. [35] Chang CK, Chang WC, Lee HS, Wu CC, Huang GS. Subcutaneous abscess in the lower leg caused by BCG-related osteomyelitis. South Med J 2010;103: 686–9. [36] Fujimoto T, Morishima T, Ueda M. Probable BCG osteomyelitis of the hard palate: a case report. Int J Oral Maxillofac Surg 1996;25:145–6. [37] Ishiwada N, Hishiki H, Watanabe M, Ohkusu K, Kohno Y. [Usefulness of PCR in rapidly diagnosing subcutaneous abscess and costal osteomyelitis caused by Mycobacterium bovis BCG]. Kansenshogaku Zasshi 2008;82:30–3. [38] Karnak I, Akcoren Z, Gogus S, Caglar M, Tanyel FC. Granulomatous osteomyelitis of the sternum presenting with a parasternal mass: a possible relation to the bacillus Calmette-Guérin vaccine. J Pediatr Surg 1999;34:1534–6. [39] Khotaei GT, Sedighipour L, Fattahi F, Pourpak Z. Osteomyelitis as a late complication of Bacille Calmette-Guérin vaccination. J Microbiol Immunol Infect 2006;39:169–72. [40] Kim SH, Kim SY, Eun BW, Yoo WJ, Park KU, Choi EH, et al. BCG osteomyelitis caused by the BCG Tokyo strain and confirmed by molecular method. Vaccine 2008;26:4379–81. [41] Kolandaivelu G, Manohar K, Bose JC, Rajagopal P. Osteitis of humerus following BCG vaccination. J Indian Med Assoc 1986;84:184–5. [42] Lin CJ, Yang WS, Yan JJ, Liu CC. Mycobacterium bovis osteomyelitis as a complication of Bacille Calmette-Guérin (BCG) vaccination: rapid diagnosis with use of DNA sequencing analysis: a case report. J Bone Joint Surg Am 1999;81:1305–11. [43] Morrone N, Antonio CD, Santilli C, Costa-Carvalho BT, Rodrigues D. Osteitis in a female infant after vaccination with BCG Moreau in the neonatal period. J Bras Pneumol 2012;38:674–6. [44] Tabatabaie P, Mahjoub F, Mehdizadeh M, Tabatabaie F. Osteomyelitis due to BCG vaccination. Indian Pediatr 2008;45:930–2. [45] Terreri MT, Yamada AF. Osteitis caused by BCG vaccination. Pediatr Radiol 2008;38:481.
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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 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 b
a r t i c l e
i n f o
Article history: Received 1 February 2015 Received in revised form 10 July 2015 Accepted 13 July 2015 Available online xxx Keywords: BCG vaccine Osteomyelitis Osteitis Disease management Review
a b s t r a c t Background: Bacillus Calmette-Guérin (BCG) osteomyelitis/osteitis in immunocompetent children is a rare but serious complication of BCG immunization. Rationale for its treatment is unclear. Methods: Due to the rarity of this complication, no randomized control trials has ever been conducted to evaluate methods of intervention. As such, we searched the literature for any reported BCG vaccinationrelated 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 cases, while noting outcomes and their medical and/or surgical interventions. Results: From 34 eligible studies gleaned from a screening of 804 articles, a total of 331 cases were enrolled. Involvement of the lower limbs was present in 55.6%, followed by the axial skeleton (26.0%), the upper limbs (15.4%), and multiple bones (3.0%). Of the 64 patients having records of detailed chemotherapy 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 interventions 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 information, further studies are needed to identify proper treatments, while infant BCG vaccination is still in use. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction 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 complication 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: [email protected] (P.-C. Chan).
promising results in human trials so far [5], understanding how to best treat BCG complications is extremely important. BCG osteomyelitis/osteitis, typically presents in children 1–2 years after BCG inoculation who develop insidious clinical symptoms/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 children 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.
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# 804 records idenfied through database searching & screened
#745 records excluded
# 59 full-text arcles assessed for eligibility
# 34 studies (331 cases) included in qualitave synthesis
# 25 full-text arcles excluded
#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)
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)
BCG not osteomyelis (n=1)
Fig. 1. Flowchart of identification of eligible patients.
Because of the low incidence [3], there are currently no available 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 summarize 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 osteomyelitis/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 biochemical 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 urogenital 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 publications and abstracts of conferences, for which the details of study could not be obtained.
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 survival 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 “osteomyelitis”) OR (“BCG” AND “osteitis”) OR (“BCG” AND “bone infection”). Studies identified by the search strategy were reviewed for eligibility based on title and abstract by the investigator (Fig. 1). Full text of the papers identified through screening was reviewed for consideration 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 reaching 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 therapy regimen and duration, surgery and outcome. For the studies
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Table 1 Summary of studies included in this review on BCG osteomyelitis/osteitis. Reference
Year
Country
Type
Case no.
Age
Definitions for BCG identification
Antimicrobial therapy
Surgery
Outcome
[7]
1995
Finland
S
222
–
Not included
Not included
(5) Poor
[8]
2009
Japan
S
20
+
+
+
+
[9] [10] [11] [12] [13] [14]
1990 1983 1978 2012 2011 1976
France Sweden Denmark Korea Japan Sweden
R R R R R S
1 1 1 1 1 18
+ + + + + –
+ + + + + Not included
+ + + + + +
+ + + + (1)Poor (1) Poor
[15]
1988
Czechoslovakia
S
26
–
Not included
Not included
(1) Poor
[16] [17]
2012 1997
Korea Chile
R S
1 10
+ –
+ +
+ Not included
+ +
[18] [19] [20] [21]a
2004 1981 2013 1984
Taiwan Switzerland Japan Finland
S R R S
4 1 1 10
– + + –
+ + + Not included
Not included + + +
+ + + (4) Poor
[26] [28] [29]
1992 1992 1977
R R R
1 1 1
+ + +
+ + +
+ + +
+ + +
[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
1984 2012 2002 1997 2010 2010 1996 2008 1999 2006 2008 1986 1999 2012 2008 2008
Austria Germany United Kingdom Saudi Arabia Saudi Arabia Turkey Japan Hong Kong Taiwan Japan Japan Turkey Iran Korea India Taiwan Brazil India Brazil
Culture (51%), histology (49%) PCRb (60%), culture (10%), histology (30%) Culture Culture Culture PCRb PCRc Culture (39%), histology (61%) Culture (35%), histology (65%) PCRb Culture (10%), histology (90%) Histology (100%) Culture PCRb , c Culture (40%), histology 6(60%) Histology Histology Histology
R R R R R R R R R R R R R R R R
1 3 1 1 1 1 1 1 2 1 2 1 1 1 1 1
+ + + + + + + + + + + + + + + +
Histology PCRb Histology PCRb PCRc PCRb PCRc PCRb Histology Culture PCRb Culture PCRb PCRb Culture 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 identified 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 fulfilled 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 significantly 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%) experienced sequelae (Table 2), including disturbance of growth in leg (5), arm deformity (1), scoliosis (1), and disability with multiple bone
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4 Table 2 Clinical data of patients with sequelae and complications. No.
Ref.
Exact site
Diagnosis
Surgery
Sequelae and complications
11
[13]
Left tibial growth plate involved
PCR
Leg shorten 1.4 cm at a 2-year follow-up
46
[14]
Bilateral elbow, multiple bone
Culture
81 86 88
[7] [7,21] [7,21]
Culturea Culture Culture
90 91
[7,21] [7,21]
Humerus right femur Head of right femur left femur Left femur
Yes, curettage twice. He started treatment with Cefazolin 2 weeks after 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. Yes, curettage. Repeated incision for abscess and Penicillin for 6 months before the definite diagnosis was made. Unknown surgical history Yes, trephination Yes, trephination
328
[27]
Spine
Histology
13
[11]
Left calcaneus
Culture
48
[15]
Proximal metaphysis of tibia
Histology
Open biopsy or drainageb
49
[15]
Histology
Open biopsy or drainageb
84
[21]
Proximal metaphysis of tibia Left fifth rib
Histology
Yes, rib resection
85
[21]
Histology
Yes, trephination
87
[21]
Culture
Yes, rib resection
a b
Neck of left femur Left fifth rib
Histology Histology
Yes, trephination Yes, sequestrectomy after knee pain for 4 weeks Yes, costotranversotomy for paravertebral abscess Yes, twice. Initial incision and debridement, followed by incision and debridement 4 months later for fistula.
Disability with multiple lesions around the elbow joint, spread to adjacent joint under treatment Arm deformity Coxa valga required osteotomy Coxa magna and subluxation Femur shorten 1 cm Knee arthritis, sequestration, femur lengthen 0.5 cm Scoliosis Secondary infection with abscess and fistula formation. After the second surgery, Streptomycin and Ethambutol were added. Gradual improvement after 3 months. No sequel Relapse in the fourth month of treatment featuring fistula and abscess formation. Resolved without sequela at 1-year follow-up. Fistula and abscess formation, resolved without sequela at 1-year follow-up Abscess development 6 months after treatment, resolved without sequela Hip arthritis, resolved without sequela Abscess development 6 years later, resolved without sequela
Diagnostic method mentioned in the case series; no special result mentioned for individual patients. 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 complications 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 confirmed 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 gibbus 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 inoculated 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 chemotherapy regimens (Table 4). A total of 37 cases (57%) started with a 2-drug regimen (isoniazid plus rifampicin with or without pyrazinamide). After escalation, de-escalation, or discontinuation of treatment, 45 patients (70%) ultimately received therapy consisting of two or fewer drugs. A total of 41 cases (64%) ended up with a 2-drug regimen (isoniazid plus rifampicin with or without 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 surgical intervention [12]. Subsequent PCR confirmed BCG strain and
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Table 3 Clinical data of patients with BCG vertebral lesions. Reference
Year
Country
Site of diagnosis
Definitions for BCG identification
Antimicrobial therapy/orthopedic cast
Duration (m)
Surgery
Outcome
[7,21]
1995
Finland
Histology
No, biopsy only
Good
1990
France
2HRS + 4HR + ?Ha /plaster bed HERZ/Stagnara brace
10–24
[9]
Lumbar spine, L4-5 Thoracic spine, T11
6
Goodb
[14]
1976
Sweden
No, paravertebral abscess, biopsy only No, curettage
[26]
1992
Austria
Good
[15] [15] [15]
1988 1988 1988
Czechoslovakia Czechoslovakia Czechoslovakia
Yes, scraped off prevertebral tumor with raspatory No No Yes, paravertebral abscess, costotranversotomy
Culture, M. bovis BCG
Thoracic spine T7-9 Thoracic spine, T2-3
Histology
HRSa /plaster bed
6
Histology
HER/plaster-cast jacket
6
Spine Spine Thoracic spine, T3-6
Clinical Clinical Histology
3HRS + 3HRa /plaster bed 3HRS + 3HRa /plaster bed 3HRS + 3HRa /plaster bed
6 6 6
Good
Good Good Developed a gibbus with 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 Chemotherapy regimens and escalation for BCG osteomyelitis/osteitis. Chemotherapy regimens
Case no.
2-drug combination (with or without Z) Escalate to HERS Remain 2-drug combination HR(Z) → HR(16), HR → HR(Z)(2) a , remain HR(Z)(6) remain HR(12) 3-drug combination (with or without Z) De-escalate to 1 drug HER → H(1), HRS(Z) → H(Z)(1) De-escalate to HR HRS(Z) → HR(3), HER(Z) → HR(1), HRS → HR(3), HER(Z) → HR(1), HRS → HR(1) Liver enzyme elevated & rash → discontinuedb Remain 3-drug combination HER(Z) (1), HER(6), HRS(2), HRS → HRS(Z) (1) remain HR + PAS(3) 4-drug combination Remain 4-drug combination (HERS) Others (non-HR-based regimen) H → HSE HS + PASc (1) remain HS(Z)(1) Total
37
% 57%
1 36
21
3.4. Chemotherapy duration 33%
2 5
1 13
3 3 3 1 1 1 64
course of diagnosis and treatment before definite diagnosis was made. Though he experienced an increased dosage of chemotherapy prescribed after the second operation, the growth of his left leg was stunted by 14 mm due to involvement and disruption of his growth plate.
5% 5%
100%
H: isoniazid, E: ethambutol, R: rifampicin, Z: pyrazinamide, S: streptomycin PAS: N para-aminosalicyclic acid a One of the two patients had poor outcome [13]. b A 9-month-old infant who suffered from both elevated liver enzymes and rash [28]. c A 3-year-old boy with a lesion of the right femur. He was put on a course of paraaminosalicyclic 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 follow-up [29].
isoniazid, ethambutol, rifampicin, and streptomycin were administered. 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 growth in the afflicted limb. Among the 64 patients with detailed chemotherapy regimens, only one had a poor outcome. It was a 1-year-old boy with a lesion on the growth plate of the left tibia, who eventually had a poor outcome due to delayed diagnosis [13]. Table 2 shows his protracted
A total of 50 patients from 30 articles had reviewable courses of chemotherapy. A total of 31 cases (62%) received a treatment course of 6 months or less; 15 cases (30%) were treated for over 6 months but less than 12 months; two cases (4%) were treated for over 12 months but for less than 18 months; and two cases (4%) terminated treatment within the first 2 months due to side effects. The duration of chemotherapy had no bearing on outcomes relative to the age of the children nor in relation to lesion sites. Among 33 patients who received chemotherapy for no more than 6 months, one of them had a poor outcome. He was the aforementioned patient with stunted left leg [13]. Among the 17 patients who received chemotherapy for more than 6 months, all of them had a good outcome. Though the number of patients who received no antituberculosis treatment is not known, nearly all of the patients lacking detailed chemotherapy regimens received chemotherapy of some kind [7,14,15]. A majority of these had backbone regimens, including isoniazid and rifampicin. In the intensive phase, streptomycin was added from 1 to 3 months; occasionally, ethambutol was used as an alternative to streptomycin. The continuation phase usually lasted from 3 to 6 months with backbone regimens. Up to 40% of the cases in the studies from Finland received the Copenhagen strain [7], isoniazid was used alone in the continuation phase after 4 months of backbone treatment regimens to complete a median 12-month treatment course. Only 15 of the remaining cases mentioned the BCG strain used [16–20]. None of the reported patients mentioned resistance to isoniazid, nor was isoniazid discontinued for any of the patients mentioned above. 3.5. Surgery Surgical intervention was mentioned in less than 25% of these children. Among 80 patients from 30 articles with mention of type of surgical intervention, 50 cases (62.5%) received procedures for diagnostic purposes, including aspiration biopsy (10),
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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 diagnostic 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 differ 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 chemotherapy 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 diagnostic purposes were helpful; however, a significant proportion of patients receiving interventional surgery as part of treatment for BCG osteomyelitis/osteitis had permanent complications postsurgery, 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 osteomyelitis/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 diagnosis (Table 2). Typical X-rays will show osteolytic lesions with mild periosteal reaction and negative bone scan [21]. Misdiagnosis 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 mortality. 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 compared 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 isoniazid plus rifampicin combination therapy could be suggested as an initial treatment option for BCG osteomyelitis/osteitis. Different 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 osteomyelitis/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 treatment 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 healthcare resources differ around the world. For places in which BCG vaccination rates are still high, BCG-related diseases are underestimated 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 consumption among children. In conclusion, 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 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.
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