The bacillus Calmette-Guérin (BCG) vaccine has been used worldwide for routine vaccination against tuberculosis, particularly meningeal tuberculosis and disseminated tuberculosis disease in children.1 However, adverse events have been reported after BCG vaccination in 0.01%–5% of recipients.1 In Japan, 815 adverse reactions (0.02%) were reported among 5.4 million BCG vaccinations in 2013 to 2018.2 The most common adverse effect of the BCG vaccine is lymphadenopathy, followed by cutaneous symptoms. More serious adverse effects include osteitis, osteomyelitis and disseminated infection, but these are extremely rare.
BCG-associated osteitis/osteomyelitis may occur as a result of direct spread from the administration site.3 This has been reported in 0.01 per million vaccinations in Japan (multipuncture technique) and 30 per million in Finland (intradermal technique).4 The most common sites of osteitis/osteomyelitis are the metaphyses of the long bones.4 However, vertebral BCG-associated osteitis/osteomyelitis is rare and accounts for 2.8% of all BCG-associated osteitis/osteomyelitis cases.3 In addition, 9 children with BCG-associated vertebral lesions have been reported to date, but no cervical lesions have ever been reported.3–6 Here, we report the case of a 3-year-old immunocompetent girl who developed BCG-associated cervical spondylitis and was successfully treated by prompt surgical drainage of the abscess plus administration of isoniazid (INH) and rifampicin (RFP) for 9 months without sequelae.
CLINICAL PRESENTATION
A 3-year-old girl with a cervical spine lesion was referred for further examination and treatment. She had complained of a sore throat for 10 days prior, had reduced vitality since the day before referral and tended to lie down. There was no family history of a tendency for any infections. Her medical history was unremarkable. She had received all vaccinations included in the Japanese routine vaccination program. She had received the BCG vaccine (Tokyo-172 strain) by percutaneous administration to her left deltoid muscle with a multipuncture device at 5 months of age.
On physical examination at admission, her body temperature was 36.6°C and SpO2 was 99% (room air). Although she could walk, she was listless and was unwilling to walk on her own. She did not complain of neck pain. There were no abnormal findings of the pharynx, lymphadenopathy, hepatosplenomegaly or rash. The Babinski reflex was positive only on the left side. Her other neurologic findings were unremarkable and her deep tendon reflexes of the upper and lower extremities were normal.
Her white blood cell count was 5220 U/μL with 55.5% neutrophils, 36.5% lymphocytes, 3.5% eosinophils and 4.5% monocytes. Her C-reactive protein was 0.17 mg/dL, and her immunoglobulin G was 1041 mg/dL. The cluster of differentiation (CD)3+ T and CD19+ B cell populations were 67% (normal, 50%–83%) and 30% (normal, 6%–23%) of the total lymphocytes, respectively. The CD4+/CD8+ T-cell ratio was normal at 1.1 (normal, 0.8–3.5). Other laboratory data were within the normal range. Cervical radiograph at admission showed C4 vertebral bony destruction and malalignment (Fig. 1A). Additional cervical computed tomography indicated that the C4 vertebral body was crushed with osteolytic change and was protruding to the spinal canal side (Fig. 1B). A mass with a contrast effect on the rear of the vertebral body was pressing on the cervical spinal cord (Fig. 1B). T2-weighted magnetic resonance imaging on the third hospital day revealed a mass lesion with a contrast effect in front of the C4 vertebra (Fig. 1C). The whole spine and brain were investigated by computed tomography and no additional lesions were noted.
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FIGURE 1.: A: Radiograph at the onset reveals C4 vertebral bony destruction and malalignment. B: Computed tomography on admission reveals a mass with contrast effect on the rear of the vertebral body, pressing on the cervical spinal cord. C: T2-weighted magnetic resonance imaging on the third hospital day reveals a mass with contrast effect in front of the C4 vertebra. D: Intraoperative findings: cloudy abscess (white circle) at the C4 vertebra level. E: Cervical lateral radiograph 9 months after operation showing cervical vertebral fusion.
On the day of admission, her neck was fixed with a Philadelphia-type brace, and the following day, cervical vertebral extracorporeal fusion (hello vest attachment) was performed. A cervical spine mass biopsy was performed on the third hospital day urgently due to the appearance of bladder/bowel dysfunction. Intraoperative findings revealed no solid components, and abscess was punctured and drained (Fig. 1D). Intraoperative rapid pathologic examination revealed only inflammatory cells and no malignant findings; therefore, the patient underwent curettage and decompression at the C4 level. Polymerase chain reaction (PCR) of the biopsy specimen was positive for Mycobacterium tuberculosis complex. After 4 weeks of culture, the isolate was confirmed as the M. bovis BCG on multiplex polymerase chain reaction (PCR) analysis.7
Based on the results of PCR, she was started on INH (10 mg/kg/day) and RFP (10 mg/kg/day) on the fourth day of hospitalization. Furthermore, a bone transplant was performed on the collapsed C4 vertebra. The curetted vertebral body was replaced with a left fibular graft with an anterior approach on the 14th day of hospitalization. However, because the bone graft had been displaced, she was refixed on the 22nd day of hospitalization. Over a period of 3 months, she was gradually released from rest by hospitalization management. After confirming that there was no displacement of the transplanted bone, she underwent halo vest removal on the 101st day and was discharged on the 115th day of hospitalization. The patient was treated with INH and RFP for a total of 9 months. Nine months after the operation, the cervical lateral radiograph showed cervical vertebral fusion (Fig. 1E). At the time of writing this report, it is 1 year after onset, and neither sequelae nor recurrence of symptoms has been observed.
To determine the possibility of mendelian susceptibility to mycobacterial disease, a genetic condition characterized by severe infections in response to intracellular parasites such as Mycobacterium tuberculosis and salmonella, the following ten genes were screened for the following mutations: IFNGR1, STAT1, IFNGR2, IL12RB1, IL12B, ISG15, IRF8, RORC, TYK2, IKBKG; however, no mutations were identified.
ETHICS APPROVAL AND INFORMED CONSENT FOR PUBLICATION
The patient’s parents provided informed consent to publish this case report. The case report was approved by the Ethics Committee of Kagoshima University Hospital (approval number 200026).
DISCUSSION
The initial symptoms and laboratory findings of BCG-associated osteomyelitis are generally nonspecific.5 In our case, the symptoms were nonspecific, but the Babinski reflex was positive. Therefore, imaging study was performed. From the cervical image findings accompanied by the osteolytic lesions, we first suspected neoplastic diseases such as Langerhans cell histiocytosis or bone tumor, but there were no solid components in the lesion and fluid collection with contrasting effect was observed at the margin. Therefore, we next suspected that the lesion was the result of inflammatory changes and abscess formation due to BCG. Typical radiographs of patients with BCG-associated osteomyelitis reveal osteolytic lesions with mild periosteal reaction.5 A biopsy was performed, and a malignant tumor was excluded by rapid intraoperative examination. Finally, the C4 vertebra was decompressed after lesion curettage. She was diagnosed with BCG-associated cervical spondylitis based on the PCR examination result of the biopsy specimen. In addition, her immune system was evaluated, but she was not considered to be in an immunocompromised state.
BCG-associated osteitis/osteomyelitis occurs 13.9 months after vaccination, on average (range: 2–46 months)5 and may occur as a result of direct spread from the administration site. BCG-associated spondylitis takes slightly longer to develop (18 months on average) than BCG-associated osteitis/osteomyelitis at other sites.6 Our patient developed cervical spondylitis 31 months after vaccination; therefore, BCG-associated cervical spondylitis may take longer to develop other forms of BCG-associated spondylitis. Physicians must maintain a clinical suspicion of BCG-associated osteitis even if it has been years since vaccination.
Treatment of BCG-associated osteomyelitis typically consists of surgical approaches for diagnosis plus the administration of INH and RFP for 6–12 months.4,5 Although surgical intervention was successful in our patient, the removal of bony lesions may be harmful.5 The efficacy of antituberculous agents for BCG-associated spondylitis has not been specifically determined. Ethambutol is often used in addition to the two antituberculous agents (INH and RFP) in reports of spondylitis after BCG intravesical therapy for bladder cancer.8 In our case, although ethambutol was not added, the clinical course was satisfactory. Due to the findings of cervical compression and the appearance of bladder/bowel dysfunction, emergency surgical intervention was performed. The patient was treated successfully without sequelae.
BCG-associated osteomyelitis is generally considered to have a good prognosis. However, it has been reported that BCG-associated spondylitis, although less common, is more likely to be associated with sequelae. Of the 9 cases of BCG-associated spondylitis reported to date, 3 exhibited some sequelae, and 2 exhibited severe kyphosis.3,5 To our knowledge, this was the first report of a case of BCG-associated cervical spondylitis. In addition, although the observation period thus far was only 1 year, she has no sequelae due to prompt surgical intervention and the administration of antituberculous drugs.
There is increasing public interest regarding BCG vaccination due to the suggestion that it may be useful in combating coronavirus disease 2019 because of its ability to broadly stimulate the immune system.9,10 Our report of a serious adverse event with BCG vaccination may discourage attempts to prevent coronavirus disease 2019 using BCG vaccination.
The BCG vaccine remains useful, but physicians should be aware that this vaccine can also cause cervical spondylitis and should initiate prompt investigation and treatment if there are suspicious symptoms or findings. Examination, rapid surgical intervention, and the administration of antituberculous agents led to complete recovery of our patient, without sequelae.
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