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Brucellosis is a global public health issue. Brucellosis of the spine presents as a wide spectrum. The aim was to present the outcome analysis of patients treated for Spinal Brucellosis in the endemic region. Secondly to assess the accuracy of IgG and IgM Elisa in the diagnosis.
Results
A retrospective study of all patients who were treated for Brucellosis of the spine from 2010 to 2020 was conducted. Confirmed cases of Brucellosis of spine and who had adequate follow up after completion of treatment were included. The outcome analysis was based on clinical, laboratory and radiological parameters. There were 37 patients enrolled with a mean age of 45 and an average follow up of 24 months. All of them presented with pain and 30% had neurological deficits. Surgical intervention was done in 24%(9/37patients). All the patients were treated with triple drug regimen for an average duration of 6 months. Those patients with relapse had a 14month period of triple drug regimen. The sensitivity and specificity of IgM was 50% and 85.71%. The sensitivity and specificity of IgG was 81.82% and 7.69%.
76% of them had good functional outcome and 82% of them had near normal neurological recovery and 97.3%(36 patients) were healed of the disease with relapse in one patient(2.7%).
Conclusions
Majority (76%) of the patients with Brucellosis of the spine were treated conservatively. Average duration of treatment of triple drug regimen was 6 months. The sensitivity of IgM & IgG was 50% and 81.82% The specificity of IgM and IgG was 85.71% and 7.69% respectively.
Brucellosis is a global public health issue and is one among the greatest socioeconomic problems in developing countries. The global incidence is 500,000 cases per year.
Middle east has been identified as a ‘high risk’ region for Brucellosis by the Centers for Disease Control and prevention (CDC). Spondylitis is the most common presentation among osteoarticular Brucellosis.
We aim to report the clinical characteristics, diagnosis, management and outcome analysis of patients treated for Spinal Brucellosis. Our secondary aim was to evaluate the efficacy of IgG and IgM in the diagnosis of Brucellosis in our subset of patients.
2. Materials and methods
A retrospective, prospective cohort study was conducted on all proven cases of Brucellosis of the spine treated in our center from 2010 to 2020 after clearance from Institutional Review Board. Patients with Brucellosis of the spine who fulfilled the inclusion criteria were enrolled in the study. Inclusion criteria included – confirmed cases of Brucellosis of the spine (proven by blood culture or standard agglutination test >1:160) as per the CDC (Centers for Disease Control and Prevention) guidelines and those who had completed treatment with adequate follow up.
Demographic profile of the patients, their presenting complaints, history of contact with Brucellosis, history of intake of raw/unpasteurized milk (camel's milk), consumption of raw meat, history of contact with infected animals, family history of brucellosis, previous infection with brucellosis, and prior treatment with anti-brucellar medications (dosage and duration) was recorded. Pre-operative pain score which was assessed using the Visual Analog Scale
were documented. Blood investigations which included haemoglobin, white blood cell counts,blood culture, Standard agglutination test, IgG and IgM ELISA, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were obtained. Plain radiographs and magnetic resonance imaging (MRI) of the affected region were performed prior to and after completion of the treatment. Surgical indications which were - severe unrelenting pain secondary to significant mechanical instability and neurological deficits (ASIA A, B, and C) was recorded. Surgery was performed by our two senior surgeons.
Treatment with triple drug regimen with Inj.Aminoglycoside for 3 weeks,oral Doxycycline or Trimethoprim/Sulphamethoxazole and oral Rifampicin as per the WHO protocol and drug related complications was documented.
Patients were followed up every 2 months for first 6 months, followed by quarterly visits for first year and twice a year thereafter.
Outcome analyses included clinical, biochemical, and radiological parameters to assess the healing status. Functional outcome was based on pain, return to pre-treatment occupational status and neurological status as per Solera et al.
Laboratory parameters included reduction in inflammatory markers like ESR and CRP. Radiological parameters included evidence of healed status – resolution of abscess, sclerosis of the vertebrae and fusion between them.
3. Statistical analysis
The sensitivity and specificity of IgM ELISA and IgG ELISA were compared with culture. Data was analyzed using MedCalc software (MEDCALC SOFTWARE, Belgium). Sensitivity, specificity were expressed as percentages. Statistical analysis was done for pre and post treatment inflammatory markers. P < 0.001 was considered to be statistically significant.
4. Results
During this 10-year period, there were totally 39patients treated for Brucellosis of the spine. 37 of them fulfilled the inclusion criteria and were enrolled in the study. There were 31 males and 6 females with a mean age of 45 (ranging from 4 to 96) years. The average duration of follow up was 24 months. The time from onset of symptoms to diagnosis ranged from 4 days to 244 days (average of 87 days.) All of them presented with low grade fever with associated constitutional symptoms. 11 patients (29.7%) presented with neurological deficits. 32 patients (84%) had history of intake of raw/un pasteurized milk, consumption of raw meat or contact with animal husbandry.
Blood investigations revealed an average hemoglobin of 12.7 gm/dl (8.1–15.4), average white blood cell count of 6336 cells/cu.mm (3570–9900), average erythrocyte sedimentation rate(ESR) of 56.67 mm/hr (2–120) and average C-reactive protein(CRP) of 31.41 mg/dl (0.16–152). Blood culture showed 40% (15/37 patients) positivity and Standard Agglutination test showed 91% (34/37 patients) positivity. IgM and IgG were positive in 29% (7/24 patients) and 87% (21/24 patients) respectively. The sensitivity and specificity of IgM when compared to culture was 50% and 85.71% [Table 1]. The sensitivity and specificity of IgG when compared with culture was 81.82% and 7.69% respectively [Table 2]. 30%(12/37) of the patients showed histopathological features suggestive of Brucellosis. Histopathology revealed Chronic granulomatous inflammation with predominantly lymphocytic infiltration, presence of epithelioid granuloma without caseous necrosis and Langerhan's giant cells and with or without new bone formation.
Table 1Efficacy of IgM in comparison with Blood culture.
Radiologically, spondylodiscitis, multilevel involvement, sacroilitis and even facet joint involvement [Fig. 1] was present in our series. Typical characteristic feature of hyperintensity of T2 weighted images and hypo intensity of T1 weighted images were present in the acute phase and homogenous hyperintensity in both T2 and T1 weighted images were found in the healed phase [Fig. 2]. Single level discitis was the most common type of involvement and lumbar vertebrae was commonlhy affected [Table 3]. Minimal epidural, paraspinal and paravertebral soft tissue enhancement with or without abscesses was also observed [Fig. 3].
Fig. 1MRI T2 weighted axial image demonstrating enhancement of spinous process, paraspinal muscles and soft tissue with abscess involving left L4,5 facet joint.
Fig. 2a,2b,2c,2d: 2a,2b - Pre-treatment T2 and T1 weighted MRI images of 43-year-old male diagnosed with L3,4 brucellar spondylodiscitis revealing typical hyperintensity in T2 weighted images and hypo intensity in T1 weighted images.
Surgical intervention was done in 24%(9/37patients). 5 patients underwent laminotomy alone with intact facet joints, debridement and decompression of the cord/cauda. 4 patients underwent laminectomy, decompression and instrumented fusion. The indications for surgery included presence of neurological deficits, mechanical instability and failed attempts for biopsy. All patients with significant pain due to mechanical instability underwent instrumented fusion.
The duration of triple drug therapy with Aminoglycoside, Rifampicin and Doxycycline varied based on the clinical response, presence of relapse and the presence of cord involvement. The mean duration of therapy was 6 months (ranging from 4 months–14 months). Prolonged duration of treatment was given for patients with relapse and those with isolated cord involvement. Drug complications was present in 3 patients (8.1%) which included 1 patient with Ciprofloxacin induced pancreatitis, 1 patient with Gentamycin induced acute renal failure and 1 patient with Rifampicin induced hepatitis and Bactrim induced neutropenia. All the drug induced complications were temporary and resolved with cessation of the drugs.
The outcome analysis in terms of change in neurological status, improvement in inflammatory markers and functional outcome have been compared to the pre-treatment period and given in detail in Table 4. There was statistically significant (p < 0.001) improvement in terms of ESR and CRP. One patient (2.7%) had relapse after 6 months of completion of treatment with fever and back pain, with elevated SAT titers. She was started again as per WHO protocol and treatment continued for a total period of 14 months. She improved and was healed of the disease. There were 3 patients (8.1%) with severe sequelae (2 patients with severe pain following treatment underwent lumbar fusion and one patient had persistent neurological deficit despite completion of treatment.)
Table 4Outcome analysis - comparison between pre and post treatment status.
Variable
Pre – Treatment Status
Post – Treatment Status
Neurological Status (No. of patients with neurological deficits – 11)
• ASIA A - 1
• ASIA A - 0
• ASIA B - 4
• ASIA B - 0
• ASIA C - 3
• ASIA C - 2
• ASIA D - 3
• ASIA D - 3
• ASIA E - 0
• ASIA E - 6
Blood Parameters
ESR – 56.67 mm/hr (2–120)
ESR – 23.18 mm/hr (2–80) (p < 0.001)
CRP – 31.41 mg% (0.16–152)
CRP- 2.72 mg%(0.15–18.7) (p < 0.001)
Functional Outcome
No sequalae - 20
Mild sequalae - 8 (pain not interfering with work)
Moderate sequalae - 6 (pain interfers with work and with mild neuro deficits)
Severe sequalae - 3 (pain requiring rest and medications and with static deficits)
Brucellosis is the most common zoonotic disease in the world. World Health Organization has included Brucellosis as one among the reportable diseases. Brucellosis has been declared as endemic in Mediterranean rim and in Arabian Peninsula. The incidence of Brucellosis in the Kingdom of Saudi Arabia is estimated as 70/100,000.
Brucellosis is caused by Brucella species which infect camel, cattle, sheep,swine and dogs. Human transmission occurs through direct contact with infected animals, consumption of unpasteurized milk or milk products and raw meat. Human to human transmission is extremely rare. Transmission can occasionally occur from nursing mothers with active brucellosis.
Human brucellosis has significant public health consequences.
Human brucellosis has a varied presentation with low grade fever, malaise, loss of weight and loss of appetite similar to a flu-like illness. Brucellosis of the spine presents as a wide spectrum in the axial skeleton in the form of Spondylitis, Spondylodiscitis, pure discitis, Sacroiliitis and even facet joint infection.
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 37-1986: a 50-year-old woman with back pain, extensive travel, and exposure to farm animals.
and difficulty to isolate the organism in culture, in this subset of patients with spondylitis. The sensitivity of blood culture in the diagnosis of Brucellosis varies from 17%–85%. In our study we had 40% positivity of blood culture in the diagnosis of Brucellosis. Memish et al. have reported excellent sensitivity and specificity of IgM which was 79.1% and 100.0% & that of IgG being 45.6% and 97.1%.
Julien et al. suggested that serological tests for Brucellosis need to be considered only in correlation with patients clinico-radiological features and the epidemiology of the region.
Our study revealed higher specificity of IgM 85.71% and a very low specificity of 7.69% with IgG.
MRI findings showed intact vertebral framework even though there was evidence of diffuse vertebral body enhancement in T2 weighted images. Lumbar vertebral involvement, no significant vertebral collapse or demonstrable kyphosis with minimal abscess were seen with Brucellar spondylodiscitis in contrast to Tuberculosis (Table 5). Intervertebral disc was preserved in the early stages and narrowing with loss of signal uniformity of the disc in MRI was appreciated in the later stages. Prevertebral, paravertebral or psoas abscesses were very small in size akin to literature.
Table 6 sums up the clinico-radiological features and salient key features suggestive for diagnosis of Brucellosis of the spine. We propose a protocol for diagnosis and treatment of Brucellosis based on the clinical, biochemical and radiological features suggestive of the disease[Fig. 4].
Table 5MRI differentiating features between Brucellar and Tubercular spondylitis.
Radiological features
Brucellosis of the spine
Tuberculosis of the spine
Commonest level of involvement
Lumbar spine
Lower thoracic spine
Hyperintense signal in T2W images and Hypointense signal in T1W images
Present
Present
Abnormal intervertebral disc signal (hyperintensity in fat suppressed T2W images with disc space reduction)
All the patients were treated with triple drug therapy with Aminoglycoside (Streptomycin or Gentamycin) for 3 weeks and Doxycycline and Rifampicin (SDR) for a mean duration of 6 months which was in line with Bayindir et al. It was a prospective randomized control study comparing five antimicrobial regimens (Streptomycin & Doxycycline - SD, Streptomycin & Tetracycline -ST, Doxycycline & Rifampicin - DR, Ofloxacin & Rifampicin - OR & Streptomycin, Doxycycline & Rifampicin - SDR) for treatment for Brucella of the spine. The study reported superior results with the SDR regimen.
Ulu-kilic et al in his multicenter study did not find any significant difference in any of the drug combinations with Streptomycin or Gentamycin with Doxycycline & Rifampicin in terms of outcome.
However, the authors reported that the SDR group required longer duration of treatment for Spinal brucellosis. They also concluded that the duration of treatment was more important than the combination of drugs. Yasser et al reported only 7.9% relapse in patients who received treatment for more than 5 months (p < 0.001) and there was no relapse in patients who received 3 drug regime -Streptomycin, Doxycycline & Rifampicin in combination (p < 0.001).
Similar results were achieved by Loannou et al. concluding that prolonged duration of treatment (at least 6 months) with triple drug therapy was effective with no relapses or sequelae in their patients with spinal brucellosis.
In our patients, prolonged treatment was given to those with isolated neural involvement and those who had frequent relapse.
Surgical intervention was done only on those patients who presented with neurological deficits and in those patients with failed biopsy which was similar to the indications proposed by Ulrich et al. The indications were for those patients who failed conservative treatment, or experienced a compressing effect due to an inflammatory mass or abscess, or suffered from spinal instability, progressive spinal collapse or neurological deficits.
Myriad presentations of Brucellosis makes it a challenge for diagnosis. Multi-disciplinary team of Spine surgeons, Radiologists and Infectious diseases specialist play a key role in early diagnosis (with a high index of suspicion in endemic region) and appropriate management of this disease. Health education to patients and their relatives regarding drug compliance is important to treat and control Brucellosis. Health education to people regarding avoidance of consumption of unpasteurized milk and milk products like cheese and ice cream, raw/undercooked meat is important. Protective use of rubber gloves, goggles and aprons must be emphasized for those handling animal tissues. Hygienic measures in animal husbandry, food handling, vaccination of animals in endemic region are imperative as preventive measures.
6. Conclusions
76% of the patients with Brucellosis of the spine were treated conservatively. Average duration of treatment of triple drug regimen was 6 months. Prolonged duration of treatment was given only for patients with history of relapse and those with pure neural involvement. One patient (2.7%) had relapse. The sensitivity and specificity of IgM to detect Brucellosis was 50% and 85.71%. The sensitivity and specificity of IgG to diagnose Brucellosis was 81.82% and 7.69% respectively.
Approval of the final version of the paper: WIT, KNM.
Funding sources
No disclosures.
There are no conflict of interest/competing interests.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethics approval done for involving human subjects from the Institutional Review Board.
Prior publication
NIL.
Pharmacological or industrial support
NIL.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We extend our gratitude towards the Research Centre, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia for all the help, support and encouragement.
References
Mirnejad R.
Jazi F.M.
Mostafaei S.
et al.
Molecular investigation of virulence factors of Brucella melitensis and Brucella abortus strains isolated from clinical and non-clinical samples.
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 37-1986: a 50-year-old woman with back pain, extensive travel, and exposure to farm animals.
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