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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 30  |  Issue : 1  |  Page : 8-14

Evaluation of daily anti-tubercular treatment in osteoarticular tuberculosis


Department of Orthopaedics, ESIC-Postgraduate Institute of Medical Science, ESI Hospital, Ring Road, Basaidarapur, New Delhi 110015, India

Date of Submission18-Feb-2022
Date of Acceptance18-May-2022
Date of Web Publication30-Jun-2022

Correspondence Address:
Lakhwani Omprakash
Department of Orthopaedics, ESI-Postgraduate Institute of Medical Science, ESI Hospital, Ring Road, Basaidarapur, New Delhi 110015
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijors.ijors_1_22

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  Abstract 

Background: Management of osteoarticular tuberculosis is primarily based on pulmonary tuberculosis guidelines. Guidelines usually do not take into consideration specific organ system affection, though tube pathology and healing of affected organ is not the same. Therefore, routine guidelines are difficult to follow in osteoarticular tuberculosis and many treatment regimes are in vague. Therefore, routine tuberculosis (TB) treatment is not followed, and many regimes are in vague. The current study is undertaken to objectively evaluate daily drug regime in osteoarticular TB and has specific guidelines. Materials and Methods: Drug-sensitive osteoarticular TB cases were evaluated for daily anti-tubercular treatment (ATT) guided by clinical and radiological healing. Patients were categorized based on stage, severity, and site of infection. Vitamin C and iron were also included in the daily treatment regime. Ethambutol was included in the continuation phase. Outcomes in terms of radiological healing and duration of daily regimen were studied. Results: All patients at 6 months of daily ATT showed clinical improvement but persistent disease on imaging. On magnetic resonance imaging, 16 out of 52 patients showed worsening at 6 months. Earliest healing appeared at 8 months. Healing appears to be faster in surgically treated patients. There was no relapse till the shortest follow-up of 2 years. Conclusion: The directly observed treatment strategy (DOTS), three times a week, is enough in osteoarticular TB. Daily drug with a minimum duration of 9 months is necessary. Diagnosis is usually delayed due to deep-seated infections, hence advance diagnosis modalities and high index of suspicion help. The study does not encounter any case of drug resistance. Addition of vitamin C appears to increase effectiveness of drugs. Duration of ATT should be determined by the pre-treatment disease activity and response to ATT.

Keywords: Anti-tubercular treatment, directly observed treatment strategy (DOTS), osteoarticular, tuberculosis


How to cite this article:
Omprakash L. Evaluation of daily anti-tubercular treatment in osteoarticular tuberculosis. Int J Orthop Surg 2022;30:8-14

How to cite this URL:
Omprakash L. Evaluation of daily anti-tubercular treatment in osteoarticular tuberculosis. Int J Orthop Surg [serial online] 2022 [cited 2022 Aug 11];30:8-14. Available from: https://www.ijos.in/text.asp?2022/30/1/8/348190




  Introduction Top


Bone and joint tuberculosis (TB) accounts for 1–2% of all cases of TB and about 10–15% of extrapulmonary TB.[1] Current strategies of treating TB including the Revised National Tuberculosis Control Program (RNTCP), Directly Observed Treatment Strategy (DOTS), and DOTS Plus are focused on guidelines for treating pulmonary TB (PTB) and only briefly consider other affected organs and systems by indication.[2] However, pathophysiology and healing of PTB and other affected organs (extrapulmonary soft tissue to bone) are not the same. Hence, uniform anti-tubercular treatment (ATT) may not be equally effective in all extrapulmonary TBs.

Bone and joint TB is known for difficulties with delay in diagnosis and assessing treatment response. The anti-tuberculosis therapy (ATT) protocol in skeletal TB remains controversial, and different protocols and durations of 6, 9, 12, and 18 months have been prescribed.[3],[4] According to the World Health Organization (WHO), the use of a daily intensive phase was associated with a significantly lower risk of failure and acquired drug resistance.[5] However, these recommendations are not included in the current ATT guidelines due to lack of enough clinical data. Hence, it is necessary to have specific osteoarticular TB guidelines in different osteoarticular TBs with evidence-based evaluation. The current study is undertaken to objectively evaluate daily drug regime in osteoarticular TB and has specific guidelines.


  Materials and Methods Top


Materials and study design

The study was conducted at a tertiary institute/hospital from the year 2014 to 2017. Overall, 64 patients of all age groups having drug-sensitive osteoarticular TB who fulfil at least one inclusion criterion [Table 1] were registered in the study. It was a prospective study, conducted with aims and objectives to evaluate the results of daily ATT in different forms of active osteoarticular TB.
Table 1: Selection criteria for inclusion in study

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Methods

All patients were screened for PTB by chest skiagram and sputum examination. Patients having co-morbidities such as diabetes mellitus, long-term steroid use (10 mg prednisolone more than 3 weeks), immunocompromised, HIV, severe other systemic illnesses (chronic renal failure, chronic liver disease), and multi-drug resistance (MDR)-TB were excluded.

All patients (with at least one inclusion criterion) were subjected to daily ATT drugs as per recommendations.[5],[6] Ethambutol was included in the continuation phase. Streptomycin was added as per guidelines.[3],[7],[8] Vitamin C, iron, and folic acids were also added, if required.[9],[10]

The specimen was obtained from affected and reasonably accessible areas in all patients. Those patients showing worsening of the disease which indicated surgical intervention or no response to therapy were subjected to surgery for confirmation of diagnosis and drug sensitivity testing by the rapid diagnostic cartridge-based nucleic acid amplification test (CBNAAT).

Patients on presentation were categorized into two groups, depending on severity, stage, and complications of the disease and subjected to two initial regimes of ATT [Table 2].
Table 2: Categorization of patient on the basis of disease severity

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Follow-up and assessment

Demographic and clinical information were systematically recorded in patients’ files and electronic database. Chest radiograph and sputum analysis were done during the pre-treatment evaluation. Complete haemogram, erythrocyte sedimentation rate, C-reactive protein, and liver and kidney function tests were done every month for the first 3 months and every 3 months thereafter, depending on the patient condition. Specific imaging skiagram/magnetic resonance imaging (MRI)/computed tomography scan was done for diagnosis and treatment plan and repeated at 6, 9, and 12 months to access disease activity, healing, and stopping treatment.

Healed status was determined by the completion of ATT and no relapse of the disease at a follow-up of 2 years, supported by imaging investigation. Treatment failure was suspected when there were persisting or worsening local and systemic symptoms and signs, no improvement, or deterioration of the lesion on repeat imaging,


  Results Top


A total of 64 patients were enrolled in the study. There were 30 males and 24 females, with the mean age of 30.69 years (9–65 years). Among 64 patients, 9 patients (14%) were resistant to the CBNAAT and hence were excluded from the current study and separately evaluated. Three patients were missed out during follow-up. Finally, 52 patients were available for follow-up with specified criteria and evaluated for results. The study patients were divided into three groups, depending on the involvement of tubercular disease with definitive diagnosis [Table 3]. Most of the cases of Pott’s spine presented with complications of neurological deficit. Out of the 32 patients of Pott’s spine, 15 patients had stage III disease, 8 patients had stage IV, 7 patients had stage I, and the remaining 3 patients had stage II at the time of presentation (as per the classification by Tuli et al., modified by Jain and Sinha).[4],[10]
Table 3: Distributions of patients by involvement of osteoarticular TB with definitive diagnosis

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Out of the 52 patients, 22 (40%) patients presented late with complications from advanced severe disease. Ten patients who received previous treatment or showed deterioration during treatment received category II treatment with daily drugs such as streptomycin [Figure 1][Figure 2][Figure 3][Figure 4]. These patients were followed with clinical and radiological improvement for continued treatment duration [Table 4].
Figure 1: (A) MRI scan showing hyperintense signal at D9 vertebra with paravertebral collection at diagnosis. (B) Six-month follow-up hyperintensities at the D9 level with partial collapse. (C) No obvious epidural, pre- or paravertebral collection. (D) Partial collapse and wedging D9 vertebra. No evidence of any paravertebral collection with sign of fibrosis and sclerosis foci

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Figure 2: (A) MRI scan showing dorsal kyphoscoliosis with angulation at the D5, D6 levels. Decreased height of D5 vertebra with erosion, D5, D6 intervertebral disc space is lost. (B) Six-month follow-up total collapse of D6 vertebral body and partial collapse of D5 vertebra with mild edema. Cord edema at the D5-D6 level (C) at 9 months total collapse of D6 with angular kyphosis, bilateral pedicle screw D3, D4 and D7, D8 level. On comparison with previous MRI, there is complete resolution of the collection and edema

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Figure 3: MRI scan left hip joint showing (A) collection with extensive edema of articular surfaces extending into ipsilateral gluteal muscles. (B) At 6-month radiological worsening of disease hip joint collection with marrow edema in the left acetabular rim and head of femur. (C1) decrease joint space erosion osteopenia (C2) healed X-ray with persisted decreased joint space and sclerosis

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Figure 4: (A) MRI scan partial destruction and collapse of D9-D10 disc, vertebral collapse, cord compression with cord edema. (B) At 6-month initial worsening inpatients large pre- and paravertebral collection, epidural collection causing canal stenosis. (C) At 1-year residual disease gibbus deformity, near total collapse of D9 and D10 vertebral bodies with fusion of both. Minimal collection. (D) MRI scan showing gibbus deformity at dorsal spine (D9 and D10 levels). In comparison to the previous scan, there is resolution of altered vertebral signal and epidural collection

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Table 4: Distribution of patients by drug regime given and clinical and radiological outcomes

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Evaluation in 6 months

All patients at 6 months of daily treatment showed clinical improvement in general well-being and systemic and local conditions. During intensive therapy, eight patients (two from Group A and six from Group B) deteriorated and hence subjected to surgical intervention. Other patients (n = 22) who presented with severe disease were also subjected to surgical intervention.

Radiological evaluation of disease activity at 6 months showed worsening of the disease, in spite of clinical improvement. Radiological evidence of healing was not evident in any patient; hence, the continuation phase was continued beyond 6 months guided by radiological MRI-based disease activity and clinical status in all patients.

Continuation of treatment after 6 months

Earliest evidence of radiological healing was found at 8 months of ATT in elbow osteomyelitis in a 6-year-old child (Group A). In Group B, earliest healing was 9 months in case of Pott’s spine stage IV in an 11-year-old male who was treated with anterior lateral decompression and spinal fixation. The average duration of therapy to achieve healing in Group A was 14.8 months. The average duration of treatment in the current study was 15 months. Going by complete resolution of disease on MRI in this study, the minimum duration was 9 months in the case of Pott’s spine and the maximum duration was still uncertain. Four cases continue to show residual disease activity even after 15 months, although clinically healed and laboratory parameters are also within normal limits. These cases (n = 4) were kept under observation with 6 monthly follow-up MRI. These show no relapse after stopping ATT after 12–14 months. In one case which at 18 months still showed residual disease, however, the patient did not show any reactivation during follow-up of more than a year after ATT was stopped.


  Discussion Top


The RNTCP was launched in India in 1997 based on the DOTS, which is a recommendation of the WHO where ATT is given three times a week. The lower cost of drugs and feasibility of supervised dosing were factors thought in favour of intermittent treatment. Although it may be pharmacologically acceptable, there was little evidence to support this fact.[14] With increasing drug resistance and relapses, the WHO in 2007, and again in 2010, advised daily treatment as the preferred drug regimen in treatment of all patients with TB.

Current guidelines of ATT lack system and affected organ-based approach which is necessary for deciding drugs and duration. The WHO in its revised guidelines of 2010 has described the lack of enough evidence in deciding specific bone and joint TB guidelines.[5] However, the WHO American Thoracic Society, Center for Diseases Control (CDC), Infectious Diseases Society of America, and other organizations have recommended individual recommendation which helps in the formulation of treatment guidelines.[6] In a regression model, treatment failure or relapse was 1.8–2.5 times more likely with intermittent, rather than daily, dosing in the intensive phase.

Site of lesion

Since study is done at a tertiary referral centre, peripheral joint TB cases were less. Most of the cases were referred for advance investigation and MRI, which is expensive and not available in the periphery. X-ray diagnosis is usually delayed and takes 3–4 months to apparent radiological feature. Diagnosis is delayed till neurological symptoms develop. In the current study, six patients of Pott’s spine were diagnosed early in screening with MRI before developing extensive disease. This has great bearing in natural history of the disease.

Treatment regime

Most of the infections, besides TB, usually do not require close adherence to the treatment regime and generally decided on a case-to-case basis depending on the response of the patients. In TB, formulation of a strict regime is emphasized because community problem and large number of cases are difficult to diagnose and treat.

Clinical evaluation at 6 months

The RNTCP and the DOTS protocol do not describe objective evaluation of treatment response and healing of the disease. In pulmonary disease, sputum conversion has been described for treatment response but not applicable in osteoarticular TB. It was observed that although patients improved clinically at 6 months of treatment, radiological disease was persistent, hence requiring further continuation of treatment. All patients continued treatment over fixed duration, which is guided by radiological MRI-based disease activity.

Duration of treatment in radiologically healed disease

Radiological healing as a sole determinant of the duration of therapy makes the duration of ATT quiet long. Peripheral location of the disease is comparatively easy for follow-up monitoring. It is also frequently subjected to surgical debridement, which can clear the dead necrotic tissues and decrease the disease burden, thereby improving vascularity during early healing.[11],[12],[16]

Overall duration of therapy

It is certain that the prescribed duration of ATT in DOTS (6 months) is not enough to stop treatment. In RNTCP, endpoint of completion of treatment remains undefined; hence, most of the orthopaedic surgeons are not convinced with the short duration of ATT in osteoarticular TB.[11],[13]

The minimum duration for radiological healing of the disease in the current study is 8 months. Some cases continue to show residual disease on MRI, but healthy even after stopping ATT and 2 years after ATT, clinically healed and laboratory parameters are also within normal limits. These cases (n = 5) were kept under observation with 6 monthly follow-up MRI. These show no relapse.

MRI as a sole guide to treatment appears to overestimate the disease; hence, serial determination of MRI for disease activity is most important. On the basis of the study, the anti-tubercular drug regime used in drug-sensitive osteoarticular TB is mentioned [Table 5].
Table 5: Modified anti-tubercular drug regimen in osteoarticular tuberculosis

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  Conclusion Top


ATT is the mainstay in the management of extra pulmonary tuberculosis. However, the issue of the ideal regimen and duration of treatment have not yet been fully resolved. In the current study, it was found that response of osteoarticular treatment is difficult to access. PTB guidelines cannot be as such implemented to all other systems. It is necessary to develop specific affected organ system treatment regime based on evidence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Maher D, Chaulet P, Spinaci S, Harries A. Treatment of Tuberculosis: Guidelines for National Programmes , Book, WHO/CDS/TB/2003.313.  Back to cited text no. 1
    
2.
Technical and Operational Guidelines for TBC India. Available from: http://tbcindia.nic.in/pdfs/Technical%20&%20Operational%20guidelines%20for%20TB%20Control.pdf [Last accessed on May 13, 2022].  Back to cited text no. 2
    
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Murali MS, Sajjan BS. DOTS strategy for control of tuberculosis epidemic. Indian J Med Sci 2002;56:16-8.  Back to cited text no. 3
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Blumberg BM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;137:603-62.  Back to cited text no. 6
    
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Jain AK. Tuberculosis of the spine: A fresh look at an old disease. J Bone Joint Surg Br 2010;92:905-13.  Back to cited text no. 7
    
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Mohan A, Sharma SK. Epidemiology. In: Sharma SK, Mohan A, editors. Tuberculosis. New Delhi: Jaypee Brothers Medical Publishers; 2001 p. 14-29.  Back to cited text no. 8
    
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Vilchèze C, Hartman T, Weinrick B, Jacobs WR Jr. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat Commun 2013;4:1881. doi:10.1038/ncomms2898.  Back to cited text no. 9
    
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Jain AK, Sinha S. Evaluation of systems of grading of neurological deficit in tuberculosis of spine. Spinal Cord 2005;43: 375-80.  Back to cited text no. 10
    
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Upadhyay SS, Saji MJ, Yau AC. Duration of antituberculosis chemotherapy in conjunction with radical surgery in the management of spinal tuberculosis. Spine (Phila Pa 1976) 1996;21: 1898-903.  Back to cited text no. 11
    
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Menzies D, Benedetti A, Paydar A, Martin I, Royce S, Pai M, et al. Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: A systematic review and meta-analysis. PLoS Med 2009;6:e1000146.  Back to cited text no. 12
    
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Tuli SM. Tuberculosis of the spine: A historical review. Clin Orthop Relat Res 2007;460:29-38.  Back to cited text no. 13
    
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DOTS-Plus Guidelines. Available from: http://www.tbonline.info/media/uploads/documents/revised_national_tuberculosis_control_programme_dots-plus_guidelines_%282010%29.pdf. [Last accessed on May 13, 2022].  Back to cited text no. 14
    
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Winterbourn CC. Toxicity of iron and hydrogen peroxide: The Fenton reaction. Toxicol Lett 1995;82-83:969-74.  Back to cited text no. 15
    
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Sai Kiran NA, Vaishya S, Kale SS, Sharma BS, Mahapatra AK. Surgical results in patients with tuberculosis of the spine and severe lower-extremity motor deficits: A retrospective study of 48 patients. J Neurosurg Spine 2007;6:320-6.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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