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The Bone & Joint Journal
Vol. 99-B, Issue 10 | Pages 1381 - 1388
1 Oct 2017
Wong YW Samartzis D Cheung KMC Luk K

Aims

To address the natural history of severe post-tuberculous (TB) kyphosis, with focus upon the long-term neurological outcome, occurrence of restrictive lung disease, and the effect on life expectancy.

Patients and Methods

This is a retrospective clinical review of prospectively collected imaging data based at a single institute. A total of 24 patients of Southern Chinese origin who presented with spinal TB with a mean of 113° of kyphosis (65° to 159°) who fulfilled inclusion criteria were reviewed. Plain radiographs were used to assess the degree of spinal deformity. Myelography, CT and MRI were used when available to assess the integrity of the spinal cord and canal. Patient demographics, age of onset of spinal TB and interventions, types of surgical procedure, intra- and post-operative complications, and neurological status were assessed.


The Bone & Joint Journal
Vol. 100-B, Issue 9 | Pages 1208 - 1213
1 Sep 2018
Ukunda UNF Lukhele MM

Aims. The surgical treatment of tuberculosis (TB) of the spine consists of debridement and reconstruction of the anterior column. Loss of correction is the most significant challenge. Our aim was to report the outcome of single-stage posterior surgery using bone allografts in the management of this condition. Patients and Methods. The study involved 24 patients with thoracolumbar TB who underwent single-stage posterior spinal surgery with a cortical bone allograft for anterior column reconstruction and posterior instrumentation between 2008 and 2015. A unilateral approach was used for 21 patients with active TB, and a bilateral approach with decompression and closing-opening wedge osteotomy was used for three patients with healed TB. Results. A median of 1.25 vertebrae were removed (interquartile range (IQR) 1 to 1.75) and the median number of levels that were instrumented was five (IQR 3 to 6). The median operating time was 280 minutes (IQR 230 to 315) and the median blood loss was 700 ml (IQR 350 to 900). The median postoperative kyphosis was 8.5° (IQR 0° to 15°) with a mean correction of the kyphosis of 71.6%. Good neurological recovery occurred, with only two patients (8%) requiring assistance to walk at a mean follow-up of 24 months (9 to 50), at which time there was a mean improvement in disability, as assessed by the Oswestry Disability Index, of 83% (90% to 72%). Conclusion. The posterior-only approach using cortical allografts for anterior column reconstruction achieved good clinical and radiological outcomes. Differentiation should be made between flexible (active) and rigid (healed) TB spine. Cite this article: Bone Joint J 2018;100-B:1208–13


The Bone & Joint Journal
Vol. 96-B, Issue 10 | Pages 1366 - 1369
1 Oct 2014
Held M Laubscher M Zar HJ Dunn RN

The lack of an accurate, rapid diagnostic test for mycobacterium tuberculosis (TB) is a major handicap in the management of spinal TB. GeneXpert, a new, rapid molecular diagnostic test is recommended as the first line investigation for suspected pulmonary TB in areas with a high prevalence of HIV or drug resistance, yet it has not been validated for the diagnosis of musculoskeletal TB. The aim of this study was to assess the accuracy of GeneXpert in diagnosing spinal TB. A prospective clinical study of 69 consecutive adults with suspected spinal TB was conducted at a tertiary hospital in an area with the highest incidence and prevalence of TB in the world. GeneXpert was used on tissue samples of the enrolled patients and its diagnostic accuracy compared with a reference standard of tissue in liquid culture. A total of 71 spine samples from 69 patients (two re-biopsies) were included in the study. The GeneXpert test showed a sensitivity of 95.6% and specificity of 96.2% for spinal TB. The results of the GeneXpert test were available within 48 hours compared with a median of 35 days (IQR 15 to 43) for cultures. All cases of multi-drug resistant TB (MDR TB) were diagnosed accurately with the GeneXpert test. The MDR TB rate was 5.8%. Cite this article: Bone Joint J 2014;96-B:1366–9


The Journal of Bone & Joint Surgery British Volume
Vol. 83-B, Issue 2 | Pages 222 - 225
1 Mar 2001
Bhojraj SY Shetty N Shah PJ

Tuberculosis of the craniocervical junction is rare even where the condition is endemic. It poses problems in both diagnosis and management. We describe 25 cases followed over a period of 12 years, and relate the presentation, diagnosis and management. Of our 25 patients 16 were managed conservatively and nine by surgery. In order to diagnose this condition a high index of suspicion and advanced imaging techniques are necessary. Early diagnosis and adequate treatment led to good results without fatal complications


The Journal of Bone & Joint Surgery British Volume
Vol. 81-B, Issue 1 | Pages 106 - 109
1 Jan 1999
Govender S Parbhoo AH

Fresh-frozen allografts from the humerus were used to help to stabilise the spine after anterior decompression for tuberculosis in 47 children with a mean age of 4.2 years (2 to 9). The average angle of the gibbus, before operation, was 53°; at follow-up, two years later, it was 15°. Rejection of the graft or deep sepsis was not seen. Cross trabeculation between the allograft and the vertebral body was observed at six months, with remodelling occurring at approximately 30 months


The Journal of Bone & Joint Surgery British Volume
Vol. 86-B, Issue 7 | Pages 1027 - 1031
1 Sep 2004
Jain AK Aggarwal A Dhammi IK Aggarwal PK Singh S

We reviewed 64 anterolateral decompressions performed on 63 patients with tuberculosis of the dorsal spine (D. 1. to L. 1. ). The mean age of the patients was 35 years (9 to 73) with no gender preponderance. All patients had severe paraplegia (two cases grade III, 61 cases grade IV). The mean number of vertebral bodies affected was 2.6; the mean pre-treatment kyphosis was 24.8° (7 to 84). An average of 2.9 ribs were removed in the course of 64 procedures. The mean time taken at surgery was 2.45 hours when two ribs were removed and 3.15 hours when three ribs were removed. Twelve patients (19%) showed signs of neurological recovery within seven days, 33 patients (52%) within one month and 12 patients (19%) after two months; but six patients (10%) showed no neurological recovery. Forty patients were followed up for more than two years. In 34 (85%) of these patients there was no significant change in the kyphotic deformity; two patients (5%) showed an increase of more than 20°


The Journal of Bone & Joint Surgery British Volume
Vol. 85-B, Issue 1 | Pages 100 - 106
1 Jan 2003
Sundararaj GD Behera S Ravi V Venkatesh K Cherian VM Lee V

We present a prospective study of patients with tuberculosis of the dorsal, dorsolumbar and lumbar spine after combined anterior (radical debridement and anterior fusion) and posterior (instrumentation and fusion) surgery. The object was to study the progress of interbody union, the extent of correction of the kyphosis and its maintenance with early mobilisation, and the incidence of graft and implant-related problems. The American Spinal Injury Association (ASIA) score was used to assess the neurological status. The mean preoperative vertebral loss was highest (0.96) in the dorsal spine. The maximum correction of the kyphosis in the dorsolumbar spine was 17.8°. Loss of correction was maximal in the lumbosacral spine at 13.7°. All patients had firm anterior fusion at a mean of five months. The incidence of infection was 3.9% and of graft-related problems 6.5%. We conclude that adjuvant posterior stabilisation allows early mobilisation and rehabilitation. Graft-related problems were fewer and the progression and maintenance of correction of the kyphosis were better than with anterior surgery alone. There is no additional risk relating to the use of an implant either posteriorly or anteriorly even when large quantities of pus are present


The Bone & Joint Journal
Vol. 101-B, Issue 12 | Pages 1542 - 1549
1 Dec 2019
Kim JH Ahn JY Jeong SJ Ku NS Choi JY Kim YK Yeom J Song YG

Aims

Spinal tuberculosis (TB) remains an important concern. Although spinal TB often has sequelae such as myelopathy after treatment, the predictive factors affecting such unfavourable outcomes are not yet established. We investigated the clinical manifestations and predictors of unfavourable treatment outcomes in patients with spinal TB.

Patients and Methods

We performed a multicentre retrospective cohort study of patients with spinal TB. Unfavourable outcome was defined according to previous studies. The prognostic factors for unfavourable outcomes as the primary outcome were determined using multivariable logistic regression analysis and a linear mixed model was used to compare time course of inflammatory markers during treatment. A total of 185 patients were included, of whom 59 patients had unfavourable outcomes.


The Journal of Bone & Joint Surgery British Volume
Vol. 83-B, Issue 6 | Pages 859 - 863
1 Aug 2001
Mehta JS Bhojraj SY

In spinal tuberculosis MRI can clearly demonstrate combinations of anterior and posterior lesions as well as pedicular involvement. We propose a classification system, using information provided by MRI, to help to plan the appropriate surgical treatment for patients with thoracic spinal tuberculosis. We describe a series of 47 patients, divided into four groups, based on the surgical protocol used in the management. Group A consisted of patients with anterior lesions which were stable with no kyphotic deformity, and were treated with anterior debridement and strut grafting. Group B comprised patients with global lesions, kyphosis and instability who were treated with posterior instrumentation using a closed-loop rectangle with sublaminar wires, and by anterior strut grafting. Group C were patients with anterior or global lesions as in the previous groups, but who were at a high risk for transthoracic surgery because of medical and possible anaesthetic complications. These patients had a global decompression of the cord posteriorly, the anterior portion of the cord being approached through a transpedicular route. Posterior instrumentation was with a closed-loop rectangle held by sublaminar wires. Group D comprised patients with isolated posterior lesions which required posterior decompression only.

An understanding of the extent of vertebral destruction can be obtained from MRI studies. This information can be used to plan appropriate surgery.


The Journal of Bone & Joint Surgery British Volume
Vol. 81-B, Issue 3 | Pages 464 - 471
1 May 1999
Parthasarathy R Sriram K Santha T Prabhakar R Somasundaram PR Sivasubramanian S

We performed a randomised, controlled clinical trial to compare ambulant short-course chemotherapy with anterior spinal fusion plus short-course chemotherapy for spinal tuberculosis without paraplegia. Patients with active disease of vertebral bodies were randomly allocated to one of three regimens: a) radical anterior resection with bone grafting plus six months of daily isoniazid plus rifampicin (Rad6); b) ambulant chemotherapy for six months with daily isoniazid plus rifampicin (Amb6); or c) similar to b) but with chemotherapy for nine months (Amb9).

Ten years from the onset of treatment, 90% of 78 Rad6, 94% of 78 Amb6 and 99% of 79 Amb9 patients had a favourable status.

Ambulant chemotherapy for a period of six months with daily isoniazid plus rifampicin (Amb6) was an effective treatment for spinal tuberculosis except in patients aged less than 15 years with an initial angle of kyphosis of more than 30° whose kyphosis increased substantially.


The Journal of Bone & Joint Surgery British Volume
Vol. 83-B, Issue 6 | Pages 864 - 867
1 Aug 2001
Govender S Parbhoo AH Kumar KPS Annamalai K

A total of 39 HIV-infected adults with spinal tuberculosis underwent anterior spinal decompression for neurological deficit. Fresh-frozen allografts were used in 38 patients. Antituberculous drugs were prescribed for 18 months, but antiretroviral therapy was not used. Six patients died within two years of surgery. Neurological recovery and allograft incorporation were observed at follow-up at a mean of 38 months, although the CD4/CD8 ratios were reversed in all patients. Adequate preoperative nutritional support and compliance with antituberculous treatment are essential in ensuring a satisfactory outcome.


The Bone & Joint Journal
Vol. 104-B, Issue 1 | Pages 120 - 126
1 Jan 2022
Kafle G Garg B Mehta N Sharma R Singh U Kandasamy D Das P Chowdhury B

Aims. The aims of this study were to determine the diagnostic yield of image-guided biopsy in providing a final diagnosis in patients with suspected infectious spondylodiscitis, to report the diagnostic accuracy of various microbiological tests and histological examinations in these patients, and to report the epidemiology of infectious spondylodiscitis from a country where tuberculosis (TB) is endemic, including the incidence of drug-resistant TB. Methods. A total of 284 patients with clinically and radiologically suspected infectious spondylodiscitis were prospectively recruited into the study. Image-guided biopsy of the vertebral lesion was performed and specimens were sent for various microbiological tests and histological examinations. The final diagnosis was determined using a composite reference standard based on clinical, radiological, serological, microbiological, and histological findings. The overall diagnostic yield of the biopsy, and that for each test, was calculated in light of the final diagnosis. Results. The final diagnosis was tuberculous spondylodiscitis in 250 patients (88%) and pyogenic spondylodiscitis in 22 (7.8%). Six (2.1%) had a noninfectious condition-mimicking infectious spondylodiscitis, and six (2.1%) had no definite diagnosis and improved without specific treatment. The diagnosis was made by image-guided biopsy in 152 patients (56%) with infectious spondylodiscitis. Biopsy was contributory in identifying 132/250 patients (53%) with tuberculous spondylodiscitis, and 20/22 patients (91%) with pyogenic spondylodiscitis. Histological examination was the most sensitive diagnostic modality, followed by Xpert MTB/RIF assay. Conclusion. Image-guided biopsy has a reasonably high diagnostic yield in patients with suspected infectious spondylodiscitis. A combination of histological examination, Xpert MTB/RIF assay, bacterial culture, and sensitivity provides high diagnostic accuracy in a country in which TB is endemic. Cite this article: Bone Joint J 2022;104-B(1):120–126


Orthopaedic Proceedings
Vol. 103-B, Issue SUPP_11 | Pages 9 - 9
1 Sep 2021
Taha A Houston A Al-Ahmed S Ajayi B Hamdan T Fenner C Fragkakis A Lupu C Bishop T Bernard J Lui D
Full Access

Introduction. Pulmonary Tuberculosis (TB) can be detected by sputum cultures. However, Extra Pulmonary Spinal Tuberculosis (EPSTB), diagnosis is challenging as it relies on retrieving a sample. It is usually discovered in the late stages of presentation due to its slow onset and vague early presentation. Difficulty in detecting Mycobacterium Tuberculosis bacteria from specimens is well documented and therefore often leads to culture negative results. Diagnostic imaging is helpful to initiate empirical therapy, but growing incidence of multidrug resistant TB adds further challenges. Methods. A retrospective analysis of cases from the Infectious Disease (ID) database with Extra Pulmonary Tuberculosis (EPTB) between 1. st. of January 2015 to 31. st. of January. Two groups were compared 1) Culture Negative TB (CNTB) and 2) Culture Positive TB (CPTB). Audit number was. Results. 31 cases were identified with EPSTB. 68% (n=21) were male. 55% (n=17) patients were Asian, (19% (n=6) were black and 16% (n=5) were of white ethnicity. 90.4% (n=28) patients presented with isolated spinal TB symptoms. No patient had evidence of HBV/HCV/HIV infections. CPTB Group was 51.6% (n=16) compared to CNTB Group with 48.4% (n=15) 48% (15) lumbar involvement, 42% (13) thoracic and 10% (3) cervical. 38.7% (12) patients presented with late neurology, equally in both groups. 56% CPTB patients showed signs of vertebral involvement on plain radiograph compared to 13.3% in CNTB patients. 68.7% CPTB patients had pathological changes or paraspinal collections seen on CT scan compared to 53.3% of CNTB patients. 81% of CPTB showed positive MRI findings compared to 86% in CNTB. Both groups were treated with Anti-TB medications according to local guidelines. 83% patients were followed up till the end of the treatment course. 22.5% (n=7) patients had Ultrasound guided aspiration. 29% (n=9) patients underwent surgical intervention. 3 patients had Laminectomy for decompression. 6 patients underwent Spinal Decompression and Fixation due to extensive bone destruction. No mortality occurred. Conclusion. TB continues to be a growing problem in the developed world with high numbers of patients travelling from endemic regions. 75% of our cases were from Asian or Black ethnicity. The thoracolumbar region was most commonly effected (90%). Approximately 50% of cases of extrapulmonary spinal TB were culture negative. Neurological deficit occurred in 40% patients and 30% of patients required surgery. Standard anti-TB treatment was however effective in all cases with no significant drug resistant variants noted. MRI and CT imaging remain the superior diagnostic tests in the presence of high CN EPSTB


The Journal of Bone & Joint Surgery British Volume
Vol. 89-B, Issue 3 | Pages 346 - 348
1 Mar 2007
Danaviah S Govender S Gordon ML Cassol S

Non-tuberculous mycobacterial infections pose a significant diagnostic and therapeutic challenge. We report two cases of such infection of the spine in HIV-negative patients who presented with deformity and neurological deficit. The histopathological features in both specimens were diagnostic of tuberculosis. The isolates were identified as Mycobacterium intracellulare and M. fortuitum by genotyping (MicroSeq 16S rDNA Full Gene assay) and as M. tuberculosis and a mycobacterium other than tuberculosis, respectively, by culture. There is a growing need for molecular diagnostic tools that can differentiate accurately between M. tuberculosis and atypical mycobacteria, especially in regions of the developing world which are experiencing an increase in non-tuberculous mycobacterial infections


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 11 | Pages 1477 - 1481
1 Nov 2008
Jain AK Dhammi IK Prashad B Sinha S Mishra P

Injury to the spinal cord and kyphosis are the two most feared complications of tuberculosis of the spine. Since tuberculosis affects principally the vertebral bodies, anterior decompression is usually recommended. Concomitant posterior instrumentation is indicated to neutralise gross instability from panvertebral disease, to protect the anterior bone graft, to prevent graft-related complications after anterior decompression in long-segment disease and to correct a kyphosis. Two-stage surgery is usually performed in these cases. We present 38 consecutive patients with tuberculosis of the spine for whom anterior decompression, posterior instrumentation, with or without correction of the kyphus, and anterior and posterior fusion was performed in a single stage through an anterolateral extrapleural approach. Their mean age was 20.4 years (2.0 to 57.0). The indications for surgery were panvertebral disease, neurological deficit and severe kyphosis. The patients were operated on in the left lateral position using a ‘T’-shaped incision sited at the apex of kyphosis or lesion. Three ribs were removed in 34 patients and two in four and anterior decompression of the spinal cord was carried out. The posterior vertebral column was shortened to correct the kyphus, if necessary, and was stabilised by a Hartshill rectangle and sublaminar wires. Anterior and posterior bone grafting was performed. The mean number of vertebral bodies affected was 3.24 (2.0 to 9.0). The mean pre-operative kyphosis in patients operated on for correction of the kyphus was 49.08° (30° to 72°) and there was a mean correction of 25° (6° to 42°). All except one patient with a neural deficit recovered complete motor and sensory function. The mean intra-operative blood loss was 1175 ml (800 to 2600), and the mean duration of surgery 3.5 hours (2.7 to 5.0). Wound healing was uneventful in 33 of 38 patients. The mean follow-up was 33 months (11 to 74). None of the patients required intensive care. The extrapleural anterolateral approach provides simultaneous exposure of the anterior and posterior aspects of the spine, thereby allowing decompression of the spinal cord, posterior stabilisation and anterior and posterior bone grafting. This approach has much less morbidity than the two-stage approaches which have been previously described


The Bone & Joint Journal
Vol. 101-B, Issue 5 | Pages 617 - 620
1 May 2019
Dunn RN Castelein S Held M

Aims. HIV predisposes patients to opportunistic infections. However, with the establishment of Highly Active Anti-Retroviral Therapy (HAART), patients’ CD4 counts are maintained, as is a near normal life expectancy. This study aimed to establish the impact of HIV on the bacteriology of spondylodiscitis in a region in which tuberculosis (TB) is endemic, and to identify factors that might distinguish between them. Patients and Methods. Between January 2014 and December 2015, 63 consecutive cases of spontaneous spondylodiscitis were identified from a single-centre, prospectively maintained database. Demographics, presenting symptoms, blood results, HIV status, bacteriology, imaging, and procedure undertaken were reviewed and comparisons made of TB, non-TB, and HIV groups. There were 63 patients (22 male, 41 female) with a mean age of 42.0 years (11 to 78; . sd. 15.0). Results. In total, 53 patients had tuberculous, nine bacterial, and one cryptococcal spondylodiscitis. There were 29 HIV-positive patients, 29 HIV-negative patients, and five patients with unknown HIV status. The local incidence of TB spondylodiscitis was 1.54/100 000 and that of non-TB spondylodiscitis was 0.29/100 000 per annum. TB patients were younger with similar clinical presentation and infective markers, but were more likely to have a paraspinal abscess. They were also less likely to have a hyperintense disc on MRI. There was no difference between the two HIV groups. Conclusion. In areas of endemic TB and HIV, TB remains the most common cause of spondylodiscitis at five times the rate of non-tuberculous causes. HIV managed with HAART increases the rate of infection but does not influence the bacteriology unless there is a low CD4. There was little to differentiate the groups. TB /HIV co-infected patients were younger than non-TB and HIV-negative patients. Non-TB patients were more likely to have disc hyperintensity on MRI and TB patients were more likely to have abscess formation, but as both groups exhibited these features, neither was diagnostic. Culture confirmation remains necessary. Cite this article: Bone Joint J 2019;101-B:617–620


The Journal of Bone & Joint Surgery British Volume
Vol. 88-B, Issue 7 | Pages 925 - 927
1 Jul 2006
Kalra KP Dhar SB Shetty G Dhariwal Q

We studied 15 patients with healed tuberculosis of the spine and a resultant kyphosis. We selected only those with no neurological deficit and performed a wedge resection of the vertebra using a transpedicular approach. The wedge was removed from the apex of the deformity. For those with a neurological deficit, we chose the conventional anterior debridement and decompression with 360° circumferential fusion. At a mean follow-up of 26.8 months (8 to 46) the outcome was good with an increase in the mean Oswestry Disability Index from 56.26 (48 to 62) pre-operatively to 11.2 (6 to 16) at the latest follow-up


Bone & Joint Open
Vol. 4, Issue 11 | Pages 832 - 838
3 Nov 2023
Pichler L Li Z Khakzad T Perka C Pumberger M Schömig F

Aims

Implant-related postoperative spondylodiscitis (IPOS) is a severe complication in spine surgery and is associated with high morbidity and mortality. With growing knowledge in the field of periprosthetic joint infection (PJI), equivalent investigations towards the management of implant-related infections of the spine are indispensable. To our knowledge, this study provides the largest description of cases of IPOS to date.

Methods

Patients treated for IPOS from January 2006 to December 2020 were included. Patient demographics, parameters upon admission and discharge, radiological imaging, and microbiological results were retrieved from medical records. CT and MRI were analyzed for epidural, paravertebral, and intervertebral abscess formation, vertebral destruction, and endplate involvement. Pathogens were identified by CT-guided or intraoperative biopsy, intraoperative tissue sampling, or implant sonication.


Bone & Joint Research
Vol. 12, Issue 9 | Pages 522 - 535
4 Sep 2023
Zhang G Li L Luo Z Zhang C Wang Y Kang X

Aims

This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD).

Methods

The gene expression profile of GSE23130 was downloaded from the Gene Expression Omnibus (GEO) database. Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases, and we used Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze the functions and pathways of EP-DEGs. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and identify hub EP-DEGs. NetworkAnalyst was used to analyze transcription factors (TFs) and microRNAs (miRNAs) that regulate hub EP-DEGs. A search of the Drug Signatures Database (DSigDB) for hub EP-DEGs revealed multiple drug molecules and drug-target interactions.


Orthopaedic Proceedings
Vol. 98-B, Issue SUPP_6 | Pages 38 - 38
1 Feb 2016
Memon K Bevan L Leiow N Democratis J Anjarwalla N
Full Access

Spondylodiscitis is an uncommon condition with an incidence of 1:100,000 to 1:250,000 in developed countries. Diagnosis and treatment can be delayed resulting in poor outcomes. A high index of suspicion is necessary considering the associated mortality, reported at 2–17%. Establishing a diagnosis can be challenging as features are non-specific and onset may be insidious. While treatment is usually conservative, certain situations require surgery. All patients however require careful assessment and monitoring for complications that may require further intervention. A review of our practice in Wexham Park and Heatherwood Hospital NHS Trust from 2009 to 2013 produced a guideline suggesting the need for blood cultures, imaging with MRI and involvement of the infectious diseases and spinal teams. We re-audited (20 cases) to assess compliance with the guidelines, which were in place to reduce the delay in diagnosis. Recurrent presentation, infections of unknown origin and deterioration after a short course of antibiotics were indicators for triggering imaging of the spine for discitis. Delays in diagnosis were more marked in bacterial cases rather than tuberculosis. It was impossible to predetermine patients that would require surgical intervention. Our compliance with the guideline had improved from 70 to over 90% and there were no relapses or mortality