Scholarly article on topic 'Early diagnosis of spinal tuberculosis'

Early diagnosis of spinal tuberculosis Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Chang-Hua Chen, Yu-Min Chen, Chih-Wei Lee, Yu-Jun Chang, Chun-Yuan Cheng, et al.

Spinal tuberculosis (STB) is a common manifestation of extrapulmonary tuberculosis (TB). STB accounts for around 2% of all cases of TB and around 15% of extrapulmonary TB cases. The World Health Organization has proposed a global strategy and targets for TB prevention, care, and control after 2015. Under this strategy, patients will receive standard care according to the recommendations and guidelines after confirmation of STB diagnosis. However, current recommendations and guidelines focus on disease and medication therapy management, and recommendations for early detection or decision-making algorithms regarding STB are lacking. In this review, we identified five key components for early diagnosis: (1) risk factors for STB; (2) common symptoms/signs of STB; (3) significant neuroradiological findings of STB; (4) significant laboratory findings of STB, including positive interferon-γ release assays and nonpyogenic evidence in initial laboratory data; and (5) significant clinical findings of STB. Individualized consideration for each patient with STB is essential, and we hope that the algorithm established in this review will provide a valuable tool for physicians who encounter cases of STB.

Academic research paper on topic "Early diagnosis of spinal tuberculosis"

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Journal of the Formosan Medical Association (2016) xx, 1-12

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.jfma-online.com

REVIEW ARTICLE

Early diagnosis of spinal tuberculosis

Chang-Hua Chen a b c *, Yu-Min Chen d, Chih-WeiLee e, Yu-Jun Changf, Chun-Yuan Cheng g, Jui-Kuo Hung h

a Division of Infectious Diseases, Department of Internal Medicine, Changhua Christian Hospital, Changhua City, Taiwan, ROC

b Center for Infectious Diseases Research, Changhua Christian Hospital, Changhua City, Taiwan, ROC c Department of Nursing, College of Medicine and Nursing, Hung Kuang University, Taichung County, Taiwan, ROC

d Department of Pharmacy, Changhua Christian Hospital, Changhua City, Taiwan, ROC e Department of Medical Imaging, Changhua Christian Hospital, Changhua City, Taiwan, ROC f Epidemiology and Biostatics Center, Changhua Christian Hospital, Changhua City, Taiwan, ROC g Division of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua City, Taiwan, ROC

h Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua City, Taiwan, ROC Received 23 December 2015; received in revised form 28 June 2016; accepted 2 July 2016

KEYWORDS

algorithm; decision-making; early diagnosis; review;

risk assessment; spine;

tuberculosis

Spinal tuberculosis (STB) is a common manifestation of extrapulmonary tuberculosis (TB). STB accounts for around 2% of all cases of TB and around 15% of extrapulmonary TB cases. The World Health Organization has proposed a global strategy and targets forTB prevention, care, and control after 2015. Under this strategy, patients will receive standard care according to the recommendations and guidelines after confirmation of STB diagnosis. However, current recommendations and guidelines focus on disease and medication therapy management, and recommendations for early detection or decision-making algorithms regarding STB are lacking. In this review, we identified five key components for early diagnosis: (1) risk factors for STB; (2) common symptoms/signs of STB; (3) significant neuroradiological findings of STB; (4) significant laboratory findings of STB, including positive interferon-g release assays and nonpyogenic evidence in initial laboratory data; and (5) significant clinical findings of STB. Individualized consideration for each patient with STB is essential, and we hope that the algorithm established in this review will provide a valuable tool for physicians who encounter cases of STB. Copyright © 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Conflicts of interest: The authors have no conflicts of interest relevant to this article.

* Corresponding author. Division of Infectious Diseases, Department of Internal Medicine, Changhua Christian Hospital, 135 Nan Hsiao Street, Changhua, Taiwan, ROC.

E-mail address: chenchanghuachad@gmail.com (C.-H. Chen).

http://dx.doi.org/10.1016Zj.jfma.2016.07.001

0929-6646/Copyright © 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Introduction: tuberculosis, spinal tuberculosis, and World Health Organization strategies

Although tuberculosis (TB) is an ancient disease, it remains a major global public health problem.1,2 After two decades of progress toward TB elimination, annual decreases of 13 cases per 100,000 persons in Taiwan3 and at least 0.2 cases per 100,000 persons in the USA4'5 have been reported. Although pulmonary TB (PTB) is the most common form, spinal TB (STB) is one of the oldest reported diseases in humans and a common manifestation of extrapulmonary TB (ETB).6 In 2011, there were an estimated 8.7 million cases of TB globally, with 1.4 million TB-related deaths.7 Additionally, in Taiwan, there were 12,338 tuberculosis cases (53 cases per 100,000 persons) and 626 TB-related deaths (2.7 cases per 100,000 persons) in 2012.8 STB comprises around 4% of all TB cases and around 15% of all ETB cases within Taiwan.8

In response to global strategy and targets post 2015, Taiwan Strategic and Technical Working Group for TB performed cost—benefit analyses and those analyses were mainly divided into two parts. First, the preferred utilization of a chest radiograph survey among high-risk populations should be justified. Second, a model for the endorsement of new diagnosis tools for TB patients and latent TB infection patients should be established and its practicability assessed.9 According to a World Health Organization (WHO) report,8 the WHO post-2015 strategy proposal contains three components (Table S1).10 Patients with a confirmed STB diagnosis receive standard care according to those recommendations and guidelines (Table S2). However, these recommendations and guidelines focus on disease and medication therapy management and lack significant evidence and constructive recommendations for early detection as well as decision-making algorithms regarding STB. Thus, there is currently a lack of adequate evidence, recommendations, and guidelines for the early diagnosis of STB.

Effective vaccination is a mainstay of long-term policies to combat and control the TB epidemic. The existing bacille Calmette—Guerin vaccine has been shown to protect against disseminated TB in young children11,12; however, its protective effects against PTB are variable.12—14 Modified TB vaccines include the Mycobacterium W15 and recombinant bacille Calmette—Gueerin vaccines16 and new vaccines include the modified Vaccinia Ankara virus expressing antigen 85A,17 adenovirus 35-vectored TB vaccine candidate AERAS-402,18 H4:IC31,19 and M72/AS01 formulations.20,21 However, these new TB vaccines require further evaluation and clinical trials to demonstrate their efficiency and safety. Thus, early diagnosis and effective treatment are the other essential long-term strategies for controlling the TB epidemic. The first component of the WHO post-2015 strategy is early diagnosis of TB,10 and a rapid TB diagnosis is listed as the second main indication for recommended diagnostic tests (Table S3).22 This review focuses on early diagnosis of STB.

Clinical aspects of STB Natural clinical course

Spinal involvement usually results from the hematogenous spread of Mycobacterium tuberculosis into the cancellous bone tissue of the vertebral bodies. The primary infection site comes from either a pulmonary focus or other extrapulmonary foci, such as the lymph nodes.23—26 Predisposing factors for STB include many categories, such as previous TB infection, malnutrition, alcoholism, diabetes mellitus, and human immunodeficiency virus infection.6,25,27

Clinical presentation

Delays in diagnosis of STB are common. In a report by Sternbach,28 the average time from presentation to diagnosis is 1 year and 7 months. Typically, the onset of symptoms is insidious, and disease progression is slow. The duration of symptoms prior to diagnosis may range from 2 weeks to several years.6,25 To date, 2040 patients with STB have been reported worldwide (Table S4). Male patients comprise 53% of the STB-positive population, with a mean age of 43.4 years (median, 43 years; Table S4). The clinical presentation and findings of physical examinations depend on the site and stage of the disease, presence of complications, and constitutional symptoms.6,25,29 The most commonly reported symptoms are back pain (1438/2040, 70.4%), fever (667/2040, 32.7%), body weight loss (620/ 2040, 30.3%), neurological abnormalities (315/2040, 30.1%), and night sweats (390/2040, 19.1%; Table S4). Additionally, the thoracic spine is the most frequently involved segment (Table S4). The complications after STB included syringomyelia, permanent neurological deficits, and spinal osseous defects.1,25 Paraplegia is the most devastating complication of STB.6,25 The incidence of neurological deficit varies from 23% to 76%.30

Clinical laboratory diagnosis

STB diagnosis is confirmed by typical clinical presentation along with systemic constitutional manifestation, evidence of past exposure to TB or concomitant visceral TB, and neuroimaging modalities.6,25,3^33 Montoux skin tests and hematological investigations, such as complete blood count, erythrocyte sedimentation rate, enzyme-linked immunosorbent assay, and polymerase chain reaction (PCR), are also helpful in diagnosing STB.6,25,32,34 Bone tissue or abscess samples stained for acid-fast bacilli, mycobacterial organisms isolated from culture, and computed tomography (CT)-guided or ultrasonography-

guided needle biopsy or surgical biopsy are also widely

used.6,25,35,36

Imaging diagnosis

Plain radiography is usually performed initially in patients suspected to have STB, and plain radiograph images show

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bird-nest appearance characteristics of the aneurysmal phenomenon.37 Magnetic resonance imaging (MRI) is the modality of choice for imaging of STB. STB can be suggested over pyogenic spondylodiscitis on the basis of several characteristic MRI features. Typical MRI abnormalities include spinal lesions that originate from the vertebral endplate, involve the anterior vertebral body corner, show evidence of subligamentous spread, exhibit multiple vertebral bodies but preserved discs, and show extensive paraspinal abscess formation, abscess calcification, and vertebral destruction or vertebral body collapse.37 The mean rates of abnormal findings in different imaging modalities are 15% in plain spinal radiography, 100% in MRI, and 100% in CT (Table S4). For radiolucent lesions to be visible on plain radiographic images, there must be 30% bone mineral loss.25'38'39 CT is more effective for defining the shape and calcification of soft tissue abscesses than plain radiography because CT provides much better visualization of the bony details of irregular lytic lesions, sclerosis, disc collapse, and disruption of bone circumference.6 However, CT is less accurate for defining the epidural extension of the disease and its effect on neural structures compared with MRI. Hypointense Tl-weighted and hyperintense T2-weighted signal intensities, short tau inversion recovery sequences, and administration of gadolinium with dieth-ylene tri-amine penta-acetic acid are useful techniques for differentiation of TB from pyogenic spondylitis .6'25'40'41

Treatment

Early diagnosis and appropriate empirical anti-TB agents combined with surgery are associated with an excellent prognosis.25,42-44 Surgical treatment is performed for decompression, debridement, and fusion 25,43,45 and has been used in ~75.7% of diagnosed patients (Table S4), at least 80% of whom have shown improvement (Table S4).

Physicians are not only familiar with the common clinical features of STB but also have an in-depth understanding of the disease; early diagnosis and effective treatment can minimize sequelae and improve clinical outcomes. The cornerstone of successful management of STB is early detection and timely judicious medical interven-tion.28,41,46,47 Since accurate and effective treatment and early diagnosis are essential, but clinical evidence required for early diagnosis of STB is still lacking. Hence, in this review, we aimed to provide a summary of our understanding of STB, emphasizing early diagnostic evidence from clinical clues, various modalities of medical imaging, and recent advances in laboratory examinations, as well as our clinical experiences with STB.

Summary of information regarding early diagnosis of STB

Most patients with STB are not accurately diagnosed during the initial stages of the disease due to delays from both the patient and doctor48; such delays may result in significant spinal damage.37 The golden standard method for diagnosis of STB is positive M. tuberculosis culture from tissue. Clinical judgment for STB has shown both poor sensitivity and specificity. Moreover, the time to detection

of mycobacterial growth may be 4e6 weeks using traditional culture methods, including methods that utilize Lowenstein-Jensen medium; however, faster culture of mycobacterial isolates has been reported, including quantitative tissue culture on solid media, an automated broth culture system from tissue specimens, quantitative nucleic acid amplification of M. tuberculosis from tissue samples, and measurement of TB antigen concentrations in tissue samples. Nucleic acid amplification tests (NAATs) provide a reliable method for increasing the specificity of diagnosis (ruling in disease), but exhibit poor sensitivity and cannot be used to rule out disease.49 Because we have focused on early diagnosis, we have not provided a literature search of current culture methods in this review. However, advanced clinical findings, laboratory methods, and medical imaging modalities could be helpful for early detection of STB. Notably, diagnosis of STB is a major challenge for physicians because of the nonspecific, wide spectrum of clinical presentations; this can result in delayed diagnosis and risk of significant potential morbidity and mortality due to the progression of the disease and subsequent complications. Early diagnosis and treatment is the key to avoiding this long-term disability. Therefore, we searched the literature to summarize the tools available for advanced detection and early diagnosis (Table 1).

A rapid biomarker-based nontissue-based test

In an effort to develop more accurate tools for immunological diagnosis of tuberculosis, two mycobacterial proteins, culture filtrate protein-10 and early secretory antigenic target-6, have been evaluated.54,61,62 These immunodiagnostic tests, the whole-blood interferon-g (IFN-g) enzyme-linked immunosorbent assay (QuantiFERON-TB Gold; Cellestis Ltd, Chadstone, Victoria, Australia) and the enzyme-linked immunospot assay (T-SPOT.TB; Oxford Immunotec, Oxford, UK), can quantitatively measure IFN-g production by lymphocytes specific to M. tuberculosis-specific immunodo-minant antigens, which are encoded by the RD1 region of the pathogen. Another commercially available IFN-g release assay (IGRA), the QuantiFERON-TB Gold in-tube assay (QFTGIT; Cellestis Ltd), is able to measure IFN-g production specific to the immunodominant antigens TB7.7, early secretory antigenic target-6, and culture filtrate protein-10. Acommercially available T-SPOT.TB assay, the ELISPOTassay (i.e., T-SPOT. TB; Oxford Immunotec),63 has been developed. In addition, detection of lipoarabinomannan and A60 mycobacterial antigen have been reported.50,51 These immunological diagnostic tools have been evaluated for diagnosis of ETB, including STB, infections.

Based on a report by Kumar et al,46 in combination with radiological criteria, bone scan, and enzyme-linked immunosorbent assay, the QuantiFERON assay was predictive of tuberculosis in 90% of cases. A report by Yuan et al53 showed that the ELISpot assay is a useful adjunct to current tests for diagnosis of STB. Feng et al52 reported that IGRA could function as a powerful immunodiagnostic test to explore PTB and ETB, and T-SPOT.TB was shown to be equally sensitive for determining PTB and ETB. Based on the data of Cho et al,64 the T-SPOT.TB assay is more

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4 C.-H. Chen et al.

Table 1 Summary of advanced information for early diagnosis of spinal tuberculosis.

Items Description Sensitivity/ PPV/NPV Comment and references

specificity (%) (%)

Gold standard

Mycobacterial Direct test of tissue for NM NM For confirmation of STB

culture result M. tuberculosis complex diagnosis24'25'32

/TB culture of tissue

Reference standard

Histopathological Granulation NM NM For suspected STB

result inflammation, caseous diagnosis24,25,32

necrosis

TB smear result TB smear of tissue NM NM For suspected STB diagnosis

24,25,32

Index tests

A rapid biomarker-based nontissue -based test

Enzyme-linked Detection of A60 74/NM NM Although sensitivity is 63%

immunosorbent mycobacterial antigen and specificity is 96%, it is

assay not a useful laboratory test

for diagnosis of active TB50

Selected panel of TB Detection of 15.6/99.3 96.1/NM Could serve as an important

antibodies lipoarabinomannan, tool for diagnosis of TB,

38-kDa antigen, and especially ETB51

16-kDa antigen

Immunodiagnostic Uses enzyme-linked 88.9/50.0 90.9 /NM The T-SPOT.TB test had a

tests, the whole- immunospot assays (T- higher sensitivity than the

blood interferon-g SPOT.TB; Oxford QFT-GIT assay for diagnosing

enzyme-linked Immunotec, Oxfordshire, ETB57

immunosorbent UK) to detect ETB

assay Uses blood T-SPOT.TB to 100/55 62/NM The T-SPOT.TB was more

(QuantiFERON-TB detect osteoarticular TB sensitive in patients with

Gold; Cellestis Ltd, chronic forms of ETB, such

Chadstone, Victoria, as lymph node or

Australia) and the osteoarticular TB (93%, 95%

enzyme-linked CI: 83-97%), than in

immunospot assay patients with acute forms of

(T-SPOT.TB; Oxford ETB, such as TB meningitis

Immunotec, Oxford, or miliary TB (79%, 95% CI:

UK) 66-87%, p = 0.03)56

Uses QuantiFERON assay 84/95 90/NM ELISA, MRI of the spine, and

to detect STB bone scanning findings

provide a reasonably certain

diagnosis in 90% of cases,

providing the grounds for

initiation of a trial to

determine the safety of

antituberculous

chemotherapy46

Enzyme-Linked Uses CFP10/ESAT6 fusion 82.7/87.2 89.6/79.1 Yuan et al showed that this

ImmunoSpot protein as antigen to method has high sensitivity

(ELISpot) assay detect spinal TB and specificity and is an

specimens effective technique for

auxiliary diagnosis of STB53

Measures the IFN-g 82.8/81.3 80.0/83.9 The ELISpot assay is a useful

response to ESAT-6 and adjunct to current tests for

CFP-10 in T cells in diagnosis of atypical STB54

samples of peripheral

blood mononuclear cells

of STB specimens

Please cite this article in press as: Chen C-H, et al., Early diagnosis of spinal tuberculosis, Journal of the Formosan Medical Association 1

(2016), http://dx.doi.org/10.1016Zj.jfma.2016.07.001

Table 1 (continued )

Items Description Sensitivity/ specificity (%) PPV/NPV (%) Comment and references

Uses IFN-g to detect STB 86.7/61.9 61.9/86.7 The ELISpot assay could

specimens provide useful support in diagnosing skeletal TB, and STB could be excluded based on a negative ELISpot assays67

Rapid tissue-based tests

Polymerase chain Uses PCR to detect STB 100/71.4 NM Although numbers in the

reaction specimens study by Van der Spoel van Dijk et al. were too low to effectively draw statistically valid conclusions, the importance of the relevance of PCR for rapid detection of low numbers of acid-fast bacilli and confirmation of mycobacterial infection in spinal biopsies has been established.56

Analysis of 94.7/83.3 94.7/83.3 Twenty-fiive formaldehyde-

formaldehyde-fixed, fixed, paraffin-embedded

paraffin-embedded tissue blocks from vertebral

tissue by PCR biopsy specimen materials with presumptive diagnosis of tuberculous spondylitis were analyzed, with an accuracy of 92%.57

Xpert® MTB/RIF Uses Xpert MTB/RIF to 81.3/99.8 NM Positive likelihood ratios:

assay, an automated detect ETB 490.5; negative: 0.2.

amplification Although the role of culture

system remains central in the microbiological diagnosis of ETB, the sensitivity of Xpert in rapidly diagnosing the disease makes it a much better choice compared with smear microscopy72

Uses GeneXpert MTB/RIF 77.3/98.2 NM Overall, the sensitivity and

(Xpert) to detect ETB specificity of the Xpert assay are very high in culture-positive specimens. The high sensitivity is not self-evident because only small amounts of DNA are expected in any extrapulmonary clinical sample71

Xpert MTB/RIF 81/99.6 NM The results of this study suggest that the Xpert test also shows good potential for the diagnosis of ETB and that its ease of use makes it applicable for countries where TB is endemic70 (continued on next page)

Table 1 (continued )

Items Description Sensitivity/ PPV/NPV Comment and references

specificity (%) (%)

Advanced medical imaging Fluorine-18-fluorodeoxyglucose positron emission tomography/ computed

tomography imaging MRI

Fluorine-18- 90/NM

fluorodeoxyglucose positron emission tomography/computed tomography imaging

Diagnosis based on NM

positive histopathology results along with supportive MRI

The maximum SUVs of early-phase PET/CT may be complementary to MRI for differentiating pyogenic and tuberculous spondylitis and reflecting the activity of infectious spondylitis60 MRI findings showed primarily shadowed areas with features such as disc destruction and thecal or cord compression. MRI scanning could be used for early detection of spinal TB, which can reduce disability and deaths in patients37

Note: NM: not mentioned.

CFP10 = culture filtrate protein 10; CT = computed tomography; DNA = deoxyribonucleic acid; ELISA = enzyme-linked immunospot assay; ESAT6 = early secretory antigen target 6; ETB = extrapulmonary tuberculosis; IFN-g = Interferon-g; IGRA = Interferon-g release assays; NPV = negative predictive value; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PET/CT = positron emission tomography/computed tomography; PPV = positive predictive value; PTB = pulmonary tuberculosis; QFT-IT = QuantiFERON-TB Gold In-Tube; TB = tuberculosis; STB = spinal tuberculosis; SUV = standardized uptake value; TST = tuberculin skin test.

sensitive in patients with chronic forms of ETB, such as lymph node or osteoarticular TB (93%; 95% confidence interval, 83—97%) than in patients with acute forms of ETB, such as TB meningitis or miliary TB (79%; 95% confidence interval, 66—87%; p = 0.03). Additionally, studies by Lai et al55 and Lai and Wang65 found that the T-SPOT.TB assay was more sensitive than the QFTGIT for the diagnosis of ETB, particularly in culture-confirmed TB cases. This suggests that the T-SPOT.TB assay may be a helpful adjunct diagnostic tool in patients with suspected ETB. However, Fan et al66 showed that IGRAs have limited value as diagnostic tools to screen and rule out ETB, particularly in low/middle-income countries. The immune status of patients does not affect the diagnostic accuracy of IGRAs for ETB. Rangaka et al67 showed that IGRAs do not have high accuracy for the prediction of active TB, although use of IGRAs in some populations may reduce the number of patients considered for preventive treatment. Although IGRA could be a powerful immunodiagnostic test for evaluation of ETB, these new methods require further investigations to determine their accuracy and safety in different populations, particularly patients with STB. Future studies are needed to address different epidemi-ological and clinical settings, evaluate the performance of common commercial assays in head-to-head comparisons, and assess the role of adding more TB-specific antigens on improving diagnostic sensitivity.

Rapid tissue-based tests

The promise of rapid diagnosis exists with the wide implementation of molecular platforms, such as PCR.56'57

Turnaround times have been reported to be as short as 24 hours.68 Based on a report by Monni et al,69 the sensitivities of culture and PCR are comparable (77% and 72%, respectively). Some newer and more sensitive NAATs, including the amplified M. tuberculosis direct test and Xpert MTB/RIF (Xpert) assays, may enhance M. tuberculosis detection in specimens. Xpert (Cepheid, Sunnyvale, CA, USA) is a fully automated real-time heminested PCR system implementing molecular beacon technology for the diagnosis of PTB infection.

According to reports by Pai et al,70'71 commercial NAATs may have a potential role in confirming the diagnosis of tuberculous meningitis and tuberculous pleuritis, although their overall low sensitivity precludes their use to rule out those types of ETB with certainty. Tortoli et al72 evaluated the performance of the Xpert system in many different extrapulmonary specimens in a country with a low incidence of TB and found that, in comparison with a reference standard consisting of combination of culture and clinical diagnosis of TB, the Xpert system exhibited an overall sensitivity and specificity of 81.3% and 99.8%, respectively. The results of Hillemann et al's59 study suggest that the Xpert test also shows good potential for the diagnosis of ETB and that its ease of use makes it applicable for countries where TB is endemic. In addition, the sensitivity and specificity of the Xpert assay are very high in culture-positive specimens. The high sensitivity is not self-evident because only small amounts of DNA are expected in any extrapulmonary clinical sample.58 Currently, there are also major clinical problems with obtaining tissue specimens for diagnosis in most patients suspected of having STB.

Table 2 Early clinical presentation, laboratory results, and neuroradiological findings of patients with confirmed spinal tuberculosis

Patient 1 2 3 4

Age (y)/sex 78/F 66/M 82/F 57/M

History of TB exposure + + + +

Initial laboratory data

White cell count (cells/mL) 4800 6200 5800 6800

ESR (mm/h) 45 45 38 68

CRP (mg/dL) 24.9 7.9 4.5 5.5

Albumin (g/dL) 4.2 3.2 3.5 3.6

Procalcitonin (ng/mL) 0.04 0.03 0.04 0.02

Positive IGRA + + + +

Initial neuroradiological findings

Originates from vertebral endplate +

Involves the anterior vertebral body corner +

Subligamentous spread +

Multiple vertebral bodies involved & preserved disc +

Extensive paraspinal abscess formation +

Calcification of abscess + Vertebral destruction, vertebral body collapse (Gibbus deformity) + Definitive diagnosis

TB smear of tissue/MtbcDT of tissue/TB culture of tissue +/+/MTBC

Histopathological results GI

No good response to traditional anti-bacterial regimens a +

Patient delay (d)/doctor delay of ATA (d)/total delay (d) 60/5/65

+/+/MTBC

GI, CN

30/5/35

+/+/MTBC

GI, CN

32/5/37

+/+/MTBC

GI, CN

60/3/63

ATA = anti-TB agent; CN = caseous necrosis; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; F = female; GI = granulation inflammation; IGRA = interferon- g release assays; M = male; Mo = month; MtbcDT = Mycobacterium tuberculosis complex direct test; TB = tuberculosis .

a No good response to traditional antibacterial regimens meant that clinical signs and symptoms and the results of laboratory examinations did not improve after 3 days of administration of combination antibacterial regimens (anti-Staphylococcal agent with an anti-Pseudomonal agent, such as oxacillin plus aminoglycosides).

Advanced medical imaging

Lee et al60 reported MRI to be superior to positron emission tomography and CT in differentiating between STB and pyogenic spondylitis. MRI could be used for early detection of STB, which could reduce the occurrence of disability and death in these patients.37 MRI is the earliest diagnostic modality for STB; however, confirmatory diagnosis can only be made on the basis of biopsy or culture results.37,73

Our experiences

A literature review revealed sparse research concerning early diagnosis of STB; therefore, we summarized our experience to analyze factors associated with early diagnosis of STB. Our experience included patients hospitalized at Changhua Christian Hospital System, Changhua City, Taiwan who were diagnosed with STB from January 1, 2010 to December 31, 2013. All adult patients diagnosed with STB by all of the following methods were included: positive vertebral osseous acid-fast bacilli; positive TB culture from fine needle aspiration cytology specimens; and characteristic pathologic findings. All patients diagnosed with STB received standard anti-TB agents, according to the Taiwanese guidelines for TB diagnosis and treatment.8

Five cases were diagnosed as having STB during the study period. Four of these cases were confirmed to have

mycobacterial infections with histopathological findings confirming TB, while the other case was a non-TB myco-bacterial infection. Thus, only four patients with confirmed STB infections were enrolled in this study. The early clinical presentations, laboratory results, and neuroradiological findings of these patients are listed in Table 2. The neuro-radiological findings of a patient with STB are shown in Figure 1. All patients received standard anti-TB agents. Two underwent surgical interventions for neurological deficits, and all survived.

We noted five key components for early diagnosis: (1) risk factors for STB; (2) common symptoms/signs of STB; (3) significant neuroradiological findings of STB; (4) significant laboratory findings of STB, including positive IGRA and nonpyogenic evidence in initial laboratory data; and (5) significant clinical findings of STB. STB has a wide variety of manifestations. However, we identified five key indicators for STB (Table 2), which were consistent with the observations in previous reports.74-78 According to a study in the Netherlands by Jutte et al,48 there was a mean delay in the diagnosis of nonspinal bone and joint TB of 35 weeks. In the current study, the total delay duration ranged from 25 days to 65 days. Early diagnosis of STB is important to prevent negative outcomes.77 Wares et al77 described the nonspecific radiological features of STB. However, we identified seven key radiological findings observed in the lesions of patients with STB (Table 2). Imaging is important for diagnosis and treatment of STB, and the diagnostic roles of

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Figure 1 Neuroradiological findings of a patient with spinal tuberculosis. (A). Postgadolinium Tl-weighted magnetic resonance imaging with fat saturation, sagittal view, showing enhancement of the T9 and T10 vertebrae with apposing endplates erosion, and enhanced soft tissue spreading along the anterior subligamentous space, from T7 to T12 level. Mild enhancement of the T8 inferior and T11 superior vertebral bodies are also noted, but the T8/9 and T10/11 discs are preserved. (B). Postgadolinium Tl-weighted magnetic resonance imaging with fat saturation, axial (at T9—10 level) view, showing extensive paraspinal abscess (arrow). (C). Computed tomography scan of the thoracic spine axial view showing calcification of the paraspinal abscess (arrow).

various imaging modalities have been discussed previ-ously.79 MRI and spiral CTare currently the most commonly used imaging methods.

An algorithm for decision-making

Advanced clinical findings, laboratory methods, and medical imaging could be helpful for early detection of STB (Table 1). However, the availability and utility of these methods are variable worldwide, including in Taiwan. A successful experience to use an algorithmic approach for patient management, and their results enable early identifies candidates at high risk of TB reactivation for anti-TB chemoprophylaxis.80 We have developed a decision-making algorithm for the diagnosis and management of STB based on our literature review and our experience; we expect that this algorithm may be useful at most institutes and facilities (Figure 2).1,74—79 Risk assessment for patients with suspicion of STB should include the five key components. The risk assessment elements are modified based on our experiences and

previous reports.74—76,78,81 MRI is one of the most useful diagnostic methods for STB, often allowing an earlier diagnosis than conventional methods. Rational orders for MRI could reduce medical resource waste, according to Taiwan's National Health Insurance regulations. Patients undergoing conservative treatment without surgery should be monitored closely with serial clinical examinations (at least weekly), ESR assessment (every 2—4 weeks), and MRI or CT (depending on the clinical situation and level of risk of the patient in order to assess abscess size and extent, until resolution). Patients take anti-TB agents regularly prior to meals under the directly observed treatment, short course program.82 Optimized care involves risk assessment of concurrent conditions, re-assessment of follow-up conditions, and administration of appropriate anti-TB agents with or without surgery.

Accurate diagnosis and adequate treatment of STB can improve patient outcomes. Hence, the algorithm established in this report (Figure 2) also includes decision-making for the diagnosis and management of STB.1,74—79 Emergent surgical decompression should be initiated for

Risk factors for TB HIV

Immunocompromised status Recent contact with patients having tuberculosis

Laboratory data for STB positive IGRA (positive IGRAs, positive Enzyme-Linked ImmunoSpot assay, or strongly positive purified protein derivative skin test results)

non-pyogenic evidence in initial laboratory data: (1) increased serum albumin levels, (2) reduced WBC, (3) lower CRP levels, & (4) reduced procalcitonin levels

Clinical response a lack of good clinical response to traditional antibacterial regimens such as oxacillin plus aminoglycosides

Suspect STB if risk factors for TB (Box A) AND symptoms & signs of STB (Box B)

Immediate investigations'^ CXR

Plain film of spin Spine MRI

CBC, LFTs, RFTs, glucose, CRP,ESR Blood culture HIV test

Re-investigations Image findings (Box C) Laboratory data (Box D) Clinical response (Box E)

Highly suspect STB

Screen for PTB

Grade 1 'b

Grade 2 'b

Grade 3 'b'

Common symptoms/signs of STB Insidious onset of back pain/ neck pain Fever

Body weight loss

Neurological abnormality, such as

paraplegia , sensory loss, bowel /bladder

dysfunction

Night sweat

Back swelling

Imaging features of STB significant neuroradiological findings: plain radiograph images showing (1) bird-nest appearance, (2) aneurysmal phenomenon, or MRI showing lesions that (1) originate from vertebral endplate, (2) involve the anterior vertebral body corner, (3) show evidence of sub-ligamentous spread, (4) include multiple vertebral bodies but preserved discs, (5) extensive para-spinal abscess formation, (6) abscess calcification, (7) vertebral destruction or vertebral body collapse (Gibbus deformities)

Differential Diagnosis

Highly suspect pyogenic SD

Medical management ± CT-guided Consider Surgical

aspiration & F/U FDC 'c' intervention

Medical management ± CT-guided aspiration & F/U FDC '<='

Poor response '

Not poor response

Conservative management & F/U FDC'C'

Recheck diagnosis, consider Surgical intervention

Poor response '

i" f I

e'd' L_ Not poor r

t poor response

Figure 2 Algorithm for diagnosis and treatment of spinal tuberculosis. a Immediate investigations included complete medical history, physical examinations, neurological examinations, laboratory examinations, and imaging examinations. b The grading system score for spondylodiscitis is shown in Table S5. c Poor response was defined as a lack of reduction in clinical symptoms and signs following administration of anti-TB agents. d Scoring for describing disability status based on functional disability classification is shown in Table S6. CBC = complete blood cell count; CRP = C-reactive protein; CT = computed tomography; CXR = chest X-ray; ESR = erythrocyte sedimentation rate; F/U = follow-up; FDC = functional disability classification; HIV = human immunodeficiency virus; IGRA = interferon-gamma release assay; LFT = liver function test; MRI: magnetic resonance imaging; PTB: pulmonary tuberculosis; RFT: renal function test; SD: spondylodiscitis; STB: spinal tuberculosis; WBC: white blood cell count.

patients with infection-induced moderate to severe neurological compromise for the duration of anti-TB agent treatment. The neurological status at the time of presentation is a critical factor for treatment decision-making and patient outcomes. If the imaging results suggest STB, the decision for operative management

should be based on risk assessment for the failure of medical treatment according to the grading system for spondylodiscitis (Table S5). Patients receiving medical treatment alone may receive CT-guided drainage of the target lesions. They should also be monitored and reassessed for signs of medical treatment failure. If these

ARTICLE IN PRESS

+ MODEL

signs are detected, surgical decompression should be promptly arranged.

Future studies

This review included a large number of studies; however, continued research on this topic is necessary to define early diagnosis of STB more accurately. Large-scale studies and clinical trials are also required in order to develop and validate more accurate modules, matrixes, or algorithms for early diagnosis of STB based on advances in medical technologies. In order to realize the incremental value of combinations of tests, particularly for samples of tissue specimens, it will be necessary to carry out large, prospective, well-designed studies recruiting representative samples of patients with STB. Longitudinal cohort studies to confirm the positive predictive value of IGRAs for subsequent development of active TB and ETB (including STB) should also be performed. M. tuberculosis transmission is limited because of genetic evolution and deviation from different geographic regions and ethnic populations in Taiwan, and it remains to be investigated.83

Conclusion

In conclusion, TB is preventable and curable, and its elimination would have widespread health, economic, and social benefits. STB is a great challenge to physicians because of the nonspecific, wide spectrum of clinical presentations, which result in delayed diagnosis and risk of significant morbidity and mortality. In this review, we have summarized knowledge on early diagnosis of STB. A high degree of clinical acumen and evaluation based on the five indicators outlined in this review are important for STB diagnosis and for starting treatment with anti-TB agents, which is the current mainstay of treatment. In addition, MRI is one of the most useful diagnostic methods for STB. Individualized consideration of each patient with STB is essential, and we hope that the algorithm developed in this report (Figure 2) will be a valuable tool for physicians.

Acknowledgments

We thank the TB case managers of Changhua Christian Hospital for their assistance in data collection and the staff of the Infection Control Committee, Clinical Microbiological Laboratory, Department of Medical Records, and Department of Computer of Changhua Christian Hospital for providing information for statistical analysis. We also wish to express their gratitude to Dr Yung-Jen Yang, who was extremely helpful and provided invaluable assistance and support. We thank Dr Fu-Chou Chen at Taichung Veterans General Hospital for reviewing this article. Grant support was received from Changhua Christian Hospital (104-CCH-IRP-001, 105-CCH-IRP-001).

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/jjfma.2016.07.001.

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