Outcomes and risk factors for spontaneous spondylodiscitis: Case series and meta-analysis of the literature

Journal of Clinical Neuroscience 68 (2019) 179–187

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Clinical study

Outcomes and risk factors for spontaneous spondylodiscitis: Case series and meta-analysis of the literature E. Giordan a,⇑, E. Marton a, G. Scotton b, G. Canova a a b

Department of Neurologic Surgery, Treviso Regional Hospital, Treviso, Italy Department of Infectious Diseases, Treviso Regional Hospital, Treviso, Italy

a r t i c l e

i n f o

Article history: Received 19 November 2018 Accepted 21 June 2019

Keywords: Spontaneous spondylodiscitis Spinal infections Community-acquired spinal infections Discitis

a b s t r a c t Despite recent improvements in surgical and antimicrobial therapies, few generally applicable guidelines exist for spondylodiscitis management. We reviewed a consecutive series of patients as well as the past 18 years of the literature and analyzed outcomes for either conservative or surgical treatment. We analyzed a consecutive series of adults with spontaneous spondylodiscitis treated at our institution over the last 6 years. We analyzed predictors for neurological deficits, vertebral collapse, and surgical treatment. We also performed a meta-analysis of the literature between 2000 and 2018, stratifying the results between surgical and conservative treatment outcomes. A younger age at diagnosis, cervical location, tubercular infection, coexistence of morbidities, and vertebral collapse were predictors of surgical intervention. Cervical spondylodiscitis, vertebral collapse, and epidural collection were associated with a higher risk of developing neurological deficits, while tubercular spondylodiscitis was associated with a higher risk of vertebral collapse. Based on the current literature, conservative treatment has success rates similar to those of surgical treatment but lower complication and mortality rates. In cases without an absolute indication for surgery, a conservative approach should be considered as the first-line treatment. A closer diagnostic and clinical follow-up should be recommended in patients with cervical tract or tubercular spondylodiscitis because of the higher risk of developing bone collapse and neurological deficits. Ó 2019 Elsevier Ltd. All rights reserved.

1. Introduction

2. Methods

The management of spontaneous spondylodiscitis is of clear interest, considering that the incidence is on the rise, mostly because of improving diagnostic techniques and the increasing number of older patients suffering from chronic diseases. Improvements in surgical and radiological procedures, together with updated antimicrobial therapy, have dramatically diminished the morbidity and mortality of this disease. However, due to the rarity of spondylodiscitis and the lack of many randomized or prospective studies, generally applicable guidelines are scarce or not supported by enough scientific evidence [1,2]. In this study, we retrospectively analyzed all the cases of spontaneous spondylodiscitis treated at our institution in the past six years, investigating predictors for surgical intervention and the development of neurologic deficits. We also reviewed the past 18 years of literature regarding spontaneous spondylodiscitis, analyzing outcomes and adverse event rates for both conservative and surgical approaches.

The study was approved by the Institutional Review Board of our institution (Treviso Regional Hospital, Italy), and only patients who gave signed consent for the utilization of their information for research purposes were included.

⇑ Corresponding author at: Treviso Regional Hospital, Department of Neurologic Surgery, Via Piazzale 1, Treviso, TV 31100, Italy. E-mail address: [email protected] (E. Giordan). https://doi.org/10.1016/j.jocn.2019.06.040 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.

2.1. Patient identification Data were collected and analyzed for consecutive patients with spontaneous spondylodiscitis who were evaluated and treated at our institution between January 2012 and January 2018. Treviso Regional Hospital is the regional referral center for spinal infections, and it covers an area of nearly 1.2 million inhabitants. Inclusion criteria were the following: 1) any pyogenic or granulomatous (tuberculous, brucellar or fungal) spontaneous spondylodiscitis, and any spontaneous epidural abscess with or without associated spondylodiscitis.

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The diagnosis was based on the identification of causative organisms, isolated from spinal or paraspinal tissues, and on compatible symptoms, signs, or radiologic evidence. Compatible symptoms or signs included were back pain, limited motion, and tenderness over the involved spine segment, fever, or neurologic manifestations. Tuberculous spondylodiscitis was diagnosed when Mycobacterium tuberculosis was isolated from spinal or paraspinal tissues, smears were positive for acid-fast bacilli, tissue examination revealed caseating granuloma formation or tissue samples were positive for M. tuberculosis by polymerase chain reaction (PCR), accompanied by compatible symptoms, signs, or radiologic evidence of spondylodiscitis. In cases in which tissue and blood samples were negative but the radiological and clinical signs were strongly suggestive of spondylodiscitis, the causative organism was labeled as ‘‘ndd” (not defined diagnosis) and included in the analysis;

Treatment failure was defined as a microbiologically confirmed persistent infection despite completion of a tailored antimicrobial therapy (both I.V. and orally administered) along with persistent pain, residual neurologic deficits, elevated markers of systemic inflammation, or radiographic findings of persistent disease. Persistent pain, residual neurologic deficits, elevated markers of systemic inflammation, or radiographic findings alone were not considered signs of treatment failure. In surgically treated patients, treatment failure was defined as the inability to revert or stabilize the patient’s neurological deficit, the failure to correct spinal instability or the occurrence of surgery-related adverse events that precipitated the patient’s clinical condition. Multiple specialists were involved in the management of a patient’s condition, including spinal surgeons, radiologists, infectious disease specialists, and therapy and rehabilitation specialists.

2) age >18; 3) no sex limitations; 4) 1 adequate radiological follow-up examinations, as defined as: - spine MR (or contrast-enhanced spine MR) scan after completion of antibiotic therapy, - spine CT scan (or contrast-enhanced spine CT scan) after completion of antibiotic therapy, after surgical treatment or in patients with documented bone deconstruction; 5) 2 clinical follow-up examinations, as defined as: - monitoring of patient’s symptoms and inflammatory markers during and after completion of antibiotic therapy.

Among included patients, data were collected on age, sex, location, causative organism, coexistence of a distal septic process, antibiotic therapy, epidural collection, location of the epidural collection (anterior, posterior, or circumferential to the spinal cord), neurological status, orthosis (yes, no, type), length of antibiotic therapy, treatment success, adverse events, coexistence of medically relevant comorbidities, back pain, and death. Neurological status was defined according to Frankel classification [4] (A to E), where grade A represents complete neurological injury and grade E represents a normal motor function. We coded both E and D grades as no or mild deficit, C grade as moderate deficit and B and A grades as a severe or complete deficit. Adverse events were considered as early (<30 days from surgery) and late complications (post-operative infections, recurrences, kyphosis or revision surgery). We considered medically relevant comorbidities: obesity, diabetes mellitus, blood hypertension, substance abuse, chronic infection, neoplasm, poor nutritional status, chronic obstructive pulmonary disease, and immunologic incompetence. Obesity was defined as a patient body mass index (BMI) of 30. Postsurgical neurological status was assessed at the latest clinical follow-up. Back pain was assessed by interviewing the patient at follow-up visits. Orthoses utilized were a rigid neck collar (or any collar with proper chin support) for disease localized from C0 to C7, a rigid lumbar brace for disease restricted to L2 to S1, and a 3-point rigid brace for disease localization between T11 and L2. A rigid thoracic brace was prescribed in case of T1 to T11 disease localization. The primary outcomes of interest were the need for surgical intervention and neurological deficit. We also evaluated predictors for surgical intervention, deficits or vertebral collapse using the above data.

Iatrogenic spondylodiscitis, defined as spinal infection consequent to a penetrating injury or surgical/radiological invasive procedures, was excluded from our study, along with all pediatric cases. Follow-up imaging was individualized to each patient and related to the patient age, severity of spondylodiscitis, treatment response, and degree of bone deconstruction. Criteria for vertebral instability were defined as: segmental kyphosis (>15°), body deconstruction >50%, and translation >5 mm [3]. In general, follow-up imaging (i.e., usually contrast-enhanced magnetic resonance [MR] or computed tomography [CT]) was performed after antibiotic treatment completion, and between 3 and 6 months after diagnosis. Since our study aimed to encompass ‘‘real life” experience, serial imaging variances that might be encountered in routine clinical practice were not excluded. These included, among others: patients with inconsistent imaging modalities, patients with imaging performed at different time points than originally planned, or patients with follow-up imaging performed at their local hospital rather than at our facility. These latter patients had their imaging transferred electronically into our system. Treatment response and recurrences were defined by inflammatory marker (c-reactive protein [CRP]) measurements and CT and/or MRI imaging, as defined above, at follow-up visits. Treatment success was defined as a microbiologically confirmed eradicated infection along with improved pain, normalization of inflammatory markers and any improvement in neurological status at the last clinical follow-up, without the occurrence of severe adverse events. In surgically treated patients, treatment success was defined as improved neurological deficit (1 point on the Frankel scale), and correction of spinal instability without the occurrence of any adverse event able to deteriorate the patient clinical condition. After the confirmation of a successful microbiological eradication of the infection, the antibiotic therapy was discontinued.

2.2. Data collection and outcomes

2.3. Meta-analysis study selection A comprehensive search of several databases from 2000 to September 2018 was designed and conducted by a medical reference librarian. Search terms were ‘‘spondylodiscitis,” ‘‘vertebral osteomyelitis”, ‘‘osteodiscitis”, ‘‘epidural abscess”, ‘‘discitis”, ‘‘treatment”, ‘‘therapy”, ‘‘antibiotics” and ‘‘surgery” used alone and in combination. Databases included were PubMed, Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Controlled vocabulary supplemented with the keywords was used to search for spondylodiscitis. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA, 2009) [5].

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Inclusion criteria were the following: 1) studies describing spine infections in both longitudinal and retrospective series; 2) series with a confirmed clinical and radiological diagnosis; 3) studies published in English; 4) consecutive series of adult patients with both surgical and conservatively managed spondylodiscitis; 5) studies with an objective outcome. Studies with <30 patients, published in a language other than English, or describing iatrogenic spine infections were excluded. Treatment success was defined as fair to excellent outcomes after treatment completion, either surgical or medical. The type of surgical treatment or antibiotic agent administered was not considered relevant in the analysis but only in the overall outcome. 2.4. Statistical analysis Descriptive statistics were reported as a median and range or mean and standard deviation for continuous variables and proportion and percentage for categorical variables. Fisher’s exact tests were used for comparing clinical parameters between two groups of variables. We then fit univariate logistic regression models specifying surgery and Frankel grade as the dependent variable and spondylodiscitis characteristics and patient demographics as independent variables. Subsequently, we fit multivariate logistic regression models to identify independent predictors of surgical intervention and Frankel score with the variables that were found to be significant from the univariate models. Studies included in our review were pooled in a random-effects model for meta-analysis as described by DerSimonian and Laird [6]. Anticipating heterogeneity between studies, we chose this model a priori because it incorporates within-study variance and between-study variance. 3. Results 3.1. Patient demographics One hundred eighty-one consecutive patients with spontaneous spondylodiscitis were examined at our institution between January 2012 and January 2018. One hundred sixty-two patients with adequate clinical and radiological follow-up were included. The median age at presentation was 67 (range: 16–89) years, with a significant proportion of patients older than 60 years (71% vs 29%, p = 0.001). Patients who underwent surgical treatment were significantly younger (mean age at presentation: 52.7 years, standard deviation (SD): 11.6 years) than patients who were medically treated (mean age at presentation: 64.8 years, SD: 13.5 years, p = 0.007). The male: female ratio was 2.06:1, and 32.7% of patients were female. Most spondylodiscitis arose from the lumbar tract (53.7%), followed by the thoracic (30.9%) and cervical (15.4%) columns, and were mostly consequent to gram-positive bacterial infection (64.2%). In 13% of patients, a causative pathogen was not identified, and almost 10% of patients had a drug-resistant bacterial infection. Regarding comorbidities, among conservatively treated patients, 35% had type II diabetes mellitus, 27% had hypertension or chronic obstructive pulmonary disease, 18.1% were obese, 3% were substance abusers, 5.2% were immunosuppressed, and 8.8% had no other medically relevant comorbidities. Approximately 46% of the patients presented with two or more comorbidities, but 8.1% had previously been diagnosed with neoplasia. Among surgically treated patients, 40% had a recent diagnosis of neoplasm, and another 40% of patients were obese with associated chronic liver or pulmonary diseases. Only two patients had a negative past medical history, and one patient was a drug abuser with an associated chronic HIV infection. Eighty percent of surgically treated patients had two or more comorbidities. Patients with a past

medical history positive for neoplasm were significantly more at risk of undergoing surgical treatment (p = 0.001), as were patients with the coexistence of two or more comorbidities (p = 0.051). In slightly more than half (52%) of patients, the spondylodiscitis was secondary to septic embolism from an infection process, localized for most in the lungs or urinary tract. In 20.5% of patients, spondylodiscitis was consequent to endocarditis. Blood cultures were positive in 78.3% of patients. Patients with a negative blood culture underwent spinal CT-guided biopsy, with a success rate of 53.0%. Antibiotic therapy was administered for a median time of 2.3 months (range: 0–5 months) and was composed of 3 weeks (median; range: 1 to 6 weeks) of intravenous therapy, and 2 months (median; range: 1 to 5 months) of orally administered antibiotic treatment. Bracing was, in almost all cases, recommended to be worn for 4 to 6 weeks. Most patients (85%) had 2 or more imaging and  three clinical follow-up visits. Full demographic data are summarized in Table 1. 3.2. Risk factors Cervical tract spondylodiscitis (Odds Ratio [OR]: 4.03, 95% CI: 1.20–13.55, p = 0.024), younger age at diagnosis (<65 years, [OR: 4.81, 95% CI: 1.27–18.20, p = 0.039]), tubercular infection (OR: 13.36, 95% CI: 1.71–104.17, p = 0.013), and vertebral collapse (OR: 10.75, 95% CI: 3.07–37.59, p < 0.001) were associated with a higher risk of undergoing surgical treatment in univariate models. Cervical tract location (OR: 4.16, 95% CI: 1.08–15.98, p = 0.038), vertebral collapse (OR: 7.13, 95% CI: 1.78–28.53, p = 0.008) and epidural collection (OR: 3.37, 95% CI: 1.45–7.8, p = 0.005) were Table 1 Spondylodiscitis baseline characteristics. Total number Age at diagnosis (mean ± SD/median, range [yr]) Female sex N (%) Location N (%) Cervical Thoracic Lumbar Multiple location Causative organsism Gram + Gram Ndd Granulomatous infection (Tunercular) Drug – resistant organism Source Septic embolism Blood culture (positive) CT-guided biopsy (positive/negative blood cultures) Surgery Brace Immobilization Antalgic purpose No Vertebral body collapse/Instability Epidural abscess Epidural absces location Anterior Posterior Circumferential Antibiotic therapy duration Neurological status (Frankel score) E D C B A

162 64.7 ± 13.4 (67, 16–89) 53 (32.7%) 25 (15.4%) 50 (30.9%) 87 (53.7%) 9 (5.6%) 104 (64.2%) 31 (19.1%) 21 (13.0%) 6 (3.7%) 14 (9.7%) 83 83 35 13

(51.6%) (78.3%) (53,03) (8%)

85 40 37 17 81

(52.5%) (24.7%) (22.8%) (10.5%) (50%)

47.5% 39.7% 12.8% 3.3 ± 1.5 (2.3, 0–5) 129 (79.6%) 15 (9.3%) 8 (4.9%) 7 (4.3%) 3 (1.9%)

Legend: Ndd: not defined diagnosis, SD: standard deviation, CT: computer tomography.

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found to be associated with a higher risk of developing severe neurological deficits, whereas tubercular infection (OR: 9.53, 95% CI: 1.25–72.65, p = 0.030) was found to be associated with a higher risk of vertebral body collapse. These associations remained significant in the multivariable analysis. Factors including sex, multifocality, drug resistance, the location of epidural abscess, administration of empiric antibiotic therapy, and length of antibiotic therapy were not associated with a higher risk of undergoing surgical intervention or developing deficits. Risk factors are summarized in Tables 2 and 3. 3.3. Outcomes Only 6.2% of patients were diagnosed with a severe/complete deficit, 4.9% with a moderate deficit, and the others (89.9%) with a mild or no deficit. Approximately 10% of patients experienced spine instability as a result of spondylodiscitis, while 35.2% developed moderate to severe neurological deficits because of spinal cord compression. Almost 50% of patients had an epidural collection, which was responsible for 72% of all moderate to severe deficits. An epidural collection was found effective in causing deficits compared to vertebral collapse (p = 0.004). Treatment success rate was 97.3% and 76.9% for conservatively and surgically treated patients, respectively. Among conservatively treated patients, only 4 (2.7%) required additional surgery to correct a developing kyphosis with consequent spinal instability. Two patients underwent posterior instrumented lumbar arthrodesis, one required dorsal cemented vertebroplasty, and one refused an L2-L3 posterior arthrodesis that was necessary for correcting spinal instability development. Spondylodiscitis recurred in 2 patients (1.3%) at 3 and 6 months, after completion of antibiotic therapy and confirmed microbiological eradication of infection. Among surgically treated patients, one patient required dorsal arthrodesis because of developing kyphosis with associated spinal instability 5 months after a D8-D9 laminectomy for spondylodiscitis with associated epidural abscess debridement, whereas another required an extension of dorsal instrumented arthrodesis after 16 months. One patient died of pulmonary embolisms at three months postsurgery, before the termination of antibiotic therapy. Regarding neurological deficit, all medically treated patients experienced amelioration (1 point on the Frankel scale) or stabilization of neurological symptoms, and 92% were pain free after treatment completion. The remaining patients needed antalgic Table 2 Predictors analysis: Fishers exact test. SURGERY

Total patients

p-value

SEX AGE AT DIAGNOSIS (>50 years) LOCATION MULTIFOCAL LOCATION CAUSATIVE ORGANISM DRUG-RESISTANT ORGANISM ABSCESS VERTEBRAL COLLAPSE EMPIRIC ANTIBIOTIC THERAPY

162 162 162 162 162 144 162 162 159

0.549 0.389 <0.001 1.000 0.087 0.329 0.079 <0.001 0.248

NEUROLOGIC STATUS

Total patients

p-value

SEX AGE AT DIAGNOSIS (>50 years) LOCATION MULTIFOCAL LOCATION CAUSATIVE ORGANISM DRUG-RESISTANT ORGANISM ABSCESS ABSCESS LOCATION VERTEBRAL COLLAPSE EMPIRIC ANTIBIOTIC THERAPY

162 162 162 162 162 144 162 78 162 159

0.549 0.271 0.020 0.228 0.792 0.301 0.045 0.863 0.012 0.509

Bold is used when a value is statistically significant.

therapy for pain control. In patients who underwent surgical treatment, six improved their neurological symptoms (1 point on the Frankel scale), whereas in two the symptoms stabilized. Two patients presented late, and surgery was not able to revert the already established neurological deficit. Among this group of patients, two experienced persistent back pain that required antalgic treatment. Most of the patients (77.2%) required immobilization with an orthosis. Among these patients, 32% required an orthosis just for antalgic purposes. No patients died in the conservatively treated group. Surgical patients were followed for a median follow-up time of 18 months (range: 12–56 months), 3 patients required late revision surgery and one patient died of a pulmonary embolism after posterior arthrodesis. 3.4. Literature search and study characteristics The initial literature search yielded 1670 articles. Upon review of abstracts and titles, 689 articles were excluded. On secondary review, an additional 48 articles were excluded because they did not match the eligibility criteria for this meta-analysis. In total, 32 studies including 3924 patients describing the occurrences of a spontaneous primary infection were included (Table 4). Fourteen of these studies described data about the surgical treatment of spondylodiscitis, 5 about conservative management, while in 13 it was not possible to differentiate between surgical and conservative management. 3.5. Meta-analysis outcomes Overall, improvement was observed in 80% (95% C.I. 74–95%) of patients and was not found to be significantly lower in conservatively managed patients compared to surgically managed ones (70% [95% C.I. 52–82%] vs 83% [95% C.I. 70–94%], respectively) (Fig. 1). A stratified analysis comparing surgically to medically treated patients highlights that patients who underwent surgery were more prone to failure because of treatment failure or complications [30% (95% C.I. 15–47%)] than patients who underwent medical treatment [10% (95% C.I. 10–47%)]. Recurrences were found in 5% (95% C.I. 2–7%) of patients overall, in 7% (95% C.I. 3–12) of conservatively treated patients, and in 3% (95% C.I. 0–10%) of surgically treated patients. Adverse events occurred overall in 19% (95% C.I. 11–28%) of patients, in 8% (95% C.I. 0–23%) of patients following conservative management, and twice as frequently in post-surgical patients (18% [95% C.I. 5–36%]). Mortality was estimated to be 4% (95% C.I. 3–6%) overall, 5% in the conservatively managed group, and slightly higher, 9% (95% C.I. 9–18%), after surgical treatment (Fig. 2).

4. Discussion The current management of spondylodiscitis aims to define the causative organism promptly and to avoid disease progression. It is estimated that every day of delay between the onset of symptoms and diagnosis leads to a significant increase in morbidity [7]. Spine immobilization (either surgical or with orthosis), tailored antibiotic therapy [8,9], debridement, and decompression of the spinal canal [10–12] are basic requirements for therapeutic success [13–15]. In conservatively managed patients, bracing is necessary for comfort and to prevent spinal deformity. In contrast, for patients not amenable to conservative treatment, a large variety of surgical techniques can be successfully utilized to immobilize

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E. Giordan et al. / Journal of Clinical Neuroscience 68 (2019) 179–187 Table 3 Univariate and Multivariable analysis. SURGERY

SEX AGE AT DIAGNOSIS (>65 years) CERVICAL LOCATION THORACIC LOCATION LUMBAR LOCATION MULTIFOCALITY CAUSATIVE ORGASNISM DRUG-RESISTANT ORGANISM EPIDURAL ABSCESS VERTEBRAL COLLAPSE/INSTABILITY NEUROLOGICAL DEFICIT SEVERE MODERATE MILD/NONE NEUROLOGICAL STATUS

SEX AGE AT DIAGNOSIS(>65 years) CERVICAL LOCATION THORACIC LOCATION LUMBAR LOCATION MULTIFOCALITY CAUSATIVE ORGASNISM DRUG-RESISTANT PATHOGEN EPIDURAL ABSCESS (moderate to severe deficit) EPIDURAL ABSCESS LOCATION VERTEBRAL COLLAPSE/ INSTABILITY VERTEBRAL COLLAPSE

SEX AGE AT DIAGNOSIS (> 65 years) CERVICAL LOCATION THORACIC LOCATION LUMBAR LOCATION MULTIFOCAL LOCATION CAUSATIVE ORGASNISM DRUG-RESISTANT PATHOGEN EPIDURAL ABSCESS EPIDURAL ABSCESS LOCATION

UNIVARIATE ANALYSIS

MULTIVARIATE ANALYSIS

N total

OR

(95% CI)

p-value

162 162 162 162 162 153 162 144 162 162

1.68 0.21 4.03 2.88 0.06 1 1.83 2 3.66 10.75

0.446.39 0.050.79 1.2013.55 0.919.05 0.010.48

0.444 0.021 0.024 0.071 0.008

1.013.3 0.3910.2 0.9713.84 3.0737.59

0.046 0.405 0.056 <0.001

162 162 162

333 1.11 0.03

36.643296 0.235.36 0.010.16

<0.001 0.898 <0.001

p-value 0.039 0.026

Sex, Location Age, Sex

0.020

Sex, Age, Location, Neurological status

<0.001

Sex, Age, Location

<0.001

Sex, Age, Location

UNIVARIATE ANALYSIS

MULTIVARIATE ANALYSIS

N total

OR

(95% CI)

p-value

p-value

1 162 162 162 162 153 162 144 162

0.50 4.16 3.68 1 1 0.93 1.17 3.37

0.141.84 1.0815.98 0.9913.68

0.295 0.038 0.052

0.039

Sex, Age

0.402.20 0.1410.13 1.457.81

0.875 0.885 0.005

0.015

Sex, Age, Location

78 162

0.67 7.13

0.321.39 1.7828.53

0.281 0.008

0.012

Sex, Age, Location

UNIVARIATE ANALYSIS

MULTIVARIATE ANALYSIS

N total

OR

(95% CI)

p-value

162 162 162 162 162 153 162 144 162 78

1.19 0.51 1.82 1.25 0.57 1 1.76 1.80 2.64 0.84

0.403.56 0.181.41 0.546.10 0.443.60 0.211.58

0.759 0.194 0.334 0.676 0.278

1.023.06 0.369.11 0.897.89 0.34 2.08

0.041 0.476 0.081 0.703

p-value

0.059

Sex, Age, Location, Neurological status

Legend: OR: odds ratio, CI: confidence interval. Bold is used when a value is statistically significant.

or decompress the spine, with the less elaborate and less invasive approaches having the better outcomes [16]. Surgical intervention is recommended in patients with progressive neurologic deficits and severe spinal instability. Surgical debridement, with or without stabilization, is also advised in patients with persistent or recurrent bloodstream infection (without an alternative source), for source of infection control, or in those patients with worsening back pain despite appropriate medical therapy [2]. Spontaneous spondylodiscitis is a rare disease, accounting for 0.15 to 7% of all spine infections. Age at diagnosis commonly ranges from 40 to 90 years [17,18], with a higher prevalence of cases diagnosed in older adults (>65 years), and a clear male predominance [19]. Tenderness and back pain are the most commonly experienced symptoms (87–98% of patients) [20], but in 15 to 30% of cases, patients are asymptomatic at presentation. Spondylodiscitis is often secondary to septic embolism (ranging from 12 to 30.8%), commonly arising from genitourinary tract infections, soft tissue abscesses, upper respiratory tract infections, septic arthritis/osteomyelitis, or endocarditis. The rate of endocarditis complication in spondylodiscitis ranges from 2.8 to 30.8% in the literature

[21]. The most commonly isolated causative organism is S. aureus, which alone is responsible for approximately 30–80% of pyogenic spondylodiscitis [22,23]. In up to 40% of cases, a causative organism is not identified [24]. Polymicrobial infections are rare and occur in <10% of cases, while multifocal infections occur in <5%. Approximately one-third of cases show mild to moderate neurological deficits, often related to myeloradicular compression by an epidural abscess, or consequent to vertebral destruction and collapse [25]. The occurrence of an epidural abscess was not found to be correlated with vertebral collapse, while it was speculated that a paraspinal abscess could induce bone loss [24,25]. The proportion of patients with vertebral body collapse is significantly higher in the tuberculous spondylodiscitis patients than in the pyogenic ones [28]. One hundred sixty-two patients were treated for spontaneous spondylodiscitis at our institution over the last 6 years. We found that conservative treatment was successful in >90% of patients, with only a tiny percentage of patients requiring additional surgical treatment because of treatment failure. Patients who underwent primary surgical treatment were <10%, and all had suffered either a severe neurological deficit (77%), or vertebral collapse

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Table 4 Summary of study characteristics. AUTHOR

PUBLICATION YEAR

RANGE

N PATIENTS

TREATMENT

STUDY DESIGN

Tschugg et al. [26] Dubost et al. [18] Dragsted et al. [31] Pola et al. [32] Ponciano et al. [17] Ascione et al. [41] Lee et al. [28] Menon et al. [19] Bernard et al. [8] Yoon et al. [31] Kehrer et al. [47] Rangaraj et al. [34] Roßbach et al. [42] Gupta et al. [45] Kim et al. [14] Park et al. [9] Valancius et al. [22] Yoshimoto et al. [13] Yee et al. [23] Hutchinson et al. [20] Karadimas et al. [24] Livorsi et al. [38] Turunc et al. [29] Ozturk et al. [10] Woertgen et al. [36] Pigrau et al. [21] Siddiq et al. [39] Lee et al. [11] Curry et al. [15] Nolla et al. [25] Hadjipavlou et al. [27] Schuster et al. [12]

2018 2017 2017 2017 2017 2017 2017 2016 2015 2015 2015 2014 2014 2014 2014 2013 2013 2011 2010 2008 2008 2008 2007 2007 2006 2005 2004 2004 2004 2002 2000 2000

2010–2016 2000–2015 2005–2010 2008–2015 2012–2017 2007–2013 2010–2016 2011–2015 2006–2011 2011–2013 1994–2009 2005–2010 1988–2007 1994–2002 1993–2011 2005–2011 2000–2010 1988–2005 2000–2004 2000–2005 1992–2002 2000–2006 2000–2005 2002–2013 2000–2004 1986–2002 1988–2002 2000–2004 1995–2001 1980–1999 1986–1996 1995–1998

104 151 65 250 135 30 69 62 351 177 298 61 135 260 355 139 196 103 91 30 163 85 75 56 62 91 57 30 48 64 101 30

Cons/Surgic Conservative Surgical Conservative Surgical Conservative Conservative Cons/Surgic Conservative Cons/Surgic Cons/Surgic Cons/Surgic Cons/Surgic Cons/Surgic Conservative Surgical Cons/Surgic Surgical Cons/Surgic Cons/Surgic Cons/Surgic Surgical Surgical Cons/Surgic Cons/Surgic Cons/Surgic Surgical Surgical Surgical Cons/Surgic Cons/Surgic Surgical

Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective

Legend: Cons: conservative treatment, Surgic: surgical treatment.

Fig. 1. Forest plot for the overall improved outcome for spondylodiscitis patients.

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Fig. 2. Forest plot for overall mortality rates.

and spine instability (23%). None of our patients required surgical treatment for source control in the setting of uncontrolled sepsis. The univariate and multivariable analyses showed that a younger age at diagnosis (<65 years), the coexistence of multiple comorbidities (two or more, especially in the case of a medical history positive for neoplasm), tubercular infection, vertebral collapse, and cervical spine location were associated with an increased risk of undergoing surgical intervention because of more severe disease, especially if the patient had severe neurological deficits at diagnosis. In contrast, in the case of moderate neurological deficits, patients did not have a significant benefit from surgical intervention, compared to conservatively treated ones (p = 0.898). Cervical spine spondylodiscitis was found to confer a higher risk of developing neurological deficits, while tubercular infections were associated with an increased risk of vertebral collapse and, thus, of undergoing surgical intervention [28,29]. Indeed, it is well documented that spondylodiscitis affecting more cephalad regions of the spine carries a significantly increased risk of secondary epidural abscess and is more prone to the development of serious neurological deficit [30]. We additionally performed the first meta-analysis of treatment outcomes and adverse events of spontaneous spondylodiscitis. We estimated that approximately 80% of patients underwent successful recovery. A stratified analysis documented that conservative treatment had a non-significant difference in overall success rates compared to surgical treatment. Nonetheless, surgical treatment compared to medical treatment was found to have higher failure (30% vs 10%, respectively), adverse event (18% vs 8%, respectively), and death (9% vs 5%, respectively) rates. The results of our metaanalysis are in line with the most recent series published in the literature [31–36]. So far, no additional long-term beneficial effect of surgical treatment was found in studies comparing surgical versus conservative treatment [16]. Antibiotic therapy alone was found to be

effective in up to 90% of patients, without significant differences in terms of overall outcomes compared to primary surgical treatment [37–39]. Conservative treatment was found to lead to good results in terms of quality of life parameters, whereas surgery often failed to improve a patient’s condition within the first 6 months after treatment, with 2-year failure rates similarly high to those at 5 and 10-years. In approximately 75% of patients, the ability to walk is restored along with the improvement of neurological status, while sensory disturbances tend to persist in up to 90% of cases after treatment completion [3,40,41]. In patients undergoing surgical intervention, the prognosis of neurological deficits was found to improve by 1 or 2 Frankel grades if a satisfactory decompression of the epidural abscess was achieved [42]. However, back pain often persists irrespective of the selected treatment approach [3]. Eventually, despite best efforts, recurrences have been reported in 0 16% of patients, usually within 6 months after resolution of the primary disease [16,38,40,43– 45]. Spontaneous spondylodiscitis seems to have a more severe course and a significantly higher mortality rate (12.5 vs. 1.8%) than iatrogenic spondylodiscitis [1], with estimated mortality ranging from 2 to 20% [30,44,46,47]. Despite the cornerstones of spondylodiscitis treatment being well defined, a widely accepted treatment algorithm is not yet available [1]. Currently, there are insufficient high-quality data available to create a complete, evidence-based guideline. Moreover, from a therapeutic point of view, the most relevant problem is not the treatment choice but the diagnosis and adequate followup. A prompt physical, laboratory and imaging examination is fundamental, along with accurate isolation and identification of the causative pathogen. However, because of the often insidious symptom presentation and rarity of the disease, a diagnostic delay or misdiagnosis is not uncommon and, for a certain part, unavoidable. Thus, management of spondylodiscitis should be more focused on adequate and close clinical and radiological follow-up, and should be, if possible, left to referral centers.

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4.1. Limitations A retrospective report of this nature has inherent limitations. Patients were identified with computer records, discharge letters, follow-up consultations and clinical-radiological records and, although data were checked several times, omissions may have occurred. In addition, follow-up for some patients may not have been completed since some patients were relocated to other hospitals after discharge. However, our institution is provided with a telemedicine system, and the patient clinical condition and imaging were monitored in a real-life fashion. The main limitation of our meta-analysis is the lack of individual patient data, which makes prognostic analysis subject to confounding bias. There was also the chance of inter- and intra-observer variability in assessing the percentage of improvement, particularly for surgical treatment. Because different treatment strategies are advocated for surgical management of spondylodiscitis, it is possible that outcomes and adverse event rates may be different for each different surgical approach, and between surgical series. 5. Conclusions Based on our findings and on the meta-analysis of the literature, we suggest that surgical treatment, if medically feasible, should be recommended in cases of severe spine instability and severe neurological deficits secondary to spinal cord compression. We did not find a difference in term of outcomes between surgical and conservative management; therefore, we suggest that in cases without an absolute indication for surgery, when neurological deficits are mild to moderate or bony destruction is minimal (or the risks of surgical intervention seem too high), a conservative approach should always be considered as the first-line treatment. We also suggest a close imaging follow-up protocol for any newly diagnosed patient at 3 and 6 months after treatment initiation and a monthly clinical follow-up until the completion of the treatment. Additionally, a closer follow-up or intervention should be recommended in patients with a cervical tract or tubercular spondylodiscitis because of the higher risk of developing bone collapse and neurological deficits. Acknowledgments None. Sources of funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosures/conflict of interest Dr. Giordan, Dr. Marton, Dr. Scotton, and Dr. Canova report no disclosures. References [1] Lener S, Hartmann S, Barbagallo GMV, Certo F, Thomé C. Management of spinal infection: a review of the literature. Am Soc Anaesthesiologists 2018:487–96. [2] Berbari EF, Kanj SS, Kowalski TJ, Darouiche RO, Widmer AF, Schmitt SK, et al. 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clinical Infectious Diseases 2015;61:26–46. https://doi.org/ 10.1093/cid/civ482. [3] Herren C, Jung N, Pishnamaz M, Breuninger M, Siewe J, Sobottke R. Spondylodiscitis: DIAGNOSIS AND TREATMENT OPTIONS: A SYSTEMATIC REVIEW. Dtsch Arztebl Int 2017;114:875–82. https://doi.org/10.3238/ arztebl.2017.0875.

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