Conservative versus early surgical treatment in the management of pyogenic spondylodiscitis: a systematic review and meta-analysis

Spondylodiscitis is the commonest spine infection, and pyogenic spondylodiscitis is the most common subtype. Whilst antibiotic therapy is the mainstay of treatment, some advocate that early surgery can improve mortality, relapse rates, and length of stay. Given that the condition carries a high mortality rate of up to 20%, the most effective treatment must be identified. We aimed to compare the mortality, relapse rate, and length of hospital stay of conservative versus early surgical treatment of pyogenic spondylodiscitis. All major databases were searched for original studies, which were evaluated using a qualitative synthesis, meta-analyses, influence, and regression analyses. The meta-analysis, with an overall pooled sample size of 10,954 patients from 21 studies, found that the pooled mortality among the early surgery patient subgroup was 8% versus 13% for patients treated conservatively. The mean proportion of relapse/failure among the early surgery subgroup was 15% versus 21% for the conservative treatment subgroup. Further, it concluded that early surgical treatment, when compared to conservative management, is associated with a 40% and 39% risk reduction in relapse/failure rate and mortality rate, respectively, and a 7.75 days per patient reduction in length of hospital stay (p < 0.01). The meta-analysis demonstrated that early surgical intervention consistently significantly outperforms conservative management in relapse/failure and mortality rates, and length of stay, in patients with pyogenic spondylodiscitis.

Data analysis.All relevant data were extracted manually using the Covidence data collection tool 16 .A list of extracted variables can be found in Supplemental Digital Content 1: Supplementary Table S3.In case of missing data, the respective studies' corresponding author was contacted.All articles were critically appraised, and the risk of bias was determined against all the domains of the ROBINS-I tool by two independent reviewers (SGT & ASMV), and a consensus was reached by discussion with a third reviewer (KV) 17 .Results of the ROBINS-I analysis can be found in Supplemental Digital Content 1: Supplementary Table S4.Furthermore, the level of evidence for each included article was scored using the Oxford Centre of Evidence-Based Medicine (OCEBM) Levels of Evidence Table (Supplemental Digital Content 1: Supplementary Table S5), as well as GRADE scoring (Supplemental Digital Content: Supplementary Table S6).Definitions of early and delayed surgery used by each study are shown in Supplemental Digital Content 1: Supplementary Table S7.An Egger's regression and asymmetry test were used to assess publication bias (p < 0.05% = significant) 18 .Data preparation, statistical analysis, and forest plot synthesis were carried out by utilizing meta package with the R software (version 4.0.4) 19,20.Firstly, a proportional meta-analysis was performed for mean proportions of mortality and relapse/failure among patients treated with early surgery and conservative treatment.The mortality and relapse data included both in-hospital and follow-up mortality.The most acute short-term postoperative outcome data (30 days, or 90 days) were used if longer or multiple follow-up periods were provided.All definitions of mortality and relapse/failure can be found in Table 1.Secondly, relative risk meta-analyses were

Results
A total of 13,209 studies were screened.From these, 75 full texts were assessed using our inclusion criteria.A total of 31 studies were included in this systematic review.From these, 21 studies were also included in the meta-analysis (Fig. 1A).The total pooled sample size of the systematic review was 48,504 and the overall pooled sample size of the meta-analysis was 10,954 patients.A world map of publication origins is shown in Fig. 1B.
Out of the 31 included studies, 14 were deemed to have a 'low' risk of bias [23][24][25][26][27][28][29][30][31][32][33][34][35][36] ; 11 a 'moderate' risk of bias 13,14,[37][38][39][40][41][42][43][44][45] ; 6 a 'serious' risk of bias [46][47][48][49][50][51] , and 1 study had a 'critical' risk of bias 52 using the ROBINS-I tool 17 .A scoring explanation is available in Supplemental Digital Content 1: Supplementary Table S4, a graphical summary in Fig. 1C.The OCEBM guidance was used to determine the level of evidence of each study.21 studies were classified as 2b, three studies as level 3b, and seven studies as level 4 (Supplemental Digital Content 1: Supplementary Table S5).The GRADE scoring is shown in Supplemental Digital Content 1: Supplementary Table S6 and showed that, in terms of the study findings' probability of being close to the estimated effect, 17 studies scored as moderate, 6 studies as high, 7 studies as low, 1 study as very low.The study characteristics are detailed in Table 1, and the main findings from each study are demonstrated in Table 2 (excluding studies that focused on purely spinal epidural abscesses) and Table 3 (including only studies that focused on purely spinal epidural abscesses).Study characteristics are additionally graphically presented in Fig. 2A-D.Egger's asymmetry plot (Fig. 3A) yielded that  13,14, . The cuntries are coloured according to whether n = 1, 2, 5 or 13 studies from these countries have been included in this systematic review.The legend at the bottom indicates the colour coding.Following countries are coloured: United States of America (n = 13), United Kingdom (n = 1), France (n = 1), Italy (n = 1), Germany (n = 5), Austria (n = 1), Denmark (n = 2), Iraq (n = 1), India (n = 1), Taiwan (n = 1), Japan (2), South Korea (2).(C) A risk of bias summary plot for non-randomized studies with bar chart of the distribution of risk-of-bias judgments for all included studies (n = 31) across the domains of the ROBINS-I tool, shown in percentages (%) is shown.In the bottom, an overall risk of bias, which represents the collated risk-ofbias judgements for all domains, is depicted.www.nature.com/scientificreports/there was a significant publication bias (p = 0.0082), however, a funnel plot (Fig. 3B) showed that there were no individual studies that skewed the publication bias regression analysis.
Relapse/Failure.For relapse/failure, defined as the need for repeat surgery or admission after initial treatment, eleven studies 13,[23][24][25][33][34][35]41,42,47,48 (two scoring serious risk of bias 47,48 and three scoring moderate risk 13,41,42  Table 3. Detailed summary of the results from each of the included studies in this systematic review that only focussed on spinal epidural abscesses. In this table, a etailed summary of the results from each of the included studies in this systematic review (including studies that focused only on spinal epidural abscesses) is presented.Following variables were extracted: study (author and date of publication), treatment, positive cultures (%), epidural abscess (%), duration of antibiotic treatment, additional surgical treatment required, length of hospital stay (days), relapse/failure, mortality, main conclusion of the article, and risk of bias scoring.PPS percutaneous pedicle screw, MIS-LLIF minimally invasive spine surgery-lateral lumbar interbody fusion, TL thoracolumbar; the number of patients who required additional surgery after having had an initial treatment regimen or procedure is shown in the ' Additional Surgical treatment required' column.The number of patients who had a relapse or representation of their condition or failed their initial treatment regimen or procedure is shown in the 'Relapse/failure' column. The bias of eah study is calculated by the ROBINS-I tool is shown in the 'Bias' column.NR data not reported, LTFU lost to follow up, SEA spontaneous epidural abscess, MRSA methicillin resistant Staphylococcus aureus, IV intravenous, MRI magnetic resonance imaging scan, D1 bias due to confounding, D2 bias due to selection of participants, D3 bias in classification of interventions, D4 bias due to deviations from intended interventions, D5 bias due to missing data, D6 bias in measurement of outcomes, D7 bias in selection of the reported result, D8 overall bias, ESR erythrocyte sedimentation rate.
Relative risk reduction.The mortality risk reduction comparing early surgery to conservative treatment was 0.61 RR (CI 95% 0.40-0.82)(p < 0.01) (Fig. 5A), indicating a 39% risk reduction when using early surgery.The pooled relative risk reduction in relapse/failure rates when comparing early surgery to conservative treatment was 0.60 RR (CI 95% 0.39-0.82)(p < 0.01) (Fig. 5B), indicating a 40% risk reduction when using early surgery over conservative treatment.
Length of stay.For length of stay, eight studies were included with a pooled overall sample size of n = 8,481 13,24,32- 34,38,50,52 , four scoring a low risk of bias 24,[32][33][34] , two scoring a moderate risk 13,38 , one scoring a serious risk 50 , and one study scoring a critical risk of bias 52 .The overall mean difference between early surgical management and conservative management was − 7.75 (CI 95% − 11.98 to − 3.51) (p < 0.01) (Fig. 5C), indicating that early surgical management of spondylodiscitis achieves a length of stay reduction of − 7.75 days per patient when compared to conservative treatment.
SEA-only and SEA-excluded analyses.Six additional subgroup meta-analyses were run, two on mortality, two on relapse/failure, and two on length of stay: for each outcome variable, a meta-analysis was computed including only studies that focus solely on patients with spinal epidural abscesses (SEA); and then a meta-analysis was computed excluding the studies that focus solely on patients with SEA (Supplemental Digital Content 1: Supplementary Fig. S1A-F).The meta-analysis on relapse/failure including studies that only focussed on patients with SEA yielded 0.74 RR (CI 95% 0.68-0.80)(p < 0.01), for mortality 0.56 RR (CI 95% 0.22-0.89)(p < 0.01), for length of stay a mean difference of − 6.53 (CI 95% − 13.13 to 0.08) (p = 0.05).The meta-analysis on relapse/ failure excluding studies that only focus on patients with SEA yielded 0.46 RR (CI 95% 0.12-0.80)(p = 0.02), for   13,[23][24][25][26]29,[32][33][34][35]37,38,[41][42][43]47,48,50,52 ; the x-axis represents the inverse of standard error, and the y-axis the standardized treatment effect (as z-score). Furthermore, at the top of the gaph different parameters of heterogeneity, including I 2 , are shown.P-value < 0.05 is deemed to be significant and implicates publication bias.Egger's asymmetry test yielded p = 0.0082, calculated running an Egger's regression (see Egger's regression line) on the collated DOR and standard errors of all data used in the meta-analysis (n = 21), indicating significant publication bias.(B) A funnel plot is shown, which plots every study included in the meta-analysis (n = 21).The observed effect sizes (diagnostic odds ratio) are on the x-axis against a measure of their standard error on the y-axis.All studies fall roughly within the parameters of the funnel plot, there are no gross outliers, indicating that there is no individual studies skewing the publication bias regression analysis.(C) The effects of early surgery versus conservative treatment for spondylodiscitis in terms of: (a) clinical [non-neurological] outcomes, (b) neurological outcomes, (c) overall outcomes, are visualized as harvest plot.The effects are stratified intro three columns: early surgery has better outcomes than conservative treatment ("Early surgery +), there is no difference between the two treatment modalities ("No difference") and conservative treatment has better outcomes than early surgery ("Conservative +).A rectangle represents a single study, unless at bottom of the rectangle a number is specified as i.e. × 2 (= two studies).The colours of the rectangles correspond to the study design: black (retrospective), grey (ambispective), white (prospective).The number on top of the rectangle specifies the risk of bias in overall risk of bias (in line with risk of bias analysis, with 4 implying low risk of bias, 3 implying moderate risk, 2 serious risk and 1 critical risk).The height of the rectangle directly correlates to the risk of bias in outcome measurement, and the aforementioned number on top of the rectangle. Dfinitions for clinical and neurological outcomes are as follows: Clinical outcomes pools different definitions used by different studies including prognosis, recurrence, hospital stay, mortality rates, and lab parameters.Further in-depth investigation of these can be seen in the meta-analysis.On the other hand, the definition of neurological outcomes was split in two categories-the first being the presence or absence of neurological deficits, and the second being a graded scale of neurological deficits based on the American Spinal Injury Association Scale (ASIA scale).mortality 0.67 RR (CI 95% 0.24-1.10),with t = 6.70 (p = 0.02), for length of stay a mean difference of − 6.53 (CI 95% − 13.13 to 0.08) (p = 0.05).
Influence analysis and linear regression.The exclusion of outlier studies based on a set of three influence analyses (Supplemental Digital Content 1: Supplementary Figs.S2, S3, S4), did not yield a significant change in effect size (Supplemental Digital Content 1: Supplementary Figs.S5, S6, S7).The exclusion of outlier studies based on high levels of risk of bias scoring did not yield any significant changes to effect size of any of the outcome variables (Supplemental Digital Content 1: Supplementary Figs.S8, S9).The meta-regressions scored the influence of all co-variates on the overall effect size of the relapse/failure meta-analysis, mortality meta-analysis, and length of stay meta-analysis (Table 4).Only for the relapse/failure meta-analysis there were significant (p < 0.05) co-variates that were found: "IVDU" and "diabetes".None of the exclusion subgroup meta-analyses (excluding studies with high proportions of diabetics, and the studies with high proportions of intravenous drug users) yielded strong differences in the meta-analysis effect size (Supplemental Digital Content 1: Supplementary Figs.S10, S11).
Multivariate correlation analysis.In Fig. 5D, a multivariate correlation matrix visualises and compares the occurrence of all numerical study characteristics and patient characteristics, extracted from all studies included in the systematic review (n = 31).It confirmed the influence of IVDU (positive prognostic factor in surgically managed patients), and diabetes (negative prognostic factor).An important positive prognostic factor was found to be a cervical localisation of infection (p < 0.01).Important negative prognostic factors were found to be: thoracic and/or lumbar location of infection (p < 0.001), positive cultures (tissues and blood) (p < 0.01), presence of epidural abscesses (p < 0.05), and advanced age (p < 0.05).A list of all correlations can be found in Supplemental Digital Content 1: Supplementary File S2. .P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study for the respective treatment arm ("Total"), number of deaths/relapses ("Events") per respective treatment arm, and proportion of deaths/relapses ("Proportion"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%). .P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).The weighting of each study represented in the percentage (%) is derived from the inverse of the variance of each study's effect estimate.This means that more weight is given to the studies that provide more detailed information or have less variability in their outcomes, giving a balanced representation of the available data in the pooled analysis.A significant pooled relative risk was yielded overall (p < 0.01), indicating that early surgical management vs conservative has a relative risk of 0.61 in the context of overall mortality.Effectively this means that early surgical management of spondylodiscitis achieves a 39% risk reduction (overall mortality) when compared to conservative management.(B) A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the relapse/failure/recurrence rate of spondylodiscitis following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the 17 studies included in the meta-analysis.The size of the grey square of the "Relative Risk" visual correlates to study sample size and the straight line indicates the confidence interval.The diamond at the bottom indicates the overall pooled relative risk ratio.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).A significant pooled relative risk was yielded overall (p < 0.01), indicating that early surgical management vs conservative has a relative risk of 0.6 in the context of leading to relapse/failure/recurrence.Effectively this means that early surgical management of spondylodiscitis achieves a 40% risk reduction (relapse/failure/recurrence) when compared to conservative management.(C) A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the mean length of hospital stay (in daysI of spondylodiscitis patients following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the studies included in the meta-analysis.The size of the grey square of the "Mean Difference" visual correlates to study sample size and the straight line indicated the confidence interval.The diamond at the bottom indicates the overall pooled mean difference.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).A significant pooled mean difference was yielded overall (p < 0.01), indicating that early surgical management vs conservative has -7.75 day mean difference in the context of overall length of stay, effectively meaning that surgery is associated with a mean

Discussion
This is the first meta-analysis, to compare early surgical versus conservative management for spondylodiscitis.The meta-analysis included 21 studies, comprising data from 10,954 patients.The findings showed that early surgery had lower mortality rates (8% vs. 13% for conservative treatment) and lower relapse/failure rates (15% vs. 21%).Early surgery also led to a shorter hospital stay of 7.75 days per patient.These results consistently favoured early surgical management for pyogenic spondylodiscitis.
Surgical debridement is a widely accepted therapy for the treatment of infectious diseases, to reduce the infection load and facilitate faster infection control, while also providing tissue samples that may help to optimise adjunct antibiotic therapy [53][54][55] .Generally, surgery is most effective for infection poorly penetrated by antibiotics, as well as locally contained infections such as abscesses [56][57][58] .However, interestingly, our meta-analysis found that while early surgery was more effective than conservative therapy for patients with purely SEA, early surgery was even more effective in spondylodiscitis (without SEA) (10.06 day versus 6.5 length of stay reduction, 44% reduction in mortality versus 33%; 54% reduction in relapse rate compared to 26%).
This finding instigates a question: Could the mechanism by which surgery achieves better outcomes for spondylodiscitis patients involve more than just debridement?One hypothesis suggests spinal stabilization achieved by surgical intervention may more substantial contributing factor [59][60][61][62] .Even though antibiotics are essential in treating the infection, they are unable to provide spinal stability [59][60][61][62][63][64][65] .Infection may lead to spinal macro-instability, predisposing patients to experience more pain, decreased postural control, and a decreased arc of movement.However, we recognize the existing evidence base may not be robust enough to draw definitive conclusions about the mechanism and invite further studies to explore this hypothesis.
So how should this study inform clinical practice?Whilst we undertook an exhaustive search, enabling the largest pooled analysis of its kind, alongside multiple robust approaches to managing data heterogeneity, ultimately the source evidence was largely retrospective and/or cohort by design, suffered heterogeneity with outcome reporting and definition, and held moderate risk of bias.Furthermore, the included studies largely did not report on the use of intra-operative, localised antibiotics, which have shown promising results in recent studies, hence it was not possible to perform a sensitivity analysis on this parameter 66 .Despite the seemingly promising outcomes associated with early surgery, we recognize and emphasize the limitations inherent in our study.The primary studies included in our meta-analysis were largely retrospective and cohort by design, harbouring a Table 4. Mixed-effects single-variate meta-regression.The results of the meta-regression of the meta-analyses for relapse/failure and mortality in spondylodiscitis management (surgical versus conservative) are presented in this table.A meta-regression analysis was run for each of the covariates (Sample size, study type, study design, age of surgically treated patients, age of conservatively treated patients, proportion of females of surgically treated patients, proportion of females of conservatively treated patients, proportion of intravenous drugs users ("IVDU"), proportion of patients with nephropathy, with epidural abscess, date of publication, infection localised in cervical, thoracic or lumbar spine) as independent variable to the dependent variable relative risk.In round brackets is the standard error.If significance is yielded (denoted with * and bold regression coefficient), the p-value of the regression coefficient is shown in squared bracket only if significant, otherwise assume non-significance.Significance is assumed for p < 0.05.If a covariate was covered by < 4 studies for a respective relapse or mortality, then a regression analysis was omitted ("-") for this respective relationship due to insufficient data for strong regression analysis, the respective cells are marked as NA ("not applicable).The different explanatory variables were calculated singularly as sole covariates in separate metaregression.www.nature.com/scientificreports/moderate risk of bias and outcome reporting heterogeneity.Also, it is crucial to account for the probable selection bias in these studies, where the healthiest patients were more likely to be selected for early surgery.This selection bias may partially explain the observed lower mortality and relapse rates in the early surgery group.Moreover, apart from differences in patient health, disease severity may also influence the choice and timing of treatment, as well as outcomes.However, most studies did not provide data on disease severity.Potentially, the surgical approach may act as a proxy marker of disease severity, however, the data on surgical approaches were too heterogeneous to be compared.Future studies reporting on disease severity, as well as using consensus-based and comparable operative protocols, will be required to allow for robust sensitivity analyses.Furthermore, there was a statistical suggestion of publication bias, albeit extensive subgroup analysis did not identify specific outlying studies or factors.Considering these limitations, the absolute changes in outcome thresholds in a population with probable selection bias, where relapse/failure of early surgery is still high (15% versus 21%), remain difficult to interpret.No study considered the health economics of early surgery, and superficially saving eight hospital bed days may not be a sufficient trade-off for the costs and risks of routine surgery.When considering the reconfiguration of services to enable early surgery would be substantial (as spinal surgery is a tertiary specialty), it is clear that there remain significant knowledge translation gaps.The most striking finding may be the lack of any randomised comparison.This is for three reasons: firstly, the strong rationale and current evidence, secondly, the significant and increasing burden of spondylodiscitis disease, and finally, the evidence of field-wide equipoise, a premise for any randomised comparison.However, it is important to acknowledge the obstacles to enabling a randomised control trial on spondylodiscitis management.Firstly, there is no clear consensus on what constitutes early surgery or conservative therapy, and perhaps most importantly what constitutes spondylodiscitis (particularly in the context of SEAs).The principal outcome measures or success criteria also remain undefined.Secondly, whilst there may be clinical equipoise at a field-wide level, this does not necessarily translate into institutional or physician-level equipoise-future efforts must be made to reduce local deviations from field-level recommendations of practice, including increased communications of the latest findings to raise awareness.Finally, the relative infrequency of spondylodiscitis, the population, and treatment heterogeneity, coupled with the discrimination of outcome measures for pain or neurological function, suggest any trial would require a large, probably multi-national collaboration.This will be an immense logistical challenge and will require a sufficient clinical buy-in and research funding.Despite these challenges, given the uncertainty of the clinical approach for spondylodiscitis, combined with variations in definitions and a lack of a uniformed ICD-10 for spondylodiscitis, the authors believe that these deficiencies demand for clinical equipoise to enable randomised comparison, as well as the need for expert consensus on treatment and pathology definitions in order to provide the best care for spondylodiscitis patients.

Conclusion
This meta-analysis, with an overall pooled sample size of 10,954 patients, suggests that early surgical management may be more effective than conservative therapy for spondylodiscitis, and is associated with a 40% risk reduction in relapse/failure, a 39% risk reduction in mortality and a 7.75 days per patient reduction in length of hospital stay (p < 0.01).Excluding SEAs, these benefits were magnified.However, given the modest quality of the source evidence, probable selection bias, and remaining unanswered questions critical for implementation, we recommend treating these findings with cautious optimism.Recognising the increasing burden of the disease and the existing limitations of current research, there is a clear call for a well-designed, multi-national randomised controlled trial.

Figure 1 .
Figure 1.(A) The preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart outlining the study selection process is shown.(B) A world map indicated the origin of publications included in this study (n = 31)13,14, . The cuntries are coloured according to whether n = 1, 2, 5 or 13 studies from these countries have been included in this systematic review.The legend at the bottom indicates the colour coding.Following countries are coloured: United States of America (n = 13), United Kingdom (n = 1), France (n = 1), Italy (n = 1), Germany (n = 5), Austria (n = 1), Denmark (n = 2), Iraq (n = 1), India (n = 1), Taiwan (n = 1), Japan (2), South Korea (2).(C) A risk of bias summary plot for non-randomized studies with bar chart of the distribution of risk-of-bias judgments for all included studies (n = 31) across the domains of the ROBINS-I tool, shown in percentages (%) is shown.In the bottom, an overall risk of bias, which represents the collated risk-ofbias judgements for all domains, is depicted.

Figure 3 .
Figure 3. (A) AnEgger's asymmetry plot of all data points included in the meta-analysis (n = 21 studies)13,[23][24][25][26]29,[32][33][34][35]37,38,[41][42][43]47,48,50,52 ; the x-axis represents the inverse of standard error, and the y-axis the standardized treatment effect (as z-score). Furthermore, at the top of the gaph different parameters of heterogeneity, including I 2 , are shown.P-value < 0.05 is deemed to be significant and implicates publication bias.Egger's asymmetry test yielded p = 0.0082, calculated running an Egger's regression (see Egger's regression line) on the collated DOR and standard errors of all data used in the meta-analysis (n = 21), indicating significant publication bias.(B) A funnel plot is shown, which plots every study included in the meta-analysis (n = 21).The observed effect sizes (diagnostic odds ratio) are on the x-axis against a measure of their standard error on the y-axis.All studies fall roughly within the parameters of the funnel plot, there are no gross outliers, indicating that there is no individual studies skewing the publication bias regression analysis.(C) The effects of early surgery versus conservative treatment for spondylodiscitis in terms of: (a) clinical [non-neurological] outcomes, (b) neurological outcomes, (c) overall outcomes, are visualized as harvest plot.The effects are stratified intro three columns: early surgery has better outcomes than conservative treatment ("Early surgery +), there is no difference between the two treatment modalities ("No difference") and conservative treatment has better outcomes than early surgery ("Conservative +).A rectangle represents a single study, unless at bottom of the rectangle a number is specified as i.e. × 2 (= two studies).The colours of the rectangles correspond to the study design: black (retrospective), grey (ambispective), white (prospective).The number on top of the rectangle specifies the risk of bias in overall risk of bias (in line with risk of bias analysis, with 4 implying low risk of bias, 3 implying moderate risk, 2 serious risk and 1 critical risk).The height of the rectangle directly correlates to the risk of bias in outcome measurement, and the aforementioned number on top of the rectangle. Dfinitions for clinical and neurological outcomes are as follows: Clinical outcomes pools different definitions used by different studies including prognosis, recurrence, hospital stay, mortality rates, and lab parameters.Further in-depth investigation of these can be seen in the meta-analysis.On the other hand, the definition of neurological outcomes was split in two categories-the first being the presence or absence of neurological deficits, and the second being a graded scale of neurological deficits based on the American Spinal Injury Association Scale (ASIA scale).

Figure 4 .
Figure 4. Four forest plot indicating and visualizing the proportion in mortality and relapse/failure in the context of spondylodiscitis following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the studies included in the meta-analysis.(A) The pooled proportional mortality after early surgery is shown, (B) pooled proportional mortality after conservative treatment, (C) pooled proportional relapse/failure after early surgery, (D) pooled proportional relapse/failure after conservative treatment.The size of the grey square of the "Proportion" visual correlates to study sample size and the straight line indicated the confidence interval.The diamond at the bottom indicates the overall pooled proportion.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study for the respective treatment arm ("Total"), number of deaths/relapses ("Events") per respective treatment arm, and proportion of deaths/relapses ("Proportion"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).

Figure 5 .
Figure 5. (A)A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the mortality rate of spondylodiscitis following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the 11 studies included in the meta-analysis.The size of the grey square of the "Relative Risk" visual correlates to study sample size and the straight line indicated the confidence interval.The diamond at the bottom indicates the overall pooled relative risk ratio.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).The weighting of each study represented in the percentage (%) is derived from the inverse of the variance of each study's effect estimate.This means that more weight is given to the studies that provide more detailed information or have less variability in their outcomes, giving a balanced representation of the available data in the pooled analysis.A significant pooled relative risk was yielded overall (p < 0.01), indicating that early surgical management vs conservative has a relative risk of 0.61 in the context of overall mortality.Effectively this means that early surgical management of spondylodiscitis achieves a 39% risk reduction (overall mortality) when compared to conservative management.(B) A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the relapse/failure/recurrence rate of spondylodiscitis following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the 17 studies included in the meta-analysis.The size of the grey square of the "Relative Risk" visual correlates to study sample size and the straight line indicates the confidence interval.The diamond at the bottom indicates the overall pooled relative risk ratio.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).A significant pooled relative risk was yielded overall (p < 0.01), indicating that early surgical management vs conservative has a relative risk of 0.6 in the context of leading to relapse/failure/recurrence.Effectively this means that early surgical management of spondylodiscitis achieves a 40% risk reduction (relapse/failure/recurrence) when compared to conservative management.(C) A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the mean length of hospital stay (in daysI of spondylodiscitis patients following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the studies included in the meta-analysis.The size of the grey square of the "Mean Difference" visual correlates to study sample size and the straight line indicated the confidence interval.The diamond at the bottom indicates the overall pooled mean difference.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).A significant pooled mean difference was yielded overall (p < 0.01), indicating that early surgical management vs conservative has -7.75 day mean difference in the context of overall length of stay, effectively meaning that surgery is associated with a mean 7.75 day reduction in length of stay.(D) A correlation matrix visualizes the relationships of following parameters among all studies included in the systematic review (n = 31): The following parameters are used here: Date of publication, lumbar location of infection, proportion of females overall, dropout rate, proportion of intravenous drug users, sample size, cervical location of infection, proportion of epidural abscesses, proportions of diabetics, mean overall relapse/failure rate, proportion of positive cultures (tissues and blood), relapse/failure rate in conservatively treated patient ("Relapse failure [C]"), relapse/failure rate in surgically treated patients ("Relapse failure [S]"), proportion of diabetics in conservatively treated patients, proportion of patients with diabetes, thoracic location of infection, mean age of study population, mortality rate overall, proportion of diabetics in surgically treated patients, combined thoracic and lumbar location of infection, mean overall mortality, mean mortality in surgically treated patients, proportion of nephropathy in surgically managed patients ("Nephropathy [S]"), and mean mortality in conservatively treated patients.The legend bar at the right of the matrix explains the coloring.Red hue indicates a negative association between two parameters, and a blue hue a positive association.One asterisk (*) indicates a statistical significance of p < 0.05, two asterisks (**) indicate p < 0.01, three asterisks (***) indicate p < 0.001.

7 .
Figure 5. (A)A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the mortality rate of spondylodiscitis following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the 11 studies included in the meta-analysis.The size of the grey square of the "Relative Risk" visual correlates to study sample size and the straight line indicated the confidence interval.The diamond at the bottom indicates the overall pooled relative risk ratio.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).The weighting of each study represented in the percentage (%) is derived from the inverse of the variance of each study's effect estimate.This means that more weight is given to the studies that provide more detailed information or have less variability in their outcomes, giving a balanced representation of the available data in the pooled analysis.A significant pooled relative risk was yielded overall (p < 0.01), indicating that early surgical management vs conservative has a relative risk of 0.61 in the context of overall mortality.Effectively this means that early surgical management of spondylodiscitis achieves a 39% risk reduction (overall mortality) when compared to conservative management.(B) A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the relapse/failure/recurrence rate of spondylodiscitis following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the 17 studies included in the meta-analysis.The size of the grey square of the "Relative Risk" visual correlates to study sample size and the straight line indicates the confidence interval.The diamond at the bottom indicates the overall pooled relative risk ratio.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).A significant pooled relative risk was yielded overall (p < 0.01), indicating that early surgical management vs conservative has a relative risk of 0.6 in the context of leading to relapse/failure/recurrence.Effectively this means that early surgical management of spondylodiscitis achieves a 40% risk reduction (relapse/failure/recurrence) when compared to conservative management.(C) A forest plot indicating and visualizing the treatment effect ("TE") size in relative risk in the context of comparing the mean length of hospital stay (in daysI of spondylodiscitis patients following early surgical management (treatment arm) versus conservative management (control arm) is shown, pooling the results of all the studies included in the meta-analysis.The size of the grey square of the "Mean Difference" visual correlates to study sample size and the straight line indicated the confidence interval.The diamond at the bottom indicates the overall pooled mean difference.The red bar below it indicates the prediction interval.Heterogeneity is indicated by the chi-squared statistic (I 2 ) with associated r 2 and p-value.The 95% confidence intervals (CI) are shown in squared bracket ([ ]).P-value < 0.05 is deemed significant.Furthermore, for every study the following are displayed: study author with publication date ("Study"), total sample size number for each study ("Total"), and standard error of the treatment effect ("seTE"), test for significance of overall effect size as t n and p-value, and weighting of each study in percentage (%).A significant pooled mean difference was yielded overall (p < 0.01), indicating that early surgical management vs conservative has -7.75 day mean difference in the context of overall length of stay, effectively meaning that surgery is associated with a mean 7.75 day reduction in length of stay.(D) A correlation matrix visualizes the relationships of following parameters among all studies included in the systematic review (n = 31): The following parameters are used here: Date of publication, lumbar location of infection, proportion of females overall, dropout rate, proportion of intravenous drug users, sample size, cervical location of infection, proportion of epidural abscesses, proportions of diabetics, mean overall relapse/failure rate, proportion of positive cultures (tissues and blood), relapse/failure rate in conservatively treated patient ("Relapse failure [C]"), relapse/failure rate in surgically treated patients ("Relapse failure [S]"), proportion of diabetics in conservatively treated patients, proportion of patients with diabetes, thoracic location of infection, mean age of study population, mortality rate overall, proportion of diabetics in surgically treated patients, combined thoracic and lumbar location of infection, mean overall mortality, mean mortality in surgically treated patients, proportion of nephropathy in surgically managed patients ("Nephropathy [S]"), and mean mortality in conservatively treated patients.The legend bar at the right of the matrix explains the coloring.Red hue indicates a negative association between two parameters, and a blue hue a positive association.One asterisk (*) indicates a statistical significance of p < 0.05, two asterisks (**) indicate p < 0.01, three asterisks (***) indicate p < 0.001.

Table 2 .
Detailed summary of the results from each of the included studies in this systematic review (excluding studies that focused only on spinal epidural abscesses).In this table, a detailed summary of the results from each of the included studies in this systematic review (excluding studies that focused only on spinal epidural abscesses) is presented.Following variables were extracted: study (author and date of publication), treatment, positive cultures (%), epidural abscess (%), duration of antibiotic treatment, additional surgical treatment required, length of hospital stay (days), relapse/failure, mortality, main conclusion of the article, and risk of bias scoring.The number of patients who required additional surgery after having had an initial treatment regimen or procedure is shown in the ' Additional Surgical treatment required' column.The number of patients who had a relapse or representation of their condition or failed their initial treatment regimen or procedure is shown in the 'Relapse/failure' column.The bias of each study is calculated by the ROBINS-I tool is shown in the 'Bias' column.NR data not reported, IV intravenous, D1 bias due to confounding, D2 bias due to selection of participants, D3 bias in classification of interventions, D4 bias due to deviations from intended interventions, D5 bias due to missing data, D6 bias in measurement of outcomes, D7 bias in selection of the reported result, D8 overall bias, COMI core outcome measure index, ESR erythrocyte sedimentation rate, CRP C-reactive protein, WBC white blood cell count, IQR inter-quartile range, PPS percutaneous pedicle screw, MIS-LLIF minimally invasive spine surgery-lateral lumbar interbody fusion, TL thoracolumbar.Vol.:(0123456789) Scientific Reports | (2023) 13:15647 | https://doi.org/10.1038/s41598-023-41381-1www.nature.com/scientificreports/Continued Vol:.(1234567890)Scientific Reports | (2023) 13:15647 | https://doi.org/10.1038/s41598-023-41381-1www.nature.com/scientificreports/