Correspondence: Hsiang-Hao Hsu M.D. Ph.D. Department of Nephrology, Kidney Research Center, Linkou Chang Gung Memorial Hospital No.5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan E-mail: [email protected] Phone: +886-(0)3-328-1200 ext. 8181 Fax: +886-(0)3-3282173 Yu-Shien Ko M.D. Ph.D. Division of Cardiology, Linkou Chang Gung Memorial Hospital No.5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan E-mail: [email protected] Phone: +886-(0)3-328-1200 ext. 8162 Fax: +886-(0)3-3271192
The manuscript submitted does not contain information about medical device(s)/drug(s). Chang Gung Memorial Hospital, Linkou (Grant CIRPD1D0031, CMRPG3B1353 and CORPG3C0152) funds were received in support of this work. No relevant financial activities outside the submitted work.
Abstract Study Design: A retrospective study of patients who were hospitalized for infectious spondylodiscitis over a 13 year period. Objective: To elucidate the epidemiology and prognostic factors of infectious spondylodiscitis in hemodialysis (HD) patients and to identify the impact of HD on infectious spondylodiscitis. Summary of Background Data: Only a few case studies of infectious spondylodiscitis in HD patients can be found in the literature. Reports of prognostic factors are limited and patients’ outcomes have not been well described. Methods: The cases of 1,402 patients who were hospitalized for infectious spondylodiscitis over a 13 year period were retrospectively reviewed. Of these, 102 patients on maintenance HD were enrolled in this study. Cox’s proportional hazard model was used to evaluate the risk factors of mortality and recurrence. Results: The 102 enrolled patients had an average age 63.3±11.2 years old and male-to-female ratio of 1:1.04. Back pain was present in 75.5% of patients and the most commonly infected site was the lumbosacral spine. Infection associated with vascular access was identified in 31.4% of patients. The prevalence of dialysis via central venous catheters was higher than prevalent HD patients. Methicillinresistant S. aureus was the most common pathogen, followed coagulase-negative staphylococci. The patients’ in-hospital survival rate was 82.4%; their vascular access survival rate was 75.5%; their oneyear survival rate was 78.4% and their one-year recurrence rate was 20.2%. Congestive heart failure was associated with an increased one-year mortality. Other variables exhibited no significant relationship with patients’ in-hospital mortality, one-year mortality or recurrence.
Conclusions: The characteristics and outcomes of infectious spondylodiscitis in HD patients were elucidated. Most of the demographic and clinical variables, evaluated upon admission, did not predict mortality or recurrence.
Keywords: infectious spondylodiscitis, spondylitis, hemodialysis, end stage renal disease, bloodstream infection, infectious disease, back pain, sepsis, epidemiology, outcome Level of Evidence: 3
Introduction Infectious spondylodiscitis, defined as the pathogenic invasion of vertebra and intervertebral disc, is an uncommon but serious disease. As the disease progresses, patients develop neurological deficits, sepsis, and even mortality. The reported incidence of infectious spondylodiscitis in developed countries is increasing1-4, probably owing to increased life expectancy, the popularity of spinal and percutaneous invasive interventions and advanced diagnostic methods5,6. Microorganisms reach vertebra and intervertebral discs in different ways, including antegrade bacteremia from the blood stream, retrograde infection from the urinary tract and direct invasion from contiguous tissue or a surgical procedure. Patients on maintenance hemodialysis (HD) have additional risk factors that contribute to blood stream infection because of the repeated vascular puncturing, long-term catheter or Gore-Tex graft indwelling, and contamination of dialysis water purification system. The characteristics and outcomes of infectious spondylodiscitis in HD patients may be different from those in the general population. Only a few case studies of infectious spondylodiscitis in HD patients can be found in the literature. Reports of prognostic factors are limited, and patients’ outcomes have not been well described. The goal of this study is to understand the epidemiology and prognostic factors that are associated with infectious spondylodiscitis among HD patients. The effect of HD on infectious spondylodiscitis is elucidated. Materials and Methods Patient Selection The medical records of patients who were with infectious spondylodiscitis between January 2002 and August 2015 in a tertiary medical center were retrospectively reviewed. A total of 1,402 patients were identified over a 13 year period. Infectious spondylodiscitis was diagnosed through clinical presentations, image studies and results of microbiological tests. Magnetic resonance imaging (MRI),
computed tomography (CT) and gallium inflammatory scan/bone scan were used for diagnostic imaging. Of these patients, 107 had end-stage renal disease (ESRD) under long-term renal replacement therapy. All of these patients were above 20 years of age. Patients who had received HD for fewer than 14 days (n=1) or who were on peritoneal dialysis (n=3) were excluded. A patient who was admitted for recurrent spondylodiscitis (n=1) and had been previously treated in another hospital was also excluded. One hundred and two patients were therefore enrolled (Fig 1). This study was approved by the Institutional Review Board. Characteristics and outcomes Baseline characteristics of age, sex, primary cause of ESRD, comorbidities, HD duration and HD access, were retrieved. Each patient’s presentation, location of infection, microbiological results, source of infection, treatment and outcome were documented. The results of a blood examination upon admission were recorded. The source of infection was obtained from the clinical course, and judged by physicians. The pathogen was confirmed by isolating the microorganism from the spine or the abscess, or from the blood of patients who yielded no positive tissue culture. Outcomes were evaluated at discharge and 12 months from admission. Statistical Analysis Analysis was conducted using R 3.2.4 software (R Project for Statistical Computing, Vienna, Austria). A two-sided p-value of 0.05 was considered to be statistically significant. The end points of this study were in-hospital mortality, one-year mortality and one-year recurrence. The follow-up time ended when patients died, or relapse, or were recurrence-free for one year. Descriptive statistics are presented as mean ± standard deviation for continuous data and count (%) for categorical data. The univariate and multivariate Cox proportional hazard models were used to estimate the risk factors for mortality and recurrence. The missing values of C-reactive protein (CRP, n=2), erythrocyte
sedimentation rate (ESR, n=34), alkaline phosphatase (Alk-P, n=29) and albumin (n=21) were managed by multivariate imputation method. Variables that were significant in the univariate model were used for adjustment in the multivariate model. Results Of 1,402 hospitalized patients with infectious spondylodiscitis, 102 under maintenance HD were identified and enrolled in this study. Their mean age was 63.3±11.2 years old and their male-to-female ratio was 1:1.04. Patient’s comorbidities are showed in table 1. Diabetic nephropathy (44.1%) and chronic glomerulonephritis (35.3%) were two major causes of ESRD. The interval from HD initiation to infectious spondylodiscitis varied from two weeks to 30 years; 27.5% of patients had received HD for less than one year. The hemodialytic vascular access were arteriovenous fistula (AVF)- 47.1%, arteriovenous graft (AVG)-18.6%, tunneled cuffed catheter (TCC)-27.5% and non-cuffed central venous catheters (CVC)-6.9%. Forty-one patients (40.2%) undergone vascular access manipulation (such as the insertion or removal of a catheter, percutaneous transluminal angioplasty, shunt creation or reconstruction) in no more than six months before hospitalization. In patients with vascular access infection associated infectious spondylodiscitis, 75.0% of patients had undergone manipulation of their HD access. The results herein indicate that 75.5% of patients presented back pain upon admission (Table 2). Only 35.3% of patients had a fever. Lumbosacral spine (86.3%) was the most common site of infection, followed by thoracic spine (12.7%) and cervical spine (8.8%). Four patients had skipping lesions that involved two discontinuous infectious sites. Abscess formation was noted in 48.0% of patients. Two patients had infectious spondylodiscitis that was combined with infective endocarditis (IE). In those with IE, the pathogens were methicillin-resistant S. aureus (MRSA) in one patient and coagulasenegative staphylococci (CoNS) in another patient.
Tissue or abscess biopsy/aspiration was performed in 65.7% of patients, and of those, 59.7% yielded positive results (Table 2). Since Taiwan is an area of endemic tuberculosis, a tissue culture or polymerase chain reaction of Mycobacterium tuberculosis was carried out. Blood culture was performed for 91.2% of patients, of whom 65.6% yielded positive results. Four patients (3.9%) yielded inconsistent results from blood and tissue cultures. Gram-positive cocci (GPC) were responsible for 66.7% of infections. MRSA was the most common pathogen (32.4%). CoNS (14.7%), methicillinsusceptible S. aureus (8.8%), Klebsiella pneumoniae (2.0%), Serratia marcescens (1%), Candida parasilosis (1%), Mycobacterium tuberculosis (1%) and Mycobacterium chelonae (1%) were also identified. One patient yielded polymicrobial isolates. Vascular access infection was associated with 31.4% of the cases of infectious spondylodiscitis in HD patients. Spinal operation (7.8%), cellulitis (3.9%), urinary tract infection (2.0%) and contiguous abscess (2.9%, psoas muscle abscess and deep neck infection) were found to be associated with infectious spondylodiscitis. The primary focus of infection was unidentified in 52.0% of patients. We did not note any case of intravenous drug user among the study group. Levels of infection/inflammation markers and alkaline phosphatase, which are elevated in bony disease, were documented upon admission (Table 3). To support diagnosis, the elevations of white blood cell count (WBC), CRP, ESRAlk-P, and neutrophil/lymphocyte ratio (NLR) were noted in 52.9%, 99.0%, 91.1%, 38.4% and 82.4% of patients. The albumin level was 3.0±0.6 g/dL and 77.8% of patients had an initial albumin level of less than 3.5 g/dL. All patients received antibiotic therapy. The duration of antibiotic treatment was 59.0±43.5 days (Table 2). Fifty-five patients (53.9%) underwent surgical treatment. Indications for surgical intervention were spinal instability, progressive neurological deficit and disease progression despite adequate antibiotic therapy. Operating methods included discectomy, laminectomy, and debridement of the infected spine in all patients as well as anterior inter-body or posterolateral fusion of the spine with
a bone graft and abscess drainage in selected patients. CT-guided drainage for an epidural, paraspinal abscess or a psoas muscle abscess was conducted in 14.7% of patients. Vascular access was removed or debrided in 75.0% of patients with a vascular access-associated infection. Sepsis was noted in 43.1% of patients and 22.5% of patients developed septic shock. The in-hospital survival rate was 82.4% and the hospital stay was 60.5±33.8 days. Of the surviving patients, 17 exhibited recurrence of infectious spondylodiscitis within one year, yielding a one-year recurrence rate of 20.2%. The time from discharge to recurrence was 106.2±91.9 days. The patients’ one-year survival rate was 78.4%. Causes of death after discharge were sepsis in three patients (including one case of recurrent infectious spondylodiscitis) and gastrointestinal bleeding-related hemorrhagic shock in one patient. The survival graph to time of death and time of recurrence over the 1 year follow up is showed in figure 2. Age, CHF, ESR and surgical treatment were associated with in-hospital mortality in the univariate analysis (Table 4), but they were not significant in the multivariate analysis (Table 5). No significant difference in in-hospital mortality was found between the S. aureus group and the non-S. aureus group. Variables include comorbidities, location of infected site, presence of abscess, levels of inflammation and infection markers, and type of vascular access was not independently associated with in-hospital mortality. In the multivariate analysis of one-year mortality, CHF was significantly related to one-year mortality (HR=2.99, CI=1.12-8.00, p=0.029). No demographic or clinical variables was correlated with disease recurrence within one year. We evaluate the association between antibiotic duration and recurrence in advance. After excluding patients who died of sepsis in the hospital, for each incremental month of antibiotic treatment, the hazard ratio of disease recurrence rises by 0.25 (HR=1.25, CI=1.04-1.50, p=0.016). Discussion Over a 13 year period, 102 incident cases of infectious spondylodiscitis under maintenance HD were diagnosed and treated in our hospital. ESRD patients accounted for 7.6% of all observed cases.
Whereas males predominate in the non-HD cases2,7,8, gender difference was not significant in HD patients9. Many patients presented prolonged back pain. This symptom can be mimicked by degenerative spinal disease, which co-existed in 84.3% of the patients, delaying the diagnosis. Fever is one of the most significant sign of infection but HD patients with infectious spondylodiscitis were often afebrile. The same as patients who did not undergo dialysis1,4, the lumbosacral spine was the most common site of infection, followed by the thoracic spine and the cervical spine in that order. Infectious spondylodiscitis can be only be definitively diagnosed with a positive culture from the infected spine or abscess. The tissue cultures yielded a 59.7% positive rate herein, which is consistent with previous studies7,8,10-12. Blood culture also helped to identify pathogens, yielding 60-70% positive results13. Although more than half of the patients were afebrile, bacteremia occurred in 65.6% of them. At least two sets of blood cultures should be obtained before antibiotics are administered, even to afebrile patients. Since 3.9% of patients yielded inconsistent blood and tissue culture results, bone or abscess biopsy/aspiration should be considered in all patients in the absence of contraindication. The primary focus of infection is often unrecognizable. Pre-existing or synchronous genitourinary tract, skin and soft tissue, endocardium, intra-abdomen, or catheter-associated infection were common sources of microorganisms 6,12,14. Vascular access infection was the most prevalent preexisting or synchronous infection in HD patients (31.4%). In the cases of vascular access-associated infection, Staphylococci contributed to 87.5% of infections and the manipulation of vascular access within six months was frequently noted. An invasive procedure or the establishment of vascular access or CVC were major risk factors for infectious spondylodiscitis in HD patients10,15,16. In the US, 18.8% of prevalent HD patients use catheter as dialysis access17. In our HD centers that served 1,550 outpatients, 10.82% of patients use catheter. TCC and non-cuffed CVC usage in this study (34.4%) is relatively high. The formation of a biofilm on the catheter may be an important pathogenic mechanism. Patients with TCC or non-cuffed CVC and those who underwent manipulation of vascular access
within months should be regarded as being at high risk for infectious spondylodiscitis. Onset of persistent back pain in a patient with a vascular catheter may be an indication for imaging and/or blood work. Leukocytosis and elevated inflammatory markers were detected. A trend toward normalization of the levels of these markers may be indicators of a satisfactory response to treatment6. However, these identifiable in the laboratory were not specific to a particular infectious disease. Appropriate image studies might be performed to improve diagnostic accuracy. MRI is the recommend diagnostic tool, with a high sensitivity that helps to distinguish among degenerative spondylitis, infectious spondylodiscitis and malignancy related bony destruction13,18,19. CT scan, gallium inflammatory scan/bone scan and positron emission tomography are also effective diagnostic methods5,20. In the non-HD patients, S. aureus is responsible for 47.5-55.2% of infectious spondylodiscitis, and is followed in that respect by streptococcal species, coagulase-negative staphylococci, Escherichia coli and Pseudomonas aeruginosa1,4,8,12,14,21,22. Compared with non-HD patients, the incidence of staphylococci infection, especially the methicillin-resistant strain, was higher in the HD cohort1,8,10,23,24. Gram-negative bacilli (GNB) infection (2.9%) in HD patients occurred less frequently
microbiological difference was probably associated with the increased risk of staphylococci infection and reduced risk or identification of urinary tract infection in HD patients. Patients without HD dependence were classified as at low risk for S. aureus bacteremia27. For patients with S. aureus bacteremia, delayed treatment and persistent fever predict the occurrence of metastatic infection, such as that associated with infectious spondylodiscitis23. CoNS bacteremia in infectious spondylodiscitis should be carefully considered as the actual pathogen, rather than as a contaminant. Fungus and mycobacteria were rarely present. The incidence of tuberculous spondylitis was lower than that reported in non-HD patients(13~33%) 8,21-23.
Guidelines that are published by the Infectious Diseases Society of America suggest the initiation of empiric antimicrobial therapy in patients with hemodynamic instability, or severe or progressive neurological symptoms19. Antibiotics should be withheld from clinically stable patients until pathogen is obtained. The recommended treatment duration of antibiotics is six weeks28. Park et al. suggested an extended antibiotic treatment duration of over eight weeks in cases of MRSA osteomyelitis because of its associated high relapse rate24. Since MRSA and CoNS are common pathogens in HD patients, vancomycin or teicoplanin alone or with one kind of anti-GNB antibiotic may be suitable in empiric therapy. Longer antibiotic use is associated with disease recurrence and this may be an example of reverse causality. While possible that long antibiotics might lead antibiotic resistance, more likely that severe infections may need longer antibiotics treatment and more likely to recurrence. The reported prevalence of combined IE in cases of infectious spondylodiscitis is 2.6~3.6%1,2,29. IE in HD patients is mostly caused by S. aureus and CoNS30. In HD patients with IE, dialysis via TCC or non-cuffed CVC contributed to a major risk of infection31. A heart murmur with GPC infectious spondylodiscitis or S. aureus bacteremia may be a hint to initiate a survey for cardiac vegetation19. HD was associated with increased in-hospital mortality of vertebral osteomyelitis patients2. The reported mortality of HD patients with infectious spondylodiscitis was 33-46%9,16, which is higher than non-HD patients (7.0-11.3%)7,8,14,21. Multi-comorbidities, incident chronic HD and a high incidence of MRSA infection may contribute to this high mortality32,33. Age, diabetes, liver cirrhosis, malignancy and IE were reported to be associated with in-hospital mortality 2. Aagaard et al. revealed that neoplasms, cardiovascular diseases, alcohol abuse-related diseases and drug abuse-related diseases increased long-term mortality after spondylodiscitis34. The present study demonstrates that most of the demographic/clinical variables that are evaluated upon admission were statistically insignificant predictors of survival or recurrence in HD patients. We suppose that an HD patient’s response to initial treatment critically predicts outcome. Hypotheses in this area must be tested in the future.
This study has limitations. Cases were reviewed retrospectively so only associations between mortality and recurrence factors could be identified, while causal relationships could not be. Since the prevalence of infectious spondylodiscitis is low, the number of cases was limited, reducing our ability to detect significance in variables. This study concerned a single center, and so may not be representative of epidemiological results. Some of cases were not completely followed up for 1 year ( 7 less than 3 months and 15 less than 1 year). It is possible that patients recurred or died within 1 year that were not reported. Despite these limitations, the clinical course, associated microorganisms, and prognostic factors in HD patients with infectious spondylodiscitis were identified. In conclusion, MRSA was the most common pathogen and the lumbosacral spine was the most frequently infected area in HD patients with infectious spondylodiscitis. Blood cultures is recommended even in afebrile patients. Tissue culture is suggested be obtained if no contraindication. Since vascular access infection was the leading cause, patients use catheter for HD and those who receive vascular access manipulation should be regarded as being at high risk. CHF was associated with an increased one-year mortality. The results herein revealed that most of the demographic/clinical variables upon admission did not predict a patient’s mortality or recurrence.
Treatment Antibiotic treatment duration, days Surgical treatment , n (%) CT-guided drainage, n (%) Access removal or debridement in vascular access associated infection, n (%) Outcome Sepsis, n (%) Shock, n (%) Hospital stay, day In-hospital survival, n (%) Vascular access survival, n (%) 1-year survival, n (%) 1-year recurrence rate, n (%) Duration from discharge to recurrence, day
Table 5 Factors associated with mortality and recurrence within one year (multivariate analysis) Population Variable In-hospital mortality Age Congestive heart failure Erythrocyte sedimentation rate Surgical treatment
HR 1.03 1.61 0.99 0.46
95% CI 0.98-1.08 0.53-4.93 0.98-1.00 0.13-1.70
One-year mortality Age Congestive heart failure Immunosuppressive status Degenerative spinal disease Back pain Lumbosacral spine Surgical treatment
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