The AO Trauma CPP Bone Infection Registry : epidemiology and outcomes on Staphylococcus aureus infection in long bones and joints CURRENT STATUS:

Background Bone infection is a serious complication orthopedic surgery, and Staphylococcus aureus ( S. aureus ) is a common pathogen. As the optimal treatment requires an understanding of the patient-specific host-pathogen interaction, we developed a biospecimen registry (the AO Trauma CPP Bone Infection Registry ) to collect clinical data, bacterial isolates, and serum from patients treated for bone infection caused by S. aureus . Methods A prospective multicenter multicontinental registry with a follow-up period of 12 months was set up to include adult patients (18 years or older) with culture-confirmed S. aureus infection in long bones after fracture fixation or arthroplasty. Baseline patient attributes and details on infections and treatments were recorded. Blood and serum samples were taken at baseline, 6, and 12 months. Patient outcomes were assessed with the Short Form-36, Parker Mobility Score, and Katz Activities of Daily Living at baseline, 1, 6, and 12 months. Complications, re-hospitalization, and outcomes were recorded. Aside from descriptive summary analyses, changes from baseline were analyzed using the mixed-effects model and Wilcoxon sign rank test. Analyses using full analysis population and per protocol population were performed, and when appropriate, additional sensitivity analyses. This study was registered in ClinicalTrials.gov: NCT01677000.


Conclusion
The AO Trauma CPP Bone Infection Registry provides unique insights into the epidemiology and outcomes of S. aureus long-bone infections. It also contains annotated biospecimens for future research.
Although patients' health status improved after treatment, less than two-thirds were cured at one year.
Background Infection represents one of the most feared complications after fracture fixation and arthroplasty (1).
The emergence of multidrug-resistant organisms such as methicillin resistant S. aureus (MRSA) have made treatment more challenging (2). Multiple revision surgeries and long-term antimicrobial therapy are often needed to treat infection and restore function. Although surgical treatment options have improved over time, a considerable knowledge gap remains with respect to the relationship between treatment protocols, risk factors, and patient outcomes (3,4).
A recently published systematic literature review (93 studies and 3701 patients) analyzed treatment concepts and outcome of fracture-related infection (FRI) (5). The authors reported an overall treatment success rate of 85% and a recurrence rate of 9%. This review underscored the heterogeneity in treatment protocols and the lack of accepted standardized outcome parameters (e.g. quality of life) and showed that critical data such as patient factors, causative pathogens, and treatment details for a better understanding of the relationship between FRI treatment protocols and patient outcomes were lacking. Further, the 2018 International Consensus Meeting on Musculoskeletal Infection (ICM 2018), comprised of 869 delegates from 92 countries (6), failed to reach an agreement that "moderate" evidence exists on the subjects of immunotherapy and immunoprophylaxis for the treatment of implant-associated infections, and concluded that the elucidation of patient-specific host-pathogen interactions is a research priority in this field (7).
To help understand the interplay among patient demographics, comorbidities, treatment modalities, patient-specific host immunity against the causal pathogen(s), and outcomes, we established an international multicenter biospecimen registry of S. aureus infection in long bones and joints (the AO Trauma CPP Bone Infection Registry) to collect clinical data, bacterial isolates, whole blood, and sera.
The development and challenges in setting up this registry have recently been reported (8), and the manuscript on the microbiological and immunological results of this registry is in preparation. Here we report our findings on the epidemiology and outcomes of S. aureus long-bone infections in this registry.

Methods
The current investigation was a prospective, observational, nonrandomized case-series of patients with bony infections (registered in ClinicalTrials.gov: NCT01677000). Study conduct, data management, patient consent (including the use of collected biomaterials for future studies), and ethics approval were as described previously (8). Baseline assessments were done at the time the patients consented to participate in the study. The follow-up (FU) period was 12 months with planned visits at 1, 6, and 12 months.

Inclusion and exclusion criteria
Adult patients (aged 18 years or older) with confirmed S. aureus (either methicillin resistant or sensitive) infection involving a long bone (femur, tibia, fibula, humerus, radius, ulna, and clavicle) due to fracture fixation, osteomyelitis or arthroplasty were eligible (8), disregarding the stage of disease progression and treatment history. S. aureus infections were confirmed by positive deep wound cultures from baseline examinations or by a prior definitive diagnosis of ongoing S. aureus infection (deep wound culture) from the surgical site by the treating surgeon. Prisoners, patients unable to give consent or could not attend the FU visits were excluded. Patients with history of substance abuse that would preclude reliable assessments were also excluded.

Objectives
The aim of this article is to describe the results of the AO Trauma CPP Bone Infection Registry: its patient population, baseline characteristics, infection details, cryopreserved biomaterials, treatment details, complications, functional outcomes, and quality of life after treatment.

Outcome measures
Patient attributes, medical history, comorbidities (Charlson comorbidity index) (9), medications, treatment approaches, and hospital course were recorded at baseline. Nasal swabs, deep wound swabs, serum, and whole blood samples were taken only at baseline; laboratory blood tests performed through the study sites and serum samples collected for later testing in central laboratories were taken at baseline, 6, and 12 months. Short Form-36 version 2 (SF-36 v2) (10, 11), Parker Mobility Score (PMS) (12), and Katz Index of Independence in Activities of Daily Living (Katz ADL) questionnaires (13,14) were used to assess patients' physical and mental health, their mobility, and their degree of independence at baseline and at all FU visits.
As this registry did not interfere with standard of care, adverse events (AEs) as defined by ISO 14155 were not recorded. Procedure-related AEs (e.g. complications caused by collection of blood, nasal, and aerobic bacterial samples) were documented. In-hospital complications that led to prolonged hospitalization or re-admission were documented in the complication form; predefined events of medical relevance that required hospital admission or prolongation of existing hospitalization were also recorded.
Short Form-36 SF-36 questionnaire consists of 36 questions in eight different scales assessing both physical and mental health status (10,11). The scores range from 0 to 100 with higher scores representing better health status.

Parker Mobility Score
The PMS assesses patient mobility. The final score ranges from 0 to 9 points, with higher scores indicating higher function (12). If any of the three questions were missing, the total score was also set to missing.

Katz Index of Independence in Activities of Daily Living
Katz ADL is a 6-item questionnaire that assesses the independence in activities of daily living (bathing, dressing, toileting, transferring, continence, and feeding) (13,14). If any of the six items was missing, the total grade was also marked as missing.

Healing status
Healing status was assessed at each FU as cured, healing, or other by the individual investigational sites according to their standard of care. Descriptive analyses of the level of glycated hemoglobin, C-reactive protein, white blood cell count, and erythrocyte sedimentation rate were performed by the local laboratories. Since these values were not particularly informative, they are not presented in this manuscript.

Statistical analysis
The current study aimed to characterize the patient demographics, disease and treatment characteristics, and outcomes, therefore no sample size calculation was required. The target sample size of 300 was calculated to allow the possibility of building a prognostic model with nine variables of interest assuming a binary outcome with an incidence of 30 events per 100 patients.
The "full analysis population" was defined as all eligible patients who gave written consent and commenced treatment within the study. The "per protocol population" was defined as patients who completed all FU visits.
Patient baseline characteristics, type of infection, hospitalization, and treatment details were analyzed using descriptive analyses. Continuous variables were summarized using mean and standard deviation (SD) for normally distributed data, whereas median and interquartile range (IQR) as well as minimum and maximum, were used for non-normally distributed data. Number and percentages were used for categorical variables.
SF-36 and PMS scores were analyzed using both descriptive statistics and mixed-effects models for repeated measures with an unstructured covariance. Katz ADL scores were analyzed by descriptive statistics and the changes from baseline were analyzed using Wilcoxon sign rank test. Outcome scores were analyzed first using data from the full analysis population and then repeated for the per protocol population.
The aggregated SF-36 physical and mental component summary scores (PCS and MCS, respectively) were transformed using the norm-based scoring with mean = 50 and standard deviation = 10 using the US population norm because its documentation of the algorithm is the best. In short, all scores above 50 can be interpreted as being above the US population average and all scores below 50 can be interpreted as being below the US population average. Although our study population was global, using this norm-based scoring helped ease the interpretation of the scores. The questionnaire used for this study was the standard (4-week recall) form. (1.0%) from South America. A patient recruitment diagram shows the details of patient recruitment from the initial screening to the end of the study (Fig. 1). A detailed description of patient dropouts and deaths is provided in our previous publication (8).

Baseline information and infection details
The patient population was predominantly male (n = 203, 69.5%), and otherwise healthy as indicated by the low Charlson comorbidity index (median = 0.0, range = 0.0 to 10.0) ( Table 1). More than half of the patients (n = 175; 59.9%) had previously (within the three years prior to their inclusion in the current study) undergone orthopedic treatment related to the bone infection with a median number of treatments of 2.0 (range = 1.0 to 20.0).   90.6%). Treatment details are summarized in Table 3.  Statistically significant improvements were similarly observed in PMS scores at 6 and 12 months.
Analyses performed on the data from the "per protocol population" produced results with no qualitative differences from those performed on the data from the "full analysis population" (data not shown). Table 5 summarizes the results of Katz ADL scores from baseline through the course of follow-up.  Table 6). At 6 and 12 months (full analysis population) the mean (SD) scores rose from 4.6 (1.9) at baseline to 5.3 (1.5) and 5.5 (1.2), respectively (p < 0.001 in both cases). At the individual patient level, approximately half of the patients maintained their independence level at each FU; some became more independent at 6 and 12 months (n = 76, 38.4% and n = 71, 39.4%, respectively) whereas a few worsened and became more dependent (n = 20, 10.1% at 6 months and n = 15, 8.3% at 12 months) compared to baseline (Table 5).

Discussion
The AO Trauma CPP Bone Infection Registry offers insight into the epidemiology and outcomes of S.
aureus infections involving long bones and joints. A few key aspects are addressed below.
The study showed that nearly 60% of the patients had been treated for the same infection within the three years before they were enrolled in the current study. These patients had received a median number of two prior treatments. At least one patient had received as many as 20 prior orthopedic treatments, demonstrating the chronic nature of S. aureus long-bone infection. This clinical finding is consistent with the recent discoveries on the unique pathogenic mechanisms of S. aureus in orthopedic infections. These include: 1) biofilm formation on the implant (15) and necrotic bone (16,17), 2) generation of staphylococcal abscess communities (SACs) in soft tissues and bone marrow (18)(19)(20), 3) intracellular infection (1), and 4) the ability to colonize the osteocyte-canalicular network of live cortical bone (21,22).
Second, less than two thirds of the patients were judged to be "cured" 12 months after treatment.
This underlines the previously mentioned chronic nature of these long-bone infections. Although the current cure rate was low in comparison to what has been reported historically (i.e., 80-100% for both Trauma CPP Bone Infection Registry suffered from a high dropout rate (8). Nevertheless, per protocol analyses and sensitivity analyses produced qualitatively similar results. Additionally, in our analyses using the full analysis population, we presume that the high dropout rate did not affect the interpretation of the data.

Conclusions
The Written informed consent was obtained from all individual participants included in the study.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.  Patient recruitment diagram