Fracture related Infection - Challenges in definition and diagnosis

Abstract

In the field of orthopedics and trauma surgery, the rise of periprosthetic joint infections following joint replacement and fracture-related infections (FRI) has become a growing concern. The recent establishment of a definitive definition for FRI aimed to standardize diagnosis and treatment approaches while considering unique aspects of implant-associated infections in the presence of concomitant bone fractures.

Diagnosing FRI can be challenging due to the varied clinical symptoms, and confirmatory criteria may not always be evident, necessitating additional diagnostic measures. Blood markers like leukocyte count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have limited specificity. Although novel biomarkers such as D-dimer and interleukin-6 (IL-6) show potential, they require further investigation. The use of microbiological diagnostics with tissue samples and sonication has improved pathogen detection. Cross-sectional imaging techniques like CT scans and MRI scans help evaluate bone status, soft tissue infiltration, and abscesses. Nuclear medicine techniques are accurate but may not always be practical in routine clinical practice.

Histopathological interpretation for FRI remains less standardized compared to periprosthetic joint infections (PJI). FRI diagnosis requires the identification of visible microorganisms in deep tissue specimens and the quantification of polymorphonuclear neutrophils (PMNs).

The defined concept of FRI has opened doors for better diagnostic and treatment approaches. However, challenges persist, especially in preoperative diagnosis, particularly for cases with unclear clinical presentations. Future endeavors aimed at optimizing diagnostic procedures and establishing a histopathological classification for FRI could lead to improved treatment recommendations and outcomes.

1. Introduction

Infections related to medical implants represent a prevalent and significant complication. It has been observed that up to 50–70 % of all nosocomial infections are associated with implanted medical devices.¹ The diagnosis of implant-associated infections can be challenging, but they often present with typical clinical signs of infection, such as redness, warmth, pain, swelling, and impaired function. These infections can lead to sepsis and potentially fatal outcomes.²

In the field of orthopedics and trauma surgery, periprosthetic joint infections following joint replacement and fracture-related infections (FRI) are increasingly becoming significant concerns.3, 4, 5, 6 The rise in the number of surgical fracture treatments involving the implantation of fracture fixation devices, coupled with an aging population, poses challenges for current and future patient care.⁷ The specific definition of FRI was introduced in 2018 to standardize diagnosis, establish treatment protocols, and account for the unique aspects of implant-associated infections in the presence of a concomitant bone fracture.⁸

1.1. Definition

In the existing body of literature, various synonyms for FRI are present, such as post-traumatic osteomyelitis, exogenous osteomyelitis, implant-associated infection, or infected nonunion.⁹ The significance of using accurate terminology and consistent definitions cannot be overstated, as it forms the foundation for effective therapy. The previous lack of a clear definition was acknowledged as early as 1996, leading to the extrapolation of diagnostic criteria from periprosthetic infections.^10,11 This limitation was highlighted again in a systematic review in 2018, where the authors emphasized that only 2 % of the 100 included randomized controlled studies published a valid definition of infection following fracture.¹² As a result, in the same year, a consensus definition for FRI was published, and expert groups composed of representatives from international societies (AO Foundation, European Bone and Joint Infection Society (EBJIS)) established both confirmatory and suggestive criteria (Table 1).⁸

Table 1.

Confirmatory and suggestive criteria for diagnosing fracture-related infection (according to Ref. 8, CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HPF, high-power field; PMNs, polymorphonuclear cells; WBC, white blood cell count.).

Confirmatory criteria	Suggestive Criteria
Clinical signs •Sinus tract •Wound breakdown •Purulent drainage or the presence of pus	Clinical signs •Local/systemic (for example, local redness, swelling, fever) •New-onset joint effusion •fever ≥38,3 °C •Persistent, increasing or new-onset wound drainage
Microbiology •Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens	Microbiology •Pathogenic microorganism identified from a single deep tissue/implant specimen
Histopathology •Presence of microorganisms in deep tissue specimens, confirmed by using specific staining techniques for bacteria and fungi •Presence of more than five PMNs per HPF in chronic/late-onset cases (for example, fracture non-union)	Radiological and/or nuclear imaging signs •Non-union, implant loosening, bone lysis, sequestra and periosteal bone formation
	Laboratory tests •Increased serum inflammatory markers (ESR, WBC, CRP)

1.2. Diagnostics

While the presence of a clinical confirmatory criterion such as a sinus tract, pus effusion, or exposed implant materials aids in diagnosing FRI and guiding treatment decisions, such cases are less frequent. A recent study by Vanvelk and colleagues demonstrated that only 30 % of the patients diagnosed with FRI through confirmatory criteria exhibited clinical confirmatory signs.¹³ Hence, it is crucial to explore diagnostic options for FRI when the diagnosis is not evident, to ensure an accurate diagnosis and appropriate therapy.

1.2.1. Clinical symptoms

Clinical examination holds great significance and serves as the cornerstone of diagnostics. However, the presentation of FRI without confirmatory diagnostic criteria is diverse. The individual signs of infection outlined as suggestive clinical FRI diagnostic criteria are relatively infrequent: redness (54 %), local warmth/calor (21 %), swelling/tumor (46 %), pain/dolor (49 %), new-onset joint effusion (8 %), wound drainage (44 %), and fever ≥38.3 °C (12 %).¹³ Therefore, further preoperative diagnostics are necessary to confirm the diagnosis.

1.2.2. Blood markers

Serum inflammatory markers like leukocyte count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been studied for their diagnostic value in identifying FRI. However, these markers lack specificity, as they can be elevated not only in the presence of infection but also after trauma or various other inflammatory conditions. Additionally, these markers may appear within normal ranges even in cases of chronic or late-stage infections. Among them, CRP shows some promise as a useful indicator, but a comprehensive examination of available literature reveals only moderate reliability in terms of sensitivity and specificity.¹⁴ Recent studies have indicated limited predictive value of blood markers for FRI.^15,16 As a result, these markers cannot be solely relied upon to definitively confirm or rule out the presence of an infection.

While several other biomarkers, such as interleukin-6 (IL-6), D-dimer, interferon alpha, and procalcitonin, are employed in diagnosing periprosthetic joint infections (PJI), their applicability in FRI lacks substantial evidence. Thus far, serum D-dimer levels have been considered a potential preoperative predictor of infected nonunions, showing a sensitivity and specificity of 75 % and 91.2 %, respectively.¹⁷ The diagnostic value of serological IL-6 levels has been found to be comparable to ESR and CRP.¹⁸ Further novel markers, including the platelet count to mean platelet volume ratio,¹⁹ wound alpha defensin20, or cluster of differentiation (CD) 64, may serve as beneficial adjunct indicators for diagnosing FRI.²¹ Intraoperative rapid diagnostics, like wound alpha defensin testing, hold promise as a practical improvement. However, their reliability requires further investigation, similar to the developments in PJI.²²

1.2.3. Microbiological diagnostics

To enhance microbiological diagnosis, it is recommended to deviate from the usual practice of collecting intraoperative swabs and instead obtain 3-5 tissue samples from the area suspected of infection adjacent to the fracture site. Implementing a standardized protocol during surgery is crucial. To prevent cross-contamination, tissue samples should be acquired using separate, sterile surgical instruments and a no-touch technique.²³ While 16S rRNA PCR-based techniques may offer improvements in diagnostics, their use on swabs from implant surfaces has resulted in lower diagnostic yield compared to conventional tissue sampling.^24,25 After obtaining tissue samples, the implant should undergo sonication.²⁶ During sonication, the foreign material is subjected to ultrasound treatment as a whole, facilitating the detachment of potential pathogens from the material surface and biofilm, ultimately improving microbe detection. A recent study demonstrated that diagnostic yield and sensitivity significantly increased from 57 % to 90 % when comparing sonication to conventional tissue cultures.²⁷ Notably, placing the sonication fluid into blood culture bottles further improved sensitivity, reaching 100 % from the previous 87 %.²⁸

1.2.4. Imaging methods

X-rays play a critical role as the primary imaging modality for diagnosing FRI. They allow for the assessment of fracture healing, alignment, and the status of the implant. In the initial two to three weeks, corresponding to the acute phase of infection, X-rays may not reveal visible signs of FRI. However, in cases of delayed or chronic FRI, certain characteristic features of chronic osteomyelitis become apparent on X-rays. These features include periosteal reactions, cortical erosions, focal osteopenia, osteolysis, and endosteal scalloping.²⁹

Sometimes, a sequestrum, which is a piece of dead bone separated from the surrounding healthy bone by connective tissue, may be observed. The presence of osteolysis indicates advanced inflammation and becomes visible on X-rays when more than 50 % of the bone matrix has been destroyed.³⁰ During the evaluation of native radiographic images, it is essential to consider the soft tissues alongside the bone. Swelling or radiolucent streaks in the images can provide supplementary information to aid in making a diagnosis. However, in certain cases, native radiographic imaging might not be sufficient, necessitating the use of additional cross-sectional imaging techniques such as CT scans and MRI scans to gain a comprehensive understanding.

CT scans are highly valuable for assessing the bone's condition, offering detailed information about various aspects such as soft tissue infiltration, abscesses, periosteal reactions, and gas accumulation. Additionally, they aid in evaluating bone consolidation and accurately depicting bone defects, which proves crucial for effective surgical planning. However, CT scans alone are unable to differentiate between viable and nonviable bone, making intraoperative findings necessary for informed decisions regarding bone debridement. The presence of metal implants can also introduce limitations due to the occurrence of artifacts. Similar challenges are observed in MRI when implants are present, although specialized techniques have been developed to address this concern. MRI presents several advantages over radiography-based imaging, notably providing improved visualization of soft tissues, bone marrow involvement, and early detection of acute inflammation. In acute bone infection cases, T1-weighted fast spin-echo images show low signals, while T2-weighted images display high signals. In contrast, chronic bone infection signals exhibit more variability due to varying levels of inflammation activity, though overall, they bear resemblance to those of acute osteomyelitis. Short tau inversion recovery (STIR) sequences play a particularly useful role in suppressing fat signals and detecting increased fluid accumulation in the bone and soft tissues.³¹ Gadolinium contrast agents can also be employed to enhance signal discrimination in MRI. However, differentiating between reactive edema and inflammation remains a challenge in MRI, often leading to an overestimation of the extent or severity of the osteomyelitis focus.³²

Nuclear medicine techniques offer additional options for assessing FRI (Fig. 1), including three-phase skeletal scintigraphy, leukocyte scintigraphy, and 18F-fluorodeoxyglucose scans. These procedures rely on capturing radiation emitted from the affected area to produce diagnostic images. Moreover, a hybrid approach called 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) combines the precision of bone imaging with positron emission tomography. 18F-FDG PET/CT has demonstrated high accuracy in diagnosing FRI, with a sensitivity of 0.89 and specificity of 0.80. However, it is worth noting that 18F-FDG PET/CT performed within one month after surgery yielded the highest predictive value for a false test result, with an absolute risk of 46 % (95 % CI 27–66 %).³³

Fig. 1.

Diagnostic imaging of a 22-year-old patient wounded in action during the Russian war in Ukraine. The patient presented with an FRI of the right femur shaft after final intramedullary nailing of a Gustilo-Anderson type 3A fracture after shrapnel injury. X-rays (A) provide sufficient information of the implant situation, fracture reduction and progress of bone healing. The radiograph taken 8 months after injury documents sufficient medial cortical bone bridging. Computed tomography (B) allows for a more detailed analysis of the bone situation and is crucial for surgical planning. FDG-PET/CT maximum intensity projection image (MIP), (C), and coronal reformatted fusion images (D), show intensive increased FDG-uptake within and around the fracture healing zone.

The practicality of 18F-FDG PET/CT is a subject of consideration due to its availability and cost when compared to well-established methods in clinical practice. Native radiographic imaging remains indispensable for screening, treatment planning, and follow-up purposes. CT scans play a crucial role in providing valuable information for surgical planning. On the other hand, MRI proves particularly beneficial for assessing the medullary cavity, soft tissues, and identifying potential secondary lesions in long bones. In routine clinical practice, the mentioned imaging procedures are generally adequate, and nuclear medicine techniques are not typically obligatory.

1.2.5. Histopathology

The evidence supporting specific guidelines for interpreting histopathological findings in the context of FRI is relatively limited. Firstly, the FRI consensus definition includes the requirement of visible microorganisms in deep tissue specimens, confirmed by using specific staining techniques for pathogens. This serves as a confirmatory criterion. Secondly, drawing parallels to PJI opens up the possibility that similar techniques could form the basis for establishing definitive histopathological standards for FRI. To achieve this goal, formalin-fixed, paraffin-embedded tissue specimens should be utilized, and each inflamed area should undergo examination in a minimum of 10 high-power fields (400 magnification). It is crucial to record the quantity of polymorphonuclear neutrophils (PMNs) present. A diagnosis of FRI can be confirmed when there are five or more PMNs per high-power field (PMNs/HPF) observed in fractures.³⁴

According to the authors' perspective, histopathological diagnostics still hold substantial potential for enhancing diagnostic tools in the context of FRI. However, it is essential to acknowledge that the tissue sample obtained from the infected fracture region comprises a significantly more heterogeneous tissue composition when compared to PJI and its synovia-like interface membrane. This tissue sample includes not only membranes that can be extracted around the potentially infected implant but also involves tissue in various stages of bone healing from the fracture region.

Drawing parallels to the development of a histopathological classification of joint implant-related pathologies by Morawietz and Krenn, which is based on histomorphological criteria, a prospective histopathological classification for FRI could be established. Such a classification system may aid in deriving treatment recommendations and further improve the understanding and management of FRI cases.^35,36

2. Conclusion

The release of the FRI Consensus Group's definition, treating FRI as a separate entity similar to PJI, marks a significant milestone and serves as a foundation for various initiatives aimed at enhancing the diagnosis and treatment of this complex and challenging condition. In cases where the clinical presentation is unclear, there remains ample room for improvement in preoperative diagnosis to streamline and enhance the diagnostic process. By focusing on optimizing preoperative diagnosis, we can potentially simplify and improve the overall diagnostic procedure, leading to more effective and targeted treatment strategies for FRI.