Pediatric Musculoskeletal Infection, Inflammatory Conditions, and Nonaccidental Trauma

Stephanie N. Moore-Lotridge, PhD

Nathaniel Lempert, MD

Jonathan G. Schoenecker, MD, PhD, FAAOS

Dr. Moore-Lotridge or an immediate family member serves as a board member, owner, officer, or committee member of Orthopaedic Research Society. Dr. Schoenecker or an immediate family member has received research or institutional support from Ionis Pharmaceuticals, OrthoPediatrics, and PXE International and serves as a board member, owner, officer, or committee member of Pediatric Orthopaedic Society of North America. Neither Dr. Lempert nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

ABSTRACT

Few conditions in pediatric orthopaedics provoke greater apprehension than a child with a suspected musculoskeletal infection (MSKI). In addition to the potential for adverse medical and musculoskeletal outcomes, the pathogenic organisms are continuously evolving, resulting in increased incidence and severity of MSKI in children and adolescents. Thus, it is essential that pediatric orthopaedic surgeons be up to date on the current epidemiologic trends, diagnosis strategies, and treatment strategies in children with suspected MSKI. Specifically, how serial monitoring of the acute-phase response can aid physicians in determining the severity of an infection, directing treatment, and prognosticating adverse medical and musculoskeletal outcomes is important information. There are alternative pathologies that an orthopaedic surgeon must distinguish from MSKIs to direct appropriate care, including inflammatory conditions, neoplasms, and nonaccidental trauma.

Keywords: acute-phase response; musculoskeletal infection; nonaccidental trauma

Introduction

In pediatric medicine, few conditions are as enigmatic or carry higher stakes for a child than a musculoskeletal infection (MSKI). Pediatric orthopaedic surgeons are frequently called on to evaluate children with suspected MSKI, accounting for nearly 1 in 10 orthopaedic consultations at academic pediatric tertiary care centers in the United States.¹ Fortunately, modern medicine has dramatically reduced childhood mortality from MSKI, which was estimated to be as high as 40% in the preantibiotic era.²,³ However, MSKIs still pose a great risk to children given their capacity to drive adverse medical and musculoskeletal outcomes with potentially lasting effects on the child.

Threats to Effective Treatment in the 21st Century

Clinical advancements over the past 2 decades have markedly improved the physician’s capacity to identify MSKIs from noninfectious etiologies, thereby supporting timely antibiotic administration and surgical interventions. Together, these effective treatment strategies have led to a dramatically reduced risk of mortality from MSKI; however, threats to effective treatment still remain, such that following an MSKI, children can experience striking morbidity because of adverse outcomes. Adverse medical outcomes can include thrombotic events such as deep vein thrombosis, pulmonary emboli, or septic emboli, as well as the need for interventions such as intensive care unit admission or placement on extracorporeal membrane oxygenation. Given the essential role for vascularity in developing bone, a thrombotic complication following an exuberant acute-phase response (APR) can also lead to adverse musculoskeletal outcomes including osteonecrosis of the epiphysis, metaphysis, or diaphysis, potentially leading to loss of joint function and abnormal limb development that can have lifelong implications for the child.

To limit adverse medical and musculoskeletal outcomes, rapid identification, diagnosis, and treatment of an MSKI are essential given that the risk for adverse outcomes is proportional to disease severity. The severity of an infection is a summation of the virulence and dissemination of the pathogen, combined with the level to which the body responds to the pathogen, referred to as the APR⁴ (Figure 1, A). In response to a severe MSKI, an exuberant APR can drive inflammation and coagulation to pathologic levels, leading to thrombotic complications (Figure 1, B) such as septic pulmonary emboli, deep vein thrombosis, and potentially death.⁵ For these reasons, rapid diagnosis and treatment of the infection is essential to mitigate an exuberant or prolonged APR (Figure 1, C). Monitoring the APR can aid in the care of children with MSKI.

MSKI Epidemiology

Under the category of pediatric MSKI, there are numerous diagnoses based on tissue location, such as pyomyositis (muscle), osteomyelitis (bone), cellulitis (skin), or septic arthritis (joint space). Importantly, the severity of the infection can vary relative to the pathogen’s virulence and dissemination. For example, MSKI can happen both focally at a single site (Figure 2) or multifocally throughout multiple tissue types (Figure 3). Additionally, it may be simultaneously disseminated within the bloodstream. As highlighted previously, given that the APR is activated in proportion to the severity of the infection, identifying the location(s) of the MSKI and if dissemination has occurred can greatly aid in directing treatment and predicting a patient’s risk of adverse outcomes.

Pyogenic organisms are the most common causative pathogens of pediatric MSKI, with Staphylococcus aureus being responsible for 40% to 90% of cases.³,⁶ Importantly, S aureus is continuously evolving, conferring virulence factors and antibiotic resistance that can markedly alter the severity of the MSKI and affect which pharmacologic interventions will be efficacious. In a 2020 multicenter study of pediatric tertiary care centers conducted by the Children’s Orthopaedic Trauma and Infection Consortium for Evidence-Based Studies (CORTICES) group, it was found that S aureus accounted for 65.1% of all culture-positive infections at the time of consultation by orthopaedic providers, of which 37.4% were found to be methicillin-resistant S aureus (MRSA).¹ Aligning with these findings, another large national study between 2009 and 2012 reported that 38% of pediatric osteomyelitis cases were caused by MRSA, with the remaining 62% being caused by methicillin-sensitive S aureus (MSSA).⁷

In addition to variation over time, there are marked geographic differences in rates of MRSA and MSSA infections in the United States and Europe.⁸,⁹ Aligning with trends reported in the national CORTICES study, pediatric patients with MSKI in the southern United States experienced a greater incidence of MSKI from MRSA compared with other regions.⁷,¹⁰ It has been hypothesized that the variance between regions and sites may be the product of variable antibiotic utilization patterns, varying patient demographics, or endemic bacteria.⁷,¹¹,¹² From the nationwide CORTICES assessment, an average MSSA:MRSA ratio of 1.84 was observed at the time of consultation for MSKI across 18 institutions.¹ This information can be used as a benchmark value for the anticipated rate of MRSA and MSSA, such that if an institution experiences a markedly greater ratio of MRSA at the time of consultation, this may indicate the need for an intervention to address a disproportionately higher relative rate.

Severity of MRSA Versus MSSA

The severity of an infection is a summation of the virulence and dissemination of the pathogen, combined with the level to which the body responds to the pathogen, known as the APR. As such, with the emergence of MRSA in the community in the early 2000s, numerous studies focused on assessing the virulence and infection severity of MRSA relative to MSSA. Importantly, early studies reported that patients with MRSA infections had poorer outcomes than patients with MSSA infections. However, the continuous evolution and gain of virulence factors in MSSA has led more recent reports to conclude similar virulence and patient outcomes. For example, a study of 91 pediatric MSKI cases reported similar clinical severity and outcomes for patients with confirmed MRSA or MSSA infections.¹³ Furthermore, when a previously effective 2009 logistic regression model based on C-reactive protein (CRP) level, temperature, white blood cell (WBC) count, pulse, and respiratory rate at presentation was applied in 2017, it no longer possessed the ability to effectively differentiate between MRSA and MSSA infections.¹³ Together, these recent findings suggest that pathogen type is but one factor that affects MSKI severity and subsequently the risk of adverse patient outcomes. Given the variance in epidemiology by region and over time, physicians should not limit their assessment of disease severity to the identity of the pathogen. Although pathogen identification is essential for applying antibiotic therapy, both MSSA and MRSA can drive the body’s APR to exuberant levels, increasing the risk of adverse medical and musculoskeletal outcomes.

Figure 1 Schematic representation of the acute-phase response (APR) following musculoskeletal infection. A, Following the establishment of an infection and the associated tissue destruction, the body must first stop bleeding and contain the infection. This is accomplished through the coordinated activities of the coagulation and survival inflammatory systems during the survival phase of the APR. B, As the infection progresses, the survival phase of the APR will progressively increase in magnitude as it attempts to respond to the growing infection and tissue destruction. The duration and severity of activation of coagulation and survival inflammation proportionally increase the patient’s risk for adverse medical outcomes such as thrombosis, acute respiratory distress syndrome (ARDS), multiorgan dysfunction (MOD), and ultimately, death. C, Through intervention with surgical débridement and antibiotic administration, the pathogen onslaught can be reduced. This allows the survival phase of the APR to be sufficient to stop bleeding and trap the remaining bacteria. However, as a result of the exuberant survival APR activated in response to infection, patients may still experience adverse musculoskeletal outcomes such as osteonecrosis (AVN), limb-length discrepancies, joint deformity, or impaired tissue healing following the resolution of the infection. (Figure permission: Schoenecker Laboratory.)

Figure 2 Magnetic resonance images showing examples of focal musculoskeletal infection. Septic arthritis surrounding the knee (A) and hip (B) indicated by magnetic resonance images. C, Magnetic resonance image showing intraosseous osteomyelitis lesion of the proximal tibia. D, Magnetic resonance image showing pyomyositis lesions within the musculature of the hip. Yellow arrows indicate the infection site. (Figure permission: Schoenecker Laboratory.)

Diagnosis and Directing Management of MSKI

Paramount to caring for children with suspected MSKI, there are four tasks that all members of the medical and surgical team should accomplish when working up a suspected MSKI.¹⁴ The team should address the following four questions: (1) Where is the suspected infection? (2) Is it an infection and if so, what is the pathogen? (3) How severe is the infection (ie, how will the infection drive the APR)? (4) How to best treat the infection? Given the heterogeneity of MSKI from one institution to another, it is beneficial for all pediatric orthopaedic surgeons who care for these children to understand the philosophy and tools of these tasks to maximize the benefit to both the child and other services involved in the child’s care.

Figure 3 Images showing examples of infection involving multiple tissues surrounding the elbow. Most severe cases of musculoskeletal infection do not involve an isolated tissue type. Radiographic evaluation (A) did not reveal diagnostic information and ultrasonography (not shown) was suggestive of a septic joint. Fast-sequence MRI (B and C) of the elbow was performed without sedation in less than 15 minutes, revealing invaluable diagnostic information for culture and débridement. T1-weighted coronal short-tau inversion recovery (STIR) sequence (B) and axial T2-weighted fat-saturated (C) magnetic resonance images show evidence of simultaneous subperiosteal osteomyelitis, septic arthritis, and pyomyositis. Without this information, culture and surgical débridement would have been primarily focused on the intra-articular space and potentially intraosseous, whereas the primary focus of the infection was extra-articular in the muscle and subperiosteal space. (Figure permission: Schoenecker Laboratory.)

Identifying Where the Infection Is Located

The child’s developing musculoskeletal system is an ideal target for bacteria, given that bacteria, similar to mesenchymal stem cells or cancers, have a tropism for damaged and regenerating tissues. Molecularly, growing bone and muscle mimic regenerative tissue, predisposing
it to similar relative risk of being targeted by bacteria.⁴ Additionally, unique characteristics of the physis, such as robust tortuous vascularity and its relative immune-privileged nature, can likewise predispose this site to initiation of infection.¹⁴ Together, these molecular factors support the long-standing observation that developing children are susceptible to spontaneous infections predominately at or around major joints. For reasons not completely understood, lower extremities are far more susceptible to spontaneous MSKI than upper extremities, with the femur (hip and knee) being the most susceptible.

Armed with the understanding that bacteria target developing musculoskeletal tissue, the most important goal of the medical and surgical team is to quickly determine which tissues and/or joint(s) are involved. In the past, an irritable joint with other diagnostic criteria suggesting MSKI was thought to be an intra-articular process, specifically septic arthritis. This previous clinical intuition was supported by use of radiographs and ultrasonography, which are excellent at revealing intra-articular effusions but poor at detecting early osteomyelitis or pyomyositis. MRI has become a practical tool in the arsenal of MSKI workup; it has been found that this prevailing clinical intuition is limited by anatomic ascertainment bias, leading to a one-dimensional understanding of this disease process. For example, as MRI has quickly become the gold standard modality for three-dimensional evaluation of MSKI, it has been shown that many cases of joint irritability—previously assumed to be isolated infections—are rather multifocal, extending into the surrounding bone and muscle. Together, these studies have changed the understanding of the incidence and heterogeneity of MSKI and markedly improved the ability to direct culture collection and treatment. Perhaps most importantly, MRI has enhanced the ability to localize the true extent of MSKI.

In pediatric care, fast-sequence MRI can be performed in nonsedated children,¹⁴ thereby allowing for relatively quick three-dimensional assessment of the intra-articular space, bone, and muscle suspected to be infected. However, the most effective tool in an orthopaedic surgeon’s toolbox remains the ability to perform a thorough physical examination and delineate musculoskeletal pain generators. Identifying and communicating where an infection may exist allows standard MRI to be performed at the region of interest as opposed to protocols requiring scanning of an entire limb, which can take hours and necessitate sedation of the child. For instance, a simple “X” marked on the region of interest can make fast-sequence, nonsedated MRI more practical in an emergency department workup of a child with suspected MSKI.

Determining the Pathogen

Rapid diagnosis of infection and identification of the causative organism is essential to properly treat pediatric patients with suspected MSKI. In cases of presumed MSKI, rapid identification of the causative organisms by culturing allows for earlier narrowing of antibiotic therapy, thus decreasing the overuse of broad-spectrum antibiotics. In addition to directing pharmacologic intervention, knowledge of the causative pathogen can likewise inform the clinical care team about the severity of the infection given that pathogens vary in their expression of virulence factors and capacity to hijack the APR. For example, the two most common bacteria that infect children, Streptococcus pyogenes and S aureus, produce virulence factors that increase disease severity by allowing the pathogen to rapidly disseminate across tissue planes and into the bloodstream.¹⁵ Alternatively, pathogens such as Kingella kingae, which has been rising in incidence as a causative pathogen for septic arthritis in children younger than 2 years, express relatively fewer virulence factors and are often associated with a minimal APR.¹⁶ For these reasons, knowledge of the causative pathogen not only aids in directing antibiotic therapy but likewise can inform treating physicians about disease severity and risk of adverse outcomes.

Current methodology and tools available for the identification of infectious organisms are frequently limited to standard bacterial blood and tissue cultures, which can take days, or weeks in cases such as K kingae, to produce results. Prior studies have reported culture positivity rates for patients with confirmed MSKI ranging between approximately 40% and 80%. In the 2020 multicenter CORTICES study, it was found that, on average, only one in three pediatric MSKI-related consultations produced a culture-positive identification at the time of orthopaedic consultation.¹⁴ Importantly, negative culture results may occur because the child does not have an infection, the causative organism is difficult to culture, the incorrect tissue was sampled, or the infection is disseminated without abscess. Clearly, this remains an area of pediatric MSKI care that requires improvement. Working within these shortcomings, the most important role of the pediatric orthopaedic surgeon is to provide a sufficient sample of the most likely infected tissue. As highlighted previously, MRI in conjunction with physical examination is vital in localizing the infected tissues and directing where cultures should optimally be obtained. Furthermore, MRI may prevent inoculation of sterile tissue by inadvertently traversing through infected tissue (such as muscle) on the way to obtain cultures of the bone or intra-articular space.

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