Diagnostically Directed Examination for Infectious, Inflammatory, and Neoplastic Conditions

Jonathan G. Schoenecker

Stephanie N. Moore-Lotridge

Samuel Johnson

Alexandre Arkader

• Introduction

Pediatric musculoskeletal infections are challenging. Given the potential for devastating complications, such as avascular necrosis, growth compromise, joint destruction, thrombosis, and even death, few consults in pediatric orthopedics provoke more apprehension and concern than a child with a potential infection. Bacteria express virulence factors that promote tropism for damaged and regenerating tissue,¹ and given that the developing musculoskeletal system in children and regenerative tissues share many common features (ie, growth factors, angiogenesis, newly forming matrices), there is an increased prevalence of infection in children as compared to adults, even independent of injury.² The principal cause of morbidity and mortality in patients with pediatric musculoskeletal infections is a prolonged or exuberant host response to the injury, referred to as the acute phase response (APR). Prior to antibiotics, the mortality rate of acute hematogenous osteomyelitis in children was nearly 50%.³,⁴ Fortunately, through the advent of antibiotics and the ability to perform surgical debridement of infected tissues, the mortality rate from pediatric infections has dropped tremendously.²,⁵,⁶

In the modern era, while cases of isolated infections do occur, infections that lead to death or disability typically involve infection of multiple tissues of the same anatomic location (eg, bone, muscle, and joint), or systemic infections involving multiple body parts (eg, bone and lung)⁶,⁷,⁸ (Figure 7.1). Opposed to single isolated infections, the APR to combinatory infections is more exuberant, correlating with the amount of tissue infected and the duration of the infection. Furthermore, pathogens have developed the capacity to “hijack” acute phase reactants, thus pathologically driving inflammation and coagulation, driving thrombotic complications, such as septic pulmonary emboli, deep vein thrombosis, and potentially death.⁹ Given the essential role for vascularity in developing bone, thrombosis following an exuberant APR can also lead to avascular necrosis of the epiphysis, metaphysis, or diaphysis, potentially leading to loss of joint function and abnormal limb development. For these reasons, rapid diagnosis and application of the appropriate antibiotics and/or surgical intervention are essential to mitigate an exuberant or prolonged APR.

In this chapter, we will examine the epidemiology and clinical presentation of common musculoskeletal infections afflicting the pediatric population, discuss the diagnostic tools available (imaging and laboratory assessments) for evaluation of infection location and progression, and highlight evidence-based treatment practices aimed at reducing the time patients spend in an exuberant survival APR to improve patient outcomes and mitigate complications. In addition, we will highlight some findings that are common to pediatric musculoskeletal neoplasia and noninfectious inflammatory conditions.

FIGURE 7.1 Infection involving multiple tissues surrounding the hip. Most severe cases of musculoskeletal infections of the hip or the knee do not involve an isolated tissue type. In these MRI cuts, there is evidence of both (A) osteomyelitis in addition to possible septic arthritis (vs reactive joint effusion) and (B) pyomyositis in the same patient within a localized environment. This is typical of cases of hip infections where pathogens rarely stay isolated to the joint. (Images reproduced with permission from Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN.)

• Musculoskeletal Infection Epidemiology

In the pediatric population, infections of the hip and knee predominate as anatomical characteristics of the bone, joint, and muscles surrounding the hip and knee predispose them to be the most common sites of infection in children.¹⁰ Pyogenic organisms are the most common causative pathogens of pediatric musculoskeletal infections with Staphylococcus aureus being responsible for 40% to 90% of cases.⁴,¹¹ However, the patterns of epidemiology related to pediatric musculoskeletal infections are regularly changing, attributable to dynamic mutations in the bacterial genome, use of antibiotics, and vaccinations. For example, with the advent of routine infant vaccination against Haemophilus influenzae, incidence of musculoskeletal infection caused by H. influenzae has decreased substantially.¹² In another example, a 2008 study found that zero children were treated for a methicillin-resistant Staphylococcus aureus (MRSA) infection in 1982; yet from 2002 to 2004, MRSA was isolated as the causative organism in 30% of children.² Thus, the epidemiology for musculoskeletal infections is ever-changing and an up-to-date understanding of disease incidence and common pathogens must be considered when diagnosing and directing treatment for patients with musculoskeletal infections.

Osteomyelitis

Acute hematogenous osteomyelitis (AHO) is defined as an inflammatory infection of the bone that will often extend to the subperiosteal space, surrounding muscle or joint. The physical examination will vary with location and severity of disease. Osteomyelitis in the extremity can lead to global limb swelling, warmth, and redness. Painful palpation and limited joint motion can be present in all infections of the limb, and differential diagnosis can be difficult to differentiate among cellulitis, pyomyositis, septic arthritis, and osteomyelitis (Figure 7.2).

Most AHO in children involves the appendicular skeleton at the metaphyseal region of long bones such as the femur, tibia, and humerus¹³ (Figure 7.3). In the United States, AHO has an estimated annual incidence rate of 1 in 5000 in children younger than 13 years of age.¹⁴ Prior studies have demonstrated that the rate of osteomyelitis is higher in males than in females.¹⁵ Several studies conducted in the United States demonstrate an increase in AHO: a research team at the University of Texas Southwestern
reported a 2.8-fold increase in the incidence of osteomyelitis from 1988 to 2008²; researchers at the Mayo Clinic found an increase in osteomyelitis between 1969 and 2009, citing changes in diagnosing patterns or increases in risk factors (eg, diabetes) among patients.¹⁵

FIGURE 7.2 Osteomyelitis of the distal tibia. A, This girl has an inflamed leg with swelling, redness, pain, and warmth. The extent of inflammation has been marked in order to follow disease progression. B, With early presentation of osteomyelitis, the radiographs are negative. C, MRI of the entire leg demonstrates diffuse inflammation that correlates with the clinical examination. D, More limited MRI demonstrates that the infection is based in the distal tibia metaphysis. (Images reproduced with permission from CHOP Orthopedics, Philadelphia, PA.)

While S. aureus remains the most common causative organism in patients with osteomyelitis,⁴,¹¹,¹⁶,¹⁷,¹⁸,¹⁹ other organisms, such as coagulase-negative Staphylococcus, group A β-hemolytic Streptococcus, Streptococcus pneumoniae, and group B Streptococcus, are also common.¹⁰ As highlighted above, due to antibiotic administration and subsequent pathogen evolution, physicians are now observing an increased rate of patients with MRSA-associated osteomyelitis. Importantly, compared to non-MRSA osteomyelitis, patients with MRSA have been shown to endure a more robust APR, have a longer hospital stay, and experience a higher rate of complications.²⁰

FIGURE 7.3 Osteomyelitis at the metaphysis. Osteomyelitis in the metaphysis can spread to the subperiosteal or extraperiosteal space. Radiographic (A) and MRI identification (B) of a distal femoral osteomyelitis with subperiosteal abscess of the distal femur that has spread into muscle. Radiographic (C) and MRI identification (D) of proximal tibial osteomyelitis of the proximal tibia with subperiosteal abcess. Yellow arrows indicate infection site. (Images reproduced with permission from Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN.)

FIGURE 7.4 Septic arthritis. A, MRI of septic arthritis of the knee. B, MRI of septic arthritis of the hip. (Images reproduced with permission from Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN.)

Septic Arthritis

Septic arthritis is an infection in a joint space, with no extension to the surrounding musculature or bone²¹ (Figure 7.4). It occurs almost twice as often as AHO and most frequently affects children under the age of 10, with 50% of cases occurring in children younger than 2 years of age. Unlike AHO, septic arthritis presents as a near equal distribution among males and females.⁵ However, upon presentation, septic arthritis can be difficult to differentiate from conditions like transient synovitis (discussed in more detail below), which poses no long-term sequela. Importantly, septic arthritis is associated with marked complications, such as early osteoarthritis of the joints, developmental deformities of the infected joint, or spreading to a systemic infection.

Hematogenous-derived septic arthritis can develop in the shoulder, elbow, and ankle, but is most prominently observed in the hip and knee joints.⁶,²²,²³ Septic arthritis can also result from either direct inoculation following a traumatic injury or contamination from an adjacent infection, such as epiphyseal osteomyelitis (Figure 7.5). Importantly, there are a few metaphyses that are intra-articular and if affected with AHO, they could lead to a higher chance of a secondary septic arthritis. These include the proximal humerus, proximal radius, proximal femur, and distal fibula.

FIGURE 7.5 Septic arthritis from epiphyseal osteomyelitis. Although rare, hematogenous osteomyelitis can begin in the epiphysis and spread to the joint presenting with septic arthritis. (Images reproduced with permission from CHOP Orthopedics, Philadelphia, PA.)

While S. aureus is the most common pathogen overall, there is a significant increase in the incidence of Kingella kingae, especially in children younger than 2 years old.²⁴ Importantly, unlike Staphylococcus species, K. kingae is a less virulent gram-negative bacillus that is associated with a lower rate of complications and joint damage compared to Staphylococcus species. Furthermore, if K. kingae is suspected, cultures should be held for 10 days to increase the recovery rate for K. kingae. In addition, yield is considerably higher when a specimen is inoculated into enriched blood culture media. PCR testing for K. kingae is now used routinely in areas of high prevalence.

Pyomyositis

Pyomyositis is defined as an infection isolated to the musculature with no extension into the bone or nearby joint. On physical examination, this usually presents with swollen and painful limb. Sometimes the child can present with compartment syndrome-like signs such as pain with passive stretch (Figure 7.6).

FIGURE 7.6 Pyomyositis of the leg. Clinical examination demonstrates a swollen calf that is tender. The child resists dorsiflexion of the foot and has pain with passive stretch. MRI exam demonstrates an abscess in the posterior compartment that requires surgical drainage. (Images reproduced with permission from CHOP Orthopedics, Philadelphia, PA.)

Pyomyositis can affect multiple muscle groups, varies in severity (associated with the amount of tissue infected), and frequently affects the musculature of the hip. It can be difficult to clinically differentiate between proximal femoral osteomyelitis, septic arthritis of the hip, or pyomyositis. In recent years, pyomyositis has been reported with greater frequency in large part due to the increased use of MRI in cases of pediatric musculoskeletal infections²⁵,²⁶,²⁷,²⁸ (Figure 7.7). A prospective study conducted at Vanderbilt Children’s Hospital from 2010 to 2012 found that in children consulted for an acutely irritable hip, cases of pyomyositis outnumbered cases of septic arthritis at a rate of 2:1.²⁹ As such, proper identification of pyomyositis (rather than septic arthritis) allows patients to be treated without the need for joint debridement. S. aureus has been reported as the most common pathogen in up to 90% of cases.

Necrotizing Fasciitis

Necrotizing fasciitis is a rare infectious process that primarily involves the deep dermis and underlying fascia of musculoskeletal tissue. Necrotizing fasciitis can occur idiopathically or be brought on by a number of identifiable causes, such as minor trauma, major trauma, or postoperatively.³⁰,³¹,³² Although it has been estimated that 70% of cases are of the lower extremity, upper extremity involvement has been described.³³,³⁴

While Group A Streptococcus remains the primary cause of monomicrobial infections, most cases of necrotizing fasciitis are caused by two or more bacterial species that work synergistically to seize control of the host APR. The mortality rate of necrotizing fasciitis in children has been reported in the range of 5% to 20%, making it one of the most feared and life-threatening orthopedic infections.³⁵,³⁶,³⁷,³⁸

FIGURE 7.7 Varying severity of pyomyositis in musculature around the hip. Three pediatric cases with MRI imaging demonstrating mild, moderate, and severe cases of pyomyositis surrounding the hip. (Images reproduced with permission from Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN.)

• Pathophysiology of Disease: Acute Phase Response—The Double Edge Sword in Infection

Musculoskeletal tissue injury evokes a cascade of carefully regulated pathways that are collectively known as the APR. The two principle roles of the APR are (1) survival and (2) tissue repair. These objectives are tackled in a temporal order, such that during the “survival” phase, damage control is initiated by a coordinated effort between coagulation and the survival inflammatory response to temporarily seal off compartments with a fibrin/platelet seal. Additionally, this sealant promotes egress of survival inflammatory cells, which help reduce the susceptibility to infection. For example, neutrophils, in cooperation with the host’s coagulation response, work to trap bacteria in DNA nets and fibrin webs and release chemotoxins to kill pathogens while macrophages clear the trapped bacteria. Once survival is ensured, the APR transitions to a reparative inflammatory response that paves the way for revascularization and regeneration of the damaged tissues.

In the context of an isolated injury, the APR is a regulated and coordinated series of events occurring over 6 weeks, allowing for a timely recovery⁹,⁵⁴ (Figure 7.8A). When the APR is insufficient, as commonly observed in patients with liver damage or cirrhosis (the liver is the principal effector organ of the APR), patients can experience hemorrhage, greater susceptibility to infection, and subsequently impaired tissue regeneration. Alternatively, an over exuberant or prolonged “survival” APR can drive excessive inflammation and a coagulopathic state, enough to increase the risk for complications, such as thrombosis, systemic inflammatory response syndrome, multiorgan dysfunction, and death (Figure 7.8B).⁵⁵ If the patient survives and enters into the repair phase, a prolonged survival phase can promote delays in healing or potential failure of the reparative phase, resulting in chronic nonhealing wounds, tissue fibrosis, and impaired tissue function.⁵⁶,⁵⁷

In the context of infection, the regulated and coordinated nature of the APR can be lost.¹,⁹ After invading the body, bacterial proliferation and the expression of virulence factors allow pathogens to evade the host containment mechanisms (fibrin/DNA webs) and migrate through tissue planes, causing damage to neighboring tissue. As the infection progresses, injury to the surrounding tissues is continuous, which, along with the bacteria’s capacity to hijack many of the acute phase reactants, leads to an exuberant “survival” APR (Figure 7.9A).

Antibiotics and surgical debridement are paramount for cessation of the continuous injury¹,⁹ (Figure 7.9B). As noted above, regulation of the APR is critical, such that continuous exuberant activation can lead to devastating complications, accounting for the majority of morbidity and mortality in pediatric patients with musculoskeletal infections. Therefore, the APR may be viewed as a “double-edged sword.” While a well-coordinated APR is essential for combating and eliminating an infection, a prolonged, excessive APR can drive devastating complications.⁹ Together, these concepts present a paradox for surgeons and health care providers caring for these patients.

To assist in overcoming this paradox, timely identification and diagnosis of musculoskeletal infections, serial monitoring of the APR, and application of the appropriate antibiotics and/or surgical intervention are essential to mitigate an exuberant or prolonged APR, thus reducing the risk of complications, patient morbidity, and mortality.

Bacterial Hijacking of the APR

To combat the body’s host response to infection, pathogenic bacteria have developed virulence factors that provide them the ability to invade, persist, and disseminate within the human body.¹ While bacteria travel through the circulation and the musculoskeletal systems every day, they rarely take hold to cause clinical infection. Though chance will play a role in determining when and where musculoskeletal infections occur, it has been established that “trauma” to musculoskeletal tissue is a major predisposing factor as to where infections establish.⁵⁸,⁵⁹ For example, when a traumatic injury occurs in the skeletal muscle, a hematoma can form and serve as a focal nidus for infection.⁶⁰ Furthermore, in the developing musculoskeletal system of pediatric patients, unique characteristics of the physis, such
as robust vascularity and its relative immune privilege nature, may predispose this site to initiation of infections. For example, the tortuous anatomy of the vasculature of the zone of ossification in the metaphysis has been demonstrated to cause turbulent blood flow, thereby permitting bacterial accumulations.⁶¹ Additionally, developing bone produces factors that inhibit innate immune cell activity in the metaphysis, but not the diaphysis.⁶² Therefore, taken together, these anatomical characteristics make the metaphysis a more permissive and nutrient-rich region in which pathologic bacteria can take hold.

FIGURE 7.8 The acute phase response—the body’s response to injury. A, Following the establishment of an infection and the associated tissue destruction, the body must first resolve bleeding and contain the bacteria via neutrophil-derived DNA nets and fibrin webs. Together, hemostasis and the survival inflammatory response comprise the “survival phase” of the APR, which is essential to preserve life. Once bleeding has been stopped and the bacteria are contained, the body can transition to the “reparative phase” where inflammatory components, such as macrophages, can enter the tissue and begin to clear dead cellular debris, bacteria, and the previously established fibrin matrices. Once cleared, revascularization and tissue regeneration of the damaged tissues can occur to reestablish the preinfection physiologic state. B, In cases of severe injury, the APR can be overexuberantly activated, provoking complications in both the “survival phase” and “repair phase.” APR, acute phase response.

Only gold members can continue reading. Log In or Register to continue