Infectious Arthritis and Osteomyelitis

Musculoskeletal infections are a significant cause of morbidity and mortality in children worldwide, and their early diagnosis is often critical. Acute infections may present clinically as osteomyelitis, septic arthritis, osteomyelitis combined with septic arthritis, spondylodiscitis, or pyomyositis.

Acute osteomyelitis is an inflammatory process in bone, usually the long bones of the lower and upper extremities, ^, accompanied by bone destruction. It is usually the result of a bacterial infection.

Septic arthritis is a mainly monoarticular infection of a joint, frequently localized to the knee and hip. ^,

Spondylodiscitis is a primary infection of the intervertebral discs of the spine with secondary infection of adjacent vertebrae.

Pyomyositis is a purulent infection of skeletal muscle that arises from hematogenous spread, usually with abscess formation. It may occur as a primary infection or complicating bone and joint infections. Pelvic involvement is not uncommon.

Septic Arthritis

Definition and Classification

Arthritis related to infection may be characterized as septic, reactive, or postinfectious. Septic arthritis occurs when a viable infectious agent is or was present in the synovial space. Direct bacterial infection of the joint is the most widely recognized form, although direct infection may also be caused by viruses, fungi, or spirochetes. Septic arthritis may be acute (history of <2 weeks), subacute (history of 2 weeks to 3 months), or chronic (history of >3 months).

Reactive arthritis occurs in response to an infectious agent that is or has been present in an area of the body other than a joint), usually the upper airway, gastrointestinal tract, or genitourinary tract. By definition, viable infectious agents are not recoverable from the synovial space. Therefore reactive arthritis may be regarded as immune-related, resulting from immunological cross-reactivity between articular structures and infectious antigens.

Postinfectious arthritis was described as a unique type of reactive arthritis with immune complexes as part of disseminated gonococcal infections.

Epidemiology

Sex Ratio and Age at Onset

Septic arthritis is usually found in the very young and the very old. The highest frequency has been reported in the under-2-years-old age group, including neonates, and it decreases with age throughout childhood. ^, In well-resourced countries, the overall incidence of acute bacterial arthritis in the pediatric population is 4 to 10 per 100,000. Rates are higher in immunocompromised patients. Boys are affected more frequently than girls. According to a 2012 study of 2592 children (age <18 years) with acute bacterial osteomyelitis or arthritis, the male-to-female ratio was 1.4:1.

Familial and Geographical Clustering

There does not appear to be a genetic predisposition to septic arthritis. Typical cases of presumed septic arthritis, in which no pathogen is identified, tend to occur in summer and fall according to one pediatric study ; however, other studies have not found a significant seasonal variation in the incidence of septic arthritis or osteomyelitis. Geographical clustering has not been reported. By contrast, marked seasonal and geographical outbreaks have been documented for the spirochetal arthritides, such as Lyme disease ( Chapter 45 ).

Pathogenesis and Risk Factors

Hematogenous spread of infection is the most common pathogenic mechanism. This may occur after joint trauma such as an open fracture or penetration of a foreign body. Sometimes the infection results from a combination of a minor trauma causing mild bleeding and bacteremia. Several studies reported a history of a mild, nonpenetrating injury to the affected extremity in approximately one-third of patients.

Extension of underlying osteomyelitis into the joint may occur in infants and neonates owing to the still-intact vascular communication between the metaphysis and epiphysis, which allows pus from the metaphysis to enter the joint space. Toward the end of the first year, formation of the physis obliterates these blood vessels, However, in certain joints such as hips and shoulders, which have intraarticular metaphyses, there is a risk of extension of the infection from bone to the joint space.

Infection of the upper respiratory tract with oral ulceration, and atopic dermatitis with erosive skin infection or varicella, may precede septic arthritis, most commonly affecting the hip joint. Intravenous drug use is an important risk factor, particularly for septic arthritis of the sacroiliac and sternoclavicular joints. Typical organisms include gram-positive bacteria, mostly Staphylococcus aureus and coagulase-negative Staphylococcus with an increasing proportion of oxacillin-resistant S. aureus infections. Gram-negative organisms and anaerobes are also involved.

Other risk factors include prosthetic joints, diabetes, and therapeutic intraarticular steroid use, which is probably extremely rare in children with juvenile idiopathic arthritis (JIA) in the absence of a systemic infection or immune deficiency. In addition, environmental factors, such as living conditions and occupations (e.g., animal handling, laboratory work) may play a role. Contact with patients with pulmonary tuberculosis or living in endemic areas poses a risk as well.

In septic arthritis, bacterial proliferation in the synovial membrane stimulates the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, which in turn stimulate the chemotaxis of neutrophils into the joint space. The neutrophils release proteolytic enzymes to mediate cartilage damage. However, the mechanisms used by neutrophils to destroy microbes can also damage the cartilaginous surfaces of the bone and supporting structures of the joint. The damage may be severe and permanent if treatment is not urgently initiated.

Causative Agents

Table 44.1 illustrates common causative pathogens of septic arthritis stratified by patient age. Septic arthritis is most commonly caused by S. aureus. Community-acquired methicillin-resistant S. aureus (CA-MRSA) is a major causative pathogen in certain areas. Rates vary across countries. A European pediatric study of invasive S. aureus disease reported an 8% prevalence of MRSA. According to a study from the Children’s Hospital of Philadelphia, the prevalence of pediatric musculoskeletal infections from CA-MRSA has increased approximately threefold over the past decade from 11.8% in 2001 to 2002 to 34.8% in 2009 to 2010. In a series from Texas, MRSA was responsible for 62% of all pediatric musculoskeletal infections. CA-MRSA was implicated significantly more often than methicillin-sensitive S. aureus (MSSA) in adverse patient outcomes, including higher C-reactive protein (CRP) levels, longer inpatient stays, need for multiple surgical procedures, increased sequelae, and more frequent admissions to the intensive care unit.

TABLE 44.1

Common Microorganisms Involved in Septic Arthritis and Osteomyelitis

Age	Organisms
Neonate	Group B Streptococcus
	Staphylococcus aureus
	E. coli and other gram-negative bacilli Candida albicans Neisseria gonorrhoeae
Infant	Staphylococcus aureus Kingella kingae (some areas)
	Group A Streptococcus
	Haemophilus influenzae (in nonimmunized population) Streptococcus pneumonia
Child	Staphylococcus aureus Kingella kingae (some areas)
Child	Group A Streptococcus
Adolescent	Staphylococcus aureus
	Group A Streptococcus
	Neisseria gonorrhoeae

Pathogens less frequently involved in septic arthritis include group A Streptococcus, Streptococcus pneumoniae, Haemophilus influenzae type B (in nonimmunized patients), and Pseudomonas spp. Group B Streptococcus (GBS) and Escherichia coli are important pathogens in newborns. Salmonella infection causes approximately 1% of all cases of septic arthritis, and it is commonly associated with sickle cell disease.

Infection with Mycobacterium tuberculosis is an unusual cause of septic monoarthritis in childhood, but because of its insidious nature, it may be confused with JIA. The introduction of molecular techniques, such as real-time polymerase chain reaction (PCR), ^, has led to increasing recognition of the role of Kingella kingae in septic arthritis in the pediatric age group. ^, In some regions, it was the second most common causative pathogen after S. aureus in children under 5 years of age and accounted for 60% of all cases in children under 2 years of age. Clinicians should consider K. kingae infection in young children with culture-negative skeletal infections.

Clinical Manifestations

Septic arthritis has an acute onset of 2 to 4 days. Preceding symptoms may include fever, malaise, vomiting, and headache in addition to localized swelling, pain, or redness, except when occult joints, such as the hip, sacroiliac joints, or vertebrae, are involved. The joint pain is usually severe. Limping or non–weight-bearing is typical when the lower limb joints are affected. Passive and active motion of the joint is often mostly or completely restricted; young children may refuse to use the limb or present with pseudoparalysis. In newborns and young infants, symptoms may be nonspecific, such as irritability, vomiting, or refusal to eat. The presence of bone pain and point tenderness (as opposed to joint pain) should alert the examiner to the possible presence of osteomyelitis accompanying the bacterial arthritis.

Affected Joints

The joints of the lower extremities are the most common sites of infection. In children, infection most often occurs in the knees (40%), followed by the hips (25%), ankles (14%), elbows (12%), and shoulders (4%). Involvement of the small joints of the hands or feet is rare. ^, ^, Pyogenic sacroiliac joint disease can occur.

Septic arthritis usually affects a single joint; one series reported a monoarthritis rate of 93.4% of patients. Multijoint septic arthritis is usually part of generalized septicemia and rarely occurs except in developing countries, where rates may reach 24%. Immune deficiencies such as chronic granulomatous disease or acquired immunodeficiency syndrome (AIDS) may predispose patients to septic arthritis in multiple joints.

Diagnosis

Laboratory Investigations

In cases of suspected septic arthritis, investigations should include a complete blood count, which reveals an elevated white blood cell (WBC) count with predominance of polymorphonuclear leukocytes. An elevated level of CRP is particularly high in patients with bacteremia. During recovery the erythrocyte sedimentation rate (ESR) returns to normal within weeks, much more slowly than the CRP.

Synovial Fluid Evaluation

Arthrocentesis is both diagnostic and therapeutic and should be performed immediately on presentation on every child with acute unexplained monoarthritis, as early treatment can considerably decrease morbidity and mortality.

The synovial fluid may appear normal, turbid, or grayish-green with bloody streaks. The synovial WBC count may be markedly elevated. Studies reported that WBC levels ranged from 50,000 to 100,000/mm ³ in 34% of affected children and reach more than 100,000/mm ³ in 51%, with 90% polymorphonuclear cells. About 15% have lower levels of less than 50,000/mm ³ . Patients with levels exceeding 50,000/mm ³ should be treated empirically for septic arthritis. Nevertheless, these levels are not specific and might overlap with other inflammatory conditions. Clinicians should be aware that patients with bacterial arthritis who are debilitated or immunosuppressed may have lower synovial fluid WBC counts. Synovial fluid Gram staining can be very informative, and it is especially important as the culture may be negative. The synovial fluid protein content is high (more than 2.5 g/dL) in septic arthritis, and the glucose concentration is low relative to plasma, although in some cases, it may be normal.

Microbiology

It is important to obtain blood cultures and diagnostic specimens from any potential source of infection prior to the administration of antibiotics. The introduction of blood culture vials for culturing synovial fluid and bone exudates has resulted in the recognition of K. kingae, a commensal bacterium of the respiratory tract, as one of the most common causes of bone and joint infections in young children (less than 5 years old) in some countries. ^, Blood cultures are positive in 10% to 40% of cases of septic arthritis, and by culturing all appropriate sites, positive cultures can be found in one-third to two-thirds of patients or more. However, no causative agents are ever identified in a significant number of children with pyogenic arthritis.

The introduction of PCR improved the detection of bacteria not isolated by culture. ^, ^, This may be very important in cases of prior use of antibiotics (synovial fluid PCR remains diagnostic up to 6 days after antibiotic initiation) or when conventional diagnostic methods remain suboptimal. ^, ^, ^, ^, ^, ^, Several studies have reported that real-time PCR identified K. kingae in a substantial number of children with culture-negative septic arthritis. ^, Furthermore, quantitative PCR assays specific for K. kingae showed no cross-reactivity with other common osteoarticular pathogens and exhibited tenfold higher sensitivity than the older seminested broad-range 16S rRNA gene assays. ^,

S. aureus infection is common in septic arthritis and most culture-negative cases of bone and joint infections and can be successfully treated with empirical antibiotics. Nevertheless, it is better to establish the microbiological diagnosis in order to tailor therapy to the responsible pathogen, thereby limiting the unnecessary use of broad-spectrum antibiotics. This is particularly important in regions with high rates of MRSA.

In the absence of positive synovial fluid or blood cultures, clinical judgment based on the history and the demonstration of frank pus on arthrocentesis (fluid sufficiently cloudy to prevent reading typed words through the test tube) is superior to laboratory or radiological investigations in the diagnosis of septic arthritis.

Imaging Studies

X-ray imaging, although not diagnostic, is helpful in excluding other disorders. It may show an underlying osteomyelitis or increased soft tissue swelling. Juxtaarticular osteoporosis indicating inflammatory hyperemia may be evident within several days after onset of the infection. In late or untreated septic arthritis, cartilage loss and narrowing of the joint space and subluxation are late findings reflecting disease progression. They are followed by marginal erosions and eventually by ankylosis ( Fig. 44.1A, D, and E ).

Fig. 44.1, A, Lateral view of the right knee in a 6-year-old boy with pain and fever demonstrates a large joint effusion. Magnetic resonance imaging (MRI) obtained a few days later confirms a large joint effusion with diffuse synovial thickening on the sagittal short tau inversion recovery (STIR) image ( B ). The sagittal T1 fat-saturated image post-gadolinium ( C ) shows avid enhancement of the thickened synovium with nonenhancing pockets of fluid. There is also abnormal enhancement of the distal femoral epiphysis in keeping with osteomyelitis with bone abscess ( arrow ). Anteroposterior (AP) ( D ) and lateral ( E ) radiographs of the right knee after treatment show resolution of the joint effusion with patchy sclerosis in the distal femoral epiphysis indicating ongoing healing from osteomyelitis.

Ultrasonography should be performed in all patients with suspected septic arthritis unless the diagnosis is easily made by physical examination. It may distinguish infection from other extraarticular causes with similar symptoms, such as cellulitis, or from psoas abscess, which can lead to referred hip pain. The detection of joint fluid by ultrasound can also help guide aspiration. The sonographic detection of an effusion in the hip in children treated for osteomyelitis of the femur often indicated the presence of septic arthritis. Doppler ultrasound may show increased capsular vascularity. Ultrasonography is the imaging modality of choice in children because it is easy to apply and may be used alone or combination with other imaging modalities.

Computed tomography (CT) is less sensitive than magnetic resonance imaging (MRI) and exposes children to high radiation doses. CT is valuable for guided procedures, such as aspiration or drainage, ^, although not recommended for children for whom ultrasound is the preferred procedure.

Bone scintigraphy with Technetium 99 (Tc-99m) may be useful during the first few days of disease, showing hyperemia with increased uptake on both sides of the joint. It cannot, however, differentiate septic arthritis from synovitis of other causes. Occasionally, uptake of isotope is decreased because the blood flow is impeded by a significant accumulation of intraarticular fluid. Bone scintigraphy is especially useful for excluding underlying osteomyelitis.

MRI is not generally indicated for the diagnosis of septic arthritis unless osteomyelitis-septic arthritis is suspected. Changes may be seen as soon as 24 hours after infection and include synovial enhancement and signal-intensity alterations in the bone marrow, namely, low signal intensity on fat-suppressed, gadolinium-enhanced, T1-weighted spin-echo images and high signal intensity on fat-suppressed, T2-weighted, fast spin-echo images. Although these findings are characteristic of septic arthritis, they are not diagnostic ( Fig. 44.1B and C ). An abnormal collection of fluid or debris, often displacing the joint capsule and eroding into other tissues or leading to subluxation (in children), supports the diagnosis of septic arthritis. MRI may be most helpful in children who do not respond to therapy in the predicted fashion, and unresolved infection or infection in adjacent sites is sought, as in associated osteomyelitis or perifocal myositis.

Treatment

Antibiotics

The treatment of septic arthritis starts with prompt administration of intravenous antibiotics after blood and synovial fluid cultures have been obtained. ^, The choice of antibiotics must take into consideration the age of the patient and the suspected causative agent and its resistance to antibiotics based on epidemiological knowledge of the local antimicrobial resistance, possibly aided by a finding on Gram stain or rapid antigen detection tests.

In hematogenous nonneonatal septic arthritis, treatment targets primarily the most common causative agents, S. aureus. First- or second-generation cephalosporins (e.g., cefazolin, cefuroxime) are suitable choices for previously healthy children in communities with low (<10%) rate of CA-MRSA. Clindamycin is an option if the prevalence of MRSA is significant (>10%) and resistance to clindamycin is low (<10%). ^, Vancomycin and linezolid are used for CA-MRSA resistant to first-line antibiotics. Trimethoprim-sulfamethoxazole has also been experiencing a renaissance because of increasing resistance to newer antibiotics. K. kingae is a regionally common causative agent among children under 4 years old. Clindamycin is not effective against K. kingae, but cephalosporins tend to be effective. Salmonella osteomyelitis may be treated with ceftriaxone, and limited use of fluoroquinolones is allowed in children when no safer alternative is available. ^, The guidelines regarding empiric antibiotic treatment change constantly and the physician should stay up to date with the most current recommendations. Fig. 44.2 shows the diagnostic workup and treatment of acute septic arthritis, and Table 44.2 shows the recommended antibiotic treatment for septic arthritis.

Fig. 44.2, Flowchart for the workup and treatment of acute septic arthritis in children. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus .

TABLE 44.2

Recommended Empiric Antibiotic Therapy by Age ^∗

<3 months	Cefotaxime + nafcillin/oxacillin (if >1 week in NICU, consider using vancomycin)
>3 months	If CA-MRSA <10%: nafcillin/oxacillin or cefazolin
>3 months	If CA-MRSA >10%: clindamycin (check for resistance) or vancomycin

CA-MRSA, Community-acquired methicillin-resistant Staphylococcus aureus ; NICU, neonatal intensive care unit.

∗ Every effort should be made to secure cultures and adjust therapy accordingly. Linezolid is an alternative to vancomycin or clindamycin if MRSA is a concern. If Kingella kingae is suspected, use cefazolin.

Duration of Treatment

A short course of 2 to 4 days of intravenous antibiotics is often sufficient for hematogenous acute septic arthritis. In most cases, especially cases presenting early, an early clinical recovery (temperature returning to normal, range of motion returning, pain diminishing) is seen, and oral antibiotic treatment may be instituted once a descending CRP confirms recovery. The suitable length of routine oral antibiotic administration is 10 days to 2 weeks in previously healthy nonneonatal children if CRP normalizes promptly and clinical recovery is seen. Serum bactericidal titer terminations are not required if large doses of well-absorbing antibiotics (cephalosporins, clindamycin) are used. When administering vancomycin, blood trough levels are measured to adjust dosing with a target of 15 to 20 μg per mL.

For CA-MRSA, an intravenous course of 1 to 2 weeks and a total course of 4 to 6 weeks is recommended by the Infectious Diseases Society of America guideline. There are also no comparative trials on the duration of antibiotic treatment among neonates, immunocompromised children, and rheumatoid septic joints, and in these patients the treatment is tailored individually by monitoring clinical recovery and inflammatory parameters. Salmonella arthritis may require longer treatment, and longer courses may be needed in patients presenting late in a subacute phase or with a chronic infection.

Aspiration and Drainage

Despite the ongoing debate regarding the need for and method of surgical treatment of septic arthritis, an initial prompt arthrocentesis is necessary to confirm the diagnosis and provide a sample for culture. The traditional rationale for surgery of a septic joint was to decompress the joint and remove bacterial debris by repeated joint punctures, lavage, arthroscopy, or open arthrotomy. ^, Several further studies have shown that joints may endure high intraarticular pressures without developing avascular necrosis, and septic joints undergoing diagnostic joint puncture only heal uneventfully. Retrospective series and randomized trials have shown that the prognosis of a septic joint is similar regardless of whether aspiration or open arthrotomy is performed.

There are currently no criteria or algorithms to aid the decision on when and how to operate on a septic joint. As operating on an inflamed joint may adversely affect recovery, it may be prudent, if possible, to wait at least 24 to 48 hours to observe recovery in stable patients with short duration of symptoms before any surgery is considered. ^, Surgery is reserved for cases that are unresponsive to antibiotic treatment or have a delayed presentation. Intraarticular administration of antibiotics is unnecessary because antibiotics penetrate joint fluid readily.

Monitoring Recovery and Follow-Up

Serial CRP measurements are an excellent tool for monitoring recovery. A decreasing CRP indicates clinical recovery even if fever persists. ESR responds too slowly to be of use in the follow-up. Because the feared sequelae, such as growth disturbance or avascular necrosis, develop slowly, it is advisable to follow the patient at least for a year.

Corticosteroids

Septic arthritis is a severe, rapidly progressive erosive disease. Even when the bacteria are eradicated with antimicrobial treatment, the inflammatory process may be prolonged, leading to delayed recovery and residual joint damage. ^,

In 1996, using a murine model of S. aureus arthritis, Sakiniene et al. found that the addition of systemic corticosteroids (dexamethasone) to antibiotic treatment decreased the persistence and severity of arthritis and lowered the mortality rate. Immunohistochemical analysis revealed a decrease in T cells and macrophages in the synovium, suggesting an inhibitory effect of the corticosteroids on T- and B-cell proliferation and differentiation, which may have led to a decrease in proinflammatory cytokine production. Evaluation of cytokine levels showed that corticosteroid treatment was associated with a lower synovial fluid concentration of IL-1, TNF-α, and metalloproteinases, and a decrease in cytokine-mediated cartilage degradation.

Three clinical studies have evaluated the effects of adjunctive therapy with corticosteroids in children with septic arthritis. Two randomized controlled trials, one performed in Costa Rica and one in Israel, involved a total of 149 children aged 3 months to 18 years who were receiving antibiotics for septic arthritis. The most commonly affected joints were the hips and knees. Patients with any degree of immunodeficiency or immunosuppression were excluded. In both studies, dexamethasone was administered intravenously for 4 days at doses ranging from 0.15 to 0.2 mg/kg/dose every 6 to 8 hours. The longest duration of follow-up was 1 year.

The results of the both studies showed that compared with the placebo group, the dexamethasone-treated patients had a significantly shorter mean duration of fever and local inflammatory signs and lower mean levels of acute phase reactants. They also required parenteral antibiotic treatment for fewer days and had a shorter hospital stay. In the study from Costa Rica, dexamethasone therapy significantly reduced residual dysfunction at all three time points evaluated: end of therapy and 6 months and 12 months after therapy. No side effects of treatment were recorded in either group. ^,

In the third, nonrandomized controlled study, the sample consisted of 116 children hospitalized with septic arthritis, and the disease course and outcome were compared with children treated with antibiotics alone (n = 90) or with adjuvant dexamethasone (n = 26). The patients on combination treatment had a shorter duration of fever, more rapid clinical improvement (pain, limited range of motion), more rapid decrease in CRP level to 1 mg/dL, shorter duration of parenteral antibiotic treatment, and shorter hospital stay. Recurrent symptoms of fever and joint pain were noted in four patients in the antibiotics with dexamethasone group after completion of the steroid course.

All three studies concluded that a 4-day course of low-dose dexamethasone given early in the course of the disease is safe and benefits children with hematogenous septic arthritis. Larger prospective studies are needed to corroborate these findings.

Neonatal Septic Arthritis

In addition to S. aureus , GBS and gram-negative agents ( E. coli , Neisseria gonorrhoeae ) cause neonatal septic arthritis through bacterial seeding from the birth canal. ^, In treatment, anti-staphylococcal penicillin (e.g., cloxacillin) may be combined with an aminoglycoside (e.g., gentamicin) to cover these agents. If needed, the antibiotic is changed once culture results are available. The disease is rare and easily missed, as the presentation may be subtle without fever, toxemia, or leukocytosis. Predisposing factors are the use of an umbilical catheter, prematurity, and septicemia. The pathognomonic finding for neonatal septic hip is a motionless hip joint, which is flexed, abducted, and externally rotated, and the knee flexed. Delayed diagnosis unfortunately tends to lead to a disastrous outcome.

Septic Hip Joint

The tightly encapsulated hip joint presents a particular challenge in early diagnosis and treatment in order to avoid avascular necrosis of the femoral head. Septic hip affects all age groups but is more common among infants and young children. The most prominent symptom is fever and the inability to bear weight or walk. Any movement of the hip joint is painful. The child prefers to keep the hip joint flexed, abducted, and externally rotated to decrease the intraarticular pressure.

The traditional management of septic arthritis in the hip and shoulder joint used to be immediate open arthrotomy and drainage. Further studies have shown that in patients presenting early, a single joint aspiration or repeated aspirations are sufficient in a majority (>80% to 90%) of patients. ^, ^, Arthroscopy or arthrotomy may be reserved for those who present late or are unresponsive to treatment or for when aspiration fails (usually because of a thick synovial fold). Casting, traction, or other forms of immobilization are not routinely needed, as the patient will automatically position the limb in the position of maximal comfort that will also help reduce intraarticular pressure. Most authors recommend more aggressive surgery for cases with CA-MRSA, especially in the hip joint, because of the fear of increased complications such as avascular necrosis of the femoral head or deep vein thrombosis.

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