Plain Radiography

The greatest value of plain radiographs is to exclude focal disease, such as tumor or trauma, that could otherwise explain the clinical presentation of a child with pain and functional limitation who is suspected of having infection. High-quality plain radiographs in at least two planes are essential and should be obtained with a technique that allows visualization of the deep soft tissues. With modern digital and computerized systems, it is possible to adjust the contrast and intensity on the viewing monitor to visualize the deep soft tissues and skeletal detail more clearly regardless of the method of film acquisition, a significant advantage.

Radiographs should be closely inspected for lytic or sclerotic lesions of bone, periosteal elevation or calcification, osteopenia, joint effusions, and cortical disruption. Deep soft tissue swelling is the first radiographic manifestation of musculoskeletal infection ( Fig. 27-4 ). Obvious changes within the bone secondary to osteomyelitis may not occur until 10 to 14 days after the onset of infection and after the loss of 30% to 50% of the bone mineral density at the site of infection.

Deep soft tissue swelling is noted over the distal fibula on the initial plain radiograph ( A ). Subsequent magnetic resonance images ( B and C ) confirm distal fibula osteomyelitis with a subperiosteal abscess.

Although plain radiographs are required in all diagnostic evaluations of infection, advanced imaging studies must be carefully considered in light of the expense, delay in definitive treatment, possible requirement for sedation, radiation exposure, and likelihood of yielding an accurate diagnosis. The decision about which supplemental studies are appropriate should be made in consultation with a radiologist who knows a given facility’s capabilities. This practice can also facilitate the interpretation of the selected studies because the radiologist will be better informed about the child’s clinical history.

Ultrasonography

Ultrasonography is most commonly used in the evaluation of septic arthritis of the hip joint ( Fig. 27-5 ). If the child’s symptoms are thought to originate from the hip, we obtain a comparative hip ultrasound examination to evaluate more carefully for joint effusion, which is difficult to detect by examination or plain radiographs.

Sonograms with line drawings of a patient with septic arthritis of the hip. A, Intraarticular fluid displaces the capsule into a convex position. The capsule is also thickened. B, The capsule on the normal side is concave (following the contour of the metaphysis) and not thickened. C, Capsule; E, epiphysis; M, metaphysis.

This study may also be used in the setting of vague symptoms related to the pelvic region to assess for the presence of a psoas abscess. The advantages of ultrasonography are its low cost, absence of radiation exposure, noninvasive nature without the need for sedation, and ability to detect and localize fluid collections for aspiration.

The detection of intraarticular fluid often helps guide decision making with regard to the need for aspiration, conservative observation, or further imaging in children with an irritable hip.

The usefulness of ultrasonography is often overlooked in the evaluation of osteomyelitis because of the availability of bone scintigraphy and magnetic resonance imaging (MRI). In isolated communities and developing countries, however, ultrasonography may prove useful in evaluating and treating bone infection. One study recommended using ultrasonography as a second step, after plain radiographs, in evaluating all patients with suspected acute hematogenous osteomyelitis (AHO) of long bones. The ultrasonographic features of osteomyelitis are deep soft tissue swelling, periosteal thickening, subperiosteal fluid collection, and cortical breach or destruction, which typically follows a course of progressive stages based on the duration of the infection. The response to treatment can also be tracked by ultrasonography, and one study found that subperiosteal collections of more than 3 mm resolved completely with antibiotics alone.

Fluoroscopy

It may be necessary to aspirate the site of suspected osteomyelitis, by using fluoroscopic guidance, in an effort to identify the causative organism before the initiation of antibiotic therapy. This aspiration is performed as a two-step procedure by placing an 11-gauge bone marrow biopsy needle adjacent to the bone, removing the stylet, and attempting to aspirate a subperiosteal collection, if present. Next, the stylet is replaced and the needle is driven into the metaphyseal bone. On entry, the stylet is again removed, and aspiration is performed. The aspiration specimen should be sent to the microbiology department for Gram stain and culture. Typically we routinely send this specimen for aerobic, anaerobic, fungal, and acid-fast bacteria (AFB) cultures. When the child is between the ages of 6 months and 4 years, we also send for Kingella kingae cultures. Separately, a core biopsy specimen should be sent to a histopathologist for microscopic evaluation. According to the animal research of Canale and associates, this aspiration method should not have an effect on subsequent nuclear imaging. Aspiration was found to yield positive results in 67% to 93% of cases of AHO. Although this may be true for bone scintigraphy, we have found in our practice that subsequent MRI interpretation may be affected by previous needle aspiration because the blush from the aspirating needle may be inadvertently interpreted as osteomyelitis. This issue may be avoided by notifying the radiologist of the previous needle aspiration location. The needle aspiration generally creates a more discrete and linear bone signal than does osteomyelitis.

Nuclear Imaging

Bone scintigraphy has several advantages over the cross-sectional imaging techniques of MRI and computed tomography (CT). It is less expensive, seldom requires sedation, allows for whole-body imaging, and may provide evidence of multifocal involvement in neonatal infections. The method is also useful in assessing a limping toddler when localization of the source of the gait disturbance is not possible by history and physical examination alone. Technetium methylene diphosphonate scanning is the most common nuclear imaging method used to evaluate for infection, although other techniques, including gallium-67 citrate, technetium sulfur colloid, fluorine-18 fluorodeoxyglucose, and indium-111 oxine, have been reported for specific purposes. Most of these other methods have limited clinical utility, as well as an excessive radiation burden that prohibits their routine use in children.

The reported sensitivity of skeletal scintigraphy for the detection of osteomyelitis ranges from 54% to 100%, and the specificity is approximately 70% to 90%, with an overall accuracy of approximately 90%. In specific locations such as the spine, pelvis, and foot, the sensitivity of bone scintigraphy is reduced. However, with modern techniques of magnified spot views, pinhole collimation, optical or electronic image magnification with camera zoom or computer magnification, and single-photon emission CT, the accuracy of nuclear imaging has been increased to more than 90%.

A three-phase bone scan consists of the following elements: (1) blood flow or angiogram phase (performed immediately after injection), (2) blood pool or soft tissue phase (performed approximately 15 minutes following injection), and (3) delayed or skeletal phase (performed 2 to 3 hours, and may be repeated up to 24 hours, after injection) ( Fig. 27-6 ). Findings in osteomyelitis include focally increased uptake on all three phases of the study. Cellulitis, deep soft tissue abscess, or pyomyositis may appear as diffusely increased soft tissue uptake on the blood flow and blood pool images, with little or no uptake on the delayed images. Septic arthritis is more difficult to diagnose with nuclear imaging. Possible findings include a diffusely increased uptake on both sides of a joint, without focal uptake in bone, or photopenia in the epiphysis on the delayed images. Unfortunately the reported false-positive (32%) and false-negative (30%) rates limit the value of nuclear imaging for assessing septic arthritis.

Components of a three-phase technetium bone scan. Initial ( A ), blood pool ( B ), and delayed ( C ) sequences demonstrate increased uptake in all three phases in this 5-year-old boy with subacute osteomyelitis of the left ulna.

Photopenic or “cold” bone scans occur when uptake is decreased compared with the uninvolved side on the delayed images ( Fig. 27-7 ). This finding has been reported in approximately 8% of cases of osteomyelitis and appears to be associated with an advanced stage of infection in which the microcirculation of the medullary canal is compressed by the intraosseous pressure created by the infection. In one report, 7 of 81 children (8.6%) with AHO were found to have a “cold” defect on bone scan; all 7 patients exhibited septic clinical features, including a mean temperature of 39.9° C, a heart rate of 145 beats per minute, and positive blood cultures. The positive predictive value of a “cold” scan was 100% in one study, compared with only 82% for a “hot” scan.

Twelve-year-old boy with a 2-week history of knee pain and fever (39.4° C). The initial laboratory findings included C-reactive protein 12.9 mg/dL, erythrocyte sedimentation rate greater than 140 mm/hr, and white blood cell count 10,400 cells/mL. Bone scan findings were consistent with “cold” osteomyelitis of the distal femur ( A ). Operative findings included a large volume of purulence surrounding the distal femur ( B ) and an extensive area of dead bone of the distal femur ( C ).

Abnormal uptake at multiple sites or even at a single unexpected axial site may be an indication of a systemic disease, such as leukemia or metastatic neuroblastoma. Uptake by a soft tissue mass and multiple skeletal sites should prompt further investigation for neuroblastoma in an infant or young child. Up to 80% of children with leukemia have skeletal scintigraphic lesions at the time of diagnosis.

Computed Tomography

Although CT is excellent for defining bony pathologic features, this method has limited application in the diagnosis and management of osteoarticular infections because the bony changes associated with osteomyelitis are usually adequately visible on plain films. CT is useful in the delineation of bony sequestra and segmental defects in chronic osteomyelitis. It may also be helpful in demonstrating deep infections of the spine or pelvis. CT-guided percutaneous biopsy is often the preferred method of obtaining tissue from axial locations and of placing drains in pelvic abscesses along the inner wall of the ilium ( Fig. 27-8 ).

Computed tomography (CT) scan ( A ) and magnetic resonance image ( B ) demonstrating a psoas abscess ( arrows ) displacing the right psoas muscle (P). CT-guided percutaneous drainage ( C ) was performed, with placement of a drainage tube ( D ).

Magnetic Resonance Imaging

MRI is the most powerful diagnostic imaging technique currently available for the evaluation of musculoskeletal infection. By precisely defining the anatomic location and spatial extent of the inflammatory process, MRI not only helps establish a definitive diagnosis, even in the challenging locations of the spine, pelvis, and foot, but also guides treatment decision making. When surgery is necessary, MRI is useful in determining the appropriate approach when more than one approach is possible. The disadvantages of MRI include the cost, the need for sedation in most children younger than 7 years, and the lack of availability in remote locations.

The sensitivity of MRI has been reported to be as high as 98%, compared with 53% for bone scintigraphy, with additional benefits of MRI in visualizing subperiosteal abscesses, pyomyositis, septic arthritis, and deep venous thrombosis. Other investigators have reported that MRI has diminished accuracy when a broader spectrum of disease is being evaluated. Erdman and colleagues noted a sensitivity of 98% and a specificity of only 75% in their series and advised that certain pitfalls be avoided to help improve the diagnostic accuracy of the study. These investigators found that fracture, infarction, and healing osteomyelitis can mimic the typical features of acute inflammation seen on standard MRI sequences in the presence of active infection. It has been recommended that clinical examination, plain radiography, and scintigraphy be used in cases of diagnostic uncertainty to increase the specificity of MRI and avoid the well-known pitfalls.

Characteristics of infection seen on MRI include marrow signal depression on T1-weighted images and increased bone marrow signal intensity on T2-weighted and short-tau inversion recovery (STIR) images ( Fig. 27-9 ). A complete study should also include fat-suppressed postgadolinium contrast images, which tend to further enhance the intensity of marrow signal changes seen on T1 and T2 images. Abscesses, subperiosteal fluid collections, and joint effusions appear as well-demarcated areas on T2 and STIR sequences. Postgadolinium images should result in ring enhancement of abscesses on T1-weighted images. The use of contrast does not appear to increase the overall sensitivity or specificity of the diagnosis, but it does help to increase the confidence of the radiologist in identifying complications, particularly abscess formation.

Magnetic resonance imaging of the distal femur demonstrates decreased marrow signal intensity on T1-weighted images ( A ), increased marrow signal intensity on T2-weighted images ( B ) and short-tau inversion recovery (STIR) images ( C ), and marrow signal enhancement along with synovial enhancement on postgadolinium T2-weighted images ( D ). These findings are consistent with distal femoral osteomyelitis. The possibility of contiguous septic arthritis is evidenced by the synovial enhancement with contrast compared with the noncontrasted T2-weighted images.

Septic arthritis results in altered bone marrow signal intensity of adjacent bone on T1 and STIR images in up to 60% of cases and may be misinterpreted as adjacent osteomyelitis. One study evaluated postgadolinium images and found that the marrow signal alterations in cases of septic arthritis alone were less extensive and were limited mainly to an area adjacent to articular surfaces; in contrast, in cases of confirmed contiguous osteomyelitis and septic arthritis, the marrow changes were more extensive and involved the metaphyseal region.

The appearance of chronic osteomyelitis on MRI can be difficult to interpret or even misleading ( Fig. 27-10 ). Extensive bone marrow signal changes may encompass an area much broader than the original focus of infection and may make it difficult to differentiate active inflammation from persistent infection and reactive bone marrow signal changes from the healing and remodeling process itself. Because of this difficulty, it is important to use good clinical judgment and consider all available information, including the appearance of plain radiographs, the trends of laboratory data, and the clinical appearance of the child, before embarking on further surgical débridement based on MRI findings alone in cases of chronic osteomyelitis.

A and B, Plain radiographs of chronic proximal tibial osteomyelitis in a 13-year-old boy after 2 months of treatment with intravenous antibiotics and seven surgical débridements. C, Magnetic resonance imaging, performed to evaluate a persistent elevation of C-reactive protein (5.0 mg/dL), demonstrates diffuse marrow and periosteal signal changes consistent with healing versus active osteomyelitis, without overt abscess. Ultimately, biopsy was performed and showed mixed acute and chronic osteomyelitis. The patient was observed and responded to further antibiotic treatment without surgical intervention.

Complete Blood Count

The complete blood count (CBC) with differential is a necessary screening study that should be performed in any child with musculoskeletal pain and functional loss suggestive of infection. A WBC count greater than 12,000 cells/mL was identified as one of four risk factors for septic arthritis of the hip by Kocher and colleagues. The differential cell count is useful for identifying an increase in the production and release of immature neutrophils (bands), which occur in the presence of infection. Although only 25% to 35% of children with AHO have elevated WBCs on admission, the study allows an assessment of all three marrow cell lines that may be affected by disorders that interfere with their production, such as leukemia. Lymphoblasts may also be detected when the differential is performed manually.

Erythrocyte Sedimentation Rate

The erythrocyte sedimentation rate (ESR) represents the rate at which red blood cells fall through plasma, as measured in millimeters per hour. The serum concentration of fibrinogen, an acute-phase reactant released by the liver in response to a variety of inflammatory conditions, is the most significant determinant of the ESR. Infection incites an increase in the ESR, which gradually increases to a mean peak value within 3 to 5 days of the onset of infection. The value slowly returns to normal within 3 weeks following effective treatment in uncomplicated cases. Because the ESR is greatly influenced by the number, size, and shape of erythrocytes, as well as by other plasma constituents, there is significant variation in measured levels, which may be misleading. The ESR should not be significantly elevated in response to trauma.

C-Reactive Protein

C-reactive protein (CRP), an acute-phase reactant synthesized in the liver, was named for its reaction with the pneumococcal C-polysaccharide in the plasma of patients during the acute phase of pneumonia. For many years clinical interest waned, but with further advances in technology, CRP is currently considered the most sensitive and reliable clinical laboratory test for detecting acute inflammatory reactions or changes in the severity of such reactions. CRP has been found to be superior to WBC count and absolute neutrophil count in detecting children with serious bacterial infection. A CRP less than 5.0 mg/dL effectively rules out serious bacterial infection with a predictive probability of only 1.9%.

In the presence of an inciting infection, CRP levels increase 1000-fold within 6 hours of onset and reach a peak within 36 to 50 hours. Because of the short half-life of CRP (24 hours) and constant clearance rate, rapid resolution to normal commonly occurs within 7 days following effective treatment in uncomplicated cases. More recent work showed that a peak CRP level was reached on day 1 (range, 0 to 7 days), with normalization occurring on day 11 (range, 0 to 31 days), in a series of 50 children with bone and joint infections.

Serial CRP determinations combined with repeated clinical evaluations are helpful in identifying sequela-prone children with contiguous septic arthritis and osteomyelitis. One study found that when the CRP level on the third day of treatment was more than 1.5 times the level at the time of admission, the child was 6.5 times more likely to have a combined bone and joint infection. Given the ease of monitoring CRP and its potential value in altering clinical decision making, it is reasonable to obtain daily or alternate-day serum levels during the early course of treatment to help identify sequela-prone children.

The test characteristics of CRP have been assessed with respect to the ability to differentiate septic arthritis and transient synovitis, with mixed results. A study at Children’s Hospital of Philadelphia found CRP to be a better negative predictor than positive predictor of disease, although overall, it was a better independent predictor than ESR (sensitivity ranged from 41% [CRP > 10.5 mg/dL] to 90% [CRP > 1 mg/dL]). Even with a normal CRP (<1 mg/dL), the probability that the child did not have septic arthritis in that study was only 87%.

A multivariate regression analysis identified five predictors to determine septic arthritis: CRP greater than 1 mg/dL, body temperature greater than 37° C, ESR greater than 20 mm/hr, WBC count greater than 11,000/mm ³ , and increased hip joint space greater than 2 mm. When all five predictors were present, the predictive probability was 99.1%, and when CRP was less than 1 mg/dL but the other four predictors were positive, the predictive probability was 90.9%.

CRP may be elevated in response to surgery and trauma. The highest response is reported in patients with tibial fractures who were undergoing open reduction and internal fixation with plates, followed by closed intramedullary nailing; the lowest values were reported in patients treated conservatively. Despite this phenomenon, Unkila-Kallio and co-workers did not find that surgery had a significant influence on CRP levels in children with osteomyelitis or septic arthritis.

Interleukin-6

Interleukin-6 (IL-6), which is released by local tissue monocytes and fibroblasts in response to infection, is thought to be the cytokine that most influences the hepatic production of CRP. Investigators have hypothesized that IL-6 may be detectable in the blood even earlier than CRP during the course of bacterial infection and may thereby enable earlier diagnosis and treatment. Factors that limit the utility of measuring cytokines in the plasma include their short half-lives, the presence of blocking factors and binding proteins, and negative inhibition feedback through an autoregulatory cycle. Although high cost, limited availability, and lack of standardization prevent the measurement of plasma cytokine levels in current clinical practice, further research may change this situation. Buck and colleagues demonstrated the clinical benefit of detecting the presence of IL-6 in newborns with blood culture–positive sepsis, with 100% sensitivity. These investigators also found that the presence of IL-6 on admission in this group of septic neonates was more sensitive than the CRP level (73% versus 58%).

Staphylococcus aureus

With few exceptions, S. aureus is the most common cause of musculoskeletal infections of all types in all age groups. The interest focused on the antibiotic resistance of this organism has led to increased knowledge about its genetic composition that may provide insight into the peculiar ability of this bacterium to cause infections of deep soft tissue, muscle, bone, and joint. It is hoped that future research will also yield improved methods to prevent and treat infections caused by this organism.

The antibiotic resistance of S. aureus is rooted in the rise of the antibiotic era. Penicillin was first used successfully to treat a human being in 1941, following the discovery of this agent in 1928 by Alexander Fleming. By 1943 Andrew Moyer patented an industrial method for the mass production of penicillin, which lowered the cost per dose from $20 in 1943 to $0.55 in 1946. Within a year, resistant bacteria began to emerge.

Penicillin-resistant S. aureus first emerged in the 1950s as the most important pathogen in neonatal nurseries, and no fully effective therapy was available until the introduction of methicillin in the 1960s. Following this early outbreak of serious nosocomial infections, penicillin-resistant S. aureus emerged in the community. Methicillin-resistant S. aureus (MRSA) has followed a similar trend. MRSA was reported in Europe in the 1960s, and the first U.S. case was reported in 1968. Since then nosocomial MRSA has become an increasing problem, and the incidence of MRSA isolates in hospitalized patients has increased from 2% in 1974 to approximately 50% in 1997.

Initial reports of community-acquired MRSA (CA-MRSA) were limited to individuals with a history of intravenous drug use and other high-risk patients with serious illness, previous antibiotic therapy, or residence in long-term care facilities. In the mid-1990s, reports surfaced of CA-MRSA strains that appeared to be different from typical nosocomial MRSA strains, and they were occurring in individuals without established risk factors; the reported incidence of CA-MRSA infections in these patients has ranged from 20% to 67%. Although skin and soft tissue infections have predominated, increasing numbers of invasive infections in children caused by CA-MRSA have been reported.

Methicillin resistance is usually conferred by the mecA gene, which encodes an altered penicillin-binding protein that causes resistance to β-lactam antibiotics, including cephalosporins. Most nosocomial MRSA strains have acquired resistance to numerous other antibiotic classes through a variety of mechanisms. With one exception, reported in Japan, nosocomial MRSA is still highly susceptible to vancomycin, despite being multidrug resistant. So far, CA-MRSA has also remained susceptible to most other antibiotics (except for β-lactam agents), including clindamycin, trimethoprim-sulfamethoxazole, rifampin, and gentamicin. However, an inducible macrolide-lincosamide-streptogramin B (MLS _B ) resistance to clindamycin has been reported in 6% to 25% of CA-MRSA isolates. Intermediate susceptibility to vancomycin was also noted in a case report, but in general MRSA remains susceptible to vancomycin.

Some clues to the manifestations of infection caused by S. aureus are being sought in the virulence factors encoded by its genes. Pulsed-field gel electrophoresis of whole-cell DNA from MRSA isolates has been performed to identify as many as 70 virulence factors in the S. aureus genome, including pvl, can, fnbB, tst, and clfA . One group of investigators found that a significantly higher proportion of CA-MRSA strains carried the pvl and fnbB genes than did community-acquired methicillin-susceptible S. aureus (CA-MSSA) isolates. These investigators also noted that the pvl gene may lead to an increased likelihood of complications such as chronic osteomyelitis and deep vein thrombosis in children with S. aureus musculoskeletal infections. Another group similarly found that osteomyelitis caused by pvl- positive strains of S. aureus was associated with more severe local disease and greater systemic inflammatory response compared with pvl- negative osteomyelitis.

Clindamycin is often preferred to treat CA-MRSA unless MLS _B resistance is demonstrated by disk diffusion, which is performed by placing clindamycin and erythromycin disks 15 to 20 mm apart on a culture medium. A D -shaped zone of inhibition around the clindamycin disk on the side of the erythromycin disk indicates an inducible MLS _B phenotype. Bactrim and rifampin are suitable oral alternatives under these circumstances. In cases of multidrug-resistant nosocomial MRSA infection, vancomycin is preferred for specific therapy. Because the bone penetration of vancomycin is less effective than that of other antibiotics more commonly used to treat osteomyelitis, rifampin is added to enhance the effects of vancomycin, as well as to address intracellular pathogens.

Streptococcus pyogenes

Most cases of group A β-hemolytic Streptococcus (GABHS) infection occur in school-age children, who have the greatest exposure to the organism. In addition to being the second most common causative organism isolated in pediatric musculoskeletal infection, Streptococcus pyogenes is associated with other notable conditions. GABHS disease may manifest as a disseminated infection. This life-threatening clinical syndrome, characterized by rash, fever, shock, and multiple organ system dysfunction, is analogous to the toxic shock syndrome caused by toxin-producing strains of S. aureus. In one report, eight children with severe streptococcal infection demonstrated renal, hepatic, and encephalopathic problems in addition to their musculoskeletal complaints. Up to 87% of children with multisystem GABHS infection have bone or joint involvement. A high index of clinical suspicion and aggressive surgical intervention are recommended to avoid poor outcomes in these children. During 2002, 986 cases of invasive group A streptococcal infection were reported through the Active Bacterial Core Surveillance Project. Based on this number, the Centers for Disease Control and Prevention (CDC) estimated that approximately 9100 cases of invasive GABHS disease and 1350 deaths occurred in the United States in 2002. Aggressive resuscitation and medical management are necessary, along with rapid decompression of foci of infection in the musculoskeletal system after a vigilant search for such sites. Involvement of the musculoskeletal system typically manifests as diffuse swelling in one or more extremities. This finding may raise concern for compartment syndrome as the infection rapidly spreads along fascial planes and creates diffuse, edematous swelling of the involved muscle groups, as opposed to discrete abscess formation ( Fig. 27-11 ).

A and B, Magnetic resonance images of the thigh in a 5-year-old boy with disseminated streptococcal infection and multiorgan system dysfunction. Diffuse edema is noted in the subcutaneous tissues as well as in the deep soft tissues, with extensive perifascial fluid accumulation but no discrete abscess formation. Surgical decompression was performed, with similar findings.

Osteomyelitis and septic arthritis caused by GABHS are frequently reported in the aftermath of varicella viral infections in otherwise immunocompetent infants and toddlers. The port of entry seems to be the varicella pocks, with subsequent hematogenous spread to bone or joint. Standard methods of treatment for septic arthritis or osteomyelitis are employed, along with penicillin, which remains the drug of choice for GABHS infections.

Group A streptococcal pharyngitis may be followed by acute rheumatic fever (ARF) or, less commonly, by poststreptococcal reactive arthritis (PSRA). These conditions should be considered in the differential diagnosis of warm, erythematous joints in children older than 4 years. The orthopaedic manifestations of ARF classically include migratory polyarthritis that usually affects the lower extremities first. The modified Jones criteria are useful in establishing a diagnosis. At least two major criteria (carditis, polyarthritis, subcutaneous nodules, erythema marginatum, and chorea) or one major and two minor criteria (fever, arthralgia, increased ESR or serum CRP level, and prolonged P-R interval on the electrocardiogram), along with evidence of preceding streptococcal infection, are necessary for the diagnosis of ARF. Salicylates and antibiotic treatment, followed by lifelong prophylaxis, play a significant role in the management and prevention of long-term sequelae in ARF.

PSRA is believed to be a variant of ARF in which the Jones criteria are not otherwise satisfied. PSRA is characterized by a shorter latency period between the inciting streptococcal infection and the onset of arthritis, a higher frequency of involvement of small joints and the axial skeleton, a poor response to nonsteroidal antiinflammatory drugs (NSAIDs), a protracted course, and the absence of other major manifestations of ARF. Approximately 6% of children with PSRA have late-onset carditis, which most commonly manifests as mitral valve disease. For this reason the current recommendation is to treat with antimicrobial (penicillin) prophylaxis for a minimum of 5 years or until age 21 years, whichever is longer.

Studies suggested that the human leukocyte antigen (HLA)-DRB1*16 allele predisposes to ARF, whereas the HLA-DRB1*01 allele is more commonly associated with PSRA. In affected individuals, antibodies that develop against group A streptococcus are believed to cross-react with joint synovium at the basement membrane.

The most reliable methods to establish antecedent group A streptococcal infection are to measure antistreptolysin O and antideoxyribonuclease B titers and to obtain throat cultures for group A streptococcus. The basic workup should also include CBC with differential, ESR, CRP, and blood cultures. If the diagnosis of ARF or PSRA is considered on the basis of the clinical evaluation and laboratory studies, an electrocardiogram, echocardiogram, and pediatric cardiology consultation should be obtained.

Kingella kingae

K. kingae was first identified as a new species by Elizabeth King in 1960. Originally designated Moraxella kingii, it was subsequently allocated to the genus Kingella after its distinctive properties were characterized in 1976. K. kingae is a fastidious, aerobic, gram-negative coccobacillus thought to colonize the upper respiratory tract and oropharynx in almost 75% of children between the ages of 6 months and 4 years, which corresponds to the age range of children who contract invasive infections from this organism. Most osteoarticular infections have been reported in children between 10 and 24 months of age. Reports suggest that K. kingae infections elicit a milder inflammatory response with mild to moderate elevation of serum inflammatory markers.

Orthopaedic infections from K. kingae were first reported in 1982, and subsequent literature reviews between 1982 and 1998 identified 58 cases of septic arthritis and 23 cases of osteomyelitis. A report from the CDC established 21 cases of osteoarticular infection (12 septic arthritis and 9 osteomyelitis) between June 2001 and November 2002, findings suggesting a substantial increase in incidence. Possible explanations for this rise in incidence include an increased awareness of this pathogen in the medical community and improved specimen handling and culture techniques.

Because K. kingae is a slow-growing organism with specific culture requirements, it is difficult to isolate from synovial fluid or bone exudates on routine solid media. Reports recommend injecting aspirated materials into aerobic blood culture bottles. The dilution of synovial fluid or pus (which may exert an inhibitory effect on the organism’s growth) in a large volume of broth is postulated to decrease the concentration of detrimental factors and facilitates recovery of the organism. Solid specimens should be plated immediately onto blood or chocolate agar. One group evaluated the difference between sending the specimen to the laboratory for routine processing and plating the specimen immediately in the operating room. In five of six cases of osteomyelitis, the investigators were able to isolate the organism from the agar plate that was inoculated during the surgical procedure, compared with only one of six samples from the same patients that were processed in the laboratory. Several authors believe that these improved methods of organism isolation have been the decisive factor in the increase in the number of K. kingae infections recorded. Because of the inherent difficulties in positively identifying Kingella in tissue culture, efforts have been directed toward polymerase chain reaction (PCR) assays to facilitate positive identification of the organism antigens in joint fluid specimens. However, although this technology may complement existing microbiologic cultures, it does not yet appear to offer results that are superior to tissue culture.

K. kingae typically demonstrates susceptibility to β-lactam antibiotics and is covered by the usual empiric treatment given to children in this age group. Resistance to a variety of antibiotics, including clindamycin, has been reported, however, thus necessitating the use of alternative antibiotics under such circumstances.

Streptococcus pneumoniae

Streptococcus pneumoniae is responsible for a small but consistent portion (approximately 4%) of bone and joint infections in infants and small children, following S. aureus, S. pyogenes, and K. kingae in incidence. The organism plays a more dominant role as a cause of bacteremia, meningitis, and respiratory tract infections. The Pediatric Multicenter Pneumococcal Surveillance Study Group (PMPSSG) identified 21 cases of septic arthritis and 21 cases of osteomyelitis caused by pneumococcus in 8 pediatric centers across the United States between September 1, 1993, and August 31, 1996. The mean age of infected children was 17 months (range, 11 days to 9 years), and most children were between 3 and 24 months of age.

A rising incidence of antibiotic resistance was reported by the PMPSSG, which identified penicillin resistance in 50% of children who had received antibiotics within 4 weeks of hospitalization and in 27% of children without previous antibiotic treatment. In 2002, the CDC reported that 11.5% of isolates in the United States were fully resistant to penicillin. Successful treatment has been accomplished using ceftriaxone and clindamycin in those children who cannot be treated with penicillin.

S. pneumoniae has been identified as a cause of purpura fulminans (PF) in children. The pneumococcal autolysin is suspected to serve the same role as the endotoxin of Neisseria meningitidis. The development of the heptavalent pneumococcal conjugate vaccine, which is recommended for all children aged 2 to 23 months, has had a substantial impact on the epidemiology of invasive pneumococcal disease.

Neisseria meningitidis

N. meningitidis is well known for its role in causing rapid-onset meningitis and severe sepsis with PF. The annual incidence of meningococcal disease is 0.6 to 1.4 cases per 100,000 population, and the case-fatality rate is 10% to 20%, with an equal number of survivors sustaining permanent sequelae, including amputation from PF. Extrameningeal involvement in overt meningococcal disease is well established, and septic arthritis (usually in large joints) was reported in 2% of children in a large epidemiologic review in the United States.

A third-generation cephalosporin, such as cefotaxime or ceftriaxone, is the favored treatment for invasive meningococcal infections. Chemoprophylaxis with rifampin, ciprofloxacin, or sulfonamides has been shown to eradicate nasopharyngeal carriage and prevent the epidemic outbreaks of invasive disease in close contacts that typically occur within 5 to 10 days of exposure.

Neisseria gonorrhoeae

Disseminated gonococcal infection (DGI) may occur in children under three circumstances: (1) neonatal infection contracted while passing through the birth canal of an infected mother, (2) pediatric or adolescent infection resulting from sexual abuse, and (3) adolescent infection through voluntary sexual activity. The onset of DGI may occur anywhere from days to months after the initial infection, and it has an incidence of 0.5% to 3% in cases of mucosal infection. The most common presenting musculoskeletal complaint is polyarthritis in up to 60% of patients, with involvement of the knee, ankle, or wrist. Associated complaints may include fever, chills, and rash. DGI should be suspected in the presence of dermatitis, tenosynovitis, and migratory polyarthritis. A rash occurs in two thirds of patients and is described as consisting of multiple painless, nonpruritic lesions involving the torso, limbs, palms, and soles.

Although the overall incidence of gonorrhea is higher in male patients, DGI is four times more common in female patients. Whenever DGI is suspected, culture specimens should be obtained from the joint fluid, cervix of postpubertal girls, and urethral or prostatic discharge of male patients, as well as from the vagina, pharynx, and rectum in children suspected of being victimized by child abuse. Because Neisseria gonorrhoeae is difficult to culture, special specimen handling instructions are required to increase the chance of positively identifying the organism. Sterile culture specimens are plated on chocolate blood agar, and nonsterile specimens are plated on Thayer-Martin medium, which contains antibiotics to inhibit the growth of oropharyngeal and anorectal flora. Cultures require a 5% to 10% carbon dioxide atmosphere. Gram staining may demonstrate intracellular gram-negative diplococci.

Treatment of DGI involves a 7-day course of intravenous or intramuscular ceftriaxone given once daily or cefotaxime in two divided doses. Doxycycline is also used concurrently in sexually active adolescents to treat chlamydia, which frequently accompanies gonococcal infection. Surgical treatment is rarely indicated except in cases of severe synovitis that is not responsive to conservative treatment, which may require arthroscopic or open synovectomy. Gonococcal osteomyelitis, though rarely reported, may require a longer course of treatment.

Borrelia burgdorferi

Lyme disease is a multisystem infection caused by the spirochete Borrelia burgdorferi. It is the most common vector-borne disease in the United States and is transmitted by the black-legged or deer tick, Ixodes scapularis. A total of 23,305 cases of Lyme disease was reported in 2005. Infection most commonly occurs in children in the northeastern, mid-Atlantic, and north-central regions of the United States. After inoculation, the time before the appearance of systemic manifestations ranges from 2 to 30 days. Because the tick bite and the premonitory erythema migrans rash may go unnoticed, a high level of suspicion is necessary to ensure that the original presenting symptoms, which may involve the musculoskeletal, neurologic, and cardiovascular systems, are recognized without delay. Although this is rarely a problem in endemic areas, physicians outside these locations may not be familiar with the common manifestations of Lyme disease.

Because juvenile arthritis, reactive arthritis, and septic arthritis may be confused with Lyme arthritis, the CDC has established diagnostic criteria, including the presence of a characteristic erythema migrans rash at least 5 cm in diameter or laboratory confirmation of infection and at least one musculoskeletal, neurologic, or cardiovascular manifestation of disease. Erythema migrans is present in 60% to 90% of patients and may occur with other early manifestations, including constitutional symptoms, migratory arthralgia, cardiac conduction defects, aseptic meningitis, and Bell palsy. Late manifestations of Lyme disease include arthritis, encephalopathy, and polyneuropathy.

The CDC recommends that clinicians use a two-step procedure when ordering antibody tests for Lyme disease: first, an enzyme-linked immunosorbent assay or immunofluorescent assay, and then, if the result is positive or equivocal, an immunoblot (Western blot) test to confirm the screening test result. Antibody test results may not be positive for the first 3 to 6 weeks of infection. In endemic regions a rapid 1-hour Lyme enzyme immunoassay (EIA) has been used to reduce the incidence of unnecessary surgical intervention in children with Lyme arthritis, given the considerable overlap in clinical, radiographic, and laboratory presentations of this condition and septic arthritis. By using the rapid Lyme EIA, the standard 3- to 5-day period for Lyme serology reporting can be significantly shortened, perhaps obviating the need for unnecessary surgery.

The medical treatment of Lyme disease initially consists of 4 weeks of oral antibiotics (amoxicillin or doxycycline). Children younger than 8 years should not be treated with doxycycline because it may cause permanent discoloration of the teeth. In one series, 88% of children were disease free before the end of 4 weeks, 7% required treatment for 8 weeks, and 5% required treatment for 12 weeks.

A post–Lyme disease syndrome has been described in individuals with long-standing unrecognized Lyme arthritis before antibiotic treatment. This syndrome may occur in dark-skinned individuals in whom the erythema migrans rash goes undetected. Some children who continue to have arthritis after antibiotic treatment may have suffered some mechanical damage to the joint structures from the inflammation and synovitis, whereas others may continue to have an autoimmune, or reactive, chronic synovitis following Lyme arthritis. Most patients with suspected post-Lyme syndrome are simply slow responders and improve with conservative observation and symptomatic support over a 6-month period.

Mycobacterium tuberculosis

During 2005, a total of 14,097 cases of tuberculosis was reported to the CDC. Non-Hispanic blacks born in the United States continue to have the highest tuberculosis rate of any racial or ethnic population, and they represent 46.5% of cases among U.S.-born persons and approximately 28% of all cases in the United States. Foreign-born individuals have a case rate more than 8 times higher than that among U.S.-born persons.

Extrapulmonary tuberculosis is more common in children younger than 5 years, and this condition occurs in approximately 5% to 10% of infected children. Thus tuberculosis must be included in the differential diagnosis of bone and joint infections in this age group, particularly children who live in high-risk households. Despite the decreasing incidence in the United States, tuberculosis remains prevalent in the developing countries.

Osteoarticular involvement occurs in approximately 1% to 3% of patients with tuberculosis. Aside from spinal involvement (addressed earlier), tubercular infection can manifest as septic arthritis, osteomyelitis of long bones, and dactylitis. This involvement may take the form of spondylitis (50%), peripheral arthritis (30%), osteomyelitis (11% to 19%), and tenosynovitis and bursitis (1%). Long bones may not become infected for 1 to 3 years, whereas dactylitis may develop in a few months. A high index of suspicion is needed to diagnose tubercular infection of the bone or joint. Positive culture can be obtained in approximately 80% of children with extrapulmonary disease, but 4 to 6 weeks of incubation may be needed to identify the organism.

Tuberculosis of joints is usually monarticular, with the knee and hip most frequently affected. The clinical presentation is variable and simulates that of other chronic inflammatory arthritic disorders. Synovitis, effusion, central and peripheral articular erosions, and active and chronic pannus are the most common manifestations. Delay in diagnosis is common. Postcontrast MRI may help differentiate effusion from synovitis and further differentiate acute synovitis from chronic synovitis.

Tubercular osteomyelitis most commonly involves the epiphysis or metaphysis. Unlike in other bone infections, the physeal plate does little to stop the spread of infection. As the infection progresses, the area of skeletal destruction may slowly expand and typically appears on radiographs as a cystic lesion with obscure margins ( Fig. 27-12 ). Because the disease process is almost entirely lytic, one sees little periosteal reaction and often no sclerotic margin. Bone lesions often resemble benign or malignant bone tumors or fungal infections. An expansile lesion may form within long bones, associated with periosteal thickening, and give the appearance of a shortened bone filled with air, termed spina ventosa.

Fifteen-month-old girl from Ethiopia who had been asymptomatic until 1 day earlier, when she fell from a chair. Plain radiographs ( A and B ) demonstrate an expansile lesion in the left proximal femur, with obscure margins and centralized cyst formation without significant periosteal reaction. Magnetic resonance images ( C and D ) show the anterior soft tissue component associated with fluid-filled cysts in the bone as well as in the soft tissues. Findings at open biopsy were consistent with extrapulmonary tuberculosis.

When bone lesions occur near an involved joint, a biopsy specimen should be taken from the area of involved bone rather than from the synovium alone because the synovium may show only nonspecific changes. Curettage of the bacilli sequestrated in the necrotic tissue within cavities and bone defects is necessary to exact a cure because systemic chemotherapeutic agents may not be able to access these locations. For tubercular bone and joint involvement, current treatment recommendations include a 12-month regimen of isoniazid, rifampin, pyrazinamide, and streptomycin for the first 2 months, followed by isoniazid and rifampin for the remaining 10 months of therapy.

Nontuberculous Mycobacteria

Nontuberculous mycobacteria are found in many parts of the natural environment, including soil and water. Infections caused by these organisms have been increasingly recognized in immunocompromised and otherwise healthy individuals. Case reports of osteoarticular infections caused by Mycobacterium fortuitum and Mycobacterium avium-intracellulare complex illustrate the characteristic features. These infections usually manifest 4 to 8 weeks after penetrating trauma, with a clinical appearance of cellulitis or a draining puncture wound. A recurring cutaneous lesion with scant serous drainage may be noted, and a fistula may form.

Surgical débridement is necessary and may be curative if the infection is well circumscribed. Otherwise, antimicrobial therapy with a combination of agents is necessary. Commonly used antibiotics include clarithromycin, ciprofloxacin, amikacin, and imipenem.

Treponema pallidum

With the advent of penicillin, the incidence of syphilis has decreased markedly; however, it remains common in developing countries. Syphilis of bone has been reported in up to 65% of cases of congenital syphilis. During 2002, a total of 412 cases of congenital syphilis was reported in the United States, and it represented a continued sharp decline in incidence.

The organism reaches bone via hematogenous dissemination and can be found in the bone marrow as early as 36 hours following infection. Pathogens tend to localize in the metaphysis and diaphysis and do not spread to joints. The most common sites of involvement are the tibia, femur, humerus, and cranial bones. Syphilitic metaphysitis is the usual finding in early infancy ( Fig. 27-13 ). Symmetric involvement of multiple bones is characteristic. The physis becomes widened, irregular, and ill-defined. The epiphyses usually are not involved. Pathologic fractures may occur through the weakened metaphyseal area. Necrosis may develop, and frank pus can form if the disease process is not stopped. In later childhood, syphilitic osteoperiostitis produces a dense, circumscribed swelling over the convex side of the bone. In the tibia, the subperiosteal apposition of bone on the anterior cortical surface produces the classic “saber shin” of congenital syphilis ( Fig. 27-14 ).

Congenital syphilis in a 3-month-old girl. Note the characteristic bilateral and symmetric metaphyseal erosions, which have progressed to diffuse osteochondritis with periosteal new bone formation.

Classic “saber shin” in an adolescent with untreated congenital syphilis.

Brucella melitensis

Brucella melitensis is most commonly transmitted to humans through the consumption of raw milk, a practice that is still common among indigenous populations in the Middle East. Other common means of exposure include ingestion of, or contact with, meat from infected animals and contact with the products of conception of infected animals, which may occur in farmers and meat packers. Other reported Brucella species include Brucella abortus (most common in North America and Europe) and Brucella suis. The control program for cattle in the United States has nearly eliminated B. abortus infection from U.S. herds; most cases in humans are identified in international travelers or recent immigrants. One of the largest reported series of brucellosis came from Kuwait, where 452 patients with brucellosis were studied. In that study, 25% of patients were younger than 15 years. Osteoarticular infections occurred in 37.4% (169) of the patients, most commonly manifesting as arthritis (79.8%) followed by spondylitis (6%), osteomyelitis (2.4%), and tendinitis or bursitis (1.2%). The most common sites of arthritis were the hip (53%), knee (36%), sacroiliac (20%), and ankle (15%) joints. Brucellar osteomyelitis is very rare in children, and only a single case was reported in patients younger than 55 years (a 17-year-old patient) in this large series.

Because the organism is identified in culture in less than 20% of cases, the diagnosis of brucellosis is often made when a rising antibody titer (or a single titer >1:160) is found in the presence of compatible symptoms and a risk of exposure. Treatment is accomplished with a 4- to 6-week course of two-drug therapy using tetracycline and streptomycin, rifampin and tetracycline, or trimethoprim-sulfamethoxazole and streptomycin. A relapse rate of 16.6% was reported using either single-drug treatment or only a 2- to 4-week course. Osteomyelitis may require 12 weeks of antibiotic treatment and wide surgical excision.

Bartonella henselae

Cat-scratch disease (CSD) is a self-limiting lymphadenopathy caused by Bartonella henselae and is most frequently reported in children and young adults. The course of the disease is usually of short duration and benign. Approximately 10% of children with CSD develop complications, however, which may include hepatic granuloma, splenic abscess, encephalitis, or osteomyelitis. Severe systemic disease, which may persist for months, has been described in 2% of patients. Since the first description of CSD in 1954, 22 cases of associated osteomyelitis have been reported, 19 of them in children.

The diagnosis of CSD is difficult because the clinical presentation and tissue histologic features are nonspecific. The diagnosis should be considered in children who present with fever and lymphadenitis when a history of contact with cats or kittens is obtained. Tissue specimens typically demonstrate noncaseating granulomas, and organisms may occasionally be identified by Warthin-Starry silver staining. The diagnosis is made by an enzyme-linked immunosorbent assay or indirect fluorescent antibody test, which demonstrates elevated titers of immunoglobulin G and immunoglobulin M to B. henselae. Elevated antibody titers are found in less than 5% of the general population who do not have CSD. PCR assays of pus or tissue have a reported sensitivity and specificity approaching 100%, but this method of testing is not available in most laboratories.

Treatment options are controversial. Antibiotic therapy is recommended, but it is uncertain whether the condition may resolve without treatment. Various antibiotics have been used with success, including aminoglycosides, azithromycin, cefazolin, and trimethoprim-sulfamethoxazole; however, only aminoglycosides display bactericidal activity against these organisms. I have occasionally encountered children with such advanced epitrochlear lymphadenopathy that the lymph node architecture was compromised to the point of abscess formation that required surgical débridement ( Fig. 27-15 ).

Coronal ( A ) and axial ( B ) magnetic resonance images of the elbow demonstrate an enlarged epitrochlear lymph node in a child with a history of exposure to cats. Enzyme-linked immunosorbent assay serologies were positive for Bartonella henselae. Surgical débridement resulted in rapid resolution of her limited elbow motion and pain.

Mycotic Organisms

Mycotic osteomyelitis and septic arthritis are extremely rare and are often specific to endemic areas ( Fig. 27-16 ). Fungal infections may occur by direct inoculation, as happens with Aspergillus species, Sporothrix schenckii, and Scedosporium species. Alternatively, organisms may infect bone by hematogenous spread from other invasive infectious loci, such as the lungs. This commonly occurs with Candida species, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Cryptococcus neoformans. Fungal osteomyelitis is often seen in immunocompromised hosts.

Endemic areas of fungal infection in the United States. Coccidioidomycosis: southwestern United States, particularly the San Joaquin Valley of California. Blastomycosis: areas extending from Wisconsin to Louisiana and from the Carolinas to Kentucky. Actinomycosis: Mississippi, western North Carolina, and the northeastern United States.

The radiographic features of fungal infections of bone are variable but have been described as similar to those seen in tuberculous osteomyelitis. Fungal infections are often inappropriately treated owing to diagnostic delay. A high level of suspicion is needed to ensure that fungal cultures are sent and a proper biopsy specimen from bone or synovium is obtained for histopathologic evaluation.

Treatment with amphotericin B has been the preferred treatment for fungal infections. More recently, the use of ketoconazole, in conjunction with operative treatment, has proved to be effective.

Coccidioides immitis

Coccidioidomycosis, a fungal infection caused by C. immitis, affects primarily the lungs. Dissemination is rare but may produce skeletal lesions, either solitary or multiple. The diagnosis is made by identifying characteristic spores under the microscope. Serologic tests and skin tests are not sufficiently specific for diagnosis. The disease is endemic in the southwestern United States, particularly the San Joaquin Valley of California and Arizona. A significant increase in the incidence of coccidioidomycosis has been reported. A high index of suspicion should be maintained in patients with a flulike illness who live in or have visited areas with endemic disease.

Blastomyces dermatitidis

Blastomycosis affects primarily the skin and lungs. Bone is the third most common location of involvement, and as many as 60% of patients with systemic illness have a skeletal infection. Blastomycosis is endemic throughout the southeastern and south-central United States, along the Mississippi and Ohio River valleys, and in central Canada. The disease is more common in rural areas and among outdoor workers. The diagnosis is made by histologic examination but may also be made by culture of the organism on Sabouraud agar. Curettage and treatment with either amphotericin B or ketoconazole appear to be effective.

Actinomyces israelii

Actinomycosis is a chronic infection caused by the organism Actinomyces israelii; the infection usually involves the soft tissues of the head and neck, followed in frequency by the lungs and intestine. Bone becomes involved by direct extension. In North America, actinomycosis is endemic in Mississippi, North Carolina, and the northeastern United States. Patients are treated with long-term administration of penicillin.

Sporothrix schenckii

Sporotrichosis is a chronic granulomatous infection caused by the organism S. schenckii; it affects primarily the skin and subcutaneous tissues. Hand involvement is common because of penetrating injury from plant thorns. Skeletal lesions may occur by direct extension from a subcutaneous lesion or, less commonly, through hematogenous spread. Sporotrichosis may be associated with sarcoidosis or tuberculosis.

Osteomyelitis

The four discernible types of pediatric osteomyelitis are based on the time of onset, the manner of clinical presentation, and the response to treatment: AHO, subacute osteomyelitis, chronic osteomyelitis, and chronic recurrent multifocal osteomyelitis (CRMO). In AHO, the child often presents within several days of the rather sudden onset of illness and localized symptoms. In contrast, in subacute osteomyelitis, medical evaluation may not be sought for 2 weeks or longer after the onset of symptoms, which are typically vague and minimized, thus leading the family or the physician to overlook or discount the child’s condition. Chronic osteomyelitis is commonly the consequence of the failure to eradicate AHO; it lasts for months to years and creates the hallmark clinical findings of dead bone (sequestrum) surrounded by reactive new bone (involucrum). The pathogenesis of CRMO is uncertain, but it typically follows a prolonged, relapsing and remitting course lasting several years and involving multiple sites.

Acute Hematogenous Osteomyelitis

Epidemiology

Evidence indicates that the epidemiology of musculoskeletal infection is evolutionary and that regional variation exists. Thus it is difficult to extrapolate the reported experience from one institution or region to predict the epidemiology in other areas reliably. Reports from a single health district in Glasgow, Scotland, identified a 44% decrease in the incidence of osteomyelitis (predominantly AHO) between 1990 and 1997 and a 50% decrease between 1970 and 1990. Other authors reported little change in the incidence of osteomyelitis since the 1970s. Within our institution, we found a 2.8-fold increase in the annualized per capita incidence of osteomyelitis over a 20-year period.

Pathophysiology

AHO most commonly affects the metaphyseal region of long bones, with lower extremity locations—femur (27%), tibia (22%), and fibula (5%)—slightly more common than upper extremity locations—humerus (12%), radius (4%), and ulna (3%). Long bone infections account for 75% of cases of osteomyelitis; nontubular bone infections occur with a reported incidence of 10% to 11% for pelvic osteomyelitis, 7% to 8% for calcaneal osteomyelitis, 5% for hand involvement, and 2% for vertebral osteomyelitis or diskitis. Isolated cases of osteomyelitis in rare locations such as the cuboid, patella, and clavicle have been reported. Bacteria can be introduced into bone by hematogenous spread from bacteremia (most common route), local invasion from a contiguous infection, or direct inoculation from penetrating trauma, such as an open fracture or foot puncture wound.

Transient bacteremia is thought to be a relatively common event in childhood; it may be a consequence of other infections such as otitis media, pharyngitis, and sinusitis that gain access to the bloodstream, or it may be related to daily activities such as tooth brushing and Valsalva-type maneuvers. It is presumed that bacteria gain access to the metaphyseal location of long bones through the branches of the nutrient arteries, which ultimately terminate in the regions adjacent to the physis as straight, narrow arterioles that form loops and connect with wider venous sinusoids ( Fig. 27-17 ). Trueta proposed that this anatomic configuration results in slow, turbulent blood flow in which the circulating bacteria can localize. Gaps in the endothelium of metaphyseal vessels in growing children may allow the passage of bacteria from the metaphyseal circulation into the extravascular space. These anatomic features differ from those of adults, in whom hematogenous osteomyelitis is rarely identified.

Metaphyseal circulation of the long bones in children. The nutrient artery terminates in end arterioles, which make a hairpin turn adjacent to the physis and feed into larger venous sinusoids. The resultant turbulent circulation enables bacteria to enter the extravascular space.

It has long been recognized that the mere presence of bacteria in bone is not enough to cause disease. Various investigators have sought to create a model of AHO that resembles the clinical disease, with limited success. However, one model that originally helped substantiate the effectiveness of antibiotics in the treatment of osteomyelitis was created by injecting sodium morrhuate directly into bone to produce an area of necrosis immediately before injecting the area with bacteria. Hypothesizing that local tissue trauma may be a supplemental causative factor essential to the initiation of osteomyelitis, Morrissy and associates studied the effects of physeal injuries in New Zealand White rabbits before inducing experimental bacteremia and demonstrated a reproducible model resembling AHO. In this research, the inflammatory response was consistently confined to the portion of bone beneath the area of injury, in the secondary spongiosa, whereas the bacteria were identified in the primary spongiosa, a relatively acellular area. It is surmised that the lack of phagocytic activity in this vulnerable region in growing children may allow the proliferation of bacteria and the initiation of AHO. Another factor that may influence the localization and proliferation of bacteria, specifically S. aureus, is the presence of surface antigens that play a key role in bacterial adherence to type 1 collagen and endotoxins that suppress the local immune response. An extensive glycocalyx that may also form around the bacteria and enhance their adherence to other bacteria and metallic implants may be protective against antibiotic treatment.

A significant anatomic feature that allows osteomyelitis to gain access to the epiphysis is the continuity of circulation across the physis, which remains open until approximately 18 months of age ( Fig. 27-18 ). Osteomyelitis originating in the metaphysis at an early age can easily spread to the epiphysis and result in the total destruction of both, with profound implications for the subsequent development of the proximal femoral and proximal humeral anatomy.

Vascular anatomy of the proximal femur. A, In the neonate, the entire epiphysis shares a blood supply with the metaphysis. Thus infection in the metaphysis can spread into the epiphysis and can produce devastating osteonecrosis of the proximal femur. B, After development of the secondary ossification center, the epiphysis and metaphysis have separate blood supplies. Thus in the older child, the physis prevents the spread of infection into the epiphysis. However, the metaphysis remains intraarticular, and infection may decompress into the joint and produce septic arthritis.

Once bacteria have gained access to the extravascular space, local macrophages and monocytes migrate to the foreign stimulus and phagocytize the pathogen; this process leads to the production and release of prostaglandins and cytokines. Prostaglandin E production is 30-fold higher in infected bone than in normal bone, and experimental treatment of osteomyelitis in rats with ibuprofen prevents bone resorption and sequestration, despite elevated bacterial counts in the local tissues. The inflammation-associated cytokines include IL-6, IL-1β, tumor necrosis factor-α (TNF-α), interferon-γ, transforming growth factor-β, and IL-8. IL-6 acts as the chief stimulator of the production and release of most acute-phase proteins by hepatocytes, including CRP, fibrinogen, the complement system, and serum amyloid A. CRP acts as an opsonin for bacteria, parasites, and immune complexes and can activate the classic complement pathway, thereby modulating the behavior of several cell types involved in the inflammatory response, including neutrophils, monocytes, natural killer cells, and platelets. The patterns of cytokine production and the acute-phase response may vary in different inflammatory conditions, with the cytokines operating both as a cascade and as a network in stimulating the production of acute-phase proteins. Altogether, the acute-phase response results in physiologic and metabolic alterations, including fever, lethargy, leukocytosis, altered vascular permeability, and changes in hepatic biosynthesis, which act in concert to neutralize the infectious agent and foster the healing of damaged tissues.

Classification

Osteomyelitis has been classified by pathogenesis, anatomic location, extent, duration, and host status. The first classification system was described in 1970 by Waldvogel and co-workers, who categorized bone infection by cause; however, this system was not useful for guiding treatment or determining prognosis. The Cierny-Mader classification, proposed in 1984, was based on anatomic type (medullary, superficial, localized, diffuse) and host status (normal, local compromise, systemic compromise) ( Table 27-1 ). Using this classification, the authors developed comprehensive treatment guidelines for 12 stages of infection. Because most children with osteomyelitis are normal hosts with localized osteomyelitis, the Cierny-Mader classification has limited application in pediatric orthopaedics.

Table 27-1

Cierny-Mader Osteomyelitis Staging System

Classification	Description
Anatomic Stage
1	Medullary osteomyelitis
2	Superficial osteomyelitis
3	Localized osteomyelitis
4	Diffuse osteomyelitis
Physiologic Host Status
A	Normal host
B	Systemic compromise Local compromise Systemic and local compromise
C	Treatment worse than the disease

 

From Mader JT, Shirtliff M, Calhoun JH: Staging and staging application in osteomyelitis, Clin Infect Dis 25:1303, 1997.

A clinically useful subclassification of AHO in children is based on the child’s age and development. Ultimately, this system may be more helpful in anticipating both the causative organism (and thus guide empiric antibiotic selection) and the clinical manifestations of infection in a given child. Children appear to have somewhat distinct age-related periods when certain types of infection have their highest incidence ( Table 27-2 ). Numerous factors may influence this relationship, including the following: exposure to specific organisms during childbirth; loss of maternally conferred immunity; developmental anatomy; exposure to specific organisms during daycare, preschool, and school; and the onset of sexual activity during adolescence. These age-related categories are neonatal (birth to 8 weeks), infantile (2 to 18 months), early childhood (18 months to 3 years), childhood (3 to 12 years), and adolescent (12 to 18 years).

Table 27-2

Causative Organisms and Empiric Antibiotics for Musculoskeletal Infections Based on Patient Age and Risk Factors

Patient Characteristics	Causative Organisms	Empiric Antibiotics
Age Group
Neonatal (birth to 8 wk)
Nosocomial infection	Staphylococcus aureus, Streptococcus species, Enterobacteriaceae, Candida species	Nafcillin or oxacillin plus gentamicin or Cefotaxime (or ceftriaxone) plus gentamicin
Community-acquired infection	S. aureus, group B streptococcus, Escherichia coli, Klebsiella species	Nafcillin or oxacillin plus gentamicin or Cefotaxime (or ceftriaxone) plus gentamicin
Infantile (2 to 18 mo)	S. aureus, Kingella kingae, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b (nonimmunized)	Immunized: nafcillin, oxacillin, or cefazolin Nonimmunized: nafcillin or oxacillin plus cefotaxime, or cefuroxime
Early childhood (18 mo to 3 yr)	S. aureus, K. kingae, S. pneumoniae, N. meningitidis, H. influenzae type b (nonimmunized)	Immunized: nafcillin, oxacillin, or cefazolin Nonimmunized: nafcillin or oxacillin plus cefotaxime, or cefuroxime
Childhood (3 to 12 yr)	S. aureus, GABHS	Nafcillin, oxacillin, or cefazolin
Adolescent (12 to 18 yr)	S. aureus, GABHS, Neisseria gonorrhoeae	Nafcillin, oxacillin, or cefazolin; ceftriaxone and doxycycline for disseminated gonococcal infection
Risk Factor
Sickle cell disease	Salmonella species, S. aureus, S. pneumoniae	Ceftriaxone
Foot puncture wound	Pseudomonas aeruginosa, S. aureus	Ceftazidime or piperacillin-tazobactam and gentamicin
HIV infection	S. aureus, Streptococcus species, Salmonella species, Nocardia asteroides, N. gonorrhoeae, cytomegalovirus, Aspergillus, Toxoplasma gondii, Torulopsis glabrata, Cryptococcus neoformans, Coccidioides immitis	Broad-spectrum antibiotics per infectious disease recommendations
CGD	Aspergillus species, Staphylococcus species, Burkholderia cepacia, Nocardia species, Mycobacterium species	Nafcillin, oxacillin, or cefazolin

 

CGD, Chronic granulomatous disease; GABHS, group A β-hemolytic streptococcus; HIV, human immunodeficiency virus.

Neonatal.

Neonatal osteomyelitis occurs in two distinct varieties. The first is encountered in infants 2 to 8 weeks of age who are typically discharged from the hospital with their mothers soon after birth, often after full-term, spontaneous vaginal delivery. The problem is often identified when parents become concerned about a lack of movement or visible swelling of an extremity in their newborn. Because the clinical features of fever and irritability are usually not present in this age group, diagnosis and treatment may be delayed. These neonates also fail to mount an inflammatory response that could be detected in common laboratory studies, and their radiographic evaluation may also be equivocal. Because of these issues, a high index of suspicion must be maintained. Aspiration of bone and joint should be performed liberally, and antibiotic therapy should be initiated when infection is identified, followed by appropriate surgical decision making.

S. aureus is the most commonly identified organism in this age group. Other common organisms include those encountered during the childbirth process, such as Streptococcus agalactiae (group B streptococcus), enterococci, and Enterobacteriaceae ( Escherichia coli, Proteus species, Klebsiella species).

The second form of neonatal osteomyelitis is encountered in the neonatal intensive care unit, typically in low-birth-weight neonates requiring endotracheal intubation, positive-pressure ventilation, intraarterial or intravenous lines, or umbilical artery or vein cannulation. Multifocal osteomyelitis or septic arthritis is commonly identified in neonates who demonstrate the typical signs and symptoms of sepsis, including temperature instability, poor color and perfusion, abdominal distention, feeding intolerance, bradycardia or apnea, increased oxygen requirements, and tachycardia or tachypnea. Outbreaks of MRSA have been reported in neonatal nurseries in Europe, Asia, the United States, and Australia, thus making this an important organism for empiric treatment. Other causative organisms in this setting include group B streptococci, Enterobacteriaceae species, Candida albicans, and Staphylococcus epidermidis. Our guidelines support the use of ampicillin/sulbactam (150 mg/kg/day divided every 6 hours), gentamicin (2 mg/kg/dose every 8 hours), and vancomycin (15 mg/kg dose every 6 hours) for neonatal infections. Because of the potentially devastating effect on the anatomic development of the proximal femur and humerus, suspicion of large joint infection in these neonates should prompt aspiration and, if positive for infection, surgical drainage. Morrissy even recommended routine aspiration of both hips in all neonates known to have osteomyelitis or septic arthritis at any other site.

Infantile and Early Childhood.

Several organisms appear to have the ability to cause deep infection in children between 3 and 36 months of age. The reasons may be, in part, the timing of the loss of maternally conferred immunity and the onset of increased exposure to specific organisms in daycare settings. The waning levels of passively transferred maternal antibodies to certain pathogens, such as meningococci, are positively correlated with the highest rates of meningococcemia in young children. During later childhood and early adolescence, the level of bactericidal antibodies rises, and disease associated with these early childhood pathogens declines. Although S. aureus remains the most common bacterial isolate in this category, other notable organisms include the following: K. kingae; S. pneumoniae; group A, B, and C streptococci; Haemophilus influenzae type b (Hib; in nonimmunized children); and N. meningitidis.

Continued vigilance is necessary when treating osteoarticular infections of the large joints in this age category, particularly up to age 18 months, when long-term sequelae from osteonecrosis and growth disturbance may result. For this reason, we endorse early aspiration and surgical débridement of the hip and shoulder whenever sepsis is encountered in early childhood.

Childhood.

Among children between 3 and 12 years of age, the most common causative organism of AHO is S. aureus (80% to 90%); S. pyogenes (GABHS) is next in frequency, accounting for approximately 10% of culture-positive cases. The age of children with GABHS AHO is consistent with the peak incidence of GABHS infection in school-age children, with a median age of 36 months reported in one series. Children who experience severe streptococcal infections with multisystem dysfunction are, on average, slightly older, with a median age of 8 years (range, 3 to 11 years). Further evidence of the age specificity of streptococci is noted in varicella-zoster viral infections (chickenpox), which typically occur in children between 5 and 9 years of age. Chickenpox is an associated risk factor in up to 17% of cases of GABHS AHO. Penicillin is the treatment of choice for GABHS infections.

Adolescent.

Invasive musculoskeletal infection in adolescents is most commonly caused by S. aureus, followed by GABHS. Additionally, sexually active adolescents are at risk for the development of disseminated infection with N. gonorrhoeae involving the skin, joints, and, rarely, the meninges, heart, and bones. According to the CDC, in 2002, rates of gonococcal infection among non-Hispanic black female patients aged 15 to 19 years were the highest of all racial-ethnic or age groups at 3300 per 100,000, compared with only 125 per 100,000 among the general population.

Treatment

Antibiotic Therapy.

The management of AHO begins with the intravenous administration of an antibiotic to cover the most likely causative organism until a more specific antibiotic can be chosen based on culture and sensitivity results (see Table 27-2 ). The empiric choice of antibiotic for AHO is generally driven by the local prevalence of CA-MRSA and the recommendations of local pediatric infectious disease consultants.

Antibiotic dosing for AHO is based on evidence that the drug penetrates the infected tissues and attains sufficient levels in the bone and pus so that concentrations exceed those minimally necessary to inhibit the pathogen’s survival. The antibiotic dosage for osteomyelitis is usually two to three times the standard dose to ensure a peak serum bactericidal titer of 1:8 or greater. Parenteral therapy is continued until an appropriate clinical and laboratory response has occurred, at which time oral antibiotic therapy can be considered. Since the 1980s, sequential parenteral-to-oral antibiotic therapy has been standard for the completion of treatment of uncomplicated osteomyelitis on an outpatient basis. * The duration of the initial intravenous antibiotic therapy varies from 3 to 14 days and is often governed by normalization of the CRP level. ^† Evidence suggests that early transition to oral therapy in the treatment of AHO has minimal risk of treatment failure while avoiding the risks of prolonged intravenous therapy.

* References .

† References .

Certain conditions should be satisfied before the transition to oral therapy, including (1) clinical and laboratory improvement toward resolution (near normal), (2) availability of an effective oral agent that is tolerated by the child, and (3) likely compliance with the antibiotic regimen, based on an assessment of familial and social circumstances. Once oral therapy is initiated, peak serum bactericidal titers or serum antibiotic levels can be determined to ensure effective dosing. A peak titer of greater than 1:8 constitutes effective dosing. Serum bactericidal titers are assessed by drawing blood 60 to 90 minutes after the second or third oral dose of antibiotic, preferably ingested by the child on an empty stomach. Results should be available within 3 to 4 days and can help guide dosing adjustments. A simplified treatment plan, which proposes to dispense with the measurement of serum bactericidal activity, was successful in two small retrospective series. However, a more traditional and conservative perspective is that measuring serum antibiotic concentration or bactericidal activity is neither burdensome nor cost prohibitive and may reveal the rare child who would benefit from prolonged parenteral therapy.

When oral treatment is not possible, outpatient parenteral antimicrobial therapy (OPAT) is an alternative that allows antibiotic administration for a prolonged period in the child’s home at a significantly lower cost compared with conventional in-hospital therapy. OPAT is typically performed with a central venous line or peripherally inserted central catheter; catheter-related complications have been reported in 30% to 50% of children, and complications related to other factors such as adverse drug reactions have occurred in 29% to 32% of children. Despite these concerns, most complications are minor and can be resolved without interruption of the antibiotic course. Excellent clinical outcomes have been reported in 93% to 98% of children in whom OPAT is used.

The end point of antibiotic treatment is difficult to standardize because of the significant variation in both disease severity and response to treatment among children with AHO. The recommended duration of antibiotics ranges from 4 to 8 weeks, but successful treatment has been reported in uncomplicated cases with a mean duration of only 23 days. Currently, no evidence-based consensus on the most appropriate route and duration of antibiotics for AHO in children exists. Our approach is to aim for an oral antibiotic duration of 6 weeks, with follow-up laboratory studies performed at approximately 1 to 2 weeks after hospital discharge, to ensure an appropriate downward trend is occurring, and again at 4 to 6 weeks, to ensure laboratory normalization before the antibiotic is discontinued. If the ESR remains elevated at the 6-week point, we continue antibiotics and repeat the laboratory studies every 2 to 3 weeks until the ESR is normal. However, if the duration exceeds 12 weeks and the laboratory indices are not trending downward in a favorable manner, MRI is considered to exclude a surgically treatable cause for the slow response to antibiotic therapy.

Surgery.

Considerable difference of opinion exists regarding the timing, extent, and necessity of surgery to treat AHO. The primary problem is the lack of clear and specific indications for surgery. One series reported an aggressive primary surgical protocol consisting of the following: extensive open irrigation and drainage of pus, hematoma, and granulation tissue; cortical drilling or fenestration; and curettage of the medullary canal on both sides, with care to avoid the growth plate. Despite this approach, however, 17% of the children developed chronic osteomyelitis. Other centers have reported a more measured approach to the surgical treatment of AHO, by basing the decision on factors that could indicate the failure of antibiotic therapy alone. These factors, which suggest a more advanced stage of AHO, include the presence of a subperiosteal or intraosseous abscess or a visible metaphyseal lytic cavity on radiographic studies, as well as a limited clinical or laboratory response to an initial course of antibiotics.

Cole and associates observed that most children with AHO could be cured with a single course of antibiotics and immobilization if treatment were initiated within 1 or 2 days of the onset of symptoms rather than within 4 to 5 days, when the condition has advanced to the stage of abscess formation (92% compared with 25%). Another series noted that the difference in the rate of chronic infection—12% for the operatively treated group and 4% for the nonoperatively treated group—depended more on the time interval between the onset of symptoms and the beginning of treatment than on other factors. Unfortunately, no prospective randomized trials have been conducted to compare the clinical outcomes of surgical and nonsurgical treatment in groups of children matched by the severity of illness. The rate of treatment failure is unavoidably higher in children subjected to surgical intervention because operations are generally performed when the presence of purulent exudate has already compromised the healing response of local tissues.

Some authors consider surgical intervention to be necessary when the proximal femur is involved, even if the infection is identified early and a discrete abscess is lacking. The risk of developing a contiguous septic arthritis or avascular necrosis is high enough that more aggressive intervention is warranted.

Complications

The most concerning adverse outcomes attributed to AHO are chronic infection, avascular necrosis, growth disturbance, deep vein thrombosis, pulmonary embolism, and multisystem involvement. The likelihood of chronic infection appears to be correlated with the length of antibiotic treatment, with up to 19% of those treated for 3 weeks or less developing this complication, compared with only 2% of children treated for longer than 3 weeks. Avascular necrosis of the proximal femur and proximal humerus appears to be mediated by the delayed recognition (>5 days) and inadequate decompression of contiguous osteomyelitis, as well as septic arthritis in the hip and shoulder.

Growth disturbance as a consequence of infection tends to be central and diffuse. This condition creates a bar that is difficult to resect and may have significant long-term consequences, including major limb length discrepancy when the arrest occurs at an early age. One series noted the difficulty of fully appreciating these growth disturbances until children reach a mean age of 9 years, and the authors recommended follow-up to skeletal maturity to identify this problem.

A report of 17 children with pathologic long bone fractures secondary to S. aureus identified a greater prevalence of subperiosteal abscess and larger circumferential size of the abscess as rick factors for fracture. A sharp zone of abnormally diminished enhancement of the marrow also was more common in patients with fractures than in those without fracture. The authors recommended protected weight bearing and activity restrictions for children at risk for pathologic fracture.

Deep vein thrombosis and pulmonary embolism are rare in childhood, with an estimated incidence of less than 0.01%. Reports have identified a possible association among AHO, deep vein thrombosis, and septic pulmonary embolism as part of a life-threatening clinical syndrome of disseminated staphylococcal disease that requires early recognition and aggressive treatment with antibiotics, surgical drainage, anticoagulation, and assisted ventilation, if needed. ^‡ Because no underlying hereditary or hematologic risk factors are identified in these children, it appears that a prothrombic tendency, which could otherwise be expected, is not essential to the development of thrombosis in the setting of musculoskeletal infection.

‡ References .

Early evidence indicates that the presence of selected genes encoding certain virulence factors may explain the occurrence of complications such as deep vein thrombosis associated with S. aureus infections. The Panton-Valentine leukocidin ( pvl ) gene was found encoded in the strains of MRSA and MSSA isolated in 5 of 28 children with musculoskeletal infection who developed deep vein thrombosis. A relationship between pvl -positive strains and other complications, such as chronic osteomyelitis and prolonged hospitalization, also was found.

Other complications of AHO include functional disability, limb length inequality, deformity, and adverse drug events from antibiotic treatment. Adverse drug reactions developed in 29% of OPAT courses in one series and prompted early discontinuation of antibiotics in most of these patients. The most common drug-related complications were neutropenia (13%), rash (12%), hepatitis (5%), and diarrhea, fever, urticaria, anaphylaxis, and ototoxicity (4% combined). The most common antibiotics associated with neutropenia were nafcillin and cefotaxime; oxacillin was associated with rash and hepatitis. Clindamycin may cause pseudomembranous colitis, with a reported incidence of 0.1% to 10%; this complication appears to be unrelated to dosage or duration of therapy.

Subacute Osteomyelitis

Epidemiology

This entity was first described by Brodie in 1836; the descriptive term subacute was added by Billroth in 1881. Modern experience with subacute osteomyelitis was introduced by Harris and Kirkaldy-Willis in 1965, followed by a report from King and Mayo in 1969 and the original four-part classification presented by Gledhill in 1973.

Subacute osteomyelitis differs from AHO in that it is more difficult to diagnose because of the lack of characteristic signs and symptoms of infection. The onset is usually insidious, and mild symptoms may be present for more than 2 weeks before medical attention is sought. Laboratory studies may be normal or only mildly elevated in these children. Radiographic features often suggest benign or malignant skeletal neoplasia. Abnormalities that resembled neoplasia were identified on plain radiographs in 50% of cases in one series. For many reasons, diagnostic delay is common, and correct diagnosis took an average of 3 to 5 months in two separate reports.

Subacute osteomyelitis is less common than AHO, with an incidence ranging from 7% to 42% of the combined cases of acute and subacute forms of osteomyelitis. Reports indicate an increasing incidence of subacute osteomyelitis compared with AHO. The ability to identify the causative organism by culture is more limited in cases of subacute osteomyelitis, and positive results are obtained in only 29% to 61% of cases. S. aureus is the most commonly identified organism. The location of bone involvement is more diverse than in AHO; diaphyseal and epiphyseal locations are reported with greater frequency in subacute osteomyelitis. Children with subacute osteomyelitis are also older than those with AHO, and they average 7.5 years of age.

Pathophysiology

Most authors support the theory that subacute osteomyelitis is a consequence of an altered host-pathogen relationship characterized by decreased bacterial virulence, increased host resistance, or a combination of these factors. ^§ Some cases are thought to occur secondary to the inadequate or partial treatment of AHO or following the administration of antibiotics for other infections; those children without any antecedent illness or treatment are considered to have primary subacute osteomyelitis. One report found that 40% of children with subacute osteomyelitis had recently received antibiotics for other infections, including tonsillitis, acne, or tooth abscess, compared with only 5% of children with AHO. Knowledge of the pathophysiology of this condition is limited. However, one theory is that the bacteria establish a nidus of infection in which only a localized inflammatory response develops. This creates local bone destruction that may or may not stimulate a sclerotic or periosteal reaction through a combination of pressure atrophy and inflammatory granulation tissue.

§ References .

Classification

A radiographic classification of subacute osteomyelitis was initially proposed by Gledhill and subsequently expanded into a six-part classification by Roberts and colleagues ( Fig. 27-19 ). This modification is based on the anatomic location (metaphyseal, diaphyseal, epiphyseal, or spinal), the morphology of the lesion and its surrounding architecture, and the similarity of the lesion to various neoplasms. Type IA lesions are metaphyseal, have a punched-out appearance, and resemble an eosinophilic granuloma; type IB lesions differ slightly, with a sclerotic margin, thus resembling a classic Brodie abscess. Type II lesions erode the metaphyseal cortex and may be difficult to differentiate from osteogenic sarcoma. Type III lesions are localized lucent lesions in the cortex of the diaphysis, with a periosteal reaction that may resemble osteoid osteoma. Type IV lesions are diaphyseal, with an onion-skin periosteal reaction that simulates the appearance of Ewing sarcoma. Type V lesions are concentric-appearing epiphyseal lucencies; chondroblastoma would be considered in the differential diagnosis. Finally, type VI lesions involve the vertebral body and may produce erosion and destruction in a manner similar to that seen in eosinophilic granuloma or tuberculosis.

Radiographic classification of subacute osteomyelitis. This classification system is based on the anatomic location, the response of the surrounding tissue to infection, and the similarity to benign or malignant tumors:

Type IA: Metaphyseal area of radiolucency without marginal sclerosis

Type IB: Metaphyseal area of radiolucency with surrounding reactive bone, the classic Brodie abscess

Type II: Metaphyseal area of radiolucency with cortical erosion (may be misinterpreted as osteosarcoma)

Type III: Localized diaphyseal lesion with periosteal reaction (may be misinterpreted as osteoid osteoma)

Type IV: Diaphyseal lesion with subperiosteal new bone formation (may be misinterpreted as Ewing sarcoma)

Type V: Epiphyseal lesion

Type VI: Vertebral lesion (also known as diskitis)

(Redrawn from Roberts JM, Drummond DS, Breed AL, et al: Subacute hematogenous osteomyelitis in children: a retrospective study, J Pediatr Orthop 2:249, 1982.)

Evaluation and Treatment

Because of the diagnostic uncertainty in these cases, it is often necessary to perform a more extensive workup before deciding on a course of treatment. At my institution, we frequently obtain a complete laboratory and radiographic evaluation, including CBC with differential, ESR, CRP, and plain radiographs. Subsequent imaging studies may include MRI with and without contrast, three-phase total-body bone scan, and CT scan with and without contrast. Findings are reviewed with a radiologist to arrive at the most likely differential diagnosis. Plans for biopsy are coordinated with an orthopaedic oncologist to ensure that clear communication is established. In cases with an aggressive and potentially malignant appearance on diagnostic studies (see Fig. 27-2 ), the orthopaedic oncologist performs the biopsy, whereas in cases without aggressive features (see Fig. 27-3 ), we perform the biopsy while carefully observing the principles outlined by Mankin and associates. A frozen section is obtained and personally reviewed with the pathologist, and intraoperative cultures are obtained for aerobic, anaerobic, fungal, and AFB organisms before initiating antibiotics.

The decision whether to perform a biopsy is controversial. Hamdy and colleagues reported excellent results after a 6-week trial of antibiotics without biopsy or débridement, and this conservative approach has found favor with a few authors. Most reports have expressed a preference for surgical management of these lesions. ^‖

‖ References .

Although I agree that surgical débridement is unnecessary from a treatment standpoint, I often sample these lesions for biopsy for the sake of diagnostic certainty and the rare chance that a prolonged course of antibiotics may be avoided if a benign skeletal neoplasm can be definitively diagnosed. Families are often unsettled by the delay in diagnosis that may have already occurred and may be in favor of a biopsy and culture procedure to reach a conclusive diagnosis. On occasion, biopsy results yield unexpected findings that alter the subsequent treatment plan and prevent further delay and frustration for the child and the family ( Fig. 27-20 ).

Three-year-old boy with a 3-week history of limp and knee swelling. Plain radiographs ( A and B ) show soft tissue swelling without an obvious skeletal lesion. Bone scan ( C ) demonstrates focal uptake in the epiphysis on delayed images. Magnetic resonance images ( D and E ) identify a well-circumscribed lesion in the upper tibial epiphysis with subtle marrow signal change in the metaphysis; this finding favors infection over a benign-appearing tumor. Biopsy was performed ( F ), and pathologic examination demonstrated mixed granulomatous tissue ( G ) and fungal elements ( H ). Candida tropicalis was cultured from the tissue and traced to hospitalization more than 1 year earlier when the child had developed line sepsis with C. tropicalis in the intensive care unit. Complete clinical resolution was achieved following treatment with amphotericin B.

A 6-week course of an oral antistaphylococcal antibiotic should be used when culture results do not identify a specific organism. These children should be followed on a long-term basis to ensure the success of treatment.

Complications

Very few complications are reported. For most children with subacute osteomyelitis, the condition resolves following appropriate treatment. However, one form of the disease, described as primary chronic sclerosing osteomyelitis, may have a prolonged course with intermittent symptoms over several years. Ultimately, this form may be found to be related to CRMO.

Chronic Osteomyelitis

Epidemiology

Chronic osteomyelitis is a consequence of AHO that may lead to extensive bone necrosis, formation of sequestra, and, ultimately, segmental bone defects. The most significant factors in reducing the incidence of chronic osteomyelitis appear to be the early diagnosis of AHO and the prompt initiation of antibiotic therapy with an appropriate duration of treatment. The prevalence of chronic osteomyelitis is much higher in developing countries as a consequence of delayed diagnosis and undertreatment, whereas this disease is becoming much less common in industrialized nations.

S. aureus is the most common causative organism in chronic osteomyelitis. The most common site of involvement is the tibia; this is likely related to the limited vascularity of this bone, which is further compromised by the extensive periosteal stripping that occurs in advanced AHO. The next most common sites are the femur and humerus. Most children who have chronic osteomyelitis have undergone surgical intervention—often multiple procedures—as part of the treatment of AHO. This situation may play a role in compromising the soft tissues and skeletal architecture during the treatment process.

Pathophysiology

In children, the metaphyseal cortex is thin, and the periosteum is loosely bound to the underlying bone. If untreated, infection in this region erupts into the subperiosteal space, travels down around the diaphysis, and eventually deprives the bone of its blood supply ( Fig. 27-21 ). The results are dead bone (sequestrum) and granulation tissue, which retard healing and harbor bacteria because neither antibodies nor antibiotics can adequately penetrate these tissues. Certain bacteria, particularly S. aureus, adhere to bone by expressing receptors for the components of bone matrix and by demonstrating intracellular survival within osteoblasts, which may explain the persistence of infection in chronic osteomyelitis. In response to the sequestrum, the body forms abundant periosteal new bone (involucrum) around the necrotic cortex. In a growing child, involucrum formation can be extensive, creating new bone around the sequestrum from which infection may be reactivated and erupt into draining sinuses.

Magnetic resonance images of a 10-year-old girl with 2 weeks of antecedent knee pain ( A and B ). An extensive subperiosteal purulent fluid collection with nearly circumferential stripping of the soft tissues from the femoral cortex is seen on the axial image ( B ). As anticipated, the child developed chronic osteomyelitis and a pathologic fracture through the distal femur secondary to the extensive area of ischemic bone ( C and D ).

Classification

Chronic osteomyelitis is often defined as the presence of ongoing bone infection for longer than 1 month in the presence of devitalized bone. The Cierny-Mader classification considers chronic osteomyelitis to be a stage 4B condition because of the presence of diffuse osteomyelitis in a host who is compromised either locally or systemically. More recently, Jones and colleagues proposed a classification of chronic hematogenous osteomyelitis in children that includes three main types: type A, Brodie abscess; type B, sequestrum involucrum; and type C, sclerotic. Type B involvement is subdivided into four subgroups: B1, localized cortical sequestrum; B2, sequestrum with normal involucrum; B3, sequestrum with sclerotic involucrum; and B4, sequestrum without structural involucrum. According to the authors, the distinction between types B2 and B3 is important because removal of the sequestrum is likely to result in resolution of the infection with a normal involucrum, whereas eradication is more difficult and recurrence is likely with a sclerotic involucrum.

Authors with experience in the treatment of this condition emphasize the importance of determining the severity of the condition with respect to the presence or absence of sequestrum, involucrum, and bone defects at the time of presentation. Each of these factors has a significant influence on the timing and method of treatment.

Evaluation

Most children with chronic osteomyelitis present with a known diagnosis and a substantial medical history as a consequence of the treatment of AHO. Occasionally, however, the diagnosis is unconfirmed, necessitating a thorough initial evaluation. Laboratory studies should include CBC with differential, CRP, ESR, and blood cultures to assess the ongoing response to the presence of infection and help guide further antibiotic treatment. Most of the time, culture material is obtained at the time of surgical débridement. However, a noninvasive method has been described to obtain cultures in cases that involve draining sinus tracts. First the sinus orifice is cleansed with povidone-iodine (Betadine). Then the nozzle of the syringe is placed into the sinus tract, and aspiration is performed while deep pressure is applied over the infected region. Using this method, Mousa was able to obtain cultures that were 88.7% sensitive and 95.7% specific for the causative organism from a total of 115 operative isolates.

Radiographic studies should include high-quality plain radiographs to evaluate for sequestrum, involucrum, avascular necrosis, and bone defects. MRI with and without gadolinium may be helpful to differentiate areas of bone infarction and sequestrum formation from areas of active osteomyelitis and abscess formation. A common pitfall of MRI, however, is the inability to distinguish clearly between acute and chronic osteomyelitis; it is also difficult to interpret the significance of extensive marrow signal abnormalities associated with advanced stages of acute and chronic osteomyelitis (see Fig. 27-10 ). Chronic osteomyelitis can also be imaged with CT, which may help evaluate the nature and magnitude of bone defects.

After radiographic and laboratory studies have been reviewed, unconfirmed chronic osteomyelitis should be cautiously approached with an open biopsy to obtain tissue for frozen and permanent sections, as well as a complete set of cultures for aerobic, anaerobic, and fungal organisms and AFB. Osteogenic sarcoma and Ewing sarcoma have been discovered at open biopsy for suspected chronic osteomyelitis.

Treatment

The ultimate goals in the treatment of chronic osteomyelitis are eradication of the causative organism, elimination of local inflammatory tissue destruction, and restoration of functional anatomy. Typically, these objectives require a multidisciplinary effort.

Antibiotic Therapy.

In most cases, decisions regarding antibiotic selection, route of administration, and duration of treatment are beyond the expertise of the orthopaedic surgeon and require consultation with an infectious disease specialist. Rifampin is favored as a supplement to first-line antistaphylococcal antibiotics in chronic infection because it achieves intraleukocytic bactericidal action and facilitates the eradication of bacteria from the tissues. Treatment for up to 6 to 9 months may be necessary, and the response should be carefully monitored by serial laboratory, radiographic, and clinical evaluations.

Although most authors would agree that effective treatment of chronic osteomyelitis requires both surgical and medical interventions, some children have been treated solely with antibiotics and demonstrated complete recovery.

Surgery.

Débridement surgery is the foundation of osteomyelitis treatment. The major goal of surgery in chronic osteomyelitis is to remove the sequestrum, abscess cavities, and granulation tissue that harbor bacteria and prevent the circulation of systemic antibiotics into the infected tissues. Most children with chronic disease require multiple procedures to achieve this goal. One series reported an average of 3.2 procedures per child. The greatest difficulty lies in determining how extensive the débridement should be; sufficient infected bone and soft tissue must be resected to allow antibiotic therapy to complete the process, but no clearly defined guidelines exist for this decision. Mader and co-workers appropriately suggested that “débridement should be direct, atraumatic, and executed with reconstruction in mind.” In general, all devitalized tissues should be excised, with débridement of bone carried down until uniform haversian or cancellous bleeding is visualized (the “paprika” sign). External stabilization is used whenever complete débridement threatens skeletal stability.

Ideally, the dead space is managed by using durable, vascularized tissue and performing complete wound closure whenever possible. Antibiotic-impregnated polymethyl methacrylate (PMMA) beads can be exchanged every 2 to 4 weeks to reduce the dead space while increasing antibiotic levels at the site of infection. Alternatively, implantable drug pumps provide a means of delivering antibiotics locally for extended periods and avoid the need for repeated exchange of PMMA beads. One group reported the successful use of an antibiotic pump system with infusions sustained for 32 to 40 days (mean, 36 days) in 21 patients, without any unintended increase in systemic antibiotic levels or adverse drug effects such as nephrotoxicity or ototoxicity.

The condition of the periosteum is important to the healing process and is best assessed by the presence of involucrum, which may take 2 to 8 months to form. In the presence of generous involucrum, most children regenerate adequate diaphyseal new bone to avoid the need for bone grafting and reconstructive procedures. Early débridement of the sequestrum is not thought to be detrimental to the subsequent formation of involucrum.

When extensive débridement, inadequate involucrum, or pathologic fracture results in significant segmental defects, reconstructive procedures must be performed to restore functional anatomy. Choices for reconstruction have included open bone grafting, tibiofibular synostosis, vascularized fibular autograft, soft tissue transfers with gastrocsoleus flaps, and the bifocal method of bone transport using the Ilizarov method. Two groups have reported successful use of the Ilizarov method in the treatment of chronic tibial osteomyelitis. Earlier work showed that the method of distraction osteogenesis increases blood flow by 3 to 10 times in the extremity and thus enhances local tissue levels of antibiotics. In children, it does not appear necessary to perform bone grafting at the docking site.

Complications

Recurrence of disease within 2 years has been reported in 20% to 30% of children with chronic osteomyelitis, despite treatment with surgical débridement and appropriate antibiotics. More aggressive débridement, such as that performed with the Ilizarov method and oblique wire bone transport ( Fig. 27-22 ), reportedly yields better results, with 80% to 100% good or excellent outcomes. Most of the complications reported in the treatment of chronic osteomyelitis are related to the reconstructive procedures; they include osteopenia, joint stiffness, angular deformity, nonunion, proximal tibiofibular joint dislocation, and pin site infections.

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