Abstract
Background:
Osteomyelitis is a common pediatric musculoskeletal infection. This infection can weaken the normal bone structure, resulting in the risk of a pathologic fracture. The purpose of this study was to evaluate the risk factors for pathologic fracture in children with Staphylococcus aureus osteomyelitis.
Methods:
Seventeen children who were treated for a pathologic long-bone fracture secondary to Staphylococcus aureus osteomyelitis between January 2001 and January 2009 at a tertiary-care pediatric hospital were identified. These patients were compared with a control group consisting of forty-nine children with Staphylococcus aureus osteomyelitis without a fracture who were matched for age, sex, and methicillin susceptibility. A retrospective review of the clinical records, magnetic resonance imaging (MRI) studies, and microbiologic findings was performed.
Results:
Patients who developed a fracture presented with osteomyelitis at a mean age of 8.8 years (range, two to seventeen years). Fifteen of the seventeen patients had methicillin-resistant Staphylococcus aureus (MRSA) isolates, and two had methicillin-susceptible Staphylococcus aureus (MSSA). The mean time from disease onset to fracture was 72.1 days (range, twenty to 150 days). The duration of hospitalization, number of surgical procedures, duration of antibiotic treatment, and total number of complications differed significantly between the two groups. MRI studies at the time of admission demonstrated a significantly greater prevalence of subperiosteal abscess and greater circumferential size of such an abscess in the patients with a fracture. A sharp zone of abnormally diminished enhancement of the marrow was also more common in these patients. The USA300-0114 pulsotype was more commonly associated with an elevated likelihood of fracture.
Conclusions:
Staphylococcus aureus osteomyelitis is a serious infection that may predispose children to pathologic fractures. Protected weight-bearing and activity restriction are recommended in children with Staphylococcus aureus osteomyelitis who have the risk factors demonstrated in this study.
Level of Evidence:
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Acute hematogenous osteomyelitis is a frequently treated infection in the pediatric population1-6. Its presence is usually suspected on the basis of a suggestive clinical history and physical examination, elevated inflammatory markers, and radiographic findings1-6. Magnetic resonance imaging (MRI) can confirm the diagnosis and determine the extent of bone and soft-tissue involvement7,8.
Staphylococcus aureus has been reported to be responsible for 67% to 89% of cases of acute hematogenous osteomyelitis in the pediatric population1-6. In recent years, an increasing proportion of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates has been detected compared with methicillin-susceptible Staphylococcus aureus (MSSA). Approximately 60% of the community-acquired Staphylococcus aureus infections in some regions in the United States are now resistant to methicillin1,2,4,8-13.
At our institution, most CA-MRSA isolates belong to the USA300 clone14, which is the most prevalent CA-MRSA clone in the United States and accounts for >90% of CA-MRSA isolates in most studies13-16. The clonal designation is based on the pattern formed by enzymatically cleaved Staphylococcus aureus during pulsed-field gel electrophoresis. USA300-0114 is the most common pulsotype pattern. Almost all USA300 Staphylococcus aureus isolates carry the genes that encode the Panton-Valentine leukocidin (PVL) toxin, which destroys white blood cells by creating pores in their membranes13-16.
Osteomyelitis caused by Staphylococcus aureus that carries the genes encoding PVL (
pvl+) typically has a more severe clinical course than osteomyelitis caused by pvl–Staphylococcus aureus isolates7,14-21. Patients with
pvl+ Staphylococcus aureus
osteomyelitis have been found to have a greater prevalence of bacteremia, a longer duration of hospitalization, and a greater number of surgical procedures17 compared with patients with pvl– isolates. The more virulent pvl+ form of osteomyelitis may cause greater structural damage to the normal architecture of the bone, potentially increasing the risk of a pathologic fracture17-20.
Pathologic fractures associated with acute bacterial hematogenous osteomyelitis are rare in all age groups. Most of the reports are in the adult population, with few cases in children22-30. We studied children with acute Staphylococcus aureus hematogenous osteomyelitis and pathologic fractures managed at a tertiary-care pediatric center to identify risk factors for fracture in this patient population.
We retrospectively reviewed our experience with acute osteomyelitis at a tertiary-care pediatric hospital between January 2001 and January 2009. Children who had been treated for Staphylococcus aureus osteomyelitis and who had sustained a pathologic long-bone fracture were identified. This study group was matched on the basis of age, sex, site of infection, and antibiotic sensitivity with a control group of children treated for Staphylococcus aureus osteomyelitis who did not sustain a fracture. Patients with osteomyelitis caused by other organisms and patients with infections associated with decubitus ulcers or sickle-cell anemia were excluded. The study was approved by the institutional review board of our medical school.
Initial Treatment Protocol
Patients who presented to the emergency center with symptoms of fever, swelling, pain, or a limp were assessed for the presence of a musculoskeletal infection. A thorough history, physical examination, baseline blood work including inflammatory markers, and radiography were performed in each case. A clinical diagnosis of musculoskeletal infection was confirmed and staged with use of advanced imaging, primarily MRI.
During the index procedure to treat the osteomyelitis, a small drill was used to decompress the bone and obtain a bone sample for culture. The osseous defect usually involved <20% of the bone diameter, as indicated by postoperative radiographs. Curets, Steinmann pins, or flexible nails were used to assist in the debridement of the infected bone. Lavage with normal saline solution containing 50 U/mL of bacitracin was performed in each case. Drainage of any associated subperiosteal abscess, intraosseous abscess, intramuscular abscess, and/or septic arthritis was also undertaken during the index procedure. Cast or splint immobilization was used postoperatively in an affected lower extremity, and an immobilizer was used if the shoulder was involved.
Empiric antibiotic treatment targeting MRSA and MSSA was begun once blood and tissue samples had been obtained for culture. Once the causative organism and its antibiotic susceptibility were identified, the patient was transitioned to the appropriate parenteral antibiotic. Clindamycin-sensitive MRSA was treated with clindamycin31,32, clindamycin-resistant MRSA was treated with vancomycin, and MSSA was treated with nafcillin or cefazolin. Vancomycin trough levels were obtained in critically ill patients at the request of the pediatric infectious disease service.
The treating infectious disease physician determined the duration of the parenteral and oral antibiotics. Patients were transitioned to oral antibiotics on the basis of clinical, inflammatory, and imaging parameters. Clindamycin-sensitive MRSA was treated with oral clindamycin31,32, clindamycin-resistant MRSA was treated with linezolid or Bactrim (sulfamethoxazole and trimethoprim), and MSSA was treated with cephalexin.
A return to the operating room was usually required when the patient did not improve clinically or experienced an associated complication. When the patient was ready for mobilization, the treating orthopaedic surgeon decided on the postoperative weight-bearing protocol on the basis of the fracture location, organism, and age of the patient.
Data Collection
Multiple parameters available at the time of hospital admission and patient outcome parameters (including the length of hospitalization, number of surgical procedures, and duration of antibiotic treatment) were reviewed. Imaging studies and microbiologic results of cultures from the patient's blood and from the operative sites were also reviewed.
The imaging findings for each patient were retrospectively reviewed by a fellowship-trained musculoskeletal radiologist (S.B.B.) with use of the MRIs acquired during the initial infection work up, including a combination of multiplanar STIR (short tau inversion recovery) and/or fat-suppressed T2-weighted, T1-weighted, and gadolinium-enhanced fat-suppressed T1-weighted sequences. Specific scan parameters, such as the field of view, matrix size, and slice thickness, varied depending on the region investigated. The MRI features reviewed for each patient included the location and extent of the osteomyelitis; the presence of a subperiosteal abscess and its characteristics, including length, thickness, and maximum circumferential size relative to the bone (measured on a selected axial image as a percentage of the bone circumference that was encircled by the abscess); the presence of an intramuscular abscess; the integrity of the cortex; the pattern of marrow signal enhancement; the presence of joint effusion; and signs of deep vein thrombosis7. Radiographs were also reviewed to confirm a subsequent fracture.
All isolates underwent testing of their susceptibility to antibiotics including clindamycin, erythromycin, oxacillin, trimethoprim-sulfamethoxazole, and vancomycin with use of the disk diffusion method, as specified by the Clinical and Laboratory Standards Institute33. Isolates were genotyped with use of pulsed-field gel electrophoresis, and the presence of the PVL gene was determined with use of the polymerase chain reaction (PCR) method34.
Statistical Analysis
Comparisons between the two groups involved analysis of clinical, radiographic, and microbiologic parameters. The Mann-Whitney U test was used to compare continuous variables (e.g., age and temperature), and the Fisher exact test was used to compare categorical variables (e.g., sex). A p value of <0.05 was considered significant.
Source of Funding
No external funding was received for the present study. An investigator-initiated Staphylococcus aureus surveillance study at our institution has been funded by Pfizer since 2001; this grant allowed for the prospective collection of the isolates as well as the molecular testing.
Fracture Group (see Appendix)
Three hundred and sixty-four patients with acute Staphylococcus aureus hematogenous osteomyelitis were evaluated and treated at our tertiary-care pediatric hospital between January 2001 and January 2009, and seventeen (4.7%) of these patients were identified as having an associated pathologic fracture.
The mean time from disease onset to fracture was 72.1 days (range, twenty to 150 days). Pathologic fractures were identified in the femur (10), fibula (4), tibia (1), and proximal aspect of the humerus (2). The fracture involved the metaphyseal-diaphyseal region of the long bone in sixteen patients; the remaining patient (patient 12) had a segmental femoral fracture, with one of the fractures also involving this region. Only one child (patient 7) had sustained a traumatic injury at the time of fracture occurrence; this patient fell in a hole fourteen months after the initial debridement surgery and fractured through pathologic bone. Another child (patient 16) sustained a fracture at the biopsy site without a history of associated trauma.
The mean duration of follow-up in the fracture group was 22.4 months (range, 6.5 to 41.5 months) from the time of initial presentation in the emergency department. In fifteen of the seventeen patients, the fracture was initially treated nonoperatively with use of cast immobilization for the lower limb or a shoulder immobilizer for the upper limb. Two of the children who were older (>12 years) and heavier (patients 13 and 15) underwent internal fixation with antegrade trochanteric nails. One of these children (patient 13) also underwent prophylactic stabilization of the infected contralateral femur, which was at risk for an impending fracture.
Osseous union was achieved in fifteen patients (88%). The remaining two patients (12%) failed to achieve union at the fracture site, requiring surgical intervention consisting of either bone-grafting with internal fixation (patient 4) or bone transport with external fixation (patient 11). A substantial angular deformity of the femur was identified in patient 2 (Figs. 1-A through 1-D). This child subsequently underwent a realignment osteotomy with internal fixation at another institution after the family relocated. In an additional six patients, the fracture healed with a mild to moderate angular deformity (bringing the percentage of healed fractures with an angular deformity to 41%). These six patients are currently being followed to allow time for remodeling of the deformity and may require future realignment surgery. One child (patient 12) developed physeal arrest and may require surgery for limb-length equalization. Two children (patients 9 and 17) with successful fracture union developed sequestrum secondary to chronic osteomyelitis; both underwent saucerization and resection of the sequestrum.
Non-Fracture Group (see Appendix)
The non-fracture group consisted of forty-nine patients with Staphylococcus aureus osteomyelitis who did not develop a fracture. These patients were matched with the patients in the fracture group with regard to age, sex, site of infection, and antibiotic sensitivity. The mean age at the time of presentation was 8.8 years (range, two to seventeen years) in the fracture group and eight years (range, 1.2 to 16.3 years) in the non-fracture group. MRSA was the causative organism in 88% of the patients in each group. The osteomyelitis was located in the femur (26), the tibia (17), the fibula (4), or the humerus (2) of the patients in the non-fracture group. The mean duration of follow-up in the non-fracture group was 10.4 months (range, three to thirty-four months) from the time of initial presentation.
Clinical and Laboratory Findings (Table I)
The patients in the fracture group presented to the emergency department with signs of osteomyelitis at a mean of 5.1 days (range, one to twenty-one days) after the onset of symptoms compared with 3.9 days (range, two to eight days) in the non-fracture group (p = 0.286).
The laboratory parameters and body temperature at the time of presentation did not differ significantly between the two groups. The mean duration of hospitalization was 25.6 days (range, eleven to sixty days) in the fracture group compared with 12.5 days (range, five to forty-six days) in the non-fracture group (p < 0.001). The percentage of patients who required admission to the pediatric intensive care unit and the mean duration of the stay in this unit were similar in the two groups.
Patients in the fracture group required a longer duration of treatment with parenteral antibiotics (p = 0.005) and with oral antibiotics (p < 0.001) compared with the patients in the non-fracture group. The mean total duration of antibiotic treatment (parenteral and/or oral) was 49.2 weeks (range, sixteen to eighty-four weeks) in the fracture group compared with 16.9 weeks (range, four to eighty-four weeks) in the non-fracture group (p < 0.001).
Surgical Management (Table II)
All of the patients in the fracture group and all but three of the patients in the non-fracture group underwent initial surgical treatment to address collections of purulent material associated with Staphylococcus aureus osteomyelitis. The surgical procedures involved bone biopsy and drainage of purulent collections such as subperiosteal abscesses, intraosseous abscesses, intramuscular abscesses, and septic arthritis. Extraskeletal foci of infection were also addressed by pediatric general surgeons. Following evacuation of purulent material, drains were inserted between the bone and the periosteum and inside septic joints. Fifteen patients in the fracture group had drains inserted, and two had the wounds packed open because of the severity of the infection. Forty-five of the children in the non-fracture group had drains inserted, and one had the wound packed open.
Some patients underwent more than one procedure during a single surgical episode because they had multiple foci of infection. A surgical episode was defined as a single anesthetization during which at least one surgical procedure was performed. Eleven (65%) of the seventeen patients in the fracture group required multiple surgical episodes to treat the infection compared with fifteen (31%) of forty-nine in the non-fracture group (p = 0.006). A mean of 2.3 surgical episodes (range, one to five) were required to control the infection in the fracture group compared with 1.4 episodes (range, zero to five) in the non-fracture group. A mean of 2.9 surgical procedures (range, one to six) were required during the initial hospitalization to manage the infection in the fracture group compared with 1.5 surgical procedures (range, zero to five) in the non-fracture group (p < 0.001). The mean time between the first and last surgical episodes was 16.1 days (range, three to forty-six days) in the fracture group compared with 8.1 days (range, two to twenty-eight days) in the non-fracture group (p = 0.153).
Surgical Complications (see Appendix)
The patients in the fracture group experienced a mean of 5.5 surgical or medical complications (range, two to fourteen) compared with 1.3 complications (range, zero to eight) in the non-fracture group (p < 0.001). The long-term sequelae of osteomyelitis required or will require further surgery in 41% (seven) of the seventeen patients in the fracture group compared with 6% (three) of the forty-nine patients in the non-fracture group (p < 0.001).
Magnetic Resonance Imaging (Table III)
MRIs were acquired at the time of admission for sixteen of the seventeen patients in the fracture group. The remaining patient underwent contrast-enhanced computed tomography (CT) scanning before MRI was readily available at our institution. The findings of these MRI studies were compared with those for the forty-nine patients in the non-fracture group.
The MRI scans demonstrated no significant difference between the two groups in the extent of osteomyelitis relative to the length of the bone. A subperiosteal abscess was identified in 94% (fifteen) of sixteen patients in the fracture group compared with 57% (twenty-eight) of the forty-nine patients in the non-fracture group (p = 0.007). The length and the thickness of the subperiosteal abscess did not differ significantly between the two groups. However, the maximum circumferential extent of the subperiosteal abscess was ≥50% of the bone circumference in 93% (fourteen) of fifteen patients in the fracture group compared with 50% (fourteen) of twenty-eight in the non-fracture group (p = 0.006) (Fig. 2-A). An intramuscular abscess was present in 69% (eleven) of sixteen patients in the fracture group compared with 16% (eight) of forty-nine in the non-fracture group (p < 0.001).
Fifteen patients in the fracture group underwent gadolinium-enhanced fat-suppressed MRI studies at admission. A sharp zone of abnormally diminished bone marrow enhancement (Fig. 2-B) was identified in fourteen (93%) of these fifteen patients compared with twelve (24%) of forty-nine patients in the non-fracture group (p < 0.001).
Microbiologic Characteristics (Table IV)
The prevalence of the PVL virulence factor and the prevalence of the USA300 clone of Staphylococcus aureus did not differ significantly between the two groups. However, the USA300-0114 pulsotype was found in 82% (fourteen) of seventeen patients in the fracture group compared with 55% (twenty-seven) of forty-nine patients in the non-fracture group (p = 0.034).
Destructive processes can cause defects in the architecture of bone. These defects reduce the strength of the bone by causing uneven stresses when the bone is loaded, which can result in a fracture35. The healthy bone of a child has greater plasticity than that of an adult, and a greater loss of normal architecture and mineral content is therefore necessary to lead to a fracture36. Pathologic fractures occur as a result of defects in the bone caused by malignancy, underlying bone disease, or infection35-37. Chronic osteomyelitis is a recognized, although infrequent, cause of pathologic fractures, which can occur during the process of bone resorption and formation of new bone23. Most cases of chronic osteomyelitis reported in the modern medical literature have occurred in children26. Although Staphylococcus aureus infection is the most common cause of osteomyelitis, cases of pathologic fracture secondary to Staphylococcus aureus osteomyelitis have been reported rarely19,22,24,27-30 compared with those caused by other microorganisms25,26,38,39.
Approximately 60% of acute hematogenous osteomyelitis cases in the United States are culture-positive, with Staphylococcus aureus being the most commonly isolated organism (in 70% of the culture-positive cases)1-4,8-12. CA-MRSA has emerged as a major pathogen in many areas of the United States and around the world, complicating the empiric approach to antibiotic treatment of suspected Staphylococcus aureus osteomyelitis8-13. Osteomyelitis caused by CA-MRSA isolates that carry the genes encoding PVL is typically associated with a more aggressive disease process and a poorer patient outcome than that associated with other Staphylococcus aureus isolates or other types of organisms7,14-21.
Multiple virulence factors have been linked to the severity of CA-MRSA infection14,17-20. It has been speculated that the epidemic clone of CA-MRSA (USA300) can lead to a more aggressive manifestation of disease in part because of its expression of PVL15, which is a cytotoxin that destroys leukocytes by creating pores in the cell membrane17,19,20. Children with
pvl+ Staphylococcus aureus
osteomyelitis have been found to experience a greater number of febrile days and have a greater complication rate than children with
pvl– isolates14,19,20. Local complications were more frequent and often required repeated surgical drainage14,17,19,20. Extraosseous complications such as pyomyositis, subperiosteal abscess, deep vein thrombosis, and septic arthritis were identified in 60% to 70% of children with CA-MRSA osteomyelitis14,17,19,20.
Dohin et al. reported that
pvl+ Staphylococcus aureus
bone and joint infections were more severe than
pvl– infections and require more prolonged treatment, and they described three pathologic fractures among fourteen patients following acute hematogenous osteomyelitis caused by
pvl+ Staphylococcus aureus
19. Gelfand et al. reported two cases of pathologic fracture in adults following acute CA-MRSA hematogenous osteomyelitis27.
CA-MRSA musculoskeletal infections require prompt recognition and treatment, including aggressive surgical drainage, debridement, and appropriate long-term antibiotics. All of the patients in one previous series required surgical intervention, and sixteen (59%) of the twenty-seven patients required multiple surgical debridements40. Nevertheless, there is a substantial potential for long-term morbidity despite aggressive management40.
To our knowledge, the present study represents the largest published report on pathologic fractures in children following Staphylococcus aureus osteomyelitis. Sixteen (94%) of the seventeen patients with a fracture in our study had a Staphylococcus aureus isolate with the USA300 pulsotype. All seventeen isolates (100%) were positive for the genes encoding the PVL toxin. However, a high percentage of the patients in the non-fracture group also had Staphylococcus aureus isolates that were of the USA300 pulsotype (88%) and were
pvl+ (92%). Nevertheless, isolates from fourteen (82%) of seventeen patients in the fracture group were of the USA300-0114 pulsotype compared with only twenty-seven (55%) of forty-nine patients in the non-fracture group (p = 0.034). It is unclear why the USA300-0114 pulsotype was associated with a greater risk of pathologic fracture. We speculate that one or more virulence factors other than PVL may also be contributing to the greater fracture risk in these patients.
The patients in the fracture group had more complex infections, which may have been the primary risk factor for fracture. The patients in the fracture group had a more prolonged hospital stay, a longer duration of parenteral and oral antibiotic treatment, and more complications, and surgical treatment of the infection was more difficult. This suggests that these patients had a more severe infection and inflammatory response, and that the pathologic fracture was a consequence of the severity of the infection.
MRI is recommended in the setting of a suspected musculoskeletal infection associated with abnormal inflammatory markers (erythrocyte sedimentation rate [ESR] > 22 mm/hr and C-reactive protein [CRP] level > 3.6 mg/dL)7-10. In our study, MRI findings such as the presence of a subperiosteal abscess or an intramuscular abscess as well as a large relative circumferential size of a subperiosteal abscess were associated with a greater likelihood of developing a fracture. A sharp zone of diminished marrow enhancement on MRI scans was also identified as a risk factor. We speculate that a combination of purulent marrow and a subperiosteal abscess with a large circumferential extent may impede both the endosteal and the periosteal blood supply to the bone, causing necrosis of the bone and placing it at a greater risk of fracture.
The radiographic appearance of many of the pathologic fractures was consistent with osteopenia. We speculate that the osteopenia was potentially related to the osseous destruction caused by the osteomyelitis and possibly also related to disuse of the extremity. CT-based structural analysis may ultimately allow the treating physician to identify additional risk factors for fracture on the basis of quantification of bone density in patients with osteomyelitis41,42.
Although this retrospective study was performed at a single institution and had a small sample size, the small number of patients was matched for age, sex, site of infection, and methicillin susceptibility with patients who did not develop a fracture. Nevertheless, the study cohort may not be entirely representative of the general population. Our results may also not apply to osteomyelitis caused by other staphylococcal clones or by other organisms.
We recognize that the short duration of follow-up in the non-fracture group (mean, 10.4 months; minimum, three months) is a potential limitation. A patient in this group was discharged at the final office visit with the infectious disease specialist after the laboratory markers had normalized, the patient had no pain, and the radiographic appearance of the affected bone was normal. Administration of antibiotics was discontinued at that time, and the patient was told to obtain follow-up as necessary. On the basis on these criteria, the probability of a pathologic fracture in a patient in this group after the end of the follow-up period would therefore be low.
Six pediatric orthopaedic surgeons (including J.W. and W.A.P.) participated in this study. Each surgeon tailored the treatment protocol to address medical and surgical complications, and the surgical protocol and the postoperative weight-bearing and activity restriction protocols could also have differed between surgeons. The sample size of this study was too small to determine whether there were surgeon-related factors that affected the fracture risk.
In summary, our experience with seventeen children with a pathologic long-bone fracture secondary to acute Staphylococcus aureus hematogenous osteomyelitis demonstrated that this group of patients had a greater risk of developing sequelae of osteomyelitis compared with children who did not develop a fracture and that many would require further surgery for management of these sequelae. We identified multiple risk factors that will potentially aid in avoiding these fractures. A prolonged hospital stay and multiple surgical procedures may be associated with increased fracture risk. Careful evaluation of imaging studies is also required, specifically including evaluation of the circumferential extent of a subperiosteal abscess and the presence of an ischemic transition zone in the marrow. The USA300-0114 pulsotype appeared to be associated with a greater propensity to cause pathologic fractures. Physicians caring for children with CA-MRSA osteomyelitis must be aware of this potential complication of pediatric hematogenous osteomyelitis.
Staphylococcus aureus osteomyelitis is a particularly difficult infection to treat in children. The risk of pathologic fractures and their sequelae may be reduced by recommending protected weight-bearing and activity restriction in pediatric patients with the risk factors identified in this study. Full weight-bearing can begin once inflammatory markers have returned to normal levels, the involved bone appears normal on radiographs, and the child no longer has pain.
Tables describing the characteristics and management of the pathologic fractures, comparing the demographic characteristics of the children with and without a pathologic fracture, and describing the complications in the patients with a pathologic fracture are available with the online version of this article as a data supplement at jbjs.org.
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