The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Floyd S. Ota. This current third edition chapter is a revision and update of the original author’s work.
A 5-year-old male presents with decreased appetite and intermittent tactile fever for the last five days. He complains of pain in his right leg and he has been having an increasingly difficult time walking over the last 2 days. He has a history of falling seven days ago. His mother denies recent weight loss, cough, or dysuria. He has no previous medical problems.
Exam: VS T 39.4, P 110, R 16, BP 95/50, oxygen saturation 99% RA. He is alert and non-toxic appearing. His heart, lungs and abdomen are normal. Examination of his extremities reveals swelling, warmth, and tenderness to his right proximal tibia. He has some palpable inguinal lymphadenopathy on the right. He has difficulty bearing weight and walks with a slight limp. There are no cutaneous skin lesions. His neurologic and joint exams are non-contributory.
Laboratory studies show WBC 18,000, 68% segs, 7% bands, 20% lymphs, 5% monos, Hgb 13.4, platelet count 290,000. ESR 60 and CRP 85. Plain radiographs of his right tibia and fibula are normal. Osteomyelitis is suspected. Thus, an MRI scan is obtained under propofol sedation, which shows a hyperintense signal in the marrow with a small pocket of pus elevating the periosteum and soft tissue swelling of the right proximal tibia suggestive of osteomyelitis.
An orthopedic consultation is obtained, and a closed needle drainage of the area is done. IV vancomycin is started empirically and subsequent blood and wound cultures grow out methicillin-sensitive Staphylococcus aureus. His antibiotics are changed from vancomycin to oxacillin. While in the hospital his fever declines and his function returns. He is discharged on oral cephalexin to complete four weeks of treatment.
Osteomyelitis by definition is inflammation of the bone generally due to infection. Acute osteomyelitis is classified as the presence of symptoms for under 2 weeks, subacute osteomyelitis symptoms range from 2 weeks to 3 months, while chronic osteomyelitis is a persistent infection for months to years with findings such as Brodie’s abscess or necrotic bone (1). The annual incidence of acute osteomyelitis is 1 in 5000 children per year (2,3,4,5). Males tend to develop osteomyelitis more often than females (5,6). Nearly half of the pediatric cases occur in patients under the age 10 but rarely, infections can occur in patients younger than 4 months old without an underlying risk factor (5,6,7). The most common cause of osteomyelitis is bacterial; however, fungal and viral causes are also possible.
There are two general categories of acute bacterial osteomyelitis: 1) hematogenous seeding, or 2) contiguous spread. Acute hematogenous osteomyelitis is the most common presentation in children. Acute hematogenous osteomyelitis has a predilection for the long bones of the body. Long bones consist of two distinct types of bone. The diaphysis or shaft is made of a dense lamellar bone, which is relatively acellular and slow growing. The ends of the bone near the growth plate (the metaphysis) are made of a maze-like bone called cancellous bone. This maze-like structure allows for spreading of the infection via small channels in the bone that leads into the subperiosteal space. The metaphysis is the most common location for osteomyelitis to develop. The process begins when thrombosis and bacterial emboli transmigrate through the end capillaries because of local trauma or stasis of local blood flow. This results in bacterial seeding creating a nidus for infection that can be difficult to eradicate due to a relative lack of reticuloendothelial cells (8). Pus collects in the subperiosteal space and surrounding edema produces a mass effect that further decreases blood flow perpetuating tissue ischemia and necrosis. Isolated pieces of dead bone, known as sequestrations, can result from this process. As the remodeling process continues, an involucrum develops which occurs when new bone is deposited over an area of dead bone. The pathophysiology of osteomyelitis differs slightly by age group (8). In neonates, blood flow from the metaphysis is continuous with the joint space and thus a concurrent septic arthritis may develop. Furthermore, in this age group the periosteum is thinner and more likely to rupture into surrounding tissue. This is in contrast to older children in which the infection is contained due to a well-developed periosteum resulting in focal physical findings.
The signs and symptoms of acute osteomyelitis may be subtle, especially in the very young (8).The chief complaint of a child suspected of having osteomyelitis may be refusal to walk and bear weight on the affected limb or the refusal to utilize a specific body part. Often a recent history of upper respiratory symptoms or trauma is elicited. The very young infant may present with only a history of a poor appetite and fever or be ill appearing in fulminant septic shock. Objective findings are fever, swelling, point tenderness, and erythema of the affected body part. The child may have a pseudoparalysis of the affected limb. The most common long bones involved in descending order are the femur, tibia, humerus, fibula, radius and ulna (1). Flat bones are affected less than 20% of the time, with the calcaneus and pelvic bones being the most common with equal incidence (1). Occasionally the physical findings are very subtle, such as a loss of natural body curvatures or normal skin creases. Contralateral assessment for symmetry is an important aspect of the physical exam. Gait assessment for limp or other anomalies may also help to make the clinical diagnosis.
Laboratory studies are helpful in making the diagnosis of osteomyelitis. The most useful laboratory values are the acute phase reactants, of which the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) are the most commonly used. These values are often highly elevated in the presence of acute osteomyelitis and are non-specific indicators of acute inflammation. The ESR is determined by the rate that red blood cells fall through plasma. Both the CRP and ESR are usually elevated when the patient presents with clinical symptoms; however, both can be falsely low, thus it is better to order both tests during the initial diagnosis. It is often taught that the CRP rises faster than the ESR, but published data refutes this confirming that both are usually elevated at the onset of disease. The white blood cell (WBC) count has been found to be unreliable in diagnosing acute osteomyelitis (5). A normal WBC count may be misleading to the clinician in the presence of osteomyelitis. A CBC is still an integral part of the workup since it can be helpful to assess the probability of other diagnoses.
Positive bacterial cultures of the blood, bone, or adjoining sites of infection are very helpful in the diagnosis and management of acute osteomyelitis. Blood cultures have been reported to be positive 30% to 50% of the time (5). Identification of the offending organism and its antibiotic sensitivity are highly useful in guiding antibiotic therapy. Isolation of a pathogen from blood, pus or tissue occurs 50% to 60% of cases, while bone culture can increase yield to 87% (9). The most common single organism isolated is Staphylococcus aureus (70% to 90%) (1,9). This is followed by group A Streptococcus, Streptococcus pneumonia and Haemophilus influenza (1). Salmonella and other enteric pathogens must be considered in patients with sickle cell disease. In the newborn period, group B Streptococci, Escherichia coli and Staphylococcus epidermis are often the cause of osteomyelitis. Kingella kingae is an emerging pathogen for osteomyelitis in patients 6 to 48 months of age (7). As Kingella kingae is difficult to isolate using traditional culture techniques, it should be considered for any culture negative infection. In these cases polymerase chain reaction amplification (PCR), RNA, or DNA amplification can be used for detection (9,10). Pseudomonas aeruginosa is a common etiology of osteomyelitis when it is associated with plantar puncture wounds that are sustained through sneakers (1); in which the mechanism is thought to be a tiny foreign body of foam rubber driven into the sole by the puncture wound. Mycobacterium tuberculosis causes osteomyelitis of the spine in infants known as Pott’s disease as a form of disseminated tuberculosis (11).
Radiographic imaging is an important component in making the diagnosis of osteomyelitis and should always start with plain radiographs of the affected area. Even though plain radiographs will only begin to show osteogenic changes five to seven days into the disease process, these radiographs are helpful to rule out other etiologies of bone pain. After two weeks of osteomyelitis, the devitalized sequestrum can be visualized on radiographs as bony lucency and can be surrounded by the involucrum which may cause elevation of the periosteum (1,12). Magnetic resonance imaging (MRI) is an extremely useful imaging modality in acute osteomyelitis. Findings on MRI accurately identify the extent and structure of the area involved in the pathologic process. MRI is the modality of choice given its reported sensitivity of 97% to 100% with a specificity of 92%, much higher than radiographs or bone scintigraphy (1,12–14). In acute osteomyelitis, the accumulation of purulent material and bone marrow edema can be seen as decreased signals on T1 weighted images or increased signaling with T2 weighted images (1). MRI is the imaging modality of choice for infections involving the spine, pelvis, and limbs due to its ability to provide fine details of the osseous changes and soft tissue extension in these areas. In the spine, loss of the border between the vertebral body and the adjacent disk is a sign of acute osteomyelitis and is only evident with MRI. MRI does have the disadvantage of requiring sedation for young children. A nuclear medicine bone scan is a very sensitive test to diagnose osteomyelitis; however, it is not used often since the test is slow (requires sedation in young children as well), nuclear medicine availability is limited, it results in some radiation exposure, and it has no advantage over MRI. The sensitivity of the bone scan is high (>90%), and this test is often helpful when the exact location and extent of the infection in the body is unknown (1). CT scanning allows for three-dimensional examination of bone and the surrounding soft tissues. This imaging modality can help to show periosteal reaction, cortical bone destruction and if any sequestration or involucrum is present (15). Ring enhancing soft tissue abscesses can also be found. CT is typically only utilized for guided aspiration or surgical planning and not used as a diagnostic tool in osteomyelitis.
The differential diagnosis of a child who presents with fever, bone pain and tenderness includes acute rheumatic fever, septic arthritis, cellulitis, Ewing sarcoma, osteosarcoma, neuroblastoma, leukemia, thrombophlebitis, bone infarction due to sickle cell disease, and toxic synovitis.
The mainstay of treatment focuses on eradication of the offending organism and the minimization of tissue damage. Before empiric antibiotic treatment, blood and bone cultures from suspected areas should be obtained; however, obtaining cultures should not delay treatment. This first is accomplished through initiating parenteral antibiotics (1,8). In the older child, the focus is against the more common gram-positive organisms of S. aureus and group A Streptococci GAS). A beta lactamase resistant penicillin (e.g. oxacillin, methicillin or nafcillin) or a cephalosporin will cover GAS, but only 70% of S. aureus. These antibiotics are considered unacceptable initial coverage since the risk of resistance is too high. All patients should be started empirically on vancomycin. In the younger child and patients with sickle cell anemia, gram negative pathogens such as Haemophilus and Salmonella must be considered, thus the addition of ampicillin or a third-generation cephalosporin (e.g. ceftriaxone) is important. If Pseudomonas aeruginosa is suspected the addition of ceftazidime can be added to the vancomycin, or oxacillin (6) .Kingella kingae is resistant to vancomycin and clindamycin, but is susceptible to cephalosporins, ampicillin or a beta-lactam/beta-lactamase inhibitor combinations (7).
The duration of treatment is somewhat controversial; however, it appears that at least four weeks is required. Shorter courses have shown to have an increased incidence of recurrence (1). Peripherally inserted central IV catheters can be placed and home antibiotics can be arranged. Recently, oral antibiotics have become an accepted option to complete therapy. The following criteria must be met: organism and antibiotic sensitivity identification, the ability to tolerate oral antibiotics, a clear response to parenteral treatment and assured routine compliance (16). Often the dose of oral agents is two to four times the normal dose to maintain adequate drug levels. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) data are useful in predicting therapeutic success with oral antibiotics (17). Trending laboratory values such as the CRP and CBC at routine intervals may be helpful to monitor treatment progress and monitor for iatrogenic side effects. In this regard, the CRP is clearly superior to the ESR since the CRP declines with therapeutic efficacy faster than the ESR (1).
Surgical debridement helps to decrease the tissue damage that occurs due to the inflammatory reaction caused by the infection. The removal of the inflammatory products optimizes the environment to maximize the efficacy of medical therapy. Two criteria indicating the need for surgical debridement are the ability to aspirate pus from the lesion and a failure to see a clinical response within 36 to 48 hours of the initiation of medical treatment (1). Samples obtained from debridement should be sent for pathology identification, cultures and antibiotic sensitivity.
Chronic osteomyelitis can occur due to a penetrating injury/inoculation or inadequate therapy, often due to non-compliance with outpatient antibiotics (1,8). This poses an extremely complicated medical and surgical task for the clinician. As in acute osteomyelitis, S. aureus is most often the organism isolated by culture. Chronic osteomyelitis also has a comparatively higher incidence of gram-negative rods, anaerobes, and non-bacterial pathogens such as fungi and yeast. Very long-term antibiotic therapy and repeat surgical interventions may be required including occasional amputation. Recovery from chronic osteomyelitis is long and complication prone with the prognosis being generally poor.
Questions
1. True/False: The most common pathogen in acute hematogenous osteomyelitis is Group A streptococci (GAS).
2. True/False: A sequestration is an area of loose necrotic bone that is a result of acute osteomyelitis
3. True/False: The duration of antibiotic therapy for acute hematogenous osteomyelitis is typically 7 to 10 days.
4. True/False: Two clinical conditions for surgical intervention in acute osteomyelitis are the ability to aspirate pus from the lesion and a lack of response to medical treatment in 36 to 48 hours.
5. True/False: Plain X-rays will always show bony changes within the first few days of the onset of acute osteomyelitis.
6. True/False: The most common bone involved in acute hematogenous osteomyelitis in children is the tibia.
7. True/False: Osteomyelitis has a propensity to involve the diaphysis of the long bones.
8. True/False: Since Staph aureus is the most common organism involved in osteomyelitis, initiating therapy with an anti-Staph aureus penicillin such as oxacillin is generally accepted as adequate.
9. True/False: The CRP rises faster and declines faster than the ESR.
References
1. Krogstad P. Chapter 55. Osteomyelitis. In: Cherry J, Demmler-Harrison GJ, Kaplan SL, et al (eds). Textbook of Pediatric Infectious Disease. 4th ed. Philadelphia: W.B. Saunders Co; 2019. pp:516–529.
2. Woods CR, Bradley JS, Chatterjee A, et al. Clinical Practice Guideline by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America: 2021 Guideline on Diagnosis and Management of Acute Hematogenous Osteomyelitis in Pediatrics. J Pediatr Infect Dis Soc. 2021;10(8):801–844. doi: 10.1093/jpids/piab027
3. Grote V, Silier CCG, Voit AM, Jansson AF. Bacterial Osteomyelitis or Nonbacterial Osteitis in Children: A Study Involving the German Surveillance Unit for Rare Diseases in Childhood. Pediatr Infect Dis J. 2017;36(5):451-456. doi: 10.1097/INF.0000000000001469
4. Juchler C, Spyropoulou V, Wagner N, Merlini L, Dhouib A, Manzano S, et al. The Contemporary Bacteriologic Epidemiology of Osteoarticular Infections in Children in Switzerland. J Pediatr. 2018;194:190-196.e1. doi: 10.1016/j.jpeds.2017.11.025
5. Stephan AM, Faino A, Caglar D, Klein EJ. Clinical Presentation of Acute Osteomyelitis in the Pediatric Emergency Department. Pediatr Emerg Care. 2022;38(1):e209–e213. doi: 10.1097/PEC.0000000000002217
6. Walter N, Bärtl S, Alt V, Rupp M. The Epidemiology of Osteomyelitis in Children. Children. 2021;8(11):1000. doi: 10.3390/children8111000
7. Wong M, Williams N, Cooper C. Systematic Review of Kingella kingae Musculoskeletal Infection in Children: Epidemiology, Impact and Management Strategies. Pediatr Health Med Ther. 2020;11:73–84. doi: 10.2147/PHMT.S217475
8. Gigante A, Coppa V, Marinelli M, Giampaolini N, Falcioni D, Specchia N. Acute osteomyelitis and septic arthritis in children: a systematic review of systematic reviews. Eur Rev Med Pharmacol Sci. 2019;23(2 Suppl):145–158. doi: 10.26355/eurrev_201904_17484
9. Gornitzky AL, Kim AE, O’Donnell JM, Swarup I. Diagnosis and Management of Osteomyelitis in Children: A Critical Analysis Review. JBJS Rev. 2020;8(6):e1900202. doi: 10.2106/JBJS.RVW.19.00202
10. Carter K, Doern C, Jo CH, Copley LAB. The Clinical Usefulness of Polymerase Chain Reaction as a Supplemental Diagnostic Tool in the Evaluation and the Treatment of Children With Septic Arthritis. J Pediatr Orthop. 2016;36(2):167–172. doi: 10.1097/BPO.0000000000000411
11. Cameron LH, Starke JR. Chapter 242. Tuberculosis (Mycobacterium tuberculosis). In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp. 1565-1582.e2.
12. Mandell JC, Khurana B, Smith JT, et al.Osteomyelitis of the lower extremity: pathophysiology, imaging, and classification, with an emphasis on diabetic foot infection. Emerg Radiol. 2018;25(2):175–188. doi: 10.1007/s10140-017-1564-9
13. Iliadis AD, Ramachandran M. Paediatric bone and joint infection. EFORT Open Rev. 2017;2(1):7–12. doi: 10.1302/2058-5241.2.160027
14. Saavedra-Lozano J, Falup-Pecurariu O, Faust SN, Girschick H, Hartwig N, et al. Bone and Joint Infections. Pediatr Infect Dis J. 2017;36(8):788–799. doi: 10.1097/INF.0000000000001635
15. Desimpel J, Posadzy M, Vanhoenacker FM. The Many Faces of Osteomyelitis: A Pictorial Review. J Belg Soc Radiol. 2017;101(1):24. doi: 10.5334/jbr-btr.1300
16. Kargel JS, Sammer DM, Pezeshk RA, Cheng J. Oral Antibiotics Are Effective for the Treatment of Hand Osteomyelitis in Children. Hand (N Y). 2020;15(2):220–223. doi: 10.1177/1558944718788666
17. Kowalska-Krochmal B, Dudek-Wicher R. The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance. Pathogens. 2021;10(2):165. doi: 10.3390/pathogens10020165
Answers to questions
1. False. S. aureus is the most common. Group A strep is the second most common.
2. True
3. False. Typically the course is 6 to 8 weeks, always starting with IV antibiotics and finishing with PO antibiotics if possible.
4. True
5. False. Plain films usually begin to show acute changes 5 to 7 days into the course of the disease process.
6. False. The femur is the most commonly involved bone. The tibia is the second most commonly involved.
7. False. The metaphysis is the most common site.
8. False. The rate of methicillin resistant S. aureus is too high to use oxacillin/methicillin as empiric therapy. Vancomycin should be initially started.
9. False. While some textbooks and reference articles have alleged that the CRP rises faster than the ESR, most the data comparing the two show that both are elevated (i.e., both are useful) at the time of the initial early diagnosis (i.e., on the front end). It is true that the CRP declines faster than the ESR when therapy effectively covers the offending organism, thus the CRP is better than the ESR at monitoring therapeutic efficacy (i.e., on the back end).