Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology

INTRODUCTION — Osteomyelitis is an infection localized to bone. It is usually caused by microorganisms (predominantly bacteria) that enter the bone hematogenously. Other pathogenic mechanisms include direct inoculation (usually traumatic, but also surgical) or local invasion from a contiguous infection (eg, cellulitis, sinusitis, periodontal disease). Other risk factors for nonhematogenous osteomyelitis include open fractures that require surgical reduction, implanted orthopedic hardware (such as pins or screws), and puncture wounds.

The epidemiology, pathogenesis, and microbiology of hematogenous osteomyelitis in children will be discussed here. The clinical features, evaluation, diagnosis, and management of osteomyelitis in children are discussed separately:

●(See "Hematogenous osteomyelitis in children: Clinical features and complications".)

●(See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

●(See "Hematogenous osteomyelitis in children: Management".)

EPIDEMIOLOGY — The incidence of osteomyelitis ranges from 1.2 to 13 cases per 100,000 children per year [1]. It varies geographically (with increased incidence in resource-limited countries) and over time with the emergence of virulent pathogen strains (eg, community-associated methicillin-resistant Staphylococcus in the United States) [2-4].

Hematogenous osteomyelitis is more common in children than in adults. Boys are affected nearly twice as often as girls [5]. More than one-half of pediatric cases occur in children younger than five years and one-quarter in children younger than two years [6]. However, osteomyelitis is uncommon in young infants (<4 months) without underlying risk factors [7]. (See 'Risk factors' below.)

RISK FACTORS — Risk factors for osteomyelitis in neonates (<30 days of age) include [7-9]:

●Complicated pregnancy, labor, or delivery

●Skin infection

●Central venous catheter

●Urinary tract anomalies

●Late-onset neonatal sepsis

Risk factors for hematogenous osteomyelitis in older infants and children include:

●Sickle cell disease (see "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis')

●Immunodeficiency disorders, such as chronic granulomatous disease (see "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections')

●Sepsis

●Minor trauma coincident with bacteremia

●Indwelling vascular catheters, including hemodialysis catheters

PATHOGENESIS

Overview — Hematogenous osteomyelitis in long (tubular) bones begins with bacterial deposition in the metaphysis (figure 1). The mechanism of deposition is unclear, although some evidence suggests that endothelial cells permit microbial passage [10-12]. Trauma or emboli may cause occlusion of the slow-flowing sinusoidal vessels, further establishing a nidus for infection.

The focus of infection in the metaphysis leads to cellulitis in the bone marrow. Inflammatory exudate in the marrow causes increased intramedullary pressure, which forces the exudate through the Haversian systems and Volkmann canals and into the cortex, where it can rupture through the periosteum. Areas of bone necrosis may develop at foci of infection within the bone. The resulting devitalized bone (known as a sequestrum) can be visualized radiographically and may be surrounded by new bone laid down by the elevated periosteum (known as the involucrum). Infection can spread to the epiphysis and adjacent joint space; contiguous extension into the joint space occurs in as many as one-third of cases overall [5,13-16].

Subacute/chronic osteomyelitis is sometimes associated with the formation of an intraosseous abscess (Brodie abscess), a central area of suppuration and necrosis contained and encapsulated by granulation tissue and sclerosis (image 1) [17,18]. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

Age-specific features — The pathogenesis of osteomyelitis in children is influenced by characteristics of the growing skeleton (figure 2) [19].

Birth to three months — Three features of the young infant skeleton facilitate the spread of bone infection [19]:

●The thin cortex and loosely applied periosteum are poorly able to contain infection, which can extend along the subperiosteal space and break through into the surrounding soft tissue.

●Nutrient metaphyseal capillaries perforate the epiphyseal growth plate, particularly in the hip, shoulder, and knee; these capillaries have previously been thought to allow spread of infection to the epiphysis and joint surface, causing concomitant septic arthritis in younger children. However, age no longer appears to be a predictor of concomitant septic arthritis and osteomyelitis, perhaps due to the change in microbiology of osteoarticular infections [20].

●The capsule of the diarthrodial joints frequently extends to, or is slightly distal to, the epiphyseal plate, allowing infection to invade the joint space and causing concomitant septic arthritis from a focus of osteomyelitis either proximal or distal to the joint. (See "Bacterial arthritis: Epidemiology, pathogenesis, and microbiology in infants and children", section on 'Pathogenesis'.)

Older infants and toddlers — The developing skeleton in older infants and toddlers is better able to contain bone infection:

●As the skeleton matures, the cortex becomes thicker and the periosteum slightly more dense. Infection rarely spreads to the soft tissues, but subperiosteal abscess and contiguous edema readily develop; subperiosteal abscess typically occurs at the metaphysis, where the cortex is the thinnest [21].

●Metaphyseal capillaries atrophy as the epiphysis becomes ossified and a distinct physeal plate is formed. This process begins as early as eight months of age, is usually complete by 18 months, and has traditionally been considered to limit the spread of infection to the joint space [22], unless the metaphysis is intracapsular, as it is in the shoulder, ankle, hip, and elbow. However, concurrent septic arthritis and osteomyelitis are now commonly encountered [23,24], and transphyseal vessels are of unclear importance.

Older children and adolescents — In older children and adolescents, the metaphyseal cortex is considerably thicker, with a dense, fibrous periosteum. These features help to contain the infection, which rarely ruptures to spread to the outer cortex. In adolescents, this may result in an intraosseous abscess in which a central area of suppuration and necrosis is contained and encapsulated by granulation tissue (Brodie abscess (image 1)). (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

Vertebral osteomyelitis — Vertebral infections can involve either the intervertebral disc (discitis) or the vertebral body. In young children, the blood supply to the intervertebral disc is rich, derived from periosteal vessels and adjacent vertebral bodies. The vessels from adjacent vertebrae begin to atrophy in the first year of life and are obliterated completely by 10 years of age [25,26]. This may account for the observation that discitis is more common in younger children [27]. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Vertebral bodies and intervertebral discs'.)

The pathogenesis of vertebral osteomyelitis may be related to sluggish blood flow and thrombosis in the vertebral veins. It is discussed separately. (See "Vertebral osteomyelitis and discitis in adults", section on 'Pathogenesis'.)

MICROBIOLOGY — Most cases of acute hematogenous osteomyelitis in children are caused by gram-positive bacteria, principally Staphylococcus aureus (table 1) [5]. However, no pathogen is isolated in routine cultures of blood and wound aspirates in up to one-half of cases [5], which usually are presumed to be caused by S. aureus and treated accordingly [28,29]. In younger children, many of these may actually be due to Kingella kingae. (See 'Kingella kingae' below and "Hematogenous osteomyelitis in children: Management", section on 'Culture-negative osteomyelitis'.)

Most cases of acute hematogenous osteomyelitis are caused by a single organism. Polymicrobial infections usually are associated with contiguous spread, trauma, vascular insufficiency, or immobility of an extremity. (See 'Polymicrobial infections' below.)

Staphylococcus

●S. aureus – S. aureus is the most common cause of osteomyelitis in children in the United States [1]. In a meta-analysis of 15 studies published between 2015 and 2019 including 806 children with confirmed osteomyelitis and an identified etiology, S. aureus accounted for 78 percent [1]; approximately one-third were methicillin resistant, but the proportion varied geographically and over time. Methicillin resistance is associated with increased severity of musculoskeletal infections (eg, multifocal disease, local abscess formation, venous thrombosis).

The high frequency of S. aureus osteomyelitis may be related to a number of extracellular and cell-associated virulence factors that promote bacterial adherence, resistance to host defense mechanisms, and proteolytic activity [30-34]. In a review of 286 children with S. aureus acute hematogenous osteoarticular infections, accessory gene regulator group III was associated with increased risk of orthopedic complications (22 versus 9 percent) [24]. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'CA-MRSA strains'.)

●Coagulase-negative staphylococci – Coagulase-negative staphylococci may cause osteomyelitis in neonates and children with indwelling vascular catheters (eg, for chronic hemodialysis). (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Chronic hemodialysis'.)

Groups A and B streptococci — Group A beta-hemolytic Streptococcus (Streptococcus pyogenes) may cause osteomyelitis in older infants and children, particularly as a complication of varicella-zoster virus infection [35]. In a 2012 systematic review, group A beta-hemolytic Streptococcus was identified in approximately 8 percent of cases occurring after 1996 [5].

Group B Streptococcus causes osteomyelitis in infants younger than three months. In a 2012 systematic review, group B Streptococcus was identified in approximately 4 percent of cases occurring after 1996 [5]. Infants with group B streptococcal osteomyelitis are usually two to four weeks of age. Generally, there is no recognized preceding infection and a single bone is involved. (See "Group B streptococcal infection in neonates and young infants", section on 'Other focal infection'.)

Streptococcus pneumoniae — Streptococcus pneumoniae (pneumococcus) may cause osteomyelitis in children who are at increased risk of invasive pneumococcal disease (eg, those with chronic heart disease, chronic lung disease, diabetes mellitus, sickle cell disease, asplenia, splenic dysfunction, immunodeficiency), including children younger than two years who are incompletely immunized against S. pneumoniae. However, in the post-pneumococcal conjugate vaccine era, most cases occur in children without risk factors and are caused by serotypes not included in the 13-valent pneumococcal conjugate vaccine (especially 35B and 33F) [36]. Serotype 33F is included in the 15-valent and 20-valent pneumococcal conjugate vaccines, which were licensed in the United States in 2022 and 2023, respectively (table 2). (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.)

Kingella kingae — K. kingae, a gram-negative organism present in oral microbiome, is being increasingly identified as a cause of osteomyelitis in children 6 to 36 months of age [13,37-40], and some reports suggest K. kingae is the most common cause of osteomyelitis in Switzerland and France [13,40-42]. It may rarely cause osteomyelitis in older children [43]. K. kingae often affects nontubular bones (eg, sternum, vertebrae, calcaneum) [38] and generally produces milder symptoms than osteomyelitis caused by gram-positive pathogens.

K. kingae is a fastidious organism that is difficult to isolate by conventional culture techniques. Inoculation of specimens into blood culture vials and, especially, molecular diagnostic methods (eg, polymerase chain reaction amplification) may increase detection [38-40,44].

The epidemiology of skeletal infections caused by K. kingae was described in a cluster of cases in children attending a day care center [45]. Within a one-week period, three children aged 17 to 21 months attending the same classroom developed hematogenous osteomyelitis and septic arthritis. Child-to-child transmission was supported by identical patterns on pulse field gel electrophoresis and the increased prevalence of nasal carriage among children in the index classroom compared with children in other classrooms (45 versus 7 percent).

Escherichia coli and other coliforms — E. coli and other coliforms can cause osteomyelitis in neonates. In a 2012 systematic review, E. coli was identified in approximately 2 percent of cases occurring after 1996 [5].

Haemophilus influenzae — Haemophilus influenzae type b (Hib) is a rare cause of osteomyelitis now that infants are routinely vaccinated against Hib [3,46,47].

Other bacteria — Other bacteria that can cause osteomyelitis include:

●Bartonella henselae osteomyelitis may occur in children with cat scratch disease [48-51]. In a literature review of 64 cases of B. henselae osteomyelitis, the vertebral column and pelvic girdle were the most frequent sites of infection; approximately one-third of patients had multifocal disease, with involvement of ≥3 bones [51]. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

●Pseudomonas aeruginosa is a cause of osteomyelitis in injection drug users. It also may occur in children with nail puncture wounds to the foot. (See "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Infection following nail puncture'.)

●Brucella osteomyelitis may occur in children with travel to or living in an endemic area and in children who ingest unpasteurized dairy products. Brucella can produce abscesses in the vertebral bodies or long bones, although bone involvement is not a striking feature of the disease. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Mycobacterium tuberculosis and nontuberculous mycobacteria can cause hematogenous osteomyelitis in children with immunodeficiency, penetrating injuries, or surgical history. (See "Bone and joint tuberculosis" and "Epidemiology, clinical manifestations, and diagnosis of osteomyelitis due to nontuberculous mycobacteria" and "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults".)

●Bacille Calmette-Guérin (BCG) vaccination rarely causes Mycobacterium bovis osteomyelitis. BCG osteomyelitis is discussed separately. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'General principles'.)

●Salmonella species – Salmonella species may cause osteomyelitis in children with sickle cell disease or related hemoglobinopathies [52], exposure to reptiles or amphibians [53], gastrointestinal symptoms, and children in resource-limited countries.

●Actinomyces may cause osteomyelitis in facial bones or vertebral bodies [54]. (See "Cervicofacial actinomycosis".)

●Anaerobic organisms rarely cause osteomyelitis, which most often results from spread of infection from the paranasal sinuses (eg, Pott puffy tumor) or devitalized tissue. However, primary Fusobacterium osteomyelitis with concomitant septic arthritis has been described [55,56].

Fungi — Coccidiomycosis, which is increasingly common in the western United States, can cause infection in cancellous bone such as vertebral bodies, distal tubular bones, and the skull [57]. Infection in multiple sites occurs in nearly one-half of all children and adults with musculoskeletal coccidioidomycosis [58-60]. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Bone and joints'.)

Bone disease caused by Aspergillus has been described in immunocompetent individuals [61]. Aspergillus is frequently a cause of osteomyelitis in patients with chronic granulomatous disease [62].

Polymicrobial infections — Polymicrobial infection is unusual in children with acute osteomyelitis [63]. Isolation of multiple bacteria from bone generally occurs with spread from a contiguous infectious focus, usually from the skull, face, hands, or feet. Distal extremities that are compromised by vascular insufficiency or are immobile, as in patients with paraplegia, spina bifida, or following trauma such as lawn mower injuries, can be sites of polymicrobial osteomyelitis.

Pathogens in abnormal hosts

●Sickle cell disease – Among patients with sickle cell disease, hematogenous osteomyelitis is most often caused by Salmonella species or other gram-negative organisms, such as E. coli [52,64-71]. S. aureus, the most common cause of osteomyelitis in normal hosts, probably accounts for only one-fourth of all cases in sickle cell disease. (See "Acute and chronic bone complications of sickle cell disease".)

●Chronic granulomatous disease – Children with chronic granulomatous disease most often develop osteomyelitis caused by Serratia and Aspergillus species. Osteomyelitis is less often attributed to staphylococci, Pseudomonas, Burkholderia, Nocardia, and other bacterial and fungal species. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections'.)

●HIV – Osteomyelitis in patients with human HIV infection is most commonly caused by S. aureus. S. pneumoniae infections are also particularly common in HIV-infected children who have not been immunized [72]. Other organisms that have been recovered in individual cases include E. coli, Salmonella enteritidis, Cryptococcus neoformans, Mycobacterium kansasii, and Histoplasma capsulatum.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Septic arthritis and osteomyelitis in children".)

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●Basics topic (see "Patient education: Osteomyelitis in children (The Basics)")

SUMMARY

●The incidence of pediatric osteomyelitis varies geographically and is greater in resource-limited than resource-abundant countries. Most cases occur in children younger than five years. Boys are affected approximately twice as often as girls. (See 'Epidemiology' above.)

●Risk factors for osteomyelitis in neonates include complicated delivery, prematurity, skin infection, central venous catheter, and urinary tract anomalies. Risk factors for osteomyelitis in older infants and children include sickle cell disease, immunodeficiency, sepsis, minor trauma with coincident bacteremia, and indwelling vascular catheter (including hemodialysis catheters). (See 'Risk factors' above.)

●The pathogenesis of hematogenous osteomyelitis involves deposition of bacteria in the metaphysis (from the metaphyseal vessels) leading to cellulitis of the bone marrow; the exudate under pressure is forced into the bony cortex, where it can lift or rupture through the periosteum (figure 1). The spread of infection is influenced by characteristics of the growing skeleton (figure 2) (see 'Pathogenesis' above):

•In the young infant, the thin cortex and loosely applied periosteum are poorly able to contain infection, which can extend into the surrounding soft tissue. The metaphyseal blood supply, which crosses the epiphyseal growth plate, permits spread of infection to the epiphysis and joint space. (See 'Birth to three months' above.)

•In older infants, children, and adolescents, the thicker cortex, denser periosteum, and atrophy of the metaphyseal capillaries prevent spread of infection to the soft tissues and epiphysis. However, joint infection may still occur if the metaphysis is intracapsular (eg, shoulder, hip, ankle, elbow) or with simultaneous hematogenous infection. Subperiosteal abscess typically occurs at the metaphysis. (See 'Older infants and toddlers' above and 'Older children and adolescents' above.)

●Most cases of acute hematogenous osteomyelitis are caused by a single organism. However, no pathogen is isolated in up to one-half of cases. Polymicrobial infections usually are associated with contiguous spread, trauma, vascular insufficiency, or immobility of an extremity. (See 'Microbiology' above.)

●Staphylococcus aureus is the most common cause of osteomyelitis in children. Community-associated methicillin-resistant S. aureus is associated with more severe infection than methicillin-sensitive S. aureus. (See 'Staphylococcus' above.)

●Other important bacterial causes of hematogenous osteomyelitis in children include groups A and B Streptococcus, Streptococcus pneumoniae, and Kingella kingae (the dominant cause of osteoarticular infections in several countries) (table 1). (See 'Microbiology' above.)