Acute osteomyelitis is a relatively rare disease with a higher incidence in children than in adults and therefore often leads to a serious adverse prognosis. In these patients, it is important to establish the correct diagnosis as early as possible, as early treatment of these patients is essential to improve their clinical prognosis. The emergence of strongly drug-resistant organisms such as MRSA, the availability of various types of antibiotics, and advances in ancillary testing measures have led to important changes in the diagnosis and treatment of acute osteomyelitis over the past few decades. This article summarizes the development and treatment of acute osteomyelitis in recent years to provide a reference for clinicians.
Definition of acute osteomyelitis
Osteomyelitis is a bone infection caused by pathogenic bacteria. The acute phase of osteomyelitis has an onset of less than 2 weeks. The bacterial source of most osteomyelitis is hematogenous and may originate from local infectious lesions such as the respiratory tract, or from trauma or surgery. Hematogenous dissemination is the most common route of bacterial infection in children, usually involving the long bone epiphysis, where blood flow is abundant but slow and bacteria can easily colonize. The femur and tibia are the most commonly affected, accounting for 27% and 26% of cases, respectively (Figure 1).
Figure 1: Parts of the human skeleton susceptible to acute osteomyelitis
In long bones where the epiphysis is located in the joint cavity, such as the shoulder, ankle, hip, and elbow joints, osteomyelitis can spread into the joint and form septic arthritis.
Population with osteomyelitis and its diagnostic importance
The incidence of osteomyelitis ranges from 1-13 per 100,000 people; it accounts for 1% of all pediatric hospitalizations. The incidence is 2 times higher in male children than in females. About 50% of patients occur under the age of 5 years, with a peak incidence under the age of 1 year. Most patients have isolated lesions, with a few patients having multiple occurrences (7% in children and 22% in newborns).
Several recent studies have shown a progressive increase in the incidence of osteomyelitis and, more seriously, an increase in the severity of osteomyelitis infections. A recently completed case-control study in the United States found a 2.8-fold increase in the incidence of osteomyelitis over the past 20 years, while the incidence of septic arthritis did not change significantly over the same period. The proportion of complex osteomyelitis with MRSA as the primary pathogen has also increased, with rates as high as 30% reported in the literature.
Delayed diagnosis of osteomyelitis can lead to septic joints, periosteal membrane abscesses, purulent myositis, deep vein thrombosis, permanent limb damage (e.g., longitudinal limb growth arrest, limb angulation, chronic infection, etc.), bacteremia, multiple organ failure, and in severe cases, possible death. The incidence of osteomyelitis combined with septic arthritis has been reported in the literature to range from 3-33%. In a study of 212 pediatric patients with osteomyelitis, approximately 8% of patients developed periosteal abscesses and 1% had purulent myositis. Predictably, the more extensive the involvement of the infection, the more severe the clinical presentation and severity, and the more complex the treatment required.
In recent years, the treatment of osteomyelitis in children has changed dramatically with the availability of childhood vaccines and improved antimicrobial treatment strategies. The death rate from osteomyelitis has been reduced from 50% to 1%. With prompt, effective treatment, the prognosis for osteomyelitis is usually good, with cure rates reaching 95%. The current strategy for treating acute osteomyelitis has evolved from improving survival to preserving limb function.
Risk factors for osteomyelitis
Approximately more than half of patients do not have associated risk factors prior to the onset of osteomyelitis or have only minor injuries. However, the probability of developing osteomyelitis is much higher in certain pediatric populations and requires more attention from clinicians. Children with immunodeficiencies such as HIV, diabetes, malignancy, hormone therapy, and malnutrition are particularly susceptible to the development of infection. In addition, premature infants are also susceptible to infections due to an underdeveloped immune system. In these patients, the bacteria are disseminated hematogenously and the systemic symptoms are usually severe and accompanied by elevated white blood cells.
Sickle cell disease is a form of hemoglobinopathy with a prevalence of about 1 in 2000 in the UK. Sickle cells block microvessels, leading to local tissue ischemia and infarction, and these patients often have a combination of immune function and splenic disorders, with an increased risk of osteomyelitis. In this group of patients, it is often difficult to distinguish whether the clinical symptoms are due to microvascular occlusion or bacterial infection, because the early clinical manifestations of both are similar, showing redness, swelling, and pain; the current clinical examination findings do not distinguish between the two. Therefore, treatment of both diseases is recommended for patients with sickle cell disease presenting with these symptoms. However, a case-control study in Daisen showed that single site edema (OR 8.4), prolonged fever (80% more likely to diagnose osteomyelitis per day as fever duration increases), and pain (20% more likely to diagnose osteomyelitis per day as pain duration increases).
Diagnosis of osteomyelitis
The typical presentation of children with elevated white blood cells is now rare, probably due to the improvement of the surrounding environment. In subacute osteomyelitis, there is a relative balance between microbial destruction and body repair processes, unlike in acute osteomyelitis.
The onset of osteomyelitis can be insidious, the clinical presentation is variable, and examination is difficult to detect positive signs. There is no single test that can diagnose or exclude acute osteomyelitis. The diagnosis of osteomyelitis in highly suspected cases requires a combination of patient history, physical examination, and reference to laboratory and imaging tests. It is important to note that acute hematologic disorders in children can present with nonspecific skeletal muscle symptoms (Table 1).
Table 1: Differential diagnosis of acute osteomyelitis
The clinical presentation and severity of children can be highly variable depending on the site of infection, age, and pathogenic organisms. A recently completed meta-analysis of 12,000 children with acute and subacute osteomyelitis found that the most common clinical manifestations were pain (81%), erythema (70%), fever (62%), decreased joint mobility or pseudarthrosis (50%), and claudication or decreased weight bearing (49%). In young children, this may manifest as reluctance to use the affected limb. The presentation of osteomyelitis in neonates is more complex because the immune system is not fully developed and the immune response mechanism is incomplete in these children. In this group of patients, fever may not be the predominant symptom and the infectious lesions may be multiple (Table 2).
Table 2: Clinical bases to look for in children with suspected acute osteomyelitis
Medical history
Listen to the child’s voice and observe the communication between him/her and the parents (there may be other factors influencing the child’s pain)
Ask about the location of the pain (at this point, attention needs to be paid to referred pain; some patients with hip disease will complain of knee pain)
Ask about the duration of symptoms (fever >7 days, or symptoms lasting more than 10 days suggest a complex course)
Ask about prodromal symptoms (e.g., recent fever, cough, chills, diarrhea, etc.)
Ask about behavioral changes (irritability, quietness, etc.)
Ask if there is a recent history of trauma (30% of children have a similar history)
Ask for a history of chronic illness (especially sickle cell anemia)
Examination
Measure the child’s temperature (about 40% of children may be nonfebrile)
Observe movement of the extremities
Observe the resting position of the extremities, which may be in flexion and external rotation of the hip or flexion of the knee (Figure 2)
If the child can walk, see if the child has a limp or difficulty in weight bearing
Check for localized redness and swelling of the symptomatic limb
Check for open wounds
Examine other parts of the body to rule out multiple osteomyelitis
Most importantly, if there is a high degree of suspicion or doubt about the diagnosis, consult a pediatrician, an infectious disease specialist, or an orthopedic surgeon.
Figure 2: Child with a temperature of 38 degrees and suspected osteomyelitis of the distal femur. The child is reluctant to bear weight, has been relatively quiet recently, and has low inflammatory markers (CRP 17 nmol/l). The picture shows the patient with mild flexion of the left knee, in flexion at rest, and with knee mobility of 30-90 degrees on physical examination. Subsequent imaging confirmed the presence of osteomyelitis of the distal femur in the child.
What tests help to confirm the diagnosis of osteomyelitis?
A systematic evaluation found that only 36% of children had elevated white blood cells, while 91% had elevated ESR and 81% had elevated CRP. Combined with CRP and sedimentation, the diagnostic sensitivity rises to 98%. The probability of diagnosing septic arthritis increases dramatically when CRP exceeds 100 mg/l, and the likelihood of complications in these patients increases, requiring prolonged intravenous antibiotic therapy at a later stage. Since the half-life of CRP is only 19 hours, it can also be used as a measure to monitor the effect of treatment at the same time.
The British Orthopaedic Association and the British Association of Paediatric Orthopaedic Surgery recommend obtaining and culturing pathogenic bacteria before starting antibiotic therapy, but this recommended measure does not imply a delay in treatment. Although the probability of a positive blood pathogen culture result is only 50%, blood culture is still recommended before empirical anti-infective therapy, so the step may be the only way to identify the infecting organism. The probability of a positive bacterial culture at bone puncture or joint aspiration is higher (70%) in patients with a definite infectious lesion.
Culture specimens can be obtained by CT-guided fine-needle aspiration or surgical biopsy, while simultaneous intra-articular fluid culture and blood culture may improve bacterial detection if the patient has intra-articular fluid. In addition, routine pathology should be performed on any tissue specimen obtained, as some pediatric patients with malignancies may have clinical manifestations similar to those of osteomyelitis.
What imaging studies are chosen in patients with suspected osteomyelitis?
In the early stages of osteomyelitis, radiography may not provide any abnormal findings for reference, but radiography can exclude other associated conditions such as fractures, bone malignancies, etc. Acute skeletal system changes, such as periosteal elevation and bone destruction (Figure 3), do not appear on X-ray until 5-10 days after acute infection, while signs of mild soft tissue swelling may appear earlier than these findings (Figure 4).
Figure 3: Anteroposterior radiograph showing extensive osteomyelitis of the forearm involving the entire radius with osteolysis in some areas (top). The infection was completely resolved after treatment and the imaging was normal (bottom).
Figure 4: Anterior posterior chest X-ray showing severe osteomyelitis and septic arthritis in the shoulder joint area. the X-ray suggests an infected lesion within the proximal humeral head with focal punctiform density shadowing, local soft tissue edema present, and fullness of the shoulder joint.
Magnetic resonance is very useful for the diagnosis of early osteomyelitis, with a sensitivity of 82-100% and a specificity of 75-99%. MRI can clearly distinguish the location and extent of the lesion and provide more imaging evidence of adjacent structures. The test is non-radioactive and non-invasive to children; its disadvantages include: children need to be sedated or under general anesthesia to complete the test because it is a longer procedure with a more pronounced sound; MRI is more expensive than ordinary X-rays; and the testing equipment is larger and more expensive and not easily available in general hospitals. Whole-body MRI can be performed for patients with suspected multiple osteomyelitis and osteomyelitis with unclear location of the lesion.
CT can provide multi-directional reconstruction and accurate assessment of bone tissue changes. However, its application in acute osteomyelitis is of limited significance because of its poor resolution of soft tissues; however, CT is very practical for the diagnosis of chronic osteomyelitis, because chronic osteomyelitis bone can show osteosclerosis, local thickening, and sinus tract formation at CT. For hospitals that do not have MRI, CT examination can be considered as an alternative.
Bone imaging can be used in pediatric patients with unclear foci of systemic osteomyelitis or suspected systemic multiple foci. Its overall sensitivity and specificity are 73-100% and 73-79%, respectively; however, in neonates, the sensitivity of bone imaging for the diagnosis of osteomyelitis decreases (32-87%). The principle of bone imaging is the uptake by the diseased tissue of the nuclide injected into the bloodstream; there is elevated uptake of nuclide at the site of bone infection, and any factor affecting the local metabolic activity of the cells may cause altered uptake of nuclide.
Ultrasound does not allow forceful assessment of the bone marrow cavity and is therefore less commonly used in the diagnosis of osteomyelitis. However, ultrasonography can detect subperiosteal and intra-articular abscesses and assist in localizing biopsies. The significance of ultrasonography is to perform additional tests in patients with suspected osteomyelitis to further establish the diagnosis of the disease. It is inexpensive, safe, noninvasive, and can be used as an adjunct to the presence of contraindications to other screening measures.
What are the types of pathogenic bacteria in acute osteomyelitis?
Staphylococcus aureus is the most common pathogen, accounting for about 70-90% of cases, followed by streptococci (Streptococcus pyogenes and Streptococcus pneumoniae) and gram-negative bacteria. Salmonella is more common in children with sickle cell anemia. It has been suggested that sickle cell tends to cause local microvascular blockage in the intestine, infarction of the intestinal wall, and entry of bacteria from the intestine into the bloodstream through the mucosal barrier, leading to infection. The treatment of acute osteomyelitis in children with sickle cell disease differs from that of other children. A recently published systematic evaluation found that there is currently no standard antibiotic treatment strategy for acute osteomyelitis in patients with sickle cell.
Over the past few decades, the types of pathogens that cause acute osteomyelitis have changed and bacterial resistance has become severe. Haemophilus influenzae, previously the most common bacterium in acute osteomyelitis, has become very rare in recent years due to factors such as vaccination of children. In contrast, the number of cases of MRSA as the pathogenic agent is increasing, and this bacterium has not only changed the strategy of antibiotic treatment, but has also increased the severity of the disease. The literature reports that the proportion of MRSA as the causative agent of osteomyelitis in children varies from 9-30%.
MRSA osteomyelitis can result in more aggressive and severe clinical symptoms, longer hospitalization cycles, higher likelihood of repeat surgery, more frequent and severe complications, and higher likelihood of late progression to chronic osteomyelitis compared to other pathogens.
B. aureus is most commonly colonized in the respiratory tract and can be transmitted through close air in children, and the incidence of osteomyelitis is currently increasing, with the majority (95%) of children younger than 3 years of age. The pathogen is less virulent and has milder symptoms, with only about 15% of children presenting with fever and 39% of patients with normal inflammatory factors, but culture of this type of bacteria is more difficult and is usually detected by molecular biology such as PCR, which is not yet clinically mature enough to detect the bacterium.
In more than half of the children with osteomyelitis, the pathogenic bacteria cannot be identified. When diagnosing a child with what may be a relatively rare pathogenic infection, communication with laboratory and microbiology laboratory testing staff is required, as for some pathogens, conventional testing means may not have a high positive rate and special testing is required to detect that type of pathogen. A systematic evaluation of the literature has found that patients with acute osteomyelitis who are negative for bacterial cultures can be managed with the same strategies as those used in the conventional treatment of staphylococcal osteomyelitis with good results.
How is acute osteomyelitis treated?
The treatment of acute osteomyelitis in children should be multidisciplinary, and its possible involvement includes pediatrics, orthopedics, infection, infectious diseases, emergency medicine, and radiology, which are important in establishing the early diagnosis of acute osteomyelitis in children. A case-control study found that multidisciplinary cooperation facilitates the early diagnosis of acute osteomyelitis in children, the identification of pathogenic organisms, and the development of rational therapeutic measures.
The fundamental goal of treatment of acute osteomyelitis in children is to control the bacterial infection by selecting the appropriate dose and mode of administration according to the sensitivity of the pathogenic bacteria to antimicrobial drugs in order to reduce the associated complications. The choice of antibiotics should be based on the results of bacterial culture sensitivity; for patients for whom bacterial sensitivity results are not available, selective antibiotics should be administered based on the recommendations of the microbiology laboratory, infection unit, and other relevant personnel. However, in order to avoid delay in treatment, antibiotics should be selected empirically before clinical culture results are available, and the selection of antibiotics should cover the most likely pathogens, which are determined based on the severity of the patient’s symptoms, age, and early Gram stain results.
A recently completed systematic analysis found that there is no clear standard for the selection of early antibiotics for acute osteomyelitis in children, the most appropriate duration of intravenous or oral antibiotic administration, and the dose to be used. The British Orthopaedic Association and the British Association of Paediatric Orthopaedic Surgery recommend flucloxacillin or cephalosporin as first-line therapy for children with suspected aureus infection, while clindamycin is recommended as first-line therapy in countries such as the United States and Finland. If the child has not been vaccinated against Haemophilus bleeding, cephalosporins or penicillin G should be considered in the treatment.
Some scholars recommend covering MRSA in the treatment of acute osteomyelitis in children, especially when bacterial culture results suggest that more than 10% of Aureus are methicillin-resistant or when the child has risk factors for MRSA infection such as previous hospitalization. However, this treatment strategy has not been widely accepted by clinicians because some scholars are concerned about the resulting widespread bacterial resistance.
Such patients are susceptible to multiple bacterial infections, such as neonates, sickle cell disease, and immunodeficient children, so it is important to cover as wide a range of possible pathogens as possible for the treatment of these children.
The usual cycle of antibiotic therapy for acute osteomyelitis is 4-6 weeks. However, a larger number of studies with smaller samples suggest that the cycle of intravenous therapy can be shorter. The transition from intravenous to oral therapy depends on the degree of improvement in the patient’s symptoms (improvement in fever and pain, return of function) and blood markers (CRP, ESR).
Only one randomized study showed similar clinical outcomes after 4 days of intravenous antibiotics and 20 and 30 days of oral antibiotic therapy. The results of this study were supported by a recently published systematic review (recommendation level 2B). There are not enough studies of neonatal treatment to change the standard minimum 4-week antibiotic regimen.
The British Orthopaedic Association and the British Association for Paediatric Orthopaedic Surgery do not currently recommend routine surgical exploration in children with acute haematogenous osteomyelitis. A recently published systematic evaluation concluded that a rational antibiotic treatment strategy can be a good treatment for acute osteomyelitis and that surgical exploration does not provide additional benefit. Surgical intervention is required only if the patient has failed antibiotic therapy or if a large local abscess is present. The need for local drainage at the site of osteomyelitis depends on the clinical setting (e.g., temperature, pain, decreased use of the affected limb, elevated CRP levels, etc.) and the patient’s response to antibiotic therapy. About 20% of pelvic abscesses and 6% of patients with long bone osteomyelitis require abscess drainage.
What is the prognosis for osteomyelitis?
Acute hematogenous osteomyelitis in children is usually curable. Early diagnosis of acute osteomyelitis in combination with various adjunctive measures and timely, judicious application of antibiotics can ensure a good prognosis of clinical function without late serious complications. However, clinicians should be alert to the changing nature of pathogenic bacteria and drug resistance. Table 3 shows the factors associated with a poorer prognosis.
Table 3: Factors associated with poorer prognosis in acute osteomyelitis
High virulence of infecting bacteria, such as MRSA, Streptococcus pneumoniae, etc.
Combination of septic arthritis, purulent myositis, and abscess
Location: the highest incidence of complications in the hip (40%), followed by the ankle (33%) and knee (10%)
Positive culture results
CRP levels persistently elevated for more than 4 days
Younger age (these patients are prone to delayed diagnosis and treatment)
Delayed treatment (especially treatment delayed for more than 5 days)
Future directions of clinical diagnosis.
1.PCR technique
Because of the low detection rate of bacterial culture and certain false positive rate, the future can be rapid and accurate determination of pathogenic bacteria through PCR and other technical means.
2.Serum calcitoninogen (PCT)
Serum calcitoninogen is a newly emerged test for bacterial infections and has been used in clinical practice with high specificity and sensitivity to differentiate between bacteria, viruses, inflammatory processes and other causes of clinical inflammation. In a study of 44 children, calcitoninogen was found to be more effective and accurate than CRP, ESR, and WBC in differentiating osteomyelitis and septic arthritis from other diseases.
3.PET-CT
PET-CT is more sensitive than MRI in the diagnosis of osteomyelitis, but its factors such as more radiation, expensive and less equipment limit its clinical application.
4.New treatment methods
Bacterial virulence and anti-infective properties of antibiotics are the key to treating osteomyelitis. Two fifth-generation cephalosporins have been developed for the treatment of MRSA (ceflorin ceftaroline and cefepime ceftobiprole). Other recent therapeutic measures include monoclonal antibodies that directly target the aggressive virulence of the pathogenic bacteria.