Abstract
Background
Pediatric acute osteomyelitis and septic arthritis can destroy growth plate cartilage and joint cartilage, causing permanent deformities and growth disorders. Preventing the contraction of osteoarticular infections is important. Various types of bacteria cause osteoarticular infections in children. Since 2013, when routine vaccination against Streptococcus pneumoniae and Haemophilus influenzae was initiated in Japan, diseases caused by these bacteria (other than osteoarticular infection) are reported to decrease. In this study, we aimed to re-confirm the actual situation including the presence of pathogenic bacteria of pediatric bone and joint infections.
Methods
The subjects were patients of 15 years old or younger who had been diagnosed with acute osteomyelitis or septic arthritis and received initial treatment in our hospital from April 1995 to March 2019. We obtained information from the medical records and analyzed them statistically.
Results
There were 65 patients with 65 bones with acute osteomyelitis, and 120 patients with 124 joints with septic arthritis. The pathogenic bacteria were identified in 26 (40.0%) osteomyelitis patients and 59 (49.2%) septic arthritis patients. Staphylococcus aureus was the most common pathogenic bacterium, and S. pneumoniae and H. influenzae were identified in four and seven patients respectively, frequently in younger patients. After routine vaccination against S. pneumoniae and H. influenzae, these bacteria were no longer detected in patients under five years old.
Conclusions
The efficacy of the S. pneumoniae and H. influenzae vaccine against orthopedic infectious diseases in Japan was indicated.
Keywords: Acute osteomyelitis, Septic arthritis, Vaccine, Streptococcus pneumoniae, Haemophilus influenzae
1. Introduction
A diagnosis of osteoarticular infections (OAIs), such as acute osteomyelitis and septic arthritis, may be difficult in infants. Unlike adults, children have growth plate and epiphyseal cartilage around their joints. Therefore, inappropriate treatment can destroy the growth plate cartilage, causing lasting dysfunction.1,2 Because one of the risk factors of sequelae in childhood OAIs is a young onset,3, 4, 5 the prevention of OAIs is presumed to be extremely important, especially in young children. Childhood OAIs are basically hematogenous bacterial infections.1,6 The basic treatment for childhood OAIs is intravenous administration of antibiotics, and in septic arthritis, source control in surgical operation is necessary.
We investigated the etiology of bacteria in childhood OAIs. Since regular vaccinations against Streptcoccus pneumoniae and Haemophilus influenzae were initiated, the prevalence of bacterial meningitis has reportedly decreased.7,8 We therefore also investigated the effects of vaccination on the pathogenic bacteria associated with OAIs, focusing on the timing of vaccination initiation. Furthermore, the relationship between sequelae and the onset age was also inspected.
2. Materials and methods
2.1. Study population
After securing the institutional review board approval, we retrospectively reviewed the medical records of the patients ≤15 years old with OAIs who were initially treated in our hospital between April 1995 and March 2019. Patients who had previously received oral antibiotics alone, prescribed by a previous doctor, were not excluded from this study. Cases in which the causative agents were mycobacteria were excluded, since the treatment policy for such cases is different.
The median age at the diagnosis was 5 years old (range: 4 days to 15 years old), and there were 129 boys and 56 girls. Sixty-five bones of 65 patients had acute osteomyelitis, and 124 joints of 120 patients had septic arthritis (total: 189 bones or joints of 185 patients).
2.2. Definitions
Acute osteomyelitis was defined as a clinical episode in which patients had one or more of the following: fever >37.5 °C, leucocyte count (WBC) >13,000/ml, C-reactive protein (CRP) >0.3 mg/dl, erythrocyte sedimentation rate (ESR) >15 mm or positive blood culture, plus local pain and findings consistent with osteomyelitis on CT (with a lack of sequestrum or involucrum) or on contrast-enhanced MRI (low intensity on T1-weighted imaging and high intensity on T2-weighted imaging, indicating bone marrow edema, and enhancement of the bone marrow on contrasted T1-weighted imaging). Cases with a chronic course, with no fever, no signs of inflammation on blood tests or sequestrums on imaging studies were excluded.
Septic arthritis other than sacroiliac arthritis was defined as a clinical episode in which patients had one or more of the following: fever >37.5 °C, WBC >13,000/ml, CRP >0.3 mg/dl, ESR >15 mm or positive cultures, plus physical examination findings indicating joint inflammation (severe joint pain, tenderness or restricted range of motion), cloudy joint fluid and findings consistent with septic arthritis on ultrasonography (retention of cloudy joint effusion) or on contrast-enhanced MRI (high intensity in T2-weighted imaging indicating existence of joint effusion and involvement of inflammation within or around the joint in contrasted T1-weighted imaging). Sacroiliac arthritis is diagnosed using almost the same criteria as other types of septic arthritis with regard to the symptoms, laboratory data and findings of contrast-enhanced MRI, but the findings indicating bacterial infection, such as a high fever, elevation of all inflammatory parameters and MRI findings, are essential.
Cases with deformities which required additional treatments after the initial treatment were defined as sequelae.
2.3. Treatment policy
All patients received the intravenous administration of antibiotics. Carbapenem antibiotics were selected first empirically. We changed the antibiotics to more appropriate ones after the detection of pathogenic bacteria in the bacterial cultures. We performed arthrotomy and debridement for 110 joints in 106 patients with septic arthritis, excluding sacroiliac arthritis. Subsequently, the patients received continuous perfusion by 2 tubes kept inserted into joints with saline containing antibiotics for 10 days. The state of the inflammation was monitored by blood tests two times a week, including the WBC, CRP and ESR. After the normalization of all values, antibiotics were exchanged to oral administration, depending on the culture results. Pathogenic bacteria were identified in bacterial cultures using samples obtained from the affected joints or blood.
2.4. Survey components
We collected information on the sex, onset age, affected site, clinical history, type of pathogenic bacteria, preceding antibiotics and vaccination histories. We also investigated the sequelae encountered over two years after the onset. The positive rates for culture tests and Gram staining as well as the influence of preceding antibiotics on these findings were evaluated. In addition to the types of pathogenic bacteria, evaluations focusing on the onset age and the transition in time course were carried out. Patients in whom S. pneumoniae or H. influenzae were detected were also evaluated for their vaccination histories against these two bacteria. We compared the age at the onset between cases with and without sequelae.
2.5. Statistical analyses
The statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan),9 which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). For comparisons between two groups, frequencies were compared by Fisher's exact test, and medians were compared using Man-Whitney U test. Differences were defined as significant when the p values were <0.05.
3. Results
3.1. Acute osteomyelitis
The femur (17 bones, 26.2% of all affected bones) was the most commonly affected site. Forty-seven bones (72.3% of all affected bones) were in the lower limbs, with most cases in the lower limbs and pelvis (58 bones, 89.23%) (Table 1). The median age of onset was 7 years old (range: 13 days to 15 years old), and the distribution was bimodal, with peaks around 1 and 10 years old (Fig. 1). The patients included more boys (45 patients, 69.2% of all patients with osteomyelitis) than girls (20 patients, 30.8%) (p < 0.01). There was one case of recurrence (onset site: tibia, onset age: 10 years old, recurring twice: at 3 and 5 months after the initial treatment, pathogenic bacterium: unknown). Nineteen affected bones of 19 patients were followed up for more than two years. One case had sequelae in the fourth metacarpal bone after treatment (onset age: 5 years old, pathogenic bacterium: unknown), which resulted in growth disturbance by 1 cm compared to the unaffected side.
Table 1.
Site of acute osteomyelitis.
| N | % | |
|---|---|---|
| Femur | 17 | 26.2 |
| Foot bones | 17 | 26.2 |
| Tibia | 11 | 16.9 |
| Pubis and ischium | 7 | 10.8 |
| Ilium | 3 | 4.6 |
| Humerus | 3 | 4.6 |
| Fibula | 2 | 3.1 |
| Hand bones | 2 | 3.1 |
| Sacrum | 1 | 1.5 |
| Clavicle | 1 | 1.5 |
|
Radius |
1 |
1.5 |
| Total | 65 | 100.0 |
Fig. 1.
Patients with acute osteomyelitis by age.
3.2. Septic arthritis
Three patients had multiple sites of septic arthritis simultaneously. Two patients had septic arthritis of the bilateral hips, and one had a right hip and bilateral knee. The affected joints were 55 hips (44.4% of all affected joints), 29 knees (23.4%), and 13 ankles (10.5%). Most lesions were in the lower extremities, as with acute osteomyelitis, with such a pattern found for 97 joints (82.2% of all affected joints) (Table 2). The median age of onset was 4 years old (range: 4 days to 15 years old), and onset occurred under 5 years old or younger in 68.3% of all cases with septic arthritis (Fig. 2). Septic arthritis was more prevalent in boys than girls: 84 boys (70.0% of all patients with septic arthritis) and 36 girls (30.0%) (p < 0.01). Furthermore, the right side was more commonly affected than the left: 73 joints (58.9% of all affected joints) and 51 joints (41.1%), respectively (p = 0.06). There were no cases of recurrence after initial treatment. Eighty-eight affected joints of 84 patients were followed up for more than two years. Ten joints (one shoulder, two knees and seven hips) in eight patients had sequelae (one example case is shown in Fig. 3), and seven of these joints in six patients required additional surgeries, including derotational varus osteotomy of the proximal femur for four patients with coxa valga and overgrowth, guided growth using an 8-plate for two patients with lower leg discrepancy, and both for one patient. The pathogenic bacteria were detected in seven of the eight patients (S. aureus in four, S. pneumoniae in one, Streptococcus in one and H. influenzae in one).
Table 2.
Site of septic arthritis.
| N | % | |
|---|---|---|
| Hip | 55 | 44.4 |
| Knee | 29 | 23.4 |
| Ankle | 13 | 10.5 |
| Sacroiliac | 12 | 9.7 |
| Shoulder | 8 | 6.4 |
| Elbow | 6 | 4.8 |
|
Wrist |
1 |
0.8 |
| Total | 124 | 100.0 |
Fig. 2.
Patients with septic arthritis by age.
Fig. 3.
An example case of sequelae from septic arthritis. The patient was a girl with septic arthritis on right hip and bilateral knee joints. (a) Intraoperative findings. Yellow pus and granulation can be seen. (b) Plain radiography of the first examination. (c) The plain radiography taken three years after the onset. The right hip and knee joints are severely deformed, resulting in a large leg length difference.
3.3. Bacterial etiology
Blood cultures were performed for 151 (79.9%) OAIs patients, and pathogenic bacteria were identified in 43 (28.5%) of them. Synovial fluid cultures were performed for 109 joints (97.3% of all septic arthritis cases excluding sacroiliac arthritis), identifying pathogenic bacteria in 54 (49.5%) of them. Smear Gram stains for 104 joints also confirmed bacteria in 33 cases (31.7% of all smear Gram stains). The pathogenic bacteria of 85 patients (46.0% of all OAIs cases) were identified conclusively, including 40.0% of acute osteomyelitis cases and 49.2% of septic arthritis cases. Among the 108 cases with negative blood cultures, pathogenic bacteria were detected by culture of joint fluid or debridement in 29 (26.9%). Eighty-two (44.3%) of all 185 patients had been prescribed antibiotics at previous clinics or hospitals. More pathogenic bacteria were identified in patients without preceding antibiotics (57 of 100 patients, 57.0%) than in patients with preceding antibiotics (27 of 82 patients, 32.9%) (p < 0.01).
The pathogenic bacteria are shown in Fig. 4. Staphylococcus aureus was the most common pathogenic bacterium (58 patients, 68.2% of all identified bacteria). Methicillin-resistant S. aureus (MRSA) was identified in 14 patients (24.1% of all S. aureus). Gram-positive cocci, which include both Staphylococci and Streptococci, accounted for 90.6% (77 in 85 patients) of all identified bacteria.
Fig. 4.
Pathogenic bacterium of osteoarticular infections. MSSA: methicillin-sensitive Staphylococcus aureus, MRSA: methicillin-resistant Staphylococcus aureus, CNS: coagulase negative Staphylococcus, S. pneumoniae: Streptococcus pneumoniae, S. pyogenes: Streptococcus pyogenes, S. agalactiae: Streptococcus agalactiae, H. influenzae: Haemophilus influenzae.
S. pneumoniae were identified in four patients, and H. influenzae were identified in seven patients. S. pneumoniae or H. influenzae accounted for 12.9% of all identified bacteria (11 of 85 patients). The proportions of these two bacteria were 2.4% (1 of 42 patients with identified bacteria) at ≥5 years old, but 23.3% (10 of 43 patients, p < 0.01) at ≤4 years old. The pathogenic bacteria identified annually are shown in Fig. 5. S. pneumoniae and H. influenzae had not been detected since 2015 and 2010, respectively. These bacteria were not detected in patient under 5 years old since 2011 (Fig. 6). For patients of <5 years of age, which is the target age for vaccination, we were able to use the data for the pneumococcal conjugate vaccine (PCV) from the patient's vaccination history; these data were available for 73 patients (83.0% of all cases of <5 years of age). Nineteen (26.0%) of the 73 patients had been already inoculated, while 54 (74.0%) had not. All three patients with OAIs of S. pneumoniae were unvaccinated. The data on H. influenzae vaccination history at <5 years of age were collected for 69 patients (78.4% of all cases <5 years of age); 19 (27.5% of the 69 cases) had already been inoculated, while 50 (72.5%) had not. Among the seven patients with OAIs caused by H. influenzae, four were unvaccinated, and the other three patients had unknown vaccination histories. The proportion of S. pneumoniae and H. influenzae among all pathogenic bacteria decreased from 10 of 63 before 2013 to 1 of 21 on and after 2013 (p = 0.28). The number of children under 5 years old decreased from 10 of 35 before 2013 to 0 of 8 on and after 2013 (p = 0.17). On the other hand, S. aureus increased from 62.5% to 85.7% (p = 0.06).
Fig. 5.
Pathogenic bacterium by year (all age).
Fig. 6.
Pathogenic bacterium by year (under 5 years old).
3.4. Observation period and the age of onset
The median observation period was 32 months (range: 12 days to 203 months) in the overall population, 10 months (range: 12 days to 134 months) in patients with osteomyelitis and 37.5 months (range: 1–203 months) in patients with arthritis.
There were 36 affected bones or joints (3 acute osteomyelitis and 33 septic arthritis) in 34 infants (<1 year old). In the neonatal period (less than one month old), six joints of six patients were observed. In addition, all pathogenic bacteria identified from five patients (no bacterium was identified in the other patient) during the neonatal period were Gram-positive cocci. The median age of onset of the 1 bone and 10 joints that caused sequelae was 8 months old (range: 7 days to 5 years old), which was lower than in the cases without sequelae (median age: 49 months old, range: 14 days to 13 years old) (p < 0.01).
4. Discussion
Childhood OAIs may cause the destruction of growth plate cartilage and joint cartilage, which is linked to permanent deformities, and can also cause serious problems in the patients’ later lives.1,2 Therefore, prevention of OAIs is prioritized in order to avoid the development of sequelae. In the present study, we retrospectively investigated cases of childhood OAIs to re-confirm the actual situation, focusing on the timing of vaccine initiation.
The affected site has been reported to be the lower limbs and pelvis in many cases,10, 11, 12, 13 with similar findings noted in our study. Furthermore, boys tend to be more frequently affected than girls,10 which was also the same result as in the present study. The onset age showed a bimodal distribution with peaks around 1 and 10 years old for acute osteomyelitis in our study, which was similar to previous findings.10 About 40% of cases of septic arthritis manifested under 2 years old, increasing slightly up to around 5 years old before showing a downward trend after 6 years old. This distribution of the onset age was also consistent with the findings of a previous study.10
Approximately 44% of patients had already been prescribed antibiotics before their first consultation. The pathogenic bacteria were identified in 57% of cases with no prior administration. In contrast, prior antibiotics likely reduced the rate from 57% to 33%. It is necessary to start treatment while keeping in mind the possibility that the pathogenic bacteria might not be identified in cases with pre-administration of antibiotics.
S. aureus was described as most common pathogenic bacteria of childhood OAIs,3,10, 11, 12,14, 15, 16 with the same findings noted in our study. The proportion of MRSA was reported to range from 11% to 63%.15 In our hospital, it accounted for about one-quarter of S. aureus cases. If Gram-positive cocci are identified on a smear examination, the administration of a combination of anti-MRSA medicines should be considered.
S. pneumoniae and H. influenzae are typical pathogenic bacteria of bacterial pneumonia and meningitis in infancy. In Japan, the rates of invasive pneumococcal disease (IPD), especially bacterial meningitis and pneumonia, have been reduced since the introduction of a vaccine against this bacterium.7 The proportion of childhood OAIs caused by S. pneumoniae has been 0%–10%.14, 15, 16, 17 In Japan, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced for children up to 5 years old as voluntary inoculation in February 2010, and it became a routine vaccination in April 2013. The 13-valent pneumococcal conjugate vaccine (PCV13) has been inoculated since November 2013. OAIs caused by S. pneumoniae were reduced after the introduction of PCV abroad.18 In the present study, there were no cases of OAIs caused by S. pneumoniae in patients under five years old, which is the target age for the vaccine since the introduction of vaccination. This is considered the effect of the vaccine. However, the total number of IPD cases has stopped falling since 2014, which is considered to be due to the increased prevalence of non-PCV13-type S. pneumoniae, which is not covered by PCV13.19, 20, 21 Therefore, some OAIs caused by S. pneumoniae may still occur. It is necessary to consider S. pneumoniae as causative bacteria in when treating such patients.
The proportion of OAIs caused by H. influenzae was 0%–7%.12,14, 15, 16, 17 In Japan, the H. influenzae type B (Hib) vaccine was introduced as a voluntary inoculation in December 2008, and it became a regular vaccination in April 2013. Childhood OAIs caused by H. influenzae decreased after Hib vaccine introduction in other countries.10 Among the seven patients under five years old with OAIs in the present study caused by H. influenzae, four were not vaccinated. Because all three patients with unknown vaccination histories developed OAIs within two years from the time of vaccination initiation, the possibility that they were uninoculated cannot be denied. There were no cases of OAIs caused by H. influenzae after the age of the introduction of routine Hib vaccination, suggesting the efficacy of this vaccine as well as PCV.
The incidence rates of S. pneumoniae and H. influenzae before and after the introduction of vaccinations decreased, but we unfortunately found no statistically significant differences. This may be due to the small number of the two bacteria and their lack of sufficient detection power. In contrast, the incidence of S. aureus increased dramatically. This may be due, albeit indirectly, to the decrease in S. pneumoniae and H. influenzae.
A younger onset has been reported to be a risk factor of sequelae.3, 4, 5 The frequency of sequelae was higher in younger patients than in older ones in the present study as well. Therefore, it is necessary to reduce the occurrence at a younger age in order to prevent serious sequelae. As described above, childhood OAIs caused by S. pneumoniae and H. influenzae are prone to occur in children under five years old, which is the vaccination target age. Therefore, these vaccines may be able to reduce childhood OAIs in younger patients, who are particularly susceptible to sequelae such as growth disturbance or joint deformity. The development of vaccines against invasive MRSA and MSSA, the most common pathogens of childhood OAIs, is expected.
Several limitations associated with the present study warrant mention. First, the number of cases was not sufficient, and information on vaccination histories could not be collected for all cases for a retrospective, single-center study. In addition, we did not perform additional tests, such as PCR in culture-negative cases, which may have led to the underestimation of causative organisms, such as Kingella kingae, which are difficult to detect in culture. Furthermore, the subtype of S. pneumoniae was not tested. In response to these facts, we need to continue to accumulate cases and pay attention to the changes in the causative organisms of OAIs. In particular, we need to investigate the subtype of S. pneumoniae.
5. Conclusion
We conducted an epidemiological study on childhood OAIs. OAIs caused by S. pneumoniae and H. influenzae have decreased since the introduction of routine vaccinations for these bacteria in 2013 in Japan. These routine vaccinations can suppress the onset of OAIs in children.
Source of funding
None declared.
Author contributions
Kengo Kawaguchi: Conceptualization, Data curation, Formal analysis, Investigation, Writing – Original Draft
Tomoyuki Nakamura: Project administration, Writing – review & editing
Akifusa Wada: Supervision, Writing – review & editing
Kazuyuki Takamura: Supervision, Resources
Haruhisa Yanagida: Resources
Toru Yamaguchi: Resources.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
This study was previously published as a preliminary report in a domestic journal for Japanese pediatric orthopedic association, which is available in Japanese only. The present report has wider survey period and more patients included than the preliminary one, and we examine some additional points.
Contributor Information
Kengo Kawaguchi, Email: kengo.98@gmail.com.
Tomoyuki Nakamura, Email: nakamura.t@fcho.jp.
Akifusa Wada, Email: ssgwada@vip.saganet.ne.jp.
Kazuyuki Takamura, Email: takamura.k@fcho.jp.
Haruhisa Yanagida, Email: yanagida.h@fcho.jp.
Toru Yamaguchi, Email: yamaguchi.to@fcho.jp.
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