| BackgroundDescription of the infectionChildhood osteoarticular infections (OAIs) are a frequent cause of hospital admission worldwide in paediatric orthopaedics. Osteoarticular infections in children require early diagnosis, identification of the causative pathogen to optimize the choice of antibiotics, rapid medical and surgical care, associated antibiotherapy and possible surgical drainage because they can have a devastating impact with a high rate of serious and long-lasting sequelae, especially on remaining growth. Depending on the localization of infection, they manifest as Osteomyelitis (OM), Septic Arthritis (SA), a combination of both (i.e., osteomyelitis with adjacent septic arthritis) or spondylodiscitis. Osteoarticular infections can be also divided into three types according to the source of infection:haematogenous; secondary to contiguous infection; or secondary to direct inoculation.Osteoarticular infections must be diagnosed and treated urgently. Empiric antimicrobial therapy should be initiated promptly after bacteriological sampling and should target the most common pathogens. However, the bacteriological diagnosis is often delayed, and bacterial cultures often remain negative. Indeed, the causative pathogens are usually identified by culturing samples from septic localizations and/or blood in one-to two-thirds of osteoarticular infections. According to most epidemiological data, Gram-positive organisms predominate and Staphylococcus aureus is the most common infective bacterial pathogen in all age groups. Apart from S. aureus, OAI with gram-negative organisms, Group B Streptococcus, and Candida are common in neonates. In children younger than 4 years, the reported number of cases of Kingella kingae-associated OAI has markedly increased since the 1980s. Indeed, several studies have demonstrated that Kingella kingae has been revealed to be the major bacterial cause of OAI in children aged between 6 and 48 months (30% to 93.8% of all culture-positive OAI).Description of the organismFor most of the four decades that have elapsed since the first description of Kingella kingae, this Gram-negative B-hemolytic member of the Neisseriaceae family was considered exceptional rare cause of human disease, infrequently isolated from infected joints, bones and cardiac valves. The serendipitous discovery that inoculation of synovial fluid and bone exudates into blood culture vials (BCVs) significantly improved detection of the organism, resulted in the appreciation of Kingella kingae as an emerging invasive pathogen in young children.Kingella kingae is a B-haemolytic aerobic and facultative anaerobic Gram-negative bacillus that is a normal component of the commensal oropharyngeal flora in young children. It is rarely identified in children less than six months, children first acquire Kingella kingae after the age of six months and the colonization rate increases to 9-12% between the ages of 12 and 24 months, with carriage rate decreasing thereafter__the overall carriage rate among children under 4 years old is approximately 10%. Carriage of the bacterium gradually declines during the third year of life and is low in school-aged children and adults, suggesting the development of a mounting immune response that eliminates the organism from the pharynx in older individuals.In recent years, Kingella kingae has emerged as an important cause of osteoarticular infections in young children as a result of improved culture methods and above all of the use of nucleic acid amplification methods. In the literature, K. kingae currently accounts for 5% to 29% of culture-positive OAIs and for up to 48% of cases of septic arthritis in children under 2 years of age. In several countries, this microorganism is currently recognized as the major bacterial pathogen in OAIs in children aged from 6 to 48 months, and was responsible for reported outbreaks of musculoskeletal infections in toddlers attending childcare centers.Despite the contribution of the studies that reported in the literature to our knowledge of Kingella kingae-associated Osteoarticular infections in children, there is not yet widespread knowledge among the medical community of the existence of this organism and its frequency in OAIs may still be underestimated. This might lead to delay of diagnosis, abuse of antibiotics and major functional consequences. There is also no contemporary comprehensive systematic analysis of the available data in the literature since 2000 using a large and detailed case analysis by which to summarize and provide such a resource for the epidemiology, clinical and biological features, diagnosis, and management of Kingella kingae-associated Osteoarticular infections.Objectives1. The main objective of this analysis was to summarize the experience with osteoarticular infections caused by Kingella kingae in children published in the English literature since 2000.2. To underline the main and basic characteristics of Kingella kingae-associated osteoarticular infections in children, including the epidemiology, clinical and biological features, diagnostic methods, radiological examinations, surgical and antibiotic treatment, and outcome of this serious infection.3. To increase awareness and improve recognition among the medical community about the frequency of this rare, Gram-negative organism in osteoarticular infections in children.Methods and materialsSearch methodsWe searched the PubMed database from January 2000 to June 2014 using the key words:Kingella kingae, osteoarticular infection, osteomyelitis, arthritis, osteoarthritis, spondylodiscitis, and pediatric. After reviewing all English references and abstracts of associated studies and reports in the literature, studies with only English abstract were excluded. We then carefully included only English full texts of single-case reports, case series or studies comprising cases of Kingella kingae-associated osteoarticular infections in children, regardless the sufficiency of the data provided. After this initial series of reports was reviewed, individual references listed in each publication were again reviewed for ascertainment of additional case reports.Selection criteriaCases selected in the initial screen were then included in the analysis if the following data were available:Documentation of Kingella kingae-associated osteoarticular infections in children, such as septic arthritis, osteomyelitis, spondylodiscitis; Confirmation of isolation of Kingella kingae by cultures or nucleic acid amplification methods (PCR assays) from specimens of joint fluid, bone aspirates and/or blood. Cases with negative cultures from specimens of joint fluid, bone aspirates but positive culture of blood samples with symptoms or imaging suggestive of osteoarticular infection were included. Cases with positive culture of blood samples but without symptoms or imaging suggestive of osteoarticular infection were excluded. Cases with only isolation of the organism in oropharyngeal swabs by culture or PCR assays with or without an established diagnosis of osteoarticular infection were also excluded.Data collection and analysisAmong the variables extracted were basic demographics, clinical and laboratory characteristics, such as temperature at admission, history of preceding illness, types of OAIs, anatomical location of infection, inflammatory markers, culture methods, PCR techniques, and outcome. Data on therapeutic modalities, such as surgical and antibiotics treatments, as well as skeletal imaging techniques including plain radiography, computed tomography (CT), magnetic resonance imaging (MRI), bone scans and ultrasound, were also extracted and analyzed.Main ResultsStudy populationTwenty-eight studies involving a total of 566 cases (children) with Kingella lingae -associated osteoarticular infections, were included. The number of cases ranged from 1 case, to 169 cases. A total of 14 studies involved 10 or more cases and 14 studies were less than 10 cases. The studies were performed in one of the following countries: France, Switzerland, Israel, The United States, Australia, Belgium, Austria, Canada, Spain, and Iran.Demographic characteristics1. Age, Gender, Seasonal distributionMeans or medians of the age of 510 cases ranged from 11.8 to 24 months, with the youngest child of 4 month and the oldest of 8-year of age. More than 80% of the 510 patients were between 4 months and 4 years of age. The male-to-female ratio among 291 pediatric patients was 1.14:1 (155 males and 136 females). Available data on seasonal distribution presented as reported in 3 studies took place in France with a total of 94 cases, which were as follows:40 cases (42.55%) in fall,25 cases (26.6%) in winter,24 cases (25.53%) in spring, and 5 cases (5.32%) in summer.Clinical features2. History of preceding or concurrent illnessSeventy-three patients (55.7%) out of 131 patients had a preceding or concurrent illness within the week prior to or coincidental with the K. Kingae-associated osteoarticular infections. Of these 73 patients,60 patients (82%) had upper respiratory tract infections (URTI),9.6% had oral mucosal lesions,2.74% had otitis media,1.37% had stomatitis,1.37% had nasal congestion, and 1.37% of the patients had trauma.4.1% of the patients had other symptoms of gastroenteritis (diarrhea).3. Symptoms duration or delay of diagnosisThe means or medians of the intervals from symptoms onset to hospitalization of 352 patients, ranged from one day to 22.3 days. We calculated that the intervals of at least 86% of the cases were< 8 days.4. Body temperature at admissionThe means or medians of body temperatures at admission in 354 patients, ranged from 36.8℃ to 38.7℃. The mean or median of body temperature of 40% of the patients was normal (< 38℃), and was slightly elevated (38.3℃) in 56% of the patients, and was below 38.7℃ in 4% of the patients. Therefore, the means or medians of body temperature at admission in 96% of the patients were below 38.3℃.Markers of inflammation5. Peripheral blood white blood cells counts (WBCs), C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR)The means or medians of WBC counts of 394 cases, ranged from 9.3×109/L to 14.8×109/L. Means or medians of the CRP levels of 385 cases, ranged from 12.7mg/L to 39mg/L, and the means or medians of ESR levels of 235 cases, ranged from 34.3mm/h to 55mm/h.6. Types and sites of Osteoarticular Infections (OAIs)Septic arthritis (73.06%) was the most reported type of K. kingae-associated osteoarticular infections among 553 cases, followed by Osteomyelitis (15.73%), spondylodiscitis (5.43%), and osteomyelitis with adjacent septic arthritis (4.88%).The most affected joint was the knee (46%), followed by hip (15.95%) and ankle (15.41%). The joints of the wrist (7.30%), shoulder (5.68%), and elbow (4.86%) were also reported, as well as 4.86% of other small joints.The most affected bone was calcaneus (20%), followed by femur (15.38%) and sternum (13.85%). The bones of the tibia (10.77%), radius (10.77%), humerus (6.15%), talus (4.62%), ulna (3.08%), fibula (3.08%), and metacarpal bones (3.08%) were also reported. The most affected site of spondylodiscitis was L4/L5 disc (70%).7. Bacteriological diagnosisRoutine laboratory culture of 411 specimens of joint fluids or bone aspirates and/or blood were positive in 178 samples (43.31%), The detection rate of the organism reached 81.37%(83/102), when the specimens of joint fluids or bone aspirates and/or blood were inoculated into blood-culture vials (BCVs). Based on the available data, all specimens (259/259,100%) where PCR technique was used on detecting the organism, were PCR-positives. There were no reported cases of positive cultures for K. kingae OAIs with negative PCR.8. Radiologic investigationsResults of 114 radiologic investigations (114/287,39.72%) showed abnormalities. Bone scans revealed abnormalities in 63.64% (21/33), MRI scans in 58.46% (38/65), ultrasound in 51.35% (38/74), and only 17 plain radiography (17/115,14.78%) showed abnormalities.9. Surgical treatmentOnly 131 patients (131/566,23.1%) of the total included patients underwent surgical interventions. Surgical treatments included open arthrotomy (80/131,61.07%), needle arthrotomy and irrigation with normal saline (24/131,18.32%), arthroscopic irrigation (19/131,14.50%), open curettage (5/131,3.82%), and surgical debridement (3/131,2.29%).10. Antibiotic treatmentDuration of intravenous (iv.) antibioticsThe medians or means of the duration of intravenous antibiotics for 161 patients, ranged from 4.5 days to 12 days, with two days as the shortest time of intravenously use of the antibiotics and 28 days the longest. We observed that the duration in at least 61% of the patients was within a week.Duration of oral antibioticsThe medians or means of the duration of oral antibiotics for 136 patients, ranged from 21 days to 35 days, with 5 days as the shortest time of orally use of the antibiotics and 45 days the longest. We observed that the duration of oral antibiotics in over a half of the patients (>60%) was varied from 2 to 4 week.The most commonly used antibiotics intravenously or orally were β-lactam antibiotics, including flucloxacillin, cefotaxime, cefuroxime, and amoxicillin.11. OutcomeThe outcome of the treatment of 287 cases was favourable in all but four cases, which developed minor sequelae and were recovered after second management without leaving permanent orthopedic sequelae.ConclusionsTo our knowledge, this analysis has reviewed the largest sample of K. kingae OAIs published in the literature to date. Therefore, it provides useful information about this fastidious organism regarding its epidemiology, clinical and laboratory features and treatment of patients with K. kingae OAIs. Based on the results, we conclude that:1. K. kingae is being increasingly recognized as a major cause, or even the leading bacterial etiology of osteoarticular infections in children between 4 months and 4 years of age.2. Osteoarticular infections caused by K. kingae have three remarkable epidemiological features:K. kingae is a pediatric disease especially affecting populations between 4 and 48 months of age, the male-to-female ratio of the disease may be approximately equal, and cases tend to cluster in fall with a nadir in summer.3. Children with K. kingae infections present with a good general condition and appear only mildly to moderately ill with preceding or concurrent upper respiratory tract infection (URTT).4. The clinical and biological inflammatory responses consist of normal or slightly elevated body temperature at admission, and mildly to moderately elevated serum levels of WBC, CRP, and ESR.5. Isolation of K. kingae by routine culture methods remains unsatisfactory, and detection rate improves to 81.90% when specimens of joint fluids or bone aspirates and/or blood inoculated into blood-culture vials (BCVs).6. PCR technique approaches higher detection rate "100%", and improve sensitivity and shorten time-to-detection.7. Cases of pediatric K. kingae OAIs respond uniformly to β-lactam antibiotic therapy and do not evolve to chronicity or leave permanent orthopedic sequelae.We recommend that a high index of suspicion of K. kingae infection be maintained for children 4 years of age and younger presenting with joint or bone complaints or other suggestive clinical features, especially if they presented mildly with preceding or concurrent URTI and with mildly-to-moderately biologic inflammatory responses. To improve the detection of this organism, blood culture drawing, inoculation of skeletal system exudates into blood culture vials are strongly recommended and nucleic acid amplification techniques, when available, should be routinely used. We recommend that when suspected of K, kingae associated OAIs, the empiric antibiotic therapy should consist of intravenous P-lactam antibiotics for a week and oral β-lactam antibiotics for 2 to 4 weeks. |
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