Kingella kingae is the leading pathogen associated with osteoarticular infection in young children in several countries.
Carriage of K. kingae is common in the oropharynx of young children, reaching 10% of prevalence in 12- to 24-month-old children; current evidence suggests capacity for transmission and dissemination.
The pharynx is considered to be the portal of entry for invasive disease, and several virulence factors and environmental factors may play a role in the pathophysiology.
Detection of K. kingae in the oropharynx may be useful for the diagnosis of osteoarticular infections, but additional data are needed to interpret positive results with confidence.
In a linked research paper,1 Gravel and colleagues evaluated the association between carriage of Kingella kingae in the oropharynx of preschool children and osteoarticular infections in a prospective case–control study in two countries. Kingella kingae is difficult to isolate in bone and joint samples, and blood cultures are frequently sterile. The oropharynx is considered to be the portal of entry for invasive K. kingae infections; therefore, assessing oropharyngeal carriage of K. kingae during osteoarticular infection could be of interest for microbiological diagnosis. However, because healthy young children may be oropharyngeal carriers of K. kingae, interpreting positive culture or polymerase chain reaction (PCR) results is tricky. Evidence suggests that oropharyngeal carriage of K. kingae is a prerequisite for developing an invasive K. kingae infection; however, the pathophysiological mechanism of infection is not yet clearly understood.
For two decades, K. kingae has been increasingly shown to be associated with osteoarticular infection in young children, and it is now recognized as the leading pathogen of this type of infection in children younger than four years of age, accounting for as many as 80% of microbiologically confirmed cases in Israel2 and France,3 but also in Switzerland,1 Spain4 and now in Montréal.1 Between 1968 and 2000, about 120 cases of invasive K. kingae infections were reported, yet a recent review found 566 cases of osteoarticular infection involving the organism in the English-language literature between 2000 and 2014.5 This highlights improved detection of K. kingae owing to molecular techniques, as well as awareness of clinicians and microbiologists, more than a real “emergence” of the pathogen. In the 1990s, improvement in culture methods allowed for increased detection of K. kingae in synovial fluid. Furthermore, in a recent review, molecular methods such as 16S rRNA gene PCR,6 followed by K. kingae–specific real-time PCR targeting either the cpn60 housekeeping gene3 or the rtxA/rtxB hemolysin genes1 showed a sensitivity of 99.5% (387/389 cases) for detecting K. kingae in children with osteoarticular infection. However, a sensitivity of 24.9% (68/273 cases) was observed with culture methods.2 Observational studies and reviews reported that most children with osteoarticular infection caused by K. kingae presented with limited clinical and biological inflammatory responses.2,5 However, whether clinical and biological features can discriminate between septic arthritis resulting from K. kingae and other pathogens remains unclear.2
Worth bearing in mind, however, is that K. kingae is commonly found in the oropharynx of young children without evidence of invasive infection. A recent review found rates of carriage of K. kingae to be similar among children in Israel and Switzerland.2 K. kingae was not isolated before the age of six months, and the colonization rate was low at six months (1.5%), increased in 12-month-old children, remained relatively stable between 12 and 24 months of age (10%), and decreased at 30 months (5%).2 Additional data are now available from Montréal and New Zealand.1,7 Data from longitudinal studies suggest that colonization with K. kingae is a dynamic process; some children carry a given strain intermittently or continuously for up to eight months and others acquire and carry sequentially diverse strains.2 Simultaneous carriage of multiple strains appears to be uncommon. A close genetic association was observed between the strains isolated among siblings and in neighbourhoods, indicating transmission and dissemination of the clones, which could explain why attending a day-care centre represents an independent risk factor for carriage of K. kingae.2
Experimental and observational studies, as well as epidemiologic data, suggest that the oropharynx is the portal of entry for K. kingae. Indeed, identical genotypes were identified between the strains isolated in the oropharynx and joint fluid in cases of osteoarticular infection caused by K. kingae.8 Different virulence factors are well identified,2 such as a hemolytic RTX toxin, responsible for a wide-spectrum cytotoxic effect, especially against macrophages, leukocytes, synoviocytes and respiratory epithelial cells; a type IV pili, which plays a role in pathogen adherence to respiratory and synovial epithelia; and a polysaccharide capsule, four types of which were recently described globally, with types a and b representing more than 95% of the invasive isolates.9 In the largest international collection of K. kingae strains published to date, some major and international clones (sequence-type complexes 6, 14, 23, 25 and 35) were associated with specific clinical syndromes, but others appeared to be associated with carriage in Israel.10
Bacterial characteristics and virulence factors cannot, however, fully explain the pathophysiology of invasive K. kingae infections. Indeed, the seasonal distribution of K. kingae invasive infections (which peak during the fall) and carriage (no substantial seasonality) appeared to be unrelated in different epidemiologic studies.2,5,11 No difference in the oropharyngeal bacterial load was shown between carriers and patients with osteoarticular infection, 11 and the risk of a healthy carrier developing osteoarticular infection caused by K. kingae was assessed to be lower than 1% per year.11 Thus, it has been suggested that co-factors such as viral infections play a role in the K. kingae pathophysiology. Invasive K. kingae infections are frequently observed to precede or coexist with viral infections, and a recent prospective observational study showed that at least one respiratory virus was identified in the oropharynx of 90.5% of children with osteoarticular infection caused by K. kingae with human rhinovirus being predominant. 12 Host susceptibility is likely to explain certain severe disease presentations. However, to the best of our knowledge, most children studied have not shown any underlying condition and, to date, no immune deficiency has been associated with K. kingae infections in the pediatric population; this is in contrast to what has been observed with severe K. kingae infections in adults.
The findings of the linked study1 show a strong association between detection of oropharyngeal K. kingae and osteoarticular infection, with an odds ratio of 38.3 (95% confidence interval 18.5–79.1). However, with a carriage rate among healthy children as high as 10% in some countries, relying on oropharyngeal detection as a proxy for diagnosis in the case of a joint infection would result in a high false-positive diagnosis. Additional data, such as genotyping, capsule typing or specific viral detection, would improve the performance of oropharyngeal screening.
Footnotes
Competing interests: None declared.
This article was solicited and has not been peer reviewed.
Contributors: Romain Basmaci wrote the first draft of the article and Stéphane Bonacorsi revised it. Both of the authors revised the article critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.