Kingae Disease Research Articles

Pathogenic determinants of Kingella kingae disease.

Kingella kingae is an emerging pediatric pathogen and is increasingly recognized as a leading etiology of septic arthritis, osteomyelitis, and bacteremia and an occasional cause of endocarditis in young children. The pathogenesis of K. kingae disease begins with colonization of the upper respiratory tract followed by breach of the respiratory epithelial barrier and hematogenous spread to distant sites of infection, primarily the joints, bones, and endocardium. As recognition of K. kingae as a pathogen has increased, interest in defining the molecular determinants of K. kingae pathogenicity has grown. This effort has identified numerous bacterial surface factors that likely play key roles in the pathogenic process of K. kingae disease, including type IV pili and the Knh trimeric autotransporter (adherence to the host), a potent RTX-family toxin (epithelial barrier breach), and multiple surface polysaccharides (complement and neutrophil resistance). Herein, we review the current state of knowledge of each of these factors, providing insights into potential approaches to the prevention and/or treatment of K. kingae disease.

Kingella kingae Virulence Factors and Insights into Pathogenicity.

The emergence of Kingella kingae as an important etiology of pediatric osteoarticular infections over the past three decades has led to significant research efforts focused on understanding the pathogenicity of this fastidious Gram-negative bacterium. This work has uncovered multiple virulence factors that likely play key roles in the ability of the organism to colonize the upper respiratory tract, breach the epithelial barrier, and disseminate to distal sites of infection. Herein the current body of knowledge about K. kingae virulence factors is reviewed in the context of K. kingae disease pathogenesis. The work summarized here has identified multiple targets for therapeutic intervention as well as potential vaccine antigens.

First documented outbreak of arthritis caused by Kingella kingae in a Spanish childcare center

BackgroundRecently, Kingella kingae (K. kingae) has been described as the most common agent of skeletal system infections in children 6 months-2 years of age. More exceptional is the clinical presentation in clusters of invasive K. kingae infections. We describe the investigation of the first outbreak of 3 cases of arthritis caused by K. kingae documented in Spain detected in a daycare center in Roses, Girona. Patients and methodsIn December of 2015 surveillance throat swabs obtained from all attendees from the same class of the index daycare center were assessed to study the prevalence of K. kingae colonization. The sample was composed of 9 toddlers (range: 16–23 months of age). Investigation was performed by culture and K. kingae-specific RT-PCR. Combined amoxicillin-rifampicin prophylaxis was offered to all attendees who were colonized by K. kingae. Following antimicrobial prophylaxis, a new throat swab was taken to confirm bacterial eradication. ResultsK. kingae was detected by RT-PCR throat swabs in the 3 index cases and 5 of the 6 daycare attendees. Cultures were negative in all cases. After administration of prophylactic antibiotics, 3 toddlers were still positive for K. kingae-specific RT-PCR. ConclusionsClusters of invasive K. kingae infections can occur in daycare facilities and closed communities. Increased awareness and use of sensitive detection methods are needed to identify and adequately investigate outbreaks of K. kingae disease. In our experience, the administration of prophylactic antibiotics could result in partial eradication of colonization. No further cases of disease were detected after prophylaxis.

Primer brote documentado de artritis séptica por Kingella kingae en una guardería de España

BackgroundRecently, Kingella kingae (K. kingae) has been described as the most common agent of skeletal system infections in children 6 months-2 years of age. More exceptional is the clinical presentation in clusters of invasive K. kingae infections. We describe the investigation of the first outbreak of 3cases of arthritis caused by K. kingae documented in Spain detected in a daycare center in Roses, Girona. Patients and methodsIn December of 2015 surveillance throat swabs obtained from all attendees from the same class of the index daycare center were assessed to study the prevalence of K. kingae colonization. The sample was composed of 9 toddlers (range: 16-23 months of age). Investigation was performed by culture and K. kingae-specific RT-PCR. Combined amoxicillin-rifampicin prophylaxis was offered to all attendees who were colonized by K. kingae. Following antimicrobial prophylaxis, a new throat swab was taken to confirm bacterial eradication. ResultsK. kingae was detected by RT-PCR throat swabs in the 3index cases and 5of the 6daycare attendees. Cultures were negative in all cases. After administration of prophylactic antibiotics, 3toddlers were still positive for K. kingae-specific RT-PCR. ConclusionsClusters of invasive K. kingae infections can occur in daycare facilities and closed communities. Increased awareness and use of sensitive detection methods are needed to identify and adequately investigate outbreaks of K. kingae disease. In our experience, the administration of prophylactic antibiotics could result in partial eradication of colonization. No further cases of disease were detected after prophylaxis.

High rate of oropharyngeal Kingella kingae carriage in New Zealand children.

This study aimed to describe the burden of disease and estimated rates of oropharyngeal carriage of Kingella kingae among New Zealand children. We compared polymerase chain reaction (PCR) and culture for the detection of this microorganism with a view to further development and implementation of K. kingae PCR in Christchurch Hospital. Oropharyngeal swabs from children between 6 and 48 months of age were analysed by culture to estimate carriage rates of K. kingae. Samples of a subgroup of children between 12 and 24 months of age were also tested by PCR. In addition, a retrospective review was performed on all cases of invasive K. kingae disease and children with osteoarticular infections. Oropharyngeal cultures were positive for K. kingae in specimens from 4 out of 176 children (2.3%). PCR was significantly more sensitive and by PCR, the carriage rate rose to 22.9% (95% CI = 9.4-33.9%) (n = 48). From 2005 to 2015, 17 children between 6 and 48 months of age were identified with invasive infections due to K. kingae. Seventy-four children were found to have an osteoarticular infection. Most of these were culture-negative with a microbiological diagnosis made in only 15 cases (20.3%), only one due to K. kingae. We found a very high carriage rate of K. kingae in New Zealand children and poor performance of K. kingae culture. It is likely that many cases of invasive K. kingae infections remain undetected. We recommend the use of a K. kingae PCR in all children under 4 years of age with a possible osteoarticular infection.

Patterns of Kingella kingae Disease Outbreaks.

Kingella kingae outbreaks occur sporadically in childcare centers but remain poorly understood and difficult to identify. To provide the basis of a better knowledge of K. kingae outbreaks patterns that may help to guide identification and management strategies, we collected epidemiological, clinical and laboratory data from all reported K. kingae outbreaks, and those from 2 new Israel outbreaks in 2014. Nine outbreaks were identified in the USA, Israel and France from 2003 to 2014. Twenty-seven children with a median age of 14 ± 4.1 months were affected, male:female ratio of 1.4:1. Outbreaks demonstrated seasonal patterns from the 10th to the 45th weeks, a mean duration of 13.1 ± 8.4 days, a mean attack rate of 17.3 ± 5.1% and a case-fatality rate of 3.7% (1/27). Seventy-four percentage of children had fever (20/27), and the mean values of white blood cell count and C-reactive protein level were 14.6 ± 4.5 × 10/L and 23.8 ± 24.1 mg/L, respectively. Osteoarticular infections accounted for 88.9% of cases (24/27), bacteremia 7.4% (2/27), endocarditis 3.7% (1/27) and meningitis 3.7% (1/27). Specific real-time polymerase chain reaction demonstrated higher performance than culture methods in the diagnosis of case patients and investigations of oropharyngeal K. kingae carriage among close contacts, and multilocus sequence typing methods revealed that ST-6 and ST-25 invasive strains were responsible for multiple country-dependent outbreaks. Coviral infections were identified in the majority of K. kingae outbreaks, notably those causing oral ulcers. K. kingae outbreaks displayed severe K. kingae diseases that were poorly confirmed with culture methods. We argue for the use of genomic technologies to investigate further K. kingae outbreaks.

Kingella kingae infections in children.

BackgroundImprovements in culture techniques and molecular detection methods have led to findings indicating that, particularly in infants and young children, Kingella kingae is a significantly more important pathogen than previously thought. However, despite this, the pediatric community is still largely unaware of the existence of this organism. The aim of this review is therefore to summarise current knowledge of the epidemiology, transmission, clinical presentation, diagnosis and treatment of K. kingae infections in children.DiscussionK. kingae is a common coloniser of the oropharynx, can be transmitted from child to child, and can cause outbreaks of infection. Invasive infections almost exclusively occur in children aged between six months and four years of age, and involve mainly joints and bone, less frequently the endocardium, and very rarely other localisations. With the exception of bacteremia and endocarditis, which can be followed by severe complications, the diseases due to K. kingae are usually accompanied by mild to moderate clinical signs and symptoms, and only slightly altered laboratory data. Moreover, they generally respond to widely used antibiotics, although resistant strains are reported. However, the mild symptoms and limited increase in the levels of acute phase reactants create problems because K. kingae disease may be confused with other clinical conditions that have a similar clinical picture.ConclusionsAlthough K. kingae was identified more than 50 years ago, it is poorly known by pediatricians and is not systematically sought in laboratories. Education is therefore necessary in order to reduce the risk of outbreaks, permit the early identification of K. kingae infections, and allow the prompt prescription of adequate therapeutic regimens capable of avoiding the risk of a negative evolution in those cases in which this elusive pathogen can cause significant clinical problems.

Outbreaks of Kingella kingae infections in daycare facilities.

During the past decade, transmission of the bacterium Kingella kingae has caused clusters of serious infections, including osteomyelitis, septic arthritis, bacteremia, endocarditis, and meningitis, among children in daycare centers in the United States, France, and Israel. These events have been characterized by high attack rates of disease and prevalence of the invasive strain among asymptomatic classmates of the respective index patients, suggesting that the causative organisms benefitted from enhanced colonization fitness, high transmissibility, and high virulence. After prophylactic antibacterial drugs were administered to close contacts of infected children, no further cases of disease were detected in the facilities, although test results showed that some children still carried the bacterium. Increased awareness of this public health problem and use of improved culture methods and sensitive nucleic acid amplification assays for detecting infected children and respiratory carriers are needed to identify and adequately investigate outbreaks of K. kingae disease.

Calcium Binding Properties of the Kingella kingae PilC1 and PilC2 Proteins Have Differential Effects on Type IV Pilus-Mediated Adherence and Twitching Motility

Kingella kingae is an emerging bacterial pathogen that is being recognized increasingly as an important etiology of septic arthritis, osteomyelitis, and bacteremia, especially in young children. The pathogenesis of K. kingae disease begins with bacterial adherence to respiratory epithelium, which is dependent on type IV pili and is influenced by two PilC-like proteins called PilC1 and PilC2. Production of either PilC1 or PilC2 is necessary for K. kingae piliation and bacterial adherence. In this study, we set out to further investigate the role of PilC1 and PilC2 in type IV pilus-associated phenotypes. We found that PilC1 contains a functional 9-amino-acid calcium-binding (Ca-binding) site with homology to the Pseudomonas aeruginosa PilY1 Ca-binding site and that PilC2 contains a functional 12-amino-acid Ca-binding site with homology to the human calmodulin Ca-binding site. Using targeted mutagenesis to disrupt the Ca-binding sites, we demonstrated that the PilC1 and PilC2 Ca-binding sites are dispensable for piliation. Interestingly, we showed that the PilC1 site is necessary for twitching motility and adherence to Chang epithelial cells, while the PilC2 site has only a minor influence on twitching motility and no influence on adherence. These findings establish key differences in PilC1 and PilC2 function in K. kingae and provide insights into the biology of the PilC-like family of proteins.

Kingella kingae: An Emerging Pathogen in Young Children

Kingella kingae is being recognized increasingly as a common etiology of pediatric osteoarticular infections, bacteremia, and endocarditis, which reflects improved culture methods and use of nucleic acid-amplification techniques in clinical microbiology laboratories. K kingae colonizes the posterior pharynx of young children and is transmitted from child to child through close personal contact. Day care attendance increases the risk for colonization and transmission, and clusters of K kingae infections among day care center attendees have been reported. Key virulence factors in K kingae include type IV pili and a potent RTX toxin. In previously healthy children, >95% of K kingae infections are diagnosed between the ages of 6 and 48 months. Among children with underlying medical conditions, K kingae disease may occur at older ages as well. The clinical presentation of K kingae disease is often subtle and may be associated with normal levels of acute-phase reactants, which underscores the importance of a high index of suspicion. K kingae is usually susceptible to ß-lactam antibiotics, and infections typically respond well to medical treatment, with the exception of cases of endocarditis.

Kingella Kingae : From Asymptomatic Colonization to Invasive Pediatric Infections

As a result of the use of blood culture vials for seeding joint and bone exudates, and the development of nucleic acid amplification methods, Kingella kingae is being increasingly recognized as an emerging invasive pathogen and the most common etiology of septic arthritis in children aged 6–36 months. K. kingae is carried asymptomatically in the pharynx, and is transmitted from child-to-child by close contact between family members and playmates. K. kingae organisms enter the bloodstream through breaches in the respiratory mucosa and disseminate to remote sites. Skeletal system infections are the most common presentations of K. kingae disease, followed by bacteremia, pneumonia and endocarditis. Children with invasive K. kingae infections frequently show a mild clinical picture and normal acute-phase reactants, requiring a high index of suspicion. The organism is usually susceptible to antibiotics and, with the exception of endocarditis cases, most patients promptly respond to adequate antimicrobial therapy with no permanent sequelae.

Kingella kingae: A Pediatric Pathogen of Increasing Importance

As the result of the use of blood culture vials for seeding joint and bone exudates, and nucleic acid amplification methods, Kingella kingae is emerging as an important pathogen in patients <3 years of age. The organism is carried asymptomatically in the oropharynx of young children, coinciding with the age of increased attack rate of invasive disease, and propagates through close personal contact. Carriage of K. kingae is a dynamic process with frequent turnover of strains after weeks or months of continuous or intermittent colonization. Colonizing K. kingae enters the bloodstream through breaches in the respiratory mucosa and disseminates to bones, joints, or the endocardium. Daycare attendance increases the risk for K. kingae acquisition and transmission, and outbreaks of invasive disease have been reported among children in daycare. The most common manifestations of K. kingae disease in children are skeletal system infections (in 56% of patients), bacteremia (in 39%), pneumonia (in 4%), and endocarditis (in 1%). The clinical presentation is often subtle and laboratory tests are frequently normal, requiring a high index of suspicion. The organism is susceptible to most antibiotics, and with the exception of cases of endocarditis, invasive K. kingae infections usually run a benign uncomplicated clinical course.

Outbreak of Osteomyelitis/Septic Arthritis Caused byKingella kingaeAmong Child Care Center Attendees

Kingella kingae often colonizes the oropharyngeal and respiratory tracts of children but infrequently causes invasive disease. In mid-October 2003, 2 confirmed and 1 probable case of K kingae osteomyelitis/septic arthritis occurred among children in the same 16- to 24-month-old toddler classroom of a child care center. The objective of this study was to investigate the epidemiology of K kingae colonization and invasive disease among child care attendees. Staff at the center were interviewed, and a site visit was performed. Oropharyngeal cultures were obtained from the staff and children aged 0 to 5 years to assess the prevalence of Kingella colonization. Bacterial isolates were subtyped by pulsed-field gel electrophoresis (PFGE), and DNA sequencing of the 16S rRNA gene was performed. A telephone survey inquiring about potential risk factors and the general health of each child was also conducted. All children and staff in the affected toddler classroom were given rifampin prophylaxis and recultured 10 to 14 days later. For epidemiologic and microbiologic comparison, oropharyngeal cultures were obtained from a cohort of children at a control child care center with similar demographics and were analyzed using the same laboratory methods. The main outcome measures were prevalence and risk factors for colonization and invasive disease and comparison of bacterial isolates by molecular subtyping and DNA sequencing. The 2 confirmed case patients required hospitalization, surgical debridement, and intravenous antibiotic therapy. The probable case patient was initially misdiagnosed; MRI 16 days later revealed evidence of ankle osteomyelitis. The site visit revealed no obvious outbreak source. Of 122 children in the center, 115 (94%) were cultured. Fifteen (13%) were colonized with K kingae, with the highest prevalence in the affected toddler classroom (9 [45%] of 20 children; all case patients tested negative but had received antibiotics). Six colonized children were distributed among the older classrooms; 2 were siblings of colonized toddlers. No staff (n = 28) or children aged <16 months were colonized. Isolates from the 2 confirmed case patients and from the colonized children had an indistinguishable PFGE pattern. No risk factors for invasive disease or colonization were identified from the telephone survey. Of the 9 colonized toddlers who took rifampin, 3 (33%) remained positive on reculture; an additional toddler, initially negative, was positive on reculture. The children of the control child care center demonstrated a similar degree and distribution of K kingae colonization; of 118 potential subjects, 45 (38%) underwent oropharyngeal culture, and 7 (16%) were colonized with K kingae. The highest prevalence again occurred in the toddler classrooms. All 7 isolates from the control facility had an indistinguishable PFGE pattern; this pattern differed from the PFGE pattern observed from the outbreak center isolates. 16S rRNA gene sequencing demonstrated that the outbreak K kingae strain exhibited >98% homology to the ATCC-type strain, although several sequence deviations were present. Sequencing of the control center strain demonstrated more homology to the outbreak center strain than to the ATCC-type strain. This is the first reported outbreak of invasive K kingae disease. The high prevalence in the affected toddler class and the matching PFGE pattern are consistent with child-to-child transmission within the child care center. Rifampin was modestly effective in eliminating carriage. DNA sequence analysis suggests that there may be considerable variability within the species K kingae and that different K kingae strains may demonstrate varying degrees of pathogenicity.

Immune response to invasive Kingella kingae infections, age-related incidence of disease, and levels of antibody to outer-membrane proteins.

The immune response to Kingella kingae was determined by enzyme-linked immunosorbent assay, using outer-membrane proteins as coating antigen, in 19 children with invasive infection. The age-related incidence of K. kingae disease in southern Israel during 1988-2002 was calculated and correlated with serum antibody levels in healthy children. Significant increases in immunoglobulin G (IgG) levels were found in children convalescing after invasive infections. The incidence was 1.3, 40.3, 23.9, 5.7, and 1.9 cases/100,000 children among those aged 0-5, 6-11, 12-23, 24-35, and 36-47 months, respectively. A low attack rate and undetectable serum IgA and high IgG levels were found during the first 6 months of life, which indicates that protection was conferred by maternally derived immunity. The high attack rate found among 6-24-month-old children coincides with the age at which antibody levels were lowest. Low incidence of disease and increasing antibody levels were found among older children, which probably represents cumulative experience with K. kingae antigens via colonization or infection.