Proinflammatory Microenvironment During Kingella kingae Infection Modulates Osteoclastogenesis.

Kingella kingae is an emerging pathogen that causes septic arthritis, osteomyelitis, and bacteremia in children from 6 to 48 months of age. The presence of bacteria within or near the bone is associated with an inflammatory process that results in osteolysis, but the underlying pathogenic mechanisms involved are largely unknown. To determine the link between K. kingae and bone loss, we have assessed whether infection per se or through the genesis of a pro-inflammatory microenvironment can promote osteoclastogenesis. For that purpose, we examined both the direct effect of K. kingae and the immune-mediated mechanism involved in K. kingae-infected macrophage-induced osteoclastogenesis. Our results indicate that osteoclastogenesis is stimulated by K. kingae infection directly and indirectly by fueling a potent pro-inflammatory response that drives macrophages to undergo functional osteoclasts via TNF-α and IL-1ß induction. Such osteoclastogenic capability of K. kingae is counteracted by their outer membrane vesicles (OMV) in a concentration-dependent manner. In conclusion, this model allowed elucidating the interplay between the K. kingae and their OMV to modulate osteoclastogenesis from exposed macrophages, thus contributing to the modulation in joint and bone damage.

[Osteo-articular infections by Kingella kingae in children in a highly complex pediatric hospital: epidemiology and associated factors]. / Infecciones osteo-articulares por Kingella kingae en niños en un hospital pediátrico de alta complejidad: epidemiología y factores asociados.

BACKGROUND: The epidemiology of osteoarticular infections (IOA) has changed in recent years. The incidence of Kingella kingae in Latin America is unknown. AIMS: To describe the epidemiology in patients with IOA in a children hospital. To estimate the incidence of IOA due to K. kingae and compare with other etiologies. METHODS: Prospective cohort. Patients older than 1 month hospitalized between March, 1th 2017 and February, 28th 2019 with suspected IOA and diagnostic procedure (biopsy or arthrocentesis) were included. STATA 13 was used. RESULTS: n: 84 patients. The etiology was identified in 58 patients (69.1%). Staphylococus aureus predominated (n: 44; 52.4%) and K. kingae (n: 9; 10.8%). In the period studied, the incidence of IOA by K. kingae was 10.8 cases per 100 hospitalized IOA. In multivariate analysis, age less than 4 years (OR 13.8, 95% CI 5.5-82.7), recent respiratory symptoms (OR 5.7, 95% CI 3.5-31.6, p 0.04) and normalization before the fifth day of C-reactive protein (CRP) (OR 3.38 95% CI 1.8-16.3, p 0.01) were associated with IOA by K. kingae. CONCLUSIONS: In this cohort of children the incidence of K. kingae was 10.8 cases per 100 IOA. Kingella kingae represented the second documented etiology, after S. aureus. Age under 4 years, recent respiratory symptoms and normalization before the fifth day of quantitative CRP were statistically associated with IOA by K. kingae.

Infecciones osteo-articulares por Kingella kingae en niños en un hospital pediátrico de alta complejidad: epidemiología y factores asociados / Osteo-articular infections by Kingella kingae in children in a highly complex pediatric hospital: epidemiology and associated factors

Resumen Introducción: La epidemiología de las infecciones osteo-articulares (IOA) se ha modificado en los últimos años. La incidencia de Kingella kingae en Latinoamérica es desconocida. Objetivo: Describir la epidemiología de los niños con IOA. Estimar la incidencia de IOA causadas por K. kingae y compararlas con otras etiologías. Material y Métodos: Cohorte prospectiva. Se incluyeron pacientes mayores de 1 mes de edad, hospitalizados entre el 1 de marzo de 2017 y 28 de febrero de 2019, con sospecha de IOA y procedimiento diagnóstico (biopsia o artrocentesis). Se utilizó STATA 13. Resultados: n: 84 pacientes. Se identificó la etiología en 58 pacientes (69,1%). Predominaron Staphylococcus aureus (n: 44; 52,4%) y K. kingae (n: 9; 10,8%). En el período estudiado, la incidencia de IOA por K. kingae fue de 10,8 casos cada 100 IOA hospitalizadas. En el análisis multivariado, la edad inferior a 4 años (OR 13,8, IC95% 5,5-82,7), el cuadro respiratorio reciente (OR 5,7, IC95% 3,5-31,6, p 0,04) y la normalización antes del quinto día de la proteína C reactiva (PCR) (OR 3,8 IC95% 1,8- 16,3, p 0,01) se asociaron con las IOA por K. kingae. Conclusiones: En esta cohorte de niños, la incidencia de K.kingae fue de 10,8 casos cada 100 IOA. Kingella kingae representó la segunda etiología documentada, luego de S. aureus. La edad inferior a 4 años, el cuadro respiratorio reciente y la normalización antes del quinto día de la PCR cuantitativa se asociaron estadísticamente con IOA por K. kingae.

Abstract Background: The epidemiology of osteoarticular infections (IOA) has changed in recent years. The incidence of Kingella kingae in Latin America is unknown. Aims: To describe the epidemiology in patients with IOA in a children hospital. To estimate the incidence of IOA due to K. kingae and compare with other etiologies. Methods: Prospective cohort. Patients older than 1 month hospitalized between March, 1th 2017 and February, 28th 2019 with suspected IOA and diagnostic procedure (biopsy or arthrocentesis) were included. STATA 13 was used. Results: n: 84 patients. The etiology was identified in 58 patients (69.1%). Staphylococus aureus predominated (n: 44; 52.4%) and K. kingae (n: 9; 10.8%). In the period studied, the incidence of IOA by K. kingae was 10.8 cases per 100 hospitalized IOA. In multivariate analysis, age less than 4 years (OR 13.8, 95% CI 5.5-82.7), recent respiratory symptoms (OR 5.7, 95% CI 3.5-31.6, p 0.04) and normalization before the fifth day of C-reactive protein (CRP) (OR 3.38 95% CI 1.8-16.3, p 0.01) were associated with IOA by K. kingae. Conclusions: In this cohort of children the incidence of K. kingae was 10.8 cases per 100 IOA. Kingella kingae represented the second documented etiology, after S. aureus. Age under 4 years, recent respiratory symptoms and normalization before the fifth day of quantitative CRP were statistically associated with IOA by K. kingae.

[ECMO support in a child with cardiogenic shock due to Kingella Kingae endocarditis]. / ECMO en un lactante con shock cardiogénico secundario a endocarditis por Kingella Kingae.

INTRODUCTION: Endocarditis is a rare disease in children, especially in those without previous heart disease, and Kingella Kingae (KK) is rarely identified as the cause. Extracorporeal membrane oxyge nation (ECMO) is a support for both heart and respiratory failure. OBJECTIVE: To report the first case of infectious endocarditis (IE) due to KK which required ECMO support secondary to refractory cardiogenic shock. CLINICAL CASE: 19-months-old previously healthy female patient, with a 2-day his tory of fever, and diagnosed with hand-foot-and-mouth disease. The patient developed refractory cardiogenic shock, multiorgan failure, acute respiratory distress syndrome, and deep hemodynamic compromise that required veno-arterial ECMO support. The echography showed an image compa tible with mitral valve vegetation, confirming IE with transthoracic echocardiography. Blood culture was positive for KK. She had an ischemic stroke and required two heart surgeries, the first one for the mass resection and the second one for mitral valve repair, which had a posterior ring pseudoa neurysm. The patient had a favorable evolution and was discharged 73 days after admission. At one year of follow-up, she had no cardiological symptoms, but a mild right brachial-crural hemiparesis persisted. CONCLUSION: This is the first reported case of IE due to KK that required extracorporeal life support. KK endocarditis is an uncommon pathology that can cause multiorgan failure, which can be successfully supported with ECMO.

Espondilodiscitis por Kingella kingae: A propósito de un caso de presentación atípica / Atypical presentation of Spondylodiscitis by Kingella Kingae: a case report

La espondilodiscitis infecciosa es una infección poco frecuente en niños, con mayor incidencia en menores de 6 años. Se presenta el caso de una paciente de 8 años, que se internó por dolor lumbar de 2 meses de evolución, afebril. La radiografía, tomografía e imagen por resonancia magnética nuclear fueron compatibles con espondilodiscitis a nivel de L4-L5. Luego de 10 días de antibioticoterapia empírica con clindamicina, con regular respuesta, se realizó punción ósea y se aisló Kingella kingae. Existe un aumento en la incidencia de infecciones osteoarticulares por Kingella kingae en lactantes y niños pequeños. La reemergencia en los últimos años se justifica por la optimización en las técnicas de cultivo, el uso de sistemas automatizados y de técnicas moleculares de diagnóstico. Kingella kingae es un patógeno que ha adquirido importancia en los últimos años en las infecciones osteoarticulares.

Infectious Spondylodiscitis is a rare infection in children. It is more frequent in patients under 6 years of age. We report the case of an 8-year-old patient with lumbar pain for 2 months, without fever. Xrays, computed tomography and magnetic resonance imaging all three showed spondylodiscitis L4-L5. After a 10-day antibiotic treatment with clindamycin with regular response, a bone puncture was performed isolating Kingella kingae (Kk). Ostearticular infections caused by Kk have increased among infants and children. Due to improvement in culture techniques, the usage of automatic systems and assessment molecular techniques, these infections re-emerged in the past few years. Kk is a pathogen that has lately become significant in osteoarticular infections.

[Atypical presentation of Spondylodiscitis by Kingella Kingae: a case report]. / Espondilodiscitis por Kingella kingae: A propósito de un caso de presentación atípica.

Infectious Spondylodiscitis is a rare infection in children. It is more frequent in patients under 6 years of age. We report the case of an 8-year-old patient with lumbar pain for 2 months, without fever. Xrays, computed tomography and magnetic resonance imaging all three showed spondylodiscitis L4-L5. After a 10-day antibiotic treatment with clindamycin with regular response, a bone puncture was performed isolating Kingella kingae (Kk). Ostearticular infections caused by Kk have increased among infants and children. Due to improvement in culture techniques, the usage of automatic systems and assessment molecular techniques, these infections re-emerged in the past few years. Kk is a pathogen that has lately become significant in osteoarticular infections.

La espondilodiscitis infecciosa es una infección poco frecuente en niños, con mayor incidencia en menores de 6 años. Se presenta el caso de una paciente de 8 años, que se internó por dolor lumbar de 2 meses de evolución, afebril. La radiografía, tomografía e imagen por resonancia magnética nuclear fueron compatibles con espondilodiscitis a nivel de L4-L5. Luego de 10 días de antibioticoterapia empírica con clindamicina, con regular respuesta, se realizó punción ósea y se aisló Kingella kingae. Existe un aumento en la incidencia de infecciones osteoarticulares por Kingella kingae en lactantes y niños pequeños. La reemergencia en los últimos años se justifica por la optimización en las técnicas de cultivo, el uso de sistemas automatizados y de técnicas moleculares de diagnóstico. Kingella kingae es un patógeno que ha adquirido importancia en los últimos años en las infecciones osteoarticulares.

ECMO en un lactante con shock cardiogénico secundario a endocarditis por Kingella Kingae / ECMO support in a child with cardiogenic shock due to Kingella Kingae endocarditis

Resumen: Introducción: La endocarditis es una enfermedad poco frecuente en niños, especialmente en los sin patología cardiaca previa, y de manera extraordinaria se identifica a Kingella Kingae (KK) como la causa. La oxigenación por membrana extracorpórea (ECMO) es una forma de soporte tanto para fa lla cardiaca como respiratoria. Objetivo: Reportar el primer caso de endocarditis infecciosa (EI) por KK que requiere soporte con ECMO por shock cardiogénico refractario. Caso clínico: Lactante de 19 meses, previamente sana, que consultó por cuadro de 2 días de fiebre, diagnosticándose síndrome pie mano boca. Evolucionó con shock, falla multiorgánica, síndrome de distress respiratorio agudo y compromiso hemodinámico profundo, por lo que se le dio soporte con ECMO veno arterial. La ecoscopía mostró imagen compatible con vegetación en válvula mitral, confirmando EI con ecocardiografía transtorácica. El hemocultivo fue positivo a KK. Presentó accidente cerebrovascular isquémico. Requirió dos cardiocirugías -la primera para resección de la masa y la segunda para la reparación de la válvula mitral, que había quedado con un pseudoaneurisma del anillo- velo posterior. La paciente tuvo una evolución favorable, siendo dada de alta a los 73 días desde el ingreso. Al año de seguimien to se encontraba asintomática cardiaca, pero persistía una hemiparesia braquiocrural derecha leve. Conclusión: Este es el primer caso reportado de EI por KK que requirió soporte vital extracorpóreo. La EI por KK es una patología infrecuente, que puede provocar falla orgánica múltiple, la que puede ser soportada exitosamente con ECMO.

Abstract: Introduction: Endocarditis is a rare disease in children, especially in those without previous heart disease, and Kingella Kingae (KK) is rarely identified as the cause. Extracorporeal membrane oxyge nation (ECMO) is a support for both heart and respiratory failure. Objective: To report the first case of infectious endocarditis (IE) due to KK which required ECMO support secondary to refractory cardiogenic shock. Clinical case: 19-months-old previously healthy female patient, with a 2-day his tory of fever, and diagnosed with hand-foot-and-mouth disease. The patient developed refractory cardiogenic shock, multiorgan failure, acute respiratory distress syndrome, and deep hemodynamic compromise that required veno-arterial ECMO support. The echography showed an image compa tible with mitral valve vegetation, confirming IE with transthoracic echocardiography. Blood culture was positive for KK. She had an ischemic stroke and required two heart surgeries, the first one for the mass resection and the second one for mitral valve repair, which had a posterior ring pseudoa neurysm. The patient had a favorable evolution and was discharged 73 days after admission. At one year of follow-up, she had no cardiological symptoms, but a mild right brachial-crural hemiparesis persisted. Conclusion: This is the first reported case of IE due to KK that required extracorporeal life support. KK endocarditis is an uncommon pathology that can cause multiorgan failure, which can be successfully supported with ECMO.

Temporal Association Between Rhinovirus Activity and Kingella kingae Osteoarticular Infections.

OBJECTIVE: To determine whether the seasonal distribution of Kingella kingae osteoarticular infections is similar to that of common respiratory viruses. STUDY DESIGN: Between October 2009 and September 2016, we extracted the results of K kingae-specific real-time polymerase chain reaction analyses performed for bone or joint specimens in patients from 2 pediatric tertiary care centers in Paris. We used data of respiratory virus detection from the Réseau National des Laboratoires network with coordination with the National Influenza Center of France. The Spearman rank correlation was used to assess a correlation between weekly distributions, with P < .05 denoting a significant correlation. RESULTS: During the 7-year study period, 322 children were diagnosed with K kingae osteoarticular infection, and 317 testing episodes were K kingae-negative. We observed high activity for both K kingae osteoarticular infection and human rhinovirus (HRV) during the fall (98 [30.4%] and 2401 [39.1%] cases, respectively) and low activity during summer (59 [18.3%] and 681 [11.1%] cases, respectively). Weekly distributions of K kingae osteoarticular infection and rhinovirus activity were significantly correlated (r = 0.30; P = .03). In contrast, no significant correlation was found between the weekly distribution of K kingae osteoarticular infection and other respiratory viruses (r = -0.17, P = .34 compared with respiratory syncytial virus; r = -0.13, P = .34 compared with influenza virus; and r = -0.22, P = .11 compared with metapneumovirus). CONCLUSION: A significant temporal association was observed between HRV circulation and K kingae osteoarticular infection, strengthening the hypothesis of a role of viral infections in the pathophysiology of K kingae invasive infection.

[Neisseria subflava bacteremia in newborns: case report and review of the literature]. / Bacteriemia por Neisseria subflava en un recién nacido.

Neisseria subflava belongs to Neisseriaceae family, is considered a comensal specie, however in certain host, mainly inmunosuppresed patientes and children, the literature has documented invasive infections. We present a case of a bacteriemia due to N. subflava in a newborn, treated with cefotaxime with good outcome. In newborns, the most common Neisseria bacteria to cause invasive infections are N. meningitidis, with highly fatal clinical course and N. gonorrhoeae which compromise the eye, oftalmia neonatorum, with uncommon invasive infections. It's very important the adequate microbiological diagnosis because the biochemical tests may be inconclusive. MALDITOF mass spectrometry technique is a useful tool.

Bacteriemia por Neisseria subflava en un recién nacido / Neisseria subflava bacteremia in newborns: case report and review of the literature

Resumen Neisseria subflava es una especie considerada comensal dentro de la familia Neisseriaceae; sin embargo, en algunos hospederos inmunocomprometidos y en niños se ha documentado como agente causal de infecciones invasoras. Se presenta el caso clínico de un recién nacido con bacteriemia por N. subflava con buena respuesta a terapia con cefotaxima. Las bacterias del género Neisseria más frecuentes de causar infecciones en recién nacidos son N. meningitidis, de alta mortalidad y N. gonorrhoeae, que se manifiesta principalmente con oftalmia neonatorum. Se destaca la importancia de realizar un diagnóstico microbiológico adecuado dado que las pruebas biquímicas pueden ser no concluyentes. La técnica de espectrometría de masas MALDITOF resulta una herramienta de utilidad.

Neisseria subflava belongs to Neisseriaceae family, is considered a comensal specie, however in certain host, mainly inmunosuppresed patientes and children, the literature has documented invasive infections. We present a case of a bacteriemia due to N. subflava in a newborn, treated with cefotaxime with good outcome. In newborns, the most common Neisseria bacteria to cause invasive infections are N. meningitidis, with highly fatal clinical course and N. gonorrhoeae which compromise the eye, oftalmia neonatorum, with uncommon invasive infections. It's very important the adequate microbiological diagnosis because the biochemical tests may be inconclusive. MALDITOF mass spectrometry technique is a useful tool.

Outbreaks of Invasive Kingella kingae Infections in Closed Communities.

OBJECTIVES: To describe the results of the epidemiologic investigation of outbreaks of invasive Kingella kingae infections among attendees at daycare facilities located in 4 closed communities in Israel. STUDY DESIGN: The preschool-aged population of communities with clusters of Kingella cases had oropharyngeal cultures performed. K kingae isolates from infected patients and healthy contacts were genotyped by pulsed field gel electrophoresis to determine the spread of outbreak strains. RESULTS: The affected closed communities (3 military bases and 1 "kibbutz" commune) were characterized by tight social and family networks and intensive mingling. The outbreaks affected 9 of 51 attendees (attack rate: 17.6%) age 8-19 months (median: 12 months), within a 21-day period. Cases included skeletal system infections (n = 8) and bacteremia (n = 1); K kingae isolates were confirmed by the use of blood culture vials and selective media. Clinical presentation was mild and acute-phase reactants were usually normal or only moderately elevated. Thirty out of 55 (54.5%) asymptomatic children carried the outbreak strains. Analysis of the 3 clusters in which the entire preschool-aged population was cultured revealed that 31 of 71 (43.7%) children younger than 24 months of age were colonized with K kingae organisms compared with 8 of 105 (7.6%) older children (P < .001). CONCLUSIONS: Clusters of invasive K kingae infections characterized by sudden onset, high attack rate, and wide dissemination of the outbreak strain can occur in daycare facilities and closed communities. Because the mild clinical presentation of invasive K kingae infections and the fastidious nature of the organism, a high index of suspicion and use of sensitive detection methods are recommended.

[Septic arthritis caused by Kingella kingae in children]. / Artritis séptica causada por Kingella kingae en pediatría.

INTRODUCTION: Approximately 50% of cases of bacterial arthritis occur in childhood. Currently Kingella kingae is considered as an emerging pathogen. CLINICAL CASE: A ten month old male patient presented joint immobility in right knee. Arthrocentesis was performed.Kingella kingae was identified. He received treatment with ampiciline for 14 days. DISCUSSION: This pathogen colonizes the posterior pharynx.Isolation in solid culture media may be difficult. CONCLUSION: It is essential to consider this pathogen when septic arthritis is suspected, and to routinely use blood culture bottles for processing samples of synovial fluid.

Differentiating Kingella kingae septic arthritis of the hip from transient synovitis in young children.

OBJECTIVE: To conduct a retrospective multicenter study to assess the ability of a predictive algorithm to differentiate between children with Kingella kingae infection of the hip and those with transient synovitis. STUDY DESIGN: Medical charts of 25 Israeli and 9 Spanish children aged 6-27 months with culture-proven K kingae arthritis of the hip were reviewed, and information on the 4 variables included in the commonly used Kocher prediction algorithm (body temperature, refusal to bear weight, leukocytosis, and erythrocyte sedimentation rate) was gathered. RESULTS: Patients with K kingae arthritis usually presented with mildly abnormal clinical picture and normal serum levels of or near-normal acute-phase reactants. Data on all 4 variables were available for 28 (82%) children, of whom 1 child had none, 6 children had 1, 13 children had 2, 5 had 3, and only 3 children had 4 predictors, implying ≤ 40% probability of infectious arthritis in 20 (71%) children. CONCLUSIONS: Because of the overlapping features of K kingae arthritis of the hip and transient synovitis in children younger than 3 years of age, Kocher predictive algorithm is not sensitive enough for differentiating between these 2 conditions. To exclude K kingae arthritis, blood cultures and nucleic acid amplification assay should be performed in young children presenting with irritation of the hip, even in the absence of fever, leukocytosis, or a high Kocher score.

[Kingella kingae pediatric septic arthritis]. / Artritis séptica pediátrica causada por Kingella kingae.

Kingella kingae is a bacterium that colonizes the upper respiratory tract. Despite its low pathogenicity in this location, previous respiratory pathological processes may favor its systemic spread causing bone and joint infections, mainly in children under five years. It can be considered an emerging pathogen in osteoarticular infection in pediatric patients. We report the case of a two-year-old girl with hips pain and limitation of both abduction and extension, and fever. Radiography and ultrasonography were compatible with transitory synovitis; showed scintigraphy inflammatory pathology of the right hip. Articular puncture was performed. The material showed altered biochemical parameters. Microbiological culture yielded isolation of a strain of K. kingae susceptible to beta-lactam antibiotics, azithromycin and trimethoprim-sulfamethoxazole. Blood cultures were negative. The patient was treated empirically with cloxacillin and cefotaxime iv. and continued with amoxicillin-clavulanate orally with osteoarticular improvement.

Artritis séptica pediátrica causada por Kingella kingae / Kingella kingae pediathric septic arthritis

Kingella kingae es un microorganismo que coloniza el tracto respiratorio superior. A pesar de su baja patogenicidad en esta localización, los procesos patológicos respiratorios previos pueden favorecer su diseminación sistémica y producir infecciones osteoarticulares, principalmente en menores de cinco años. En pacientes pediátricos, se considera un patógeno emergente en la infección osteoarticular. Presentamos el caso de una niña de dos años de edad con cuadro clínico de dolor de caderas, limitación de la abducción y extensión, y fiebre. La radiografía y la ecografía eran compatibles con sinovitis transitoria y la gammagrafía con patología osteoarticular infamatoria de la cadera derecha. Se realizó punción articular y los parámetros bioquímicos arrojaron resultados alterados. Se procesó microbiológicamente y se aisló K. kingae sensible a antibióticos betalactámicos, azitromicina y trimetoprima-sulfametoxazol. Los hemocultivos fueron negativos. Se trató empíricamente con cloxacilina y cefotaxima IV y se continuó oralmente con amoxicilina-clavulánico, con mejoría osteoarticular.

Kingella kingae is a bacterium that colonizes the upper respiratory tract. Despite its low pathogenicity in this location, previous respiratory pathological processes may favor its systemic spread causing bone and joint infections, mainly in children under five years. It can be considered an emerging pathogen in osteoarticular infection in pediatric patients. We report the case of a two-year-old girl with hips pain and limitation of both abduction and extension, and fever. Radiography and ultrasonography were compatible with transitory synovitis; showed scintigraphy infammatory pathology of the right hip. Articular puncture was performed. The material showed altered biochemical parameters. Microbiological culture yielded isolation of a strain of K. kingae susceptible to beta-lactam antibiotics, azithromycin and trimethoprim-sulfamethoxazole. Blood cultures were negative. The patient was treated empirically with cloxacillin and cefotaxime iv. and continued with amoxicillin-clavulanate orally with osteoarticular improvement.