Continuing Education Activity

This activity reviews the microbiology, epidemiology, pathophysiology and the clinical manifestations of Kingella kingae infection. It also highlights the recent advances in the diagnosis and management of patients with this disease.

Objectives:

• Describe the microbiology and epidemiology of Kingella kingae.
• Review the pathophysiology of Kingella kingae along with its virulence factors.
• Outline the various modes of clinical presentation of Kingella infections and the current recommendations for its management.
• Explain interprofessional team strategies for improving care coordination and communication to manage complications of Kingella infections and improve outcomes.

Introduction

Until the recent advancement in diagnostic techniques, Kingella kingae was thought to be a rare bacteria.[1] Kingella kingae is now considered a significant cause of pediatric bacteremia and bone infections in children aged 6 to 48 months.[2][3] It is one of the etiologies of daycare disease outbreaks in the United States and other countries.[4] Though Kingella kingae is the natural flora of oropharyngeal lining of children between 6 to 48 months, it can get access to the bloodstream through a damaged mucosa to cause system infections.[5] Except in the case of endocarditis and osteoarticular infections, K. kingae infections usually present with mild symptoms.[2]

Etiology

K. kingae is a fastidious, gram-negative, facultative anaerobic coccobacillus of the Neisseriaceae family. It is a beta-hemolytic bacterium producing a faint ring of hemolysis. It is a non-motile and non-spore producing organism. Though all strains have high oxidase activity, they exhibit no reactions with catalase, indole, and urease.[5] K. kingae grows on blood agar, chocolate agar, and GC-based media but not on MacConkey or Krigler agar. Growth patterns of K. kingae can be of spreading and non-spreading, both with fringes, or it can dome-shaped without any fringe.[2]

Epidemiology

There is an increasing incidence of invasive K. kingae in the United States, Western Europe, and Israel, though the global impact of the disease is not yet fully understood[6][7][6] Kingella kingae is mostly a bacterial infection of children, especially those less than four years old. The colonization rate of K. kingae in children ages 1 to 4 years old ranges from 10 to 28% compared to colonization rates of less than 1% for age group 0 to 6 months and in adults. It is believed to be more common in males than in females. Social factors like daycare attendance are associated with a high risk of invasive Kingella kingae infection.

Pathophysiology

K. kingae expresses different structures for successful colonization, carriage, transmission, virulence, and pathogenesis. K. kingae is acquired via direct contact from person to person. Though the mechanism of communication is not well known, there is a high possibility of its spread via droplets. K. kingae produces type IV pili (T4P) under the regulation of rho 54, pilS, and pilR genes.[8] The pili are adhesive proteinous appendages to the respiratory mucosa and synovial membranes. Invasion of the respiratory mucosa by the bacteria is almost always associated with a prior or coincident viral infection[8]. Commonly implicated viruses are human rhinovirus, herpes simplex virus, and herpangina virus, which causes the hand-foot and mouth disease.[8] Invasive K. kingae infection establishes itself via a previous virus-induced mucosal damage in addition to the RTA toxin produced by the organism. RTA toxin also has cytotoxic effects on leukocytes, macrophages, and synovial cells. The polysaccharides capsules on the outer-membrane confer protection against phagocytosis of the bacterial cells. The tendency for K. kingae to produce biofilms assist the pathogen in evading host immunity and defenses. Also, the exopolysaccharides of K. kingae has inhibitory effects on biofilm production from other microorganisms and also facilitates the periodic release of the bacteria cells from biofilms, thereby promoting easier dissemination.[2]

History and Physical

Most infections occur in healthy children under the age of four or immunocompromised older children and adults.[3] The symptoms of K. kingae are usually mild with or without mild fever, except in case of rapidly progressive endocarditis when high fever, back pain, night sweats are common. Preceding or current upper respiratory tract symptoms or diarrhea is typical and may be a clue to initial suspicion.

Skeletal system infections

K. kingae is the most frequent etiology for skeletal system infection in children under the ages of four[9] The symptoms may be insidious in onset and patient usually present during the second week of infection due to the less profound inflammatory response induced by the bacteria, unlike other typical organisms causing osteoarticular infections.

Septic arthritis

This condition is the most common form of osteoarticular disease of K. kingae. The infection tends to affect the lower extremity the most, and the knee is often involved. There may be involvement of more than one joint. Patients may present with the common symptoms of septic arthritis, such as localized pain, swelling, warmth, erythema, immobility, or joint effusion. Fever may be less pronounced.

Osteomyelitis

Most often present in a subacute form, and affects long bones of the lower extremity the most. Bones like the clavicle, sternum, and the calcaneus may be involved, highlighting K. kingae association with atypical locations.[10]

Spondylodiscitis

Spondylodiscitis is an infection of the intervertebral disk space and adjacent vertebrae resulting in difficulty in walking or sitting. Children also present with back pain or stiffness, and abnormal gait. A single interverbal disk, most often the lumbar region, is most frequently affected. Spondylodiscitis of K. kingae may also correlate with intervertebral and spinal subdural abscess formation.

Bacteremia

K. kingae may be isolated from the blood without any focal infection (occult bacteremia), or concomitantly with other invasive infections. Occult bacteremia is the second most common form of presentation in pediatrics patients.[2] Others may present with skeletal system complaints without any evidence of bone or joint infections. Many children may have concurrent symptoms of acute infections such as upper respiratory or gastrointestinal tract infections. Few patients with occult bacteremia may present with a disseminated maculopapular rash similar to that of meningococcal or gonococcal infections.[2] Fever is usually mild if present.

Soft-tissue infections

Kingella kingae may present with a wide range of soft tissue infections such as cellulitis, bursitis, tenosynovitis, and dactylitis, and abscesses in different locations.

Endocarditis

Kingella kingae is a significant cause of endocarditis in pediatric patients. It is one of the HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Elkenella corrodens, and Kingella species). Kingella endocarditis typically affects adults and older children, unlike the skeletal system infections, which are predominantly in younger children. Antecedent dental health or procedures are the risk factors for HACEK endocarditis. Other predisposing factors are cardiac anomalies and rheumatic fever. A native valve is affected in more than 90% of the cases in young children, whereas native and prosthetic valves have similar incidence in older children and adults.[2] The mitral valve is affected in more than 90% of cases. Patients may present with cardiac symptoms like cardiogenic shock, congestive heart failure, or complication of embolism to the brain, bones, and the lungs.

Meningitis

Meningitis may result from hematogenous spread of the organism to the brain or from septic embolism from the heart.

Other clinical manifestations

Other symptoms of invasive Kingella include ocular infections like keratitis, endophthalmitis, urinary tract infections, and pericarditis.

Evaluation

Both microbiological culture and nucleic acid amplification assays can be used to detect the organisms. Blood culture vials (BCV) and other solid media like blood agar permit the growth of the organism, although with inconsistent findings. The bacteria can be cultured from the skeletal system specimens, blood, and respiratory cultures.  The nucleic acid amplification assays are now in use in advanced countries. It is faster and has higher sensitivity than blood cultures.

Additional workups should include complete blood counts, C- reactive protein (CRP) levels, and radiological investigations as appropriate.

A transthoracic echocardiogram is a recommendation for all children with invasive disease because of concern about endocarditis.[11]

Treatment / Management

As a standard protocol for managing serious bacterial infections, there should be an administration of initial empiric therapy pending culture results; this should consist of intravenous broad second/third-generation cephalosporin or a penicillinase-stable beta-lactam antibiotic. Once K. kingae is isolated, the regimen should be changed to parenteral ampicillin if there are no beta-lactamase-producing strains or ampicillin/sulbactam if beta-lactamase-producing strains are present. Other cephalosporins like Ccefuroxime and ceftriaxone are also options.

Septic Arthritis: Current recommendation is 2 to 3 weeks of sequential intravenous-oral antibiotics.

Osteomyelitis: Traditional treatment is from 3 weeks to 6 months.

Spondylodiscitis: Conventional antibiotic therapy is for 3 to 12 weeks

Nowadays, current recommendations for the management of osteoarticular infections include shorter duration of antibiotic therapy, early switch to oral medications, and the use of serum CRP levels for monitoring clinical response. Generally, a good clinical response and a fall of serum CRP to less than 20mg/l are indications for switching to oral antibiotics and may as well guide on deciding when treatment should cease. Most infections respond to antibiotic therapy without the need for repeated aspirations or surgical washout.

Differential Diagnosis

• Haemophilus influenza type b
• Neisseria meningitidis
• HACEK infections
• Streptococcus pneumonia
• Staphylococcal septic arthritis

Prognosis

Most invasive Kingella kingae infections are benign if diagnosed and treated timely. Most strains of Kingella kingae except the beta-lactamase resistant species are susceptible to commonly prescribed antibiotics for children. Children often recover fully from osteoarticular infections without any complications. Though intravertebral abscess may develop from Kingella spondylodiscitis, it responds well to antibiotics. Complications resulting in narrowing of the intervertebral disks are not common.

Endocarditis from Kingella kingae can be life-threatening, with mortality close to 20%. Aggressive management is often necessary for a favorable outcome.

Complications

As discussed above, complications include osteoarticular diseases and endocarditis.

Deterrence and Patient Education

Kingella infection may present with subtle symptoms. All febrile children with suspicious presentation should have a proper workup for possible K. kingae infection. Parents with children between 6 months and 4 years with fever and acute joint problems, rash, or cardiovascular collapse should present immediately for evaluation.

Enhancing Healthcare Team Outcomes

Management of complications of Kingella infections requires an interprofessional team approach. Such an approach can include infectious disease specialists, a pharmacist with an infectious disease specialty certification, who can help direct agent selection based on the most current antibiogram data. Nurses with training infection control can also offer counsel to parents on helping therapy move forward and preventing reinfection.

There is a need for interdependence, communication, and collaboration among physicians, nurses, pharmacists, and other health care professionals on the interprofessional team involved in Kingella infection management to enhance patient-centered care, improve outcomes, patient safety, and improve interprofessional team performance. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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Principi N, Esposito S. Kingella kingae infections in children. BMC Infect Dis. 2015 Jul 07;15:260. [PMC free article: PMC4494779] [PubMed: 26148872]

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Yagupsky P. Diagnosing Kingella kingae infections in infants and young children. Expert Rev Anti Infect Ther. 2017 Oct;15(10):925-934. [PubMed: 28918656]

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Yagupsky P. Kingella kingae: carriage, transmission, and disease. Clin Microbiol Rev. 2015 Jan;28(1):54-79. [PMC free article: PMC4284298] [PubMed: 25567222]

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El Houmami N, Minodier P, Dubourg G, Mirand A, Jouve JL, Basmaci R, Charrel R, Bonacorsi S, Yagupsky P, Raoult D, Fournier PE. Patterns of Kingella kingae Disease Outbreaks. Pediatr Infect Dis J. 2016 Mar;35(3):340-6. [PubMed: 26658382]

5.

Kaplan JB, Sampathkumar V, Bendaoud M, Giannakakis AK, Lally ET, Balashova NV. In vitro characterization of biofilms formed by Kingella kingae. Mol Oral Microbiol. 2017 Aug;32(4):341-353. [PMC free article: PMC5384882] [PubMed: 27714987]

6.

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7.

Yagupsky P, Peled N, Katz O. Epidemiological features of invasive Kingella kingae infections and respiratory carriage of the organism. J Clin Microbiol. 2002 Nov;40(11):4180-4. [PMC free article: PMC139679] [PubMed: 12409394]

8.

Valaikaite R, El Houmami N, Spyropoulou V, Braendle G, Ceroni D. Kingella kingae: from oropharyngeal carriage to paediatric osteoarticular infections. Expert Rev Anti Infect Ther. 2018 Feb;16(2):85-87. [PubMed: 29291633]

9.

Dubnov-Raz G, Ephros M, Garty BZ, Schlesinger Y, Maayan-Metzger A, Hasson J, Kassis I, Schwartz-Harari O, Yagupsky P. Invasive pediatric Kingella kingae Infections: a nationwide collaborative study. Pediatr Infect Dis J. 2010 Jul;29(7):639-43. [PubMed: 20182400]

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Mooney ML, Haidet K, Liu J, Ebraheim NA. Hematogenous Calcaneal Osteomyelitis in Children. Foot Ankle Spec. 2017 Feb;10(1):63-68. [PubMed: 27881832]

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Evangelista A, Gonzalez-Alujas MT. Echocardiography in infective endocarditis. Heart. 2004 Jun;90(6):614-7. [PMC free article: PMC1768290] [PubMed: 15145856]

Disclosure: Ebenezer Adebiyi declares no relevant financial relationships with ineligible companies.

Disclosure: Folusakin Ayoade declares no relevant financial relationships with ineligible companies.