Introduction

Septic arthritis in children can lead to serious local and systemic consequences, as joint destruction, growth plate damage, angular deformity, septicemia. Staphylococcus aureus (SA) is the pathogen most commonly associated with musculoskeletal infections in children, and it may express toxins as Panton-Valentine leukocidin (PVL)¹, which is more common in methicillin-resistant SA (MRSA) than in methicillin-susceptible SA (MSSA)². PVL is a synergohymenotropic toxin with two nonassociated components acting synergistically on membranes of polymorphonuclear leukocytes, monocytes and macrophages^3-5. The two components, LukS-PV and LukF-PV are secreted before they assemble into a pore-forming heptamer, which bind to complement receptors on the target cells inducing membrane channel formation and cell lysis; the toxin also induces the release of pro-inflammatory cytokines and nuclear factor-kappa B in neutrophils^3-5. The incidence of PVL-positive SA varies widely by region. In United States and Colombia^2,6, 60-100% of Community-Associated MRSA (CA-MRSA) carry PVL genes and, in children with septic arthritis in Texas, 61% of SA were found⁷ to be PVL-positive. Recent studies^8,9 documented the emergence and the increasing prevalence of PVL-positive CA-MRSA in Europe, where CA-MRSA infections occur far less commonly². In 2016, in a multicenter European study¹⁰ on pediatric CA-SA infections (7.8% MRSA, 92.2% MSSA), PVL was found in 18.6% of cases (22/118 strains) and, among the 70 SA in bone and joint infections, 17.1% of patients was PVL-producing. In the most recent multicenter European study¹¹ on pediatric osteoarticular infections, published in 2022 and reporting data from the EUCLIDS database, SA was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) MRSA, but only 24 cases were investigated for PVL, which was detected in 25% (6/24) of the samples. In Italy, PVL is still an emerging problem, but it has not been adequately recognized as in other countries¹². PVL-positive SA, known for causing skin and soft tissue infections (SSTIs), was also found in children with life-threatening infections, such as necrotizing pneumonia, necrotizing fasciitis and osteomyelitis¹³.

Case Presentation

A 11-year-old boy was admitted at Emergency Department for left knee pain. Local trauma with superficial skin wound two weeks before and other two falls on the same knee in the previous days were reported. Knee X-ray was normal, and he was discharged. In the following days, he presented growing pain and fever and he was re-evaluated: blood tests showed mildly elevated C-reactive protein (CRP) and neutrophilic leukocytosis; arthrocentesis was performed but no fluid was obtained. Oral amoxicillin-clavulanate was started. Three days later, magnetic resonance (MR) evidenced significant intra-articular effusion (Figure 1) and he was admitted to our Emergency Department. A second arthrocentesis was performed, and synovial fluid resulted consistent with septic arthritis (cloudy aspects, red color, glucose 1 mg/dl, total proteins 5.8 g/dl, leukocytes 7,500 x10^9/l, 80% polymorphonucleocytes). Laboratory tests showed increased inflammatory markers (leukocytes 17.9 x10⁹/l, CRP 161 mg/l, procalcitonin 3.17 ng/ml). Intravenous teicoplanin and amoxicillin-clavulanate were started.

Figure 1. Magnetic resonance at diagnosis.

Two days later, fever and joint swelling increased, and surgical joint wash, curettage and placement of drainage were performed. Cultures of synovial fluid, from this sample and from the previous arthrocentesis, tested positive for MRSA and the two antibiograms showed resistance to penicillins, gentamycin, clindamycin, tetracycline and fusidic acid. Amoxicillin-clavulanate was replaced by rifampicin, maintaining teicoplanin. Two days later the drainage was removed. In the following days inflammatory markers decreased, but he presented remitting fever with high peaks. Teicoplanin was replaced by intravenous linezolid and then meropenem was started instead of rifampicin because a new antibiogram of pus sample from the wound showed resistance to this drug, in addition to those already identified in previous antibiograms. The fever persisted and eleven days after the admission a second MR (Figure 2) still showed joint effusion and synovial thickness. Considering the worsening clinical condition, five days later, knee arthroscopy with synovectomy (the synovial tissue was widely hypertrophic and inflammatory with some areas with bluish-red nodular appearance with vascular spots) and placement of drainage with continuous joint wash was performed. Synovial fluid culture still tested positive for MRSA resistant to clindamycin and rifampicin. Synovial fluid was tested for PVL and resulted positive.

Figure 2. Magnetic resonance 1 week after the first surgical joint wash and curettage.

After the arthroscopy, clinical improvement, resolution of fever and normalization of inflammatory markers were noticed. Meropenem was discontinued, maintaining oral linezolid. Drainage was removed after twelve days. Three weeks later, MR evidenced significant improvement (Figure 3), with edema in periarticular space and soft tissue, but without intra-articular effusion, and the child was discharged.

Figure 3. Magnetic resonance on discharge.

Linezolid was administered for overall 6 weeks; MR at 6 and 12 months (Figure 4) showed synovial thickness without growth plates damage and an asymptomatic osteochondral patellar lesion. The patient was asymptomatic and returned to swimming and snowboarding. Two years later he had mild lower limb length discrepancy (the left one was 1 cm longer), knee flexion had a 10° limitation, the extension was complete.

Figure 4. Magnetic resonance one year later.

Discussion

The role of PVL as a marker of severity is controversial: Shallcross et al³, in a systematic review and meta-analysis, concluded that PVL-positive SSTIs were more often treated surgically, but there was no evidence that PVL affected outcome in pneumonia, bacteremia and colonizing strains. Current evidence^1,3,10,14 suggests that musculoskeletal infections in children caused by PVL-positive SA have increased morbidity, with more aggressive and rapid disease progression, more surgical interventions and complications (abscesses, pneumonia, deep vein thrombosis), longer duration of fever, longer intensive care unit admission, higher inflammatory markers¹.

In a recent systematic literature review, Bouiller and David¹⁵ analyzed the studies between 2000 and 2022 reporting the genetic characteristics of SA and the outcomes of bone and joint infections: PVL genes resulted associated with poor outcomes in children, while no specific genes were similarly reported in adults¹⁵.

In our case, the patient had high persistent fever, poor response to antibiotics and repeated surgical procedures. We excluded complications as local abscesses with MR, deep vein thrombosis with Doppler ultrasound and pulmonary, abdominal and cardiac involvement with chest X-ray, abdominal ultrasound and echocardiogram.

Where PVL-positive MRSA is common, toxin testing is not routinely performed; in some countries³ it is recommended in CA invasive diseases or recurrent SSTIs SA infections. In pediatric osteoarticular infections, PVL should be suspected in particular if the patient or close family contacts have recurrent SSTIs infections or in cases of severe sepsis, multiple sites of infection/abscesses, extensive local lesions, myositis/pyomyositis, local venous thrombosis, very high CRP and repeated surgical procedures¹⁶. No other specific clue (not even with regard to the synovial liquid characteristics) to suspect its presence are reported in literature, but the knowledge of conditions related to PVL can lead to precocious diagnosis and adequate treatment, which are essential to avoid severe clinical consequences.

In osteoarticular infections with PVL-positive SA, aggressive early orthopedic intervention to drain focus of infection is recommended¹⁶. In septic arthritis of the knee in children, arthroscopic drainage plus antibiotic treatment is an effective treatment, also for recurrences¹⁷.

PVL detection is important to guide antibiotic treatment. In cases of PVL-positive SA, sub-inhibitory concentrations of beta-lactams can enhance expression of PVL, while clindamycin, linezolid, fusidic acid and rifampicin are inhibitory and vancomycin, tetracycline, ofloxacin and co-trimoxazole have no significant effect¹⁸. According to the UK Health Protection Agency Guidance¹⁶, in children, once PVL-positive SA is confirmed in deep-seated infections, intravenous clindamycin plus rifampicin, possibly with the addition of linezolid, is indicated. The linezolid alone for bone and joint infections could be effective, but it is limited by potential toxicity in prolonged therapy⁴. As continuation therapy for pediatric joint infections, clindamycin plus rifampicin is suggested¹⁶.

In our case, considering the resistance to clindamycin and the subsequent resistance also to rifampicin (likely due to selection of resistant strains during antibiotic treatment), linezolid was administered for 6 weeks.

Conclusions

We reported a case of pediatric septic arthritis of the knee complicated by the high virulence of PVL-producing MRSA, which is related to difficult course of musculoskeletal infections with poor response to antibiotics and necessity of aggressive and sometimes repeated surgical procedures. Early detection of the toxin is crucial to define an appropriate treatment program to improve the outcome and PVL testing must be considered in the diagnostic path.

Founding

No funding is declared for this article.

Authors’ Contributions

SS, AA, RB and GP conceived the paper. SS, RB and GP wrote the manuscript and carried out the references search. SS, IT, AV, CS and AA have followed the patient over the time and reviewed the manuscript. All authors read and approved the final manuscript.

ORCID ID

Spolaore S: 0000-0001-5241-7201; Buganza R: 0000-0003-1850-2300; Pruccoli G: 0000-0003-2250-6048; Tardivo I: n.a.; Versace A: n.a.; Scolfaro C: 0000-0001-9158-319X; Andreacchio A: 0000-0001-7729-3890.

Conflict of Interest

The authors declare that they have no conflict of interest to disclose.

Availability of Data and Materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Informed Consent

Written informed consent was obtained from the patient’s parents for the publication of this case report.

Ethics Approval

Not applicable.

References

1. Ritz N, Curtis N. The role of Panton-Valentine leukocidin in Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J 2012; 31: 514-518.
2. David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010; 23: 616-687.
3. Shallcross LJ, Fragaszy E, Johnson AM, Hayward AC. The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13: 43-54.
4. Saeed K, Gould I, Esposito S, Ahmad-Saeed N, Ahmed SS, Alp E, Bal AM, Bassetti M, Bonnet E, Chan M, Coombs G, Dancer SJ, David MZ, De Simone G, Dryden M, Guardabassi L, Hanitsch LG, Hijazi K, Krüger R, Lee A, Leistner R, Pagliano P, Righi E, Schneider-Burrus S, Skov RL, Tattevin P, Van Wamel W, Vos MC, Voss A, International Society of Chemotherapy. Panton-Valentine leukocidin-positive Staphylococcus aureus: a position statement from the International Society of Chemotherapy. Int J Antimicrob Agents 2018; 51: 16-25.
5. Kaneko J, Kamio Y. Bacterial two-component and hetero-heptameric pore-forming cytolytic toxins: structures, pore-forming mechanism, and organization of the genes. Biosci Biotechnol Biochem 2004; 68: 981-1003.
6. Correa-Jiménez O, Pinzón-Redondo H, Reyes N. High frequency of Panton-Valentine leukocidin in Staphylococcus aureus causing pediatric infections in the city of Cartagena-Colombia. J Infect Public Health 2016; 9: 415-420.
7. Carrillo-Marquez MA, Hulten KG, Hammerman W, Mason EO, Kaplan SL. USA300 is the predominant genotype causing Staphylococcus aureus septic arthritis in children. Pediatr Infect Dis J 2009; 28: 1076-1080.
8. Klein S, Menz MD, Zanger P, Heeg K, Nurjadi D. Increase in the prevalence of Panton-Valentine leukocidin and clonal shift in community-onset methicillin-resistant Staphylococcus aureus causing skin and soft-tissue infections in the Rhine-Neckar Region, Germany, 2012-2016. Int J Antimicrob Agents 2019; 53: 261-267.
9. van der Mee-Marquet N, Poisson DM, Lavigne JP, Francia T, Tristan A, Vandenesch F, Quentin R, Bertrand X. The incidence of Staphylococcus aureus ST8-USA300 among French pediatric inpatients is rising. Eur J Clin Microbiol Infect Dis 2015; 34: 935-942.
10. Gijón M, Bellusci M, Petraitiene B, Noguera-Julian A, Glikman D, Saavedra-Lozano J, Neth O, Daskalaki M, Zilinskaite V, Kaiser-Labusch P, Prieto L, Rojo P. Pediatric Community-Acquired Bone and Joint Staphylococcus Aureus Infections In Europe: Severe Infections are Associated to Panton-Valentine Leucocidin Presence. Pediatr Infect Dis J 2020; 39: e73-e76.
11. Trobisch A, Schweintzger NA, Kohlfürst DS, Sagmeister MG, Sperl M, Grisold AJ, Feierl G, Herberg JA, Carrol ED, Paulus SC, Emonts M, van der Flier M, de Groot R, Cebey-López M, Rivero-Calle I, Boeddha NP, Agapow PM, Secka F, Anderson ST, Behrends U, Wintergerst U, Reiter K, Martinon-Torres F, Levin M, Zenz W, EUCLIDS consortium. Osteoarticular Infections in Pediatric Hospitals in Europe: A Prospective Cohort Study From the EUCLIDS Consortium. Front Pediatr 2022; 10: 744182.
12. Montrucchio G, Sales G, Urbino R, Corcione S, Cavallo R, Brazzi L. Staphylococcus aureus producing Panton-Valentine Leukocidin: an emerging problem in Italian ICUs. Minerva Anestesiol 2018; 84: 641-642.
13. Hoppe PA, Holzhauer S, Lala B, Bührer C, Gratopp A, Hanitsch LG, Humme D, Kieslich M, Kallinich T, Lau S, Leistner R, Niebank M, Pokrywka A, Ringe H, Schaper AS, Schröder JT, Schwarz C, Staab D, Stegemann MS, Thee S, Varnholt V, von Bernuth H, Weber-Carstens S, Wendt A, Krüger R. Severe infections of Panton-Valentine leukocidin positive Staphylococcus aureus in children. Medicine (Baltimore) 2019; 98: e17185.
14. Sheikh HQ, Aqil A, Kirby A, Hossain FS. Panton-Valentine leukocidin osteomyelitis in children: a growing threat. Br J Hosp Med (Lond) 2015; 76: 18-24.
15. Bouiller K, David MZ. Staphylococcus aureus Genomic Analysis and Outcomes in Patients with Bone and Joint Infections: A Systematic Review. Int J Mol Sci 2023; 24: 3234.
16. Health Protection Agency. Guidance in the diagnosis and management of PVL-associated Staphylococcus aureus infections (PVL-SA) in England, 2nd ed. 2008. Available at: https://www.gov.uk/government/publications/pvl-staphylococcus-aureus-infections-diagnosis-and-management.
17. Agout C, Lakhal W, Fournier J, de Bodman C, Bonnard C. Arthroscopic treatment of septic arthritis of the knee in children. Orthop Traumatol Surg Res 2015; 101: S333-336.
18. Dumitrescu O, Badiou C, Bes M, Reverdy ME, Vandenesch F, Etienne J, Lina G. Effect of antibiotics, alone and in combination, on Panton-Valentine leukocidin production by a Staphylococcus aureus reference strain. Clin Microbiol Infect 2008; 14: 384-388.