Background

Staphylococcus aureus (SA) is one of the major cause of bacterial infections in humans [1].

Panton-Valentine leukocidin (PVL) is an exotoxin that destroys leukocytes and that is secreted by 2–5% of SA strains [2].

The presence of PVL genes is associated with an increased risk of a more serious infection requiring intensive care, such as necrotising pneumonia, osteomyelitis, septic arthritis, sepsis and multiorgan failure [3].

Due to the potential association with life-threatening and complicated infections, a high suspicion and vigilance for a PVL-positive SA (PLV-SA) infection is essential for a prompt diagnosis and for starting an adequate treatment to achieve the best outcome.

We describe a case of an infant with a severe PLV-SA infection and we perform a literature review since 2010 on this topic in paediatric age.

Case presentation

A 6 month-old male was admitted to our emergency department for fever since 7 days, erythematous non pruritic skin rash on the trunk, vomiting, diarrhoea and cough.

The child in his first 5 months of life reported four hospitalizations: the first because of an episode of apnoea, the second due to an upper respiratory tract infection, the third and the last one because of two episodes of bronchiolitis. During these hospitalizations, the child performed some immunological investigations which resulted normal and a chest computed tomography (CT) scan that showed a reduced left lower lobe bronchus calibre with accessible segmental and sub-segmental bronchi.

On admission, he was in good general conditions, with normal vital signs, moist mucous membranes, tongue and lips dry, tears when crying, mild tachypnoea (respiratory rate 40/min) and wheezes all over the chest. Laboratory tests showed a C-reactive protein (CRP) of 3.5 mg/dl (normal value < 0.5 mg/dl) and a white blood cell count (WBC) of 11,250/μL, with 22.9% of neutrophils. The stool culture, the research of viruses on faeces and isolation of respiratory viruses on nasopharyngeal aspirate were performed and resulted negative. The patient received inhaled bronchodilator and oral steroid therapy with improving of the respiratory symptoms. The child was hospitalized for further investigations for his history of recurrent respiratory infections.

On day three, he performed a bronchoscopy with a bronchoalveolar lavage (BAL). Four days later, the patient’s clinical conditions worsened, presenting high fever, clinical signs suggestive of sepsis and a swelling of his left shoulder. He was transferred to the paediatric intensive care unit. The blood tests showed an elevation of CRP 65 mg/dl and a WBC of 3800/μL with 55% of neutrophils. A blood culture was also performed. We prescribed a broad spectrum intravenous antibiotic treatment with cefotaxime 100 mg/kg/day. The echocardiography resulted negative. The abdominal ultrasound showed hepatosplenomegaly.

A contrast-enhanced CT scan of chest and abdomen showed multiple abscesses in the posterior-superior muscles of the shoulder, in the deltoid muscle and in the subscapularis muscle, with pulmonary septic embolisms and fluid collection in the right hip joint. The subsequent whole-body magnetic resonance imaging (WB-MRI) confirmed the flogistic findings of the lungs, demonstrated a wide spread of muscular inflammation in almost all the muscle of the upper part of the body with flogistic collections in the muscle around the shoulder and in the left paravertebral muscles of neck. In addition, osteomyelitis of the proximal metaphyseal region of the right femur and the proximal diaphysis of the left humerus was noted (Fig. 1).

Fig. 1
figure 1

a-CT and b-Axial T1W-MR image showed scattered lung nodules consisntent with septic emboli. c-Axial T1W-FS MR image with contrast medium showed a huge muscular abscess around the left shoulder (arrowhead). d- Coronal STIR MR image demonstrated diffuse hyperintense signal of the muscles and the subcutaneous fat throughout the entire body and signal alteration of the right femoral neck associated with right hip effusion (arrow) consistent with osteoarthritis

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The blood culture resulted positive for a Methicillin-Resistant SA (MRSA), as well the culture of the BAL. The polymerase chain reaction revealed that it was a PVL-MRSA, in particular the ST-121 strain. Of note, also Streptococcus pneumoniae and Haemophilus influenzae were detected in the BAL culture. Therefore, we replaced the antibiotic therapy with a combination of intravenous ceftaroline 24 mg/kg/day, daptomycin 12 mg/kg/day and clindamycin 30 mg/kg/day. This antibiotic regimen was continued for 2 weeks and then with only intravenous ceftaroline for others 4 weeks. Five days after the start of the triple antibiotic therapy, the infant underwent a surgical drainage of the extended abscess of the left shoulder, and the culture of the purulent exudate resulted positive for the same PVL-MRSA.

There was a gradual normalization of the CRP values and an improvement of symptoms and general conditions. Immunological investigations including immunoglobulins and IgG subclasses, lymphocyte subpopulations and tests for complement function (CH50, AP50) resulted normal. The WB-MRI performed 1 month later showed a resolution of the colliquative area in the muscular tissue, an improvement of the bone structure and oedema of the left humerus and the right femur, a reduction of the focal lung lesions with persistence of pleural thickening (Fig. 2).

Fig. 2
figure 2

a-axial and b-coronal STIR MR images performed about 1 month later showed complete resolution of muscular involvement and improvement of lungs and bone flogistic involvement

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He was discharged in good general conditions after 7 weeks of hospital stay with oral linezolid 30 mg/kg/day divided in 3 doses for 2 weeks.

In order to eradicate the bacterial colonization, the patient and his close family members received daily bathing with chlorhexidine 2% and intranasal application of mupirocin, because of the positivity of the father’s nasal swab for PVL- MRSA.

The WB-MRI performed 6 months later showed a complete radiological resolution.

Discussion and conclusion

Here we have described a case of a 6-month-old infant with a severe disseminated PVL-MRSA infection with the aim of increasing attention and knowledge on this type of infection, in which a high suspicious is essential for a prompt diagnosis and to start adequate treatment [4, 5].

PVL is one of the most important virulence factors of SA and it is encoded by LukS-PV and LukF-PV genes [6].

PVL may be produced by different strains of SA, in particular both Methicillin-Sensitive SA (MSSA) and MRSA [7]. In a recent multicentre prospective European study the prevalence of PVL-SA amounted to 18,6 and 7,8% of the isolates were MRSA [8].

Ritz et al. demonstrated that the proportion of PVL-SA is higher in infections caused by MRSA (74–100%) than those caused by MSSA (9–46%). The proportion is dependent on the prevalence of MRSA in the respective regions [9]. The PVL positivity rate is 77–100% in community-associated MRSA infections, while it is less than 4% in hospital-associated MRSA infections [10].

In our patient, the genotype of the PVL-MRSA was ST121, that is, to our knowledge, the first reported in a paediatric patient in Italy. This PVL-SA ST121 strain has been described in literature as mainly disseminated in Africa, Asia and Europe [11].

PVL toxin determines a pore formation in the cytoplasmatic membranes, resulting in leucocyte destruction, tissue necrosis and it contributes to the inhibition of infection clearance by the host immune-system [12]. Therefore, PVL-SA associated infections may be more aggressive and life-threatening. In a retrospective study of Hardy et al., among the six patients with PVL-SA bone and joint infections, there were 2 cases of necrotizing pneumonia, 2 cases of pericarditis and 1 death caused by cardiac tamponade. The microorganism isolated was always a MSSA, due to the low rate of MRSA in the paediatric population of the geographic area where the study was conducted [13]. Recently, in a retrospective study by Hoppe et al. of the 75 children treated for PVL-SA infections, 10 contracted a severe infection including necrotizing pneumonia, necrotizing fasciitis, pyomyositis, mastoiditis with cerebellitis, preorbital cellulitis and recurrent deep furuncolosis in an immunosuppressed patient; MRSA was detected in 4 cases [14].

Since 2010, we have identified 15 reported cases of paediatric PVL-SA severe infections and Table 1 summarizes the main results of these reports regarding the clinical presentations, radiological findings, treatment and outcome [2,3,4,5, 15,16,17,18,19,20,21,22,23].

Table 1 Summary of the reported cases of severe PLV S. aureus infections in children from 2010 to 2020
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Among these reports, only Montagnani et al. described 3 cases of severe PVL-SA infection in infants [18]. We have also described the case of severe PVL-SA infection in a 6 month-old infant. Therefore, even though life-threating infections due to PVL-SA usually occur in older children, we suggest to consider this pathogen also in infants, especially in those with more severe clinical presentation. Furthermore, PVL-SA infection should be suspected in previously healthy young patients with a history of necrotizing skin and soft tissue infections, recurrent abscesses or household cluster infections. Furthermore, it should be suspected in patients with severe musculoskeletal infections and rapidly progressive pneumonia which is usually preceded by a “flu-like” syndrome and in those children with high fever, leukopenia and increased inflammatory markers [18].

PVL-SA strains can be identified by detection of genes encoding PVL or the toxin itself [9]. Conventional bacterial cultures does not differentiate SA producing or not producing PVL [24].

In our patient WB-MRI was really helpful for the detection and location of multifocal flogistic processes and was a valid and sensitive tool during the follow-up period, without radiation exposure of the child. Whole-body MRI is a fast and accurate modality for detection and monitoring of disease throughout the entire body with a variety of applications in the paediatric patient population [25].

Once diagnosed, PVL-SA infection must be treated appropriately, without delay. Initial empirical coverage generally includes an anti-staphylococcal regimen (amoxicillin-clavulanic acid or flucloxacillin when MSSA is suspected and vancomycin when MRSA is suspected) and, an anti-toxic agent able to block the production of the toxin (clindamycin, rifampicin, linezolid, or gentamicin) [26, 27].

In our case report, the child had a life-threatening infection, community-acquired, in a country with a prevalence of MRSA greater than 10%. We chose ceftaroline as anti-MRSA agent as it is effective and safe similarly to vancomycin [28, 29]. Furthermore, concentration below the Minimum Inhibitory Concentration of β-lactams and, to a lesser extent, vancomycin have been shown to enhance PVL secretion, determining more aggressive symptoms [7, 30]. We associated clindamycin, as inhibitor of PVL production. Moreover, in PICU, daptomycin was included in the regimen for the bacteraemia and the osteo-articular infection. This antibiotic regimen was well tolerated by the patient and without adverse reaction. In a recent retrospective study of Syrogiannopoulos et al. it was observed that in children with complicated staphylococcal infections, daptomycin administration alone or in combination with other antimicrobial agents was efficacious and well tolerated [31]. Furthermore, daptomycin was successfully used in 14-year-old boy with tibial osteomyelitis, multilobar pneumonia, pericardial effusion, and septicaemia [16]. In our case, it was an off label use of this antimicrobial agent, introduced due to the severity of the infection.

Generally, a long duration antibiotic therapy is usually needed, in particular in complicated cases [17]. Unfortunately, antibiotic treatment alone is often insufficient, as antibiotic distribution is reduced in necrotic tissue. Surgery plays a major role in achieving a good outcome, with early and complete removal of PVL suppuration from the body and debridement of necrotic tissues. Furthermore, patients with bone and joint infections require more than one surgical procedure [26]. Patients with PVL positive severe infections needed a prolonged hospital stay and a longer recovery times [5].

Decolonisation is part of the process to completely eradicate bacterial colonisation and should involve all household members. Although the optimal eradication strategy for PVL-SA is not known, it is likely to be used the same for MRSA. It includes nasal mupirocin 2% ointment and chlorhexidine 4% body wash [27, 32]. In our case, the origin of the infection is not clear, as previous hospitalizations maybe a risk factor. Also his father may have been the source of the infection, as he was an asymptomatic carrier. Surely, the decolonisation therapy, extended to all the family members, brought to the complete eradication of the bacterial colonisation.

In conclusion, this case highlights the importance of considering PLV-SA as the etiologic agent of life-threatening infection in children. A prompt identification of the toxin is essential in order to start an adequate treatment, that is based not only on prolonged antibiotic treatment but also on surgical drainage in case of abscess or musculoskeletal infection.