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Panton-Valentine Leukocidin Is Associated with Exacerbated Skin Manifestations and Inflammatory Response in Children with Community-Associated Staphylococcal Scarlet Fever

  1. Wen-Tsung Lo,
  2. Ching-Shen Tang,
  3. Shyi-Jou Chen,
  4. Ching-Feng Huang,
  5. Min-Hua Tseng, and
  6. Chih-Chien Wang
  1. Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
  1. Reprints or correspondence: Dr. Chih-Chien Wang, Dept. of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, No. 325, Cheng-Kung Rd., Section 2, Nei-hu 114, Taipei, Taiwan (ndmcccw{at}yahoo.com.tw).
 
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Abstract

Background.Staphylococcal scarlet fever (SSF), a rare disease, was first described in 1900. The clinical features and outcomes in children with SSF caused by Panton-Valentine leukocidin (PVL)-positive and PVL-negative Staphylococcus aureus strains have not been compared prospectively.

Methods.The demographic data, selected clinical features, laboratory values, and outcomes for 49 consecutive children with community-acquired S. aureus SSF prospectively identified during an 11-year period were collected for analysis.

Results.The male-to-female ratio was 1.88, and the median age of the patients was 37 months. Cutaneous abscesses predominated among children with SSF. Methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) caused SSF in 26 and 23 children, respectively. Twenty-four isolates had results that were positive for PVL (5 MSSA and 19 MRSA isolates), and 25 had results that were negative for PVL (21 MSSA and 4 MRSA isolates). Polymerase chain reaction revealed that most (92%) contained only staphylococcal enterotoxin B (23 MSSA and 22 MRSA isolates). By multivariate analysis, children with PVL-positive isolates had significantly larger abscess sizes, higher white blood cell counts, higher C-reactive protein levels, and longer durations of fever, generalized scarlatiniform rashes, and hospital stays. Most (17 isolates; 89%) of the 19 PVL-positive MRSA isolates carried the staphylococcal cassette chromosome mec V T and all were multilocus sequence type 59.

Conclusion.SSF caused by PVL-positive S. aureus strains were associated with more-exacerbated skin manifestations and a greater systemic inflammatory response, compared with those cases caused by PVL-negative S. aureus . Clinical improvement after incision and drainage was achieved for most children with SSF caused by PVL-positive MRSA strains, despite treatment with an ineffective antibiotic.

In 1900, Dukes first described 3 outbreaks of staphylococcal scarlet fever (SSF) at a Rugby School in the United Kingdom and proposed that this rash be officially recognized as the “fourth disease” [1, 2]. In 1979, Keith Powel resurrected the idea that SSF was a distinct exanthem and argued that this rare disease was caused by epidermolytic toxin-producing staphylococci [3]. Clinically, SSF causes a generalized scarlatiniform rash but no enanthem, bullae, or exfoliation. At present, it is one of the staphylococcal toxin-mediated syndromes, and based on certain clinical similarities, it is hypothesized that SSF is a milder or abortive form of staphylococcal scalded skin syndrome (SSSS), caused by an exfoliative toxin. The toxin causes large superficial bullae that exfoliate, with a positive Nikolsky sign, followed by desquamation [4-6]. However, on the basis of toxin production, toxic shock syndrome toxin 1 (TSST-1) or enterotoxins A-D, G, I (SEA-SED, SEG, and SEI), and—very rarely—an exfoliative toxin are linked to SSF [7-9].

Panton-Valentine leukocidin (PVL) is a 2-component cytotoxin that targets human and rabbit polymor phonuclear cells and monocytes or macrophages (or both) [10]. The products of pvl genes (lukS-PV and lukF-PV), which are encoded by contiguously located, cotranscribed genes (lukS-PV and lukF-PV ), assemble as hetero-oligomers and synergistically exert cytolytic pore-forming activity [10]. It is mainly secreted by Staphylococcus aureus associated with primary cutaneous infections, especially furuncles, and also with rapidly progressive and life-threatening necrotizing pneumonia [11-13]. Despite the fact that its role as a major virulence factor in community-associated (CA) methicillin-resistant S. aureus (MRSA) pathogenesis has recently been disputed [14], the PVL locus is present in most CA-MRSA isolates studied and is a stable marker of CA-MRSA strains worldwide [15].

Although there is no evidence that the presence of PVL genes confers a greater risk of SSF, in a study of 27 children with SSF, 63% of cases were caused by S. aureus isolates carrying the pvl genes [16]. On the basis of a comprehensive literature search, it is clear that the clinical features of children with SSF caused by PVL-positive versus PVL-negative S. aureus have not been characterized prospectively. The objective of our study was to compare clinical characteristics and selective laboratory findings among children with SSF caused by PVL-positive and PVL-negative S. aureus , to investigate the role of PVL as an independent factor contributing to these findings, and to characterize the PVL-positive S. aureus infecting strains via molecular analyses.

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Patients, Materials, and Methods

Study design, location, and medical chart review. This prospective observational program was conducted at the Tri-Service General Hospital (TSGH), a tertiary care medical center in northern Taiwan, which had 1200 beds in 1985 and 1700 beds in 2005. The central microbiology laboratory was responsible for management of all clinical specimens. The study proposal was reviewed and approved by the National Defense Medical Center Institutional Review Board. Since proceeding with the first preliminary study of 20 cases of SSF [9], we have prospectively collected cases of documented SSF. From 1 January 1998 through 31 December 2008, all S. aureus strains isolated by the TSGH clinical microbiology laboratory were collected as part of a prospective surveillance program. A standardized form that included antibiotic susceptibility and patient demographic and diagnostic information was recorded for each S. aureus strain, and this information was entered into a computerized patient database. For this study, all children <18 years of age with cultures from skin and soft-tissue specimens taken within 48 h after admission to the pediatric ward that were positive S. aureus and compatible clinical findings were defined as having SSF. The diagnosis of SSF was made via the consistent clinical manifestation of generalized scarlatiniform rash; no enanthem, bullae, or exfoliation; and no evidence of streptococcal infection. Affected children who were hospitalized for >48 h, who were discharged from any hospital within the 48 h before receiving the infection diagnosis, or who had a prior history of MRSA infection or colonization were excluded from this study. We included children with CA SSF who had not resided in a long-term care facility, had not been hospitalized in an acute care facility, had not been treated with central intravenous catheters or long-term venous access devices, had not used urinary catheters, had not used other long-term percutaneous devices, had not undergone prior surgical procedures, and were not receiving dialysis within 1 year before the onset of SSF [17, 18].

All affected children were evaluated using a structured recording form. The clinical course of infection and infection foci of SSF were evaluated and recorded according to information supplied by primary care physicians and medical records. The diagnosis of the infection focus of SSF was based on clinical, bacteriological, and radiological investigations. Cutaneous abscess was defined as a collection of pus within the dermis and deeper skin tissue [19]. The following data were recorded in each case: demographic data, clinical presentation, hospital course (including duration of symptoms before hospitalization, site of infection, surgical treatment, empirical antimicrobial therapy used before culture and susceptibility test results were available, antimicrobial agents used, outcome, duration of generalized scarlatiniform rash, and duration of hospital stay), and laboratory results during the first 48 h of hospitalization (including C-reactive protein [CRP] level, white blood cell [WBC] count, and platelet count).

Microbiological studies. S. aureus isolates were identified according to methods previously described [20, 21] and further screened for methicillin resistance following the Clinical Laboratory Standards Institute (CLSI; formerly known as NCCLS) guidelines [22]. All S. aureus isolates were frozen at −70°C for additional testing of organism characteristics. Susceptibilities to clindamycin, erythromycin, gentamicin, trimethoprim-sulfamethoxazole, ciprofloxacin, fusidic acid, mupirocin, rifampin, vancomycin, and teicoplanin were determined using the disk-diffusion method and minimum inhibitory concentration test [23]. In vitro macrolide-lincosamide-streptogramin-inducible phenotypes were detected by the double-disk diffusion assay [24].

Chromosomal DNA from 3–5 isolated colonies was prepared by using the Puregene DNA purification kit (Gentra) as recommended by the manufacturer, with lysostaphin at 2 mg/mL and RNase at 4 mg/mL for the lysis step. The presence of the lukS-PV and lukF-PV genes encoding PVL components was determined by a polymerase chain reaction (PCR)-based method with the primer pair and thermocycler conditions, as reported by Lina et al [11]. Sequences specific for sea to see , seg to sei , sek , seq , eta , etb , and tst , encoding staphylococcal enterotoxins (SEA-SEE, SEG-SEI, SEK, and SEQ), exfoliative toxins (ETA and ETB), and toxic shock syndrome toxin-1 (TSST-1), respectively, were detected using methods described by Jarraud et al and Diep et al [7, 25]. SCCmec typing was performed using a multiplex PCR strategy with sets of region-specific primers, as described elsewhere [26]. Screening for SCCmec V T was performed with the primer and thermocycler conditions reported by Boyle-Vavra et al [27]. Multilocus sequence typing (MLST) was performed by PCR amplification and sequencing of 7 housekeeping genes using primers designed by Enright et al [28]. Each sequence was submitted to the MLST database Web site for assignment of the allelic profile and sequence type (ST).

Statistical analysis. Data were entered into Microsoft Access XP software and exported into SPSS statistical software, version 10.0 (SPSS), which was used for data analyses. The χ2test, Student's t test, Wilcoxon rank-sum test, and multivariate analysis using logistic regression were used for statistical analysis. All analyses were 2-tailed, and a P value of <.05was defined as statistically significant.

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Results

Patients and demographic analysis. During the 11-year study period, 49 unduplicated, consecutive children with SSF caused by CA S. aureus were treated. The baseline characteristics of all children with CA-MSSA and CA-MRSA SSF are summarized in Table 1. The male-to-female ratio was 1.88 (32 male and 17 female patients), and the median patient age was 37 months. Twenty-five S. aureus isolates had test results negative for PVL (21 MSSA and 4 MRSA isolates), and 24 had test results that were positive for PVL (5 MSSA and 19 MRSA isolates; P<.001).

Table 1
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Table 1

Baseline Characteristics of 49 Children with Staphylococcal Scarlet Fever

SSF presentation and biological features. All 49 children had cutaneous abscesses. Of these, 25 children (51%) had abscesses confined to the thighs (Table 1). The numbers of children with single abscess (23 children; 47%) and multiple abscesses (26 children; 53%) were similar.

Antimicrobial susceptibility testing of the 49 S. aureus isolates showed uniform susceptibility to vancomycin, teicoplanin, and trimethoprim-sulfamethoxazole. Furthermore, 41 isolates (84%) had resistance to both clindamycin and erythromycin, and the macrolide-lincosamide-streptogramin-constitutive phenotype. In contrast, resistance to gentamicin, amoxicillin-clavulanate, ciprofloxacin, rifampin, and fusidic acid was sporadic. Of the 49 isolates, 45 (92%) produced SEB only (23 MSSA and 22 MRSA isolates), 1 produced SEA only, 2 produced both SEG and SEI, and 1 produced TSST-1 only.

Treatment and outcome. Antibiotic therapy was initiated on the first hospital day for all 49 children, before culture and susceptibility test results were available. Between 24 and 72 h after hospital admission, at least 1 of the prescribed drugs was active against S. aureus in 26 (53%) of the 49 children. Among the other 23 children with SSF caused by CA-MRSA in whom initial antibiotic treatment was inappropriate, no active antibiotic was started after 72 h of hospitalization. However, clinical improvement was noted among the 23 children not receiving effective antibiotic therapy, and all responded to incision and drainage, manual expression of pustule contents, or spontaneous drainage, with fair outcomes.

Clinical and laboratory features of children with SSF caused by pvl+seb+and pvl−seb+ S. aureus isolates. To gain insight into the role of PVL in children with SSF, we designed a comparative study to investigate clinical characteristics and selective laboratory findings of SSF caused by 24 pvl +seb +(5 MSSA and 19 MRSA isolates) and 21 pvl −seb +S. aureus isolates (18 MSSA and 3 MRSA isolates; P<.001). The demographic data for all children with pvl +seb +and pvl −seb +S. aureus infections are summarized in Table 2. There was no statistically significant difference in age, sex, or duration of symptoms before diagnosis.

Table 2
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Table 2

Comparison of Children with pvl +seb +and pvl −seb +Staphylococcal Scarlet Fever

Children with SSF caused by pvl +seb +S. aureus were more likely to have multiple abscesses (62.5%) and to have abscesses confined to the thighs (66.6%), compared with children with pvl −seb +S. aureus (42.9% and 28.6%, respectively), although this difference was not statistically significant. pvl +seb +S. aureus isolates were more likely to cause larger abscesses that required incision and drainage than were pvl −seb +isolates (P<.001). Spontaneous drainage occurred in a high percentage of children in the pvl −seb +group (P=.005). Children with pvl +seb +S. aureus isolates had significantly higher WBC counts and CRP levels at presentation (P<.001). Likewise, children with pvl +seb +S. aureus isolates had longer durations of fever after antibiotic therapy (P=.039), scarlatiniform rashes after antibiotic therapy (P<.001), and total hospital stay (P=.022).

Multivariate analysis. Age, sex, duration of symptoms prior to hospital admission, methicillin susceptibility, number of abscesses, and pvl status were included in a multivariate analysis to determine which factors correlated independently with the clinical and laboratory parameters. Only the presence of pvl remained significantly and independently associated with higher WBC counts (P=.013) and CRP levels (P=.009), larger abscesses (P=.003), as well as longer durations of fever (P<.001) and scarlatiniform rashes after antibiotic therapy (P=.013). The pvl +status (P<.001) and younger age (P=.001) were associated with longer duration of total hospital stay.

Bacteriological study. From 24 children with SSF caused by pvl +seb +S. aureus , 19 unduplicated MRSA isolates were available for further bacteriologic study including SCCmec typing and MLST typing. SCCmec V T (17 of 19 isolates; 89%) was the most common SCCmec type among the pvl +seb +MRSA isolates; the remaining 2 isolates (11%) carried SCCmec IV. MLST typing showed that all isolates were ST59.

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Discussion

SSF is a rare disease and has been tentatively described as a milder form of SSSS caused by exfoliative toxins [4-6, 29-31]. However, previous studies have shown that TSST-1 or enterotoxins, or both, are the major toxins involved in SSF [7-9, 32, 33]. SEB (18 of 20 isolates; 90%) is the most common enterotoxin associated with SSF in Taiwan [9]. In the present study, 49 S. aureus isolates from children diagnosed with SSF were analyzed, and 45 (92%) produced SEB only, 1 produced SEA only, 2 produced both SEG and SEI, and 1 produced TSST-1 only. The 3 isolates producing both SEG and SEI or TSST-1 suggest that SEG and SEI or TSST-1 are capable of causing SSF [7, 8]. Furthermore, on the basis of previous reports and our present findings, enterotoxins or TSST-1 were most frequently associated with SSF, and SEB has high protein-sequence homology with streptococcal pyrogenic exotoxin type A, which causes scarlet fever; our data reinforce the notion that most cases of SSF are not a clinical subtype of SSSS [7-9, 32-35].

None of the aforementioned reports have indicated that PVL genes were involved in patients with SSF. Of particular interest is a prospective analysis involving children with different types of staphylococcal infections, in which PVL-producing strains were isolated from children with SSF at a rate of 63% [16]. In this series of 49 SSF cases, the overall prevalence (49%) of PVL-producing S. aureus was slightly lower than that in the reference study [16], probably because the molecular epidemiology of S. aureus is constantly changing; nonetheless, during the 11-year study period, the prevalence of SSF caused by PVL-producing strains remained stable over time. These observations prompted us to assess the role of PVL in children with SSF.

We believe that this is the first report of a case series to compare children who had SSF caused by PVL-positive S. aureus with children who had SSF caused by PVL-negative S. aureus in a nonoutbreak setting. In our current study, multivariate analysis of several factors, including the presence of pvl genes and methicillin susceptibility, showed an association between pvl and more severe systemic inflammatory response and exacerbated skin manifestations, compared with those associated with pvl −S. aureus isolates. The children with pvl +seb +S. aureus isolates had significantly increased systemic inflammatory responses compared to children with pvl −seb +S. aureus , as evidenced by higher CRP levels, WBC counts, longer durations of fever and scarlatiniform rashes during hospitalization. Additionally, both higher CRP levels and the development of larger abscesses were likely secondary to the development of more invasive diseases and could be a consequence of S. aureus organisms with increased virulence secondary to a factor such as PVL. Thus, PVL likely contributes to the severity of SSF caused by CA S. aureus .

In our current study, antibiotic therapy was started promptly during the first 24 h after hospital admission and, based on the in vitro activity, the initial antibiotics were effective against the S. aureus isolate in only 53% of the patients. Although younger children with SSF caused by PVL-positive S. aureus were hospitalized longer than were children with SSF caused by PVL-negative S. aureus , the outcomes of children with PVL-positive isolates were excellent and comparable to those of children with PVL-negative isolates. From a management standpoint, our findings indicate that SSF with cutaneous abscesses caused by CA-MRSA strains resolves well in otherwise healthy children after incision and drainage, manual expression, or spontaneous drainage, despite administration of ineffective antibiotic therapy. On the basis of statistical analysis of our sample population, no significant association was demonstrated between ineffective antimicrobial therapy and clinical outcome. These findings complement the results of a previous study by Lee et al [36], which found that surgical drainage without adjunctive antibiotic therapy was effective for management of small CA-MRSA skin and soft-tissue abscesses in otherwise healthy children.

The ST59 strain was recently identified as a major MSSA genotype causing CA abscesses and soft tissue infections among drug users in the United Kingdom [37]. In addition, ST59 was also detected in a study conducted in San Francisco [25]. With regard to bacteriological study, the majority (89%) of our PVL-positive MRSA isolates carried SCCmec V T , and all were ST59. This is in agreement with previous studies that have shown that ST59, SCCmec V T , and PVL-positive MRSA comprises the major clone of CA-MRSA infecting children in Taiwan [16, 27, 38, 39]. This unique characteristic of the predominant CA-MRSA strain in Taiwan is not found on other continents.

In conclusion, this prospective observational study supports the hypothesis that pvl is associated with the severity of SSF caused by S. aureus in children. Because cutaneous abscesses predominate among children with SSF, clinical improvement with incision and drainage was noted in most children with SSF caused by PVL-positive MRSA strains, despite treatment with an ineffective antibiotic.

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Acknowledgments

We thank L. K. Siu at the National Health Research Institute (Taipei, Taiwan) for laboratory support, and Shu-Ying Tsai, for providing assistance with and maintaining the MRSA database.

Financial support. The National Science Council (grants NSC94-2314-B-016-029 and NSC95-2314-B-016-052) and Tri-Service General Hospital (grants TSGH-C92-77, TSGH-C94-12, TSGH-C95-11-S01, TSGH-C96-12-S01, TSGH-C97-21, TSGH-C98-19, and TSGH-C98-20).

Potential conflicts of interest. All authors: no conflicts.

  • Received March 2, 2009.
  • Accepted May 20, 2009.
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  1. Clin Infect Dis. (2009) 49 (7): e69-e75. doi: 10.1086/605580
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