ArticlesThe role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis
Introduction
Staphylococcus aureus harmlessly colonises the skin and mucosa of about 30% of healthy adults1 and is the commonest cause of mild to moderate skin and soft-tissue infections, such as abscesses and wound infections. Such infections account for many consultations in primary care but rarely result in hospital admission or surgical treatment. The incidence of invasive community-onset staphylococcal infections such as pneumonia or osteomyelitis is low,2 but S aureus is a common cause of health-care-associated infections, with meticillin-resistant S aureus (MRSA) strains reported from hospitals and health-care facilities in most industrialised countries.3, 4
Panton-Valentine leucocidin (PVL) is a toxin composed of two components, LukS-PV and LukF-PV. These two components are secreted before they assemble into a pore-forming heptamer on neutrophil membranes, leading to neutrophil lysis.5 Epidemiological, historical, and biochemical research all point towards a role for PVL in pathogenesis but whether the toxin affects clinical presentation, disease severity, and outcome is unclear. The toxin has been linked to community-onset MRSA disease worldwide,6 but some community-acquired MRSA strains do not carry the PVL genes,7, 8, 9 particularly in Australia.10 Sequencing data suggest that circulating community-onset MRSA strains might be directly descended from a historical PVL-producing penicillin-resistant clone phage type 80/81 that circulated in the 1950s and 1960s and was highly virulent.11 Additionally, PVL has well established leucocidal properties,12 and causes dermonecrosis when injected into rabbits,13 but direct evidence from experimental studies with animal models that the PVL toxin causes invasive disease is scarce.14, 15, 16, 17
The molecular epidemiology and burden of community-onset staphylococcal disease is geographically disparate. In the USA, community-onset staphylococcal disease is endemic and is mainly meticillin-resistant associated with a PVL-producing clone, ST8/USA300.18 All USA300 isolates are sequence type 8 (ST8) but only a subset of ST8 isolates are USA300. Until about 2003, these infections were predominantly community-acquired, affecting people without risk factors for health-care-acquired infection, but USA300 has become a common cause of health-care-associated infection.19 In Europe, USA300 is rare, and community-onset MRSA is epidemiologically and clonally diverse.20 Many PVL strains are meticillin-sensitive S aureus (MSSA),21, 22, 23, 24 and the commonest community-onset PVL-positive MRSA clone is ST80. PVL-positive community-onset MRSA strains are rarely reported in England and Ireland,7, 21 but are common in parts of Europe, such as Greece, where PVL-positive MRSA circulates in both community and hospital settings.25 Different clones predominate in Australia where USA300 is rare and community MRSA and MSSA clones both have PVL genes.26 Although disease burden varies, clinical syndromes associated with community-onset staphylococcal disease are consistent across all regions. Skin and soft-tissue infections are common and often present as abscesses, furuncles, and carbuncles.27 A few patients develop necrotising pneumonia,24 sepsis syndrome,28, 29 necrotising fasciitis,30 and musculoskeletal disease.31, 32 Disease has been described in diverse populations including children,31, 33 athletes,34 the military,35 men who have sex with men,36 and prisoners;37 a common feature is prolonged close contact, which is thought to play an important part in disease transmission.
Many studies have reported an association between PVL genes and invasive disease, implying that PVL is an epidemiological marker of a syndrome of severe infection. In some countries this notion has led to public health measures for individuals infected with PVL-producing strains.38, 39 Importantly, aggressive clinical and public health responses, such as screening and decolonisation, might be more justifiable if PVL-positive disease is rare and mainly severe than if disease is common and not associated with severity or invasion. Modelling suggests decolonisation of patients with MRSA in settings such as intensive-care units is cost effective and improves health outcomes.40 By contrast, evidence from randomised trials that decolonisation reduces recurrence of community-onset S aureus skin infections is scarce,41, 42 and no studies have addressed the cost effectiveness of disease control measures specifically for PVL-positive infection.
We review international evidence for the association between PVL genes, colonisation, disease, and outcome for S aureus pneumonia, bacteraemia, musculoskeletal infection, and skin and soft-tissue disease. In this Article the terms PVL-producing and PVL-carrying S aureus denote isolates of S aureus that contain the PVL genes. PVL-positive disease refers to S aureus pneumonia, bacteraemia, musculoskeletal infection, and skin and soft-tissue disease caused by strains containing the PVL genes. Invasive disease is defined as isolation of S aureus from a normally sterile body site. The term unselected isolates refers to studies that assessed prevalence of PVL genes among all S aureus specimens submitted to a laboratory in a defined time period, without additional exclusion criteria.
Section snippets
Search strategy and selection criteria
We searched Medline and Embase for articles reporting the proportion of isolates from S aureus pneumonias, bacteraemias, musculoskeletal infections, and skin and soft-tissue disease that produced PVL. English or French language articles published after 1946 (Medline) or 1980 (Embase) and before Oct 1, 2011, were eligible for inclusion. We used the following keywords in various combinations to search the scientific literature: “Staphylococcus aureus”, “meticillin resistance”, “community
Results
After exclusion of duplicates, the Medline search identified 504 articles and we identified five more articles through hand searching reference lists (figure 1). We excluded 264 studies on review of the abstract. Of the remaining 245 articles, 76 met our inclusion criteria. The commonest reasons for exclusion were insufficient clinical information to determine prevalence for each disease category (77 studies) and small sample size (57 studies). We included 12 studies of pneumonia, 13 studies of
Discussion
PVL is strongly associated with skin and soft-tissue disease and is comparatively less common in colonisation and in other forms of invasive disease, such as pneumonia, musculoskeletal disease, and bacteraemia. Results from observational studies suggest that infection with a PVL-positive strain does not predict poor clinical outcome for staphylococcal pneumonia, musculoskeletal disease, or bacteraemia in adults, but patients with PVL-positive skin and soft-tissue disease are more likely to
References (93)
- et al.
Methicillin resistance in staphylococci
Lancet
(1963) - et al.
The emergence of community-associated methicillin-resistant Staphylococcus aureus at a London teaching hospital, 2000–2006
Clin Microbiol Infect
(2008) - et al.
Re-emergence of early pandemic Staphylococcus aureus as a community-acquired meticillin-resistant clone
Lancet
(2005) - et al.
Staphylococcal toxin
Lancet
(1932) - et al.
Panton-Valentine leukocidin associated staphylococcal disease: a cross-sectional study at a London hospital, England
Clin Microbiol Infect
(2010) - et al.
Spread of Staphylococcus aureus clinical isolates carrying Panton-Valentine leukocidin genes during a 3-year period in Greece
Clin Microbiol Infect
(2006) - et al.
Detection of Panton-Valentine leukocidin gene in Staphylococcus aureus by LightCycler PCR: clinical and epidemiological aspects
Clin Microbiol Infect
(2004) - et al.
Epidemiology of methicillin-susceptible Staphylococcus aureus lineages in five major African towns: high prevalence of Panton-Valentine leukocidin genes
Clin Microbiol Infect
(2011) - et al.
Clinical isolates of Pantone-Valentine leucocidin and gamma-haemolysin-producing Staphylococcus aureus: prevalence and association with clinical infections
J Hosp Infect
(2010) - et al.
Virulence factors and genotypes of Staphylococcus aureus from infection and carriage in Gabon
Clin Microbiol Infect
(2011)
Community-associated Staphylococcus aureus infections and nasal carriage among children: molecular microbial data and clinical characteristics
Clin Microbiol Infect
Clinical features, epidemiology, antimicrobial resistance, and exotoxin genes (including that of Panton-Valentine leukocidin) of gentamicin-susceptible methicillin-resistant Staphylococcus aureus (GS-MRSA) isolated at a paediatric teaching hospital in New South Wales, Australia
Pathology
Molecular epidemiology of community-associated meticillin-resistant Staphylococcus aureus in Europe
Lancet Infect Dis
Community-associated meticillin-resistant Staphylococcus aureus
Lancet
The nose is not the only relevant MRSA screening site
Clin Microbiol Infect
Case definition for community-associated methicillin-resistant Staphylococcus aureus
J Hosp Infect
Proposed definitions of community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA)
J Hosp Infect
Community-associated meticillin-resistant Staphylococcus aureus strains as a cause of healthcare-associated infection
J Hosp Infect
Comparative evaluation of epidemiology and outcomes of methicillin-resistant Staphylococcus aureus (MRSA) USA300 infections causing community- and healthcare-associated infections
Int J Antimicrob Agents
Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 2001–2004
J Infect Dis
Increasing hospitalizations and general practice prescriptions for community-onset staphylococcal disease, England
Emerg Infect Dis
Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999
Clin Infect Dis
Bacterial two-component and hetero-heptameric pore-forming cytolytic toxins: structures, pore-forming mechanism, and organization of the genes
Biosci Biotechnol Biochem
Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence
Emerg Infect Dis
The emergence and importation of diverse genotypes of methicillin-resistant Staphylococcus aureus (MRSA) harboring the Panton-Valentine leukocidin gene (pvl) reveal that pvl is a poor marker for community-acquired MRSA strains in Ireland
J Clin Microbiol
Coexistence of Panton-Valentine leukocidin-positive and -negative community-associated methicillin-resistant Staphylococcus aureus USA400 sibling strains in a large Canadian health-care region
J Infect Dis
Diversity among community isolates of methicillin-resistant Staphylococcus aureus in Australia
J Clin Microbiol
Identification of staphylococcal Panton-Valentine leukocidin as a potent dermonecrotic toxin
Infect Immun
Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?
J Infect Dis
Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia
Nat Med
Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease
J Infect Dis
Transcription of inflammatory genes in the lung after infection with community-associated methicillin-resistant Staphylococcus aureus: a role for panton-valentine leukocidin?
Infect Immun
Methicillin-resistant S aureus infections among patients in the emergency department
N Engl J Med
Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections
Clin Infect Dis
Comparison of community-associated methicillin-resistant Staphylococcus aureus from teaching hospitals in London and the USA, 2004–2006: where is USA300 in the UK?
Eur J Clin Microbiol Infect Dis
Staphylococcus aureus isolates carrying Panton-Valentine leucocidin genes in England and Wales: frequency, characterization, and association with clinical disease
J Clin Microbiol
Clinical isolates of Staphylococcus aureus from the Arkhangelsk region, Russia: antimicrobial susceptibility, molecular epidemiology, and distribution of Panton-Valentine leucocidin genes
APMIS
Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin
Clin Infect Dis
Methicillin-resistant Staphylococcus aureus in the Australian community: an evolving epidemic
Med J Aust
Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia
Clin Infect Dis
Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children
N Engl J Med
Severe Staphylococcus aureus infections caused by clonally related community-acquired methicillin-susceptible and methicillin-resistant isolates
Clin Infect Dis
Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles
N Engl J Med
Infective pyomyositis and myositis in children in the era of community-acquired, methicillin-resistant Staphylococcus aureus infection
Clin Infect Dis
Pediatric bone and joint infections caused by panton-valentine leukocidin-positive Staphylococcus aureus
Pediatr Infect Dis J
Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, 1997–1999
MMWR Morb Mortal Wkly Rep
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