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 require surgical treatment (appendix p 4
provides a discussion of limitations of methods used in these studies). In children with musculoskeletal disease we identified some evidence that infection with a PVL-positive strain is associated with surgical treatment, lengthy hospital stay, and chronic osteomyelitis. As far as we are aware, this is the first review to systematically assess the association between PVL genes, colonisation, and S aureus
disease and to investigate whether PVL predicts clinical outcome.
Although strains carrying PVL genes are commonly identified in invasive staphylococcal disease, direct evidence increasingly suggests that PVL is not the main determinant of severity or outcome. Clinical studies from Australia46,53,69
have directly compared outcome for PVL-positive and PVL-negative strains for a range of invasive infections, consistently reporting outcome to be independent of PVL, with the exception of increased surgical treatment for skin and soft-tissue infections. Results of two studies62,70
of clinical outcome among patients with hospital-acquired pneumonia showed similar clinical outcome and mortality among patients irrespective of PVL, even after adjustment for potential confounders. In-vitro studies have failed to correlate the amount of PVL toxin produced by different S aureus
strains with the severity of clinical disease,70,71
and experimental studies of animal models of skin and soft-tissue infection and pneumonia have not convincingly shown PVL to have an effect on the development of disease independent of bacterial strain.14,16,17,72
Much of the work linking PVL genes to invasive staphylococcal disease is derived from the USA where most community-onset staphylococcal disease and even some hospital-acquired strains are meticillin-resistant USA300.18,19
This situation contrasts with Europe where USA300 is rare and a high proportion of PVL-positive strains are meticillin-sensitive,21,22,73
and Australia where half of community-MRSA clones are PVL-positive,26
and MSSA strains contribute a large burden of PVL-positive disease.53
The epidemiological association between invasive disease and PVL genes might be confounded by USA300, and this potential confounding effect has become more apparent as investigators have examined the role of PVL in settings where USA300 is not common.
We report that PVL-producing strains are mainly associated with disease rather than colonisation. Because S aureus
colonises a third of the healthy population,1
high rates of colonisation with PVL-producing strains might be expected in regions where disease is prevalent. This theory is not borne out by data from the USA, where community-acquired PVL-positive MRSA infection is common but most individuals are colonised with PVL-negative MSSA strains.1
This finding suggests that disease can occur in the absence of nasal colonisation,74
and evidence increasingly suggests that non-nasal sites such as the throat75
and inguinal areas might be important colonisation sites for PVL-positive S aureus
Results of a large study77
of S aureus
transmission in the household suggest interplay between colonisation and disease-causing isolates is complex and might depend on bacterial strain. More than a quarter of 350 infected index case patients in this study were colonised with a strain type discordant from their infecting isolate and only 12% were colonised with a concordant strain. The relation between bacterial strain and disease potential was further investigated in a study from China,78
in which investigators sequenced carriage and disease isolates from children, concluding that disease potential of a strain carrying PVL genes depended partly on the bacterial genetic background. Screening of patients for PVL carriage might not accurately assess their risk of disease, and if colonising and disease-causing isolates are systematically different, eradication of a strain type rarely associated with disease could render a patient vulnerable to recolonisation with a more pathogenic strain.77
Evidence that PVL is associated with skin and soft-tissue infections is strong and independent of strain type among both MRSA and MSSA strains.21,22,54,73
Compared with PVL-negative strains, PVL-positive strains are more likely to be truly community-acquired, occurring in individuals who have not had contact with health care.22,53
When MRSA first emerged in the community in the early 1990s, an epidemiological definition of community-acquisition was developed on the basis of risk factors for health-care use to distinguish between hospital-acquired and community-acquired MRSA.79
Community strains then started to enter hospitals in the USA, blurring the distinction between hospital and community-acquisition and limiting the usefulness of a definition based on health-care contact.19
Genotypic definitions focusing on molecular markers such as PVL,7,80
or susceptibility to specific antibiotics can imperfectly discriminate between health-care or community-acquisition in a local setting,81,82
but DNA sequencing techniques are required to reliably compare strains between regions or laboratories.73
Increasingly, so-called community strains cause a spectrum of nosocomial disease and genotypic definitions cannot reliably predict clinical presentation.83–85
In a retrospective study86
of 160 patients infected with USA300 about 20% had invasive disease, mainly among those with health-care-associated infection. Such patients were older and had more comorbidities compared with those with community-acquired S aureus
, suggesting characteristics of the patients rather than the bacterial strain are a major determinant of disease presentation and outcome.
Individuals with PVL-positive skin and soft-tissue infections are more likely to require surgery than are those with PVL-negative infection, but we identified little data suggesting that they have a worse clinical outcome, provided that they receive appropriate surgical treatment and the correct antibiotics, although this finding might simply be indicative of the younger age and scarcity of comorbidities among this group. Patients with PVL-positive skin and soft-tissue infections might have more recurrent infections than those with PVL-negative disease, but most studies do not collect detailed data for outcomes. A clinical syndrome is clearly associated with PVL-positive skin and soft-tissue infections, but whether this syndrome warrants specific clinical and public health action is uncertain.
The decision to test for the PVL toxin is triggered by the presence of either invasive or recurrent (mainly skin) disease, as an instrument to guide clinical and public health measures.38
If PVL is assumed to be rare and mainly associated with invasive disease then aggressive antibiotic treatment combined with a low threshold for surgical intervention and a so-called search and destroy policy around the patient with screening and decolonisation of close contacts is potentially justified. Conversely if infection with a PVL strain is not exclusively associated with invasive disease and does not predict poor clinical outcome then aggressive clinical and public health actions might do more harm than good. Decolonisation has been shown to improve clinical outcome in high-risk settings such as renal units,87
but we are unaware of any data for the clinical or cost effectiveness of community-based screening and decolonisation for PVL strains.
The approach to management and control of PVL-positive disease contrasts between the USA and Canada and the UK.91
In the USA, where PVL-positive MRSA is common, toxin testing is not routinely recommended. Patients with skin and soft-tissue infections are advised on simple hygiene measures to restrict the spread of infection and public health measures, such as contact screening and decolonisation, are only required when a defined outbreak occurs outside the household.92
Much the same guidance is in place in Canada.93
In England where a high proportion of PVL cases are associated with MSSA strains,22
PVL toxin testing is recommended for any patient who presents either with community-associated invasive disease or with recurrent skin and soft-tissue infection caused by S aureus,
such as boils, abscesses, or eyelid infections.38
All patients with recurrent infection or community-onset invasive disease should be tested for PVL, and when positive, be offered decolonisation after appropriate treatment, irrespective of clinical presentation. Household contacts might be offered screening or decolonisation, or both, after risk assessment. This policy is based on the assumption that decolonisation can reduce risk of further disease, but because PVL strains are common and usually not highly pathogenic this policy might not be justified. Moreover we identified little evidence that decolonisation is effective for individuals with PVL-positive disease,38,91
and treatment could risk elimination of a colonising strain that is rarely associated with disease.77
Estimation of the burden of PVL-associated disease in the community is challenging because surveillance systems rely on specimens sent to reference units and mainly focus on MRSA, and research studies predominantly analyse retrospective collections of clinical isolates. Both methods are biased towards severe disease because minor skin and soft-tissue infections are not sampled in routine clinical practice and a high proportion of PVL strains are meticillin-sensitive. These methods tend to provide a false impression of the prevalence of severe disease because they represent the so-called tip of the clinical iceberg of S aureus infection (). Without population-based studies we cannot know what absolute proportion of PVL-positive specimens are associated with colonisation and mild, moderate, and invasive disease. More research is needed to test the hypothesis that PVL strains are also associated with minor skin and soft-tissue infections that are undiagnosed and treated uneventfully in the community without recourse to secondary care. If this hypothesis is true, it strongly questions the need for a search and destroy policy around individuals who are infected with PVL-positive strains.
Clinical iceberg of Panton-Valentine leucocidin-associated infection
More research is needed to understand the interplay between host factors, colonisation, bacterial virulence, and PVL to identify individuals at risk of invasive disease with a poor prognosis. This research in turn should guide a proportionate and evidence-based approach to clinical and public health control measures.