A Comparison of Group A Streptococci from Invasive and Uncomplicated Infections: Are Virulent Clones Responsible for Serious Streptococcal Infections?

From the mid-1980s, numerous reports of invasive group A streptococcal infections suggested that “highly virulent clones” were responsible. However, there have been virtually no extensive reports and comparisons of diverse temporal and geographic community isolates from uncomplicated throat infections to confirm the hypothesis. A unique collection of such “control” strains allowed in-depth assessment of association of M serotypes 1, 3, and 28 “clones” with invasive infections. Clones were defined by using small-fragment chromosomal restriction-enzyme analysis, pulsed-field gel electrophoresis, and M protein gene (emm) sequencing. After comparison with controls, no clone within these M serotypes had statistically increased association with invasive infections. The prevalence of specific virulence-associated clones appeared to essentially reflect their normal population prevalence. Although this does exclude other potential streptococcal factors, these findings suggest that host factors including individual and population-based immunity must also be significant in influencing infection potential. Although never completely relinquishing their ability to cause outbreaks of serious infections and life-threatening sequelae, by the middle of the twentieth century, group A streptococci (GAS) were almost as likely to be considered nuisance infections in most industrialized countries. Streptococcal infections were not uncommon but they relatively seldom proved to be serious [1, 2]. As a result, it was surprising in the mid- and late 1980s when significant outbreaks of both suppurative and nonsuppurative complications of group A streptococcal infections began to be reported worldwide [3]. There was no obvious explanation for these apparent epidemiologic changes. Attempts to explain the problem by clinicians, epidemiologists, and laboratory scientists continued as the problem persisted through the decade of the 1990s. One logical approach was to attempt to document and define changes in the virulence of the responsible organisms, even though it became clear that multiple serotypes were involved [4]. Early reports suggested the possibility of specific disease-producing “clones” that caused this unexpected epidemiologic phenomenon. [5‐12]. However, none of the relatively few attempts contained appropriate comparisons with sufficiently large and diverse samples of prevalent group A streptococcal isolates circulating in multiple communities to definitively confirm a role for “highly virulent” strains. Researchers were left with the concern that there was not sufficient documentation, either epidemiologic or laboratory and molecular, and that there were, in fact, definable specific highly “virulent” clones present in the general population. During the time of this apparent reemergence of group A streptococcal invasive infections, our laboratory continuously received numerous group A streptococcal isolates from persons with severe systemic infections from North America and from abroad. Of equal importance, however, we amassed a large collection of isolates from children and adults with only uncomplicated pharyngeal infections, because of our continuing interest in the epidemiology and management of uncomplicated group A streptococcal pharyngitis. These latter strains originated from most US states and were collected essentially during the entire period of the reemergence (1986‐2001). Our laboratory’s isolate collections have provided a unique opportunity to address the issue of inherent virulence by enabling comparison of the similarities and differences of the strains isolated from patients with severe group A streptococcal infections with those associated with patients with only clinically uncomplicated pharyngitis (UP). In the present study, we compared isolates belonging to M serotypes 1, 3, and 28 by using several specific molecular techniques previously reported by other investigators as being able to identify virulent clones of GAS. These techniques included small-fragment chromosomal restriction-enzyme analy