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Expanding the definition beyond surveillance criteria reveals a large burden of osteomyelitis caused by group B Streptococcus in the United States Veterans Health Administration | BMC Infectious Diseases

In this national cohort of patients from the VA, we analyzed more than 1250 cases of osteomyelitis caused by GBS. Of these, 40% were identified using an expanded case definition that included a diagnostic code for osteomyelitis and isolation of GBS from cultures of anatomically relevant non-sterile sites. These cases would not have been captured by case definitions conventionally used to conduct population-based surveillance of invasive GBS disease, including GBS osteomyelitis. By incorporating cases identified through our expanded criteria for osteomyelitis that included GBS recovered from non-sterile sites, we demonstrated that the burden of disease caused by GBS osteomyelitis appears to be greater than previously recognized.

As reported by both the US CDC as well as in our previous assessment of a cohort of US Veterans, osteomyelitis is among the most common invasive infections caused by GBS among non-pregnant adults [3, 5]. A study of 3 large counties in California found that, between 1995 and 2021, the rate of GBS osteomyelitis increased from 0.7 to 2.4 cases per 100,000 population [14]. These studies all used well-established definitions of invasive disease, requiring either positive bone or blood cultures to diagnose osteomyelitis. In clinical practice, however, the diagnosis of osteomyelitis may require serologic, imaging, and microbiological investigations, all of which need to be interpreted within the context of individual patients. For this study, we applied less stringent microbiological criteria, coupled with diagnostic and procedure (diagnostic imaging) codes available from clinical and administrative databases, to allow for recognition of probable GBS osteomyelitis. These aligned with criteria used by Kremers et al. in their description of the epidemiology of osteomyelitis in Olmsted County, Minnesota, in which they characterized cases as possible, probable and definite osteomyelitis based on the availability of pathologic and microbiologic data as well as quality of sample collected [10]. Including an expanded definition that considered cultures from non-sterile sites, deemed here as probable GBS osteomyelitis, nearly doubled the number of cases in our cohort, with few clinical differences between those deemed to have definite and probable GBS osteomyelitis. Even consideration only of cases monomicrobial GBS osteomyelitis, where the pathogenic role of GBS is less questionable, yields an additional 20% cases using the expanded definition. A population-based study that assessed hospitalizations due to invasive and non-invasive GBS infections in Louisville, Kentucky, also confirmed osteomyelitis as a common presentation of GBS infection and found rates of non-invasive disease that were 3ā€“4 times higher than those of invasive disease; that study relied on clinical and microbiological criteria that differ from the ones we applied here [15]. Those observations, together with our findings, suggests that the strict case definitions used to assess invasive GBS disease in population-surveillance studies may overlook a notable proportion of cases of GBS osteomyelitis.

The cases of GBS osteomyelitis identified using the strict case definitions of invasive disease (classified as definite GBS osteomyelitis) had similar demographic and clinical characteristics than cases identified with GBS using our expanded criteria (probable GBS osteomyelitis). As in previous epidemiologic studies of invasive GBS infection, obesity and especially diabetes mellitus were prevalent in this cohort of patients with GBS osteomyelitis [4, 16]. Diabetes mellitus that was not well controlled (HbA1Cā€‰>ā€‰7.5%) occurred more commonly among those with definite GBS osteomyelitis, consistent with previous reports that describe elevated HbA1c as an important risk factor for invasive GBS disease (5). A high proportion of cases also had peripheral vascular disease. Taken together, these findings suggest that diabetic foot infections were contributory to a large proportion of cases with GBS osteomyelitis in this cohort.

The grave outcomes of GBS osteomyelitis in this cohort of US Veterans deserve comment. Short term mortality, even for cases of invasive GBS infection, appeared low. This may be a function of the susceptibility of GBS against most empiric regimens in patients with suspected osteomyelitis. It is notable, however, that 1 in 10 patients with GBS osteomyelitis are dead within a year, which may reflect the burden of comorbidities in this group of patients, and that mortality was similar among patients with definite compared to probable GBS osteomyelitis. In contrast, among cases with GBS osteomyelitis of a lower extremity, those deemed to have definite osteomyelitis were more likely to proceed to an amputation. This difference may result from selection bias, in that patients who proceeded to amputation were also more likely to have a bone specimen available for culture and GBS isolation, thereby fulfilling the criteria for invasive disease.

The large proportion of cases deemed to have probable GBS osteomyelitis that had polymicrobial infection may also reflect differences in the types of samples collected, which included non-sterile sites like wounds and ulcers. For these samples, the microbiology laboratory may choose to only report GBS if it grows in significant quantities, whereas any presence of S. aureus and P. aeruginosa is typically reported. If this is the case, GBS can likely be considered a pathogen, giving credence to polymicrobial osteomyelitis. Alternatively, the microbiology laboratory may report any presence of GBS regardless of the presence of other pathogens, in which case the pathogenic role of GBS is more difficult to discern. Unfortunately, in this study we were not able to assess the protocols and practices of microbiology laboratories that processed these samples.

Cultures collected from patients with definite osteomyelitis were significantly less likely to have other organisms, including S. aureus and P. aeruginosa. Nevertheless, these pathogens were found in up to a quarter of cases defined by isolation of GBS from a sterile site (i.e., bone and blood). In this scenario, it is difficult to establish which is the predominant pathogen, as they may display synergistic interactions that enhance their colonization, virulence and persistence [17]. The rates of mortality and of lower extremity amputation among patients with cultures that were monomicrobial for GBS were similar to those for the entire cohort. These results suggests that GBS has as much pathogenic potential as other bacterial species commonly recognized in association with osteomyelitis, such as S. aureus. As most antibiotic regimens that treat S. aureus osteomyelitis are effective against GBS, the risk of inadvertently selecting inappropriate therapy against GBS is low [18].

Our study has several important limitations. First, the results of this study may not be generalizable to other populations because of the different sociodemographic and health patterns that exist in the VA population. Specifically, VA patients are predominantly white, non-Latinx males with a high burden of chronic medical conditions [19]. Second, the definitions employed in this study were based on clinical and administrative data, including ICD codes, CPT codes for amputation and imaging studies, and identification of the site of the GBS culture; ambiguity in labeling and coding errors may have led to misclassification of some cases. Third, we did not examine the results of imaging studies to confirm the diagnosis of osteomyelitis because radiologic interpretations are not readily available through the CDW, thus potentially overestimating the number of cases of probable GBS osteomyelitis. Fourth, there is potential for misclassification of cases with GBS identified from abscesses that occur in a sterile site or from exposed bone that is no longer sterile, and of cases with discrepancies between blood and bone cultures. Finally, practices to isolate and report GBS in clinical specimens, especially in polymicrobial cultures from non-sterile sites, may not be uniform across different microbiology laboratories and may have changed over the study period. Similarly, this retrospective study did not report the serotypes or the antibiotic susceptibilities of GBS isolates since these are not routinely determined at microbiology laboratories serving VA medical centers.

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