Lack of Humoral Immunity Against Glucosaminidase Is Associated with Postoperative Complications in Staphylococcus aureus Osteomyelitis

Abstract

Background: Glucosaminidase (Gmd) is known to be a protective antigen in animal models of Staphylococcus aureus osteomyelitis. We compared the endogenous anti-Gmd antibody levels in sera of patients with culture-confirmed S. aureus bone infections to their sera at 1 year after operative treatment of the infection.

Methods: A novel global biospecimen registry of 297 patients with deep-wound culture-confirmed S. aureus osteomyelitis was analyzed to assess relationships between baseline anti-Gmd serum titers (via custom Luminex assay), known host risk factors for infection, and 1-year postoperative clinical outcomes (e.g., infection control, inconclusive, refracture, persistent infection, septic nonunion, amputation, and septic death).

Results: All patients had measurable humoral immunity against some S. aureus antigens, but only 20 patients (6.7%; p < 0.0001) had high levels of anti-Gmd antibodies (>10 ng/mL) in serum at baseline. A subset of 194 patients (65.3%) who completed 1 year of follow-up was divided into groups based on anti-Gmd level: low (<1 ng/mL, 54 patients; 27.8%), intermediate (<10 ng/mL, 122 patients; 62.9%), and high (>10 ng/mL, 18 patients; 9.3%), and infection control rates were 40.7%, 50.0%, and 66.7%, respectively. The incidence of adverse outcomes in these groups was 33.3%, 16.4%, and 11.1%, respectively. Assessing anti-Gmd level as a continuous variable showed a 60% reduction in adverse-event odds (p = 0.04) for every tenfold increase in concentration. No differences in patient demographics, body mass index of >40 kg/m, diabetes status, age of ≥70 years, male sex, Charlson Comorbidity Index of >1, or Cierny-Mader host type were observed between groups, and these risk factors were not associated with adverse events. Patients with low anti-Gmd titer demonstrated a significant 2.68-fold increased odds of adverse outcomes (p = 0.008).

Conclusions: Deficiency in circulating anti-Gmd antibodies was associated serious adverse outcomes following operative treatment of S. aureus osteomyelitis. At 1 year, high levels of anti-Gmd antibodies were associated with a nearly 3-fold increase in infection-control odds. Additional prospective studies clarifying Gmd immunization for osteomyelitis are needed.

Level of evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Fig. 1

Figs. 1-A and 1-B Anti-S. aureus antibody IgG titers in patients with orthopaedic infections. The data in Figure 1-A are of all 297 patients. Antibody titers are represented as the MFI. Fig. 1-A The anti-Gmd IgG titers are presented in rank, ordered from lowest to highest, and are stratified into 3 groups: undetectable or low anti-Gmd (MFI <1,550, cyan), intermediate anti-Gmd (MFI 1,550 to 9,000, yellow), and high anti-Gmd (MFI >9,000, red). Note that 29% of osteomyelitis patients have undetectable levels of anti-Gmd titers. Fig. 1-B Heat maps of serum IgG levels of antibodies against the 8 antigens are presented for the 194 patients who completed the study out to 1 year postoperatively. Baseline and available 6-month and 12-month measurements illustrate that detectable anti-S. aureus antibodies against at least 1 antigen were evident over the course of therapy. Also of note is that IsdB is by far the most immunogenic antigen among these patients, whereas Gmd is one of the lowest (IsdB > Amd > SCIN > IsdA > Hla > IsdH = CHIPS = Gmd).