TSST-1+Staphylococcus aureus in Bullous Pemphigoid

Abstract

A potential role of Staphylococcus aureus in bullous pemphigoid was explored by examining the colonization rate in patients with new-onset disease compared with that in age- and sex-matched controls. S. aureus colonization was observed in 85% of bullous pemphigoid lesions, 3-6-fold higher than the nares or unaffected skin from the same patients (P ≤ 0.003) and 6-fold higher than the nares or skin of controls (P ≤ 0.0015). Furthermore, 96% of the lesional isolates produced the toxic shock syndrome toxin-1 superantigen, and most of these additionally exhibited homogeneous expression of the enterotoxin gene cluster toxins. Toxic shock syndrome toxin-1‒neutralizing antibodies were not protective against colonization. However, S. aureus colonization was not observed in patients who had recently received antibiotics, and the addition of antibiotics with staphylococcal coverage eliminated S. aureus and resulted in clinical improvement. This study shows that toxic shock syndrome toxin-1‒positive S. aureus is prevalent in bullous pemphigoid lesions and suggests that early implementation of antibiotics may be of benefit. Furthermore, our results suggest that S. aureus colonization could provide a source of infection in patients with bullous pemphigoid, particularly in the setting of high-dose immunosuppression.

Figure 1.. Patients with BP exhibit an increased rate of Staphylococcus aureus colonization, and most of these isolates produce TSST-1.

(a) Staphylococcal colonization was categorized as S. aureus (coagulase positive) or coagulase-negative staphylococci or no growth, and their relative distribution is shown as a percentage of the total number (above bars). BP lesions were six-fold more likely to be colonized by S. aureus than control Ns or S (Fisher’s exact test, 95% CI = 2.790–15.78, P < 0.0001). (b) Staphylococcal colonization of the S or Ns of 128 healthy individuals aged 40–99 years shows that bacterial distribution is not influenced by age (logistic regression models, AUC ~0.5). (c) Most S. aureus isolates from patients with BP produce TSST-1, whereas most of the control isolates do not. Using Fisher’s exact test, BP lesions were >4-fold more likely to be colonized by TSST-1⁺ S. aureus than control Ns (95% CI = 2.422–9.468, P < 0.0001) or S (95% CI = 2.215–9.144, P < 0.0001). AUC, area under the curve; BP, bullous pemphigoid; CI, confidence interval; N, nare; S, skin; TSST-1, toxic shock syndrome toxin-1.

Figure 2.. TSST-1 IgG does not prevent TSST-1⁺ Staphylococcus aureus colonization of BP lesions.

Serum titers of TSST-1–specific IgG were measured by ELISA. Titers ≤40 (shaded area) are not considered protective. TSST-1 IgG titers were similar in the sera from 28 patients with BP and 28 matched controls (Mann–Whitney test, P = 0.787), with 50% and 57% of each respective group showing protective titers. TSST-1⁺ S. aurous colonization (filled dot) was not correlated with the level of TSST-1 IgG (Spearman’s r² = 0.005, P = 0.9796). Each point represents the average of triplicate wells for an individual patient, with the median indicated by the solid line. BP, bullous pemphigoid; LLD, lower limit of detection; TSST-1, toxic shock syndrome toxin-1.

Figure 3.. Rapid reduction in disease activity with antibiotic treatment in a patient with BP colonized with TSST-1⁺ Staphylococcus aureus.

Disease activity in a male aged 67 years who had been treated with prednisone, 60 mg/day, and mycophenolate mofetil, 3 g/day, for 6 weeks (front is shown in a; back is shown in b). Bacterial swabs were obtained, and his therapeutic regimen was altered to reduce immune suppression (mycophenolate, 1 g) and inClude an antibiotic with staphylococcal coverage (Clindamycin, 450 mg, three times per day). TSST-1⁺ S. aurous was isolated from lesions and nares but not from the unaffected skin. (c, d) The patient reported a cessation of new blisters by day 10; by day 23, a 44% decrease in BPDAI was observed, and repeat cultures yielded no growth of S. aurous from the skin surface or the nares. The patient granted permission to publish Clinical images. BP, bullous pemphigoid; BPDAI, Bullous Pemphigoid Disease Area Index; TSST-1, toxic shock syndrome toxin-1.