Variation in Diagnostic Test Use and Associated Outcomes in Staphylococcal Scalded Skin Syndrome at Children's Hospitals.

OBJECTIVES: The incidence of staphylococcal scalded skin syndrome (SSSS) is rising, but current practice variation in diagnostic test use is not well described. Our aim was to describe the variation in diagnostic test use in children hospitalized with SSSS and to determine associations with patient outcomes. METHODS: We performed a retrospective (2011-2016) cohort study of children aged 0 to 18 years from 35 children's hospitals in the Pediatric Health Information System database. Tests included blood culture, complete blood count, erythrocyte sedimentation rate, C-reactive protein level, serum chemistries, and group A streptococcal testing. K-means clustering was used to stratify hospitals into groups of high (cluster 1) and low (cluster 2) test use. Associations between clusters and patient outcomes (length of stay, cost, readmissions, and emergency department revisits) were assessed with generalized linear mixed-effects modeling. RESULTS: We included 1259 hospitalized children with SSSS; 84% were ≤4 years old. Substantial interhospital variation was seen in diagnostic testing. Blood culture was the most commonly obtained test (range 62%-100%), with the most variation seen in inflammatory markers (14%-100%). Between hospital clusters 1 and 2, respectively, there was no significant difference in adjusted length of stay (2.6 vs 2.5 days; P = .235), cost ($4752 vs $4453; P = .591), same-cause 7-day readmission rate (0.8% vs 0.4%; P = .349), or emergency department revisit rates (0.1% vs 0.6%; P = .148). CONCLUSIONS: For children hospitalized with SSSS, lower use of diagnostic tests was not associated with changes in outcomes. Hospitals with high diagnostic test use may be able to reduce testing without adversely affecting patient outcomes.

Use of the frozen section 'jelly-roll' technique to aid in the diagnosis of bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis).

Frozen section is a valuable tool that is often underutilized in the setting of in-patient dermatology. Traditionally, frozen section has been used in dermatology to diagnose toxic epidermal necrolysis, with some additional utility in staphylococcal scalded skin syndrome in the new born period. We report a newborn female with ruptured bullae on the face, chest, back and extremities with a clinical differential diagnosis that included staphylococcal scalded skin, bullous congenital ichthyosiform erythroderma/epidermolytic hyperkeratosis and epidermolysis bullosa. A thin detached skin sample ('jelly-roll') taken from a ruptured bulla on the abdomen was prepared for frozen section analysis. Characteristic findings of epidermolytic hyperkeratosis were seen which included hyperkeratosis with granular layer degeneration, vacuolization and eosinophilic globules. The 'jelly-roll' technique can be used for quick diagnosis with minimal trauma to the patient. Epidermolytic hyperkeratosis was subsequently confirmed by a biopsy fixed in formalin and by genetic testing. A novel missense mutation in KRT1 (I479N) was identified. Herein, we discuss the use of the frozen section 'jelly roll' technique for rapid diagnosis in a case of bullous congenital ichthyosis erythroderma/epidermolytic hyperkeratosis.

Removal of amino-terminal extracellular domains of desmoglein 1 by staphylococcal exfoliative toxin is sufficient to initiate epidermal blister formation.

BACKGROUND: In both bullous impetigo and staphylococcal scalded-skin syndrome (SSSS), exfoliative toxins (ETs) produced by Staphylococcus aureus cause superficial intraepidermal blisters. ETs are known to cleave specifically a single peptide bond in the extracellular domains 3 and 4 of desmoglein (Dsg) 1. However, the precise mechanisms underlying ET-induced epidermal blister formation remain poorly understood. OBJECTIVE: To determine whether cleavage of Dsg1 by an ET is sufficient to induce blister formation in vivo or if the subsequent internalization of cleaved Dsg1 or other desmosomal components is required. METHODS: Skin samples obtained from neonatal mice injected with ETA were analyzed by time-lapse immunofluorescence and transmission electron microscopy for desmosomal components. RESULTS: Epidermal blister formation was observed as early as 60 min after ETA treatment. At this time, the amino-terminal extracellular domains of Dsg1 disappeared from the surface of keratinocytes, while the cleaved carboxy-terminal domain of Dsg1 (Dsg1-C) as well as the extracellular domains of desmocollin 1 (Dsc1-N) remained on the cell surface. Half-split desmosomes with intracytoplasmic dense plaques and attached tonofilaments were recognized ultrastructurally on the split surface of keratinocytes at 60 min. Subsequent to this, Dsg1-C and Dsc1-N gradually disappeared from the surface layer of keratinocytes. CONCLUSION: Our findings suggest that the removal of amino-terminal extracellular domains of Dsg1 by ETs is sufficient to initiate epidermal blister formation in bullous impetigo and SSSS.

Staphylococcal scalded skin syndrome: loss of desmoglein 1 in patient skin.

Staphylococcal scalded skin syndrome (SSSS) is a blistering disease of the skin caused by an infection with certain strains of Staphylococcus aureus. In vitro studies have suggested that exfoliative toxins secreted by these bacteria cleave the desmosomal adhesion molecule desmoglein 1 leading to loss of cell-cell contact in the superficial epidermis. In this study we investigated the fate of desmoglein 1 in biopsies of patients with SSSS to see whether the ectodomain of desmoglein 1 is cleaved. Our data largely confirm previous in vitro data. The different biopsies demonstrated the loss of the ectodomain of desmoglein 1 to different degrees. The endodomain of desmoglein 1 meanwhile remained present. Most remarkably, in one of our patients, the immunofluorescent analysis demonstrated that not desmoglein1 but desmocollin 1, another desmosomal cadherin, became affected. This raises the question if other toxins and/or other bacteria than Staphylococcus aureus might also induce SSSS.

Cytokine and nitric oxide production in an adult patient with staphylococcal scalded skin syndrome.

Staphylococcal scalded-skin syndrome (SSSS) is an exfoliative dermatitis resultant from the infection with exfoliative-toxin-producing (ET) Staphylococcus aureus. This syndrome usually occurs in children, while adult cases are generally linked to renal-deficiency or immunossupresion. A case of a 74 year old woman presenting SSSS after hospital admission due to cardiovascular disorders is presented and discussed. Cytokines (TNF-alpha, IFN-gamma, IL-6, IL-13 and IL-10) and nitric oxide (NO) production in vitro by whole blood leukocytes (WBL) were investigated. Leukocytes stimulated by lipopolysaccharide or phytohemagglutinin produced increased IFN-gamma, TNF-alpha, IL-13 and NO levels after treatment. Based on these results, immunological aspects of the disease are discussed.

Differential pathomechanisms of epidermal necrolytic blistering diseases.

Staphylococcal scalded skin syndrome (SSSS) results from the effect of exfoliative-toxins produced by staphylococcal strains. The disease affects predominantly children, and is rare in adults. We report two cases of the adult type of SSSS. Corticotherapy, chronic alcohol abuse and epilepsy-related immune changes might have been predisposing factors in these patients. The immunopathological characteristics of the inflammatory cell infiltrate in adults SSSS have not been thoroughly explored so far in the literature. Biopsies from 2 patients with bullous SSSS skin were studied by means of immunochemistry using a panel of 10 antibodies directed to FXIIIa, CD15, CD31, CD45R0, CD50, CD54, CD62E, CD95, CD106, and L1-protein, respectively. Cutaneous biopsies from related blistering diseases were compared. They included drug-induced toxic epidermal necrolysis (TEN), bullous impetigo and superficial pemphigus. A dense cell infiltrate composed of granulocytes (CD15+), macrophages (L1 protein+) and memory T cells (CD45R0+) and a strong expression of ICAM-3 (CD50) were present in the epidermis. CD95+ keratinocytes were lining the intraepidermal blisters. Type I dermal dendrocytes (Factor XIIIa+) were numerous and plump in the dermis. Bullous impetigo exhibited the same pattern of inflammatory cells, but with a lower density in type I dermal dendrocytes. TEN differed from SSSS by both the absence of CD15+ granulocytes and a stronger expression of the pro-apoptotic CD95 antigen in the epidermis. In superficial pemphigus, CD95 antigen was not expressed, and CD15+ granulocytes, CD45R0+ lymphocytes and L1 protein+ monocytes were much less numerous. It is concluded that the specific binding of SSSS-induced exotoxins to the desmosomes alters the keratinocyte metabolism leading to an inflammatory reaction followed by focal apoptosis. Our findings are in line with the concept that SSSS exotoxins might be superantigens. A common pathomechanism leading to epidermal destruction is likely operative in SSSS and bullous impetigo. The inflammatory cell composition in TEN and superficial pemphigus markedly differs from that in SSSS.

Staphylococcal exfoliative toxin B specifically cleaves desmoglein 1.

Staphylococcal scalded skin syndrome and its localized form, bullous impetigo, show superficial epidermal blister formation caused by exfoliative toxin A or B produced by Staphylococcus aureus. Recently we have demonstrated that exfoliative toxin A specifically cleaves desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study we determine the target molecule for exfoliative toxin B. Exfoliative toxin B injected in neonatal mice caused superficial epidermal blisters, abolished cell surface staining of desmoglein 1, and degraded desmoglein 1 without affecting desmoglein 3 or E-cadherin. When adenovirus-transduced cultured keratinocytes expressing exogenous mouse desmoglein 1 or desmoglein 3 were incubated with exfoliative toxin B, desmoglein 1, but not desmoglein 3, was cleaved. Furthermore, cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal human skin were incubated with exfoliative toxin B, suggesting that living cells were not necessary for exfoliative toxin B cleavage of desmoglein 1. Finally, in vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 with exfoliative toxin B demonstrated that both mouse and human desmoglein 1, but not desmoglein 3, were directly cleaved by exfoliative toxin B in a dose-dependent fashion. These findings demonstrate that exfoliative toxin A and exfoliative toxin B cause blister formation in staphylococcal scalded skin syndrome and bullous impetigo by identical molecular pathophysiologic mechanisms.

Staphylococcal exfoliative toxins cleave alpha- and beta-melanocyte-stimulating hormones.

The staphylococcal exfoliative toxins (ETs) A and B (ETA and ETB) are 27-kDa exotoxins produced by certain strains of Staphylococcus aureus and are the causative agents of staphylococcal scalded-skin syndrome. The crystal structures of the ETs strongly indicate that the proteins are members of the serine protease family of enzymes, although protease activity until now has not yet been conclusively demonstrated. Here, we show that the peptide beta-melanocyte-stimulating hormone (beta-MSH) is cleaved by ETA and that both ETA and ETB are capable of cleaving alpha-MSH. Both toxins exhibit cleavage at specific glutamic acid residues in MSH peptides. Moreover, biologically inactive mutants of ETA were incapable of cleaving beta-MSH.

Toxin involvement in staphylococcal scalded skin syndrome.

The production of staphylococcal exfoliative toxin A (ETA) and toxin B (ETB), toxic shock syndrome toxin (TSST-1), and enterotoxins A-E was analyzed in 60 Staphylococcus aureus strains isolated from children with scalded skin syndrome (15 with generalized exfoliative syndrome, 28 with bullous impetigo, and 17 with staphylococcal scarlet fever). All strains isolated from patients with generalized exfoliative syndrome or bullous impetigo produced ETA and/or ETB and caused a Nikolsky's sign when injected subcutaneously into newborn mice. In contrast, exfoliative toxin was detected in an S. aureus strain from only one of 17 case of staphylococcal scarlet fever; the 16 other S. aureus strains produced TSST-1 and/or an enterotoxin. In conclusion, enterotoxins or TSST-1 are more frequently associated with staphylococcal scarlet fever than are exfoliative toxins. Hence staphylococcal scarlet fever may well represent an abortive form of toxic shock syndrome rather than a milder form of staphylococcal scalded skin syndrome.

Functional evidence that the Ser-195 residue of staphylococcal exfoliative toxin A is essential for biological activity.

The substitution of the serine 195 residue of staphylococcal exfoliative toxin A by a cysteine residue led to a biologically inactive protein. This result is consistent with the hypothesis that exfoliative toxin A could be a protease or a lipase. However, no protease or lipase activity was detected with the native toxin.