The exfoliative (epidermolytic) toxins of Staphylococcus aureus are the causative agents of the staphylococcal scalded-skin syndrome (SSSS), a blistering skin disorder that predominantly affects children. Clinical features of SSSS vary along a spectrum, ranging from a few localized blisters to generalized exfoliation covering almost the entire body. The toxins act specifically at the zona granulosa of the epidermis to produce the characteristic exfoliation, although the mechanism by which this is achieved is still poorly understood. Despite the availability of antibiotics, SSSS carries a significant mortality rate, particularly among neonates with secondary complications of epidermal loss and among adults with underlying diseases. The aim of this article is to provide a comprehensive review of the literature spanning more than a century and to cover all aspects of the disease. The epidemiology, clinical features, potential complications, risk factors, susceptibility, diagnosis, differential diagnoses, investigations currently available, treatment options, and preventive measures are all discussed in detail. Recent crystallographic data on the toxins has provided us with a clearer and more defined approach to studying the disease. Understanding their mode of action has important implications in future treatment and prevention of SSSS and other diseases, and knowledge of their specific site of action may provide a useful tool for physiologists, dermatologists, and pharmacologists.

Clinical, Microbial, and Biochemical Aspects of the Exfoliative Toxins Causing Staphylococcal Scalded-Skin Syndrome

• The essential clinical features of staphylococcal scalded skin syndrome (SSSS) and other forms of toxic epidermal necrolysis (TEN) are contrasted. Whereas TEN is a devastating disease of multiple causes and of high fatality affecting all age groups, SSSS comprises many clinical entities that occur primarily in early childhood and is caused by certain phage group 2 staphylococci. Because of the high cleavage plane, the barrier is only transiently perturbed, and rapid recovery is the rule. Although the early stages of SSSS may resemble other widespread dermatoses clinically, the correct diagnosis is suggested, even prior to frank exfoliation, by the presence of cutaneous tenderness and a positive Nikolski sign. However, rapid bedside confirmation is now possible with exfoliative cytology and frozen sections. Recent availability of in vivo and in vitro animal models of SSSS have advanced the knowledge of the disease: the responsible epidermolytic toxin has been characterized, and the purely extracellular pathogenesis of SSSS has been established. The epidermolytic toxin is strikingly species and tissue specific, attacking only certain keratinizing epithelia of mice, hamsters, monkeys, and man. The lower incidence of SSSS in adults is primarily due to a superior capacity to metabolize and excrete the toxin, as well as more efficient immune capabilities. The mechanisms of epidermolytic toxin action and the molecular site of action are still the focus of active investigation. ( Arch Dermatol 113:207-219, 1977)

Staphylococcal Scalded Skin Syndrome: Clinical Features, Pathogenesis, and Recent Microbiological and Biochemical Developments

https://mmbr.asm.org/content/mmbr/43/3/320.full.pdf

Nonenteric toxins of Staphylococcus aureus.

Staphylococcal Exfoliative Toxin B Specifically Cleaves Desmoglein 1

Bullous impetigo due to Staphylococcus aureus is one of the most common bacterial infections of man, and its generalized form, staphylococcal scalded skin syndrome (SSSS), is a frequent manifestation of staphylococcal epidemics in neonatal nurseries. Both diseases are mediated by exfoliative toxins (ETs), which show exquisite pathologic specificity in blistering only the superficial epidermis. We show that these toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. Mutation of the predicted catalytically active serine to alanine completely inhibits cleavage. The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmunoprecipitation. Thus, ETs, through specific recognition and proteolytic cleavage of one structurally critical peptide bond in an adhesion molecule, cause its dysfunction and allow S. aureus to spread under the stratum corneum, the main barrier of the skin, explaining how, although they circulate through the entire body in SSSS, they cause pathology only in the superficial epidermis.

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Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome

The purpose of this study was to demonstrate morphologic correlates of exposure of skin to exfoliative toxin derived from live phage group II staphylococci. Human infection with these staphylococci has been associated with scarlatiniform rash, generalized exfoliation, or bullous impetigo. Histologically, the skin lesions in patients and animals injected with the exfoliative toxin appear indistinguishable. The characteristic change is an intraepidermal cleavage through the granular cell layer. Electron microscopically, this cleavage appears to result from disruption of otherwise normal attachment structures (desmosomes) through their intercellular contact area. This disruption may be related to disappearance of extracellular globules which are proposed possibly to contain proteolytic enzymes.

Site of action of exfoliative toxin in the staphylococcal scaled-skin syndrome.

The term “Ritter’s disease” stands as a tribute to the clinical acumen of Ritter von Rittershain, who in 1878 described a bullous exfoliative disease that affects newborn infants. His remarkable description of 287 infants seen in a foundling hospital in Prague remains the largest and most complete clinical description of this c0ndition.l By 1898, Winternitz had linked Ritter’s disease to infection with Staphylococcus aureus.2 A particular subgroup of coagulasepositive staphylococcus, those strains that belong to phage group 11, were identified as associated with Ritter’s disease by the early 1 9 6 0 ~ , ~ . A and since that time all outbreaks in which phage type has been reported have been associated with staphylococci of this phage group.

The staphylococcal epidermolytic toxin: its isolation, characterization, and site of action.

The effect on gastric mucosa of chronic administration of ethanol in excessive amounts was studied electron microscopically in nutritionally replete dogs. Point volumetric analysis was performed on electron micrographs of a control group and an alcohol-fed group of dogs. The mean volume of oxyntic cells increased threefold. Mitochondria appeared damaged and their mean volume was nearly doubled. The mean number of mitochondria per cell remained unchanged in the alcohol-fed dogs. The vesicotubules of the secretory tubular apparatus assumed a predominantly flattened vesicular conflguration but increased in number approximately threefold. Zymogenic cells appeared unchanged. These alterations in electron microscopic morphology suggest that the oxyntic cell is quite susceptible to ethanol, and that the previously reported increase in maximal acid output results from mitochondrial hypertrophy and vesicotubular hyperplasia.

Observations on the ultrastructure of oxyntic cells in alcohol-fed dogs.

Human gastric mucosal zymogen granules.

Gastric mucosal biopsies from eight new untreated patients with cystic fibrosis (CF) and two normal subjects were studied by quantitative techniques of electron microscopy (EM) to determine whether presecreted gastric mucus was more compact (viscid) than normal. Analysis of variance techniques show no differences between means of all groups studied. These observations suggest that mucus may not be viscid prior to secretion. Electron microscopy of gastric mucus does not appear to be of diagnostic value in CF.

Clinton B. Lillibridge

Papers

Site of action of exfoliative toxin in the staphylococcal scaled-skin syndrome.

The staphylococcal epidermolytic toxin: its isolation, characterization, and site of action.

Observations on the ultrastructure of oxyntic cells in alcohol-fed dogs.

Human gastric mucosal zymogen granules.

The Electron Microscopic Appearance of Presecreted Gastric Mucus in Cystic Fibrosis