Staphylococcal scalded skin syndrome: An uncommon symptomatology revealing an immune deficiency.

Primary immune deficiencies associated with hyper-IgE syndrome are rare diseases with clinical features dominated by recurring cutaneous and visceral bacterial infections, particularly infections due to Staphylococcus species. Most of these infections are associated with milder inflammation compared to normal. We report a primary immune deficiency associated with a hyper-IgE syndrome revealed by a staphylococcal scalded skin syndrome in a 5-year-old girl. The patient presented with a severe staphylococcal infection with extensive skin lesions and disseminated intravascular coagulation. She received intravenous fluids to compensate for fluid losses and anti-staphylococcal antibiotics. Coagulopathy was also corrected. However, the progression was rapidly fatal.

Exfoliative toxin A staphylococcal scalded skin syndrome in preterm infants.

UNLABELLED: Staphylococcal scalded skin syndrome (SSSS) demonstrates dermal symptoms due to exfoliative toxin (ET) A or ETB produced by Staphylococcus aureus. We examined the association between anti-ETA antibodies and SSSS onset in neonates. Three preterm infants carried an ETA-producing strain of S. aureus, manifesting as either SSSS or bullous impetigo; a full-term infant carrying the same strain was asymptomatic. The infants (n=106) were categorized into three groups according to their gestational age (GA) as follows: <30 weeks, 30-37 weeks, and >37 weeks. The measured levels of anti-ETA antibody in the three infants displaying SSSS were low before the onset of dermal symptoms; only the asymptomatic full-term infant displayed a high antibody level. Anti-ETA antibody levels in the preterm group with a GA of <30 weeks were statistically lower than those in the term infant group; the prevalences of anti-ETA antibodies above a cutoff value in the three groups of neonates were 55 % (18/33) among preterm infants with a GA <30 weeks, 73 % (25/34) among those with a GA of 30-37 weeks, and 90 % (35/39) among infants with a GA >37 weeks. CONCLUSION: The presence of anti-ETA antibodies below a particular cutoff level might be associated with SSSS onset in preterm infants.

Antibiotic sensitivity and resistance patterns in pediatric staphylococcal scalded skin syndrome.

Historical resistance patterns often guide empiric antibiotic choices in staphylococcal scalded skin syndrome (SSSS), but little is known about the difference in susceptibility between SSSS and other childhood staphylococcal infections. A retrospective chart review of culture-confirmed cases of SSSS seen in the inpatient dermatology consultation service at the Children's Hospital of Philadelphia between 2005 and 2011 was performed. Most cases of SSSS at our institution are due to oxacillin-susceptible Staphylococcus aureus, and approximately half of the cases are due to clindamycin-resistant strains. Clindamycin and a penicillinase-resistant penicillin are suggested as empiric treatment for SSSS until culture susceptibility data are available to guide therapy.

Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome.

Epidermal Langerhans cells (LCs) extend dendrites through tight junctions (TJs) to survey the skin surface, but their immunological contribution in vivo remains elusive. We show that LCs were essential for inducing IgG(1) responses to patch-immunized ovalbumin in mice that lacked skin dendritic cell subsets. The significance of LC-induced humoral responses was demonstrated in a mouse model of staphylococcal scalded skin syndrome (SSSS), a severe blistering disease in which the desmosomal protein Dsg1 (desmoglein1) is cleaved by Staphylococcus aureus-derived exfoliative toxin (ET). Importantly, ET did not penetrate TJs, and patch immunization did not alter epidermal integrity. Nevertheless, neutralizing anti-ET IgG(1) was induced after patch immunization and abolished upon LC depletion, indicating that antigen capture through TJs by LCs induced humoral immunity. Strikingly, the ET-patched mice were protected from developing SSSS after intraperitoneal ET challenge, whereas LC-depleted mice were susceptible to SSSS, demonstrating a vital role for LC-induced IgG(1) in systemic defense against circulating toxin in vivo. Therefore, LCs elicit humoral immunity to antigens that have not yet violated the epidermal barrier, providing preemptive immunity against potentially pathogenic skin microbes. Targeting this immunological process confers protection with minimal invasiveness and should have a marked impact on future strategies for development of percutaneous vaccines.

Superantigens in dermatology.

Superantigens (SAgs) are virulent polypeptides that are produced by a variety of infectious organisms. They are capable of causing nonspecific T cell activation by circumventing normal antigen processing in the human host. The genetic makeup of the host plays a role in conferring susceptibility or protection against SAgs. They are linked to a variety of conditions, ranging from toxic shock syndrome to recurrent toxin-mediated perineal erythema. The early recognition of signs and symptoms of SAg-mediated illnesses is important to ensure prompt medical treatment.

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.

[Desmoglein, the target molecule in autoimmunity and infection].

To form the human body and maintain the integrity of its complex tissues, individual cells need to hold tightly to each other. The desmosome is the major type of intercellular adhesive junction, and has desmoglein (Dsg), a cadherin type cell-cell adhesion molecule, as a transmembrane component. Dsg is now known to be targeted in autoimmune diseases, infectious diseases, as well as inherited diseases. Patients with pemphigus, an autoimmune blistering disease of the skin and mucous membrane, have IgG autoantibodies directed against Dsg1 and Dsg3. A subset of patients with pemphigus have Dsg1/Dsg4 crossreacting IgG autoantibodies. Exfoliative toxins produced by Staphylococcal aureus, which causes Staphylococcal Scalded Skin Syndrome (SSSS) and bullous impetigo, specifically digest Dsg1. A subset of patients with SSSS develop a low titer of anti-Dsg1 IgG autoantibodies. A mutation in DSG1 gene causes striate palmoplantar keratoderma and a mutation in DSG4 gene causes inherited hypotrichosis. It is not clear why so many diseases are clustered in desmogleins, but there must be a reason for this. Studies on desmogleins will provide an important framework to understand the mysteries between autoimmunity and infection.

Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome.

Desmogleins (Dsgs), cadherin-type cell adhesion molecules, are targeted in skin-blistering diseases such as pemphigus and staphylococcal scalded skin syndrome (SSSS). The role of Dsg4, a new isoform, was investigated in these diseases. Dsg4 was recognized by 30 (77%) of 39 pemphigus sera containing anti-Dsg1 IgG but not by 16 pemphigus sera containing no anti-Dsg1 IgG or by 34 normal control sera. The Dsg4 immunoreactivity of these sera was abolished by removal of anti-Dsg1 IgG. Conversely, the removal of anti-Dsg4 IgG from pemphigus sera reduced the immunoreactivity against Dsg1 only 13.8% +/- 8.8% (n = 23) and did not affect its ability to induce blisters in neonatal mice. IgG that was affinity-purified on Dsg4 recognized Dsg1 but failed to induce blisters, while IgG purified on Dsg1 from the same pemphigus foliaceus sera induced blisters. Thus, pemphigus sera show Dsg4 reactivity due to cross-reactivity of a subset of anti-Dsg1 IgG, and the Dsg4/Dsg1-cross-reacting IgG has no demonstrable pathogenic effect. In addition, Dsg4 was not cleaved by exfoliative toxins that induce blisters in SSSS. These findings suggest that Dsg4 may play a role other than adhesion and that the cross-reactivity of desmoglein autoantibodies should be factored into the framework of future studies of autoimmune mechanisms in pemphigus.

Desmoglein as a target in autoimmunity and infection.

Clinical phenotypes of most diseases are complex. However, once the mechanism behind the scene is clarified, the nature shows amazing beauty. There is a simple logic behind a complex disease. The exact molecular mechanism of the blister formation in staphylococcal scalded skin syndrome (SSSS) remained to be elucidated for 3 decades since exfoliative toxin was discovered by Melish and Glasgow in 1970. A knowledge accumulated to understand the pathogenesis of pemphigus and cell-cell adhesion of keratinocytes led us to solve this question. Desmoglein 1, which is a cadherin type cell-cell adhesion molecule in desmosomes, is targeted in two different skin diseases, pemphigus foliaceus, and SSSS. In pemphigus foliaceus IgG autoantibodies are developed against desmoglein 1 and inhibit its adhesive function with resultant blister formation in the superficial epidermis. In SSSS, exfoliative toxin produced by Staphylococcus aureus specifically binds and cleaves desmoglein 1 with resultant blister formation at the identical site.

Toxin levels in serum correlate with the development of staphylococcal scalded skin syndrome in a murine model.

Staphylococcal scalded skin syndrome (SSSS) is an exfoliative dermatitis that results from infection with exfoliative toxin-producing Staphylococcus aureus. SSSS is seen primarily in infants and children. Here we ask if there is a specific maturation process that protects healthy adults from this syndrome. For these studies, an active recombinant exfoliative toxin A (rETA) was used in a neonatal mouse model. A time course generated on the susceptibility to the toxin as a function of mouse age indicated that BALB/c mice developed the characteristic symptoms of SSSS until day 7 of life. Between day 7 and day 8 of life there was a dramatic decrease in susceptibility, such that mice at day 9 of life were resistant to the effects of the toxin. This time course corresponds approximately to the time needed for maturation of the adaptive immune response, and SSSS in adults is often identified with immunocompromised states. Therefore, mice deficient in this response were examined. Adult mice thymectomized at birth and adult SCID mice did not develop the symptoms of SSSS after injection with the toxin, indicating that the adaptive immune response is not responsible for the lack of susceptibility observed in the older mice. SSSS in adults is also associated with renal disorders, suggesting that levels of toxin in serum are important in the development of the disease. rETA was not cleared as efficiently from the serum of 1-day-old mice compared to clearance from 10-day-old mice. Ten-day-old mice were given repeated injections of toxin so that the maximal level of toxin was maintained for a sustained period of time, and exfoliation occurred in these mice. Thus, whereas the adaptive immune response is not needed for protection of adult mice from SSSS, efficient clearance of the toxin from the bloodstream is a critical factor.

Mutational analysis of the superantigen staphylococcal exfoliative toxin A (ETA).

Exfoliative toxin A (ETA) is known to be a causative agent of staphylococcal scalded skin syndrome (SSSS). Although relatively little is known about exactly how the exfoliative toxins (ETs) cause SSSS, much has been discovered recently that may help elucidate the mechanism(s) by which ETA exhibits activities such as lymphocyte mitogenicity and epidermolytic activity. Here, we have shown that highly purified ETA does have T lymphocyte mitogenic activity in that wild-type ETA induced T cell proliferation whereas several single amino acid mutants lacked significant activity. Neither wild-type ETA nor any single amino acid mutants were proteolytic for a casein substrate, yet esterase activity was detected in wild-type ETA and several mutants, but eliminated in other mutants. A mutation in aa 164 (Asp to Ala) showed a 9-fold increase in esterase activity as well. Finally, we correlated esterase activity with epidermolytic activity. All mutants that lost esterase activity also lost epidermolytic activity. Conversely, mutants that retained esterase activity also retained exfoliative activity, implicating serine protease or serine protease-like activity in the causation of SSSS. Moreover, the mutants that displayed markedly reduced T cell superantigenic activity retained their epidermolytic activity (although some of these mutants required higher doses of toxin to cause disease), which suggests an ancillary role for this activity in SSSS causation.

Chronic staphylococcal scalded skin syndrome.

Staphylococcal scalded skin syndrome (SSSS), not previously recorded as a chronic disease, persisted for 2 years in a 50-year-old woman with epilepsy and cerebellar ataxia. Lesions initially suggestive of erythema multiforme and toxic epidermal necrolysis evolved over 2 years into those typical for SSSS, with extensive erosions and subcorneal blisters, showing an epidermal split at the granular cell layer. Exfoliatin A-producing phage I-III Staphylococcus aureus, previously linked only to acute mild adult cases of SSSS, was cultured from purulent discharge in the patient's eyes, ears and open skin lesions. The roles of epilepsy and antiepileptic medications are discussed as possible predisposing factors.

[Immunological investigations on pathogenesis of staphylococcal scalded skin syndrome].

Staphylococcal exfoliative toxin (ET) is an extracellular product of Staphylococcus aureus isolated from patients with staphylococcal scalded skin syndrome (SSSS) which includes Ritter's disease, bullous impetigo and staphylococcal scarlet fever, and has been regarded as the causative agent of SSSS. The ET has not only a splitting effect at the granular layer of skin in human and mice but also an immunogenicity to human and mice. Using experimental animals and clinical specimens of patients with or without SSSS, the immunological investigation were performed and following results were obtained. 1) When some inbred and congenic resistant strains of mice were immunized with serotype A ET (ETA), they were divided into the high anti-ETA antibody producers (high responders) and the low responders. The gene controlling antibody response to ETA in mice is located in the I-A subregion in the major histocompatible complex (H-2 complex), and its function seems to be at least related to antigen recognition at the T-lymphocyte level. 2) Neonatal mice are generally susceptible to ETA regardless of their H-2 haplo-type. However, the neonatal mice born to a high-responder mother immunized with ETA were resistant to the subcutaneous challenge of ETA, but those born to an immunized low-responder mother were susceptible to the challenge. 3) The relationship between susceptibility and immune response to ETA in some mammalians could be divided into three groups: the possession of resistant skin and high production of antibody to ETA (rabbits and rats); the possession of resistant skin and low production of antibody to ETA (golden hamsters and guinea pigs); the possession of sensitive skin and various titers of antibody to ETA (humans and mice). 4) The incidence of ET producing strains of Staphylococcus aureus in various clinical specimens obtained from patients without SSSS was 12% (50 out of 418 strains) in our epidemiological investigation. The percentages of antibody to ETA in sera obtained from healthy males and females were 23% and 29%, respectively. Eventually, ET-producing strains of Staphylococcus aureus seem to be spread out wider than the microbiological result obtained from clinical specimens. 5) The mitogenic responses of lymphocytes isolated from patients with the first impetigo could be measured by using PHA, and the five-of them were in the low range, whereas lymphocytes from patients with recurrent impetigo were in the normal range on this survey. Maybe this results suggest the T lymphocyte functions of some patients with impetigo are deteriorated.(ABSTRACT TRUNCATED AT 400 WORDS)

Staphylococcal scalded skin syndrome in an adult. Influence of immune and renal factors.

We report a case of staphylococcal scalded skin syndrome in a 77-year-old man with an infected surgical wound. The patient was immunocompetent and had only mildly impaired renal function. The pathogenic and aetiological factors of the condition are discussed.