Review
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CONTENTS
Historical overview
Clinical features
Diagnostic criteria &
differential diagnosis
Natural history
& susceptibility
Treatment, prognosis
& prevention
Microbiology of SSSS
Molecular basis of SSSS
Five-year view: the
unanswered questions
Expert opinion
Key issues
References
Affiliation
Department of Dermatology,
University of Wales College of
Medicine, Heath Park, Cardiff
CF14 4XN, UK
Tel.: +44 292 074 7747
Fax: +44 292 074 5161
patelgk@cf.ac.uk
KEYWORDS:
blistering disease, dermatitis
exfoliativa neonatorum,
desmoglein-1, drug therapy,
epidermolytic toxin, exfoliative
toxin, Gram-positive bacterial
infections, Ritter’s disease,
staphylococcal scalded skin
syndrome, Staphylococcus aureus
www.future-drugs.com
Treatment of staphylococcal
scalded skin syndrome
Girish K Patel
Humans are a natural reservoir for Staphylococcal aureus. Colonization begins soon
after birth and predisposes to infection. S. aureus is one of the most common causes of skin
infection, giving rise to folliculitis, furunculosis, carbuncles, ecthyma, impetigo, cellulitis
and abscesses. In addition, S. aureus may cause a number of toxin-mediated
life-threatening diseases, including staphylococcal scalded skin syndrome (SSSS).
Epidermolytic toxins released by certain S. aureus strains cause SSSS by cleaving the
epidermal cell adhesion molecule, desmogelin-1, resulting in superficial skin erosion.
Recent experiments have revealed similarities in the pathophysiology of SSSS and
pemphigus foliaceus, an autoimmune disorder that is characterized by antibodies
targeting the same epidermal attachment protein. SSSS typically affects neonates and
infants but may also occur in predisposed adults. It is painful and distressing for the
patient and parents, although most cases respond to antibiotic treatment.
Mortality is low in infants but can be as high as 67% in adults, and is dependent on the
extent of skin involvement and the comorbid state. Thus, the management of adults who
develop SSSS remains a major therapeutic challenge. The antibody response against the
toxins neutralizes their effect and prevents recurrence or limits the effects to the area of
infection, which is known as bullous impetigo.
Expert Rev. Anti-infect. Ther. 2(4), 575–587 (2004)
Staphylococcus aureus, a member of the after birth; approximately 30% of newborns
micrococcaceae family, is a Gram-positive are colonized with S. aureus within their first
coccus that can be distinguished from other week of life and this may rise in to 90% dur-
staphylococci by its ability to form golden ing S. aureus epidemics [5,6]. S. aureus coloni-
colored colonies and test positive for coagu- zation is associated with a greater risk of infec-
lase, mannitol-fermentation and deoxyribo- tion [7] and is more common amongst atopics
nuclease [1]. In addition, S. aureus can be [8], diabetics [9], intravenous drug users [10],
subdivided into 11 serotypes based upon the HIV sufferers [11], and those receiving renal
composition of the antiphagocytic polysac- dialysis [12]. The incidence of S. aureus infec-
charide microcapsule. Serotypes 5 and 8 are tion is increasing; it is currently amongst the
responsible for three-quarters of all human most common causes of skin infection, and
S. aureus infections [2]. despite the development of antibiotics, it is
Humans are the natural reservoir for associated with morbidity and mortality in all
S. aureus, which frequently colonizes the skin, age groups [13–16].
in particular the anterior nares from where it Staphylococci produce various enzymes to
can invariably be isolated if enrichment tech- destroy tissue and facilitate the spread of
niques are used [3]. Using conventional tech- infection, such as proteases, lipases and
niques and serial nasal sampling of healthy hyaluronidase. In addition, staphylococci
nurses, Hutchinson and colleagues found that produce numerous toxins secreted during
20% were persistent carriers, 60% intermit- the stationary phase of bacterial division,
tent carriers and 20% appeared resistant to which are characterized according to their
nasal carriage [4]. Colonization begins soon mechanism of action. The α-toxin results in
© Future Drugs Ltd. All rights reserved. ISSN 1478-7210 575
Patel
cell wall pore formation within the mammalian cell and
induces a proinflammatory response that manifests as septi-
cemia [17]. The enterotoxins are superantigenic pyrogenic
toxins that induce T-cell proliferation and cytokine release
by binding to major histocompatibility complex class II pro-
teins. They include toxic shock syndrome protein 1, entero-
toxin B and C, which manifest as toxic shock syndrome and
food poisoning, respectively [18]. The exfoliative toxins
include epidermolytic toxins (ETs)-A and -B, which cause
skin separation and erythema and are responsible for both
bullous impetigo and staphylococcal scalded skin syndrome
(SSSS) [19].
Historical overview
Von Rittershain was the first to describe SSSS in 1878 as a
disease of the newborn that he called dermatitis exfolitiva
neonatorum [20]. Later it was referred to as Ritter’s disease and
is now known as SSSS. Over a 10-year period in a Prague hos-
pital, von Rittershain observed 297 cases [20]. Later in that dec-
ade, Almquist established the link between SSSS and S. aureus,
which he called micrococcus pemphigi neonatorum [21].
Improvements in standards of hygiene have led to a steady
decline in the incidence of SSSS since the initial description.
In 1956, Lyell erroneously grouped SSSS together with a
new disease, characterized by epidermal necrosis caused by a
circulating toxin, for which he coined the term toxic epider-
mal necrolysis (TEN) [22]. The prominence of Lyell within the
field of dermatology at that time perpetuated the confusion
and resulted in a number of publications describing SSSS but
erroneously called TEN [23–27]. However, the evidence of a
causal association between SSSS and S. aureus continued to be
apparent, even Lyell in his review of 128 cases described how
the disease in children under 10 years of age was often associ-
ated with S. aureus infection [24,28]. Later, Lyell accepted
responsibility for his error in grouping TEN and SSSS
together in a published historical perspective on SSSS [29].
Figure 1. Staphylococcal scalded skin syndrome often affects the face with superficial periorbital
erosions. Sometimes conjunctivitis is also present, which is a frequent source for the identification of the
causative organism [COURTESY OF C MILLS, ROYAL GWENT HOSPITAL, NEWPORT, UK].
576
In 1970, the landmark studies by Melish and Glasgow
established SSSS as being caused by an ET released by
S. aureus [19,30,31]. They showed that passive transfer of
S. aureus cultured supernatant derived from patients with
SSSS into neonatal mice caused superficial epidermal blister-
ing within the granular layer of the skin, the same as seen in
humans with SSSS. By doing so, they successfully created an
animal model. These findings were reproduced by a number of
other researchers [32,33]. The toxin responsible for SSSS was
subsequently isolated and when injected into newborn mice
peritoneum, blistering was observed in a dose-dependent man-
ner [34]. Interestingly, mice 5 days or older were not suscepti-
ble to blistering and demonstrated suppressed serum levels of
epidermolytic exotoxin [19,31,35].
The first adult case of SSSS was described in 1972 [36]. Adult
onset SSSS is a rare disorder, although there are now over
50 documented cases, it is almost always observed in individuals
who are susceptible to S. aureus infection [37].
A century after the initial clinical description of SSSS, it is
only now understood, at the dawn of a new millennium, how
the S. aureus-derived ETs cause the disease. Through a series
of elegant experiments, Amagai and colleagues clearly demon-
strated how the toxin selectively targets and cleaves desmo-
glein (DG)-1, an important epidermal cell–cell attachment
protein [38–41].
Clinical features
SSSS is a dramatic, rapidly progressing and painful disease that
is frightening for both the child and parents. It usually begins
with a short prodrome of malaise, restlessness and fever in asso-
ciation with a sore throat or conjunctivitis; then skin lesions
appear. The conjunctivitis can be severe, with periorbital edema
and purulent discharge (FIGURE 1).
Within 48 h the malaise and fever worsen. Extremely tender
erythematous patches develop, most commonly affecting the
face, neck, axilla and perineum (FIGURE 2). Within these ery-
thematous areas, the skin is extremely fri-
able and flaccid bullae develop that easily
rupture to reveal moist, glistening ery-
thematous skin resembling a scald. The
flexural distribution of the skin lesions
makes any movement extremely painful,
causing patients to develop a fixed pos-
ture. Over the subsequent days the area
of skin affected gradually increases, as
does the pain and discomfort. In general,
the skin is extremely fragile and shears
easily, displaying a positive Nikolsky sign
[42,43]. In most cases the disease is self lim-
iting, although with appropriate antibiot-
ics given through a parentral route,
improvement in fever, discomfort,
demeanor and then skin can be evident
within days. Re-epithelialization thereafter
is rapid and scarless.
Expert Rev. Anti-infect. Ther. 2(4), (2004)
 Staphylococcal scalded skin syndrome

A localized variant of the disorder has been described on a

number of occasions [44–46]. In one case, a 72-year-old woman
developed exfoliation limited to her left flank [46], whilst in a
second case a 54-year-old man developed erosions limited to
his right arm and upper chest [44].
Skin histology reveals separation of epidermal cells just
beneath the uppermost horny layer, within the granular cell
layer (FIGURE 3). The cells in this region appear to lose con-
nection with each other (acantholysis), reminiscent of a
dilapidated brick-wall, with no sign of cell necrosis [47].
There is also an absence of inflammatory cells or microbes
within the epidermis.

Diagnostic criteria & differential diagnosis

The diagnosis of SSSS is based on clinical features, histology,
immunofluorescence and microbiological findings [37,48,49]:
• Skin tenderness, erythema, desquamation and/or the
formation of bullae
• Histogical evidence of intraepidermal acantholysis within
the granular cell layer
• Negative direct and indirect immunofluorescence for
immunoglobulins targeting the epidermis
• Isolation of S. aureus producing an ET
Prior to the formation of skin blisters and erosions, the clinical
features of SSSS may resemble Kawasaki’s disease, toxic shock
syndrome, scarlet fever, viral exathama and drug eruptions, as
well as TEN, in which blistering of the skin may also occur.
TEN is usually a manifestation of an adverse drug reaction and
in contrast to SSSS, tends to occur in isolated cases in those over Figure 2. Characteristically, the disease affects the flexures. The
20 years of age where there is usually a clear history of prior drug involved skin shears easily, revealing a painful erythematous base.
ingestion. The skin lesions in TEN are also tender, but involve Superficial blisters may be evident and exhibit a positive Nikolsky sign.
acral sites and mucous membranes. TEN is clearly distin- Often uninvolved skin also shears easily, which can result in iatrogenic
injury from the application of adherent dressings such as those that may
guishable from SSSS by conventional histology. In TEN there
be used to maintain intravenous canuli [COURTESY OF C MILLS, ROYAL
is full thickness epidermal necrosis, whilst in SSSS, epidermal GWENT HOSPITAL, NEWPORT, UK].
detachment occurs at the uppermost layer [50].
In the presence of blistering, SSSS should be distinguished
from bullous impetigo and pemphigus (in particular the variant Natural history & susceptibility
pemphigus foliaceus). In contrast to SSSS, bullous impetigo is Despite the high prevalence of ET-producing S. aureus in up to
caused by a direct innoculum of S. aureus that results in a local- 25% of S. aureus isolates, there appear to be a number of other
ized but not systemic release of S. aureus exfoliative exotoxin and factors necessary for the development of SSSS [52,53]. For exam-
therefore, localized blistering. Upon rupture, the blister oozes ple, healthy adults rarely develop SSSS and currently only five
serous exudates that gives rise to an adherent golden-yellow such cases have been reported [49,54–56].
crust that is rich in bacteria. The surrounding skin in bullous An explanation for this rarity is the formation of antibodies
impetigo is inflamed, reflecting the acute localized inflammatory against the ETs that protect against the effect of the toxins;
response (FIGURE 4), which, histologically, is neutrophil rich indeed, 91% of adults have antibodies to ET-A [35]. However,
(FIGURE 5). Subcorneal immunoglobulin (Ig)A pemphigus and antibody levels are detectable in only 30% of babies aged
pemphigus foliaceus are autoimmune disorders characterized by 3 months to 2 years, but then rise steadily so that at 2 to
antibodies that target epidermal proteins within the upper layers 5 years, 42% have ET-A antibodies, and over the age of
of the epidermis and similarly cause a split along the granular 40 years, 91% have antibodies [35]. These findings are compati-
cell layer. Both conditions are associated with positive direct ble with the clinical observation of SSSS predominantly affect-
immunofluorescence and a dermal lymphocyte rich inflamma- ing young children and rarely adults. Toxins are initially absent
tory cell infiltrate, helping to distinguish them from SSSS. In in patients with SSSS antibodies against the ETs but are present
pemphigus foliaceus, the target antigen is also DG-1, whereas in in the convalescent sera [57–59]. Therefore, this theory would
subcorneal IgA pemphigus the antigen is desmocollin-1 [51]. explain why SSSS tends not to reoccur. In fact, there are only

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Patel
three reported cases of recurrent SSSS [60,61]. The first case was in
a 50-year-old woman, with epilepsy and cerebellar ataxia, who
had repeated episodes of SSSS over 2 years [60]. The second and
third cases were in two male siblings aged 5 and 12 years old
who had localized SSSS that reoccurred once, within 12 months
[61]. It is unclear if these patients had or were able to mount an
antibody response to the S. aureus ETs. In contrast to SSSS,
patients with bullous impetigo have circulating antibodies
throughout the illness [35].
The severity of SSSS is closely related to the amount of
circulating ETs and at very high concentrations may be enough
to overcome the protective effects of circulating antitoxin anti-
bodies [39,62]. Thus, adults who develop SSSS often have severe
S. aureus infection with a high ET production and an inability
to mount a sufficient immune response [63]. Frequently, and
not surprisingly, adult SSSS develops in individuals who have a
suppressed immune system, caused by:
• An inherited defect in the immune system [44]
• HIV [64–68]
Figure 3. Skin histology from a perilesional skin biopsy. Acantholysis
can be seen within the granular cell layer, in the absence of inflammatory
cells or microbes within the epidermis.
578
• Immunosuppressant drugs [69–71]
• Malignancy [47,69,72–74]
• Chronic alcohol abuse [72,75]
• Heroin addiction [76]
• Severe sepsis [72,77]
Many of these cocontributory conditions are also associated
with an increased risk of S. aureus colonization that increases
the likelihood of ET-secreting S. aureus infection [4,7–12].
Melish and colleagues were able to clearly demonstrate, using a
mouse model, that the development of SSSS is dependent on age
[19,30,31]. In their study, they showed how only neonatal mice
under 5 days of age developed the disease after subcutaneous or
intraperitoneal inoculation with S. aureus derived from SSSS
patients. In their attempt to explain this phenomena, prior to the
discovery of epidermolytic exotoxin or antibodies against them,
they went on to show that the toxins were unaffected by liver
metabolism and excreted by the kidney. Healthy adult kidneys
were able to excrete the toxin burden more efficiently than those
of neonatal mice, 33 versus 7% within the first 3 h, respectively
[78]. Moreover, adult mice could be induced to develop SSSS after
nephrectomy [78], explaining why the majority of adults who
develop SSSS have renal impairment often requiring dialysis
[36,54,64,75,79–84]. Patients with renal impairment also have much
higher rates of S. aureus colonization, in particular those receiving
dialysis, and are also at greater risk of inoculation from invasive
procedures or investigations [12,85].
Rarely, otherwise healthy adults have developed SSSS whilst
taking nonsteroidal anti-inflammatory drugs (NSAIDs), possibly
due to impaired renal excretion of the ET [86,87]. The concurrent
administration of NSAIDs has also been shown to aggravate dis-
eases caused by other S. aureus toxin, such as toxic shock syndrome
toxins and α-toxin [88]. In these diseases it is believed that NSAIDs
potentiate the disease by modulation of cytokine release.
Treatment, prognosis & prevention
SSSS should be subdivided based upon the extent of body
surface affected into:
• Mild (≤10%)
• Moderate (≤20%)
• Severe (>20%)
In all cases, early diagnosis, assessment and prompt treatment
with an appropriate parenteral antistaphylococcal antibiotic are
essential for the successful management of SSSS [54].
Mild disease is the most common presentation. Such
patients are best managed with strict isolation and barrier nurs-
ing to prevent crossinfection. Prompt administration of antibi-
otics, either through oral or parentral routes should begin as
soon as SSSS is clinically suspected and prior to confirmation
of the diagnosis by microbiology, histology and immunofluo-
rescence. Topical administration of antibiotics is ineffective,
since the focus of infection is usually not known and often dis-
tant to the site of blistering. All reported strains of S. aureus
associated with SSSS have been penicillin-resistant, but are
Expert Rev. Anti-infect. Ther. 2(4), (2004)
 Staphylococcal scalded skin syndrome

usually sensitive to semisynthetic penicillin,

although the choice of which antibiotic
to use should be based on local knowl-
edge of antibiotic resistance [19,31]. As
SSSS is an extremely painful condition,
adequate analgesia should not be over-
looked. The choice of analgesia is based
on the needs of the patient and opiates
are preferred to NSAIDs. Blisters should
be left intact and eroded skin treated with
an emollient or covered with Vaseline®
(Elida Fabergé Ltd) impregnated gauze to
maintain the skin barrier function, as
well as reduce further skin trauma. Anti-
septics, such as those combined with
emollients, can be employed to reduce
secondary colonization. Sulphdiazine
should be used with caution when the
body surface area involved is greater than
5%, due to the risk of systemic absorp-
tion of silver. If there is conjunctivitis,
the eyes should be cleansed regularly and
a topical antibiotic applied. Once fever
and discomfort have subsided, no new
blisters develop and existing affected
areas show signs of re-epithelialization,
antibiotics can safely be administered
Figure 4. Bullous impetigo, in contrast to staphylococcal scalded skin syndrome, is
orally. Treated correctly, the mortality characterized by local inflammatory blisters that are also fragile. Blisters rupture easily, leaving
rate for mild-to-moderate disease should an adherent golden yellow crust.
be negligible. Corticosteroids, adminis-
tered either by the oral or topical route, are associated with a requirement based on burn injury data, and these should be strictly
worsening of the disease and so are contraindicated in the adhered to [91]. The eroded skin and intravenous access can act as
management of SSSS [30,89,90]. portals of secondary infection and sepsis. There should be regular
In addition to the management strategy mentioned above, use of antiseptics, careful monitoring of patients for sepsis and a
additional factors need to be addressed when the area of skin low threshold for broadening the antibiotic spectrum. Immobility,
involvement is greater than 10%: the presence of moisture, loss of skin barrier, poor nutritional status
• Consider admission to an intensive care unit and potential shearing forces all increase the risk of pressure sores.
• Infection risk assessment and management Appropriate measures to address the risk factors for pressure injury
should be instituted, including good nursing care, regular turning
• Temperature regulation
of the patient, adequate nutrition and the use of an appropriate
• Fluid management
pressure-relieving mattresses. The mortality in childhood SSSS is
• Pain management approximately 4% and usually occurs when there is extensive skin
• Nutritional care involvement, overwhelming sepsis and a resultant electrolyte
• Skin care imbalance [50].
• Mattress requirement Management of adult-onset SSSS remains a major medical
In severe disease there is loss of the skin barrier function, challenge. The mortality rate in adult onset SSSS is over 60%
akin to a burns injury. Indeed, many patients with extensive SSSS [37,54,89]. In addition to the measures mentioned so far, there is a
are managed in burns units [91]. Thermal dysregulation is com- need to identify and treat the focus of infection as well as managing
mon, although the patient is febrile, peripheral vasodilatation adds the predisposing disease. The most common cofactors leading to
to loss of heat and may cause a drop in the core temperature. The the development of adult SSSS are severe sepsis, immunosuppres-
core temperature and room temperature need to be monitored sion and renal impairment. The choice of antibiotics should be
carefully and alteration in room temperature made to compensate broadened to treat both penicillinase resistance, as well as the possi-
for changes in core body temperature. Fluid loss can also be con- bility of methicillin resistance, thus ciprofloxacin, gentamicin, van-
siderable during such illness and needs to be replaced by either oral comycin (Vancocin®, Eli Lilly, Ltd.) and clindamycin
or parenteral route. There are set criteria for managing fluid (Dalacin C®, Pfizer Ltd) should be considered. Many of these

www.future-drugs.com 579
Patel

In a study of pregnant women attending

an antenatal clinic, 1% were asympto-
matic carriers of exfolitative toxin secret-
ing S. aureus, from nose, axilla and peri-
neal swab cultures [99]. In another study,
3% of neonates were asymptomatic carri-
ers [52]. In children, transmission of exfo-
liative toxin-producing S. aureus is by
asymptomatic carriers, such as nursery
attendants and parents [5,100]. Exfolita-
tive toxin-secreting S. aureus have even
been cultured from animals and inani-
mate objects, although whether this has a
direct relationship with the development
of SSSS is unknown [101,102]. Despite
such high colonization and exposure
rates, SSSS is relatively uncommon.
In addition to these potential sources of
infection for neonates and children, SSSS
has been attributed to exfoliative toxin-pro-
ducing S. aureus infection from passage
Figure 5. The histology of bullous impetigo is characterized by acantholysis within the granular
through the maternal vaginal flora during
cell layer, associated with a heavy neutrophilic infiltrate. birth [103], and maternal breast abscesses
during breastfeeding [104]. Outbreaks of
SSSS within neonatal baby units have been
antibiotics have the added advantage of having good tissue attributed to asymptomatic carriage of S. aureus by staff on a
penetration and inhibiting bacterial protein synthesis, including number of separate occasions [92,93,105,106].
production of the exfoliative exotoxins. The focus of S. aureus infection causing SSSS in children is
Where there is a risk of an SSSS outbreak, such as in a neonatal often not clinically overt, except in cases where conjunctivitis is
unit or maternity ward, simultaneous screening for carriers present. The skin blister is sterile and only 3% of children have a
should be undertaken [5,92,93]. Swabs from the anterior nares, positive blood culture [54]. In contrast, SSSS in adults is associated
throat, axilla, perineum and any eroded skin should be taken with a more obvious focus of S. aureus infection, including cardiac
from all potential asymptomatic carriers. It is not uncommon catherization [55,77], abscesses [36,72], septic arthritis [54,72], infected
to find more than one carrier. Carriers should be withdrawn arteriovenous shunt [64,80] and parenteral injection [77]. The source
from looking after those at risk of SSSS and treated along simi- of infection is not apparent in all cases, although S. aureus can be
lar lines to carriers of methicillin-resistant S. aureus (MRSA). identified from blood culture in most adult cases of SSSS [54].
However, in the case of SSSS, carriers have been successfully Most cases of SSSS in Europe and the USA are caused by
treated with oral β-lactamase resistant semisynthetic penicillins, S. aureus phage group II [107]. Phage group II strains are character-
such as flucloxacillin (Floxapen®, GlaxoSmithKline) [94]. ized by their ability to make serum agar opaque, produce a nega-
tive egg-yolk reaction and cause a zone of inhibition when cul-
Microbiology of SSSS tured alongside Corynebacterium diphtheriae [108]. SSSS is usually
Approximately 3% of all S. aureus isolates cultured in a hospital associated with S. aureus phage group II serotypes 3A, B and C,
laboratory secrete exfoliative exotoxins [53]. In most clinical sce- 55 and 71 [19,109]. Infrequently, SSSS is caused by S. aureus phage
narios, phage typing of S. aureus is sufficient to aid diagnosis of groups I and III [105,110]. There appears to be great geographical
SSSS, particularly in Europe and the Americas, where phage variation in the phage groups causing SSSS [102,107,110]. Although
Type II is the most common cause. A number of methods are SSSS has occasionally been associated with MRSA strains, MRSA
now available to determine the presence of S. aureus that pro- is usually associated with phage Type V [111,112].
duces exfoliative exotoxins, of which the newborn mouse assay is As alluded to above, SSSS is caused by systemic circulation
still considered the reference test [31]. There are now a number of of the epidermolytic exotoxin, leading to a generalized erup-
immunological methods for accurate characterization of the exfo- tion [19]. The same exotoxins are responsible for the localized
liative exotoxins that include double immunodiffusion, slide latex blistering seen in some cases of SSSS and also bullous
hemagglutination, radioimmunologic assay, enzyme-linked immu- impetigo [39]. The major factor that determines which of
nosorbent assay and DNA hybridization [95–97]. However, even these clinical presentations manifests is dependent upon the
greater accuracy can be achieved by the use of specific polymerase effectiveness of antitoxin antibodies in limiting the systemic
chain reaction-generated probes to the exotoxin genes [98]. effects [35].

580 Expert Rev. Anti-infect. Ther. 2(4), (2004)


Table 1. There are at least five ETs identified thus far. Of these, ET-A and -B are known to cause SSSS and bullous impetigo
in humans.
ET Host Frequency Origin Molecular Heat
mass
(kDa)
ET-A Human Common S. aureus 30,000
ET-B Human Common S. aureus 29,500
ET-C Horse ? S. aureus 27,000
ET-D Human Unlikely, as yet not identified S. aureus 27,000
in SSSS or bullous impetigo
ShET Piglets ? S. hyicus 27,000
ET: Epidermolytic toxin; S. aureus: Staphylococcus aureus; ShET: S. hyicus ET; S. hyicus: Staphylococcal hyicus; SSSS: Staphylococcal scalded skin syndrome.
Currently, five different ETs have been identified (TABLE 1,
FIGURE 6): ET-A, -B, -C and -D and Staphylococcus hyicus
(Sh)ET [105,105,110,113–117]. Of the ETs mentioned, only ET-A
and -B are known to cause SSSS and bullous impetigo in
humans. The nucleotide sequences of both ET-A and -B have
been established [110,118,119], their respective genes have been
sequenced [119–121] and the ET-A gene has been cloned in
Escherichia coli [122]. ET-A is the most commonly secreted
toxin, is a heat stable protein, is encoded on the bacterial chro-
mosome and is produced by 89% of isolates [113]. ET-B is a
plasmid-derived heat labile protein, which is produced by 4%
of isolates [113]. In approximately 17% of S. aureus from
patients with SSSS, ET-A and -B are cosecreted [113]. There are
geographic differences in the incidence of the different strains
of S. aureus. In Japan, S. aureus appears to secrete ET-B rather
than ET-A. Furthermore, the prevalence of ET-B secreting
S. aureus appears to be increasing [95,105,123].
Molecular basis of SSSS
Recently, the target antigen for ET-A, -B and -D has been
identified as the epidermal cell attachment protein DG-1
[38,41,116]. DG-1 has been suspected to be the target antigen
for the exfoliative exotoxins due to the histological and clini-
cal similarities between SSSS and pemphigus foliaceus
[38,124]. Although DG-1 is expressed throughout the epider-
mis, in the lower epidermis DG-3 is coexpressed and is able
to compensate for the loss of DG-1 function (FIGURE 1) [125].
In a series of experiments, Amagai and colleagues showed
DG-1 to be the target antigen for ET-A [38]. Through the
injection of ET-A into neonatal skin, followed by direct
immunofluorescence on skin epidermis using antibodies that
target DG-1 and -3, the authors observed reduced, disrupted
and cytoplasmic staining of DG-1 instead of the normal
membrane staining. In contrast, the DG-3 staining pattern
remained normal. Human keratinocytes adult skin epider-
mis, calcium reduced level, temperature elevated (HaCaT)
cells were then transfected with cDNA encoding mouse DG-
1 and -3, containing a flagellar antigen (FLAG) octapeptide
epitope on its carboxyl termini. The transfected cells were
www.future-drugs.com
Staphylococcal scalded skin syndrome
Genetic Mouse model
sensitivity control
Heat stable Chromosome Causes intraepidermal split
Heat labile Plasmid Causes intraepidermal split
Heat labile Chromosome Causes intraepidermal split
Heat stable? Chromosome Causes intraepidermal split
Heat labile ? Does not cause intraepidermal split
then incubated with ET-A and western blot analysis with
antibodies against the FLA G peptide revealed degradation
of DG-1, but not the closely related DG-3. Subsequently,
neonatal mice were injected with ET-A and western blot
analysis was used for DG-1, -3 and other epidermal cadher-
ins on the skin extracts of superficial blisters. This showed
degradation of DG-1 only, revealing a cleaved 113 kDa frag-
ment instead of the normal 160 kDa. ET-B and -D have
been shown to similarly cleave DG-1, with an identical
cleavage product [116,126].
It has been believed for some time that ETs are proteolytic
enzymes that cause epidermal separation through cleavage of
attachment molecules. Indeed, early studies demonstrated
structural similarities to the staphylococcal V8 serine pro-
tease, a trypsin-like serine protease, with sequence homology
to the active site a serine–aspartic acid–histidine catalytic
triad [134]. Mutational analysis of the ET showed that substi-
tution of any one of the three central amino acids resulted in
complete loss of their biological activity, when injected into
newborn mice [127]. Later, computer modelling [128] and crys-
tallography [129] of the three dimensional structure revealed a
high degree of similarity with known glutamate specific
trypsin-like serine proteases. After Amagai and colleagues had
identified DG-1 as the target of the ETs, they went on to
show that the cleavage site of DG-1, as determined by protein
0.423 ShET-A
0.158
0.087 0.171 ShET-B
ORF1
0.134 0.202
ET-B
0.291
0.476 ET-A
ET-C
Figure 6. Phylogenetic tree. Using pair-wise analysis to calculate a
distance matrix, Yamaguchi and colleagues have proposed a phylogenetic
tree illustrating the relationships between the different ETs. The distance is
equal to the number of exact matches divided by the overall nucleotide
sequence length, using a conventional 0.05 scale [116].
ET: Epidermolytic toxin; ORF: Open reading frame;
ShET: Staphylococcus hyicus ET.
581
Patel
sequencing of the resultant cleaved products, was consistent with
specific cleavage at glutamic acid residue 381 [38,39]. This cleavage
site is located between the third and forth extracellular domains,
and mutation of the predicted site completely inhibited cleavage
[39]. Furthermore, the group went on to demonstrate dose-
dependent cleavage of the extracellular domain of mouse and
human DG-1 [38,39]. The proteolytic activity of ET-A is depend-
ent upon a calcium binding mechanism that can be inhibited by
ethylenediaminetetra-acetic acid (EDTA) [130]. Based upon struc-
tural studies of the DG cadherin protein family, calcium binding,
which stabilizes the rigidity and orientation of the protein, has
been shown to be critical [131]. Therefore, it can be assumed that
the presence of calcium within the DG complex facilitates prote-
olysis. Also, if proteolysis was to impair the ability of DG to bind
calcium, this would lead to the functional loss of DG-1 and
therefore cell separation would occur. However, it remains
unclear why in vitro and in vivo studies using protease inhibitors
have failed to prevent epidermolysis [50].
Five-year view: the unanswered questions
The comparison between pemphigus foliaceus and SSSS has
many virtues and clearly there are important overlaps, includ-
ing sharing the same antigenic target, DG-1. However, further
experimentation is needed to elucidate the obvious differences
that exist between SSSS and pemphigus foliaceus (TABLE 2).
One central question that remains to be addressed is how
SSSS targets neonates, when our current understanding of the
pathophysiology would suggest that two independent proc-
esses protect neonates. Firstly, in approximately 90% of new-
borns, cord blood samples contain effective antitoxin anti-
bodies, as part of the maternal transfer of immunoglobulin
protection [132]. Maternal antibodies are usually present for up
to 6 months, yet SSSS is still able to occur within this period.
The second factor is based upon the DG compensation the-
ory, derived from our understanding of pemphigus, which sug-
gests that the presence of DG-3 protects the lower epidermis
Table 2. PF autoantibodies and SSSS ETs disrupt the desmosomal cell–cell attachment complex by binding to DG-1.
Both result in superficial blistering disease in humans and when injected into mice. Important differences remain
despite the obvious overlap in pathogenesis, some of which can be explained by the presence of antibodies against ETs
that prevent SSSS from developing.
PF, caused by autoantibodies
Neonate
Mouse Blistering, due to adult pattern DG expression
Human No blistering, due to epidermal DG-3 expression
Child or adult
Mouse Blistering
Human Blistering
DG: Desmoglein; ET: Epidermolytic toxin; PF: Pemphigus foliaceus; SSSS: Staphylococcal scalded skin syndrome.
582
and mucosa from also undergoing epidermal cell detachment
(FIGURE 7).This theory is used to explain why maternal anti-
body transfer containing the pemphigus vulgaris autoanti-
body (targeting DG-3) can cause neonatal pemphigus vul-
garis, but that maternal transfer of the pemphigus foliaceus
autoantibody (targeting DG-1) is unable to cause neonatal
pemphigus foliaceus (FIGURE 3). Wu and colleagues found that
neonatal skin expresses DG-3 throughout the epidermis,
which would protect against the development of neonatal
pemphigus foliaceus [133]. Yet it appears that neonates are not
protected against the development of SSSS.
It also remains to be determined how and why NSAIDS
and corticosteroids, administered either by the topical or
oral route, are detrimental in SSSS and not in pemphigus
foliaceus. It is hoped that over the next 5 years the answers
to these questions will greatly enhance our knowledge of the
pathogenesis of SSSS.
Expert opinion
In conclusion, a century after von Rittershain described SSSS,
our understanding of the cause and management of this devas-
tating condition has come a long way. However, over and above
the theory, SSSS remains a dramatic, painful experience for
patients and parents. Appropriate management with antibiotics
and supportive care, including analgesia, is essential, whilst tak-
ing care to avoid cross infection. When the affected body sur-
face area of skin exceeds 25%, supportive care needs to consider
fluid loss, temperature dysregulation and nutritional needs. In
all cases, good nursing care is needed to minimize the discom-
fort associated with this condition. Corticosteroids should not
be used, as they clearly have a detrimental effect.
The advent of improved hygiene and effective antibiotic
therapy has dramatically altered the prognosis for children
suffering with SSSS. However, there remain individuals for
whom antibiotics alone are not effective, in particular adults
with SSSS where the prognosis remains grim. For this group,
SSSS, caused by ETs
Blistering
Blistering, despite epidermal expression of DG-3 and maternal
transfer of antitoxin antibodies
No blistering
No blistering, believed to be due to presence of
antitoxin antibodies
Expert Rev. Anti-infect. Ther. 2(4), (2004)
 Staphylococcal scalded skin syndrome

Adult Oral mucosa Neonate Mice

Normal
DG-3
and DG-1

DG-3 and
low/absent
DG-1

DG-1 and
low/absent
PV
DG-3

Hemidesmosomes
binding to the basement
membrane zone

PF

SSSS

Figure 7. The basis of blistering in SSSS and PF has been explained by the distribution of DG proteins and the DG compensation theory. However,
important differences between the two conditions remain that are not easily explained by this theory. As epidermal cells differentiate and pass through the
various layers of the epidermis, the composition of the desmosomal complexes binding them together changes. Within the lower layers of the adult epidermis
DG-3 is predominantly expressed. But with each successive subsequent layer of the epidermis, expression of DG-3 diminishes, whilst there is a reciprocal increase
in the expression of DG-1. In contrast, in the oral mucosa, DG-1 is not expressed within the lower layers, but beyond this both types of DG are expressed. In
contrast, in neonatal skin and that of the mouse, both DGs are expressed throughout.
The DG compensation theory was put forward to explain the differences in epidermal involvement between PV and PF. The theory supposes that where both DGs
are present, disruption of one DG does not result in blister formation, due to the presence of the remaining DG that maintains the integrity of the desmosomal
complex. In early PV, when only autoantibodies against DG-3 are present, blistering occurs only within the oral mucosa. If autoantibodies develop against both
DGs, then the skin also becomes involved. Neonates born to mothers with cutaneous PV also develop blisters that result from maternal transfer of IgG antibodies.
Furthermore, there is a mouse model of PV. On the other hand PF, a disorder characterized by autoantibodies against DG-1, only affects adults. The oral mucosa,
neonatal skin and mouse skin is protected against developing blisters due to DG-3 coexpression. Mouse models of PF require DG-3 knockout mice. It is
interesting that neonates are protected from developing PF following maternal transfer of IgG antibodies due to the presence of DG-3 throughout
the epidermis.
However, SSSS does not behave as one would anticipate if the same theory were to apply. SSSS characteristically affects neonates and neonatal mice. Neonatal
and adult mice are believed to have the same DG expression throughout the epidermis, but with respect to SSSS may differ in renal function and presence of
antitoxin antibodies. Currently, there is no explanation as to why SSSS targets only the upper epidermis and affects human and mouse neonatal skin.
DG: Desmoglein; Ig: Immunoglobulin; PF: Pemphigus foliaceus; PV: Pemphigus vulgaris; SSSS: Staphylococcal scalded skin syndrome.

new adjuvant approaches to the management of SSSS need
to be developed that can reduce the burden of the ET, allow-
ing a greater time for antibiotic therapy to be effective.
Examples of such therapeutic manoeuvres are already availa-
ble and in use for other indications and could be modified
for SSSS. Immunoabsorption is used to selectively absorb
harmful antibodies in certain life threatening conditions and
may be modified to include a filter that absorbs ET using a
DG-1 lined filter. Alternatively, pooled globulins may be
administered that are rich in antibodies targeting the ETs.

www.future-drugs.com 583
Patel
Key issues
• The prevalence of Staphylococcus aureus is high and is thought to be associated with high population densities within cities.
• Certain strains of S. aureus release epidermolytic toxins that can cause bullous impetigo or staphylococcal scalded skin syndrome
(SSSS), depending upon the host immune response and predisposition.
• Epidermolytic toxins target and cleave the epidermal cell attachment protein desmoglein-1.
• SSSS is a disorder that mainly affects neonates and young children, but may rarely occur in susceptible adults.
• SSSS is a very painful condition, and the overall morbidity relates to the extent of skin involved.
• Mortality due to SSSS is now low in neonates and children, but remains very high in adults.
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Affiliation
• Girish K Patel, PhD
Dermatology Specialist Registrar, Department of
Dermatology, University of Wales College of
Medicine, Heath Park, Cardiff CF14 4XN, UK
Tel.: +44 292 074 7747
Fax: +44 292 074 5161
patelgk@cf.ac.uk
587