Review

Superantigens

Superantigens: microbial agents that

corrupt immunity
Martin Llewelyn and Jon Cohen

Microbial superantigens are a family of protein

exotoxins that share the ability to trigger excessive
and aberrant activation of T cells. The best
characterised are the staphylococcal enterotoxins and
the streptococcal pyrogenic exotoxins that trigger
the staphylococcal and streptococcal toxic shock
syndromes. It is now apparent that superantigens have
a wider role in the pathology of infectious diseases
than has previously been appreciated. Staphylococcus
aureus and Streptococcus pyogenes together produce 19
different superantigens. The range of microorganisms
known to produce superantigens has expanded to
include Gram negative bacteria, mycoplasma, and
viruses. Research is beginning to shed light on the
more subtle parts these molecules play in causing
disease and to produce some real possibilities for
specific treatment of superantigen-induced toxicity.
We aim to highlight these new developments and
review the science behind these fascinating molecules.
Lancet Infectious Diseases 2002; 2: 15662

T cell
T cell receptor

Variable region
Ag

MHC class II

Antigen presenting cell

1/105 T cells activated
CD4 T cells

T cell

Superantigen

IL2, IFN, IL12

Ag

Immunology of superantigens
Microbial superantigens are a family of proteins with
particular structural and sequence features that result in the
shared ability to bypass the mechanisms of conventional,
MHC-restricted, antigen processing.1 Conventional
antigens are processed within antigen-presenting cells such
as monocytes into peptide fragments that are loaded into
the peptide binding groove of the MHC class II molecule
for presentation at the cell surface to T cells. T cells will only
respond if they recognise the class II molecule through
CD4 and the specific peptide being presented. Thus only a
tiny fraction of the hosts T-cell repertoire (<001%) will be
activated. By contrast, superantigens bind, as intact
proteins, directly to the MHC class II molecule and to the
T-cell receptor, extracellularly, at sites away from
conventional peptide-binding sites (figure 1). On the T-cell
receptor, binding is to the variable region of the beta chain
(the V region). Since the number of different V regions
in the human T-cell repertoire is restricted to less than
50 and since most superantigens can bind more than one,
up to 25% of an individuals T cells can be activated in this
way.2 Each superantigen is associated with a characteristic
V signature, so for example staphylococcal enterotoxin
A (SEA) will trigger activation and expansion of
T cells bearing V1, 53, 63, 64, 69, 74, 91, and 23.3
Superantigens have also evolved diverse mechanisms
for binding to the MHC class II molecule.4 Some bind
exclusively at the alpha chain, some the beta, and some
156

TNF, IL1
Antigen presenting cell
Up to 1/5 T cells activated
CD4 and CD8 T cells
Figure 1. Contrasting mechanisms of conventional antigen (upper panel)
and superantigen presentation (lower panel).

both. Most staphylococcal enterotoxins (SEs) bind

HLA-DR preferentially, whereas many streptococcal
pyrogenic exotoxins (SPEs) bind better to DQ. Differences
between different HLA DR and DQ alleles might lead to
differences between individuals in susceptibility to
particular superantigens.5 For a detailed review of
superantigen interactions with T-cell receptor and the class
II molecule see reference 6.
ML is a clinical research fellow in the Department of Infectious
Diseases at Hammersmith Hospital, London, UK; and JC is
professor of infectious diseases and chairman of the Department of
Infectious Diseases at Imperial College School of Science and
Medicine.
Correspondence: Dr Martin Llewleyn, Department of Infectious
Diseases, Hammersmith Hospital, Du Cane Road, London
W12 0NN, UK. Tel +44 (0)20 8383 4238; fax +44 (0)20 8383 3394;
email m.llewelyn@ic.ac.uk

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Review

Superantigens

By binding to the T-cell receptor and the MHC

class II molecule on antigen-presenting cells, superantigens
trigger T-cell activation that results in the release of
proinflammatory cytokines, initially tumour necrosis
factor alpha (TNF), followed by interleukin (IL) 6,
interferon gamma (IFN), and IL2. Other consequences
of T-cell activation are recruitment of further T and
B cells to the site of infection and co-activation of the
antigen-presenting cell, which responds with release of
proinflammatory mediators such as IL1 and TNF.7 The
excessive uncoordinated release of proinflammatory
cytokines, and in particular TNF, is thought to be
responsible for many of the clinical features of toxic shock
syndrome.8
Superantigen-induced cytokine release from T cells is
accompanied by V specific proliferation that is heavily
skewed towards a Th1 proinflammatory response.9 Initial
T-cell activation is followed by inhibition of production of
some cytokines such as IL-2,10 anergy (failure to respond to
further activation),11 and under some circumstances V
specific deletion.12

Other properties of superantigens

Several other important properties of superantigens are
unrelated to superantigenicity per se but are nevertheless
likely to contribute to their role in disease.
Augmentation of endotoxin activity.

The toxic effects of bacterial superantigen and endotoxin

are synergistic. Their co-administration to experimental
animals is associated with a reduction of the LD50 of either
toxin given alone by up to 50 000 times.13 Studies with
mutated forms of superantigens suggest this property is
distinct from superantigenicity. The implications of
endotoxinsuperantigen synergy for the clinical impact of
superantigen production are two fold. First, the circulation
of bacterial superantigen may reduce the threshold for
endotoxicity to a degree at which circulation of endogenous
endotoxin may be sufficient to contribute to shock. Second,
coexistence of gram positive and gram negative organisms,
for instance as colonisation of critically ill patients, may
through a double hit of endotoxin and superantigen result
in shock in the absence of a typical focus of bacterial
infection.14
Emesis

The staphylococcal exotoxins SEA-E and SEG-I, as well

as being superantigens implicated in the causation of
non-menstrual toxic shock, are potent gastrointestinal
toxins responsible for staphylococcal food poisoning.
The precise mechanism by which the SEs induce vomiting
has not been established. However, the superantigenicity
and gastrointestinal toxicity functions are distinct from
one another in that these activities are located in different
domains of the molecule.15 Only tiny quantities of toxin
(<1g) are required to cause symptoms and only 103
organisms per gram of food are required to produce
detectable levels of toxin. Furthermore, the toxins are
resistant to heat. Temperatures of above 120C for 510
minutes are required to cause inactivation.16
THE LANCET Infectious Diseases Vol 2 March 2002

Local inflammation

A third action of bacterial superantigens is their ability

to stimulate neutrophil recruitment to a site of infection.
Again this effect appears to be independent of their
superantigenicity since subcutaneous injection of
staphylococcal enterotoxin B (SEB) in mice leads to
neutrophil influx independent of T-cell stimulation. The
mechanism appears to be release of TNF from monocytic
cells, which triggers upregulation of chemokines and
adhesion molecules.17 The importance of this process in
infection remains to be determined but in mice, which by
virtue of MHC class II differences are resistant to the
superantigen effects of SPEA, infection by SPEA-producing
strains of Streptococcus pyogenes results in a more vigorous
neutrophil response and better outcome than infection by
strains lacking the speA gene.18

Clinical significance of superantigens

Toxic shock syndrome

Toxic shock syndrome is primarily a capillary leak

syndrome, mediated like endotoxic shock principally
through TNF and characterised by hypoalbuminaemia,
oedema, hypotension, and acute respiratory distress
syndrome. Other direct effects of the toxins such as
vasodilation and myocardial depression probably
compound the pathology.19 Although case definitions for
staphylococcal and streptococcal toxic shock syndrome
exist,20 21 these are designed for research rather than
clinical practice. Furthermore they fail to identify
near-miss cases where the full syndrome does not
develop, or microbiology may not be obtained, because
of early intervention. Although most patients that are
normotensive at presentation go on to develop shock
within 4 h,22 some discriminatory clinical features may
allow early diagnosis and intervention (table 1). A 34 day
flu-like prodrome usually precedes shock. Also, signs
of infection and features such as erythema and
strawberry tongue (figure 2), excessive pain at a site of
minor trauma, tachycardia out of proportion to fever,
and renal impairment with normal blood pressure may
all precede the fulminant phase of the illness. Streptococcal
toxic shock is characteristically associated with deep-seated
infections such as necrotising fasciitis. Signs of toxaemia in
a patient with painful cellulitis are an indication for urgent
surgical review (figure 3). Among factors said to
predispose to development of toxic shock only recent
chickenpox in children is of clinical significance. In one
study, 15% of children with invasive S pyogenes infections
had chickenpox in the preceding month.24
Each year there are approximately 10 000 cases of
severe streptococcal disease in the USA and 2000 in the UK,
of which about one fifth will be associated with toxic
shock.25 Whereas invasive disease overall is most common in
the elderly or in those with pre-existing disease such as
alcohol abuse or diabetes, the incidence of toxic shock is
distributed evenly throughout life. Due to changes in the
manufacture and use of tampons, the incidence of
staphylococcal toxic shock has declined sharply since the
1980s. There are probably less than 50 cases per annum
in the UK of which half are menstrual, and the remainder

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Review

Superantigens

Table 1. Contrasting features of staphylococcal and streptococcal toxic shock syndromes

Staphylococcal toxic shock
Prodrome Malaise, myalgia, chills
Illness
Fever, diarrhoea, confusion.
Superficial site of infectioneg,
impetigo, burns, nappy rash,
genital tract, surgical-site infection

Streptococcal toxic shock

Sore throat, malaise, myalgia, lymphadenopathy
Fever, diarrhoea, confusion.
Abrupt, severe pain.
Deep site of infectionsite of blunt trauma,
necrotising fasciitis, myositis, septic joint,
surgical site infection.
Sometimes multiple sites of infection

class II binding are reflected by

differences in T-cell response.29 The
impact of such differences in the
course of infection remains to be
determined.
Other syndromes of superantigen
production

Bacterial superantigens have been

implicated in the aetiology of a
range of apparently disparate clinical
syndromes other than toxic shock.
This spectrum of disease probably
results from differences in both
rate and site of superantigen
production, and the immune
Bacteraemia rare
Bacteraemia common.
Elevated creatine kinase in fasciitis/myonecrosis
response of the host.
Kawasaki syndrome (or mucoDesquamation at 714 days
Desquamation less common
cutaneous lymph node syndrome)
Mortality
About 6%
3070%
is a multisystem vasculitis most
From references 19 and 23.
common in children aged 6 months
to 8 years, which occurs in spring
occur in the context of burns, surgical procedures, and epidemics. Following the acute illness, up to 25% of children
skin infectionsincluding impetigo and nappy rash. develop aneurysmal dilatation of the coronary arteries.
Mortality associated with streptococcal toxic shock remains Acute V-specific changes (particularly V2 expansion)
around 3050%, while that of staphylococcal toxic shock, have been observed in many cases.30 Although no single
as a consequence of the generally superficial site of infection superantigen has been implicated, and there is still
in this condition, is much lower at around 6%.26 considerable debate about the precise aetiology of
Nevertheless, the recent identification in Japan of a strain Kawasakis disease, the condition is probably the outcome of
of meticillin-resistant Staphylococcus aureus that has exposure to one of a number of superantigens in a
acquired the phage coding for toxic shock syndrome toxin susceptible host.31
Other non- infectious syndromes that may be triggered
(TSST)-127 serves as a worrying reminder that staphylococcal
toxic shock syndrome will continue to be an important by infection through the actions of superantigens include,
clinical entity.
eczema, guttate psoriasis, rheumatoid arthritis, and diabetes
In the years following the first descriptions of toxic mellitus.
shock syndrome much interest was focused on the
hypothesis that these conditions were the result of new Superantigens as agents of biological warfare
virulent strains of bacteria carrying a superantigen gene. Under certain circumstances, superantigens will cross
For example there is a good association, at least in Europe epithelial surfaces to enter the body as intact proteinsfor
and North America, between toxic shock syndrome and example, TSST-1 crosses the vaginal mucosa in menstrual
strains of S pyogenes carrying the speA gene. Also, modern toxic shock syndrome,32 and SEB crosses the intestinal
isolates from toxic shock syndrome cases appear to express mucosa possibly through a specific receptor mechanism.33
the speA3 allele, whereas isolates from the early 20th SEB toxicity by inhalation is well established and although
century express speA1 or 2.28 A number of lines of evidence exposure through this route is not a feature of S aureus
support the additional hypothesis that certain individuals infection, this characteristic makes SEB a candidate for
may be genetically more susceptible to the effects of
individual superantigens than others. If streptococcal toxic
shock was purely the result of infection by a virulent clone
in a non-immune host, the resulting epidemiology would
be characterised by a high secondary attack rate. Instead,
secondary cases are very unusual and while many contacts
will be carrying the same virulent clone as the index case,
most will have only trivial symptoms.25 Based on the
mechanism of superantigenicity outlined above, one likely
explanation for such differences in susceptibility is that
different HLA class II haplotypes may be associated with
differences in presentation of particular superantigens and
so differences in susceptibility to developing toxic shock
syndrome. The sites at which superantigens bind HLA class
II are polymorphic4 and differences in superantigen HLA Figure 2. Strawberry tongue and rash.
Tachycardia, tachypnoea, hypotension,
erythema, oedema. Neutrophilia,
thrombocytopenia, renal impairment
(which may precede hypotension),
hypoalbuminaemia deranged
coagulation, transaminitis, adult
respiratory distress syndrome

158

Tachycardia, tachypnoea, hypotension,

erythema, oedema.
Neutrophilia, thrombocytopenia, renal
impairment (which may precede hypotension),
hypoalbuminaemia deranged
coagulation, transaminitis, adult respiratory
distress syndrome.

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Review

Superantigens

use in terrorism or biological warfare.34 This threat

underlines the importance of developing vaccines against
specific superantigens and other superantigen-blocking
strategies.
Superantigens in sepsis

Most of the superantigens associated with S aureus and

S pyogenes are coded for by phage-mediated genes and hence
are only present in certain toxigenic strains. The genome of
S pyogenes is now published for several strains and screening
has identified two superantigens, SPEJ and streptococcal
mitogenic exotoxin Z (SMEZ), which are chromosomal and
so present in all strains.35 SMEZ is particularly interesting
because it is produced only in very small quantities
and yet is the most potent superantigen identified.36
These observations, taken in conjunction with the
superantigenendotoxin synergy effect, raise the possibility
that staphylococci and streptococci may contribute to the
aetiology of sepsis more commonly than has previously been
appreciated. Through the two-hit hypothesis outlined
above, such constitutive superantigens, present at possibly
undetectable levels, may trigger intractable sepsis in patients
sensitised by Gram negative infection.14

Endogenous superantigens
The first superantigens discovered, in 1974, were not bacterial
toxins but were the minor lymphocyte stimulating (Mls)
antigens expressed in thymic stromal cells of mice.37 Like
bacterial superantigens, Mls antigens cause T-cell proliferation
with characteristic V signatures and this proliferation is
followed by complete deletion of these V T cells. Mice
carrying such endogenous superantigen genes are born with
holes in their T cell V repertoire. Mls antigens are now
known to be encoded by superantigen genes integrated into
the mouse genome from the genome of the mouse mammary
tumour virus (MMTV). These same superantigens have a
central role in the life-cycle of MMTV. In susceptible strains of
mice, neonatal infection is established when the MMTV
superantigen triggers a 105 fold expansion in viral load by
stimulating massive T-cell help for infected B cells. Strains
of mice that have integrated an MMTV superantigen gene
into their genome, by expressing this as Mls antigen, have
deleted the V T cells responsive to that MMTV superantigen
and so are resistant to exogenous infection by that MMTV.
The V repertoire of man does not contain holes
analogous to those found in mice and despite extensive
research human equivalents of mouse Mls antigens have not
been identified. There is now good evidence, however, that
endogenous superantigens do exist in the human genome
and may play an important part in viral infection. Although
it has been known for some time that Epstein-Barr virus
(EBV) infected cells express a superantigen exhibiting V
13 specificity, no superantigen gene has been identified
in the EBV genome. The superantigen secreted by EBVinfected cells is actually coded for by the env gene of
human endogenous retrovirus (HERV) K18. Expression
of this gene is upregulated by EBV infection. Just as
MMTV uses superantigens to establish infection, EBV may
depend on this superantigen to expand a population
of host T cells in which it can establish latency.38 Such
THE LANCET Infectious Diseases Vol 2 March 2002

Figure 3. Necrotising fasciitis, before (top) and after (bottom) surgical

exploration and debridement.

a mechanism might also explain the failure to identify

superantigens of other viruses, including cytomegalovirus,
rabies, and HIV, for which V-specific T-cell proliferation
has been reported.
Superantigens lacking a V signature

A further suggestion of the broader role that microbial

superantigens may have in infection comes from recent
research into the Mycoplasma arthritidis superantigen
(MAM). Little is known about the structure or function
of this molecule other than the sequence of the MAM
gene and the superantigenicity of recombinant toxin.
It seems that MAM interacts with the T-cell receptor V
region, not just at complementarity determining regions
(CDR) 1 and 2 (which are germ-line encoded) but also at
CDR3, which is generated by somatic mutation.
Consequently MAM does not produce a characteristic
superantigen V signature or massive T-cell expansion.39 If
this is true for MAM it means that V expansion can no
longer be regarded as a sine qua non of superantigenicity and
raises the possibility that superantigens may be at work
much more subtly in the pathogenesis of infection than in
the dramatic syndromes of toxic shock.

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Superantigens

Table 2. Organisms associated with confirmed or putative superantigen production

Organism

Superantigen toxins identified

Syndrome associated with toxin production

Staphylococcus aureus*

TSST-1
SEA, B, C1-3, D, E
SEG-I

Menstrual toxic shock;47 neonatal toxic shock like exanthem27

Non-menstrual toxic shock27
Kawasaki syndrome?
Staphylococcal food poisoning

Streptococcus pyogenes

SPEA (4 alleles)
SPEC (4 alleles)
SSA
Mitogenic factor (MF)
SPEG,H,J
SMEZ (21 alleles)

Streptococcal toxic shock35, 48

Yersinia pseudotuberculosis

YPM (3 alleles)

Role in yersinia enteritis unclear49

Kawasaki syndrome?

Yersinia enterocolitica

Undetermined

Clostridium perfringens

C perfringens enterotoxin

Superantigenic activity in vitro?50

Mycoplasma arthritidis

MAM

Experimental arthritis51
Aetiological role in rheumatoid arthritis?52

EBV

HERV-K18 env?

Induction of endogenous retrovirus superantigen?38

Rabies

Undetermined

HIV

Undetermined

*Exfoliative toxins ETA and ETB were previously considered to be superantigens but are trypsin proteases. Recombinant toxins have no superantigen activity.53
SPEB and SPEF were previously considered to be superantigens. Neither is structurally related to other superantigens and observed superantigenicity was probably due to
contamination. SPEB is a cysteine protease and SPEF is immunologically and genetically identical to streptococcal DNase B.54 V T cell expansion demonstrated but superantigen
not yet defined.

Strategies to combat superantigens

Supportive therapy, incorporating fluid resuscitation and
vasopressors, and appropriate antibiotics remain the
central elements of the management of toxic shock
syndrome. There are now compelling reasons to include
clindamycin in the antibiotic regimen for this condition.
From a theoretical point of view, this drug may switch off
toxin production by bacteria at sites and at concentrations
where particularly betalactam antibiotics are ineffective.40
Similarly, clindamycin down-regulates expression of
penicillin-binding proteins and streptococcal M protein,
so inhibiting bacterial cell wall synthesis and aiding
phagocytosis. Although there are no randomised
controlled trial data evaluating different antibiotic
regimens in this setting, in the context of invasive
S pyogenes infection, regimens including protein-synthesis
inhibitors such as clindamycin are associated with better
outcome than those relying on betalactam antibiotics
alone.41
Intravenous immunoglobulin

Several lines of evidence support the notion that early

administration of pooled immunoglobulin should be of
benefit in the treatment of toxic shock. The presence
in the blood of neutralising antibodies to SPEs has
been shown to correlate with better outcome following
Strep pyogenes infection. Immunoglobulin preparations
contain superantigen-neutralising antibodies. In vitro,
immunoglobulin can block T-cell activation by SEs
and SPEs. Finally serum from toxic shock syndrome
patients treated with pooled immunoglobulin completely
neutralises toxins produced by the infecting organism.42
There are no randomised controlled clinical trial data
on the use of immunoglobulin in this setting. In a
160

small study of 21 cases, the use of immunoglobulin

was associated with improved survival compared with
historical controls (30 day survival of 67% vs 34%),
although imbalances in treatment and control groups
mean these data should be interpreted with caution.43
Additionally, it is unclear whether any effect of
immunoglobulin in toxic shock is distinct from the
broad beneficial effect reported in sepsis and septic
shock.44 On the basis of currently available data, it
would be reasonable for clinicians to consider the use
of pooled immunoglobulin in toxic shock syndrome,
weighing up the possible benefit against risks, which
include risk of anaphylaxis.
Superantigen-blocking peptides and antibodies

Although it seems to be the tertiary structure of

superantigens that is crucial for their biological
activity and sequence conservation between various
superantigens is relatively low, two regions of marked
sequence homology have been identified in the SE/SPE
toxins.45 Research with peptides constructed to mimic
these regions shows that both the peptides and
antibodies raised against the peptides have blocking
activity against a range of bacterial superantigens.46
The mechanism of action is probably blocking of
the superantigen-MHC class II binding interaction.45
This approach has produced some very encouraging
results in animal models of toxic shock, but clinical
trials are still some way off.

Why have microorganisms evolved

superantigens?
That a wide range of microorganisms express toxins
that differ in structure and regulation but remain

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Review

Superantigens

Search strategy and selection criteria

The data reviewed in this paper were primarily identified
through searches of the files of the authors. To ensure
recent publications in the field were included we
conducted Medline (through Biomed) and Pubmed
(through National Library of Medicine) searches using the
search terms superantigens, Staphylococcus aureus, and
Streptococcus pyogenes.
superantigens (table 2) testifies to the evolutionary
advantage associated with superantigen production. The
wide allelic variation observed for SMEZ, of which the
dominant feature is antigenic variation rather than
differences in activity,36 confirms that host immunity is
driving evolution of superantigens. Since nothing in
biology makes sense except in the light of evolution,55 if we
could provide answers to the question of why
microorganisms should have evolved superantigens we
might go a long way towards devising more effective
strategies to combat superantigenicity.
It seems likely that the advantage conferred by
superantigen production involves corruption of the
immune response to infection, thereby promoting carriage
and transmission of the organism. The genes that regulate
superantigen expression also regulate mechanisms of
immune evasion such as M protein and capsule
expression,56 and intriguingly the smez gene is located close
to the mga regulon in the S pyogenes genome.57 Much of
the research in this field has understandably focused
on superantigens as causes of systemic shock. Taking
S pyogenes as an example, such research may have missed
the crucial site at which superantigens exert their intended
biological effect since the primary site of infection
and transmission is the pharynx. The V signature
of T-cell expansion seen experimentally with streptococcal
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THE LANCET Infectious Diseases Vol 2 March 2002

superantigens is absent in the blood of patients

with streptococcal toxic shock syndrome,58,59 but tonsillar
T cells obtained after tonsillectomy show V-specific
expansion matching that expected from SMEZ and
SMEZ2.60
How might superantigens prevent the normal
development of immunity to infection? One plausible
mechanism is through their ability to induce T-cell anergy.
T-cell anergy induced by administration of SEB systemically
to experimental animals is associated with failure to mount
an antibody response, not just to SEB itself but to other
antigens administered simultaneously or subsequently.61 In
vitro, T-cell anergy can be reversed with IL2.61 Since
superantigen stimulation of T cells to produce IL2 is
followed by inhibition of IL2 release,10 and the main route
of IL2 clearance is through its receptor, superantigen
stimulation is likely to lead to a local deficiency of IL2
which in turn could limit the expansion of antigen-specific
T cells.62 Taken together these observations suggest that at a
focus of infection, superantigens may cause depletion of
IL2, anergy of T cells, and failure of T-cell help to establish
humoral immunity not just to the superantigen but to other
microbial antigens.

Conclusions
Microbial superantigens can no longer be regarded as
playing a part only in the pathogenesis of toxic shock
syndrome. The data reviewed here suggest multiple
mechanisms for evasion and corruption of the host
immune response to infection. Strategies that succeed in
blocking superantigenicity might therefore find a broad
role in the treatment of infectious diseases.

Conflict of interest

We have no conflicts of interest connected with this work.

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19 McCormick JK, Yarwood JM,

Schlievert PM. Toxic shock syndrome and bacterial
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