Toxic shock syndrome
Current Hypotheses Regarding
Mechanisms of Shock and Tissue Destruction Caused by Virulent Group A
Dennis L. Stevens, Ph.D., M.D
Pyrogenic exotoxins cause fever in
humans and animals and also help induce shock by lowering the threshold
to exogenous endotoxin (5). Streptococcal pyrogenic exotoxins A and B
induce human mononuclear cells to synthesize not only tumor necrosis
factor-a (TNFa) (44) but also interleukin-1▀ (IL-1▀) (45) and
interleukin-6 (IL-6) (45), suggesting that TNF could mediate the fever,
shock, and tissue injury observed in patients with streptococcal TSS
(8). Pyrogenic exotoxin C has been associated with mild cases of scarlet
fever in the United States (author's observations) and in England (46).
The roles of two newly described pyrogenic exotoxins, SSA and MF (see
section on "Clinical Isolates"), in streptococcal TSS have not been
M protein contributes to invasiveness
through its ability to impede phagocytosis of streptococci by human
polymorphonuclear leukocytes (47). Conversely, type-specific antibody
against the M protein enhances phagocytosis (47). After infection with a
particular M type, specific antibody confers resistance to challenge to
viable GAS of that M type (47). While M types 1 and 3 strains have
accounted for most strains isolated from cases of streptococcal TSS,
many other M types, including some nontyp-able strains, have also been
isolated from such cases. M types 1 and 3 are also commonly isolated
from asymptomatic carriers, patients with pharyngitis, and patients with
mild scarlet fever (7,29).
Could streptococcal TSS be related to
the ability of pyrogenic exotoxin or M proteins type 1 or 3 to act as
"super antigens"(48)? Data suggest that this exotoxin and a number of
staphylococcal toxins (toxic shock syndrome toxin-1 [TSST-1] and
staphylococcal enterotoxins A, B, and C) can stimulate T-cell responses
through their ability to bind to both the Class II major
histocompatibility ability complex of antigen-presenting cells and the
Vb region of the T-cell receptor (48). The net effect would be to induce
T-cell stimulation with production of cytokines capable of mediating
shock and tissue injury. Recently, Hackett and Stevens demonstrated that
pyrogenic exotoxin A induced both TNFa and TNF▀ from mixed cultures of
monocytes and lymphocytes (49), supporting the role of lymphokines (TNF▀)
in shock associated with strains producing that exotoxin. Kotb et al.
(50) have shown that a digest of M protein type 6 can also stimulate
T-cell responses by this mechanism; however, the role of specific
superantigens in this or any other infectious disease has not been
proven. Proof would require demonstration of massive expansion of T-cell
subsets bearing a V▀ repertoire specific for the putative superantigen.
However, quantitation of such T-cell subsets in patients with acute
streptococcal TSS demonstrated deletion rather than expansion,
suggesting that perhaps the life span of the expanded subset was
shortened by a process of apoptosis (51). In addition, the subsets
deleted were not specific for streptococcal pyrogenic exotoxins A, B, C,
or mitogenic factor, suggesting that an as yet undefined superantigen
may play a role (51).
Cytokine production by less exotic
mechanisms likely contributes as well to the genesis of shock and organ
failure. Peptidoglycan, lipoteichoic acid (52), and killed organisms
(53,54) are capable of inducing TNFa production by mononuclear cells in
vitro (6,54,55). Exotoxins such as streptolysin O (SLO) are also potent
inducers of TNFa and IL-1▀. Pyrogenic exotoxin B, a proteinase
precursor, has the ability to cleave pre-IL-1▀ to release preformed IL-1
(56). Finally, SLO and exotoxin A together have additive effects in the
induction of IL-1▀ by human mononuclear cells (49). Whatever the
mechanisms, induction of cytokines in vivo is likely the cause of shock,
and these two exotoxins, cell wall components, and the like, are potent
inducers of TNF and IL-1.
The mere presence of virulence factors,
such as M protein or pyrogenic exotoxins, may be less important in
streptococcal TSS than the dynamics of their production in vivo.
Recently, Cleary et al. proposed a regulon in GAS that controls the
expression of a group of virulence genes coding for known virulence
factors such as M protein and C5 peptidase (57). When DNA fingerprinting
was used, differences were shown between M1 strains isolated from
patients with invasive disease and strains from patients with
noninvasive GAS infections (58). Finally, genetic information coding for
exotoxins A or C may be introduced to strains of GAS by certain
bacteriophage; after lysogenic conversion, synthesis of exotoxin A would
occur during growth of the streptococcus (31,59,60). Multilocus enzyme
electrophoresis demonstrates two patterns that correspond to the M1 and
M3 type organisms that produce pyrogenic exotoxin A, a finding that
supports epidemiologic studies implicating these strains in invasive GAS
The interaction between these microbial
virulence factors and an immune or nonimmune host determines the
epidemiology, clinical syndrome, and outcome. Since horizontal
transmission of GAS in general is well documented, the only explanation
for the absence of a high attack rate of invasive infection is
significant herd immunity against one or more of the virulence factors
responsible for streptococcal TSS. This hypothetical model explains why
epidemics have not materialized and why a particular strain of GAS can
cause different clinical manifestations in the same community (8,61)
Figure 1. Pathogenesis of scarlet
fever, bacteremia, and toxic shock syndrome. M-1+SPEA+=aGAS strain that
contains M protein type 1 and streptococcal pyrogenic exotoxin A (SPEA);
+ anti-M-1 = the presence of antibody to M protein type 1; -anti-M-1 =
the absence of antibody to M protein type 1;anti-SPEA+=antibody to SPEA;
and DIC = disseminated intravascular coagulation.
Antibiotic Therapy'Cures and
Failures with Penicillin
S. pyogenes continues to be
exquisitely susceptible to ▀-lactam antibiotics, and numerous studies
have demonstrated the clinical efficacy of penicillin preparations for
streptococcal pharyngitis. Similarly, penicillins and cephalosporins
have proven efficacy in treating erysipelas, impetigo, and cellulitis,
all of which are most frequently caused by S. pyogenes.
addition, Wannamaker et al. (6) demonstrated that penicillin therapy
prevents the development of rheumatic fever following streptococcal pharyngitis if therapy is begun within 8 to 10 days of the onset of
throat. Nonetheless, some clinical failures of penicillin treatment of
streptococcal infection do occur. Penicillin treatment of S. pyogenes
has failed to eradicate bacteria from the pharynx of 5% to 20% of
patients with documented streptococcal pharyngitis (62-64). In addition,
more aggressive GAS infections (such as, necrotizing fasciitis, empyema,
burn wound sepsis, subcutaneous gangrene, and myositis) respond less
well to penicillin and continue to be associated with high mortality
rates and extensive morbidity (6,8,9,12,15,38,65). For example, in a
recent report, 25 cases of streptococcal myositis had an overall
mortality rate of 85% in spite of penicillin therapy (38). Finally,
several studies in experimental infection suggest that penicillin fails
when large numbers of organisms are present (66,67).
The Efficacy of Penicillin, Compared
to Clindamycin, In Fulminant Experimental S. pyogenes Infection
In a mouse model of myositis caused by
S. pyogenes, penicillin was ineffective when treatment was
delayed up to 2 hours after initiation of infection (67). Survival of
erythromycin-treated mice was greater than that of both
penicillin-treated mice and untreated controls, but only if treatment
was begun within 2 hours. Mice receiving clindamycin, however, had
survival rates of 100%, 100%, 80%, and 70%, even if treatment was
delayed 0, 2, 6, and 16.5 hours, respectively (67,68).
Eagle suggested that penicillin failed
in this type of infection because of the "physiologic state of the
organism"(66). This phenomenon has recently been attributed to both in
vitro and in vivo inoculum effects (69,70).
Inoculum Size and the "Physiologic
State of the Organism": Differential Expression of Penicillin-Binding
Penicillin and other ▀-lactam
antibiotics are most efficacious against rapidly growing bacteria. We
hypothesized that large inocula reach the stationary phase of growth
sooner than smaller inocula both in vitro and invivo. That high
concentrations of S. pyogenes accumulate in deep-seated infection is
supported by data from Eagle et al. (66). We compared the
penicillin-binding protein patterns from membrane proteins of group A
streptococci isolated from different stages of growth, i.e., mid-log
phase and stationary phase. Binding of radiolabeled penicillin by all
penicillin-binding proteins was decreased in stationary cells; however,
PBPs 1 and 4 were undetectable at 36 hours (69). Thus, the loss of
certain penicillin-binding proteins during stationary-phase growth in
vitro may be responsible for the inoculum effect observed in vivo and
may account for the failure of penicillin in treatment of both
experimental and human cases of severe streptococcal infection.
The Greater Efficacy of Clindamycin
in Experimental S. pyogenes Infections: Mechanisms of Action
The greater efficacy of clindamycin is
likely multifactorial: First, its efficacy is not affected by inoculum
size or stage of growth (69,71); secondly, clindamycin is a potent
suppressor of bacterial toxin synthesis (72,73); third, it facilitates
phagocytosis of S. pyogenes by inhibiting M-protein synthesis
(73); fourth, it suppresses synthesis of penicillin-binding proteins,
which, in addition to being targets for penicillin, are also enzymes
involved in cell wall synthesis and degradation (71); fifth, clindamycin
has a longer postantibiotic effect than ▀-lactams such as penicillin;
and lastly, clindamycin causes suppression of LPS-induced monocyte
synthesis of TNF (74). Thus, clindamycin's efficacy may also be related
to its ability to modulate the immune response.
Other Treatment Measures
Though antibiotic selection is
critically important, other measures, such as prompt and aggressive
exploration and debridement of suspected deep-seated S. pyogenes
infection, are mandatory. Frequently, the patient has fever and
excruciating pain. Later, systemic toxicity develops, and definite
evidence of necrotizing fasciitis and myositis appears. Surgical
debridement may be too late at this point. Prompt surgical exploration
through a small incision with visualization of muscle and fascia, and
timely Gram stain of surgically obtained material may provide an early
and definitive etiologic diagnosis. Surgical colleagues should be
involved early in such cases, since later in the course surgical
intervention may be impossible because of toxicity or because infection
has extended to vital areas impossible to debride (i.e., the head and
neck, thorax, or abdomen).
Anecdotal reports suggest that
hyperbaric oxygen has been used in a handful of patients, though no
controlled studies are under way, nor is it clear that this treatment is
Because of intractable hypotension and
diffuse capillary leak, massive amounts of intravenous fluids (10 to 20
liters/day) are often necessary. Pressors such as dopamine are used
frequently, though no controlled trials have been performed in
streptococcal TSS. In patients with intractable hypotension,
vasoconstrictors such as epinephrine have been used, but symmetrical
gangrene of digits seems to result frequently (author's unpublished
observations), often with loss of limb. In these cases it is difficult
to determine if symmetrical gangrene is due to pressors, infection, or
Neutralization of circulating toxins
would be desirable; however, appropriate antibodies are not commercially
available in the United States or Europe. Two reports describe the
successful use of intravenous gamma globulin in treating streptococcal
TSS in two patients (75,76).
In summary, if a wild "flesh-eating
strain" has recently emerged, a major epidemic with a high attack rate
would normally be expected. Clearly, epidemics of streptococcal
infections, including impetigo, pharyngitis, scarlet fever, and rheumatic fever have occurred in the past. However, in the last decade,
subsequent to early reports of streptococcal TSS, we have observed that
the incidence has remained relatively low. I hypothesize that large
outbreaks have not occurred because 1) most of the population probably
has immunity to one or more streptococcal virulence factors (6,25); 2)
predisposing conditions (e.g., varicella, and use of NSAIDs) are
required in a given patient; and 3) only a small percentage of the
population may have an inherent predisposition to severe streptococcal
infection because of constitutional factors such as HLA Class II antigen
type (77,78), B-cell (79), or specific Vb regions on lymphocytes. This
last hypothesis is further supported by the observation that secondary
cases of streptococcal TSS, though reported (80), have been rare.
Dr. Stevens is chief, Infectious
Diseases Section, Veterans Affairs Medical Center, Boise, Idaho, and
professor of medicine, University of Washington School of Medicine,
Seattle. He is a member of CDC's Working Group on Streptococcal
Infections and a consultant to the National Institutes of Health and the
World Health Organization on Streptococcal Infections. On July 1994, he
testified before Congress on Severe Streptococcal Infections and is
currently President of the American Lancefield Society.
Address for correspondence: Infectious
Disease Section Veterans Affairs Medical Center, 500 West Fort Street
(Bldg 6), Boise, ID 83702, USA, fax: 208-389-7965
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Toxic shock syndrome
> 1 >
3 > 4
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