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Toxic shock syndrome

Current Hypotheses Regarding Mechanisms of Shock and Tissue Destruction Caused by Virulent Group A Streptococci

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-1ß (IL-1ß) (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 elucidated.

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 TNFß from mixed cultures of monocytes and lymphocytes (49), supporting the role of lymphokines (TNFß) 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 Vß 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-1ß. Pyrogenic exotoxin B, a proteinase precursor, has the ability to cleave pre-IL-1ß to release preformed IL-1 (56). Finally, SLO and exotoxin A together have additive effects in the induction of IL-1ß 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 infections (33).

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.)

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.

Treatment

Antibiotic Therapy'Cures and Failures with Penicillin

S. pyogenes continues to be exquisitely susceptible to ß-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.

• Cellulitis
• Impetigo
• Sore throat
• Rheumatic fever

In 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 sore 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 Proteins

Penicillin and other ß-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 ß-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 useful.

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 both.

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.

• Impetigo
• Rheumatic fever

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

References

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