TOXIC SHOCK SYNDROME
Key diagnostic and therapeutic points
• Toxic shock syndrome (TSS) secondary to Staphylococcus aureus and Streptococcus pyogenes (Group A Streptococcus [GAS]) is an acute- onset illness causing systemic symptoms of fever, hypotension, and desquamative rash with the potential for high morbidity and rapid mortality. Clostridium species TSS may lack fever and rash but is often fatal.
• TSS secondary to staphylococcus and streptococcus is associated with elaboration of bacterial toxins, with a resultant vigorous cytokine cascade leading to multiorgan failure. Clostridium species toxins have a direct cellular effect on vascular endothelium.
• Diagnosis of TSS is based on fulfillment of criteria that involve identification of a constellation of clinical and laboratory data.
• A strong suspicion, early recognition, and aggressive management may decrease overall mortality and morbidity. Treatment consists of strategies to control the source of infection, decrease toxin production, and provide appropriate antibiotic therapy, surgical intervention, and clinical support with close monitoring of end- organ function. Three major causes of TSS have been identified.
Those caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes produce an acute, desquamative febrile illness. Clostridium species (Clostridium sordellii, Clostridium perfringens) TSS lacks the febrile illness or rash but may rapidly lead to multiorgan system failure with substantial morbidity and mortality.
Staphylococcal toxic shock syndrome (TSS) was first reported in 1978 in previously healthy children with Staphylococcus aureus infection.
Estimated incidence peaked in the early 1980s, with between 6.2 and 12.3 cases per 100,000 population. Ninety percent of cases were associated with tampon use in healthy, young menstruating With a decrease in tampon absorbency, changes in tampon composition and usage patterns, standardized labeling, and greater awareness among women and physicians, incidence fell to about 1 case per 100,000 population in the United States. By 1986 rates of menstrual and nonmenstrual TSS cases were 1 and 0.3 per 100,000, respectively. Menstrual TSS declined from 91% of all TSS cases (1979– 1980) to 59% (1987–1996). Of nonmenstrual causes, almost 20% were reported following surgery, 11.5% were postpartum or postabortion, and 23% were associated with nonsurgical cutaneous lesions. Incidence of postoperative cases of TSS following all types of surgery was estimated to be 3 per 100,000 population and was higher following ear, nose, and throat surgery, likely related to nasal packing. The latest population-based report of incidence between 2000 and 2006 in Minneapolis–St. Paul showed menstrual cases at 0.69 and nonmenstrual cases at 0.32 per 100,000 population. The crude mortality rate from staphylococcal TSS is 5% to 8%, with acute respiratory distress syndrome being a major cause of death.
The incidence of streptococcal TSS corresponds to that of invasive group A streptococcal (GAS) disease. In the United States approximately 10,000 cases of invasive GAS occur each year, with an annual incidence of 3 to 3.5 cases per 100,000 population. TSS complicates 10% to 15% of cases. The crude mortality rate is significantly higher than with staphylococcal TSS and reaches 30% to 80% in adults and 5% to 10% in children.
The current passive surveillance system for TSS is limited given the complexity of the clinical diagnosis and lack of a single test. Because studies related to incidence of both staphylococcal and streptococcal TSS use the Centers for Disease Control and Prevention (CDC) case definition that identifies the most severe cases, they may underestimate the total TSS disease burden.
Clostridium species are uncommon causes of TSS but have been reported to cause fatal disease after medical or spontaneous abortion. These organisms are found in the vaginal tract of pregnant women and likely ascend to cause disease after abortion with or without cervical instrumentation. There are no available incidence data for clostridium species TSS, but it has been reported in case series and is associated with a case fatality rate of at least 70%.
In patients with staphylococcal TSS, previous antibiotic treatment and hospital exposure may predispose to colonization with toxigenic strains of Staphylococcus aureus. Primary staphylococcal infections such as pneumonia, postsurgical state, disruption of skin or mucous membranes, abscesses or burns, and foreign body placement have also been noted as risk factors. The absence of protective antitoxin antibodies may be a predisposing factor.
A major risk factor for streptococcal TSS is extremes of age. This is more common in persons ≥ 65 years old, followed by those < 2 years old. Higher incidence was also observed in persons with underlying chronic illnesses, in pregnancy as well as childbirth, after varicella infection, and with use of nonsteroidal antiinflammatory drugs. Any disease or injury compromising the mucosal surface or skin barrier may predispose a patient to streptococcal TSS. Transfer of the disease from one individual to another may also occur, as clusters of GAS infections have been described in nursing homes and among health- care workers and family members.
Main risk factors of clostridium species TSS are pregnancy, abortion, injection drug use, recent trauma, or (less commonly) cadaveric musculoskeletal graft surgery.
The hypothesis for the development of TSS is that infection with Staphylococcus aureus or Streptococcus pyogenes results in the production of toxins that act as superantigens. Staphylococcal TSS is normally associated with TSST-1, staphylococcal enterotoxin (SE) serotype B (SEB) or serotype C (SEC). Most cases of streptococcal TSS have been associated with streptococcal pyrogenic exotoxin (SPE) serotypes A (SPE A) and C (SPE C). These proteins share the ability to trigger excessive T-cell activation. Whereas conventional antigens stimulate on the order of 1 in 10,000 T cells, superantigens may stimulate over 20% of all T cells. This large expansion of T cells is believed to be responsible for severe clinical consequences such as capillary leakage leading to hypotension, shock, multiorgan failure, and death.
Clostridium sordellii and C. perfringens secrete lethal and hemorrhagic toxins. Unlike staphylococcal or streptococcal TSS, these toxins do not act as superantigens. Rather, they are large molecular weight proteins that have glycosyl transferase activity, modifying members of the Rho GTPase superfamily to disrupt crucial cell processes that particularly affect vascular endothelial cells. These culminate in vascular leak and are suggested to be the main virulence factors that lead to rapid progression to shock and death.
Staphylococcal TSS typically presents abruptly with an influenza-like prodrome consisting of fever, gastrointestinal upset, and myalgia, followed commonly by confusion, lethargy, and agitation. Symptoms of hypovolemia are common. If present, a focus of infection is more likely to be superficial, may complicate burns or a surgical wound, or may result from a foreign body. Desquamation is a characteristic late feature. Blood cultures are positive in < 5% of cases. After the onset of symptoms, progression is rapid and multiorgan failure can present in 8 to 12 hours.
Streptococcal TSS more commonly arises from deep-seated, invasive, soft-tissue infections such as necrotizing fasciitis and myositis. An influenza-like illness is also common in the early stage with fever, sore throat, swollen lymph nodes, and gastrointestinal upset. Local pain may be severe and is one of the most common reasons for seeking medical attention. Patients with a defined entry site may have early and visible signs of inflammation. In the absence of a definite portal of entry, clinical evidence of a deep infection becomes more obvious as the illness progresses. The initiating injury may be blunt trauma, muscle strain, and hematoma or joint effusion and may seem trivial. Like staphylococcal TSS, hypotension and organ dysfunction are rapidly progressive but unlike it, most (60%) patients with streptococcal TSS have positive blood cultures. Bacteremia alone, however, is not sufficient to explain the complications and increased mortality associated with streptococcal TSS.
Clostridium species toxic shock was suggested in previously healthy women with recent mifepristone (Mifeprex) and misoprostol (Cytotec) pregnancy termination. Women were noted to have nonspecific complaints of sudden onset of weakness, nausea, vomiting, diarrhea, and abdominal pain. A rapid sequence of progressive hypotension and local and spreading edema was associated with severe hemoconcentration and marked leukemoid reaction. The syndrome was described with the identification of Clostridium sordellii or C. perfringens and exclusion of a staphylococcal cause of the rapidly progressive shock. Absence of fever, presence of refractory tachycardia, local edema at the infected site, and subsequent pleural and peritoneal effusions are seen.
The diagnostic criteria for TSS are based on the clinical case definitions updated by the CDC in 2010 and 2011 for streptococcal TSS and staphylococcal TSS, respectively. They are presented in Table 1.
Diagnostic Criteria for Toxic Shock Syndrome (TSS)
Additional laboratory abnormalities include an increase in bands, anemia, hypocalcemia, and hypoproteinemia. Cultures from sites of infection are usually positive and should be sought.
In clostridium species TSS, case definition is incomplete. The clinical manifestations as described should be confirmed by additional laboratory tests such as anaerobic culture of the cervix, histopathologic, immunohistochemical, and molecular studies of surgical or autopsy tissue to confirm necrotizing endometritis, and presence of clostridium species.
TSS can be confused with acute pyelonephritis, acute rheumatic fever, acute viral syndrome such as measles, Legionnaire disease, leptospirosis, Lyme disease, pelvic inflammatory disease, osteomyelitis, scarlet fever, typhus, meningococcemia, Rocky Mountain spotted fever, ehrlichiosis, and gram-negative sepsis.
Noninfectious illnesses that lead to septic shock, severe drug reactions, Kawasaki disease (in children), flares of autoimmune illnesses such as systemic lupus erythematosus, tumors, and hemolytic uremic syndrome may also mimic the syndrome.
Poor outcome is due in part to the nonspecific features at presentation leading to missed or delayed diagnosis and underestimation of the aggressive nature of the infection delaying treatment. Highest probability for successful outcome lies with early identification and a therapeutic strategy that involves hemodynamic stabilization and specific antibiotics to eradicate the bacteria and control toxin synthesis. Vigorous attempts at source control are mandatory. Timely management of hypovolemic shock is critical. Microbial documentation is rarely available at the onset of management; thus early antimicrobial therapy should be broad. At present the best empiric choices for serious gram-positive infections include vancomycin (Vancocin), linezolid (Zyvox), daptomycin (Cubicin), and tigecycline (Tygacil). The dosing schedule is summarized in Table 2.
Antimicrobial coverage may then be narrowed as the clinical picture and culture results become available to the clinician.
Empiric Antibiotics for Gram-Positive Infections
|Agent Dose (adjust for renal dysfunction)|
|Vancomycin* (Vancocin)||15–20 mg/kg q12h (up to 4 g daily)3|
|Tigecycline (Tygacil)||Start with 100 mg × 1, then 50 mg q12h|
|Daptomycin* (Cubicin)||6–8 mg/kg q24h3|
|Clindamycin (Cleocin)||900 mg q8h|
|Linezolid (Zyvox)||600 mg q12h|
3 Exceeds dosage recommended by the manufacturer.
* Requires renal adjustment.
Semisynthetic penicillins and cephalosporins increase TSST-1 in culture, probably by lysis or increased cell membrane permeability. In the setting of increasing incidence of methicillin-resistant Staphylococcus aureus, these drugs should be avoided as empiric therapy. There is no obvious direct effect of vancomycin on toxin production while clindamycin has been shown to reduce TSST-1 by 90%. Thus, use of clindamycin in combination with a second agent such as vancomycin results in a potentially beneficial effect by decreasing the synthesis of TSST-1.
For streptococcal TSS, clindamycin is more effective because its antimicrobial activity is not affected by the inoculum size or dependent on penicillin-binding proteins; because it acts by inhibiting protein synthesis, it also inhibits the synthesis of antiphagocyte M protein and bacterial toxins (SPEs), subsequently reducing the superantigenicity of SPEs. It has a longer postantibiotic effect than β- lactams. Thus clindamycin is recommended although not as empiric monotherapy because up to 20% of GAS are resistant to it. Linezolid also has the ability to suppress toxin synthesis and may be an alternative as monotherapy or in combination with vancomycin.
Antimicrobial therapy should be continued for at least 10 to 14 days to eradicate the organism and prevent recurrences. The total duration should be based on the usual duration established for the underlying focus of infection.
A thorough and continuous search for possible sites of infection is key to eliminate any preformed toxin and to prevent further synthesis of toxins. Removal of suspect foreign bodies especially tampons is mandatory. Surgical wounds should be considered as possible reservoirs of infection, even if no superficial signs of local infection or purulent discharge are present. Infected wounds should be inspected, any packing should be removed, and abscesses should be drained and irrigated. Culture specimens from all possible sites should be obtained. Patients suspected of having necrotizing fasciitis should have urgent surgical intervention for fasciotomy and debridement.
With clostridium species, the presence of an anaerobic environment enhances growth and toxin production. Thus drainage and aggressive removal of necrotic tissue is important. Older literature suggests that total hysterectomy is often required. Antimicrobial agents with anaerobic coverage should be foremost for gram-positive infection.
Inhibitors of protein synthesis such as clindamycin, linezolid, and fluoroquinolones may be of additional benefit.
Intravenous immunoglobulin (IVIG)1 may be of value when given in addition to appropriate antimicrobial therapy. The neutralizing and protective activity against the superantigenic toxins has been reviewed but results appear variable. There are no current guidelines for the use of IVIG, but it may be used for TSS resulting from an infection refractory to several hours of aggressive therapy.
Control and monitoring of shock and individual organ dysfunction are best achieved in the setting of the intensive-care unit. There, active fluid resuscitation, early use of vasopressors or inotropes, or both, and mechanical ventilation if required are done. Appropriate management of associated problems such as renal failure and adult respiratory distress syndrome must be addressed. Monitoring of hemodynamic status and constant surveillance by repeated clinical examination and laboratory investigation searching for evidence of increasing burden of toxin production and subsequent clearance of the source of infections provide the highest chances of survival and equally prevention of further comorbidities related to irreversible organ system damage. Table 3 summarizes the characteristics of TSS by organism.
Summary of Toxic Shock Syndrome by Organism
Abbreviations: SEB = staphylococcal enterotoxin serotype B; SEC = staphylococcal enterotoxin serotype C; SPE A = streptococcal pyrogenic exotoxin serotype A; SPE C = streptococcal pyrogenic exotoxin serotype C.
1 Not FDA approved for this indication.
Besides the obvious mortality, long-term morbidity was observed in up to 90% of TSS cases, with 20% experiencing recurrent episodes, 50% having long-term memory loss and abnormal electrocardiographic findings, and 23% having recurrent syncope or cardiomyopathy.
1. Andrews M., Parent E.M., Barry M., Parsonnet J. Recurrent nonmenstrual toxic shock syndrome: clinical manifestations, diagnosis, and treatment. Clin Infect Dis. 2001;32:1470–1479.
2. Annane D., Clair B., Salomon J. Managing toxic shock syndrome with antibiotics. Expert Opin Pharmacother. 2005;5:1701–1710.
3. Aranoff D.M., Ballard J.D. Clostridium sordellii toxic shock syndrome. Lancet Infect Dis. 2009;9:725–726.
4. Centers for Disease Control and Prevention. Toxic Shock Syndrome. Case definition. 2011. https://wwwn.cdc.gov/nndss/conditions/streptococcal-toxic- shock-syndrome/case-definition/2010 . [Accessed August 11, 2016].
5. Centers for Disease Control and Prevention. Streptococcal Toxic Shock Syndrome. Case definition. 2010. https://wwwn.cdc.gov/nndss/conditions/toxic-shock- syndrome-other-than-streptococcal/case-definition/2011 . [Accessed August 11, 2016].
6. Cohen A.L., Bhatnagar J., Reagan S., et al. Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion. Obstet Gynecol. 2007;110:1027–1033.
7. Devries A.S., Lesher L., Schlievert P.M., et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics. PLoS One. 2011;6(8):e22997. doi:10.1371/journal.pone.0022997 [accessed 01.12.11].
8. Herzer C.M. Toxic shock syndrome: broadening the differential diagnosis. J Am Board Fam Pract. 2001;14:131–136.
9. Lappin E., Ferguson A.J. Gram-positive toxic shock syndromes. Lancet Infect Dis. 2009;9:281–290.
10. McCormick J.K., Yarwood J.M., Schlievert P.M. Toxic shock syndrome and bacterial superantigens: an update. Annu Rev Microbiol. 2001;55:77–104.
11. Stevens D.L. Streptococcal toxic-shock syndrome: spectrum of disease, pathogenesis, and new concepts in treatment. Emerg Infect Dis. 1995;1:69–78.
12. Stevens D.L., Wallace R.J., Hamilton S.M., Bryant A.E. Successful treatment of staphylococcal toxic shock syndrome with linezolid: a case report and in vitro eradication of the production of toxin shock syndrome staphylococcal toxin type 1 in the presence of antibiotics. Clin Infect Dis. 2006;42:729–730.
1 Not FDA approved for this indication.