eMedicine Specialties > Emergency Medicine > Infectious Diseases

Toxic Shock Syndrome

Author: Vicken Y Totten, MD, MS, FACEP, FAAFP, Assistant Professor, Case Western Reserve University School of Medicine; Director of Research, Department of Emergency Medicine, University Hospitals, Case Medical Center
Coauthor(s): Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center
Contributor Information and Disclosures

Updated: Jan 6, 2010

Introduction

Background

Toxic shock syndrome (TSS) is a shock syndrome caused by the inflammatory response to toxins produced by various bacteria, most commonly Streptococcus and Staphylococcus species. Staphylococcal toxic shock syndrome was first described by Todd et al in 1978.1 He described 7 children aged 8-17 years who had shock from Staphylococcus aureus infection, distinguishable from the scalded skin syndrome. Cone et al, in 1987, published observations on 2 patients with streptococcal toxic shock.2

The image below shows group A streptococci on Gram stain of blood isolated from a patient who developed toxic shock syndrome.

Group A streptococci on Gram stain of blood isola...

Group A streptococci on Gram stain of blood isolated from a patient who developed toxic shock syndrome. Courtesy of T. Matthews.

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Group A streptococci on Gram stain of blood isola...

Group A streptococci on Gram stain of blood isolated from a patient who developed toxic shock syndrome. Courtesy of T. Matthews.


The syndrome gained notoriety after the publication in 1981 of an association between TSS and tampon use in healthy menstruating women.3 The findings of the informal Working Group on Severe Streptococcal Infections, published in 1993, differentiated TSS from other severe invasive group A streptococci (GAS) infections by the early development of hypotension.4 The disease has subsequently been described in patients of all ages and races and in both genders.

In 1995, the Centers for Disease Control and Prevention (CDC) published a Case Definition for Streptococcal Toxic Shock Syndrome and updated it in 1996. In 1997, the CDC published a Confirmed Case Definition for Toxic Shock Syndrome (TSS), which removed the requirement for culture-positive streptococcal species and specifically permitted Staphylococcus aureus infection to be included in the definition.5 The case definition no longer requires confirmation of infection by a specific organism.

TSS has been linked to many initiating bacterial infections, including pneumonia, osteomyelitis, sinusitis, and skin, as well as gynecologic conditions and infections.

The case definition of TSS includes a temperature higher than 38.9°C, hypotension (septic shock), the typical diffuse erythroderma followed by desquamation (unless the patient dies before desquamation can occur), and involvement of at least 3 organ systems. Criteria for a probable case are met when a patient lacks only one of the characteristics of the confirmed case definition.5 For more information, see Toxic-Shock Syndrome Clinical Case Definition from the CDC.

Pathophysiology

Toxic shock syndrome is the result of the immune system’s reaction to one or more of a large family of true exotoxins referred to collectively as pyrogenic toxin superantigens, which are produced by certain streptococci and staphylococci. Superantigens (Sags) cause T-cell activation, which, in turn, activates other cell types, and causes prodigious release of cytokines and chemokines. Sags bind to various T-cell receptors, which can activate up to 20-30% of T cells. (Typical antigens activate only 0.01% of T cells.) The structures of the specific toxins vary by bacterial genetic subtype. Superantigen and endotoxin are clearly both toxic, with the latter responsible for septic shock in gram-negative sepsis. Both given together, however, is 50,000 times more lethal than with either toxin given by itself.6
 
Additionally, some of the bacteria that cause TTS may also express a complement-inhibiting protein (also known as streptococcal inhibitor of compliment or sic), an exotoxin (speA), an iron (III) binding factor, collagen binding factor (cpa), and fibrinogen binding factor (prt2-like).7 Not all of these factors are expressed by every bacterium that has been implicated in toxic shock syndrome (TSS).

Most cases of menstrual TSS (mTSS) are associated with superantigen exotoxin TSS toxin-1 (TSST-1). Nonmenstrual TSS can be caused by TSST-1 (50%) or by staphylococcal enterotoxin B (SEB) or staphylococcal enterotoxin C (SEC) (together account for nearly 50%), but nonmenstrual TSS can be associated with any of the 15 other described Sags. They are most often associated with S aureus strains that make TSST-1, staphylococcal enterotoxin B (SEB), or staphylococcal enterotoxin C (SEC). Nonmenstrual TSS commonly follows bacterial superinfection of the upper respiratory tract after viral infection.

Many of the enterotoxins have been characterized. Sequencing studies indicate that there is overlap among many of these enterotoxins, streptococcal pyrogenic exotoxins, and staphylococcal enterotoxins. Staphylococcal enterotoxins B and C were found to share nearly 50% sequence homology with streptococcal scarlet fever toxin A, although they share no homology with TSST-1.9 TSST-1 and streptococcal pyrogenic exotoxin B and C share little, if any, sequence similarity with any of the other toxins.8

It is the surface-exposed group A streptococcal (GAS) protein M (of which over a hundred subtypes have been identified) that is a primary determinant of virulence.

Endotoxin mechanism of action
Normal antigens are taken up by T cells and processes before recognitions. Superantigens, on the other hand, do not require processing by antigen-presenting cells. They instead interact directly with the invariant region of the class II major histocompatibility complex (MHC) molecule of human T cells.

In typical T-cell recognition, an antigen is taken up by an antigen-presenting cell, processed, expressed on the cell surface in complex with class II MHC in a groove formed by the alpha and beta chains of class II MHC. This complex is recognized by an antigen-specific T-cell receptor.11 The superantigen-MHC complex then interacts with the T-cell receptor and directly stimulates human T cells (up to 20% at a time) to release massive amounts of the cytokines that cause the main clinical features of TSS.

These cytokines cause the typical clinical features of TSS. These cytokines include interleukin-1β (an endogenous pyrogen), which is probably responsible for the high fevers associated with TSS; tumor necrosis factor-α and β (TNF α and β), which cause capillary leakage hypotension and edema; and finally interferon-γ and interleukin 2, which are implicated in the typical rash.12 Additionally, interleukin 1 (IL-1) is released. It is an endogenous pyrogen and thus causes the high fevers associated with TSS. IL-1 mediates skeletal muscle proteolysis and probably accounts for the myalgia and elevated creatine phosphokinase (CPK) level seen in TSS.13,11 The superantigen-MHC complex then interacts with the T-cell receptor and directly stimulates human T cells (up to 20% at a time) to release massive amounts of the cytokines that cause the main clinical features of TSS.

TNF inhibits both random and chemotactic migratory polymorphonuclear leukocyte (PMN) functions. TSST-1–producing S aureus do not engender a purulent response, which, in part, may be explained by PMN inhibition.14 The streptococcal pyrogenic exotoxin B (SpeB) probably also damages PMNs via mitochondria damage and thus impedes early immune clearance.15 TSST-1 and enterotoxin B may repress the production of other S aureus exoproteins. These responses may explain the absence of purulence in TSS caused by S aureus infections.16

Frequency

United States

In 1980, the rates of staphylococcal TSSranged from 2.4-16 cases per 100,000 persons.17 Subsequently, rates of menstrual-related TSS (mTSS) declined thereafter, likely secondary to a decrease in the use of superabsorbent tampons.

The 1995-1999 epidemiology of invasive group A streptococcal disease in the United States was investigated by O'Brien et al who found 3.5 cases per 100,000 persons. Rates varied by age (higher among those <2 or >65 years old), surveillance area, and race (higher among black individuals), but the rate did not increase during the study period. They found that certain M subtypes (1, 28, 12, 3, and 11) accounted for 49.2% of isolates.

Thereafter, the incidence of staphylococcal TSS in Minneapolis-St. Paul, Minnesota, rose from 0.8 per 100,000 in January 2000 to 3.4 per 100,000 by December 2003.8,9

Schlievert hypothesized, in a letter to the editor,20 that the increase in incidence resulted partly from the emergence of 3 new strains of methicillin-resistant Staphylococcus aureus (MRSA) and partly from a decreasing age of menarche, which may have put more women at risk of menstrual TSS, and possibly because of a broader definition on the part of the reporting physicians than the strict CDC definition.

These 3 newly emerging MRSA strains are in CDC nomenclature:

  • USA 1100 (TSST-1 positive)
  • USA 400 (SEB/SEC, Panton–Valentine leukocidin [PVL] positive)
  • USA 300, which is positive for an unknown superantigen as well as PVL)
Two of these are emerging worldwide.

Schlievert et al found that the USA 1100 strains (which, in 2004, comprised 20% of submitted isolates, compared to none before the year 2000) were particularly virulent.8,19 These strains produce 10-100 times more TSST-1 in vitro than their MRSA counterparts and may cause menstrual TSS even in women using lower-absorbency tampons.

The USA 400 and USA 300 strains are also emerging and are associated with increases in nonmenstrual toxic shock syndrome. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts.8

International

The prevalence and distributions of group A streptococci (GAS) in Canada have historically been similar to those in the United States. During 1993-1999, the National Centre for Streptococcus (NCS) in Canada detected 54 M types, of which 10 different M types constituted 73.5% of the samples. M1 was the most common GAS M and responsible for more than a quarter of the isolates. The most common throat isolates differed in M-type and proportion from invasive isolates.10

O'Grady et al reported in 2007 that, in Victoria, Australia, the average annual incidence rate of invasive GAS was 2.7 (95% confidence interval [CI], 2.3-3.2) per 100,000 population per year. They also found rates highest in the very young and very old (<5 and >65). The case-fatality rate was 7.8%. Streptococcal toxic shock syndrome occurred in 48 patients (14.4%), with a case-fatality rate of 23%. They reported no MRSA, and only 4% of isolates were resistant to erythromycin.21

In Sweden in 1994 and 1995, Svensson et al found a lethality of 37% in the 113 patients who developed streptococcal toxic shock syndrome. Serotype T1 dominated during the study period. They did not describe the population incidence.22 Denmark maintains a National Streptococcus Unit. In 2005, Ekelund et al reported that the incidence of invasive GAS infections in the Danish population was 2.3 per 100,000 per year, and STTS occurred in 10% of patients, of whom 56% died. Seventy-two percent of 493 emm types isolated were types 1, 3, 4, 12, 28, and 89. From 1999-2002, the percentage of emm 1 increased from 16% to 40%, and emm 3 decreased from 23% to 2%. The emm 1 isolates predominantly carried speA, although the frequency decreased from 94% in 1999 to 71% in 2002. During the same period, the emm1-specific prevalence of speC increased from 25% to 53%.23

In the Netherlands, Gooskens et al reported that, in 2005, a macrolide-lincosamide-streptogramin B antibiotic–resistant GAS (cMLS or iMLS phenotype) associated with streptococcal toxic shock syndrome (STSS) was caused by an iMLS resistant T28 M77 Streptococcus.24

In Japan between 2001 and 2005, 5 toxic shocklike syndrome cases in nonpregnant adults grew Streptococcus agalactiae, serotypes Ib, III, V, and VII, a previously rarely reported isolate.25

Mortality/Morbidity

Independent predictors of death from toxic shock syndrome (TSS) include infection with streptococci of serotype T1, diabetes, age younger than 2 or older than 75 years, presence of streptococcal toxic shock syndrome, concomitant meningitis or pneumonia, and infection with genetic variant types emm 1 or emm 3. 

O'Brien et al estimated that 9,600-9,700 cases of invasive group A streptococci (GAS) disease occur in the United States each year, resulting in 1,100-1,300 deaths.18

Race

Little information is available on the effect of race per se on toxic shock syndrome (TSS). Parsonnet et al studied more than 3000 women in North America and found that 25% were colonized by S aureus and 9% were vaginally colonized. Although the vast majority of women had adequate antibody titers, a significantly lower percentage of black women than women of white or Hispanic ethnicity were found to have high antibody titers to TSST-1.26  

Related race information comes from sepsis studies. Dombrovskiy et al studied the influence of race on occurrence and outcomes of sepsis. They found that blacks who were hospitalized for sepsis were significantly younger than whites, blacks had greater hospitalization rates than whites, blacks had higher age-adjusted rates for hospitalization and mortality, but similar case-fatality rates, and concluded that hospital care was equally as good for blacks as whites. The differences, they postulated, were due to preexisting factors. Black patients had a greater likelihood of preexisting human immunodeficiency virus infection, diabetes, obesity, burns, and chronic renal failure than white patients. They had a smaller likelihood of cancer, trauma, and urinary tract infection.27

Thus, the effect of race is most likely due to other factors.

Sex

  • Menstrual-associated toxic shock syndrome (TSS) is a disease affecting only women. 
  • Nonmenstrual TSS affects either gender equally.

Age

Incidence: The lethality of toxic shock syndrome (TSS) is, in part, due to the invasiveness of the organisms and, in larger part, due to the hyperstimulation of the immune system. Young adults have the most vigorous immune system and may be more likely than individuals with less reactive immune systems to develop the full toxic shock syndrome.

Death: Untreated, however, the very young, very old, and otherwise feeble are more likely to succumb to TSS.

  • Staphylococcal TSS occurs primarily in patients aged 15-35 years.
  • Streptococcal TSS occurs primarily in patients aged 20-50 years.
  • Menstrual TSS predominantly occurs in young, healthy, menstruating women who use tampons.

Clinical

History

The symptoms are similar for streptococcal TSS and staphylococcal TSS.

Symptoms may include the following:

  • Prodromal period of 2-3 days
  • Fever and/or chills
  • Nausea and/or vomiting
  • Profuse watery diarrhea with abdominal pain
  • Lightheadedness and/or syncope
  • Myalgias and/or arthralgias
  • Pharyngitis and/or headache
  • Confusion (more common with staphylococcal TSS than with streptococcal TSS)
  • Pain (severe) at site of infection (most common symptom of streptococcal TSS): This pain is way out of proportion to the findings, which may be trivial, such as muscle strain, blunt trauma, hematoma, or joint effusion.
  • Additionally, one may find concomitant meningitis, pneumonia, and soft tissue infection.

Physical

To meet CDC criteria for toxic shock syndrome (TSS), one must find fever, rash, shock, and multisystem involvement. See Toxic-Shock Syndrome Clinical Case Definition from the CDC.

  • Temperature >38.9°C (102°F)
  • Rash 
    • Initial diffuse, macular, red rash that is sometimes patchy; may have sand-paper-like texture
    • Appears initially on the trunk, then spreads to the arms and legs; will involve the palms and soles
    • If the patient survives, the rash typically desquamates 1-2 weeks after onset of illness.
    • Desquamation is especially prominent on the palms, as shown in the image below, and soles.

A 46-year-old man presented with nonnecrotizing c...

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The patient had diffuse erythroderma, a characteristic feature of the syndrome. The patient improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over palms and soles. Courtesy of Rob Green, MD.

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A 46-year-old man presented with nonnecrotizing c...

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The patient had diffuse erythroderma, a characteristic feature of the syndrome. The patient improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over palms and soles. Courtesy of Rob Green, MD.


    • Hyperemia of mucus membranes, such as conjunctiva and vaginal or oral mucosa, as shown in the image below, may be a confluent version of the cutaneous rash.

A 46-year-old man presented with nonnecrotizing c...

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. This patient also had streptococcal pharyngitis. Courtesy of Rob Green, MD.

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A 46-year-old man presented with nonnecrotizing c...

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. This patient also had streptococcal pharyngitis. Courtesy of Rob Green, MD.


  • Shock 
    • Systolic blood pressure (SBP) less than or equal to 90 mm Hg (for adults); less than 5th percentile by age for children younger than 16 years, or
    • orthostatic drop in diastolic blood pressure greater than or equal to 15 mm Hg from lying to sitting, or
    • orthostatic syncope, or
    • orthostatic dizziness
  • Multisystem involvement requires 3 or more of the following: 
    • Gastrointestinal - Vomiting or diarrhea at onset of illness
    • Muscular - Severe myalgia or creatine phosphokinase level at least twice the upper limit of normal; necrotizing fasciitis and/or myositis
    • Mucous membrane hyperemia - Vaginal, oropharyngeal, or conjunctival
    • Central nervous system - Disorientation or alteration in consciousness without focal neurologic signs when fever has been controlled, and when hypotension is absent; CNS abnormalities particularly associated with nonmenstrual staphylococcal toxic shock syndrome
    • Respiratory - Acute respiratory distress syndrome; pneumonia; reactive airways may be more reactive28
    • Hematologic - Disseminated intravascular coagulation (DIC); thrombocytopenia
    • Renal - Renal complications particularly associated with nonmenstrual staphylococcal toxic shock syndrome

Causes

Toxic shock syndrome (TSS) is caused by the reaction of the human immune system to bacterial superantigens. A defect of protective immunity is postulated to be a major risk factor for recurrence of TSS.

Superantigens are produced by various species of coagulase-positive staphylococci, most notably Staphylococcus aureus but also the zoonoses Streptococcus suis (common in pigs), Streptococcus mitis (in mice), and Streptococcus agalactiae. Group A beta-hemolytic streptococci notably (Streptococcus pyogenes) also produce superantigens. 

Most people acquire both streptococcal and staphylococcal infections in childhood and have some level of protective immunity against the bacteria. Immunity against the toxins is less widespread, but as many as 80% of young women have been reported to have antibodies to TSST-1.13

With staphylococcal toxic shock syndrome, a menstrual type is associated with menstruation and use of tampons and a nonmenstrual variety is associated with antibiotic usage or nosocomial etiology. Risk factors include the following:

  •  Body cavity packing 
    • Use of superabsorbent tampons
    • Nasal packing
    • Wound packing
    • Uterine packing after postpartum hemorrhage
    • Rhinosinusitis in children29
  • Other risk factors 
    • Postoperative wound infection
    • Postpartum state
    • Common bacterial infections
    • Viral infection with influenza A or varicella
    • Group A streptococcal pharyngitis in a healthy man with death in 24 hours30
    • Diabetes mellitus
    • HIV infection  
    • Chronic cardiac and/or pulmonary disease
    • An association of TSS with prior use of nonsteroidal anti-inflammatory drugs has been suggested, but a causal relationship has not been established.
    • Nipple piercing31
Antibody responses

Both streptococci and staphylococci are prevalent in the environment, and most persons encounter both the bacteria and their toxins in early life without developing toxic shock syndrome. About 75% of adults have antibodies against TSST-1, and, by mid-adult life, the percentage is more than 90%.32,13 Unfortunately, some persons fail to develop antibodies to some of the less common staphylococcal enterotoxins. Patients with clinical TSS lack antibody to TSST-1 and often fail to develop appropriate antibodies even in convalescent serum.33 Individuals with TSS may fail to develop an appropriate antibody response because superantigen-mediated production of IFN-gamma inhibits polyclonal immunoglobulin production.9 These people are more likely to relapse after a first episode of TSS. Those with menstrual toxic shock syndrome frequently experience recurrence, but this occurs rarely in the nonmenstrual variety.

More on Toxic Shock Syndrome

Overview: Toxic Shock Syndrome
Differential Diagnoses & Workup: Toxic Shock Syndrome
Treatment & Medication: Toxic Shock Syndrome
Follow-up: Toxic Shock Syndrome
Multimedia: Toxic Shock Syndrome
References
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Further Reading

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Keywords

toxic shock syndrome, TSS, toxic shock, toxic shock syndrome symptoms, toxic shock syndrome causes, toxic shock syndrome treatment, endotoxin, exotoxin,  Streptococcus pyogenes exotoxin A, SPEA, S pyogenes exotoxin B, SPEB, streptococcal toxic shock syndrome, staphylococcal toxic shock syndrome, pyrogenic toxin superantigens, menstrual toxic shock, nonmenstrual toxic shock

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Contributor Information and Disclosures

Author

Vicken Y Totten, MD, MS, FACEP, FAAFP, Assistant Professor, Case Western Reserve University School of Medicine; Director of Research, Department of Emergency Medicine, University Hospitals, Case Medical Center
Vicken Y Totten, MD, MS, FACEP, FAAFP is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Theodore J Gaeta, DO, MPH, FACEP, Clinical Associate Professor, Department of Emergency Medicine, Joan and Sanford Weill Medical College at Cornell University; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine
Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: Alliance for Clinical Education, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council of Emergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Mark L Plaster, MD, JD, Executive Editor, Emergency Physicians Monthly
Mark L Plaster, MD, JD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians
Disclosure: M L Plaster Publishing Co LLC Ownership interest Management position

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

 
 
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