Toxic Shock Syndromes

INTRODUCTION

The two classic toxic shock syndromes are attributed to Staphylococcus aureus or to group A Streptococcus (Streptococcus pyogenes). Each is a life-threatening illness stemming from toxin production by gram–positive organisms, creating hemodynamic compromise and fulminant multiorgan dysfunction. This cascade makes diagnosis a challenge, with the features looking like the more common entities of sepsis and septic shock. Characteristic epidemiology, pathophysiology, clinical presentations, and management strategies set these syndromes apart (Table 150-1). Early recognition and definitive treatment are the keys to improving patient outcomes.

TABLE 150-1 Distinguishing Characteristics of Toxic Shock Syndrome and Streptococcal Toxic Shock Syndrome

	Toxic Shock Syndrome (TSS)	Streptococcal Toxic Shock Syndrome (STSS)
Organism	Staphylococcus aureus (including MRSA)	Group A Streptococcus(Streptococcus pyogenes)
Toxin	Toxic shock syndrome toxin-1 (TSST-1) Staphylococcal enterotoxins	Streptococcal pyrogenic exotoxins (most commonly A and B)
Risk factors	Retained foreign body (e.g., tampon, female barrier contraceptive) Skin and soft tissue infections Varicella Surgery Trauma Childbirth Influenza	Necrotizing soft tissue infections Varicella Surgery Trauma Childbirth Influenza
Presence of pain	Uncommon	Common
Presence of rash	Common	Uncommon
Blood culture positivity	5%	60%
Mortality	≤5%	20%–45%

STAPHYLOCOCCAL TOXIC SHOCK SYNDROME

INTRODUCTION AND EPIDEMIOLOGY

Staphylococcal toxic shock syndrome (TSS) was first described in 1978 in a series of seven children presenting with systemic illness punctuated by fever, headache, confusion, vomiting, diarrhea, scarlatiniform rash, desquamation, hypotension, and multiorgan dysfunction.¹ A toxigenic strain of S. aureus isolated from mucosal (nasopharyngeal, tracheal, vaginal) and sequestered sites (abscess, empyema) in five of the patients was the causative organism. During the early 1980s, TSS was linked to tampon use in young menstruating women,^2,3 with incidence rates as high as 13.7 per 100,000 menstruating women between the ages of 15 and 24.⁴ Education on the proper frequency and duration of use of tampons coupled with the removal of highly absorbent tampons from the market are widely credited with reducing menstrual TSS rates, although tampon use remains an important risk factor for menstrual TSS to this day in the United States, Canada, and Western Europe.

Nonmenstrual TSS is associated with a wide range of skin and soft tissue infections including abscesses, cellulitis, mastitis, and infected surgical and postpartum wounds, including vaginal and cesarean deliveries.⁵ Sinusitis and superimposed infections of burns, abrasions, and varicella lesions have been described in other cases, particularly in children. Patients with influenza may develop TSS in the setting of secondary S. aureus respiratory tract infections (e.g., pneumonia, tracheitis).⁶ Because the vagina and nares are known sites of S. aureus colonization, retained foreign bodies, including female barrier contraceptives (e.g., diaphragm, contraceptive sponge) and nasal packing material, are risk factors for developing nonmenstrual TSS. Nasal packing is not a current common trigger, and routine prescription of antibiotics is not needed to stop this from occurring.⁸ Nonmenstrual TSS affects men and women alike, and patients tend to be older and have more comorbid illnesses than those seen with the menstrual form of the disease.

Population-based surveillance shows that TSS incidence has been sTable in the United States for the past 30 years.^9,10 Women between the age of 13 and 24 years have a higher incidence of menstrual TSS, at a rate of 1.41 per 100,000 persons.⁹ The overall case fatality rate for TSS is 4.1%, with higher rates in nonmenstrual TSS (5%) compared to menstrual TSS (3%).¹¹

PATHOPHYSIOLOGY

TSS is a superantigen-mediated disease. Toxigenic S. aureus strains produce pyrogenic exotoxins including toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxins that bind directly to the major histocompatibility complex class II molecule and T-cell receptor on antigen-presenting cells.¹² Massive T-cell and antigen-presenting cell activation leads to enhanced cytokine expression (e.g., interleukin-1, -2, and -6; tumor necrosis factor-α; interferon-γ), establishing a proinflammatory state. Increased vascular permeability, hemodynamic shock, metabolic acidosis, coagulopathy, and multiorgan dysfunction ensue, mirroring that of the cascade triggered by lipopolysaccharide (endotoxin) in gram-negative sepsis.

Almost all menstrual TSS cases are tied to TSST-1.^13,14 Disease starts with colonization of the vagina by a toxigenic strain of S. aureus capable of producing TSST-1. Approximately 9% of women are vaginally colonized with S. aureus, only 1% of whom are considered toxigenic.¹⁵ TSST-1 must cross the vaginal epithelium for clinical disease to occur, and the host cannot possess neutralizing antibodies to TSST-1 that might confer immunity. One reason why menstrual TSS rates have remained low yet consistent throughout the years may be due to the development of durable immunity to TSST-1,¹⁵ perhaps from either transient or persistent asymptomatic colonization with toxigenic S. aureus.¹⁶

In contrast to menstrual TSS, TSST-1 is implicated in only half of nonmenstrual TSS cases,¹⁷ with the remaining share attributed to staphylococcal enterotoxin B and other members of that family.¹⁸ Vulnerability to nonmenstrual TSS usually starts with infection or colonization involving a toxigenic strain of S. aureus at a localized site, notably mucosa, skin, wound, lung, or a foreign body.

CLINICAL FEATURES

A case definition created for the National Notifiable Diseases Surveillance System by the U.S. Centers for Disease Control and Prevention (Table 150-2) provides criteria for reporting TSS in its most severe form, although many of these symptoms may not be evident on initial evaluation of the patient presenting to the emergency department and should not be used to exclude the diagnosis of TSS. These definitions are periodically updated at the National Notifiable Diseases Surveillance System Web page (http://wwwn.cdc.gov/nndss).

TABLE 150-2 Case Definition for Toxic Shock Syndrome

Clinical criteria:

• Fever: temperature ≥38.9°C or 102.0°F

• Rash: diffuse macular erythroderma

• Desquamation: 1–2 weeks after onset of rash

• Hypotension: systolic blood pressure ≤90 mm Hg (adult) or <5th percentile by age (children <16 years of age)

• Multiorgan involvement (≥3 organ systems):

Gastrointestinal: vomiting and/or diarrhea at onset of illness
Muscular: severe myalgia or CPK ≥2 times the upper limit of normal
Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia
Renal: BUN or serum Cr ≥2 times the upper limit of normal for laboratory or urinary sediment with pyuria (≥5 leukocytes per high-power field) in the absence of urinary tract infection
Hepatic: total bilirubin, ALT, or AST ≥2 times the upper limit of normal
Hematologic: platelet count <100,000/mm³
Central nervous system: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent

Laboratory criteria:Negative results on the following tests, if obtained:

• Blood or cerebrospinal fluid cultures (blood culture may be positive for Staphylococcus aureus)

• Serologies for Rocky Mountain spotted fever, leptospirosis, or measles

Case classification:

• Probable: ≥4 clinical criteria + laboratory criteria met

• Confirmed: 5 clinical criteria + laboratory criteria met, including desquamation (unless death occurs prior to desquamation)

Time of onset of initial symptoms is highly variable, ranging from as little as 48 hours in postoperative nonmenstrual TSS⁵ to several days after the start of menstruation in menstrual TSS.³ Patients presenting early on in the disease process may exhibit a nonspecific prodrome consisting of any combination of fever, chills, malaise, myalgias, headache, sore throat, vomiting, diarrhea, or abdominal pain. The progression of an unexplained febrile illness to include hypotension, erythroderma, and multiorgan dysfunction should raise clinical suspicion for TSS. Hypotension with a systolic blood pressure of ≤90 mm Hg in adults or less than the fifth percentile for children <16 years of age heralds severe disease as a consequence of systemic vasodilation and increased capillary permeability. Decreased urinary output signals acute kidney injury, which may result from renal hypoperfusion, rhabdomyolysis, or other causes. Lethargy, agitation, and confusion can result from shock or be related to cerebral edema. Respiratory failure can occur from acute respiratory distress syndrome or pulmonary edema from toxic cardiomyopathy. Patients with TSS may also present to care with second- or third-degree heart block or, more rarely, ventricular arrhythmias.

The erythroderma of TSS is characterized as a painless, diffuse, red, macular rash resembling “sunburn.” The rash can be either patchy or confluent, and it can be modest and evanescent, involving the palms and soles. Desquamation, notably of the hands and feet, begins anywhere from 1 to 3 weeks after the initial onset of symptoms. Mucosal involvement can include conjunctival and scleral hemorrhage as well as vaginal, cervical, or oropharyngeal hyperemia (“strawberry tongue”) and ulceration. In the patient at risk for menstrual TSS, pelvic examination gauges mucosal disease and allows a look for retained foreign bodies such as tampons.

Surgical wounds infected or colonized with toxigenic S. aureus in nonmenstrual TSS patients may have little or no erythema, induration, or purulent drainage to raise clinical suspicion of infection,^5,19 likely due to unique properties associated with TSST-1 and staphylococcal enterotoxin B. Any wound in a patient presenting with concern for TSS should be considered a potential source for toxigenic S. aureus.

DIAGNOSIS

Timely diagnosis of TSS relies on identifying patient risk factors; recognizing an evolving pattern of febrile illness, hemodynamic compromise, and organ injury; and considering the diagnosis before profound illness occurs even if all of the case criteria are not met. TSS is a clinical diagnosis.

Laboratory evaluation reveals the adverse sequelae of organ hypoperfusion and dysfunction, but nothing more specific. Usually, a CBC, comprehensive metabolic panel with liver function tests, coagulation studies, creatine phosphokinase level (particularly if myalgias are a primary complaint), urinalysis, chest radiograph, and an ECG are obtained to assess organ function. Leukocytosis, anemia, or thrombocytopenia may be present. Azotemia indicative of acute kidney injury can be accompanied by electrolyte disturbances including hyponatremia, hypocalcemia, and hypophosphatemia.²⁰ Metabolic acidosis in the presence of hypotension is common. Hypoalbuminemia from capillary leakage and liver function abnormalities with coagulopathy can also be seen. Absent coagulopathy, CT of the brain accompanied by lumbar puncture is often needed in those with altered sensorium.

Obtain blood cultures, but positive blood cultures are uncommon: S. aureus is grown in less than 5% of TSS cases.⁵ In contrast, cultures from wounds, mucosal sites, and retained foreign materials are frequently positive for S. aureus. Get all possible cultures early, optimally before initiating antibiotic therapy, to facilitate identification of a toxin-producing strain of S. aureus and to allow antibiotic susceptibility testing.