SUMMARY

The Authors examined toxic shock syndrome

INTRODUCTION

Toxic shock syndrome (TSS) is a severe, life-threatening syndrome characterized by high fever, profound hypotension, diffuse erythroderma, mucous membrane hyperemia, pharyngitis, diarrhea, and constitutional symptoms. It can rapidly progress to multisystem dysfunction with severe electrolyte disturbances, renal failure, and shock. Although first described in 1978 by Todd in seven children with Staphylococcus aureus infections, TSS has been associated primarily with tampon use. In 1981, a nationwide epidemic of TSS associated with continuous tampon use was widely recognized among otherwise healthy young women.

The TSS case definition is given in Table 1. This definition was formulated in 1980 by the Centers for Disease Control and Prevention (CDC) to ensure that cases included in various surveillance studies were the same clinical entity as TSS. In the absence of a definitive laboratory marker, the strict application of the case definition is warranted but undoubtedly excludes the less severe (subclinical) cases.

Since 1980, there have been significant advances in the understanding of the clinical and epidemiologic aspects of TSS. The incidence of reported cases has declined, with a decrease in both the case fatality ratio and the proportion of cases associated with menstruation. At present, the majority of cases occur in settings not related to menstruation and cross all segments of society.

Pathophysiology

Pathophysiology Etiology and Pathogenesis

Most cases of TSS have been directly associated with colonization or infection with S. aureus. Approximately 67 percent of the organisms are phage type I, while 25 percent are nontypable. An exotoxin, toxic shock syndrome toxin (TSST-1) is produced by 20 percent of randomly tested S. aureus isolates. TSST-1 has been implicated as a significant factor in the production of symptoms associated with TSS, either through direct toxic effects on the host or through stimulation of secondary mediators in response to TSST-1. The biologic properties of TSST-1 include the ability to: (1) induce fever directly on the hypothalamus or indirectly via interleukin 1 (IL-1) and tumor necrosis factor (TNF) production; (2) promote T-lymphocyte "superantigenization" and overstimulation; (3) induce interferon production; (4) enhance delayed hypersensitivity; (5) suppress neutrophil migration and immunoglobulin secretion; and (6) enhance host susceptibility to endotoxins.

Ninety percent of menstrual-related cases of TSS (MRTSS) are caused by S. aureus strains that produce TSST-1, whereas only 40 percent of isolates from non-menstrual-related TSS (NMTSS) produce this exotoxin. Enterotoxins B and C have been identified from isolates of NMTSS, with almost identical biochemical structure to TSST-1. This explains the similarity in clinical manifestations seen with both MRTSS and NMTSS. Although an endotoxin of possibly gastrointestinal or genitourinary origin may be involved in the development of TSS associated with TSST-1 and the enterotoxins, there are no data to support its existence.

The amount of TSST-1 produced by toxigenic strains of S. aureus is dependent on a number of factors. Its production in MRTSS is enhanced by certain vaginal conditions: temperature of 39 to 40°C, a neutral pH, a PO2 of > 5%, and supplemental CO2. These conditions can be met with the change in vaginal pH from acidic to neutral during menses and an increase in O2 and CO2 content of the vagina with the introduction of tampons or intravaginal devices. It has also been demonstrated that TSST-1 production is influenced by the concentration of magnesium, the composition of fibers used in tampons, and by a synergistic relationship between S. aureus and Escherichia coli involving tryptophan substrate production.

The most impressive aspect of the pathophysiology is the massive vasodilatation and rapid movement of the serum proteins and fluids from the intravascular to the extravascular space. Hypotension is accounted for by (1) decreased vasomotor tone, causing pooling of blood in the periphery and therein decreased central venus pressure and pulmonary capillary wedge pressure; (2) nonhydrostatic leakage of fluid into the interstitium, causing decreased intravascular volume and generalized nonpitting edema, primarily of the head and neck; (3) depressed cardiac function, including decreased wall motion and decreased shortening fraction; and (4) total body water deficits secondary to vomiting, diarrhea, and fever.

TSST-1 is a potent activator of the immunostimulant cytokines IL-1 and TNF, which appear to be pivotally involved in generating TSS. IL-1 is capable of producing hypoalbuminemia, hypoferrinemia, and proteolysis of skeletal muscle, consistent with the peripheral edema, anemia, and rhabdomyolysis seen in TSS. A potent pyrogen, TNF has been shown in animal models to induce profound acidosis, shock, and multisystem organ failure within hours of infusion. In TSS, this can result in the rapid onset of oliguria, hypotension, and low central venous pressure. The multisystem involvement seen in TSS may be a reflection of the rapid onset of hypotension and decreased perfusion, or there may be direct effects of the toxin or toxins on the parenchymal cells of different organs, yet to be elucidated.

The immunologic status of the individual may play a role in the pathogenesis of TSS. An age-related rise in anti-TSST-1 antibodies has been found in both sexes, with 70 to 80 percent having measurable antibodies by early adulthood and 90 to 95 percent by age 40. Convalescent titers are low in the majority of patients with TSS for up to 1 year after infection.

Epidemiology

Since the CDC began surveillance of TSS in 1979, 3295 definite cases have been reported. The CDC reported a decrease from 900 cases in 1980 to 351 cases in 1988. In 1992, only 44 definite cases of TSS were reported, 51 probable cases, and 3 deaths (only 1 death was definitely due to TSS). Of the 44 definite cases, slightly less than half (20) occurred during menstruation. The decrease in cases is presumably due to changes in the composition of tampons, the general public's awareness of the risks from tampon use, and increased medical awareness and detection. Although the use of contraceptive sponges and diaphragms places the individual at risk, their exact contribution to the development of TSS is unclear.

TSS was initially a disease of young, healthy, menstruating women; 50 percent of cases reported in 1986 and 1987 were found in this group. Tampon use carried a 33 times greater risk of TSS developing in susceptible females. S. aureus has been isolated from the vaginas of 98 percent of women with TSS, compared to an 8 to 10 percent carrier rate in controls. It is presumed that women who develop menstrual TSS are colonized with S. aureus before the onset of menstruation.

The proportion of cases not associated with menstruation (NMTSS) has increased since 1980, primarily because of the decrease in the number of menstruation-related cases. The absolute number of cases of NMTSS has remained relatively constant, however. Nearly 25 percent of NMTSS cases are associated with postpartum and S. aureus vaginal infections. There is an increasing incidence of NMTSS in males. Men comprise one-third of patients with TSS, with a mortality rate 3.3 times that of MRTSS in women. A 50 percent mortality rate has been reported in non-TSST-1 S. aureus infections (i.e., enterotoxin B or C) but only 10 percent in TSST-1 producing S. aureus infections.

The means by which S. aureus enters the host in TSS are numerous and have been well documented in a wide variety of clinical settings. TSS has also been reported following influenza and influenza-like illnesses and is associated with significant mortality (43 percent). Nasal packing (nasal tampons) is also associated with TSS, with 20 to 40 percent of the adult population carrying S. aureus in the nasal vestibule.

Clinical Features and Diagnosis

Clinical Features and Diagnosis Differential Diagnosis

There are other systemic illnesses that are characterized by fever, rash, diarrhea, myalgias, and multisystem involvement and that resemble TSS (Table 2). Kawasaki disease (mucocutaneous lymph node syndrome) is characterized by fever, conjunctival hyperemia, and erythema of the mucous membranes with desquamation. Although the exanthems may be quite similar, Kawasaki disease may present with target lesions resembling erythema multiforme, and the bright-red appearance of the vermillion border is not common in TSS. Further differentiation of Kawasaki disease from TSS lies in the fact that more than 99 percent of those afflicted with Kawasaki disease are under 10 years of age and that Kawasaki disease is not characterized by hypotension, renal failure, or thrombocytopenia.

Staphylococcal scalded skin syndrome (SSSS) is most commonly seen in children less than 5 years of age and is characterized by fever, generalized painful erythroderma, and conjunctivitis. SSSS may be distinguished from TSS by its lack of multisystem involvement. In contrast, staphylococcal scarlet fever is so similar to TSS with the full-thickness desquamation that only pathology specimens or serologic evidence of the exfoliatin toxin will differentiate the two entities. In streptococcal scarlet fever, the "sandpaper" rash is distinct from the macular "sunburn" rash of TSS.

Rocky Mountain spotted fever, a rickettsial infection acquired from tick bites, has a presentation similar to TSS, but the rash is usually petechial and delayed in onset. TEN (toxic epidermal necrolysis) resembles SSSS and occurs primarily in adults. Non-toxin-mediated, it is related to drug exposure and has a bullous component. Erythema multiforme can be associated with fever, pharyngeal erythema, and toxemia. The rash is multiform with symmetric involvement of the lower extremities. Immunologically mediated from a drug exposure or infectious agent, it can progress to Stevens-Johnson syndrome.

Septic shock must always be considered in the differential diagnosis of TSS. In general, the appearance of a rash and the laboratory abnormalities associated with TSS will aid in distinguishing these two entities.

Clinical Presentation

TSS should be considered in any unexplained febrile illness associated with erythroderma, hypotension, and diffuse organ pathology, especially in menstruating women. Diagnostic criteria for TSS are listed in Table 121-1. Patients with MRTSS usually present between the third and fifth day of menses. The median time to onset of illness in postsurgical NMTSS is two postoperative days. There appears to be a spectrum of severity of TSS. Mild cases of TSS may be excluded from the CDC case definition. Mild TSS is generally characterized by fever and chills, myalgias, abdominal pain, sore throat, nausea, vomiting, and diarrhea. Hypotension is usually not present, and the illness is self-limited. Severe TSS is an acute-onset, multisystem disease with symptoms, signs, and laboratory abnormalities reflecting multiple-organ involvement. Headache is the most common complaint. Some patients may experience a prodrome consisting of malaise, myalgias, headache, nausea, vomiting, and diarrhea. Sudden onset of fever and chills occurs approximately 1 to 4 days prior to presentation. Diffuse myalgias, particularly in the proximal aspects of the extremities, abdomen, and back are reported by virtually all patients; arthralgias are also common. Profuse, watery diarrhea and repeated vomiting are reported by 90 to 98 percent of patients. Orthostatic lightheadedness or syncope may be present. Patients also complain of sore throat, headache, paresthesias, and photophobia. The patient may complain of abdominal pain, cough, or sore throat.

Physical examination reveals hypotension or an orthostatic decrease in systolic pressure of 15 mm Hg in all cases. In general, victims of TSS appear acutely ill. The initial state usually lasts about 24 to 48 h; the patient may be obtunded, disoriented, oliguric, and hypotensive. There is an overall body fluid deficit due to losses from fever, vomiting, diarrhea, and decreased systemic vascular resistance. Depressed cardiac function may also be present. Patients may show nonpitting edema of the face and extremities secondary to nonhydrostatic leakage of intravascular fluid into the interstitium. Other prominent signs may include profound muscle weakness and tenderness or abdominal tenderness. The diarrhea is usually watery and profuse, frequently with associated incontinence. One-half to three-quarters of patients have pharyngitis with a strawberry-red tongue; conjunctival hyperemia and vaginitis are also seen. Tender, edematous external genitalia, diffuse vaginal hyperemia, strawberry cervix, scant purulent cervical discharge, and bilateral adnexal tenderness are seen in 25 to 35 percent of patients with menstruation-related TSS.

The rash of TSS is a diffuse blanching erythroderma, classically described as painless "sunburn," which fades within 3 days of its appearance and is followed by full-thickness desquamation during convalescence, especially of the palms and soles. This CDC criterion is most often missed as it may be subtle or difficult to detect in darkly pigmented patients. Variations include patchy erythroderma and localized maculopustular eruptions. In all cases, a fine, generalized desquamation of the skin, with peeling over the soles, fingers, toes, and palms, occurs from 6 to 14 days after the onset of illness. More than 50 percent of severely ill patients experience loss of hair and nails 2 to 3 months later.

Specific focal neurologic findings rarely occur. Patients present with varying degrees of altered consciousness. Approximately 75 percent of patients have nonfocal neurologic abnormalities without signs of meningeal irritation. Confusion, disorientation, agitation, hysteria, somnolence, and seizures have been reported, consistent with a toxic encephalopathy from cerebral edema. If the clinical picture is unclear, CT scan and lumbar puncture should be performed.

Abnormal laboratory values reflect the multisystem involvement in TSS. Leukocytosis with an increase in immature forms is frequently seen; lymphocytopenia has also been reported. A mild anemia with acute hypoferrinemia and abnormal peripheral smears consistent with microangiopathic hemolytic anemia or disseminated intravascular coagulation may be found. Azotemia, myoglobinuria, and abnormal urinary sediment (sterile pyuria and red blood cell casts) are seen as acute renal failure develops. Liver function abnormalities and hyperbilirubinemia are seen in approximately 3 percent of patients with clinical evidence of coagulopathy. Metabolic acidosis secondary to hypotension is also seen. Electrolyte abnormalities, including hypocalcemia, hypophosphatemia, hyponatremia, and hypokalemia, are common. Hypocalcemia will be out of proportion to the degree of hypoalbuminemia and may be difficult to correct if there is a concomitant decrease in the serum magnesium.

Acute renal failure secondary to acute tubular necrosis is a complication of TSS. It appears to be secondary to prerenal deficits, renal ischemia caused by hypotension, rhabdomyolysis, and possibly direct damage from TSST-1 mediators. Ventricular arrhythmias, bundle branch block, first degree heart block, and T-wave and ST-T-wave changes have been reported. Echocardiography of patients with TSS show wall motion abnormalities and decreased shortening fraction suggestive of toxic cardiomyopathy. Adult respiratory distress syndrome (ARDS) with refractory hypotension represents the ultimate end-organ damage secondary to TSS.

Treatment

Management of TSS depends on its severity. The most important aspect of initial management is the aggressive management of circulatory shock. Continuous monitoring of the heart rate, respiratory rate, blood pressure, urinary output, central venous pressure, and pulmonary capillary wedge pressure is necessary. During the first 24 h, patients may require 4 to 20 L of crystalloid and fresh-frozen plasma. There have been reports of patients requiring up to 20 L of fluid in the first 24 h of hospitalization. A dopamine infusion beginning at 5 to 20 µg/kg per minute may be used if volume correction fails to restore normal arterial pressure. Large amounts of intravenous fluid and pressors to treat refractory hypotension can result in the rapid onset of pulmonary edema. ARDS may then complicate TSS and require mechanical ventilation with positive end-expiratory pressure.

Evaluation must include arterial blood gases, CBC screen with peripheral smear, serum electrolytes including Mg2+ and Ca2+, coagulation studies, urinalysis, and chest radiograph. Patients with abnormal coagulation profiles and evidence of bleeding require colloid replacement, fresh-frozen plasma, or transfusions. Thrombocytopenia may require platelet transfusions. An electrocardiogram and echocardiogram may also be indicated.

A focus of infection should be aggressively sought and promptly treated. Cultures of all potentially infected sites should be obtained, including blood cultures, prior to initiating antibiotic therapy. Women with tampon-related TSS should have the tampon removed. Some authors recommend irrigation of the vagina with saline or povidoneiodine solution. Early consultation with a surgeon or a gynecologist is recommended if drainage or debridement of infectious sites is warranted.

Although antimicrobial agents have not been shown to affect the outcome of the acute illness, they are recommended and have been given to most patients to eradicate the focus of toxin-producing staphylococci as well as to decrease the recurrence rate. Antibiotic selection should include an antistaphylococcal penicillin or cephalosporin with b-lactamase stability. Nafcillin or oxacillin in doses of 1 to 2 g every 4 h provides adequate antimicrobial coverage. Cefazolin, 2 g every 6 h, also provides adequate coverage, but the first-generation cephalosporins are less b-lactamase-stable than the antistaphylococcal penicillins. In penicillin-allergic patients clindamycin, vancomycin, and first-generation cephalosporins can be used. Vancomycin, trimethoprim/sulfamethoxazole, or rifampin may be used if methicillin-resistant strains are encountered. Although data on the optimum duration of antimicrobial therapy are not available, it seems prudent to administer parenteral antibiotics for at least 3 days or until the patient clinically improves. Oral antistaphylococcal antibiotics (dicloxacillin or clindamycin in penicillin-allergic patients), should then be administered for an additional 10 to 14 days. Although prospective studies are lacking, the addition of rifampin to the oral regimen is suggested because of the ability of this drug to eradicate the carrier state. Methylprednisolone and intravenous immunoglobulin have shown improvement in TSS in animal studies, but routine use of either of these therapies is currently not recommended.

Most patients become afebrile and normotensive within 48 h of hospitalization. Initial laboratory abnormalities resolve within 1 to 2 weeks, although full anemia correction occurs in 4 to 6 weeks.

Numerous sequelae of TSS have been reported and include late onset of maculopapular rash, decreased renal function, reversible loss of hair and nails, prolonged neuromuscular abnormalities, and cyanotic extremities. Neurologic deficits are common, with 50 percent of patients exhibiting residual memory deficits, decreased ability to concentrate, and diffuse electroencephalographic abnormalities.

The exact mechanism responsible for these sequelae is not yet clear; it has been suggested that they are due to either the delayed effects of the toxin or circulating immune complexes or are drug-mediated.

Up to 60 percent of patients not treated with b-lactamase-stable antimicrobial drugs have recurrence of the disease. Most recurrent episodes of MRTSS occur by the second month following the initial episode and happen on the same day of menses as the prior attack, although some have recurred in less than 1 month and some more than 1 year later. In the majority of patients having recurrence, convalescent antibody titers are low and nonprotective. The initial episode is the most severe, although deaths have resulted from recurrences of initially mild cases of TSS.

STREPTOCOCCAL TOXIC SHOCK-LIKE SYNDROME

In 1987, Cone et al. published a report on two patients having a clinical presentation similar to toxic shock syndrome but due to severe streptococcal infection. In 1993, the CDC responded to the rising number of similar cases and formulated a consensus definition for this apparently new, severe streptococcal infection. Streptococcal toxic shock-like syndrome (TSLS) is now recognized as a life-threatening infection characterized by fever, hypotension, rash, and progressive soft tissue infection caused by Streptococcus pyogenes, a group A hemolytic streptococcus. Similar in presentation to TSS, TSLS progresses rapidly to multisystem organ failure with shock. It is associated with a significantly higher mortality than that of TSS (30 percent versus 5 percent). Since the first report, more than 50 cases of TSLS have been reported in the United States and over 300 cases worldwide.

The CDC case definition of streptococcal toxic shock syndrome is identical to that of TSS (see Table 121-1), except that TSLS develops in association with a severe soft tissue infection and cultures from a normally sterile site (i.e., blood, pleural fluid, surgical wound) must be positive for S. pyogenes. Positive cultures from nonsterile sites (i.e., throat, sputum, vagina) designate a probable case of TSLS. TSLS is reported most often in healthy females (68 percent) with soft tissue infection. However, 20 percent of cases can result from pharyngitis, sinusitis, and abdominal or pelvic sources. Bacteremia is present in 50 percent of cases of TSLS; in contrast, TSS must have negative blood cultures to meet the CDC criterion.

Pathophysiology

Pathophysiology Etiology

The resurgence of invasive streptococcal infection appears to be the result of the production of more virulent exotoxins from isolates of S. pyogenes. Streptococcal pyrogenic exotoxins (SPEs) are produced by 90 percent of group A streptococcal isolates. Three distinct exotoxins (SPEs A, B, and C) have been identified. SPE A, also known as the scarlet fever toxin, is the most powerful of the SPEs and has a similar molecular structure to enterotoxin B of NMTSS. SPE A displays features similar to TSS-mediated exotoxins, including pyrogenicity, superactivation of T cells, and enhanced susceptibility to endotoxinmediated shock. SPE B is associated with a streptococcal cysteine proteinase that inhibits fibrin clot formation and causes myocardial necrosis and death in animal models. Recent studies have demonstrated an association between the lack of antibodies to SPE and the severity of disease. SPE C has been found in fewer S. pyogenes isolates and its role in TSLS is unclear.

Clinical Features

Clinical Features Clinical Presentation

The presentation of TSLS is remarkably similar to TSS. The major difference is that patients with TSLS have an identifiable source of infection, usually a skin or soft tissue infection that is often necrotizing. TSLS has also been caused by pharyngitis, sinusitis, and pneumonia. Patients with TSLS lack the profound CNS changes seen in TSS. The multisystem organ damage of TSLS frequently precedes the onset of hypotension, whereas hypotension is part of the initial presentation of TSS. TSLS appears to progress more rapidly than TSS, particularly in immunocompromised patients in whom death may occur within 24 h of the onset of symptoms and mortality approaches 60 percent. The macular erythroderma is delayed in onset in TSLS, but the rash ultimately progresses to desquamation and occasionally alopecia during convalescence. Laboratory values may show less liver involvement and more profound renal failure than TSS, with positive steptozyme assay and antistreptolysin O titers.

Differential Diagnosis

Treatment

The evaluation and treatment of TSLS and TSS are the same, with aggressive management of shock and organ failure. Frequently, drainage and debridement of necrotic areas are necessary to control infection. Early surgical consultation is appropriate. Unequivocal differentiation of TSLS from TSS is not possible until final culture results are available. Antimicrobial therapy should cover both S. pyogenes and S. aureus. S. pyogenes is sensitive to penicillin G or erythromycin for penicillin-allergic patients. These antibiotics must be included in the treatment for TSS when the causative organism is unknown.

TABLE 1

Criteria for Diagnosis (Must Have All)

1. Temperature >38.9°C (102°F)
2. Systolic BP <90 mmHg, orthostatic decrease of systolic BP by 15 mmHg, or syncope
3. Rash (diffuse, macular erythroderma) with subsequent desquamation, especially on palms or soles of feet
4. Involvement of three of the following organ systems clinically or by abnormal laboratory tests:
   • Gastrointestinal: Vomiting, profuse diarrhea
   • Musculoskeletal: Severe myalgias or twofold increase in CPK
   • Renal: Increase in BUN and creatinine two times normal; pyuria without evidence of infection
   • Mucosal inflammation: Vaginal, conjunctival, or pharyngeal hyperemia
   • Hepatic involvement: Hepatitis (twofold elevation of bilirubin, SGOT, SGPT)
   • Hematologic: Thrombocytopenia < 100,000 platelets/mm3
   • CNS: Disorientation without focal neurologic signs
5. Negative serologic tests for Rocky Mountain spotted fever, leptospirosis, measles, hepatitis B surface antigen, fluorescent antinuclear antibody, VDRL, and monospot; and negative blood, urine, and throat cultures

TABLE 2

Differential Diagnosis of Toxic Shock Syndrome

BIBLIOGRAPHY

1. Centers for Disease Control: Historical perspectives: Reduced incidence of menstrual toxic-shock syndrome—United States, 1980–1990. MMWR 39(25):421, 1990.
2. Cone LA, Woodard DR, Schlievert PM, Tomory GS: Clinical and bacteriological observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 317:146, 1987.
3. Freedman JD, Beer DJ: Expanding perspectives on the toxic shock syndrome. Adv Intern Med 36:363, 1991.
4. Hackett SP, Stevens DL: Superantigens associated with staphylococcal and streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor-b synthesis. J Infect Dis 168:232, 1993.
5. Kain KC, Schulzer M, Chow AW: Clinical spectrum of nonmenstrual toxic shock syndrome (TSS): Comparison with menstrual TSS by multivariate discriminant analyses. Clin Infect Dis 16:100, 1993.
6. The Working Group on Severe Streptococcal Infections of the Center for Disease Control: Defining the group A streptococcal toxic shock syndrome: Rational and consensus definition. JAMA 269(3):390, 1993.