Chapter 60: Toxic Shock Syndrome

• Toxic shock syndrome (TSS) is an acute, toxin-mediated illness characterized by fever, erythematous rash, hypotension, multi-organ involvement, and desquamation.

• Most cases of TSS have been associated with Staphylococcus aureus, However, Group A Streptococcus (GAS) can cause a similar disease known as streptococcal TSS (STSS).

• Menstrual and nonmenstrual cases of TSS are now reported with almost equal frequency. Predisposing factors for nonmenstrual TSS are surgical and nonsurgical trauma, burns, and postpartum conditions. Predisposing factors for STSS are varicella, NSAID use, and deep-seated GAS infections.

• STSS patients may have severe pain and hyperesthesia out of proportion to the degree of skin involvement.

• Management depends on prompt recognition, identification, and removal of the infectious focus. In addition, antibiotics and hemodynamic support are essential.

• Clindamycin has been recommended as the antibiotic of choice for both TSS and STSS (along with penicillin G for GAS).

• TSS can mimic many common diseases and should be considered in any patient who has unexplained fever, rash, and a toxic condition out of proportion to local findings.

TSS is a rare acute febrile disease characterized by fever, diffuse erythroderma (that later desquamates), vomiting, abdominal pain, diarrhea, myalgia, and nonspecific neurologic abnormalities.¹ It can progress rapidly to hypotension, multi-organ failure, and death.²

It was first described in 1978 in seven children with S. aureus infections.³ An epidemic was noted in menstruating women associated with continuous tampon use in 1980. With the withdrawal of superabsorbent tampons from the market and other public health interventions, the incidence of menstrual TSS decreased from 13.7 per 100,000 persons in 1980 to 0.3 per 100,000 in 1986.^4,5 Nonmenstrual TSS has been described in both children and adults in various clinical scenarios ^6,7 Since 1987, a toxic shock-like syndrome similar to that attributable to staphylococcus has been reported due to highly invasive streptococcal infections. Several studies have reported that invasive STSS is more common in adults than children.^8–10 The Centers for Disease Control and Prevention (CDC) use “STSS” to distinguish streptococcal from TSS caused by staphylococcal infection in their case definition.¹¹

Because TSS and STSS are syndromes, the diagnosis is made when several clinical signs are found together (Tables 60-1 and 60-2 for CDC case definitions).^11,12 The rarity of such cases and the difficulty meeting the strict definition are reasons for the paucity of medical literature and specifically prospective studies on TSS. In addition, since 1986, there has not been ongoing population-based active surveillance to assess the incidence or disease burden of TSS.

The pathogenesis of TSS is thought to be related to the production of toxins, referred to as TSS toxin-1 (TSST-1) and to staphylococcal enterotoxins (SE).⁷ It is likely that more than one toxin may be involved. These toxins are thought to be superantigens, which are a group of proteins that can overactivate the immune system bypassing certain steps in the usual antigen-mediated immune response sequence.¹³ This causes massive T-cell stimulation and an overwhelming immune cascade with cytokines that is destructive to all end organs. The conventional antigen presentation activates around 0.01% of the host T-cell population whereas the superantigen binding activates up to 20% to 30% of host T-cells.¹⁴ The majority of cases of TSS are caused by coagulase-positive S. aureus, although recently, coagulase-negative strains have been isolated. It often develops from a site of colonization rather than infection.¹ There have been reports of TSST-1 in association with Methicillin-resistant Staphylococcus aureus (MRSA); therefore, it is important to consider TSS in patients with MRSA and shock.¹⁵

STSS is caused by invasive Group A streptococci (GAS) which are thought to produce the streptococcal enterotoxin. It occurs most commonly following varicella in previously healthy children and/or during the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Sites of infection in STSS are much deeper than in staphylococcal TSS, such as infection following blunt trauma.¹ The interactions between the host immune system and the pathogen play a major role in determining which patients colonized or infected with toxin producing S. aureus or Streptococcus pyogenes go on to develop TSS.¹⁶

When superantigens come in contact with cells, they react with various consequences: activation of blood vessel muscle cells leads to vasodilation and hypotension, activation of skin cells leads to rash, activation of gut cells leads to diarrhea, and activation of muscle cells leads to pain and cramps.¹ The most impressive aspect of the pathophysiology of TSS is the massive vasodilatation and rapid movement of serum proteins and fluid from the intravascular to the extravascular space. This results in oliguria, hypotension, edema, and low central venous pressure. The multisystem collapse seen in TSS may be either a reflection of the rapid onset of shock or may be from the direct effects of toxin(s) on the parenchymal cells of the involved organs.

The CDC has reported a decrease in the annual incidence of TSS, presumably from the increased awareness of risk associated with tampon use. In addition, aggressive supportive care such as early goal-directed fluid resuscitation likely prevents severe manifestation of TSS decreasing the number of cases that fulfill all the CDC diagnostic criteria. Approximately half of the cases of TSS are associated with tampon use, whereas the other half occurs in children, men, and nonmenstruating women.¹⁷ Nonmenstrual cases occur in a variety of clinical settings, but are chiefly associated with postpartum or cutaneous/subcutaneous S. aureus infections. Predisposing factors include relatively small body surface area burns, abrasions, abscesses, nasal packing, and, infected surgical wounds.

In the United Kingdom, it was estimated that 3% to 13% of children admitted to a burn unit developed TSS.¹⁸ TSS is more common in children with burns of relatively low body surface area. Although children have a higher incidence of minor S. aureus infection than adults, the incidence and mortality of TSS in children are lower. Studies have shown that patients with TSS do not develop a significant antibody response to TSST-1. Therefore, there is a significant recurrence rate for TSS (30%). Secondary cases are milder and occur within 3 months of the original episode; the overall mortality rate is 5 %.⁴ The incidence of STSS corresponds to the incidence of invasive GAS disease, which varies according to geographic location and occurs in clusters.

Both TSS and STSS are characterized by an acute illness with fever, hypotension, and multisystem organ involvement (including renal failure). Because this can be difficult to distinguish from other childhood illnesses in their early stages, the CDC has established clinical criteria for diagnosis, which may not be applicable to children. Thus, in 1990, abbreviated diagnostic criteria were proposed for use in children (Table 60-3).¹⁹

TSS should be considered in any patient who has unexplained fever, rash, and a toxic appearance. Patients with menstrual TSS usually present between the third and fifth day of menses. For a child there may be a sudden onset of high fever, over 38.9°C (with chills), vomiting, diarrhea, myalgia, dizziness, and diffuse rash. Additional signs and symptoms may include headache, arthralgia, sore throat, abdominal pain, stiff neck with orthostatic dizziness or syncope. Diarrhea (which may be profuse and watery) and vomiting occur in about half of the cases.¹³

Physical examination may reveal hypotension or orthostatic blood pressure changes. In the acute stage, which lasts 24 to 48 hours, the patient may be agitated, disoriented, or obtunded. Hyperemia of the conjunctiva and vagina is seen (Fig. 60-1). Tender edematous external genitalia, vaginal mucosal erythema, scant purulent cervical discharge, and bilateral–adnexal tenderness are seen in menstruation-related TSS.

Skin findings can be dramatic and present as a severe erythroderma and erythema of mucus membranes (Fig. 60-2).

Between the fifth and tenth hospital day, a generalized pruritic maculopapular rash develops in about 25% of patients. The skin rash is diffuse and blanches. It fades within 3 days of its appearance and is followed by a fine generalized desquamation of the skin, with peeling over the soles, fingers, toes, and palms.

Nonspecific, but frequently found abnormal laboratory values reflect the multisystem involvement in TSS. Leukocytosis, with an increase in immature forms, is frequently seen. Lymphopenia has been reported as a useful way to confirm diagnosis. Platelet count may be low. Azotemia and abnormal urinary sediment are seen with the development of acute renal failure. Liver function tests frequently show some elevation of liver enzymes and bilirubin. Electrolyte abnormalities vary and may include hyponatremia. With severe hypotension, the patient may be acidotic. Clotting studies are normal or mildly abnormal; untreated patients may show clinical evidence of coagulopathy. Cultures of blood, throat, and cerebrospinal fluid may be useful. Vaginal culture should be done, as well as culture from any identifiable focus of infection. Staphylococcus will be cultured from the cervix or vagina of more than 85% of patients with menstrual TSS. The majority of the above tests return to normal by 7 to 10 days after onset of illness.

Mild episodes of TSS are more difficult to diagnose. The presence of any combination of fever, headache, sore throat, diarrhea, vomiting, orthostatic dizziness, syncope, or myalgias in a menstruating woman should raise the possibility of TSS. The presence of S. aureus on culture is not diagnostic because non-TSST-1–producing S. aureus may be cultured from the cervix or vagina of up to 10% of well women. However, the presence of desquamation during a febrile illness should prompt the clinician to obtain cultures for S. aureus. Other laboratory data do not reflect multisystem involvement in mild cases. Thus, strong support for mild TSS will depend on the development of the typical desquamation of palms, soles, toes, and fingers.

STSS presents as sudden onset of shock and organ failure in the presence of any streptococcal infection. Tender erythroderma is the most suggestive symptom of STSS. It appears abruptly and the hyperesthesia may seem out of proportion to the degree of skin involvement. These patients should be evaluated for GAS necrotizing fasciitis.² STTS, compared to staphylococcal TSS, is often associated with focal tissue infection and bacteremia with more fulminant course and greater mortality.²⁰

The initial presentation of STSS may not be obvious; those most suspect includes children with varicella, skin injury, well-localized or unusually severe tenderness, and infection at sites of blunt trauma.

Several other systemic illnesses with fever, rash, diarrhea, myalgias, and multisystem involvement resemble TSS. Kawasaki disease also is characterized by fever, conjunctival hyperemia, erythema of mucus membranes and desquamation but lacks the diffuse myalgia, vomiting, abdominal pain, diarrhea, azotemia, thrombocytopenia, and shock that accompanies TSS. Both staphylococcal scarlet fever and TSS are caused by toxin-producing staphylococci. Pathology specimens or serologic evidence of the exfoliation toxin differentiates the two entities. Streptococcal scarlet fever is rare after the age of 10. The nontender “sandpaper” rash of scarlet fever is distinct from the macular rash of TSS or the tender erythroderma seen with STSS.

In sepsis syndrome (once called septic shock), inflammation and the immune response occur without the development of superantigens.²¹ Hypotension is common to both sepsis and TSS; therefore, initial management is the same. However, the appearance of a rash and the laboratory abnormalities associated with TSS will aid in distinguishing these two entities.

Other conditions, such as Rocky Mountain spotted fever, leptospirosis, meningococcemia, Stevens–Johnson syndrome, and staphylococcal scalded skin syndrome, may resemble TSS.

Management depends on prompt recognition. It is aimed at blocking the effects of the toxin and removing bacteria that might synthesize more toxins, as well as supporting the major organ systems. Early identification of the infectious focus is critical. The focus must be drained and foreign material (such as nasal packing or a retained tampon) promptly removed. Cultures should be obtained. Antibiotic therapy is essential for recovery from the acute episode, but is also important for eradication of the organism to reduce the recurrence rate. Traditionally, β-lactamase-resistant anti-staphylococcal antibiotics, such as oxacillin or nafcillin, had been the recommended treatment. However, because of the recent emergence of community-associated MRSA, clindamycin or vancomycin is now recommended.^1,22 Although of unproven efficacy, elimination of nasal carriage of bacteria with mupirocin or rifampin may be considered.²² For STSS, combination therapy with intravenous penicillin G and clindamycin is recommended.¹ Penicillin acts against replicating bacteria and clindamycin may reduce toxin production.

Initial parenteral antibiotic coverage for both GAS and S. aureus infection should be instituted because of the similarity in the clinical appearance of TSS and STSS. Therefore, clindamycin usually is the antibiotic of choice for both TSS and STSS (in addition to penicillin G for GAS).

Adjunctive therapy to neutralize toxins includes intravenous immunoglobulins (IVIG) or fresh frozen plasma, either providing passive immunity with antibodies that bind to superantigens. However, the efficacy of IVIG has not been established.^23,24

The remainder of therapy depends on the severity and extent of symptoms. The most important initial therapy is aggressive management of hypovolemic shock with appropriate continuous monitoring. If acute respiratory distress syndrome occurs, mechanical ventilation will become necessary. Corticosteroids, aimed at reducing the host response contribution to the inflammatory cascade, have not been shown conclusively to affect the outcome.

Some authors recommend that all patients with fever and erythroderma be hospitalized for at least 24 hours of close monitoring.⁶ The majority of patients become afebrile and normotensive within 48 hours of hospitalization. The erythema disappears within a few days and the muscle pain and weakness resolve in 7 to 10 days.

More than half of the patients not treated with a β-lactamase-resistant antibiotic have recurrences. Most recurrent episodes occur by the second month following the initial episode, on the same day of menses as the prior attack. In the majority of patients, the initial episode is the most severe. Recurrences in nonmenstrual TSS cases are rare.²⁴