Emily Rose
Staphylococcal Toxic Shock Syndrome
Toxic shock syndrome (TSS) associated with Staphylococcus aureus is a toxin-mediated, multisystem illness that occurs in primarily healthy people of any age group. It was originally described in 1978. The peak reported incidence, in 1980, was linked to the use of highly absorbent tampons containing polyacrylate rayon. Owing to federal regulations for tampons and public awareness, the incidence of TSS has declined. The incidence of TSS and probable TSS (including menstrual and nonmenstrual categories) is 1 to 3 per 100,000 with a case : fatality rate of 3% to 10% (1,2). The majority of reported cases of TSS have been due to methicillin- susceptible S. aureus (MSSA), but cases due to methicillin-resistant S. aureus (MRSA) have emerged in association with increased rates of community-acquired MRSA infections (3). Staphylococcal TSS cases are now occasionally associated with necrotizing fasciitis and myositis (1).
Nonmenstrual staphylococcal TSS currently accounts for approximately half of all cases and may occur with any type of S. aureus infection. Clinical scenarios associated with nonmenstural TSS include surgical and postpartum wound infections, mastitis, septorhinoplasty, sinusitis, osteomyelitis, arthritis, burns, skin lesions (including varicella zoster), respiratory infections (e.g., influenza, tracheitis, pharyngitis), HIV infection, and enterocolitis. Occasionally, no source is found (3,4). Influenza associated with TSS has a mortality as high as 90% (5). Patients with AIDS may develop recalcitrant erythematous desquamating disorder, a prolonged clinical course with severe and persistent desquamation (6).
TSS is a superantigen-mediated disease mediated by S. aureus exotoxins. Superantigens may activate up to 20% of T cells at one time, resulting in massive cytokine production (1,3). These cytokines are responsible for capillary leak syndrome and account for many of the clinical signs of TSS. Toxic shock syndrome toxin-1 (TSST-1) was the initial exotoxin isolated from S. aureus isolates associated with TSS in 1981 (1,7). It is the cause of nearly all menstrual cases of TSS because of its superior ability over other superantigens to penetrate mucosal surfaces (1). Oxygen is required for TSST-1 production. Tampons introduce oxygen into the typically anaerobic human vagina which allows TSST-1 proliferation and mucosal penetration. TSST-1 also causes approximately 50% of nonmenstrual TSS.
Numerous other superantigens, most commonly staphylococcal enterotoxins B and C, contribute to nonmenstrual TSS. Host antibody responses to the S. aureus exotoxins play an important role in the pathogenesis of TSS. Up to 40% of humans may be colonized with S. aureus and those with damaged skin such as atopic dermatitis are almost always colonized on skin surfaces (1). Approximately 70% to 80% of those in late teenage years and 90% to 95% of individuals in the fourth decade have developed antibodies to TSST-1. Passive immunity is conferred to babies at birth but wanes with time (3). Patients with clinical TSS lack antibody to TSST-1 and often fail to develop appropriate antibodies in their serum secondary to toxin-mediated excessive inflammatory response, cytokine production, and inhibition of antibody production (1). Only 50% of patients develop antibodies after TSS (4,6). Lack of protective antibodies places patients at risk for recurrent TSS and up to one-third of patients will have recurrence (6).
CLINICAL PRESENTATION AND ED EVALUATION
The most common features of TSS include fever, hypotension, and rash. Patients often present with an abrupt onset of flu-like symptoms including fever, malaise, myalgias, chills, headache, sore throat, vomiting, diarrhea, abdominal pain, or dizziness. Severe hypotension can be relatively unresponsive to fluids, last for days, and lead to tissue ischemia, encephalopathy, and organ failure.
A major feature of TSS is the erythematous rash, resembling sunburn, which may be diffuse or patchy in distribution and involves the palms and soles. The rash may be subtle and fleeting, complicating diagnosis. There may also be hyperemia of the conjunctiva, pharynx, tongue, and vaginal mucosa. Desquamation of the skin occurs in 7 to 14 days at the sites of the previous rash. A delayed pruritic maculopapular rash may also occur with desquamation weeks after the disease (3).
Criteria for the diagnosis of staphylococcal TSS defined by the Center for Disease Control (CDC) are provided in Table 192.1. However, TSS can involve every organ system and can produce a wide constellation of symptoms. The diagnosis should be considered if even all criteria are not met.
TABLE 192.1
Criteria for Staphylococcal Toxic Shock Syndrome
The clinical presentations of menstrual and nonmenstrual TSS are similar. Super antigen toxins (such as TSST-1) have the ability to inhibit the migration of polymorphic neutrophils (PMNs) to infection and often there is a lack of inflammation around the site of infection. Surgical wound sites and cutaneous infections that harbor toxin-producing S. aureus are frequently benign appearing and without with obvious purulence (5).
The diagnosis of TSS is often made on clinical grounds and must be considered in a hypotensive febrile patient with a rash (on examination or by history). The disorder is toxin mediated; therefore, blood cultures are rarely positive (5%) (3). Isolation of S. aureus is not required for the diagnosis of staphylococcal TSS, though 80% to 90% of patients with TSS have S. aureus isolated from the mucosa or wound sites. Laboratory examination may demonstrate signs of multiorgan involvement including thrombocytopenia (platelets <100,000), elevated blood urea nitrogen (BUN) and creatinine, and elevated liver function tests.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of TSS includes streptococcal TSS (discussion to follow), Kawasaki disease, staphylococcal scalded-skin syndrome, scarlet fever, Stevens–Johnson syndrome, Rocky Mountain spotted fever, ehrlichiosis, leptospirosis, meningococcemia, typhoid fever, dengue hemorrhagic fever, atypical measles, viral illness, anaphylaxis, heat stroke, gram-negative sepsis, and drug reactions.
ED MANAGEMENT AND DISPOSITION
Initial treatment consists of intravenous fluid replacement. Large volumes (10 to 20 L) of crystalloid are often required to maintain normal perfusion. Hemodynamic monitoring and vasopressors are sometimes necessary. Tampons, nasal packs, or other foreign bodies must be removed. Surgical wounds or areas of infection need to be irrigated; abscesses must be incised and drained. Cultures of the vaginal canal or of the infectious focus or surgical wound should be submitted for culture and susceptibility testing, as TSS is caused by both MSSA and MRSA.
Antibiotics may not affect the clinical course but may be beneficial if the patient is bacteremic or if there is a site of ongoing infection. Antibiotic therapy reduces the likelihood of recurrent TSS in those that previously failed to develop an appropriate antibody response to staphylococcal toxins (1,3,8). Clindamycin (600 to 900 mg IV every 8 hours) suppresses protein synthesis and toxin production. Vancomycin (10 to 20 mg/kg/dose) is added to cover MRSA. If culture and susceptibility results are available and indicate MSSA, clindamycin plus oxacillin or nafcillin are recommended.
Commercially available intravenous immune globulin (IVIG) has anti–TSST-1 antibodies present in varying amounts which may neutralize the toxin in TSS. Many experts recommend its use in severe cases. However, there are no data from controlled clinical trials demonstrating a reduction in morbidity or mortality with the use of IVIG. Risk versus benefit should be considered prior to its use. The role of steroids is unclear and not currently recommended.
Patients with suspected TSS should be admitted to the hospital. Unstable patients should be admitted to the intensive care unit.
Common Pitfalls
• Failure to recognize TSS in young healthy patients with fever and an erythematous rash
• Failure to administer adequate fluid volumes to maintain tissue perfusion
• Failure to seek an occult source of staphylococcal colonization or infection
• Failure to debride or irrigate benign-appearing wounds
• Failure to remove foreign bodies
Streptococcal Toxic Shock Syndrome
In the late 1980 s, a disease similar to staphylococcal TSS, but caused by a strain of group A streptococci (GAS), was recognized (9). This illness, characterized by hypotension and multiorgan failure, was termed streptococcal toxic shock syndrome (STSS). The Centers for Disease Control and Prevention case definition of this syndrome is shown in Table 192.2.
TABLE 192.2
Case Definition for the Streptococcal Toxic Shock Syndrome
Group A streptococcal TSS, like staphylococcal TSS, is mediated by toxins that act as superantigens and cause significant release of inflammatory cytokines. Initial infection most commonly occurs through the skin, vagina, or pharynx. Cases of STSS are often associated with minor nonpenetrating trauma or soft tissue infection (10–12). Viral infections, such as varicella and influenza, are thought to provide a portal of entry in other cases, but in many patients, no source of the organism can be identified. Bacterial toxins produced by GAS, particularly streptococcal pyrogenic exotoxins (SPEs), as well as host factors, are thought to play an important role in determining disease severity (13). In contrast to staphylococcal TSS, blood cultures are generally positive (60%). Streptococcal TSS often occurs in the presence of necrotizing fasciitis and myositis. Young children, the elderly, and the immunosuppressed are at greatest risk, but a large proportion of patients with STSS are young, healthy adults. Risk factors for GAS infection include minor trauma, soft tissue injuries (hematoma, bruising or muscle strain), surgical procedures, viral infections (especially influenza and varicella), and use of nonsteroidal anti-inflammatory drugs (NSAIDs) (13). It is unclear if the association of STSS with NSAIDs is causal, but NSAID use may mask presenting symptoms and contribute to a delay in diagnosis. Invasive GAS infections are increasing in frequency with an estimated 3.5 cases per 100,000 and a case : fatality rate of 36% to 43% for STSS (13).
CLINICAL PRESENTATION AND ED EVALUATION
Streptococcal TSS is typically an acute illness with fever, rapid-onset hypotension, and signs of multiorgan involvement including rapidly progressive renal failure. Flu-like symptoms such as malaise, myalgias, nausea, vomiting, and diarrhea often occur. In distinction to staphylococcal TSS, the diffuse scarlatina-like rash is uncommon in STSS (<10%). Patients often have signs of soft tissue infection such as localized swelling and erythema. The extremities are most commonly affected, but the chest, abdomen, or pelvis may be involved. Pain out of proportion to physical findings, rapid escalation of pain and the presence of vesicles or bullae on the skin are concerning signs of progression to necrotizing fasciitis. About 20% of STSS occur without soft tissue findings. Invasive infections such as pneumonia, pleural empyema, osteomyelitis, pyarthrosis, endophthalmitis, peritonitis, myocarditis, endocarditis, postpartum infections, or overwhelming sepsis may occur in association with STSS (13). Streptococcal TSS nearly always occurs in association with bacteremia (1). Complications include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and renal failure (often requiring dialysis).
ED MANAGEMENT AND DISPOSITION
Essential management of STSS includes hemodynamic support, early antibiotic therapy, and, when indicated, surgical therapy.
Massive quantities of intravenous fluids (up to 20 L/d) may be necessary to maintain perfusion secondary to intractable hypotension and diffuse capillary leak. Vasopressors may also be required.
Early treatment with antibiotics is critical. Broad-spectrum coverage should be used. Clindamycin is first-line therapy as it suppresses the synthesis of bacterial toxins and has been associated with better outcomes than β-lactam antibiotics alone in patients with STSS (14). In addition to clindamycin (900-mg IV every 8 hours), a carbapenem (imipenem 500 mg every 6 hours or meropenem 1 g every 8 hours) or a combination of drug containing penicillin plus a β-lactamase inhibitor (ticarcillin–clavulanate 3.1 g every 4 hours or piperacillin–tazobactam 4.5 g every 6 hours) should be used (14).
Significant pain to the soft tissue must trigger suspicion for serious infection such as myositis or necrotizing fasciitis regardless of lack of erythema or history of seemingly insignificant trauma. These serious infections require prompt and aggressive surgical debridement. Early surgical consultant is of paramount importance to reduce morbidity and mortality.
IVIG is also recommended by several experts in STSS but the supporting data are limited (14). Anecdotal reports of hyperbaric oxygen have been used in a handful of patients (14).
Patients with suspected TSS should be admitted to the hospital. Unstable patients should be admitted to the intensive care unit.
KEY TESTING
Toxic Shock Syndromes
• CBC
• Electrolytes, BUN, creatinine, glucose
• Liver function tests/liver enzymes
• PT/PTT/INR
• Lactate
• Urinalysis
• Blood cultures
• Wound culture if wound present
• Throat culture if pharyngitis
• CSF if suspected meningitis
• CXR
CRITICAL INTERVENTIONS
• Toxic Shock Syndromes
• Administer aggressive intravenous fluid replacement to maintain perfusion.
• Remove tampons, nasal packs, surgical dressings, or other foreign bodies.
• Incise and drain abscesses, irrigate surgical wounds, and debride areas of infection.
Common Pitfalls
• Failure to consider the diagnosis of STSS early and to institute antibiotics promptly
• Failure to debride soft tissue infections aggressively
• Failure to recognize pain out of proportion to examination even without physical findings could be a sign of STSS
REFERENCES
1. Brosnahan AJ. Gram-positive bacterial superantigen outside-in signaling causes toxic shock syndrome. FEBS J. 2011;278:4649–4667.
2. Chan KH, Kraai TL, Richter GT, et al. Toxic shock syndrome and rhinosinusitis in children. Arch Otolaryngol Head Neck Surg. 2009;135(6):538–524.
3. Chu VH. Staphylococcal toxic shock syndrome. UpToDate serial online. Accessed 5/27/2013.
4. Murray RJ. Recognition and management of Staphylococcus aureus toxin- mediated disease. Internal Med J. 2005;35:S106–S119.
5. McCormick JK, Schlievert PM. Toxic Shock Syndrome. In: eLS. Chichester: John Wiley & Sons Ltd; 2001. Available online at http://onlinelibrary.wiley.com/doi/10.1038/npg.els.0002185/abstract
6. DeVries A. Toxic shock syndrome. In: Crossley KB, Jefferson KK, Archer GL, et al., eds. Staphylococcal in Human Disease, 2nd ed. Hoboken, NJ: Blackwell; 2009:470–483. (Obtained from Norris medical library website 5/20/2013)
7. Schlievert PM, McCormick JK, Bohach GA, et al. Exotoxins. In: Crossley KB, Jefferson KK, Archer GL, et al., eds. Staphylocci in Human Disease, 2nd Ed. Hoboken, NJ: Blackwell; 2009:125–146. (Obtained from Norris medical library website 5/20/2013)
8. Dellaripa PF. Toxic shock syndrome. J Intensive Care Med. 2000;15:314–320.
9. Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 1989;321:1–7.
10. Lin JN, Chang LL, Lai CH, et al. Trivial trauma, lethal outcome: streptococcal toxic shock syndrome presenting to the ED. Am J Emerg Med. 2013.http://dx.doi.org/1.106/j.ajem.2013/04.011.
11. Madhusudhan TR, Sambamurthy S, Williams E, et al. Surviving streptococcal toxic shock syndrome: A case report. J Med Case Rep. 2007;118:1–6.
12. Prashanth HV, Saldanha DR, Shenoy S, et al. An unusual clinical presentation of Group A Streptococcal infection. Int J Bio Adv Res. 2011;2(11):450–452.
13. Stevens DL. Epidemiology, clinical manifestations, and diagnosis of streptococcal toxic shock syndrome. UpToDate serial online. Accessed 5/27/2013.
14. Stevens DL. Treatment of streptococcal toxic shock syndrome. UpToDate serial online. Accessed 5/27/2013.