Toxic shock syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has toxic shock syndrome? What should you expect to find?

  • The symptoms of staphylococcal toxic shock syndrome (staph TSS) are the following: fever, chills, nausea, vomiting, diarrhea, and confusion.

  • The symptoms of streptococcal toxic shock syndrome (strep TSS) are the following: fever, chills, nausea, vomiting, diarrhea, confusion, and in those with necrotizing fasciitis, severe unrelenting pain.

  • The physical findings for staph TSS are fever, tachycardia, hypotension, sun burn type rash (90%), and altered mental status.

  • The physical findings for strep TSS are fever, tachycardia, hypotension, sun burn type rash (10%), altered mental status, and early in the course severe pain and tenderness for those with necrotizing fasciitis. Late physical findings in strep TSS with associated necrotizing fasciitis include purple violaceous bullae, skin sloughing, and ecchymoses.

How did the patient develop toxic shock syndrome? What was the primary source from which the infection spread?

  • Staph TSS is most commonly associated with tampon use during menstruation. Thus, the source of infection is the vaginal vault. Less commonly staph TSS may occur postoperatively, particularly in patients with packing of the wound. The classic example is rhinoplasty with nasal packing.

  • Strep TSS can develop following any group A streptococcal (GAS) infection including pneumonia, soft tissue infection, postpartum sepsis, or following chicken pox in children. Fifty percent of patients with strep TSS have a defined portal of entry such as a cut, burn, or insect bite and 50% do not have a defined portal of entry and develop infection at the exact site of nonpenetrating trauma such as a bruise, muscle strain, or joint sprain.

  • Staph TSS had its greatest frequency in the 1980s in association with super-absorbent tampons such as Rely. Sporadic cases still occur, suggesting that the materials used for those tampons was not the sole risk factor. Because of the reduced incidence of menstrually related staph TSS, roughly 50% of cases of staph TSS now occur in postsurgical patients.

  • Strep TSS occurs sporadically with a frequency of 1 to 3 cases per 100,000 population per year. There have been clusters of strep TSS cases associated with postpartum sepsis in several hospitals in the United States and Canada and following a variety of surgical procedures including thyroidectomies, suction lipectomy, and mammoplasties.

Which individuals are at greater risk of developing toxic shock syndrome?

  • Menstruating females who use tampons and patients undergoing certain surgical procedures that require packing material are at greatest risk of developing staph TSS. The elderly, the very young, and patients with diabetes and alcoholism are at greatest risk for developing strep TSS. In otherwise healthy individuals, childbirth, surgical procedures, and viral infections such as influenza and chicken pox are the major risk factors.

  • For staph TSS, the greatest predisposing factor is tampon use. For strep TSS compromise of barriers such as the skin and or vaginal mucosa are the greatest risk factors.

Beware: there are other diseases that can mimic toxic shock syndrome:

  • Scarlet fever can mimic both staph and strep TSS. Sunburn plus dehydration, and gastroenteritis can mimic staph and strep TSS. Deep vein thrombophlebitis can mimic strep TSS in patients with necrotizing fasciitis and myonecrosis.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • In both staph and strep TSS, the white blood cell count is modestly elevated and the differential count shows increased bands, metamyelocytes, and myelocytes.

  • Transaminases (serum glutamic oxaloacetic transaminase, alanine transanimase) and bilirubin are elevated modestly in patients with staph and strep TSS. Serum creatinine is two to three times normal in both staph and strep TSS. Serum albumin and calcium are markedly reduced in both staph and strep TSS.

Results that confirm the diagnosis

  • Blood cultures are rarely positive in staph TSS, but are positive in 60% of patients with strep TSS.

  • Vaginal cultures or surgical site cultures are positive in patients with staph TSS. In patients with strep TSS with necrotizing fasciitis/myonecrosis, deep cultures of the soft tissues are universally positive for group A Streptococcus. Cerebrospinal fluid cultures may be positive in patients with meningitis, though this is a rare occurrence.

What imaging studies will be helpful in making or excluding the diagnosis of toxic shock syndrome?

  • Imaging studies are rarely necessary in patients with staph TSS. In patients with necrotizing fasciitis and strep TSS, computed tomography (CT) scans and magnetic resonance imaging (MRI) scans show stranding and edema within the deep muscle compartments. Gas and abscess formation are not found. Thus, the level of involvement can be discerned. However in patients with muscle trauma or in postpartum sepsis, imaging studies do not distinguish infection from trauma alone.

  • The cost of CT and MRI scans varies widely from $400 to $800.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

For staph TSS and strep TSS patients, consultation with critical care specialists, infectious disease specialists, and surgical specialties would be helpful. In the case of staph TSS, obstetrics and gynecology, or ear, nose and throat specialists should be consulted since females who are menstruating or rhinoplasties constitute the most common predisposing factors. For strep TSS, obstetrics and gynecology consultation is crucial in women with postpartum sepsis. Similarly, in patients with necrotizing fasciitis consultations with specialists in general surgery, orthopedics, or ear nose and throat are appropriate depending upon the site of infection.

If you decide the patient has toxic shock syndrome, what therapies should you initiate immediately?

Since shock and organ failure—including respiratory failure—are common, admission to an intensive care unit, aggressive intravenous fluid support, intubation, and ventilator support are crucial early goals.

Key principles of therapy

For staph TSS, two principles are crucial. The first is the antibiotic susceptibilty of the organism and this can vary widely and include resistance to clindamycin or β-lactam antibiotics (methicillin-resistant Staphylococcus aureus). The second principle is the mechanism of action of the antibiotic. Since staph and strep TSS are caused by potent toxin producing strains, inhibition of toxin production with protein synthesis inhibitors such as clindamycin or linezolid is recommended. It should be noted that this recommendation is based largely on in vitro results and case reports and not large double blind studies. Inducible clindamycin resistance is increasing in both methicillin-sensitive and methicillin-resistant S. aureus (MRSA). Resistance to linezolid is rare.

For strep TSS the same principles apply. In the United States erythromycin resistance occurs in about 5% of isolates of GAS, but epidemics of erythromycin-resistant GAS have been documented in Japan, Finland, and the United States. Macrolide resistance is not translated to clindamycin resistance very often in the United States, but approaches 50% in Italy. Linezolid has excellent activity against GAS infections that are both erythromycin and/or clindamycin resistant. Animal studies have demonstrated that clindamycin and erythromycin are superior to penicillin in animal models of necrotizing fasciitis/strep TSS.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

If early clinical findings and appropriate cultures and Gram stains do not provide a definitive diagnosis, the empiric broad spectrum antibiotic treatment is crucial. Coverage for MRSA, other Gram-positive microbes, Gram-negative aerobic microbes, and anaerobes is important. Necrotizing fasciitis can be caused by mixed aerobic/anaerobic microbes and thus early in the course of strep TSS necrotizing fasciitis it is reasonable to over these agents broadly. Several empiric regimens have been suggested and the reader is referred to the section on Treatment of Septic Shock. Piperacillin/tazobactam (3.375g every 6 hours) plus vancomycin (1g every 12 hours), or meropenem (0.5–1g every 8 hours) plus vancomycin (1g every 12 hours) are reasonable choices. Linezolid could be substituted for vancomycin if meningitis or endocarditis are excluded, since linezolid is bacteriostatic. In general, if clinical suspicion suggests a toxic shock syndrome but empiric broad spectrum coverage is desired, clindamycin or linezolid should be used early in the course. Specific treatment options are summarized in Table I.

Table I.
Organism Antibiotic Dose Alternative
Staphylococcus aureus (MSSA) Nafcillin + clindamycinCefuroxime + clindamycin Nafcillin 12g/day (divided every 6 hours)Cefuroxime 2–4g/day (divided every 12 hours) Clindamycin 1,800–2,700mg/day (divided every 8 hours) Linezolid 1,200 mg/day (divided every 12 hours)
Staphylococcus aureus (MRSA) Vancomycin + clindamycin Vancomycin 2g/day (divided every 12 hours)Clindamycin 1,800–2,700mg/day (divided every 8 hours) Linezolid
Streptococcus pyogenes Penicillin + clindamycin Penicillin 20–24 million units/day (divided every 4 hours)Clindamycin 1,800–2,700mg/day (divided every 8 hours) Ceftriaxone + clindamycin Linezolid

MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus.

2. Other key therapeutic modalities

Other therapies that are helpful for reducing complications
  • Aggressive fluid replacement with normal saline. Note both strep and staph TSS are associated with capillary leak syndrome, thus crystalloid requirements may be large, i.e. 10–12 L/day.

  • Intravenous albumin is generally required if hypotension persists, largely because of the capillary leak syndrome and profound hypoalbuminemia that ensues.

  • Ventilator support

  • Hemodialysis

  • Pressors such as dobutamine or vasopressin may be necessary for intractable hypotension. Goal is to maintain a mean arterial pressure (MAP) of greater than 65mm Hg. Caution, severe symmetrical gangrene has been described in patients receiving pressors in doses sufficient to cause MAP to reach much higher levels. Thus, perfusion of vital organs and extremities is also an important goal and an arbitrary goal of greater than 65mm of Hg may not be reasonable in all patients.

Controversial or evolving therapies
  • Activated protein C (APC) has not been studied in either staph or strep TSS, and should be considered carefully, particularly in those patients with strep TSS and necrotizing fasciitis, since surgery is commonly needed and APC may promote excessive bleeding.

  • Intravenous γ-globulin (IGIV) has been studied in strep TSS in studies using historical controls and in one comparative trial involving approximately 20 patients. In the first study, mortality was reduced but patients receiving IGIV were more likely to have received surgical intervention and were more likely to have received clindamycin. In the second study enrollment was prematurely stopped for funding reasons.

What complications could arise as a consequence of toxic shock syndrome?

Both strep and staph TSS can cause shock and organ failure including the lungs, liver, and kidneys. In strep TSS approximately 60% of patients develop acute respiratory distress syndrome requiring intubation and ventilator support. In strep TSS approximately 80% of patients develop renal dysfunction and may require acute dialysis. Because nearly 50% of patients with strep TSS have associated necrotizing fasciitis, emergent surgical debridement may be necessary and this may include amputation of a limb or in the case of postpartum sepsis, hysterectomy. If the primary infection is on the head and neck, surgical intervention may not be possible and these are associated with high mortality. Death may also be a complication of either staph or strep TSS. For staph TSS, mortality is generally less than 5%, however for strep TSS mortalities reported range from 30% to 70%.

What should you tell the family about the patient's prognosis?

  • For patients with staph TSS the mortality is less than 5%. For strep TSS mortality is 30% to 70% and patients may require surgical debridement, depending upon the site of the initial infection. In some cases loss of limb is a consequence.

  • Poor outcomes for staph TSS are related to the degree of initial organ dysfunction and the timeliness of appropriate diagnosis. Since the mortality of staph TSS is less than 5%, most patients respond to antibiotics and aggressive fluid replacement. For patients presenting late, shock, ventilator support, and dialysis are measures of poor prognosis. Among patients with either staph or strep TSS severe hypotension which is not responsive to aggressive intravenous fluids and therefore requiring vasopressor support symmetrical gangrene of the extremities and cognitive dysfunction may result.

What-if scenarios:

  • If a sunburn type rash is absent and patient has hypotension, evidence of organ dysfunction, and tachycardia, then other etiologies should also be considered and this would include Gram-negative sepsis or meningococcal sepsis (particularly if meningitis and rash suggestive of disseminated intravascular coagulation is present). In summer months Rocky Mountain spotted fever should be considered, particularly if petechial rash is present. If patients present with hypotension and evidence of a necrotizing process have crepitus or radiographic evidence of gas in the tissue, either gas gangrene caused by Clostridium species or mixed aerobic/anaerobic necrotizing fasciiitis should be considered.

How do you contract toxic shock syndrome and how frequent is this disease?

Staph TSS occurs sporadically either in menstruating women using tampons or in patients of either sex who have undergone surgical procedures requiring packing material.

Strep TSS occurs in all age groups but with the highest incidence in the very young, the elderly, and among patients with diabetes and alcoholism

Currently staph TSS occurs with an annual incidence of less than 0.1 cases per 100,000 population per year and there is no seasonal variation. Since superabsorbent methyl-cellulose tampons are no longer in use there has been a dramatic decline in the annual incidence from a high of 10 to 15 cases per 100,000 population per year. Postsurgical cases of staph TSS are rarer still but with the decline in menstrual cases account for nearly 50% of the total.

Strep TSS has had an annual incidence of 3 to 5 cases per 100,000 population for the last 20 years. Most cases are sporadic, though one epidemic occurred in rural Minnesota caused by an M-3 strain of group A streptococcus and with an incidence of 13 cases per 100,000 population. Streptococcal infections including pharyngitis are more common in the winter months in temperate climates.

There is no evidence that staph TSS is spread from person to person. Requirements for infection are colonization with a strain of S. aureus that produces the toxic shock syndrome toxin-1 (TSST-1) and an absence of neutralizing antibodies against it. Packing material including hyperabsorbent methyl-cellulose tampons are also requirements, however the exact mechanism that might involve enhanced toxin production has been elusive.

Strep TSS occurs in individuals who lack antibody against the M-protein of colonizing strains. M-1 and M-3 types of group A streptococcus are the most common, though a dozen other strains have also been implicated. Novel M-types of group A streptococcus cause epidemics of pharyngitis largely in young children. Appearance of a new strain causing epidemic pharyngitis has been associated with an increase in the incidence of invasive group A streptococcal infections including strep TSS. Acquisition of anti-M protein antibody in a community has been associated with a decline the the prevalence of that strain causing pharyngitis. It is generally assumed that acquisition of antibody against multiple M-types of GAS is the reason that pharyngitis is most common in younger individuals and less common in adults. Still colonization of the throat in up to 5% of adults despite repeated episodes of streptococcal pharyngitis during childhood.

Staph and strep TSS are reportable diseases. There has been a dramatic decline in staph TSS since the mid 1980s in part due to a reduction in use of methyl cellulose to manufacture superabsorbent tampons. Currently, the incidence is less than 0.1 case per 100,000 population per year in the United States. Strep TSS was first reported in 1989 and the incidence has remained around 1 per 100,000 population per year in the United States. Note that invasive infections which include strep TSS, necrotizing fasciitis, and bacteremia account for about 3.5 cases per 100,000 population. Most cases are sporadic but small epidemics have been reported in rural Minnesotta, and in association with child delivery in Chicago and Maryland. Since GAS is transmitted from person to person, the potential for secondary cases is real. Studies done by the US Centers for Disease Control and Prevention (CDC) and in Canada suggest that the rate of secondary cases is roughly 50 times greater among close contacts. This could mean that 50 per 100,000 population could develop strep TSS. Thus the risk is real but very small. Still it is likely that close contacts may become colonized wtih GAS, usually in the throat, and may even develop pharyngitis, but the risk of strep TSS is very low. Thus, the incidence of GAS infection in hospitals is low, but the CDC recommends a careful epidemiological evaluation if more than two cases occur in a 12-month period.

No zoonotic transmissions are known.

What pathogens are responsible for this disease?

Group A streptococcus and S. aureus are responsible for this disease.

How do these pathogens cause toxic shock syndrome?

S. aureus produces two toxins that are responsible for staph TSS. The first TSST-1 has been associated with most cases of menstrual toxic shock syndrome. Staphylococcal enterotoxin B has been implicated primarily in patients who acquire the infection in the hospital and is associated with use of surgical packing material.

Strep TSS is largely the result of streptococcal pyrogenic exotoxin A (SpeA). Interestingly this toxin and the two S. aureus toxins mentioned above are superantigens that interact concomittantly with V β regions of the T-cell receptor and the major histocompatibility complex class II receptor on macrophages with the resultant production of tumor necrosis factor (TNF)-α, interleukin (IL)-1 β, and IL-6 from macrophages and IL-2, γ-interferon and TNF-β from T-lymphocytes. This cytokine storm is thought to drive the rapid onset of hypotension, fever, tachycardia, and multiorgan failure so characteristic of the toxic shock syndromes.

What other clinical manifestations may help me to diagnose and manage toxic shock syndrome?

Early in the course of infection patients with both staph and strep TSS may initially have fever, chills, nausea, vomiting, and diarrhea.

Recent surgery or use of tampons may be an initial clue to staph TSS. Fifty percent of patients with strep TSS may have a defined portal of entry with surrounding cellulitis. Portals may be burns, insect bites, slivers, or surgical procedures. The remaining 50% of patients have no portal of entry but will proved a history of muscle strain, tendon tear, hematoma, etc. These patients will have fever but remarkably have severe unrelenting pain at the site of the nonpenetrating trauma.

Sepsis inflammatory response syndrome (SIRS) associated with severe pain at the site of an injury should suggest strep TSS. Cutaneous findings of inflammation may be absent early but will quickly evolve to purple violaceous bullae, ecchymoses, and skin sloughing.

SIRS associated with recent surgery or tampon use in patients with diffuse sunburn type rash suggests staph TSS.

What other additional laboratory findings may be ordered?

C-reactive protein levels that are above 13 have been used to diagnose necrotizing fasciitis in Norway. While this is a nonspecific test, a high level in the setting of a patient with severe pain and SIRS could suggest necrotizing fasciitis and could distinguish between trauma and infection. Similarly, a markedly elevated creatine phosphokinase level would favor a diagnosis of a necrotizing infection of the deep soft tissue compared with trauma alone or cellulitis.

How can toxic shock syndrome be prevented?

There are no vaccines available for either staph or strep TSS. There are no data to support drugs to prevent either infection. Clearly, selective antibotic administration to intimate contacts could be considered, particularly for those who are compromised, very young, very old, or who have concurrent infections such as chickenpox or influenza.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

“Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition”. JAMA. vol. 269. 1993. pp. 390-1. (This paper describes the clinical and laboratory criteria necessary to define a definite and/or probable cause of strep TSS.)

Stevens, DL. “The toxic shock syndromes”. Infect Dis Clin North Am. vol. 10. 1996. pp. 727-46. (Detailed review article that compares and contrasts the clinical presentation of staph and strep TSS. In addition, it supplies in depth discussion of pathogenic mechanisms, important virulence factors, and concepts important in the treatment of these conditions.)

Bryant, AE, Bayer, CR, Chen, RY, Guth, PH, Wallace, RJ, Stevens, DL. “Vascular dysfunction and ischemic destruction of tissue in infections. The role of streptolysin O-induced platelet/neutrophil complexes”. J Infect Dis. vol. 92. 2005. pp. 1014-22. (These experimental results demonstrate that streptolysin O causes a rapid reduction blood flow which is irreversible and associated with platelet and neutrophil complexes that occlude both arteries and veins. This provides a mechanism for the rapid destruction of tissue in patients with strep TSS associated with necrotizing fasciitis and myonecrosis.)

Stevens, DL, Bisno, AL, Chambers, HF. “Practice guidelines for the diagnosis and management of sin and soft-tissue infections”. Clin Infect Dis. vol. 41. 2005. pp. 1373-406. (This 33-page manuscript reviews the evidence and provides guidelines for treating and diagnosing all types of skin and soft tissue infections including streptococcal and staphylococcal TSS.)

Stevens, DL, Wallace, RJ, Hamilton, SM, Bryant, AE. “Successful treatment of staphylococcal toxic shock syndrome with linezolid: a case report and evaluation of toxic shock syndrome toxin type 1 production in the presence of antibiotics”. Clin Infect Dis. vol. 42. 2006. pp. 729-30. (With the emergence of methicillin-resistant strains of S. aureus, some of which are also resistant to clindamycin by either constitutive or inducible mechanism, additional empiric strategies to treat severe staphylococcal infections were warranted. This study demonstrates that linezolid was efficacious in treating such a patient and that in vitro linezolid and clindamycin had potent toxin suppressing effects.)

Stevens, DL, Ma, Y, Salmi, DB, McIndoo, E, Wallace, RJ, Bryant, AE. “Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant “. J Infect Dis. vol. 195. 2007. pp. 202-11. (This study demonstrates that β-lactam antibiotics such as nafcillin up-regulate TSST-1, α-toxin, and the Panton–Valentine leukotoxin in subinhibitory concentrations and this translates to increased production of those same toxins. In contrast, linezolid and clindamycin suppress toxin production because they are both protein synthesis inhibitors.)

Hamilton, SM, Bayer, CR, Stevens, DL, Lieber, RI, Bryant, AE. “Muscle injury, vimentin expression, and nonsteroidal anti-inflammatory drugs predispose to crypti group A streptococcal necrotizing infection”. J Infect Dis. vol. 198. 2008. pp. 1692-8. (This study investigates the mechanism whereby 50% of the patients with strep TSS develop the initial infection at the exact site of nonpenetrating trauma such as a muscle strain or hematoma. Investigators demonstrated that vimentin expressed by injured muscle cells avidly bind group A streptococci. This process is enhanced in the presence of certain nonsteroidal anti-inflammatory agents.)

Zimbleman, J, Palmer, A, Todd, J. “Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive infection”. Pediatr Infect Dis J. vol. 18. 1999. pp. 1096-100. (This retrospective study in children showed that treatment with clindamycin was associated with better outcomes than treatment with β-lactam antibiotics.)

Norrby-Teglund, A, Stevens, DL. “Novel therapies in streptococcal toxic shock syndrome: attenuation of virulence factor expression and modulation of the host response”. Curr Opin Infect Dis. vol. 11. 1998. pp. 285-91. (Review article that explores the evidence for and rationale for antibiotic treatment, attenuation of the innate immune response, and use of intravenous γ-globulin in the treatment of strep TSS.)

Darenberg, J, Ihendyane, N, Sjölin, J. “Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial”. Clin Infect Dis. vol. 37. 2003. pp. 333-40. (Well-designed clinical trial that demonstrated improved survival in patients with strep TSS treated with IVIG. Statistical significance was marginal due to premature closure of the study due to low enrollment.)

Kaul, R, McGeer, A, Norrby-Teglund, A. “Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—a comparative observational study”. Clin Infect Dis. vol. 28. 1999. pp. 800-7. (Patients in the IVIG arm had marked reduction in mortality. Study was hampered by use of historical controls and patients in the IVIG arm were more likely to have surgical intervention and were more likely to have received clindamycin.)

DRG CODES and expected length of stay

Length of stay for staph TSS is usually 5 to 10 days. Length of stay for strep TSS is much longer due to a high association with necrotizing infections. About 10% of patients die within 2 to 3 days of admission. Patients with strep TSS who have necrotizing soft tissue infections require multiple surgeries and have prolonged requirements for ventilator and hemodialysis support. Thus, some patients are hospitalized for 2 to 3 months. Precise data for each is not available.

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