Staphylococcal toxic shock syndrome Nicolas C. Issa, MD; Rodney L. Thompson, MD VOL 110 / NO 4 / OCTOBER 2001 / POSTGRADUATE MEDICINE Preview: The incidence of staphylococcal toxic shock syndrome (TSS) has decreased steadily since the 1980s, when it was first linked with use of superabsorbent tampons by menstruating women. Nonetheless, the disorder still occurs and sometimes is overlooked as a possible cause of acute illness. TSS now is recognized as a toxin-mediated, multisystem illness that strikes primarily in healthy people of any age. It is characterized by early onset of shock with multiorgan failure and continues to be associated with high morbidity and mortality. In this article, Drs Issa and Thompson discuss clinical presentation, pathogenesis, treatment, and outcome of staphylococcal TSS. Issa NC, Thompson RL. Staphylococcal toxic shock syndrome: suspicion and prevention are keys to control. Postgrad Med 2001:110(4):55-62 Although TSS initially attracted attention because of its link to use of tampons, it has been reported in a variety of medical and surgical conditions and is usually caused by either Staphylococcus aureus or Streptococcus pyogenes. Both these infections share certain features, but major differences are apparent in clinical findings, signs, symptoms, morbidity, and mortality. Other bacterial causes of TSS include non-group A beta- hemolytic streptococci and viridans-group streptococci. Epidemiologic factors TSS was first reported by Todd and associates (1) in 1978 in seven children who had high fever, erythroderma, confusion, profuse diarrhea, and shock with organ failure. Desquamation of the skin on the palms, soles, and trunk was noted during convalescence. Phage group I S aureus was isolated from five of the children, and it was thought that a new staphylococcal epidermal toxin may have been the cause. In 1980, Shrock (2) observed a similar syndrome in menstruating women and postulated that herpes infection could be playing a role. Later that same year, another report (3) confirmed the association of TSS with menstruation, S aureus, and superabsorbent tampons, which were quickly withdrawn from the market. The highest incidence of TSS was reported in 1980 (3 to 14.4 cases per 100,000 menstruating women per year) (3,4). The greatest risk was in white women less than 30 years of age (3,5). A novel toxin called toxic shock syndrome toxin 1 (TSST-1) was found in more than 90% of S aureus strains isolated from menstruating women who had TSS (6). Nonmenstrual cases of TSS were also reported in the early 1980s and were associated with a variety of surgical procedures (eg, rhinoplasty, nasal packing, postpartum procedures) and medical conditions (eg, pneumonia, influenza, infection). Nonetheless, the incidence of TSS decreased significantly after hyperabsorbable tampons were removed from the market and federal regulations for tampons were put in place. Currently, the number of cases of menstrual TSS is estimated to be about 1/100,000, and the case-fatality ratio is 3.3% (compared with 5.6% initially) (7). The incidence of nonmenstrual TSS now exceeds that of menstrual TSS (8,9). A review of surveillance data for 1979 through 1996 confirmed the decline in the incidence of TSS and the increase in the proportion of nonmenstrual cases (10). Pathogenetic mechanisms TSS is thought to be a superantigen-mediated disease. Superantigens are a group of proteins (S aureus toxins in the case of TSS) that are able to activate the immune system by bypassing certain steps in the usual antigen-mediated immune response sequence. Superantigens are not processed within the antigen-presenting cell before being presented to T cells. Instead, they bind directly to molecules of the major histocompatibility complex, class II, which requires recognition of only one element of the T-cell receptor (V beta) to trigger a massive T-cell activation (figure 1: not shown). Between 5% and 30% of the entire T-cell population may be activated. Conventional antigens activate only about 0.01% to 0.1% of the T-cell population (11,12). Superantigens lead to a massive release of cytokines, especially tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. These cytokines are responsible for a capillary leak syndrome and account for many of the clinical signs of TSS (13). TSST-1 and staphylococcal enterotoxins are the major toxins associated with staphylococcal TSS. TSST-1 is found in more than 90% of menstrual TSS and in 50% of nonmenstrual TSS. Various staphylococcal enterotoxins are found in the other 50% of nonmenstrual TSS (14-16). Host-pathogen interaction, local factors (pH, glucose level, magnesium level), age, and absence or presence of humoral immunity all have a direct impact on the clinical expression of this toxin-mediated illness (17,18). Arnow and associates (19) reported that they found a TSS-producing strain of S aureus in 16 patients and nurses who had no symptoms, further supporting the concept of host-pathogen interaction. Clinical presentation Nonmenstrual TSS is seen more often nowadays than menstrual TSS. The nonmenstrual form is observed in a variety of medical and surgical conditions, mainly in surgical wound infection with S aureus, postpartum infections, and rhinoplasty in which stents or nasal packing is used. Among the nonsurgical focal infections associated with TSS are cellulitis, subcutaneous abscesses, infected burns, suppurative hidradenitis, bursitis, and pneumonia with or without an antecedent influenza infection. Predisposing factors include nasal packing, influenza infection, and prior use of antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), or barrier contraceptives. Postsurgical TSS usually occurs 2 days after the procedure and is associated with a benign-appearing wound in 40% of cases. It is crucial to suspect TSS in these circumstances and to obtain cultures from the wound. Delay in recognizing the early signs of TSS is associated with increased morbidity and mortality. Malaise, myalgias, diarrhea, and chills often precede the onset of the other physical manifestations of staphylococcal TSS. Fever, confusion, and lethargy develop soon after the prodromal syndrome, which is associated with symptoms of hypovolemia (eg, palpitations, light-headedness, orthostasis) related to capillary leakage and diarrhea. Fever, hyperventilation, hypotension, tachycardia, and erythematous rash are often evident on physical examination. The rash is described as diffuse macular erythroderma that is confluent or scarlatiniform in most of the cases but also could be patchy in distribution. Other signs include strawberry tongue, conjunctival hyperemia, and erythema and edema of palms and soles. Hematologic, hepatic, muscular, renal, gastrointestinal, and central nervous system involvement is common. Desquamation (figure 2: not shown) usually occurs 1 to 2 weeks after the onset of illness (20). In nonmenstrual TSS, classic signs of localized infection at the surgical site may be absent, which makes clinical diagnosis challenging (8). Complications of TSS include acute renal failure, adult respiratory distress syndrome, disseminated intravascular coagulation, electrolyte disturbances (hypocalcemia, hypophosphatemia, hypomagnesemia), cardiomyopathy, encephalopathy, and hair and nail loss. Nonmenstrual TSS is associated with more renal and nervous system complications than menstrual TSS. In addition, the case-fatality rate is higher with the nonmenstrual form of the disorder, possibly because of delay in making the appropriate diagnosis. When TSS is treated appropriately, full recovery is the rule, although some patients may have persistent neuropsychologic dysfunction (eg, memory loss, lack of concentration), mild renal failure, late-onset rash, or onset of new allergies. For epidemiologic purposes, a clinical case definition of TSS was developed by the Centers for Disease Control and Prevention in 1980, and it still plays an important role in diagnosis (table 1). However, milder cases of TSS that do not fulfill all the criteria certainly are likely to occur. Table 1. Case definition of staphylococcal toxic shock syndrome developed by the Centers for Disease Control and Prevention Major criteria (all 4 must be met) Fever: temperature >38.9°C (102°F) Rash: diffuse macular erythroderma Desquamation: 1 to 2 wk after onset of illness, particularly of palms and soles Hypotension: systolic blood pressure <90 mm Hg for adults or <5th percentile by age for children <16 yr of age, or orthostatic syncope Multisystem involvement (3 or more must be met) Gastrointestinal: vomiting or diarrhea at onset of illness Muscular: severe myalgia or creatine kinase level twice upper limit of normal for laboratory Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia Renal: blood urea nitrogen or creatinine level at least twice upper limit of normal for laboratory, or >5 white blood cells per high-power field in absence of urinary tract infection Hepatic: total bilirubin, aspartate aminotransferase, or alanine aminotransferase at least twice upper limit of normal for laboratory Hematologic: platelets <100,000/mm 3 Central nervous system: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent Normal results on the following tests (if performed) Blood, throat, or cerebrospinal fluid cultures (blood culture may be positive for S aureus) Rise in titer in antibody tests for Rocky Mountain spotted fever, leptospirosis, or measles Adapted from Greenman RL, Immerman RP. Toxic shock syndrome: what have we learned? Postgrad Med 1987;81(4):147-60. Differential diagnosis A number of illnesses share some physical manifestations of TSS and should be ruled out because treatment and management are different. Streptococcal TSS caused by group A streptococcus is usually associated with fasciitis or myositis. Severe pain is the major symptom, along with fever and shock. The erythematous rash is less likely to be present. Bacteremia occurs in about 60% of patients who have streptococcal TSS, compared with less than 3% of those with staphylococcal infection. Predisposing factors for streptococcal TSS include cuts, burns, bruises, varicella infection, and use of NSAIDs. Staphylococcal scarlet fever has a similar clinical presentation, characterized by sudden onset of generalized erythema, fever, and leukocytosis. It results from the production of exfoliatin, an exotoxin produced by S aureus phage group II. Skin biopsy and serologic evidence of exfoliatin differentiate this entity from TSS. Exfoliatin causes a separation of the epidermis at the granular cell layer, whereas separation occurs at or below the basal layer in patients who have TSS (21). Streptococcal scarlet fever is usually seen in children after an upper respiratory tract infection. The rash has a characteristic "sandpaper" appearance and is followed by desquamation during convalescence. The causative agents are group A streptococci, and antibodies against antistreptolysin O are usually present. Other illnesses that could be confused with TSS include Rocky Mountain spotted fever (petechial rash), leptospirosis, Kawasaki disease (mucocutaneous lymph node syndrome), meningococcemia (petechial or purpuric rash), toxic epidermal necrolysis, and Stevens- Johnson syndrome, to name a few. Treatment Immediate and aggressive management of hypovolemic shock caused by capillary leakage, vasodilatation, and fluid loss is essential in staphylococcal TSS. To ensure adequate perfusion of vital organs, fluid replacement with large volumes of crystalloid solutions (isotonic sodium chloride, lactated Ringer's) or colloidal solutions is important and is considered the mainstay of treatment. Patients may require 8 to 20 L of fluid during the first 24 hours to maintain blood pressure. Placement of a central venous pressure line or a pulmonary arterial catheter is recommended for hemodynamic monitoring. A thorough search for possible sites of staphylococcal infection is mandatory to eliminate any preformed toxin and to prevent synthesis of new toxins. Vaginal examination and removal of a tampon or other foreign body are mandatory. Surgical wounds should be considered possible reservoirs of infection, even if no superficial signs of local infection or purulent discharge are present. Infected wounds should be opened and debrided, and any packing should be removed. Abscesses need to be drained and irrigated (figure 3: not shown). Culture specimens from all mucous membranes (vagina, oropharynx, and conjunctiva), wounds, blood, and urine should be obtained. Use of high-dose beta-lactamase-resistant antibiotics, singly or in combination with other agents, is recommended. Nafcillin sodium (Nallpen, Unipen), oxacillin sodium (Bactocill), and first-generation cephalosporins are also first-line agents. Vancomycin hydrochloride (Vancocin, Vancoled) can be used in patients who are allergic to penicillin. Clindamycin (Cleocin), erythromycin, rifampin (Rifadin, Rimactane), and fluoroquinolones have been shown to reduce TSST-1 by 90%, whereas beta-lactamase inhibitors, including nafcillin and first-generation cephalosporins, increase TSST-1 in culture, probably by lysis or increased cell membrane permeability (22). Thus, it is suggested that clindamycin be used in combination with a beta- lactamase-resistant antistaphylococcal agent, at least for the first days of treatment, to decrease the synthesis of TSST-1. Duration of treatment need not exceed 10 to 15 days in the absence of bacteremia or other complications (eg, osteomyelitis). Antibiotics do not appear to shorten the duration of acute illness, but they are useful in decreasing the organism load, the risk of bacteremia, and the rate of relapse (5,23). Complications should be anticipated, and appropriate monitoring and prompt management are essential. Because patients in whom staphylococcal TSS occurs have few or no antibodies against TSST-1 and enterotoxins, intravenous immunoglobulins have been used sporadically in severe cases. Corticosteroids are not currently considered an effective treatment. Prevention Patient education about early signs and symptoms, risk factors, and avoidance of tampons is necessary to prevent relapses. Studies have shown that as many as 30% of women who had menstrual TSS relapse during subsequent menses (4,24). Primary prevention is achieved by encouraging limited use of high-absorbency tampons and educating women about the proper use of tampons and other catamenial products as well as the importance of early recognition of TSS. If symptoms of TSS occur, tampons should be removed and prompt medical attention should be sought. For women who have recurrent menstrual TSS, tampon use should be discontinued and oral antistaphylococcal antibiotics administered before and during each menstrual period until anti-TSST-1 titers rise. Summary TSS is still very much with us and can mimic a variety of disorders. Early recognition of the various manifestations of this multisystem disease and careful inspection of possible sites of infection, removal of tampons, and debridement of surgical wounds, along with early aggressive supportive treatment and antibiotic therapy, are critical to prevent complications and ensure recovery. In menstrual TSS, prevention of subsequent relapses is achieved by patient education about proper use of tampons and recognition of early signs of the disease. References 1. Todd J, Fishaut M, Kapral F, et al. Toxic-shock syndrome associated with phage-group-1 staphylococci. Lancet 1978;2(8100):1116-8 2. Schrock CG. Disease alert. (Letter) JAMA 1980;243(12):1231 3. Centers for Disease Control. Follow-up on toxic-shock syndrome--United States. MMWR Morb Mortal Wkly Rep 1980;29(25):297-9 4. Centers for Disease Control. Toxic-shock syndrome--Utah. MMWR Morb Mortal Wkly Rep 1980;29(41):495-6 5. Davis JP, Chesney PJ, Wand PJ, et al. Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med 1980;303(25):1429-35 6. Bonventre PF, Weckbach L, Harth G, et al. Distribution and expression of toxic shock syndrome toxin 1 gene among Staphylococcus aureus isolates of toxic shock syndrome and non-toxic shock syndrome origin. Rev Infect Dis 1989;11(Suppl 1):S90-5 7. Osterholm MT, Davis JP, Gibson RW, et al. Tri-state toxic-shock syndrome study I: epidemiologic findings. J Infect Dis 1982;145(4):431-40 8. Strausbaugh LJ. Toxic shock syndrome: Are you recognizing its changing presentations? Postgrad Med 1993;94(6):107-18 9. Gaventa S, Reingold AL, Hightower AW, et al. Active surveillance for toxic shock syndrome in the United States, 1986. Rev Infect Dis 1989;11(Suppl 1):S28- 34 10. Hajjeh RA, Reingold A, Weil A, et al. Toxic shock syndrome in the United States: surveillance update, 1979-1996. Emerg Infect Dis 1999;5(6):807-10 11. Makida R, Hofer MF, Takase K, et al. Bacterial superantigens induce V beta- specific T cell receptor internalization. Mol Immunol 1996;33(10):891-900 12. Herman A, Kappler JW, Marrack P, et al. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol 1991;9:745-72 13. Manders SM. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998;39(3):383-98 14. Bohach GA, Kreiswirth BN, Novick RP. Analysis of toxic shock syndrome isolates producing staphylococcal enterotoxins B and C1 with use of southern hybridization and immunologic assays. Rev Infect Dis 1989;11(Suppl 1):S75-81 15. Crass BA, Bergdoll MS. Toxin involvement in toxic shock syndrome. J Infect Dis 1986;153(5):918-26 16. Schlievert PM. Staphylococcal enterotoxin B and toxic-shock syndrome toxin-1 are significantly associated with non-menstrual TSS. (Letter) Lancet 1986;1(8490):1149-50 17. Schlievert PM, Blomster DA. Production of staphylococcal pyrogenic exotoxin type C: influence of physical and chemical factors. J Infect Dis 1983;147(2):236- 42 18. Kass EH, Schlievert PM, Parsonnet J, et al. Effect of magnesium on production of toxic-shock-syndrome toxin-1: a collaborative study. J Infect Dis 1988;158(1):44-51 19. Arnow PM, Chou T, Weil D, et al. Spread of a toxic-shock syndrome-associated strain of Staphylococcus aureus and measurement of antibodies to staphylococcal enterotoxin F. J Infect Dis 1984;149(1):103-7 20. Chesney PJ. Clinical aspects and spectrum of illness of toxic shock syndrome: overview. Rev Infect Dis 1989;11(Suppl 1):S1-7 21. Weston WL, Todd JK. Toxic-shock syndrome. J Am Acad Dermatol 1981;4(4):478-80 22. Parsonnet J, Modern PA, Giacobbe K. Effect of subinhibitory concentrations of antibiotics on production of toxic shock syndrome toxin-1 (TSST-1). (Abstr) Program and abstracts of the 32nd meeting of the Infectious Disease Society of America, Orlando, Fla, Oct 7-9, 1994: 6A 23. Tofte RW, Williams DN. Toxic shock syndrome: clinical and laboratory features in 15 patients. Ann Intern Med 1981;94(2):149-56 24. Shands KN, Schmid GP, Dan BB, et al. Toxic-shock syndrome in menstruating women: association with tampon use and Staphylococcus aureus and clinical features in 52 cases. N Engl J Med 1980;303(25):1436-42 Dr Issa is a fellow, division of infectious diseases, Mayo Clinic, and Dr Thomp- son is assistant professor of medicine, Mayo Medical School, and consultant, division of infectious diseases, Mayo Clinic, Rochester, Minnesota. Correspondence: Rodney L. Thompson, MD, Department of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: email@example.com.