A 16 year old girl in previously good health became ill 2 days ago with fever to 39 degrees, myalgias, abdominal pain, and profuse vomiting and diarrhea. Yesterday she noticed a sunburn-like rash that covered her entire body but was most intense on her inner thighs and her palms and soles. This morning she was unable to get out of bed due to feeling "too sick", and when she was helped to stand, she nearly fainted from "light-headedness". She is having her menstrual period and is wearing a tampon.
Exam: T 32.2, P 160, RR 30, BP 60/40 supine. She is an ill-appearing adolescent female who is poorly oriented to her surroundings and only responds to questions with much coaxing, and her answers are incoherent. Her conjunctivae are injected. She has oral mucosal hyperemia and hypertrophy of her tongue papillae. Her tonsils are not enlarged. Total body erythroderma is noted, most pronounced on the inner thighs, and palms and soles, with prolonged capillary refill time of about 6 seconds. Her neck is supple. Her heart exam demonstrates tachycardia with a I/VI systolic ejection murmur without radiation. S1 and S2 are normal with no gallops. Her lungs are clear. Her abdomen is soft and nontender, with hyperactive bowel sounds. She is drowsy and disoriented. Her strength is weak, but her DTR's are normal. Her genitalia exam (normal Tanner 4) is significant for a tampon in the vagina and menses are noted without any other type of discharge. The tampon is removed and sent for culture.
Labs: CBC with WBC 16,000, H/H: 12/36, 50% segs, 30% bands, 15% lymphs, 5% monos, platelet count 70,000. Na 140, K 4.0, Cl 110, bicarbonate 12, BUN 20, Creatinine 0.6, AST 30, ALT 40.
She is given an IV fluid bolus and a dopamine infusion. Her blood pressure, perfusion and mentation improve. IV clindamycin and vancomycin are administered. She is hospitalized in the ICU, where her condition gradually improves. Culture of her tampon grows 4+ Staphylococcus aureus the next day. Her blood cultures are negative.
Simple or trivial skin infections or mere colonization with Staphylococcus aureus may produce toxin-mediated life-threatening disease known as staphylococcal toxic shock syndrome (TSS). This syndrome was first described by Todd et al. in 1978 who reported seven children aged 8 to 17 years who had high fever, headache, vomiting, watery diarrhea, oliguria, and a propensity to acute renal failure, hepatic abnormalities, disseminated intravascular coagulation, and severe prolonged shock (1). S. aureus related to phage-group I was isolated from mucosal (nasopharyngeal, vaginal, tracheal) or sequestered (empyema, abscess) sites, but not from blood. The illness was associated with the isolation of Group 1, type 29 staphylococci from skin, abscesses, empyema fluid or mucous membranes, and Todd named the disease "toxic shock syndrome" (1).
Between 1980 and 1986, 2960 cases of staphylococcal TSS were reported to the CDC, 90% of which were associated with menses. In 1980, a link was discovered between the use of newly introduced superabsorbent tampons and staphylococcal TSS. One brand was removed from the market and all tampons containing superabsorbent polyacrylate fibers were removed in 1985. Non-menstrual staphylococcal TSS also occurs in women, men and children (2,3). Menstrual and non-menstrual TSS are similar in their clinical appearance, but they differ in their target populations and in their outcomes. The prevalence of menstrual TSS has decreased markedly with the institution of preventive measures. Non-menstrual TSS has decreased less dramatically, and now accounts for about one-third of all staphylococcal TSS cases (3).
Menstrual TSS occurs at a rate of 1 per 100,000 menstruating women per year, and 99% of menstrual TSS occurs in women who use tampons (2). The current incidence of staphylococcal TSS has decreased greatly from the early 1980's, which is probably due to greater awareness of its presentation and the removal from the market of hyperabsorbent tampons (4). Risk factors for menstrual TSS include adolescence, lack of antibody to TSST-1 or staphylococcal enterotoxins, Caucasian ethnicity, continuous tampon use, and high absorbency potential of the tampon. Risk factors for non-menstrual TSS include any interruption of the integrity of the skin, mucous membrane colonization with a toxin-producing S. aureus isolate, or any S. aureus infection (2,3).
Todd et al. realized that their patients had clinical features similar to other known staphylococcal toxin related diseases, such as staphylococcal scalded skin syndrome and staphylococcal food poisoning (1). Also, S. aureus was isolated from 2 patients at foci of infection but not from the blood, cerebrospinal fluid, or urine, and an association with staphylococcal toxin was investigated. All staphylococcal strains isolated by Todd elaborated a previously undescribed epidermal toxin which produced a cleavage at or below the basal layer of the skin. Unlike exfoliatin, this new toxin was inactivated by heating to 60 degrees C for 30 minutes and was neutralized by staphylococcal antitoxin, but not by exfoliatin antitoxin (1). All of the staphylococcal isolates in Todd's patients reacted with group-I phages. This unique epidermal toxin has been named staphylococcal toxic shock syndrome toxin-1 (TSST-1). Expression of TSST-1 is determined by oxygen, temperature, pH, and glucose levels (5). It belongs to a large family of toxins called pyrogenic toxin superantigens which are potent stimulators of the immune cell system (i.e., cell mediated immunity), pyrogenicity, and enhancement of endotoxin shock.
Eighteen percent of healthy children and 1% to 5% of healthy menstruating women are colonized with TSST-1-producing strains of S. aureus. These healthy individuals have antibody to TSST-1, but patients with staphylococcal TSS have decreased or absent levels of anti-TSST-1 or anti-enterotoxin antibody, suggesting that anti-TSST-1 and anti-enterotoxin antibodies are protective or mitigating against staphylococcal TSS (2).
Staphylococcal toxic shock syndrome is an illness with the following clinical manifestations (6):
1) Fever with a temperature greater than 38.9 degrees (102.0 degrees F).
2) Rash, which is a diffuse macular erythroderma. In some patients with tampon-associated menstrual TSS, the rash is more intense on the medial aspect of the thighs. 3) Desquamation which occurs 1-2 weeks after onset of illness, particularly on the palms and soles.
4) Hypotension with a systolic blood pressure less than 90 mmHg for adults or less than the 5th percentile for children, or an orthostatic drop in diastolic blood pressure greater than 15 mmHg from lying to sitting, orthostatic syncope, or orthostatic dizziness.
5) Multisystem involvement with three or more of the following: a) Gastrointestinal: Vomiting or diarrhea at the onset of illness. b) Muscular: Severe myalgia or creatine phosphokinase level at least twice the upper limit of normal. c) Mucous membranes: Vaginal, oropharyngeal, or conjunctival hyperemia. d) Renal: Blood urea nitrogen or creatinine at least twice the upper limit of normal, or urinary sediment with pyuria in the absence of urinary tract infection. e) Hepatic: Total bilirubin, alanine aminotransferase or aspartate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory. f) Hematologic: Platelet count less than 100,000. g) Central nervous system: Disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent.
6) Laboratory Criteria: Blood and CSF cultures are generally negative if done. Positive cultures for S. aureus may identify the source of the toxin-producing staph. Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles are negative.
7) A case is classified as probably TSS if five of the six clinical findings described above are present. A case is classified as confirmed if all six of the clinical findings described above are present, including desquamation, unless the patient dies before desquamation occurs.
The focus of the staphylococcal infection may appear surprisingly normal or may have only minimal signs of inflammation or purulence, such as with impetigo or paronychia. The toxin interferes with the release of inflammatory mediators, so signs of inflammation may be absent (2). Thus it is very important to carefully inspect the skin to identify a possible focus of staphylococcal infection that lacks the typical erythema, warmth, and edema of these infections. Bass et al. have speculated that formes frustes, or mild versions of staphylococcal TSS may exist, which may not have hypotension, for example, but do have the other clinical features of staphylococcal TSS (7).
Five to 7 days after the onset of symptoms, patients with staphylococcal TSS exhibit a desquamating rash. It progresses to full thickness peeling by days 10 to 12. The desquamation begins on the trunk and extremities before localizing to fingers, palms, toes and soles. This desquamation is at or below the basal layer. It may be helpful diagnostically when desquamation occurs, since S. aureus is almost never cultured from the blood or CSF of patients with staphylococcal TSS, and it may not be recovered from any site.
The differential diagnosis of a severe systemic illness with fever and erythematous rash includes: invasive group A streptococcal diseases, Staphylococcal toxin-mediated diseases, septic shock of other bacterial etiologies including meningococcemia, scarlet fever, Rocky Mountain spotted fever, Kawasaki syndrome, leptospirosis, measles, systemic lupus erythematosus, Stevens Johnson syndrome, Epstein-Barr virus, adenovirus infection, enterovirus infection, human parvovirus B19 infection, Yersinia pseudotuberculosis infection (Izumi fever), drug reactions, juvenile rheumatoid arthritis, polyarteritis nodosa, Reiter's syndrome, mercury poisoning, etc.
Early recognition of staphylococcal toxic shock syndrome with intervention by removing the focus of infection and providing intravenous fluids and appropriate antibiotics before shock develops may preclude the development of shock and multiple organ failure, which in this disease appears to be secondary to shock (7). With this approach, mortality has decreased significantly below the 10% level observed in the epidemics reported in the early 1980s. The presence of cardiovascular compromise with either myocardial depression and or vascular instability should be treated with appropriate inotropes and/or vasoactive pressors in addition to fluids in an intensive care unit. Antimicrobial therapy should be selected with knowledge of the local rate of methicillin resistance. If the rate of methicillin resistance is significant, IV vancomycin and clindamycin are preferred over anti-staphylococcal penicillins and cephalosporins. Additionally, anti-ribosomal antibiotics such as clindamycin inhibit protein synthesis which may reduce the rate of toxin excretion.
Non-menstrual TSS has a higher mortality rate than menstrual TSS (3,8). Multiorgan failure, particularly renal failure and adult respiratory distress syndrome, are major sequelae of staphylococcal TSS. Unlike streptococcal TSS, in which multiorgan failure is present on admission or within a few hours of admission, multiorgan failure due to staphylococcal TSS tends to occur slightly later in the course of hospitalization. It may occur well after the acute phase of illness. Death is usually due to shock, cardiac arrhythmias, or bleeding abnormalities. In cases of non-fatal staphylococcal TSS, the patient usually improves quickly. After hypotension responds to therapy, respiratory, cardiac, renal and hepatic abnormalities improve quickly and without permanent sequelae (2,3). In cases of prolonged hypotension, chronic renal failure may result. Patients may experience persistent pain, weakness, and fatigue. There may be permanent cognitive impairment, such as memory loss, distractibility, emotional or personality alteration, and persistently cyanotic extremities (2,3).
Menstrual TSS has a risk of recurrence (2). It may recur multiple times in a patient, with each recurrence of decreasing severity. This phenomenon may be due to a delayed or low-level expression of anti-TSST-1 or anti-enterotoxin antibody (2). Women who have had a previous episode of menstrual TSS should be advised to discontinue tampon use and barrier contraceptive methods such as diaphragms. Additionally, some physicians prescribe prophylactic antibiotics to these women during menstruation. Recurrence after non-menstrual TSS is uncommon (2,3).
Since staphylococcal toxic shock syndrome and streptococcal toxic shock-like syndrome are both serious life-threatening diseases that can develop from minor skin infections and fatal consequences can develop in hours, constant vigilance and concern must be maintained when treating staphylococcal and streptococcal skin infections. The serious consequences of staphylococcal and streptococcal toxic shock syndromes demand early recognition of symptoms and aggressive treatment.
A common scenario is a febrile child with impetigo or secondarily infected varicella lesions, who presents with an erythroderma. Early toxic shock syndrome should be considered. Laboratory studies should be obtained, but these may not be very helpful in diagnosing early toxic shock. It may be best to administer parenteral antibiotics in the outpatient setting and observe the patient for several hours in the office or emergency department. Any worsening would suggest toxic shock syndrome. If any uncertainty exists, it is reasonable to hospitalize these patients.
Streptococcci can also cause toxic shock syndrome. Virulent group A beta-hemolytic streptococci (GABHS) strains were prevalent in the early part of this century in the pre-antibiotic era when fatal scarlet fever was common. These virulent strains became less prevalent after the 1950s, then recently reappeared. In the late 1980s several reports of outbreaks of rheumatic fever occurred across the United States after a marked decline in the incidence of the disease over the previous four decades. Along with these outbreaks came reports of numerous individuals who had invasive fulminant infections with GABHS with septicemia, shock, and multiple organ failure. A high mortality was reported. Some of the individuals had skin and mucous membrane findings similar to those seen in staphylococcal TSS, and subsequently streptococcal TSS was identified (9,10,11).
To determine whether these isolated reports represented an increasing incidence of invasive GABHS disease, Hoge et al. performed a retrospective review of invasive cases of GABHS disease in Pima County, Arizona over a 5-year period (12). Reporting an annual incidence of 4.3/100,000, they found that the incidence of severe infection and death due to GABHS disease was increasing, and that those affected tended to be younger and healthier than in the past. In a prospective, population-based study, Zurawski et al. reported similar results in Atlanta with a 5.2/100,000 annual incidence (13).
Hoge's study resulted in a clinical case definition for invasive GABHS disease, which has recently been updated (14). Risk factors for invasive GABHS disease are diabetes, cardiovascular disease, alcoholism, neurologic disease (paraplegia, dementia), chronic pulmonary disease, intravenous drug use, cirrhosis, malignancy, dialysis, use of corticosteroids or other immunosuppressive medications, rheumatoid arthritis, recent varicella infection, human immunodeficiency virus infection, lack of skin integrity, recent surgery, abortion, childbirth, and obesity (12,15).
Most outbreaks of invasive GABHS disease in communities do not represent common-source outbreaks, but rather are a clustering of sporadic cases (15). These severe, invasive forms of GABHS disease do not usually follow episodes of acute GABHS pharyngitis (10,16). No focus of infection is identified in 20-25% of cases. Zurawski et al. determined that use of nonsteroidal anti-inflammatory drugs (NSAIDS) in the week prior to the diagnosis of invasive GABHS disease was statistically associated with mortality (13); however other studies have not established this relationship.
The pathogenic mechanisms of invasive GABHS infections are complex and have not yet been completely defined (10,13,17,18).
Streptococcal TSS is a severe illness associated with invasive or noninvasive group A streptococcal (Streptococcus pyogenes) infection. Streptococcal TSS may occur with infection at any site but most often occurs in association with infection of a cutaneous lesion. Signs of toxicity and a rapidly progressive clinical course are characteristic, and the case-fatality rate may exceed 50% (19).
The prodromal illness of streptococcal TSS is nonspecific and includes symptoms such as fever and myalgia. Therefore clinicians may not have reason to suspect group A streptococcal infection when they are confronted with a patient appearing to have signs of toxicity with shock and multiorgan failure following a nonspecific prodromal illness. This may lead to delay in the diagnostic workup and institution of definitive therapy.
There is often a history of minor trauma preceding the prodromal illness. This trauma is of such a minor nature as to seem inconsequential, such as falling off a small children's swingset or tripping over a toy while running. It has been postulated that this minor trauma may become a locus minoris resistensiae, a site of lessened resistance, allowing GABHS in the bloodstream to focalize and multiply (20).
The earliest clue that a patient has streptococcal TSS is often the presence of multiorgan failure either at the time of presentation or soon after admission to the hospital. The kidneys are among the first organs to fail. Renal impairment is present early in the hospital course and precedes hypotension in 40-50% of patients (10). The physical examination is remarkable for shock. Examination of the skin initially reveals cool, clammy skin with poor perfusion, which progresses to mottling and purpura. Worsening of perfusion and shock may lead to tissue necrosis and frank gangrene.
Early clues in the laboratory evaluation of streptococcal TSS are hemoglobinuria and serum creatinine values that are on average more than 2.5 times normal (10). Hypocalcemia and hypoalbuminemia are present on admission and coexist throughout hospitalization (10). Serum creatinine kinase may be helpful in detecting underlying tissue involvement and destruction; when the level is elevated or rising, there is good correlation with underlying necrotizing fasciitis or myositis (10). Blood cultures are usually positive for GABHS within 24 hours or less after collection.
The prodrome of staphylococcal TSS nearly always includes gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain; the prodrome of streptococcal TSS only rarely includes these symptoms.
Patients with staphylococcal TSS are less likely to have multiorgan failure at the time of hospital admission, whereas multiorgan failure on or within hours of hospital admission occurs frequently with streptococcal TSS. We believe that with early recognition of a staphylococcal toxin-related illness, hypotension may be averted by administration of fluids and antibiotics. However, fluids and antibiotics do not appear to prevent shock in streptococcal TSS. We believe that the multiorgan failure of staphylococcal TSS may be a secondary effect of hypoperfusion due to shock, whereas the multiorgan failure of streptococcal TSS may be due to a primary effect of the toxin.
Streptococcus pyogenes remains exquisitely sensitive to penicillin. However some studies have reported mortality rates from invasive GABHS disease as high as 80% despite treatment with penicillin. In 1952 Eagle demonstrated a reduced efficacy of penicillin with high inoculum size (21). This has subsequently been named "the Eagle effect". In 1988 Stevens et al. compared the use of penicillin, erythromycin and clindamycin in GABHS myositis in mice and demonstrated that penicillin-treated mice fared no better than untreated controls if penicillin treatment was delayed for as little as 2 hours (22). Erythromycin-treated mice fared better than penicillin-treated mice and untreated controls, but only if treatment was started within 2 hours. However clindamycin-treated mice had survival rates of 100%, 100%, 80%, and 70%, even if treatment was delayed for 0, 2, 6, and 16.5 hours respectively (22).
Clindamycin is superior to penicillin in the treatment of invasive GABHS disease (10) because its efficacy is not affected by inoculum size or stage of growth. Clindamycin is a potent suppressor of bacterial toxin synthesis and it facilitates phagocytosis of GABHS by inhibiting M-protein synthesis. Clindamycin suppresses synthesis of penicillin-binding proteins and it has a longer post-antibiotic effect than beta-lactams. Clindamycin suppresses lipopolysaccharide-induced monocyte synthesis of TNF-alpha.
The patient with suspected invasive GABHS disease should be admitted to the intensive care unit for monitoring and treatment with intravenous fluids and pressors. With use of vasoconstrictors such as epinephrine, gangrene of the digits and toes often develops (10). It is not clear whether this gangrene is due to the pressors, the GABHS infection, or both.
Most patients with streptococcal TSS have fulminating septicemia with severe multiple organ failure, frequently before shock develops. These events appear to be toxin-mediated, and by the time the diagnosis is suspected and treatment is initiated, the outcome may already be determined, since streptococcal TSS has a 30-70% mortality rate (9,10,11). Complications of streptococcal TSS include shock (100%), acute respiratory distress syndrome (55%), renal impairment (80%), amputation (10%) and death (30%).
1. True/False: The prevalence of menstrual TSS has decreased markedly with the removal from the market of superabsorbent polyacrylate fiber tampons.
2. True/False: Vomiting, diarrhea, and abdominal pain are nearly ALWAYS seen in staphylococcal TSS but are rare in streptococcal TSS.
3. True/False: Oral mucosa hyperemia and hypertrophy of the tongue papillae are often seen in staphylococcal TSS but are seen in few patients with streptococcal TSS.
4. True/False: Blood cultures are usually positive in streptococcal TSS, but are usually negative in staphylococcal TSS.
5. True/False: Mortality for both staphylococcal and streptococcal TSS is about 50%.
6. True/False: In both staphylococcal and streptococcal TSS, desquamation of the hands and feet begins at about day 5-7, and is complete by day 10-12.
7. True/False: Multiorgan failure is usually present at the time of admission with streptococcal TSS, but appears later in the course with staphylococcal TSS.
8. True/False: Even though GABHS are sensitive to penicillin, the efficacy of penicillin may be reduced during overwhelming streptococcal sepsis due to the Eagle effect.
9. True/False: The prodrome of streptococcal TSS is very vague and may be associated with some seemingly unrelated minor trauma.
10. True/False: The source of staphylococcal TSS may be a superficial skin or mucocutaneous lesion which appears insignificant.
1. Todd J, Fishaut M, Kapral F, Welch T. Toxic-shock syndrome associated with phage-group-1 staphylococci. Lancet 1978;2:1116-1118.
2. Jain A, Daum RS. Staphylococcal infections in children: part 3. Pediatr Rev 1999;20:261-265.
3. Lowry FD. Staphylococcus aureus infections. New Engl J Med 1998;339:520-532.
4. Melish ME, Murata S, Fukunaga C, Frogner K, McKissick C. Vaginal tampon model for toxic shock syndrome. Rev Infect Dis 1989;11Suppl 1:S238-246; discussion 1989:S246-247.
5. Schmitt CK, Meysick KC, O'Brien AD. Bacterial toxins: friends or foes? Emerg Infect Dis 1999;5:224-234.
6. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. Toxic-shock syndrome. MMWR 1997;46(RR-10):39-40.
7. Bass JW, Harden LB, Peixotto JH. Toxic shock syndrome without shock. Pediatrics 1982;70:279-281.
8. Bass JW. Treatment of skin and skin structure infections. Pediatr Infect Dis J 1992;11:152-155.
9. Cone LA, Woodard DR, Schlievert PM, Tomory GS. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 1987;317:146-149.
10. Stevens DL. Streptococcal toxic-shock syndrome: spectrum of disease, pathogenesis, and new concepts in treatment. Emerging Infect Dis 1995;1:69-78.
11. 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. New Engl J Med 1989;321:1-7.
12. Hoge CW, Schwartz B, Talkington DF, et al. The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome. JAMA 1993;269:384-389.
13. Zurawski CA, Bardsley MS, Beall B, et al. Invasive group A streptococcal disease in metropolitan Atlanta: a population-based assessment. Clin Infect Dis 1998;27:150-157.
14. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. Streptococcal disease, invasive, group A (adopted 3/95). MMWR 1997;46(RR-10):32.
15. Centers for Disease Control and Prevention. Use of pulsed-field gel electrophoresis for investigation of a cluster of invasive group A streptococcal illness - Spokane, Washington, 1999. MMWR 1999;48(31):681-683.
16. American Academy of Pediatrics, Diseases. Severe invasive group A streptococcal infections: a subject review. Pediatrics 1998;101:136-140.
17. Schlievert PM, Assimacopoulos AP, Cleary PP. Severe invasive group A streptococcal disease: Clinical description and mechanisms of pathogenesis. J Lab Clin Med 1996;127:13-22.
18. Norrby-Teglund A, Kaul R, Low DE, et al. Evidence for the presence of streptococcal-superantigen-neutralizing antibodies in normal polyspecific immunoglobulin G. Infect Immun 1996;64:5395-5398.
19. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. Streptococcal toxic-shock syndrome (Revised 9/96) MMWR 1997;46(RR-10):33-34.
20. Vincent JM, Demers DM, Bass JW. Infectious exanthems and unusual infections. Adolescent Medicine: State of the Art Reviews 2000;11(2):327-358.
21. Eagle H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med 1952;13:389-399.
22. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis 1988;158:23-28.
Answers to questions
5. False. The mortality rate for Strep TSS is 30-70%. The mortality rate for Staph TSS is much lower.
10. True. Examples include impetigo and paronychia.