Staphylococcal toxic shock syndrome

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					Staphylococcal toxic shock syndrome
Nicolas C. Issa, MD; Rodney L. Thompson, MD


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tampons, which were quickly withdrawn from the market.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

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

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
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
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.


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

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

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.


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.


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.


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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: