Toxic Shock Syndrome: Broadening the Differential Diagnosis

MEDICAL PRACTICE
Toxic Shock Syndrome: Broadening the Differential
Diagnosis
Christopher M. Herzer, MD
Background: Toxic shock syndrome is a rare but potentially fatal toxin-mediated febrile illness. Al-
though classically associated with tampon use, it is now known that many nonmenstrual conditions are
related to this syndrome. Serious morbidity and mortality can occur if this syndrome is not promptly
recognized.
Methods: MEDLINE was searched from 1978 to the present using the phrase “toxic shock syndrome.”
Case reports and articles related to tampon-associated toxic shock syndrome were excluded from the
literature review except when de?ning toxic shock syndrome or discussing the cause of the syndrome. A
case of nonmenstrual toxic shock syndrome associated with an intrauterine device and a review of the
de?nition, cause, diagnostic criteria, and management are reported.
Results and Conclusions: Toxic shock syndrome can mimic many common diseases. Because it can
be associated with a number of nonmenstrual-related conditions, patients with unexplained fever and
rash and a toxic condition out of proportion to local ?ndings should have the diagnosis of toxic shock
syndrome in their differential diagnosis. Early recognition and aggressive management can decrease the
overall morbidity and mortality. (J Am Board Fam Pract 2001;14:131– 6.)
Toxic shock syndrome is an acute, toxin-mediated
from the literature review were case reports and
febrile illness that rapidly leads to multiorgan sys-
articles related to tampon-associated toxic shock
tem failure with serious morbidity and mortality.
syndrome, except when de?ning toxic shock syn-
Although classically associated with tampon use,
drome or discussing the cause of the syndrome.
toxic shock syndrome has also been associated with
Reported is a case of nonmenstrual toxic shock
a variety of nonmenstrual-related conditions. No
syndrome associated with an IUD, followed by a
reports in the literature have speci?cally cited a
review of the de?nition, cause, diagnostic criteria,
direct relation between toxic shock syndrome and
and management.
intrauterine device (IUD) use. A case of toxic shock
syndrome and septicemia associated with copper T
Case Report
IUD use is described, with a brief review of the
A 31-year-old woman came to the emergency de-
clinical presentation and differential diagnosis of
partment of a military community hospital com-
toxic shock syndrome. Although the potential link
plaining of a 2-day history of fever, headache, and
between toxic shock syndrome and IUD use is
myalgia. She reported nausea, nonbloody emesis,
equivocal, this case clearly illustrates that tampon
and diarrhea. A complete blood cell count showed
use is not the only clinical situation associated with
a normal white cell count with considerable imma-
this syndrome.
ture leukocytosis. An acute viral syndrome was di-
agnosed, and she was released from the emergency
Methods
department. She returned to the clinic 2 days later
MEDLINE was searched from 1978 to the present
complaining of increasing muscle pain. She had
using the phrase “toxic shock syndrome.” Excluded
started her menses 2 days previously but denied
tampon use. She had had an IUD placed 5 years
earlier. There were no acute respiratory tract or
urinary tract symptoms.
Submitted, revised, 24 August 2000.
From the Family Practice Department, Naval Hospital,
Her blood pressure, temperature, respirations,
Camp Pendleton, Calif. Address reprint requests to Chris-
and heart rate were normal. When examined, she
topher M. Herzer, MD, 447 Koelper St, Oceanside, CA
92054.
had diffuse muscle tenderness over her proximal
Toxic Shock Syndrome 131

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extremities, back, and abdomen. She had petechiae
similar toxins, and (3) the toxins have a route of
over the lower extremities, as well as palmar and
entry into the circulatory system.
medial thigh erythema. A bloody vaginal discharge
Toxic shock syndrome is caused by a strain of S
consistent with menses was found during a pelvic
aureus that produces the toxins TSST-1 and en-
examination. IUD strings were present, and there
terotoxins A through E.2 TSST-1 suppresses neu-
was mild uterine tenderness to palpation. A repeat
trophil chemotaxis, induces T-suppressor function,
complete blood cell count showed a normal white
and blocks the reticuloendothelial system.3 The
cell count with an elevated immature leukocyte
toxins act together as superantigens that stimulate
count. Further tests showed thrombocytopenia, el-
the release of various cytokines, prostaglandins, and
evated liver enzymes, and a creatine phosphokinase
leukotrienes, which produce the signs and symp-
reading twice the normal level. She was hypoalbu-
toms of the syndrome.4 TSST-1 produces an anti-
minemic and hypocalcemic, and she had pyuria,
body response in vivo that is believed to be protec-
hematuria, and proteinuria. Blood, urine, and gen-
tive. By middle age, 90% to 95% of women have
ital samples were obtained for culture. The patient
detectable antibody titers.5 Patients with toxic
was admitted for presumed pyelonephritis and
shock syndrome produce a poor response to
started on broad-spectrum antibiotics. The patient
TSST-1 with titers of ?1:5, whereas healthy pa-
became tachycardic and hypotensive, requiring
tients have titers of ?1:100.6
large volumes of ?uid to maintain her blood pres-
The typical signs and symptoms of toxic shock
sure. She was transferred to intensive care, where,
syndrome are a high fever (?38.9°C), headache,
despite aggressive ?uid replacement, shock and dis-
vomiting, diarrhea, myalgias, and an erythematous
seminated intravascular coagulation ensued. She
rash characterized as a sunburn. Other signs and
was transferred to a tertiary care facility for more
symptoms can include meningismus,7 pharyngitis,
intensive care after being intubated. Her IUD was
conjunctivitis, vaginitis, edema, arthralgias, irrita-
removed by the accepting facility.
bility, fatigue, and abdominal pain.8 Shock, adult
Blood and vaginal cultures grew Staphylococcus
respiratory distress syndrome, disseminated intra-
aureus. Urine cultures were negative. Her antibiot-
vascular coagulation, and renal failure can develop.
ics were changed to oxacillin, vancomycin, and
Laboratory abnormalities that are found in greater
clindamycin. Ten days after admission she had ex-
than 85% of affected patients include immature
foliation of her skin. She also developed adult re-
pleocytosis, hypoalbuminemia, hypocalcemia, ele-
spiratory distress syndrome, staphylococcal endo-
vated liver enzyme levels, and elevated creatine
carditis and myocarditis, and septic emboli to the
phosphokinase levels.9 Thrombocytopenia, pyuria,
brain, kidney, spleen, and liver. She was released
proteinuria, and elevated blood urea nitrogen and
from the hospital after 2 months of inpatient ther-
creatinine levels can also occur. Figure 19 repre-
apy and is undergoing physical and occupational
sents the typical chronology of symptoms in toxic
therapy.
shock syndrome. Table 110 displays the Centers for
Disease Control (CDC) guidelines for diagnosis.
The case described here clearly meets the criteria
Discussion
for classi?cation as a true case of toxic shock syn-
Toxic shock syndrome was ?rst coined in 1978 by
drome within the CDC guidelines.
Todd et al,1 who reported the symptom complex in
Toxic shock syndrome is separated into two dis-
a group of 7 children aged 8 to 17 years with an
tinct categories: menstrual and nonmenstrual.
acute febrile illness. During the next few years, the
More than 99% of menstrual cases of toxic shock
number of cases increased, and toxic shock syn-
syndrome are associated with tampon use.11 With
drome became associated with young menstruating
increased awareness and reporting of toxic shock
women. When cases began to occur in men as well
syndrome in the 1980s, it became evident that
as nonmenstruating women, it became apparent
women could develop toxic shock syndrome unre-
that this syndrome could affect any population. It is
lated to their menses. As increasing emphasis was
now known that three criteria are required to de-
placed on the criteria than on the source of toxic
velop toxic shock syndrome: (1) the patient is col-
shock syndrome, it became evident that men could
onized or infected with S aureus, (2) the bacteria
have similar signs and symptoms. Up to 45% of all
produce toxic shock syndrome toxin-1 (TSST-1) or
cases of toxic shock syndrome are nonmenstrual.12
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Figure 1. Composite drawing of major systemic, skin, and mucous membrane manifestations of toxic shock
syndrome. (From JAMA 1981;246:741– 8, Figure 1.9 Copyrighted 1981, American Medical Association).
Nonmenstrual cases have been attributed to ab-
cultures of 5% to 20% of women,17,18 with the
scesses, cellulitis, bursitis, postpartum infections,
highest prevalence in women using diaphragms and
postsurgical procedures, and vaginal infections. Ta-
IUDs as contraception.19 One study found that a
ble 2 gives a comprehensive list of conditions asso-
small percentage (4%) of IUDs was colonized with
ciated with subsequent toxic shock syndrome.
S aureus.20 This ?nding clearly illustrates that S
To date, there have been two documented cases
aureus infection is possible in women with IUDs.
in the literature of toxic shock syndrome in patients
IUDs cause an in?ammatory response and mi-
related to IUD use.13 Two cases exist where IUD
crotrauma in the uterus that can allow bacteria or
use was concurrent with tampon use.14 Although
toxins to enter the systemic circulation. Microul-
IUD use has not been cited as a risk factor for toxic
cerations of the cervix might also serve as a portal
shock syndrome, epidemiologic studies show that
of entry. It has been shown that tampon use leads to
up to one third of cases come from an unknown
ulcerations of the cervix and vagina,21 and that toxic
focus of infection.15 IUD use might be a more
shock syndrome can be associated with this disrup-
common and heretofore unrecognized cause of
tion in mucosal integrity.22 It could be argued that
toxic shock syndrome. IUD use has been shown to
the strings from the IUD also form microulcer-
be associated with an increased incidence of pelvic
ations on the cervix and vagina, which might allow
in?ammatory disease most commonly seen in the
bacteria and toxin to enter the circulation, leading
?rst 4 months after insertion.16 These infections
to toxic shock syndrome and subsequent bactere-
are commonly polymicrobial and are consistent
mia, as seen in this patient.
with the typical vaginal ?ora of healthy women.
An IUD as the focus of infection in this patient
Some studies have reported S aureus in vaginal
can be debated. S aureus bacteremia has been found
Toxic Shock Syndrome 133

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Table 1. Case De?nition of Toxic Shock Syndrome.
Clinical Manifestation
Characteristic
Fever
?38.9°C or 102°F
Rash
Diffuse macular erythroderma
Hypotension
Systolic blood pressure ?90 mm Hg for adults or less than the 5th percentile by age for
children ?16 years, orthostatic drop in diastolic blood pressure ?15 mm Hg from lying to
sitting, orthostatic syncope, or orthostatic dizziness
Multisystem involvement of
3 or more of the
following:
Gastrointestinal
Vomiting or diarrhea at onset of illness
Muscular
Severe myalgia or creatine phosphokinase levels at least twice the upper limit of normal for
laboratory
Mucous membrane
Vaginal, oropharyngeal, or conjunctival hyperemia
Renal
Blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or
urinary sediment with pyuria (?5 leukocytes per high-power ?eld) in the absence of
urinary tract infection
Hepatic
Platelets ?100,000/?L
Central nervous system
Disoriented or alterations in consciousness without focal neurologic signs when fever and
hypotension are absent
Negative results on tests, if
Blood, throat, or cerebrospinal ?uid cultures (blood may be positive for Staphylococcus aureus)
obtained
Rise in body titer to Rocky Mountain spotted fever, leptospirosis, or measles
Case classi?cation
Probable
A case with 5 of the 6 clinical ?ndings above
Con?rmed
A case with all 6 of the ?ndings described above, including desquamation, unless the patient
dies before desquamation can occur
Note: As de?ned by the Centers for Disease Control and Prevention.
to have no focus in up to one third of cases, and the
Table 2. Clinical Situations in Which Toxic Shock
initial infection by S aureus leading to toxic shock
Syndrome Has Occurred.
syndrome can be subclinical. This patient, on
Abscesses
closer examination at the hospital to which she was
Animal bite
transferred, was found to have a mild case of
Barrier contraception (cervical cap, diaphragm, sponge)
chronic scalp folliculitis with impetigo. Although a
Breast augmentation surgery
dermatologist dismissed this infection as clinically
Burn wounds
important, it could have served as the portal of
Bursitis
entry for the bacteria and toxins. Her viral syn-
Chemical face peel
drome might have contributed as well. In?uenza
Croup
has been shown to act as a precursor to toxic shock
Deep and super?cial soft tissue infections
Dermatological surgery
syndrome in clinical studies.23,24 One might also
Empyema
debate whether the diagnosis of toxic shock syn-
Endometritis
drome was accurate in this patient. It could be
In?uenza
argued that the patient’s signs and symptoms, in-
Insect bite
cluding acute respiratory distress syndrome, dis-
Lymphadenitis
seminated intravascular coagulation, and shock,
Nasal packing
were caused by S aureus septicemia from an un-
Postoperative complication
known source. Although the sequelae of adult re-
Postpartum period
spiratory distress syndrome, disseminated intravas-
Septic abortion
cular coagulation, shock, and endocarditis could be
Sinusitis
easily attributed to bacteremia, her initial symp-
Tampon use
toms, including her prodrome, are more consistent
Tracheitis
Varicella zoster
with toxic shock syndrome.
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Table 3. Differential Diagnosis in Toxic Shock
therapy have been bene?cial in slowing disease pro-
Syndrome.
gression in toxic shock syndrome.28,29
Acute pyelonephritis
Acute rheumatic fever
Conclusion
Acute viral syndrome
Toxic shock syndrome is associated with a wide
Gastroenteritis
range of nonmenstrual-related conditions. Because
Hematoma
it mimics a number of more common diseases, it is
Hemolytic uremic syndrome
not always considered in the differential diagnosis.
Kawasaki disease
When patients have fever, rash, hypotension, a
Legionnaire disease
toxic condition out of proportion to local ?ndings,
Leptospirosis
rapid decompensation, and unanticipated labora-
Lyme disease
tory abnormalities, physicians should include the
Meningococcemia
Osteomyelitis
diagnosis of toxic shock syndrome in their differ-
Pelvic in?ammatory disease
ential diagnosis. A thorough evaluation for any foci
Rocky Mountain spotted fever
of infection is necessary, including an IUD. If the
Septic shock
patient has an IUD, it should be removed promptly
Streptococcal or staphylococcal scarlet fever
and sent for culture. It is imperative that clinicians
Systemic lupus erythematosus
not think narrowly of toxic shock syndrome as a
Thrombophlebitis
disease related to tampon use. The diagnosis of this
Tumor
syndrome should be based on the case de?nition,
Typhus
not solely on the clinical situation. A strong suspi-
cion, early recognition, and aggressive manage-
ment of this syndrome will decrease overall mor-
The differential diagnosis of toxic shock syn-
bidity and mortality.
drome is broad (Table 3),25,26 but a few features
should alert the provider. Although headache, my-
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