Toxic shock syndrome

• Toxic shock syndrome (TSS) is an acute, life-threatening illness caused by bacterial superantigen exotoxins, most often toxic shock syndrome toxin 1 (TSST-1) from Staphylococcus aureus or the pyrogenic exotoxins of Streptococcus pyogenes (group A streptococcus).
• The staphylococcal form that matters most in gynaecology is menstrual (tampon-associated) TSS, in which a toxin-making S. aureus colonises the vagina and uses a tampon or other inserted device as a growth niche.
• Its classic picture is sudden: high fever, dangerously low blood pressure, and a diffuse sunburn-like rash with later peeling of the palms and soles, plus at least three other failing organ systems. ^[4]
• It is a sepsis syndrome: remove the tampon or device, resuscitate with fluids and vasopressors, and start intravenous antibiotics, one of which must block toxin production (a protein synthesis inhibitor such as clindamycin or linezolid).
• Menstrual staphylococcal TSS kills fewer than 1% of patients; streptococcal TSS kills 14 to 64%, so the two must not be confused. ^[4]

By the end of this page you should be able to:

1. Define TSS and distinguish staphylococcal menstrual, staphylococcal non-menstrual and streptococcal TSS.
2. Apply the 2011 CDC clinical and laboratory criteria to a suspected case and explain why they are a surveillance tool, not a bedside test. ^[1]
3. Explain how a vaginal tampon lets TSST-1 enter the circulation and why blood cultures are often negative in the menstrual form.
4. Build a differential diagnosis of fever, rash and shock in a menstruating woman or postpartum patient.
5. Plan the first hour of care: resuscitation, source control and empiric antibiotics, with the right supplementary drug for MSSA, MRSA and streptococci.
6. Advise a survivor on why TSS returns, which devices to avoid, and what to say about tampon use.

Toxic shock syndrome is one clinical syndrome with three common settings.

• Staphylococcal menstrual TSS (m-TSS). TSST-1 (very rarely another staphylococcal enterotoxin) is produced by S. aureus colonising the vagina, usually in a healthy young woman. No S. aureus infection need be present; the illness is driven by the toxin alone, and blood cultures are negative ^[2]. Device-associated cases have been reported with tampons, menstrual cups, intrauterine devices, diaphragms, contraceptive sponges, cervical caps and pessaries ^[2][3][4].
• Staphylococcal non-menstrual TSS (nm-TSS). A toxin-producing S. aureus infects a wound, the skin, the lung, the postpartum or post-abortion genital tract, or a surgical site. Blood cultures are positive for S. aureus in about 50% of cases, so this is a mixed septic and toxin-mediated shock rather than pure toxin shock ^[2].
• Streptococcal TSS. Group A beta-haemolytic streptococci produce pyrogenic exotoxins during an invasive infection, usually of skin or soft tissue. Blood cultures are commonly positive and the illness behaves like severe sepsis, with a high death rate ^[2][5].

A useful fourth label is toxin-mediated staphylococcal disease, suggested for a patient who is clearly ill with a toxin-producing S. aureus but who does not meet enough of the CDC surveillance criteria to be called TSS. These cases carry the same risk and need the same treatment, which is why the CDC criteria should never be treated as a bedside gate ^[3].

The 2011 CDC clinical case definition for staphylococcal TSS requires fever of at least 38.9 degrees C, a diffuse macular erythroderma, desquamation, hypotension, and multisystem involvement, together with negative blood and cerebrospinal fluid cultures (blood may still grow S. aureus) and exclusion of Rocky Mountain spotted fever, leptospirosis and measles. A case with all five clinical features is confirmed; one with four of the five is probable. The same definition deliberately states that it is a surveillance tool for counting cases consistently, not a test for individual patients ^[1][3]. In practice a single large French series of menstrual TSS found that none of 102 cases met the definition of confirmed TSS and only half met it of probable TSS, even though all of them were unequivocally ill ^[2].

For comparison, the staphylococcal form needs fever, rash, desquamation, hypotension and multisystem involvement, whereas streptococcal TSS needs hypotension plus only two of a different list of organ failures, and microbiological proof of group A streptococcus. See the Infectious Disease section of the library for the full streptococcal treatment pathway and for non-menstrual staphylococcal TSS. ^[5]

Staphylococcal TSS is rare. A recent review estimates an annual incidence of 0.03 to 0.07 cases per 100,000 population, with the highest incidence (1.41 per 100,000) among women aged 13 to 24 years, and the older literature still gives figures up to 0.5 per 100,000 healthy people ^[2][4]. A peak of 13.7 per 100,000 was seen in the USA in the early 1980s with the marketing of highly absorbent tampons; incidence fell after the absorbency labelling and content changes that followed ^[2][3]. More recent estimates: in the UK 0.09 per 100,000 for the menstrual form and 0.04 per 100,000 for the non-menstrual form ^[2].

• Menstrual TSS is now the less common pattern in some settings and the one generally found in healthy young women. A 2005 to 2020 French multicentre series of 102 menstrual cases reported a median age of 18 years (range 16 to 24), no other illness in 87% of patients, tachycardia with a median heart rate of 128 per minute, median fever 39.4 degrees C, skin rash in 87%, mucosal involvement in 50%, vasopressor support in 84% and mechanical ventilation in 21% ^[2]. Every patient in that series was using a tampon at the time ^[2].
• Age and setting. Between 20% and 80% of humans carry S. aureus in the nose, and 4.2% of women in one US cohort carried TSST-1 producing strains vaginally during both menstruation and non-menstruation, without being ill ^[2][3].
• Non-menstrual TSS is more common in older patients (median 33 years, range 0 to 84, against 19 years for menstrual TSS) and is most often postoperative, with onset a median of four days after surgery ^[2].
• Staphylococcal TSS of the genital tract is also reported after childbirth and after abortion, which is why a rapidly deteriorating postpartum woman should be managed as for TSS and not just as endometritis ^[4].

Toxic shock syndrome is a disease of the toxin, not of the organism alone. In menstrual TSS the TSST-1 gene sits on a pathogenicity island (SaPI 1 or SaPI 2) of the USA 200 clonal complex (clonal complex 30), which also makes the toxin in unusually large amounts (up to 15,000 micrograms per millilitre in biofilm) ^[3]. Almost all menstrual TSS is caused by TSST-1; the remaining half of non-menstrual cases are driven by staphylococcal enterotoxins A, B or C ^[2].

The pathway for the menstrual form is well understood.

1. A healthy woman carries a TSST-1 producing S. aureus in the vagina without making protective neutralising antibodies ^[2][3].
2. A tampon (or other device) raises the vaginal oxygen tension and provides a surface on which the organism grows in biofilm, turning on toxin production in a niche that is normally anaerobic ^[2][3].
3. TSST-1 binds to CD40 on vaginal epithelium, crosses the mucosal barrier and acts as a superantigen, cross-linking MHC II on antigen-presenting cells to the V beta 2 T-cell receptor and flooding the circulation with cytokines (tumour necrosis factor, interleukin 1 and interleukin 6) ^[3]. Capillary leak and vasodilatation follow rapidly.
4. The estimated lethal human dose of TSST-1 is 0.1 microgram, which explains how a colonised but uninfected woman can become shocked in hours ^[3].

Risk factors for menstrual TSS are therefore:

• vaginal carriage of a TSST-1 producing S. aureus without protective antibody;
• intravaginal device use, particularly highly absorbent tampons left in place;
• a past episode (recovery does not induce reliable immunity, and negative TSST-1 seroconversion in convalescent sera marks women at higher genetic risk through HLA class II associations) ^[4];
• and, for non-menstrual disease, surgery, skin and soft-tissue infection, burns, postpartum infection and other S. aureus foci ^[2][4].

Recurrence is common in women who continue to use tampons or similar devices during the first four months after an episode; recurrence also occurs in women who have stopped using tampons, confirming that lack of antibody rather than the device itself is the deeper risk ^[3][4].

Everything the patient shows can be read from three facts: the toxin is a superantigen, it activates 5 to 30% of all T cells at once, and that activation releases a tidal wave of inflammatory mediators. ^[2]

• Fever. Superantigen stimulation of T cells and macrophages releases interleukin 1, which resets the hypothalamus. Temperatures of 39 to 40.5 degrees C that stay high are typical ^[4].
• Rash. A diffuse erythroderma is driven by earlier contact with the toxin and delayed hypersensitivity to it. At least one prior exposure appears to be needed, which is why the rash can be absent in a first episode. It fades and then peels, classically in one to two weeks, particularly on the palms and soles ^[1][3][4].
• Hypotension and shock. Tumour necrosis factor causes capillary leakage and vasodilatation. Blood pressure falls to below 90 mm Hg systolic in adults, and is often refractory, because fluid leaks into tissues throughout the body ^[1][4].
• Capillary leak. Systemic capillary leak syndrome explains the oedema, hypoalbuminaemia and sometimes pleural or peritoneal effusions that confuse the picture ^[4].
• Organ failure. Each failing system is the direct result of cytokine injury and hypoperfusion: vomiting and diarrhoea at the onset, myalgia with a creatine phosphokinase level of two or more times the normal ceiling, mucosal hyperaemia, renal impairment, hepatic injury, thrombocytopenia below 100,000 per millilitre, and confusion without focal signs ^[1].
• Disseminated intravascular coagulation and tissue necrosis can complicate both forms and are more typical of streptococcal disease.

A helpful distinction for the ward: menstrual TSS is pure toxin-mediated shock (blood cultures negative, no organism at a sterile site), whereas non-menstrual and streptococcal TSS are mixed, with bacteraemia in roughly half of the former and most of the latter ^[2]. ^[5]

Onset is sudden and dramatic. Patients often look like sepsis from an unknown source, and the tampon question is the one that turns the diagnosis around.

History. Ask about:

• menstruation dates and intravaginal devices currently in place;
• postpartum or post-abortion course;
• recent surgery, wounds, burns or skin infection;
• symptoms in the hours before admission, especially vomiting, diarrhoea, myalgia, sore throat, headache, dizziness and a spreading red rash;
• personal or family history of TSS or S. aureus colonisation (about 5% of menstrual cases recur) ^[2].

A slipped menstrual cup or forgotten tampon is a prompt to examine the vagina directly. Group A streptococcal TSS, by contrast, usually announces itself with excruciating pain out of proportion to the skin findings at a soft-tissue site, often with necrotising fasciitis or cellulitis.

Examination.

• Temperature is high (39 to 40.5 degrees C) and usually stays high despite antipyretics ^[4].
• Hypotension is often present on arrival and may be refractory to the first litre of fluid ^[4].
• Rash. A diffuse macular erythroderma, often most obvious on the palms and soles, appears in the first day or two. Desquamation follows 3 to 7 days after the onset in many patients and, in the surveillance definition, within 1 to 2 weeks ^[1][4].
• Mucosae. Vaginal, oropharyngeal or conjunctival hyperaemia is part of the case definition ^[1].
• Multiple organ systems. Look for vomiting or diarrhoea, severe myalgia, renal impairment, hepatic injury, thrombocytopenia and confusion without focal neurological signs ^[1].
• Local source. Inspect the vagina and cervix, the postoperative wound, any skin lesion, and the postpartum genital tract for necrotic tissue or retained products.

Be prepared for the patient who has no rash yet, who meets only three or four of the five CDC criteria, or who has already been given antibiotics and is deteriorating. Treat them all as having toxin-mediated disease if S. aureus or streptococcus is a credible source.

The closest gynaecological differential in the postpartum woman is group A streptococcal or clostridial uterine infection with micro-abscesses and shock. Unlike pure m-TSS these usually raise pyrexia with a local, painful, expanding tender uterus and require surgical source control as well as antibiotics. See the Postpartum infection topic for that comparison.

TSS is a clinical diagnosis supported by microbiology, not the other way round.

Cultures. Take blood cultures (these are positive in streptococcal TSS and in roughly half of non-menstrual staphylococcal cases, but not in menstrual TSS), and swab the nose, throat, vagina or other potential source with S. aureus or S. pyogenes in mind ^[4]. Do not wait for culture results before treating.

Blood tests. A full blood count, renal panel, liver function tests, creatine phosphokinase and clotting screen will document the "at least three organ systems" involvement and are what the 2011 case definition counts. Platelets below 100,000 per millilitre, creatinine or blood urea nitrogen two or more times the normal ceiling, bilirubin or transaminases at least twice normal, and creatine phosphokinase at least twice normal are the cut-offs ^[1]. Serial lactate and base deficit track resuscitation. ^[5]

Imaging. Soft-tissue MRI or CT helps to localise deep infection, abscess and necrotising fasciitis, and echocardiography may be needed when the differential includes infective endocarditis. In the tampon-associated form there is no radiological abnormality to find; the swab is the diagnosis.

Other tests.

• Anti-TSST-1 antibody measurement in acute and convalescent paired sera is a research and epidemiological tool, not a bedside test, but a negative seroconversion in a recovered woman tells you she may be genetically predisposed and should stop using intravaginal devices ^[4].
• Fundal height or imaging play no specific role.

A woman with sudden fever, rash and hypotension may have several immediately life-threatening alternatives.

The crucial move in the emergency department is to look rather than to diagnose perfectly: a tampon removed and a vaginal swab taken in the first 10 minutes of care is cheap, harmless and often settles the question.

Treat every case as sepsis, because it is one. The sequence is taken from a current review and from the Merck Manual, both of which treat resuscitation and source control as inseparable from antibiotics.

1. Call for help. Activate the sepsis pathway, arrange critical care and, for gynaecological sources, obstetrics and gynaecology.
2. Remove the source. Take the tampon, menstrual cup, diaphragm, contraceptive sponge or pessary out as soon as the patient arrives, and irrigate the vagina with normal saline ^[4]. Reswab the vagina, and swab the nose and throat. If the source is a wound, irrigate and debride devitalised tissue ^[2][4]. Removal is the single most effective anti-toxin measure.
3. Resuscitate. Because of the systemic capillary leak, fluid losses can be profound and refractory: give crystalloid early, add noradrenaline or adrenaline for hypotension that does not respond, and support oxygenation, ventilation and renal replacement as needed ^[2][4]. Continuous monitoring of renal, hepatic, marrow and cardiorespiratory function is mandatory ^[4].
4. At the same time, take cultures from blood, the suspected source, and, if relevant, cerebrospinal fluid.

Empiric therapy must cover the likely Gram-positive cocci and stop toxin production.

• Because of the risk of MRSA, the Merck Manual recommends starting a beta-lactam such as a first or later-generation cephalosporin or anti-staphylococcal penicillin, or vancomycin, daptomycin or ceftaroline when MRSA is proven or likely, together with clindamycin or linezolid while cultures are pending ^[4].
• A review of the literature frames this as targeting Gram-positive cocci generally, reserving broad Gram-negative and anaerobic cover for necrotising soft-tissue infection and for patients with risk factors for resistant or extended-spectrum organisms ^[2].
• Once the organism is identified, narrow the regimen ^[2][4]:
  • methicillin-susceptible S. aureus: clindamycin plus oxacillin or nafcillin;
  • methicillin-resistant S. aureus: vancomycin or daptomycin plus clindamycin or linezolid, depending on susceptibility;
  • group A streptococcus: clindamycin or linezolid plus a beta-lactam (penicillin G) ^[4].
• The protein synthesis inhibitor is the important partner drug, because in vitro and observational data suggest that clindamycin and linezolid suppress exotoxin production and may improve outcome in invasive streptococcal infection. Its optimal duration is unknown ^[2][4].
• Staphylococcal sensitivity to clindamycin varies geographically, and resistant strains are common in some regions, so linezolid is a useful alternative where resistance is suspected ^[2].
• Duration of therapy has not been settled by randomised trials. In necrotising soft-tissue infection, recent data suggest that antibiotics can be stopped 48 to 72 hours after the final surgical debridement when local and systemic recovery is clear ^[2].

Antibiotics started during the acute illness may also eradicate the S. aureus carriage that caused the episode and prevent recurrence ^[4].

IVIG neutralises superantigens in vitro, and retrospective studies suggest that it may reduce mortality in streptococcal TSS, although a randomised trial was stopped early and did not reach significance ^[2]. For staphylococcal TSS the evidence is weaker, with some authors advising against use and others advising higher doses ^[5]. The sensible line for gynaecology is to involve infectious diseases and critical care before giving it, rather than to treat it as a standard step. Where a regimen is needed, local protocols vary (some use a single 2 g per kilogram dose), and dosing should follow local guidance rather than this page. ^[4]

• Continue broad monitoring until organ function recovers.
• Repeat surgical source control for postoperative TSS if there is any doubt about complete debridement.
• Send convalescent and acute paired sera for TSST-1 seroconversion if available; a negative result identifies women at higher genetic risk (HLA class II associations), who should avoid tampons, menstrual cups, cervical caps, contraceptive sponges, intrauterine devices, diaphragms and pessaries afterwards ^[4].
• Eradicate carriage where found: topical mupirocin for S. aureus nasal carriage and chlorhexidine bathing for extra-nasal colonisation can be used ^[4].
• Every patient should be taught about tampon and device hygiene before discharge.

• Shock lasting hours to days, resistant to fluids and vasopressors because of capillary leak.
• Renal failure, sometimes needing dialysis; hepatic injury and coagulopathy.
• Acute respiratory distress syndrome and mechanical ventilation.
• Disseminated intravascular coagulation and tissue necrosis, particularly in streptococcal TSS and necrotising soft-tissue infection.
• Permanent complications after surgery, including additional procedures, amputations, reduced joint movement and death, reported in about a quarter of patients in one postoperative TSS series ^[2].
• Recurrence in tampon users unless the device is stopped; recurrent episodes are usually milder ^[3][4].

The prognosis depends heavily on whether the form is staphylococcal or streptococcal.

• Menstrual staphylococcal TSS has a mortality under 1% in large series (no deaths among 102 French menstrual cases, and 0 to 5.7% across other series) ^[2]. Non-menstrual staphylococcal TSS is deadlier, at 4 to 22%, in older and more comorbid patients ^[2]. Overall staphylococcal TSS mortality is about 5% ^[2].
• Streptococcal TSS carries a mortality of 14 to 64% in published series, but drops below 1% in postpartum cases ^[2].
• Streptococcal TSS is also an independent risk factor for death in invasive group A streptococcal infection, roughly increasing the odds 13-fold ^[2].
• Children have a mortality of about 28% in streptococcal TSS, against up to 45% in adults ^[4].
• Most patients who survive menstrual TSS make a full recovery, although each relapse is a warning that neutralising antibodies did not develop.
• Recovery after the acute insult may be complicated by prolonged ICU stay and rehabilitation, particularly after renal or respiratory failure.

There is no vaccine in routine use. Practical prevention in gynaecology is about the device and the recurrence risk.

• Avoid hyperabsorbent tampons, change tampons frequently rather than keeping them in for long periods, and never leave a device in place for longer than the manufacturer states ^[3][4].
• After a menstrual TSS episode, advise against tampon use and against use of menstrual cups, cervical caps, contraceptive sponges, intrauterine devices, diaphragms and pessaries, especially in women with negative TSST-1 seroconversion or HLA class II associations ^[4].
• Treat vaginal and nasal S. aureus carriage when found ^[4].
• National surveillance relies on the CDC case definitions and is why a reported TSS case matters even when the bedside diagnosis was already clear ^[1].
• There is no "screening" test for carriers. Targeted high-risk groups (recurrences, HLA-associated women) are advised individually, not population-wide.

Experimental and future-directed approaches reported in the literature include disruption of S. aureus growth with probiotics such as Lactobacillus acidophilus and Lacticaseibacillus rhamnosus, and a recombinant TSST-1 variant vaccine that has reached phase 1 trials ^[2]. Neither is ready for clinical use.

Pregnancy and the puerperium. Staphylococcal TSS can follow childbirth or abortion, and group A streptococcal TSS can arise in the postpartum genital tract, sometimes with early micro-abscesses and rapid shock ^[2][4]. Treat any postpartum or post-abortion woman with fever, rash and hypotension as for TSS: remove retained tissue or products promptly, take high vaginal and blood cultures, start broad Gram-positive antibiotics with a protein synthesis inhibitor, and arrange source control. Fluid resuscitation and organ support are the same as in non-pregnant adults; IVIG can be considered in severe or refractory cases with specialist input ^[2][4]. Streptococcal postpartum TSS has the lowest mortality (under 1%), which argues for early recognition rather than caution.

Children. Paediatric TSS is rare; sudden fever, rash and shock in a child can also be staphylococcal scalded skin syndrome, scarlet fever, invasive meningococcal disease or Kawasaki disease, and the clinical features and criteria separate them (see the Kawasaki disease topic in the Paediatrics section). Paediatric streptococcal TSS carries a mortality of about 28% ^[4]. Post-influenza staphylococcal TSS is a historic but serious complication of TSST-1 positive S. aureus superinfection ^[3].

Older adults. Streptococcal TSS is more common in patients aged 50 to 69 years and in those with diabetes, cancer, chronic renal or hepatic disease, heart disease, alcohol misuse or recent NSAID use, and mortality is higher in adults than children ^[2][4]. NSAID use has been suspected as a risk factor but the role is debated and the association may reflect delayed diagnosis rather than causation ^[2]. ^[5]

Immunocompromised or chronically colonised patients. Carriage of TSST-1 producing strains does not guarantee disease, but any woman with a first episode, negative seroconversion and HLA class II associations should be counselled as high risk ^[4].

• Where laboratory support is limited, the diagnosis is clinical. Confirm what you can: vaginal or wound swab for S. aureus or beta-haemolytic streptococcus, and basic counts and chemistry. Do not delay treatment for them.
• Gynaecological menstrual TSS is often missed because it looks like gastroenteritis or influenza. A nurse practitioner can make the diagnosis from a careful tampon history in the first five minutes.
• Remove the source and irrigate before referring.
• Empiric antibiotics in settings where MRSA is uncommon: flucloxacillin, oxacillin or nafcillin plus clindamycin; where MRSA is likely or confirmed, add or switch to vancomycin with clindamycin or linezolid ^[4].
• Fluid resuscitation with local crystalloid and vasopressor support; transfer to a centre with intensive care. Oxygen and renal support save lives in this syndrome.
• Record every case for the national surveillance system and refer unusual cases for public-health follow-up.

• Sepsis and septic shock, shock states, and the management of the critically ill patient (acute care).
• Postpartum infection, pelvic inflammatory disease, endometritis and surgical site infection (obstetrics and gynaecology).
• Infective endocarditis, acute rheumatic fever and staphylococcal and streptococcal skin infections (infectious diseases).
• Kawasaki disease and staphylococcal scalded skin syndrome (paediatrics).
• Necrotising soft-tissue infection and the approach to the shocked postoperative patient (surgery and critical care).