A woman in her fifties with a post-operative infection, generalised rash and organ failure - Tidsskrift for Den norske legeforening

Discussion

The incidence of staphylococcal and streptococcal toxic shock syndrome is approximately 0.5 and 0.4 per 100,000 per year, respectively (4). The aetiology with staphylococci was under the spotlight around the 1980s when the condition was frequently associated with the use of hyper-absorbent tampons. Today, the condition is generally not related to menstruation, but it can occur post-operatively, post-partum, or with IUDs, burns or skin and soft tissue infections. Mortality in menstruation-related cases is < 5 %, while in non-menstruation-related cases it can be as high as 22 % (4, 5).

The condition is caused by exotoxins that act as bacterial superantigens. Twenty-four staphylococcal and 12 streptococcal superantigens have been identified. Among the most common is toxic shock syndrome toxin-1 (TSST-1), which up to 50 % of Staphylococcus aureus strains can produce (6). Over 90 % of individuals develop antibodies against TSST-1 in adulthood (3).

In a normal immune response, antigens are eliminated by antigen-presenting cells and presented in major histocompatibility complex II (MHC class II) molecules to antigen-specific T cells. Only 0.01–0.001 % of T cells are specific to the relevant antigen and will be activated. However, superantigens are able to bind directly to MHC II molecules and then to a part of the T cell receptor found on all T cells. The exotoxins can thus activate up to 30 % of the T cells (Figure 2) (7).

The activation leads to a massive release of proinflammatory cytokines such as lymphotoxin-alpha, interleukin-1, -2, and -6, interferon-gamma and tumour necrosis factor. Interleukin-1 can induce muscle proteolysis. The TSST-1 superantigen has a direct effect on blood vessels, resulting in capillary leakage and hypotension. Classic focal signs of infection can be modest, as superantigens inhibit macrophage infiltration in the infected area through overproduction of tumour necrosis factor (4, 8, 9) – as observed in our patient, for whom the findings at and around the surgical wound were sparse.

Symptoms of toxic shock syndrome develop rapidly (within 48 hours). The direct effects of toxins and cytokines, along with hypotension, result in multiorgan failure typically occurring 8–12 hours after symptom onset (10). Rapid diagnosis and treatment are therefore crucial to reduce mortality and morbidity. The diagnosis is based on clinical investigations, and there is no paraclinical test to differentiate toxic shock syndrome from other staphylococcal or streptococcal infections. The Centers for Disease Control and Prevention in the United States has developed diagnostic criteria, but these cannot be used to rule out toxic shock syndrome in individual suspected cases (11).

The classical presentation of diffuse erythema originates in the thorax and spreads to the extremities, particularly the palms of the hands and soles of the feet. This is typically followed by desquamation in these areas (Figure 1). Other typical symptoms and signs include high fever, low blood pressure, muscle pain (rhabdomyolysis), renal failure, liver failure, cardiomyopathy, pulmonary oedema and pleural effusion, vomiting and diarrhoea, headache, conjunctival, oropharyngeal and vaginal hyperaemia, anaemia, thrombocytopenia and disseminated intravascular coagulation (10). Important differential diagnoses are septic shock caused by other pathogens, adverse drug reaction, meningococci and inflammatory multisystem syndrome associated with COVID-19.

Treatment consists of supportive care to reverse the shock state, as well as surgery and antibiotics. Wounds may appear innocuous due to a weakened inflammatory response, but surgical debridement is still necessary (12). It is also important to remove any foreign bodies at suspected sites, such as tampons, IUDs, soiled dressings and piercings (9, 10, 13). According to the guidelines on antibiotic therapy, empiric antibiotic therapy is benzylpenicillin 2.4 g × 6 intravenously for streptococci, and cloxacillin 2 g × 6 intravenously for staphylococci (14). Using penicillin as a bactericidal agent inhibits the formation of bacterial cell walls, and it is important to add clindamycin 900 mg × 3 intravenously, which inhibits bacterial protein synthesis and thus the formation of toxins (6). This combination of beta-lactam antibiotics and clindamycin has been shown to have the best efficacy and should be the first-line treatment (6). Intravenous immunoglobulin can be given as adjunctive therapy, as it has an anti-inflammatory and immunomodulating effect, including inactivation of circulating superantigens (4, 13). Several observational studies point to lower mortality with the use of intravenous immunoglobulin, but the evidence is uncertain due to the absence of randomised controlled trials (4).

Over 90 % of individuals develop antibodies against TSST-1 by the age of 25. Toxic shock syndrome with TSST-1 only affects the 10 % who do not have antibodies (15). Half of these patients do not seroconvert and they have a reduced ability to produce antibodies after an illness, putting them at increased risk of a new episode (15).

Toxic shock syndrome is believed to be underdiagnosed as some patients only meet the criteria retrospectively (8). Today, the condition is not typically associated with menstruation, and toxic shock syndrome should be considered in recently operated patients who rapidly develop a high fever, rash and multiorgan failure.