Multi-Organ Failure from Cellulitis – Streptococcal Toxic Shock Syndrome (STSS)

Toxic Shock Syndrome (TSS) is a clinical syndrome first described by James Todd in 1978. He published a case series (1) of a new condition seen in children with a clinical presentation of fever, scarlatiniform rash with subsequent desquamation, injected conjunctiva, hypotension, and multi-organ injury. S. Aureus was isolated from different sites in these children. He realized this clinical picture was different than any currently known diseases, thus defining it as a novel clinical syndrome. In 1985, Wiessenthal and colleagues published a paper that put forth an official definition for toxic shock syndrome due to S. aureus (2).

Dr. Cone (not really)

In 1987, Dr. Cone and colleagues noted a similar clinical syndrome caused by Group A Strep (GAS), which can produce similar exotoxins to those seen in S. aureus (3). The definition for TSS due to GAS – streptococcal toxic shock syndrome – was officially declared in 1993. Streptococcal toxic shock syndrome (STSS) is a significantly more deadly disease entity, and this is what we will discuss here.

Streptococcal toxic shock syndrome (STSS) is a severe illness associated with invasive or noninvasive group A streptococcal (Streptococcus pyogenes) infection. STSS 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.

While the fatality rate of S. aureus-mediated TSS is around 5%, the fatality rate of streptococcal TSS exceeds 50% even with adequate treatment (4). These patient often have a rapid clinical decline with sudden onset of refractory hypotension. Traditional measures such as antibiotics and IV fluids often do not lead to significant clinical improvement.

TSS caused by S. aureus is primarily toxin-mediated with systemic absorption of toxic shock syndrome toxin 1 (TSST-1) causing the majority of clinical symptoms. Most cases are from tampon use in women with S. aureus colonization of the genital tract. Blood cultures are almost always negative in these patients. In contrast, streptococcal TSS is from invasive GAS infection and typically involves positive blood cultures.

Clinical Criteria for STSS (5)

Image courtesy of Rosen’s Emergency Medicine, 2018

Laboratory Criteria for Diagnosis:

Isolation of group A Streptococcus from typically sterile sites – blood, CSF, joint aspirate, pericardial or pleural fluid.

Broad spectrum antibiotics should be administered. A beta-lactam antibiotic (piperacillin/tazobactam or carbapenem are good choices) plus clindamycin are recommended. Vancomycin will often be added for MRSA coverage in an undifferentiated septic shock patient.

GAS remains surprisingly susceptible to all beta-lactams, which are bactericidal and will help eliminate the infection. The addition of clindamycin will theoretically block synthesis of the toxins that are responsible for such severe clinical manifestations. Clindamycin inhibits the 50S subunit of bacterial ribosomes, thus inhibiting protein (toxin) production. This mechanism has been shown to inhibit toxin production in animal studies (6), yet the clinical evidence for clindamycin efficacy is not robust. One retrospective study of 56 patients showed that adding clindamycin to a beta-lactam improved mortality in children with invasive GAS (7). The only prospective study on clindamycin use in GAS infection (including necrotizing fasciitis, STSS or cellulitis with shock) did not find a statistically significant mortality benefit (8).

IVIG is recommended for cases where patients remain hemodynamically unstable despite adequate fluid resuscitation, antibiotics, and vasopressors. The proposed mechanism of action is multifactorial, including direct binding and neutralization of toxins and improvement in bacterial destruction by host immune system and immunomodulatory effects (9). Again, the evidence for this is poor. The only RCT on IVIG had only 21 patients and showed no mortality benefit (10). A meta-analysis including this study and 4 nonrandomized studies concluded there may be a benefit to IVIG (11), however, none of the studies found a mortality benefit alone. There was significant bias in every study – most notably differences between treatment and control groups – and the total number of patients in the meta-analysis was only 165. Trials of IVIG in septic shock show equally ambivalent results with a trend toward mortality benefit (12). IVIG currently remains an experimental treatment.

Finally, for those patients with a cutaneous source, it is important to definitively rule out necrotizing fasciitis (NF) because imaging may be negative. STSS tends to have macro-level normal fascia, but signs of necrosis at the microscopic level.

Initially, NF was recognized as a component of STSS and was included in the diagnostic criteria. However, it is now recognized as a separate entity. It is defined as GAS infection of the subcutaneous tissue and fascia that results in necrosis with relative sparing of the underlying muscle. Severe pain and tenderness disproportionate to physical findings are the clinical hallmark that differentiates NF from more superficial infection. NF can be its own disease, however, about half of patients with GAS-associated NF go on to develop STSS.

Image courtesy of WD Harrison et al (14)

Surgical exploration is the mainstay for diagnosis and treatment for NF (13). The finger test is a bedside procedure performed under local anesthesia in which a 2-cm incision is made down to the deep fascia. Gentle probing of the index finger is applied. The presence of characteristic “dishwater pus,” along with the lack of bleeding and tissue resistance to blunt finger dissection are positive findings that correlate with NF. Another useful bedside test is an incisional biopsy down to the fascial level with an immediate frozen section, culture, and Gram stain. NF patients will almost always have to go to the operating room for surgical debridement.