Toxic Shock Syndrome: Keys in Diagnosis and Management

Author: Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX) and Michael Gottlieb, MD, RDMS (EM Attending Physician, Rush Medical Center)  // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Before we get started, emDocs has a downloadable handout detailing considerations of TSS and diagnostic criteria:

TSS Handout

Case

A 42-year-old female presents with fever, myalgias, weakness, and a diffuse erythematous  rash for two days. She appears sick, with VS: T 38.4, HR 118, BP 88/45, RR 22, Sat 98% RA. She says she has no major medical problems, and you rapidly order CBC, electrolytes, VBG with lactate, liver and renal function, TSH, and ECG with IV fluids and acetaminophen.

What is going on?

Toxic shock syndrome (TSS) is an acute, toxin-mediated sickness with fever, hypotension, multi-organ dysfunction, and a diffuse rash with desquamation.1 TSS is treatable if diagnosed, but if missed, it can be rapidly lethal. The annual incidence is between 1.5-11 per 100,000 people.1-10  Cases occur most commonly at the extremes of age, with one study finding that the highest incidence occurred in adults aged > 45 years, followed by children < 5 years.5  Another study found higher rates among children < 2 years of age and adults ≥ 65 years of age.6

The usual organisms include Staphylococcus aureus and Streptococcus pyogenes, though others include Streptococcus agalactiae, Streptococcus viridans, Group C Streptococcus, Group G Streptococcus, and Clostridium soredellii are also involved.13-21  Staphylococcal TSS was first described in 1978 in kids due to S. aureus, followed by the 1980s with an epidemic in association with tampons.1,22,23  Following changes in tampon manufacturing and use, a decline in menstrual-related staphylococcal TSS occurred, though non-menstrual staphylococcal TSS has increased.1,24,25

Other causes of staphylococcal TSS include post-surgical, post-partum, post-abortion, intrauterine device placement, burns, soft tissue injuries, and focal infections (pneumonia).1,10,21-37  Streptococcal TSS is more common after viral infections, pharyngitis, and local soft tissue trauma.1,10,21-41  Streptococcal TSS is more common with deeper sites of infection and has greater morbidity and mortality than staphylococcal TSS.1  Mortality rates in adults ranges from 30-80%, while pediatric patients demonstrate lower rates (3-10%).1,9,10,25,42

What is the pathogenesis, and what’s a superantigen?

Where should we place the blame for TSS? It’s those horrible superantigens resulting in a massive host response. These superantigens are proteins that directly activate T-cells and bypass steps of the normal antigen-mediated immune response sequence, associated with disease morbidity and mortality.1,43,44,46,47,49  This results in a massive, uncontrolled T-cell activation and a large release of cytokines, resulting in more B and T cell activity.1,43,44,46-49

Antibodies against these superantigens reduce the risk of TSS.1,50,51  These antibodies against toxic shock syndrome toxin 1 (TSST-1) are present in over 90% of adults (but less in children), and they may be the result of mucosal colonization with TSST-1 producing S. aureus.1,52-56 

What can you find on history and exam?

TSS causes symptoms due to two factors: toxin secretion and the site of infection. Patients usually demonstrate fever, hypotension, and skin changes/rash.57-60  The first symptoms typically are myalgias and generalized weakness, along with diarrhea, sore throat, and headache. Other non-specific, flu-like symptoms early in the infection include chills, abdominal pain, and lightheadedness.23,56-66  This stage is typically where the disease is missed, as physicians can chalk these symptoms to flu-like or viral illness.  The disease then progresses rapidly (especially in otherwise healthy patients), with diffuse erythroderma, watery diarrhea, oliguria, and extremity edema within two days.63-66  Headache, confusion, somnolence, or agitation may occur later, with severe neurological conditions due to cerebral edema.66-70   Cardiopulmonary complications include heart failure with pulmonary edema and decreased cardiac function, as well as effusions.59,70,71  Hypotension is due to decreased vascular resistance and increased leakage from the intravascular compartment, and hypotension is one of the defining criteria for diagnosis.63,66,72  This hypotension may cause tissue ischemia and end organ damage with failure.63,66,71

Rash is one of the classic findings in TSS, first appearing as a diffuse, red, macular rash resembling sunburn, which is often pruritic and worsens over two weeks.63,66  The rash can involve the mucous membranes (the conjunctiva, vaginal mucosa, or oral mucosa, producing a “strawberry tongue”).63,66,72  Superficial ulcerations may occur along the mucosal surfaces in severe cases. However, do not rely on these classic findings such as diffuse erythroderma or mucosal changes.63-66  In postoperative TSS, erythema is often greatest around the surgical site, and it may not be present anywhere else. Increased interstitial fluid can result in peripheral nonpitting edema.63-66  Desquamation of the palms and soles often occurs 1-3 weeks after first symptoms of the disease.72  Notice something? If this rash occurs late, it probably won’t be present in the ED if the patient presents early in the disease course.

There are several differences between streptococcal and staphylococcal TSS, though they can present similarly. Staphylococcal TSS symptoms more commonly result from the toxin, rather than the site of infection and include fever, diarrhea, vomiting, influenza-like symptoms (headache, soreness, and sore throat), confusion, or lethargy.57-63,73 Unfortunately, patients with staphylococcal TSS are often misdiagnosed with gastroenteritis, influenza, or viral illness.73  Streptococcal TSS more commonly presents with symptoms from the local site of invasive infection such as cellulitis, pharyngitis, pneumonia, or necrotizing fasciitis.1,26-37  However, up to 45% of patients do not display a localized site of infection.59  Invasive streptococcal infections are associated with TSS in 10-30% of infections and 50% of necrotizing fasciitis cases.47  ARDS is also a major complication of TSS, which can occur in close to 45% of patients.47

 

You go back into the room after you have placed your orders to obtain a more focused history and exam. She says she recently had a large abscess drained along her leg, with packing placed. This occurred three days ago. She did not change the packing or bandage, and she then noted worsening weakness, diffuse redness, fevers, decreased urine output, and nausea. She has a diffuse red rash with red eyes.  You remove the packing from the abscess, which is covered in white discharge. The area around the wound is markedly painful.  You now are strongly suspicious of local necrotizing infection from the wound site, as well as TSS. You go back to your computer, order another liter of IV fluid, and pull up your handy antibiotic guide.

What lab findings occur in TSS?

Lab findings reflect the degree of illness, shock, and organ failure.59,63-66,74  CBC may show elevated WBC with left shift and neutrophil predominance, though this is not always the case.57,59,63,66  Anemia, thrombocytopenia, and abnormal coagulation tests may be discovered, which can resemble DIC (thrombocytopenia, prolonged coagulation tests, fibrinogen degradation products, and decreased fibrinogen levels).57,59  BUN and creatinine are usually elevated due to renal injury, and muscle injury can cause rhabdomyolysis and an elevation in creatinine kinase (CK).59,63,75-77  Hyponatremia, hypocalcemia, hypophosphatemia, and hypoalbuminemia are commonly present.77  A major differentiating factor is whether blood cultures are positive. Blood cultures are positive in 60% of patients with streptococcal TSS, but less than 5% of patients with staphylococcal TSS.59,60,62,63,78

How do you diagnose the disease?

The CDC recommends using several criteria for diagnosis of TSS, though streptococcal and staphylococcal TSS differ in several components (Table 1).57-63,70,78  Based on these criteria, you can see that official diagnosis in the ED is difficult. Patients may not exhibit the necessary signs or symptoms to meet the complete CDC criteria for diagnosis. In fact, these criteria were initially designed for research, not clinical use, and most of the criteria develop later in the disease course.63,66,79  Another difficult aspect is that many other dangerous conditions may present in a similar fashion including meningococcemia, septic shock, and primary adrenal insufficiency.62,66,80,81  If the disease is likely but does not meet official CDC criteria, treatment for TSS is recommended, while focusing on resuscitation and broad-spectrum antibiotics. Remember, this disease is deadly. The key in management is to suspect the disease based on the clinical situation, rather than meeting all CDC criteria for diagnosis. Keys in considering this disease are shown in Table 2.

The patient is hyponatremic and has a lactate of 3.8 mmol/L with markedly elevated CK, coagulation tests, and LFTs.  Her creatinine is markedly elevated at 2.3, and it appears her baseline is 0.8. You are strongly suspicious of TSS, and you have already placed a call to surgery for the suspected deep space infection and have ordered imaging of the affected extremity.

How do you manage the patient with TSS?

These patients can decompensate quickly and need immediate resuscitation.1,63,66,81  Fluid resuscitation with multiple fluid boluses is often needed due to severe volume depletion and third spacing from capillary leakage.1  Broad-spectrum antibiotic coverage is a must. Antibiotics must be started with coverage targeting S. aureus and S. pyogenes.1  Previously this included a penicillinase-resistant penicillin (oxacillin or nafcillin) or a first-generation cephalosporin (cephalexin).1,41,49  However, due to the severity of illness, broader-spectrum antibiotics such as piperacillin-tazobactam or cefepime are needed.  With the increased prevalence of methicillin-resistant S. aureus (MRSA), vancomycin or linezolid should be used as part of the initial antibiotic regimen.29,33,37,49,82-90  Interestingly, several antibiotics can reduce superantigen production by up to 90%, such as clindamycin, erythromycin, rifampin, fluoroquinolones, and linezolid.1,91-96  Literature has demonstrated clindamycin in particular is effective in treatment of TSS and improves mortality, and this medication should be used as part of broad-spectrum therapy.41,91-94,97,98  Linezolid reduces toxin production by S. aureus and group A Streptococcus. Combining clindamycin and linezolid may be better than using either alone (though this is based on case reports).85,95,96

As with every case of sepsis, a thorough search for a source and causative agents to target source control is vital as well. This should include a full skin exam and removal of foreign bodies (tampons, nasal packing, wound packing, intrauterine device).1,30,31,41,49  Wounds that appear infected should be opened and debrided, and packing should be replaced.1,41,49  Any concern for deeper wounds such as necrotizing fasciitis warrants prompt surgical consultation and potential imaging if unsure.1,41

Intravenous immunoglobulin (IVIG) 1 g/kg on the first day of hospitalization (0.5 mg/kg on days 2-3) is a possible adjunctive medication.1,42,48,94,98-107  IVIG may inhibit T-cell activation by blocking or inactivating the superantigens, resulting in decreased cytokine release.48,100-105  While current data are limited, this medication is probably safe and can reduce the severe immune response.1,41,42,48,98-107 Corticosteroids may also help, though literature is limited to a retrospective study and a case report.108,109  Finally, plasmapheresis has been explored, but thus far does not improve outcomes.110-113

You order clindamycin, cefepime, and vancomycin, with another liter of IV fluid. The patient has slowly started to improve with therapy. The surgeon on call has evaluated the patient and is concerned for deep space infection. You also discuss the patient with the ICU team.

 

Key Points:

– TSS is a potentially lethal, toxin-mediated illness that can mimic several other diseases.

– Disease results from toxin production (superantigens) and the local site of infection.

– Staphylococcus aureus and Streptococcus pyogenes are the most common microbes associated with disease, which is due to superantigens triggering massive immune response.

– Sources of TSS include burns, soft tissue injuries, post-surgical wounds, post-partum, post-abortion, pharyngitis, and focal infections.

– Symptoms are non-specific and include fever, chills, rash, vomiting, diarrhea, and hypotension. Staph TSS is associated with symptoms from toxin production, while symptoms from strep TSS are more commonly linked to the site of infection.

– Labs may show anemia, thrombocytopenia, elevated liver enzymes, renal injury, elevated lactate, and abnormal coagulation studies.

– Diagnostic criteria from the CDC are available to facilitate the diagnosis, but they miss early disease.

– Management involves IV fluids, source control, and antibiotics. Antibiotics should include a penicillinase-resistant penicillin or cephalosporin (piperacillin-tazobactam or cefepime), vancomycin (in methicillin-resistant S. aureus prevalent areas), and clindamycin or linezolid. IVIG is an adjunctive therapy.

– Knowledge of the clinical features, laboratory testing, and treatment can assist emergency clinicians in diagnosing and management this condition.

 

More FOAMed:

– PulmCrit Part 1 – Diagnosis

– PulmCrit Part 2 – Management

– WikEM

– LIFTL Microbial Mystery

 

References/Further Reading:

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