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Introduction
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Toxic shock syndrome (TSS) is critical to recognize because it can be rapidly lethal and yet is usually treatable. TSS is a relatively new disease, first described in 1978. The prevalence has increased over the last few decades due to shifts in the circulating strains of Group A streptococcus (Low 2013). However, awareness of this disorder remains low. The following two cases illustrate how this disease may present in different ways.
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Case #1: Rory Staunton
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Rory Staunton was a very high-profile case of delayed diagnosis of streptococcal TSS. He initially suffered minor trauma playing basketball, and later presented to his pediatrician with fever, vomiting, severe leg pain, tachypnea, and tachycardia. Initially he was misdiagnosed as having gastroenteritis. He was later evaluated at the emergency department of a prominent medical center and discharged home, only to return days later with worsening shock. He died, and his case launched a campaign to improve sepsis awareness. While it's easy to place blame, this case is not uncommon. Most cases of TSS are diagnosed late. Early differentiation of TSS from gastroenteritis or influenza is a bit like finding a needle in a haystack. However, a clear understanding of TSS can facilitate early diagnosis. The constellation of severe extremity pain out of proportion to exam, nausea/vomiting, fever, and tachycardia in this case might have suggested a streptococcal necrotizing soft tissue infection complicated by TSS.
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Case #2
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A 60-year-old man presented to Genius General Hospital with cellulitis, hypotension, and acute renal failure. Examination disclosed a toxic-appearing man with confluent erythematous cellulitis involving his left calf. He was treated with volume resuscitation, norepinephrine, vancomycin, and piperacillin-tazobactam. However, his hemodynamics worsened, he developed increasing confusion, and was intubated due to tachypnea and agitation. Given that the severity of his septic shock seemed out of proportion to his cellulitis, he was treated emperically for TSS with clindamycin and intravenous immunoglobulin (IVIG). Following administration of IVIG he was promptly weaned off vasopressors. The next day he was extubated, and continued to improve rapidly. Blood cultures eventually returned positive for Group A Streptococcus.
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Pathophysiology of toxic shock syndromes
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Some streptococcal and staphylococcal strains secrete a toxin which causes widespread activation of T-lymphocytes. Activating this many leukocytes causes massive cytokine release, creating a syndrome that mimics septic shock. Most people acquire antibodies to these toxins. Toxic shock syndrome occurs if toxigenic bacteria colonize or invade a person without protective antibodies. This often causes the disease to occur in younger people who have not yet encountered these toxins and lack immunity to them.
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Epidemiology
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Staphylococcal TSSis classically associated with colonization of superabsorbant tampons. With discontinuation of these tampon brands in the 1980s, the incidence of menstrual staph TSS has declined, but this still constitutes about half of staph TSS cases. Nonmenstrual cases occur due to toxin secretion from various sources such as soft tissue infection, sinusitis or sinus packing, or pneumonia. Both menstrual and nonmenstrual staph TSS tend to occur in younger people (i.e. 20s-40s).
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Streptococcal TSS may be seen in people of all ages and always results from tissue invasion. The most common focus of infection involves the soft tissue including cellulitis, surgical site infection, necrotizing fasciitis, and myositis. Other possible sources of infection include pneumonia and septic arthritis. Strep TSS most often occurs with Group A streptococcal infection, but has also been associated with Groups B, C, and G Streptococci.
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Clinical presentation: Overview
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Patients may present with a combination of symptoms due to toxin secretion plus any symptoms from an invasive focus of infection. Thus, different patients will fall along a spectrum (figure below). Patients with menstrual TSS due to colonization with toxigenic staph present with purely toxigenic symptoms ([a] below). Some patients may present with TSS due to minor skin infection from staph or strep ([b] below). Patients with strep TSS often have a significant primary focus of infection (e.g., necrotizing fasciitis or pneumonia) combined with toxigenic symptoms ([c] below).
Clinical Presentation of Staph TSS
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Staph TSS generally occurs in immunologically naive younger people with a clinical picture dominated by toxigenic symptoms. Initially this presents in a very nonspecific fashion with some combination of fever, gastrointestinal symptoms (diarrhea more than nausea/vomiting), flu-like symptoms (headache, myalgias, sore throat), and confusion. Subsequently patients may progress to develop hypotension, shock, and renal failure.
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A diffuse erythematous blanching rash, resembling a sunburn, often occurs which may be very helpful in diagnosis (above). Unfortunately, it may be subtle or transient. This can be associated with hyperemia of the pharynx and conjunctiva, possibly with a “strawberry tongue” appearance (below). Eventually during recovery there is often desquamation of the palms and soles.
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| “Strawberry tongue” in staphylococcal toxic shock syndrome (Drage 1999). Hyperemia of the mucus membranes may be especially useful in people with darker skin color, which can mask the erythematous blanching rash. |
Staph TSS typically is associated with few symptoms from the primary site of infection or colonization. The staphylococcal toxin actually suppresses neutrophil function, thus muting local signs of infection. Therefore, in nonmenstrual staph TSS cases, the infectious focus (e.g. soft tissue abscess, infected foreign body, or surgical site) may appear misleadingly benign.
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Staph TSS is usually diagnosed late, because nobody expects a young healthy person to have septic shock. Patients may be misdiagnosed with gastroenteritis, influenza, or a “viral illness.” These patients typically have excellent physiologic reserve, so they may not develop frank hypotension until late in the illness. It is possible that an elevated shock index could be an early sign of hemodynamic instability, particularly if this is refractory to volume resuscitation.
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Clinical Presentation of Strep TSS
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Strep TSS occurs at all ages complicating various invasive streptococcal infections. The presentation of strep TSS is more variable than staph TSS.
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Strep TSS manifesting with primarily toxigenic symptoms
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Strep TSS may result from an occult focus of infection (e.g., small abscess). In these cases, the presentation will be dominated by toxigenic symptoms, and may resemble staph TSS. It may be impossible to distinguish these diseases initially, and therefore in practice it is often safest to treat empirically for both of them simultaneously.
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Strep TSS manifesting with focal infection
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In most cases the initial presentation is marked by features of local invasive streptococcal infection. Unlike staph TSS, strep TSS typically manifests as a painful necrotizing soft tissue infection (e.g., necrotizing fasciitis or myositis). Other invasive streptococcal infections such as cellulitis, pneumonia, and even pharyngitis can also present as the primary focus. Toxigenic symptoms may be less prominent compared to staph TSS. For example, diffuse erythematous rash and gastrointestinal symptoms occur in a minority of cases.
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| Pain out of proportion to exam is the most sensitive physical finding in necrotizing fasciitis. It is also useful because it is typically present early (Tobin 2009). Late in the disease course, necrosis of the nerves may produce central anesthesia. |
Staph TSS may be misdiagnosed as garden-variety septic shock (e.g., Case #2 above was initially diagnosed as septic shock due to cellulitis). Prominent gastrointestinal symptoms or erythematous rash may be helpful clues if present. The degree of illness is typically out of proportion to the focus of infection. Poor response to standard treatments for sepsis can also suggest TSS.
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| Thickened, fluid-filled fascia of a middle-aged man with diabetes and obesity who developed group A streptococcal necrotizing fasciitis and TSS. Streptococci are not gas-forming, making this more subtle on ultrasonography than some other forms of necrotizing fasciitis. This patient was treated with surgical debridement, IVIG, toxin-suppressive antibiotics, and aggressive supportive care with gradual recovery. |
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About 10-30% of all invasive group A streptococcal infections, and 50% of streptococcal necrotizing fasciitis, are complicated by TSS (Lappin 2009). This is an important consideration when treating any critically ill patient with invasive group A streptococcal infection.
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| A violaceous bullae should always raise the question of necrotizing fasciitis (Drage 1999). |
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(c) Pregnancy-related Strep TSS
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Pregnant women have 20-fold increased incidence of Group A Streptococcal infection, possibly due to changes in maternal immunity (Anderson 2014). Although infection is most often in the postpartum period, 15% precede delivery. Sites of infection include endometritis, necrotizing fasciitis, urinary tract, surgical sites, and breast. These may be complicated by TSS. Presentation typically includes abdominal pain, fever, and shock.
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Laboratory studies
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Laboratory studies are generally nonspecific in TSS (e.g., renal failure, disseminated intravascular coagulation with thrombocytopenia, leukocytosis, and elevated bilirubin). Blood cultures eventually return positive in 60% of strep TSS and <5% of staph TSS, but this is neither sensitive nor fast enough to be relied upon.
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Formal diagnostic criteria for TSS
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Complex diagnostic criteria exist for both staph and strep TSS, but they are unhelpful and potentially dangerous. These criteria are designed for research purposes, not clinical use. Treatment should never be withheld because a patient doesn't meet formal diagnostic criteria. Many criteria in these definitions only occur in the later phases of illness or during convalescence (e.g., desquamation, positive cultures). For example, in Case #2 above, the patient had already received treatment and recovered before he met diagnostic criteria for TSS. Ideally, a patient who is diagnosed early and treated aggressively will never develop full-blown illness and may never meet diagnostic criteria.
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Once the full range of symptoms become manifest, the diagnosis is usually straightforward. However, the patient may have developed irreversible organ failure by the time this occurs.
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Practical approach to diagnosing suspecting TSS
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Diagnosing TSS is challenging, and in some cases it is impossible to ever reach a definitive diagnosis. Some patients will not develop positive cultures, leaving TSS as a diagnosis of exclusion. Alternative possibilities such as meningococcemia, primary adrenal insufficiency, and other foci of infection must be carefully evaluated.
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It is essential to treat TSS as early as possible. Thus, in situations of diagnostic uncertainty, empiric treatment for TSS should be started while continuing to evaluate for alternative diagnoses. Rather than conceptualizing the diagnostic process as an all-or-none phenomena, it may be more useful to imagine varying levels of suspicion leading to different empiric treatments. If there is any suspicion of TSS, it is reasonable to initiate toxin-suppressive antibiotics. Since intravenous immunoglobulin is expensive, a higher level of suspicion is required to initiate this treatment as well.
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Conclusion: Red flags for TSS
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Unfortunately, TSS may manifest differently in different patients. TSS should be considered in many situations, especially the following:
- Systemic illness plus a diffuse blanchable erythematous rash.
- Younger person initially develops a gastroenteritis-like illness and subsequently progresses to septic shock without alternative explanation.
- Severe focal soft tissue pain out of proportion to examination plus systemic toxicity (e.g., high fever or elevated shock index).
- Peripartum septic shock.
- Septic shock due to proven or probable Group A streptococcal infection (e.g., cellulitis, necrotizing fasciitis), with sepsis severity out of proportion to the infectious source.
Next week: We will continue with the resuscitioninst's approach to treating toxic shock syndrome. Stay tuned.
Image credits:
https://drhem.wordpress.com/2012/04/ [erythroderma image]
http://www.freeimages.com/photo/pain-1366480 [leg pain image]
Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.
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Hi
I’m a pediatric emergency Physician from India.
We had a child with SSSS and indicates edema of an arm, diarrhea .She was acidotic ‘ prob due to dehydration and sepsis , no shock .Her liver enzymes were elevated with deranged renal parameters and thrombocytopenia which fits into minor criteria for TSS.How do I differentiate at this point if it is staph sepsis or TSS?
HI, I just wanted to say that don’t be afraid of this because I HAVE CURE CANCER!!!!