Etiology and Pathogenesis
Superantigens are a group of microbial and viral proteins that differ in several important respects from conventional peptide antigens (Fig. 177-7).10,11 First, unlike conventional protein antigens, which are taken up and processed by antigen presenting cells, superantigens exert their effects as globular intact proteins. Similar to peptide antigens, they are presented by class II major histocompatibility complex (MHC) molecules; however, they do not interact with the MHC peptide β-antigen binding groove, but instead bind to conserved amino acid residues that are on the outer walls of the peptide antigen-binding groove. Thus, whereas recognition of conventional peptide antigens by the T-cell receptor is restricted by MHC alleles, recognition of superantigens is generally not MHC restricted. Second, superantigens primarily recognize and bind to the variable region of the T-cell receptor β chain (Vβ). This is in contrast to nominal peptide antigens, which require recognition by all five variable elements (i.e., Vβ, Dβ, Jβ, Vα, Jα) of the T-cell receptor. Therefore, the responding frequency of a superantigen for resting T cells is several orders of magnitude greater (up to 20%–30%) than a conventional peptide antigen (0.01%–0.1%) The unique ability of a superantigen to bind directly to (and signal through) MHC class II molecules, and cross-link (and thus activate) a large percentage of T cells expressing relevant T-cell receptor Vβ chains, provides an explanation for the potent immune stimulation seen with these molecules. Of note, in comparison to nominal antigens, superantigen-mediated T-cell activation tends to generate increased numbers of T cells expressing the skin homing receptor cutaneous lymphocyte antigen (CLA).12 Given that CLA-positive T cells are the T-cell type that traffics readily to the skin, the increased numbers of CLA-positive T cells generated by these agents is thought to be responsible for the high propensity of cutaneous manifestations in these conditions. Superantigens lead to a massive release of cytokines, including tumor necrosis factor-α, interleukin 1, and interleukin 6. This cytokine “storm” is in great part responsible for a capillary leak syndrome and accounts for the majority of the clinical manifestations seen in superantigen-mediated diseases. The prototypical disease due to superantigens is TSS caused by staphylococcal or streptococcal toxins. Although specific syndromes such as TSS and scarlet fever have characteristic findings, overlap syndromes have been described. Because the individual clinical findings are the summation of amount and type(s) of toxins and the types of cells responding to activation, it should not be surprising that heterogeneity in clinical presentations occurs.
T-cell activation in the presence of nominal peptide antigens (left) or superantigens (right). The peptide antigen binds in the groove of the major histocompatibility complex (MHC) class II molecule and activates only antigen-specific T cells through the T-cell receptor. In contrast, a superantigen is a large globular protein that binds to the MHC class II molecule outside the antigen-binding groove and directly cross-links the MHC class II molecule and the Vβ chain of the T-cell receptor, leading to polyclonal T-cell activation.
Unlike syndromes associated with ETs that usually do not have significant systemic symptoms, those due to superantigens are characterized by systemic manifestations. Superantigen-mediated toxin syndromes can be divided into intermediate cutaneous and systemic and predominantly systemic due to the relative amounts of systemic toxicity. Disorders that have predominantly systemic manifestations are scarlet fever and the most ominous toxin-mediated disease, TSS. The intermediate cutaneous and systemic category includes syndromes such as recalcitrant erythematous desquamating disorder (REDD) and toxin-mediated erythema, which are less systemic versions of TSS and scarlet fever, respectively. All of these superantigen-mediated disorders are diagnosed based upon clinical findings and can be due to toxins produced by either S. aureus or group A Streptococcus (see Table 177-2).
TSS is an inflammatory response characterized by fever, rash, hypotension, and multiorgan involvement representing the severe end of the spectrum of superantigen-mediated diseases. Although first described in 1978 in a series of children with S. aureus infection,13 TSS became more broadly recognized with reports of epidemics associated with use of highly absorbent tampons in menstruating women in the early 1980s.14 Presumably, the tampon served as a nidus for infection: the blood added protein and neutralized the normally bacteriocidal acidic vaginal pH. Since the first descriptions of the disease, TSS has been shown to be associated with many types of staphylococcal and streptococcal infections.
Staphylococcal Toxic Shock Syndrome
The most common staphylococcal toxin associated with TSS is TSS toxin-1 (TSST-1), and it is the predominant toxin associated with menstrual-associated cases. TSST-1 appears unique among superantigens in its ability to cross-mucosal surfaces. With the removal of highly absorbent tampons from the market along with patient education, the incidence of menstruation-associated TSS decreased steadily, and at present the incidence of nonmenstrual TSS exceeds that of menstrual-associated cases. Nonmenstrual TSS is associated with postsurgical wounds, sinusitis, osteomyelitis, influenza, intravenous drug use, burn wounds, and gynecologic infection (especially in the postpartum period). Other staphylococcal toxins, including staphylococcal enterotoxins B and C (SEB and SEC), can also be found, and the latter two superantigenic toxins comprise approximately 50% of nonmenstrual TSS. The host response is an important factor in the development of TSS, as studies have shown an increased susceptibility in patients who do not have neutralizing antibodies against TSST-1.15
The symptoms of TSS begin with the acute onset of fever, sore throat, and myalgia. Diarrhea is common, and vomiting may also occur. The rash is most often a macular erythema but a scarlatiniform type can also sometimes be seen. The eruption usually begins on the trunk and spreads to extremities and can involve palms and soles (Fig. 177-8). If the patient is hypotensive, the eruption tends to be more prominent on the trunk than extremities. Symptoms of hypotension include orthostatic dizziness, fainting, or overt shock. Nonpurulent conjunctival hyperemia, pharyngeal inflammation, and strawberry tongue (see “Scarlet Fever”) are invariably present. Signs of decreased mentation can also occur. The rash will desquamate within 1–2 weeks after it appears. The Centers for Disease Control and Prevention criteria for TSS are listed in Table 177-3. Cases of lesser severity that do not meet the full definition probably do occur frequently, especially with earlier recognition and treatment. In nonmenstruation cases, especially those associated with postoperative infections, the classic signs of a localized infection such as erythema, pain, and purulence can be absent. This is often in contrast to streptococcal TSS.
Toxic shock syndrome (TSS). Patient in intensive care unit with TSS due to Staphylococcus aureus. Note patient's eruption is nonspecific erythema around intertriginous areas and face. The eruption associated with staphylococcal TSS varies and could be morbilliform, scarlatiniform, or even pustular.
Table 177-3 Centers for Disease Control and Prevention Case Definition of Staphylococcal Toxic Shock Syndrome ||Download (.pdf)
Table 177-3 Centers for Disease Control and Prevention Case Definition of Staphylococcal Toxic Shock Syndrome
Major Criteria (All Four Must Be Met)
Multisystem Involvement (Three or More Must Be Met)
Normal Test Results (If Performed)
- Temperature >38.9°C (102°F)
- Diffuse macular erythroderma
- 1–2 week after onset of illness, particularly on palms/soles
- Vomiting or diarrhea at onset of illness
- Severe myalgia or creatine kinase level twice upper limit of normal
- Mucous membrane
- Oropharyngeal, conjunctival, or vaginal hyperemia
- Blood, throat, or cerebrospinal fluid cultures (blood cultures may be positive for Staphylococcus aureus)
- No rise in titer in antibody tests for Rocky Mountain spotted fever, leptospirosis, or measles
- Systolic blood pressure <95 mm Hg for adults, or less than fifth percentile by age for children <16 years of age, or orthostatic syncope
- Blood urea nitrogen or creatinine level twice upper limit of normal, or >5 white blood cells per high-power field in urine in absence of urinary tract infection
- Total bilirubin, aspartate aminotransferase, or alanine aminotransferase level at least twice upper limit of normal
- Central nervous system
- Disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent
Streptococcal Toxic Shock Syndrome
Streptococcal TSS was described in the late 1980s as a disease similar to staphylococcal TSS, but caused by invasive group A Streptococcus. Recent reports have suggested streptococcal TSS is more commonly encountered than the staphylococcal form. The majority of cases of streptococcal TSS are due to streptococcal pyrogenic exotoxin A (SPEA), yet other superantigenic toxins including SPEB, SPEC, and involvement of other nongroup A Streptococcus have also been reported. Although not associated with tampon use, streptococcal TSS can result from nearly any type of group A streptococcal infection. The most common types of infections appear to be wounds, and streptococcal TSS has been well described as a complication of varicella and influenza A. However, in many cases the route of infection cannot be determined. In contrast to staphylococcal TSS, disease induced by group A Streptococcus is from skin in 80% of cases. The initial presentation is skin pain that is localized to an extremity in many cases. The localized pain often progresses over several days to localized erythema (see Chapter 179) and edema. Then cellulitis associated with necrotizing fasciitis and myositis with concomitant streptococcal invasion of the bloodstream develops. It should be noted that blood cultures are positive in more than one-half of patients with streptococcal TSS, in contrast to only one-tenth of patients with staphylococcal TSS. Thus, a patient with signs of TSS and a localized cellulitis should suggest streptococcal TSS as soft-tissue infections are not usually seen with staphylococcal TSS. Although very young, elderly, diabetic, or immunocompromised patients would be more susceptible to streptococcal TSS, the majority of cases have occurred in otherwise healthy adults.
The differential diagnosis of staphylococcal TSS includes septic shock, staphylococcal exfoliative syndromes, Rocky Mountain spotted fever, viral hemorrhagic shock, measles, leptospirosis, and Stevens–Johnson syndrome. Although Kawasaki syndrome has many similar clinical findings, including swelling of extremities and desquamation of palms and soles during convalescence, Kawasaki syndrome differs in that the course of fever is prolonged, and there is absence of diarrhea and hypotension. Streptococcal-mediated syndromes including scarlet fever and especially streptococcal TSS can mimic staphylococcal TSS.
In a patient with fever, rash, and hypotension, a thorough search for possible sites of staphylococcal and streptococcal infection is critical. Surgical wounds should be carefully examined even if no clinical signs of infection are apparent. Vaginal examination and removal of tampon or other foreign body should be done, and vaginal irrigation with saline or povidone iodine has been recommended.
The treatment of TSS is supportive (and usually in the intensive care setting) and focused on eradicating the offending S. aureus. Large doses of a β-lactamase-resistant, antistaphylococcal antibiotics (e.g., nafcillin) have been used historically. Because these agents have been known to increase TSST-1 in vitro (probably as a result of cell lysis), concomitant clindamycin (which will inhibit bacterial protein toxin production) is often prescribed. Because of the increasing frequency of methicillin-resistant Staphylococci in the community, vancomycin is often recommended. β-lactamase-resistant penicillins are of lesser value, not only because of emerging resistance, but also they are less effective with high levels of bacteria (in contrast to clindamycin or vancomycin). Todd has recommended a combination of vancomycin and clindamycin for suspected serious staphylococcal infections pending culture and sensitivity.16 Recently intravenous immunoglobulin (IVIG; which presumably acts in part via neutralizing antibodies against toxins) has been used and appears to have significant promise.17 At present, IVIG is used in severe or recalcitrant cases. Contraindications to IVIG include previous hypersensitivity to it or immunoglobulin A deficiency. Systemic corticosteroids are controversial and probably have less impact than considered, as superantigen-mediated immune cell activation is associated with corticosteroid resistance.
Staphylococcal TSS is clearly a life-threatening disease but the mortality rate is only approximately 5%, most likely because the majority of cases occur in otherwise healthy young individuals. Unfortunately, recurrence can be seen in up to 20%. Women who have had TSS should avoid using tampons during menstruation as it will increase the likelihood of reinfection. Diaphragms and contraceptive sponges should also be avoided in this population.
The treatment of streptococcal TSS is similar to that for staphylococcal TSS. For cases associated with necrotizing fasciitis/myositis, rapid recognition and surgical débridement are imperative. IVIG is becoming increasingly recognized as an important part of treatment of streptococcal TSS, especially because the mortality rate in this disease can be greater than 30%.18
Recalcitrant Erythematous Desquamating Disorder
A new presentation of a toxin-mediated disorder, termed recalcitrant erythematous desquamating disorder, was first described in 1992.19 The clinical findings include fever and hypotension. The rash of REDD consists of diffuse macular erythema with delayed desquamation. Other findings in common with TSS include ocular and oral mucosal injection and strawberry tongue. Staphylococci producing TSST-1, staphylococcal enterotoxin A or B (SEA, SEB), have been isolated from various places, including nasal sinuses, soft tissues, or blood. Although the majority of patients described to date have had acquired immunodeficiency syndrome, some REDD patients without acquired immunodeficiency syndrome have been reported. In contrast to TSS, this is a prolonged disease (measured in weeks to several months) in which only several of the TSS criteria are met. The diagnosis is often established by careful examination for occult colonization and/or infection in a susceptible individual.
Scarlet fever is a syndrome characterized by exudative pharyngitis, fever, and scarlatiniform rash. It is most commonly due to pyrogenic exotoxin-producing group A Streptococcus, although staphylococcal infections can produce a similar-appearing disease. The exact mechanism by which toxins produce the symptom complex is unclear. Compelling studies by Schlievert demonstrated that the scarlatiniform eruption could only be induced in mice that were previously sensitized against toxins. This suggests that a combination of conventional delayed type and superantigen-mediated processes are occurring.20 It should be noted that streptococcal toxins, especially SPEA, have areas of significant homology with collagen, which could provide a mechanism for rare autoimmune sequelae of streptococcal scarlet fever, including renal failure and rheumatic fever.21 Scarlet fever is no longer the major public health threat it was in the past because of antibiotic treatment, and because most streptococcal isolates causing scarlet fever express the less virulent SPEB and SPEC rather than SPEA.
Streptococcal Scarlet Fever
Streptococcal scarlet fever is a childhood disease that occurs most commonly in winter and early spring. It is estimated that up to 10% of childhood group A streptococcal pharyngitis patients develop scarlet fever. Approximately 12 hours to 5 days after exposure, an abrupt prodrome consisting of pharyngitis, headache, vomiting, abdominal pain, and fever develops. The rash appears 1–2 days after onset of the illness, first on the neck and then extending to the trunk and extremities, although it spares the palms and soles. The exanthem texture is usually coarse, like fine-grade sandpaper, and the erythema blanches with pressure (Fig. 177-9). The skin can be mildly pruritic but usually is not painful. A few days after generalization of the exanthem, the rash becomes more intense around skin folds and lines of confluent petechiae, due to increased capillary fragility (Pastia's sign), can be seen. The generalized exanthem begins to fade 3–4 days after onset and a desquamative phase begins, usually starting on the face. Peeling from the palms and fingers and, sometimes, soles occurs approximately 1 week later and can last for up to 1 month (see Fig. 177-9D).
Scarlet fever. A. Exanthematous rash with a sandpaper texture in the axilla. B. Exanthematous rash with a sandpaper feel on the chest. C. Perioral pallor and strawberry tongue. D. Poststreptococcal desquamation.
Oral findings of streptococcal scarlet fever include edematous, erythematous tonsils sometimes covered with a yellow, gray, or white exudate. Tender anterior cervical lymphadenopathy is common. Petechiae and punctate red macules are seen on the soft palate and uvula (Forchheimer's spots). A flushed face with circumoral pallor is also commonly noted (see Fig. 177-9C). In scarlet fever, the tongue demonstrates characteristic changes. During the first 2 days of the disease, the tongue has a white coat through which the red and edematous papillae project (white strawberry tongue). After 2 days, desquamation occurs, resulting in a red tongue with prominent papillae (red strawberry tongue) (see Fig. 177-9C).
The diagnosis of scarlet fever is made by the characteristic clinical signs and confirmed by the rapid streptococcal test or throat culture. Scarlet fever usually follows a benign course, and any undue morbidity or mortality is likely due to suppurative complications, including peritonsillar abscess, sinusitis, pneumonia, and meningitis or nonsuppurative complications associated with immune-related rheumatic fever or glomerulonephritis. The risk of acute rheumatic fever following an untreated group A streptococcal infection has been estimated to be approximately 3% in epidemics and 0.3% in endemic circumstances. Glomerulonephritis can occur in up to 10%–15% after infection with nephritogenic group A streptococcal strain. In addition to pharyngitis, group A streptococcus can cause scarlet-fever-like eruptions from skin (often surgical wounds) or uterine infections.
Scarlet fever is treated by antibiotics (penicillin or erythromycin for a 10-day course) and supportive care. Fever usually abates within 12–24 hours after initiation of antibiotic therapy. Recurrences are common.
Staphylococcal Scarlet Fever
Staphylococcal scarlet fever, also known as scarlatiniform erythroderma or rash, was first described almost 90 years ago and, until recently, was considered to be a milder or abortive form of SSSS. Patients usually develop a generalized erythroderma with a roughened, sandpaper-like texture very much like in streptococcal scarlet fever. However, the exanthem of staphylococcal scarlet fever tends to be more tender than corresponding streptococcal scarlet fever. Systemic signs including malaise and fever are invariably present. Within a few days of initiation of the rash, thick flakes develop, and the entire skin desquamates over the subsequent week. Unlike generalized SSSS, the scarlatiniform eruption is not associated with the formation of bullae or superficial exfoliation and can be very difficult to differentiate from other infectious erythrodermal causes such as TSS and streptococcal scarlet fever. Scarlet fever induced by Staphylococci differs from streptococcal-mediated disease by the lack of pharyngitis. A recent study by Wang and colleagues examined the clinical characteristics and toxin detected in 20 children with staphylococcal scarlet fever.22 They found that all of the patients’ staphylococcal infections arose from the skin; 16 of 20 cases from furuncles/carbuncles; and two each from abscesses or wound infections. All of the S. aureus strains expressed SEB. Of note, SEB shows significant protein sequence homology with SPEA, a known exotoxin associated with streptococcal scarlet fever. Yet other studies have implicated other staphylococcal enterotoxins.23 One explanation for this heterogeneity of toxins associated with this disorder is that the diagnosis is made upon clinical grounds. It is indeed possible that staphylococcal scarlet fever represents an incomplete form of TSS, in which toxins spread from the skin, thus activating the skin-associated lymphoid tissue rather than mucosal-associated lymphoid tissue. Because most cases of streptococcal scarlet fever arise from a pharyngitis, the lack of a pharyngitis in a patient with characteristic rash and other clinical signs of scarlet fever should alert the clinician to look for a localized nidus of infection (e.g., furuncle) that could be cultured to establish the diagnosis.
The diagnosis of scarlet fever is made on clinical grounds with supporting positive bacterial cultures. The differential diagnosis should include other toxin-mediated disorders including SSSS. Although Kawasaki syndrome (see Chapter 167) has many similar clinical findings including mucosal involvement (e.g., strawberry tongue), swelling of extremities, and desquamation of palms and soles during convalescence, Kawasaki syndrome differs in that the course of fever is prolonged and cultures would be expected to be negative. Atypical drug hypersensitivity reactions can have some cutaneous features, but would lack the mucosal signs. There is usually a history of offending drug and peripheral eosinophilia. Scarlet fever from group A Streptococcus can usually be differentiated from that induced by S. aureus as the usual nidus of infection in streptococcal scarlet fever is from a pharyngitis while the staphylococcal variant usually has its infectious nidus in the skin.
The treatment of scarlet fever includes antibiotics to eradicate the offending bacteria. If the localized nidus of infection is an abscess or furuncle/carbuncle, it should be drained. Acute rheumatic fever or glomerulonephritis is not associated with staphylococcal scarlet fever. For situations in which more systemic signs resemble TSS, the treatment should be that of TSS.
Toxin-Mediated Erythema (Recurrent Toxin-Mediated Perineal Erythema)
In 1996, Manders and colleagues recognized a previously unreported toxin-mediated disorder, they termed recurrent toxin-mediated perineal erythema.24 Recurrent toxin-mediated perineal erythema is characterized by a striking diffuse macular perineal erythema that occurs within 24–48 hours after a pharyngitis with a toxin-producing group A Streptococcus or S. aureus. Clinical findings seen in scarlet fever, including a strawberry tongue, as well as erythema, edema, and later, palmoplantar desquamation, are commonly found in recurrent perineal erythema. Fever, hypotension, and other systemic signs of scarlet fever or TSS are characteristically absent although diarrhea is a common feature. Recurrences are more frequently found in this localized form. It has been proposed by Manders that that the term toxin-mediated erythema be used to describe the following clinical settings in which a toxin-producing Staphylococcus or Streptococcus can be found: recurrent erythroderma associated with a preceding bacterial pharyngitis, isolated episodes of toxin-mediated erythema without recurrences, and patients with episodic mild hypotension, fever, and typical mucocutaneous findings in the absence of full criteria for TSS.25
Diseases Initiated and/or Exacerbated by Superantigens
In addition to the ability of superantigens to induce characteristic diseases including TSS, scarlet fever, and gastroenteritis, recent evidence is accumulating, which indicates that these potent immunomodulatory agents can initiate or exacerbate other skin disorders.
Psoriasis is an autoimmune T-cell-driven keratinocyte hyperproliferative disease involving skin and rarely joints. Superantigens have been implicated in psoriasis in at least two settings: (1) the guttate (acute eruptive) form and (2) in situations where psoriasis flares in response to secondary infection.11
The acute guttate form of psoriasis is characterized by the rapid onset of small erythematous psoriasiform papules that can be generalized. This form can develop during or most commonly, right after a group A streptococcal infection (usually pharyngitis). More commonly found in children and young adults, guttate psoriasis has been estimated to be the initiation of psoriasis in up to 20% of patients. Studies examining a series of guttate psoriasis patients have demonstrated the association of a SPEC-expressing group A Streptococcus along with expansion of the appropriate T-cell receptor B Vβ pattern in the skin lesions and in perilesional skin.26 These and other supporting studies do suggest that the superantigen-mediated systemic activation of T cells and MHC II-expressing accessory cells, resulting in the uncovering of the specific oligoclonal activation seen in chronic lesions is a plausible explanation for how infection could initiate this form of psoriasis.
In addition to the ability of systemic activation by a superantigen to initiate psoriasis, accumulating evidence has emerged that a localized infection with a superantigen-secreting microbe could be the trigger for worsening of psoriasis. For example, subjects with psoriasis have an increased cutaneous reactivity to the topical application of small (nanogram) amounts of superantigens, which is due to the increased levels of keratinocyte MHC II expression seen in subjects with activated psoriasis.27 Thus, guttate psoriasis and flaring of existing psoriasis should prompt a careful examination and treatment for microbial infections. In women, a history of possible menstrual-associated flares of psoriasis (especially with tampon use) should prompt appropriate investigations and treatment.
Autoeczematization (Id) Response
The autoeczematization (id) response is an acute, generalized skin reaction to a variety of stimuli. This stimulus may be a preexisting or new dermatitis (most often on the lower leg), or skin infection with fungi, bacteria, viruses, or parasites. The erythematous and papular pruritic rash often develops at distant sites and tends to be symmetric. No concomitant systemic toxicities are usually seen. One common clinical scenario is a patient with known stasis dermatitis who develops an allergic skin reaction to a topical agent (neomycin-containing antibiotic) used on the leg. Because of the ability of superantigens to stimulate significantly high numbers of T cells that tend to home to the skin, localized bacterial infection with a superantigen-producing S. aureus or group A Streptococcus could result in an autoeczematization response. Thus, careful examination for a microbial trigger is warranted in any patient with an autoeczematization response.
Secondary infection with S. aureus or group A Streptococcus is a well-known trigger of atopic dermatitis.28 It is estimated that S. aureus can be cultured from essentially all subjects with atopic dermatitis.28 Recent studies have demonstrated that skin from subjects with active atopic dermatitis has decreased levels of antimicrobial proteins.29 This lack of antimicrobial proteins may provide one explanation for the almost universal bacterial infection associated with flaring atopic dermatitis. Moreover, superantigen-expressing S. aureus have been associated with steroid-resistant AD cases.30 The mechanisms by which bacterial infection can worsen atopic dermatitis is an active area of study, and not surprisingly, superantigens have been implicated. In addition to the “usual” mechanism of cross-linking T-cell receptor and MHC-II molecules, it has been shown that many atopic dermatitis patients have immunoglobulin E antibodies that recognize these globular proteins.31 Thus, in addition to being a superantigen, these toxins can act as allergens in this population.