Amy Paller and Anthony J Mancini. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence.

4th ed. Elsevier - Health Sciences Division. 2011.

Staphylococcal Scalded Skin Syndrome

Staphylococcal scalded skin syndrome (SSSS) is a term used to describe a blistering skin disease caused by the epidermolytic toxin-producing S. aureus. It was previously known as Ritters disease or pemphigus neonatorum, and tends to occur most often in ne onates and young children. Its severity may range from mild, localized blistering to widespread exfoliation. The pathogenesis of SSSS relates to the production of epidermolytic (or exfoliative) toxins (ET), of which there are two serotypes affecting humans, ETA and ETB. These toxins have high sequence homology and are both capable of cleaving the epidermis at the superficial level of the stratum granulosum. The pathogenic mechanisms of ETA and ETB have been clearly elucidated, and they have been shown to target desmoglein 1, a cell-cell adhesion molecule found in desmosomes of the superficial epidermis.7779 Desmoglein 1 is the same molecule targeted in the autoimmune blistering disease, pemphigus foliaceus. 77 There are two main theories for the observation that SSSS preferentially affects neonates and children lack of protection from antitoxin antibodies, and decreased renal excretion of the toxin.80 In adults, SSSS is quite rare and usually occurs in the setting of immunosuppression, malignancy, heart disease, or diabetes.81 Outbreaks of SSSS have been reported in neonatal intensive care units and well baby nurseries. In these settings, asymptomatic or clinically infected health care workers often act as carriers of the epidemic strain of S. aureus, and given the potential severity of infection in the premature infant, prompt recognition with institution of strict infection control strategies is vital to prevent further nosocomial spread. 82,83 SSSS generally begins with localized infection of the conjunctivae, nares, perioral region, perineum, or umbilicus. Separation of perioral crusts often leaves behind radial fissures around the mouth, resulting in the characteristic facial appearance of SSSS (Figs 14.21, 14.22). Other infections that may serve as the initial nidus for SSSS include pneumonia, septic arthritis, endocarditis, or pyomyositis. Fever, malaise, lethargy, irritability, and poor feeding subsequently develop, and the generalized eruption begins. The rash is characterized by erythema that progresses to large, superficial fragile blisters that rupture easily, leaving behind denuded, desquamating, erythematous, and tender skin (Figs 14.22, 14.23). The eruption is most marked in flexural creases, but may involve the entire surface area of skin. The Nikolsky sign (progression of the blister cleavage plane induced by gentle pressure on the edge of the bulla) is positive. With extensive denudation of skin, patients may have decreased thermoregulatory ability, extensive fluid losses, and electrolyte imbalance, and are at serious risk for secondary infection and sepsis. With appropriate management, the skin heals without scarring given the superficial cleavage plane of the blisters. SSSS is usually diagnosed based on the clinical presentation. The main differential diagnosis is toxic epidermal necrolysis (TEN), a severe exfoliative condition that is usually drug-induced and has a high mortality rate. The most helpful distinguishing feature of TEN is mucosal involvement, including of the mouth, conjunctivae, trachea, and genital mucosa, which is lacking in SSSS. 80 Other less common differential diagnoses include scalding burns, epidermolysis bullosa, graft-versus-host disease, nutritional deficiency dermatosis, and bullous ichthyosis (in the neonate). The diagnosis of SSSS is confirmed by isolation of S. aureus. It must be remembered that the majority of blisters in SSSS are sterile, as they are caused by the hematogenous dissemination of the bacterial toxin, not the bacteria itself. The organism is most easily recovered from pyogenic (not exfoliative) foci on the skin, conjunctivae, nares, or nasopharynx. When the diagnosis remains in question, differentiation from TEN can be made by microscopic examination of a skin snip of the blister roof or a skin biopsy. In SSSS, cleavage occurs in the superficial epidermis at the level of the granular layer; whereas in TEN the split occurs below the dermal-epidermal junction. Treatment of SSSS is directed at the eradication of toxin-producing staphylococci, thus terminating toxin production. A penicillinase-resistant penicillin, first- or second-generation cephalosporin, or clindamycin are all appropriate initial choices, with modification based on sensitivity testing. In patients with MRSA infection, parenteral vancomycin or other agents (as dictated by local resistance patterns) would be indicated. As SSSS is usually a more mild disease in older children, ambulatory therapy may be an option in this population. In neonates, or in infants or children with severe infection, hospitalization is mandatory, with attention to fluid and electrolyte management, infection control measures, pain management, and meticulous wound care with contact isolation. In particularly severe disease, care in an intensive care or burn unit is required. Neutralizing antibodies that inhibit the binding of ETs to desmoglein 1 are under investigation, given concerns about the development of antibiotic-resistant, exfoliative-toxin-producing staphylococci.84

Toxic Shock Syndrome

Toxic shock syndrome (TSS) is an acute febrile illness characterized by fever, rash, hypotension, and multisystem organ involvement. Although classically described in menstruating women in relation to the use of superabsorbent tampons, TSS is now recognized in both menstrual and non-menstrual forms, the latter now being more common.85 Non-menstrual TSS may occur in association with surgical procedures, nasal packing, the postpartum state, and a variety of S. aureus infections. TSS is caused by toxin-producing strains of S. aureus. Manifestations of the disease are mediated primarily by the toxic shock syndrome toxin (TSST-1) and staphylococcal enterotoxins (SEA, SEB, SEC). These toxins are capable of widespread polyclonal activation of T cells, which results in massive cytokine release and in the clinical picture of TSS. Both TSST-1 and the staphylococcal enterotoxins are considered superantigens, given their ability to activate T cells without intracellular processing and via specific binding to MHC class II molecules.86,87 A prodrome of mild constitutional symptoms, including malaise, myalgias, and chills, often precedes the symptoms of TSS. Eventually fever develops, along with lethargy, diarrhea, chills, nausea, and altered mental status. Symptoms of hypovolemia, including hyperventilation, palpitations, and orthostatic dizziness, may be present.88 Physical findings include high fever, hypotension, a diffuse rash, and pharyngitis with hyperemia of mucous membranes. The cutaneous eruption is a diffuse, macular erythroderma, occasionally reminiscent of the rash of scarlet fever. Accentuation of the eruption in skin folds is a common finding, and in rare cases, the inguinal or perineal regions may be the only skin surfaces involved.89 Edema of the hands, feet, and face may be present, and desquamation of the affected skin surfaces (Fig. 14.24) eventually ensues. The nails may be shed, and telogen effluvium may occur up to several months later. Oral examination often reveals a strawberry tongue (Fig. 14.25), and palatal petechiae may be present. Diffuse myalgia is almost always present, and many patients complain of exquisite skin or muscle tenderness when they are touched or moved. In addition to the fever, desquamating rash, and hypotension, evidence of multiorgan involvement is present. To meet the case definition of TSS, three or more of seven other organ systems must be involved (Table 14.3). 90 The diagnosis of TSS generally rests on clinical criteria, although isolation of S. aureus from a normally sterile site, especially if toxin production can be demonstrated, is supportive. Histopathologic findings on skin biopsy are not pathognomonic. The differential diagnosis of TSS includes streptococcal TSS (see below), Kawasaki disease, scarlet fever, drug reaction, atypical measles, Rocky Mountain spotted fever, and other exanthematous illnesses. The presence of shock and multiorgan involvement is unusual in the other entities, except for streptococcal TSS, which usually has some distinguishing features. A neonatal TSS-like disease has been reported, and in some of these patients MRSA was recovered. 91 When studied, several of these MRSA isolates were positive for TSST-1 production. Most of the reported neonates had a mild course with a fairly rapid recovery.91

Since the late 1980s, a disease similar to TSS yet with some distinguishing features has been recognized. This disorder is associated with toxin-producing GABHS, and is now well recognized as streptococcal toxic shock syndrome. Although the pathogenic mechanisms are not entirely clear, streptococcal pyrogenic exotoxins (SPEA, SPEB, SPEC), mitogenic factor, and streptococcal superantigen appear to be associated with the clinical findings. Streptococcal TSS is similarly characterized by the acute onset of shock and multisystem organ failure, but unlike staphylococcal TSS, patients usually have a focal, invasive tissue or blood infection with GABHS (Table 14.4). Most patients with streptococcal TSS have pain localized to an extremity in association with necrotizing fasciitis or myonecrosis. This pain is usually out of proportion to the clinical findings on physical examination. Varicella is a particularly important risk factor for invasive GABHS infections in children, and in the child with varicella who becomes febrile after having been afebrile, or who has any fever beyond the fourth day of illness, GABHS infection should be considered. 92 A prodromal illness with influenza-like symptoms is present in up to 20% of patients with streptococcal TSS. Subsequently, shock develops rapidly and often the patients develop renal impairment, disseminated intravascular coagulopathy, and an adult respiratory distress syndrome -like illness. Physical examination reveals a diffuse macular erythroderma and mucous membrane findings, similar to those seen in staphylococcal TSS. Examination of the site of primary infection (usually an extremity) reveals localized swelling and erythema, with eventual development of vesicles and hemorrhagic bullae.93 Laboratory aberrations include leukocytosis, anemia, thrombocytopenia, elevation of serum creatinine and creatine phosphokinase, hypocalcemia, abnormal liver function studies, and evidence of disseminated coagulopathy. Management of TSS is similar for both staphylococcal and streptococcal disease. Supportive therapy, vasopressors, and antibiotics are the mainstays of therapy. Identification of sites of infection is vital, with appropriate drainage or, in the case of streptococcal TSS, aggressive and early surgical exploration and debridement as indicated. Many experts recommend combination antibiotic therapy including clindamycin, given its effects on protein (i.e., toxin) synthesis inhibition, although clindamycin should not be used alone.92 Intravenous immunoglobulin (IVIG) may be beneficial when used in combination with antibiotics for TSS because IVIG blocks superantigen-induced T-cell activation. Use of IVIG should be considered in patients in whom there has been no clinical response within the first several hours of aggressive supportive therapy. 90,94
Table 14.3 Case definition of toxic shock syndrome Table 14.4 Case definition of streptococcal toxic shock syndrome

Temperature >38.9C (102.0F) Diffuse macular erythroderma Desquamation, 12 weeks after onset, particularly of the palms and soles Hypotension Multisystem involvement (3 or more of the following): Gastrointestinal (vomiting, diarrhea) Muscular (severe myalgia, increased creatine phosphokinase level) Mucous membrane (vaginal, oropharyngeal, or conjunctival hyperemia) Renal (elevated serum urea nitrogen or serum creatinine level more than twice the upper limit of normal, or urinary sediment with >5 WBC per field in absence of UTI) Hepatic (total bilirubin, AST or ALT greater than twice the upper limit of normal) Hematologic (platelet count 100 000/mm3) Central nervous system (disorientation, altered consciousness without focal neurologic signs when fever and hypotension are absent) Laboratory criteria: Negative results on the following tests (if obtained): Blood, throat, or CSF cultures (except blood culture may be + for S. aureus) Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles Probable disease: meets laboratory criteria, and 4 of the 5 bulleted findings are present Confirmed disease: meets laboratory criteria, and all 5 of the bulleted findings, including desquamation (unless patient expires before desquamation occurs)

Isolation of GABHS: from a normally sterile site (i.e., blood, CSF, peritoneal fluid, tissue biopsy)* OR from a non-sterile site (i.e., throat, sputum, vagina)** AND Hypotension or shock AND At least 2 of the following: renal impairment (creatinine >2 mg/dL or >twice the upper limit for age) coagulopathy (DIC or thrombocytopenia) hepatic involvement (AST, ALT or total bilirubin >twice the upper limit for age) adult respiratory distress syndrome generalized erythematous rash with or without desquamation soft-tissue necrosis (i.e., necrotizing fasciitis or myositis or gangrene)

Definite case: * and both bulleted findings Probable case: ** and both bulleted findings