Staphylococcal scalded skin syndrome

Staphylococcal scalded skin syndrome (SSSS, pemphigus neonatorum or Ritter’s disease) is used to described a specific skin disorder characterized by a range of blistering skin disorders incited by specific exfoliative toxins from Staphylococcus aureus (S. aureus)[8, 9]. This disorder is most commonly seen in patients lacking the necessary antibodies to S. aureus [10], namely neonates, infants, and toddlers.. The majority of cases are seen in neonates, infants, and toddlers > 5 years old, and carries with it overall low mortality rates of approximately 4% [10–15]. While there are reported cases of SSSS in adults it is exceedingly rare. However, it does have a much higher mortality when present, approaching 60%–70% in some reports [13, 15–17].

S. Aureus contains a variety of properties that confer a high degree of virulence. These include: disruption of epithelial barriers, use of antibodies and complement to inhibit opsonization, interference with neutrophil chemotaxis, neutrophil cytolysis, and inactivation of antimicrobial peptides. The exfoliative toxins, more specifically exfoliative toxin-A, released by S. aureus disrupt cell-to-cell adhesions by cleaving desmoglein-1, leading rapid intraepithelial spread of the organism [18 – 20]. Through the expression of exotoxins, which act as superantigens, the bacteria is also able to induce T- cell activation resulting in ultimate immunosuppression from T-cell anergy. This rapid onset, lifethreatening illness is seen is toxic shock syndrome (TSS) and has been shown to be caused by S. aureus toxin-1 (TSST-1) [13, 21].

Clinical presentation

The clinical course in patients often begins with a prodrome of generalized erythema and fever followed by formation of large, friable blisters within 48 hours of onset of symptoms. Once these blisters rupture, the patient is left with large areas of partial thickness skin loss leading to severe pain, hypothermia, hypoproteinemia, hypovolemia, electrolyte imbalances, and secondary infections (Fig. 1) [8, 15, 22].

Fig. 1. Patient with Staphylococcal scalded skin syndrome (SSSS) with partial thickness skin loss over head, chest, and upper extremity

Treatment

Initial evaluation of any patient presenting with a skin disorder should include determination of depth of infection as well as whether or not the infection appears to be rapidly spreading [23]. Often times fluid may be culture from ruptured blisters to help in directing further antibiotic therapy [14]. After the initial evaluation is complete, appropriate intravenous antibiotics should be started for empiric coverage of all possible inciting organisms [24]. Children carry more challenge in antibiotic selection, as certain antibiotics have known side effects resulting in growth deformities. Appropriate initial antibiotics include: penicillins, macrolides, and secondand third-generation cephalosporins as most of these may be initiated in an inpatient setting and continued once patient is ready for discharge as an oral alternative [23].

Autoimmune blistering diseases

This group of heterogenous autoimmune bullous diseases is characterized by autoantibody-mediated desquamation leading to significant morbidity and possible mortality. This class of diseases may be further divided according to the subclass of autoantibodies involved as well as the dermal level affected. Each antibody targets specific structural proteins within the epidermis, basement membrane, and dermis leading to intraor subdermal blistering.

Subtle differences are present within each subclass of disease that is readily detectable using direct immunofluorescence, immunoblotting, and ELISA [25–31].

Epidermolysis bullosa acquisita

This is a subclass of the autoimmune blistering diseases which is an IgG mediated process against type VII collagen. One of the major components of the anchoring fibrils which help to form bonds along epithelial basement membrane cells is type VII collagen. The autoantibodies in epidermolysis bullosa acquisita specifically attack the amino-terminal non-collagenous (NC1) domain of the basement membrane leading to formation of tense vesicles and bullae primarily on extensor surfaces and areas of local trauma. A more severe form of the disease may also occur causing generalized erythema, with rapid formation of widespread vesicles and bullae not related to traumatized areas. At times these vesicles and bullae may be hemorrhagic in nature [32, 33]. A rare congenital form of epidermolysis bullosa, with variable severity of disease, is also present in which patients have an inherited defect in basement membrane structural proteins [34]. Treatment should be directed at controlling the autoimmune response through the use of corticosteroids or other immunosuppressants.

Bullous pemphigoid

Bullous pemphigoid (BP) IgG autoantibodies associate with the basal membrane hemidesmosomes and lead to a separation at the dermal-epidermal junction causing subepidermal desquamation. BP usually is seen in older individuals with onset usually occurring between 60 and 80 years of age. Symptoms begin as a urticarial eruption and gradually progresses over the course of weeks to months into large, tense bullae. Discrete lesions are scattered in the axilla, medial thighs and groin, abdomen, flexor surface of forearm and lower legs (Fig. 2a and 2b). There have been reports of mucosal surface involvement in 10–25% of patients. Pemphigoid usually has a more prolonged course and often times spontaneous remission. Histologically, BP is characterized by the presence of IgG autoantibodies against specific hemidesmosome autoantigens, BP230 and BP180 [26, 30, 42].

Pemphigus vulgaris/Pemphigus foliaceus

In pemphigus vulgaris (PV) IgG autoantibodies bind to autoantigens located on keratinocyte desmosomes, causing intraepidermal blistering. PV almost always displays mucosal involvement, with the disease beginning in the oral mucosa, soon followed by painful blistering of the skin. Pem-

Linear IgA bullous dermatosis

This disease process is driven by either IgA autoantibodies or antibodies formed from drug reactions which act against specific proteins in the basement membrane along the dermal-epidermal junction [35 – 37]. Any portion of the skin may be involved, most commonly seen over the extensor surfaces and the buttocks, including mucous membranes of the aerodigestive and reproductive tracts [26, 38]. The acquired drug induced form of the disease has been reportedly caused most commonly by exposure to vancomycin, but phenytoin and other medications have also been implicated [39 – 41]. Initial treatment should begin with dapsone, but due to its ability to cause hemolytic anemia, alternative agents such as sulfapyridine or prednisone may need to be started [26].

Fig. 2a and 2b. Forearm of patient with bullous pemphigoid demonstrating characteristic lesions. Axilla of patient with bullous pemphigoid

phigus foliaceus (PF) has a similar presentation to PV except that it does not display mucosal involvement. These diseases differ in that PF autoantibodies bind to only desmoglein 1 (Dsg1), while PV autoantibodies bind to desmoglein 3 (Dsg3) or both Dsg1 and Dsg3 [43].

Commonly affected areas of these diseases include: conjunctiva, esophagus, labia, vagina, cervix, penis, urethra, and anus. There are two tests which are suggestive of, but not diagnostic of PV/PF. The first is Nikolsky’s sign in which when pressure is applied to seemingly normal skin, it induces epidermal detachment. The second is the Asboe-Hansen sign where, when vertical pressure is applied to a blister, it causes lateral extension of epidermal detachment into normal skin [27]. There is believed to be a genetic predisposition to PV due to the identification of common major histocompatibility complexes (MHC) class II molecules, DR4 and DRw6. Likewise, PV has been found to be associated with other autoimmune diseases such as myasthenia gravis and the presence of thymomas. If not treated promptly, the loss of natural mucosal barriers often times leads to sepsis with high mortality rates [26, 30, 42].

Diagnosis

For diagnosis of these diseases a tissue biopsy is needed for immuno testing. Two punch biopsies should be taken, the first involving the margin of a bullae with the biopsy containing half normal and half affected tissue. The second biopsy should be taken of normal skin located approximately 2 cm from the edge of a bullae. These samples should then be sent immediately to pathology for further examination.

Treatment

The mainstay treatment of both diseases is through corticosteroids alone or in combination with other immunosuppressants. In patients with BP, remission of disease has been demonstrated to occur within 1.5–5 years of beginning treatment. For those patients who have contraindications to corticosteroids or for those whom conventional therapy has been unsuccessful, plasmapheresis has been shown to be an effective treatment option [26, 44, 45].

Necrotizing fasciitis

Necrotizing fasciitis (NF) is a severe, rapidly progressing soft tissue infection involving the superficial fascial layers of the extremities, abdomen, and/or perineum, which if not identified and treated rapidly may have fatal outcomes. Estimated survival rates in the literature range from 50–96% [46–48]. Higher survival rates are directly dependent on immediate diagnosis, swift surgical debridement, and intensive critical care. However, if a patient is able to survive the acute illness, there is evidence to suggest that these same patients have a decreased long-term survival due to various infectious processes [49]. Other factors shown to significantly increase mortality are age > 1 or > 60 years old, history of intravenous drug use, presence of cancer, renal insufficiency/failure, heart failure, positive blood cultures, trunk or perineal involvement, peripheral vascular disease, and positive wound cultures for -Streptococcus or anaerobes [50].

Group A Streptococcus is the mostly commonly isolated bacteria cultured from patients with NF, however the majority ( > 70%) of cases are polymicrobial in nature, containing Gram-positive, Gramnegative, aerobic, and anaerobic bacteria [5, 51, 52]. The pathogenesis of NF is still not completely understood, but it is believed that the initial inciting infection produces local toxins that subsequently damage local fascia by causing vasoconstriction of blood vessels supplying the cutaneous fascial spaces [50, 51]. This now avascular tissue serves as an ideal medium to support further bacterial growth and propagation leading to additional vascular thrombosis and tissue destruction. It is believed that these rapidly spreading infections occur due to a synergist effect between-hemolytic Streptococcus and the other microbes present in the tissue [53].

Clinical presentation

The inciting event leading to NF may be traumatic in nature or seemingly otherwise harmless events such as minor ecchymosis or erythema, with rapid progression of disease along superficial facial planes [5, 51]. When a patient presents with cellulitis or impetigo, it is imperative to closely monitor erythema and induration with a high index of suspicion for ad-

vancement of disease. One of the main symptoms that is able to differentiate NF from simple cellulitis is pain out of proportion to degree of injury [50, 51]. The patients will present early with erythema, few blisters and intense pain on palpation of involved areas. Other non-specific symptoms may also be present on initial exam such as malaise, GI distress, and fevers. If lesions are observed and the patient does have NF, they will quickly transform from erythematous lesions into larger blisters, then to large areas of edematous, cellulitic tissue with central areas of dusky, necrotic tissue (Fig. 3.) [50, 51].

Initial evaluation should begin with a thorough history and physical, focusing on predisposing factors to NF such as: immunocompromise, vascular disease, and systemic diseases such as diabetes [51]. Laboratory data is oftentimes unspecific in diagnosis

(WBC) > 15,400 may be suggestive of active NF on initial presentation [54]. If a patient presents later in the disease course they are likely to have findings more consistent with sepsis: high fevers, hypotension, tachycardia, mental status changes, and WBC > 25,000 [50]. Diagnostic imaging such as CT or MRI may be considered looking for edema or air but must be weighed against the time delay needed to complete the testing. A quick bedside maneuver that has been described is the “finger test”. This is performed by anesthetizing the skin overlying the tissue in question. A 2 cm incision is then made and carried down to the deep fascia. In the presence of NF there is usually a lack of bleeding with dissection and an expression of “dishwater” fluid. A finger is then inserted down to the deep fascia and if one is able to dissect free the overlaying subcutaneous tissue from the deep fascia with little to no resistance, this is considered a positive “finger test” and that patient should be taken to the operating immediately for surgical debridement [50].

Management

Surgical debridement is the primary mode of definitive management in NF. Patients presenting to non burn centers for initial care will likely need eventual transfer to a burn center for definitive management. One study reported that 87% of patients who pres-

Fig. 3. Patient with necrotizing fasciitis of the lower extremity on presentation

ented with a diagnosis of NF were definitively treated at a burn center most likely due to severity of illness and acuity of care [55]. It has been shown that through early referral to burn centers for care, patients have increased rates of survival with improved patient outcomes [56, 57]. With rapid diagnosis, wide surgical debridement, and intensive critical care management survival rates may be as high as 83% with 54% of survivors able to return home with no further rehabilitation needs [58].

Once the diagnosis is made, patients should be started on broad-spectrum antibiotics and taken to the operating room. In the operating room wide debridement must be carried out until the skin and soft tissue can no longer be separated off of the underlying deep fascia and until healthy bleeding occurs along wound margins. Even if undermined skin appears to be macroscopically healthy, one study found that microscopically this tissue was still found to have early thrombosis which would lead to eventual full thickness necrosis [50]. It is better to perform an initial wide debridement then leave thrombotic tissue behind, allowing for further spread of disease (Fig. 4 a and 4 b). Wounds should be check daily on rounds to assess for the need for further surgical debridement. Patients should return to the operating room as often as needed to ensure no additional progression of disease. One report estimated that patients require approximately 4 operative procedures before wounds are able to be definitively closed [59].

Fig. 4a. Postoperative photo of patient with necrotizing fasciitis after wide surgical debridement of abdominal wall

Fig. 4b. After wide local debridement of necrotizing fascitis, tissue appears healthy at wound edges with no signs of necrosis, but still with good active bleeding

Equally important as the initial management of these patients is their postoperative care and nutrition. The main post-operative principles are continued resuscitation and critical care, management of the wound, continued therapeutic coverage with broad-spectrum antibiotics, and initiation of aggressive nutritional management. Multiple daily dressing changes should be performed until the wound bed is clean and free of debris. If at any time there is question about the viability of tissue, the patient should be taken back down to the operating room for further surgical debridement. Once dressing changes are completed, wound vacuum assisted closure (VAC) devices assist in formation of granulation tissue and prepare the wound bed for eventual skin grafting (Fig. 5) [60]. Antibiotics should be continued for a complete course of treatment and until signs of systemic and local infection have resolved. There is some debate regarding the efficacy of hyperbaric oxygen in these patients. Recent studies have shown hyperbaric oxygen to not be beneficial in treatment of NF [61].

As long as there are no contraindications to enteral feedings, a feeding tube should be inserted with feeds initiated as soon as possible. For patients who would not tolerate enteral feedings due to an ileus, obstruction, or other mechanical cause, a central venous line should be inserted and total parenteral nutrition (TPN) started. These patients have profoundly accelerated metabolic demands due to the stress of sepsis and surgery. It is estimated that their basal en-

ergy expenditure (BEE) is approximately 60%–200% above normal, requiring an increase in caloric feedings of up to 124% basal rate [62]. Weekly nutritional labs should be followed and feedings adjusted as needed to improve protein calorie malnutrition caused by the disease process.

Fournier’s Gangrene

Fournier’s Gangrene (FG) is a subclass of necrotizing soft tissue infections with similar etiology to NF involving the soft tissue of the genitals and perineum. Treatment for this disease is the same as it is with NF; rapid diagnosis with wide surgical debridement and broad-spectrum antibiotics. Predisposing factors identified in patients presenting with FG are the presence of diabetes, immunosuppression, and morbid obesity (BMI > 40)[63]. Poor prognostic factors associated with FG are chronic renal failure, length of duration of symptoms prior to presentation, TBSA involvement > 6%, presence of shock on admission, and female gender [63, 64]. Postoperative care for patients with FG is very similar to those patients with NF. One main difference however is that patients with FG may require fecal or urinary diversion through the placement of a suprapubic catheter or an ostomy in order to allow for wound healing. These patients also require aggressive wound care, nutritional management, and critical care usually best provided at a burn center.