Staphylococcal scalded skin syndrome – the importance of early differential diagnosis based on clinical symptoms

Introduction

Staphylococcal scalded skin syndrome (SSSS), also referred to as Ritter’s disease or bullous exfoliative dermatitis, is caused by skin colonization with a strain of Staphylococcus aureus which produces epidermolytic (exfoliative) toxin (ET). The toxin binds to desmoglein 1, disrupting the integrity of the junctions between keratinocytes in the granular layer of the epidermis, leading to acantholysis. As a result of this process, blisters develop within the epidermis, just beneath the stratum corneum [1]. The syndrome progresses dynamically, beginning as a localized infection and potentially advancing to widespread skin involvement, as a risk of sepsis. Nikolsky’s sign is a key diagnostic indicator in dermatologic emergencies involving the formation of peeling skin blisters in children.

Objective

The aim of the study was to highlight the importance of Nikolsky’s sign as a key finding in the diagnosis of acute blistering skin conditions in children.

Case report

A four-year-old boy was admitted to the Emergency Department (ED) presenting with erythema and erythematous-edematous skin lesions, without blistering, accompanied by hyperesthesia. The medical history indicated that the boy had been playing in hay and swimming in the family pool the day prior to his admission. Following an examination in the ED, he was initially diagnosed with allergic contact dermatitis due to the initial exposure to hay. Treatment with dexamethasone and cetirizine hydrochloride was initiated, resulting in partial improvement of the skin lesions and allowing the patient to be discharged.
After 24 h, the boy was readmitted to the hospital and transferred to the Pediatric Department due to severe skin hyperesthesia and the development of bullous lesions. The bullous eruption was localized in the skin folds. Radial fissures around the mouth with signs of impetiginization were observed (fig. 1), along with facial vesicles accompanied by purulent nasal discharge (fig. 2), “wet newspaper” sign on the back and nape of the neck, with visible epidermal desquamation (fig. 3), flaccid bullae located on the boy’s temple and forehead (fig. 4), and positive Nikolsky’s sign (fig. 5). Physical examination revealed generalized weakness, skin hyperesthesia, erythroderma, and diffuse bullous lesions, including erosions with purulent crusts around the mouth and nasal vestibule, and in the vermillion zone. Positive Nikolsky’s sign was observed on both affected and unaffected skin. Laboratory tests were within normal limits, and both blood and urine cultures were negative. However, nasal, throat, and skin swabs demonstrated growth of Staphylococcus aureus (SA) colonies.
Based on the clinical presentation and laboratory findings, a diagnosis of SSSS was confirmed. Antibiotic therapy with cloxacillin was initiated as the treatment of choice. The boy required continuous pain management, intravenous fluid therapy, and the local application of mupirocin ointment and non-stick dressings. The lesions were observed to spread to the scalp and limbs. No changes were noted in the oral mucosa or conjunctiva. Additionally, redness of the foreskin with an erosive lesion at the base of the penis was seen, while the glans penis remained unaffected. In the following days, the boy’s general condition deteriorated to a moderately severe level, requiring the administration of morphine for pain relief. As a result, he was transferred to the Pediatric Intensive Care Unit. Following treatment, his condition improved, and the skin lesions resolved completely. The boy is developing normally, with no apparent deficits (fig. 6 − post-inflammatory hypopigmentation, fig. 7 A, B − desquamation in the healing stage).

Discussion

The clinical presentation of SSSS is caused by the hydrolysis of the amino-terminal extracellular domain of desmoglein 1 by exfoliative staphylococcal toxins. This disrupts keratinocyte adhesion and leads to their separation in the stratum granulosum, resulting in blister formation [1]. Skin colonization by the S. aureus strain and microinjuries demonstrate a synergistic effect of epidermolytic toxins A and B, which have serine protease properties. The interaction between exfoliative toxin and desmoglein disrupts the desmosomes in the granular layer, leading to epidermal detachment [2–4].
The diagnosis is primarily based on the characteristic clinical presentation. Skin changes include tenderness, erythematous lesions, flaccid bullae, and epidermal desquamation. The skin in these areas develops a burn-like appearance, which is particularly noticeable in regions subjected to friction, such as skin folds.
Positive Nikolsky’s sign is a key diagnostic feature. It involves easy separation of the superficial layers of the epidermis upon gentle skin rubbing, indicating a weakening of the attachments between epidermal cells (acantholysis). The course of the syndrome can range from a localized skin infection to generalized involvement accompanied by symptoms of sepsis. According to the literature data, the incidence of SSSS is estimated at 0.09 to 0.56 cases per million in the general population. The frequency is higher in children, with 7.67 cases per million, compared to 0.98 cases per million in adults [3, 5, 6]. The syndrome typically affects newborns (aged 3 to 7 days) and children under 5 years old, with the highest incidence occurring between 2 and 3 years of age. The higher frequency in the pediatric population is attributed to the absence of protective antibodies against exfoliative toxins and the reduced renal clearance of these toxins in children. The disease is rare in adults, with reported cases typically occurring in individuals with low socioeconomic status, immunodeficiency, or renal impairment.
The progression of SSSS symptoms unfolds in several distinct stages. Initially, non-specific flu-like symptoms including fever, general malaise, and irritability appear, followed by a rash resembling scarlet fever, with skin tenderness and erythema, most prominent around the mouth and in the diaper area. After 24–48 h, erythema develops, accompanied by extensive flaccid bullae that rupture, resulting in erosions on either involved or uninvolved skin. The epidermis easily separates when the skin is gently rubbed, indicating positive Nikolsky’s sign, which can be classified into two types based on the method of induction.
Nikolsky’s sign I involves applying pressure to clinically normal-appearing skin adjacent to pathological lesions, resulting in epidermal detachment and desquamation. The mechanism is associated with acantholysis, the loss of intercellular connections in the epidermis, which is characteristic of autoimmune diseases like pemphigus vulgaris and pemphigus foliaceus. It primarily affects areas with intact epidermis, helping to differentiate it from conditions with deeper acantholysis, such as pemphigus vulgaris, and superficial dermatoses. Positive Nikolsky’s sign I indicates an ongoing disease process within the epidermal layers and helps in differentiating pemphigoid from other bullous dermatoses. Nikolsky’s sign II is elicited by gentle pressure on a skin blister, causing its enlargement or the movement of fluid within the skin. It results from a loss of adhesion between the epidermis and the basal layer of the skin. Nikolsky’s sign II is characteristic of conditions where blisters form subepidermally, such as toxic epidermal necrolysis (Lyell’s syndrome) and certain forms of Stevens-Johnson syndrome. It helps differentiate between diseases characterized by subepidermal bullae without acantholysis – such as bullous pemphigoid – and pemphigoid variants that involve acantholysis. Both types of Nikolsky’s sign serve as important diagnostic tools, aiding in the precise differentiation of bullous dermatoses and guiding further diagnostic assessments and treatment.
In subsequent stages, extensive superficial skin desquamation and exudation develop, a phenomenon referred to as the “wet newspaper” sign. Key characteristics include crusting around the mouth, eyes, and nose, along with radial fissures in these areas. In the convalescence phase, the epidermis regenerates within 7−14 days, and healing occurs without scarring.
Diagnosis is confirmed by culturing SA from the infection site or a potential carrier site, such as the nasal vestibule, conjunctival sac, nasopharynx, umbilicus, or perineum. Cultures taken from exfoliative or bullous skin lesions are generally not helpful diagnostically, as bullous eruptions are caused by circulating exfoliative toxins and are typically sterile unless secondarily infected. In rare cases, SSSS can develop due to the spread of ETs from extracutaneous infection sites, such as pneumonia, abscesses, myositis, endocarditis, urinary tract infections, or septic arthritis.
Although not usually necessary, a skin biopsy can be helpful in the diagnosis of SSSS [4]. Biopsy, including frozen sections, reveals superficial subcorneal cleavage and can aid in differentiating SSSS from other acute bullous and desquamative conditions, such as Lyell’s syndrome (toxic epidermal necrolysis – TEN) or Stevens-Johnson syndrome (SJS). In contrast, SJS and TEN are characterized microscopically by subepidermal detachment and significant necrosis of the basal layer of the epidermis [2].
Patients with SSSS require prompt initiation of antibiotic therapy, which is the treatment of choice. Patients should be hospitalized and receive systemic antibiotic therapy, considering the drug sensitivity and resistance mechanisms of Staphylococcus aureus to cloxacillin, the drug of choice. In empirical antibiotic therapy, the use of first- and second-generation cephalosporins, as well as clindamycin, may also be considered. There are also literature reports mentioning nafcillin, oxacillin, dicloxacillin, or flucloxacillin, recommended for treatment until culture results are available. If the patient has a history of penicillin allergy, clarithromycin or cefuroxime may be considered as alternative treatment options.
Vancomycin should be used to treat SSSS in populations with a high prevalence of methicillin-resistant Staphylococci or when the patient’s condition is critical [1, 2]. In addition to causal treatment, fluid therapy, monitoring of electrolyte levels, body temperature, and hemodynamic parameters, analgesic treatment, and the use of non-stick dressings for topical care are also implemented. Glucocorticosteroids should be avoided. Potential complications include sepsis, secondary infections, electrolyte imbalances, fluid loss, and hypothermia. The prognosis of SSSS is generally favorable in older children but requires more cautious evaluation in infants. The mortality rate is below 5% in children but exceeds 60% in adults [1, 7], likely due to immunodeficiencies or underlying comorbidities [3].
The nature of the lesions, their location and extent suggest the need to differentiate SSSS from other conditions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme exudativum, epidermolysis bullosa hereditaria (EBH), epidermolysis bullosa acquisita (EBA), pemphigus vulgaris, Kawasaki disease, and scarlet fever.
The diagnosis is primarily determined by the overall clinical presentation. Nikolsky’s sign can serve as a valuable indicator in differentiating flaccid blisters which are a hallmark of dermatological emergencies. In SSSS, positive Nikolsky’s sign is present on both unaffected and affected skin, whereas in SJS and TEN, it is limited to involved areas. This symptom does not occur in erythema multiforme, scarlet fever, or Kawasaki disease (table 1).
Due to its clinical resemblance to various dermatological conditions, including early-stage allergic dermatitis, heightened clinical vigilance is necessary. Careful monitoring of the progression of skin lesions and utilizing Nikolsky’s sign as a diagnostic aid can help differentiate autoimmune bullous dermatoses (AIBD). Linear IgA bullous dermatosis (LABD) is a chronic autoimmune subepidermal bullous dermatosis that occurs in both children and adults [8]. In children, it most commonly manifests before the age of 5. A hallmark of the disease is the presence of linear deposits of immunoglobulin A (IgA) along the dermal-epidermal junction. LABD in children may present with systemic symptoms such as fever and appetite loss. The lesions typically affect the hands, feet, vermilion zone, and genital areas. Skin lesions appear on both erythematous and unaffected areas, frequently forming rings of elongated vesicles surrounding centrally located scabs or healing lesions. The vesicles, arranged in linear or ring-like patterns on an inflamed base, create a characteristic “string of pearls” appearance. Mucosal involvement is rarely observed, and Nikolsky’s sign is absent. Skin lesions may appear on various body areas, including the face, trunk, genitals, and extremities. Characteristic features include itching and burning sensations [8, 9].
Pemphigus vulgaris (PV) is characterized by the early onset of oral mucosal erosions or bullae on the scalp in approximately half of patients, which may precede the development of widespread skin lesions by several months. Subsequently, vesicles and bullae spread to the trunk, scalp, face − particularly in seborrheic areas − and the extremities. Pain, itching, burning, and exudation from lesions may contribute to dehydration and cachexia. At times, patients may report a cough, often linked to irritation of the pharyngolaryngeal mucosa. Nikolsky’s sign I is a highly sensitive indicator in pemphigus vulgaris. When combined with clinical features of the disorder (including bullae and erosions) and histopathological findings (blisters above the basal layer and within the intermediate epidermal layers), it supports a definitive diagnosis. Although not entirely specific to pemphigus vulgaris, this symptom is an important diagnostic feature that helps differentiate it from other bullous dermatoses, such as bullous pemphigoid, where Nikolsky’s sign is typically negative.
Pemphigus foliaceus (PF) is characterized by the appearance of flaccid vesicles and erosions on an erythematous base, primarily in seborrheic areas. Unlike in pemphigus vulgaris, mucous membranes are unaffected. Nikolsky’s sign in PF is also an important diagnostic indicator. In this condition, similar to pemphigus vulgaris, Nikolsky’s sign is identified by easy detachment of the epidermis when gentle pressure or friction is applied to the skin, leading to the formation of erosions and blisters. Since in patients with PF this phenomenon mainly affects the stratum spinosum, Nikolsky’s sign I is present, but its manifestation may differ slightly from that in pemphigus vulgaris, where blisters form in the deeper layers of the epidermis (suprabasal and intermediate).
Bullous pemphigoid (BP) is rarely diagnosed in children. In the early stages of the disease, the lesions may be nonspecific (urticarial, erythematous-edematous, or eczematous). The condition is characterized by the development of diffuse well-tense bullae either on healthy or inflamed skin [10].
Dermatitis herpetiformis (DH) typically manifests as symmetrical, itchy vesicles, 3–4 mm in diameter, found on the extensor surfaces of the limbs, in the lumbosacral region, and on the buttocks. Lesions may occur on both intact and inflamed skin. The skin lesions are polymorphic, with typical presentations including vesicles on an erythematous base, urticarial wheals, and papules, which typically resolve without scarring [11]. Nikolsky’s sign in DH is negative because the skin lesions primarily result from immunological reactions to the antibodies against transglutaminase 3 (TG3), causing skin damage in the dermal papillae beneath the epidermis, rather than in the deeper layers of the epidermis as seen in pemphigoid. Although Nikolsky’s sign is rarely present in DH, it may occasionally appear due to epidermal damage within inflamed areas. Since DH is mainly associated with celiac disease, Nikolsky’s sign can aid in distinguishing it from other bullous dermatoses, such as pemphigoid, where the sign is more frequently positive.
Acquired epidermolysis bullosa (epidermolysis bullosa acquisita – EBA) is a subepidermal bullous dermatosis that affects both the skin and mucous membranes. Clinically and histologically, the condition resembles pemphigoid. Blisters most commonly develop on the extensor surfaces of the limbs, where the skin is prone to mechanical trauma. Characteristic features include well-tense blisters, which may be filled with hemorrhagic fluid, along with erosions primarily affecting the skin of the hands – especially the extensor surfaces of the hands, knees, elbows, and areas over the hand and ankle joints. The formation of milia and scarring during lesion healing are distinctive traits. The blisters on the mucous membranes rupture easily, resulting in erosions. Nail damage and scarring alopecia may also be observed. In the inflammatory form of EBA, the disease has a sudden onset, with lesions often becoming generalized and appearing in areas not directly exposed to injury. Typically, urticarial wheals, severe pruritus, and erythema are observed. The form of the disease characterized by blistering and scarring – primarily affecting the mucous membranes of the mouth, eyes, and genitals – can lead to significant impairment in the function of these organs [12]. Nikolsky’s sign in EBA is typically negative, meaning that, unlike in pemphigus, there is no easy separation of the epidermis with pressure or rubbing of the skin. In EBA, blisters primarily arise due to damage at the epidermal-dermal junction, rather than within the epidermis itself, which explains the absence of the typical Nikolsky’s sign.

Conclusions

Nikolsky’s sign does not occur in the course of BP, LABD, and EBA. In contrast, a hallmark feature of PV is the characteristic involvement of the mucous membranes, which serves as a key diagnostic indicator. In DH, blisters are extremely rare, which is also an important factor in differentiating this condition from other pathologies. Accurate clinical and histopathological analysis is essential for correct diagnosis of each of these diseases and initiating appropriate therapy. Erythroderma secondary to SSSS can present significant diagnostic challenge in the early stage of the disease. Nikolsky’s sign in SSSS is present in both erythematous and intact skin, making it a key diagnostic feature in bullous dermatoses.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The author declares no conflict of interest.

References