Dermatologic Manifestations of Staphylococcal Scalded Skin Syndrome


Background

Staphylococcal scalded skin syndrome (SSSS) is a toxin-mediated exfoliative dermatitis. Toxin-mediated staphylococcal syndromes comprise a group of blistering skin diseases, ranging in severity from localized bullous impetigo to SSSS. SSSS is a systemic toxigenic process producing constitutional symptoms and widespread superficial blistering and exfoliation of the skin following generalized painful erythema.

Pathophysiology

Staphylococcal scalded skin syndrome (SSSS) is caused by toxigenic strains of Staphylococcus aureus, a gram-positive, catalase-positive bacterium. Only 5% of all S aureus strains produce the epidermolytic toxins responsible for SSSS. The specific toxigenic strains usually belong to phage group 2 (types 3A, 3B, 3C, 55, or 71). Two exotoxins (ETs), epidermolytic toxin A (ET-A) and epidermolytic toxin B (ET-B), are responsible for the pathologic changes seen in SSSS. [1These toxins cause intraepidermal splitting through the granular layer of the epidermis, or stratum granulosum, by specific cleavage of desmoglein 1 (Dsg-1) (also the target protein in the autoimmune blistering dermatosis, pemphigus foliaceus). DSG1 is a desmosomal cadherin protein that mediates cell-to-cell adhesion of keratinocytes in all layers of the epidermis, including the skin and mucosa, but is in greatest abundance within the stratum granulosa. Desmoglein 3 (Dsg-3) (the target protein in the autoimmune blistering dermatosis, pemphigus vulgaris) is also present in the epidermis; it is expressed in the deeper layers of the skin and present in all layers of the mucosa. The distribution of desmogleins in the epidermis explains the preferential blistering of SSSS in the superficial skin and lack of blistering in mucous membranes. Despite cleavage of Dsg-1 by ET-A and ET-B, Dsg-3 maintains the integrity of the deeper layers of the skin, beginning with the stratum spinosum, and all layers of the mucosa. [234]

Specific targeting of Dsg-1 by ETs allows S aureus to proliferate and spread beneath the barrier of the skin. Crystal structures and amino acid sequences indicate that these toxins are calcium-dependent, atypical serine proteases and exhibit substrate specificity for glutamic acid. Therefore, these toxins cleave Dsg-1 at the N-terminus of glutamic acid residue 381 between extracellular domains 3 and 4. The ET-A and ET-B amino acid sequences are approximately 40% identical with each other. ET-A is expressed in more than 80% of toxigenic strains of S aureus and represents the more prevalent ET seen in SSSS. ET-B was found to be the more prevalent toxin in toxigenic strains only in Japan. [5]

An additional ET family member, ET-D, has been identified by screening the genomes of S aureus isolated from patients with skin infections. Studies demonstrated that ET-D specifically digests Dsg-1. However, ET-D is less common in S aureus isolated from SSSS cases and only ET-A and ET-B have been firmly linked to human SSSS. The ET-D gene was detected mainly in isolates from patients with skin and soft-tissue infections, namely furuncles, abscesses, and finger pulp infections. [67]

In addition to the cleavage of Dsg-1, ET-A is correlated with a blunted inflammatory response within the affected superficial skin. While no direct effect by ET-A on white blood cells (WBCs) has been shown, it is hypothesized that Dsg-1 cleavage somehow triggers inhibition of the WBC infiltration of the local environment. Interleukin 6 (IL-6) production and subsequent release by keratinocytes is increased without similar increases in acute, proinflammatory cytokines following Dsg-1 cleavage. Both phenomena contribute to the local modulation of the immune response in SSSS. [8]

It has been suggested that ET-B is more frequently isolated than ET-A in children with SSSS. This link between ET-B and generalized SSSS might be due to increased virulence of ET-B or to more abundant ET-B release. Because ET-A is chromosome borne and ET-B is plasmid borne, multiple intracellular copies of ET-B may exist, which would lead to higher ET-B production. However, levels of ET-A and ET-B are quite similar in vitro. The link between ET-B and generalized SSSS may be explained, at least in part, by lower levels of anti–ET-B antibodies compared with anti–ET-A antibodies in the general population.

The mechanism of neonatal infection is through an asymptomatic adult carrier introducing the causative bacteria into nurseries. Nursery attendants have been identified as the source more commonly than infant mothers. Asymptomatic nasal carriage of S aureus occurs in 20-40% of healthy individuals. The bacterium is also commonly isolated from the hands, perineum, and axillae in a smaller portion of the general population. Common foci of infection in the affected patient include the conjunctivae, periumbilical and perioral regions, nares, and perineum. These sites should be targeted for isolation of S aureus in affected patients.

Epidemiology

Frequency

United States

Staphylococcal scalded skin syndrome (SSSS) most commonly occurs in infants and in young children, and it tends to occur in outbreaks in neonatal nurseries or in daycare nurseries. [91011Large outbreaks of SSSS in neonatal nurseries have been described, but the occurrence of SSSS in adults as a nosocomial infection appears to be exceptional; epidemics have never been observed. Adult infection and disease development are seen in specific instances involving either predisposition to SSSS development, such as HIV infection or chronic kidney disease, or a procedure or trauma that creates a potential nidus for S aureus infection.

Epidemiologic data on strains of S aureus that produce ET are scarce. In a prospective clinical and bacteriologic study, 5.1% of 944 isolates of S aureus were identified as ET producers. SSSS in adults is an exceedingly rare disorder; however, more than 50 cases have been documented.

International

A retrospective study at the Lagos University Teaching Hospital in Nigeria over a 12-year period (January 1995 to December 2006) reviewed the presentation, etiology, and prognosis of nonburn epidermal loss. Only 2 (9%) of 19 patients had confirmed SSSS. The first patient was an 18-day-old boy and the other was a 26-day-old girl admitted with a left lateral thigh abscess. Cultures in both cases yielded the growth of S aureus, which responded well to antibiotic treatment and dressings. [12]

In another retrospective study in England, hospital admissions were reviewed to identify trends in community-onset disease that were likely to be caused by pathogenic staphylococci. Hospital admission rates for staphylococcal septicemia, staphylococcal pneumonia, SSSS, and impetigo increased greater than 5-fold from 1989 through 2004. SSSS was seen primarily in individuals older than 16 years. This reflects the real increases in pathogenic community-onset staphylococcal disease over the past 15 years. [13An outbreak in a maternity unit in England from December 2012 to March 2013 reinforced the importance of the role of healthcare workers in the nosocomial transmission of the syndrome. [14A similar outbreak in a maternity unit in Italy from November 2014 to December 2014 identified 3 (4.5%) of 66 infants with SSSS. The infection was traced to methicillin-resistant S aureus (MRSA) colonization of three nurses and one mother. Overall, carriage of S aureus in the nares among the healthcare workers in the maternity unit was 24.1%. This report further supports the prevalence of asymptomatic carriers and their impact in neonatal outbreaks. [15]

Race

Black children are less prone to staphylococcal scalded skin syndrome (SSSS) than white children. This finding could be explained by the greater percentage of white individuals colonized with S aureus within the nasal mucosa compared with all other races. It has been well documented that carriage of S aureus is associated with increased risk of infection. The greater percentage of carriage in the white population may be correlated with the larger number of documented cases of SSSS within this population. [16]

Sex

Staphylococcal scalded skin syndrome occurs equally in both males and females in children. However, a slight male-to-female predominance of 2:1 exists in adults.

Age

Three significant factors determine the age distribution of staphylococcal scalded skin syndrome (SSSS): (1) antibody-mediated immunity to the epidermolytic toxins, (2) renal clearance of the toxins, and (3) general immune status of an individual. Antibodies to ET-A and ET-B develop over time and are seen in older children and adult sera. A lack of specific toxin immunity (antibodies) in neonates is one factor that puts this group at highest risk. Both ET-A and ET-B are cleared by the kidneys; therefore, a decreased ability to achieve renal clearance of toxins puts both neonates and all individuals with chronic kidney disease at a greater risk. Immunodeficiency in adults due to HIV infection, advanced stage of cancer, or numerous comorbid conditions, also increases the risk of SSSS. The immature immune system of the neonate and child also contributes to the prevalence of disease in this population.

Owing to these factors, SSSS most commonly affects children younger than 5 years, particularly neonates. Older children and adults also may develop the disease. Although most cases can be explained by renal insufficiency or immunodeficiency, not all adults have an underlying condition. Infection in healthy adults usually occurs from a massive production of toxins as opposed to the mode of disease in the previously mentioned groups, which occurs through deficiency in toxin elimination. Affected adults range in age from 19-91 years, with half the cases occurring in adults older than 60 years. [17181920]

Prognosis

The prognosis of the disease in children is favorable, as the mortality rate is less than 5% with appropriate treatment. In adult cases of staphylococcal scalded skin syndrome (SSSS), the mortality rate is high, reaching 60% in some studies, despite appropriate antibiotic therapy. [5]

Children generally do well and are not as ill as their dramatic eruptions might suggest. SSSS is usually associated with a trivial infective focus in the conjunctivae or the skin; however, severe infections, such as sepsis, do contribute to a low but appreciable fatality rate (<10%).<ref>21 </ref>Morbidity in the occasional child who develops cellulitis, sepsis, and pneumonia can be significant. In children, the foci of staphylococcal infections are usually the nasopharynx or localized skin infections.

Adults with SSSS often have blood cultures positive for toxigenic S aureus, and mortality rates can be high (40-63%). [21The predisposing conditions are renal failure and an immunocompromised state. In older patients, underlying consumptive infectious diseases contribute to the high mortality rates. [22]

SSSS in the adult population has been reported as a complication of septic arthritis after an elective right knee arthroscopy, diffuse large B-cell lymphoma following a right groin biopsy, and lupus nephritis associated with chronic immunosuppressant therapy and renal impairment. [2324]

A single report describes concurrent SSSS and toxic shock syndrome (TSS), an acute life-threatening illness caused by TSS toxin also produced by S aureus, in a 43-year-old man associated with an abscess from previous dental work. This patient had normal renal function, but the amount of toxin produced from the abscess may have overwhelmed the kidneys' capacity to remove it. Although colonization with a strain of S aureus capable of producing TSS toxin and ET-A or ET-B is possible, the clinical presentation of both SSSS and TSS is extremely uncommon. [25Only one other such case has been reported.

CLINICAL PRESENTATION


History

Staphylococcal scalded skin syndrome (SSSS) originates from a focus of infection that may be a purulent conjunctivitis, otitis media, or occult nasopharyngeal infection. A case of SSSS from a nasal septal abscess, presumably arising from a traumatic hematoma (a tsunami survivor), has been reported, as well as adult infection in a previously healthy man following a dental procedure. [2527In premature infants, a previous amniocentesis procedure and intrauterine infection have been reported as triggers for SSSS, although reports of outbreaks within nurseries is well described and should still be considered in premature infants in addition to all term infants. [2829]

Circumcision sites and the umbilicus are other common niduses of infection in the newborn period. SSSS usually begins with fever, irritability, and a generalized, faint, orange-red, macular erythema with cutaneous tenderness. Irritability in children is very commonly reported. Children may complain of vague pain in regions of developing lesions, such as abdominal pain with a superficial abdominal lesion.

SSSS can present with immediate widespread erythema or may begin with a localized site of exudative erythema and rapidly spread, usually within hours. An area of local, painful bullae that remains localized over days is unlikely to be SSSS and is more likely to be bullous impetigo. These lesions should be treated appropriately, but monitored closely as there have been reports of misdiagnosis, missing SSSS completely, and bullous impetigo evolving into SSSS. [3031]

Periorificial and flexural accentuation may be observed. A positive Nikolsky sign (separation of the superficial layer of the epithelium on gentle pressure) can often be elicited at this stage.

Physical Examination

Patients usually present with fever and pain associated with a generalized, macular, salmon-colored to bright-red rash, as shown in the image below. Within 24-48 hours, the rash progresses from a scarlatiniform rash to an edematous, blistering eruption.

An infant with characteristic coloring of the skinAn infant with characteristic coloring of the skin that looks as though the child has been scalded. Exfoliation of thin sheets of skin is present.

Characteristic tissue paper–like wrinkling of the epidermis is followed by the appearance of large, flaccid bullae in the axillae, in the groin, and around the body orifices. Perioral involvement is commonly seen in children and adults. Periumbilical and perineal involvement is more common in infants. Extremity involvement is seen more often in older children. The Nikolsky sign, the sloughing of superficial epidermis with gentle shearing force applied to the top of a lesion, is present in staphylococcal scalded skin syndrome (SSSS). See the image below.

Staphylococcal scalded skin syndrome in an adult. Staphylococcal scalded skin syndrome in an adult.

Subsequent generalized involvement occurs elsewhere on the body, but infection spares the mucous membranes, owing to the presence of unaffected Dsg-3 throughout all strata of the mucosa.

As sheets of epidermis are shed, a moist erythematous base is revealed. Patients experience pain throughout the evolution of the disease owing to the intact free nerve endings terminating in the epidermis. Twenty-four hours following the exfoliation of the skin, the underlying epidermis dries, resulting in a shiny crust. With drying, perioral and periorbital lesions may fissure.

Despite the dramatic clinical picture, the entire process usually subsides with superficial desquamation if antibiotics are administered. Healing is typically rapid, with complete resolution within 5-7 days, although 2-3 weeks is more commonly expected. Children may undergo a second phase of desquamation around day 10, but the disease process still completely resolves around day 14.

In adults, SSSS is frequently followed by bacteremia and pneumonia, favoring a poor prognosis.

Cultures obtained from intact bullae usually are sterile; this finding is consistent with hematogenous dissemination of a toxin produced at a distant focus of staphylococcal infection. Blood cultures usually are negative in infants and children, but commonly positive in adults.

An abortive form of SSSS, known as the scarlatiniform variant, shows the early erythrodermic and final desquamative stages seen in SSSS, but the bullous stage does not occur.

Other intermediate forms of scalded skin syndrome begin as localized bullous impetigo, but they evolve to produce regionally limited bullae and denuded areas that may or may not harbor staphylococci.

Causes

See Pathophysiology.

ET-A and ET-B are atypical glutamic acid–specific serine proteases that specifically target Dsg-1. They are also sources of superantigenic activity and activate macrophages to produce proinflammatory cytokines, such as tumor necrosis factor-alpha and IL-6, and keratinocytes to produce IL-6. ET-A with an active site mutation was shown to possess similar inflammatory activity, indicating that the inflammatory activity of ET-A was separate from its epidermolytic activity, although it has not been shown to directly modulate cytokine release and may likely be due to a downstream effect after Dsg-1 cleavage. [532The preferential production of IL-6 from keratinocytes in response to ET-A activity results in localized immune dysregulation and lack of a significant WBC infiltrate. Systemic symptoms, particularly the characteristic rash, are very likely a direct result of the toxin.

A small number of patients with staphylococcal scalded skin syndrome (SSSS) develop low titers of immunoglobulin G antibodies specific for Dsg-1 after binding and systemic digestion of Dsg-1 by staphylococcal exfoliative toxins. [33The relevance of this finding to the onset of autoimmune diseases remains to be proven. Other genetic or environmental factors may be needed to propagate production of pathogenic antibodies and to produce overt clinical pemphigus foliaceus. [34]

Complications

Cellulitis, sepsis, and pneumonia are possible complications that may occur in children with staphylococcal scalded skin syndrome (SSSS). Cellulitis occurs after spreading of the infection to deeper layers of the skin. Dsg-1 is present in the deeper layers of the skin, and while Dsg-3 protects sloughing of the deeper layers, the effects of ET-A and ET-B create a weakened stratum spinosum, leading to the potential for cellulitis. Sepsis is the most serious complication and is the most common cause of mortality in neonates with SSSS.

Dehydration and secondary infection due to loss of the superficial layer of the skin are significant causes of morbidity and are critical issues early on in the disease process. Considerable electrolyte disturbances may ensue if dehydration is not managed at the first sign of disease.

Scarring is not seen in SSSS, owing to the sparing of the deeper layers of the skin.

DIFFERENTIAL DIAGNOSIS

Differential Diagnoses

TREATMENT AND MANAGEMENT

Medical Care

Direct the therapy for staphylococcal scalded skin syndrome (SSSS) at eradication of the staphylococcal focus of infection, which generally requires intravenous (IV), penicillinase-resistant, antistaphylococcal antibiotics. The empiric choice of antibiotics should include a penicillinase-resistant penicillin, first- or second-generation cephalosporin, and clindamycin. Susceptibility testing should direct changes in antibiotics as soon as results are available.

Oral antibiotic therapy can be substituted within several days or sooner, but initial IV antibiotics should be started in all patients. Corticosteroids should be avoided in SSSS treatment. Antibiotics, supportive care, and appropriate attention to fluid and electrolyte management for the disrupted epidermal barrier function usually ensure rapid recovery. Moist, denuded areas should be lubricated with a bland emollient to decrease pruritus and tenderness. Skin-substitute therapy with synthetic wound coverings has been described in a study with seven infants with SSSS and may be considered if extensive skin involvement is present. [36Pain management should be considered throughout the disease process. Affected areas should be gently cleansed to avoid secondary infection. Desquamated skin should be left in place as a natural barrier. Lastly, patients should be placed in contact isolation.

Exchange transfusion has been shown to be beneficial in a preterm infant with severe SSSS with sepsis and hyperbilirubinemia, by reducing the bacterial load and exfoliative toxins in the blood. [37]

Plasma exchange was also shown to be effective in a 68-year-old man with sepsis, infective endocarditis, and disseminated intravascular coagulation. [38In another case report of SSSS in a premature neonate, a single dose of intravenous immunoglobulin (IVIG) was administered at 1 g/kg dose, with clinical improvement occurring within a few days. The presence of antiexfoliative toxin antibodies in commercial IVIG preparations has been reported previously.

Recognizing the potential for epidemic scalded skin syndrome in neonatal care units is important. [39 Identification of health care workers colonized or infected with toxigenic S aureus is an integral part of managing the problem. Receiving more than one early umbilical care procedure by the same ancillary nurse was the only risk factor identified in a nosocomial outbreak in a maternity unit in France. The ancillary nurse had chronic dermatitis on her hands that favored S aureus carriage. [40Control measures include strict enforcement of chlorhexidine hand washing, barrier nursing protocols, administration of an oral antibiotic therapy for workers who are infected, and application of mupirocin ointment for eradication of persistent nasal carriage.

Further inpatient care

Developments in the understanding of the exfoliative toxins of SSSS should lead to new and improved diagnostic and therapeutic strategies, including the use of specific antitoxins to prevent exfoliation. [41]

Infusing anti-ET antibodies into mice was shown to halt progression of exfoliation in a study performed more than 2 decades ago, but this has never been applied to humans.

A recent surge has occurred in reports of MRSA strains causing SSSS, often with a fatal outcome. Additionally, a multiple-drug resistance gene has been identified on plasmids carrying the ET-B gene. These cases emphasize the need to develop alternative treatment strategies before multiple antibiotic resistance becomes a problem.

Animal model studies have demonstrated that subinhibitory concentrations of antibiotics such as clindamycin can significantly inhibit toxin production by methicillin-sensitive and methicillin-resistant staphylococcal strains, and anti-inflammatory agents such as pentoxifylline can further inhibit activation of the body's inflammatory response to these toxins. Currently, little clinical evidence supports their routine use in the management of SSSS.

Prevention of progression of SSSS by molluscum contagiosum has been observed and indicates possible interference by a viral anticytokine molecule, such as interleukin 18–binding protein. The development of drugs based on inflammatory cytokines, including interleukin 18, may be invaluable for halting the progression of severe cases. [42]

Consultations

Children with severe staphylococcal scalded skin syndrome (SSSS) (>50% body surface area) may need to be transferred to a tertiary pediatric burn unit for multidisciplinary care in a critical care environment.

A dermatologist is often consulted to provide management guidance and direct wound care.

Fluid overload and hyponatremia are common complications of SSSS. This is not surprising because hyponatremia is common in severe infections and inappropriate vasopressin secretion occurs in patients with burns. Rapid fluid resuscitation also contributes to this complication and should be avoided. [43]

For treatment of toxemia in children, fresh frozen plasma (FFP) at 10 mL/kg may be beneficial, as it contains exotoxin antibodies. If a second dose is required, it should come from a different donor because the possibility exists that the first donor did not have antibodies against the epidermolytic toxins. A 5-day course of pooled human immunoglobulin (0.4 g/kg/d) should also be considered if little or no improvement is noted after two doses of FFP.

Many children require an opioid infusion, such as fentanyl (1-4 mcg/kg/h), for analgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in the acute phase because the damaged skin is already prone to bleeding and renal excretion of the exotoxins makes maximized renal function important. Gabapentin is useful for severe pruritus (100 mg/kg once on day 1, twice a day on day 2, and then three times each day) and may need to be continued for a few months.

Diet

Enteral nutrition must be commenced if oral intake is not possible. This may be achieved with a nasogastric tube, but a nasojejunal tube is preferable because it avoids the need to discontinue feeds prior to anesthesia. Nasojejunal (or nasogastric) tubes are likely to require suturing into place to avoid epidermal damage from adhesives.

Activity

Physiotherapy is important to encourage mobilization in general, and specifically of the affected limbs. Because staphylococcal scalded skin syndrome tends to affect the flexures most severely, children often limit flexion of the limbs owing to discomfort, and physiotherapy is very helpful in preventing this. Involvement of play therapists also helps encourage gentle mobilization and prevents boredom.

Prevention

Investigate the possibility of a staphylococcal carrier in the vicinity. Typical measures that reduce infection rates in hospitals should be take,n including regular hand washing, cleansing stethoscopes or other devices between each patient interaction, and ensuring proper cleansing of linens and clothing.

Nasal bacterial carriage or colonization under fingernails can be minimized with antibiotic creams or petroleum jelly several times daily, 1 week per month.

MEDICATION


Medication Summary

The goal of pharmacotherapy for staphylococcal scalded skin syndrome (SSSS) is to reduce morbidity and to prevent complications. [4445]

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. The empiric antibiotic regime should include a penicillinase-resistant penicillin and clindamycin. First- or second-generation cephalosporins can be used in place of penicillins.

Dicloxacillin (Dycill, Dynapen)

Dicloxacillin is for the treatment of infections caused by penicillinase-producing staphylococci. It should be used as empiric therapy in combination with clindamycin when staphylococcal infection is suspected and susceptibilities are pending.

Clindamycin (Cleocin, Cleocin Pediatric, ClindaMax Vaginal)

Clindamycin is a bacteriostatic protein synthesis inhibitor that has efficacy in treating MRSA. It should be used as empiric therapy in combination with a penicillinase-resistant penicillin when staphylococcal infection is suspected and susceptibilities are pending.

Mupirocin (Bactroban)

Mupirocin inhibits bacterial growth by inhibiting RNA and protein synthesis and should be used only at the site of S aureus infection. 

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