Secondary bacterial infection of atopic eczema is a common complication, with Staphylococcus aureus being the most common etiology, followed by Streptococcus pyogenes. Of patients with AD, more than 90% are colonized with S. aureus.28 In contrast, S. aureus can be found on the skin of only 5–30% of normal individuals. S. aureus is isolated from clinically affected and unaffected skin, and both acute and chronic AD lesions may be colonized.29 Recent studies suggest that the skin of patients with AD has increased avidity for binding to S.aureus and is deficient in its ability to generate antimicrobial peptides needed to eradicate infectious agents.30 Impaired skin integrity, increased S. aureus adherence, and abnormal innate immune responses all predispose patients to more invasive cutaneous infections (e.g., cellulitis, furuncles, abscesses).31 Recurrence of bacterial infection, usually with S. aureus, is common, occurring in up to 40% of children with AD.24
Clinical signs of impetiginization, such as weeping and crusting, fissuring, or small superficial pustules are very common signs indicating that skin colonization with S. aureus may have occurred (Figure 58–6).32 Extensive crusting, folliculitis, or impetigo, or the development of pyoderma, are indicators of bacterial skin infection that requires antibiotic therapy. Regional lymphadenopathy is common in such patients. Patients with extensive skin involvement may develop an exfoliative dermatitis as a result of superinfection with toxin-producing S. aureus. This is associated with generalized redness, scaling, weeping, crusting, systemic toxicity, lymphadenopathy, and fever. In contrast to impetiginization with S. aureus, infection with S. pyogenes often presents with either well-demarcated erythematous, eroded patches favoring intertriginous areas such as the popliteal and antecubital fossae, or with impetigo.
The diagnosis of a bacterial superinfection can usually be made based upon the appearance of the skin. Given the increasing prevalence of antibiotic-resistant strains of S. aureus, the identification of the organism from superficial skin lesions or bullae by Gram stain and culture is recommended prior to the initiation of systemic antibiotics.
Standard treatment for bacterial infection with S. aureus often involves topical and/or oral administration of antibacterial agents; however, resistance to standard antibacterial regimens is an increasing problem, and mupirocin-resistant and methicillin-resistant S.aureus are present worldwide. While the use of a topical antibiotic such as mupirocin or bacitracin may be adequate for mild, localized disease, systemic antibiotic therapy may be necessary to treat AD when more widespread bacterial infection with S. aureus or S. pyogenes is present or in the presence of systemic symptoms such as fever or pain. Semisynthetic penicillins or first- or second-generation cephalosporins given for 7–10 days are usually effective. Rarely, longer treatment courses of up to 14 days may be required. Erythromycin-resistant organisms are fairly common, making macrolides less useful alternatives. The presence of an atypical skin infection in patients with AD, particularly those unresponsive to conventional penicillinase-resistant penicillins and cephalosporins, should alert the clinician to the possibility of methicillin-resistant S. aureus as the underlying etiology, and intervention should be directed accordingly. Methicillin-resistant strains may be treated with clindamycin, trimethoprim-sulfamehoxazole, or a tetracycline, although antibiotic resistance to these agents also occurs. Infections with S. pyogenes are best treated with penicillin or amoxicillin.
Unfortunately, recolonization of the skin after a course of antistaphylococcal therapy occurs rapidly. Maintenance antibiotic therapy, however, should be avoided, because it may result in colonization by antibiotic-resistant organisms. The use of topical regimens to control skin colonization with S. aureus may be more helpful. Although antibacterial skin cleansers are effective in reducing bacterial skin flora, they can cause significant skin irritation. Additionally, studies of antiseptics have shown conflicting evidence in the treatment of AD.33,34 A recent double-blind, placebo-controlled study found that daily bathing with an antimicrobial soap containing 1.5% triclocarban resulted in reductions in S. aureus colonization and significantly greater clinical improvement than with the placebo soap.33 Other agents that may be used intermittently (1–2 times per week) to reduce colonization with S. aureus include chlorhexidine topical cleanser (Hibiclens®), benzoyl peroxide 5% wash, and 0.25% sodium hypochlorite soaks (1 capful of Clorox® bleach per gallon of water). Topical mupirocin applied three times daily to the nares, fingertips, and perianal area for 5 contiguous days per month may also be effective in reducing colonization rates.
Although significant reduction of bacterial colonization in the skin of AD patients by oral antibiotics has been demonstrated, there is little evidence for clinical improvement in the severity of the dermatitis.35 Several studies have demonstrated that the combination of appropriate topical corticosteroids with a topical antibiotic is significantly more effective at reducing skin inflammation caused by AD than using the topical corticosteroid or topical antibiotic alone.30,31,36 However, there is no conclusive clinical evidence suggesting that patients with AD may benefit from specific antibiotic treatment in the absence of clinical signs of infection.37
As a result of the increased risk of bacterial resistance that may occur with frequent use of antibiotics, it is important to combine antimicrobial therapy with effective skin care since it is well established that the impaired skin barrier in patients with poorly-controlled AD predisposes to S. aureus colonization and infection. Use of topical emollients and an appropriate skin care regimen as detailed above to restore skin barrier function, combined with use of effective anti-inflammatory therapy, is the most efficacious way to reduce the frequency of cutaneous superinfection.30
Children with AD are also predisposed to the development of viral skin infections. Infection with the human papillomavirus (HPV), herpes simplex virus (HSV), varicella-zoster virus (VZV) and molluscum contagiosum virus is common in children with AD. Extensive infection with these viruses may develop in children with poorly controlled AD caused by the impaired skin barrier. Eczema vaccinatum is a potentially fatal complication of inadvertent exposure to the vaccinia virus in a patient with AD. Close contact with a patient with AD is a contraindication to receiving the smallpox vaccine.
Eczema herpeticum is an acute cutaneous HSV infection in a patient with AD. Children of all ages and ethnic groups may be affected by eczema herpeticum, with the highest incidence occurring in children 2–3 years of age.38 A history of a close relative with recurrent HSV labialis is common. Patients with AD may also develop widespread varicella during a primary infection with the varicella zoster virus.
Eczema herpeticum usually presents as an acute deterioration of the child's AD. Monomorphous punched-out erosions are the most common lesions seen but papules, vesicles, pustules, and crusts may also be seen (Figure 58–7). Although lesions initially develop as vesicles, rupture of the vesicles commonly occurs as a result of scratching, leaving punched-out erosions in the skin. Oozing may occur from raw areas. Lesions may be discrete or confluent and tend to occur in crops. Associated clinical symptoms include fever, itching, malaise, vomiting, anorexia, diarrhea, and lymphadenopathy.38 At the height of the vesicular phase, widespread dissemination of virus may occur and lead to systemic involvement.38
Eczema herpeticum. Note the characteristic monomorphous, punched-out erosions.
The diagnosis of HSV infection can be made by a variety of techniques including viral culture, direct immunofluorescence, polymerase chain reaction (PCR), or a Tzanck preparation. Proper technique in obtaining a specimen for analysis is crucial. An intact vesicle should be gently “unroofed” with a sterile blade. The base of the vesicle should be rubbed vigorously with a sterile cotton swab and placed in viral culture medium. If no intact vesicles are available for sampling, an erosion or crusted lesion may be used; however, any exudates or crust should be removed prior to sampling. While viral culture has remained the standard diagnostic method for isolating HSV, real-time HSV PCR assays have emerged as a more sensitive method to confirm HSV infection. The Tzanck smear, which relies on the demonstration of multinucleated giant cells in infected tissue, is now of predominantly historical interest, although it can be performed at the bedside by specialists who are trained in processing and interpreting the specimen. Differentiating between HSV-1 and HSV-2 infection is rarely indicated. Although much less common, evaluation for VZV infection should also be considered in any patient with suspected eczema herpeticum. PCR, direct immunofluorescence, and viral culture are all available diagnostic tests.
Early recognition of infection and initiation of appropriate treatment is important as the virus may disseminate rapidly, especially in immunocompromised patients. Infants and children who appear ill may require intravenous acyclovir. Children who do not have systemic symptoms and have localized involvement usually respond well to oral acyclovir. Adolescents may be treated with valacyclovir. Topical or systemic antibiotic therapy may be required if secondary bacterial infection develops. The use of tap water soaks twice daily may help to remove any adherent crusts. Topical steroid therapy is often discontinued in the acute phase of eczema herpeticum because of the concern that concomitant use of topical steroids may perpetuate the spread of the infection, although there is no clear evidence to support this conjecture. In our practice, use of topical steroids on involved areas is held for 24–48 hours after initiation of antiviral therapy and until further development of new lesions has ceased.
Following peripheral inoculation, HSV undergoes retrograde axonal transport and establish chronic latent infections in sensory neurons of the trigeminal and dorsal root ganglia. Intermittent reactivation of HSV leads to peripheral shedding of infectious virus particles, which under favorable conditions cause inflammation and lesion formation on cutaneous and mucosal surfaces. Shedding of HSV in and around the eyes occurs frequently.39 Conjunctivitis and keratoconjunctivitis may occur as manifestations of either a primary or a recurrent infection. The conjunctiva may appear congested and swollen, but there is usually little, if any, purulent discharge. Corneal lesions may be superficial, in the form of a dendritic ulcer, or deep, as a disciform keratitis. Dendritic keratitis is unique to HSV eye involvement. The diagnosis is suggested by the presence of herpetic vesicles on the lids; it is established by the isolation of the virus. Topical corticosteroid use will worsen HSV ocular disease. Recurrent herpetic corneal infection may result in scarring of the cornea and vision impairment. Any patient with periocular involvement should be evaluated by an ophthalmologist for evidence of keratitis.
Secondary bacterial infection of the skin may also be present, usually caused by S. aureus and group A β-hemolytic Streptococcus, which may be a potential focus for the development of septicemia. Evaluation with surface cultures for bacteria and initiation of appropriate antibiotic therapy is recommended in all cases of eczema herpeticum.
Molluscum contagiosum is a common pediatric skin infection caused by the molluscum contagiosum virus, a large double-stranded virus that is the most common poxvirus infecting humans.40 Infection in otherwise healthy children is self-limiting. The infection can spread rapidly and produce hundreds of lesions in children with AD.
The lesions of molluscum contagiosum are discrete, pearly, skin-colored, dome-shaped, smooth papules varying in size from 1 to 5 mm (Figure 58–8). Typically, they have a central umbilication from which a plug of keratinaceous material can be expressed. Papules can occur anywhere on the body, but there is predilection for the face, eyelids, neck, axillae, and thighs.
Molluscum contagiosum with molluscum dermatitis in AD.
The diagnosis of molluscum contagiosum is generally a clinical one. A magnifying lens and illumination aids in the visualization of the pathognomonic central umbilication. If the diagnosis is uncertain, a Tzank preparation can be performed on a scraping of a lesion, which will demonstrate numerous discrete ovoid intracytoplasmic inclusion bodies, called molluscum bodies.
The average infection lasts 9–15 months, although lesions can persist for years. Affected persons should be advised to avoid sharing baths and towels until the infection has cleared. The use of swimming pools while infected should also be discouraged as water is thought to facilitate transmission of the virus. Active nonintervention has been the most common therapy; however, in patients with AD, therapy may indicated. Optimization of the treatment of the underlying AD is critical in minimizing the dissemination of the infection. Use of a rapid mechanical or localized treatment such as curettage or cryotherapy is preferable to use of a topical agent such as a topical retinoid or cantharidin, which may cause significant skin irritation and worsening of underlying AD.
Cryotherapy, or topical application of liquid nitrogen or another cryogen, is very effective and, in many instances, is the treatment of choice. Each lesion should be frozen with liquid nitrogen on a cotton-tipped swab for 5–10 seconds; this should be repeated at 2–4 week intervals as needed. There is a small risk of postinflammatory hyperpigmentation and hypopigmentation after cryotherapy.
Curettage has the advantage of providing tissue specimens to confirm the diagnosis. The major disadvantages are that there is a small risk of scarring with the procedure, and the procedure is messy (because of local bleeding) and uncomfortable. In children, curettage must be accompanied by the use of a local anesthetic. Application of topical anesthetic (e.g., lidocaine/prilocaine cream) 15–30 minutes prior to the procedure has been shown to significantly reduce any associated pain.41 Manual extraction with the use of a comedo extractor may also be efficacious but is associated with pain and bleeding.
Particularly in younger children in whom liquid nitrogen therapy and curettage are not well tolerated, cantharidin 0.9% can be applied to each lesion without occlusion; this agent causes the development of an epidermal blister with sloughing of infected skin. There is no pain during the actual application of the drug. Furthermore, there is a greater than 90% efficacy rate with limited local discoloration or scarring. There is also a high satisfaction rate (95%) among parent of children treated with cantharidin. The substance is generally washed off in 2–6 hours with little discomfort afterward, although the occasional side effects of blistering and pain may be disturbing, especially if this medication is injudiciously applied or left on too long. For this reason, application on the face or genital area is not recommended. Tylenol may be used adjunctively at home to reduce any pain associated with vesiculation. On average, 2 treatment sessions are required to clear most patients.42 Due to the risk of systemic absorption and toxicity, application should generally be limited to no more than 20 lesions per session. In addition, cantharidin should never be dispensed to the family for home use. Applications should always be performed in the office.
Other topical therapies include the off-label use of topical retinoids and topical imiquimod. Imiquimod 5% cream is a topical immunomodulator that is approved by the FDA for the treatment of genital warts in adults. It is of questionable efficacy in the treatment of molluscum infections in healthy children, with clearance rates of approximately 40% reported in several small clinical trials; local irritation is the most common side effect.43–47 New FDA labeling changes for imiquimod 5% cream states that two large clinical trials failed to demonstrate efficacy for the treatment of molluscum. Although there are no clinical studies addressing the use of topical retinoids to treat molluscum in children, use of a topical retinoid such as tretinoin 0.025% cream or tretinoin 0.1% gel may also be efficacious, although significant irritation can develop during treatment.48 With both topical retinoids and imiquimod, treatment of a few selected lesions may enhance the ability of the child's immune system to eliminate additional lesions. Use of these agents in patients with poorly-controlled AD is discouraged because of the risk of an exacerbation of the underlying AD should significant irritation develop.
Particularly common in patients with AD is the development of an eczematous dermatitis around individual lesions or groups of lesions, also known as “molluscum dermatitis,” which should be treated with topical corticosteroids and antihistamines. The presence of molluscum dermatitis increases the risk of autoinoculation and spreading of the virus.42 The issue of superinfection is a controversial one, as bacterial superinfection of molluscum contagiosum is uncommon with the exception of children with AD and those who scratch or manipulate the lesions. In cases where bacterial superinfection is suspected, use of a topical antibiotic such as mupirocin is usually sufficient unless widespread involvement develops, in which case use of an oral anti-Staphylococcal antibiotic such as a cephalexin is warranted.
HPV infects epithelial tissues of skin and mucous membranes. The most common clinical manifestation of these viruses is warts (verrucae). There are more than 150 distinct HPV subtypes; some tend to infect specific body sites and produce characteristic lesions at those sites. Warts commonly occur in children and young adults, especially in infants and toddlers. AD predisposes patients with warts for either more extensive or recalcitrant involvement.
Warts typically present as single or grouped flesh-colored, scaly, keratotic papules from 1–10 mm in diameter (Figure 58–9). They are most commonly located on the hands and knees but may be found on any skin area. Several general types of warts can be distinguished clinically. The common wart (verruca vulgaris) appears as a solitary papule with an irregular, rough surface. Filiform warts appear as spiny projections with a narrow stalk; these are usually smaller and are found on the face, with a predilection for the nares and periorbital area. Flat warts, as the name suggests, appear as flat, smooth, flesh- colored papules, usually 1–5 mm in diameter. They are most commonly located on the face, hands, and shins. Plantar warts present as rough papules on the weight-bearing areas on the feet and may also occur on the palms. Unlike most warts, which are usually asymptomatic, plantar warts are often very painful when they occur on weight-bearing surfaces. Periungual warts occur around the cuticles of fingers and toes. Plantar and periungual warts are often recalcitrant to therapy. Venereal warts (condylomata acuminata) are multiple discrete or confluent papules with a rough surface that appear on the genital mucosa or skin. Common warts also appear on genital or perigenital skin, particularly in toddlers.49
Extensive verruca vulgaris on the knee of a patient with AD.
The diagnosis of warts is based upon clinical appearance. Useful clinical signs include the presence of multiple small black dots (thrombosed capillaries) within the lesion that may be more readily visualized if the lesion is pared down with a sharp blade; the disruption of normal dermatoglyphics on the palms and soles also indicates the presence of warts. Rarely, a shave biopsy is indicated to confirm the diagnosis.
The type and aggressiveness of therapy for verrucae will depend upon the type of wart, its location, the degree of symptoms, and the patient's cooperation and immune status. Most warts will resolve spontaneously within several months to years, and therefore active nonintervention is a viable option for many children. The presence of recalcitrant warts, those that are actively spreading through autoinoculation, or the presence of a significant number of warts or warts in cosmetically sensitive areas such as the face and that cause emotional distress to the child warrant treatment.
It is important to remember when treating verrucae that the virus is microscopic and, although the skin may look normal after treatment, there often is virus still present in the remaining tissue. Unless that tissue also is removed, a few months later the warts will recur. Thus, most topical treatments are more effective if the wart is pared down with a sharp blade or pumice stone after a brief soak in warm water before the application of any topical agents. This strategy helps to remove excess stratum corneum and allows for better penetration of the medication into the lower layers of the epidermis.48
Current therapies for HPV are not specific for the virus; all work by tissue destruction, with the goal of destroying the virus-containing epidermis and preserving as much uninvolved tissue as possible. The most commonly employed treatments involve destroying the affected tissue by freezing, burning, curetting, or applying topical acids. The least painful methods should be used initially, especially in young children. More destructive therapies should be reserved for areas where scarring is not a consideration or for recalcitrant lesions.
Warts exposed to heat—either through immersion in hot water or application of exothermic patches—appear to clear more quickly when compared with controls. This is a benign, well-tolerated modality that may be used adjunctively with other therapies.48
The simple method of occlusion of warts with duct tape or waterproof medical tape, either alone or in combination with other treatment modalities, is a relatively pain-free method that can be useful in younger children. The mechanism for its utility remains unknown, although some hypothesize that occlusion slows the abnormal keratinization within the wart or may induce a local irritant contact dermatitis. In addition, removal of the tape often aids in the debridement of the affected area.
Snip excision is useful for the removal of filiform warts. The area is anesthetized with subcutaneous lidocaine 1%, then the wart is removed with curved scissors. Hemostasis can be achieved with electrocautery or aluminum chloride.
Salicylic acid functions as a keratolytic. It is generally well tolerated and is among the best-studied modalities for the treatment of warts, with several placebo-controlled trials available to validate its effectiveness.50–52 Seventeen percent salicylic acid solutions are readily available as an over the counter remedy for common warts, while 40% salicylic acid plasters are available for the treatment of plantar warts. Salicylic acid formulations can also be combined with occlusion for home use following an office-based treatment such as cryotherapy or cantharidin. Advantages of this treatment modality are that it is available over the counter and is inexpensive. The main disadvantage is that clinical resolution may require several months of treatment.
Cantharidin 1% preparations that are combined with 8% podophyllin and 30% salicylic acid are available for the treatment of warts. Despite its widespread use, no controlled trials evaluating its use in the treatment of warts have been performed. Because of its toxicity when ingested, in-office application is recommended. Occlusive tape is generally applied to the treated area. The lipophilic medication is then washed off by the parent or caregiver at home after 1–4 hours using soap and water. It may be particularly useful for patients with multiple lesions and in young children because application is painless in the office. However, pain may occur 2–24 hours after application, and repeat applications may be required every 2–4 weeks until clear. Side effects include significant blistering, although scarring is unlikely unless subsequent superinfection has occurred. As with treatment for molluscum, cantharidin products are not recommended on the face or genital areas as a result of the potential for excessive blistering.48
Liquid nitrogen therapy is useful in older children and adults but is painful for younger children. Up to 75% of warts eventually resolve with liquid nitrogen therapy, although plantar warts may be somewhat more resistant. In general, liquid nitrogen is applied so that there is a freeze ball of the lesion and 1–2 mm of surrounding normal tissue, usually 10–20 seconds for common, plantar, or palmar warts, and 5–10 seconds or less for flat warts. Treatment intervals every 2–3 weeks produce a cure rate of between 70% and 80%, while intervals greater than 4 weeks have a significantly lower cure rate of 40%.48,53 Liquid nitrogen must be used cautiously on the digits, especially where nerves are located, to prevent severe pain and possible neuropathy, and to avoid over-treatment in the periungual region, which can result in permanent nail dystrophy. Side effects include pain, blistering, and, rarely, scarring. Hypopigmentation may occur in the treated area; thus, dark skinned patients should be treated cautiously with cryotherapy. The use of a topical anesthetic such as lidocaine/prilocaine cream may be helpful for those with large lesions and in younger children.
Pulsed dye laser therapy can selectively target hemoglobin contained in blood vessels within the wart, leading to cauterization of blood vessels. The result is a necrotic wart that eventually sloughs off.54 Studies examining the effectiveness of pulsed dye laser therapy after an average of two or three treatments have reported overall cure rates of 48–93% for warts located at various sites.55,56 Advantages of pulsed dye laser therapy include minimal pain, little risk of scarring, and ease and speed of use. Disadvantages include the expense and the need to refer patients to a specialist.
Imiquimod is a topical immunomodulator that is believed to act by local cytokine induction. Although more commonly used for anogenital warts, imiquimod 5% cream (Aldara) can be used to treat nongenital warts as well. Various imiquimod regimens have been used and none has been extensively studied. One small study in children has documented moderate efficacy in the treatment of recalcitrant warts in children.57 Imiquimod is nonscarring and it is painless to apply. Local irritation is common and can be significant, and there are rare reports of systemic side effects including flu-like symptoms. Imiquimod may be useful in the treatment of periungual and subungual warts, which are often recalcitrant to standard therapy. Imiquimod is expensive compared with many other therapies for warts.
The purported mechanism of action of topical retinoids such as tretinoin in the treatment of warts is the induction of a local inflammatory response, although there are no good studies documenting its efficacy. It is applied once or twice a day, with a goal of inducing mild irritation. Several months of treatment are often required. Benefits of this therapy include the ability to easily treat multiple lesions, including smaller lesions. It can also be safely used to treat warts on the face or on other sensitive areas. Local irritation, secondary eczematization, and photo-sensitivity may be seen but are usually well tolerated.48
5-Fluorouracil is an antimetabolite that inhibits DNA synthesis and topical 5% 5-fluorouracil (Efudex 5% cream) is FDA-approved for the treatment of actinic keratoses, a precursor to squamous cell carcinoma, and superficial basal cell carcinomas. It has been reported to be efficacious in the treatment of warts, in a small number of clinical studies.58–60 Its use is limited by the potential for significant local irritation. The cream is applied to affected areas twice daily for 3–5 weeks. Sun protection is essential because the drug is photosensitizing.
Cimetidine, an H2-receptor antagonist, has been used to treat recalcitrant warts based upon the theory that H2-receptor antagonists stimulate cell-mediated immunity and have been reported to enhance the resolution of warts in immunocompetent children.61–64 This is usually used in conjunction with another treatment modality and should be reserved for treatment-resistant warts. Side effects include impaired metabolism of drugs that use the cytochrome P450 enzyme system with risk of systemic toxicity, renal impairment, and sedation.
More aggressive therapies reported for recalcitrant warts include the use of intralesional bleomycin, intralesional interferon-alpha, intralesional immunotherapy with candida antigen and topical or intravenous cidofovir, which is a potent but prohibitively expensive antiviral drug. These therapies are reserved for patients who have failed multiple standard therapies or who are immunosuppressed.
Fungi may play an important role as aggravating factors in AD.65,66 Colonization of the skin with Malassezia species is more prevalent in AD patients compared to healthy individuals and a substantial proportion of AD patients have positive prick tests, positive intradermal reactions and positive scarification patch tests to Malassezia antigens.67–69 An anti-Malassezia-specific immunoglobulin E antibody is produced in patients with AD who have disrupted skin barrier function, while healthy subjects do not produce the immunoglobulin E antibody.70 Although generally considered to be nonpathogenic, Malassezia yeasts can, under appropriate circumstances, cause skin diseases such as pityriasis versicolor and folliculitis, and have also been associated with seborrheic dermatitis. Because these yeasts are also frequently isolated from healthy control subjects, it has been hypothesized that they act as allergens in patients who are susceptible, rather than as infectious agents, leading to skin inflammation that may exacerbate the underlying dermatitis.71,72 The use of antifungal agents in selected patients has been shown to improve the symptoms of AD.68,73 Patients with AD also develop chronic dermatophyte infections more easily, which are often more severe and more difficult to eradicate.65
Optimal treatment dosages and duration remain to be determined. Comparative placebo-controlled, double-blind clinical studies are warranted to determine the place of antimycotic therapy in the management of AD.66