(United States
Pharmacopeia)
Although topical steroids are very effective in controlling acute and chronic inflammatory dermatoses, they are not necessarily disease-modifying agents [50]. Therefore, upon stopping topical steroid therapy, the dermatosis may often recur, particularly as an acute rebound flare. Local side-effects, although not life-threatening, are more common than systemic side-effects, often insidious in their onset and frequently troublesome. Potential side-effects associated with topical corticosteroids include striae, petechiae, telangiectasia, atrophy and acne or rosacea [49,51]. In general, these side-effects are correlated with the length of use and potency of the corticosteroid [51]. The choice of topical corticosteroid depends on the age of the patient, severity of the disease, and the area of the body being treated.
In childhood, except for very high potency, topical steroids may be used safely on non-extensive body surface areas for short, intermittent periods of time on unoccluded skin. Avoidance of occluded steroids in the paediatric population is imperative, as significant skin atrophy is sometimes irreversible and can develop within 7 days of superpotent topical steroid application (e.g. clobetasol propionate), and as early as 2 weeks without occlusion [52]. As occlusion raises the concentration of the topically applied steroid in the upper layers of the stratum corneum to a relatively high level, steroid may be detected in the stratum corneum for many days or even a few weeks after the initial application to the skin [52]. Other common complications seen with occlusion of topical steroids include miliaria and overgrowth of skin yeast and bacteria [53].
Based on these considerations, it is advisable to follow some general guidelines when treating children with topical steroids.
1 Choose the steroid potency according to the anatomical area requiring treatment. In infants, excessive skin folding may be seen and this may result, if treating these areas topically, in a natural occlusive phenomenon. In skinfold areas, as well as the napkin area that is virtually under airtight occlusion, the use of low-potency steroids is recommended. Treatment of intertriginous areas, such as axillae, groin or breasts where the skin is thin, moist and to some degree occluded, also requires particular caution. On the trunk and extremities, moderate potency steroids can be used more safely.
2 Limit applications to up to twice per day and limit duration of therapy (e.g. 14 days).
3 Avoid use of superpotent steroids.
4 If the child does not respond to therapy, do not continue and consider alternative therapies.
Topical steroids are categorized by the USP (United States Pharmacopeia) into four groups with respect to clinical potency (Table 181.2). Topical corticosteroids are most effective in higher doses for 1–2 weeks. Lower-potency corticosteroids are recommended for infants with mild disease, while medium-potency agents are recommended for moderate to severe disease and are limited to 5–10-day treatments. Superpotent agents should not be used in children under 12 years of age and are limited to 1–2 week use [51]. The protracted use of topical steroids may also be associated with significant systemic side-effects.
Table 181.2 United States Pharmacopeia steroid potency listing
Reproduced with permission from Corticosteroids (Topical). In: Drug Information for the Health Care Professional. USPDI, 23rd edn. Thomson Micromedex, 2003.
| Steroid potency | Use | Restrictions |
| Low potency | Chronic application | May be used on the face and intertriginous areas, with occlusion, and in infants and young children |
| Medium potency | Moderate inflammatory dermatoses | May be used on the face and intertriginous areas for a limited duration |
| High potency | Severe inflammatory dermatoses (intermediate duration or for longer if the skin is thickened) | May be used on the face and intertriginous areas for short treatment duration |
| Very high potency | Thick, chronic lesions | For short duration of therapy and on small surfaces; not to be used with occlusive dressings; high likelihood of skin atrophy |
With regard to systemic side-effects, infants and toddlers are at high risk as they have a greater surface–bodyweight ratio [54] and they may be less able to metabolize potent glucocorticoids adequately. Systemic side-effects from topical steroids include hypothalamic–pituitary–adrenal axis suppression, failure to thrive, overt Cushing syndrome, glaucoma and benign cephalic hypertension [49].
Factors that may influence the risk of systemic side-effects include the amount of drug applied, extent of skin surface treated, frequency of application, length of treatment and potency/use of occlusion.
Intralesional steroids in paediatric patients are selectively used, as the side-effects are potentially more serious.
Immune Response Modifiers
Cytokine Inhibition
Topical calcineurin inhibitors such as tacrolimus and pimecrolimus offer significant and targeted therapeutic alternatives for the treatment of atopic dermatitis [55].
Systemic tacrolimus is used as an immunosuppressant in transplant medicine. Topical tacrolimus and pimecrolimus cause inhibition of interleukin 2 (IL-2) and T-cell-derived cytokines (tissue necrosis factor alpha (TNF-α) and other interleukins), known inflammatory mediators in the pathogenesis of atopic dermatitis [56,57]. Tacrolimus ointment can be effective against atopic dermatitis that is difficult to treat with topical steroids [58].
Multiple studies have demonstrated the efficacy and relative safety of these compounds for alleviating the signs and symptoms of atopic dermatitis; 0.03% tacrolimus (Protopic) and pimecrolimus (Elidel) are licensed for use in children over 2 years of age. They provide an alternative treatment for those children with moderate to severe atopic dermatitis requiring regular potent steroids and are particularly useful on the face instead of topical steroids [58].
There are theoretical concerns about the risk of malignancy, in particular lymphoma. The evidence is based on animal studies at systemic doses but only minimal blood levels are achieved when applied topically in the clinical situation. It is therefore important to advise the family that the child should be protected from sun exposure if using these topical medications, and for these preparations not to be prescribed to children who are immunosuppressed.
Since 2006, the topical calcineurin inhibitors (tacrolimus and pimecrolimus) have had a boxed warning that highlights the possible increased risk of skin cancer and lymphoma. The label clarified that these drugs are indicated as second-line therapy for short-term treatment of atopic dermatitis in patients who do not respond adequately to topical corticosteroids. According to the latest knowledge, there is no scientific evidence of an increased risk for malignancy due to a topical treatment with calcineurin inhibitors. However, caution prevails. Long-term safety data and studies of a sufficient number of patients using these drugs are necessary to exclude enhanced risk [59].
Long-term studies have shown a low risk of side-effects and no loss of effectiveness in treating atopic dermatitis [59]. However, the use of topical tacrolimus for skin conditions other than licensed indications should be considered with caution and with monitoring of blood levels [60]. Side-effects other than local irritation (pruritus and warmth or transient skin burning sensation) for the first several days of treatment are rare [61].
Cytokine Upregulation
Imiquimod is an immune response modifier that is approved for the topical treatment of anogenital warts in patients 12 years and older [62]. Its mechanism of action includes stimulation of the local immune response by promoting cytokine upregulation (TNF-α, IL-1, IL-6, IL-8 and interferons), all capable of stimulating a cytotoxic reaction towards HPV infection. Good results with imiquimod treatment have been reported in some studies for the treatment of long-lasting cutaneous warts and molluscum contagiosum in children although one large multicentre study sponsored by the manufacturer showed that the clinical benefit of imiquimod for molluscum was not superior to placebo. An advantage in children is the convenience of a home-based therapy without the pain often associated with other therapies. Overall, imiquimod cream is well tolerated, and the most common adverse reactions include erythema, burning, itching, erosion and tenderness, frequently localized to the application site [63]. Topical imiquimod is also used in the treatment of recurrent and resistant periungual and common warts in children [64,65].
Sinecatechins are derived from green tea, and these extracts have been shown to have activity against external genital warts (EGW). The exact mechanism, however, remains unknown. As a topical agent, a commercially available preparation that has been approved for use against EGW sinecatechins appears to be well tolerated and associated with a decreased rate of wart recurrence.
Insect Repellents
An effective insect repellent for use on skin in children should be non-toxic, non-irritant, non-allergic, harmless to clothing, odourless and easy to apply, and should offer protection for several hours in variable weather conditions.
Diethyltoluamide
Diethyltoluamide (DEET) is the most universally accepted repellent for skin application to date. Product forms include aerosols, pump sprays, lotion creams, liquids, roll-on sticks and impregnated towelettes, in various concentrations [66]. The American Academy of Pediatrics Committee on Environmental Health recommends that only children older than 2 months be exposed to DEET products, and the recommended concentration range is10–30%. DEET is broadly effective against mosquitoes, ticks and other arthropods when used on the skin [67]. DEET should be used cautiously as cases of systemic toxicity have been reported following topical use. Reported reactions include hypotension, seizures, respiratory distress and death. Conclusions show a low overall risk of toxicity and lack of a dose-dependent relationship between exposure and the severity of neurological manifestations.
Oil of Citronella
Oil of citronella, mixed with inert ingredients, is also used as a topical repellent in children over 2 years of age. It is rarely cited as a cause of systemic toxicity or allergic contact sensitization [68].
Picaridin
Picaridin is a commonly used active ingredient in Europe, Australia and more recently the United States, and is becoming increasingly popular because of its relatively low toxicity, comparable efficacy and customer approval. Picaridin is odourless, does not feel sticky or greasy on application, will not damage fabrics and is less likely to irritate the skin. In Europe, concentrations of up to 20% have been shown to be protective for up to 8–10 hours. Picaridin is not recommended for use in children younger than 2 years of age. Although picaridin seems to have similar efficacy to DEET, there are limited data to date supporting the assumption [67].
Human Skin Substitutes
Treatment of full-thickness burn injury consists of excision of the affected area with donor skin grafted onto the wound. If there is not sufficient skin available, the wound may be covered until sufficient skin is available. Unfortunately, for extensive full-thickness burn injuries, sufficient skin is often not readily available, so alternative therapies are desirable [69].
One possible alternative is the use of human skin substitutes (HSSs), which may be made by various processes including cultured autologous keratinocytes. HSSs have been used in combination with artificial bilayer (dermis and epidermis) temporary skin substitutes with nearly equivalent results to skin grafting. Immediately after excision of the full-thickness burn, the artificial skin is placed to minimize fluid loss and infection. HSSs are useful not only in the treatment of full-thickness burn excision, but also for grafting after removal of giant naevi in children [70,71].
Some difficulties have arisen with the use of HSSs. Compared with the use of an autograft, HSSs seem to require a longer period of time for the graft to take. Occasionally, there may be subsequent depigmentation of the affected area, or wrinkling of the grafted HSS over the scar. In general, however, scarring from these grafts usually appears to be minimal with nearly normal pigmentation [72].
Keratolytics
These substances are used to reduce or promote exfoliation of hyperkeratotic skin. Topical salicylic acid dissolves the intercellular matrix and thereby softens hyperkeratotic areas by enhancing the shedding of scales [73]. Salicylic acid is available in various dosage forms such as gels, ointments, creams, transdermal patches or adhesive plasters, in concentrations of up to 70%. Salicylic acid preparations to extensive areas of skin, particularly in children, should be used with great caution as they may induce systemic toxicity (see Chapter 3).
Potassium Hydroxide
Potassium hydroxide (KOH) has been shown to be effective in treating the lesions of molluscum contagiosum when applied in an aqueous solution to the affected areas. Potassium hydroxide is an alkali known to dissolve keratin when applied topically to skin [74]. It can also act as a concentration-dependent irritant to the skin. Side-effects are usually limited to a stinging sensation at application sites. Some children may demonstrate transient hyper- and/or hypopigmentation in the treated areas [74]. However, KOH is a safe, inexpensive and non-invasive alternative for the treatment of molluscum contagiosum in children.
Retinoids
Tazarotene
Tazarotene is a topical acetylenic retinoid that normalizes keratinization of the follicular epithelium. It is currently used for the treatment of acne and psoriasis and has been reported to produce a clinical improvement in the treatment of childhood Darier disease [75] and is also commonly employed for the topical management of various autosomal recessive congenital ichthyoses.
Squaric Acid Dibutylester
A useful treatment for warts is squaric acid dibutylester (SADBE) immunotherapy. Although not commercially available, SADBE is an extemporaneously compounded topical sensitizing agent with some long-term safety data for use in children. Topical SADBE generates an anti-HPV response via cell-mediated immune reactivity, which provides long-term remission. Side-effects are usually local application site reactions (erythema, burning and pruritus), which are reversible. A major benefit of SADBE is that application is painless and it is easy to use, both of obvious benefit in treating the paediatric population [76,77].
Cantheridin
Cantharidin, derived from blister beetle extract, is a common modality in the treatment of molluscum contagiosum amongst paediatric dermatologists. Cantharidin is a topical treatment that produces a small intraepidermal blister that heals without scarring. Side-effects are common and include discomfort/pain, severe blisters, irritation or inflammation, hypo- and hyperpigmentation, infection, scarring and itching [78].
Trichloroacetic Acid
Although cantharidin is an effective treatment for molluscum contagiosum, treatment of facial lesions is not recommended with this agent. Trichloroacetic acid is a safe and effective agent most commonly used in the treatment of verrucae. Topical trichloroacetic acid is an effective treatment of facial molluscum contagiosum that erodes the skin and is generally not absorbed systemically. Patients describe only a mild stinging sensation and the agent is generally well tolerated [79].
Sunscreens
Most sunscreen ingredients are considered safe for use in children over 6 months old. Although infants under 6 months of age should not be exposed to prolonged direct sunlight, a physical blocking agent such as micronized zinc oxide is considered safe for use in selected patients [80]. Sunscreen products are arbitrarily divided into UVA blockers, active in the range 320–400 nm, and UVB blockers, active in the range 290–320 nm [81]. The current method of rating sunscreen effectiveness is the sun protection factor (SPF) number. SPF represents a multiple of the amount of time it takes for skin to turn red – the minimal erythema dose (MED). Hence, an SPF of 15 should allow an individual to be exposed to sun 15 times longer before turning red. This method, however, is representative of UVB (290–320 nm) activity, which is more responsible for erythema. UVA has some erythogenic potential in the lower wavelengths (320–340 nm) but, otherwise, erythema is a poor indicator of UVA activity.
Most currently available sunscreen formulations aim for coverage of both UVB and UVA spectra. UVA protection in addition to UVB is advertised as ‘full-spectrum’ sun protection [81]. Products may be categorized as chemical sunscreens and/or physical blockers. Chemical sunscreens such as octocrylene and oxybenzone have some UVA activity in the 320–340 nm range. Avobenzone, benzopheonomes and dicamphor sulphonic acid are effective in most of the UVA range [81]. Methoxyphenyltriazene is a new sunscreen in Europe with a broad-spectrum filter that stabilizes avobenzone-containing sunscreens and offers excellent broad-spectrum protection [81]. The physical blockers zinc oxide and titanium dioxide are effective in both the UVB and UVA ranges [82].
Some compounds are effective in both ranges; the usual formulations aim to cover most of both and are termed ‘broad-spectrum’ blockers. The efficiency of each agent is related to the spectrum of wavelengths absorbed, amount of product applied (2 mg/cm2 recommended), time for which sunscreen dries prior to UV exposure (15 minutes recommended) and the resistance to washing off during swimming or sweating [81,83].
Vitamin D3 Analogues
Various vitamin D3 analogues are currently available for topical use, including calcitriol, calcipotriol (calcipotriene in the USA) and tacalcitol.
Calcipotriol is a vitamin D3 analogue that has a high binding affinity to cellular receptors for the biologically active form of vitamin D3 (1,25-dihydroxy-vitamin D3) (calcitriol). Receptors for calcitriol have been demonstrated in various cells, including keratinocytes and fibroblasts. These analogues produce dose-dependent inhibition of proliferation and stimulation of terminal differentiation in cultured human keratinocytes [84]. Unlike calcitriol, however, calcipotriol and tacalcitol present a lower risk of inducing calcium-related side-effects. Favourable results in the treatment of psoriasis in children have been reported with calcitriol [85,86], whereas calcipotriol has been shown to be effective for congenital ichthyoses [84] and on localized linear scleroderma and morphoea [87,88]. A less proven use for topical calcipotriol is in the treatment of vitiligo in children [89], especially if used in combination with sunlight therapy [90,91]. A long-term study (106 weeks) in child patients with psoriasis who were treated with topical calcipotriol showed significant improvement in psoriasis assessment severity index (PASI) scores compared with baseline. In this study values of 1,25-dihydroxyvitamin D3 were decreased and 50% of patients had levels below the normal range. Therefore, monitoring of vitamin D metabolites is suggested for chronic paediatric vitamin D3 analogue topical therapy [92].
References
1 Lehr VT, Taddio A. Topical anesthesia in neonates: clinical practices and practical considerations. Semin Perinatol 2007;31(5):323–9.
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