Pediatric Dermatology Roundup

New developments and controversies in pediatric dermatology. Data on new approaches to dermatological conditions affecting children and issues surrounding their treatment have recently been topics in the news and at meetings. Two new treatments for infantile hemangiomas that may offer a much-needed alternative to systemic corticosteroids are propranolol, a non-selective beta-adrenergic antagonist, and Timolol gel, a topical non-selective beta-adrenergic antagonist. Benzyl alcohol lotion 5% has emerged as a new first-line treatment for head lice. Acne-related issues include the familiar controversy about the impact of milk on acne as well similar questions concerning the role of glycemic load of diet. Here we review some of these topics and also summarize CDC’s general recommendations for outpatient treatment of CA-MRSA infections, and examine literature related to a possible association between atopic dermatitis and attention deficit/hyperactivity disorder.

INFANTILE HEMANGIOMAS: NEW FIRST-LINE TREATMENT POSSIBILITIES

Although infantile hemangiomas are benign, self-limiting vascular tumors, treatment is oftentimes required depending upon location and growth rate. Currently, systemic corticosteroids are regarded as first-line treatment for these infantile tumors;1 however, due to their well-known adverse side effects, an alternate, equally effective therapy is in high demand. We discuss two potential treatments below. PROPRANOLOL TREATMENT The use of propranolol, a non-selective beta-adrenergic antagonist, as a treatment for hemangiomas was incidentally discovered while treating infants for heart failure. Within 24 hours of administering propranolol, changes consistent with involution were noted, including color change and palpable softening.2 The finding prompted an observational study where 32 children were given 2 mg/kg to 3 mg/kg of propanolol in two to three doses daily with monthly follow-up. 3 Improvement was observed in all children within days of the first dose. After a period of 2 to 10 months, treatment was discontinued in 15 patients due to resolution; follow-up revealed no relapse of tumor in 10 of these children. Other noteworthy results include complete resolution of ulceration of lesions by 2 weeks, and a mean regression of 40% at 60 days. Major side effects included hypotension and wheezing. Guidelines to Minimize Size Effects As a non-selective beta-adrenergic antagonist, propranolol expected side effects include hypotension, bradycardia and hypoglycemia. A small case series noted these complications in two children treated with propranolol for hemangiomas, and proposed some guidelines to limit adverse effects.4 As per these guidelines, children should first receive a cardiology consult, as well as a magnetic resonance angiography if coexisting cerebrovascular anomalies are suspected, as in the case of patients with large facial, segmental hemangiomas due to PHACES Syndrome. Infants under 3 months of age should be monitored more closely due to the increased risk of hypoglycemia. Gradual dose escalation is recommended in all patients with inpatient induction for the first six to eight doses for close monitoring of vitals and glucose levels. Mechanism of Action While the exact mechanism of action is not fully understood, propranolol appears to act on endothelial cells in several ways. A recently proposed mechanism reveals early, intermediate, and late effects as being attributed to vasoconstriction and the decreased release of nitric oxide, blocking of pro-angiogenic factors such as VEGF, bFGF, which are over expressed in hemangiomas, and induction of apoptosis. 5 Dosing Despite the impressive efficacy propranolol illustrated in observational studies and case reports, a large, prospective, well-controlled trial is lacking to determine a safe, therapeutic dose for children. Once this is established, a large randomized double-blinded trial investigating corticosteroids compared to propranolol will determine the optimal first-line treatment for infantile hemangiomas. TIMOLOL GEL A topical non-selective beta-adrenergic antagonist, in the form of Timolol gel, has recently been reported as a potential treatment for hemangiomas. In a retrospective chart review analysis, Timolol 0.5% gel applied topically twice daily was used to treat six patients with uncomplicated head and neck hemangiomas. 6 Although these patients were treated only for an average of 3.33 months, a visual analog scale used to assess changes in the hemangioma revealed that longer periods of treatment resulted in better treatment response in all patients. As no systemic effects were reported, Timolol appears to be a safe and promising new treatment. However, to establish efficacy, safety, and optimal regimen of Timolol for use in the treatment of hemangioma, further prospective studies are needed.

IS THERE AN ASSOCIATION BETWEEN ATOPIC DERMATITIS AND ATTENTION-DEFICIT/HYPERACTIVITY DISORDER?

There is a paucity of literature studying the relationship, if any, between atopic dermatitis (AD) and attention-deficit/hyperactivity disorder (ADHD). However, sleep disturbance has been associated with both disorders, and may be a linking factor. Data on AD-ADHD Connection It appears children with ADHD have increased sleep disturbances, when using objective measures, compared to controls. 7 On the other hand, a population-based questionnaire study sampled 68,418 participants examining sleeping habits and comorbidities and found adolescents with inadequate sleep were more likely to have atopic conditions. However, they did not find an association between inadequate sleep and ADHD. 8 A more recent population-based study found a strong association between ADHD and AD (OR 1.54; 95% CI 1.24 to 1.93; P<0.001), as well as an association between ADHD and AD in children with sleep problems (OR 2.67 95% CI 1.51 to 4.71; P=0.001; n=1112), but not in children without sleep problems (OR 1.24 95% CI 0.83 to 1.84; P=0.30; n=5796). 9 This may suggest that AD and ADHD are a cause and consequence of decreased sleep, respectively. Another controlled population-based study found ADHD to be associated with AD, and that the prevalence of ADHD increased with each physician visit for AD. 10 This may suggest that the severity of AD results in worsening sleep due to symptoms of pruritus, and consequently results either in exacerbation of ADHD or in symptoms that may resemble ADHD, but the data is conflicting on whether sleep deprivation causes ADHD-like symptoms or exacerbates ADHD. In one study, sleep duration has not been associated with changes in ADHD scores when measuring behavior in 7-year-old children, 11 but in another study, insomnia symptoms were associated with ADHD and other learning, psychiatric and behavioral disorders. 12 As two of the most commonly diagnosed childhood diseases, 13,14 it may be coincidental that there appears to be an association. Sleep efficacy may play a role in linking the two disorders; however, more studies are needed to elucidate these questions. Regardless, as the evidence suggests the existence of an association between AD, ADHD and sleep, it is critical to optimize treatment of AD in order to minimize nocturnal breakthrough symptoms in an attempt to improve sleep patterns. Consider addressing sleep patterns in every patient with AD. The use of hydroxyzine or diphenhydramine at night to prevent pruritus-induced disrupted sleep may be crucial to not only controlling AD, but also preventing progression to ADHD.

BENZYL ALCOHOL LOTION 5%: NEW FIRST-LINE TREATMENT FOR HEAD LICE?

Approximately 6 to 12 million cases of head lice are diagnosed each year, with the majority in children aged 3 to 12 years old. 15 Despite known increasing resistance, the American Academy of Pediatrics recommends permethrin 1% as first-line treatment due to efficacy and safety profile. 15 Yet there are several over-the-counter treatments, including pyrethrins with piperonyl butoxide, malathion, as well as prescription requiring permethrin 5%, lindane and ivermectin. Many of these agents result in adverse effects including local irritation, and, more seriously, possible central nervous toxicity. 16 Attempts at suffocating lice using benign home remedies, such as Cetaphil and mayonnaise have been attempted with minimal results. 17 For refractory head lice, oral ivermectin is significantly more effective than malathion lotion 0.5% and generally well tolerated. However, safety and efficacy of ivermectin has not been established in children <15kg. 18 Need for Non-Pesticide Treatment With recent studies linking pesticides to childhood leukemia, a new first-line treatment is in demand. 19 Ulefsia, benzyl alcohol lotion 5%, is a new promising pediculicide therapy approved by the FDA for treatment of head lice in children as young as 6 months of age. Ulefsia is superior to other pesticides because it is non-neurotoxic. The mechanism of action is asphyxiation of lice by stunning breathing spiracles open, which normally close during attempt at emollient suffocation. This approach allows for lung infiltration by inactive substances, 20 and subsequent louse death. Data on Ulefsia After several Phase II and III trials, Ulefsia is found to be significantly effective, with 92.2% success (live lice absent) when hair was saturated for 10 minutes with two treatments 1 week apart. 20 However, treatment success was only 75% on day 22 after initial treatment, likely a result of reinfection. Additional Recommendations These findings emphasize the importance of decontamination, as lice can be transmitted by direct contact and fomites, such as combs, clothing, linens, etc. 21 Thus in addition to topical treatment, recommendations include laundering clothing and linens in contact with patient within 2 days of diagnosis in water of at least 50°F, sealing non-washable items in a plastic bag for 2 weeks, as well as vacuuming floors and upholstery in order to prevent reinfection and spread to others. 16,21

EVIDENCE SUGGESTS MILK CONSUMPTION AND GLYCEMIC-LOAD OF DIET MAY PLAY A ROLE IN ACNE VULGARIS

The most common dermatologic condition, acne vulgaris, affects more than 40 million Americans, with a prevalence of about 85% in adolescence. 22 As is well known, there is an elevation of hormones, including androgens, insulin-like growth factor (IGF) I, glucocorticoids and growth hormone, during this period of growth, resulting in increased sebum production, hyperproliferation, differentiation, and blockage of follicles. Therefore, factors, such as diet or systemic disease that result in an increase in specific acne-related hormones, may similarly result in acne. Several systemic diseases are associated with acne, including polycystic ovarian syndrome and Cushing’s disease, which both result in an increase in androgen production. 23 Both endocrinopathies are characterized by insulin resistance, and an increase in IGF-I levels, thus contributing to acne via the direct effect of IGF-1 on sebaceous glands. 24 Thus, if certain foods stimulate circulating levels of “acne-philic” hormones, we expect acne to result. Milk consumption and high glycemic load (HGL) result in significant insulin and IGF-1 production, and both hormones may exacerbate acne via stimulation of sebaceous lipogenesis, proliferation and differentiation. 24 Literature Findings While some recent review articles have failed to elicit a significant association between diet and acne, 25,26 others have more closely examined a positive correlation between milk and glycemic-load. Currently, the literature suggests that skim milk and a high-glycemic diet result in an increased number of acneiform lesions. Prospective studies, using food frequency questionnaires, following both male and female cohorts, have established a positive association between milk consumption, particularly skim, and acne. 27,28 It is perplexing that only skim milk has been repeatedly associated with acne when all milk contains acne-causing hormones. Particularly, bovine milk contains IGF-1 that may remain bioactive post digestion, which can bind to human IGF-1 receptors potentiating acne. 24 One hypothesis is that the processing to create skim milk increases bioavailablity of these hormones. 29 Another differentiating factor may be the glycemic index (GI) of skim compared to whole milk. 30 Randomized clinical trials as well as trials in highly controlled settings have examined the association between dietary glycemic load and acne. One study assigned an experimental group to a low-glycemic load (LGL) consisting of protein, whole grain, fruits and vegetables while the control group was assigned a conventional diet and urged to consume carbohydrates to produce a high-glycemic load (HGL).31 Using investigator-masked dermatologic assessments, a significant reduction in total lesion (P=0.01) and inflammatory counts (P=0.02) were found in the LGL group. Hormonal regulation also differed significantly between the two groups; sex hormone binding globulin (SHBG) and IGF binding protein-1 (IGFBP-1) were higher in the LGL group, with lower free androgen index (FAI), insulin resistance assessment and fasting insulin observed in this group as well. Following these results, a pilot study was conducted to examine the effect of glycemic load on hormone production and regulation. 32 Twelve adolescent males were housed in a well-controlled feeding environment where seven received LGL and five received HGL. Significant findings were similar to the initial study where LGL resulted in decreased insulin resistance and decreased FAI relative to the HGL group, however LGL resulted in increased IGFBP-1 and 3 relative to baseline, while HGL resulted in decreased SHBG and increased FAI relative to baseline. Thus, it appears glycemic load plays a role in hormone regulation, where HGL may augment sex hormone activity, and LGL may decrease IGF-1 activity, both of which are involved in acne development. Although further investigation would help provide more evidence to make a specific recommendation regarding diet and acne, the evidence, thus far, is convincing enough to recommend dietary changes to patients who may be refractory to medical therapy, or to patients willing to make any changes possible in order to decrease the onset of new lesions. Recommending a low-glycemic diet may not be such a terrible idea, as it will not only help the acne epidemic, but it will also help to decrease the obesity and diabetes epidemic affecting children as well.

METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS: CURRENT MANAGEMENT

Background The incidence of skin and soft tissue infections caused by community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) continues to increase. Prevalence, sensitivities, and colonization characteristics are geographic and community-dependent. Here we summarize the CDC’s general recommendations for outpatient treatment of CA-MRSA infections. 33 Management MRSA infections can take the form of cellulitis, furuncles, carbuncles or skin abscesses, presenting with redness, pain, swelling and warmth. According the CDC, first-line treatment for purulent infections is incision and drainage (I&D), along with a wound culture. Studies have found no difference in morbidity between wound packing compared to sterile dressing, except for reduced pain with the latter. 34 If systemic symptoms, severe local symptoms, immunosupression, or failure to respond to I&D occurs then antimicrobial therapy covering MRSA should be implemented. For non-purulent mild to moderate lesions, empiric antimicrobial treatment should first include beta-lactams, such as penicillins or cephalosporins, with MRSA coverage only if a patient is refractory to initial therapy, or there is a high community prevalence of MRSA. Antibiotics Trimethoprim-Sulfamethoxazole is commonly used in the treatment of staphylococcal infection, and is first-line outpatient therapy for suspected MRSA in this author’s experience. Allergic skin reactions may occur, and although rare, fatalities associated with sulfonamide administration have occurred due to Stevens-Johnson Syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. There is limited data on the use of this antibiotic in children under 2 years of age. Doxycycline is FDA-approved to treat S. aureus skin infections, and has activity against group A streptococcus, however, it is not recommended for children under the age of 8 because it may cause permanent discoloration of the teeth, as well as retardation of skeletal growth in infants. Children taking this drug should not be exposed to direct sunlight due to the risk of an exaggerated sunburn reaction. Clindamycin is FDA-approved to treat serious infections due to S. aureus, however, patients should be informed to return for follow-up if loose stools occur due to increased risk of Clostridium difficile while taking clindamycin. Linezolid is FDA approved for the treatment of complicated skin infections, including MRSA. Prior to use, the CDC recommends consulting an infectious disease specialist. Serious adverse effects include myelosuppresion, neuropathy, and lactic acidosis during prolonged use. Decolonization Colonization of MRSA among affected and healthy individuals varies with population, and may contribute to infections. The CDC does not recommend for or against decolonization, however, a meta-analysis of 9 randomized clinical trials found intranasal mupirocin ointment reduces Staphylococcus aureus infections in nasal carriers. 35 Another study pooled 8 trials comparing mupirocin with placebo or with no treatment, and also found a statistically significant reduction in the rate of S. aureus infection associated with intranasal mupirocin; however, infection rate caused by micro-organisms other than S. aureus was significantly higher in patients, mainly diabetics, treated with mupirocin compared with control patients. 36 A recent in vitro study found >99,9% effectiveness in decreasing viable colonies with a 5 minute bath in 2.5μL/mL dilution of bleach, which is equivalent to one half cup (120mL) of bleach in one-quarter filled 50-gallon standard tub of water (13 gallons). 37 We typically recommend this decolonization bathing therapy once weekly in patients who experience frequent re-infection. Recommendations for decolonization, in order to prevent recurrence of infection, require further clinical trials. Dr. Buka is Section Chief, Department of Dermatology, Mount Sinai School of Medicine, New York, NY. Ms. Noce is a third year medical student at New York University School of Medicine, New, York, NY. Disclosures: The authors have no real or apparent conflicts of interest with any material presented in this article.