Atopic Dermatitis in the Pediatric Population: Pathogenesis, Treatment, and Quality of Life Issues

Atopic dermatitis (AD) is an inflammatory skin condition also known to many people as eczema. The first sign is usually rash, but in many cases this decreases over time. The majority of patients with AD will have the first sign of the condition before their second birthday.¹ The rash can be localized to certain places on the body depending on the age of the child, with the face and trunk of the body being the main areas affected in infants and young children. The skin may appear bumpy and lighten or darken in complexion, and the area may thicken and itch constantly.¹

Several studies have been performed to determine the pathogenesis of AD, but its cause still remains a mystery. Researchers are not sure if the filaggrin gene plays a role in the destruction of the skin barrier. There have also been links to cytokines and the role they play in the regulation or down-regulation of other cells to sites of inflammation and rashes on AD patients.² While there are different classes of medications that help relieve pain, itching, and inflammation of the skin, there is currently no cure for AD.

Quality of Life in Patients and Children

The quality of life and well-being of a child with AD can be affected negatively throughout the years of dealing with the condition. Many children feel embarrassed by the rashes that form on their skin and may even become depressed about their appearance. Parents and caregivers have to deal with their child’s affliction and are faced with the same feelings and attitudes toward the condition. Moore et al have shown that parents of children with AD are more likely to have difficulty disciplining their child, can feel stressed and socially isolated, and may elect not to work.² It has also been determined that children with moderate-to-severe atopic dermatitis have twice as many psychological issues than children without the condition.³

Educational programs have been studied to determine if they help improve treatment and quality of life of patients with moderate-to-severe AD as well as their parents’ attitude toward the condition. Staab et al confirmed that educational programs, which are designed to focus on treatment, emotions, and concerns while coping with the condition, are more effective in the long-term management of AD than only managing the physical effects.³ During this study, parents also reported reduced severity of eczema and improved quality of life.³

The quality of life of children affects not only themselves but also the parents or guardians caring for them. Sleep disturbances are dramatically increased in parents of children experiencing moderate-to-severe AD. Mothers were more likely to suffer from sleep disturbances, anxiety, and depression than fathers.² Anxiety and depression are believed to be caused by the sleep disturbances and not by the child’s skin condition directly. It was also determined that parents experience more sleep disturbances if the child is younger and when the eczema is known to be more severe.²

Etiology and Pathophysiology

Between 10% and 20% of children worldwide have AD.⁴ Most children with AD also have family members with the condition. It is more common in industrialized areas but affects all ages, sexes, and races equally.^2,3

The filaggrin gene is responsible for the formation of the cornified cell structure needed for an intact skin barrier. During the development of this structure, filaggrin helps in the formation of keratins, which induce the cytoskeleton to collapse and form corneocytes.⁵ The structure helps protect against allergens and infections that may come in contact with the skin. Filaggrin has been proven to have a decrease in expression and also to have mutations that affect its proper function. Researchers have narrowed down the mutations in patients to R501X, 2282del4, R2447X, S3247X, 3702delG, and 3673delC.⁶ Recent studies have determined that mutations in these genes are more likely to lead to a defective skin barrier.⁶ Although this theory proves to be true in a significant number of cases, there has been debate as to whether the filaggrin gene is underexpressed rather than having a mutation.

During the production of the skin barrier, there is an increase in T-helper type 2 (Th2) cytokines (interleukin [IL]-4 and IL-13) in children with AD, which leads to production of less filaggrin to help the formation of keratins. Only one-third of patient populations with AD have a mutation on their filaggrin gene.⁵ This has led researchers to a different conclusion—that there may be an underexpression of filaggrin in patients with AD. One study proved that patients with AD did not have a mutation in every case.⁶ There was a decrease in filaggrin in the localized areas affected by AD but normal filaggrin expression in the areas that were not affected. Could this be due to an increase in IL-4 and IL-13 production in certain areas of the skin? So far, all we know is that a localized decrease in filaggrin does not mean a mutation in the gene if there is no problem in other areas of the skin as well.

Chemokines are proteins used in the migration of cytokines and lymphocytes. There are two types of chemokines that have been related to topical lesions. Th1- and Th2-derived chemokines are either increased or decreased depending on the child’s skin status and age. It is believed that the imbalance in Th1 and Th2 contributes to AD in pediatric patients.¹

Chemokines such as CXCL-9, CXCL-10, and CXCL-11 help in migrating lymphocytes to the Th1-type site, while CCL-11, CCL-17, and CCL-22 lead to a Th2-dominated pattern.¹ Several studies have shown an increase in these chemokines relating to AD, but there are two known chemokines present in many studies. A study was performed to determine if there is a difference in the amount of chemokines present in two age groups of AD and non-AD patients (ages 1-10 years and ≥11 years).¹ In the pediatric age group (1-10 years), CCL-17 was proven to be lower in patients with AD when compared with patients who have normal skin.¹ Some tests have contradicted this result, but most studies arrived at the conclusion that CCL-17 does play an important role in AD.¹ The group of patients ≥11 years had elevated levels of each chemokine.¹ This suggested a difference in the quantity of chemokines at different ages. This is important because these results show that there may be different causes of AD at different ages, which may also be indicated by the localization of rashes at different ages. With more research, we may be able to determine a better treatment regimen for different age groups.

Lymphocytes are mediated by chemokines (CCL-17 and CCL-22) and are known to release Th2 cytokines (IL-4 and IL-13). In recent studies, IL-4 and IL-13 have been shown to be in abundance in active skin lesions in patients with AD due to an overexpression of chemokines.¹ Th2 cytokines may also play an important role in the skin lesions caused by AD, but Th1 has not been proven in as many studies. Therefore, there is a belief that Th2 cytokines play an important role in the pathogenesis of AD.⁷

The increase in Th2 cytokines may be caused by IL-18 present on the lesions of a person with AD. IL-18 has been proven to induce the production of immunoglobulin E (IgE). The serum IgE level is increased in allergic diseases and is also found in higher concentrations in AD.⁷ When IgE binds to the surface antigen of mast cells, the mast cells degranulate and mediators are released, causing dermatitis to form.⁷

Pediatric Treatment Options

Atopic dermatitis usually appears during the early years of life as a rash and itchiness. If this is a normal rash or superficial dermatosis, applying moisture to the area helps to clear it within a few days or a week; however, AD is a long-lasting rash that does not go away with moisture alone. If the rash does fade, it usually reappears rather quickly and will require additional attention. Topical corticosteroids are the primary treatment of AD.^8,9 Emollients are used during maintenance, while topical corticosteroids and immunomodulators are also used during intensive therapy.⁸ Some parents may consider nonpharmacologic methods of healing, while others may choose to take the pharmacologic approach to therapy.

Bathing and moisture have been used for several decades in the treatment of dry skin and have been shown to help improve the appearance of mild-to-moderate AD in children. The most common cause of flares in children with stable AD is improper moisturizing and bathing techniques (e.g., the timer for proper bathing technique is the wrinkled appearance of the fingertips).⁹ Chiang and Eichenfield found that applying moisture to the skin, whether immediately or 30 minutes after bathing, has the same effect on skin hydration of a child with eczema.⁸ Moisture can be provided with either topical corticosteroids or emollients. Ointments and creams are favored over lotions, but lotions are preferred during the summer months. The greasy feel of thick ointments and the luster they leave behind may discourage their use in children.⁹ An infant may experience rashes in specific areas due to chronic wetting and drying of these areas. A thick emollient barrier is helpful to maintain proper hydration of the skin of an infant or young child.⁹

Pharmacologic Therapies: Many parents may not realize at first that their child has AD, but once the condition is diagnosed, initial therapy with hydrocortisone cream is usually recommended.⁹ This will allow the rash to heal in some cases, while other cases will need something more potent to alleviate symptoms. There are two ways a dermatologist might want to approach this condition—start the child on step-up therapy or use a step-down approach.^9,10 Topical corticosteroids remain primary treatment for AD in children of any age.⁹ Usually, this consists of using different strengths of corticosteroid creams. High-potency topical steroids (class II) or oral steroids may be useful in adolescents with severe cases of AD (TABLE 1).¹¹ You may treat older children and adolescents with mild cases of AD with a low-potency (class VI or VII) topical steroid twice a day to decrease inflammation. Intermediate-potency steroids (classes III, IV, and V) may be used for moderate cases of AD to help control eczematous flares. Consequently, low-potency steroids can be used to prevent eczema from returning. High-potency steroids should not be used on the face, axillae, and groin areas because of increased absorption and increased local steroid side effects.¹¹

The administration of corticosteroids relieves flares in mild-to-moderate eczema.¹² While steroids are helpful in the treatment of AD in children, there are several side effects that caregivers should watch for in the early years of life. Skin thinning and possible hypothalamic-pituitary-adrenal (HPA) axis suppression remain the major side effects of corticosteroids.^9,13,14 Many parents may not understand the difference between the side effects of the medication and the signs of eczema. Hypopigmentation is seen in a majority of AD cases and should be recognized as a part of the skin condition and not a side effect of the medication.⁹ Although topical corticosteroids have questionable side effects in children, their use is widely approved as treatment because it is proven to be effective (TABLE 1).¹¹

The calcineurin inhibitors tacrolimus and pimecrolimus are two fairly new medications used in the treatment of AD. Unlike corticosteroids, their use is only warranted for children older than 2 years of age for short-term or intermittent long-term use.⁹ They can be used for acute exacerbations and usually for moderate-to-severe AD.¹⁵ Stinging and burning at the site can be a major side effect when dealing with small children who are already irritated and bothered by the pain of their eczema.^9,16 The use of these immunomodulators may not be considered in some children if this effect proves to be a problem.

Research has also been conducted to determine if malignancies are formed due to immunomodulators. A black box warning is now attached to these medications stemming from reports of cancer or cancer-related adverse events following their use.^9,16 The exact exposure in terms of the population-based incidence rates, dosage, and duration of treatment is not known. A systematic review by Callen et al provided information to confirm that there is a higher ratio of cancer-related events following the use of pimecrolimus than of tacrolimus in children.¹⁶ Tacrolimus 0.03% ointment is recommended for children aged 2 to 15 years twice daily, with the 0.1% formulation reserved for adults. Pimecrolimus is available as a 1% cream for children ≥2 years twice daily.¹⁶

There has been some debate as to whether tacrolimus and pimecrolimus can suppress the immune system. A study by Hofman et al concluded that if immunosuppression is a side effect of this medication, it is not known to affect the generation of immune memory or humoral and cell-mediated immunity.¹⁵ During the early years of life, children undergo a series of immunizations, but the immunomodulators are not proven to interact with the process. While immunomodulators are effective in the treatment of AD, there is still some unknown information pertaining to their safety in small children. Therefore, these drugs should be considered as second-line agents in treatment of long-term therapy and not be used in children under the ages of 2 years.⁹

The colonization of Staphylococcus aureus is one of the most common aggravating factors of AD.¹⁷ Antibiotics may be very helpful in the treatment of patients who are heavily colonized with S aureus. Patients with AD should reserve topical antibiotics for short-term use in obvious secondary bacterial infection. Topical antiseptics (e.g., triclosan, chlorhexidine, crystal violet) or antibiotic skin creams (e.g., mupirocin) are frequently prescribed to treat acute flares with clinical signs of bacterial impetiginization.¹⁸ Localized involvement should respond to topical therapy with mupirocin 2% applied 3 times a day for 10 days.⁹ Widespread skin lesions may require systemic therapy (cephalexin 25-50 mg/kg tid for 5-10 days).⁹

Antihistamines may be effective in small children to help alleviate itching during the night.⁹ Sleep loss as a result of itchiness may benefit from a sedating antihistamine such as hydroxyzine 1 mg/kg. Nonsedating antihistamines can be used during the day to help children who also suffer from allergic rhinitis.⁹

Conclusion

Atopic dermatitis is a chronic inflammatory skin disorder that affects children and may lead to significant disruption in quality of life. Although there are medications that have been proven to help AD, there is still no cure. Research remains ongoing to determine the exact mechanism of this disease. Until a cure is discovered, physicians, dermatologists, patients, and parents should work together to control the flares of AD and maintain a healthy skin barrier.

REFERENCES

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