Growth retardation in children with Atopic Dermatitis

TABLE OF CONTENTS

LIST OF TABLES

ABSTRACT

INTRODUCTION

REVIEW OF LITERATURE
ATOPIC DERMATITIS
EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
EXACERBATING FACTORS FOR ATOPIC DERMATITIS
HISTOPATHOLOGY OF ATOPIC DERMATITIS
DIAGNOSIS OF ATOPIC DERMATITIS
DIFFERENTIAL DIAGNOSIS18 OF ATOPIC DERMATITIS
COMPLICATIONS OF ATOPIC DERMATITIS
GROWTH IMPAIRMENT
ASSESSMENT OF GROWTH

OBJECTIVE

OPERATIONAL DEFINITIONS
ATOPIC DERMATITIS
SEVERITY
GROWTH RETARDATION

MATERIAL AND METHODS
SETTING
DURATION OF STUDY
SAMPLE SIZE
SAMPLING TECHNIQUE
STUDY DESIGN
SAMPLE SELECTION
DATA ANALYSIS

FREQUENCY OF GROWTH RETARDATION IN CHILDREN WITH MODERATE TO SEVERE ATOPIC DERMATITIS

RESULTS

DISCUSSION
CONCLUSION

REFERENCES

Annexure 1

Annexure 2

LIST OF TABLES

i. Table 1: Demographic data

LIST OF FIGURES

i. Figure 1: Age distribution

ii. Figure 2: Sex distribution

iii Figure 3: Height distribution

iv Figure 4: Weight distribution

v Figure 5: Comparison of normal and growth retarded children

vi Figure 6: Comparison of growth retardation between moderate and severe atopic dermatitis

vii Figure 7: Comparison of growth retardation in male and female

LIST OF ABBREVIATIONS

Abbildung in dieser Leseprobe nicht enthalten

ABSTRACT

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disorder, associated with significant morbidity. One of the complications associated with AD is growth retardation. Objective: The objective of this study was to determine the frequency of growth retardation in children with moderate to severe atopic dermatitis.

Study Design: Cross sectional survey

Setting: WAPDA Hospital, Lahore, a 300 bedded facility

Method: Forty children with AD fulfilling the inclusion criteria were entered in the study. Height was recorded, in centimeters, using infantometer in children ≤ 3 years and with stadiometer in patients > 3 years. Weight was taken, in kilograms, using Tanita baby scale for children ≤ 3 years and Bath room weighing scale for patients > 3 years. Growth charts were selected according to age and gender of patients. Measurements and percentile ranks of patients were noted on appropriate charts, if they were below 3rd percentile on any of these charts, then child was taken as suffering from growth retardation. Results: Twenty five (62.5%) children had normal growth while 15 (37.5%) patients had growth retardation. Among these 15 retarded children, 9 (22.5%) were suffering from moderate disease and 6 (15%) had severe disease. Out of total 40 patients, 11 had severe disease and 6 (54.54%) of them were suffering from growth retardation, while 29 had moderate disease and 9 (31.03%) of them showed impaired growth. Nine (22.5%) of patients with growth impairment were female and 6 (15%) were male.

Conclusion: These results show growth retardation in children with atopic dermatitis. The frequency of growth impairment was relatively more in severe disease and among girls, as depicted by growth charts.

Keywords: Atopic dermatitis; Growth retardation; Growth chart; Lahore; Pakistan

INTRODUCTION

AD is a chronic, relapsing, inflammatory skin disorder which is characterized by itchy papules, vesicles, excoriations and lichenification.1 It is often associated with personal or family history of other atopic conditions such as asthma, allergic rhinitis or hay fever.2 Diagnosis is made clinically on the basis of history and examination.3 Genetic, environmental, skin barrier defects and immunological factors are involved in its pathogenesis.4

The prevalence of AD varies greatly in children, with less than 2% in China and Iran and upto 20% in northern and western Europe, Australia and the United States.5 AD is the most common type of eczema seen in children in Pakistan.6 About 70% cases of atopic dermatitis begin in children under 5 years.7

AD has profound impact on quality of life and causes significant morbidity. One of the complications associated with AD is growth impairment in affected children.8 In majority of cases aetiology of growth retardation is not clear, but atopy related imbalance in local growth factors like prostaglandin E2 (which is a substance important for both allergic reactions and bone metabolism), disturbed sleep and failure of nocturnal growth hormone release during stage 4 sleep can be postulated to impair growth in atopic children.9,10 Factors like topical, oral or inhaled steroids, co-existing asthma, unnecessary dietary restrictions and vitamin D deficiency may contribute.11,12

Growth retardation can be directly related to disease as it was seen in patients of AD before advent of corticosteroids.12 Association of allergic disorders with growth impairment, had been first described by Cohen et al in 1940.8 Since that time various studies have been carried out to support the fact. Massarano et al13 studied 68 children, aged 2-12 years, with AD at University of Manchester and found that mean height of 41 patients with less than 50% of surface area affected was normal while 27 children with more than 50% area affected were significantly shorter. Similarly, Dhar et al12 studied growth in 100 Indian children with moderate to severe AD and found that 42% of children had weight below 3rd percentile for age and 34% had height below 3rd percentile for age.

The importance of regular growth monitoring in children with AD needs to be emphasized, as if modifiable factors causing growth impairment are taken care of, it will have an impact on overall patient management. There is lack of data on growth pattern of Pakistani children afflicted with AD.

REVIEW OF LITERATURE

ATOPIC DERMATITIS

Definition

AD is a chronic, relapsing inflammatory skin disorder, characterized by itchy skin lesions and personal or family history of other atopic diseases, including asthma and allergic rhinitis.1

Atopy

In 1923, Coca and Cooke introduced the term ‘atopy’ to describe the clinical presentation of type 1 hypersenstivity reactions that exhibit a strong familial predisposition and are associated with elevated IgE levels. The common clinical manifestations of atopy include AD, asthma, hay fever, urticaria and food allergies.1, 14

EPIDEMIOLOGY

AD is a common disease, affecting 15 to 30% of children and 2 to 10% of adults. Different studies demonstrate a definite trend towards the increase in AD cases, particularly in industrialized nations over the past few decades.15, 16 The prevalence of AD varies greatly, with less than 2% in China and Iran and upto 20% in northern and western Europe, Australia and the United States.5 AD is the most common type of eczema seen in children in Pakistan.6

ETIOLOGY AND PATHOGENESIS

A complex interaction of genetic and environmental factors are believed to induce immunological changes, that result in inflammation of skin.17

Genetic Factors

Atopic dermatitis is a complex genetic disease that arises from gene–gene and gene–environment interactions. The disease results from abnormalities in genes encoding epidermal structural proteins or major elements of the immune system. AD runs in families, with a strong maternal influence. The concordance rate for AD is higher among monozygotic twins than the dizygotic twins.18 The prevalence of AD in children is about 50% when one parent has AD, while it may be as high as about 80% when both parents have the disease.19 A number of genes related to AD have been identified, including genes on chromosomes 1q21, 3p26, 5q31-33, 13q21, 16p11.2-12, 17q11, 17q25 and 20p.15 Genetic aberrations may result in predominance of Th2 cytokines, increase IgE synthesis, defective epidermal barrier proteins or imbalance between proteases versus protease inhibitors activity, contributing to inflammation.15, 18

Immunologic Abnormalities

In response to various allergens, AD patients are genetically prone to produce high levels of IgE.20 The major disturbance in immune regulatory system that results in this IgE production appears to be the differentiating pathway of helper T cells towards Th2 type cells. The precursor Th0 cells have the potential to differentiate into either Th1 or Th2 type cells, depending upon the signal they receive during interaction with dendritic antigen presenting cells. Th1 cells help in cell mediated immunity; while Th2 cells help B cell function and results in antibody mediated immunity.1 Epidermal-barrier dysfunction is a prerequisite for the penetration of high-molecular-weight allergens in pollens, house-dust-mite products and microbes. Langerhans' cells are activated on binding of allergens by means of specific IgE receptors and present antigen to Th0 cells. There is the genetic predisposition of atopics to demonstrate predominance of Th2 cells activity over Th1 cells, leading to releases of interleukin-3 (IL-3), IL-4, IL-5, IL-10 and IL-13, which produce eosinophilia in tissue and peripheral blood and increased IgE production, resulting in inflammatory response.15, 21, 22

Prostaglandin E2 (PGE2) concentration is also increased in atopics, which also directs differentiation into Th2 type cells. Tissue specificity of the Th2 cell response is explained by cutaneous lymphocyte antigen expression on circulating T cells that specifically home to the skin17.

Chronic AD lesions principally have a Th1 response with the cytokines IL-12 and interferon-γ playing a dominant role.17

Defective Skin Barrier Function

As a part of innate immune system of body, skin is the first line of defense. In AD this barrier function of skin is disrupted through the following:

- Loss of function mutation of epidermal barrier protein, filaggrin
- Reduced ceramide level
- Increased level of endogenous enzymes in skin
- Down regulation of antimicrobial peptides

This impaired barrier function of atopic skin allows greater absorption of allergens, triggering the release of pro-inflammatory mediators.17, 18, 23

Loss of Function Mutation of Filaggrin

AD shows genetic linkage to Chromosome 1q21. This region contains the epidermal differentiation complex, which consists of genes that form essential components of epidermal surface and filaggrin (FLG) is one of these. Loss of function mutations of FLG have been identified in AD, which results in defective skin barrier in these patients.24-28

Profilaggrin is found in the keratohyalin granules in the stratum granulosum. It is dephosphorylated and proteolytically cleaved to FLG during terminal differentiation of the granular cells. FLG then aggregates keratin filaments, which collapse the granular cells into anuclear squames. The cytoskeleton is then crosslinked by trans-glutaminases to form the cornified cell envelope of the stratum corneum, which is the outer most barrier of skin. Moreover, breakdown products of FLG contribute to the water-binding capacity of the stratum corneum.24-28

Reduced Ceramide Level

Stratum corneum lipids are an important determinant for both water retaining and permeability-barrier function in the stratum corneum. Abnormalities in lipid metabolism with reduced synthesis of ceramide may lead to decreased water-binding capacity of skin. Essential fatty acids (EFA's), such as linoleic and linolenic acid, are important components of the epidermal barrier. In atopic dermatitis, Δ 6 -desaturase activity is deficient, which leads to decreased linoleic and linolenic acid metabolites. Loss of EFA's results in increased transepidermal water loss and subsequent xerosis. Dryness causes microfissures on the skin surface that promotes entry of irritants, allergens and microbes.22, 29

Increased Levels of Endogenous Enzymes in Skin

There are increased levels of endogenous protease enzymes in stratum corneum of AD patients, which break down cellular adhesions, leading to epidermal barrier dysfunction.30

Down Regulation of Antimicrobial Peptides

Skin, the first line of defense of the innate immune system, constantly challenged by microbes, have a variety of sensing structures, which include the toll-like receptors, that bind to bacterial, fungal or viral structures and activates epithelial cells to produce antimicrobial peptides known as defensins, cathelicidins, dermicidin and sphingosine. In the case of infection or injury, antimicrobial peptide expression in the skin is upregulated due to increased synthesis by keratinocytes and deposition from degranulation of recruited neutrophils. The inflammatory cytokines, IL-4, IL-10 and IL-13 down regulates these antimicrobial peptides in the skin of patients with AD, resulting in decreased resistance to bacterial, viral and fungal infections.31-34

Autoimmunity in Atopic Dermatitis

Patients with atopic dermatitis often have elevated serum IgE levels and sensitization against a variety of environmental allergens, but there is also evidence that exacerbation of the disease occurs in the absence of exposure to external allergens. The IgE antibodies against keratinocytes and endothelial cells are also found in serum of patients with severe AD. These intracellular proteins, which are released as a result of scratching could mimic microbial structures and induce IgE mediated immune response against self proteins, resulting in inflammation.15

Abnormalities in Sweating

Sweating is an important trigger of pruritus in AD. This may be due to neuropeptides released in neurogenic control of sweating and IgE mediated allergic reaction to components of sweat. There is altered response to neurogenic stimuli in atopics and increased number of nerve fibers has been found around the sweat glands in their skin.1

Abnormal Vascular Reactivity

The small blood vessels in atopics show abnormal vascular reactivity and vasoconstriction responses as:1

- White dermographism (Pallor of skin after stroking)
- Delayed blanch phenomenon with acetylcholine
- Marked vasoconstriction on cold exposure and low finger temperature
- Abnormal response to histamine
- White reaction to nicotinic acid esters

Hygiene Hypothesis

AD is a fairly common problem, which in the past half century, has become more prevalent. This increase in atopic diseases has been rationalized by a "hygiene hypothesis," which attributes the propensity towards the atopy associated diseases due to reduced microbial exposure in early life, especially in developed countries. Early life exposure to environmental microbes may cause maturation of the immune system so that dysregulation associated with production of IgE antibody does not occur and this could explain the difference between the western and the developing world regarding the incidence of atopic dermatitis.35-38

EXACERBATING FACTORS FOR ATOPIC DERMATITIS

1. Irritants and Contactants

The skin of patients with AD is very sensitive and vulnerable to irritants. Hot water, soaps, toiletries containing alcohol, astringents, or fragrances, cigarette smoke exposure, enzyme rich laundry detergents, disinfectants, clothing made with synthetic fibers or wool, and juice from fresh fruits such as tomatoes, strawberries and occupational irritants may trigger the itch-scratch cycle.1,14, 22

2. Airborne Allergens

House dust mite, pollens, moulds, animal dander can aggravate atopic dermatitis.1

3. Foods

Dairy products, beef, eggs, chicken, fish, wheat, citrus fruits, food additives, chocolate and nuts, vasodilatory agents, such as alcohol, spices, and hot drinks, histamine-containing foods such as cheese, very ripe vegetables as tomatoes and red wines are common food allergens.1,14

4. Microorganisms

Staphylococcus aureus can aggravate AD, and there is usually its overpopulation in atopic patients. The organism is able to induce formation of IgE antibodies and superantigen reactions. Anti staphylococcal therapy can improve AD. In head and neck dermatitis, IgE antibodies to Malassezia furfur can sometimes be demonstrated.1

5. Hormones

Exacerbations and remissions in pregnancy, menopause, menses has been noted.22

6. Stress

Situations of anxiety, depression, family or work maladaptation may prolong AD and in such situations, neuropeptides are released which exacerbate itching.22

7. Climate

Most patients with AD are aware of seasonal variations; disease may improve in summer and worsen in winter. However, heat and exercise induced sweating can trigger AD at anytime of the year.1, 22

MECHANISM OF PRURITUS

The most disturbing symptom of AD is pruritus, which impairs patient’s quality of life. Atopics have an inherently lowered threshold for itching and perceive light mechanical stimuli as itch and not as touch, a phenomenon called allokinesis. Cutaneous free nerve endings in patients with AD appear to be structurally normal, but the density and diameter has been found to be much higher than in normal controls.22 The effects of therapeutic agents on itching also help us understanding the mediators of pruritus, as the lack of effect of antihistamine argues against the role of histamine, while effectiveness of ciclosporin, capsaicin, opioid antagonist indicate the role of cytokines, neuropeptides and opioids in itching related to AD respectively. Proteases, kinins, and acetylcholine also play a part in pruritus.1, 39

Several stimuli are known to trigger the pruritus of AD, common triggers that induce itching in these patients include heat, sweating, wool, xerosis, irritants as soaps, detergents, disinfectants, contact with certain foods, occupational chemicals, emotional stress, alcohol, upper respiratory infections, aeroallergens, cutaneous microbial infections and hormones.14

CLINICAL FEATURES

The diagnosis of AD is made clinically on the basis of history and examination. The UK refinement of Hanifin and Rajka's diagnostic criteria is usually applied for diagnosing patients. According to this criteria the child must have:1

- an itchy skin condition (or parental report of scratching or rubbing in a child) Plus 3 or more of following׃
- Onset below 2 years (not used if child is under 4 years)
- History of skin crease involvement (and/or cheeks in children under 10 years)
- History of generally dry skin
- Personal history of other atopic disease (or history of any atopic disease in a first degree relative in children under 4 years)
- Visible flexural dermatitis (or dermatitis of cheeks/ forehead and outer limbs in children under 4 years)

In addition to these diagnostic points, the patients with atopic dermatitis may have following clinical features:19

- Anterior subcapsular cataract
- Dennie-Morgan infraorbital fold
- Keratoconus
- Orbital darkening
- Recurrent conjunctivitis
- Cheilitis
- Facial pallor or facial erythema
- Ichthyosis
- Palmar hyperlinearity
- Keratosis pilaris
- Itch when sweating
- Nipple eczema
- Perifollicular accentuation
- Pityriasis alba
- Tendency toward cutaneous infections (especially Staphylococcus aureus and herpes simplex) or impaired-cell mediated immunity
- Tendency toward nonspecific hand or foot dermatitis
- White dermatographism or delayed blanch to cholinergic agents
- Food intolerance
- Intolerance to wool and lipid solvents

Approximately 45 percent of cases of AD begin within the first 6 months of life, 60 percent develop their disease during the first year and 85% begin before 5 years of age.15

There are three phases of AD according to age of onset1:

1. Infantile phase
2. Childhood phase
3. Adult phase

1. Infantile Atopic Dermatitis

Atopic dermatitis develops from 2 months to 2 years of age.19 Eruption is more acute and usually starts on face and later on extensor surfaces are involved, as child begins to crawl. The diaper area is usually spared.1

2. Childhood Atopic Dermatitis

AD develops from 2 to 10 years of age.19 The most common sites involved are the antecubital fossae, popliteal fossae, wrists, ankles, and sides of neck.1

3. Adult Atopic Dermatitis

The clinical picture of AD in adults is similar to childhood phase, with lichenification, especially of flexural surfaces and hands. In young atopic women, localized patches of eczema may involve the nipples.1

Pruritus is the hallmark of the disease in all stages. AD is “the itch that rashes˝. Lesions of AD may be acute, subacute or chronic. In acute eczema, erythematous papules, plaques, vesicles, serous exudation and excoriations are present. Subacute eczema is characterized by scaly, erythematous, excoriated papules and plaques, while in chronic dermatitis lichenified plaques forms.14

HISTOPATHOLOGY OF ATOPIC DERMATITIS

The histopathology shows non specific changes of hyperkeratosis, acanthosis, spongiosis, dermal oedema and infiltration with lymphocytes, histiocytes, plasma cells and eosinophils.1

DIAGNOSIS OF ATOPIC DERMATITIS

The diagnosis of AD is made clinically; skin biopsy and other tests are of little value in this regard. Skin-prick, radioallergosorbent tests and serum IgE levels may be useful for assessing the contribution of foods and environmental allergens to disease expression in children with severe disease. Serum IgE levels are normal in about 20 percent of atopic patients. Patch test may be helpful in excluding superimposed allergic contact dermatitis.1

If immunodeficiency is suspected in a child, then immunoglobulin and complement levels & functions, white blood cells, platelets, T lymphocytes, B lymphocytes and phagocyte cells counts & functions should be assessed.1

DIFFERENTIAL DIAGNOSIS18 OF ATOPIC DERMATITIS

Most likely

- Contact dermatitis
- Seborrheic dermatitis
- Scabies
- Psoriasis
- Ichthyosis vulgaris
- Keratosis pilaris
- Dermatophytosis
- Impetigo
- Drug reaction
- Pityriasis alba
- Nummular eczema

Less common/Rare (Predominantly in infants/children)

Metabolic/Nutritional

- Zinc deficiency
- Phenylketonuria

Primary immunodeficiency disorders

- Severe combined immunodeficiency
- DisGeorge syndrome
- Hypogammaglobulinemia
- Agammaglobulinemia
- Wiskott-Aldrich syndrome
- Ataxia talengiectasia

Genetic syndromes

- Netherton syndrome
- Hurler syndrome

Others

- Neonatal lupus erythematosus
- Langerhans cell histiocytosis

Less common/Rare (Predominantly in adolescents and adults)

- Cutaneous T cell lymphoma
- Human immunodeficiency virus associated dermatoses
- Lupus erythematosus
- Dermatomyositis
- Graft versus host disease
- Pemphigus foliaceus
- Dermatitis herpetiformis

COMPLICATIONS OF ATOPIC DERMATITIS

Ocular Complications

Eyelid dermatitis, chronic blepharitis, keratoconjuctivitis, uveitis, keratoconus, subcapsular cataract, corneal scarring and retinal detachment are the ocular complications seen in these patients.40-43

Infections

AD can be complicated by recurrent viral infections due to defective local T cell function. The most serious is herpes simplex, resulting in eczema herpeticum. Multiple umblicated vesiculopustular lesions forms.44, 45 In head and neck dermatitis, IgE antibodies to Malassezia furfur can sometimes be demonstrated.46,47 Staphylococcus aureus aggravates AD, and there is usually its overpopulation in atopic individuals. The organism is able to induce formation of IgE antibodies and superantigen reactions.48, 49

Exfoliative Dermatitis

AD may be complicated by exfoliative dermatitis, which is characterized by generalized erythema, scaling, crusting, weeping and constitutional symptoms. It is usually due to superimposed Staphylococcus aureus or herpes simplex infection.18

Psychosocial Effects

AD has a significant affect on quality of life secondary to stigmatization of the condition, psychological stress, lack of sleep secondary to pruritus and pain and effects on social and financial well being.1

GROWTH IMPAIRMENT

AD can be complicated by growth retardation in affected children, therefore regular growth assessment is an integral part of child care.1

Physiology of Growth

Growth is a dynamic and complex physiological process that starts with the fertilization of the ovum and is completed with the fusion of epiphyses and metastases of the long bones, marking the completion of adolescence. Growth occurs in phases, which are influenced mainly by genetic factors, thyroid hormone, cortisol, growth hormone (GH), insulin like growth factor-1(IGF-1), nutritional status and vitamin D.50

There are 4 phases of human growth: 50

Fetal Phase

It is dependent on placental nutritional supply, which in turn affects fetal growth factors, as insulin like growth factor-2 (IGF-2), human placental lactogen and insulin. Intrauterine growth retardation can result in short stature.50, 51

Infantile Phase

It is influenced by nutrition and normal thyroid function.50

Childhood Phase

Growth hormone secretion from pituitary gland is the main determinant of child's rate of growth, which mediates its effect by producing IGF-1 at epiphyses of bone. Along with this, good nutrition, thyroid hormone, vitamin D and steroids also affect growth.50

Pubertal phase

Sex hormones, mainly testosterone and oestradiol, play an important role in GH secretion and growth at puberty.50

CAUSES OF GROWTH RETARDATION52, 53, 54

Non-Organic/ Environmental

- Poor nutrition
- Psychosocial problems
- Neglect or child abuse55

Organic

- Impaired suck/swallow (cleft palate, cleft lip)
- Chronic diseases (Crohn΄s disease, cystic fibrosis, chronic renal failure, congenital heart disease, thyrotoxicosis, liver disease, severe asthma)
- Malabsorption (Celiac disease, cystic fibrosis, cow's milk protein intolerance, short gut syndrome)
- Chromosomal disorders e.g. Down's syndrome
- Intrauterine growth retardation, prematurity
- Congenital infections
- Chronic infections e.g. tuberculosis, HIV,56,57 parasitic infestation
- Metabolic disorder (Thyrotoxicosis, congenital hypothyroidism, growth hormone deficiency, diabetes insipidus, diabetes mellitus, adrenal insufficiency)
- Malignancy
- Neurological (cerebral palsy, central nervous system tumors, neuromuscular or neurodegenerative disorders)
- Collagen vascular disorder
- Primary immunodeficiency
- Transplantation
- Adenoid/ tonsillar hypertrophy
- Inborn error of metabolism (Organic acidosis, storage disease)
- Sickle cell disease

PATHOGENESIS OF GROWTH RETARDATION IN ATOPIC DERMATITIS

One of the complications associated with atopic dermatitis is growth impairment in affected children, which may be attributed to following factors:1, 9, 58

- Decreased nocturnal growth hormone release
- Dysregulation of prostaglandin E2
- Hypoproteinemia
- Food allergy and unnecessary dietary restriction
- Coexisting asthma
- Corticosteroid therapy
- Severity of disease

Decreased Nocturnal Growth Hormone Release

GH is secreted from anterior pituitary. It is a major determinant of growth and metabolism and mediates its effects on target cells primarily by IGF-I, that is secreted from the liver and other tissues in response to growth hormone. IGF-I acts via activation of the IGF-I receptor. This receptor is widely distributed, which enables it to coordinate balanced growth among multiple tissues and organs, stimulating proliferation and differentiation of chondrocytes, myoblasts and protein synthesis. Deficiency in GH or defects in its binding to receptor are clinically manifested by growth retardation or dwarfism.59-62

Secretion of GH is affected by many factors, including stress, exercise, nutrition and sleep. Growth hormone secretion is also controlled by various hormones, such as growth hormone-releasing hormone (GHRH), a hypothalamic peptide and ghrelin from the stomach, stimulates its secretion, while somatostatin inhibits growth hormone release. GH is mainly secreted at night, shortly after the onset of deep sleep.59, 63

Sleep is an important physiological process, which is regulated by various cytokines and hormones. Altered sleep can also in turn affect their expression. GHRH promotes non-rapid eye movement sleep, while ghrelin and pro-inflammatory cytokines, such as IL-1 and TNF-α increase slow wave sleep and anti-inflammatory cytokines, such as IL-4 and IL-10 inhibit sleep.59, 64 Sleep deprivation also tends to alter various cytokines expression, as loss of sleep decreases the nocturnal IL-6, which is a potent stimulator of hypothalamic pituitary axis, causing adrenocorticotrophic hormone (ACTH), cortisol and GH release.65, 66 As it is hard for atopic dermatitis children to have a deep sleep since they frequently wake up at night to itch67, 68, they are unable to release GH after falling asleep.69,70 Ghrelin levels are also affected by sleep deprivation in atopics, so resulting in impaired growth hormone release.71

The release of growth hormone and its effects may also be influenced by poor nutrition. Fibroblast growth factor 21 (FGF21), a hormone induced by fasting, causes GH resistance. FGF21 decreases the formation of the active form of signal transducer and activator of transcription 5 (STAT5) in liver, which is a major mediator of GH actions, and causes corresponding reduction in the expression of its target genes, including insulin-like growth factor 1 (IGF-1), and results in growth stunting. Patients with atopic dermatitis may have food allergy or on unnecessary dietary restriction, which may result in poor nutrition and growth impairment.72

The secretion of GH is also affected by stress, and atopic patients are known to suffer from psychological stress due to their disease, which can impair growth of child.1, 60

Dysregulation of Prostaglandin E2

Atopy related imbalance in local growth factors like prostaglandin E2 (PGE2), which is a substance important for both allergic reactions and bone metabolism, can also be a factor responsible for growth failure in children with atopic dermatitis. Prostaglandins are important regulators of bone metabolism. They stimulate bone remodeling, which depends on the target cell population, concentration of PGE2 and its receptors. It might have an inhibitory effect on bone metabolism under pathological conditions when PGE2 is present in high concentrations and for long periods73. The secretion of PGE2 is increased in AD due to persistent macrophages activation, the resulting abnormality in the production of PGE2 in atopics, may impair growth of child.9, 22

Hypoproteinemia

Children suffering from extensive AD fail to thrive, because of hypoalbuminaemia. Severity of disease is a risk factor for hypoproteinemia in AD, as large amounts of protein rich exudate is lost through the skin, at a rate that outstrips the synthesis of proteins. Food allergy can also result in decrease dietary intake and loss through gastrointestinal tract, resulting in hypoproteinemia.74, 75

Food Allergy and Unnecessary Dietary Restriction

Atopic patients may have allergy to certain foods, which may aggravate their disease. The prevalence of food allergy in patients with atopic dermatitis varies with the age of the patient, as it is more common in younger children than in older children and adults.1 Dairy products, beef, eggs, chicken, fish, wheat, citrus fruits, food additives, chocolate and nuts, vasodilatory agents, such as alcohol, spices, and hot drinks, histamine-containing foods such as cheeses, very ripe vegetables such as tomatoes are common food allergens. Food allergy can be confirmed by food challenge test or by measuring specific IgE or prick testing. If there is a clearly identified aggravating factor in food, elimination of relevant dietary agent can lead to improvement in skin symptoms, but unnecessary dietary restrictions may cause malnutrition and growth failure in child.1, 14

Coexisting Asthma

Other allergic disorders of atopic diathesis such as asthma and allergic rhinitis, are also found to impair growth due to change in local growth factors PGE2 and IGF-1. So coexisting asthma or allergic rhinitis may further increase the risk of growth failure. Early onset, duration and severity of disease, hypoxemia, chronic anorexia and use of corticosteroids may be the precipitating factors for growth retardation in asthmatics.76

Corticosteroids

Growth impairment is a side effect of high-dose glucocorticoid therapy in childhood, when given in supraphysiological doses. Corticosteroids impair release of growth hormone and decreased activity of IGF-1 in growing bones. In proliferative chondrocytes, GH, parathyroid hormone (PTH) and 1, 25-dihydroxyvitamin D [1α, 25(OH)2 D3] stimulates growth through secretion of IGF-I. Corticosteroids decrease GH, PTH or 1α, 25(OH)2 D3 stimulated cells growth by reducing basal and hormone-stimulated IGF-I secretion. It also reduces levels of GH and the expression of the GH and IGF- I receptors.77, 78

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