Medications for Allergy

Cough is one of the most common reasons for physician office visits. The majority of cough is self-limiting and often treated symptomatically. In some epidemiologic surveys, however, up to 18% of the population has a persistent cough. If the cough persists for longer than 8 weeks, it is considered a chronic cough. When this occurs, a more comprehensive approach needs to be taken to discern the etiology of the cough. Allergic diseases, also known as atopy, are among the chief causes of cough. Atopy is the sixth leading cause of chronic disease in the United States. Thus, it is important to understand how allergic diseases can cause cough.

Definition and physiology

Cough is a protective mechanism to expel offending agents from the respiratory tract. The mechanics of cough can usually be characterized into four phases:

1.  Inspiration

2.  Compression (expiration against a closed glottis)

3.  Expulsion (opening of glottis with expulsive airflow)

4.  Recovery (restorative inspiration)

This combination of actions is orchestrated by an extensive neuron network. Involuntary cough is primarily initiated by the vagus afferent nerves. The pharynx is innervated by the glossopharyngeal nerve and a branch of the superior laryngeal nerve. The larynx is innervated by the superior and recurrent laryngeal nerves, which join the vagus nerve. The trachea and bronchi are innervated by three types of nerve fibers called rapid adapting receptor, slowly adapting stretch receptor (seasonal allergic rhinitis), and C fibers. RARs are triggered mainly by mechanical stimuli and some inflammatory mediators. SARs are nerve fibers that inhibit inspiration. C fibers are triggered primarily by noxious chemicals and some mechanical irritants.

Causes of cough

Symptomatic treatment of cough

The goal in treating cough is always to find the etiology. However, symptomatic relief is needed if the source of the cough is unknown or the treatment of the underlying process requires a prolonged course. Usually, the medications are divided into peripheral and central acting agents.

First-generation antihistamines have some local anti-cholinergic effects in the nasal passages and seem to have some consequence in reducing cough symptoms for upper respiratory tract infections. Inhaled iprat-ropium bromide also has peripheral cough suppressing effects for upper respiratory tract infection and COPD. Interestingly, other anti-cholinergic inhalers do not seem to have the same effect. In some studies, guaifenesin, an expectorant, decreases symptom of cough in upper respiratory tract infection and bronchiectasis.

The central acting cough suppressants are believed to act on the brainstem. Dextromethorphan is the most commonly used nonsedating, nonaddicting agent.

Codeine and other opioids have modest effects on chronic bronchitis cough. Some studies suggest codeine is not very effective for upper respiratory tract infections.

Conclusion

Cough can be a common presentation for many diseases. Because allergic diseases can affect up to 25% of the general population, atopy should always be a consideration in the differential diagnosis of cough. Allergic diseases play a significant part in upper airway cough syndrome (postnasal drip) and asthma, which are the two most common causes of cough. The advent of modern allergy medications has allowed for a powerful way of teasing out the atopic component of cough. It can be used as a diagnostic tool as well as a therapeutic treatment. Having the patient assign a percentage of effectiveness to the different medications can help distinguish between the primary and secondary causes. Thus, integrating therapeutic trials with the history and diagnostic testing can help elucidate the complex etiologies of cough.

Evidence-based medicine

Hartl D, Griese M, Nicolai T, et al. Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough.

This study attempts to use bronchioalveolar lavage fluid chemokines and their receptors to distinguish between children with allergic asthmatic cough from children with chronic nonatopic cough. A total of 37 children were sampled: 12 patients with allergic asthmatic cough, 15 patients with idiopathic nonatopic chronic cough, and 10 healthy control patients, ranging from ages 3 to 17. The allergic asthmatic children had a significantly higher level of CCR4⁺CD4⁺ cells (TH2), thymus- and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) as compared to the nonatopic chronic cough children and control. In the nonatopic chronic cough group: CXCR3⁺CD8⁺ cells (TH1) and levels of IFN-gamma-inducible T cell alpha chemoattractant (ITAC) were significantly elevated as compared to the atopic asthmatics as well as the controls. This study helps validate the association of atopy and TH2 chemokines, providing a useful method for distinguishing atopic cough versus nonatopic cough.

This study tries to evaluate if there are unique characteristics of inflammation or remodeling as a result of asthmatic cough versus nonasthmatic cough. A group of 62 patients were subdivided into: 33 nonasthmatic chronic cough patients, 14 asthmatic cough patients, and 15 healthy controls. These patients underwent bronchoscopy with biopsies and had capsaicin cough sensitivity assessment. The group with nonasthmatic cough had significant mast cell hyperplasia, increased smooth muscle area, and increased cough sensitivity not seen in the asthmatic cough patients or the control. There was also a positive correlation between the increased cough sensitivity in relation to goblet cell hyperplasia and epithelial shedding. The asthmatic cough group had increased submucosal eosinophils and neutrophils. The results show that airway remodeling was prominent in nonasthmatic as well as asthmatic cough patients. This suggests that the chronic cough itself is the cause of the airway remodeling.

The causes of cough are numerous and can be multifactorial. The etiology of a cough can be sought out by a careful history, diagnostic tests, and response to treatment. The most common causes of cough are upper airway cough syndrome, previously known as postnasal drip syndrome, asthma, and gastroe-sophageal reflux disease.

The American College of Chest Physicians’ Evidence-Based Clinical Practice Guidelines concluded from four prospective studies that these three etiologies comprised greater than 92% of patients with cough (who had normal chest radiographs, were nonsmokers and not on angiotensin-converting enzyme inhibitors).

Upper Airway Cough Syndrome (Postnasal Drip Cough)

Upper airway cough syndrome, or postnasal drip syndrome, is the most common cause of cough. The physical drainage of nasal mucus down the posterior pharynx to the larynx and upper airway induces cough. Upper airway cough syndrome includes allergic, nonallergic, and infectious rhinitis. Note that the cough may be due to more than one of these etiologies. The strategy is to discern the primary and secondary causes. The history that suggests upper airway cough syndrome includes tickling of the throat, hoarseness, throat clearing, and congestion of the throat. This type of postnasal drip cough is often alleviated by drinking or eating. The action of swallowing causes the reflexive closure of the epiglottis. A closed epiglottis shunts the postnasal drip to the esophagus bypassing the posterior pharynx and larynx. This may be the main reason why taking a cough drop and drinking water both help relieve symptoms of cough.

Allergic Rhinitis and Cough

Allergic rhinitis affects as many as 20% to 25% of the population. It is defined as an inflammatory response of the nasal mucosa to airborne antigens. This action is mediated by an IgE antibody. Allergic rhinitis often presents as postnasal drip, nasal congestion, rhinorrhea, and eustachian tube dysfunction. Postnasal drip causes both mechanical and inflammatory mediators to trigger the cough reflex in the larynx and trachea.

Table. Respiratory innervations.

Table. Causes of cough.

The history attained from the patient can usually be subdivided into seasonal versus perennial symptoms. Patients who suffer from these symptoms in spring are affected by grass and tree pollen. Symptoms occurring during the fall are typically caused by weed pollen. The perennial symptoms are usually triggered by dust mites, animal proteins, and mold spores. Itching of the nose and eyes is the key symptom that distinguishes allergic rhinitis from other causes. Although sneezing is an associated symptom, it is not unique to allergic rhinitis. Sneezing can be due to infectious, mechanical, or chemical nasal irritation.

Physical examination findings that may help in ascertaining allergic rhinitis include the appearance of posterior pharynx “cobblestoning” and/or observation of mucus draining down the posterior pharynx. Tests such as allergy skin tests and the radioallergosorbent test (radioallergosorbent test) can help establish or rule out allergic causes. However, allergy testing alone without a clinically significant history will lead to an inaccurate diagnosis. Ultimately, the use of a daily intranasal corticosteroid for 2 weeks is the most practical solution for discerning allergic rhinitis from other causes. If symptoms improve, then the likely cause is allergic rhinitis. Asking the patient to assign a percentage of improvement with this therapy is helpful in modifying the treatment plan. If the patient is still symptomatic after using the intranasal corticosteroid, adjunctive therapy with a daily leukotriene receptor antagonist for an additional 2 weeks may be beneficial.

Nonallergic Rhinitis and Cough

A significant etiology of chronic cough that is often overlooked is nonallergic rhinitis with postnasal drip. It encompasses vasomotor rhinitis, nonallergic rhinitis with eosinophilia syndrome, rhinitis medicamentosa, and gustatory rhinitis. Nonallergic rhinitis is usually perennial, triggered by irritants, and has negative IgE allergy skin tests or radioallergosorbent test.

Vasomotor Rhinitis

Vasomotor rhinitis is defined as rhinorrhea, nasal congestion, and postnasal drip cough caused by nasal mucosal autonomic nerve instability or dysfunction. The autonomic nerve instability causes vasodilation and vascular leakage leading to mucosal edema as well as triggering an overproduction of mucus. The stimuli for vasomotor rhinitis usually consist of physical and chemical irritants. These common irritants include odors, smoke, fumes, changes in temperature, and changes in barometric pressure/humidity. A positive correlation between the patient’s history and exposure to the irritants is the key to diagnosing this entity. Avoidance of the offending agent, if possible, is the first course of action. However, if this is not possible, medications can serve as a diagnostic tool as well as a treatment option.

If nasal congestion is elicited in the patient’s history, the use of azelastine nasal spray two puffs per nostril twice a day for a 2-week trial would be in order. If the nonallergic rhinitis symptom is mostly rhinorrhea, then a 2-week trial of nasal ipratropium bromide, 0.03% or 0.06% one to two puffs per nostril up to four times a day, would reduce mucus production.

Nonallergic rhinitis with eosinophilia syndrome

Nonallergic rhinitis with eosinophilia syndrome occurs when eosinophils are found in the nasal mucosa. This syndrome has all of the symptoms of vaso-motor rhinitis with the addition of itching of the nose and eyes. The IgE allergy skin test or radioallergosorbent test is negative in nonallergic rhinitis with eosinophilia syndrome. A nasal swab for eosinophils is conducted with Hansel’s stain to help make the diagnosis. nonallergic rhinitis with eosinophilia syndrome is treated with an intranasal corticosteroid to inhibit the eosinophils and inflammatory mediators.

Rhinitis Medicamentosa

Rhinitis medicamentosa is defined as paradoxical nasal congestion due to the overuse of topical nasal vasoconstrictors (e.g., oxymetazoline). The long-term use of topical vasoconstrictors (typically alpha agonists) can cause tachyphylaxis or a need for more of the drug to maintain the effect that was initially attained with the medication. Withdrawal of the topical vasoconstrictor causes a rebound vasodilatory effect, which leads to nasal congestion. Associated with this phenomenon is a postnasal drip cough due to overproduction of mucus. The treatment is cessation of the topical nasal vasoconstrictor. It may take up to 2 weeks before the congestion resolves completely.

Gustatory Rhinitis

Gustatory rhinitis is rhinorrhea, nasal congestion, and/or postnasal drip caused by the act of eating or drinking. This is a vagal reflex that causes vasodilation of the nasal mucosa and an increase in mucus production. Rhinorrhea is the most common symptom, and ipratropium bromide nasal spray is the drug of choice. Again, if there is a nasal congestion component, azelastine may be helpful.

Infectious Rhinitis and Cough

Infectious postnasal drip cough can occur with viral infection, sinusitis, and/or from a postinfectious cause. Patients who have viral infections experience malaise, clear mucus drainage, nasal congestion, postnasal drip cough, myalgia, and sometimes fevers. Treatment using saline rinses, decongestants and mucolytics usually help resolve symptoms of cough in a couple of weeks. If coughing persists, bacterial sinusitis needs to be considered.

Bacterial sinusitis can be diagnosed with a history of purulent drainage that persists for longer than 10 days and sometimes with symptoms of maxillary tooth pain. Sinus radiographs or computed tomography scans tend to be the studies of choice. The common bac-terias associated with sinusitis are Streptococcus pneumonia, Haemophilus influenzae, and Moraxella catarrhalis in children. In chronic sinusitis, anaerobic bacteria may play a role. The treatment method should consist of a three-step approach:

1.  Decrease nasal mucosa swelling with intranasal corticosteroid with or without a short burst of oral steroids to allow for proper mucus drainage.

2.  Loosen up thick mucus with a mucolytic (e.g., guaifenesin).

3.  Neutralize the bacteria with the appropriate antibiotic (e.g., amoxicillin or penicillin alternative).

Acute sinusitis requires 2 weeks of treatment; chronic sinusitis requires 4 to 6 weeks of treatment. If a sinus radiograph or computed tomography sinus is positive, and the patient does not respond to antibiotics, fungal sinusitis needs to be considered. Fungal sinusitis requires surgical resection.

Postinfectious cough can comprise 11% to 15% of upper respiratory tract infections. This is the type of cough that lingers for longer than 3 weeks. It usually resolves before the eighth week of symptoms. The two organisms of interest are Bordetella pertussis and Mycoplasma pneumoniae. Although culturing or antibody titers can be attempted, a trial of an oral macrolide for 2 weeks would be the most practical course of action.

Angiotensin-Converting Enzyme Inhibitor Cough

With the rise of diabetes and hypertension in the general population, the use of angiotensin-converting enzyme inhibitors has become more prevalent. It can cause a persistent cough in up to 35% of its users. The mechanism is believed to be the inhibition of ACE, which normally degrades bradykinin and substance P. These mediators induce upper airway cough. This class of medications is unusual because the cough can occur much later after the initial use of the medication. The cough may take up to 3 months to resolve after discontinuation of the angiotensin-converting enzyme inhibitors.

Asthma and Cough

Cough is one of many symptoms associated with asthma. However, there tends to be an overdiagnosis of asthma as the cause of chronic cough. The definition of asthma can be elusive. Its most basic definition is hyperresponsive airway disease that is reversible. This hyperresponsive airway is driven most of the time by chronic inflammation of the bronchioles triggered by atopic, physical, or chemical irritation. The chronic inflammatory mediators then cause bronchial smooth muscle constriction and an overproduction of mucus that necessitates clearing the airway with coughing.

Although symptoms of cough, dyspnea, and wheezing may suggest asthma, the need for allergy skin tests/radioallergosorbent test, pulmonary function tests, and response to treatment are important. Spirometry with pre- and post-short-acting bronchodilator agents (e.g., albuterol) showing a forced expiratory volume in 1 second (FEV,) increase of greater than 12% and 200 mL is a practical approach to showing reversible airway disease. However, if the patient is not actively having bronchospasm, the spirometry may yield a normal result. A better and more definitive test is a methacholine challenge. This test induces airway reactivity if the patient has underlying asthma. Patients are given increasing sequential doses of methacholine, and spirometry is administered after every dilution. A provocative concentration that causes a 20% reduction from the baseline forced expiratory volume in the first second (PC20FEV,) or a decrease in specific conductance of 35% to 45% from the baseline at less than 16 mg/mL of methacholine is considered a positive methacholine challenge.

An adequate trial of asthma medications is the last step to diagnosing asthma, after having considered and treated upper airway cough syndrome and other potential causes of cough. An inhaled corticosteroid used on a daily maintenance schedule with or without a long-acting beta agonist is the drug of choice depending on severity. If the patient has a severe cough or shortness of breath, using a trial of pred-nisone, 40 mg once a day for 7 days, will help control the inflammation more efficiently. Leukotriene receptor antagonists can also be added later, if symptoms persist.

Cough Variant Asthma

Cough variant asthma is a subset of asthma that can present as cough alone with a normal physical examination and a normal spirometry. Patients with Cough variant asthma tend to have a more sensitive cough reflex but less bronchial reactivity when compared to classic asthmatics. A methacholine challenge may assist in confirming bronchial reactivity, but it does not necessarily establish the diagnosis of Cough variant asthma. The definitive diagnosis depends on resolution of symptoms after being treated with asthma medications.

Nonasthmatic Eosinophilic Bronchitis

Nonasthmatic eosinophilic bronchitis is a steroid responsive chronic cough found in nonsmokers who have sputum eosinophils without variable airflow obstruction. The sputum should contain a nonsquamous cell sputum eosinophil count of greater than 3%. Methacholine challenges in patients with no asthmatic eosinophilic bronchitis usually yield a normal result. It can be associated with occupational exposures as well as allergens. The treatment is avoiding offending agents and using asthma anti-inflammatory medications.

Gastroesophageal Reflux Disease and Cough

Gastroesophageal reflux disease frequently causes a persistent cough. It is defined as a retrograde movement of gastric material from the stomach to the esophagus. Common symptoms of gastroe-sophageal reflux disease include heartburn, regurgitation, sour taste in the back of the mouth, and coughing. In a normal individual, it can occur 50 times a day. Some studies suggest that the patient may not detect symptoms of gastroesophageal reflux disease 75% of the time.

Gastroesophageal reflux disease causes cough in two ways. Gastric material (frequently acid) can make its way up the esophagus to the larynx and cause direct irritation. However, this is not always necessary. Acid or other caustic agents (e.g., pancreatic enzymes or bile) can irritate the distal esophagus. This stimulation of the vagal reflexes can cause bronchoconstriction or cough. The diagnostic procedures that may be helpful are 24-hour esophageal pH monitoring and barium esophagography. The 24-hour esophageal pH monitoring is the most sensitive and specific test for measuring acid in the esophagus. However, by itself this test does not establish causation. Barium esophagography helps determine if there is an esophageal lesion from nonacid gastroe-sophageal reflux disease. Perhaps the most helpful information for diagnosing gastroe-sophageal reflux disease is a significant resolution of the persistent cough after a 1- to 3-month trial of antireflux treatment. The preferential choice of antireflux treatment is a proton pump inhibitor. This therapy would then be followed by changes in diet and lifestyle modifications to reduce acid production.

General considerations

The ear has multiple targets for allergic diseases. The external ear may be afflicted with contact dermatitis to earrings or hearing aid molds, eczema, or sensitization to ear drops or fungus. The middle ear may be plagued with persistent effusion secondary to eustachian tube dysfunction or chronic inflammatory response to allergens. The inner ear may be troubled by Meniere’s disease and cochlear hydrops, both disorders with possible allergic bases.

Allergic diseases of the external ear

Chronic Otitis Externa

The skin of the pinna and external ear may be afflicted in two major ways. Eczema of the auricle or external auditory canal may manifest as erythematous, scaling, and pruritic dermatitis. Atopic eczema is the most common type of eczema and closely associated with asthma and allergic rhinitis. The usual treatments are with emollients that maintain skin hydration and topical steroids to reduce inflammation. Another type of eczema seen is seborrheic eczema, which is most commonly seen on the scalp as dandruff but can spread to the face and ears. The condition is thought to be caused by yeast and can be treated with an antifungal cream if necessary. Chronic otitis externa that follows the use of topical antimicrobial drops, particularly those containing neomycin, can actually be a Cell and Coombs Type IV hypersensitivity reaction. Symptoms generally resolve with discontinuation of the offending agent; however, occasionally topical steroid drops may be needed to accelerate recovery.

Contact Sensitivity

Some patients may develop contact sensitivity to certain plastic molds attached to hearing aids. The problem manifests as a localized skin reaction. Boiling the hearing aid mold in water for 30 seconds, substituting a different material for the mold, or plating a thin film of gold onto the mold may reduce symptoms. Along this vein, patients may develop contact sensitivity to nickel and chromium in earrings. Treatment often involves use of earring posts of surgical stainless steel or 14-karat gold or titanium.

Dermatophytid Reaction

The auricle or external auditory canal can be the site of a dermatophytid reaction in a sensitized individual. Usually there is a primary site of fungal infection. The fungus or their aller-genic products spread hematogenously to a secondary site, causing an allergic skin eruption. Resolution requires treatment of the primary fungal infection, desensitization with an allergenic extract of the infecting fungus, and control of any secondary bacterial infections. The most common fungus involved is Trichophyton, although Candida (Oidiomycetes) and Epidermophyton have also been described. Common sites for the primary fungal infection include the nails (onychomycoses), skin, and vagina (monilial vaginitis).

Allergic diseases of the middle ear

Allergic diseases of the inner ear

Meniere’s Disease

Meniere’s disease is characterized by aural fullness, tinnitus, vertigo, and fluctuating sensorineural hearing loss. Two related variants are cochlear hydrops (fluctuating sensorineural hearing loss without vertigo) and vestibular hydrops (imbalance without fluctuating sensorineural hearing loss). The etiology of Meniere’s disease is unclear and has been attributed to anatomic, infectious, immunologic, and allergic factors. The target organ appears to be the endolymphatic sac. The mainstays of medical therapy have included diuretic therapy (particularly thiazide diuretics), carbonic anhydrase inhibitors, vasodilators, salt reduction (<1.5 g/day) and dietary restrictions. Surgical therapy is reserved for cases refractory to medical management. These include chemical labyrinthectomy (intratympanic aminoglycoside), surgical labyrinthectomy, endolymphatic shunt, and vestibular nerve section.

Both inhalant and food allergies have been linked with symptoms of Meniere’s disease and cochlear hydrops. Patients with Meniere’s disease have a 40% rate of allergy, as measured by skin or in vitro testing, which is twice as high as that reported for the general population. The success of sedating antihistamines in the treatment of Meniere’s disease is usually attributed to vestibular suppressant effects, but allergic reaction suppressant properties may also contribute to clinical improvement. Dietary restrictions on sodium, caffeine, nicotine, alcohol, and foods containing theophylline (e.g., chocolate) improve symptoms in patients with Meniere’s disease, although the mechanism has usually been attributed to fluid regulation of the endolymphatic sac. Regardless, immunotherapy and food elimination diets have mitigated both allergic and labyrinthine symptoms in Meniere’s disease.

Evidence-based medicine

Studies over the last few years have focused on the possible roles of allergy in Otitis media with effusion. Allergic rhinitis and nasal/nasopharyngeal inflammation resulting in Eustachian tube dysfunction is associated with increased rates of Otitis media with effusion. Allergy-related mediators (IL-4, IL-5, IL-6, regulated on activation, normal T-cell expressed and secreted [RANTES], eosinophil cationic protein [ECP], tryptase, IgE) isolated from middle ear effusions have been shown to be elevated. The role of food allergy in Otitis media with effusion and in other allergic diseases of the ear is under active investigation. For Otitis media with effusion and Meniere’s disease, an allergic basis of disease and treatment should be considered in cases refractory to conventional medical and/or surgical management.

Otitis media with effusion can impair hearing significantly, cause profound mucosal changes, delay speech development, and result in permanent middle ear damage. Otitis media with effusion is the most common cause of hearing loss in children today and causes a conductive hearing loss with a flat tympanogram. Of particular interest is Otitis media with effusion refractory to conventional antibiotic treatment and surgical therapy such as myringotomy, tonsillectomy, adenoidectomy, tympanostomy tube placement, and even radical mastoidec-tomy. Chronic mucosal inflammation is a major finding in these cases. The role of allergy in these cases is under active investigation and discussed in the following sections.

Table. Otologic manifestations of allergy.

Eustachian Tube Dysfunction

Eustachian tube dysfunction is a major factor in the development of Otitis media with effusion. Upper respiratory infections and allergies contribute to Eustachian tube dysfunction, and in some cases contribute to a patulous Eustachian tube. Patients with patulous Eustachian tube may complain of autophony (abnormal awareness of their own voice), reverberation, or tinnitus resembling the sound of an ocean roar. Provocative intranasal challenges of pollen, house dust mites, and histamine worsen Eustachian tube dysfunction. Allergic rhinitis results in a significantly higher rate of Eustachian tube dysfunction, particularly during childhood, as demonstrated by nasal turbinate changes. Bernstein proposes that Eustachian tube dysfunction in the setting of allergy may be a result of retrograde spread of edema and congestion of nasal mucosa, decreased mucociliary function that permits secretions to cover the ostium and subsequent intraluminal inflammation, or obstruction of the Eustachian tube orifice from hypersecretion by seromucous glands. These symptoms can be alleviated with specific allergy therapy, including immunotherapy and elimination diets depending on the offending agent.

Otitis Media with Effusion

Otitis media with effusion often results from Eustachian tube dysfunction or can be the result of chronic inflammation or microbial infection. The causative contribution of allergy to Otitis media with effusion is unknown, with a broad range of attribution (0% to 95%) reported in the literature. The controversy regarding the role of allergy in Otitis media with effusion is reflected in different types of skin and in vitro testing, and heterogeneous types of allergens included in each study. Many would agree that Otitis media with effusion caused by allergy is most likely from Eustachian tube dysfunction secondary to an allergic reaction in the proximal Eustachian tube or nasopharynx. However, some studies have demonstrated the presence of histamine and other biologic mediators of inflammation in the middle ear fluid of patients with Otitis media with effusion, suggesting that the middle ear is also a primary target of allergic reactions.

An argument against a significant role of allergy in the pathogenesis of Otitis media with effusion is that although allergy is typically considered seasonal with regional variation, Otitis media with effusion has its highest incidence in the winter, regardless of region. In addition, an IgE-mediated reaction is brief and not typically long enough to cause significant Eustachian tube dysfunction. Also, there is no clear evidence for an intranasal challenge directly producing a middle ear effusion. Although intranasal challenges have resulted in Eustachian tube dysfunction, the duration of dysfunction is insufficient to result in Otitis media with effusion. Even complete Eustachian tube obstruction produced by sectioning the tensor veli palatine muscle in an animal model takes 1 to 4 weeks to result in a middle ear effusion. Intranasal provocative challenge persists for only several hours to a few days.

Counter arguments contend that winter is the time of year when dust and mold counts tend to be highest. Intranasal challenges of histamine, pollen, and house dust mites result in Eustachian tube dysfunction, albeit of unclear sufficient duration to cause Otitis media with effusion. Epidemiologic studies have shown that patients with Otitis media with effusion have an increased prevalence of atopic conditions, such as allergic rhinitis, eczema, and asthma. More than 50% of patients with Otitis media with effusion have allergic rhinitis, whereas 21% of patients with allergic rhinitis have Otitis media with effusion. One study of 20 patients with Otitis media with effusion refractory to medical and surgical management showed that allergy immunotherapy in patients tested with the radioallergosorbent test resulted in preservation of hearing and elimination of recurrent infections for 3 years when compared with controls. Although small, this study encourages consideration of allergic factors in patients with refractory Otitis media with effusion to conventional treatments.

Food Allergy in Otitis Media with Effusion

Few studies address the role of food antigens in Otitis media with effusion. One study of 56 children found food allergies in children with Otitis media with effusion (45%) were significantly higher than in children without complaints of food allergy or Otitis media with effusion (18%). Another study of 104 children with recurrent otitis media found that 78% had food allergy diagnosed by skin prick or IgE tests and food challenge. They reported that 86% of the children with food allergy who were treated with food elimination had significant amelioration of Otitis media with effusion, as documented by clinical examination and tympanometry. Food challenge resulted in recurrence of Otitis media with effusion in 94% of the children with food allergies who underwent challenge. A few studies have suggested that cow’s milk allergy in infancy, even when treated properly, is associated with significantly higher rates of recurrent Otitis media with effusion. A few of these studies address possible mechanisms for this association. These include nasal congestion induced by food allergy, direct middle ear mucosal damage by food immune complexes, and other hypersensitivity response. One study demonstrated elevated serum IgG response, but a lack of IgE response, to foods in oti-tis-prone children compared with controls. More definitive studies are needed in this area. Nevertheless, current results encourage consideration of a food elimination diet in select patients before surgical intervention.

Atopic dermatitis is a complex, multif actorial disorder that first develops in most patients before the age of five. The diagnosis relies on information compiled from all aspects of clinical history, physical examination, and laboratory data. Strong correlations exist between atopic dermatitis and other atopic conditions such as asthma and allergic rhinitis. Underlying immunoglobulin E-mediated sensitivitiy to both aeroallergens and foods have been shown to be strong triggering factors in atopic dermatitis. In addition, Staphylococcus aureus can exacerbate atopic dermatitis both by causing secondary infection of compromised skin and by secreting exotoxins that function as “superantigens” directly stimulating T-cell proliferation. Successfut treatment of atopic dermatitis involves a multifaceted approach that addresses avoidance of underlying triggering factors, proper care of dry skin, and pharmacologic management, including oral antipruritic agents, topical corticosteroids, and oral antibiotics when necessary.

Atopic dermatitis is a complex, multifactorial disorder that was first described in the medical literature more than 100 yr ago. Although clinicians and researchers agree that this disorder is caused by many factors, the role of allergic disease has remained at the forefront of clinical research. In the late 19th century, Besnier provided a detailed description of a chronic, pruritic dermatitis beginning in infancy and showing associations with asthma and rhinitis. The term prurigo Besnier was subsequently used to describe these patients. In 1902, Brocq coined the term neurodermatitis to refer to achronic, pruritic skin condition seen in patients with apparent nervous disorders. Coca (1933) was the first to denote the familial occurrence of hay fever, asthma and eczema and introduced the term atopy to describe the inherited nature of human hypersensitivity disorders. In 1933, Wise and Sulzberger condensed the past terminology into the descriptive term we use today — atopic dermatitis.

Key Clinical Features of Atopic Dermatitis

•   A chronic eczematoid dermatitis with 90% of cases beginning before age 5

•   Characteristic distribution pattern that varies with age

•   Intensely pruritic

•   50-80% of patients will suffer from allergic respiratory disorders later in life

Natural history

Prevalence

Although Atopic dermatitis is known to be a common skin disorder, its true prevalence has been difficult to define. With wide variation in the severity and time course of disease as well as differing diagnostic criteria used, the prevalence of Atopic dermatitis has been the subject of much debate among physicians and clinical investigators. However, within the last decade, the development of unifying diagnostic criteria and methodology for epidemiological studies has allowed a better understanding of how much of the population is affected by this disease. Estimates place the lifetime prevalence of Atopic dermatitis in industrialized nations in children between 10 and 20% and the 1 -yr prevalence in adults at 1 to 3 %. It is well recognized that Atopic dermatitis is more prevalent in industrialized countries compared with non-industrialized countries or tropical regions. Over the past three decades, the prevalence has increased two- to three-fold, following the trend for increasing prevalence in other atopic disease, especially asthma.

Disease Course

Atopic dermatitis is a chronic disease of infants, children, and young adults. Onset of disease is typically during early infancy. Sixty percent of affected individuals manifest characteristic lesions during the first year of life. Ninety percent of individuals will be affected by age 5 yr. The remaining individuals will typically manifest disease during late childhood or adolescence. It is rare for symptoms to begin during adulthood and should be a clue to question the accuracy of diagnosis.

The clinical course is variable and unpredictable. Some infants and children will have a mild course with spontaneous remission by 2-3 yr of age. Others will have more persistent disease with a chronic unremitting course throughout childhood and even into adulthood. Still others will have a waxing and waning course highlighted by unexplained remissions of varying degrees followed by equally unexplained exacerbations.

Characteristic Distribution

Atopic dermatitis is typically divided into three clinical phases based on age of onset. The infantile phase is from birth to 2 yr of age. The onset in this group is typically after 2 mo of age, but onset during the first few weeks of life may be seen. The childhood phase is between 2 and 11 yr. The adolescent and adult phase begins at age 12 yr and proceeds through adulthood. Each of these phases has a typical distribution of skin lesions that can prove useful in diagnosis.

The infantile phase is characterized by erythematous, pruritic, exudative, maculopapular lesions that contrast to the more dry, lichenified lesions seen later in childhood and adult life. In infancy these lesions first appear on the cheeks, forehead, and scalp. Progression then occurs to involve the trunk and extensor surfaces of the extremities. As the infant grows older the distribution of lesions may change to involve the entire extremity surface or the more typical flexural distribution of childhood.

During the childhood phase, lesions of atopic dermatitis are typically dry and involve a more flexural distribution of the extremities. The face, with the exception of the lips and perioral region, is less commonly affected by the age of 4-5 yr. The hands can be especially difficult areas to control in this age group. Intense pruritus and secondary scratching can produce a very anxious, hyperactive child.

The adolescent and adult phase is most commonly manifested as lichenified, pruritic macular lesions involving the face, neck, upper trunk and flexural regions of the extremities. Many young women in their 20s experience hand involvement (i.e., hand eczema) as the first or only manifestation of Atopic dermatitis. As previously noted, the onset of disease later in life is very uncommon and should be a clue to search for other etiological factors or diseases.

Table Common Allergens in Atopic Dermatitis

Pathogenesis

Genetic associations

Like other atopic conditions, Atopic dermatitis has a strong genetic predisposition. As many as 60-80% of patients with Atopic dermatitis have a family history of a first-degree relative with Atopic dermatitis, asthma or allergic rhinitis. In studies of twins, Rajka reported a much higher concordance for atopy in monozygotic twins, whereas Atopic dermatitis alone revealed only a 50% concordance in both monozygotic and dizygotic twins. Rajka’s data cast doubt on the strictly hereditary influence, yet underscore the importance of the combination of hereditary and environmental factors in the disease process. Numerous reports have suggested HLA associations among families with atopic disease in general and Atopic dermatitis specifically. Based on genomic studies assessing for susceptibility loci for atopic dermatitis, multiple pathophysiologically relevant candidate genes have been identified including areas on chromosome 3q21, lq21,17q25, and 20p. An area on chromosome 5q31 -33 that contains a clustered family of Th₂ cytokine genes has been of particular interest. Other genetic variations reported in Atopic dermatitis include a mutation in the promoter region of RANTES, a gain-of-function polymorphism in the a-subunit of the IL-4 receptor and IL-13 coding variants. These data are not definitive at present and suggest that a single set of genes is not responsible for atopic disease inheritance. Multiple patterns of disease inheritance such as autosomal dominance, autosomal-recessive and multifactorial inheritance have been found, emphasizing the obvious complexity of genetic influence on the disease process. Throughout all these studies, however, it is maintained that individuals from atopic families are at greater risk for development of atopic disease in some form.

Clinical manifestations

Laboratory findings

Histopathology

Immunopathology

Although the full understanding of the immunopathology of Atopic dermatitis remains to be elucidated, various immune abnormalities can be routinely detected in these patients. Findings include increased serum immunoglobulin E, abnormal delayed-type skin reactivity to common antigens (i.e., tetanus antigen), decreased incidence of contact dermatitis (i.e., poison ivy dermatitis) and increased susceptibility to cutaneous viral infections such as herpes simplex, verruca vulgaris, molluscum contagiosum, and vaccinia. In vitro experiments also show a decreased lymphocyte response to mitogens (i.e., phytohemagglutinin) and recall antigens (i.e., tetanus) and a defective cytotoxic T-cell response. Reduced chemotaxis of monocytes and polymorphonuclear leukocytes has also been reported in Atopic dermatitis. These data indicate that a combination of mechanisms may be important in the immunopathogenesis of Atopic dermatitis.

Immunological Abnormalities

•   Uncontrolled synthesis of immunoglobulin E with T-cell profile of immediate hyper-sensitivity (TH2 cells predominate)

•   Decreased   delayed   hypersensitivity   with   increased   susceptibility to cutaneous viral infections

•   High spontaneous basophil histamine release

Role of immunoglobulin E in Atopic dermatitis

Support for an immunoglobulin E-mediated mechanism in Atopic dermatitis is suggested by the following findings typical of Atopic dermatitis: elevated serum immunoglobulin E concentration, positive immediate skin tests and radioallergosorbent to a variety of food and aeroallergens, association with other atopic diseases (i.e., asthma and allergic rhinitis) and apositive family history for atopy in 80-90% of patients. In addition, bone marrow transplant data have documented the ability to transfer immunoglobulin E antibody, specific allergen sensitivity, and Atopic dermatitis to previously nonatopic bone marrow recipients. Although the histological appearance of Atopic dermatitis lesions suggests a type IV, cell-mediated hypersensitivity reaction caused by the cellular infiltrative pattern, recent information on the allergic late-phase reaction (LPR) has shown a distinctive cellular infiltrate that is consistent with that seen in Atopic dermatitis. Following allergen challenge, immunoglobulin E-bearing mast cells bind allergen and become activated, releasing cytokines and mediators that perpetuate the allergic response. This immediate or early reaction occurs within 15-60 min of allergen challenge and is characterized by erythema, pruritus, and increased capillary permeability. Approximately 4-8 h after the initial allergen challenge, the LPR begins with infiltration of eosinophils, neutrophils, lymphocytes, and monocytes into the site of inflammation. At 24-48 h, lymphocytes and monocytes predominate the cellular infiltrate. This infiltrate seen during the LPR following antigen challenge is similar to the infiltrate noted in the lesions of Atopic dermatitis.

Clinical and laboratory correlates have been made in numerous studies in patients with food hypersensitivity and Atopic dermatitis. Following positive food challenge, Sampson and colleagues have shown a rise in plasma histamine, without a change in complement activity, basophil number or total basophil histamine content. Skin biopsy specimens obtained 4 and 14 h after challenge revealed eosinophil infiltrate and deposition of major basic protein. They concluded that food allergen-induced mast cell activation was shown to trigger both an early and a late-phase reaction in the skin of patients with Atopic dermatitis.

immunoglobulin E molecules have also been found to participate in the inflammatory response via mechanisms other than direct mast cell activation. Sampson has shown that children with Atopic dermatitis and food hypersensitivity have high spontaneous basophil histamine release in vitro when compared with normal controls or Atopic dermatitis patients without food hypersensitivity. Mononuclear cells from these patients also secreted high levels of histamine-releasing factor. These levels were associated with cutaneous hyperreactivity to a variety of minor stimuli. After an appropriate food elimination diet was implemented for approx 1 yr, spontaneous basophil histamine releasibility and production of histamine-releasing factor fell to baseline levels and correlated clinically to less cutaneous hyperreactivity. In addition, passive transfer of this releasing factor could be demonstrated in nonatopic controls. Basophils from nonatopic individuals were stripped of all immunoglobulin E molecules and sensitized with immunoglobulin E from food-allergic patients. This rendered the “normal” basophils capable of secreting histamine in response to histamine-releasing factor.

The observation that Langerhans’ cells and macrophages infiltrating into the dermis of Atopic dermatitis skin lesions bear immunoglobulin E surface molecules provides an important link to understanding the immunopathology of Atopic dermatitis. These immunoglobulin E-bearing cells also express the low-affinity receptor for immunoglobulin E (CD23) and presumably function in antigen processing and presentation. Mudde and coworkers demonstrated that in vitro, immunoglobulin E-bearing Langerhans’ cells from dust mite allergic patients were capable of capturing house dust mite allergen for antigen presentation, whereas immunoglobulin E-negative cells from normal controls or atopic controls who were not dust mite allergic were unable to capture the allergen. Once activated, these cells have been shown to produce cytokines, such as IL-1 and tumor necrosis factor, that are important in lymphocyte attraction and activation at the inflammatory site. In Mudde’ s study, immunoglobulin E-positive cells were shown to activate lymphocytes after specific allergen challenge, whereas immunoglobulin E-negative cells did not result in lymphocyte activation. In addition to mast cells, these cells likely function as a bridge between initial allergen contact and processing and subsequent lymphocyte activation and perpetuation of the immune response.

Role ofT Cells in Atopic dermatitis

The role of T-lymphocytes in the pathogenesis of Atopic dermatitis has been the subject of many investigative studies during the last 15-20 yr. The concept that T-cells play a critical role in immunoglobulin E regulation has been elegantly demonstrated in the murine model. Recently, evidence for this same type of interaction has been found in human studies. Cytokines produced by activated lymphocyte clones regulate the immune response. In the murine model, T-helper (TH) cells are divided into two distinct subpopulations based on the cytokine profile secreted. T-helper type 1 (THj) cells produce IL-2, IL-3, IL-10 and IFN-y and function in cell-mediated immunity responses (i.e., infection and delayed-type hypersensitivity). TH₂ cells produce IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13 and GM-CSF and function in hypersensitivity responses. These same profiles have been seen in human studies, but with some degree of overlap.

It has been demonstrated that IL-4 acts as an isotype switch factor that commits B -cells to produce immunoglobulin E. Furthermore, B-cells from patients with Atopic dermatitis have been shown to spontaneously produce higher levels of immunoglobulin E than normal controls. These B-cells also have increased expression of the low-affinity immunoglobulin E receptor (CD23) on their surface. In vitro data have also shown that IL-4 not only increases immunoglobulin E production but also up-regulates the expression of CD23. Numerous investigators have shown an imbalance in cytokine profiles in patients with Atopic dermatitis. These patients typically have a TH₂-like cytokine profile with increased secretion of IL-4 and IL-5, in particular. Human T-cell clones from such patients demonstrate decreased production of IFN-y and increased production of IL-4, resulting in an ability to induce immunoglobulin E synthesis. This reciprocal relationship between IFN-y and IL-4 and subsequent induction of immunoglobulin E synthesis has been documented by several groups. Many have shown that production of IFN-y or its addition to cell culture will inhibit immunoglobulin E production and will downregulate the expression of CD23. Van der Heij den and coworkers have also demonstrated a high frequency of IL-4-producing allergen-specific T cells in lesional skin from Atopic dermatitis patients. Van Reij sen noted the same allergen-specific clones from lesional skin with 70% demonstrating a TH₂ phenotype. Both groups suggested that percutaneous sensitization to aeroallergens (e.g., dust mite) may occur and that activation of TH₂-type allergen-specific T cells may be responsible for the high levels of specific immunoglobulin E found in 80% of Atopic dermatitis patients. These data suggest that atopic patients, and those with Atopic dermatitis in particular, have an inability to produce IFN-y and therefore have a predominance of TH₂-type cells, resulting in increased IL-4 production, increased immunoglobulin E synthesis and continuation of the allergic immune response. Recent data have also suggested that this TH₂-like cytokine profile can be demonstrated from CD8+ (T suppressor) T-cells, in addition to CD4+ (T-helper) T-cells in Atopic dermatitis patients when compared to nonatopic controls.

Some groups have suggested a model of sequential T helper cell activation in Atopic dermatitis involving both TH₂- and TH_rtype T-cells. These investigators have noted more abundant expression of IFN-y in some chronic Atopic dermatitis lesions, suggesting the possible role of TH_rtype cytokines in maintaining the inflammatory response of Atopic dermatitis. Of further interest is the apparent differential expression of certain cytokines in acute versus chronic Atopic dermatitis skin lesions. Increased expression of IL-16 has been noted in acute Atopic dermatitis skin lesions only. IL-16 has chemotactic activity specific for CD4+ (T helper) cells; therefore, it may play a role in the initiation of skin inflammation in Atopic dermatitis via enhanced recruitment of CD4+ T-cells. Differential expression of IL-13 and IL-12 has also been demonstrated in acute vs chronic Atopic dermatitis skin lesions, respectively. These data provide further evidence for a TH₂ phenotype (i.e., IL-13) in acute lesions leading to inflammation. In contrast, the increase in IL-12 in chronic lesions suggests a possible role for IL-12 producing cells in modulating chronic inflammation, possibly via preferred activation of TH_rtype cells instead of TH₂-type cells. Of additional interestis the role of memory T-cells in recognizing skin-related allergens. Memory T-cells display the cutaneous lymphocyte-associated antigen (CLA) that acts as a skin homing receptor for T-cells recognizing skin-related allergens. In vivo studies have demonstrated activation and increased expression of CLA+ T-cells in patients with Atopic dermatitis compared to controls.

Table Differential Diagnosis for Atopic Dermatitis

These CLA+ T-cells demonstrate an increased production of the TH₂-type cytokine, IL-13, and induction of immunoglobulin E antibodies, indicating their potential pivotal role in the allergic inflammation of Atopic dermatitis. Obviously, the immunological aspects of Atopic dermatitis are very complex, but provide an intriguing look at interactions between the skin and the immune system that are being continually updated by experts in both fields.

Differential diagnosis

Complications

Treatment

Prognosis

Currently there are no prospective, longitudinal studies evaluating the prognosis and disease remission of Atopic dermatitis. Vickers retrospectively evaluated 2000 children with Atopic dermatitis after 20 yr and noted an overall clearance rate of 84%. Vowles likewise evaluated 84 patients after 13 yr and found only 45% resolution of disease. These and other studies reflect the difficulty in assessing prognosis with reports of disease resolution ranging from 37 to 84% in various retrospective surveys. In addition, no specific disease factors are predictive of the disease severity or course. Some patients are noted to have spontaneous resolution of their disease during infancy and early childhood. Improvement may also be seen during puberty in some patients, but exacerbations noted in others. Cases in adults will often resolve or significantly improve after the second decade of life. As is common with atopic diseases, some cases of Atopic dermatitis resolve, but patients develop other forms of atopy such as allergic rhinitis and asthma. Until a well-designed, prospective, longitudinal survey of Atopic dermatitis is conducted, predictions of disease outcome will remain purely speculative and based on clinical experience. These factors reiterate the need for consistent long-term follow-up and management to best serve the needs of patients with Atopic dermatitis.

Role of Allergens

There is a strong correlation of atopic dermatitis with other atopic conditions such as asthma and allergic rhinitis. The term “atopic march” has been coined to define the natural history of atopic diseases characterized by a sequence of progression in the clinical signs of atopic disease with some manifestations becoming more prominent while others subside. Typically, the cutaneous manifestations represented by Atopic dermatitis represent the beginning of the “atopic march,” with approx 50% of patients with Atopic dermatitis (especially severe Atopic dermatitis) developing asthma and approx 66% developing allergic rhinitis. Because of earlier historical observations of Atopic dermatitis associated with other atopic diseases, investigators have explored the role of various allergens as causal factors in these diseases.

Aeroallergens

Pollens were the first aeroallergens reported in association with Atopic dermatitis. Ragweed pollinosis has been of particular interest, with clinicians citing case reports of patients with seasonal exacerbation of Atopic dermatitis and of clearing in a pollen-free environment. In the 1950s Tuft performed intranasal challenges with ragweed pollen and noted rhinorrhea and itching of affected skin areas in Atopic dermatitis patients. More recently, investigators have shown positive prick skin tests and patch tests to common pollens in patients with seasonal distribution of their Atopic dermatitis. In a study of children, 90% of Atopic dermatitis children tested with epicutaneous patch testing developed eczematous lesions in one or more Atopic dermatitis predilection sites when tested with dust mite, cockroach, mold and grass mix. Others have shown positive immediate skin tests to birch pollen in Atopic dermatitis patients who had worsening of their disease during the birch pollen season.

Mold allergens have also been implicated as causal factors in patients with Atopic dermatitis. Tuft induced symptoms of dermatitis in his patients following inhalation challenge with Alternaria when compared with talc powder or pine pollen. Rajka has also demonstrated eczematous lesions in two of five atopic individuals with Atopic dermatitis following inhalation of mold extract.

Key Features of the Pathogenesis of Atopic Dermatitis

•   Immediate hypersensitivity may be key to pathogenesis in the majority of patients.

•   Exacerbations clearly related to contact with aeroallergens or the ingestion of foods to which a patient is allergic.

•   Many patients have immunoglobulin E-mediated allergic responses to microorganisms growing on the skin.

•   Nonimmunological factors, such as climate and nonspecific irritants, may play a role.

The largest body of scientific and clinical data regarding aeroallergens and atopic diseases exists in reference to dust mite allergy. Sensitivity to dust mite was first examined in patients with asthma. Reports soon followed of improvement in Atopic dermatitis when patients were placed in a dust-free environment and subsequent aggravation of symptoms after exposure to dust. Extensive studies of dust mite antigen and atopic disease association have been performed. They and others have shown positive prick skin testing and patch testing to dust mite antigen in patients with Atopic dermatitis. In a recent epidemiological survey, the homes of patients with moderate to severe Atopic dermatitis showed a higher dust mite concentration than homes of controls. Elevated serum levels of dust mite-specific antibody and increased basophil sensitivity have also been shown in Atopic dermatitis patients when compared with controls. Several groups of investigators have also demonstrated an increased lymphocyte response and specific cytokine profile (e.g., TH₂-type profile with IL-4, IL-5) production in patients with Atopic dermatitis and evidence of dust mite allergy. Perhaps the best clinical evidence for dust mite allergen playing a role in the Atopic dermatitis condition of some patients comes from reports of patients showing improvement when living in a dust-free environment and having flares of disease upon return to an environment of exposure to dust mite.

Two other types of aeroallergens are felt to play a role in the pathogenesis of Atopic dermatitis — animal dander and cockroach allergens. Both of these allergen groups have been studied in association with asthma and allergic rhinitis and are felt to be important factors in certain susceptible individuals. Less scientific information is available with regard to Atopic dermatitis; however, anedoctal clinical experience would support their causative roles. Of the animal danders, cat and dog dander are implicated most commonly in atopic disease states. Cat dander allergy, in particular, can manifest as severe in some atopic individuals, especially those with asthma. Cockroach allergens have been recognized more recently in atopic disease, especially in endemic areas and climates. In a study of atopic children, many of them had positive prick and intradermal skin tests to animal dander and cockroach, indicating the possible relevance of these allergens in atopic disease. More study is needed to define further the role of animal dander and cockroach allergens in Atopic dermatitis.

Foods

Adverse reactions to foods have been reported in the medical literature since the early 1900s when Smith reported the case of a man with “buckwheat poisoning.” In 1918 Talbot was one of the first physicians to observe an improvement in a patient’s eczema while on a milk and egg restriction diet. Tuft (1950s) considered food allergy to be the most important pathogenic factor in infants and young children with Atopic dermatitis, yielding to inhalant allergies in older children and adults. Since that time many investigators have studied children with Atopic dermatitis and food hypersensitivity. In general, they have shown that dietary manipulation has resulted in dramatic improvement in many patients with Atopic dermatitis, especially young children.

Bock and colleagues were the first to establish the use of double-blind, placebo-controlled food challenges to assess patients with suspected food hypersensitivity. Because there is poor correlation between allergen-specific immunoglobulin E antibodies (skin tests or radioallergosorbent tests [radioallergosorbent]) and clinical symptoms related to food hypersensitivity, oral food challenges (both open and blinded) have been crucial in assisting many investigative groups in the study of food hypersensitivity and Atopic dermatitis. Sampson first reported findings of food hypersensitivity in 26 children with Atopic dermatitis. These findings were confirmed during a study in our institution in which 46 children with Atopic dermatitis were studied with double-blind, placebo-controlled food challenges. Positive challenges were detected in 33% of patients, with 91% reacting to only one or two foods. These groups have shown a direct correlation between hypersensitivity to foods and the development of Atopic dermatitis. In addition, these groups have consistently reported improvement in Atopic dermatitis in food protein-sensitive patients while on food elimination diets.

Perhaps the largest body of information regarding Atopic dermatitis and food hypersensitivity has been provided by Sampson and coworkers. They have evaluated hundreds of children with Atopic dermatitis for food hypersensitivity with more than 1000 double-blind, placebo-controlled food challenges. The most commonly implicated foods in causing a reaction were egg, milk, peanut, fish, and tree nuts. Cutaneous symptoms were seen in 75% of positive challenges. The most common cutaneous manifestation consisted of a pruritic, erythematous morbilliform rash involving the Atopic dermatitis predilection sites. Other symptoms noted during positive challenge included respiratory (stridor, wheezing, nasal congestion, rhinorrhea, and sneezing) and gastrointestinal (nausea, vomiting, abdominal cramping, and/or diarrhea). All patients found to be allergic to particular foods were placed on an appropriate avoidance diet of that food. Virtually all patients reported improvement in symptoms, either noted as complete resolution or marked clearing.

In a more recent study in our institution we sought to further delineate the role of food hypersensitivity in Atopic dermatitis and to determine if patients with Atopic dermatitis who had food hypersensitivity could be identified by screening prick skin tests using a limited number of food allergens. Patients with Atopic dermatitis attending the Arkansas Children‘s Hospital Pediatric Allergy Clinic were enrolled. After a detailed medical history and physical examination, the patients underwent allergy prick skin testing to a battery of food antigens. Patients with positive prick skin tests underwent double-blind, placebo-controlled food challenges; 165 patients were enrolled and completed the study; patients ranged in age from 4 mo to 21.9 yr (mean 48.9 mo); 98 (60%) patients had at least one positive prick double-blind, placebo-controlled food challenges. A total of 266 double-blind, placebo-controlled food challenges were performed. Sixty-four patients (38.7% of total) were interpreted as having a positive challenge; seven foods (milk, egg, peanut, soy, wheat, cod/catfish, cashew) accounted for 89% of the positive challenges. Utilizing screening prick skin tests for these seven foods we could identify 99% of the food allergic patients correctly. This study confirms that the majority of children with Atopic dermatitis have food allergy that can be diagnosed by a prick skin test for the seven foods.

Sampson and colleagues have presented studies of mediator release that provide further evidence that food-specific immunoglobulin E-mediated mechanisms play a role in the pathogenesis of Atopic dermatitis. They have demonstrated increased plasma histamine levels in Atopic dermatitis patients following a positive food challenge, increased spontaneous histamine release from basophils in patients with Atopic dermatitis and food hypersensitivity, spontaneous release of a cytokine (histamine-releasing factor) from mononuclear cells in these patients and increased cutaneous hyperirritability to a variety of minor stimuli. These mediators and the associated cutaneous hyperirritability were all noted to be diminished to normal levels after 6-9 mo of food allergen avoidance.

In an earlier study examining the natural history of patients with Atopic dermatitis and food hypersensitivity, Sampson reported that 26% of patients lost their clinical hypersensitivity during the first year of allergen avoidance, and 11 % lost reactivity during the second year. Therefore, Sampson and others have shown that most children tend to “outgrow” their food hypersensitivity to most foods early in life. Some of these children also show subsequent resolution of their Atopic dermatitis, whereas others manifest aeroallergen sensitivity that seems to perpetuate the Atopic dermatitis cycle.

Through the years, much attention has been focused on the role of maternal dietary restriction during pregnancy and lactation in the prevention of Atopic dermatitis and food hypersensitivity. The most current and comprehensive information to date comes from a study that followed 288 American children from birth through age 4 yr and 125 of these children through age 7 yr. Some mothers and infants were randomized to a prophylactic group consisting of maternal avoidance of cow’s milk, eggs, and peanuts during the third trimester of pregnancy and during lactation; use of a casein hydrolysate formula for supplementation or weaning; avoidance of all solid foods for 6 mo; and avoidance of defined allergenic foods for up to 24 mo. Others provided a control or “untreated” group in which no prophylaxis was implemented. After 7 years the only atopic parameters affected between groups were the prevalence of food allergy and milk sensitization prior to age 2 yr. No difference was seen in the prevalence of Atopic dermatitis, asthma, allergic rhinitis, food sensitization, or positive skin tests to inhalant allergens. Other studies in children have shown a direct correlation between the number of solid foods introduced before age 6 mo and the prevalence of Atopic dermatitis at age 2 yr. These and other studies indicate the potential role of food allergens in the development of Atopic dermatitis and the potential benefits of early allergen avoidance in some high-risk infants.

Microorganisms

The role of microorganisms in the pathogenesis of Atopic dermatitis has received much attention in recent years. Their potential role as complicating skin pathogens has long been recognized as important, but more recently their role as “allergens” perpetuating the allergic response has been of particular interest. It is postulated that the altered skin barrier seen in patients with Atopic dermatitis provides a portal of entry for various pathogens to gain access to the immune system, thus activating mast cells, basophils, Langerhans’ cells and other immune cells. Recently, Ong and coworkers demonstrated that atopic dermatitis skin is deficient in antimicrobial peptides that are needed for host defense against bacteria, fungi, and viruses, thus enhancing the susceptibility of patients with atopic dermatitis to secondary skin infections. The primary classes of microorganisms involved include bacteria and yeasts.

The most extensively studied and widely recognized microorganism of importance in the disease process of Atopic dermatitis is Staphylococcus aureus (S. aureus). S. aureus skin colonization of both affected and normal skin has been shown to be increased in patients with Atopic dermatitis compared to controls. Some investigators have demonstrated colonization in more than 90% of lesions in some individuals with Atopic dermatitis. In addition increased immunoglobulin E-specific antistaphylococcal antibodies have been demonstrated in sera of patients with Atopic dermatitis. More recently investigators have focused on the role of staphylococcal exotoxins in the disease cycle of Atopic dermatitis. These studies have focused on the role of stimulating T-cell-dependent immunoglobulin E production and subsequent enhancement of the allergic response. Evidence for an immunoglobulin E-mediated mechanism has been supported by Neuber’s reports of increased CD23 (low-affinity receptor for immunoglobulin E) expression in cells from Atopic dermatitis individuals following stimulation with S. aureus. Leung and coworkers have reported specific immunoglobulin E antibodies to staphylococcal exotoxins produced from staphylococcal organisms grown from the skin of 32 of 56 Atopic dermatitis patients. Basophils from 10 Atopic dermatitis patients with immunoglobulin E antibodies to these exotoxins released histamine in response to specific staphylococcal exotoxins. Basophils from normal individuals or from patients with Atopic dermatitis but without immunoglobulin E anti-exotoxin antibodies failed to release histamine after exotoxin stimulation. Other data show that low concentrations of toxic shock syndrome toxin-1 (TSST-1) are able to stimulate mononuclear cells from Atopic dermatitis patients to produce immunoglobulin E in a T-cell-dependent fashion. These groups and others have also suggested that these exotoxins may function as “superantigens,” thereby perpetuating the immune response by stimulating T-cell proliferation independent of the usual allergic mechanisms. To further emphasize the role of S. aureus in the Atopic dermatitis process, it has been clearly demonstrated that patients with Atopic dermatitis show a better clinical response when treated with combinations of antistaphylococcal antibiotics and topical steroids than with steroids alone. Other bacteria, such as streptococcal species, may also be important, but little clinical or investigative information exists to document their role. Various species of yeast organisms have been implicated as causal factors in the pathogenesis of Atopic dermatitis. Malassezia furfur is now the unifying name for a fungus with both yeast forms (Previously classified as Pityrosporum orbiculare and P. ovale) and a mycelial form (previously classified as M. furfur) that commonly inhabits the seborrheic regions of the skin and the scalp in normal individuals. Colonization is more commonly seen in older children and adults than in infants and younger children. Many investigators have shown a strong correlation between active Atopic dermatitis lesions and specific antibodies to P. ovale. The antibodies have been demonstrated viaprick skin testing and serum analysis via radioallergosorbent. Wessels showed the presence of P. ovale-specific immunoglobulin E antibodies in 49% of Atopic dermatitis patients. In addition, patients with head, neck, and upper trunk distribution of Atopic dermatitis lesions and evidence of specific antibodies to P. ovale, have been reported to show clinical improvement following ketoconazole therapy. Mononuclear cells from Atopic dermatitis patients have been shown to demonstrate a higher proliferative response and atopic cytokine pattern to P. orbiculare stimulation than nonatopic controls. Although not conclusive, these data suggest the pathogenic role of Malassezia species in some patients with Atopic dermatitis and emphasize the need for consideration when refractory Atopic dermatitis is seen in the typical head and neck distribution, especially in older children and adults. A possible role of other yeasts, such as Candida albicans, Trichophyton, has been implicated in the pathogenesis of Atopic dermatitis. Specific immunoglobulin E antibodies to M. furfur have been detected in 70% of sera from Malassezia furfur-sensitized patients with Atopic dermatitis. More extensive study is needed to draw firm conclusions regarding the role of these yeasts in the pathogenesis of Atopic dermatitis.

Role of Environmental Factors

Atopic dermatitis is a complex, multifactorial disease. The course of the disease is influenced by many primary and secondary factors that are often difficult to tease apart. Environmental factors frequently act as “triggers,” causing exacerbations of disease, yet they are not primary causes of the underlying disease.

Climate

Several environmental factors can influence the course of disease in Atopic dermatitis. One of the most important, yet often obscure, factors is climate. Individuals will respond differently to various climatic influences. Most authors report disease intensification during the winter months and patients having the most comfort during the months of summer. Rajka has reported that improvement during the summer may be due to better sebum and sweat secretion, ultraviolet rays from sun exposure, exposure to water during swim activities, reduced exposure to indoor allergens (i.e., dust mite and molds), less exposure to infection and less psychosocial stressors during summer vacations. He also mentions that some of these same influences may in fact aggravate the skin condition of other patients. Clinical researchers have noted the impaired sweating mechanism in patients with Atopic dermatitis, making excess sweating and strong heat-adverse factors in those individuals. Ultraviolet light exposure without appropriate skin protection can also be harmful. Although indoor allergen exposure may be minimized during summer months, outdoor allergen exposure (i.e., grass pollens) may be exacerbating in some regions. As a general rule, cold dry weather is more aggravating to patients with Atopic dermatitis secondary to the drying effect. Hot humid weather may also be aggravating as a result of increased perspiration and the increased potential for secondary skin infection. Extremes or sudden changes of any climatic condition (i.e., temperature and humidity) can be aggravating to patients with Atopic dermatitis, most likely secondary to an impaired ability for immediate skin adaptation. Several reports have emphasized the beneficial effect of sunny climates such as California or Florida or dry, warm climates as found in Arizona. As previously stated, these factors are only secondary in the large majority of patients and are vary individually.

Irritants

Factors other than primary irritants (i.e., allergens and infection) may complicate the course of Atopic dermatitis. Clothing fabrics can influence the comfort level and the amount of pruritus experienced by Atopic dermatitis patients. Wool fabrics clearly provide the most irritation and should be avoided in patients with Atopic dermatitis. Synthetic fibers such as nylon and polyester may also be poorly tolerated by some individuals. Cotton is generally the fabric that provides the most comfort and least pruritic potential, and its use should be emphasized to patients.

Certain laundry detergents, bleaches, soaps and household cleaning chemicals act as irritants for patients with Atopic dermatitis. Mild laundry detergents without bleach are generally better tolerated. Washing clothing through a rinse cycle twice usually ensures removal of the detergent and may be beneficial in some sensitive patients. Mild skin soaps should also be used for bathing by Atopic dermatitis patients. They are generally less drying, less irritating and less likely to induce pruritus. Skin should be protected from household cleaners by wearing protective gloves or clothing. The skin barrier is frequently altered in Atopic dermatitis and will not withstand the general intrusions that normal skin can endure.

Some foods can also act as triggers of irritation and pruritus. Certain fruits and vegetables, such as tomatoes and citrus fruits, are especially irritating in some individuals. These foods are not primary allergens, but rather irritants causing pruritus secondary to their acidic composition.

Psychosocial Factors

Most clinicians agree that psychosocial factors influence the disease process of Atopic dermatitis and further agree that these factors remain secondary and not primary in disease etiology. Emotional upset, stress, job or school tension and unstable or unsupportive home environments all can contribute as exacerbating factors. Some investigators have stated that these psychological influences may lead to autonomic dysregulation, abnormal vascular responses and mediator release, all of which act to trigger an adverse response. In addition, the chronic pruritus seen in all patients with Atopic dermatitis, especially those with severe disease, will cause sleep disturbance, hyperirritability and emotional distress, which contribute to the vicious cycle. Although not primary causes of disease, these issues must be addressed in caring for patients with Atopic dermatitis to provide maximal symptomatic relief during periods of disease exacerbation. These issues are especially important in children and adolescents and may occasionally require psychological as well as medical intervention.

Occupation

Choice of career or occupation may strongly influence the disease state for some adult patients with Atopic dermatitis. Surveys have reported Atopic dermatitis more frequently in occupations in which exposure to dust, wool, textiles, or chemicals is common. The dry, hyperirritable skin of Atopic dermatitis is prone to cracking, scaling, and infection following exposure to irritants. For this reason, patients in a workplace of high exposure have frequent or persistent flares of disease. Studies have reported that 65-75% of Atopic dermatitis patients report hand eczema, often related to nonspecific irritants in the workplace. The consequences of hand dermatitis and exacerbation of Atopic dermatitis may be quite serious in some individuals, requiring a change of duties or occupation to minimize exposure to irritants.

Key Features of Diagnosis

•   There is no single diagnostic marker; therefore, the diagnosis is dependent on a global evaluation.

•   Morphology, distribution, pruritus, and associated atopic diseases are note worthy features of history and physical examination.

•   Laboratory findings of peripheral eosinophilia, increased serum immunoglobulin E, positive allergy skin tests, and positive food challenge can be markers of disease.

History

Atopic dermatitis typically begins early in life, most commonly with skin lesions developing within the first 6 mo. Although this pattern is typical, alterations in presentation frequently occur. A careful history can therefore be useful in making the diagnosis of Atopic dermatitis. As noted previously, a family history of atopic disease may provide a clue to the etiology of a patient’s skin disease. As many as 80% of patients with Atopic dermatitis have apositive family history of atopy. A comprehensive history with regard to possible exacerbating triggers can also be helpful. These triggers may include foods, seasonal allergens, environmental conditions, irritants, emotional distress, and occupational exposures. A careful history will often uncover an exacerbating factor that is unapparent to the patient or the physician. The most prominent and persistent feature detected by historical evaluation is intense pruritus associated with a chronically relapsing course of skin disease.

Physical Findings

Although typical distribution of lesions can be detected during various stages of development, no firm diagnostic pattern is seen among all patients. The diagnosis of Atopic dermatitis therefore relies on information compiled from all aspects of the clinical history, physical examination and laboratory data. Hanafin and Rajka have provided useful guidelines to assist in diagnosing Atopic dermatitis.

Fhe rash of Atopic dermatitis typically begins as an erythematous,  papulovescicular eruption that, with time, progresses to a scaly, lichenified maculopapular dermatitis. Weeping, crusting lesions of the head, neck and extensor surfaces of the extremities are common in infancy. These lesions may involve the entire body surface, yet the diaper area may be spared. The scalp is often affected in infants with some having features of concomitant scalp seborrhea. Because of intense pruritus and scratching, traumatic injury occurs over time, providing a portal of entry for secondary bacterial infection. The early erythematous lesions will frequently discolor after a while and become dry, hyperpigmented lesions as seen in chronic dermatitis of the older child. Older children and adults have a more flexural distribution of lesions. Lesions are typically dry, lichenfied maculopapular lesions. These lesions commonly remain intensely pruritic with resultant scratching, traumatic skin injury and secondary infection. Hyperpigmentation of chronic lesions is seen with areas of hypopigmentation from older, healed Atopic dermatitis lesions. Dry skin, ichthyosis, hand eczema, and chronic chelitis may also be prominent features of the disease. Skin lichenification may be persistent long after “active” dermatitis lesions resolve.

Clinicians have long recognized that patients with Atopic dermatitis have a generalized “pallor” to their skin. This has been attributed to an abnormal vascular response that can be demonstrated by the abnormal “blanching” response seen in these patients. This delayed blanching response can be seen in both affected and normal skin of Atopic dermatitis patients, as demonstrated by application of pressure or cold on the skin. In addition, these patients will frequently demonstrate “white dermographism.” When the skin of an Atopic dermatitis patient is stroked with a blunt object, a red line will form and then will be rapidly replaced by a white line without an associated wheal. Under the same conditions, normal skin will develop a red line owing to capillary dilatation, an erythematous flare caused by arteriolar dilatation, followed by a wheal secondary to the leaky, dilated capillaries. These abnormal vascular responses of Atopic dermatitis have also been implicated in the temperature instability and poor regulatory responses seen in some patients.

Table Guidelines for the Diagnosis of Atopic Dermatitis

Another prominent physical finding in patients with Atopic dermatitis is an impaired sweating mechanism. Several investigators have documented this phenomenon, with patients demonstrating less sweating underperiods of stimulation. In addition, patients frequently complain of increased pruritus during periods of sweating. Increased transepidermal water loss has also been noted in patients with Atopic dermatitis. This has been attributed to fewer sebaceous glands and less total lipid content of Atopic dermatitis skin. All of these findings contribute to the clinical manifestations of dry skin and increased pruritus.

Laboratory tests provide few clues to the diagnosis of Atopic dermatitis. Several parameters can be helpful in eliciting triggering agents and underlying causes of disease, but none is diagnostic.

Hematological Findings

Peripheral blood eosinophilia is commonly seen in patients with Atopic dermatitis. Eosinophils usually comprise 5-10% of the total white blood cell count in Atopic dermatitis patients. The degree of eosinophilia typically does not correlate with the degree of disease severity and is generally not a useful parameter to follow disease activity. Eosinophil mediators, such as major basic protein and eosinophil cationic protein, have been found in the circulation and biopsy specimens of patients with Atopic dermatitis. Eosinophil cationic protein has been found in increased amounts in the circulation of Atopic dermatitis patients with disease activation compared to Atopic dermatitis patients with inactive disease or with normal controls. Additionally, soluble IL-2 receptor (IL-2R) and the eosinophil-specific vascular adhesion molecule, E-selectin, have both been seen in higher circulating levels in patients with Atopic dermatitis than in controls and appear to correlate with disease severity in preliminary study. These parameters (eosinophil cationic protein, IL-2R, E-selectin) have therefore been proposed as useful markers for disease activity. More information in larger, controlled trials is needed to determine if these parameters are actually valid means of following the disease status in Atopic dermatitis.

Serum immunoglobulin E Antibody

Many investigators have found a correlation between elevated serum immunoglobulin E concentrations and the presence of Atopic dermatitis. Juhlin reported that 82% of Atopic dermatitis patients observed had elevated serum immunoglobulin E levels. In two subsequent surveys, Johnson and O ‘Loughlin reported the incidence of elevated immunoglobulin E in Atopic dermatitis to be 43% and 76%, respectively. Both noted that increased levels were seen more commonly in patients suffering from more severe disease and in those with concomitant atopic respiratory disease. In addition, these investigators reported a significant number of patients with typical Atopic dermatitis and normal immunoglobulin E concentrations. Other groups have also found elevated immunoglobulin E levels in nonatopic individuals. At present, most investigators agree that the finding of an elevated serum immunoglobulin E concentration is a secondary, not a primary, phenomenon. Serum immunoglobulin E determinations in patients with Atopic dermatitis provide little practical benefit in the diagnosis or management of Atopic dermatitis.

Skin Test Reactions

Prick and intradermal skin tests to various aeroallergens and food allergens are commonly used in the assessment of Atopic dermatitis and provide the most sensitive test for allergen detection. Controversy exists among allergists and dermatologists with regard to the clinical relevance of positive tests. Some investigators have reported that as many as 80% of individuals with Atopic dermatitis will have positive specific immunoglobulin E to a variety of allergens. This finding has been explained by some groups to be nonspecific and only an indicator of a generalized atopic state. Others report the clinical significance of specific immunoglobulin E antibody and skin test reactivity in some patients with Atopic dermatitis and report the observation of clinical improvement while instituting specific allergen avoidance. Knowledge of the allergens eliciting positive skin test reactions can be used as a clinical guide for the management of disease and detection of exacerbating conditions. These tests must be interpreted with caution. The presence of a positive skin test to an aeroallergen or a food allergen may not have strict clinical relevance and must be analyzed in light of the clinical history. For aeroallergen sensitivity, findings of seasonal distribution of other associated disease, such as allergic rhinitis and asthma, may provide additional clues for interpreting positive skin tests and instituting appropriate avoidance procedures. In the case of food allergen sensitivity, Sampson found prick skin tests to have an excellent negative predictive accuracy of 82-100%, but a poor, highly variable, positive predictive accuracy of 25-75% when compared to blinded food challenge. Positive results must be correlated with the clinical history and dietary assessment and then confirmed with a trial of an allergen-elimination diet and subsequent food challenge.

Radioallergosorbent

Radioallergosorbent tests provide another method of evaluating a patient for the presence of immunoglobulin E antibody to specific allergens in the serum. Radioallergosorbent can be performed on patients with Atopic dermatitis in whom the extent of body surface involvement and severity of the dermatitis prohibits skin testing. Care must be taken when ordering such testing because there is a distinction between a standard radioallergosorbent that provides a more qualitative measure and a newer form of radioallergosorbent, Pharmacia ImmunoCAP® fluorescence enzyme-linked immunosorbent assay (CAP-FEIA), which is a quantitative measure of specific immunoglobulin E. Standard radioallergosorbent is less reliable than skin testing, especially when assessing for food-allergen sensitivity. However, Sampson has reported the correlation of specific immunoglobulin E, as measured using CAP-FEIA, with improved clinical predictabilty for food allergy diagnosis for at least some of the major food allergens. Using CAP-FEIA results, Sampson has established decision points for several major food allergens that represented a 95% likelihood of reaction on challenge.

The appearance of Atopic dermatitis lesions on routine histological specimens is not pathognomonic and can frequently be seen in a variety of inflammatory skin disorders, such as contact dermatitis, acute photoallergic dermatitis and inflammatory pityriasis rosea. The histopathological changes detected depend on the stage of the lesion. These stages are typically divided into acute and chronic.

The acute Atopic dermatitis lesion is characterized by hyperkeratosis, parakeratosis, and hyperplasia of the epidermis, with absence or diminution of the granular cell layer. In addition, spongiosis, secondary to intercellular and intracellular edema of keratinocytes, is prominent. A marked mononuclear cell infiltrate, composed primarily of lymphocytes and occasional monocytes, is seen around the dermal venous plexes. Normal numbers of mast cells, basophils, eosinophils and Langerhans’ cells are found in the acute lesions.

Chronic lesions of Atopic dermatitis are characterized by marked hyperkeratosis of the epidermis with elongation of the rete ridges, prominent parakeratosis and papillomatosis of the dermis. Only minimal amounts of spongiosis are detected. There is a marked inflammatory infiltrate in both the perivenular and intervascular areas that consists of monocytes, macrophages and lymphocytes. Increased numbers of mast cells and Langerhans’ cells can also be detected, but eosinophils are rarely found. Demyelination and fibrosis of the cutaneous nerves can be seen at all levels of the dermis.

Immunohistochemical staining using monoclonal antibodies in specimens from acute and chronic skin lesions, reveals that the predominant lymphocytic infiltrate consists of T-cells bearing the CD3, CD4 surface antigens (i.e., helper/inducer T-cell phenotype) and only occasional CD8 positive surface antigens (i.e., cytotoxic/suppressor T-cell phenotype). There are no natural killer cells or B cells in the lymphocytic infiltrate. In addition, most cells express major histocompatibility complex (MHC) class II surface antigens, indicating an “activated” state. Increased numbers of Langerhans’ cells (i.e., CDla and HLA-DR antigen-positive cells) are detected in lesional biopsies, especially chronic lesions. These Langerhans’ cells and associated infiltrating macrophages display immunoglobulin E molecules bound to their surface. Epidermal keratinocytes located in the dermis of lesional skin also show evidence of activation with increased surface expression of MHC class II antigens and expression of the adhesion molecule, intracellular adhesion molecule- 1 (ICAM-1). These cells are felt to be of importance with regard to antigen presentation and processing and subsequent lymphocyte activation and trafficking.

Although biopsy specimens from lesional skin of Atopic dermatitis show few eosinophils, large amounts of major basic protein (major basic protein) are deposited in the chronic skin lesions. major basic protein is a cationic protein released by activated eosinophils and has been found to have cytolytic activity in lesional skin of patients with Atopic dermatitis, as well as in respiratory biopsies from asthmatics. In addition, major basic protein has been shown capable of stimulating mast cell and basophil degranulation. Other investigators have found increases of other eosinophil mediators (i.e., eosinophil cationic protein and eosinophil-derived neurotoxin) in the biopsy specimens and skin blister fluid of patients with Atopic dermatitis following allergen challenge. These findings support the important role of eosinophils and their mediators in the pathogenesis of Atopic dermatitis.

Many types of primary skin disorders, metabolic disorders and immunological diseases have associated skin conditions that resemble Atopic dermatitis. Certain characteristics of these conditions help to distinguish them from Atopic dermatitis.

Skin Diseases

Seborrheic dermatitis is is the most common skin disorder confused with Atopic dermatitis. It is characterized by a greasy yellow or salmon-colored scaly dermatitis that begins within the first few weeks of life, usually before the typical age of onset of Atopic dermatitis. Lesions are primarily distributed on the scalp, cheeks and postauricular areas, but may also occur on the trunk, perineum and intertriginous regions of the hands and feet. In contrast to Atopic dermatitis, significant pruritus is generally not a feature of seborrhea.

Nummular eczema is a disorder characterized by well-circumscribed, circular lesions occurring primarily on the extensor surfaces of the extremities in areas of dry skin. Lesions begin as vesicles and papules that coalesce to form the discrete nonexudative, coin-shaped lesions. Lesions are only mildly pruritic. This disorder is not typically associated with atopy or increased serum immunoglobulin E.

Contact dermatitis, both irritant and allergic, can be seen in infants and young children. The skin eruption of irritant dermatitis varies with etiological agent, but is commonly seen on the cheeks, chin, extensor surfaces of the extremities, and the diaper area. Irritant dermatitis is typically less pruritic than Atopic dermatitis and improves with removal of the irritant (i.e., soaps, detergents, abrasive bedding). Allergic contact dermatitis is characterized by a pruritic, erythematous papulovescicular eruption that involves exposed areas of contact. This dermatitis is uncommon during the first few months of life and can frequently be delineated by a careful history.

Psoriasis is a primary skin disorder that is most commonly seen in older children and adults, but may be seen on occasion in younger children. Fully developed lesions are distinctively different in appearance from those of Atopic dermatitis. Lesions are usually erythematous and covered by a silvery scale. Distribution is primarily on the scalp, extensor surfaces of the extremities and the genital region. Nail involvement is commonly seen with pitting or punctate deformities of the nail surface.

Metabolic Disorders

Phenylketonuriais an inherited disorder caused by inability to metabolize phenylalanine secondary to a defect in the enzyme phenylalanine hydroxylase. Affected individuals have fair complexion and blond hair. If untreated, seizures and mental retardation result. Approximately 25% of these individuals have an eczematous-like rash associated with their disease.

Acrodermatits enteropathica is a lethal autosomal recessive disorder with clinical symptoms resulting from profound zinc deficiency secondary to an undefined defect in zinc absorption. The condition is characterized by dermatitis, failure to thrive, diarrhea, alopecia, nail dystrophy, severe gastrointestinal disturbances and frequent infections. Dermatitis lesions are vesciculobullous and are distributed in a symmetrical pattern in the acral and perioral regions. Treatment of choice is elemental zinc replacement.

Celiac disease is a malabsorption disorder secondary to sensitivity to gliadin, the alcohol-soluble portion of gluten found in cereal grains. An eczematous dermatitis, dermatitis herpetiformis, has been reported to occur in some patients. Dermatitis herpetiformis is ahighly pruritic skinrashthatis characterized by achronic papulovescicular eruption on the extensor surfaces and buttocks. This disorder is associated with celiac disease in up to 85% of patients. Treatment for celiac disease is life-long dietary avoidance of gluten-containing foods.

Immunological Diseases

Wiskott-Aldrich syndrome is an X-linked disorder characterized by the triad of throm-bocytopenia, recurrent infections and eczema. Patients have impairment of both humoral and cellular immune function. Increased serum immunoglobulin E is frequently found. The distribution of the eczematous rash is different from that typically seen in Atopic dermatitis and is less responsive to usual medical management.

Nezelof and DiGeorge syndromes are disorders of T-cell immunity. Both have been associated with eczematous rashes and elevated serum immunoglobulin E concentrations in some patients. The cause of the rash is unknown, but it is likely associated with the underlying immune dysfunction.

Severe combined immune deficiency is a disorder of profound humoral and cellular immune deficiency. In the first 6 months of life, infants frequently have failure to thrive, recurrent infections, diarrhea and dermatitis. Like other immune deficiency syndromes, the eczematous-appearing rash is in an atypical distribution and less responsive to conventional therapy.

Selective IgA deficiency is the most common immune deficiency disorder, affecting approx 1 in 400 individuals. It is characterized by decreased mucosal immunity, resulting in recurrent sinopulmonary, gastrointestinal and genitoureteral infections. Some patients remain asymptomatic while others manifest evidence of disease. IgA deficiency may be seen in association with atopic disease in some patients. These patients may develop asthma, allergic rhinitis or atopic dermatitis. The dermatitis is more typical of Atopic dermatitis, both in character and distribution.

Hyper-immunoglobulin E syndrome is an immune deficiency disorder characterized by markedly elevated serum immunoglobulin E concentrations primarily in association with recurrent, severe staphylococcal abscesses of the skin and lungs. A chronic, pruritic dermatitis is commonly seen, but does not occur in the same distribution or have the same course as Atopic dermatitis. Immunological abnormalities have been found in both humoral and cellular function.

Other Disorders

Leiner’s disease (erythroderma desquamativum) is a disorder that usually begins during the first few months of life and is characterized by severe generalized seborrheic dermatitis, intractable diarrhea, recurrent infections (usually Gram-negative organisms), and marked wasting and dystrophy. The dermatitis involves an intense erythema of the entire body and extensive large, yellow, greasy scales affecting large portions of the body surface. These scales are desquamative, and large skin areas may slough. immunoglobulin E levels are typically normal and eosinophils are not present. The exact etiology of this disease is unknown but a familial form exists and has been associated with dysfunction of the fifth component of complement (C5).

Langerhans’ cell histiocytosis disease is a lethal disorder that is a spectrum of diseases affecting the reticuloendothelial system. A subset of that spectrum, previously known as Letterer-Siwe disease, involves a dermatitis that displays features of both seborrhea and Atopic dermatitis. The eruption usually begins on the scalp and postauricular areas as a scaly, erythematous rash resembling seborrhea. The rash progresses to involve the trunk with dark, crusted papules that may be associated with petechiae or purpuric papules.