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Allergic skin diseases

2009; Elsevier BV; Volume: 125; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2009.05.039

1097-6825

Luz Fonacier, Stephen C. Dreskin, Donald Y.M. Leung,

Urticaria and Related Conditions

The skin is one of the largest immunologic organs and is affected by both external and internal factors, as well as innate and adaptive immune responses. Many skin disorders, such as atopic dermatitis, contact dermatitis, urticaria, angioedema, psoriasis, and autoimmune blistering disorders, are immune mediated. Most of these diseases are chronic, inflammatory, and proliferative, in which both genetic and environmental factors play important roles. These immunologic mechanisms might have implications for potential targets of future therapeutic interventions. The skin is one of the largest immunologic organs and is affected by both external and internal factors, as well as innate and adaptive immune responses. Many skin disorders, such as atopic dermatitis, contact dermatitis, urticaria, angioedema, psoriasis, and autoimmune blistering disorders, are immune mediated. Most of these diseases are chronic, inflammatory, and proliferative, in which both genetic and environmental factors play important roles. These immunologic mechanisms might have implications for potential targets of future therapeutic interventions. The skin is one of the largest immunologic organs and is often a target for allergic and immunologic responses. Many skin disorders, such as atopic dermatitis (AD), contact dermatitis (CD), urticaria, angioedema, psoriasis, and autoimmune blistering disorders, are immune mediated, with abnormalities in innate and adaptive immunity. Most of these diseases are chronic, inflammatory, and proliferative, in which both genetic and environmental factors play important roles. These immunologic mechanisms might have implications for potential targets of future therapeutic interventions. This review will examine some recent research advances in allergic and immunologic skin diseases. Allergists and clinical immunologists are seeing increasing numbers of patients with eczema and CD and are performing more patch testing. Cohort population-based studies in Europe showed point prevalence rates of 0.7% to 18.6% for allergic contact dermatitis (ACD).1Mortz C.G. Lauritsen J.M. Bindslev-Jensen C. Andersen K.E. Prevalence of atopic dermatitis, asthma, allergic rhinitis, and hand and contact dermatitis in adolescents. The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis.Br J Dermatol. 2001; 144: 523-532Crossref PubMed Scopus (270) Google Scholar, 2Nielsen N.H. Linneberg A. Menne T. Madsen F. Frølund L. Dirksen A. et al.Allergic contact sensitization in an adult Danish population: two cross-sectional surveys eight years apart (the Copenhagen Allergy Study).Acta Derm Venereol. 2001; 81: 31-34Crossref PubMed Scopus (163) Google Scholar Allergists trained in patch testing are more confident about the clinical relevance of such testing, especially for the differential diagnosis of the common eczematous diseases.3Fonacier L. Charlesworth E.M. Mak W.Y. Bahna S.L. American College of Allergy, Asthma & Immunology Patch Testing and Allergic Dermatologic Disease Survey: use of patch testing and effect of education on confidence, attitude, and usage.Am J Contact Dermat. 2002; 13: 164-169Crossref PubMed Scopus (14) Google Scholar CD can be allergic (20%) or irritant (80%). The morphology, severity, and location of CD is affected by the innate allergenicity or irritancy of the allergen, the site and degree of contact, the thickness and integrity of the skin involved, exposure time, environmental conditions, the immunocompetency of the patient, and even genetics. ACD is the prototype of the type IV cell-mediated hypersensitivity reaction. The allergens in ACD are usually small-molecular-weight molecules or haptens that conjugate with proteins in the skin and induce activated epidermal keratinocytes to release proinflammatory cytokines. The Langerhans cells endocytose, process, and combine specific hapten peptides with HLA class I molecules and then migrate to the draining regional lymph nodes, where they activate and sensitize naive CD4+ T cells (TH0 cells). Activated TH cells then proliferate and generate clones of hapten-specific CD4+CD25+ regulatory and CD8+ effector cells, which become either memory or effector cells. This is known as the afferent limb of the immune reaction. The CD4+ regulatory/effector and CD8+ effector cells then “home” to the original skin site and there function as the efferent limb of the immune response. Both CD4+ and CD8+ sensitized effector cells release proinflammatory cytokines/cytotoxins (INF-γ, TNF-α, GM-CSF, IL-2, perforin, and granzyme), which cause an intense perivascular inflammatory infiltrate and spongiosis. CD4+ CCR10 chemokine–expressing memory lymphocytes are retained for long periods of time in the original ACD sites, accounting for the shortened latent period (anamnesis) on subsequent exposure. In mice mast cells at the site of ACD have been shown to recruit polymorphonuclear leukocytes to the site through the release of the mediators TNF-α and IL-8. Irritant contact dermatitis (ICD) is the result of nonimmunologic, multifactorial, direct tissue reaction. T cells activated by means of nonimmune, irritant, or innate mechanisms release inflammatory cytokines (TNF-α, IL-1, IL-8, and GM-CSF) that contribute to the dose-dependent inflammation seen in patients with ICD.4Beltrani V. Bernstein L. Cohen D. Fonacier L. Berardesca E. Caraffini S. Corazza M. et al.Contact dermatitis, a practice parameter.Ann Allergy Asthma Immunol. 2006; 97: S1-S38Abstract Full Text PDF PubMed Google Scholar There is usually a higher concentration of offending agents, such as solvents, detergents, chemicals, and alcohol. Lesions with erythema, edema, desquamation, and fissures are sharply demarcated typically and limited to the area in direct contact with the offending agent. They can burn or sting. Scratching, scrubbing, washing, excessive wetness, improper drying, perspiration, and extremes of temperature contribute to the reaction (Table I).Table IDifferentiation between ICD and ACDCriteriaIICDACDAt riskAnyone, especially if repeated exposure and occupational exposurePreviously sensitized and genetically predisposedMechanismNonimmunologic, direct tissue damageImmunologic, delayed-type hypersensitivity reactionConcentration of offending agentUsually high, dose effectMight be low threshold dose, all or nothingCommon causative agentsWater, soaps, solvents detergents, acids, bases, saliva, urine, stoolPoison ivy, poison oak, poison sumac, metals, cosmetics, medications, rubber, resins, adhesivesRisk if atopicIncreasedDecreasedSymptomsBurning, stinging, sorenessItchingMorphologyErythema, edema, desquamation, fissuresErythema, edema, vesicles, papules, lichenificationDemarcationUsually sharp, limited to area in contact with agentSometimes sharpTypical onsetMinutes to hourHours to daysHistologySpongiosis, primarily neutrophilic infiltratesSpongiosis, primarily lymphocytic infiltrates Open table in a new tab ACD and ICD frequently overlap because many allergens at high enough concentrations can also act as irritants. Impairment of the epidermal barrier layer, such as fissuring, can increase allergen entry into the epidermis. The diagnosis of ACD is suspected from the clinical presentation of the rash and the possible exposure to a contact allergen. Fifty-five percent to 63.5% of eyelid dermatitis might be from ACD, 15% from ICD, less than 10% from AD, and 4% from seborrheic dermatitis.5Ayala F. Fabbrocini G. Bacchilega R. Berardesca E. Caraffini S. Corazza M. et al.Eyelid dermatitis: an evaluation of 447 patients.Am J Contact Dermat. 2003; 14: 69-74PubMed Google Scholar Data collected by the North American Contact Dermatitis Group (NACDG) showed that in 193 (72%) of 268 patients with only eyelid dermatitis, gold was the most common allergen. Fragrances, preservatives, nickel, thiuram (rubber), cocamidopropyl betaine (CAPB) and amidoamine (shampoos), and tosylamide formaldehyde resins (nail polish) are other allergens to consider in the evaluation of eyelid dermatitis.6Rietschel R.L. Warshaw E.M. Sasseville D. Fowler J.F. DeLeo V.A. Belsito D.V. et al.Common contact allergens associated with eyelid dermatitis: data from the North American Contact Dermatitis Group 2003-2004 study period.Dermatitis. 2007; 18: 78-81Crossref PubMed Scopus (45) Google Scholar In patients with mixed facial and eyelid dermatitis, nickel, Kathon, and fragrance had the most positive patch test responses.7Guin J.D. Eyelid dermatitis: experience in 203 cases.J Am Acad Dermatol. 2002; 47: 755-765Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 8Valsecchi R. Imberti G. Martino D. Cainelli T. Eyelid dermatitis: an evaluation of 150 patients.Contact Dermatitis. 1992; 27: 143-147Crossref PubMed Scopus (83) Google Scholar Hand dermatitis can be due to ICD, ACD, AD, dyshidrosis, or psoriasis. It can be extremely difficult to distinguish the cause of hand dermatitis, particularly because of tremendous overlap. Neither ACD nor ICD has pathognomonic clinical or histologic features. A thorough medical, work, and recreational history, together with a physical examination, ancillary laboratory tests, and patch tests, is critical in the evaluation of patients with hand eczema. Patch tests in patients with hand eczema showed that the relevant allergens include nickel sulfate (17.6%), potassium dichromate (7.2%), rubber elements (19.6%, including thiuram mix, carba mix, paraphenylenediamine [PPD], and mercaptobenzothiazole), and cobalt chloride (6.4%).9Duarte I. Terumi Nakano J. Lazzarini R. Hand eczema: evaluation of 250 patients.Am J Contact Dermat. 1998; 9: 216-223Crossref PubMed Google Scholar A Swedish study of 5700 patients showed that patients whose entire hands were involved were more likely to react to thiuram mix, PPD, chromate, and balsam of Peru. Patients with involvement of the fingers and interdigital spaces and those with palm involvement reacted more to nickel, cobalt, and 5-chloro-2-methyl-4-isothiazolin-3-one/2-methyl-4-isothiazolin-3-one.10Edman B. Statistical relations between hand eczema and contact allergens.in: Menné T. Maibach H.I. Hand eczema. 2nd ed. CRC Press, Boca Raton (LA)2000: 75-83Google Scholar The prevalence of hand eczema in patients with AD is 2- to 10-fold higher than that seen in nonatopic subjects, and 16% had nail dystrophy. The increasing prevalence of hand involvement with increasing age is probably due to increased water exposure and occupational insults, along with coexisting irritant dermatitis. Certain morphologic features can help distinguish the different contributing factors to hand eczema. Involvement of the dorsal hand and finger combined with the volar wrist suggest AD as a contributing causative factor.11Simpson E.L. Thompson M.M. Hanifin J.M. Prevalence and morphology of hand eczema in patients with atopic dermatitis.Dermatitis. 2006; 17: 123-127Crossref PubMed Scopus (49) Google Scholar ICD commonly presents as a localized dermatitis without vesicles in the webs of fingers; it extends onto the dorsal and ventral surfaces (“apron” pattern; Fig 1), dorsum of the hands, palms, and ball of the thumb. On the other hand, ACD often has vesicles and favors the fingertips, nail folds, and dorsum of the hands and less commonly involves the palms. ICD often precedes ACD, and therefore some pattern changes, such as increasing dermatitis from web spaces to fingertips or from palms to dorsal surfaces, should prompt patch testing or a repeat of it.12Warshaw E. Lee G. Storrs F.J. Hand dermatitis: a review of clinical features, therapeutic options, and long-term outcomes.Am J Contact Dermat. 2003; 14: 119-137PubMed Google Scholar Although ICD can cause dermatitis of the feet, ACD seem to be more common. ACD of the feet is usually located on the dorsum of the feet and toes (especially the hallux) but can also involve the sole and calcaneus. The interdigital areas are rarely involved. Humidity, heat, friction, and AD can contribute to or facilitate the development of CD of the feet. The most common positive patch test reactions in patients with ACD exclusively on the feet are rubber compounds (mercaptobenzothiazole mix, thiuram mix, carba mix, and PPD mix), with some patients sensitive to more than 1 of the agents. Other chemicals in footwear (eg, leather, adhesives, glues, and dyes) or in topical agents used for treatment (eg, creams, ointments, and antiperspirants) can cause ACD. Chemical agents used in the tanning and dyeing processes of leather (chrome), glues (colophony) used in soles and insoles, and nickel sulfate used in footwear buckles, eyelets, and ornaments13Lazzarini R. Duarte I. Marzagao C. Contact dermatitis of the feet: a study of 53 cases.Dermatitis. 2004; 15: 125-130Crossref PubMed Scopus (34) Google Scholar can be sensitizing agents. Systemic contact dermatitis (SCD) is a systemic disease that demonstrates the inherent role of the skin as an immunologic organ. In the event that the suppressor function is inadequate, systemic administration of an allergen can lead to a full-blown effector response. SCD is a localized or generalized inflammatory skin disease in contact-sensitized individuals exposed to the hapten orally, transcutaneously, intravenously, or by means of inhalation. It manifests as dermatitis at the cutaneous site of exposure, at previously sensitized sites (eg, an old lesion or the site of a previously positive patch test response), or in previously unaffected areas.14Jacob S.E. Zapolanski T. Systemic contact dermatitis.Dermatitis. 2008; 19: 9-15PubMed Google Scholar A variety of metals (cobalt, copper, chromium, gold, mercury, nickel, and zinc) have been found to cause SCD. The exposure type, duration, and environmental conditions (sweat and oxygen) in proximity to the metal are critical for mobilization of the ions inducing immune reactions. Medications reported to cause SCD include corticosteroids, antihistamines (diphenhydramine, ethylenediamine, hydroxyzine, and doxepin), miconazole, terbinafine, neomycin, gentamicin, erythromycin, pseudoephedrine, cinchocaine, benzocaine, tetracaine, oxycodone, intravenous immunoglobulin (IVIG), aminopenicillins, 5-aminosalicylic acid, naproxen, allopurinol, mitomycin C, 5-fluorouracil, and suxamethonium. In drug-induced SCD the clinical picture is frequently that of symmetric drug-related intertriginous and flexural exanthema. The criteria for the diagnosis of symmetric drug-related intertriginous and flexural exanthema include the following:1exposure to a systemic drug at first or repeated dosing (contact allergens excluded);2erythema of the gluteal/perianal area, V-shaped erythema of the inguinal/perianal area, or both;3involvement of at least 1 other intertriginous/flexural localization;4symmetry of affected areas; and5absence of systemic signs and symptoms.15Hausermann P. Harr T. Bircher A.J. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome?.Contact Dermatitis. 2004; 51: 297-310Crossref PubMed Scopus (221) Google Scholar With alternative medicine's increasing popularity, more patients are using herbal preparations, homeopathy, and herbs in food, spices, and cosmetics that might contain plants and botanical extracts. Ragweed, chamomile, feverfew (Tanacetum parthenium), Arnica species, marigold, Echinacea species, mugwort, cinnamon oil, vanilla oil, and balsam of Peru have been reported to cause SCD. CD in the occupational setting can be benign and short lived or lead to severe disabling dermatitis. Patients with severe cases have poorer prognosis despite improvements in general working conditions, better availability of diagnostic patch testing, improved understanding of cutaneous biology, and treatment with topical and systemic steroids. ACD to nickel or chromium, a history of chronic dermatitis, delay of adequate treatment, a history of AD, and poor understanding by the worker of his or her disease is associated with a worse prognosis. Treatment of ACD in the workplace includes a timely diagnosis, identification of allergens or irritants, elimination of causal exposures, patient education, and use of therapeutic agents. AD is an important factor in susceptibility to persistent postoccupational dermatitis, and potential involvement of genetic predisposition to chemicals is observed. Two genomic screens16Lee Y.A. Wahn U. Kehrt R. Tarani L. Businco L. Gustafsson D. et al.A major susceptibility locus for atopic dermatitis maps to chromosome 3q21.Nat Genet. 2000; 26: 470-473Crossref PubMed Scopus (235) Google Scholar, 17Cookson W.O. Ubhi B. Lawrence R. Abecasis G.R. Walley A.J. Cox H.E. et al.Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci.Nat Genet. 2001; 27: 372-373Crossref PubMed Scopus (332) Google Scholar showed areas of genetic linkage on several chromosomes. Patch testing is the only practical, scientific, and objective method for the diagnosis of ACD. It is indicated in patients with a chronic, pruritic, eczematous, or lichenified dermatitis in whom ACD is suspected. Patch test reactions are affected by oral corticosteroids (>20 mg of prednisone per day or its equivalent), cancer chemotherapy, or immunosuppressive drugs but not by antihistamines. Topical corticosteroids on the patch test site should be discontinued for 5 to 7 days before patch testing. Commercially available, standardized patch testing allergens have been calibrated with respect to nonirritant concentrations and compatibility with the test vehicle. Test systems currently available are the thin-layer rapid-use epicutaneous test (T.R.U.E. TEST) and certain screening panels that are not US Food and Drug Administration (FDA) approved but conform to the standards of care recommended by CD experts. Commercial sources of customized patch testing materials include Smart Practice Canada (Calgary, Alberta, Canada); Hermal Pharmaceutical Laboratories, Inc (Hawthorne, NY); Dormer Laboratories, Inc (Rexdale, Ontario, Canada); and Trolab Allergens (Omniderm Pharma Canada, Inc, Vaudreuil-Dorion, Quebec, Canada). The standardized allergens are loaded in Finn chambers or AllergEaze patch testing chambers (Haye's Service B.V., Alphen aan den Rijn, The Netherlands). Although the usefulness of patch testing is enhanced with the number of allergens tested, the ideal number of patch tests to be applied remains controversial. The T.R.U.E. Test contains 29 allergens, and the NACDG series ranges from 65 to 70 allergens. Studies show that the T.R.U.E. Test has higher false-negative reactions to neomycin, thiuram mix, balsam of Peru, fragrance mix, cobalt, and lanolin. Also, gold, bacitracin, methyldibromoglutaronitrile/phenoxyethanol, propylene glycol, bromonitropropane, cinnamic aldehyde, DMDM hydantoin, and ethylene urea/melamine formaldehyde have a prevalence of more than 2% in the NACDG 2004 but are not included in the current T.R.U.E. Test. Allergens not found on commercially available screening series in the United States frequently result in relevant reactions, and personal products are a useful supplement, especially in facial or periorbital dermatitis. The T.R.U.E. Test might serve as a triage or screening tool in an allergists' practice, but occupational exposures can benefit from early referral for supplemental testing. Patches are applied to upper or middle back areas (2.5 cm lateral to a midspinal reference point) free of dermatitis and hair and kept in place for 48 hours. Test results are read 30 minutes after removal of the patches to allow resolution of erythema caused by the tape, chamber, or both if present. A second reading should be done 3 to 5 days after the initial application. Thirty percent of relevant allergens eliciting negative reactions at the 48-hour reading elicit positive reactions in 96 hours. Irritant reactions tend to disappear by 96 hours. Metals (gold, potassium dichromate, nickel, and cobalt), topical antibiotics (neomycin and bacitracin), topical corticosteroids, and PPD can elicit positive reactions after 7 days. More than 50% of positive gold test results are delayed for about 1 week. Nonstandardized patch tests, such as with the patient's personal products, allergens from cosmetics, or industrial allergens, might be needed. Leave-on cosmetics (makeup, perfume, moisturizer, and nail polish), clothing, and most foods are tested “as is,” whereas wash-off cosmetics (soap and shampoo) are tested at 1:10 to 1:100 dilutions. Household and industrial products should only be tested after ascertaining their safety and patch test concentrations in the MSDS information. The relevance of positive reactions to clinical ACD can only be established by carefully correlating the history, including sources of antigen in the patient's environment. A positive patch test reaction might be relevant to present or previous dermatitis, multiple true-positive results can occur, and mild responses can still represent an allergic reaction. A positive patch test reaction is considered to be a “definite” reaction of ACD if the result of a “use test” with the suspected item was positive or the reaction to patch testing with the object or product was positive, “probable” if the antigen could be verified as present in known skin contactants and the clinical presentation was consistent, and “possible” if skin contact with materials known to contain allergen was likely. Multiple sensitivities can occur when different allergens are present in different products used simultaneously. Likewise, concomitant sensitization of allergens can occur when multiple allergens are present in the same product; both processes induce sensitization. Cross-sensitization can also occur. Common combinations of positive patch test results are PPD and benzocaine (cross-sensitize); thiuram mix, carba mix, and mercapto mix (rubber products); quaternium 15 and paraben (quarternium-15, a formaldehyde releaser and formaldehyde are frequently combined and cosensitize); and cobalt and nickel (cobalt used in alloys with nickel and chromium and cosensitized). Patients older than 40 years are prone to multiple sensitivities. The repeat open application test (ROAT) might confirm the presence or absence of ACD. The suspected allergens are applied to the antecubital fossa twice daily for 7 days and observed for dermatitis. The absence of reaction makes CD unlikely. If eyelid dermatitis is considered, ROAT can be performed on the back of the ear. The prevalence rate of a positive patch test reaction to nickel in North America is consistently increasing. The most recent patch test data from the NACDG18Warshaw E.M. Belsito D.V. DeLeo V.A. Fowler Jr., J.F. Maibach H.I. Marks J.G. et al.North American Contact Dermatitis Group patch-test results, 2003-2004 study period.Dermatitis. 2008; 19: 129-136PubMed Google Scholar reported that 18.7% of patients evaluated for ACD had a positive patch test reaction to nickel. Female subjects' sensitization to nickel is higher because of increased ear piercing. Laws regulating nickel products (eg, limiting the migration limit of nickel, the nickel ion release threshold of nickel-plated objects in prolonged contact with the skin, and the nickel content of post assemblies) in Europe appear to decrease sensitization in the younger population. Evidence supports the contribution of dietary nickel to vesicular hand eczema.19Kornik R. Zug K.A. Nickel.Dermatitis. 2008; 19: 3-8PubMed Google Scholar A meta-analysis of SCD estimated that about 1% of patients with nickel allergy would have systemic reactions to the nickel content of a normal diet. Ten percent would react to exposures to 0.55 to 0.89 mg of nickel.20Jensen C.S. Menne T. Johansen J.D. Systemic contact dermatitis after oral exposure to nickel: a review with a modified meta-analysis.Contact Dermatitis. 2006; 54: 79-86Crossref PubMed Scopus (103) Google Scholar Foods with higher nickel content include soybean, fig, cocoa, lentil, cashew, nuts, and raspberry (Table II).Table IINickel content of certain foods>50 μgSoybean, boiled, ∼1 cup: 895 μg Cocoa, 1 tbsp: 147 μg Cashew, ∼18 nuts: 143 μgFigs, ∼5: 85 μg Lentils, ½ cup cooked: 61 μg Raspberry: 56 μg20-50 μgVegetables, canned ½ cup: 40 μg Lobster, 3 oz: 30 μg Peas, frozen ½ cup: 27 μgAsparagus, 6 spears: 25 μg Oat flakes, ⅔ cup: 25 μg Pistachios, 47 nuts: 23 μg<20 μgStrawberries, 7 medium: 9 μg Wheat bread, 1 slice: 5 μg Poultry, 3.5 oz: 5 μg Carrots, 8 sticks: 5 μg Apple, 1 medium: 5 μgCheese, 1.5 oz: 3 μg Yogurt, 1 cup: 3 μg Mineral water, 8 fl oz: 3 μg Mushroom, raw ½ cup: 2 μg Corn flakes, 1 cup: 2 μg Open table in a new tab Previous NACDG data reported that 389 (9.5%) of 4101 patients had positive patch test reactions to gold. The most common sites of dermatitis were in the hands (29.6%); the face, with seborrheic distribution (19.3%); and the eyelids (7.5%).21Fowler Jr., J. Taylor J. Storrs F. Sherertz E. Rietschel R. Pratt M. et al.Gold allergy in North America.Am J Contact Dermat. 2001; 12: 3-5Crossref PubMed Scopus (65) Google Scholar Although mostly used for fashion appeal, gold is also an anti-inflammatory medication, is used in the electroplating industry, and is part of dental appliances. Patients with gold dental appliances (especially if present for more than 10 years) can present with oral symptoms. A subset of patients with facial dermatitis clear with gold avoidance, mostly women with titanium dioxide in facial cosmetics, which adsorbs gold released from jewelry. Patients with gold allergy and eyelid dermatitis have cleared by not wearing gold jewelry, and therefore a trial of gold avoidance might be warranted with positive patch test reactions to gold. The avoidance period required for demonstrating benefit is long and might only be partially mitigating.22Ehrlich A. Belsito D.V. Allergic contact dermatitis to gold.Cutis. 2000; 65: 323-326PubMed Google Scholar An individual is exposed to more than 100 chemical contactants in a typical day. Common allergens in these products include fragrances, preservatives, excipients, glues, and sun blocks. Fragrance, the allergen of the year for 2007, is the most common cause of ACD from cosmetics and results in positive patch test reactions in 10.4% of patients. There are more than 2800 fragrance ingredients listed in the database of the Research Institute for Fragrance Materials, Inc,23Johansen J.D. Fragrance contact allergy: a clinical review.Am J Clin Dermatol. 2003; 4: 789-798Crossref PubMed Scopus (101) Google Scholar and more new chemicals and botanical extracts are frequently used as fragrances. A manufacturer's label of “unscented” might erroneously suggest absence of fragrance when, in fact, a masking fragrance is present. “Fragrance-free” products are typically free of classic fragrance ingredients and are generally acceptable for the allergic patient. However, botanical extracts can be added to improve odor characteristics. Because fragrances are complex substances, a perfume can contain hundreds of different chemicals that are difficult to identify individually. Fragrance mix I contains allergens found in 15% to 100% of cosmetic products23Johansen J.D. Fragrance contact allergy: a clinical review.Am J Clin Dermatol. 2003; 4: 789-798Crossref PubMed Scopus (101) Google Scholar and might detect approximately 85% of subjects with fragrance allergy.24Storrs F.J. Fragrance.Dermatitis. 2007; 18: 3-7Crossref PubMed Scopus (39) Google Scholar The addition of other commonly used fragrance ingredients (ylang ylang oil, narcissus oil, sandalwood oil, and balsam of Peru) increases the yield to 96%. The actual fragrance mix widely used in cosmetics and household products are seldom used in patch testing by the NACDG. Thus a positive patch test reaction to fragrance must correlate with distribution of the dermatitis and an evaluation of clinical relevance, such as a positive ROAT reaction. Lanolin is a common component of consumer products. Unfortunately, its composition has not been fully characterized. Medicaments containing lanolin are more sensitizing than lanolin-containing cosmetics. It is a weak sensitizer on normal skin but a stronger sensitizer on damaged skin. Thus patients with chronic dermatitis, especially stasis dermatitis, are at higher risk of lanolin sensitivity.25Lee B. Warshaw E. Lanolin allergy: history, epidemiology, responsible allergens, and management.Dermatitis. 2008; 19: 63-72Crossref PubMed Google Scholar Cosmetic preservatives can be grouped into formaldehyde releasers and non–formaldehyde releasers. Paraben, a non–formaldehyde releaser, is the most commonly used preservative in cosmetics, as well as in pharmaceutical and industrial products, because of its broad spectrum of activity against yeasts, molds, and bacteria. Type I immediate hypersensitivity reactions (contact urticaria) and SCD from ingestion of paraben-containing medications or foods have been reported.26Cashman A.L. Warshaw E.M. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties.Dermatitis. 2005; 16: 57-66Crossref PubMed Google Scholar Hair products are second only to skin products as the most common cause of cosmetic allergy. PPD is currently the most common cause of CD in hairdressers. In hair dye users the dermatitis often spares the scalp and usually involves the face near the hairline, eyelids, and neck. Nevertheless, generalized eruptions can occur. IgE–mediated contact urticaria and anaphylaxis, as well as lymphomatoid reactions, have also been reported. PPD cross-reacts with other chemicals, such as COX-2 inhibitor (celecoxib), sunscreens, and antioxidants used in the manufacture of rubber products (N-isopropyl-N′-phenyl-p-phenylenediamine). Theoretically, once oxidized, the PPD is no longer allergenic, but in reality, it is likely that PPD is never completely oxidized.27DeLeo V.A. p-Ph