Contact Dermatitis

What is the world’s most dangerous tree? According to Guinness World Records¹ (and one unlucky contestant on the wilderness survival reality show Naked and Afraid,² who got its sap in his eyes and needed to be evacuated for treatment), the manchineel tree (Hippomane mancinella) has earned this designation.^1-3 Manchineel trees are part of the strand vegetation of islands in the West Indies and along the Caribbean coasts of South and Central America, where their copious root systems help reduce coastal erosion. In the United States, this poisonous tree grows along the southern edge of Florida’s Everglades National Park; the Florida Keys; and the US Virgin Islands, especially Virgin Islands National Park. Although the manchineel tree appears on several endangered species lists,^4-6 there are places within its distribution where it is locally abundant and thus poses a risk to residents and visitors.

The first European description of manchineel toxicity was by Peter Martyr d’Anghiera, a court historian and geographer of Christopher Columbus’s patroness, Isabella I, Queen of Castile and Léon. In the early 1500s, Peter Martyr wrote that on Columbus’s second New World voyage in 1493, the crew encountered a mysterious tree that burned the skin and eyes of anyone who had contact with it.⁷ Columbus called the tree’s fruit manzanilla de la muerte (“little apple of death”) after several sailors became severely ill from eating the fruit.^8,9 Manchineel lore is rife with tales of agonizing death after eating the applelike fruit, and several contemporaneous accounts describe indigenous Caribbean islanders using manchineel’s toxic sap as an arrow poison.¹⁰

Eating manchineel fruit is known to cause abdominal pain, burning sensations in the oropharynx, and esophageal spasms.¹¹ Several case reports mention that consuming the fruit can create an exaggerated parasympathomimetic syndrome due to suspected anticholinesteraselike compounds.^3,11,12 Ophthalmologic injuries include severe conjunctivitis—sometimes extensive enough to cause superficial punctate epithelial keratitis.⁵ Dermatologic injuries have been described, but reports on its histopathologic features are limited. We present a case of manchineel dermatitis in a patient who subsequently underwent a skin biopsy.

Case Report

A 64-year-old physician (S.A.N.) came across a stand of manchineel trees while camping in the Virgin Islands National Park on St. John in the US Virgin Islands (Figure 1). The patient—who was knowledgeable about tropical ecology and was familiar with the tree—was curious about its purported cutaneous toxicity and applied the viscous white sap of a broken branchlet (Figure 2) to a patch of skin measuring 4 cm in diameter on the medial left calf. He took serial photographs of the site on days 2, 4 (Figure 3), 6, and 10 (Figure 4), showing the onset of erythema and the subsequent development of follicular pustules. On day 6, a 4-mm punch biopsy specimen was taken of the most prominent pustule. Histopathology showed a subcorneal acantholytic blister and epidermal spongiosis overlying a mixed perivascular infiltrate and follicular necrosis, which was consistent with irritant contact dermatitis (Figure 5). On day 8, the region became indurated and tender to pressure; however, there was no warmth, edema, purulent drainage, lymphangitic streaks, or other signs of infection. The region was never itchy; it was uncomfortable only with firm direct pressure. The patient applied hot compresses to the site for 10 minutes 1 to 2 times daily for roughly 2 weeks, and the affected area healed fully (without any additional intervention) in approximately 6 weeks.

Comment

Manchineel is a member of the Euphorbiaceae (also known as the euphorb or spurge) family, a mainly tropical or subtropical plant family that includes many useful as well as many toxic species. Examples of useful plants include cassava (Manihot esculenta) and the rubber tree (Hevea brasiliensis). Many euphorbs have well-described toxicities, and many (eg, castor bean, Ricinus communis) are useful in some circumstances and toxic in others.^6,12-14 Many euphorbs are known to cause skin reactions, usually due to toxins in the milky sap that directly irritate the skin or to latex compounds that can induce IgE-mediated contact dermatitis.^9,14

Manchineel contains a complex mix of toxins, though no specific one has been identified as the main cause of the associated irritant contact dermatitis. Manchineel sap (and sap of many other euphorbs) contains phorbol esters that may cause direct pH-induced cytotoxicity leading to keratinocyte necrosis. Diterpenes may augment this cytotoxic effect via induction of proinflammatory cytokines.¹² Pitts et al⁵ pointed to a mixture of oxygenated diterpene esters as the primary cause of toxicity and suggested that their water solubility explained occurrences of keratoconjunctivitis after contact with rainwater or dew from the manchineel tree.

All parts of the manchineel tree—fruit, leaves, wood, and sap—are poisonous. In a retrospective series of 97 cases of manchineel fruit ingestion, the most common symptoms were oropharyngeal pain (68% [66/97]), abdominal pain (42% [41/97]), and diarrhea (37% [36/97]). The same series identified 1 (1%) case of bradycardia and hypotension.³ Contact with the wood, exposure to sawdust, and inhalation of smoke from burning the wood can irritate the skin, conjunctivae, or nasopharynx. Rainwater or dew dripping from the leaves onto the skin can cause dermatitis and ophthalmitis, even without direct contact with the tree.^4,5

Management—There is no specific treatment for manchineel dermatitis. Because it is an irritant reaction and not a type IV hypersensitivity reaction, topical corticosteroids have minimal benefit. A regimen consisting of a thorough cleansing, wet compresses, and observation, as most symptoms resolve spontaneously within a few days, has been recommended.⁴ Our patient used hot compresses, which he believes helped heal the site, although his symptoms lasted for several weeks.

Given that there is no specific treatment for manchineel dermatitis, the wisest approach is strict avoidance. On many Caribbean islands, visitors are warned about the manchineel tree, advised to avoid direct contact, and reminded to avoid standing beneath it during a rainstorm (Figure 6).

Conclusion

This article begins with a question: “What is the world’s most dangerous tree?” Many sources from the indexed medical literature as well as the popular press and social media state that it is the manchineel. Although all parts of the manchineel tree are highly toxic, human exposures are uncommon, and deaths are more apocryphal than actual.

What is the world’s most dangerous tree? According to Guinness World Records¹ (and one unlucky contestant on the wilderness survival reality show Naked and Afraid,² who got its sap in his eyes and needed to be evacuated for treatment), the manchineel tree (Hippomane mancinella) has earned this designation.^1-3 Manchineel trees are part of the strand vegetation of islands in the West Indies and along the Caribbean coasts of South and Central America, where their copious root systems help reduce coastal erosion. In the United States, this poisonous tree grows along the southern edge of Florida’s Everglades National Park; the Florida Keys; and the US Virgin Islands, especially Virgin Islands National Park. Although the manchineel tree appears on several endangered species lists,^4-6 there are places within its distribution where it is locally abundant and thus poses a risk to residents and visitors.

The first European description of manchineel toxicity was by Peter Martyr d’Anghiera, a court historian and geographer of Christopher Columbus’s patroness, Isabella I, Queen of Castile and Léon. In the early 1500s, Peter Martyr wrote that on Columbus’s second New World voyage in 1493, the crew encountered a mysterious tree that burned the skin and eyes of anyone who had contact with it.⁷ Columbus called the tree’s fruit manzanilla de la muerte (“little apple of death”) after several sailors became severely ill from eating the fruit.^8,9 Manchineel lore is rife with tales of agonizing death after eating the applelike fruit, and several contemporaneous accounts describe indigenous Caribbean islanders using manchineel’s toxic sap as an arrow poison.¹⁰

Eating manchineel fruit is known to cause abdominal pain, burning sensations in the oropharynx, and esophageal spasms.¹¹ Several case reports mention that consuming the fruit can create an exaggerated parasympathomimetic syndrome due to suspected anticholinesteraselike compounds.^3,11,12 Ophthalmologic injuries include severe conjunctivitis—sometimes extensive enough to cause superficial punctate epithelial keratitis.⁵ Dermatologic injuries have been described, but reports on its histopathologic features are limited. We present a case of manchineel dermatitis in a patient who subsequently underwent a skin biopsy.

Case Report

A 64-year-old physician (S.A.N.) came across a stand of manchineel trees while camping in the Virgin Islands National Park on St. John in the US Virgin Islands (Figure 1). The patient—who was knowledgeable about tropical ecology and was familiar with the tree—was curious about its purported cutaneous toxicity and applied the viscous white sap of a broken branchlet (Figure 2) to a patch of skin measuring 4 cm in diameter on the medial left calf. He took serial photographs of the site on days 2, 4 (Figure 3), 6, and 10 (Figure 4), showing the onset of erythema and the subsequent development of follicular pustules. On day 6, a 4-mm punch biopsy specimen was taken of the most prominent pustule. Histopathology showed a subcorneal acantholytic blister and epidermal spongiosis overlying a mixed perivascular infiltrate and follicular necrosis, which was consistent with irritant contact dermatitis (Figure 5). On day 8, the region became indurated and tender to pressure; however, there was no warmth, edema, purulent drainage, lymphangitic streaks, or other signs of infection. The region was never itchy; it was uncomfortable only with firm direct pressure. The patient applied hot compresses to the site for 10 minutes 1 to 2 times daily for roughly 2 weeks, and the affected area healed fully (without any additional intervention) in approximately 6 weeks.

Comment

Manchineel is a member of the Euphorbiaceae (also known as the euphorb or spurge) family, a mainly tropical or subtropical plant family that includes many useful as well as many toxic species. Examples of useful plants include cassava (Manihot esculenta) and the rubber tree (Hevea brasiliensis). Many euphorbs have well-described toxicities, and many (eg, castor bean, Ricinus communis) are useful in some circumstances and toxic in others.^6,12-14 Many euphorbs are known to cause skin reactions, usually due to toxins in the milky sap that directly irritate the skin or to latex compounds that can induce IgE-mediated contact dermatitis.^9,14

Manchineel contains a complex mix of toxins, though no specific one has been identified as the main cause of the associated irritant contact dermatitis. Manchineel sap (and sap of many other euphorbs) contains phorbol esters that may cause direct pH-induced cytotoxicity leading to keratinocyte necrosis. Diterpenes may augment this cytotoxic effect via induction of proinflammatory cytokines.¹² Pitts et al⁵ pointed to a mixture of oxygenated diterpene esters as the primary cause of toxicity and suggested that their water solubility explained occurrences of keratoconjunctivitis after contact with rainwater or dew from the manchineel tree.

All parts of the manchineel tree—fruit, leaves, wood, and sap—are poisonous. In a retrospective series of 97 cases of manchineel fruit ingestion, the most common symptoms were oropharyngeal pain (68% [66/97]), abdominal pain (42% [41/97]), and diarrhea (37% [36/97]). The same series identified 1 (1%) case of bradycardia and hypotension.³ Contact with the wood, exposure to sawdust, and inhalation of smoke from burning the wood can irritate the skin, conjunctivae, or nasopharynx. Rainwater or dew dripping from the leaves onto the skin can cause dermatitis and ophthalmitis, even without direct contact with the tree.^4,5

Management—There is no specific treatment for manchineel dermatitis. Because it is an irritant reaction and not a type IV hypersensitivity reaction, topical corticosteroids have minimal benefit. A regimen consisting of a thorough cleansing, wet compresses, and observation, as most symptoms resolve spontaneously within a few days, has been recommended.⁴ Our patient used hot compresses, which he believes helped heal the site, although his symptoms lasted for several weeks.

Given that there is no specific treatment for manchineel dermatitis, the wisest approach is strict avoidance. On many Caribbean islands, visitors are warned about the manchineel tree, advised to avoid direct contact, and reminded to avoid standing beneath it during a rainstorm (Figure 6).

Conclusion

This article begins with a question: “What is the world’s most dangerous tree?” Many sources from the indexed medical literature as well as the popular press and social media state that it is the manchineel. Although all parts of the manchineel tree are highly toxic, human exposures are uncommon, and deaths are more apocryphal than actual.

What is the world’s most dangerous tree? According to Guinness World Records¹ (and one unlucky contestant on the wilderness survival reality show Naked and Afraid,² who got its sap in his eyes and needed to be evacuated for treatment), the manchineel tree (Hippomane mancinella) has earned this designation.^1-3 Manchineel trees are part of the strand vegetation of islands in the West Indies and along the Caribbean coasts of South and Central America, where their copious root systems help reduce coastal erosion. In the United States, this poisonous tree grows along the southern edge of Florida’s Everglades National Park; the Florida Keys; and the US Virgin Islands, especially Virgin Islands National Park. Although the manchineel tree appears on several endangered species lists,^4-6 there are places within its distribution where it is locally abundant and thus poses a risk to residents and visitors.

The first European description of manchineel toxicity was by Peter Martyr d’Anghiera, a court historian and geographer of Christopher Columbus’s patroness, Isabella I, Queen of Castile and Léon. In the early 1500s, Peter Martyr wrote that on Columbus’s second New World voyage in 1493, the crew encountered a mysterious tree that burned the skin and eyes of anyone who had contact with it.⁷ Columbus called the tree’s fruit manzanilla de la muerte (“little apple of death”) after several sailors became severely ill from eating the fruit.^8,9 Manchineel lore is rife with tales of agonizing death after eating the applelike fruit, and several contemporaneous accounts describe indigenous Caribbean islanders using manchineel’s toxic sap as an arrow poison.¹⁰

Eating manchineel fruit is known to cause abdominal pain, burning sensations in the oropharynx, and esophageal spasms.¹¹ Several case reports mention that consuming the fruit can create an exaggerated parasympathomimetic syndrome due to suspected anticholinesteraselike compounds.^3,11,12 Ophthalmologic injuries include severe conjunctivitis—sometimes extensive enough to cause superficial punctate epithelial keratitis.⁵ Dermatologic injuries have been described, but reports on its histopathologic features are limited. We present a case of manchineel dermatitis in a patient who subsequently underwent a skin biopsy.

Case Report

A 64-year-old physician (S.A.N.) came across a stand of manchineel trees while camping in the Virgin Islands National Park on St. John in the US Virgin Islands (Figure 1). The patient—who was knowledgeable about tropical ecology and was familiar with the tree—was curious about its purported cutaneous toxicity and applied the viscous white sap of a broken branchlet (Figure 2) to a patch of skin measuring 4 cm in diameter on the medial left calf. He took serial photographs of the site on days 2, 4 (Figure 3), 6, and 10 (Figure 4), showing the onset of erythema and the subsequent development of follicular pustules. On day 6, a 4-mm punch biopsy specimen was taken of the most prominent pustule. Histopathology showed a subcorneal acantholytic blister and epidermal spongiosis overlying a mixed perivascular infiltrate and follicular necrosis, which was consistent with irritant contact dermatitis (Figure 5). On day 8, the region became indurated and tender to pressure; however, there was no warmth, edema, purulent drainage, lymphangitic streaks, or other signs of infection. The region was never itchy; it was uncomfortable only with firm direct pressure. The patient applied hot compresses to the site for 10 minutes 1 to 2 times daily for roughly 2 weeks, and the affected area healed fully (without any additional intervention) in approximately 6 weeks.

Comment

Manchineel is a member of the Euphorbiaceae (also known as the euphorb or spurge) family, a mainly tropical or subtropical plant family that includes many useful as well as many toxic species. Examples of useful plants include cassava (Manihot esculenta) and the rubber tree (Hevea brasiliensis). Many euphorbs have well-described toxicities, and many (eg, castor bean, Ricinus communis) are useful in some circumstances and toxic in others.^6,12-14 Many euphorbs are known to cause skin reactions, usually due to toxins in the milky sap that directly irritate the skin or to latex compounds that can induce IgE-mediated contact dermatitis.^9,14

Manchineel contains a complex mix of toxins, though no specific one has been identified as the main cause of the associated irritant contact dermatitis. Manchineel sap (and sap of many other euphorbs) contains phorbol esters that may cause direct pH-induced cytotoxicity leading to keratinocyte necrosis. Diterpenes may augment this cytotoxic effect via induction of proinflammatory cytokines.¹² Pitts et al⁵ pointed to a mixture of oxygenated diterpene esters as the primary cause of toxicity and suggested that their water solubility explained occurrences of keratoconjunctivitis after contact with rainwater or dew from the manchineel tree.

All parts of the manchineel tree—fruit, leaves, wood, and sap—are poisonous. In a retrospective series of 97 cases of manchineel fruit ingestion, the most common symptoms were oropharyngeal pain (68% [66/97]), abdominal pain (42% [41/97]), and diarrhea (37% [36/97]). The same series identified 1 (1%) case of bradycardia and hypotension.³ Contact with the wood, exposure to sawdust, and inhalation of smoke from burning the wood can irritate the skin, conjunctivae, or nasopharynx. Rainwater or dew dripping from the leaves onto the skin can cause dermatitis and ophthalmitis, even without direct contact with the tree.^4,5

Management—There is no specific treatment for manchineel dermatitis. Because it is an irritant reaction and not a type IV hypersensitivity reaction, topical corticosteroids have minimal benefit. A regimen consisting of a thorough cleansing, wet compresses, and observation, as most symptoms resolve spontaneously within a few days, has been recommended.⁴ Our patient used hot compresses, which he believes helped heal the site, although his symptoms lasted for several weeks.

Given that there is no specific treatment for manchineel dermatitis, the wisest approach is strict avoidance. On many Caribbean islands, visitors are warned about the manchineel tree, advised to avoid direct contact, and reminded to avoid standing beneath it during a rainstorm (Figure 6).

Conclusion

This article begins with a question: “What is the world’s most dangerous tree?” Many sources from the indexed medical literature as well as the popular press and social media state that it is the manchineel. Although all parts of the manchineel tree are highly toxic, human exposures are uncommon, and deaths are more apocryphal than actual.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49 Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49 Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49 Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

The mango tree (Mangifera indica) produces ­nutrient-dense fruit—known colloquially as the “king of fruits”—that is widely consumed across the world. Native to southern Asia, the mango tree is a member of the Anacardiaceae family, a large family of flowering, fruit-bearing plants.¹ Many members of the Anacardiaceae family, which includes poison ivy and poison oak, are known to produce urushiol, a skin irritant associated with allergic contact dermatitis (ACD).² Interestingly, despite its widespread consumption and categorization in the Anacardiaceae family, allergic reactions to mango are comparatively rare; they occur as either immediate type I hypersensitivity reactions manifesting with rapid-onset symptoms such as urticaria, wheezing, and angioedema, or delayed type IV hypersensitivity reactions manifesting as ACD.³ Although exposure to components of the mango tree has been most characteristically linked to type IV hypersensitivity reactions, there remain fewer than 40 reported cases of mango-induced ACD since it was first described in 1939.⁴

Evaluation of ACD most commonly includes a thorough clinical assessment with diagnostic support from patch testing and histopathologic review following skin biopsy. In recent years, reflectance confocal microscopy (RCM) has shown promising potential to join the ­repertoire of diagnostic tools for ACD by enabling dynamic and high-resolution imaging of contact dermatitis in vivo.^5-10 Reflectance confocal microscopy is a noninvasive optical imaging technique that uses a low-energy diode laser to penetrate the layers of the skin. The resulting reflected light generates images that facilitate visualization of cutaneous structures to the depth of the papillary dermis.¹¹ While it is most commonly used in skin cancer diagnostics, preliminary studies also have shown an emerging role for RCM in the evaluation of eczematous and inflammatory skin disease, including contact dermatitis.^5-10 Herein, we present a unique case of mango sap–induced ACD imaged and diagnosed in real time via RCM.

Case Report

A 39-year-old woman presented to our clinic with a pruritic vesicular eruption on the right leg of 2 weeks’ duration that initially had developed within 7 days of exposure to mango tree sap (Figure 1). The patient reported having experienced similar pruritic eruptions in the past following contact with mango sap while eating mangos but denied any history of reactions from ingestion of the fruit. She also reported a history of robust reactions to poison ivy; however, a timeline specifying the order of first exposure to these irritants was unknown. She denied any personal or family history of atopic conditions.

The affected skin was imaged in real time during clinic using RCM, which showed an inflammatory infiltrate represented by dark spongiotic vesicles containing bright cells (Figure 2). Additional RCM imaging at the level of the stratum spinosum showed dark spongiotic areas with bright inflammatory cells infiltrating the vesicles, which were surrounded by normal skin showing a typical epidermal honeycomb pattern (Figure 3). These findings were diagnostic of ACD secondary to exposure to mango sap. The patient was advised to apply clobetasol cream 0.05% to the affected area. Notable improvement of the rash was noted within 10 days of treatment.

Comment

Exposure to the mango tree and its fruit is a rare cause of ACD, with few reported cases in the literature. The majority of known instances have occurred in non–mango-cultivating countries, largely the United States, although cases also have been reported in Canada, Australia, France, Japan, and Thailand.^3,12 Mango-induced contact allergy follows a roughly equal distribution between males and females and most often occurs in young adults during the third and fourth decades of life.^4,12-21 Importantly, delayed-type hypersensitivity reactions to mango can manifest as either localized or systemic ACD. Localized ACD can be induced via direct contact with the mango tree and its components or ingestion of the fruit.^3,12,22 Conversely, systemic ACD is primarily stimulated by ingestion of the fruit. In our case, the patient had no history of allergy following mango ingestion, and her ACD was prompted by isolated contact with mango sap. The time from exposure to symptom onset of known instances of mango ACD varies widely, ranging from less than 24 hours to as long as 9 days.^3,12 Diagnosis of mango-induced ACD largely is guided by clinical findings. Presenting symptoms often include an eczematous, vesicular, pruritic rash on affected areas of the skin, frequently the head, neck, and extremities. Patients also commonly present with linear papulovesicular lesions and periorbital or perioral edema.

The suspected allergens responsible for mango-induced ACD are derived from resorcinol—specifically heptadecadienyl resorcinol, heptadecenyl resorcinol, and pentadecyl resorcinol, which are collectively known as mango allergens.²³ These allergens can be found within the pulp and skin of the mango fruit as well as in the bark and leaves of the mango tree, which may explain observed allergic reactions to components of both the mango fruit and tree.¹² Similar to these resorcinol derivatives, the urushiol resin found in poison ivy and poison oak is a catechol derivative.² Importantly, both resorcinols and catechols are isomers of the same aromatic ­phenol—dihydroxybenzene. Because of these similarities, it is thought that the allergens in mangos may cross-react with urushiol in poison ivy or poison oak.²³ Alongside their shared categorization in the Anacardiaceae family, it is hypothesized that this cross-reactivity underlies the sensitization that has been noted between mango and poison ivy or poison oak exposure.^12,23,24 Thus, ACD often can occur on initial contact with the mango tree or its components, as a prior exposure to poison ivy or poison oak may serve as the inciting factor for hypersensitization. The majority of reported cases in the literature also occurred in countries where exposure to poison ivy and poison oak are common, further supporting the notion that these compounds may provide a sensitizing trigger for a future mango contact allergy.¹²

A detailed clinical history combined with adjunctive diagnostic support from patch testing and histopathology of biopsied skin lesions classically are used in the diagnosis of mango-induced ACD. Due to its ability to provide quick and noninvasive in vivo imaging of cutaneous lesions, RCM's applications have expanded to include evaluation of inflammatory skin diseases such as contact dermatitis. Many features of contact dermatitis identified via RCM are common between ACD and irritant contact dermatitis (ICD) and include disruption of the stratum corneum, parakeratosis, vesiculation, spongiosis, and exocytosis.^6,10,25 Studies also have described features shown via RCM that are unique to ACD, including vasodilation and intercellular edema, compared to more distinct targetoid keratinocytes and detached corneocytes seen in ICD.^6,10,25 Studies by Astner et al^5,6 demonstrated a wide range of sensitivity from 52% to 96% and a high specificity of RCM greater than 95% for many of the aforementioned features of contact dermatitis, including disruption of the stratum corneum, parakeratosis, spongiosis, and exocytosis. Additional studies have further strengthened these findings, demonstrating sensitivity and specificity values of 83% and 92% for contact dermatitis under RCM, respectively.²⁶ Importantly, given the similarities and potentially large overlap of features between ACD and ICD identified via RCM as well as findings seen on physical examination and histopathology, an emphasis on clinical correlation is essential when differentiating between these 2 variants of contact dermatitis. Thus, taken in consideration with clinical contexts, RCM has shown potent diagnostic accuracy and great potential to support the evaluation of ACD alongside patch testing and histopathology.

Final Thoughts

Contact allergy to the mango tree and its components is uncommon. We report a unique case of mango sap–induced ACD evaluated and diagnosed via dynamic visualization under RCM. As a noninvasive and reproducible imaging technique with resolutions comparable to histopathologic analysis, RCM is a promising tool that can be used to support the diagnostic evaluation of ACD.

The mango tree (Mangifera indica) produces ­nutrient-dense fruit—known colloquially as the “king of fruits”—that is widely consumed across the world. Native to southern Asia, the mango tree is a member of the Anacardiaceae family, a large family of flowering, fruit-bearing plants.¹ Many members of the Anacardiaceae family, which includes poison ivy and poison oak, are known to produce urushiol, a skin irritant associated with allergic contact dermatitis (ACD).² Interestingly, despite its widespread consumption and categorization in the Anacardiaceae family, allergic reactions to mango are comparatively rare; they occur as either immediate type I hypersensitivity reactions manifesting with rapid-onset symptoms such as urticaria, wheezing, and angioedema, or delayed type IV hypersensitivity reactions manifesting as ACD.³ Although exposure to components of the mango tree has been most characteristically linked to type IV hypersensitivity reactions, there remain fewer than 40 reported cases of mango-induced ACD since it was first described in 1939.⁴

Evaluation of ACD most commonly includes a thorough clinical assessment with diagnostic support from patch testing and histopathologic review following skin biopsy. In recent years, reflectance confocal microscopy (RCM) has shown promising potential to join the ­repertoire of diagnostic tools for ACD by enabling dynamic and high-resolution imaging of contact dermatitis in vivo.^5-10 Reflectance confocal microscopy is a noninvasive optical imaging technique that uses a low-energy diode laser to penetrate the layers of the skin. The resulting reflected light generates images that facilitate visualization of cutaneous structures to the depth of the papillary dermis.¹¹ While it is most commonly used in skin cancer diagnostics, preliminary studies also have shown an emerging role for RCM in the evaluation of eczematous and inflammatory skin disease, including contact dermatitis.^5-10 Herein, we present a unique case of mango sap–induced ACD imaged and diagnosed in real time via RCM.

Case Report

A 39-year-old woman presented to our clinic with a pruritic vesicular eruption on the right leg of 2 weeks’ duration that initially had developed within 7 days of exposure to mango tree sap (Figure 1). The patient reported having experienced similar pruritic eruptions in the past following contact with mango sap while eating mangos but denied any history of reactions from ingestion of the fruit. She also reported a history of robust reactions to poison ivy; however, a timeline specifying the order of first exposure to these irritants was unknown. She denied any personal or family history of atopic conditions.

The affected skin was imaged in real time during clinic using RCM, which showed an inflammatory infiltrate represented by dark spongiotic vesicles containing bright cells (Figure 2). Additional RCM imaging at the level of the stratum spinosum showed dark spongiotic areas with bright inflammatory cells infiltrating the vesicles, which were surrounded by normal skin showing a typical epidermal honeycomb pattern (Figure 3). These findings were diagnostic of ACD secondary to exposure to mango sap. The patient was advised to apply clobetasol cream 0.05% to the affected area. Notable improvement of the rash was noted within 10 days of treatment.

Comment

Exposure to the mango tree and its fruit is a rare cause of ACD, with few reported cases in the literature. The majority of known instances have occurred in non–mango-cultivating countries, largely the United States, although cases also have been reported in Canada, Australia, France, Japan, and Thailand.^3,12 Mango-induced contact allergy follows a roughly equal distribution between males and females and most often occurs in young adults during the third and fourth decades of life.^4,12-21 Importantly, delayed-type hypersensitivity reactions to mango can manifest as either localized or systemic ACD. Localized ACD can be induced via direct contact with the mango tree and its components or ingestion of the fruit.^3,12,22 Conversely, systemic ACD is primarily stimulated by ingestion of the fruit. In our case, the patient had no history of allergy following mango ingestion, and her ACD was prompted by isolated contact with mango sap. The time from exposure to symptom onset of known instances of mango ACD varies widely, ranging from less than 24 hours to as long as 9 days.^3,12 Diagnosis of mango-induced ACD largely is guided by clinical findings. Presenting symptoms often include an eczematous, vesicular, pruritic rash on affected areas of the skin, frequently the head, neck, and extremities. Patients also commonly present with linear papulovesicular lesions and periorbital or perioral edema.

The suspected allergens responsible for mango-induced ACD are derived from resorcinol—specifically heptadecadienyl resorcinol, heptadecenyl resorcinol, and pentadecyl resorcinol, which are collectively known as mango allergens.²³ These allergens can be found within the pulp and skin of the mango fruit as well as in the bark and leaves of the mango tree, which may explain observed allergic reactions to components of both the mango fruit and tree.¹² Similar to these resorcinol derivatives, the urushiol resin found in poison ivy and poison oak is a catechol derivative.² Importantly, both resorcinols and catechols are isomers of the same aromatic ­phenol—dihydroxybenzene. Because of these similarities, it is thought that the allergens in mangos may cross-react with urushiol in poison ivy or poison oak.²³ Alongside their shared categorization in the Anacardiaceae family, it is hypothesized that this cross-reactivity underlies the sensitization that has been noted between mango and poison ivy or poison oak exposure.^12,23,24 Thus, ACD often can occur on initial contact with the mango tree or its components, as a prior exposure to poison ivy or poison oak may serve as the inciting factor for hypersensitization. The majority of reported cases in the literature also occurred in countries where exposure to poison ivy and poison oak are common, further supporting the notion that these compounds may provide a sensitizing trigger for a future mango contact allergy.¹²

A detailed clinical history combined with adjunctive diagnostic support from patch testing and histopathology of biopsied skin lesions classically are used in the diagnosis of mango-induced ACD. Due to its ability to provide quick and noninvasive in vivo imaging of cutaneous lesions, RCM's applications have expanded to include evaluation of inflammatory skin diseases such as contact dermatitis. Many features of contact dermatitis identified via RCM are common between ACD and irritant contact dermatitis (ICD) and include disruption of the stratum corneum, parakeratosis, vesiculation, spongiosis, and exocytosis.^6,10,25 Studies also have described features shown via RCM that are unique to ACD, including vasodilation and intercellular edema, compared to more distinct targetoid keratinocytes and detached corneocytes seen in ICD.^6,10,25 Studies by Astner et al^5,6 demonstrated a wide range of sensitivity from 52% to 96% and a high specificity of RCM greater than 95% for many of the aforementioned features of contact dermatitis, including disruption of the stratum corneum, parakeratosis, spongiosis, and exocytosis. Additional studies have further strengthened these findings, demonstrating sensitivity and specificity values of 83% and 92% for contact dermatitis under RCM, respectively.²⁶ Importantly, given the similarities and potentially large overlap of features between ACD and ICD identified via RCM as well as findings seen on physical examination and histopathology, an emphasis on clinical correlation is essential when differentiating between these 2 variants of contact dermatitis. Thus, taken in consideration with clinical contexts, RCM has shown potent diagnostic accuracy and great potential to support the evaluation of ACD alongside patch testing and histopathology.

Final Thoughts

Contact allergy to the mango tree and its components is uncommon. We report a unique case of mango sap–induced ACD evaluated and diagnosed via dynamic visualization under RCM. As a noninvasive and reproducible imaging technique with resolutions comparable to histopathologic analysis, RCM is a promising tool that can be used to support the diagnostic evaluation of ACD.

The mango tree (Mangifera indica) produces ­nutrient-dense fruit—known colloquially as the “king of fruits”—that is widely consumed across the world. Native to southern Asia, the mango tree is a member of the Anacardiaceae family, a large family of flowering, fruit-bearing plants.¹ Many members of the Anacardiaceae family, which includes poison ivy and poison oak, are known to produce urushiol, a skin irritant associated with allergic contact dermatitis (ACD).² Interestingly, despite its widespread consumption and categorization in the Anacardiaceae family, allergic reactions to mango are comparatively rare; they occur as either immediate type I hypersensitivity reactions manifesting with rapid-onset symptoms such as urticaria, wheezing, and angioedema, or delayed type IV hypersensitivity reactions manifesting as ACD.³ Although exposure to components of the mango tree has been most characteristically linked to type IV hypersensitivity reactions, there remain fewer than 40 reported cases of mango-induced ACD since it was first described in 1939.⁴

Evaluation of ACD most commonly includes a thorough clinical assessment with diagnostic support from patch testing and histopathologic review following skin biopsy. In recent years, reflectance confocal microscopy (RCM) has shown promising potential to join the ­repertoire of diagnostic tools for ACD by enabling dynamic and high-resolution imaging of contact dermatitis in vivo.^5-10 Reflectance confocal microscopy is a noninvasive optical imaging technique that uses a low-energy diode laser to penetrate the layers of the skin. The resulting reflected light generates images that facilitate visualization of cutaneous structures to the depth of the papillary dermis.¹¹ While it is most commonly used in skin cancer diagnostics, preliminary studies also have shown an emerging role for RCM in the evaluation of eczematous and inflammatory skin disease, including contact dermatitis.^5-10 Herein, we present a unique case of mango sap–induced ACD imaged and diagnosed in real time via RCM.

Case Report

A 39-year-old woman presented to our clinic with a pruritic vesicular eruption on the right leg of 2 weeks’ duration that initially had developed within 7 days of exposure to mango tree sap (Figure 1). The patient reported having experienced similar pruritic eruptions in the past following contact with mango sap while eating mangos but denied any history of reactions from ingestion of the fruit. She also reported a history of robust reactions to poison ivy; however, a timeline specifying the order of first exposure to these irritants was unknown. She denied any personal or family history of atopic conditions.

The affected skin was imaged in real time during clinic using RCM, which showed an inflammatory infiltrate represented by dark spongiotic vesicles containing bright cells (Figure 2). Additional RCM imaging at the level of the stratum spinosum showed dark spongiotic areas with bright inflammatory cells infiltrating the vesicles, which were surrounded by normal skin showing a typical epidermal honeycomb pattern (Figure 3). These findings were diagnostic of ACD secondary to exposure to mango sap. The patient was advised to apply clobetasol cream 0.05% to the affected area. Notable improvement of the rash was noted within 10 days of treatment.

Comment

Exposure to the mango tree and its fruit is a rare cause of ACD, with few reported cases in the literature. The majority of known instances have occurred in non–mango-cultivating countries, largely the United States, although cases also have been reported in Canada, Australia, France, Japan, and Thailand.^3,12 Mango-induced contact allergy follows a roughly equal distribution between males and females and most often occurs in young adults during the third and fourth decades of life.^4,12-21 Importantly, delayed-type hypersensitivity reactions to mango can manifest as either localized or systemic ACD. Localized ACD can be induced via direct contact with the mango tree and its components or ingestion of the fruit.^3,12,22 Conversely, systemic ACD is primarily stimulated by ingestion of the fruit. In our case, the patient had no history of allergy following mango ingestion, and her ACD was prompted by isolated contact with mango sap. The time from exposure to symptom onset of known instances of mango ACD varies widely, ranging from less than 24 hours to as long as 9 days.^3,12 Diagnosis of mango-induced ACD largely is guided by clinical findings. Presenting symptoms often include an eczematous, vesicular, pruritic rash on affected areas of the skin, frequently the head, neck, and extremities. Patients also commonly present with linear papulovesicular lesions and periorbital or perioral edema.

The suspected allergens responsible for mango-induced ACD are derived from resorcinol—specifically heptadecadienyl resorcinol, heptadecenyl resorcinol, and pentadecyl resorcinol, which are collectively known as mango allergens.²³ These allergens can be found within the pulp and skin of the mango fruit as well as in the bark and leaves of the mango tree, which may explain observed allergic reactions to components of both the mango fruit and tree.¹² Similar to these resorcinol derivatives, the urushiol resin found in poison ivy and poison oak is a catechol derivative.² Importantly, both resorcinols and catechols are isomers of the same aromatic ­phenol—dihydroxybenzene. Because of these similarities, it is thought that the allergens in mangos may cross-react with urushiol in poison ivy or poison oak.²³ Alongside their shared categorization in the Anacardiaceae family, it is hypothesized that this cross-reactivity underlies the sensitization that has been noted between mango and poison ivy or poison oak exposure.^12,23,24 Thus, ACD often can occur on initial contact with the mango tree or its components, as a prior exposure to poison ivy or poison oak may serve as the inciting factor for hypersensitization. The majority of reported cases in the literature also occurred in countries where exposure to poison ivy and poison oak are common, further supporting the notion that these compounds may provide a sensitizing trigger for a future mango contact allergy.¹²

A detailed clinical history combined with adjunctive diagnostic support from patch testing and histopathology of biopsied skin lesions classically are used in the diagnosis of mango-induced ACD. Due to its ability to provide quick and noninvasive in vivo imaging of cutaneous lesions, RCM's applications have expanded to include evaluation of inflammatory skin diseases such as contact dermatitis. Many features of contact dermatitis identified via RCM are common between ACD and irritant contact dermatitis (ICD) and include disruption of the stratum corneum, parakeratosis, vesiculation, spongiosis, and exocytosis.^6,10,25 Studies also have described features shown via RCM that are unique to ACD, including vasodilation and intercellular edema, compared to more distinct targetoid keratinocytes and detached corneocytes seen in ICD.^6,10,25 Studies by Astner et al^5,6 demonstrated a wide range of sensitivity from 52% to 96% and a high specificity of RCM greater than 95% for many of the aforementioned features of contact dermatitis, including disruption of the stratum corneum, parakeratosis, spongiosis, and exocytosis. Additional studies have further strengthened these findings, demonstrating sensitivity and specificity values of 83% and 92% for contact dermatitis under RCM, respectively.²⁶ Importantly, given the similarities and potentially large overlap of features between ACD and ICD identified via RCM as well as findings seen on physical examination and histopathology, an emphasis on clinical correlation is essential when differentiating between these 2 variants of contact dermatitis. Thus, taken in consideration with clinical contexts, RCM has shown potent diagnostic accuracy and great potential to support the evaluation of ACD alongside patch testing and histopathology.

Final Thoughts

Contact allergy to the mango tree and its components is uncommon. We report a unique case of mango sap–induced ACD evaluated and diagnosed via dynamic visualization under RCM. As a noninvasive and reproducible imaging technique with resolutions comparable to histopathologic analysis, RCM is a promising tool that can be used to support the diagnostic evaluation of ACD.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Brazilian peppertree (Schinus terebinthifolia), a member of the Anacardiaceae family, is an internationally invasive plant that causes allergic contact dermatitis (ACD) in susceptible individuals. This noxious weed has settled into the landscape of the southern United States and continues to expand. Its key identifying features include its year-round white flowers as well as a peppery and turpentinelike aroma created by cracking its bright red berries. The ACD associated with contact—primarily with the plant’s sap—stems from known alkenyl phenols, cardol and cardanol. Treatment of Brazilian peppertree–associated ACD parallels that for poison ivy. As this pest increases its range, dermatologists living in endemic areas should familiarize themselves with Brazilian peppertree and its potential for harm.

Brazilian Peppertree Morphology and Geography

Plants in the Anacardiaceae family contribute to more ACD than any other family, and its 80 genera include most of the urushiol-containing plants, such as Toxicodendron (poison ivy, poison oak, poison sumac, Japanese lacquer tree), Anacardium (cashew tree), Mangifera (mango fruit), Semecarpus (India marking nut tree), and Schinus (Brazilian peppertree). Deciduous and evergreen tree members of the Anacardiaceae family grow primarily in tropical and subtropical locations and produce thick resins, 5-petalled flowers, and small fruit known as drupes. The genus name for Brazilian peppertree, Schinus, derives from Latin and Greek words meaning “mastic tree,” a relative of the pistachio tree that the Brazilian peppertree resembles.¹ Brazilian peppertree leaves look and smell similar to Pistacia terebinthus (turpentine tree or terebinth), from which the species name terebinthifolia derives.²

Brazilian peppertree originated in South America, particularly Brazil, Paraguay, and Argentina.³ Since the 1840s,⁴ it has been an invasive weed in the United States, notably in Florida, California, Hawaii, Alabama, Georgia,⁵ Arizona,⁶ Nevada,³ and Texas.^5,7 The plant also grows throughout the world, including parts of Africa, Asia, Central America, Europe,⁶ New Zealand,⁸ Australia, and various islands.⁹ The plant expertly outcompetes neighboring plants and has prompted control and eradication efforts in many locations.³

Identifying Features and Allergenic Plant Parts

Brazilian peppertree can be either a shrub or tree up to 30 feet tall.⁴ As an evergreen, it retains its leaves year-round. During fruiting seasons (primarily December through March⁷), bright red or pink (depending on the variety³) berries appear (Figure 1A) and contribute to its nickname “Florida holly.” Although generally considered an unwelcome guest in Florida, it does display white flowers (Figure 1B) year-round, especially from September to November.⁹ It characteristically exhibits 3 to 13 leaflets per leaf.¹⁰ The leaflets’ ovoid and ridged edges, netlike vasculature, shiny hue, and aroma can help identify the plant (Figure 2A). For decades, the sap of the Brazilian peppertree has been associated with skin ­irritation (Figure 2B).⁶ Although the sap of the plant serves as the main culprit of Brazilian peppertree–­associated ACD, it appears that other parts of the plant, including the fruit, can cause irritating effects to skin on contact.^11,12 The leaves, trunk, and fruit can be harmful to both humans and animals.⁶ Chemicals from flowers and crushed fruit also can lead to irritating effects in the respiratory tract if aspirated.¹³

Urushiol, an oily resin present in most plants of the Anacardiaceae family,¹⁴ contains many chemicals, including allergenic phenols, catechols, and resorcinols.¹⁵ Urushiol-allergic individuals develop dermatitis upon exposure to Brazilian peppertree sap.⁶ Alkenyl phenols found in Brazilian peppertree lead to the cutaneous manifestations in sensitized patients.^11,12 In 1983, Stahl et al¹¹ identified a phenol, cardanol (chemical name ­3-pentadecylphenol¹⁶) C15:1, in Brazilian peppertree fruit. The group further tested this compound’s effect on skin via patch testing, which showed an allergic response.¹¹ Cashew nut shells (Anacardium occidentale) contain cardanol, anacardic acid (a phenolic acid), and cardol (a phenol with the chemical name ­5-pentadecylresorcinol),^15,16 though Stahl et al¹¹ were unable to extract these 2 substances (if present) from Brazilian peppertree fruit. When exposed to cardol and anacardic acid, those allergic to poison ivy often develop ACD,¹⁵ and these 2 substances are more irritating than cardanol.¹¹ A later study did identify cardol in addition to cardanol in Brazilian peppertree.¹²

Cutaneous Manifestations

Brazilian peppertree–induced ACD appears similar to other plant-induced ACD with linear streaks of erythema, juicy papules, vesicles, coalescing erythematous plaques, and/or occasional edema and bullae accompanied by intense pruritus.

Treatment

Avoiding contact with Brazilian peppertree is the first line of defense, and treatment for a reaction associated with exposure is similar to that of poison ivy.¹⁷ Application of cool compresses, calamine lotion, and topical astringents offer symptom alleviation, and topical steroids (eg, clobetasol propionate 0.05% twice daily) can improve mild localized ACD when given prior to formation of blisters. For more severe and diffuse ACD, oral steroids (eg, prednisone 1 mg/kg/d tapered over 2–3 weeks) likely are necessary, though intramuscular options greatly alleviate discomfort in more severe cases (eg, intramuscular triamcinolone acetonide 1 mg/kg combined with betamethasone 0.1 mg/kg). Physicians should monitor sites for any signs of superimposed bacterial infection and initiate antibiotics as necessary.¹⁷

Brazilian peppertree (Schinus terebinthifolia), a member of the Anacardiaceae family, is an internationally invasive plant that causes allergic contact dermatitis (ACD) in susceptible individuals. This noxious weed has settled into the landscape of the southern United States and continues to expand. Its key identifying features include its year-round white flowers as well as a peppery and turpentinelike aroma created by cracking its bright red berries. The ACD associated with contact—primarily with the plant’s sap—stems from known alkenyl phenols, cardol and cardanol. Treatment of Brazilian peppertree–associated ACD parallels that for poison ivy. As this pest increases its range, dermatologists living in endemic areas should familiarize themselves with Brazilian peppertree and its potential for harm.

Brazilian Peppertree Morphology and Geography

Plants in the Anacardiaceae family contribute to more ACD than any other family, and its 80 genera include most of the urushiol-containing plants, such as Toxicodendron (poison ivy, poison oak, poison sumac, Japanese lacquer tree), Anacardium (cashew tree), Mangifera (mango fruit), Semecarpus (India marking nut tree), and Schinus (Brazilian peppertree). Deciduous and evergreen tree members of the Anacardiaceae family grow primarily in tropical and subtropical locations and produce thick resins, 5-petalled flowers, and small fruit known as drupes. The genus name for Brazilian peppertree, Schinus, derives from Latin and Greek words meaning “mastic tree,” a relative of the pistachio tree that the Brazilian peppertree resembles.¹ Brazilian peppertree leaves look and smell similar to Pistacia terebinthus (turpentine tree or terebinth), from which the species name terebinthifolia derives.²

Brazilian peppertree originated in South America, particularly Brazil, Paraguay, and Argentina.³ Since the 1840s,⁴ it has been an invasive weed in the United States, notably in Florida, California, Hawaii, Alabama, Georgia,⁵ Arizona,⁶ Nevada,³ and Texas.^5,7 The plant also grows throughout the world, including parts of Africa, Asia, Central America, Europe,⁶ New Zealand,⁸ Australia, and various islands.⁹ The plant expertly outcompetes neighboring plants and has prompted control and eradication efforts in many locations.³

Identifying Features and Allergenic Plant Parts

Brazilian peppertree can be either a shrub or tree up to 30 feet tall.⁴ As an evergreen, it retains its leaves year-round. During fruiting seasons (primarily December through March⁷), bright red or pink (depending on the variety³) berries appear (Figure 1A) and contribute to its nickname “Florida holly.” Although generally considered an unwelcome guest in Florida, it does display white flowers (Figure 1B) year-round, especially from September to November.⁹ It characteristically exhibits 3 to 13 leaflets per leaf.¹⁰ The leaflets’ ovoid and ridged edges, netlike vasculature, shiny hue, and aroma can help identify the plant (Figure 2A). For decades, the sap of the Brazilian peppertree has been associated with skin ­irritation (Figure 2B).⁶ Although the sap of the plant serves as the main culprit of Brazilian peppertree–­associated ACD, it appears that other parts of the plant, including the fruit, can cause irritating effects to skin on contact.^11,12 The leaves, trunk, and fruit can be harmful to both humans and animals.⁶ Chemicals from flowers and crushed fruit also can lead to irritating effects in the respiratory tract if aspirated.¹³

Urushiol, an oily resin present in most plants of the Anacardiaceae family,¹⁴ contains many chemicals, including allergenic phenols, catechols, and resorcinols.¹⁵ Urushiol-allergic individuals develop dermatitis upon exposure to Brazilian peppertree sap.⁶ Alkenyl phenols found in Brazilian peppertree lead to the cutaneous manifestations in sensitized patients.^11,12 In 1983, Stahl et al¹¹ identified a phenol, cardanol (chemical name ­3-pentadecylphenol¹⁶) C15:1, in Brazilian peppertree fruit. The group further tested this compound’s effect on skin via patch testing, which showed an allergic response.¹¹ Cashew nut shells (Anacardium occidentale) contain cardanol, anacardic acid (a phenolic acid), and cardol (a phenol with the chemical name ­5-pentadecylresorcinol),^15,16 though Stahl et al¹¹ were unable to extract these 2 substances (if present) from Brazilian peppertree fruit. When exposed to cardol and anacardic acid, those allergic to poison ivy often develop ACD,¹⁵ and these 2 substances are more irritating than cardanol.¹¹ A later study did identify cardol in addition to cardanol in Brazilian peppertree.¹²

Cutaneous Manifestations

Brazilian peppertree–induced ACD appears similar to other plant-induced ACD with linear streaks of erythema, juicy papules, vesicles, coalescing erythematous plaques, and/or occasional edema and bullae accompanied by intense pruritus.

Treatment

Avoiding contact with Brazilian peppertree is the first line of defense, and treatment for a reaction associated with exposure is similar to that of poison ivy.¹⁷ Application of cool compresses, calamine lotion, and topical astringents offer symptom alleviation, and topical steroids (eg, clobetasol propionate 0.05% twice daily) can improve mild localized ACD when given prior to formation of blisters. For more severe and diffuse ACD, oral steroids (eg, prednisone 1 mg/kg/d tapered over 2–3 weeks) likely are necessary, though intramuscular options greatly alleviate discomfort in more severe cases (eg, intramuscular triamcinolone acetonide 1 mg/kg combined with betamethasone 0.1 mg/kg). Physicians should monitor sites for any signs of superimposed bacterial infection and initiate antibiotics as necessary.¹⁷

Brazilian peppertree (Schinus terebinthifolia), a member of the Anacardiaceae family, is an internationally invasive plant that causes allergic contact dermatitis (ACD) in susceptible individuals. This noxious weed has settled into the landscape of the southern United States and continues to expand. Its key identifying features include its year-round white flowers as well as a peppery and turpentinelike aroma created by cracking its bright red berries. The ACD associated with contact—primarily with the plant’s sap—stems from known alkenyl phenols, cardol and cardanol. Treatment of Brazilian peppertree–associated ACD parallels that for poison ivy. As this pest increases its range, dermatologists living in endemic areas should familiarize themselves with Brazilian peppertree and its potential for harm.

Brazilian Peppertree Morphology and Geography

Plants in the Anacardiaceae family contribute to more ACD than any other family, and its 80 genera include most of the urushiol-containing plants, such as Toxicodendron (poison ivy, poison oak, poison sumac, Japanese lacquer tree), Anacardium (cashew tree), Mangifera (mango fruit), Semecarpus (India marking nut tree), and Schinus (Brazilian peppertree). Deciduous and evergreen tree members of the Anacardiaceae family grow primarily in tropical and subtropical locations and produce thick resins, 5-petalled flowers, and small fruit known as drupes. The genus name for Brazilian peppertree, Schinus, derives from Latin and Greek words meaning “mastic tree,” a relative of the pistachio tree that the Brazilian peppertree resembles.¹ Brazilian peppertree leaves look and smell similar to Pistacia terebinthus (turpentine tree or terebinth), from which the species name terebinthifolia derives.²

Brazilian peppertree originated in South America, particularly Brazil, Paraguay, and Argentina.³ Since the 1840s,⁴ it has been an invasive weed in the United States, notably in Florida, California, Hawaii, Alabama, Georgia,⁵ Arizona,⁶ Nevada,³ and Texas.^5,7 The plant also grows throughout the world, including parts of Africa, Asia, Central America, Europe,⁶ New Zealand,⁸ Australia, and various islands.⁹ The plant expertly outcompetes neighboring plants and has prompted control and eradication efforts in many locations.³

Identifying Features and Allergenic Plant Parts

Brazilian peppertree can be either a shrub or tree up to 30 feet tall.⁴ As an evergreen, it retains its leaves year-round. During fruiting seasons (primarily December through March⁷), bright red or pink (depending on the variety³) berries appear (Figure 1A) and contribute to its nickname “Florida holly.” Although generally considered an unwelcome guest in Florida, it does display white flowers (Figure 1B) year-round, especially from September to November.⁹ It characteristically exhibits 3 to 13 leaflets per leaf.¹⁰ The leaflets’ ovoid and ridged edges, netlike vasculature, shiny hue, and aroma can help identify the plant (Figure 2A). For decades, the sap of the Brazilian peppertree has been associated with skin ­irritation (Figure 2B).⁶ Although the sap of the plant serves as the main culprit of Brazilian peppertree–­associated ACD, it appears that other parts of the plant, including the fruit, can cause irritating effects to skin on contact.^11,12 The leaves, trunk, and fruit can be harmful to both humans and animals.⁶ Chemicals from flowers and crushed fruit also can lead to irritating effects in the respiratory tract if aspirated.¹³

Urushiol, an oily resin present in most plants of the Anacardiaceae family,¹⁴ contains many chemicals, including allergenic phenols, catechols, and resorcinols.¹⁵ Urushiol-allergic individuals develop dermatitis upon exposure to Brazilian peppertree sap.⁶ Alkenyl phenols found in Brazilian peppertree lead to the cutaneous manifestations in sensitized patients.^11,12 In 1983, Stahl et al¹¹ identified a phenol, cardanol (chemical name ­3-pentadecylphenol¹⁶) C15:1, in Brazilian peppertree fruit. The group further tested this compound’s effect on skin via patch testing, which showed an allergic response.¹¹ Cashew nut shells (Anacardium occidentale) contain cardanol, anacardic acid (a phenolic acid), and cardol (a phenol with the chemical name ­5-pentadecylresorcinol),^15,16 though Stahl et al¹¹ were unable to extract these 2 substances (if present) from Brazilian peppertree fruit. When exposed to cardol and anacardic acid, those allergic to poison ivy often develop ACD,¹⁵ and these 2 substances are more irritating than cardanol.¹¹ A later study did identify cardol in addition to cardanol in Brazilian peppertree.¹²

Cutaneous Manifestations

Brazilian peppertree–induced ACD appears similar to other plant-induced ACD with linear streaks of erythema, juicy papules, vesicles, coalescing erythematous plaques, and/or occasional edema and bullae accompanied by intense pruritus.

Treatment

Avoiding contact with Brazilian peppertree is the first line of defense, and treatment for a reaction associated with exposure is similar to that of poison ivy.¹⁷ Application of cool compresses, calamine lotion, and topical astringents offer symptom alleviation, and topical steroids (eg, clobetasol propionate 0.05% twice daily) can improve mild localized ACD when given prior to formation of blisters. For more severe and diffuse ACD, oral steroids (eg, prednisone 1 mg/kg/d tapered over 2–3 weeks) likely are necessary, though intramuscular options greatly alleviate discomfort in more severe cases (eg, intramuscular triamcinolone acetonide 1 mg/kg combined with betamethasone 0.1 mg/kg). Physicians should monitor sites for any signs of superimposed bacterial infection and initiate antibiotics as necessary.¹⁷

TOPLINE:

Pigments in permanent makeup inks include those that have been reported to cause allergic contact dermatitis (ACD), but the ability to identify these allergies in patients is limited.

METHODOLOGY:

• While the allergenic potential of pigments in traditional tattoos has been documented, there is less clarity about pigments used in inks contained in cosmetic tattoos, also known as permanent makeup, and their association with ACD.
• Researchers conducted an Internet search and identified 974 individual permanent makeup ink products sold in the United States and also identified 79 unique pigments in those products.
• They evaluated the safety data sheets of these products and performed a PubMed search to identify documented ACD cases related to these pigments.

TAKEAWAY:

• Of the 79 pigments, 20 contained inorganic metals, which included iron, aluminum, silicone, chromium, copper, titanium, molybdenum, and manganese.
• Organic pigments were more common: 59 of the remaining pigments were organic compounds, mostly azo, quinacridone, or anthraquinone dyes, including 4 black pigments made from carbon only.
• A literature search identified 29 cases where patients had developed ACD thought to be caused by at least one of the 79 pigments identified by the authors of the current study and included 10 of the 79 pigments (12%).
• In 18 of the 29 cases in the literature, patch testing to the suspected pigment had been performed; in 3 cases, ACD was suspected without confirmatory testing.

IN PRACTICE:

Permanent makeup is becoming more popular, and there have been reports of ACD related to pigments contained in the inks, the authors wrote. “Traditional patch testing methods may not be useful in confirming the presence of a pigment allergy, even if one is suspect,” they added. “Consumers and patch testing physicians would benefit from better labeling of tattoo inks and the development of protocols designed to specifically test for tattoo pigment allergies.”

SOURCE:

The study was led by Sarah Rigali, MS, of Rosalind Franklin University, Chicago Medical School, Chicago, and coauthors from the Department of Dermatology, Northwestern University, Chicago, published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The study is limited by incomplete safety data sheets. So, many brands of permanent makeup ink could not be investigated. In addition, some pigments may not be fully disclosed in ingredient lists and precise ink content measurements were not available.

DISCLOSURES:

The study reported receiving no funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Pigments in permanent makeup inks include those that have been reported to cause allergic contact dermatitis (ACD), but the ability to identify these allergies in patients is limited.

METHODOLOGY:

• While the allergenic potential of pigments in traditional tattoos has been documented, there is less clarity about pigments used in inks contained in cosmetic tattoos, also known as permanent makeup, and their association with ACD.
• Researchers conducted an Internet search and identified 974 individual permanent makeup ink products sold in the United States and also identified 79 unique pigments in those products.
• They evaluated the safety data sheets of these products and performed a PubMed search to identify documented ACD cases related to these pigments.

TAKEAWAY:

• Of the 79 pigments, 20 contained inorganic metals, which included iron, aluminum, silicone, chromium, copper, titanium, molybdenum, and manganese.
• Organic pigments were more common: 59 of the remaining pigments were organic compounds, mostly azo, quinacridone, or anthraquinone dyes, including 4 black pigments made from carbon only.
• A literature search identified 29 cases where patients had developed ACD thought to be caused by at least one of the 79 pigments identified by the authors of the current study and included 10 of the 79 pigments (12%).
• In 18 of the 29 cases in the literature, patch testing to the suspected pigment had been performed; in 3 cases, ACD was suspected without confirmatory testing.

IN PRACTICE:

Permanent makeup is becoming more popular, and there have been reports of ACD related to pigments contained in the inks, the authors wrote. “Traditional patch testing methods may not be useful in confirming the presence of a pigment allergy, even if one is suspect,” they added. “Consumers and patch testing physicians would benefit from better labeling of tattoo inks and the development of protocols designed to specifically test for tattoo pigment allergies.”

SOURCE:

The study was led by Sarah Rigali, MS, of Rosalind Franklin University, Chicago Medical School, Chicago, and coauthors from the Department of Dermatology, Northwestern University, Chicago, published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The study is limited by incomplete safety data sheets. So, many brands of permanent makeup ink could not be investigated. In addition, some pigments may not be fully disclosed in ingredient lists and precise ink content measurements were not available.

DISCLOSURES:

The study reported receiving no funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Pigments in permanent makeup inks include those that have been reported to cause allergic contact dermatitis (ACD), but the ability to identify these allergies in patients is limited.

METHODOLOGY:

• While the allergenic potential of pigments in traditional tattoos has been documented, there is less clarity about pigments used in inks contained in cosmetic tattoos, also known as permanent makeup, and their association with ACD.
• Researchers conducted an Internet search and identified 974 individual permanent makeup ink products sold in the United States and also identified 79 unique pigments in those products.
• They evaluated the safety data sheets of these products and performed a PubMed search to identify documented ACD cases related to these pigments.

TAKEAWAY:

• Of the 79 pigments, 20 contained inorganic metals, which included iron, aluminum, silicone, chromium, copper, titanium, molybdenum, and manganese.
• Organic pigments were more common: 59 of the remaining pigments were organic compounds, mostly azo, quinacridone, or anthraquinone dyes, including 4 black pigments made from carbon only.
• A literature search identified 29 cases where patients had developed ACD thought to be caused by at least one of the 79 pigments identified by the authors of the current study and included 10 of the 79 pigments (12%).
• In 18 of the 29 cases in the literature, patch testing to the suspected pigment had been performed; in 3 cases, ACD was suspected without confirmatory testing.

IN PRACTICE:

Permanent makeup is becoming more popular, and there have been reports of ACD related to pigments contained in the inks, the authors wrote. “Traditional patch testing methods may not be useful in confirming the presence of a pigment allergy, even if one is suspect,” they added. “Consumers and patch testing physicians would benefit from better labeling of tattoo inks and the development of protocols designed to specifically test for tattoo pigment allergies.”

SOURCE:

The study was led by Sarah Rigali, MS, of Rosalind Franklin University, Chicago Medical School, Chicago, and coauthors from the Department of Dermatology, Northwestern University, Chicago, published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The study is limited by incomplete safety data sheets. So, many brands of permanent makeup ink could not be investigated. In addition, some pigments may not be fully disclosed in ingredient lists and precise ink content measurements were not available.

DISCLOSURES:

The study reported receiving no funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

The filamentous cyanobacterium Lyngbya majuscula causes irritant contact dermatitis in beachgoers, fishers, and divers in tropical and subtropical marine environments worldwide.¹ If fragments of L majuscula lodge in swimmers’ bathing suits, the toxins can become trapped against the skin and cause seaweed dermatitis.² With climate change resulting in warmer oceans and more extreme storms, L majuscula blooms likely will become more frequent and widespread, thereby increasing the risk for human exposure.^3,4 Herein, we describe the irritants that lead to dermatitis, clinical presentation, and prevention and management of seaweed dermatitis.

Identifying Features and Distribution of Plant

Lyngbya majuscula belongs to the family Oscillatoriaceae; these cyanobacteria grow as filaments and exhibit slow oscillating movements. Commonly referred to as blanketweed or mermaid’s hair due to its appearance, L majuscula grows fine hairlike clumps resembling a mass of olive-colored matted hair.¹ Its thin filaments are 10- to 30-cm long and vary in color from red to white to brown.⁵ Microscopically, a rouleauxlike arrangement of discs provides the structure of each filament.⁶

First identified in Hawaii in 1912, L majuscula was not associated with seaweed dermatitis or dermatotoxicity by the medical community until the first outbreak occurred in Oahu in 1958, though fishermen and beachgoers previously had recognized a relationship between this particular seaweed and skin irritation.^5,7 The first reporting included 125 confirmed cases, with many more mild unreported cases suspected.⁶ Now reported in about 100 locations worldwide, seaweed dermatitis outbreaks have occurred in Australia; Okinawa, Japan; Florida; and the Hawaiian and Marshall islands.^1,2

Exposure to Seaweed

Lyngbya majuscula produces more than 70 biologically active compounds that irritate the skin, eyes, and respiratory system.^2,8 It grows in marine and estuarine environments attached to seagrass, sand, and bedrock at depths of up to 30 m. Warm waters and maximal sunlight provide optimal growth conditions for L majuscula; therefore, the greatest risk for exposure occurs in the Northern and Southern hemispheres in the 1- to 2-month period following their summer solstices.⁵ Runoff during heavy rainfall, which is rich in soil extracts such as phosphorous, iron, and organic carbon, stimulates L majuscula growth and contributes to increased algal blooms.⁴

Dermatitis and Irritants

The dermatoxins Lyngbyatoxin A (LA) and debromoaplysiatoxin (DAT) cause the inflammatory and necrotic appearance of seaweed dermatitis.^1,2,5,8 Lyngbyatoxin A is an indole alkaloid that is closely related to telocidin B, a poisonous compound associated with Streptomyces bacteria.⁹ Sampling of L majuscula and extraction of the dermatoxin, along with human and animal studies, confirmed DAT irritates the skin and induces dermatitis.^5,6 Stylocheilus longicauda (sea hare) feeds on L majuscula and contains isolates of DAT in its digestive tract.

Samples of L majuscula taken from several Hawaiian Islands where seaweed dermatitis outbreaks have occurred were examined for differences in toxicities via 6-hour patch tests on human skin.⁶ The samples obtained from the windward side of Oahu contained DAT and aplysiatoxin, while those obtained from the leeward side and Kahala Beach primarily contained LA. Although DAT and LA are vastly different in their molecular structures, testing elicited the same biologic response and induced the same level of skin irritation.⁶ Interestingly, not all strands of L majuscula produced LA and DAT and caused seaweed dermatitis; those that did lead to irritation were more red in color than nontoxic blooms.^5,9

Cutaneous Manifestations

Seaweed dermatitis resembles chemical and thermal burns, ranging from a mild skin rash to severe contact dermatitis with itchy, swollen, ulcerated lesions.^1,7 Patients typically develop a burning or itching sensation beneath their bathing suit or wetsuit that progresses to an erythematous papulovesicular eruption 2 to 24 hours after exposure.^2,6 Within a week, vesicles and bullae desquamate, leaving behind tender erosions.^1,2,6,8 Inframammary lesions are common in females and scrotal swelling in males.^1,6 There is no known association between length of time spent in the water and severity of symptoms.⁵

Most reactions to L majuscula occur from exposure in the water; however, particles that become aerosolized during strong winds or storms can cause seaweed dermatitis on the face. Inhalation of L majuscula may lead to mucous membrane ulceration and pulmonary edema.^1,5,6 Noncutaneous manifestations of seaweed dermatitis include headache, fatigue, and swelling of the eyes, nose, and throat (Figures 1 and 2).^1,5

Prevention and Management

To prevent seaweed dermatitis, avoid swimming in ocean water during L majuscula blooms,¹⁰ which frequently occur following the summer solstices in the Northern and Southern hemispheres.⁵ The National Centers for Coastal Ocean Science Harmful Algae Bloom Monitoring System provides real-time access to algae bloom locations.¹¹ Although this monitoring system is not specific to L majuscula, it may be helpful in determining where potential blooms are. Wearing protective clothing such as coveralls may benefit individuals who enter the water during blooms, but it does not guarantee protection.¹⁰

Currently, there is no treatment for seaweed dermatitis, but symptom management may reduce discomfort and pain. Washing affected skin with soap and water within an hour of exposure may help reduce the severity of seaweed dermatitis, though studies have shown mixed results.^6,7 Application of cool compresses and soothing ointments (eg, calamine) provide symptomatic relief and promote healing.⁷ The dermatitis typically self-resolves within 1 week.

The filamentous cyanobacterium Lyngbya majuscula causes irritant contact dermatitis in beachgoers, fishers, and divers in tropical and subtropical marine environments worldwide.¹ If fragments of L majuscula lodge in swimmers’ bathing suits, the toxins can become trapped against the skin and cause seaweed dermatitis.² With climate change resulting in warmer oceans and more extreme storms, L majuscula blooms likely will become more frequent and widespread, thereby increasing the risk for human exposure.^3,4 Herein, we describe the irritants that lead to dermatitis, clinical presentation, and prevention and management of seaweed dermatitis.

Identifying Features and Distribution of Plant

Lyngbya majuscula belongs to the family Oscillatoriaceae; these cyanobacteria grow as filaments and exhibit slow oscillating movements. Commonly referred to as blanketweed or mermaid’s hair due to its appearance, L majuscula grows fine hairlike clumps resembling a mass of olive-colored matted hair.¹ Its thin filaments are 10- to 30-cm long and vary in color from red to white to brown.⁵ Microscopically, a rouleauxlike arrangement of discs provides the structure of each filament.⁶

First identified in Hawaii in 1912, L majuscula was not associated with seaweed dermatitis or dermatotoxicity by the medical community until the first outbreak occurred in Oahu in 1958, though fishermen and beachgoers previously had recognized a relationship between this particular seaweed and skin irritation.^5,7 The first reporting included 125 confirmed cases, with many more mild unreported cases suspected.⁶ Now reported in about 100 locations worldwide, seaweed dermatitis outbreaks have occurred in Australia; Okinawa, Japan; Florida; and the Hawaiian and Marshall islands.^1,2

Exposure to Seaweed

Lyngbya majuscula produces more than 70 biologically active compounds that irritate the skin, eyes, and respiratory system.^2,8 It grows in marine and estuarine environments attached to seagrass, sand, and bedrock at depths of up to 30 m. Warm waters and maximal sunlight provide optimal growth conditions for L majuscula; therefore, the greatest risk for exposure occurs in the Northern and Southern hemispheres in the 1- to 2-month period following their summer solstices.⁵ Runoff during heavy rainfall, which is rich in soil extracts such as phosphorous, iron, and organic carbon, stimulates L majuscula growth and contributes to increased algal blooms.⁴

Dermatitis and Irritants

The dermatoxins Lyngbyatoxin A (LA) and debromoaplysiatoxin (DAT) cause the inflammatory and necrotic appearance of seaweed dermatitis.^1,2,5,8 Lyngbyatoxin A is an indole alkaloid that is closely related to telocidin B, a poisonous compound associated with Streptomyces bacteria.⁹ Sampling of L majuscula and extraction of the dermatoxin, along with human and animal studies, confirmed DAT irritates the skin and induces dermatitis.^5,6 Stylocheilus longicauda (sea hare) feeds on L majuscula and contains isolates of DAT in its digestive tract.

Samples of L majuscula taken from several Hawaiian Islands where seaweed dermatitis outbreaks have occurred were examined for differences in toxicities via 6-hour patch tests on human skin.⁶ The samples obtained from the windward side of Oahu contained DAT and aplysiatoxin, while those obtained from the leeward side and Kahala Beach primarily contained LA. Although DAT and LA are vastly different in their molecular structures, testing elicited the same biologic response and induced the same level of skin irritation.⁶ Interestingly, not all strands of L majuscula produced LA and DAT and caused seaweed dermatitis; those that did lead to irritation were more red in color than nontoxic blooms.^5,9

Cutaneous Manifestations

Seaweed dermatitis resembles chemical and thermal burns, ranging from a mild skin rash to severe contact dermatitis with itchy, swollen, ulcerated lesions.^1,7 Patients typically develop a burning or itching sensation beneath their bathing suit or wetsuit that progresses to an erythematous papulovesicular eruption 2 to 24 hours after exposure.^2,6 Within a week, vesicles and bullae desquamate, leaving behind tender erosions.^1,2,6,8 Inframammary lesions are common in females and scrotal swelling in males.^1,6 There is no known association between length of time spent in the water and severity of symptoms.⁵

Most reactions to L majuscula occur from exposure in the water; however, particles that become aerosolized during strong winds or storms can cause seaweed dermatitis on the face. Inhalation of L majuscula may lead to mucous membrane ulceration and pulmonary edema.^1,5,6 Noncutaneous manifestations of seaweed dermatitis include headache, fatigue, and swelling of the eyes, nose, and throat (Figures 1 and 2).^1,5

Prevention and Management

To prevent seaweed dermatitis, avoid swimming in ocean water during L majuscula blooms,¹⁰ which frequently occur following the summer solstices in the Northern and Southern hemispheres.⁵ The National Centers for Coastal Ocean Science Harmful Algae Bloom Monitoring System provides real-time access to algae bloom locations.¹¹ Although this monitoring system is not specific to L majuscula, it may be helpful in determining where potential blooms are. Wearing protective clothing such as coveralls may benefit individuals who enter the water during blooms, but it does not guarantee protection.¹⁰

Currently, there is no treatment for seaweed dermatitis, but symptom management may reduce discomfort and pain. Washing affected skin with soap and water within an hour of exposure may help reduce the severity of seaweed dermatitis, though studies have shown mixed results.^6,7 Application of cool compresses and soothing ointments (eg, calamine) provide symptomatic relief and promote healing.⁷ The dermatitis typically self-resolves within 1 week.

The filamentous cyanobacterium Lyngbya majuscula causes irritant contact dermatitis in beachgoers, fishers, and divers in tropical and subtropical marine environments worldwide.¹ If fragments of L majuscula lodge in swimmers’ bathing suits, the toxins can become trapped against the skin and cause seaweed dermatitis.² With climate change resulting in warmer oceans and more extreme storms, L majuscula blooms likely will become more frequent and widespread, thereby increasing the risk for human exposure.^3,4 Herein, we describe the irritants that lead to dermatitis, clinical presentation, and prevention and management of seaweed dermatitis.

Identifying Features and Distribution of Plant

Lyngbya majuscula belongs to the family Oscillatoriaceae; these cyanobacteria grow as filaments and exhibit slow oscillating movements. Commonly referred to as blanketweed or mermaid’s hair due to its appearance, L majuscula grows fine hairlike clumps resembling a mass of olive-colored matted hair.¹ Its thin filaments are 10- to 30-cm long and vary in color from red to white to brown.⁵ Microscopically, a rouleauxlike arrangement of discs provides the structure of each filament.⁶

First identified in Hawaii in 1912, L majuscula was not associated with seaweed dermatitis or dermatotoxicity by the medical community until the first outbreak occurred in Oahu in 1958, though fishermen and beachgoers previously had recognized a relationship between this particular seaweed and skin irritation.^5,7 The first reporting included 125 confirmed cases, with many more mild unreported cases suspected.⁶ Now reported in about 100 locations worldwide, seaweed dermatitis outbreaks have occurred in Australia; Okinawa, Japan; Florida; and the Hawaiian and Marshall islands.^1,2

Exposure to Seaweed

Lyngbya majuscula produces more than 70 biologically active compounds that irritate the skin, eyes, and respiratory system.^2,8 It grows in marine and estuarine environments attached to seagrass, sand, and bedrock at depths of up to 30 m. Warm waters and maximal sunlight provide optimal growth conditions for L majuscula; therefore, the greatest risk for exposure occurs in the Northern and Southern hemispheres in the 1- to 2-month period following their summer solstices.⁵ Runoff during heavy rainfall, which is rich in soil extracts such as phosphorous, iron, and organic carbon, stimulates L majuscula growth and contributes to increased algal blooms.⁴

Dermatitis and Irritants

The dermatoxins Lyngbyatoxin A (LA) and debromoaplysiatoxin (DAT) cause the inflammatory and necrotic appearance of seaweed dermatitis.^1,2,5,8 Lyngbyatoxin A is an indole alkaloid that is closely related to telocidin B, a poisonous compound associated with Streptomyces bacteria.⁹ Sampling of L majuscula and extraction of the dermatoxin, along with human and animal studies, confirmed DAT irritates the skin and induces dermatitis.^5,6 Stylocheilus longicauda (sea hare) feeds on L majuscula and contains isolates of DAT in its digestive tract.

Samples of L majuscula taken from several Hawaiian Islands where seaweed dermatitis outbreaks have occurred were examined for differences in toxicities via 6-hour patch tests on human skin.⁶ The samples obtained from the windward side of Oahu contained DAT and aplysiatoxin, while those obtained from the leeward side and Kahala Beach primarily contained LA. Although DAT and LA are vastly different in their molecular structures, testing elicited the same biologic response and induced the same level of skin irritation.⁶ Interestingly, not all strands of L majuscula produced LA and DAT and caused seaweed dermatitis; those that did lead to irritation were more red in color than nontoxic blooms.^5,9

Cutaneous Manifestations

Seaweed dermatitis resembles chemical and thermal burns, ranging from a mild skin rash to severe contact dermatitis with itchy, swollen, ulcerated lesions.^1,7 Patients typically develop a burning or itching sensation beneath their bathing suit or wetsuit that progresses to an erythematous papulovesicular eruption 2 to 24 hours after exposure.^2,6 Within a week, vesicles and bullae desquamate, leaving behind tender erosions.^1,2,6,8 Inframammary lesions are common in females and scrotal swelling in males.^1,6 There is no known association between length of time spent in the water and severity of symptoms.⁵

Most reactions to L majuscula occur from exposure in the water; however, particles that become aerosolized during strong winds or storms can cause seaweed dermatitis on the face. Inhalation of L majuscula may lead to mucous membrane ulceration and pulmonary edema.^1,5,6 Noncutaneous manifestations of seaweed dermatitis include headache, fatigue, and swelling of the eyes, nose, and throat (Figures 1 and 2).^1,5

Prevention and Management

To prevent seaweed dermatitis, avoid swimming in ocean water during L majuscula blooms,¹⁰ which frequently occur following the summer solstices in the Northern and Southern hemispheres.⁵ The National Centers for Coastal Ocean Science Harmful Algae Bloom Monitoring System provides real-time access to algae bloom locations.¹¹ Although this monitoring system is not specific to L majuscula, it may be helpful in determining where potential blooms are. Wearing protective clothing such as coveralls may benefit individuals who enter the water during blooms, but it does not guarantee protection.¹⁰

Currently, there is no treatment for seaweed dermatitis, but symptom management may reduce discomfort and pain. Washing affected skin with soap and water within an hour of exposure may help reduce the severity of seaweed dermatitis, though studies have shown mixed results.^6,7 Application of cool compresses and soothing ointments (eg, calamine) provide symptomatic relief and promote healing.⁷ The dermatitis typically self-resolves within 1 week.

To the Editor:

Langerhans cell histiocytosis (LCH) is a rare inflammatory neoplasia caused by accumulation of clonal Langerhans cells in 1 or more organs. The clinical spectrum is diverse, ranging from mild, single-organ involvement that may resolve spontaneously to severe progressive multisystem disease that can be fatal. It is most prevalent in children, affecting an estimated 4 to 5 children for every 1 million annually, with male predominance.¹ The pathogenesis is driven by activating mutations in the mitogen-activated protein kinase pathway, with the BRAF V600E mutation detected in most LCH patients, resulting in proliferation of pathologic Langerhans cells and dysregulated expression of inflammatory cytokines in LCH lesions.² A biopsy of lesional tissue is required for definitive diagnosis. Histopathology reveals a mixed inflammatory infiltrate and characteristic mononuclear cells with reniform nuclei that are positive for CD1a and CD207 proteins on immunohistochemical staining.³

Langerhans cell histiocytosis is categorized by the extent of organ involvement. It commonly affects the bones, skin, pituitary gland, liver, lungs, bone marrow, and lymph nodes.⁴ Single-system LCH involves a single organ with unifocal or multifocal lesions; multisystem LCH involves 2 or more organs and has a worse prognosis if risk organs (eg, liver, spleen, bone marrow) are involved.⁴

Skin lesions are reported in more than half of LCH cases and are the most common initial manifestation in patients younger than 2 years.⁴ Cutaneous findings are highly variable, which poses a diagnostic challenge. Common morphologies include erythematous papules, pustules, papulovesicles, scaly plaques, erosions, and petechiae. Lesions can be solitary or widespread and favor the trunk, head, and face.⁴ We describe an atypical case of hypopigmented cutaneous LCH and review the literature on this morphology in patients with skin of color.

A 7-month-old Hispanic male infant who was otherwise healthy presented with numerous hypopigmented macules and pink papules on the trunk and groin that had progressed since birth. A review of systems was unremarkable. Physical examination revealed 1- to 3-mm, discrete, hypopigmented macules intermixed with 1- to 2-mm pearly pink papules scattered on the back, chest, abdomen, and inguinal folds (Figure 1). Some lesions appeared koebnerized; however, the parents denied a history of scratching or trauma.

Histopathology of a lesion in the inguinal fold showed aggregates of mononuclear cells with reniform nuclei and abundant amphophilic cytoplasm in the papillary dermis, with focal extension into the epidermis. Scattered eosinophils and multinucleated giant cells were present in the dermal inflammatory infiltrate (Figure 2). Immunohistochemical staining was positive for CD1a (Figure 3) and S-100 protein (Figure 4). Although epidermal Langerhans cell collections also can be seen in allergic contact dermatitis,⁵ predominant involvement of the papillary dermis and the presence of multinucleated giant cells are characteristic of LCH.⁴ Given these findings, which were consistent with LCH, the dermatopathology deemed BRAF V600E immunostaining unnecessary for diagnostic purposes.

The patient was referred to the hematology and oncology department to undergo thorough evaluation for extracutaneous involvement. The workup included a complete blood cell count, liver function testing, electrolyte assessment, skeletal survey, chest radiography, and ultrasonography of the liver and spleen. All results were negative, suggesting a diagnosis of single-system cutaneous LCH.

Three months later, the patient presented to dermatology with spontaneous regression of all skin lesions. Continued follow-up—every 6 months for 5 years—was recommended to monitor for disease recurrence or progression to multisystem disease.

Cutaneous LCH is a clinically heterogeneous disease with the potential for multisystem involvement and long-term sequelae; therefore, timely diagnosis is paramount to optimize outcomes. However, delayed diagnosis is common because of the spectrum of skin findings that can mimic common pediatric dermatoses, such as seborrheic dermatitis, atopic dermatitis, and diaper dermatitis.⁴ In one study, the median time from onset of skin lesions to diagnostic biopsy was longer than 3 months (maximum, 5 years).⁶ Our patient was referred to dermatology 7 months after onset of hypopigmented macules, a rarely reported cutaneous manifestation of LCH.

A PubMed search of articles indexed for MEDLINE from 1994 to 2019 using the terms Langerhans cell histiocytotis and hypopigmented yielded 17 cases of LCH presenting as hypopigmented skin lesions (Table).^7-22 All cases occurred in patients with skin of color (ie, patients of Asian, Hispanic, or African descent). Hypopigmented macules were the only cutaneous manifestation in 10 (59%) cases. Lesions most commonly were distributed on the trunk (16/17 [94%]) and extremities (8/17 [47%]). The median age of onset was 1 month; 76% (13/17) of patients developed skin lesions before 1 year of age, indicating that this morphology may be more common in newborns. In most patients, the diagnosis was single-system cutaneous LCH; they exhibited spontaneous regression by 8 months of age on average, suggesting that this variant may be associated with a better prognosis. Mori and colleagues²¹ hypothesized that hypopigmented lesions may represent the resolving stage of active LCH based on histopathologic findings of dermal pallor and fibrosis in a hypopigmented LCH lesion. However, systemic involvement was reported in 7 cases of hypopigmented LCH, highlighting the importance of assessing for multisystem disease regardless of cutaneous morphology.²¹Langerhans cell histiocytosis should be considered in the differential diagnosis when evaluating hypopigmented skin eruptions in infants with darker skin types. Prompt diagnosis of this atypical variant requires a higher index of suspicion because of its rarity and the polymorphic nature of cutaneous LCH. This morphology may go undiagnosed in the setting of mild or spontaneously resolving disease; notwithstanding, accurate diagnosis and longitudinal surveillance are necessary given the potential for progressive systemic involvement.

To the Editor:

Langerhans cell histiocytosis (LCH) is a rare inflammatory neoplasia caused by accumulation of clonal Langerhans cells in 1 or more organs. The clinical spectrum is diverse, ranging from mild, single-organ involvement that may resolve spontaneously to severe progressive multisystem disease that can be fatal. It is most prevalent in children, affecting an estimated 4 to 5 children for every 1 million annually, with male predominance.¹ The pathogenesis is driven by activating mutations in the mitogen-activated protein kinase pathway, with the BRAF V600E mutation detected in most LCH patients, resulting in proliferation of pathologic Langerhans cells and dysregulated expression of inflammatory cytokines in LCH lesions.² A biopsy of lesional tissue is required for definitive diagnosis. Histopathology reveals a mixed inflammatory infiltrate and characteristic mononuclear cells with reniform nuclei that are positive for CD1a and CD207 proteins on immunohistochemical staining.³

Langerhans cell histiocytosis is categorized by the extent of organ involvement. It commonly affects the bones, skin, pituitary gland, liver, lungs, bone marrow, and lymph nodes.⁴ Single-system LCH involves a single organ with unifocal or multifocal lesions; multisystem LCH involves 2 or more organs and has a worse prognosis if risk organs (eg, liver, spleen, bone marrow) are involved.⁴

Skin lesions are reported in more than half of LCH cases and are the most common initial manifestation in patients younger than 2 years.⁴ Cutaneous findings are highly variable, which poses a diagnostic challenge. Common morphologies include erythematous papules, pustules, papulovesicles, scaly plaques, erosions, and petechiae. Lesions can be solitary or widespread and favor the trunk, head, and face.⁴ We describe an atypical case of hypopigmented cutaneous LCH and review the literature on this morphology in patients with skin of color.

A 7-month-old Hispanic male infant who was otherwise healthy presented with numerous hypopigmented macules and pink papules on the trunk and groin that had progressed since birth. A review of systems was unremarkable. Physical examination revealed 1- to 3-mm, discrete, hypopigmented macules intermixed with 1- to 2-mm pearly pink papules scattered on the back, chest, abdomen, and inguinal folds (Figure 1). Some lesions appeared koebnerized; however, the parents denied a history of scratching or trauma.

Histopathology of a lesion in the inguinal fold showed aggregates of mononuclear cells with reniform nuclei and abundant amphophilic cytoplasm in the papillary dermis, with focal extension into the epidermis. Scattered eosinophils and multinucleated giant cells were present in the dermal inflammatory infiltrate (Figure 2). Immunohistochemical staining was positive for CD1a (Figure 3) and S-100 protein (Figure 4). Although epidermal Langerhans cell collections also can be seen in allergic contact dermatitis,⁵ predominant involvement of the papillary dermis and the presence of multinucleated giant cells are characteristic of LCH.⁴ Given these findings, which were consistent with LCH, the dermatopathology deemed BRAF V600E immunostaining unnecessary for diagnostic purposes.

The patient was referred to the hematology and oncology department to undergo thorough evaluation for extracutaneous involvement. The workup included a complete blood cell count, liver function testing, electrolyte assessment, skeletal survey, chest radiography, and ultrasonography of the liver and spleen. All results were negative, suggesting a diagnosis of single-system cutaneous LCH.

Three months later, the patient presented to dermatology with spontaneous regression of all skin lesions. Continued follow-up—every 6 months for 5 years—was recommended to monitor for disease recurrence or progression to multisystem disease.

Cutaneous LCH is a clinically heterogeneous disease with the potential for multisystem involvement and long-term sequelae; therefore, timely diagnosis is paramount to optimize outcomes. However, delayed diagnosis is common because of the spectrum of skin findings that can mimic common pediatric dermatoses, such as seborrheic dermatitis, atopic dermatitis, and diaper dermatitis.⁴ In one study, the median time from onset of skin lesions to diagnostic biopsy was longer than 3 months (maximum, 5 years).⁶ Our patient was referred to dermatology 7 months after onset of hypopigmented macules, a rarely reported cutaneous manifestation of LCH.

A PubMed search of articles indexed for MEDLINE from 1994 to 2019 using the terms Langerhans cell histiocytotis and hypopigmented yielded 17 cases of LCH presenting as hypopigmented skin lesions (Table).^7-22 All cases occurred in patients with skin of color (ie, patients of Asian, Hispanic, or African descent). Hypopigmented macules were the only cutaneous manifestation in 10 (59%) cases. Lesions most commonly were distributed on the trunk (16/17 [94%]) and extremities (8/17 [47%]). The median age of onset was 1 month; 76% (13/17) of patients developed skin lesions before 1 year of age, indicating that this morphology may be more common in newborns. In most patients, the diagnosis was single-system cutaneous LCH; they exhibited spontaneous regression by 8 months of age on average, suggesting that this variant may be associated with a better prognosis. Mori and colleagues²¹ hypothesized that hypopigmented lesions may represent the resolving stage of active LCH based on histopathologic findings of dermal pallor and fibrosis in a hypopigmented LCH lesion. However, systemic involvement was reported in 7 cases of hypopigmented LCH, highlighting the importance of assessing for multisystem disease regardless of cutaneous morphology.²¹Langerhans cell histiocytosis should be considered in the differential diagnosis when evaluating hypopigmented skin eruptions in infants with darker skin types. Prompt diagnosis of this atypical variant requires a higher index of suspicion because of its rarity and the polymorphic nature of cutaneous LCH. This morphology may go undiagnosed in the setting of mild or spontaneously resolving disease; notwithstanding, accurate diagnosis and longitudinal surveillance are necessary given the potential for progressive systemic involvement.

To the Editor:

Langerhans cell histiocytosis (LCH) is a rare inflammatory neoplasia caused by accumulation of clonal Langerhans cells in 1 or more organs. The clinical spectrum is diverse, ranging from mild, single-organ involvement that may resolve spontaneously to severe progressive multisystem disease that can be fatal. It is most prevalent in children, affecting an estimated 4 to 5 children for every 1 million annually, with male predominance.¹ The pathogenesis is driven by activating mutations in the mitogen-activated protein kinase pathway, with the BRAF V600E mutation detected in most LCH patients, resulting in proliferation of pathologic Langerhans cells and dysregulated expression of inflammatory cytokines in LCH lesions.² A biopsy of lesional tissue is required for definitive diagnosis. Histopathology reveals a mixed inflammatory infiltrate and characteristic mononuclear cells with reniform nuclei that are positive for CD1a and CD207 proteins on immunohistochemical staining.³

Langerhans cell histiocytosis is categorized by the extent of organ involvement. It commonly affects the bones, skin, pituitary gland, liver, lungs, bone marrow, and lymph nodes.⁴ Single-system LCH involves a single organ with unifocal or multifocal lesions; multisystem LCH involves 2 or more organs and has a worse prognosis if risk organs (eg, liver, spleen, bone marrow) are involved.⁴

Skin lesions are reported in more than half of LCH cases and are the most common initial manifestation in patients younger than 2 years.⁴ Cutaneous findings are highly variable, which poses a diagnostic challenge. Common morphologies include erythematous papules, pustules, papulovesicles, scaly plaques, erosions, and petechiae. Lesions can be solitary or widespread and favor the trunk, head, and face.⁴ We describe an atypical case of hypopigmented cutaneous LCH and review the literature on this morphology in patients with skin of color.

A 7-month-old Hispanic male infant who was otherwise healthy presented with numerous hypopigmented macules and pink papules on the trunk and groin that had progressed since birth. A review of systems was unremarkable. Physical examination revealed 1- to 3-mm, discrete, hypopigmented macules intermixed with 1- to 2-mm pearly pink papules scattered on the back, chest, abdomen, and inguinal folds (Figure 1). Some lesions appeared koebnerized; however, the parents denied a history of scratching or trauma.

Histopathology of a lesion in the inguinal fold showed aggregates of mononuclear cells with reniform nuclei and abundant amphophilic cytoplasm in the papillary dermis, with focal extension into the epidermis. Scattered eosinophils and multinucleated giant cells were present in the dermal inflammatory infiltrate (Figure 2). Immunohistochemical staining was positive for CD1a (Figure 3) and S-100 protein (Figure 4). Although epidermal Langerhans cell collections also can be seen in allergic contact dermatitis,⁵ predominant involvement of the papillary dermis and the presence of multinucleated giant cells are characteristic of LCH.⁴ Given these findings, which were consistent with LCH, the dermatopathology deemed BRAF V600E immunostaining unnecessary for diagnostic purposes.

The patient was referred to the hematology and oncology department to undergo thorough evaluation for extracutaneous involvement. The workup included a complete blood cell count, liver function testing, electrolyte assessment, skeletal survey, chest radiography, and ultrasonography of the liver and spleen. All results were negative, suggesting a diagnosis of single-system cutaneous LCH.

Three months later, the patient presented to dermatology with spontaneous regression of all skin lesions. Continued follow-up—every 6 months for 5 years—was recommended to monitor for disease recurrence or progression to multisystem disease.

Cutaneous LCH is a clinically heterogeneous disease with the potential for multisystem involvement and long-term sequelae; therefore, timely diagnosis is paramount to optimize outcomes. However, delayed diagnosis is common because of the spectrum of skin findings that can mimic common pediatric dermatoses, such as seborrheic dermatitis, atopic dermatitis, and diaper dermatitis.⁴ In one study, the median time from onset of skin lesions to diagnostic biopsy was longer than 3 months (maximum, 5 years).⁶ Our patient was referred to dermatology 7 months after onset of hypopigmented macules, a rarely reported cutaneous manifestation of LCH.

A PubMed search of articles indexed for MEDLINE from 1994 to 2019 using the terms Langerhans cell histiocytotis and hypopigmented yielded 17 cases of LCH presenting as hypopigmented skin lesions (Table).^7-22 All cases occurred in patients with skin of color (ie, patients of Asian, Hispanic, or African descent). Hypopigmented macules were the only cutaneous manifestation in 10 (59%) cases. Lesions most commonly were distributed on the trunk (16/17 [94%]) and extremities (8/17 [47%]). The median age of onset was 1 month; 76% (13/17) of patients developed skin lesions before 1 year of age, indicating that this morphology may be more common in newborns. In most patients, the diagnosis was single-system cutaneous LCH; they exhibited spontaneous regression by 8 months of age on average, suggesting that this variant may be associated with a better prognosis. Mori and colleagues²¹ hypothesized that hypopigmented lesions may represent the resolving stage of active LCH based on histopathologic findings of dermal pallor and fibrosis in a hypopigmented LCH lesion. However, systemic involvement was reported in 7 cases of hypopigmented LCH, highlighting the importance of assessing for multisystem disease regardless of cutaneous morphology.²¹Langerhans cell histiocytosis should be considered in the differential diagnosis when evaluating hypopigmented skin eruptions in infants with darker skin types. Prompt diagnosis of this atypical variant requires a higher index of suspicion because of its rarity and the polymorphic nature of cutaneous LCH. This morphology may go undiagnosed in the setting of mild or spontaneously resolving disease; notwithstanding, accurate diagnosis and longitudinal surveillance are necessary given the potential for progressive systemic involvement.

To the Editor:

The term palisaded neutrophilic and granulomatous dermatitis (PNGD) has been proposed to encompass various conditions, including Winkelmann granuloma and superficial ulcerating rheumatoid necrobiosis. More recently, PNGD has been classified along with interstitial granulomatous dermatitis and interstitial granulomatous drug reaction under a unifying rubric of reactive granulomatous dermatitis (RGD).^1-4 The diagnosis of RGD can be challenging because of a range of clinical and histopathologic features as well as variable nomenclature.^1-3,5

Palisaded neutrophilic and granulomatous dermatitis classically manifests with papules and small plaques on the extensor extremities, with histopathology showing characteristic necrobiosis with both neutrophils and histiocytes.^1,2,6 We report 6 cases of RGD, including an index case in which a predominance of neutrophils in the infiltrate impeded the diagnosis.

An 85-year-old woman (the index patient) presented with a several-week history of asymmetric crusted papules on the right upper extremity—3 lesions on the elbow and forearm and 1 lesion on a finger. She was an avid gardener with severe rheumatoid arthritis treated with Janus kinase (JAK) inhibitor therapy. An initial biopsy of the elbow revealed a dense infiltrate of neutrophils and sparse eosinophils within the dermis. Special stains for bacterial, fungal, and acid-fast organisms were negative.

Because infection with sporotrichoid spread remained high in the differential diagnosis, the JAK inhibitor was discontinued and an antifungal agent was initiated. Given the persistence of the lesions, a subsequent biopsy of the right finger revealed scarce neutrophils and predominant histiocytes with rare foci of degenerated collagen. Sporotrichosis remained the leading diagnosis for these unilateral lesions. The patient subsequently developed additional crusted papules on the left arm (Figure 1). A biopsy of a left elbow lesion revealed palisades of histiocytes around degenerated collagen and collections of neutrophils compatible with RGD (Figures 2 and 3). Incidentally, the patient also presented with bilateral lower extremity palpable purpura, with a biopsy showing leukocytoclastic vasculitis. Antifungal therapy was discontinued and JAK inhibitor therapy resumed, with partial resolution of both the arm and right finger lesions and complete resolution of the lower extremity palpable purpura over several months.

The dense neutrophilic infiltrate and asymmetric presentation seen in our index patient’s initial biopsy hindered categorization of the cutaneous findings as RGD in association with her rheumatoid arthritis rather than as an infectious process. To ascertain whether diagnosis also was difficult in other cases of RGD, we conducted a search of the Yale Dermatopathology database for the diagnosis palisaded neutrophilic and granulomatous dermatitis, a term consistently used at our institution over the past decade. This study was approved by the institutional review board of Yale University (New Haven, Connecticut), and informed consent was waived. The search covered a 10-year period; 13 patients were found. Eight patients were eliminated because further clinical information or follow-up could not be obtained, leaving 5 additional cases (Table). The 8 eliminated cases were consultations submitted to the laboratory by outside pathologists from other institutions.

In one case (patient 5), the diagnosis of RGD was delayed for 7 years from first documentation of an RGD-compatible neutrophil-predominant infiltrate (Table). In 3 other cases, PNGD was in the clinical differential diagnosis. In patient 6 with known eosinophilic granulomatosis with polyangiitis, biopsy findings included a mixed inflammatory infiltrate with eosinophils, and the clinical and histopathologic findings were deemed compatible with RGD by group consensus at Grand Rounds.

In practice, a consistent unifying nomenclature has not been achieved for RGD and the diseases it encompasses—PNGD, interstitial granulomatous dermatitis, and interstitial granulomatous drug reaction. In this small series, a diagnosis of PNGD was given in the dermatopathology report only when biopsy specimens were characterized by histiocytes, neutrophils, and necrobiosis. Histopathology reports for neutrophil-predominant, histiocyte-predominant, and eosinophil-predominant cases did not mention PNGD or RGD, though potential association with systemic disease generally was noted.

Given the variability in the predominant inflammatory cell type in these patients, adding a qualifier to the histopathologic diagnosis—“RGD, eosinophil rich,” “RGD, histiocyte rich,” or “RGD, neutrophil rich”¹—would underscore the range of inflammatory cells in this entity. Employing this terminology rather than stating a solely descriptive diagnosis such as neutrophilic infiltrate, which may bias clinicians toward an infectious process, would aid in the association of a given rash with systemic disease and may prevent unnecessary tissue sampling. Indeed, 3 patients in this small series underwent more than 2 biopsies; multiple procedures might have been avoided had there been better communication about the spectrum of inflammatory cells compatible with RGD.

The inflammatory infiltrate in biopsy specimens of RGD can be solely neutrophil or histiocyte predominant or even have prominent eosinophils depending on the stage of disease. Awareness of variability in the predominant inflammatory cell in RGD may facilitate an accurate diagnosis as well as an association with any underlying autoimmune process, thereby allowing better management and treatment.¹

To the Editor:

The term palisaded neutrophilic and granulomatous dermatitis (PNGD) has been proposed to encompass various conditions, including Winkelmann granuloma and superficial ulcerating rheumatoid necrobiosis. More recently, PNGD has been classified along with interstitial granulomatous dermatitis and interstitial granulomatous drug reaction under a unifying rubric of reactive granulomatous dermatitis (RGD).^1-4 The diagnosis of RGD can be challenging because of a range of clinical and histopathologic features as well as variable nomenclature.^1-3,5

Palisaded neutrophilic and granulomatous dermatitis classically manifests with papules and small plaques on the extensor extremities, with histopathology showing characteristic necrobiosis with both neutrophils and histiocytes.^1,2,6 We report 6 cases of RGD, including an index case in which a predominance of neutrophils in the infiltrate impeded the diagnosis.

An 85-year-old woman (the index patient) presented with a several-week history of asymmetric crusted papules on the right upper extremity—3 lesions on the elbow and forearm and 1 lesion on a finger. She was an avid gardener with severe rheumatoid arthritis treated with Janus kinase (JAK) inhibitor therapy. An initial biopsy of the elbow revealed a dense infiltrate of neutrophils and sparse eosinophils within the dermis. Special stains for bacterial, fungal, and acid-fast organisms were negative.

Because infection with sporotrichoid spread remained high in the differential diagnosis, the JAK inhibitor was discontinued and an antifungal agent was initiated. Given the persistence of the lesions, a subsequent biopsy of the right finger revealed scarce neutrophils and predominant histiocytes with rare foci of degenerated collagen. Sporotrichosis remained the leading diagnosis for these unilateral lesions. The patient subsequently developed additional crusted papules on the left arm (Figure 1). A biopsy of a left elbow lesion revealed palisades of histiocytes around degenerated collagen and collections of neutrophils compatible with RGD (Figures 2 and 3). Incidentally, the patient also presented with bilateral lower extremity palpable purpura, with a biopsy showing leukocytoclastic vasculitis. Antifungal therapy was discontinued and JAK inhibitor therapy resumed, with partial resolution of both the arm and right finger lesions and complete resolution of the lower extremity palpable purpura over several months.

The dense neutrophilic infiltrate and asymmetric presentation seen in our index patient’s initial biopsy hindered categorization of the cutaneous findings as RGD in association with her rheumatoid arthritis rather than as an infectious process. To ascertain whether diagnosis also was difficult in other cases of RGD, we conducted a search of the Yale Dermatopathology database for the diagnosis palisaded neutrophilic and granulomatous dermatitis, a term consistently used at our institution over the past decade. This study was approved by the institutional review board of Yale University (New Haven, Connecticut), and informed consent was waived. The search covered a 10-year period; 13 patients were found. Eight patients were eliminated because further clinical information or follow-up could not be obtained, leaving 5 additional cases (Table). The 8 eliminated cases were consultations submitted to the laboratory by outside pathologists from other institutions.

In one case (patient 5), the diagnosis of RGD was delayed for 7 years from first documentation of an RGD-compatible neutrophil-predominant infiltrate (Table). In 3 other cases, PNGD was in the clinical differential diagnosis. In patient 6 with known eosinophilic granulomatosis with polyangiitis, biopsy findings included a mixed inflammatory infiltrate with eosinophils, and the clinical and histopathologic findings were deemed compatible with RGD by group consensus at Grand Rounds.

In practice, a consistent unifying nomenclature has not been achieved for RGD and the diseases it encompasses—PNGD, interstitial granulomatous dermatitis, and interstitial granulomatous drug reaction. In this small series, a diagnosis of PNGD was given in the dermatopathology report only when biopsy specimens were characterized by histiocytes, neutrophils, and necrobiosis. Histopathology reports for neutrophil-predominant, histiocyte-predominant, and eosinophil-predominant cases did not mention PNGD or RGD, though potential association with systemic disease generally was noted.

Given the variability in the predominant inflammatory cell type in these patients, adding a qualifier to the histopathologic diagnosis—“RGD, eosinophil rich,” “RGD, histiocyte rich,” or “RGD, neutrophil rich”¹—would underscore the range of inflammatory cells in this entity. Employing this terminology rather than stating a solely descriptive diagnosis such as neutrophilic infiltrate, which may bias clinicians toward an infectious process, would aid in the association of a given rash with systemic disease and may prevent unnecessary tissue sampling. Indeed, 3 patients in this small series underwent more than 2 biopsies; multiple procedures might have been avoided had there been better communication about the spectrum of inflammatory cells compatible with RGD.

The inflammatory infiltrate in biopsy specimens of RGD can be solely neutrophil or histiocyte predominant or even have prominent eosinophils depending on the stage of disease. Awareness of variability in the predominant inflammatory cell in RGD may facilitate an accurate diagnosis as well as an association with any underlying autoimmune process, thereby allowing better management and treatment.¹

To the Editor:

The term palisaded neutrophilic and granulomatous dermatitis (PNGD) has been proposed to encompass various conditions, including Winkelmann granuloma and superficial ulcerating rheumatoid necrobiosis. More recently, PNGD has been classified along with interstitial granulomatous dermatitis and interstitial granulomatous drug reaction under a unifying rubric of reactive granulomatous dermatitis (RGD).^1-4 The diagnosis of RGD can be challenging because of a range of clinical and histopathologic features as well as variable nomenclature.^1-3,5

Palisaded neutrophilic and granulomatous dermatitis classically manifests with papules and small plaques on the extensor extremities, with histopathology showing characteristic necrobiosis with both neutrophils and histiocytes.^1,2,6 We report 6 cases of RGD, including an index case in which a predominance of neutrophils in the infiltrate impeded the diagnosis.

An 85-year-old woman (the index patient) presented with a several-week history of asymmetric crusted papules on the right upper extremity—3 lesions on the elbow and forearm and 1 lesion on a finger. She was an avid gardener with severe rheumatoid arthritis treated with Janus kinase (JAK) inhibitor therapy. An initial biopsy of the elbow revealed a dense infiltrate of neutrophils and sparse eosinophils within the dermis. Special stains for bacterial, fungal, and acid-fast organisms were negative.

Because infection with sporotrichoid spread remained high in the differential diagnosis, the JAK inhibitor was discontinued and an antifungal agent was initiated. Given the persistence of the lesions, a subsequent biopsy of the right finger revealed scarce neutrophils and predominant histiocytes with rare foci of degenerated collagen. Sporotrichosis remained the leading diagnosis for these unilateral lesions. The patient subsequently developed additional crusted papules on the left arm (Figure 1). A biopsy of a left elbow lesion revealed palisades of histiocytes around degenerated collagen and collections of neutrophils compatible with RGD (Figures 2 and 3). Incidentally, the patient also presented with bilateral lower extremity palpable purpura, with a biopsy showing leukocytoclastic vasculitis. Antifungal therapy was discontinued and JAK inhibitor therapy resumed, with partial resolution of both the arm and right finger lesions and complete resolution of the lower extremity palpable purpura over several months.

The dense neutrophilic infiltrate and asymmetric presentation seen in our index patient’s initial biopsy hindered categorization of the cutaneous findings as RGD in association with her rheumatoid arthritis rather than as an infectious process. To ascertain whether diagnosis also was difficult in other cases of RGD, we conducted a search of the Yale Dermatopathology database for the diagnosis palisaded neutrophilic and granulomatous dermatitis, a term consistently used at our institution over the past decade. This study was approved by the institutional review board of Yale University (New Haven, Connecticut), and informed consent was waived. The search covered a 10-year period; 13 patients were found. Eight patients were eliminated because further clinical information or follow-up could not be obtained, leaving 5 additional cases (Table). The 8 eliminated cases were consultations submitted to the laboratory by outside pathologists from other institutions.

In one case (patient 5), the diagnosis of RGD was delayed for 7 years from first documentation of an RGD-compatible neutrophil-predominant infiltrate (Table). In 3 other cases, PNGD was in the clinical differential diagnosis. In patient 6 with known eosinophilic granulomatosis with polyangiitis, biopsy findings included a mixed inflammatory infiltrate with eosinophils, and the clinical and histopathologic findings were deemed compatible with RGD by group consensus at Grand Rounds.

In practice, a consistent unifying nomenclature has not been achieved for RGD and the diseases it encompasses—PNGD, interstitial granulomatous dermatitis, and interstitial granulomatous drug reaction. In this small series, a diagnosis of PNGD was given in the dermatopathology report only when biopsy specimens were characterized by histiocytes, neutrophils, and necrobiosis. Histopathology reports for neutrophil-predominant, histiocyte-predominant, and eosinophil-predominant cases did not mention PNGD or RGD, though potential association with systemic disease generally was noted.

Given the variability in the predominant inflammatory cell type in these patients, adding a qualifier to the histopathologic diagnosis—“RGD, eosinophil rich,” “RGD, histiocyte rich,” or “RGD, neutrophil rich”¹—would underscore the range of inflammatory cells in this entity. Employing this terminology rather than stating a solely descriptive diagnosis such as neutrophilic infiltrate, which may bias clinicians toward an infectious process, would aid in the association of a given rash with systemic disease and may prevent unnecessary tissue sampling. Indeed, 3 patients in this small series underwent more than 2 biopsies; multiple procedures might have been avoided had there been better communication about the spectrum of inflammatory cells compatible with RGD.

The inflammatory infiltrate in biopsy specimens of RGD can be solely neutrophil or histiocyte predominant or even have prominent eosinophils depending on the stage of disease. Awareness of variability in the predominant inflammatory cell in RGD may facilitate an accurate diagnosis as well as an association with any underlying autoimmune process, thereby allowing better management and treatment.¹

To the Editor:

A 32-year-old man presented to our clinic with acute-onset erythroderma associated with severe itching of 1 month’s duration. The patient developed the eruption after receiving the second dose of the Sinopharm BBIBP COVID-19 vaccine (BBIBP-CorV) 2 weeks prior to presentation. His medical history was unremarkable. There was no personal or family history of skin disease and no history of drug intake. Physical examination revealed orange-red erythroderma (Figure 1A) with islands of sparing, keratotic follicular orange-red papules on both legs and feet (Figure 1B), well-defined waxy palmoplantar keratoderma (Figures 1C and 1D), and fine scales on the face and scalp. The clinical and laboratory workup were normal, including a negative test for HIV infection.

Histopathology of two 4-mm punch biopsies of the skin on the trunk and lower limb showed irregular epidermal hyperplasia with thick suprapapillary plates and hypergranulosis (Figure 2A) along with alternating orthokeratosis and parakeratosis in vertical and horizontal directions (checkerboard parakeratosis)(Figure 2B). Follicular plugging with shoulder parakeratosis also was seen. The dermis showed a mild, superficial, perivascular lymphohistiocytic infiltrate. These features were diagnostic of pityriasis rubra pilaris (PRP). The patient received acitretin 25 mg/d and methotrexate 17.5 mg/wk (0.4 mg/kg/wk) and showed marked improvement after 2 months of therapy.

Pityriasis rubra pilaris is a rare papulosquamous skin disease of unknown etiology with several theories including genetic factors, aberrant metabolism of vitamin A, infection, drug reaction, autoimmune disease, and malignancy.¹ Clinically, there are 6 types of PRP: type I (classical adult), type II (atypical adult), type III (classical juvenile), type IV (circumscribed juvenile), type V (atypical juvenile), and type VI (HIV associated). Classic features include orange-red keratotic follicular papules that coalesce into plaques with characteristic islands of sparing.¹

Pityriasis rubra pilaris is a rare sequela following administration of certain vaccines, including diphtheria, pertussis, and tetanus; measles-mumps-rubella; and polio vaccines.^2,3 Among the various skin reactions that have been reported following COVID-19 vaccination, PRP has been reported in 19 patients: 7 (36.8%) after AstraZeneca vaccination, 3 (15.8%) after CoronaVac, 3 (15.8%) after Moderna, 5 (26.3%) after Pfizer-BioNTech,⁴ and 1 (5.3%) after Sinopharm.⁵ Our patient represents an additional case of a reaction after the Sinopharm vaccine. The condition developed after the first dose of vaccine in 11 patients, after the second dose in 6 patients, and after the third dose in 2 patients.

Other papulosquamous skin reactions have been reported after the Sinopharm BBIBP-CorV vaccine including psoriasis, lichen planus, and pityriasis rosea. Skin manifestations occurred sporadically, as some happened after the first or second dose or even after booster doses. The exact pathogenic mechanism(s) underlying the development of these conditions following vaccination still are not understood, though they may be attributed to COVID-19 vaccine–induced immune dysregulation.⁶

Pityriasis rubra pilaris can be self-limited in some cases and may not require treatment. Topical therapies such as keratolytics, emollients, and vitamin D may be utilized, especially for localized disease. Systemic therapy may be needed for refractory cases, including retinoids or immunosuppressive medications such as methotrexate, which is considered a second-line treatment for refractory PRP (after retinoids) and was used in our case. Azathioprine and cyclosporine also may be used. Phototherapy may play a role in PRP treatment, but the response is variable.⁷

Pityriasis rubra pilaris should be added to the list of cutaneous adverse reactions that can occur following vaccination with the Sinopharm BBIBP-CorV vaccine. Dermatologists must be aware of the possibility of vaccine-induced PRP, especially in de novo cases.

To the Editor:

A 32-year-old man presented to our clinic with acute-onset erythroderma associated with severe itching of 1 month’s duration. The patient developed the eruption after receiving the second dose of the Sinopharm BBIBP COVID-19 vaccine (BBIBP-CorV) 2 weeks prior to presentation. His medical history was unremarkable. There was no personal or family history of skin disease and no history of drug intake. Physical examination revealed orange-red erythroderma (Figure 1A) with islands of sparing, keratotic follicular orange-red papules on both legs and feet (Figure 1B), well-defined waxy palmoplantar keratoderma (Figures 1C and 1D), and fine scales on the face and scalp. The clinical and laboratory workup were normal, including a negative test for HIV infection.

Histopathology of two 4-mm punch biopsies of the skin on the trunk and lower limb showed irregular epidermal hyperplasia with thick suprapapillary plates and hypergranulosis (Figure 2A) along with alternating orthokeratosis and parakeratosis in vertical and horizontal directions (checkerboard parakeratosis)(Figure 2B). Follicular plugging with shoulder parakeratosis also was seen. The dermis showed a mild, superficial, perivascular lymphohistiocytic infiltrate. These features were diagnostic of pityriasis rubra pilaris (PRP). The patient received acitretin 25 mg/d and methotrexate 17.5 mg/wk (0.4 mg/kg/wk) and showed marked improvement after 2 months of therapy.

Pityriasis rubra pilaris is a rare papulosquamous skin disease of unknown etiology with several theories including genetic factors, aberrant metabolism of vitamin A, infection, drug reaction, autoimmune disease, and malignancy.¹ Clinically, there are 6 types of PRP: type I (classical adult), type II (atypical adult), type III (classical juvenile), type IV (circumscribed juvenile), type V (atypical juvenile), and type VI (HIV associated). Classic features include orange-red keratotic follicular papules that coalesce into plaques with characteristic islands of sparing.¹

Pityriasis rubra pilaris is a rare sequela following administration of certain vaccines, including diphtheria, pertussis, and tetanus; measles-mumps-rubella; and polio vaccines.^2,3 Among the various skin reactions that have been reported following COVID-19 vaccination, PRP has been reported in 19 patients: 7 (36.8%) after AstraZeneca vaccination, 3 (15.8%) after CoronaVac, 3 (15.8%) after Moderna, 5 (26.3%) after Pfizer-BioNTech,⁴ and 1 (5.3%) after Sinopharm.⁵ Our patient represents an additional case of a reaction after the Sinopharm vaccine. The condition developed after the first dose of vaccine in 11 patients, after the second dose in 6 patients, and after the third dose in 2 patients.

Other papulosquamous skin reactions have been reported after the Sinopharm BBIBP-CorV vaccine including psoriasis, lichen planus, and pityriasis rosea. Skin manifestations occurred sporadically, as some happened after the first or second dose or even after booster doses. The exact pathogenic mechanism(s) underlying the development of these conditions following vaccination still are not understood, though they may be attributed to COVID-19 vaccine–induced immune dysregulation.⁶

Pityriasis rubra pilaris can be self-limited in some cases and may not require treatment. Topical therapies such as keratolytics, emollients, and vitamin D may be utilized, especially for localized disease. Systemic therapy may be needed for refractory cases, including retinoids or immunosuppressive medications such as methotrexate, which is considered a second-line treatment for refractory PRP (after retinoids) and was used in our case. Azathioprine and cyclosporine also may be used. Phototherapy may play a role in PRP treatment, but the response is variable.⁷

Pityriasis rubra pilaris should be added to the list of cutaneous adverse reactions that can occur following vaccination with the Sinopharm BBIBP-CorV vaccine. Dermatologists must be aware of the possibility of vaccine-induced PRP, especially in de novo cases.

To the Editor:

A 32-year-old man presented to our clinic with acute-onset erythroderma associated with severe itching of 1 month’s duration. The patient developed the eruption after receiving the second dose of the Sinopharm BBIBP COVID-19 vaccine (BBIBP-CorV) 2 weeks prior to presentation. His medical history was unremarkable. There was no personal or family history of skin disease and no history of drug intake. Physical examination revealed orange-red erythroderma (Figure 1A) with islands of sparing, keratotic follicular orange-red papules on both legs and feet (Figure 1B), well-defined waxy palmoplantar keratoderma (Figures 1C and 1D), and fine scales on the face and scalp. The clinical and laboratory workup were normal, including a negative test for HIV infection.

Histopathology of two 4-mm punch biopsies of the skin on the trunk and lower limb showed irregular epidermal hyperplasia with thick suprapapillary plates and hypergranulosis (Figure 2A) along with alternating orthokeratosis and parakeratosis in vertical and horizontal directions (checkerboard parakeratosis)(Figure 2B). Follicular plugging with shoulder parakeratosis also was seen. The dermis showed a mild, superficial, perivascular lymphohistiocytic infiltrate. These features were diagnostic of pityriasis rubra pilaris (PRP). The patient received acitretin 25 mg/d and methotrexate 17.5 mg/wk (0.4 mg/kg/wk) and showed marked improvement after 2 months of therapy.

Pityriasis rubra pilaris is a rare papulosquamous skin disease of unknown etiology with several theories including genetic factors, aberrant metabolism of vitamin A, infection, drug reaction, autoimmune disease, and malignancy.¹ Clinically, there are 6 types of PRP: type I (classical adult), type II (atypical adult), type III (classical juvenile), type IV (circumscribed juvenile), type V (atypical juvenile), and type VI (HIV associated). Classic features include orange-red keratotic follicular papules that coalesce into plaques with characteristic islands of sparing.¹

Pityriasis rubra pilaris is a rare sequela following administration of certain vaccines, including diphtheria, pertussis, and tetanus; measles-mumps-rubella; and polio vaccines.^2,3 Among the various skin reactions that have been reported following COVID-19 vaccination, PRP has been reported in 19 patients: 7 (36.8%) after AstraZeneca vaccination, 3 (15.8%) after CoronaVac, 3 (15.8%) after Moderna, 5 (26.3%) after Pfizer-BioNTech,⁴ and 1 (5.3%) after Sinopharm.⁵ Our patient represents an additional case of a reaction after the Sinopharm vaccine. The condition developed after the first dose of vaccine in 11 patients, after the second dose in 6 patients, and after the third dose in 2 patients.

Other papulosquamous skin reactions have been reported after the Sinopharm BBIBP-CorV vaccine including psoriasis, lichen planus, and pityriasis rosea. Skin manifestations occurred sporadically, as some happened after the first or second dose or even after booster doses. The exact pathogenic mechanism(s) underlying the development of these conditions following vaccination still are not understood, though they may be attributed to COVID-19 vaccine–induced immune dysregulation.⁶

Pityriasis rubra pilaris can be self-limited in some cases and may not require treatment. Topical therapies such as keratolytics, emollients, and vitamin D may be utilized, especially for localized disease. Systemic therapy may be needed for refractory cases, including retinoids or immunosuppressive medications such as methotrexate, which is considered a second-line treatment for refractory PRP (after retinoids) and was used in our case. Azathioprine and cyclosporine also may be used. Phototherapy may play a role in PRP treatment, but the response is variable.⁷

Pityriasis rubra pilaris should be added to the list of cutaneous adverse reactions that can occur following vaccination with the Sinopharm BBIBP-CorV vaccine. Dermatologists must be aware of the possibility of vaccine-induced PRP, especially in de novo cases.