Contact Dermatitis

To the Editor:

A fixed drug eruption (FDE) is a well-documented form of cutaneous hypersensitivity that typically manifests as a sharply demarcated, dusky, round to oval, edematous, red-violaceous macule or patch on the skin and mucous membranes. The lesion often resolves with residual postinflammatory hyperpigmentation, most commonly as a reaction to ingested drugs or drug components.¹ Lesions generally occur at the same anatomic site with repeated exposure to the offending drug. Typically, a single site is affected, but additional sites with more generalized involvement have been reported to occur with subsequent exposure to the offending medication. The diagnosis usually is clinical, but histopathologic findings can help confirm the diagnosis in unusual presentations. We present a novel case of a patient with an FDE from medroxyprogesterone acetate, a contraceptive injection that contains the hormone progestin.

A 35-year-old woman presented to the dermatology clinic for evaluation of a lesion on the left lower buttock of 1 year’s duration. She reported periodic swelling and associated pruritus of the lesion. She denied any growth in size, and no other similar lesions were present. The patient reported a medication history of medroxyprogesterone acetate for birth control, but she denied any other prescription or over-the-counter medication, oral supplements, or recreational drug use. Upon further inquiry, she reported that the recurrence of symptoms appeared to coincide with each administration of medroxyprogesterone acetate, which occurred approximately every 3 months. The eruption cleared between injections and recurred in the same location following subsequent injections. The lesion appeared approximately 2 weeks after the first injection (approximately 1 year prior to presentation to dermatology) and within 2 to 3 days after each subsequent injection. Physical examination revealed a 2×2-cm, circular, slightly violaceous patch on the left buttock (Figure 1). A biopsy was recommended to aid in diagnosis, and the patient was offered a topical steroid for symptomatic relief. A punch biopsy revealed subtle interface dermatitis with superficial perivascular lymphoid infiltrate and marked pigmentary incontinence consistent with an FDE (Figure 2).

An FDE was first reported in 1889 by Bourns,² and over time more implicated agents and varying clinical presentations have been linked to the disease. The FDE can be accompanied by symptoms of pruritus or paresthesia. Most cases are devoid of systemic symptoms. An FDE can be located anywhere on the body, but it most frequently manifests on the lips, face, hands, feet, and genitalia. Although the eruption often heals with residual postinflammatory hyperpigmentation, a nonpigmenting FDE due to pseudoephedrine has been reported.³

Common culprits include antibiotics (eg, sulfonamides, trimethoprim, fluoroquinolones, tetracyclines), nonsteroidal anti-inflammatory medications (eg, naproxen sodium, ibuprofen, celecoxib), barbiturates, antimalarials, and anticonvulsants. Rare cases of FDE induced by foods and food additives also have been reported.⁴ Oral fluconazole, levocetirizine dihydrochloride, loperamide, and multivitamin-mineral preparations are other rare inducers of FDE.^5-8 In 2004, Ritter and Meffert⁹ described an FDE to the green dye used in inactive oral contraceptive pills. A similar case was reported by Rea et al¹⁰ that described an FDE from the inactive sugar pills in ethinyl estradiol and levonorgestrel, which is another combined oral contraceptive.

The time between ingestion of the offending agent and the manifestation of the disease usually is 1 to 2 weeks; however, upon subsequent exposure, the disease has been reported to manifest within hours.¹ CD8⁺ memory T cells have been shown to be major players in the development of FDE and can be found along the dermoepidermal junction as part of a delayed type IV hypersensitivity reaction.¹¹ Histopathology reveals superficial and deep interstitial and perivascular infiltrates consisting of lymphocytes with admixed eosinophils and possibly neutrophils in the dermis. In the epidermis, necrotic keratinocytes can be present. In rare cases, FDE may have atypical features, such as in generalized bullous FDE and nonpigmenting FDE, the latter of which more commonly is associated with pseudoephedrine.¹

The differential diagnosis for FDE includes erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, autoimmune progesterone dermatitis, and large plaque parapsoriasis. The number and morphology of lesions in erythema multiforme help differentiate it from FDE, as erythema multiforme presents with multiple targetoid lesions. The lesions of generalized bullous FDE can be similar to those of Stevens-Johnson syndrome/toxic epidermal necrolysis, and the pigmented patches of FDE can resemble large plaque parapsoriasis.

It is important to consider any medication ingested in the 1- to 2-week period before FDE onset, including over-the-counter medications, health food supplements, and prescription medications. Discontinuation of the implicated medication or any medication potentially cross-reacting with another medication is the most important step in management. Wound care may be needed for any bullous or eroded lesions. Lesions typically resolve within a few days to weeks of stopping the offending agent. Importantly, patients should be counseled on the secondary pigment alterations that may be persistent for several months. Other treatment for FDEs is aimed at symptomatic relief and may include topical corticosteroids and oral antihistamines.¹

Medroxyprogesterone acetate is a highly effective contraceptive drug with low rates of failure.¹² It is a weak androgenic progestin that is administered as a single 150-mg intramuscular injection every 3 months and inhibits gonadotropins. Common side effects include local injection-site reactions, unscheduled bleeding, amenorrhea, weight gain, headache, and mood changes. However, FDE has not been reported as an adverse effect to medroxyprogesterone acetate, both in official US Food and Drug Administration information and in the current literature.¹²

Autoimmune progesterone dermatitis (also known as progestin hypersensitivity) is a well-characterized cyclic hypersensitivity reaction to the hormone progesterone that occurs during the luteal phase of the menstrual cycle. It is known to have a variable clinical presentation including urticaria, erythema multiforme, eczema, and angioedema.¹³ Autoimmune progesterone dermatitis also has been reported to present as an FDE.^14-16 The onset of the cutaneous manifestation often starts a few days before the onset of menses, with spontaneous resolution occurring after the onset of menstruation. The mechanism by which endogenous progesterone or other secretory products become antigenic is unknown. It has been suggested that there is an alteration in the properties of the hormone that would predispose it to be antigenic as it would not be considered self. In 2001, Warin¹⁷ proposed the following diagnostic criteria for autoimmune progesterone dermatitis: (1) skin lesions associated with menstrual cycle (premenstrual flare); (2) a positive response to the progesterone intradermal or intramuscular test; and (3) symptomatic improvement after inhibiting progesterone secretion by suppressing ovulation.¹⁷ The treatment includes antiallergy medications, progesterone desensitization, omalizumab injection, and leuprolide acetate injection.

Our case represents FDE from medroxyprogesterone acetate. Although we did not formally investigate the antigenicity of the exogenous progesterone, we postulate that the pathophysiology likely is similar to an FDE associated with endogenous progesterone. This reasoning is supported by the time course of the patient’s lesion as well as the worsening of symptoms in the days following the administration of the medication. Additionally, the patient had no history of skin lesions prior to the initiation of medroxyprogesterone acetate or similar lesions associated with her menstrual cycles.

A careful and detailed review of medication history is necessary to evaluate FDEs. Our case emphasizes that not only endogenous but also exogenous forms of progesterone may cause hypersensitivity, leading to an FDE. With more than 2 million prescriptions of medroxyprogesterone acetate written every year, dermatologists should be aware of the rare but potential risk for an FDE in patients using this medication.¹⁸

To the Editor:

A fixed drug eruption (FDE) is a well-documented form of cutaneous hypersensitivity that typically manifests as a sharply demarcated, dusky, round to oval, edematous, red-violaceous macule or patch on the skin and mucous membranes. The lesion often resolves with residual postinflammatory hyperpigmentation, most commonly as a reaction to ingested drugs or drug components.¹ Lesions generally occur at the same anatomic site with repeated exposure to the offending drug. Typically, a single site is affected, but additional sites with more generalized involvement have been reported to occur with subsequent exposure to the offending medication. The diagnosis usually is clinical, but histopathologic findings can help confirm the diagnosis in unusual presentations. We present a novel case of a patient with an FDE from medroxyprogesterone acetate, a contraceptive injection that contains the hormone progestin.

A 35-year-old woman presented to the dermatology clinic for evaluation of a lesion on the left lower buttock of 1 year’s duration. She reported periodic swelling and associated pruritus of the lesion. She denied any growth in size, and no other similar lesions were present. The patient reported a medication history of medroxyprogesterone acetate for birth control, but she denied any other prescription or over-the-counter medication, oral supplements, or recreational drug use. Upon further inquiry, she reported that the recurrence of symptoms appeared to coincide with each administration of medroxyprogesterone acetate, which occurred approximately every 3 months. The eruption cleared between injections and recurred in the same location following subsequent injections. The lesion appeared approximately 2 weeks after the first injection (approximately 1 year prior to presentation to dermatology) and within 2 to 3 days after each subsequent injection. Physical examination revealed a 2×2-cm, circular, slightly violaceous patch on the left buttock (Figure 1). A biopsy was recommended to aid in diagnosis, and the patient was offered a topical steroid for symptomatic relief. A punch biopsy revealed subtle interface dermatitis with superficial perivascular lymphoid infiltrate and marked pigmentary incontinence consistent with an FDE (Figure 2).

An FDE was first reported in 1889 by Bourns,² and over time more implicated agents and varying clinical presentations have been linked to the disease. The FDE can be accompanied by symptoms of pruritus or paresthesia. Most cases are devoid of systemic symptoms. An FDE can be located anywhere on the body, but it most frequently manifests on the lips, face, hands, feet, and genitalia. Although the eruption often heals with residual postinflammatory hyperpigmentation, a nonpigmenting FDE due to pseudoephedrine has been reported.³

Common culprits include antibiotics (eg, sulfonamides, trimethoprim, fluoroquinolones, tetracyclines), nonsteroidal anti-inflammatory medications (eg, naproxen sodium, ibuprofen, celecoxib), barbiturates, antimalarials, and anticonvulsants. Rare cases of FDE induced by foods and food additives also have been reported.⁴ Oral fluconazole, levocetirizine dihydrochloride, loperamide, and multivitamin-mineral preparations are other rare inducers of FDE.^5-8 In 2004, Ritter and Meffert⁹ described an FDE to the green dye used in inactive oral contraceptive pills. A similar case was reported by Rea et al¹⁰ that described an FDE from the inactive sugar pills in ethinyl estradiol and levonorgestrel, which is another combined oral contraceptive.

The time between ingestion of the offending agent and the manifestation of the disease usually is 1 to 2 weeks; however, upon subsequent exposure, the disease has been reported to manifest within hours.¹ CD8⁺ memory T cells have been shown to be major players in the development of FDE and can be found along the dermoepidermal junction as part of a delayed type IV hypersensitivity reaction.¹¹ Histopathology reveals superficial and deep interstitial and perivascular infiltrates consisting of lymphocytes with admixed eosinophils and possibly neutrophils in the dermis. In the epidermis, necrotic keratinocytes can be present. In rare cases, FDE may have atypical features, such as in generalized bullous FDE and nonpigmenting FDE, the latter of which more commonly is associated with pseudoephedrine.¹

The differential diagnosis for FDE includes erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, autoimmune progesterone dermatitis, and large plaque parapsoriasis. The number and morphology of lesions in erythema multiforme help differentiate it from FDE, as erythema multiforme presents with multiple targetoid lesions. The lesions of generalized bullous FDE can be similar to those of Stevens-Johnson syndrome/toxic epidermal necrolysis, and the pigmented patches of FDE can resemble large plaque parapsoriasis.

It is important to consider any medication ingested in the 1- to 2-week period before FDE onset, including over-the-counter medications, health food supplements, and prescription medications. Discontinuation of the implicated medication or any medication potentially cross-reacting with another medication is the most important step in management. Wound care may be needed for any bullous or eroded lesions. Lesions typically resolve within a few days to weeks of stopping the offending agent. Importantly, patients should be counseled on the secondary pigment alterations that may be persistent for several months. Other treatment for FDEs is aimed at symptomatic relief and may include topical corticosteroids and oral antihistamines.¹

Medroxyprogesterone acetate is a highly effective contraceptive drug with low rates of failure.¹² It is a weak androgenic progestin that is administered as a single 150-mg intramuscular injection every 3 months and inhibits gonadotropins. Common side effects include local injection-site reactions, unscheduled bleeding, amenorrhea, weight gain, headache, and mood changes. However, FDE has not been reported as an adverse effect to medroxyprogesterone acetate, both in official US Food and Drug Administration information and in the current literature.¹²

Autoimmune progesterone dermatitis (also known as progestin hypersensitivity) is a well-characterized cyclic hypersensitivity reaction to the hormone progesterone that occurs during the luteal phase of the menstrual cycle. It is known to have a variable clinical presentation including urticaria, erythema multiforme, eczema, and angioedema.¹³ Autoimmune progesterone dermatitis also has been reported to present as an FDE.^14-16 The onset of the cutaneous manifestation often starts a few days before the onset of menses, with spontaneous resolution occurring after the onset of menstruation. The mechanism by which endogenous progesterone or other secretory products become antigenic is unknown. It has been suggested that there is an alteration in the properties of the hormone that would predispose it to be antigenic as it would not be considered self. In 2001, Warin¹⁷ proposed the following diagnostic criteria for autoimmune progesterone dermatitis: (1) skin lesions associated with menstrual cycle (premenstrual flare); (2) a positive response to the progesterone intradermal or intramuscular test; and (3) symptomatic improvement after inhibiting progesterone secretion by suppressing ovulation.¹⁷ The treatment includes antiallergy medications, progesterone desensitization, omalizumab injection, and leuprolide acetate injection.

Our case represents FDE from medroxyprogesterone acetate. Although we did not formally investigate the antigenicity of the exogenous progesterone, we postulate that the pathophysiology likely is similar to an FDE associated with endogenous progesterone. This reasoning is supported by the time course of the patient’s lesion as well as the worsening of symptoms in the days following the administration of the medication. Additionally, the patient had no history of skin lesions prior to the initiation of medroxyprogesterone acetate or similar lesions associated with her menstrual cycles.

A careful and detailed review of medication history is necessary to evaluate FDEs. Our case emphasizes that not only endogenous but also exogenous forms of progesterone may cause hypersensitivity, leading to an FDE. With more than 2 million prescriptions of medroxyprogesterone acetate written every year, dermatologists should be aware of the rare but potential risk for an FDE in patients using this medication.¹⁸

To the Editor:

A fixed drug eruption (FDE) is a well-documented form of cutaneous hypersensitivity that typically manifests as a sharply demarcated, dusky, round to oval, edematous, red-violaceous macule or patch on the skin and mucous membranes. The lesion often resolves with residual postinflammatory hyperpigmentation, most commonly as a reaction to ingested drugs or drug components.¹ Lesions generally occur at the same anatomic site with repeated exposure to the offending drug. Typically, a single site is affected, but additional sites with more generalized involvement have been reported to occur with subsequent exposure to the offending medication. The diagnosis usually is clinical, but histopathologic findings can help confirm the diagnosis in unusual presentations. We present a novel case of a patient with an FDE from medroxyprogesterone acetate, a contraceptive injection that contains the hormone progestin.

A 35-year-old woman presented to the dermatology clinic for evaluation of a lesion on the left lower buttock of 1 year’s duration. She reported periodic swelling and associated pruritus of the lesion. She denied any growth in size, and no other similar lesions were present. The patient reported a medication history of medroxyprogesterone acetate for birth control, but she denied any other prescription or over-the-counter medication, oral supplements, or recreational drug use. Upon further inquiry, she reported that the recurrence of symptoms appeared to coincide with each administration of medroxyprogesterone acetate, which occurred approximately every 3 months. The eruption cleared between injections and recurred in the same location following subsequent injections. The lesion appeared approximately 2 weeks after the first injection (approximately 1 year prior to presentation to dermatology) and within 2 to 3 days after each subsequent injection. Physical examination revealed a 2×2-cm, circular, slightly violaceous patch on the left buttock (Figure 1). A biopsy was recommended to aid in diagnosis, and the patient was offered a topical steroid for symptomatic relief. A punch biopsy revealed subtle interface dermatitis with superficial perivascular lymphoid infiltrate and marked pigmentary incontinence consistent with an FDE (Figure 2).

An FDE was first reported in 1889 by Bourns,² and over time more implicated agents and varying clinical presentations have been linked to the disease. The FDE can be accompanied by symptoms of pruritus or paresthesia. Most cases are devoid of systemic symptoms. An FDE can be located anywhere on the body, but it most frequently manifests on the lips, face, hands, feet, and genitalia. Although the eruption often heals with residual postinflammatory hyperpigmentation, a nonpigmenting FDE due to pseudoephedrine has been reported.³

Common culprits include antibiotics (eg, sulfonamides, trimethoprim, fluoroquinolones, tetracyclines), nonsteroidal anti-inflammatory medications (eg, naproxen sodium, ibuprofen, celecoxib), barbiturates, antimalarials, and anticonvulsants. Rare cases of FDE induced by foods and food additives also have been reported.⁴ Oral fluconazole, levocetirizine dihydrochloride, loperamide, and multivitamin-mineral preparations are other rare inducers of FDE.^5-8 In 2004, Ritter and Meffert⁹ described an FDE to the green dye used in inactive oral contraceptive pills. A similar case was reported by Rea et al¹⁰ that described an FDE from the inactive sugar pills in ethinyl estradiol and levonorgestrel, which is another combined oral contraceptive.

The time between ingestion of the offending agent and the manifestation of the disease usually is 1 to 2 weeks; however, upon subsequent exposure, the disease has been reported to manifest within hours.¹ CD8⁺ memory T cells have been shown to be major players in the development of FDE and can be found along the dermoepidermal junction as part of a delayed type IV hypersensitivity reaction.¹¹ Histopathology reveals superficial and deep interstitial and perivascular infiltrates consisting of lymphocytes with admixed eosinophils and possibly neutrophils in the dermis. In the epidermis, necrotic keratinocytes can be present. In rare cases, FDE may have atypical features, such as in generalized bullous FDE and nonpigmenting FDE, the latter of which more commonly is associated with pseudoephedrine.¹

The differential diagnosis for FDE includes erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, autoimmune progesterone dermatitis, and large plaque parapsoriasis. The number and morphology of lesions in erythema multiforme help differentiate it from FDE, as erythema multiforme presents with multiple targetoid lesions. The lesions of generalized bullous FDE can be similar to those of Stevens-Johnson syndrome/toxic epidermal necrolysis, and the pigmented patches of FDE can resemble large plaque parapsoriasis.

It is important to consider any medication ingested in the 1- to 2-week period before FDE onset, including over-the-counter medications, health food supplements, and prescription medications. Discontinuation of the implicated medication or any medication potentially cross-reacting with another medication is the most important step in management. Wound care may be needed for any bullous or eroded lesions. Lesions typically resolve within a few days to weeks of stopping the offending agent. Importantly, patients should be counseled on the secondary pigment alterations that may be persistent for several months. Other treatment for FDEs is aimed at symptomatic relief and may include topical corticosteroids and oral antihistamines.¹

Medroxyprogesterone acetate is a highly effective contraceptive drug with low rates of failure.¹² It is a weak androgenic progestin that is administered as a single 150-mg intramuscular injection every 3 months and inhibits gonadotropins. Common side effects include local injection-site reactions, unscheduled bleeding, amenorrhea, weight gain, headache, and mood changes. However, FDE has not been reported as an adverse effect to medroxyprogesterone acetate, both in official US Food and Drug Administration information and in the current literature.¹²

Autoimmune progesterone dermatitis (also known as progestin hypersensitivity) is a well-characterized cyclic hypersensitivity reaction to the hormone progesterone that occurs during the luteal phase of the menstrual cycle. It is known to have a variable clinical presentation including urticaria, erythema multiforme, eczema, and angioedema.¹³ Autoimmune progesterone dermatitis also has been reported to present as an FDE.^14-16 The onset of the cutaneous manifestation often starts a few days before the onset of menses, with spontaneous resolution occurring after the onset of menstruation. The mechanism by which endogenous progesterone or other secretory products become antigenic is unknown. It has been suggested that there is an alteration in the properties of the hormone that would predispose it to be antigenic as it would not be considered self. In 2001, Warin¹⁷ proposed the following diagnostic criteria for autoimmune progesterone dermatitis: (1) skin lesions associated with menstrual cycle (premenstrual flare); (2) a positive response to the progesterone intradermal or intramuscular test; and (3) symptomatic improvement after inhibiting progesterone secretion by suppressing ovulation.¹⁷ The treatment includes antiallergy medications, progesterone desensitization, omalizumab injection, and leuprolide acetate injection.

Our case represents FDE from medroxyprogesterone acetate. Although we did not formally investigate the antigenicity of the exogenous progesterone, we postulate that the pathophysiology likely is similar to an FDE associated with endogenous progesterone. This reasoning is supported by the time course of the patient’s lesion as well as the worsening of symptoms in the days following the administration of the medication. Additionally, the patient had no history of skin lesions prior to the initiation of medroxyprogesterone acetate or similar lesions associated with her menstrual cycles.

A careful and detailed review of medication history is necessary to evaluate FDEs. Our case emphasizes that not only endogenous but also exogenous forms of progesterone may cause hypersensitivity, leading to an FDE. With more than 2 million prescriptions of medroxyprogesterone acetate written every year, dermatologists should be aware of the rare but potential risk for an FDE in patients using this medication.¹⁸

In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.

Pathophysiology and Pathomechanism

Dupilumab functions through the blockade of T helper 2 (T_H2) cells; ACD is propagated through the T helper 1 (T_H1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I¹ and balsam of Peru^1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,^2,3p-phenylenediamine,¹ Compositae,⁴ and non–formaldehyde-releasing preservatives (non-FRPs).⁵ Therefore, not all ACD is propagated through the T_H1 cellular pathway.

As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the T_H2 pathway or when patient characteristics favor a T_H2 response. It has been suggested that AD patients are more susceptible to T_H2-mediated contact sensitization to less-potent allergens, such as fragrances.⁶

Patch Test Results

Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.⁷ Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).⁷ The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde⁸; persistence of allergy to corticosteroids (budesonide and alclometasone)⁹; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde⁹; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)¹⁰; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.¹¹ Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,^12-14 nickel,¹⁴ textile dyes,¹⁴ cosmetic and hair care additives,^12,14,15 corticosteroids,¹⁵ FRPs,¹⁵ fragrances,^15,16 emulsifiers,¹⁶ and non-FRPs.¹⁷

An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely T_H1 response to at least a partial T_H2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.

Final Thoughts

We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.

If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible T_H2-mediated ACD.

In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.

Pathophysiology and Pathomechanism

Dupilumab functions through the blockade of T helper 2 (T_H2) cells; ACD is propagated through the T helper 1 (T_H1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I¹ and balsam of Peru^1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,^2,3p-phenylenediamine,¹ Compositae,⁴ and non–formaldehyde-releasing preservatives (non-FRPs).⁵ Therefore, not all ACD is propagated through the T_H1 cellular pathway.

As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the T_H2 pathway or when patient characteristics favor a T_H2 response. It has been suggested that AD patients are more susceptible to T_H2-mediated contact sensitization to less-potent allergens, such as fragrances.⁶

Patch Test Results

Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.⁷ Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).⁷ The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde⁸; persistence of allergy to corticosteroids (budesonide and alclometasone)⁹; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde⁹; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)¹⁰; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.¹¹ Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,^12-14 nickel,¹⁴ textile dyes,¹⁴ cosmetic and hair care additives,^12,14,15 corticosteroids,¹⁵ FRPs,¹⁵ fragrances,^15,16 emulsifiers,¹⁶ and non-FRPs.¹⁷

An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely T_H1 response to at least a partial T_H2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.

Final Thoughts

We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.

If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible T_H2-mediated ACD.

In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.

Pathophysiology and Pathomechanism

Dupilumab functions through the blockade of T helper 2 (T_H2) cells; ACD is propagated through the T helper 1 (T_H1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I¹ and balsam of Peru^1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,^2,3p-phenylenediamine,¹ Compositae,⁴ and non–formaldehyde-releasing preservatives (non-FRPs).⁵ Therefore, not all ACD is propagated through the T_H1 cellular pathway.

As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the T_H2 pathway or when patient characteristics favor a T_H2 response. It has been suggested that AD patients are more susceptible to T_H2-mediated contact sensitization to less-potent allergens, such as fragrances.⁶

Patch Test Results

Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.⁷ Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).⁷ The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde⁸; persistence of allergy to corticosteroids (budesonide and alclometasone)⁹; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde⁹; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)¹⁰; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.¹¹ Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,^12-14 nickel,¹⁴ textile dyes,¹⁴ cosmetic and hair care additives,^12,14,15 corticosteroids,¹⁵ FRPs,¹⁵ fragrances,^15,16 emulsifiers,¹⁶ and non-FRPs.¹⁷

An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely T_H1 response to at least a partial T_H2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.

Final Thoughts

We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.

If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible T_H2-mediated ACD.

Practice Gap

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are US Food and Drug Administration approved for the treatment of atopic dermatitis.¹ In addition, these 2 drugs are utilized off label for many other dermatologic conditions, including vitiligo, psoriasis, and periorificial dermatitis. They can be used safely for prolonged periods and on sensitive areas, including the face.

Treatment with a TCI provides advantages over topical steroids, which can cause atrophy, telangiectasia, dyspigmentation, ocular hypertension, cataracts, and tachyphylaxis after prolonged use. Adverse events resulting from use of a TCI most commonly include transient burning, warmth, and erythema in areas of application. Patients typically acclimate to these effects after a few consecutive days of use.

Localized flushing after alcohol ingestion is a known potential side effect of TCIs¹; however, this association may be underappreciated and underreported to patients.

Counseling Patients Taking TCIs

Topical calcineurin inhibitors cause alcohol-induced flushing on areas of application (Figures 1 and 2) in approximately 3.4% to 6.9% of patients.¹ The reaction has been reported with both topical TCIs but more often is noted with tacrolimus.^2,3 Typically, flushing begins 2 to 4 weeks after treatment is initiated and within 5 to 20 minutes after alcohol intake.⁴ The phenomenon is self-limited; erythema typically resolves in 20 to 60 minutes.

Topical calcineurin inhibitors are hypothesized to cause alcohol-induced flushing by locally inhibiting acetaldehyde dehydrogenase, an enzyme necessary for alcohol metabolism. This leads to accumulation of acetaldehyde, a by-product of alcohol metabolism, which indirectly causes concentrated vasodilation by means of prostaglandins, histamines, and other vasodilatory mediators. The combination of ethanol and a TCI also might induce release of neuropeptides, which could cause vasodilation.⁴

Alcohol-related flushing commonly is seen among individuals who are aldehyde dehydrogenase 2 (ALDH2) deficient; it is sometimes accompanied by nausea, headache, and tachycardia. The same pathway is implicated in disulfiram reactions, to a more intense and systemic degree, to discourage alcohol intake.

Oral calcineurin inhibitors are not reported to cause generalized flushing, perhaps because of differences in the relative dose. For example, topical tacrolimus 0.1% is 1 mg/g that is applied to a relatively small body surface area; oral calcineurin inhibitors are dosed at a range of 1 to 15 mg for an entire person.

Techniques to Avoid Flushing

Discontinuing a TCI altogether leads to resolution of associated adverse effects, including flushing, typically within weeks to 1 month.⁵ Alternatively, oral aspirin (81 mg) might eliminate or attenuate symptoms, as documented in a double-blind, controlled trial in which relief of TCI-induced flushing after consuming wine was investigated.⁶

Another approach (albeit nontraditional) is for patients who experience this phenomenon to “wet their whistles” with an alcoholic drink before a social engagement. After flushing resolves in 20 to 60 minutes, subsequent drinks do not appear to elicit symptoms again in most patients. That said, we stop short of calling this tip “doctor’s orders.”

Practical Implication

Counseling patients who will be using a TCI—tacrolimus or pimecrolimus—about the potential for these drugs to produce localized flushing after alcohol ingestion as well as techniques for lessening or eliminating this adverse effect are important facets of their dermatologic care.

Practice Gap

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are US Food and Drug Administration approved for the treatment of atopic dermatitis.¹ In addition, these 2 drugs are utilized off label for many other dermatologic conditions, including vitiligo, psoriasis, and periorificial dermatitis. They can be used safely for prolonged periods and on sensitive areas, including the face.

Treatment with a TCI provides advantages over topical steroids, which can cause atrophy, telangiectasia, dyspigmentation, ocular hypertension, cataracts, and tachyphylaxis after prolonged use. Adverse events resulting from use of a TCI most commonly include transient burning, warmth, and erythema in areas of application. Patients typically acclimate to these effects after a few consecutive days of use.

Localized flushing after alcohol ingestion is a known potential side effect of TCIs¹; however, this association may be underappreciated and underreported to patients.

Counseling Patients Taking TCIs

Topical calcineurin inhibitors cause alcohol-induced flushing on areas of application (Figures 1 and 2) in approximately 3.4% to 6.9% of patients.¹ The reaction has been reported with both topical TCIs but more often is noted with tacrolimus.^2,3 Typically, flushing begins 2 to 4 weeks after treatment is initiated and within 5 to 20 minutes after alcohol intake.⁴ The phenomenon is self-limited; erythema typically resolves in 20 to 60 minutes.

Topical calcineurin inhibitors are hypothesized to cause alcohol-induced flushing by locally inhibiting acetaldehyde dehydrogenase, an enzyme necessary for alcohol metabolism. This leads to accumulation of acetaldehyde, a by-product of alcohol metabolism, which indirectly causes concentrated vasodilation by means of prostaglandins, histamines, and other vasodilatory mediators. The combination of ethanol and a TCI also might induce release of neuropeptides, which could cause vasodilation.⁴

Alcohol-related flushing commonly is seen among individuals who are aldehyde dehydrogenase 2 (ALDH2) deficient; it is sometimes accompanied by nausea, headache, and tachycardia. The same pathway is implicated in disulfiram reactions, to a more intense and systemic degree, to discourage alcohol intake.

Oral calcineurin inhibitors are not reported to cause generalized flushing, perhaps because of differences in the relative dose. For example, topical tacrolimus 0.1% is 1 mg/g that is applied to a relatively small body surface area; oral calcineurin inhibitors are dosed at a range of 1 to 15 mg for an entire person.

Techniques to Avoid Flushing

Discontinuing a TCI altogether leads to resolution of associated adverse effects, including flushing, typically within weeks to 1 month.⁵ Alternatively, oral aspirin (81 mg) might eliminate or attenuate symptoms, as documented in a double-blind, controlled trial in which relief of TCI-induced flushing after consuming wine was investigated.⁶

Another approach (albeit nontraditional) is for patients who experience this phenomenon to “wet their whistles” with an alcoholic drink before a social engagement. After flushing resolves in 20 to 60 minutes, subsequent drinks do not appear to elicit symptoms again in most patients. That said, we stop short of calling this tip “doctor’s orders.”

Practical Implication

Counseling patients who will be using a TCI—tacrolimus or pimecrolimus—about the potential for these drugs to produce localized flushing after alcohol ingestion as well as techniques for lessening or eliminating this adverse effect are important facets of their dermatologic care.

Practice Gap

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are US Food and Drug Administration approved for the treatment of atopic dermatitis.¹ In addition, these 2 drugs are utilized off label for many other dermatologic conditions, including vitiligo, psoriasis, and periorificial dermatitis. They can be used safely for prolonged periods and on sensitive areas, including the face.

Treatment with a TCI provides advantages over topical steroids, which can cause atrophy, telangiectasia, dyspigmentation, ocular hypertension, cataracts, and tachyphylaxis after prolonged use. Adverse events resulting from use of a TCI most commonly include transient burning, warmth, and erythema in areas of application. Patients typically acclimate to these effects after a few consecutive days of use.

Localized flushing after alcohol ingestion is a known potential side effect of TCIs¹; however, this association may be underappreciated and underreported to patients.

Counseling Patients Taking TCIs

Topical calcineurin inhibitors cause alcohol-induced flushing on areas of application (Figures 1 and 2) in approximately 3.4% to 6.9% of patients.¹ The reaction has been reported with both topical TCIs but more often is noted with tacrolimus.^2,3 Typically, flushing begins 2 to 4 weeks after treatment is initiated and within 5 to 20 minutes after alcohol intake.⁴ The phenomenon is self-limited; erythema typically resolves in 20 to 60 minutes.

Topical calcineurin inhibitors are hypothesized to cause alcohol-induced flushing by locally inhibiting acetaldehyde dehydrogenase, an enzyme necessary for alcohol metabolism. This leads to accumulation of acetaldehyde, a by-product of alcohol metabolism, which indirectly causes concentrated vasodilation by means of prostaglandins, histamines, and other vasodilatory mediators. The combination of ethanol and a TCI also might induce release of neuropeptides, which could cause vasodilation.⁴

Alcohol-related flushing commonly is seen among individuals who are aldehyde dehydrogenase 2 (ALDH2) deficient; it is sometimes accompanied by nausea, headache, and tachycardia. The same pathway is implicated in disulfiram reactions, to a more intense and systemic degree, to discourage alcohol intake.

Oral calcineurin inhibitors are not reported to cause generalized flushing, perhaps because of differences in the relative dose. For example, topical tacrolimus 0.1% is 1 mg/g that is applied to a relatively small body surface area; oral calcineurin inhibitors are dosed at a range of 1 to 15 mg for an entire person.

Techniques to Avoid Flushing

Discontinuing a TCI altogether leads to resolution of associated adverse effects, including flushing, typically within weeks to 1 month.⁵ Alternatively, oral aspirin (81 mg) might eliminate or attenuate symptoms, as documented in a double-blind, controlled trial in which relief of TCI-induced flushing after consuming wine was investigated.⁶

Another approach (albeit nontraditional) is for patients who experience this phenomenon to “wet their whistles” with an alcoholic drink before a social engagement. After flushing resolves in 20 to 60 minutes, subsequent drinks do not appear to elicit symptoms again in most patients. That said, we stop short of calling this tip “doctor’s orders.”

Practical Implication

Counseling patients who will be using a TCI—tacrolimus or pimecrolimus—about the potential for these drugs to produce localized flushing after alcohol ingestion as well as techniques for lessening or eliminating this adverse effect are important facets of their dermatologic care.

Global climate change is hitting home for dermatologists, according to a recent survey in which the majority of participants said their patients are already being impacted.

Almost 80% of the 148 participants who responded to an electronic survey reported this belief.

The survey was designed and distributed to the membership of various dermatological organizations by Misha Rosenbach, MD, and coauthors. The results were published in the British Journal of Dermatology.

Asked also about specific types of climate-driven phenomena with a current – or future – impact on their patients, 80.1% reported that they believed that increased exposure to ultraviolet radiation (UVR) is impactful, or will be. Changes in temporal or geographic patterns of vector-borne illnesses were affirmed by 78.7%, and an increase in social displacement caused by extreme weather or other events was affirmed by 67.1% as having an impact on their patients currently or in the future.

Other phenomena affirmed by respondents as already having an impact or impacting patients in the future were an increased incidence of heat exposure or heat-related illness (58.2%); an increase in rates of inflammatory skin disease flares (43.2%); increased incidence of waterborne infections (42.5%); and increased rates of allergic contact dermatitis (29.5%).

The survey was sent to the membership of the American Society of Dermatologic Surgery, the Society for Pediatric Dermatology, the Society for Investigative Dermatology, and the American Academy of Dermatology’s Climate Change Expert Resource Group (ERG), among other organizations.

The study design and membership overlap made it impossible to calculate a response rate, the authors said, but they estimated it to be about 10%.

Almost all respondents were from the United States, and most (86.3%) practiced in an academic setting. The findings are similar to those of an online survey of members of the International Society of Dermatology (ISD), published in 2020, which found that 89% of 158 respondents believed climate change will impact the incidence of skin diseases in their area.

“Physicians, including dermatologists, are starting to understand the impact of the climate crisis on both their patients and themselves ... both through lived experiences and [issues raised] more in the scientific literature and in meetings,” Dr. Rosenbach, associate professor of dermatology at the University of Pennsylvania, Philadelphia, said in an interview.

A majority of participants in the U.S. survey agreed they have a responsibility to bring awareness of the health effects of climate change to patients (77.2%) and to policymakers (88.6%). (In the ISD survey, 88% said they believed that dermatologists should play an advocacy role in climate change-related issues).

Only a minority of respondents in the U.S. survey said that they would feel comfortable discussing climate change with their patients (37.2%). Almost one-third of the respondents said they would like to be better informed about climate change before doing so. And 81.8% said they would like to read more about the dermatological effects of climate change in scientific journals.

“There continues to be unfilled interest in education and advocacy regarding climate change, suggesting a ‘practice gap’ even among dermatologists,” Dr. Rosenbach and his colleagues wrote, noting opportunities for professional organizations and journals to provide more resources and “actionable items” regarding climate change.

Some dermatologists have been taking action, in the meantime, to reduce the carbon footprint of their practices and institutions. Reductions in facility energy consumption, and reductions in medical waste/optimization of recycling, were each reported by more than one-third of survey respondents.

And almost half indicated that their practice or institution had increased capacity for telemedicine or telecommuting in response to climate change. Only 8% said their practice or institution had divested from fossil fuel stocks and/or bonds.

“There are a lot of sustainability-in-medicine solutions that are actually cost-neutral or cost-saving for practices,” said Dr. Rosenbach, who is a founder and co-chair of the AAD’s ERG on Climate Change and Environmental Issues.

Research in dermatology is starting to quantify the environmental impact of some of these changes. In a research letter also published in the British Journal of Dermatology, researchers from Cardiff University and the department of dermatology at University Hospital of Wales, described how they determined that reusable surgical packs used for skin surgery are more sustainable than single-use packs because of their reduced cost and reduced greenhouse gas emissions.

Such single-site reports are “early feeders” into what will become a stream of larger studies quantifying the impact of measures taken in dermatology, Dr. Rosenbach said.

Across medicine, there is evidence that health care professionals are now seeing climate change as a threat to their patients. In a multinational survey published last year in The Lancet Planetary Health, 77% of 3,977 participants said that climate change will cause a moderate or great deal of harm for their patients.

Climate change will be discussed at the AAD’s annual meeting in late March in a session devoted to the topic, and as part of a broader session on controversies in dermatology.

Dr. Rosenbach and two of the five authors of the dermatology research letter are members of the AAD’s ERG on climate change, but in the publication they noted that they were not writing on behalf of the AAD. None of the authors reported any disclosures, and there was no funding source for the survey.

Global climate change is hitting home for dermatologists, according to a recent survey in which the majority of participants said their patients are already being impacted.

Almost 80% of the 148 participants who responded to an electronic survey reported this belief.

The survey was designed and distributed to the membership of various dermatological organizations by Misha Rosenbach, MD, and coauthors. The results were published in the British Journal of Dermatology.

Asked also about specific types of climate-driven phenomena with a current – or future – impact on their patients, 80.1% reported that they believed that increased exposure to ultraviolet radiation (UVR) is impactful, or will be. Changes in temporal or geographic patterns of vector-borne illnesses were affirmed by 78.7%, and an increase in social displacement caused by extreme weather or other events was affirmed by 67.1% as having an impact on their patients currently or in the future.

Other phenomena affirmed by respondents as already having an impact or impacting patients in the future were an increased incidence of heat exposure or heat-related illness (58.2%); an increase in rates of inflammatory skin disease flares (43.2%); increased incidence of waterborne infections (42.5%); and increased rates of allergic contact dermatitis (29.5%).

The survey was sent to the membership of the American Society of Dermatologic Surgery, the Society for Pediatric Dermatology, the Society for Investigative Dermatology, and the American Academy of Dermatology’s Climate Change Expert Resource Group (ERG), among other organizations.

The study design and membership overlap made it impossible to calculate a response rate, the authors said, but they estimated it to be about 10%.

Almost all respondents were from the United States, and most (86.3%) practiced in an academic setting. The findings are similar to those of an online survey of members of the International Society of Dermatology (ISD), published in 2020, which found that 89% of 158 respondents believed climate change will impact the incidence of skin diseases in their area.

“Physicians, including dermatologists, are starting to understand the impact of the climate crisis on both their patients and themselves ... both through lived experiences and [issues raised] more in the scientific literature and in meetings,” Dr. Rosenbach, associate professor of dermatology at the University of Pennsylvania, Philadelphia, said in an interview.

A majority of participants in the U.S. survey agreed they have a responsibility to bring awareness of the health effects of climate change to patients (77.2%) and to policymakers (88.6%). (In the ISD survey, 88% said they believed that dermatologists should play an advocacy role in climate change-related issues).

Only a minority of respondents in the U.S. survey said that they would feel comfortable discussing climate change with their patients (37.2%). Almost one-third of the respondents said they would like to be better informed about climate change before doing so. And 81.8% said they would like to read more about the dermatological effects of climate change in scientific journals.

“There continues to be unfilled interest in education and advocacy regarding climate change, suggesting a ‘practice gap’ even among dermatologists,” Dr. Rosenbach and his colleagues wrote, noting opportunities for professional organizations and journals to provide more resources and “actionable items” regarding climate change.

Some dermatologists have been taking action, in the meantime, to reduce the carbon footprint of their practices and institutions. Reductions in facility energy consumption, and reductions in medical waste/optimization of recycling, were each reported by more than one-third of survey respondents.

And almost half indicated that their practice or institution had increased capacity for telemedicine or telecommuting in response to climate change. Only 8% said their practice or institution had divested from fossil fuel stocks and/or bonds.

“There are a lot of sustainability-in-medicine solutions that are actually cost-neutral or cost-saving for practices,” said Dr. Rosenbach, who is a founder and co-chair of the AAD’s ERG on Climate Change and Environmental Issues.

Research in dermatology is starting to quantify the environmental impact of some of these changes. In a research letter also published in the British Journal of Dermatology, researchers from Cardiff University and the department of dermatology at University Hospital of Wales, described how they determined that reusable surgical packs used for skin surgery are more sustainable than single-use packs because of their reduced cost and reduced greenhouse gas emissions.

Such single-site reports are “early feeders” into what will become a stream of larger studies quantifying the impact of measures taken in dermatology, Dr. Rosenbach said.

Across medicine, there is evidence that health care professionals are now seeing climate change as a threat to their patients. In a multinational survey published last year in The Lancet Planetary Health, 77% of 3,977 participants said that climate change will cause a moderate or great deal of harm for their patients.

Climate change will be discussed at the AAD’s annual meeting in late March in a session devoted to the topic, and as part of a broader session on controversies in dermatology.

Dr. Rosenbach and two of the five authors of the dermatology research letter are members of the AAD’s ERG on climate change, but in the publication they noted that they were not writing on behalf of the AAD. None of the authors reported any disclosures, and there was no funding source for the survey.

Global climate change is hitting home for dermatologists, according to a recent survey in which the majority of participants said their patients are already being impacted.

Almost 80% of the 148 participants who responded to an electronic survey reported this belief.

The survey was designed and distributed to the membership of various dermatological organizations by Misha Rosenbach, MD, and coauthors. The results were published in the British Journal of Dermatology.

Asked also about specific types of climate-driven phenomena with a current – or future – impact on their patients, 80.1% reported that they believed that increased exposure to ultraviolet radiation (UVR) is impactful, or will be. Changes in temporal or geographic patterns of vector-borne illnesses were affirmed by 78.7%, and an increase in social displacement caused by extreme weather or other events was affirmed by 67.1% as having an impact on their patients currently or in the future.

Other phenomena affirmed by respondents as already having an impact or impacting patients in the future were an increased incidence of heat exposure or heat-related illness (58.2%); an increase in rates of inflammatory skin disease flares (43.2%); increased incidence of waterborne infections (42.5%); and increased rates of allergic contact dermatitis (29.5%).

The survey was sent to the membership of the American Society of Dermatologic Surgery, the Society for Pediatric Dermatology, the Society for Investigative Dermatology, and the American Academy of Dermatology’s Climate Change Expert Resource Group (ERG), among other organizations.

The study design and membership overlap made it impossible to calculate a response rate, the authors said, but they estimated it to be about 10%.

Almost all respondents were from the United States, and most (86.3%) practiced in an academic setting. The findings are similar to those of an online survey of members of the International Society of Dermatology (ISD), published in 2020, which found that 89% of 158 respondents believed climate change will impact the incidence of skin diseases in their area.

“Physicians, including dermatologists, are starting to understand the impact of the climate crisis on both their patients and themselves ... both through lived experiences and [issues raised] more in the scientific literature and in meetings,” Dr. Rosenbach, associate professor of dermatology at the University of Pennsylvania, Philadelphia, said in an interview.

A majority of participants in the U.S. survey agreed they have a responsibility to bring awareness of the health effects of climate change to patients (77.2%) and to policymakers (88.6%). (In the ISD survey, 88% said they believed that dermatologists should play an advocacy role in climate change-related issues).

Only a minority of respondents in the U.S. survey said that they would feel comfortable discussing climate change with their patients (37.2%). Almost one-third of the respondents said they would like to be better informed about climate change before doing so. And 81.8% said they would like to read more about the dermatological effects of climate change in scientific journals.

“There continues to be unfilled interest in education and advocacy regarding climate change, suggesting a ‘practice gap’ even among dermatologists,” Dr. Rosenbach and his colleagues wrote, noting opportunities for professional organizations and journals to provide more resources and “actionable items” regarding climate change.

Some dermatologists have been taking action, in the meantime, to reduce the carbon footprint of their practices and institutions. Reductions in facility energy consumption, and reductions in medical waste/optimization of recycling, were each reported by more than one-third of survey respondents.

And almost half indicated that their practice or institution had increased capacity for telemedicine or telecommuting in response to climate change. Only 8% said their practice or institution had divested from fossil fuel stocks and/or bonds.

“There are a lot of sustainability-in-medicine solutions that are actually cost-neutral or cost-saving for practices,” said Dr. Rosenbach, who is a founder and co-chair of the AAD’s ERG on Climate Change and Environmental Issues.

Research in dermatology is starting to quantify the environmental impact of some of these changes. In a research letter also published in the British Journal of Dermatology, researchers from Cardiff University and the department of dermatology at University Hospital of Wales, described how they determined that reusable surgical packs used for skin surgery are more sustainable than single-use packs because of their reduced cost and reduced greenhouse gas emissions.

Such single-site reports are “early feeders” into what will become a stream of larger studies quantifying the impact of measures taken in dermatology, Dr. Rosenbach said.

Across medicine, there is evidence that health care professionals are now seeing climate change as a threat to their patients. In a multinational survey published last year in The Lancet Planetary Health, 77% of 3,977 participants said that climate change will cause a moderate or great deal of harm for their patients.

Climate change will be discussed at the AAD’s annual meeting in late March in a session devoted to the topic, and as part of a broader session on controversies in dermatology.

Dr. Rosenbach and two of the five authors of the dermatology research letter are members of the AAD’s ERG on climate change, but in the publication they noted that they were not writing on behalf of the AAD. None of the authors reported any disclosures, and there was no funding source for the survey.

To the Editor:

A 71-year-old Hispanic man with a history of vitiligo presented with an acute-onset blistering rash on the face, arms, and hands. Physical examination demonstrated photodistributed erythematous plaques with overlying vesicles and erosions with hemorrhagic crust on the face, neck, dorsal aspects of the hands, and wrists (Figure). Further history revealed that the patient applied a new cream that was recommended to treat vitiligo the night before the rash onset; he obtained the cream from a Central American market without a prescription. He had gone running in the park without any form of sun protection and then developed the rash within several hours. He denied taking any other medications or supplements. The involvement of sun-protected areas (ie, upper eyelids, nasolabial folds, submental area) was explained when the patient further elaborated that he had performed supine exercises during his outdoor recreation. He brought his new cream into the clinic, which was found to contain prescription-strength methoxsalen (8-methoxypsoralen), confirming the diagnosis of acute phototoxic contact dermatitis. The acute reaction had subsided, and the patient already had discontinued the causative agent. He was counseled on further avoidance of the cream and sun-protective measures.

The photosensitizing properties of certain compounds have been harnessed for therapeutic purposes. For example, psoralen plus UVA therapy has been used for psoriasis and vitiligo and photodynamic therapy for actinic keratoses and superficial nonmelanoma skin cancers.¹ However, these agents can induce severe phototoxicity if UV light exposure is not carefully monitored, as seen in our patient. This case is a classic example of phototoxic contact dermatitis and highlights the importance of obtaining a detailed patient history to allow for proper diagnosis and identification of the causative agent. Importantly, because prescription-strength topical medications are readily available over-the-counter, particularly in stores specializing in international goods, patients should be questioned about the use of all topical and systemic medications, both prescription and nonprescription.²

To the Editor:

A 71-year-old Hispanic man with a history of vitiligo presented with an acute-onset blistering rash on the face, arms, and hands. Physical examination demonstrated photodistributed erythematous plaques with overlying vesicles and erosions with hemorrhagic crust on the face, neck, dorsal aspects of the hands, and wrists (Figure). Further history revealed that the patient applied a new cream that was recommended to treat vitiligo the night before the rash onset; he obtained the cream from a Central American market without a prescription. He had gone running in the park without any form of sun protection and then developed the rash within several hours. He denied taking any other medications or supplements. The involvement of sun-protected areas (ie, upper eyelids, nasolabial folds, submental area) was explained when the patient further elaborated that he had performed supine exercises during his outdoor recreation. He brought his new cream into the clinic, which was found to contain prescription-strength methoxsalen (8-methoxypsoralen), confirming the diagnosis of acute phototoxic contact dermatitis. The acute reaction had subsided, and the patient already had discontinued the causative agent. He was counseled on further avoidance of the cream and sun-protective measures.

The photosensitizing properties of certain compounds have been harnessed for therapeutic purposes. For example, psoralen plus UVA therapy has been used for psoriasis and vitiligo and photodynamic therapy for actinic keratoses and superficial nonmelanoma skin cancers.¹ However, these agents can induce severe phototoxicity if UV light exposure is not carefully monitored, as seen in our patient. This case is a classic example of phototoxic contact dermatitis and highlights the importance of obtaining a detailed patient history to allow for proper diagnosis and identification of the causative agent. Importantly, because prescription-strength topical medications are readily available over-the-counter, particularly in stores specializing in international goods, patients should be questioned about the use of all topical and systemic medications, both prescription and nonprescription.²

To the Editor:

A 71-year-old Hispanic man with a history of vitiligo presented with an acute-onset blistering rash on the face, arms, and hands. Physical examination demonstrated photodistributed erythematous plaques with overlying vesicles and erosions with hemorrhagic crust on the face, neck, dorsal aspects of the hands, and wrists (Figure). Further history revealed that the patient applied a new cream that was recommended to treat vitiligo the night before the rash onset; he obtained the cream from a Central American market without a prescription. He had gone running in the park without any form of sun protection and then developed the rash within several hours. He denied taking any other medications or supplements. The involvement of sun-protected areas (ie, upper eyelids, nasolabial folds, submental area) was explained when the patient further elaborated that he had performed supine exercises during his outdoor recreation. He brought his new cream into the clinic, which was found to contain prescription-strength methoxsalen (8-methoxypsoralen), confirming the diagnosis of acute phototoxic contact dermatitis. The acute reaction had subsided, and the patient already had discontinued the causative agent. He was counseled on further avoidance of the cream and sun-protective measures.

The photosensitizing properties of certain compounds have been harnessed for therapeutic purposes. For example, psoralen plus UVA therapy has been used for psoriasis and vitiligo and photodynamic therapy for actinic keratoses and superficial nonmelanoma skin cancers.¹ However, these agents can induce severe phototoxicity if UV light exposure is not carefully monitored, as seen in our patient. This case is a classic example of phototoxic contact dermatitis and highlights the importance of obtaining a detailed patient history to allow for proper diagnosis and identification of the causative agent. Importantly, because prescription-strength topical medications are readily available over-the-counter, particularly in stores specializing in international goods, patients should be questioned about the use of all topical and systemic medications, both prescription and nonprescription.²

In the first part of this 2-part series (Cutis. 2021;108:271-275), we discussed topical medicament allergic contact dermatitis (ACD) from acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations. In part 2 of this series, we focus on topical corticosteroids, immunomodulators, and anesthetics.

Corticosteroids

Given their anti-inflammatory and immune-modulating effects, topical corticosteroids are utilized for the treatment of contact dermatitis and yet also are frequent culprits of ACD. The North American Contact Dermatitis Group (NACDG) demonstrated a 4% frequency of positive patch tests to at least one corticosteroid from 2007 to 2014; the relevant allergens were tixocortol pivalate (TP)(2.3%), budesonide (0.9%), hydrocortisone-17-butyrate (0.4%), clobetasol-17-propionate (0.3%), and desoximetasone (0.2%).¹ Corticosteroid contact allergy can be difficult to recognize and may present as a flare of the underlying condition being treated. Clinically, these rashes may demonstrate an edge effect, characterized by pronounced dermatitis adjacent to and surrounding the treatment area due to concentrated anti-inflammatory effects in the center.

Traditionally, corticosteroids are divided into 4 basic structural groups—classes A, B, C, and D—based on the Coopman et al² classification (Table). The class D corticosteroids were further subdivided into classes D1, defined by C16-methyl substitution and halogenation of the B ring, and D2, which lacks the aforementioned substitutions.⁴ However, more recently Baeck et al⁵ simplified this classification into 3 main groups of steroids based on molecular modeling in combination with patch test results. Group 1 combines the nonmethylated and (mostly) nonhalogenated class A and D2 molecules plus budesonide; group 2 accounts for some halogenated class B molecules with the C16, C17 cis ketal or diol structure; and group 3 includes halogenated and C16-methylated molecules from classes C and D1.⁴ For the purposes of this review, discussion of classes A through D refers to the Coopman et al² classification, and groups 1 through 3 refers to Baeck et al.⁵

Tixocortol pivalate is used as a surrogate marker for hydrocortisone allergy and other class A corticosteroids and is part of the group 1 steroid classification. Interestingly, patients with TP-positive patch tests may not exhibit signs or symptoms of ACD from the use of hydrocortisone products. Repeat open application testing (ROAT) or provocative use testing may elicit a positive response in these patients, especially with the use of hydrocortisone cream (vs ointment), likely due to greater transepidermal penetration.⁶ There is little consensus on the optimal concentration of TP for patch testing. Although TP 1% often is recommended, studies have shown mixed findings of notable differences between high (1% petrolatum) and low (0.1% petrolatum) concentrations of TP.^7,8

Budesonide also is part of group 1 and is a marker for contact allergy to class B corticosteroids, such as triamcinolone and fluocinonide. Cross-reactions between budesonide and other corticosteroids traditionally classified as group B may be explained by structural similarities, whereas cross-reactions with certain class D corticosteroids, such as hydrocortisone-17-butyrate, may be better explained by the diastereomer composition of budesonide.^9,10 In a European study, budesonide 0.01% and TP 0.1% included in the European Baseline Series detected 85% (23/27) of cases of corticosteroid allergies.¹¹ Use of inhaled budesonide can provoke recall dermatitis and therefore should be avoided in allergic patients.¹²

Testing for ACD to topical steroids is complex, as the potent anti-inflammatory properties of these medications can complicate results. Selecting the appropriate test, vehicle, and concentration can help avoid false negatives. Although intradermal testing previously was thought to be superior to patch testing in detecting topical corticosteroid contact allergy, newer data have demonstrated strong concordance between the two methods.^13,14 The risk for skin atrophy, particularly with the use of suspensions, limits the use of intradermal testing.¹⁴ An ethanol vehicle is recommended for patch testing, except when testing with TP or budesonide when petrolatum provides greater corticosteroid stability.^14-16 An irritant pattern or a rim effect on patch testing often is considered positive when testing corticosteroids, as the effect of the steroid itself can diminish a positive reaction. As a result, 0.1% dilutions sometimes are favored over 1% test concentrations.^14,15,17 Late readings (>7 days) may be necessary to detect positive reactions in both adults and children.^18,19

The authors (M.R., A.R.A.) find these varied classifications of steroids daunting (and somewhat confusing!). In general, when ACD to topical steroids is suspected, in addition to standard patch testing with a corticosteroid series, ROAT of the suspected steroid may be necessary, as the rules of steroid classification may not be reproducible in the real world. For patients with only corticosteroid allergy, calcineurin inhibitors are a safe alternative.

Immunomodulators

Calcipotriol is a vitamin D analogue commonly used to treat psoriasis. Although it is a well-known irritant, ACD to topical calcipotriol rarely has been reported.^20-23 Topical calcipotriol does not seem to cross-react with other vitamin D analogues, including tacalcitol and calcitriol.^21,24 Based on the literature and the nonirritant reactive thresholds described by Fullerton et al,²⁵ recommended patch test concentrations of calcipotriol in isopropanol are 2 to 10 µg/mL. Given its immunomodulating effects, calcipotriol may suppress contact hypersensitization from other allergens, similar to the effects seen with UV radiation.²⁶

Calcineurin inhibitors act on the nuclear factor of activated T cells signaling pathway, resulting in downstream suppression of proinflammatory cytokines. Contact allergy to these topical medications is rare and mainly has involved pimecrolimus.^27-30 In one case, a patient with a previously documented topical tacrolimus contact allergy demonstrated cross-reactivity with pimecrolimus on a double-blinded, right-vs-left ROAT, as well as by patch testing with pimecrolimus cream 1%, which was only weakly positive (+).²⁷ Patch test concentrations of 2.5% or higher may be required to elicit positive reactions to tacrolimus, as shown in one case where this was attributed to high molecular weight and poor extrafacial skin absorption of tacrolimus.³⁰ In an unusual case, a patient reacted positively to patch testing and ROAT using pimecrolimus cream 1% but not pimecrolimus 1% to 5% in petrolatum or alcohol nor the individual excipients, illustrating the importance of testing with both active and inactive ingredients.²⁹

Anesthetics

Local anesthetics can be separated into 2 main groups—amides and esters—based on their chemical structures. From 2001 to 2004, the NACDG patch tested 10,061 patients and found 344 (3.4%) with a positive reaction to at least one topical anesthetic.³¹ We will discuss some of the allergic cutaneous reactions associated with topical benzocaine (an ester) and lidocaine and prilocaine (amides).

According to the NACDG, the estimated prevalence of topical benzocaine allergy from 2001 to 2018 was roughly 3%.³² Allergic contact dermatitis has been reported in patients who used topical benzocaine to treat localized pain disorders, including herpes zoster and dental pain.^33,34 Benzocaine may be used in the anogenital region in the form of antihemorrhoidal creams and in condoms and is a considerably more common allergen in those with anogenital dermatitis compared to those without.^35-38 Although cross-reactions within the same anesthetic group are common, clinicians also should be aware of the potential for concomitant sensitivity between unrelated local anesthetics.^39-41

From 2001 to 2018, the prevalence of ACD to topical lidocaine was estimated to be 7.9%, according to the NACDG.³² A topical anesthetic containing both lidocaine and prilocaine often is used preprocedurally and can be a source of ACD. Interestingly, several cases of ACD to combination lidocaine/prilocaine cream demonstrated positive patch tests to prilocaine but not lidocaine, despite their structural similarities.^42-44 One case report described simultaneous positive reactions to both prilocaine 5% and lidocaine 1%.⁴⁵

There are a few key points to consider when working up contact allergy to local anesthetics. Patients who develop positive patch test reactions to a local anesthetic should undergo further testing to better understand alternatives and future use. As previously mentioned, ACD to one anesthetic does not necessarily preclude the use of other related anesthetics. Intradermal testing may help differentiate immediate and delayed-type allergic reactions to local anesthetics and should therefore follow positive patch tests.⁴⁶ Importantly, a delayed reading (ie, after day 6 or 7) also should be performed as part of intradermal testing. Patients with positive patch tests but negative intradermal test results may be able to tolerate systemic anesthetic use.⁴⁷

Patch Testing for Potential Medicament ACD

In this article, we touched on several topical medications that have nuanced patch testing specifications given their immunomodulating effects. A simplified outline of recommended patch test concentrations is provided in the eTable, and we encourage you to revisit these useful resources as needed. In many cases, referral to a specialized patch test clinic may be necessary. Although they are not reviewed in this article, always consider inactive ingredients such as preservatives, softening agents, and emulsifiers in the setting of medicament dermatitis, as they also may be culprits of ACD.

Final Interpretation

In this 2-part series, we covered ACD to several common topical drugs with a focus on active ingredients as the source of allergy, and yet this is just the tip of the iceberg. Topical medicaments are prevalent in the field of dermatology, and associated cases of ACD have been reported proportionately. Consider ACD when topical medication efficacy plateaus, triggers new-onset dermatitis, or seems to exacerbate an underlying dermatitis.

In the first part of this 2-part series (Cutis. 2021;108:271-275), we discussed topical medicament allergic contact dermatitis (ACD) from acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations. In part 2 of this series, we focus on topical corticosteroids, immunomodulators, and anesthetics.

Corticosteroids

Given their anti-inflammatory and immune-modulating effects, topical corticosteroids are utilized for the treatment of contact dermatitis and yet also are frequent culprits of ACD. The North American Contact Dermatitis Group (NACDG) demonstrated a 4% frequency of positive patch tests to at least one corticosteroid from 2007 to 2014; the relevant allergens were tixocortol pivalate (TP)(2.3%), budesonide (0.9%), hydrocortisone-17-butyrate (0.4%), clobetasol-17-propionate (0.3%), and desoximetasone (0.2%).¹ Corticosteroid contact allergy can be difficult to recognize and may present as a flare of the underlying condition being treated. Clinically, these rashes may demonstrate an edge effect, characterized by pronounced dermatitis adjacent to and surrounding the treatment area due to concentrated anti-inflammatory effects in the center.

Traditionally, corticosteroids are divided into 4 basic structural groups—classes A, B, C, and D—based on the Coopman et al² classification (Table). The class D corticosteroids were further subdivided into classes D1, defined by C16-methyl substitution and halogenation of the B ring, and D2, which lacks the aforementioned substitutions.⁴ However, more recently Baeck et al⁵ simplified this classification into 3 main groups of steroids based on molecular modeling in combination with patch test results. Group 1 combines the nonmethylated and (mostly) nonhalogenated class A and D2 molecules plus budesonide; group 2 accounts for some halogenated class B molecules with the C16, C17 cis ketal or diol structure; and group 3 includes halogenated and C16-methylated molecules from classes C and D1.⁴ For the purposes of this review, discussion of classes A through D refers to the Coopman et al² classification, and groups 1 through 3 refers to Baeck et al.⁵

Tixocortol pivalate is used as a surrogate marker for hydrocortisone allergy and other class A corticosteroids and is part of the group 1 steroid classification. Interestingly, patients with TP-positive patch tests may not exhibit signs or symptoms of ACD from the use of hydrocortisone products. Repeat open application testing (ROAT) or provocative use testing may elicit a positive response in these patients, especially with the use of hydrocortisone cream (vs ointment), likely due to greater transepidermal penetration.⁶ There is little consensus on the optimal concentration of TP for patch testing. Although TP 1% often is recommended, studies have shown mixed findings of notable differences between high (1% petrolatum) and low (0.1% petrolatum) concentrations of TP.^7,8

Budesonide also is part of group 1 and is a marker for contact allergy to class B corticosteroids, such as triamcinolone and fluocinonide. Cross-reactions between budesonide and other corticosteroids traditionally classified as group B may be explained by structural similarities, whereas cross-reactions with certain class D corticosteroids, such as hydrocortisone-17-butyrate, may be better explained by the diastereomer composition of budesonide.^9,10 In a European study, budesonide 0.01% and TP 0.1% included in the European Baseline Series detected 85% (23/27) of cases of corticosteroid allergies.¹¹ Use of inhaled budesonide can provoke recall dermatitis and therefore should be avoided in allergic patients.¹²

Testing for ACD to topical steroids is complex, as the potent anti-inflammatory properties of these medications can complicate results. Selecting the appropriate test, vehicle, and concentration can help avoid false negatives. Although intradermal testing previously was thought to be superior to patch testing in detecting topical corticosteroid contact allergy, newer data have demonstrated strong concordance between the two methods.^13,14 The risk for skin atrophy, particularly with the use of suspensions, limits the use of intradermal testing.¹⁴ An ethanol vehicle is recommended for patch testing, except when testing with TP or budesonide when petrolatum provides greater corticosteroid stability.^14-16 An irritant pattern or a rim effect on patch testing often is considered positive when testing corticosteroids, as the effect of the steroid itself can diminish a positive reaction. As a result, 0.1% dilutions sometimes are favored over 1% test concentrations.^14,15,17 Late readings (>7 days) may be necessary to detect positive reactions in both adults and children.^18,19

The authors (M.R., A.R.A.) find these varied classifications of steroids daunting (and somewhat confusing!). In general, when ACD to topical steroids is suspected, in addition to standard patch testing with a corticosteroid series, ROAT of the suspected steroid may be necessary, as the rules of steroid classification may not be reproducible in the real world. For patients with only corticosteroid allergy, calcineurin inhibitors are a safe alternative.

Immunomodulators

Calcipotriol is a vitamin D analogue commonly used to treat psoriasis. Although it is a well-known irritant, ACD to topical calcipotriol rarely has been reported.^20-23 Topical calcipotriol does not seem to cross-react with other vitamin D analogues, including tacalcitol and calcitriol.^21,24 Based on the literature and the nonirritant reactive thresholds described by Fullerton et al,²⁵ recommended patch test concentrations of calcipotriol in isopropanol are 2 to 10 µg/mL. Given its immunomodulating effects, calcipotriol may suppress contact hypersensitization from other allergens, similar to the effects seen with UV radiation.²⁶

Calcineurin inhibitors act on the nuclear factor of activated T cells signaling pathway, resulting in downstream suppression of proinflammatory cytokines. Contact allergy to these topical medications is rare and mainly has involved pimecrolimus.^27-30 In one case, a patient with a previously documented topical tacrolimus contact allergy demonstrated cross-reactivity with pimecrolimus on a double-blinded, right-vs-left ROAT, as well as by patch testing with pimecrolimus cream 1%, which was only weakly positive (+).²⁷ Patch test concentrations of 2.5% or higher may be required to elicit positive reactions to tacrolimus, as shown in one case where this was attributed to high molecular weight and poor extrafacial skin absorption of tacrolimus.³⁰ In an unusual case, a patient reacted positively to patch testing and ROAT using pimecrolimus cream 1% but not pimecrolimus 1% to 5% in petrolatum or alcohol nor the individual excipients, illustrating the importance of testing with both active and inactive ingredients.²⁹

Anesthetics

Local anesthetics can be separated into 2 main groups—amides and esters—based on their chemical structures. From 2001 to 2004, the NACDG patch tested 10,061 patients and found 344 (3.4%) with a positive reaction to at least one topical anesthetic.³¹ We will discuss some of the allergic cutaneous reactions associated with topical benzocaine (an ester) and lidocaine and prilocaine (amides).

According to the NACDG, the estimated prevalence of topical benzocaine allergy from 2001 to 2018 was roughly 3%.³² Allergic contact dermatitis has been reported in patients who used topical benzocaine to treat localized pain disorders, including herpes zoster and dental pain.^33,34 Benzocaine may be used in the anogenital region in the form of antihemorrhoidal creams and in condoms and is a considerably more common allergen in those with anogenital dermatitis compared to those without.^35-38 Although cross-reactions within the same anesthetic group are common, clinicians also should be aware of the potential for concomitant sensitivity between unrelated local anesthetics.^39-41

From 2001 to 2018, the prevalence of ACD to topical lidocaine was estimated to be 7.9%, according to the NACDG.³² A topical anesthetic containing both lidocaine and prilocaine often is used preprocedurally and can be a source of ACD. Interestingly, several cases of ACD to combination lidocaine/prilocaine cream demonstrated positive patch tests to prilocaine but not lidocaine, despite their structural similarities.^42-44 One case report described simultaneous positive reactions to both prilocaine 5% and lidocaine 1%.⁴⁵

There are a few key points to consider when working up contact allergy to local anesthetics. Patients who develop positive patch test reactions to a local anesthetic should undergo further testing to better understand alternatives and future use. As previously mentioned, ACD to one anesthetic does not necessarily preclude the use of other related anesthetics. Intradermal testing may help differentiate immediate and delayed-type allergic reactions to local anesthetics and should therefore follow positive patch tests.⁴⁶ Importantly, a delayed reading (ie, after day 6 or 7) also should be performed as part of intradermal testing. Patients with positive patch tests but negative intradermal test results may be able to tolerate systemic anesthetic use.⁴⁷

Patch Testing for Potential Medicament ACD

In this article, we touched on several topical medications that have nuanced patch testing specifications given their immunomodulating effects. A simplified outline of recommended patch test concentrations is provided in the eTable, and we encourage you to revisit these useful resources as needed. In many cases, referral to a specialized patch test clinic may be necessary. Although they are not reviewed in this article, always consider inactive ingredients such as preservatives, softening agents, and emulsifiers in the setting of medicament dermatitis, as they also may be culprits of ACD.

Final Interpretation

In this 2-part series, we covered ACD to several common topical drugs with a focus on active ingredients as the source of allergy, and yet this is just the tip of the iceberg. Topical medicaments are prevalent in the field of dermatology, and associated cases of ACD have been reported proportionately. Consider ACD when topical medication efficacy plateaus, triggers new-onset dermatitis, or seems to exacerbate an underlying dermatitis.

In the first part of this 2-part series (Cutis. 2021;108:271-275), we discussed topical medicament allergic contact dermatitis (ACD) from acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations. In part 2 of this series, we focus on topical corticosteroids, immunomodulators, and anesthetics.

Corticosteroids

Given their anti-inflammatory and immune-modulating effects, topical corticosteroids are utilized for the treatment of contact dermatitis and yet also are frequent culprits of ACD. The North American Contact Dermatitis Group (NACDG) demonstrated a 4% frequency of positive patch tests to at least one corticosteroid from 2007 to 2014; the relevant allergens were tixocortol pivalate (TP)(2.3%), budesonide (0.9%), hydrocortisone-17-butyrate (0.4%), clobetasol-17-propionate (0.3%), and desoximetasone (0.2%).¹ Corticosteroid contact allergy can be difficult to recognize and may present as a flare of the underlying condition being treated. Clinically, these rashes may demonstrate an edge effect, characterized by pronounced dermatitis adjacent to and surrounding the treatment area due to concentrated anti-inflammatory effects in the center.

Traditionally, corticosteroids are divided into 4 basic structural groups—classes A, B, C, and D—based on the Coopman et al² classification (Table). The class D corticosteroids were further subdivided into classes D1, defined by C16-methyl substitution and halogenation of the B ring, and D2, which lacks the aforementioned substitutions.⁴ However, more recently Baeck et al⁵ simplified this classification into 3 main groups of steroids based on molecular modeling in combination with patch test results. Group 1 combines the nonmethylated and (mostly) nonhalogenated class A and D2 molecules plus budesonide; group 2 accounts for some halogenated class B molecules with the C16, C17 cis ketal or diol structure; and group 3 includes halogenated and C16-methylated molecules from classes C and D1.⁴ For the purposes of this review, discussion of classes A through D refers to the Coopman et al² classification, and groups 1 through 3 refers to Baeck et al.⁵

Tixocortol pivalate is used as a surrogate marker for hydrocortisone allergy and other class A corticosteroids and is part of the group 1 steroid classification. Interestingly, patients with TP-positive patch tests may not exhibit signs or symptoms of ACD from the use of hydrocortisone products. Repeat open application testing (ROAT) or provocative use testing may elicit a positive response in these patients, especially with the use of hydrocortisone cream (vs ointment), likely due to greater transepidermal penetration.⁶ There is little consensus on the optimal concentration of TP for patch testing. Although TP 1% often is recommended, studies have shown mixed findings of notable differences between high (1% petrolatum) and low (0.1% petrolatum) concentrations of TP.^7,8

Budesonide also is part of group 1 and is a marker for contact allergy to class B corticosteroids, such as triamcinolone and fluocinonide. Cross-reactions between budesonide and other corticosteroids traditionally classified as group B may be explained by structural similarities, whereas cross-reactions with certain class D corticosteroids, such as hydrocortisone-17-butyrate, may be better explained by the diastereomer composition of budesonide.^9,10 In a European study, budesonide 0.01% and TP 0.1% included in the European Baseline Series detected 85% (23/27) of cases of corticosteroid allergies.¹¹ Use of inhaled budesonide can provoke recall dermatitis and therefore should be avoided in allergic patients.¹²

Testing for ACD to topical steroids is complex, as the potent anti-inflammatory properties of these medications can complicate results. Selecting the appropriate test, vehicle, and concentration can help avoid false negatives. Although intradermal testing previously was thought to be superior to patch testing in detecting topical corticosteroid contact allergy, newer data have demonstrated strong concordance between the two methods.^13,14 The risk for skin atrophy, particularly with the use of suspensions, limits the use of intradermal testing.¹⁴ An ethanol vehicle is recommended for patch testing, except when testing with TP or budesonide when petrolatum provides greater corticosteroid stability.^14-16 An irritant pattern or a rim effect on patch testing often is considered positive when testing corticosteroids, as the effect of the steroid itself can diminish a positive reaction. As a result, 0.1% dilutions sometimes are favored over 1% test concentrations.^14,15,17 Late readings (>7 days) may be necessary to detect positive reactions in both adults and children.^18,19

The authors (M.R., A.R.A.) find these varied classifications of steroids daunting (and somewhat confusing!). In general, when ACD to topical steroids is suspected, in addition to standard patch testing with a corticosteroid series, ROAT of the suspected steroid may be necessary, as the rules of steroid classification may not be reproducible in the real world. For patients with only corticosteroid allergy, calcineurin inhibitors are a safe alternative.

Immunomodulators

Calcipotriol is a vitamin D analogue commonly used to treat psoriasis. Although it is a well-known irritant, ACD to topical calcipotriol rarely has been reported.^20-23 Topical calcipotriol does not seem to cross-react with other vitamin D analogues, including tacalcitol and calcitriol.^21,24 Based on the literature and the nonirritant reactive thresholds described by Fullerton et al,²⁵ recommended patch test concentrations of calcipotriol in isopropanol are 2 to 10 µg/mL. Given its immunomodulating effects, calcipotriol may suppress contact hypersensitization from other allergens, similar to the effects seen with UV radiation.²⁶

Calcineurin inhibitors act on the nuclear factor of activated T cells signaling pathway, resulting in downstream suppression of proinflammatory cytokines. Contact allergy to these topical medications is rare and mainly has involved pimecrolimus.^27-30 In one case, a patient with a previously documented topical tacrolimus contact allergy demonstrated cross-reactivity with pimecrolimus on a double-blinded, right-vs-left ROAT, as well as by patch testing with pimecrolimus cream 1%, which was only weakly positive (+).²⁷ Patch test concentrations of 2.5% or higher may be required to elicit positive reactions to tacrolimus, as shown in one case where this was attributed to high molecular weight and poor extrafacial skin absorption of tacrolimus.³⁰ In an unusual case, a patient reacted positively to patch testing and ROAT using pimecrolimus cream 1% but not pimecrolimus 1% to 5% in petrolatum or alcohol nor the individual excipients, illustrating the importance of testing with both active and inactive ingredients.²⁹

Anesthetics

Local anesthetics can be separated into 2 main groups—amides and esters—based on their chemical structures. From 2001 to 2004, the NACDG patch tested 10,061 patients and found 344 (3.4%) with a positive reaction to at least one topical anesthetic.³¹ We will discuss some of the allergic cutaneous reactions associated with topical benzocaine (an ester) and lidocaine and prilocaine (amides).

According to the NACDG, the estimated prevalence of topical benzocaine allergy from 2001 to 2018 was roughly 3%.³² Allergic contact dermatitis has been reported in patients who used topical benzocaine to treat localized pain disorders, including herpes zoster and dental pain.^33,34 Benzocaine may be used in the anogenital region in the form of antihemorrhoidal creams and in condoms and is a considerably more common allergen in those with anogenital dermatitis compared to those without.^35-38 Although cross-reactions within the same anesthetic group are common, clinicians also should be aware of the potential for concomitant sensitivity between unrelated local anesthetics.^39-41

From 2001 to 2018, the prevalence of ACD to topical lidocaine was estimated to be 7.9%, according to the NACDG.³² A topical anesthetic containing both lidocaine and prilocaine often is used preprocedurally and can be a source of ACD. Interestingly, several cases of ACD to combination lidocaine/prilocaine cream demonstrated positive patch tests to prilocaine but not lidocaine, despite their structural similarities.^42-44 One case report described simultaneous positive reactions to both prilocaine 5% and lidocaine 1%.⁴⁵

There are a few key points to consider when working up contact allergy to local anesthetics. Patients who develop positive patch test reactions to a local anesthetic should undergo further testing to better understand alternatives and future use. As previously mentioned, ACD to one anesthetic does not necessarily preclude the use of other related anesthetics. Intradermal testing may help differentiate immediate and delayed-type allergic reactions to local anesthetics and should therefore follow positive patch tests.⁴⁶ Importantly, a delayed reading (ie, after day 6 or 7) also should be performed as part of intradermal testing. Patients with positive patch tests but negative intradermal test results may be able to tolerate systemic anesthetic use.⁴⁷

Patch Testing for Potential Medicament ACD

In this article, we touched on several topical medications that have nuanced patch testing specifications given their immunomodulating effects. A simplified outline of recommended patch test concentrations is provided in the eTable, and we encourage you to revisit these useful resources as needed. In many cases, referral to a specialized patch test clinic may be necessary. Although they are not reviewed in this article, always consider inactive ingredients such as preservatives, softening agents, and emulsifiers in the setting of medicament dermatitis, as they also may be culprits of ACD.

Final Interpretation

In this 2-part series, we covered ACD to several common topical drugs with a focus on active ingredients as the source of allergy, and yet this is just the tip of the iceberg. Topical medicaments are prevalent in the field of dermatology, and associated cases of ACD have been reported proportionately. Consider ACD when topical medication efficacy plateaus, triggers new-onset dermatitis, or seems to exacerbate an underlying dermatitis.

Jellyfish stings are one of the most common marine injuries, with an estimated 150 million stings occurring annually worldwide.¹ Most jellyfish stings result in painful localized skin reactions that are self-limited and can be treated with conservative measures including hot water immersion and topical anesthetics. Life-threatening systemic reactions (eg, anaphylaxis, Irukandji syndrome) can occur with some species.^2-4 Mainstream media reports do not reflect the true incidence and variability of jellyfish-related injuries that are commonly encountered in the clinic.³

Characteristics of Jellyfish

There are roughly 10,000 known species of jellyfish, with approximately 100 of them posing danger to humans.⁵ Jellyfish belong to the phylum Cnidaria, which is comprised of 5 classes of both free-floating and sessile animals: Staurozoa (stauromedusae), Hydrozoa (hydroids, fire corals, and Portuguese man-of-war), Scyphozoa (true jellyfish), Anthozoa (corals and sea anemones), and Cubozoa (box jellyfish and Irukandji jellyfish).^1,2,6 Jellyfish typically have several tentacles suspended from a free-floating gelatinous body or bell; these tentacles are covered with thousands of cells unique to Cnidaria called nematocytes or cnidocytes containing specialized stinging organelles known as nematocysts. When triggered by physical (eg, human or foreign-body contact) or chemical stimuli, each nematocyst ejects a hollow filament or barb externally, releasing venom into the victim.^7,8

The scyphozoan, hydrozoan, and cubozoan life cycles generally consist of a bottom-dwelling, sessile polyp form that produces multiple free-swimming ephyrae through an asexual reproductive process called strobilation. These ephyrae grow into the fully mature medusae, recognizable as jellyfish (Figure 1).⁵ Additionally, jellyfish populations experience cycles of temporal and spatial population abundance and crashes known as jellyfish blooms. In 2017, Kaffenberger et al⁹ reviewed the shifting landscape of skin diseases in North America attributable to major changes in climate and weather patterns, including the rise in jellyfish blooms and envenomation outbreaks worldwide (eg, Physalia physalis [Portuguese man-of-war][Figure 2] along the southeastern US coastline, Porpita pacifica off Japanese beaches). Some research suggests jellyfish surges relate to climate change and human interactions with jellyfish habitats by way of eutrophication and fishing (removing predators of jellyfish).^9,10

Clinical Presentation

Jellyfish injuries can vary greatly in clinical symptoms, but they do follow some basic patterns. The severity of pain and symptoms is related to the jellyfish species, the number of stinging cells (nematocysts) that are triggered, and the potency of the venom that is absorbed by the victim.^11-13 Most stings are minor, and patients experience immediate localized pain with serpiginous raised erythematous or urticarial lesions following the distribution of tentacle contact; these lesions have been described as tentaclelike and resembling a string of beads (Figure 3).¹² Pain usually lasts a couple hours, while the skin lesions can last hours to days and can even recur years later. This pattern fits that of the well-known hydrozoans P physalis and Physalia utriculus (bluebottle), which are endemic to the Atlantic and Indo-Pacific Oceans, respectively. The scyphozoan jellyfish causing similar presentations include Pelagia noctiluca (Mauve stinger), Aurelia aurita (Moon jellyfish), and Cyanea species. The cubozoan Chironex fleckeri (Australian box jellyfish or sea wasp) also causes tentaclelike stings but is widely considered the most dangerous jellyfish, as its venom is known to cause cardiac or respiratory arrest.^4,11 More than 100 fatalities have been reported following severe envenomations from C fleckeri in Australian and Indo-Pacific waters.⁶

Stings from another box jellyfish species, Carukia barnesi, cause a unique presentation known as Irukandji syndrome. Carukia barnesi is a small box jellyfish with a bell measuring roughly 2 cm in diameter. It has nematocysts on both its bell and tentacles. It inhabits deeper waters and typically stings divers but also can wash ashore and injure beach tourists. Although Irukandji syndrome usually is associated with C barnesi, which is endemic to Northern Australian beaches, other jellyfish species including P physalis rarely have been linked to this potentially fatal syndrome.^6,11 Unlike the immediate cutaneous and systemic findings described in C fleckeri encounters, symptoms of Irukandji-like stings can be delayed by up to 30 minutes. Patients may present with severe generalized pain (lower back, chest, headache), signs of excess catecholamine release (tachycardia, hypertension, anxiety, diaphoresis, agitation), or cardiopulmonary decompensation (arrhythmia, cardiac arrest, pulmonary edema).^6,11,14.15 Anaphylactic reactions also have been reported in those sensitized by prior stings.¹⁶

Management

Prevention of drowning is key in all marine injuries. Rescuers should remove the individual from the water, establish the ABCs—airway, breathing, and circulation—and seek acute medical attention. If immediate resuscitation is not required, douse the wound as soon as possible with a solution that halts further nematocyst discharge, which may contain alcohol, vinegar, or bicarbonate, depending on the prevalent species. General guidance is available to providers through evidence-based, point-of-care databases including UpToDate and DynaMed, as well as through the American Heart Association (AHA) or a country’s equivalent council on emergency care if residing outside the United States. Pressure immobilization bandages as a means of decreasing venom redistribution is no longer recommended by the AHA because animal studies have shown increased nematocyst discharge after pressure application.¹⁷ As such, touching or applying pressure to the affected area is not recommended until after a proper rinse solution has been applied. Tentacles may be removed mechanically with gloved hands or sand and seawater with minimal compression or agitation.

When acetic acid is appropriate, such as for cubozoan stings, commercially available vinegar (5% acetic acid in the United States) is preferred.^16,17 Tap water can cause discharge of nematocysts, and seawater is preferred when no other solution is available.¹⁸ Most marine venoms are heat labile. Immersion in hot water can produce pain relief, but ice can be just as efficacious and is preferred by some patients. Prior reports of patients stung by Physalia species demonstrated greater pain relief with hot water immersion compared to ice pack application.^18,19

In the setting of anaphylaxis, patients should receive epinephrine and be transported to a hospital with appropriate hemodynamic monitoring and supportive care. If the species of jellyfish has been identified, species-specific antivenin also may be available in certain regions (eg, C fleckeri antivenin manufactured in Australia), but it is unclear if it improves outcomes when compared with supportive care alone.^6,16

Conclusion

Following jellyfish stings, most skin lesions will spontaneously resolve. Patients likely will present days to weeks following the inciting event with mild cutaneous symptoms that are amenable to topical corticosteroids. Recurrent dermatitis following a jellyfish sting is uncommon and is thought to be due to an immunologic mechanism consistent with type IV hypersensitivity reactions. Patients may require multiple courses of treatment before complete resolution.²⁰

Patient education regarding marine envenomation and mechanical barriers such as wetsuits or stinger suits can reduce the risk for injury from jellyfish stings. Sting-inhibiting lotions also are commercially available, though more research is needed.²¹ Many beaches that are known to harbor the dangerous box jellyfish provide stinger nets to direct travelers to safer waters. Complete avoidance during jellyfish season is recommended in highly endemic areas.¹

Jellyfish stings are one of the most common marine injuries, with an estimated 150 million stings occurring annually worldwide.¹ Most jellyfish stings result in painful localized skin reactions that are self-limited and can be treated with conservative measures including hot water immersion and topical anesthetics. Life-threatening systemic reactions (eg, anaphylaxis, Irukandji syndrome) can occur with some species.^2-4 Mainstream media reports do not reflect the true incidence and variability of jellyfish-related injuries that are commonly encountered in the clinic.³

Characteristics of Jellyfish

There are roughly 10,000 known species of jellyfish, with approximately 100 of them posing danger to humans.⁵ Jellyfish belong to the phylum Cnidaria, which is comprised of 5 classes of both free-floating and sessile animals: Staurozoa (stauromedusae), Hydrozoa (hydroids, fire corals, and Portuguese man-of-war), Scyphozoa (true jellyfish), Anthozoa (corals and sea anemones), and Cubozoa (box jellyfish and Irukandji jellyfish).^1,2,6 Jellyfish typically have several tentacles suspended from a free-floating gelatinous body or bell; these tentacles are covered with thousands of cells unique to Cnidaria called nematocytes or cnidocytes containing specialized stinging organelles known as nematocysts. When triggered by physical (eg, human or foreign-body contact) or chemical stimuli, each nematocyst ejects a hollow filament or barb externally, releasing venom into the victim.^7,8

The scyphozoan, hydrozoan, and cubozoan life cycles generally consist of a bottom-dwelling, sessile polyp form that produces multiple free-swimming ephyrae through an asexual reproductive process called strobilation. These ephyrae grow into the fully mature medusae, recognizable as jellyfish (Figure 1).⁵ Additionally, jellyfish populations experience cycles of temporal and spatial population abundance and crashes known as jellyfish blooms. In 2017, Kaffenberger et al⁹ reviewed the shifting landscape of skin diseases in North America attributable to major changes in climate and weather patterns, including the rise in jellyfish blooms and envenomation outbreaks worldwide (eg, Physalia physalis [Portuguese man-of-war][Figure 2] along the southeastern US coastline, Porpita pacifica off Japanese beaches). Some research suggests jellyfish surges relate to climate change and human interactions with jellyfish habitats by way of eutrophication and fishing (removing predators of jellyfish).^9,10

Clinical Presentation

Jellyfish injuries can vary greatly in clinical symptoms, but they do follow some basic patterns. The severity of pain and symptoms is related to the jellyfish species, the number of stinging cells (nematocysts) that are triggered, and the potency of the venom that is absorbed by the victim.^11-13 Most stings are minor, and patients experience immediate localized pain with serpiginous raised erythematous or urticarial lesions following the distribution of tentacle contact; these lesions have been described as tentaclelike and resembling a string of beads (Figure 3).¹² Pain usually lasts a couple hours, while the skin lesions can last hours to days and can even recur years later. This pattern fits that of the well-known hydrozoans P physalis and Physalia utriculus (bluebottle), which are endemic to the Atlantic and Indo-Pacific Oceans, respectively. The scyphozoan jellyfish causing similar presentations include Pelagia noctiluca (Mauve stinger), Aurelia aurita (Moon jellyfish), and Cyanea species. The cubozoan Chironex fleckeri (Australian box jellyfish or sea wasp) also causes tentaclelike stings but is widely considered the most dangerous jellyfish, as its venom is known to cause cardiac or respiratory arrest.^4,11 More than 100 fatalities have been reported following severe envenomations from C fleckeri in Australian and Indo-Pacific waters.⁶

Stings from another box jellyfish species, Carukia barnesi, cause a unique presentation known as Irukandji syndrome. Carukia barnesi is a small box jellyfish with a bell measuring roughly 2 cm in diameter. It has nematocysts on both its bell and tentacles. It inhabits deeper waters and typically stings divers but also can wash ashore and injure beach tourists. Although Irukandji syndrome usually is associated with C barnesi, which is endemic to Northern Australian beaches, other jellyfish species including P physalis rarely have been linked to this potentially fatal syndrome.^6,11 Unlike the immediate cutaneous and systemic findings described in C fleckeri encounters, symptoms of Irukandji-like stings can be delayed by up to 30 minutes. Patients may present with severe generalized pain (lower back, chest, headache), signs of excess catecholamine release (tachycardia, hypertension, anxiety, diaphoresis, agitation), or cardiopulmonary decompensation (arrhythmia, cardiac arrest, pulmonary edema).^6,11,14.15 Anaphylactic reactions also have been reported in those sensitized by prior stings.¹⁶

Management

Prevention of drowning is key in all marine injuries. Rescuers should remove the individual from the water, establish the ABCs—airway, breathing, and circulation—and seek acute medical attention. If immediate resuscitation is not required, douse the wound as soon as possible with a solution that halts further nematocyst discharge, which may contain alcohol, vinegar, or bicarbonate, depending on the prevalent species. General guidance is available to providers through evidence-based, point-of-care databases including UpToDate and DynaMed, as well as through the American Heart Association (AHA) or a country’s equivalent council on emergency care if residing outside the United States. Pressure immobilization bandages as a means of decreasing venom redistribution is no longer recommended by the AHA because animal studies have shown increased nematocyst discharge after pressure application.¹⁷ As such, touching or applying pressure to the affected area is not recommended until after a proper rinse solution has been applied. Tentacles may be removed mechanically with gloved hands or sand and seawater with minimal compression or agitation.

When acetic acid is appropriate, such as for cubozoan stings, commercially available vinegar (5% acetic acid in the United States) is preferred.^16,17 Tap water can cause discharge of nematocysts, and seawater is preferred when no other solution is available.¹⁸ Most marine venoms are heat labile. Immersion in hot water can produce pain relief, but ice can be just as efficacious and is preferred by some patients. Prior reports of patients stung by Physalia species demonstrated greater pain relief with hot water immersion compared to ice pack application.^18,19

In the setting of anaphylaxis, patients should receive epinephrine and be transported to a hospital with appropriate hemodynamic monitoring and supportive care. If the species of jellyfish has been identified, species-specific antivenin also may be available in certain regions (eg, C fleckeri antivenin manufactured in Australia), but it is unclear if it improves outcomes when compared with supportive care alone.^6,16

Conclusion

Following jellyfish stings, most skin lesions will spontaneously resolve. Patients likely will present days to weeks following the inciting event with mild cutaneous symptoms that are amenable to topical corticosteroids. Recurrent dermatitis following a jellyfish sting is uncommon and is thought to be due to an immunologic mechanism consistent with type IV hypersensitivity reactions. Patients may require multiple courses of treatment before complete resolution.²⁰

Patient education regarding marine envenomation and mechanical barriers such as wetsuits or stinger suits can reduce the risk for injury from jellyfish stings. Sting-inhibiting lotions also are commercially available, though more research is needed.²¹ Many beaches that are known to harbor the dangerous box jellyfish provide stinger nets to direct travelers to safer waters. Complete avoidance during jellyfish season is recommended in highly endemic areas.¹

Jellyfish stings are one of the most common marine injuries, with an estimated 150 million stings occurring annually worldwide.¹ Most jellyfish stings result in painful localized skin reactions that are self-limited and can be treated with conservative measures including hot water immersion and topical anesthetics. Life-threatening systemic reactions (eg, anaphylaxis, Irukandji syndrome) can occur with some species.^2-4 Mainstream media reports do not reflect the true incidence and variability of jellyfish-related injuries that are commonly encountered in the clinic.³

Characteristics of Jellyfish

There are roughly 10,000 known species of jellyfish, with approximately 100 of them posing danger to humans.⁵ Jellyfish belong to the phylum Cnidaria, which is comprised of 5 classes of both free-floating and sessile animals: Staurozoa (stauromedusae), Hydrozoa (hydroids, fire corals, and Portuguese man-of-war), Scyphozoa (true jellyfish), Anthozoa (corals and sea anemones), and Cubozoa (box jellyfish and Irukandji jellyfish).^1,2,6 Jellyfish typically have several tentacles suspended from a free-floating gelatinous body or bell; these tentacles are covered with thousands of cells unique to Cnidaria called nematocytes or cnidocytes containing specialized stinging organelles known as nematocysts. When triggered by physical (eg, human or foreign-body contact) or chemical stimuli, each nematocyst ejects a hollow filament or barb externally, releasing venom into the victim.^7,8

The scyphozoan, hydrozoan, and cubozoan life cycles generally consist of a bottom-dwelling, sessile polyp form that produces multiple free-swimming ephyrae through an asexual reproductive process called strobilation. These ephyrae grow into the fully mature medusae, recognizable as jellyfish (Figure 1).⁵ Additionally, jellyfish populations experience cycles of temporal and spatial population abundance and crashes known as jellyfish blooms. In 2017, Kaffenberger et al⁹ reviewed the shifting landscape of skin diseases in North America attributable to major changes in climate and weather patterns, including the rise in jellyfish blooms and envenomation outbreaks worldwide (eg, Physalia physalis [Portuguese man-of-war][Figure 2] along the southeastern US coastline, Porpita pacifica off Japanese beaches). Some research suggests jellyfish surges relate to climate change and human interactions with jellyfish habitats by way of eutrophication and fishing (removing predators of jellyfish).^9,10

Clinical Presentation

Jellyfish injuries can vary greatly in clinical symptoms, but they do follow some basic patterns. The severity of pain and symptoms is related to the jellyfish species, the number of stinging cells (nematocysts) that are triggered, and the potency of the venom that is absorbed by the victim.^11-13 Most stings are minor, and patients experience immediate localized pain with serpiginous raised erythematous or urticarial lesions following the distribution of tentacle contact; these lesions have been described as tentaclelike and resembling a string of beads (Figure 3).¹² Pain usually lasts a couple hours, while the skin lesions can last hours to days and can even recur years later. This pattern fits that of the well-known hydrozoans P physalis and Physalia utriculus (bluebottle), which are endemic to the Atlantic and Indo-Pacific Oceans, respectively. The scyphozoan jellyfish causing similar presentations include Pelagia noctiluca (Mauve stinger), Aurelia aurita (Moon jellyfish), and Cyanea species. The cubozoan Chironex fleckeri (Australian box jellyfish or sea wasp) also causes tentaclelike stings but is widely considered the most dangerous jellyfish, as its venom is known to cause cardiac or respiratory arrest.^4,11 More than 100 fatalities have been reported following severe envenomations from C fleckeri in Australian and Indo-Pacific waters.⁶

Stings from another box jellyfish species, Carukia barnesi, cause a unique presentation known as Irukandji syndrome. Carukia barnesi is a small box jellyfish with a bell measuring roughly 2 cm in diameter. It has nematocysts on both its bell and tentacles. It inhabits deeper waters and typically stings divers but also can wash ashore and injure beach tourists. Although Irukandji syndrome usually is associated with C barnesi, which is endemic to Northern Australian beaches, other jellyfish species including P physalis rarely have been linked to this potentially fatal syndrome.^6,11 Unlike the immediate cutaneous and systemic findings described in C fleckeri encounters, symptoms of Irukandji-like stings can be delayed by up to 30 minutes. Patients may present with severe generalized pain (lower back, chest, headache), signs of excess catecholamine release (tachycardia, hypertension, anxiety, diaphoresis, agitation), or cardiopulmonary decompensation (arrhythmia, cardiac arrest, pulmonary edema).^6,11,14.15 Anaphylactic reactions also have been reported in those sensitized by prior stings.¹⁶

Management

Prevention of drowning is key in all marine injuries. Rescuers should remove the individual from the water, establish the ABCs—airway, breathing, and circulation—and seek acute medical attention. If immediate resuscitation is not required, douse the wound as soon as possible with a solution that halts further nematocyst discharge, which may contain alcohol, vinegar, or bicarbonate, depending on the prevalent species. General guidance is available to providers through evidence-based, point-of-care databases including UpToDate and DynaMed, as well as through the American Heart Association (AHA) or a country’s equivalent council on emergency care if residing outside the United States. Pressure immobilization bandages as a means of decreasing venom redistribution is no longer recommended by the AHA because animal studies have shown increased nematocyst discharge after pressure application.¹⁷ As such, touching or applying pressure to the affected area is not recommended until after a proper rinse solution has been applied. Tentacles may be removed mechanically with gloved hands or sand and seawater with minimal compression or agitation.

When acetic acid is appropriate, such as for cubozoan stings, commercially available vinegar (5% acetic acid in the United States) is preferred.^16,17 Tap water can cause discharge of nematocysts, and seawater is preferred when no other solution is available.¹⁸ Most marine venoms are heat labile. Immersion in hot water can produce pain relief, but ice can be just as efficacious and is preferred by some patients. Prior reports of patients stung by Physalia species demonstrated greater pain relief with hot water immersion compared to ice pack application.^18,19

In the setting of anaphylaxis, patients should receive epinephrine and be transported to a hospital with appropriate hemodynamic monitoring and supportive care. If the species of jellyfish has been identified, species-specific antivenin also may be available in certain regions (eg, C fleckeri antivenin manufactured in Australia), but it is unclear if it improves outcomes when compared with supportive care alone.^6,16

Conclusion

Following jellyfish stings, most skin lesions will spontaneously resolve. Patients likely will present days to weeks following the inciting event with mild cutaneous symptoms that are amenable to topical corticosteroids. Recurrent dermatitis following a jellyfish sting is uncommon and is thought to be due to an immunologic mechanism consistent with type IV hypersensitivity reactions. Patients may require multiple courses of treatment before complete resolution.²⁰

Patient education regarding marine envenomation and mechanical barriers such as wetsuits or stinger suits can reduce the risk for injury from jellyfish stings. Sting-inhibiting lotions also are commercially available, though more research is needed.²¹ Many beaches that are known to harbor the dangerous box jellyfish provide stinger nets to direct travelers to safer waters. Complete avoidance during jellyfish season is recommended in highly endemic areas.¹

Causes of Lepidopterism

Caterpillars are wormlike organisms that serve as the larval stage of moths and butterflies, which belong to the order Lepidoptera. There are almost 165,000 discovered species, with 13,000 found in the United States.^1,2 Roughly 150 species are known to have the potential to cause an adverse reaction in humans, with 50 of these in the United States.¹Lepidopterism describes systemic and cutaneous reactions to moths, butterflies, and caterpillars; erucism describes strictly cutaneous reactions.¹

Although the rate of lepidopterism is thought to be underreported because it often is self-limited and of a mild nature, a review found caterpillars to be the cause of roughly 2.2% of reported bites and stings annually.² Cases increase in number with seasonal increases in caterpillars, which vary by region and species. For example, the Megalopyge opercularis (southern flannel moth) caterpillar was noted to have 2 peaks in a Texas-based study: 12% of reported stings occurred in July; 59% from October through November.³ In general, the likelihood of exposure increases during warmer months, and exposure is more common in people who work outdoors in a rural area or in a suburban area where there are many caterpillar-infested trees.⁴

Most cases of lepidopterism are caused by caterpillars, not by adult butterflies and moths, because the former have many tubular, or porous, hairlike structures called setae that are embedded in the integument. Setae were once thought to be connected to poison-secreting glandular cells, but current belief is that venomous caterpillars lack specialized gland cells and instead produce venom through secretory epithelial cells located above the integument.¹ Venom accumulates in the hemolymph and is stored in the setae or other types of bristles, such as scoli (wartlike bumps that bear setae) or spines.⁵ With a large amount of chitin, bristles have a tendency to fracture and release venom upon contact.¹ It is thought that some species of caterpillars formulate venom by ingesting toxins or toxin precursors from plants; for example, the tiger moth (family Arctiidae) is known to produce venom containing biogenic amines, pyrrolizidine, alkaloids, and cardiac glycosides obtained through food sources.⁵

Even if a caterpillar does not produce venom, its setae might embed into skin or mucous membranes and cause an adverse irritant reaction.¹ Setae also might dislodge and be transported in the air to embed in objects—some remaining stable in the environment for longer than a year.² In contrast to setae, spines are permanently fixed into the integument; for that reason, only direct contact with the caterpillar can result in an adverse reaction. Although it is mostly caterpillars that contain setae and spines, certain species of moths also might contain these structures or might acquire them as they emerge from the cocoon, which often contains incorporated setae.²

Reactions in Humans

Lepidopterism encompasses 3 principal reactions in humans: sting reaction, hypersensitivity reaction, and lonomism (a hemorrhagic diathesis produced by Lonomia caterpillars). The type and severity of the reaction depends on (1) the species of caterpillar or moth and (2) the individual patient.² There are approximately 12 families of caterpillars, mainly of the moth variety, that can cause an adverse reaction in humans.¹ Tables 1 and 2 list examples of species that cause each type of reaction.⁶

Chemicals and toxins contained in the poison of setae and spines vary by species of caterpillar. Numerous kinds have been isolated from different venoms,^1,2 including several peptides, histamine, histamine-releasing substances, acetylcholine, phospholipase A, hyaluronidase, formic acid, proteins with trypsinlike activity, serine proteases such as kallikrein, and other enzymes with vasodegenerative and fibrinolytic properties

Stings: An Immediate Adverse Reaction—Depending on the venom, a sting might result in mild to severe burning pain, accompanied by welts, vesicles, and red papules or plaques.² Figure 1 demonstrates a particularly mild sting from a caterpillar of the family Automeris, examples of which are seen in Figures 2 and 3 and eFigure 1. Components of the venom determine the mechanism of the sting and the pain that accompanies it. For example, a recent study demonstrated that the venom of the Latoia consocia caterpillar induces pain through the ion-channel receptor known as transient receptor potential vanilloid 1, which integrates and sends painful stimuli from the peripheral nervous system to the central nervous system.⁷ It is thought that a variety of ion channels are targets of the venom of caterpillars.

One of the most characteristic sting patterns is that of the caterpillar of family Megalopygidae (flannel moth)(eFigures 2 and 3). The stings of these caterpillars create a unique tram-track pattern of hemorrhagic macules or papules (Figure 4).⁴ A study found that 90% of reported M opercularis envenomations consist primarily of cutaneous symptoms, with 84% of those symptoms being irritation or pain; 45% a puncture or wound; 29% erythema; and 15% edema.³ Systemic findings can include headache, fever, adenopathy, nausea, vomiting, abdominal pain, and chest pain.⁴ Symptoms normally are self-limited, though they can last minutes or hours.

Hypersensitivity Reaction—Studies demonstrate that the symptoms of this reaction are a mixture of type I hypersensitivity, type IV hypersensitivity, and a foreign-body response.² The specific hypersensitivity reaction depends on the venom and the exposed individual—most commonly including a combination of pruritic papules, urticarial wheals, flares, and dermatitis.² A reaction that is a result of direct contact with the caterpillar or moth will appear on exposed areas; however, because setae embed in linens and clothing, they might cause a reaction anywhere on the body. Although usually self-limited, a hypersensitivity reaction might develop within minutes and can last for days or weeks.

Stings and hypersensitivity reactions to caterpillars and moths tend to lead to a nonspecific histologic presentation characterized by epidermal edema and a superficial perivascular lymphocytic infiltrate, often with eosinophils.⁶ After approximately 1 week, a foreign-body response to setae can lead to tuberculoid granulomas accompanied by neutrophils in the dermis and occasionally in subcutaneous tissues (Figures 5 and 6).⁸ If setae have not yet been removed, they also might be visible in skin scrapings.

Additional complications can accompany the hypersensitivity reaction to setae or spines. Type I hypersensitivity reactions can lead to severe reactions on second contact due to previously sensitized IgE antibodies. Although the first reaction appears mild, second contact might result in angioedema, wheezing, dyspnea, or anaphylaxis, or a combination of these findings.⁹ In addition, some patients who come in contact with Dendrolimus caterpillars might develop a condition known as dendrolimiasis, characterized by dermatitis in addition to arthritis or chondritis.⁶ The arthritis is normally monoarticular and can result in complete destruction of the joint. Pararamose, a condition with a similar presentation, is caused by the Brazilian moth Premolis semirufa.⁶

Contact of setae or spines with mucous membranes or inhalation of setae also might result in edema, dysphagia, dyspnea, drooling, rhinitis, or conjunctivitis, or a combination of these findings.⁶ In addition, setae can embed in the eye and cause an inflammatory reaction—ophthalmia nodosa—most commonly caused by caterpillars of the pine processionary moth (Thaumetopoea pityocampa) and characterized by immediate chemosis, which can progress to liquefactive necrosis and hypopyon, later developing into a granulomatous foreign-body response.^2,10 The process is thought to be the result of a combination of the thaumetopoein toxin in the setae and an IgE-mediated response to other proteins.¹⁰

Due to their harpoon shape and forward-only motion, setae might migrate deeper, potentially even to the optic nerve.¹¹ Because migration might take years and the barbed shape of setae does not always allow removal, some patients require lifetime monitoring with slit-lamp examination.Chronic problems, such as cataracts and persistent posterior uveitis, have been reported.^10,11

Lonomism—One of the most serious (though rarest) reactions to caterpillars is lonomism, a condition caused by the caterpillars of Lonomia achelous and Lonomia obliqua moths. These caterpillars have a unique combination of toxins filling their branched spines, which ultimately leads to the same outcome: a hemorrhagic diathesis.

The toxin of L achelous comprises several proteases that degrade fibrin, fibrinogen, and factor XIII while activating prothrombin. In contrast, L obliqua poison causes a hemorrhagic diathesis by promoting a consumptive coagulopathy through enzymes that activate factor X and prothrombin.

With initial contact with either of these Lonomia caterpillars, the patient experiences severe pain accompanied by systemic symptoms, including headache, nausea, and vomiting. Shortly afterward, symptoms of a hemorrhagic diathesis manifest, including bleeding gums, hematuria, bleeding from prior wounds, and epistaxis.⁵ Serious complications of the hemorrhagic diathesis, such as hemorrhage of major organs, leads to death in 4% of patients.⁵ A reported case of a patient whose Lonomia caterpillar sting went unrecognized until a week after the accident ended with progression to stage V chronic renal disease.¹²

Recent research has focused on the specific mechanism of injury caused by Lonomia species. A study found that the venom of L obliqua causes cytoskeleton rearrangement and migration in vascular smooth muscle cells (VSMCs) by inducing formation of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate oxidase.¹³ Thus, the venom directly contributes to the proinflammatory phenotype of endothelial cells seen following envenomation. The same study also demonstrated that elevated reactive oxygen species trigger extracellular signal-regulated kinase pathway activation in VSMCs, leading to cell proliferation, re-stenosis, and ischemia.¹³ This finding was confirmed by another study,¹⁴ which demonstrated an increase in Rac1, a signaling protein involved in the extracellular signal-regulated kinase pathway, in VSMCs upon exposure to L obliqua venom. These studies propose potential new targets for treatment to prevent vascular damage.

Reactions to Adult Organisms—Although it is more common for the caterpillar form of these organisms to cause an adverse reaction, the adult moth also might be capable of causing a similar reaction by retaining setae from the cocoon or by their own spines. The most notable example of this is female moths of the genus Hylesia, which possess spines attached to glands on the abdomen. The poison in these spines—a mixture of proteases and chitinase—causes a dermatitis known as Caripito itch—the name derived from a river port in Venezuela where this moth caused a memorable epidemic of moth-induced dermatitis.^7,15 Caripito itch is known for intense pruritus that most commonly lasts days or weeks, possibly longer than 1 year.

Diagnostic Difficulties

The challenge of diagnosing a caterpillar- or moth-induced reaction in humans arises from (1) the lack of clinical history (the caterpillar might not be seen at all by the patient or the examiner) and (2) the similarity of these reactions to those with more common triggers.

When setae remain embedded in the skin or mucous membranes, skin scrapings allow accelerated diagnosis. On a skin scraping prepared with 20% potassium hydroxide, setae appear as tapered and barbed hairlike structures, which allows them to be distinguished from other similar-appearing but differently shaped structures, such as glass fibers.

When setae do not remain embedded in the skin or when the cause of the reaction is due to spines, the physician is left with a nonspecific histologic picture and a large differential diagnosis to be narrowed down based on the history and occasionally the pattern of the skin lesion.

A challenge in sting diagnosis is differentiating a caterpillar or moth sting from that of another organism. In certain cases, such as those of the family Megalopygidae, specific patterns of stings might assist in making the diagnosis. Hypersensitivity reactions are associated with a wider differential diagnosis, including irritant or allergic dermatitis from other causes, scabies, eczema, lichen planus, lichen simplex chronicus, seborrheic dermatitis, and tinea corporis, to name a few.⁶ Skin scrapings can be examined for other features, such as burrows in the case of scabies, to further narrow the differential.

Stings and hypersensitivity reactions lacking a proper history and associated with more severe systemic symptoms have caused misdiagnosis or led to a workup for the wrong condition; for example, the picture of abdominal pain, nausea, vomiting, tachycardia, leukocytosis, hypokalemia, and metabolic acidosis can simulate appendicitis.¹⁶ Upon discovery of a puss caterpillar sting in a patient, her symptoms resolved after treatment with ondansetron, morphine, and intravenous fluids.¹⁶

In lonomism, the diagnosis must be established by laboratory measurement of the fibrinogen level, clotting factors, prothrombin time, and activated partial thromboplastin time.⁴ The differential diagnosis associated with lonomism includes disseminated intravascular coagulation (DIC), snakebite, and a hereditary bleeding disorder.⁴ The combination of laboratory tests and an extensive medical history allows a diagnosis. Absence of a personal or family history of bleeding excludes a diagnosis of hereditary bleeding disorder, whereas the absence of known causes of DIC or thrombocytopenia allows DIC to be excluded from the differential.

Treatment Options and Prevention

Treatment—The first step is to remove any embedded setae from the skin or mucous membranes. The stepwise recommendation is to remove any constricted clothing, detach setae with adhesive tape, wash with soap and water, and dry without touching the skin.¹ Any remaining setae can be removed with additional tape or forceps; setae tend to be fragile and are difficult to remove in their entirety.

Other than removal of the setae, skin reactions are treated symptomatically. Ice packs and isopropyl alcohol have been utilized to cool burning or stinging areas. Pain, pruritus, and inflammation have been alleviated with antihistamines and topical corticosteroids.¹ When pain is severe, oral codeine or local injection of anesthetic can be used. For severe and persistent skin lesions, a course of an oral glucocorticoid can be administered. Intramuscular triamcinolone acetonide has been shown to treat pain, dermatitis, and subcutaneous nodules otherwise refractory to treatment.⁸

Antivenin specific for L obliqua exists to treat lonomism and is therefore effective only when lonomism is caused by that species. Lonomism caused by L achelous is treated with cryoprecipitate, purified fibrinogen, and antifibrinolytic drugs, such as aprotinin.⁶ Whole blood and fresh-frozen plasma have been noted to make hemorrhage worse when utilized to treat lonomism. Because the mechanism of action of the venom of Lonomia species is based, in part, on inducing a proinflammatory profile in endothelial cells, studies have demonstrated that inhibition of kallikrein might prevent vascular injury and thus prevent serious adverse effects, such as renal failure.¹⁷

Prevention—People should wear proper protective clothing when outdoors in potentially infested areas. Measures should be taken to ensure that linens and clothing are not left outside in areas where setae might be carried on the wind. Infestation control is necessary if the population of caterpillars reaches a high enough level.

Conclusion

Several species of caterpillars and moths cause adverse reactions in humans: stings, hypersensitivity reactions, and lonomism. Although most reactions are self-limited, some might have more serious effects, including organ failure and death. Mechanisms of injury vary by species of caterpillar, moth, and butterfly; current research is focused on further defining venom components and signaling pathways to isolate potential targets to aid in the diagnosis and treatment of lepidopterism.

Causes of Lepidopterism

Caterpillars are wormlike organisms that serve as the larval stage of moths and butterflies, which belong to the order Lepidoptera. There are almost 165,000 discovered species, with 13,000 found in the United States.^1,2 Roughly 150 species are known to have the potential to cause an adverse reaction in humans, with 50 of these in the United States.¹Lepidopterism describes systemic and cutaneous reactions to moths, butterflies, and caterpillars; erucism describes strictly cutaneous reactions.¹

Although the rate of lepidopterism is thought to be underreported because it often is self-limited and of a mild nature, a review found caterpillars to be the cause of roughly 2.2% of reported bites and stings annually.² Cases increase in number with seasonal increases in caterpillars, which vary by region and species. For example, the Megalopyge opercularis (southern flannel moth) caterpillar was noted to have 2 peaks in a Texas-based study: 12% of reported stings occurred in July; 59% from October through November.³ In general, the likelihood of exposure increases during warmer months, and exposure is more common in people who work outdoors in a rural area or in a suburban area where there are many caterpillar-infested trees.⁴

Most cases of lepidopterism are caused by caterpillars, not by adult butterflies and moths, because the former have many tubular, or porous, hairlike structures called setae that are embedded in the integument. Setae were once thought to be connected to poison-secreting glandular cells, but current belief is that venomous caterpillars lack specialized gland cells and instead produce venom through secretory epithelial cells located above the integument.¹ Venom accumulates in the hemolymph and is stored in the setae or other types of bristles, such as scoli (wartlike bumps that bear setae) or spines.⁵ With a large amount of chitin, bristles have a tendency to fracture and release venom upon contact.¹ It is thought that some species of caterpillars formulate venom by ingesting toxins or toxin precursors from plants; for example, the tiger moth (family Arctiidae) is known to produce venom containing biogenic amines, pyrrolizidine, alkaloids, and cardiac glycosides obtained through food sources.⁵

Even if a caterpillar does not produce venom, its setae might embed into skin or mucous membranes and cause an adverse irritant reaction.¹ Setae also might dislodge and be transported in the air to embed in objects—some remaining stable in the environment for longer than a year.² In contrast to setae, spines are permanently fixed into the integument; for that reason, only direct contact with the caterpillar can result in an adverse reaction. Although it is mostly caterpillars that contain setae and spines, certain species of moths also might contain these structures or might acquire them as they emerge from the cocoon, which often contains incorporated setae.²

Reactions in Humans

Lepidopterism encompasses 3 principal reactions in humans: sting reaction, hypersensitivity reaction, and lonomism (a hemorrhagic diathesis produced by Lonomia caterpillars). The type and severity of the reaction depends on (1) the species of caterpillar or moth and (2) the individual patient.² There are approximately 12 families of caterpillars, mainly of the moth variety, that can cause an adverse reaction in humans.¹ Tables 1 and 2 list examples of species that cause each type of reaction.⁶

Chemicals and toxins contained in the poison of setae and spines vary by species of caterpillar. Numerous kinds have been isolated from different venoms,^1,2 including several peptides, histamine, histamine-releasing substances, acetylcholine, phospholipase A, hyaluronidase, formic acid, proteins with trypsinlike activity, serine proteases such as kallikrein, and other enzymes with vasodegenerative and fibrinolytic properties

Stings: An Immediate Adverse Reaction—Depending on the venom, a sting might result in mild to severe burning pain, accompanied by welts, vesicles, and red papules or plaques.² Figure 1 demonstrates a particularly mild sting from a caterpillar of the family Automeris, examples of which are seen in Figures 2 and 3 and eFigure 1. Components of the venom determine the mechanism of the sting and the pain that accompanies it. For example, a recent study demonstrated that the venom of the Latoia consocia caterpillar induces pain through the ion-channel receptor known as transient receptor potential vanilloid 1, which integrates and sends painful stimuli from the peripheral nervous system to the central nervous system.⁷ It is thought that a variety of ion channels are targets of the venom of caterpillars.

One of the most characteristic sting patterns is that of the caterpillar of family Megalopygidae (flannel moth)(eFigures 2 and 3). The stings of these caterpillars create a unique tram-track pattern of hemorrhagic macules or papules (Figure 4).⁴ A study found that 90% of reported M opercularis envenomations consist primarily of cutaneous symptoms, with 84% of those symptoms being irritation or pain; 45% a puncture or wound; 29% erythema; and 15% edema.³ Systemic findings can include headache, fever, adenopathy, nausea, vomiting, abdominal pain, and chest pain.⁴ Symptoms normally are self-limited, though they can last minutes or hours.

Hypersensitivity Reaction—Studies demonstrate that the symptoms of this reaction are a mixture of type I hypersensitivity, type IV hypersensitivity, and a foreign-body response.² The specific hypersensitivity reaction depends on the venom and the exposed individual—most commonly including a combination of pruritic papules, urticarial wheals, flares, and dermatitis.² A reaction that is a result of direct contact with the caterpillar or moth will appear on exposed areas; however, because setae embed in linens and clothing, they might cause a reaction anywhere on the body. Although usually self-limited, a hypersensitivity reaction might develop within minutes and can last for days or weeks.

Stings and hypersensitivity reactions to caterpillars and moths tend to lead to a nonspecific histologic presentation characterized by epidermal edema and a superficial perivascular lymphocytic infiltrate, often with eosinophils.⁶ After approximately 1 week, a foreign-body response to setae can lead to tuberculoid granulomas accompanied by neutrophils in the dermis and occasionally in subcutaneous tissues (Figures 5 and 6).⁸ If setae have not yet been removed, they also might be visible in skin scrapings.

Additional complications can accompany the hypersensitivity reaction to setae or spines. Type I hypersensitivity reactions can lead to severe reactions on second contact due to previously sensitized IgE antibodies. Although the first reaction appears mild, second contact might result in angioedema, wheezing, dyspnea, or anaphylaxis, or a combination of these findings.⁹ In addition, some patients who come in contact with Dendrolimus caterpillars might develop a condition known as dendrolimiasis, characterized by dermatitis in addition to arthritis or chondritis.⁶ The arthritis is normally monoarticular and can result in complete destruction of the joint. Pararamose, a condition with a similar presentation, is caused by the Brazilian moth Premolis semirufa.⁶

Contact of setae or spines with mucous membranes or inhalation of setae also might result in edema, dysphagia, dyspnea, drooling, rhinitis, or conjunctivitis, or a combination of these findings.⁶ In addition, setae can embed in the eye and cause an inflammatory reaction—ophthalmia nodosa—most commonly caused by caterpillars of the pine processionary moth (Thaumetopoea pityocampa) and characterized by immediate chemosis, which can progress to liquefactive necrosis and hypopyon, later developing into a granulomatous foreign-body response.^2,10 The process is thought to be the result of a combination of the thaumetopoein toxin in the setae and an IgE-mediated response to other proteins.¹⁰

Due to their harpoon shape and forward-only motion, setae might migrate deeper, potentially even to the optic nerve.¹¹ Because migration might take years and the barbed shape of setae does not always allow removal, some patients require lifetime monitoring with slit-lamp examination.Chronic problems, such as cataracts and persistent posterior uveitis, have been reported.^10,11

Lonomism—One of the most serious (though rarest) reactions to caterpillars is lonomism, a condition caused by the caterpillars of Lonomia achelous and Lonomia obliqua moths. These caterpillars have a unique combination of toxins filling their branched spines, which ultimately leads to the same outcome: a hemorrhagic diathesis.

The toxin of L achelous comprises several proteases that degrade fibrin, fibrinogen, and factor XIII while activating prothrombin. In contrast, L obliqua poison causes a hemorrhagic diathesis by promoting a consumptive coagulopathy through enzymes that activate factor X and prothrombin.

With initial contact with either of these Lonomia caterpillars, the patient experiences severe pain accompanied by systemic symptoms, including headache, nausea, and vomiting. Shortly afterward, symptoms of a hemorrhagic diathesis manifest, including bleeding gums, hematuria, bleeding from prior wounds, and epistaxis.⁵ Serious complications of the hemorrhagic diathesis, such as hemorrhage of major organs, leads to death in 4% of patients.⁵ A reported case of a patient whose Lonomia caterpillar sting went unrecognized until a week after the accident ended with progression to stage V chronic renal disease.¹²

Recent research has focused on the specific mechanism of injury caused by Lonomia species. A study found that the venom of L obliqua causes cytoskeleton rearrangement and migration in vascular smooth muscle cells (VSMCs) by inducing formation of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate oxidase.¹³ Thus, the venom directly contributes to the proinflammatory phenotype of endothelial cells seen following envenomation. The same study also demonstrated that elevated reactive oxygen species trigger extracellular signal-regulated kinase pathway activation in VSMCs, leading to cell proliferation, re-stenosis, and ischemia.¹³ This finding was confirmed by another study,¹⁴ which demonstrated an increase in Rac1, a signaling protein involved in the extracellular signal-regulated kinase pathway, in VSMCs upon exposure to L obliqua venom. These studies propose potential new targets for treatment to prevent vascular damage.

Reactions to Adult Organisms—Although it is more common for the caterpillar form of these organisms to cause an adverse reaction, the adult moth also might be capable of causing a similar reaction by retaining setae from the cocoon or by their own spines. The most notable example of this is female moths of the genus Hylesia, which possess spines attached to glands on the abdomen. The poison in these spines—a mixture of proteases and chitinase—causes a dermatitis known as Caripito itch—the name derived from a river port in Venezuela where this moth caused a memorable epidemic of moth-induced dermatitis.^7,15 Caripito itch is known for intense pruritus that most commonly lasts days or weeks, possibly longer than 1 year.

Diagnostic Difficulties

The challenge of diagnosing a caterpillar- or moth-induced reaction in humans arises from (1) the lack of clinical history (the caterpillar might not be seen at all by the patient or the examiner) and (2) the similarity of these reactions to those with more common triggers.

When setae remain embedded in the skin or mucous membranes, skin scrapings allow accelerated diagnosis. On a skin scraping prepared with 20% potassium hydroxide, setae appear as tapered and barbed hairlike structures, which allows them to be distinguished from other similar-appearing but differently shaped structures, such as glass fibers.

When setae do not remain embedded in the skin or when the cause of the reaction is due to spines, the physician is left with a nonspecific histologic picture and a large differential diagnosis to be narrowed down based on the history and occasionally the pattern of the skin lesion.

A challenge in sting diagnosis is differentiating a caterpillar or moth sting from that of another organism. In certain cases, such as those of the family Megalopygidae, specific patterns of stings might assist in making the diagnosis. Hypersensitivity reactions are associated with a wider differential diagnosis, including irritant or allergic dermatitis from other causes, scabies, eczema, lichen planus, lichen simplex chronicus, seborrheic dermatitis, and tinea corporis, to name a few.⁶ Skin scrapings can be examined for other features, such as burrows in the case of scabies, to further narrow the differential.

Stings and hypersensitivity reactions lacking a proper history and associated with more severe systemic symptoms have caused misdiagnosis or led to a workup for the wrong condition; for example, the picture of abdominal pain, nausea, vomiting, tachycardia, leukocytosis, hypokalemia, and metabolic acidosis can simulate appendicitis.¹⁶ Upon discovery of a puss caterpillar sting in a patient, her symptoms resolved after treatment with ondansetron, morphine, and intravenous fluids.¹⁶

In lonomism, the diagnosis must be established by laboratory measurement of the fibrinogen level, clotting factors, prothrombin time, and activated partial thromboplastin time.⁴ The differential diagnosis associated with lonomism includes disseminated intravascular coagulation (DIC), snakebite, and a hereditary bleeding disorder.⁴ The combination of laboratory tests and an extensive medical history allows a diagnosis. Absence of a personal or family history of bleeding excludes a diagnosis of hereditary bleeding disorder, whereas the absence of known causes of DIC or thrombocytopenia allows DIC to be excluded from the differential.

Treatment Options and Prevention

Treatment—The first step is to remove any embedded setae from the skin or mucous membranes. The stepwise recommendation is to remove any constricted clothing, detach setae with adhesive tape, wash with soap and water, and dry without touching the skin.¹ Any remaining setae can be removed with additional tape or forceps; setae tend to be fragile and are difficult to remove in their entirety.

Other than removal of the setae, skin reactions are treated symptomatically. Ice packs and isopropyl alcohol have been utilized to cool burning or stinging areas. Pain, pruritus, and inflammation have been alleviated with antihistamines and topical corticosteroids.¹ When pain is severe, oral codeine or local injection of anesthetic can be used. For severe and persistent skin lesions, a course of an oral glucocorticoid can be administered. Intramuscular triamcinolone acetonide has been shown to treat pain, dermatitis, and subcutaneous nodules otherwise refractory to treatment.⁸

Antivenin specific for L obliqua exists to treat lonomism and is therefore effective only when lonomism is caused by that species. Lonomism caused by L achelous is treated with cryoprecipitate, purified fibrinogen, and antifibrinolytic drugs, such as aprotinin.⁶ Whole blood and fresh-frozen plasma have been noted to make hemorrhage worse when utilized to treat lonomism. Because the mechanism of action of the venom of Lonomia species is based, in part, on inducing a proinflammatory profile in endothelial cells, studies have demonstrated that inhibition of kallikrein might prevent vascular injury and thus prevent serious adverse effects, such as renal failure.¹⁷

Prevention—People should wear proper protective clothing when outdoors in potentially infested areas. Measures should be taken to ensure that linens and clothing are not left outside in areas where setae might be carried on the wind. Infestation control is necessary if the population of caterpillars reaches a high enough level.

Conclusion

Several species of caterpillars and moths cause adverse reactions in humans: stings, hypersensitivity reactions, and lonomism. Although most reactions are self-limited, some might have more serious effects, including organ failure and death. Mechanisms of injury vary by species of caterpillar, moth, and butterfly; current research is focused on further defining venom components and signaling pathways to isolate potential targets to aid in the diagnosis and treatment of lepidopterism.

Causes of Lepidopterism

Caterpillars are wormlike organisms that serve as the larval stage of moths and butterflies, which belong to the order Lepidoptera. There are almost 165,000 discovered species, with 13,000 found in the United States.^1,2 Roughly 150 species are known to have the potential to cause an adverse reaction in humans, with 50 of these in the United States.¹Lepidopterism describes systemic and cutaneous reactions to moths, butterflies, and caterpillars; erucism describes strictly cutaneous reactions.¹

Although the rate of lepidopterism is thought to be underreported because it often is self-limited and of a mild nature, a review found caterpillars to be the cause of roughly 2.2% of reported bites and stings annually.² Cases increase in number with seasonal increases in caterpillars, which vary by region and species. For example, the Megalopyge opercularis (southern flannel moth) caterpillar was noted to have 2 peaks in a Texas-based study: 12% of reported stings occurred in July; 59% from October through November.³ In general, the likelihood of exposure increases during warmer months, and exposure is more common in people who work outdoors in a rural area or in a suburban area where there are many caterpillar-infested trees.⁴

Most cases of lepidopterism are caused by caterpillars, not by adult butterflies and moths, because the former have many tubular, or porous, hairlike structures called setae that are embedded in the integument. Setae were once thought to be connected to poison-secreting glandular cells, but current belief is that venomous caterpillars lack specialized gland cells and instead produce venom through secretory epithelial cells located above the integument.¹ Venom accumulates in the hemolymph and is stored in the setae or other types of bristles, such as scoli (wartlike bumps that bear setae) or spines.⁵ With a large amount of chitin, bristles have a tendency to fracture and release venom upon contact.¹ It is thought that some species of caterpillars formulate venom by ingesting toxins or toxin precursors from plants; for example, the tiger moth (family Arctiidae) is known to produce venom containing biogenic amines, pyrrolizidine, alkaloids, and cardiac glycosides obtained through food sources.⁵

Even if a caterpillar does not produce venom, its setae might embed into skin or mucous membranes and cause an adverse irritant reaction.¹ Setae also might dislodge and be transported in the air to embed in objects—some remaining stable in the environment for longer than a year.² In contrast to setae, spines are permanently fixed into the integument; for that reason, only direct contact with the caterpillar can result in an adverse reaction. Although it is mostly caterpillars that contain setae and spines, certain species of moths also might contain these structures or might acquire them as they emerge from the cocoon, which often contains incorporated setae.²

Reactions in Humans

Lepidopterism encompasses 3 principal reactions in humans: sting reaction, hypersensitivity reaction, and lonomism (a hemorrhagic diathesis produced by Lonomia caterpillars). The type and severity of the reaction depends on (1) the species of caterpillar or moth and (2) the individual patient.² There are approximately 12 families of caterpillars, mainly of the moth variety, that can cause an adverse reaction in humans.¹ Tables 1 and 2 list examples of species that cause each type of reaction.⁶

Chemicals and toxins contained in the poison of setae and spines vary by species of caterpillar. Numerous kinds have been isolated from different venoms,^1,2 including several peptides, histamine, histamine-releasing substances, acetylcholine, phospholipase A, hyaluronidase, formic acid, proteins with trypsinlike activity, serine proteases such as kallikrein, and other enzymes with vasodegenerative and fibrinolytic properties

Stings: An Immediate Adverse Reaction—Depending on the venom, a sting might result in mild to severe burning pain, accompanied by welts, vesicles, and red papules or plaques.² Figure 1 demonstrates a particularly mild sting from a caterpillar of the family Automeris, examples of which are seen in Figures 2 and 3 and eFigure 1. Components of the venom determine the mechanism of the sting and the pain that accompanies it. For example, a recent study demonstrated that the venom of the Latoia consocia caterpillar induces pain through the ion-channel receptor known as transient receptor potential vanilloid 1, which integrates and sends painful stimuli from the peripheral nervous system to the central nervous system.⁷ It is thought that a variety of ion channels are targets of the venom of caterpillars.

One of the most characteristic sting patterns is that of the caterpillar of family Megalopygidae (flannel moth)(eFigures 2 and 3). The stings of these caterpillars create a unique tram-track pattern of hemorrhagic macules or papules (Figure 4).⁴ A study found that 90% of reported M opercularis envenomations consist primarily of cutaneous symptoms, with 84% of those symptoms being irritation or pain; 45% a puncture or wound; 29% erythema; and 15% edema.³ Systemic findings can include headache, fever, adenopathy, nausea, vomiting, abdominal pain, and chest pain.⁴ Symptoms normally are self-limited, though they can last minutes or hours.

Hypersensitivity Reaction—Studies demonstrate that the symptoms of this reaction are a mixture of type I hypersensitivity, type IV hypersensitivity, and a foreign-body response.² The specific hypersensitivity reaction depends on the venom and the exposed individual—most commonly including a combination of pruritic papules, urticarial wheals, flares, and dermatitis.² A reaction that is a result of direct contact with the caterpillar or moth will appear on exposed areas; however, because setae embed in linens and clothing, they might cause a reaction anywhere on the body. Although usually self-limited, a hypersensitivity reaction might develop within minutes and can last for days or weeks.

Stings and hypersensitivity reactions to caterpillars and moths tend to lead to a nonspecific histologic presentation characterized by epidermal edema and a superficial perivascular lymphocytic infiltrate, often with eosinophils.⁶ After approximately 1 week, a foreign-body response to setae can lead to tuberculoid granulomas accompanied by neutrophils in the dermis and occasionally in subcutaneous tissues (Figures 5 and 6).⁸ If setae have not yet been removed, they also might be visible in skin scrapings.

Additional complications can accompany the hypersensitivity reaction to setae or spines. Type I hypersensitivity reactions can lead to severe reactions on second contact due to previously sensitized IgE antibodies. Although the first reaction appears mild, second contact might result in angioedema, wheezing, dyspnea, or anaphylaxis, or a combination of these findings.⁹ In addition, some patients who come in contact with Dendrolimus caterpillars might develop a condition known as dendrolimiasis, characterized by dermatitis in addition to arthritis or chondritis.⁶ The arthritis is normally monoarticular and can result in complete destruction of the joint. Pararamose, a condition with a similar presentation, is caused by the Brazilian moth Premolis semirufa.⁶

Contact of setae or spines with mucous membranes or inhalation of setae also might result in edema, dysphagia, dyspnea, drooling, rhinitis, or conjunctivitis, or a combination of these findings.⁶ In addition, setae can embed in the eye and cause an inflammatory reaction—ophthalmia nodosa—most commonly caused by caterpillars of the pine processionary moth (Thaumetopoea pityocampa) and characterized by immediate chemosis, which can progress to liquefactive necrosis and hypopyon, later developing into a granulomatous foreign-body response.^2,10 The process is thought to be the result of a combination of the thaumetopoein toxin in the setae and an IgE-mediated response to other proteins.¹⁰

Due to their harpoon shape and forward-only motion, setae might migrate deeper, potentially even to the optic nerve.¹¹ Because migration might take years and the barbed shape of setae does not always allow removal, some patients require lifetime monitoring with slit-lamp examination.Chronic problems, such as cataracts and persistent posterior uveitis, have been reported.^10,11

Lonomism—One of the most serious (though rarest) reactions to caterpillars is lonomism, a condition caused by the caterpillars of Lonomia achelous and Lonomia obliqua moths. These caterpillars have a unique combination of toxins filling their branched spines, which ultimately leads to the same outcome: a hemorrhagic diathesis.

The toxin of L achelous comprises several proteases that degrade fibrin, fibrinogen, and factor XIII while activating prothrombin. In contrast, L obliqua poison causes a hemorrhagic diathesis by promoting a consumptive coagulopathy through enzymes that activate factor X and prothrombin.

With initial contact with either of these Lonomia caterpillars, the patient experiences severe pain accompanied by systemic symptoms, including headache, nausea, and vomiting. Shortly afterward, symptoms of a hemorrhagic diathesis manifest, including bleeding gums, hematuria, bleeding from prior wounds, and epistaxis.⁵ Serious complications of the hemorrhagic diathesis, such as hemorrhage of major organs, leads to death in 4% of patients.⁵ A reported case of a patient whose Lonomia caterpillar sting went unrecognized until a week after the accident ended with progression to stage V chronic renal disease.¹²

Recent research has focused on the specific mechanism of injury caused by Lonomia species. A study found that the venom of L obliqua causes cytoskeleton rearrangement and migration in vascular smooth muscle cells (VSMCs) by inducing formation of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate oxidase.¹³ Thus, the venom directly contributes to the proinflammatory phenotype of endothelial cells seen following envenomation. The same study also demonstrated that elevated reactive oxygen species trigger extracellular signal-regulated kinase pathway activation in VSMCs, leading to cell proliferation, re-stenosis, and ischemia.¹³ This finding was confirmed by another study,¹⁴ which demonstrated an increase in Rac1, a signaling protein involved in the extracellular signal-regulated kinase pathway, in VSMCs upon exposure to L obliqua venom. These studies propose potential new targets for treatment to prevent vascular damage.

Reactions to Adult Organisms—Although it is more common for the caterpillar form of these organisms to cause an adverse reaction, the adult moth also might be capable of causing a similar reaction by retaining setae from the cocoon or by their own spines. The most notable example of this is female moths of the genus Hylesia, which possess spines attached to glands on the abdomen. The poison in these spines—a mixture of proteases and chitinase—causes a dermatitis known as Caripito itch—the name derived from a river port in Venezuela where this moth caused a memorable epidemic of moth-induced dermatitis.^7,15 Caripito itch is known for intense pruritus that most commonly lasts days or weeks, possibly longer than 1 year.

Diagnostic Difficulties

The challenge of diagnosing a caterpillar- or moth-induced reaction in humans arises from (1) the lack of clinical history (the caterpillar might not be seen at all by the patient or the examiner) and (2) the similarity of these reactions to those with more common triggers.

When setae remain embedded in the skin or mucous membranes, skin scrapings allow accelerated diagnosis. On a skin scraping prepared with 20% potassium hydroxide, setae appear as tapered and barbed hairlike structures, which allows them to be distinguished from other similar-appearing but differently shaped structures, such as glass fibers.

When setae do not remain embedded in the skin or when the cause of the reaction is due to spines, the physician is left with a nonspecific histologic picture and a large differential diagnosis to be narrowed down based on the history and occasionally the pattern of the skin lesion.

A challenge in sting diagnosis is differentiating a caterpillar or moth sting from that of another organism. In certain cases, such as those of the family Megalopygidae, specific patterns of stings might assist in making the diagnosis. Hypersensitivity reactions are associated with a wider differential diagnosis, including irritant or allergic dermatitis from other causes, scabies, eczema, lichen planus, lichen simplex chronicus, seborrheic dermatitis, and tinea corporis, to name a few.⁶ Skin scrapings can be examined for other features, such as burrows in the case of scabies, to further narrow the differential.

Stings and hypersensitivity reactions lacking a proper history and associated with more severe systemic symptoms have caused misdiagnosis or led to a workup for the wrong condition; for example, the picture of abdominal pain, nausea, vomiting, tachycardia, leukocytosis, hypokalemia, and metabolic acidosis can simulate appendicitis.¹⁶ Upon discovery of a puss caterpillar sting in a patient, her symptoms resolved after treatment with ondansetron, morphine, and intravenous fluids.¹⁶

In lonomism, the diagnosis must be established by laboratory measurement of the fibrinogen level, clotting factors, prothrombin time, and activated partial thromboplastin time.⁴ The differential diagnosis associated with lonomism includes disseminated intravascular coagulation (DIC), snakebite, and a hereditary bleeding disorder.⁴ The combination of laboratory tests and an extensive medical history allows a diagnosis. Absence of a personal or family history of bleeding excludes a diagnosis of hereditary bleeding disorder, whereas the absence of known causes of DIC or thrombocytopenia allows DIC to be excluded from the differential.

Treatment Options and Prevention

Treatment—The first step is to remove any embedded setae from the skin or mucous membranes. The stepwise recommendation is to remove any constricted clothing, detach setae with adhesive tape, wash with soap and water, and dry without touching the skin.¹ Any remaining setae can be removed with additional tape or forceps; setae tend to be fragile and are difficult to remove in their entirety.

Other than removal of the setae, skin reactions are treated symptomatically. Ice packs and isopropyl alcohol have been utilized to cool burning or stinging areas. Pain, pruritus, and inflammation have been alleviated with antihistamines and topical corticosteroids.¹ When pain is severe, oral codeine or local injection of anesthetic can be used. For severe and persistent skin lesions, a course of an oral glucocorticoid can be administered. Intramuscular triamcinolone acetonide has been shown to treat pain, dermatitis, and subcutaneous nodules otherwise refractory to treatment.⁸

Antivenin specific for L obliqua exists to treat lonomism and is therefore effective only when lonomism is caused by that species. Lonomism caused by L achelous is treated with cryoprecipitate, purified fibrinogen, and antifibrinolytic drugs, such as aprotinin.⁶ Whole blood and fresh-frozen plasma have been noted to make hemorrhage worse when utilized to treat lonomism. Because the mechanism of action of the venom of Lonomia species is based, in part, on inducing a proinflammatory profile in endothelial cells, studies have demonstrated that inhibition of kallikrein might prevent vascular injury and thus prevent serious adverse effects, such as renal failure.¹⁷

Prevention—People should wear proper protective clothing when outdoors in potentially infested areas. Measures should be taken to ensure that linens and clothing are not left outside in areas where setae might be carried on the wind. Infestation control is necessary if the population of caterpillars reaches a high enough level.

Conclusion

Several species of caterpillars and moths cause adverse reactions in humans: stings, hypersensitivity reactions, and lonomism. Although most reactions are self-limited, some might have more serious effects, including organ failure and death. Mechanisms of injury vary by species of caterpillar, moth, and butterfly; current research is focused on further defining venom components and signaling pathways to isolate potential targets to aid in the diagnosis and treatment of lepidopterism.

Despite the clinical value of medical devices, there is a potential for these products to cause adverse skin reactions in some patients. Findings from a European retrospective study, published in the European Journal of Allergy and Clinical Immunology, show that nearly one-quarter of patients with suspected allergic contact dermatitis were referred for patch testing for contact allergies associated with medical devices, highlighting the possibility of a high prevalence of contact allergens in these devices.

“We found it important to publish these findings, because up until now no clear figures have been reported regarding this particular clinical problem,” said study author Olivier Aerts, MD, a researcher in the contact allergy unit at the University Hospital Antwerp, Belgium, in an interview with this news organization.

For the study, Dr. Aerts and colleagues conducted a retrospective analysis of medical device users with suspected allergic contact dermatitis. All patients had been patch tested at a tertiary European clinic between 2018 and 2020.

The cohort included patients who experienced suspected contact allergy from medical adhesives (n = 57), gloves (n = 38), topical and surface medical devices (n = 38), glucose sensors and insulin pumps (n = 74), and prostheses (n = 75). Other medical products associated with contact allergy in another 44 patients included surgical glues, face masks, compression stockings, condoms, and suture materials.

Overall, 326 patients had been patch-tested during the 30-month study period. Approximately 25.8% of all patients – including 299 adults and 27 children – were referred for contact allergy associated with medical devices.

Acrylates were the most frequently encountered contact allergens and were found in diabetes devices and medical adhesives. Potential skin sensitizers included colophonium-related substances, D-limonene, isothiazolinone derivatives, salicylates, and sulphites, all of which were identified across most products.

According to the investigators, many of the labels for the medical devices made no mention of the potential skin sensitizers, except in the cases of some topical and surface disinfectants. And many topical products are often marketed as medical devices rather than cosmetics, further complicating labeling issues, according to Dr. Aerts.

“What should be done to help any patient suffering from allergic contact due to medical devices is that these devices should be labeled with all their components, or at the very least with the potential skin sensitizers these may contain,” Dr. Aerts explained. He added that manufacturers should “establish more cooperation with physicians/dermatologists who evaluate such patients,” a cooperation that often exists with cosmetic companies.

Dr. Aerts noted that while it’s important for patch testers and dermatologists to be aware of the prevalence of allergic contact dermatitis in medical device users, companies producing these devices should also be aware of these potential issues. “Additionally, legislators/regulators should perhaps focus some more on the cutaneous side effects these products may provoke,” he said, “as this awareness may hopefully also serve as a stimulant to perform more clinical allergy research in this field.”

Leonard Bielory, MD, an allergist at Robert Wood Johnson University Hospital in Rahway, New Jersey, told this news organization that the findings are “alarming” and should heighten clinicians’ awareness of the possibility of allergic contact dermatitis among medical device users.

Dr. Bielory, who wasn’t involved in the research, noted that the findings from this study may not be entirely generalizable to the U.S., given the study was performed in Europe. “In contrast to other countries, the U.S. is very conscientious about allergic responses to items being used in hospitals,” he added, “or such that the issue here is that many of these things would be an adverse reaction, which you have to report.” He suggested that further research in this field is needed to determine the prevalence of possible skin sensitizers in products specifically developed and marketed in the U.S.

The study had no specific funding. Dr. Aerts and Dr. Bielory have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Despite the clinical value of medical devices, there is a potential for these products to cause adverse skin reactions in some patients. Findings from a European retrospective study, published in the European Journal of Allergy and Clinical Immunology, show that nearly one-quarter of patients with suspected allergic contact dermatitis were referred for patch testing for contact allergies associated with medical devices, highlighting the possibility of a high prevalence of contact allergens in these devices.

“We found it important to publish these findings, because up until now no clear figures have been reported regarding this particular clinical problem,” said study author Olivier Aerts, MD, a researcher in the contact allergy unit at the University Hospital Antwerp, Belgium, in an interview with this news organization.

For the study, Dr. Aerts and colleagues conducted a retrospective analysis of medical device users with suspected allergic contact dermatitis. All patients had been patch tested at a tertiary European clinic between 2018 and 2020.

The cohort included patients who experienced suspected contact allergy from medical adhesives (n = 57), gloves (n = 38), topical and surface medical devices (n = 38), glucose sensors and insulin pumps (n = 74), and prostheses (n = 75). Other medical products associated with contact allergy in another 44 patients included surgical glues, face masks, compression stockings, condoms, and suture materials.

Overall, 326 patients had been patch-tested during the 30-month study period. Approximately 25.8% of all patients – including 299 adults and 27 children – were referred for contact allergy associated with medical devices.

Acrylates were the most frequently encountered contact allergens and were found in diabetes devices and medical adhesives. Potential skin sensitizers included colophonium-related substances, D-limonene, isothiazolinone derivatives, salicylates, and sulphites, all of which were identified across most products.

According to the investigators, many of the labels for the medical devices made no mention of the potential skin sensitizers, except in the cases of some topical and surface disinfectants. And many topical products are often marketed as medical devices rather than cosmetics, further complicating labeling issues, according to Dr. Aerts.

“What should be done to help any patient suffering from allergic contact due to medical devices is that these devices should be labeled with all their components, or at the very least with the potential skin sensitizers these may contain,” Dr. Aerts explained. He added that manufacturers should “establish more cooperation with physicians/dermatologists who evaluate such patients,” a cooperation that often exists with cosmetic companies.

Dr. Aerts noted that while it’s important for patch testers and dermatologists to be aware of the prevalence of allergic contact dermatitis in medical device users, companies producing these devices should also be aware of these potential issues. “Additionally, legislators/regulators should perhaps focus some more on the cutaneous side effects these products may provoke,” he said, “as this awareness may hopefully also serve as a stimulant to perform more clinical allergy research in this field.”

Leonard Bielory, MD, an allergist at Robert Wood Johnson University Hospital in Rahway, New Jersey, told this news organization that the findings are “alarming” and should heighten clinicians’ awareness of the possibility of allergic contact dermatitis among medical device users.

Dr. Bielory, who wasn’t involved in the research, noted that the findings from this study may not be entirely generalizable to the U.S., given the study was performed in Europe. “In contrast to other countries, the U.S. is very conscientious about allergic responses to items being used in hospitals,” he added, “or such that the issue here is that many of these things would be an adverse reaction, which you have to report.” He suggested that further research in this field is needed to determine the prevalence of possible skin sensitizers in products specifically developed and marketed in the U.S.

The study had no specific funding. Dr. Aerts and Dr. Bielory have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Despite the clinical value of medical devices, there is a potential for these products to cause adverse skin reactions in some patients. Findings from a European retrospective study, published in the European Journal of Allergy and Clinical Immunology, show that nearly one-quarter of patients with suspected allergic contact dermatitis were referred for patch testing for contact allergies associated with medical devices, highlighting the possibility of a high prevalence of contact allergens in these devices.

“We found it important to publish these findings, because up until now no clear figures have been reported regarding this particular clinical problem,” said study author Olivier Aerts, MD, a researcher in the contact allergy unit at the University Hospital Antwerp, Belgium, in an interview with this news organization.

For the study, Dr. Aerts and colleagues conducted a retrospective analysis of medical device users with suspected allergic contact dermatitis. All patients had been patch tested at a tertiary European clinic between 2018 and 2020.

The cohort included patients who experienced suspected contact allergy from medical adhesives (n = 57), gloves (n = 38), topical and surface medical devices (n = 38), glucose sensors and insulin pumps (n = 74), and prostheses (n = 75). Other medical products associated with contact allergy in another 44 patients included surgical glues, face masks, compression stockings, condoms, and suture materials.

Overall, 326 patients had been patch-tested during the 30-month study period. Approximately 25.8% of all patients – including 299 adults and 27 children – were referred for contact allergy associated with medical devices.

Acrylates were the most frequently encountered contact allergens and were found in diabetes devices and medical adhesives. Potential skin sensitizers included colophonium-related substances, D-limonene, isothiazolinone derivatives, salicylates, and sulphites, all of which were identified across most products.

According to the investigators, many of the labels for the medical devices made no mention of the potential skin sensitizers, except in the cases of some topical and surface disinfectants. And many topical products are often marketed as medical devices rather than cosmetics, further complicating labeling issues, according to Dr. Aerts.

“What should be done to help any patient suffering from allergic contact due to medical devices is that these devices should be labeled with all their components, or at the very least with the potential skin sensitizers these may contain,” Dr. Aerts explained. He added that manufacturers should “establish more cooperation with physicians/dermatologists who evaluate such patients,” a cooperation that often exists with cosmetic companies.

Dr. Aerts noted that while it’s important for patch testers and dermatologists to be aware of the prevalence of allergic contact dermatitis in medical device users, companies producing these devices should also be aware of these potential issues. “Additionally, legislators/regulators should perhaps focus some more on the cutaneous side effects these products may provoke,” he said, “as this awareness may hopefully also serve as a stimulant to perform more clinical allergy research in this field.”

Leonard Bielory, MD, an allergist at Robert Wood Johnson University Hospital in Rahway, New Jersey, told this news organization that the findings are “alarming” and should heighten clinicians’ awareness of the possibility of allergic contact dermatitis among medical device users.

Dr. Bielory, who wasn’t involved in the research, noted that the findings from this study may not be entirely generalizable to the U.S., given the study was performed in Europe. “In contrast to other countries, the U.S. is very conscientious about allergic responses to items being used in hospitals,” he added, “or such that the issue here is that many of these things would be an adverse reaction, which you have to report.” He suggested that further research in this field is needed to determine the prevalence of possible skin sensitizers in products specifically developed and marketed in the U.S.

The study had no specific funding. Dr. Aerts and Dr. Bielory have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.