Contact Dermatitis

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

Telaprevir is a hepatitis C virus (HCV) protease inhibitor used with ribavirin and interferon for the treatment of increased viral load clearance in specific HCV genotypes. We report a case of eruptive seborrheic keratoses (SKs) secondary to telaprevir-related dermatitis.

A 65-year-old woman with a history of depression, basal cell carcinoma, and HCV presented 5 months after initiation of antiviral treatment with interferon, ribavirin, and telaprevir. Shortly after initiation of therapy, the patient developed a diffuse itch with a “pricking” sensation. The patient reported that approximately 2 months after starting treatment she developed an erythematous scaling rash that covered 75% of the body, which led to the discontinuation of telaprevir after 10 weeks of therapy; interferon and ribavirin were continued for a total of 6 months. In concert with the eczematous eruption, the patient noticed many new hyperpigmented lesions with enlargement of the few preexisting SKs. She presented to our clinic 6 weeks after the discontinuation of telaprevir for evaluation of these lesions.

On examination, several brown, hyperpigmented, stuck-on papules and plaques were noted diffusely on the body, most prominently along the frontal hairline (Figure 1). A biopsy of the right side of the forehead showed a reticulated epidermis, horn pseudocysts, and increased basilar pigment diagnostic of an SK (Figure 2).

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Telaprevir is an HCV protease inhibitor that is given in combination with interferon and ribavirin for increased clearance of genotype 1 HCV infection. Cutaneous reactions to telaprevir are seen in 41% to 61% of treated patients and include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, sarcoidosis, pityriasis rubra pilaris–like drug eruption, and most commonly telaprevir-related dermatitis.^1-3 Telaprevir-related dermatitis accounts for up to 95% of cutaneous reactions and presents at a median of 15 days (interquartile range, 4–41 days) after initiation of therapy. Nearly 25% of cases occur in the first 4 days and 46% of cases occur within 4 weeks. It presents as an erythematous eczematous dermatitis commonly associated with pruritus in contrast to the common morbilliform drug eruption. Secondary xerosis, excoriation, and lichenification can be appreciated. With appropriate treatment, resolution occurs in a median of 44 days.¹ Treatment of the dermatitis can allow completion of the recommended 12-week course of telaprevir and involves oral antihistamines and topical corticosteroids. Severe cases may require oral corticosteroids and discontinuation of telaprevir. If the cutaneous eruption does not resolve, discontinuation of ribavirin also may be required, as it can cause a similar cutaneous eruption.⁴

To the Editor:

Telaprevir is a hepatitis C virus (HCV) protease inhibitor used with ribavirin and interferon for the treatment of increased viral load clearance in specific HCV genotypes. We report a case of eruptive seborrheic keratoses (SKs) secondary to telaprevir-related dermatitis.

A 65-year-old woman with a history of depression, basal cell carcinoma, and HCV presented 5 months after initiation of antiviral treatment with interferon, ribavirin, and telaprevir. Shortly after initiation of therapy, the patient developed a diffuse itch with a “pricking” sensation. The patient reported that approximately 2 months after starting treatment she developed an erythematous scaling rash that covered 75% of the body, which led to the discontinuation of telaprevir after 10 weeks of therapy; interferon and ribavirin were continued for a total of 6 months. In concert with the eczematous eruption, the patient noticed many new hyperpigmented lesions with enlargement of the few preexisting SKs. She presented to our clinic 6 weeks after the discontinuation of telaprevir for evaluation of these lesions.

On examination, several brown, hyperpigmented, stuck-on papules and plaques were noted diffusely on the body, most prominently along the frontal hairline (Figure 1). A biopsy of the right side of the forehead showed a reticulated epidermis, horn pseudocysts, and increased basilar pigment diagnostic of an SK (Figure 2).

[[{"attributes":{},"fields":{}}]][[{"attributes":{},"fields":{}}]]

Telaprevir is an HCV protease inhibitor that is given in combination with interferon and ribavirin for increased clearance of genotype 1 HCV infection. Cutaneous reactions to telaprevir are seen in 41% to 61% of treated patients and include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, sarcoidosis, pityriasis rubra pilaris–like drug eruption, and most commonly telaprevir-related dermatitis.^1-3 Telaprevir-related dermatitis accounts for up to 95% of cutaneous reactions and presents at a median of 15 days (interquartile range, 4–41 days) after initiation of therapy. Nearly 25% of cases occur in the first 4 days and 46% of cases occur within 4 weeks. It presents as an erythematous eczematous dermatitis commonly associated with pruritus in contrast to the common morbilliform drug eruption. Secondary xerosis, excoriation, and lichenification can be appreciated. With appropriate treatment, resolution occurs in a median of 44 days.¹ Treatment of the dermatitis can allow completion of the recommended 12-week course of telaprevir and involves oral antihistamines and topical corticosteroids. Severe cases may require oral corticosteroids and discontinuation of telaprevir. If the cutaneous eruption does not resolve, discontinuation of ribavirin also may be required, as it can cause a similar cutaneous eruption.⁴

To the Editor:

Telaprevir is a hepatitis C virus (HCV) protease inhibitor used with ribavirin and interferon for the treatment of increased viral load clearance in specific HCV genotypes. We report a case of eruptive seborrheic keratoses (SKs) secondary to telaprevir-related dermatitis.

A 65-year-old woman with a history of depression, basal cell carcinoma, and HCV presented 5 months after initiation of antiviral treatment with interferon, ribavirin, and telaprevir. Shortly after initiation of therapy, the patient developed a diffuse itch with a “pricking” sensation. The patient reported that approximately 2 months after starting treatment she developed an erythematous scaling rash that covered 75% of the body, which led to the discontinuation of telaprevir after 10 weeks of therapy; interferon and ribavirin were continued for a total of 6 months. In concert with the eczematous eruption, the patient noticed many new hyperpigmented lesions with enlargement of the few preexisting SKs. She presented to our clinic 6 weeks after the discontinuation of telaprevir for evaluation of these lesions.

On examination, several brown, hyperpigmented, stuck-on papules and plaques were noted diffusely on the body, most prominently along the frontal hairline (Figure 1). A biopsy of the right side of the forehead showed a reticulated epidermis, horn pseudocysts, and increased basilar pigment diagnostic of an SK (Figure 2).

[[{"attributes":{},"fields":{}}]][[{"attributes":{},"fields":{}}]]

Telaprevir is an HCV protease inhibitor that is given in combination with interferon and ribavirin for increased clearance of genotype 1 HCV infection. Cutaneous reactions to telaprevir are seen in 41% to 61% of treated patients and include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, sarcoidosis, pityriasis rubra pilaris–like drug eruption, and most commonly telaprevir-related dermatitis.^1-3 Telaprevir-related dermatitis accounts for up to 95% of cutaneous reactions and presents at a median of 15 days (interquartile range, 4–41 days) after initiation of therapy. Nearly 25% of cases occur in the first 4 days and 46% of cases occur within 4 weeks. It presents as an erythematous eczematous dermatitis commonly associated with pruritus in contrast to the common morbilliform drug eruption. Secondary xerosis, excoriation, and lichenification can be appreciated. With appropriate treatment, resolution occurs in a median of 44 days.¹ Treatment of the dermatitis can allow completion of the recommended 12-week course of telaprevir and involves oral antihistamines and topical corticosteroids. Severe cases may require oral corticosteroids and discontinuation of telaprevir. If the cutaneous eruption does not resolve, discontinuation of ribavirin also may be required, as it can cause a similar cutaneous eruption.⁴

Inundating our popular and academic media circles is information regarding the Zika virus. A recent article by Farahnik et al in the Journal of the American Academy of Dermatology (2016;74:1286-1287) briefly outlines what is known about Zika infection thus far and its dermatologic manifestations. Pairing this article with Centers for Disease Control and Prevention guidelines on the topic, we are presented with an evolving introduction to this new entity. Here’s what we know:

What’s the issue?

As with any new outbreak, the applicability to the general population and true risks remain to be seen. Each of our clinics recalls the stark changes in patient intake and screening questions with infections as ubiquitous as methicillin-resistant Staphylococcus aureus to much rarer exposures such as Ebola virus, each with progressive understanding of risk groups, disease manifestations, and eradication and prevention measures.

By mid-June 2016, 30 hits on PubMed addressing Zika had already been cited just within the month, outlining various aspects of the infection, and many specialties, particularly neurology, obstetrics, primary care, infectious disease, and dermatology, are weighing in. Unfortunately, the majority of cases of primary Zika infection do not manifest with skin or systemic symptoms, and even cases that do are nonspecific, exanthematous, and flulike.

Vague as it may be so far, it is nonetheless imperative that clinicians be familiar with what is concretely known about Zika virus and acquaint ourselves with the travel distribution and restrictions, disease risk factors, known sequelae, testing availability and limitations, and reporting guidelines. From personal experience, as I traveled to Belize earlier this year during my first trimester of pregnancy before the travel restrictions were outlined, even obstetricians are not wholly familiar with the manner in which to order testing and the appropriate window to do so. I have been asymptomatic, my blood was drawn in a period of time that exceeded the interval for accurate results (as outlined above) and was therefore inappropriately recommended/ordered, and now serial fetal ultrasonography is being implemented every few weeks.

With lack of ubiquitous knowledge about the infection, clinicians are not universally certain of the appropriate next steps when a patient presents with Zika risk factors, and therefore anxiety remains high for pregnant patients and their contacts. The Centers for Disease Control and Prevention website is the official home base, and we should review it and await their further evolving specific recommendations as more cases unfortunately accumulate.

Have you encountered any patients this year with exposure to or symptoms of Zika infection, and what, if anything, have you outlined for them?

We want to know your views! Tell us what you think.

Inundating our popular and academic media circles is information regarding the Zika virus. A recent article by Farahnik et al in the Journal of the American Academy of Dermatology (2016;74:1286-1287) briefly outlines what is known about Zika infection thus far and its dermatologic manifestations. Pairing this article with Centers for Disease Control and Prevention guidelines on the topic, we are presented with an evolving introduction to this new entity. Here’s what we know:

What’s the issue?

As with any new outbreak, the applicability to the general population and true risks remain to be seen. Each of our clinics recalls the stark changes in patient intake and screening questions with infections as ubiquitous as methicillin-resistant Staphylococcus aureus to much rarer exposures such as Ebola virus, each with progressive understanding of risk groups, disease manifestations, and eradication and prevention measures.

By mid-June 2016, 30 hits on PubMed addressing Zika had already been cited just within the month, outlining various aspects of the infection, and many specialties, particularly neurology, obstetrics, primary care, infectious disease, and dermatology, are weighing in. Unfortunately, the majority of cases of primary Zika infection do not manifest with skin or systemic symptoms, and even cases that do are nonspecific, exanthematous, and flulike.

Vague as it may be so far, it is nonetheless imperative that clinicians be familiar with what is concretely known about Zika virus and acquaint ourselves with the travel distribution and restrictions, disease risk factors, known sequelae, testing availability and limitations, and reporting guidelines. From personal experience, as I traveled to Belize earlier this year during my first trimester of pregnancy before the travel restrictions were outlined, even obstetricians are not wholly familiar with the manner in which to order testing and the appropriate window to do so. I have been asymptomatic, my blood was drawn in a period of time that exceeded the interval for accurate results (as outlined above) and was therefore inappropriately recommended/ordered, and now serial fetal ultrasonography is being implemented every few weeks.

With lack of ubiquitous knowledge about the infection, clinicians are not universally certain of the appropriate next steps when a patient presents with Zika risk factors, and therefore anxiety remains high for pregnant patients and their contacts. The Centers for Disease Control and Prevention website is the official home base, and we should review it and await their further evolving specific recommendations as more cases unfortunately accumulate.

Have you encountered any patients this year with exposure to or symptoms of Zika infection, and what, if anything, have you outlined for them?

We want to know your views! Tell us what you think.

Inundating our popular and academic media circles is information regarding the Zika virus. A recent article by Farahnik et al in the Journal of the American Academy of Dermatology (2016;74:1286-1287) briefly outlines what is known about Zika infection thus far and its dermatologic manifestations. Pairing this article with Centers for Disease Control and Prevention guidelines on the topic, we are presented with an evolving introduction to this new entity. Here’s what we know:

What’s the issue?

As with any new outbreak, the applicability to the general population and true risks remain to be seen. Each of our clinics recalls the stark changes in patient intake and screening questions with infections as ubiquitous as methicillin-resistant Staphylococcus aureus to much rarer exposures such as Ebola virus, each with progressive understanding of risk groups, disease manifestations, and eradication and prevention measures.

By mid-June 2016, 30 hits on PubMed addressing Zika had already been cited just within the month, outlining various aspects of the infection, and many specialties, particularly neurology, obstetrics, primary care, infectious disease, and dermatology, are weighing in. Unfortunately, the majority of cases of primary Zika infection do not manifest with skin or systemic symptoms, and even cases that do are nonspecific, exanthematous, and flulike.

Vague as it may be so far, it is nonetheless imperative that clinicians be familiar with what is concretely known about Zika virus and acquaint ourselves with the travel distribution and restrictions, disease risk factors, known sequelae, testing availability and limitations, and reporting guidelines. From personal experience, as I traveled to Belize earlier this year during my first trimester of pregnancy before the travel restrictions were outlined, even obstetricians are not wholly familiar with the manner in which to order testing and the appropriate window to do so. I have been asymptomatic, my blood was drawn in a period of time that exceeded the interval for accurate results (as outlined above) and was therefore inappropriately recommended/ordered, and now serial fetal ultrasonography is being implemented every few weeks.

With lack of ubiquitous knowledge about the infection, clinicians are not universally certain of the appropriate next steps when a patient presents with Zika risk factors, and therefore anxiety remains high for pregnant patients and their contacts. The Centers for Disease Control and Prevention website is the official home base, and we should review it and await their further evolving specific recommendations as more cases unfortunately accumulate.

Have you encountered any patients this year with exposure to or symptoms of Zika infection, and what, if anything, have you outlined for them?

We want to know your views! Tell us what you think.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

To the Editor:

A 52-year-old man presented with recalcitrant dermatitis of 6 years’ duration. He was otherwise in excellent health. On initial presentation, physical examination revealed symmetrical, erythematous, blanching plaques with areas of erosions and overlying hemorrhagic crust on the eyebrows, scalp, back, dorsal aspects of the hands, axillae, abdomen (Figure), buttocks, groin, scrotum, pubis, and lower legs. Some areas showed slight necrosis. He denied any fevers, chills, night sweats, cough, chest pain, shortness of breath, dizziness, lightheadedness, weight loss, or appetite change.

Throughout the disease course the patient had visited numerous dermatologists seeking treatment. He had response to higher doses of oral prednisone (80 mg taper), but the condition would recur at the end of an extended taper. Treatment with narrowband UVB, mycophenolate mofetil, methotrexate, acitretin, topical clobetasol, and topical pimecrolimus provided no relief. Eventually he was placed on azathioprine 100 mg twice daily, which led to near-complete resolution. Outbreaks continued every few months and required courses of prednisone.

Multiple biopsies over the years revealed subacute spongiotic or psoriasiform dermatitis. At multiple visits it was noted that during flares there were areas of crusting and mild necrosis, which led to an extensive biochemical investigation. The glucagon level was markedly elevated at 630 ng/L (reference range, 40–130 ng/L), as was insulin at 71 μIU/mL (reference range, 6–27 μIU/mL). Complete blood cell counts over the disease course showed mild normochromic normocytic anemia. The abnormal laboratory findings led to computed tomography of the abdomen, which revealed a mass in the body of the pancreas measuring 3×3.8 cm. After computed tomography, the patient underwent a laparoscopic distal pancreatectomy and splenectomy. Histologic examination revealed a well-differentiated pancreatic endocrine tumor (glucagonoma) confined to the pancreas. After the surgery, the patient’s rash resolved within a few days and he discontinued all medications.

Diagnosis of glucagonomas often is delayed due to their rarity and lack of classical signs and symptoms. The distribution of the lesions seen in necrolytic migratory erythema (NME) usually involves the inguinal crease, perineum, lower extremities, buttocks, and other intertriginous areas.¹ Our patient had involvement in the typical distribution but also had involvement of the scalp, face, and upper body. The typical histology for NME is crusted psoriasiform dermatitis with a tendency for the upper epidermis to have necrosis and a vacuolated pale epidermis.² Our patient’s histologic findings were less specific showing epidermal spongiosis with a scant lymphocytic infiltrate and at times acanthosis. The lack of classical skin findings and histology delayed diagnosis. In more than 50% of patients, metastasis has already occurred by the time the patient is diagnosed.³ Treatment is aimed at complete removal of the pancreatic tumor, which typically leads to a rapid improvement in symptoms. For patients unable to undergo surgery, chemotherapy agents and octreotide are used; unfortunately, symptoms may persist.⁴ The response to azathioprine in our patient suggests it is a possible alternate therapy for those with persistent NME.

This patient highlights the difficulty of diagnosing a glucagonoma when the only clinical manifestation may be NME. Moreover, skin biopsies that can sometimes be diagnostic may be nonspecific. This patient also shows a potential benefit of azathioprine in the treatment of NME.

To the Editor:

A 52-year-old man presented with recalcitrant dermatitis of 6 years’ duration. He was otherwise in excellent health. On initial presentation, physical examination revealed symmetrical, erythematous, blanching plaques with areas of erosions and overlying hemorrhagic crust on the eyebrows, scalp, back, dorsal aspects of the hands, axillae, abdomen (Figure), buttocks, groin, scrotum, pubis, and lower legs. Some areas showed slight necrosis. He denied any fevers, chills, night sweats, cough, chest pain, shortness of breath, dizziness, lightheadedness, weight loss, or appetite change.

Throughout the disease course the patient had visited numerous dermatologists seeking treatment. He had response to higher doses of oral prednisone (80 mg taper), but the condition would recur at the end of an extended taper. Treatment with narrowband UVB, mycophenolate mofetil, methotrexate, acitretin, topical clobetasol, and topical pimecrolimus provided no relief. Eventually he was placed on azathioprine 100 mg twice daily, which led to near-complete resolution. Outbreaks continued every few months and required courses of prednisone.

Multiple biopsies over the years revealed subacute spongiotic or psoriasiform dermatitis. At multiple visits it was noted that during flares there were areas of crusting and mild necrosis, which led to an extensive biochemical investigation. The glucagon level was markedly elevated at 630 ng/L (reference range, 40–130 ng/L), as was insulin at 71 μIU/mL (reference range, 6–27 μIU/mL). Complete blood cell counts over the disease course showed mild normochromic normocytic anemia. The abnormal laboratory findings led to computed tomography of the abdomen, which revealed a mass in the body of the pancreas measuring 3×3.8 cm. After computed tomography, the patient underwent a laparoscopic distal pancreatectomy and splenectomy. Histologic examination revealed a well-differentiated pancreatic endocrine tumor (glucagonoma) confined to the pancreas. After the surgery, the patient’s rash resolved within a few days and he discontinued all medications.

Diagnosis of glucagonomas often is delayed due to their rarity and lack of classical signs and symptoms. The distribution of the lesions seen in necrolytic migratory erythema (NME) usually involves the inguinal crease, perineum, lower extremities, buttocks, and other intertriginous areas.¹ Our patient had involvement in the typical distribution but also had involvement of the scalp, face, and upper body. The typical histology for NME is crusted psoriasiform dermatitis with a tendency for the upper epidermis to have necrosis and a vacuolated pale epidermis.² Our patient’s histologic findings were less specific showing epidermal spongiosis with a scant lymphocytic infiltrate and at times acanthosis. The lack of classical skin findings and histology delayed diagnosis. In more than 50% of patients, metastasis has already occurred by the time the patient is diagnosed.³ Treatment is aimed at complete removal of the pancreatic tumor, which typically leads to a rapid improvement in symptoms. For patients unable to undergo surgery, chemotherapy agents and octreotide are used; unfortunately, symptoms may persist.⁴ The response to azathioprine in our patient suggests it is a possible alternate therapy for those with persistent NME.

This patient highlights the difficulty of diagnosing a glucagonoma when the only clinical manifestation may be NME. Moreover, skin biopsies that can sometimes be diagnostic may be nonspecific. This patient also shows a potential benefit of azathioprine in the treatment of NME.

To the Editor:

A 52-year-old man presented with recalcitrant dermatitis of 6 years’ duration. He was otherwise in excellent health. On initial presentation, physical examination revealed symmetrical, erythematous, blanching plaques with areas of erosions and overlying hemorrhagic crust on the eyebrows, scalp, back, dorsal aspects of the hands, axillae, abdomen (Figure), buttocks, groin, scrotum, pubis, and lower legs. Some areas showed slight necrosis. He denied any fevers, chills, night sweats, cough, chest pain, shortness of breath, dizziness, lightheadedness, weight loss, or appetite change.

Throughout the disease course the patient had visited numerous dermatologists seeking treatment. He had response to higher doses of oral prednisone (80 mg taper), but the condition would recur at the end of an extended taper. Treatment with narrowband UVB, mycophenolate mofetil, methotrexate, acitretin, topical clobetasol, and topical pimecrolimus provided no relief. Eventually he was placed on azathioprine 100 mg twice daily, which led to near-complete resolution. Outbreaks continued every few months and required courses of prednisone.

Multiple biopsies over the years revealed subacute spongiotic or psoriasiform dermatitis. At multiple visits it was noted that during flares there were areas of crusting and mild necrosis, which led to an extensive biochemical investigation. The glucagon level was markedly elevated at 630 ng/L (reference range, 40–130 ng/L), as was insulin at 71 μIU/mL (reference range, 6–27 μIU/mL). Complete blood cell counts over the disease course showed mild normochromic normocytic anemia. The abnormal laboratory findings led to computed tomography of the abdomen, which revealed a mass in the body of the pancreas measuring 3×3.8 cm. After computed tomography, the patient underwent a laparoscopic distal pancreatectomy and splenectomy. Histologic examination revealed a well-differentiated pancreatic endocrine tumor (glucagonoma) confined to the pancreas. After the surgery, the patient’s rash resolved within a few days and he discontinued all medications.

Diagnosis of glucagonomas often is delayed due to their rarity and lack of classical signs and symptoms. The distribution of the lesions seen in necrolytic migratory erythema (NME) usually involves the inguinal crease, perineum, lower extremities, buttocks, and other intertriginous areas.¹ Our patient had involvement in the typical distribution but also had involvement of the scalp, face, and upper body. The typical histology for NME is crusted psoriasiform dermatitis with a tendency for the upper epidermis to have necrosis and a vacuolated pale epidermis.² Our patient’s histologic findings were less specific showing epidermal spongiosis with a scant lymphocytic infiltrate and at times acanthosis. The lack of classical skin findings and histology delayed diagnosis. In more than 50% of patients, metastasis has already occurred by the time the patient is diagnosed.³ Treatment is aimed at complete removal of the pancreatic tumor, which typically leads to a rapid improvement in symptoms. For patients unable to undergo surgery, chemotherapy agents and octreotide are used; unfortunately, symptoms may persist.⁴ The response to azathioprine in our patient suggests it is a possible alternate therapy for those with persistent NME.

This patient highlights the difficulty of diagnosing a glucagonoma when the only clinical manifestation may be NME. Moreover, skin biopsies that can sometimes be diagnostic may be nonspecific. This patient also shows a potential benefit of azathioprine in the treatment of NME.

In parts 1 and 2 of this series on atopic dermatitis (AD),^1,2 the current putative pathogenesis, scoring systems for severity grading, and epidemiology were reviewed. Part 3 reviews the differential diagnosis, with an emphasis on the difficulty of differentiation from some rare but notable illnesses, as well as the recently expanding data on comorbidities that identify AD as a multisystem disorder with widespread health implications for the patient.

Differential Diagnosis for Pediatric AD

The differential diagnosis for pediatric AD includes chronic dermatoses (eg, seborrheic dermatitis, psoriasis), congenital disorders (eg, Netherton syndrome), malignant diseases (eg, cutaneous T-cell lymphoma [CTCL]), immunodeficiencies, infections, and metabolic disorders.³ Netherton syndrome must be ruled out to prevent extensive drug absorption when treating with topical calcineurin inhibitors (TCIs).⁴ Due to the presence of bamboo hairs in these patients, a hair mount may aid in the diagnosis of Netherton syndrome. Misdiagnosis of CTCL as AD may complicate the analysis of safety data on TCIs.^4,5 Multiple skin biopsies are essential in cases of suspected CTCL to provide an accurate diagnosis. Biopsy can be considered in AD cases with changing and/or unusual morphology, erythrodermic skin changes, and disease that is poorly responsive to multiple therapeutic modalities.

Comorbidities in Pediatric AD

Psychosocial Comorbidities

Pediatric AD often takes a psychological toll on patients as well as household members. Almost half of children with AD are reported to have a severely impaired quality of life (QOL).⁶ Contributing factors include fatigue, sleep disturbance, activity restriction (eg, inability to participate in sports), and depression.⁷

Chamlin et al⁸ developed the Childhood Atopic Dermatitis Impact Scale (CADIS), a 45-item instrument (refined from a 62-item prototype), to measure QOL in young children with AD and their family members. Responses were evaluated with consideration of 5 domains: symptoms and activity limitations/behaviors in children, as well as family/social function, sleep, and emotions in parents. The top 12 factors that parents found most bothersome about AD included itching/scratching, child’s pain/discomfort, sleep issues, embarrassment or worry about appearance, child’s fussiness/irritability/crying/unhappiness, helplessness/can’t control it/predict it, worry about skin infection, dryness of skin/nonsmooth skin, skin bleeding, worry about damage/scars, stares/comments of strangers and other children, and rashes/redness of skin/discoloration. Parents were asked to respond to items about their emotional health and social functioning, such as “My child’s skin condition has strained my relationship with my spouse or partner,” “My child’s skin condition makes me feel sad or depressed,” and “I am bothered by the reaction of strangers to this skin condition.”⁸

Kiebert et al⁹ found that AD patients had lower scores on the Short Form-36 Health Survey’s vitality, social functioning, and mental health subscales compared to individuals in the general population. The authors noted that anxiety in AD patients is of particular concern, as stress has been found to trigger the itch-scratch cycle, potentially setting off AD flare-ups.⁹ Family impact of AD is aggravated by disease severity. Sleeplessness, relationship stress, and time management can all cause family problems in patients with AD.⁸

In a survey of 3775 older teenagers aged 18 to 19 years (80% response rate out of 4774 prospective participants), 9.7% of participants reported having current AD.¹⁰ Suicidal ideation was higher in those with current AD than those without AD (15.5% vs 9.1%). The prevalence of suicidal ideation rose to 23.8% in those with both AD and itch. Diagnosis of AD (as determined through participant responses to the question, ‘‘Do you have, or have you had eczema?’’) was associated with mental health problems in 16.0% of those with AD compared to 10.1% of those without AD, with an especially reduced likelihood of romantic relationships for adolescent boys with AD, as measured using the Strength and Difficulties Questionnaire, which measures 4 problem domains and assesses presence of mental health issues in the past 6 months, and the Hopkins Symptom Checklist 10, which uses 10 questions to measure anxiety and depression symptoms in the past week.¹⁰

Dalgard et al¹¹ assessed whether the psychological burden of AD persists in adulthood in an international, multicenter, observational, cross-sectional study conducted in 13 European countries. Each dermatology clinic recruited 250 consecutive adult outpatients to complete a questionnaire along with a control group of 125 hospital employees without skin disease from the same institution but from different departments. The study included a total of 4994 participants (3635 patients and 1359 controls). Clinical depression and anxiety were present in 10.1% and 17.6% of patients, respectively, versus 4.3% and 11.1% of controls, respectively. The prevalence of depression and anxiety was highest in patients with leg ulcers, hand eczema, psoriasis, and AD.¹¹ This study demonstrated that the psychological comorbidities of childhood conditions such as AD may persist into adulthood.

Lymphoma

In a systematic review of the literature and a separate meta-analysis, Legendre et al¹² identified a slight increase in lymphoma among AD patients, with an uncertain but potential increase associated with topical corticosteroid application. This finding is similar to trends seen in other systemic inflammatory conditions that involve the skin, such as psoriasis, and is felt to relate to long-term inflammation.

Obesity

Obesity has been associated with a greater risk for moderate to severe AD in children.^13,14

Infections

Children with AD are at a higher risk for cutaneous infections and generalization of these infections. The leading infections would be with Staphylococcus aureus, but group A streptococci infections do occur. Herpes simplex virus, vaccinia virus or Kaposi varicelliform eruption (KVE), molluscum with or without dermatitis, and fungal infections occur less commonly but with greater morbidity, largely due to the impaired barrier and some innate reduction in cutaneous immunity.¹⁵

Atopic dermatitis in children also is associated with a higher prevalence of extracutaneous infections such as influenza, pneumonia, urinary tract infections, varicella-zoster virus, recurrent ear infections, sinus infections, sore throat, and head or chest colds.¹⁶ Children with AD and warts (human papillomavirus infection) have an even greater risk for these comorbidities.¹⁷ Warts and molluscum infections may become more extensive in children with AD.¹⁸ Generalization of herpetic infections occurs more easily in AD patients due to the impaired skin barrier, which includes generalized skin surface extension of herpes simplex virus type 1, varicella-zoster virus, and historically smallpox. A similar clinical appearance of generalized vesiculopustular lesions with fever can be seen when coxsackievirus A6 infections occur in AD patients; these conditions are called eczema herpeticum due to herpes simplex virus, KVE due to varicella-zoster virus and smallpox, and eczema coxsackium due to coxsackievirus A6,¹⁹ though some authors refer to all of these as KVE.²⁰ These generalized viral illnesses overlying AD often result in fever, malaise, pain, and life-threatening skin denudation with risk for dehydration and superinfection with S aureus.^7,18 It has been shown that the occurrence of eczema herpeticum in AD is associated with and may be caused by an inability to induce human β-defensin 2 and 3 as well as cathelicidin.²¹

Staphylococcus aureus colonization has been noted in 90% to 100% of AD cases, which can be associated with a higher eczema area and severity index score.^22-24 The role of S aureus in AD includes flare triggering through release of superantigens, leading to IL-31–induced pruritis.²⁵ Recurrent infection with either methicillin-sensitive or methicillin-resistant S aureus has been noted in AD.^18,26 Skin infections also occur in AD and appear as erosions and pustules, and coinfection with Streptococcus and Staphylococcus does occur; therefore, cultures often are needed to determine the type of bacteria present on the skin in severe cases and when infection is suspected.²⁷ Perianal bacterial dermatitis is a variant of infected AD occurring in the anal/groin area that is associated with S aureus and/or streptococcal superinfection in which topical corticosteroids and topical anti-infectives can be used. In some severe cases, oral antibiotics may be needed.²⁸

Injury/Hyperactivity

Children aged 0 to 5 years with AD carry an increased risk for injuries requiring medical attention, with association in part due to attention deficit disorder, depression, and anxiety. Antihistamines are believed to aggravate this issue by promoting daytime somnolence²⁹; however, pruritus-induced sleep disturbances in AD also may be responsible for daytime somnolence.³⁰

Contact Allergy and Sensitization

Children with AD may become sensitized to environmental allergens through delayed-type hypersensitivity. The presumed mechanism is that these agents include ingredients added into applied medicaments and application occurs over an impaired skin barrier allowing for absorption and greater risk of antigen presentation. Approximately 50% of children with difficult-to-control AD will react to 1 or more epicutaneous allergens, and patch testing can be performed to identify relevant allergens that can improve skin severity.⁷ Severe dermatitis and id generalized hypersensitivity reactions in patients with AD and nickel allergic contact dermatitis have been described and may aggravate underlying AD.³¹

Family Burden of AD

Parents or caregivers of children with moderate and severe AD spend nearly 3 hours a day caring for their child’s skin and experience QOL impairments including lack of sleep and/or privacy, often due to cosleeping; treatment-related financial expenditures; and feelings of hopelessness, guilt, and depression.⁷

Steroid Phobia

Steroid phobia is the fear of topical application of corticosteroids resulting in systemic side effects including unrealistic fears (eg, fear that the child will develop muscles such as an anabolic steroid user) as well as realistic but statistically low-risk fears (eg, fear of systemic absorption). These fears often result in underutilization of prescribed topical corticosteroid therapies and undertreatment of children with AD.^32,33

Financial Burden

The cost of AD can be high in the United States, with adult data demonstrating costs ranging from $371 to $489 per person.³⁴ The last published cost data for pediatric AD was from 2003, with an average cost of $219 per year.³⁵ Costs include time lost from work, household purchases (eg, skin care products), and co-pays for visits and medication, with an estimated average expenditure per person (SE) of $601.06 ($137.26) annually in 2012.³⁶ The cost of ambulatory care and emergency department visits for AD in children in the United States in 1993 was estimated at $364 million.^37-39 In 2002, Ellis et al⁴⁰ estimated the overall cost of AD to be between $900 million and $3.8 billion in the United States (1997-1998) based on projections from claims, prescriptions, and comorbidities reported to a private insurer and Medicaid. Ellis et al⁴¹ further determined that topical tacrolimus was similar in cost to high-potency corticosteroids.

Pediatric AD often progresses to adult hand eczema and leads to further morbidity, especially in health care workers.⁴² Kemp⁴³ reviewed the cost of AD in children and concluded that AD was a condition with major handicap with personal, financial, and social effects. A cost review of studies conducted in 163,700 children with AD showed that costs related to AD totaled $316.7 million per year. The author concluded that there were substantial psychosocial and financial stresses associated with pediatric AD but no clear path to potential reduction in related costs.⁴³

Sleep Disturbances

Sleep disturbances are common in pediatric AD patients. Pruritus usually is exacerbated at bedtime due to reduced humidity and lack of distractions to prevent scratching. Sleep deprivation has a substantial impact on both the patient and his/her household. Parental frustration increases with sleep disturbance.^18,44 Sleep deprivation is associated with greater severity, both because it is one of the most difficult aspects of illness and because the associated pruritus makes for greater damage done to the skin through injurious scratching.

Sleep disturbances also may interfere with growth and overnight release of growth hormones.^18,44 This latter issue can result in reduced linear growth velocity. Furthermore, sleep deprivation can cause increased risk of accidents and poor school performance.^18,44,45

Many children do not outgrow AD. In adults, AD-associated sleep deprivation has been shown to have an association with fatigue, regular daytime sleepiness, and regular insomnia, correlating to number of sick days, doctor visits, and poorer overall health status.⁴⁵

Inadequate Disease Control

Inadequate disease control has been described by Eichenfeld⁴⁶ as an important issue in AD at this time. Untreated, undertreated, and improperly treated AD are important issues affecting long-term AD care. He further cited steroid phobia as a contributor to undertreatment.⁴⁶ Fleischer⁴⁷ has cited the black box warning present on TCIs as a further deterrent to adequate therapeutic control in our current therapeutic paradigm. Undertreatment may result in uncontrolled disease activity, impaired QOL, infections, and sleep disturbances. The role of undertreatment as a driver of the atopic march is unknown.

Conclusion

Atopic dermatitis is a multisystem disorder that has wide-reaching comorbidities and may mimic a variety of skin conditions. The topic of comorbidities is new and emerging and bears further review to define risk factors, prevention strategies, and long-term monitoring requirements.

In parts 1 and 2 of this series on atopic dermatitis (AD),^1,2 the current putative pathogenesis, scoring systems for severity grading, and epidemiology were reviewed. Part 3 reviews the differential diagnosis, with an emphasis on the difficulty of differentiation from some rare but notable illnesses, as well as the recently expanding data on comorbidities that identify AD as a multisystem disorder with widespread health implications for the patient.

Differential Diagnosis for Pediatric AD

The differential diagnosis for pediatric AD includes chronic dermatoses (eg, seborrheic dermatitis, psoriasis), congenital disorders (eg, Netherton syndrome), malignant diseases (eg, cutaneous T-cell lymphoma [CTCL]), immunodeficiencies, infections, and metabolic disorders.³ Netherton syndrome must be ruled out to prevent extensive drug absorption when treating with topical calcineurin inhibitors (TCIs).⁴ Due to the presence of bamboo hairs in these patients, a hair mount may aid in the diagnosis of Netherton syndrome. Misdiagnosis of CTCL as AD may complicate the analysis of safety data on TCIs.^4,5 Multiple skin biopsies are essential in cases of suspected CTCL to provide an accurate diagnosis. Biopsy can be considered in AD cases with changing and/or unusual morphology, erythrodermic skin changes, and disease that is poorly responsive to multiple therapeutic modalities.

Comorbidities in Pediatric AD

Psychosocial Comorbidities

Pediatric AD often takes a psychological toll on patients as well as household members. Almost half of children with AD are reported to have a severely impaired quality of life (QOL).⁶ Contributing factors include fatigue, sleep disturbance, activity restriction (eg, inability to participate in sports), and depression.⁷

Chamlin et al⁸ developed the Childhood Atopic Dermatitis Impact Scale (CADIS), a 45-item instrument (refined from a 62-item prototype), to measure QOL in young children with AD and their family members. Responses were evaluated with consideration of 5 domains: symptoms and activity limitations/behaviors in children, as well as family/social function, sleep, and emotions in parents. The top 12 factors that parents found most bothersome about AD included itching/scratching, child’s pain/discomfort, sleep issues, embarrassment or worry about appearance, child’s fussiness/irritability/crying/unhappiness, helplessness/can’t control it/predict it, worry about skin infection, dryness of skin/nonsmooth skin, skin bleeding, worry about damage/scars, stares/comments of strangers and other children, and rashes/redness of skin/discoloration. Parents were asked to respond to items about their emotional health and social functioning, such as “My child’s skin condition has strained my relationship with my spouse or partner,” “My child’s skin condition makes me feel sad or depressed,” and “I am bothered by the reaction of strangers to this skin condition.”⁸

Kiebert et al⁹ found that AD patients had lower scores on the Short Form-36 Health Survey’s vitality, social functioning, and mental health subscales compared to individuals in the general population. The authors noted that anxiety in AD patients is of particular concern, as stress has been found to trigger the itch-scratch cycle, potentially setting off AD flare-ups.⁹ Family impact of AD is aggravated by disease severity. Sleeplessness, relationship stress, and time management can all cause family problems in patients with AD.⁸

In a survey of 3775 older teenagers aged 18 to 19 years (80% response rate out of 4774 prospective participants), 9.7% of participants reported having current AD.¹⁰ Suicidal ideation was higher in those with current AD than those without AD (15.5% vs 9.1%). The prevalence of suicidal ideation rose to 23.8% in those with both AD and itch. Diagnosis of AD (as determined through participant responses to the question, ‘‘Do you have, or have you had eczema?’’) was associated with mental health problems in 16.0% of those with AD compared to 10.1% of those without AD, with an especially reduced likelihood of romantic relationships for adolescent boys with AD, as measured using the Strength and Difficulties Questionnaire, which measures 4 problem domains and assesses presence of mental health issues in the past 6 months, and the Hopkins Symptom Checklist 10, which uses 10 questions to measure anxiety and depression symptoms in the past week.¹⁰

Dalgard et al¹¹ assessed whether the psychological burden of AD persists in adulthood in an international, multicenter, observational, cross-sectional study conducted in 13 European countries. Each dermatology clinic recruited 250 consecutive adult outpatients to complete a questionnaire along with a control group of 125 hospital employees without skin disease from the same institution but from different departments. The study included a total of 4994 participants (3635 patients and 1359 controls). Clinical depression and anxiety were present in 10.1% and 17.6% of patients, respectively, versus 4.3% and 11.1% of controls, respectively. The prevalence of depression and anxiety was highest in patients with leg ulcers, hand eczema, psoriasis, and AD.¹¹ This study demonstrated that the psychological comorbidities of childhood conditions such as AD may persist into adulthood.

Lymphoma

In a systematic review of the literature and a separate meta-analysis, Legendre et al¹² identified a slight increase in lymphoma among AD patients, with an uncertain but potential increase associated with topical corticosteroid application. This finding is similar to trends seen in other systemic inflammatory conditions that involve the skin, such as psoriasis, and is felt to relate to long-term inflammation.

Obesity

Obesity has been associated with a greater risk for moderate to severe AD in children.^13,14

Infections

Children with AD are at a higher risk for cutaneous infections and generalization of these infections. The leading infections would be with Staphylococcus aureus, but group A streptococci infections do occur. Herpes simplex virus, vaccinia virus or Kaposi varicelliform eruption (KVE), molluscum with or without dermatitis, and fungal infections occur less commonly but with greater morbidity, largely due to the impaired barrier and some innate reduction in cutaneous immunity.¹⁵

Atopic dermatitis in children also is associated with a higher prevalence of extracutaneous infections such as influenza, pneumonia, urinary tract infections, varicella-zoster virus, recurrent ear infections, sinus infections, sore throat, and head or chest colds.¹⁶ Children with AD and warts (human papillomavirus infection) have an even greater risk for these comorbidities.¹⁷ Warts and molluscum infections may become more extensive in children with AD.¹⁸ Generalization of herpetic infections occurs more easily in AD patients due to the impaired skin barrier, which includes generalized skin surface extension of herpes simplex virus type 1, varicella-zoster virus, and historically smallpox. A similar clinical appearance of generalized vesiculopustular lesions with fever can be seen when coxsackievirus A6 infections occur in AD patients; these conditions are called eczema herpeticum due to herpes simplex virus, KVE due to varicella-zoster virus and smallpox, and eczema coxsackium due to coxsackievirus A6,¹⁹ though some authors refer to all of these as KVE.²⁰ These generalized viral illnesses overlying AD often result in fever, malaise, pain, and life-threatening skin denudation with risk for dehydration and superinfection with S aureus.^7,18 It has been shown that the occurrence of eczema herpeticum in AD is associated with and may be caused by an inability to induce human β-defensin 2 and 3 as well as cathelicidin.²¹

Staphylococcus aureus colonization has been noted in 90% to 100% of AD cases, which can be associated with a higher eczema area and severity index score.^22-24 The role of S aureus in AD includes flare triggering through release of superantigens, leading to IL-31–induced pruritis.²⁵ Recurrent infection with either methicillin-sensitive or methicillin-resistant S aureus has been noted in AD.^18,26 Skin infections also occur in AD and appear as erosions and pustules, and coinfection with Streptococcus and Staphylococcus does occur; therefore, cultures often are needed to determine the type of bacteria present on the skin in severe cases and when infection is suspected.²⁷ Perianal bacterial dermatitis is a variant of infected AD occurring in the anal/groin area that is associated with S aureus and/or streptococcal superinfection in which topical corticosteroids and topical anti-infectives can be used. In some severe cases, oral antibiotics may be needed.²⁸

Injury/Hyperactivity

Children aged 0 to 5 years with AD carry an increased risk for injuries requiring medical attention, with association in part due to attention deficit disorder, depression, and anxiety. Antihistamines are believed to aggravate this issue by promoting daytime somnolence²⁹; however, pruritus-induced sleep disturbances in AD also may be responsible for daytime somnolence.³⁰

Contact Allergy and Sensitization

Children with AD may become sensitized to environmental allergens through delayed-type hypersensitivity. The presumed mechanism is that these agents include ingredients added into applied medicaments and application occurs over an impaired skin barrier allowing for absorption and greater risk of antigen presentation. Approximately 50% of children with difficult-to-control AD will react to 1 or more epicutaneous allergens, and patch testing can be performed to identify relevant allergens that can improve skin severity.⁷ Severe dermatitis and id generalized hypersensitivity reactions in patients with AD and nickel allergic contact dermatitis have been described and may aggravate underlying AD.³¹

Family Burden of AD

Parents or caregivers of children with moderate and severe AD spend nearly 3 hours a day caring for their child’s skin and experience QOL impairments including lack of sleep and/or privacy, often due to cosleeping; treatment-related financial expenditures; and feelings of hopelessness, guilt, and depression.⁷

Steroid Phobia

Steroid phobia is the fear of topical application of corticosteroids resulting in systemic side effects including unrealistic fears (eg, fear that the child will develop muscles such as an anabolic steroid user) as well as realistic but statistically low-risk fears (eg, fear of systemic absorption). These fears often result in underutilization of prescribed topical corticosteroid therapies and undertreatment of children with AD.^32,33

Financial Burden

The cost of AD can be high in the United States, with adult data demonstrating costs ranging from $371 to $489 per person.³⁴ The last published cost data for pediatric AD was from 2003, with an average cost of $219 per year.³⁵ Costs include time lost from work, household purchases (eg, skin care products), and co-pays for visits and medication, with an estimated average expenditure per person (SE) of $601.06 ($137.26) annually in 2012.³⁶ The cost of ambulatory care and emergency department visits for AD in children in the United States in 1993 was estimated at $364 million.^37-39 In 2002, Ellis et al⁴⁰ estimated the overall cost of AD to be between $900 million and $3.8 billion in the United States (1997-1998) based on projections from claims, prescriptions, and comorbidities reported to a private insurer and Medicaid. Ellis et al⁴¹ further determined that topical tacrolimus was similar in cost to high-potency corticosteroids.

Pediatric AD often progresses to adult hand eczema and leads to further morbidity, especially in health care workers.⁴² Kemp⁴³ reviewed the cost of AD in children and concluded that AD was a condition with major handicap with personal, financial, and social effects. A cost review of studies conducted in 163,700 children with AD showed that costs related to AD totaled $316.7 million per year. The author concluded that there were substantial psychosocial and financial stresses associated with pediatric AD but no clear path to potential reduction in related costs.⁴³

Sleep Disturbances

Sleep disturbances are common in pediatric AD patients. Pruritus usually is exacerbated at bedtime due to reduced humidity and lack of distractions to prevent scratching. Sleep deprivation has a substantial impact on both the patient and his/her household. Parental frustration increases with sleep disturbance.^18,44 Sleep deprivation is associated with greater severity, both because it is one of the most difficult aspects of illness and because the associated pruritus makes for greater damage done to the skin through injurious scratching.

Sleep disturbances also may interfere with growth and overnight release of growth hormones.^18,44 This latter issue can result in reduced linear growth velocity. Furthermore, sleep deprivation can cause increased risk of accidents and poor school performance.^18,44,45

Many children do not outgrow AD. In adults, AD-associated sleep deprivation has been shown to have an association with fatigue, regular daytime sleepiness, and regular insomnia, correlating to number of sick days, doctor visits, and poorer overall health status.⁴⁵

Inadequate Disease Control

Inadequate disease control has been described by Eichenfeld⁴⁶ as an important issue in AD at this time. Untreated, undertreated, and improperly treated AD are important issues affecting long-term AD care. He further cited steroid phobia as a contributor to undertreatment.⁴⁶ Fleischer⁴⁷ has cited the black box warning present on TCIs as a further deterrent to adequate therapeutic control in our current therapeutic paradigm. Undertreatment may result in uncontrolled disease activity, impaired QOL, infections, and sleep disturbances. The role of undertreatment as a driver of the atopic march is unknown.

Conclusion

Atopic dermatitis is a multisystem disorder that has wide-reaching comorbidities and may mimic a variety of skin conditions. The topic of comorbidities is new and emerging and bears further review to define risk factors, prevention strategies, and long-term monitoring requirements.

In parts 1 and 2 of this series on atopic dermatitis (AD),^1,2 the current putative pathogenesis, scoring systems for severity grading, and epidemiology were reviewed. Part 3 reviews the differential diagnosis, with an emphasis on the difficulty of differentiation from some rare but notable illnesses, as well as the recently expanding data on comorbidities that identify AD as a multisystem disorder with widespread health implications for the patient.

Differential Diagnosis for Pediatric AD

The differential diagnosis for pediatric AD includes chronic dermatoses (eg, seborrheic dermatitis, psoriasis), congenital disorders (eg, Netherton syndrome), malignant diseases (eg, cutaneous T-cell lymphoma [CTCL]), immunodeficiencies, infections, and metabolic disorders.³ Netherton syndrome must be ruled out to prevent extensive drug absorption when treating with topical calcineurin inhibitors (TCIs).⁴ Due to the presence of bamboo hairs in these patients, a hair mount may aid in the diagnosis of Netherton syndrome. Misdiagnosis of CTCL as AD may complicate the analysis of safety data on TCIs.^4,5 Multiple skin biopsies are essential in cases of suspected CTCL to provide an accurate diagnosis. Biopsy can be considered in AD cases with changing and/or unusual morphology, erythrodermic skin changes, and disease that is poorly responsive to multiple therapeutic modalities.

Comorbidities in Pediatric AD

Psychosocial Comorbidities

Pediatric AD often takes a psychological toll on patients as well as household members. Almost half of children with AD are reported to have a severely impaired quality of life (QOL).⁶ Contributing factors include fatigue, sleep disturbance, activity restriction (eg, inability to participate in sports), and depression.⁷

Chamlin et al⁸ developed the Childhood Atopic Dermatitis Impact Scale (CADIS), a 45-item instrument (refined from a 62-item prototype), to measure QOL in young children with AD and their family members. Responses were evaluated with consideration of 5 domains: symptoms and activity limitations/behaviors in children, as well as family/social function, sleep, and emotions in parents. The top 12 factors that parents found most bothersome about AD included itching/scratching, child’s pain/discomfort, sleep issues, embarrassment or worry about appearance, child’s fussiness/irritability/crying/unhappiness, helplessness/can’t control it/predict it, worry about skin infection, dryness of skin/nonsmooth skin, skin bleeding, worry about damage/scars, stares/comments of strangers and other children, and rashes/redness of skin/discoloration. Parents were asked to respond to items about their emotional health and social functioning, such as “My child’s skin condition has strained my relationship with my spouse or partner,” “My child’s skin condition makes me feel sad or depressed,” and “I am bothered by the reaction of strangers to this skin condition.”⁸

Kiebert et al⁹ found that AD patients had lower scores on the Short Form-36 Health Survey’s vitality, social functioning, and mental health subscales compared to individuals in the general population. The authors noted that anxiety in AD patients is of particular concern, as stress has been found to trigger the itch-scratch cycle, potentially setting off AD flare-ups.⁹ Family impact of AD is aggravated by disease severity. Sleeplessness, relationship stress, and time management can all cause family problems in patients with AD.⁸

In a survey of 3775 older teenagers aged 18 to 19 years (80% response rate out of 4774 prospective participants), 9.7% of participants reported having current AD.¹⁰ Suicidal ideation was higher in those with current AD than those without AD (15.5% vs 9.1%). The prevalence of suicidal ideation rose to 23.8% in those with both AD and itch. Diagnosis of AD (as determined through participant responses to the question, ‘‘Do you have, or have you had eczema?’’) was associated with mental health problems in 16.0% of those with AD compared to 10.1% of those without AD, with an especially reduced likelihood of romantic relationships for adolescent boys with AD, as measured using the Strength and Difficulties Questionnaire, which measures 4 problem domains and assesses presence of mental health issues in the past 6 months, and the Hopkins Symptom Checklist 10, which uses 10 questions to measure anxiety and depression symptoms in the past week.¹⁰

Dalgard et al¹¹ assessed whether the psychological burden of AD persists in adulthood in an international, multicenter, observational, cross-sectional study conducted in 13 European countries. Each dermatology clinic recruited 250 consecutive adult outpatients to complete a questionnaire along with a control group of 125 hospital employees without skin disease from the same institution but from different departments. The study included a total of 4994 participants (3635 patients and 1359 controls). Clinical depression and anxiety were present in 10.1% and 17.6% of patients, respectively, versus 4.3% and 11.1% of controls, respectively. The prevalence of depression and anxiety was highest in patients with leg ulcers, hand eczema, psoriasis, and AD.¹¹ This study demonstrated that the psychological comorbidities of childhood conditions such as AD may persist into adulthood.

Lymphoma

In a systematic review of the literature and a separate meta-analysis, Legendre et al¹² identified a slight increase in lymphoma among AD patients, with an uncertain but potential increase associated with topical corticosteroid application. This finding is similar to trends seen in other systemic inflammatory conditions that involve the skin, such as psoriasis, and is felt to relate to long-term inflammation.

Obesity

Obesity has been associated with a greater risk for moderate to severe AD in children.^13,14

Infections

Children with AD are at a higher risk for cutaneous infections and generalization of these infections. The leading infections would be with Staphylococcus aureus, but group A streptococci infections do occur. Herpes simplex virus, vaccinia virus or Kaposi varicelliform eruption (KVE), molluscum with or without dermatitis, and fungal infections occur less commonly but with greater morbidity, largely due to the impaired barrier and some innate reduction in cutaneous immunity.¹⁵

Atopic dermatitis in children also is associated with a higher prevalence of extracutaneous infections such as influenza, pneumonia, urinary tract infections, varicella-zoster virus, recurrent ear infections, sinus infections, sore throat, and head or chest colds.¹⁶ Children with AD and warts (human papillomavirus infection) have an even greater risk for these comorbidities.¹⁷ Warts and molluscum infections may become more extensive in children with AD.¹⁸ Generalization of herpetic infections occurs more easily in AD patients due to the impaired skin barrier, which includes generalized skin surface extension of herpes simplex virus type 1, varicella-zoster virus, and historically smallpox. A similar clinical appearance of generalized vesiculopustular lesions with fever can be seen when coxsackievirus A6 infections occur in AD patients; these conditions are called eczema herpeticum due to herpes simplex virus, KVE due to varicella-zoster virus and smallpox, and eczema coxsackium due to coxsackievirus A6,¹⁹ though some authors refer to all of these as KVE.²⁰ These generalized viral illnesses overlying AD often result in fever, malaise, pain, and life-threatening skin denudation with risk for dehydration and superinfection with S aureus.^7,18 It has been shown that the occurrence of eczema herpeticum in AD is associated with and may be caused by an inability to induce human β-defensin 2 and 3 as well as cathelicidin.²¹

Staphylococcus aureus colonization has been noted in 90% to 100% of AD cases, which can be associated with a higher eczema area and severity index score.^22-24 The role of S aureus in AD includes flare triggering through release of superantigens, leading to IL-31–induced pruritis.²⁵ Recurrent infection with either methicillin-sensitive or methicillin-resistant S aureus has been noted in AD.^18,26 Skin infections also occur in AD and appear as erosions and pustules, and coinfection with Streptococcus and Staphylococcus does occur; therefore, cultures often are needed to determine the type of bacteria present on the skin in severe cases and when infection is suspected.²⁷ Perianal bacterial dermatitis is a variant of infected AD occurring in the anal/groin area that is associated with S aureus and/or streptococcal superinfection in which topical corticosteroids and topical anti-infectives can be used. In some severe cases, oral antibiotics may be needed.²⁸

Injury/Hyperactivity

Children aged 0 to 5 years with AD carry an increased risk for injuries requiring medical attention, with association in part due to attention deficit disorder, depression, and anxiety. Antihistamines are believed to aggravate this issue by promoting daytime somnolence²⁹; however, pruritus-induced sleep disturbances in AD also may be responsible for daytime somnolence.³⁰

Contact Allergy and Sensitization

Children with AD may become sensitized to environmental allergens through delayed-type hypersensitivity. The presumed mechanism is that these agents include ingredients added into applied medicaments and application occurs over an impaired skin barrier allowing for absorption and greater risk of antigen presentation. Approximately 50% of children with difficult-to-control AD will react to 1 or more epicutaneous allergens, and patch testing can be performed to identify relevant allergens that can improve skin severity.⁷ Severe dermatitis and id generalized hypersensitivity reactions in patients with AD and nickel allergic contact dermatitis have been described and may aggravate underlying AD.³¹

Family Burden of AD

Parents or caregivers of children with moderate and severe AD spend nearly 3 hours a day caring for their child’s skin and experience QOL impairments including lack of sleep and/or privacy, often due to cosleeping; treatment-related financial expenditures; and feelings of hopelessness, guilt, and depression.⁷

Steroid Phobia

Steroid phobia is the fear of topical application of corticosteroids resulting in systemic side effects including unrealistic fears (eg, fear that the child will develop muscles such as an anabolic steroid user) as well as realistic but statistically low-risk fears (eg, fear of systemic absorption). These fears often result in underutilization of prescribed topical corticosteroid therapies and undertreatment of children with AD.^32,33

Financial Burden

The cost of AD can be high in the United States, with adult data demonstrating costs ranging from $371 to $489 per person.³⁴ The last published cost data for pediatric AD was from 2003, with an average cost of $219 per year.³⁵ Costs include time lost from work, household purchases (eg, skin care products), and co-pays for visits and medication, with an estimated average expenditure per person (SE) of $601.06 ($137.26) annually in 2012.³⁶ The cost of ambulatory care and emergency department visits for AD in children in the United States in 1993 was estimated at $364 million.^37-39 In 2002, Ellis et al⁴⁰ estimated the overall cost of AD to be between $900 million and $3.8 billion in the United States (1997-1998) based on projections from claims, prescriptions, and comorbidities reported to a private insurer and Medicaid. Ellis et al⁴¹ further determined that topical tacrolimus was similar in cost to high-potency corticosteroids.

Pediatric AD often progresses to adult hand eczema and leads to further morbidity, especially in health care workers.⁴² Kemp⁴³ reviewed the cost of AD in children and concluded that AD was a condition with major handicap with personal, financial, and social effects. A cost review of studies conducted in 163,700 children with AD showed that costs related to AD totaled $316.7 million per year. The author concluded that there were substantial psychosocial and financial stresses associated with pediatric AD but no clear path to potential reduction in related costs.⁴³

Sleep Disturbances

Sleep disturbances are common in pediatric AD patients. Pruritus usually is exacerbated at bedtime due to reduced humidity and lack of distractions to prevent scratching. Sleep deprivation has a substantial impact on both the patient and his/her household. Parental frustration increases with sleep disturbance.^18,44 Sleep deprivation is associated with greater severity, both because it is one of the most difficult aspects of illness and because the associated pruritus makes for greater damage done to the skin through injurious scratching.

Sleep disturbances also may interfere with growth and overnight release of growth hormones.^18,44 This latter issue can result in reduced linear growth velocity. Furthermore, sleep deprivation can cause increased risk of accidents and poor school performance.^18,44,45

Many children do not outgrow AD. In adults, AD-associated sleep deprivation has been shown to have an association with fatigue, regular daytime sleepiness, and regular insomnia, correlating to number of sick days, doctor visits, and poorer overall health status.⁴⁵

Inadequate Disease Control

Inadequate disease control has been described by Eichenfeld⁴⁶ as an important issue in AD at this time. Untreated, undertreated, and improperly treated AD are important issues affecting long-term AD care. He further cited steroid phobia as a contributor to undertreatment.⁴⁶ Fleischer⁴⁷ has cited the black box warning present on TCIs as a further deterrent to adequate therapeutic control in our current therapeutic paradigm. Undertreatment may result in uncontrolled disease activity, impaired QOL, infections, and sleep disturbances. The role of undertreatment as a driver of the atopic march is unknown.

Conclusion

Atopic dermatitis is a multisystem disorder that has wide-reaching comorbidities and may mimic a variety of skin conditions. The topic of comorbidities is new and emerging and bears further review to define risk factors, prevention strategies, and long-term monitoring requirements.

Atopic dermatitis (AD) may be triggered by viral infections, food allergens, weather, and other causes, and it may trigger an inflammatory progression known as the atopic march. This article reviews research on triggers of pediatric AD so that dermatologists may discuss trigger avoidance with patients and guardians. Other factors affecting AD development include genetics and hygiene. Grading of AD also is discussed.

The Atopic March

The persistence of AD in untreated skin can trigger an inflammatory progression called the atopic march in which food and environmental allergies as well as asthma may occur progressively due to ongoing inflammatory triggering.¹ In a study of asthma and food allergy reporting and management in public schools in Chicago, Illinois, food allergies were seen in 9.3% of asthmatic students (n=18,000), and 40.1% of food allergic students (n=4000) had asthma.² An observational study by Flohr et al³ in London, England, included 619 exclusively breastfed infants who were recruited at 3 months of age. The investigators determined that food sensitization was unrelated to the presence of filaggrin mutations, type of eczema (flexural vs nonflexural), and transepidermal water loss but was associated with AD severity as determined by SCORAD (SCORing Atopic Dermatitis), a composite score of AD that includes pruritus as a factor in severity. Other AD associations included 3 leading food allergens: eggs, milk, and peanuts. No association with cod, wheat, or sesame allergy was noted. The investigators concluded that AD and AD severity were the leading skin-related risk factors for food allergies and therefore food allergy development in breastfed infants was probably mediated by cutaneous antigen-presenting cells.³

The skin has been documented to react to contact with known food allergens⁴ and is known to be a route of allergic sensitization to allergens such as fragrance in patients with AD.^5,6 Two phenotypes of eczema that have been associated with asthma development are severe AD disease and multiple environmental allergies, supporting the theory of the atopic march.⁷ There also is evidence that release of danger-associated proteins from an impaired barrier also may trigger asthma.⁸ An analysis of the 2007 National Survey of Children’s Health, a population-based study of91,642 children aged 0 to 17 years, showed that children with AD had a higher prevalence of comorbid asthma (25.1% vs 12.3%), hay fever (34.4% vs 14.3%), and food allergies (15.1% vs 3.6%) compared to children without AD.⁹ A recent article provided detailed information on how food and diet interplay with AD.¹⁰

Triggers of Disease Flares

Triggers are the leading source of AD flare initiation, and avoidance of triggers is an important mechanism by which patients can control disease activity. Despite the best skin care and trigger avoidance, disease flares occur, sometimes due to ongoing inflammation and other times due to inability to prevent flares such as heat and humidity. A survey of patients with AD in Spain identified the following triggers: cosmetic products, clothing, mites, detergents/soaps, and temperature changes.¹¹ In childhood, wool also is a known trigger of AD.¹² Viral infections including respiratory syncytial virus may trigger the first onset of AD.¹³ Patients with AD may become allergic to fragrance and metals causing disease exacerbation on exposure.^14,15 Food allergens contribute to approximately 40% of cases of AD in infancy but are not the cause of AD. The best evidence for improvement of AD with food allergen avoidance exists for egg white allergy.¹⁶ Food avoidance programs should be developed in conjunction with an allergist, as it is no longer advised in many cases to completely withdraw foods; therefore, an allergist has to assess the level of allergic severity and the risk-benefit ratio of food avoidance or introduction.¹⁷ Emotional stressors, heat, and humidity, as well as indoor heating in the winter months, can cause AD flares.¹⁸

A study by Silverberg et al¹⁹ provided evidence of climate influences on the US prevalence of childhood eczema using a merged analysis of the 2007 National Survey of Children’s Health and the 2006-2007 National Climate Data Center and Weather Service. Results showed that eczema prevalence was significantly lower when associated with higher annual relative humidity (P=.01), UV index (P<.0001), and highest-quartile air temperature (P=.002).¹⁹ The Pediatric Eczema Elective Registry also showed that warm, humid, and high-sun-exposure climates are associated with poorly controlled eczema in affected patients.²⁰ The association of eczema with latitude as well as its negative association with mean annual outdoor temperature has been described by Weiland et al²¹ in the ISAAC (International Study of Asthma and Allergies in Childhood) study. Long airplane flights in low humidity can trigger eczema in adults. Climate has been postulated to affect eczema through alterations in filaggrin and skin barrier function.²² Indoor temperature and humidity regulation may be used adjunctively for daily flare prevention.

Genetics and AD

Of 762 infants in a birth cohort with a parent with atopy in Cincinnati, Ohio, 39% developed eczema by the age of 3 years. Single nucleotide polymorphisms of IL-4Rα 175 V and CD14-159 C/T were linked to greater eczema risk at 2 to 3 years of age.²³ Monozygotic twins have a concordance rate of 0.72 to 0.86 versus 0.21 to 0.23 in dizygotic twins, demonstrating a strong genetic component in the development of AD.²⁴ Linkage to AD has been positively made to the epidermal differentiation complex on human chromosome 1q21, which contains the genes for filaggrin and other proteins such as loricrin. Other genes linked to AD include the serine protease inhibitor SPINK5 (serine peptidase inhibitor, Kazal type 5) implicated in Netherton syndrome (triad of ichthyosis linearis circumflexa, bamboo hair, and atopic disorders); RANTES (regulated on activation, normal T-expressed, and secreted), which has been associated with severity of AD; IL-4; and IL-13.^5,25,26

The Hygiene Hypothesis

Atopic dermatitis is more common in wealthy developed countries, leading some to believe that hygiene and relative reduction in illness via vaccination have contributed to the rise of AD prevalence in developed nations.^13,27 There currently is evidence demonstrating that wild-type varicella infection confers long-standing protection against AD and mediates reduced total IgE and peripheral blood lymphocytes.²⁷

Grading of AD

Grading of AD is a subject of controversy, as there currently are no uniform grading scales.²⁸ A recent outcomes group attempted to determine the best scale for disease monitoring. Schmitt et al²⁹ presented the Harmonizing Outcome Measures for Eczema (HOME) roadmap, which was intended to determine a core outcome set for eczema; however, because these outcome measurements have not yet been standardized, only the eczema assessment and severity index (EASI) scoring system meets criteria for standardization. In clinical practice, physicians often assign mild, moderate, or severe labeling based on their general sense of the disease extent using an investigator global assessment score.²⁸

The EASI score is a well-validated composite score of AD severity based on 4 body regions: (1) head and neck, (2) trunk (including genital area), (3) upper limbs, and (4) lower limbs (including buttocks). The total area of involvement in each region is graded on a scale of 0 to 6, and AD severity is graded as a composite of 4 parameters (ranked on a scale of 0–3), including redness (erythema, inflammation), thickness (induration, papulation, swelling [acute eczema]), scratching (excoriation), and lichenification (prurigo nodules [chronic eczema]). The surface area of each region relative to body size is used as a multiplying factor, resulting in the following severity strata: 0=clear; 0.1–1.0=almost clear; 1.1–7.0=mild; 7.1–21.0=moderate; 21.1–50.0=severe; 50.1–72.0=very severe (κ=0.75).^30-32 The six area, six sign AD (SASSAD) score^32,33 is a similar score without adjustment for body surface area by region.³⁴

An older, now less frequently used eczema score is the SCORAD, which addressed surface area by rule of nines and severity of 6 features—redness, swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness (assessed in an area with no inflammation)—by region on a scale of 0 to 3. A subjective symptom parameter for itching and sleeplessness helped highlight that these comorbidities are important in gauging disease activity and impact on a child’s life.³⁵

Natural History of AD

The clinical dogma has been that AD would improve with age, with reduction at grade school entry and perhaps full disappearance in adulthood; however, 3 recent surveys have suggested otherwise. The ISAAC group has found prevalence of AD in wealthy developed countries among children aged 6 to 7 years to be at a consistent increase.³⁶ A US-based survey from the National Health Interview Survey showed a 1-year prevalence of 10.2% of active AD in adults and 9.8% when occupational dermatitis was excluded.³⁷ Halvorsen et al³⁸ demonstrated that eczema prevalence is 9.7% in individuals aged 18 to 19 years.

A prospective trial of eighth graders followed from 1995 to 2010 demonstrated that AD persisted in 50% at school age. Persistent eczema into adulthood was associated with early-onset childhood allergic rhinitis and hand eczema.³⁹ In a cohort of hand eczema patients (N=368), 28% had AD and 39% had an atopic illness.⁴⁰ An association with allergic contact dermatitis and increased IgE to Malassezia furfur was further associated.⁴¹

Conclusion

The role of triggers and allergens in disease activity in AD is an important consideration in children with AD and requires ongoing consideration with age and varied exposures. Understanding the grading of AD is important in evaluating clinical trial data. The natural history of AD has changed, which is important for the practitioner to note when counseling patients and guardians.

Atopic dermatitis (AD) may be triggered by viral infections, food allergens, weather, and other causes, and it may trigger an inflammatory progression known as the atopic march. This article reviews research on triggers of pediatric AD so that dermatologists may discuss trigger avoidance with patients and guardians. Other factors affecting AD development include genetics and hygiene. Grading of AD also is discussed.

The Atopic March

The persistence of AD in untreated skin can trigger an inflammatory progression called the atopic march in which food and environmental allergies as well as asthma may occur progressively due to ongoing inflammatory triggering.¹ In a study of asthma and food allergy reporting and management in public schools in Chicago, Illinois, food allergies were seen in 9.3% of asthmatic students (n=18,000), and 40.1% of food allergic students (n=4000) had asthma.² An observational study by Flohr et al³ in London, England, included 619 exclusively breastfed infants who were recruited at 3 months of age. The investigators determined that food sensitization was unrelated to the presence of filaggrin mutations, type of eczema (flexural vs nonflexural), and transepidermal water loss but was associated with AD severity as determined by SCORAD (SCORing Atopic Dermatitis), a composite score of AD that includes pruritus as a factor in severity. Other AD associations included 3 leading food allergens: eggs, milk, and peanuts. No association with cod, wheat, or sesame allergy was noted. The investigators concluded that AD and AD severity were the leading skin-related risk factors for food allergies and therefore food allergy development in breastfed infants was probably mediated by cutaneous antigen-presenting cells.³

The skin has been documented to react to contact with known food allergens⁴ and is known to be a route of allergic sensitization to allergens such as fragrance in patients with AD.^5,6 Two phenotypes of eczema that have been associated with asthma development are severe AD disease and multiple environmental allergies, supporting the theory of the atopic march.⁷ There also is evidence that release of danger-associated proteins from an impaired barrier also may trigger asthma.⁸ An analysis of the 2007 National Survey of Children’s Health, a population-based study of91,642 children aged 0 to 17 years, showed that children with AD had a higher prevalence of comorbid asthma (25.1% vs 12.3%), hay fever (34.4% vs 14.3%), and food allergies (15.1% vs 3.6%) compared to children without AD.⁹ A recent article provided detailed information on how food and diet interplay with AD.¹⁰

Triggers of Disease Flares

Triggers are the leading source of AD flare initiation, and avoidance of triggers is an important mechanism by which patients can control disease activity. Despite the best skin care and trigger avoidance, disease flares occur, sometimes due to ongoing inflammation and other times due to inability to prevent flares such as heat and humidity. A survey of patients with AD in Spain identified the following triggers: cosmetic products, clothing, mites, detergents/soaps, and temperature changes.¹¹ In childhood, wool also is a known trigger of AD.¹² Viral infections including respiratory syncytial virus may trigger the first onset of AD.¹³ Patients with AD may become allergic to fragrance and metals causing disease exacerbation on exposure.^14,15 Food allergens contribute to approximately 40% of cases of AD in infancy but are not the cause of AD. The best evidence for improvement of AD with food allergen avoidance exists for egg white allergy.¹⁶ Food avoidance programs should be developed in conjunction with an allergist, as it is no longer advised in many cases to completely withdraw foods; therefore, an allergist has to assess the level of allergic severity and the risk-benefit ratio of food avoidance or introduction.¹⁷ Emotional stressors, heat, and humidity, as well as indoor heating in the winter months, can cause AD flares.¹⁸

A study by Silverberg et al¹⁹ provided evidence of climate influences on the US prevalence of childhood eczema using a merged analysis of the 2007 National Survey of Children’s Health and the 2006-2007 National Climate Data Center and Weather Service. Results showed that eczema prevalence was significantly lower when associated with higher annual relative humidity (P=.01), UV index (P<.0001), and highest-quartile air temperature (P=.002).¹⁹ The Pediatric Eczema Elective Registry also showed that warm, humid, and high-sun-exposure climates are associated with poorly controlled eczema in affected patients.²⁰ The association of eczema with latitude as well as its negative association with mean annual outdoor temperature has been described by Weiland et al²¹ in the ISAAC (International Study of Asthma and Allergies in Childhood) study. Long airplane flights in low humidity can trigger eczema in adults. Climate has been postulated to affect eczema through alterations in filaggrin and skin barrier function.²² Indoor temperature and humidity regulation may be used adjunctively for daily flare prevention.

Genetics and AD

Of 762 infants in a birth cohort with a parent with atopy in Cincinnati, Ohio, 39% developed eczema by the age of 3 years. Single nucleotide polymorphisms of IL-4Rα 175 V and CD14-159 C/T were linked to greater eczema risk at 2 to 3 years of age.²³ Monozygotic twins have a concordance rate of 0.72 to 0.86 versus 0.21 to 0.23 in dizygotic twins, demonstrating a strong genetic component in the development of AD.²⁴ Linkage to AD has been positively made to the epidermal differentiation complex on human chromosome 1q21, which contains the genes for filaggrin and other proteins such as loricrin. Other genes linked to AD include the serine protease inhibitor SPINK5 (serine peptidase inhibitor, Kazal type 5) implicated in Netherton syndrome (triad of ichthyosis linearis circumflexa, bamboo hair, and atopic disorders); RANTES (regulated on activation, normal T-expressed, and secreted), which has been associated with severity of AD; IL-4; and IL-13.^5,25,26

The Hygiene Hypothesis

Atopic dermatitis is more common in wealthy developed countries, leading some to believe that hygiene and relative reduction in illness via vaccination have contributed to the rise of AD prevalence in developed nations.^13,27 There currently is evidence demonstrating that wild-type varicella infection confers long-standing protection against AD and mediates reduced total IgE and peripheral blood lymphocytes.²⁷

Grading of AD

Grading of AD is a subject of controversy, as there currently are no uniform grading scales.²⁸ A recent outcomes group attempted to determine the best scale for disease monitoring. Schmitt et al²⁹ presented the Harmonizing Outcome Measures for Eczema (HOME) roadmap, which was intended to determine a core outcome set for eczema; however, because these outcome measurements have not yet been standardized, only the eczema assessment and severity index (EASI) scoring system meets criteria for standardization. In clinical practice, physicians often assign mild, moderate, or severe labeling based on their general sense of the disease extent using an investigator global assessment score.²⁸

The EASI score is a well-validated composite score of AD severity based on 4 body regions: (1) head and neck, (2) trunk (including genital area), (3) upper limbs, and (4) lower limbs (including buttocks). The total area of involvement in each region is graded on a scale of 0 to 6, and AD severity is graded as a composite of 4 parameters (ranked on a scale of 0–3), including redness (erythema, inflammation), thickness (induration, papulation, swelling [acute eczema]), scratching (excoriation), and lichenification (prurigo nodules [chronic eczema]). The surface area of each region relative to body size is used as a multiplying factor, resulting in the following severity strata: 0=clear; 0.1–1.0=almost clear; 1.1–7.0=mild; 7.1–21.0=moderate; 21.1–50.0=severe; 50.1–72.0=very severe (κ=0.75).^30-32 The six area, six sign AD (SASSAD) score^32,33 is a similar score without adjustment for body surface area by region.³⁴

An older, now less frequently used eczema score is the SCORAD, which addressed surface area by rule of nines and severity of 6 features—redness, swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness (assessed in an area with no inflammation)—by region on a scale of 0 to 3. A subjective symptom parameter for itching and sleeplessness helped highlight that these comorbidities are important in gauging disease activity and impact on a child’s life.³⁵

Natural History of AD

The clinical dogma has been that AD would improve with age, with reduction at grade school entry and perhaps full disappearance in adulthood; however, 3 recent surveys have suggested otherwise. The ISAAC group has found prevalence of AD in wealthy developed countries among children aged 6 to 7 years to be at a consistent increase.³⁶ A US-based survey from the National Health Interview Survey showed a 1-year prevalence of 10.2% of active AD in adults and 9.8% when occupational dermatitis was excluded.³⁷ Halvorsen et al³⁸ demonstrated that eczema prevalence is 9.7% in individuals aged 18 to 19 years.

A prospective trial of eighth graders followed from 1995 to 2010 demonstrated that AD persisted in 50% at school age. Persistent eczema into adulthood was associated with early-onset childhood allergic rhinitis and hand eczema.³⁹ In a cohort of hand eczema patients (N=368), 28% had AD and 39% had an atopic illness.⁴⁰ An association with allergic contact dermatitis and increased IgE to Malassezia furfur was further associated.⁴¹

Conclusion

The role of triggers and allergens in disease activity in AD is an important consideration in children with AD and requires ongoing consideration with age and varied exposures. Understanding the grading of AD is important in evaluating clinical trial data. The natural history of AD has changed, which is important for the practitioner to note when counseling patients and guardians.

Atopic dermatitis (AD) may be triggered by viral infections, food allergens, weather, and other causes, and it may trigger an inflammatory progression known as the atopic march. This article reviews research on triggers of pediatric AD so that dermatologists may discuss trigger avoidance with patients and guardians. Other factors affecting AD development include genetics and hygiene. Grading of AD also is discussed.

The Atopic March

The persistence of AD in untreated skin can trigger an inflammatory progression called the atopic march in which food and environmental allergies as well as asthma may occur progressively due to ongoing inflammatory triggering.¹ In a study of asthma and food allergy reporting and management in public schools in Chicago, Illinois, food allergies were seen in 9.3% of asthmatic students (n=18,000), and 40.1% of food allergic students (n=4000) had asthma.² An observational study by Flohr et al³ in London, England, included 619 exclusively breastfed infants who were recruited at 3 months of age. The investigators determined that food sensitization was unrelated to the presence of filaggrin mutations, type of eczema (flexural vs nonflexural), and transepidermal water loss but was associated with AD severity as determined by SCORAD (SCORing Atopic Dermatitis), a composite score of AD that includes pruritus as a factor in severity. Other AD associations included 3 leading food allergens: eggs, milk, and peanuts. No association with cod, wheat, or sesame allergy was noted. The investigators concluded that AD and AD severity were the leading skin-related risk factors for food allergies and therefore food allergy development in breastfed infants was probably mediated by cutaneous antigen-presenting cells.³

The skin has been documented to react to contact with known food allergens⁴ and is known to be a route of allergic sensitization to allergens such as fragrance in patients with AD.^5,6 Two phenotypes of eczema that have been associated with asthma development are severe AD disease and multiple environmental allergies, supporting the theory of the atopic march.⁷ There also is evidence that release of danger-associated proteins from an impaired barrier also may trigger asthma.⁸ An analysis of the 2007 National Survey of Children’s Health, a population-based study of91,642 children aged 0 to 17 years, showed that children with AD had a higher prevalence of comorbid asthma (25.1% vs 12.3%), hay fever (34.4% vs 14.3%), and food allergies (15.1% vs 3.6%) compared to children without AD.⁹ A recent article provided detailed information on how food and diet interplay with AD.¹⁰

Triggers of Disease Flares

Triggers are the leading source of AD flare initiation, and avoidance of triggers is an important mechanism by which patients can control disease activity. Despite the best skin care and trigger avoidance, disease flares occur, sometimes due to ongoing inflammation and other times due to inability to prevent flares such as heat and humidity. A survey of patients with AD in Spain identified the following triggers: cosmetic products, clothing, mites, detergents/soaps, and temperature changes.¹¹ In childhood, wool also is a known trigger of AD.¹² Viral infections including respiratory syncytial virus may trigger the first onset of AD.¹³ Patients with AD may become allergic to fragrance and metals causing disease exacerbation on exposure.^14,15 Food allergens contribute to approximately 40% of cases of AD in infancy but are not the cause of AD. The best evidence for improvement of AD with food allergen avoidance exists for egg white allergy.¹⁶ Food avoidance programs should be developed in conjunction with an allergist, as it is no longer advised in many cases to completely withdraw foods; therefore, an allergist has to assess the level of allergic severity and the risk-benefit ratio of food avoidance or introduction.¹⁷ Emotional stressors, heat, and humidity, as well as indoor heating in the winter months, can cause AD flares.¹⁸

A study by Silverberg et al¹⁹ provided evidence of climate influences on the US prevalence of childhood eczema using a merged analysis of the 2007 National Survey of Children’s Health and the 2006-2007 National Climate Data Center and Weather Service. Results showed that eczema prevalence was significantly lower when associated with higher annual relative humidity (P=.01), UV index (P<.0001), and highest-quartile air temperature (P=.002).¹⁹ The Pediatric Eczema Elective Registry also showed that warm, humid, and high-sun-exposure climates are associated with poorly controlled eczema in affected patients.²⁰ The association of eczema with latitude as well as its negative association with mean annual outdoor temperature has been described by Weiland et al²¹ in the ISAAC (International Study of Asthma and Allergies in Childhood) study. Long airplane flights in low humidity can trigger eczema in adults. Climate has been postulated to affect eczema through alterations in filaggrin and skin barrier function.²² Indoor temperature and humidity regulation may be used adjunctively for daily flare prevention.

Genetics and AD

Of 762 infants in a birth cohort with a parent with atopy in Cincinnati, Ohio, 39% developed eczema by the age of 3 years. Single nucleotide polymorphisms of IL-4Rα 175 V and CD14-159 C/T were linked to greater eczema risk at 2 to 3 years of age.²³ Monozygotic twins have a concordance rate of 0.72 to 0.86 versus 0.21 to 0.23 in dizygotic twins, demonstrating a strong genetic component in the development of AD.²⁴ Linkage to AD has been positively made to the epidermal differentiation complex on human chromosome 1q21, which contains the genes for filaggrin and other proteins such as loricrin. Other genes linked to AD include the serine protease inhibitor SPINK5 (serine peptidase inhibitor, Kazal type 5) implicated in Netherton syndrome (triad of ichthyosis linearis circumflexa, bamboo hair, and atopic disorders); RANTES (regulated on activation, normal T-expressed, and secreted), which has been associated with severity of AD; IL-4; and IL-13.^5,25,26

The Hygiene Hypothesis

Atopic dermatitis is more common in wealthy developed countries, leading some to believe that hygiene and relative reduction in illness via vaccination have contributed to the rise of AD prevalence in developed nations.^13,27 There currently is evidence demonstrating that wild-type varicella infection confers long-standing protection against AD and mediates reduced total IgE and peripheral blood lymphocytes.²⁷

Grading of AD

Grading of AD is a subject of controversy, as there currently are no uniform grading scales.²⁸ A recent outcomes group attempted to determine the best scale for disease monitoring. Schmitt et al²⁹ presented the Harmonizing Outcome Measures for Eczema (HOME) roadmap, which was intended to determine a core outcome set for eczema; however, because these outcome measurements have not yet been standardized, only the eczema assessment and severity index (EASI) scoring system meets criteria for standardization. In clinical practice, physicians often assign mild, moderate, or severe labeling based on their general sense of the disease extent using an investigator global assessment score.²⁸

The EASI score is a well-validated composite score of AD severity based on 4 body regions: (1) head and neck, (2) trunk (including genital area), (3) upper limbs, and (4) lower limbs (including buttocks). The total area of involvement in each region is graded on a scale of 0 to 6, and AD severity is graded as a composite of 4 parameters (ranked on a scale of 0–3), including redness (erythema, inflammation), thickness (induration, papulation, swelling [acute eczema]), scratching (excoriation), and lichenification (prurigo nodules [chronic eczema]). The surface area of each region relative to body size is used as a multiplying factor, resulting in the following severity strata: 0=clear; 0.1–1.0=almost clear; 1.1–7.0=mild; 7.1–21.0=moderate; 21.1–50.0=severe; 50.1–72.0=very severe (κ=0.75).^30-32 The six area, six sign AD (SASSAD) score^32,33 is a similar score without adjustment for body surface area by region.³⁴

An older, now less frequently used eczema score is the SCORAD, which addressed surface area by rule of nines and severity of 6 features—redness, swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness (assessed in an area with no inflammation)—by region on a scale of 0 to 3. A subjective symptom parameter for itching and sleeplessness helped highlight that these comorbidities are important in gauging disease activity and impact on a child’s life.³⁵

Natural History of AD

The clinical dogma has been that AD would improve with age, with reduction at grade school entry and perhaps full disappearance in adulthood; however, 3 recent surveys have suggested otherwise. The ISAAC group has found prevalence of AD in wealthy developed countries among children aged 6 to 7 years to be at a consistent increase.³⁶ A US-based survey from the National Health Interview Survey showed a 1-year prevalence of 10.2% of active AD in adults and 9.8% when occupational dermatitis was excluded.³⁷ Halvorsen et al³⁸ demonstrated that eczema prevalence is 9.7% in individuals aged 18 to 19 years.

A prospective trial of eighth graders followed from 1995 to 2010 demonstrated that AD persisted in 50% at school age. Persistent eczema into adulthood was associated with early-onset childhood allergic rhinitis and hand eczema.³⁹ In a cohort of hand eczema patients (N=368), 28% had AD and 39% had an atopic illness.⁴⁰ An association with allergic contact dermatitis and increased IgE to Malassezia furfur was further associated.⁴¹

Conclusion

The role of triggers and allergens in disease activity in AD is an important consideration in children with AD and requires ongoing consideration with age and varied exposures. Understanding the grading of AD is important in evaluating clinical trial data. The natural history of AD has changed, which is important for the practitioner to note when counseling patients and guardians.

What do your patients need to know at the first visit?

Patients with chronic dermatitis are frequently referred for patch testing. An in-depth conversation reviewing the patch test procedure and the many potential causes of dermatitis (eg, endogenous, allergic, irritant, seborrheic) is needed. Patients should understand the patch test process. The testing extends over a week, requiring 3 days of visits. The patches are applied at day 1 and must be kept dry and in place for 48 hours, then they are removed and evaluated. A second follow-up visit at 96 hours to 1 week after the patches are applied is done to perform a final read, interpret, and explain the final results. The patient needs to know that we are looking for an allergen that might be causing the eruption through contact exposure with the skin. The difference between patch testing and prick testing often needs to be discussed, as patients are not always aware of the difference. Explaining the need to avoid topical steroids at the patch test site, sunburn, or systemic steroids during the patch test period is also important to obtain optimal testing conditions.

Querying all exposures including work, home, personal care products, and hobbies is important to help determine which allergen series should be tested to obtain the best results. Patients need to understand that even small intermittent exposures can cause an ongoing dermatitis. If a causative allergen(s) is identified, strict avoidance can lead to clearance and resolution.

Setting expectations is important, and therefore you should discuss the possibility that no allergen will be identified while letting the patient know that this information is also useful. Also, let patients know there are other things that can be done if patch testing is negative to try and gain control of the dermatitis including laboratory tests and biopsies, which may be needed to help direct future management.

What are your go-to treatments? What are the side effects?

The beauty of patch testing is that finding a relevant allergen and subsequent avoidance of that allergen often is sufficient to improve or clear the dermatitis. Detailed education regarding the allergen, where it is found, and how to avoid it are imperative in patient management. I provide the patient with information sheets or narratives found on the American Contact Dermatitis Society website (http://www.contactderm.org) as well as a list of safe products found on the Contact Allergen Management Program (CAMP) area of the site. These tools help in patient compliance.

Go-to treatments for relevant patch test dermatitis involve topical steroids to calm the acute dermatitis while educating and instituting a personal environment free of the identified allergens. Occasionally, systemic steroids are used to provide relief and calm down an extensive dermatitis while educating, identifying, and eliminating known allergens from the patient’s environment. Identifying and eliminating an allergen can mitigate the need for chronic steroids, and the resultant side effects of hypertension, osteoporosis, avascular necrosis, hyperglycemia, and gastrointestinal tract problems can be avoided. Likewise, avoidance of allergens can lead to the elimination of the need for chronic topical steroids and the resultant atrophy and striae.

Side effects of the patch test procedure itself include an allergic reaction to one of the chemicals tested (eg, gold), which is what you are looking for; persistent reactions; flaring of existing dermatitis; irritation; hyperpigmentation; and rarely anaphylaxis or infection at a patch test site. If no allergy is found, treatment of generalized dermatitis can include topical steroids. Topical calcineurin inhibitors can be useful as well as narrowband UV light. Several oral medications can be used for recalcitrant patch test–negative dermatitis and the selection of the right medication is based on the patient’s comorbidities and extent of dermatitis, including systemic steroids, though long-term use is not recommended. Mycophenolate mofetil, methotrexate, cyclosporine, and azathioprine all have side effects including liver and renal toxicity, immunosuppression, and risk for malignancy and therefore need to be considered on a case-by-case basis.

How do you keep the patient compliant with treatment?

Treating allergic contact dermatitis once an allergen(s) has been identified can be challenging. Education is key so that the patient understands where the allergen is found in his/her environment and how to avoid it. Teaching the patient to read labels also is important. Providing a list of safe products simplifies compliance. Reinforcing the need for ongoing vigilance in allergen avoidance is critical to resolution of the dermatitis. Reinforcing the need for continuous avoidance is imperative, as patients sometimes become less vigilant once the dermatitis resolves and the allergen can sneak back into their environment.

What do I do if a patient refuses treatment?

Sometimes patients are so attached to a product that they do not want to stop using it even though they know it is the cause of their dermatitis. If I can help them identify a comparable product, I introduce them to it, but ultimately they get to decide if they prefer to use a product that they know is the cause of their rash or if they want to avoid it and be clear of the dermatitis. For those who do not have an allergen identified through patch testing, alternative treatments can be used. If they do not want systemic medication, I try and optimize their skin care regimen with mild soaps, bland moisturizing creams, and short lukewarm showers, which often is not enough and eventually due to ongoing itch patients decide to discuss and pursue treatment options.

What do your patients need to know at the first visit?

Patients with chronic dermatitis are frequently referred for patch testing. An in-depth conversation reviewing the patch test procedure and the many potential causes of dermatitis (eg, endogenous, allergic, irritant, seborrheic) is needed. Patients should understand the patch test process. The testing extends over a week, requiring 3 days of visits. The patches are applied at day 1 and must be kept dry and in place for 48 hours, then they are removed and evaluated. A second follow-up visit at 96 hours to 1 week after the patches are applied is done to perform a final read, interpret, and explain the final results. The patient needs to know that we are looking for an allergen that might be causing the eruption through contact exposure with the skin. The difference between patch testing and prick testing often needs to be discussed, as patients are not always aware of the difference. Explaining the need to avoid topical steroids at the patch test site, sunburn, or systemic steroids during the patch test period is also important to obtain optimal testing conditions.

Querying all exposures including work, home, personal care products, and hobbies is important to help determine which allergen series should be tested to obtain the best results. Patients need to understand that even small intermittent exposures can cause an ongoing dermatitis. If a causative allergen(s) is identified, strict avoidance can lead to clearance and resolution.

Setting expectations is important, and therefore you should discuss the possibility that no allergen will be identified while letting the patient know that this information is also useful. Also, let patients know there are other things that can be done if patch testing is negative to try and gain control of the dermatitis including laboratory tests and biopsies, which may be needed to help direct future management.

What are your go-to treatments? What are the side effects?

The beauty of patch testing is that finding a relevant allergen and subsequent avoidance of that allergen often is sufficient to improve or clear the dermatitis. Detailed education regarding the allergen, where it is found, and how to avoid it are imperative in patient management. I provide the patient with information sheets or narratives found on the American Contact Dermatitis Society website (http://www.contactderm.org) as well as a list of safe products found on the Contact Allergen Management Program (CAMP) area of the site. These tools help in patient compliance.

Go-to treatments for relevant patch test dermatitis involve topical steroids to calm the acute dermatitis while educating and instituting a personal environment free of the identified allergens. Occasionally, systemic steroids are used to provide relief and calm down an extensive dermatitis while educating, identifying, and eliminating known allergens from the patient’s environment. Identifying and eliminating an allergen can mitigate the need for chronic steroids, and the resultant side effects of hypertension, osteoporosis, avascular necrosis, hyperglycemia, and gastrointestinal tract problems can be avoided. Likewise, avoidance of allergens can lead to the elimination of the need for chronic topical steroids and the resultant atrophy and striae.

Side effects of the patch test procedure itself include an allergic reaction to one of the chemicals tested (eg, gold), which is what you are looking for; persistent reactions; flaring of existing dermatitis; irritation; hyperpigmentation; and rarely anaphylaxis or infection at a patch test site. If no allergy is found, treatment of generalized dermatitis can include topical steroids. Topical calcineurin inhibitors can be useful as well as narrowband UV light. Several oral medications can be used for recalcitrant patch test–negative dermatitis and the selection of the right medication is based on the patient’s comorbidities and extent of dermatitis, including systemic steroids, though long-term use is not recommended. Mycophenolate mofetil, methotrexate, cyclosporine, and azathioprine all have side effects including liver and renal toxicity, immunosuppression, and risk for malignancy and therefore need to be considered on a case-by-case basis.

How do you keep the patient compliant with treatment?

Treating allergic contact dermatitis once an allergen(s) has been identified can be challenging. Education is key so that the patient understands where the allergen is found in his/her environment and how to avoid it. Teaching the patient to read labels also is important. Providing a list of safe products simplifies compliance. Reinforcing the need for ongoing vigilance in allergen avoidance is critical to resolution of the dermatitis. Reinforcing the need for continuous avoidance is imperative, as patients sometimes become less vigilant once the dermatitis resolves and the allergen can sneak back into their environment.

What do I do if a patient refuses treatment?

Sometimes patients are so attached to a product that they do not want to stop using it even though they know it is the cause of their dermatitis. If I can help them identify a comparable product, I introduce them to it, but ultimately they get to decide if they prefer to use a product that they know is the cause of their rash or if they want to avoid it and be clear of the dermatitis. For those who do not have an allergen identified through patch testing, alternative treatments can be used. If they do not want systemic medication, I try and optimize their skin care regimen with mild soaps, bland moisturizing creams, and short lukewarm showers, which often is not enough and eventually due to ongoing itch patients decide to discuss and pursue treatment options.

What do your patients need to know at the first visit?

Patients with chronic dermatitis are frequently referred for patch testing. An in-depth conversation reviewing the patch test procedure and the many potential causes of dermatitis (eg, endogenous, allergic, irritant, seborrheic) is needed. Patients should understand the patch test process. The testing extends over a week, requiring 3 days of visits. The patches are applied at day 1 and must be kept dry and in place for 48 hours, then they are removed and evaluated. A second follow-up visit at 96 hours to 1 week after the patches are applied is done to perform a final read, interpret, and explain the final results. The patient needs to know that we are looking for an allergen that might be causing the eruption through contact exposure with the skin. The difference between patch testing and prick testing often needs to be discussed, as patients are not always aware of the difference. Explaining the need to avoid topical steroids at the patch test site, sunburn, or systemic steroids during the patch test period is also important to obtain optimal testing conditions.

Querying all exposures including work, home, personal care products, and hobbies is important to help determine which allergen series should be tested to obtain the best results. Patients need to understand that even small intermittent exposures can cause an ongoing dermatitis. If a causative allergen(s) is identified, strict avoidance can lead to clearance and resolution.

Setting expectations is important, and therefore you should discuss the possibility that no allergen will be identified while letting the patient know that this information is also useful. Also, let patients know there are other things that can be done if patch testing is negative to try and gain control of the dermatitis including laboratory tests and biopsies, which may be needed to help direct future management.

What are your go-to treatments? What are the side effects?

The beauty of patch testing is that finding a relevant allergen and subsequent avoidance of that allergen often is sufficient to improve or clear the dermatitis. Detailed education regarding the allergen, where it is found, and how to avoid it are imperative in patient management. I provide the patient with information sheets or narratives found on the American Contact Dermatitis Society website (http://www.contactderm.org) as well as a list of safe products found on the Contact Allergen Management Program (CAMP) area of the site. These tools help in patient compliance.

Go-to treatments for relevant patch test dermatitis involve topical steroids to calm the acute dermatitis while educating and instituting a personal environment free of the identified allergens. Occasionally, systemic steroids are used to provide relief and calm down an extensive dermatitis while educating, identifying, and eliminating known allergens from the patient’s environment. Identifying and eliminating an allergen can mitigate the need for chronic steroids, and the resultant side effects of hypertension, osteoporosis, avascular necrosis, hyperglycemia, and gastrointestinal tract problems can be avoided. Likewise, avoidance of allergens can lead to the elimination of the need for chronic topical steroids and the resultant atrophy and striae.

Side effects of the patch test procedure itself include an allergic reaction to one of the chemicals tested (eg, gold), which is what you are looking for; persistent reactions; flaring of existing dermatitis; irritation; hyperpigmentation; and rarely anaphylaxis or infection at a patch test site. If no allergy is found, treatment of generalized dermatitis can include topical steroids. Topical calcineurin inhibitors can be useful as well as narrowband UV light. Several oral medications can be used for recalcitrant patch test–negative dermatitis and the selection of the right medication is based on the patient’s comorbidities and extent of dermatitis, including systemic steroids, though long-term use is not recommended. Mycophenolate mofetil, methotrexate, cyclosporine, and azathioprine all have side effects including liver and renal toxicity, immunosuppression, and risk for malignancy and therefore need to be considered on a case-by-case basis.

How do you keep the patient compliant with treatment?

Treating allergic contact dermatitis once an allergen(s) has been identified can be challenging. Education is key so that the patient understands where the allergen is found in his/her environment and how to avoid it. Teaching the patient to read labels also is important. Providing a list of safe products simplifies compliance. Reinforcing the need for ongoing vigilance in allergen avoidance is critical to resolution of the dermatitis. Reinforcing the need for continuous avoidance is imperative, as patients sometimes become less vigilant once the dermatitis resolves and the allergen can sneak back into their environment.

What do I do if a patient refuses treatment?

Sometimes patients are so attached to a product that they do not want to stop using it even though they know it is the cause of their dermatitis. If I can help them identify a comparable product, I introduce them to it, but ultimately they get to decide if they prefer to use a product that they know is the cause of their rash or if they want to avoid it and be clear of the dermatitis. For those who do not have an allergen identified through patch testing, alternative treatments can be used. If they do not want systemic medication, I try and optimize their skin care regimen with mild soaps, bland moisturizing creams, and short lukewarm showers, which often is not enough and eventually due to ongoing itch patients decide to discuss and pursue treatment options.

Although psoriasis was once at the forefront of therapeutic advancements in dermatology, atopic dermatitis (AD) is now taking center stage with several new treatments in the pipeline. Dr. Emma Guttman-Yassky provides an overview of the future of AD treatment, which includes new topical and systemic agents that currently are moving forward in advanced clinical trials or are close to registration. She also discusses strategies for improving disease management in AD patients, noting that prevention and education of both patients and their caregivers are key to effective treatment.

Although psoriasis was once at the forefront of therapeutic advancements in dermatology, atopic dermatitis (AD) is now taking center stage with several new treatments in the pipeline. Dr. Emma Guttman-Yassky provides an overview of the future of AD treatment, which includes new topical and systemic agents that currently are moving forward in advanced clinical trials or are close to registration. She also discusses strategies for improving disease management in AD patients, noting that prevention and education of both patients and their caregivers are key to effective treatment.

Although psoriasis was once at the forefront of therapeutic advancements in dermatology, atopic dermatitis (AD) is now taking center stage with several new treatments in the pipeline. Dr. Emma Guttman-Yassky provides an overview of the future of AD treatment, which includes new topical and systemic agents that currently are moving forward in advanced clinical trials or are close to registration. She also discusses strategies for improving disease management in AD patients, noting that prevention and education of both patients and their caregivers are key to effective treatment.

Case Reports

A platoon of 24 US Marines participated in a 1-week outdoor training exercise (February 4–8) at the Marine Corps Training Area Bellows in Oahu, Hawaii. During the last 3 days of training, 15 (62.5%) marines presented to the same primary care provider with what appeared to be diffuse scattered lesions on the face, neck, and dorsal aspect of the hands. All 15 patients reported that they noticed the lesions upon waking up the morning after their second night at the training area. The patients were unable to recollect specific direct arthropod interactions, but they reported the presence of “bugs” in the training area and denied use of any insect repellents, insect nets, or sunscreen. Sleeping arrangements varied from covered vehicles and cots to sleeping bags on the ground, which were laundered independently by each marine and thereby were ruled out as a commonality. The patients denied working with any chemicals or cleansers while in the field. Further questioning of all 15 patients revealed a history of extended contact with live foliage as branches were broken off to build camouflaged sites.

The following week, a second platoon of 20 marines occupied a separate undisturbed portion of the same training area for a similar 1-week training evolution. Manifestation of similar symptoms among members of the second group, who had no contact with the initial 15 patients, supported the likely environmental etiology of the eruptions.

Figure 1. Numerous well-circumscribed, discrete, pink-red papules diffusely scattered across the face.

Figure 2. Papules with classic anemic halos.

Referral

Two patients from the first group were evaluated at the dermatology clinic at Tripler Army Medical Center (Honolulu, Hawaii) on day 10 of the initial outbreak. Cutaneous examination revealed numerous discrete, pink-red, well-circumscribed, 2- to 4-mm, dome-shaped papules exclusive to exposed areas on the face, neck, and dorsal aspect of the hands (Figures 1 and 2). Anemic halos surrounding the hand papules were noted (Figure 2). A punch biopsy in both patients revealed spongiotic dermatitis with superficial perivascular and interstitial lymphohistiocytic inflammation with eosinophils, suggestive of an arthropod bite (Figure 3). No retained arthropod parts wereidentified. Both patients were treated with triamcinolone ointment twice daily for 7 days with total resolution of the lesions.

Site Survey Results

Five days following the initial presentation of the first outbreak, a daytime site survey of the training area was conducted by a medical entomologist, an environmental health scientist, and a wildlife biologist. Records indicated that prior to the current utilization, the training area had not been used for 9 months. Approximately half of the training area was covered with mixed scrub vegetation and the remainder was clear pavement or sand (clear of vegetation). Feral hogs (Sus scrofa), cats (Felis domesticus), and mongooses (Herpestes javanicus) were observed at the site. Patient interviews and site survey ruled out a number of potential environmental irritants, including contact with fresh or salt water and chemical contaminants in the air or soil.

Because biting insects were suspected as the cause of the eruptions, an overnight entomological survey was conducted 3 weeks after the first outbreak under similar weather conditions and was centered in the area of an Australian pine (Casuarina equisetifolia) forest where most of the marines had slept during training. Mosquitoes (Aedes albopictus and Culex quinquefasciatus) were observed in the area, with an estimated biting rate of 1 to 2 bites per hour. Centipedes (Scolopendra subspinipes) were commonly observed after dark. There was no sign of heavy bird roosting or nesting, which would be a possible source of biting ectoparasites. Other than the Australian pine, notable vegetation present included Christmasberry (Schinus terebinthifolius), koa haole (Leucaena leucocephala), and Chinese banyan (Ficus microcarpa). A survey of the vegetation uncovered no notable insects, and no damage to the leaves of the Chinese banyans, which is typical of thrip infestation, was noted.

Figure 3. Superficial and deep perivascular and interstitial dermatitis (A)(H&E, original magnification ×10) with lymphocytic predominance (B)(H&E, original magnification ×40).

After completion of a resource-intensive investigation that included site survey, literature review, detailed patient history including thrips-associated skin manifestations, and thorough consultation with local dermatologists and entomologists, the findings seemingly pointed to thrips as the most likely etiology of the eruption seen in our patients and a diagnosis of Thysanoptera dermatitis was made.

Comment

Thrips are small winged insects in the order Thysanoptera, which comprises more than 5000 identified species ranging in size from 0.5 to 15 mm, though most are approximately 1 mm.¹ The insects typically are phytophagous (feeding on plants) and are attracted to humidity and seemingly the sweat of animals and humans.² Although largely a phytophagous organism, a few published cases of thrips exposure reported papular skin eruptions known as Thysanoptera dermatitis.^3-8 Several species of thrips across the globe have been associated with incidental attacks on humans to include “Heliothrips indicus Bagnall, a cotton pest of the Sudan; Thrips imagines Bagnall, reported in Australia; Limothrips cerealium (Haliday), in Germany; Gynaitkothrips uzeli Zimmerman, in Algeria; and other species.”⁷ In Hawaii, Gynaikothrips ficorum (Cuban laurel thrips) is a common pest of the Chinese banyan tree (F microcarpa) tree.⁹

A case series reported by Goldstein and Skipworth⁵ in the late 1960s of military personnel stationed in Oahu described exposure to similar environmental conditions with resultant lesions that were nearly identical to those seen in our patients. The final conclusion of the investigation was that Cuban laurel thrips were the likely etiology, though mites also were considered.⁵ In a subsequent commentary in 1968, Waisman¹⁰ reported similar eruptions in hospitalized patients with further comment regarding the nocturnal occurrence of the bites. Additionally, the eruptions were reported to be short lasting and devoid of discomfort, similar to our patient population.¹⁰

Following suit, Aeling⁶ published a case series in 1974 depicting several service members who presented with symptoms that were nearly identical to the symptoms experienced by our patients as well as those of Goldstein and Skipworth.⁵ The investigator coined the term hypoanesthetic halos in Hawaii to describe the findings and further reported that Hawaiian dermatologists were familiar with the symptoms and clinical presentation of the disease. Patients in this outbreak had observed small flying insects, similar to the reports from our patients, and postulated that the symptoms occurred secondary to insect bites.⁶

Since the report by Goldstein and Skipworth⁵ in 1968, the majority of the literature regarding Thysanoptera dermatitis has largely been in case reports. In 1987, Fishman⁷ reported the case of a 43-year-old woman who presented with a palm-sized area of grouped red puncta on the lateral neck with the subsequent entrapment and identification of a flower thrips from the patient’s clothing. In 2005, Leigheb et al² reported the case of a 30-year-old man with an erythematous papular cutaneous eruption on the anterior chest. In this case, the causative etiology was unequivocally confirmed upon identification of the presence of thrips on biopsy.² In 2006, Guarneri et al¹ reported the case of a 59-year-old farmer who had tentatively been diagnosed with delusional parasitosis until persistent presentation to a dermatologist for evaluation enabled the capture and identification of grain thrips. More recently, another case of likely Thysanoptera dermatitis was published in 2012 after a man presented with a slide-mounted thrip from his skin for evaluation as to a potential cause of a recurrent rash he had been experiencing.¹¹ In all of these cases, it was fortunate that a specific organism could be identified for 2 reasons: (1) members of the order Thysanoptera have a biological cycle of only 11 to 36 days, and (2) thrips may go virtually unnoticed by humans, as they are often difficult to see due to their small size.^2,12 Perhaps the most extensive report, however, comes from Childers et al⁸ in a descriptive case series published in 2005. In this report, the investigators provided a thorough detailing of multiple encounters dating back to 1883 through which patients were inadvertently exposed to various species of thrips and subsequently presented with arthropod bites.

Conclusion

The rapid and clustered manner of patient presentation in this case series makes it unique and highlights the need for further consideration of Thysanoptera dermatitis as a potential etiology for an outbreak of a papular eruption. Further reporting may help to better contextualize the true epidemiology of the condition and subsequently may trigger its greater inclusion in the differential diagnosis for a pruritic papular eruption.

Acknowledgments

We would like to extend our appreciation to Amy Spizuoco, DO (New York, New York), for her assistance with the initial diagnosis; Steve Montgomery, PhD (Honolulu, Hawaii), for his assistance with further entomological discussion of potential etiologies; and John R. Gilstad, MD (Honolulu, Hawaii), for contributing his thoughts on the differential diagnosis of the presenting symptoms.

Case Reports

A platoon of 24 US Marines participated in a 1-week outdoor training exercise (February 4–8) at the Marine Corps Training Area Bellows in Oahu, Hawaii. During the last 3 days of training, 15 (62.5%) marines presented to the same primary care provider with what appeared to be diffuse scattered lesions on the face, neck, and dorsal aspect of the hands. All 15 patients reported that they noticed the lesions upon waking up the morning after their second night at the training area. The patients were unable to recollect specific direct arthropod interactions, but they reported the presence of “bugs” in the training area and denied use of any insect repellents, insect nets, or sunscreen. Sleeping arrangements varied from covered vehicles and cots to sleeping bags on the ground, which were laundered independently by each marine and thereby were ruled out as a commonality. The patients denied working with any chemicals or cleansers while in the field. Further questioning of all 15 patients revealed a history of extended contact with live foliage as branches were broken off to build camouflaged sites.

The following week, a second platoon of 20 marines occupied a separate undisturbed portion of the same training area for a similar 1-week training evolution. Manifestation of similar symptoms among members of the second group, who had no contact with the initial 15 patients, supported the likely environmental etiology of the eruptions.

Figure 1. Numerous well-circumscribed, discrete, pink-red papules diffusely scattered across the face.

Figure 2. Papules with classic anemic halos.

Referral

Two patients from the first group were evaluated at the dermatology clinic at Tripler Army Medical Center (Honolulu, Hawaii) on day 10 of the initial outbreak. Cutaneous examination revealed numerous discrete, pink-red, well-circumscribed, 2- to 4-mm, dome-shaped papules exclusive to exposed areas on the face, neck, and dorsal aspect of the hands (Figures 1 and 2). Anemic halos surrounding the hand papules were noted (Figure 2). A punch biopsy in both patients revealed spongiotic dermatitis with superficial perivascular and interstitial lymphohistiocytic inflammation with eosinophils, suggestive of an arthropod bite (Figure 3). No retained arthropod parts wereidentified. Both patients were treated with triamcinolone ointment twice daily for 7 days with total resolution of the lesions.

Site Survey Results

Five days following the initial presentation of the first outbreak, a daytime site survey of the training area was conducted by a medical entomologist, an environmental health scientist, and a wildlife biologist. Records indicated that prior to the current utilization, the training area had not been used for 9 months. Approximately half of the training area was covered with mixed scrub vegetation and the remainder was clear pavement or sand (clear of vegetation). Feral hogs (Sus scrofa), cats (Felis domesticus), and mongooses (Herpestes javanicus) were observed at the site. Patient interviews and site survey ruled out a number of potential environmental irritants, including contact with fresh or salt water and chemical contaminants in the air or soil.

Because biting insects were suspected as the cause of the eruptions, an overnight entomological survey was conducted 3 weeks after the first outbreak under similar weather conditions and was centered in the area of an Australian pine (Casuarina equisetifolia) forest where most of the marines had slept during training. Mosquitoes (Aedes albopictus and Culex quinquefasciatus) were observed in the area, with an estimated biting rate of 1 to 2 bites per hour. Centipedes (Scolopendra subspinipes) were commonly observed after dark. There was no sign of heavy bird roosting or nesting, which would be a possible source of biting ectoparasites. Other than the Australian pine, notable vegetation present included Christmasberry (Schinus terebinthifolius), koa haole (Leucaena leucocephala), and Chinese banyan (Ficus microcarpa). A survey of the vegetation uncovered no notable insects, and no damage to the leaves of the Chinese banyans, which is typical of thrip infestation, was noted.

Figure 3. Superficial and deep perivascular and interstitial dermatitis (A)(H&E, original magnification ×10) with lymphocytic predominance (B)(H&E, original magnification ×40).

After completion of a resource-intensive investigation that included site survey, literature review, detailed patient history including thrips-associated skin manifestations, and thorough consultation with local dermatologists and entomologists, the findings seemingly pointed to thrips as the most likely etiology of the eruption seen in our patients and a diagnosis of Thysanoptera dermatitis was made.

Comment

Thrips are small winged insects in the order Thysanoptera, which comprises more than 5000 identified species ranging in size from 0.5 to 15 mm, though most are approximately 1 mm.¹ The insects typically are phytophagous (feeding on plants) and are attracted to humidity and seemingly the sweat of animals and humans.² Although largely a phytophagous organism, a few published cases of thrips exposure reported papular skin eruptions known as Thysanoptera dermatitis.^3-8 Several species of thrips across the globe have been associated with incidental attacks on humans to include “Heliothrips indicus Bagnall, a cotton pest of the Sudan; Thrips imagines Bagnall, reported in Australia; Limothrips cerealium (Haliday), in Germany; Gynaitkothrips uzeli Zimmerman, in Algeria; and other species.”⁷ In Hawaii, Gynaikothrips ficorum (Cuban laurel thrips) is a common pest of the Chinese banyan tree (F microcarpa) tree.⁹

A case series reported by Goldstein and Skipworth⁵ in the late 1960s of military personnel stationed in Oahu described exposure to similar environmental conditions with resultant lesions that were nearly identical to those seen in our patients. The final conclusion of the investigation was that Cuban laurel thrips were the likely etiology, though mites also were considered.⁵ In a subsequent commentary in 1968, Waisman¹⁰ reported similar eruptions in hospitalized patients with further comment regarding the nocturnal occurrence of the bites. Additionally, the eruptions were reported to be short lasting and devoid of discomfort, similar to our patient population.¹⁰

Following suit, Aeling⁶ published a case series in 1974 depicting several service members who presented with symptoms that were nearly identical to the symptoms experienced by our patients as well as those of Goldstein and Skipworth.⁵ The investigator coined the term hypoanesthetic halos in Hawaii to describe the findings and further reported that Hawaiian dermatologists were familiar with the symptoms and clinical presentation of the disease. Patients in this outbreak had observed small flying insects, similar to the reports from our patients, and postulated that the symptoms occurred secondary to insect bites.⁶

Since the report by Goldstein and Skipworth⁵ in 1968, the majority of the literature regarding Thysanoptera dermatitis has largely been in case reports. In 1987, Fishman⁷ reported the case of a 43-year-old woman who presented with a palm-sized area of grouped red puncta on the lateral neck with the subsequent entrapment and identification of a flower thrips from the patient’s clothing. In 2005, Leigheb et al² reported the case of a 30-year-old man with an erythematous papular cutaneous eruption on the anterior chest. In this case, the causative etiology was unequivocally confirmed upon identification of the presence of thrips on biopsy.² In 2006, Guarneri et al¹ reported the case of a 59-year-old farmer who had tentatively been diagnosed with delusional parasitosis until persistent presentation to a dermatologist for evaluation enabled the capture and identification of grain thrips. More recently, another case of likely Thysanoptera dermatitis was published in 2012 after a man presented with a slide-mounted thrip from his skin for evaluation as to a potential cause of a recurrent rash he had been experiencing.¹¹ In all of these cases, it was fortunate that a specific organism could be identified for 2 reasons: (1) members of the order Thysanoptera have a biological cycle of only 11 to 36 days, and (2) thrips may go virtually unnoticed by humans, as they are often difficult to see due to their small size.^2,12 Perhaps the most extensive report, however, comes from Childers et al⁸ in a descriptive case series published in 2005. In this report, the investigators provided a thorough detailing of multiple encounters dating back to 1883 through which patients were inadvertently exposed to various species of thrips and subsequently presented with arthropod bites.

Conclusion

The rapid and clustered manner of patient presentation in this case series makes it unique and highlights the need for further consideration of Thysanoptera dermatitis as a potential etiology for an outbreak of a papular eruption. Further reporting may help to better contextualize the true epidemiology of the condition and subsequently may trigger its greater inclusion in the differential diagnosis for a pruritic papular eruption.

Acknowledgments

We would like to extend our appreciation to Amy Spizuoco, DO (New York, New York), for her assistance with the initial diagnosis; Steve Montgomery, PhD (Honolulu, Hawaii), for his assistance with further entomological discussion of potential etiologies; and John R. Gilstad, MD (Honolulu, Hawaii), for contributing his thoughts on the differential diagnosis of the presenting symptoms.

Case Reports

A platoon of 24 US Marines participated in a 1-week outdoor training exercise (February 4–8) at the Marine Corps Training Area Bellows in Oahu, Hawaii. During the last 3 days of training, 15 (62.5%) marines presented to the same primary care provider with what appeared to be diffuse scattered lesions on the face, neck, and dorsal aspect of the hands. All 15 patients reported that they noticed the lesions upon waking up the morning after their second night at the training area. The patients were unable to recollect specific direct arthropod interactions, but they reported the presence of “bugs” in the training area and denied use of any insect repellents, insect nets, or sunscreen. Sleeping arrangements varied from covered vehicles and cots to sleeping bags on the ground, which were laundered independently by each marine and thereby were ruled out as a commonality. The patients denied working with any chemicals or cleansers while in the field. Further questioning of all 15 patients revealed a history of extended contact with live foliage as branches were broken off to build camouflaged sites.

The following week, a second platoon of 20 marines occupied a separate undisturbed portion of the same training area for a similar 1-week training evolution. Manifestation of similar symptoms among members of the second group, who had no contact with the initial 15 patients, supported the likely environmental etiology of the eruptions.

Figure 1. Numerous well-circumscribed, discrete, pink-red papules diffusely scattered across the face.

Figure 2. Papules with classic anemic halos.

Referral

Two patients from the first group were evaluated at the dermatology clinic at Tripler Army Medical Center (Honolulu, Hawaii) on day 10 of the initial outbreak. Cutaneous examination revealed numerous discrete, pink-red, well-circumscribed, 2- to 4-mm, dome-shaped papules exclusive to exposed areas on the face, neck, and dorsal aspect of the hands (Figures 1 and 2). Anemic halos surrounding the hand papules were noted (Figure 2). A punch biopsy in both patients revealed spongiotic dermatitis with superficial perivascular and interstitial lymphohistiocytic inflammation with eosinophils, suggestive of an arthropod bite (Figure 3). No retained arthropod parts wereidentified. Both patients were treated with triamcinolone ointment twice daily for 7 days with total resolution of the lesions.

Site Survey Results

Five days following the initial presentation of the first outbreak, a daytime site survey of the training area was conducted by a medical entomologist, an environmental health scientist, and a wildlife biologist. Records indicated that prior to the current utilization, the training area had not been used for 9 months. Approximately half of the training area was covered with mixed scrub vegetation and the remainder was clear pavement or sand (clear of vegetation). Feral hogs (Sus scrofa), cats (Felis domesticus), and mongooses (Herpestes javanicus) were observed at the site. Patient interviews and site survey ruled out a number of potential environmental irritants, including contact with fresh or salt water and chemical contaminants in the air or soil.

Because biting insects were suspected as the cause of the eruptions, an overnight entomological survey was conducted 3 weeks after the first outbreak under similar weather conditions and was centered in the area of an Australian pine (Casuarina equisetifolia) forest where most of the marines had slept during training. Mosquitoes (Aedes albopictus and Culex quinquefasciatus) were observed in the area, with an estimated biting rate of 1 to 2 bites per hour. Centipedes (Scolopendra subspinipes) were commonly observed after dark. There was no sign of heavy bird roosting or nesting, which would be a possible source of biting ectoparasites. Other than the Australian pine, notable vegetation present included Christmasberry (Schinus terebinthifolius), koa haole (Leucaena leucocephala), and Chinese banyan (Ficus microcarpa). A survey of the vegetation uncovered no notable insects, and no damage to the leaves of the Chinese banyans, which is typical of thrip infestation, was noted.

Figure 3. Superficial and deep perivascular and interstitial dermatitis (A)(H&E, original magnification ×10) with lymphocytic predominance (B)(H&E, original magnification ×40).

After completion of a resource-intensive investigation that included site survey, literature review, detailed patient history including thrips-associated skin manifestations, and thorough consultation with local dermatologists and entomologists, the findings seemingly pointed to thrips as the most likely etiology of the eruption seen in our patients and a diagnosis of Thysanoptera dermatitis was made.

Comment

Thrips are small winged insects in the order Thysanoptera, which comprises more than 5000 identified species ranging in size from 0.5 to 15 mm, though most are approximately 1 mm.¹ The insects typically are phytophagous (feeding on plants) and are attracted to humidity and seemingly the sweat of animals and humans.² Although largely a phytophagous organism, a few published cases of thrips exposure reported papular skin eruptions known as Thysanoptera dermatitis.^3-8 Several species of thrips across the globe have been associated with incidental attacks on humans to include “Heliothrips indicus Bagnall, a cotton pest of the Sudan; Thrips imagines Bagnall, reported in Australia; Limothrips cerealium (Haliday), in Germany; Gynaitkothrips uzeli Zimmerman, in Algeria; and other species.”⁷ In Hawaii, Gynaikothrips ficorum (Cuban laurel thrips) is a common pest of the Chinese banyan tree (F microcarpa) tree.⁹

A case series reported by Goldstein and Skipworth⁵ in the late 1960s of military personnel stationed in Oahu described exposure to similar environmental conditions with resultant lesions that were nearly identical to those seen in our patients. The final conclusion of the investigation was that Cuban laurel thrips were the likely etiology, though mites also were considered.⁵ In a subsequent commentary in 1968, Waisman¹⁰ reported similar eruptions in hospitalized patients with further comment regarding the nocturnal occurrence of the bites. Additionally, the eruptions were reported to be short lasting and devoid of discomfort, similar to our patient population.¹⁰

Following suit, Aeling⁶ published a case series in 1974 depicting several service members who presented with symptoms that were nearly identical to the symptoms experienced by our patients as well as those of Goldstein and Skipworth.⁵ The investigator coined the term hypoanesthetic halos in Hawaii to describe the findings and further reported that Hawaiian dermatologists were familiar with the symptoms and clinical presentation of the disease. Patients in this outbreak had observed small flying insects, similar to the reports from our patients, and postulated that the symptoms occurred secondary to insect bites.⁶

Since the report by Goldstein and Skipworth⁵ in 1968, the majority of the literature regarding Thysanoptera dermatitis has largely been in case reports. In 1987, Fishman⁷ reported the case of a 43-year-old woman who presented with a palm-sized area of grouped red puncta on the lateral neck with the subsequent entrapment and identification of a flower thrips from the patient’s clothing. In 2005, Leigheb et al² reported the case of a 30-year-old man with an erythematous papular cutaneous eruption on the anterior chest. In this case, the causative etiology was unequivocally confirmed upon identification of the presence of thrips on biopsy.² In 2006, Guarneri et al¹ reported the case of a 59-year-old farmer who had tentatively been diagnosed with delusional parasitosis until persistent presentation to a dermatologist for evaluation enabled the capture and identification of grain thrips. More recently, another case of likely Thysanoptera dermatitis was published in 2012 after a man presented with a slide-mounted thrip from his skin for evaluation as to a potential cause of a recurrent rash he had been experiencing.¹¹ In all of these cases, it was fortunate that a specific organism could be identified for 2 reasons: (1) members of the order Thysanoptera have a biological cycle of only 11 to 36 days, and (2) thrips may go virtually unnoticed by humans, as they are often difficult to see due to their small size.^2,12 Perhaps the most extensive report, however, comes from Childers et al⁸ in a descriptive case series published in 2005. In this report, the investigators provided a thorough detailing of multiple encounters dating back to 1883 through which patients were inadvertently exposed to various species of thrips and subsequently presented with arthropod bites.

Conclusion

The rapid and clustered manner of patient presentation in this case series makes it unique and highlights the need for further consideration of Thysanoptera dermatitis as a potential etiology for an outbreak of a papular eruption. Further reporting may help to better contextualize the true epidemiology of the condition and subsequently may trigger its greater inclusion in the differential diagnosis for a pruritic papular eruption.

Acknowledgments

We would like to extend our appreciation to Amy Spizuoco, DO (New York, New York), for her assistance with the initial diagnosis; Steve Montgomery, PhD (Honolulu, Hawaii), for his assistance with further entomological discussion of potential etiologies; and John R. Gilstad, MD (Honolulu, Hawaii), for contributing his thoughts on the differential diagnosis of the presenting symptoms.