GLASGOW – Individuals given COVID-19 vaccination may experience a wide range of dermatologic reactions, some of which may be life-threatening, reveals a prospective Indian study that suggests histopathological assessment is key to understanding the cause.

Studying more than 130 patients who presented with vaccine-related dermatologic reactions, the researchers found that the most common acute adverse events were acute urticaria, generalized pruritus, and maculopapular rash.

Dermal hypersensitivity reactions occurred within 3 days of vaccination, which suggests the culprit is an immediate type 1 hypersensitivity reaction, said study presenter Alpana Mohta, MD, department of dermatology, Sardar Patel Medical College, Bikaner, Rajasthan, India. Most of the patients had received the AstraZeneca vaccine, she said.

The most common delayed events were pityriasis rosea and lichen planus, which occurred within 3-4 weeks of vaccination and could be a result of delayed hypersensitivity or a T cell–mediated skin reaction caused by “molecular mimicry with a viral epitope,” Dr. Mohta said.

The research was presented at the British Association of Dermatologists (BAD) 2022 Annual Meeting on July 5.

Dr. Mohta said that, given the “surge” in the number of people who have been vaccinated, it is “imperative as dermatologists” to maintain a “very high index of suspicion to differentiate reactions caused by vaccination” from other causes, and a proper assessment should be performed in “every patient” who presents with a possible reaction.

She also emphasized that “since so many clinical [COVID-19] variants are being encountered,” histopathological assessment could “help in better understanding the underlying pathophysiology” of every reaction.

Dr. Mohta began her presentation by explaining that India is running one of the “world’s largest vaccination drives” for COVID-19, with almost 90% of adults fully vaccinated.

She added that studies have indicated that the incidence of cutaneous adverse reactions following COVID-19 vaccination ranges from 1.0% to 1.9% and that dermatologists have encountered a “plethora” of related reactions.

Dr. Mohta emphasized that the “myriad presentations” of these reactions means that correlating clinical and pathological findings is “key” to understanding the underlying pathophysiology.

She and her colleagues therefore conducted a prospective, hospital-based study of patients who self-reported mucocutaneous adverse reactions from April to December 2021, within 4 weeks of receiving a COVID-19 vaccine.

They gathered information on the patients’ signs and symptoms, as well as the date of vaccine administration and the type of vaccine given, alongside a detailed medical history, including previous allergies, prior COVID-19 infection, and any comorbidities.

The patients also underwent a clinical examination and laboratory investigations, and their cases were assessed by two senior dermatologists to determine whether the association between the adverse event and COVID-19 vaccination was likely causal.

Dr. Mohta said that 132 adult patients, with an average age of 38.2 years, were identified as having vaccine-related reactions.

This included 84 (63.6%) patients with a mild reaction, defined as resolving with symptomatic treatment; 43 (32.6%) patients with a moderate reaction, defined as extensive and lasting for more than 4 weeks; and five (3.8%) patients with severe reactions, defined as systemic and potentially life-threatening.

The mild group included 21 patients with acute urticaria, with a mean onset of 1.2 days following vaccination, as well as 20 cases of maculopapular rash, with a mean onset of 2.4 days; 18 cases of pityriasis rosea, with a mean onset of 17.4 days; and nine cases of eruptive pseudoangioma, with a mean onset of 3.5 days.

There were 16 cases of lichen planus in the moderate group, with a mean onset of 22.7 days after COVID-19 vaccination; nine cases of herpes zoster, with a mean onset of 15.3 days; and one case of pityriasis lichenoides et varioliformis acuta (PLEVA), among others.

The severe group included two cases of erythroderma, with a mean onset of 9 days after vaccination; one case of drug rash with eosinophilia and systemic symptoms (DRESS), with a mean onset of 20 days; and one case each of subacute cutaneous lupus erythematosus (SCLE) and bullous pemphigoid, with mean onsets of 15 days and 14 days, respectively.

Turning to the histopathological results, Dr. Mohta explained that only 57 patients from their cohort agreed to have a skin biopsy.

Results of those skin biopsies showed that 21 (36.8%) patients had vaccine-related eruption of papules and plaques, predominantly spongiotic dermatitis. This correlated with the clinical diagnoses of pityriasis rosea, maculopapular and papulosquamous rash, and DRESS.

Lichenoid and interface dermatitis were seen in 13 (22.8%) patients, which correlated with the clinical diagnoses of lichen planus, PLEVA, and SCLE. Eleven (19.3%) patients had a dermal hypersensitivity reaction, equated to the clinical diagnoses of urticaria, and eruptive pseudoangioma.

Dr. Mohta acknowledged that the study was limited by the inability to calculate the “true prevalence of vaccine-associated reactions,” and because immunohistochemistry was not performed.

Session chair Saleem Taibjee, MD, department of dermatology, Dorset County Hospital NHS Foundation Trust, Dorchester, United Kingdom, congratulated Dr. Mohta on her “very interesting” presentation, highlighting their “extensive experience in such a large cohort of patients.”

He asked what type of COVID-19 vaccines the patients had received, and whether Dr. Mohta could provide any “insights into which patients you can safely give the vaccine again to, and those [to whom] you may avoid giving further doses.”

Dr. Mohta said that the majority of the patients in the study received the AstraZeneca COVID-19 vaccine, as that was the one most commonly used in India at the time, with around 30 patients receiving the Indian Covishield version of the AstraZeneca vaccine. (The two-dose AstraZeneca vaccine, which is cheaper to manufacture and easier to store at typical refrigerated temperatures than mRNA-based vaccines, has been authorized by the World Health Organization, the European Medicines Agency, and over 50 countries but has not been authorized in the United States.)

She added that none of the patients in the study with mild-to-moderate skin reactions were advised against receiving further doses” but that those with severe reactions “were advised not to take any further doses.”

Consequently, in the case of mild reactions, “further doses are not a contraindication,” Dr. Mohta said, but patients with more severe reactions should be considered on a “case by case basis.”

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

GLASGOW – Individuals given COVID-19 vaccination may experience a wide range of dermatologic reactions, some of which may be life-threatening, reveals a prospective Indian study that suggests histopathological assessment is key to understanding the cause.

Studying more than 130 patients who presented with vaccine-related dermatologic reactions, the researchers found that the most common acute adverse events were acute urticaria, generalized pruritus, and maculopapular rash.

Dermal hypersensitivity reactions occurred within 3 days of vaccination, which suggests the culprit is an immediate type 1 hypersensitivity reaction, said study presenter Alpana Mohta, MD, department of dermatology, Sardar Patel Medical College, Bikaner, Rajasthan, India. Most of the patients had received the AstraZeneca vaccine, she said.

The most common delayed events were pityriasis rosea and lichen planus, which occurred within 3-4 weeks of vaccination and could be a result of delayed hypersensitivity or a T cell–mediated skin reaction caused by “molecular mimicry with a viral epitope,” Dr. Mohta said.

The research was presented at the British Association of Dermatologists (BAD) 2022 Annual Meeting on July 5.

Dr. Mohta said that, given the “surge” in the number of people who have been vaccinated, it is “imperative as dermatologists” to maintain a “very high index of suspicion to differentiate reactions caused by vaccination” from other causes, and a proper assessment should be performed in “every patient” who presents with a possible reaction.

She also emphasized that “since so many clinical [COVID-19] variants are being encountered,” histopathological assessment could “help in better understanding the underlying pathophysiology” of every reaction.

Dr. Mohta began her presentation by explaining that India is running one of the “world’s largest vaccination drives” for COVID-19, with almost 90% of adults fully vaccinated.

She added that studies have indicated that the incidence of cutaneous adverse reactions following COVID-19 vaccination ranges from 1.0% to 1.9% and that dermatologists have encountered a “plethora” of related reactions.

Dr. Mohta emphasized that the “myriad presentations” of these reactions means that correlating clinical and pathological findings is “key” to understanding the underlying pathophysiology.

She and her colleagues therefore conducted a prospective, hospital-based study of patients who self-reported mucocutaneous adverse reactions from April to December 2021, within 4 weeks of receiving a COVID-19 vaccine.

They gathered information on the patients’ signs and symptoms, as well as the date of vaccine administration and the type of vaccine given, alongside a detailed medical history, including previous allergies, prior COVID-19 infection, and any comorbidities.

The patients also underwent a clinical examination and laboratory investigations, and their cases were assessed by two senior dermatologists to determine whether the association between the adverse event and COVID-19 vaccination was likely causal.

Dr. Mohta said that 132 adult patients, with an average age of 38.2 years, were identified as having vaccine-related reactions.

This included 84 (63.6%) patients with a mild reaction, defined as resolving with symptomatic treatment; 43 (32.6%) patients with a moderate reaction, defined as extensive and lasting for more than 4 weeks; and five (3.8%) patients with severe reactions, defined as systemic and potentially life-threatening.

The mild group included 21 patients with acute urticaria, with a mean onset of 1.2 days following vaccination, as well as 20 cases of maculopapular rash, with a mean onset of 2.4 days; 18 cases of pityriasis rosea, with a mean onset of 17.4 days; and nine cases of eruptive pseudoangioma, with a mean onset of 3.5 days.

There were 16 cases of lichen planus in the moderate group, with a mean onset of 22.7 days after COVID-19 vaccination; nine cases of herpes zoster, with a mean onset of 15.3 days; and one case of pityriasis lichenoides et varioliformis acuta (PLEVA), among others.

The severe group included two cases of erythroderma, with a mean onset of 9 days after vaccination; one case of drug rash with eosinophilia and systemic symptoms (DRESS), with a mean onset of 20 days; and one case each of subacute cutaneous lupus erythematosus (SCLE) and bullous pemphigoid, with mean onsets of 15 days and 14 days, respectively.

Turning to the histopathological results, Dr. Mohta explained that only 57 patients from their cohort agreed to have a skin biopsy.

Results of those skin biopsies showed that 21 (36.8%) patients had vaccine-related eruption of papules and plaques, predominantly spongiotic dermatitis. This correlated with the clinical diagnoses of pityriasis rosea, maculopapular and papulosquamous rash, and DRESS.

Lichenoid and interface dermatitis were seen in 13 (22.8%) patients, which correlated with the clinical diagnoses of lichen planus, PLEVA, and SCLE. Eleven (19.3%) patients had a dermal hypersensitivity reaction, equated to the clinical diagnoses of urticaria, and eruptive pseudoangioma.

Dr. Mohta acknowledged that the study was limited by the inability to calculate the “true prevalence of vaccine-associated reactions,” and because immunohistochemistry was not performed.

Session chair Saleem Taibjee, MD, department of dermatology, Dorset County Hospital NHS Foundation Trust, Dorchester, United Kingdom, congratulated Dr. Mohta on her “very interesting” presentation, highlighting their “extensive experience in such a large cohort of patients.”

He asked what type of COVID-19 vaccines the patients had received, and whether Dr. Mohta could provide any “insights into which patients you can safely give the vaccine again to, and those [to whom] you may avoid giving further doses.”

Dr. Mohta said that the majority of the patients in the study received the AstraZeneca COVID-19 vaccine, as that was the one most commonly used in India at the time, with around 30 patients receiving the Indian Covishield version of the AstraZeneca vaccine. (The two-dose AstraZeneca vaccine, which is cheaper to manufacture and easier to store at typical refrigerated temperatures than mRNA-based vaccines, has been authorized by the World Health Organization, the European Medicines Agency, and over 50 countries but has not been authorized in the United States.)

She added that none of the patients in the study with mild-to-moderate skin reactions were advised against receiving further doses” but that those with severe reactions “were advised not to take any further doses.”

Consequently, in the case of mild reactions, “further doses are not a contraindication,” Dr. Mohta said, but patients with more severe reactions should be considered on a “case by case basis.”

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

GLASGOW – Individuals given COVID-19 vaccination may experience a wide range of dermatologic reactions, some of which may be life-threatening, reveals a prospective Indian study that suggests histopathological assessment is key to understanding the cause.

Studying more than 130 patients who presented with vaccine-related dermatologic reactions, the researchers found that the most common acute adverse events were acute urticaria, generalized pruritus, and maculopapular rash.

Dermal hypersensitivity reactions occurred within 3 days of vaccination, which suggests the culprit is an immediate type 1 hypersensitivity reaction, said study presenter Alpana Mohta, MD, department of dermatology, Sardar Patel Medical College, Bikaner, Rajasthan, India. Most of the patients had received the AstraZeneca vaccine, she said.

The most common delayed events were pityriasis rosea and lichen planus, which occurred within 3-4 weeks of vaccination and could be a result of delayed hypersensitivity or a T cell–mediated skin reaction caused by “molecular mimicry with a viral epitope,” Dr. Mohta said.

The research was presented at the British Association of Dermatologists (BAD) 2022 Annual Meeting on July 5.

Dr. Mohta said that, given the “surge” in the number of people who have been vaccinated, it is “imperative as dermatologists” to maintain a “very high index of suspicion to differentiate reactions caused by vaccination” from other causes, and a proper assessment should be performed in “every patient” who presents with a possible reaction.

She also emphasized that “since so many clinical [COVID-19] variants are being encountered,” histopathological assessment could “help in better understanding the underlying pathophysiology” of every reaction.

Dr. Mohta began her presentation by explaining that India is running one of the “world’s largest vaccination drives” for COVID-19, with almost 90% of adults fully vaccinated.

She added that studies have indicated that the incidence of cutaneous adverse reactions following COVID-19 vaccination ranges from 1.0% to 1.9% and that dermatologists have encountered a “plethora” of related reactions.

Dr. Mohta emphasized that the “myriad presentations” of these reactions means that correlating clinical and pathological findings is “key” to understanding the underlying pathophysiology.

She and her colleagues therefore conducted a prospective, hospital-based study of patients who self-reported mucocutaneous adverse reactions from April to December 2021, within 4 weeks of receiving a COVID-19 vaccine.

They gathered information on the patients’ signs and symptoms, as well as the date of vaccine administration and the type of vaccine given, alongside a detailed medical history, including previous allergies, prior COVID-19 infection, and any comorbidities.

The patients also underwent a clinical examination and laboratory investigations, and their cases were assessed by two senior dermatologists to determine whether the association between the adverse event and COVID-19 vaccination was likely causal.

Dr. Mohta said that 132 adult patients, with an average age of 38.2 years, were identified as having vaccine-related reactions.

This included 84 (63.6%) patients with a mild reaction, defined as resolving with symptomatic treatment; 43 (32.6%) patients with a moderate reaction, defined as extensive and lasting for more than 4 weeks; and five (3.8%) patients with severe reactions, defined as systemic and potentially life-threatening.

The mild group included 21 patients with acute urticaria, with a mean onset of 1.2 days following vaccination, as well as 20 cases of maculopapular rash, with a mean onset of 2.4 days; 18 cases of pityriasis rosea, with a mean onset of 17.4 days; and nine cases of eruptive pseudoangioma, with a mean onset of 3.5 days.

There were 16 cases of lichen planus in the moderate group, with a mean onset of 22.7 days after COVID-19 vaccination; nine cases of herpes zoster, with a mean onset of 15.3 days; and one case of pityriasis lichenoides et varioliformis acuta (PLEVA), among others.

The severe group included two cases of erythroderma, with a mean onset of 9 days after vaccination; one case of drug rash with eosinophilia and systemic symptoms (DRESS), with a mean onset of 20 days; and one case each of subacute cutaneous lupus erythematosus (SCLE) and bullous pemphigoid, with mean onsets of 15 days and 14 days, respectively.

Turning to the histopathological results, Dr. Mohta explained that only 57 patients from their cohort agreed to have a skin biopsy.

Results of those skin biopsies showed that 21 (36.8%) patients had vaccine-related eruption of papules and plaques, predominantly spongiotic dermatitis. This correlated with the clinical diagnoses of pityriasis rosea, maculopapular and papulosquamous rash, and DRESS.

Lichenoid and interface dermatitis were seen in 13 (22.8%) patients, which correlated with the clinical diagnoses of lichen planus, PLEVA, and SCLE. Eleven (19.3%) patients had a dermal hypersensitivity reaction, equated to the clinical diagnoses of urticaria, and eruptive pseudoangioma.

Dr. Mohta acknowledged that the study was limited by the inability to calculate the “true prevalence of vaccine-associated reactions,” and because immunohistochemistry was not performed.

Session chair Saleem Taibjee, MD, department of dermatology, Dorset County Hospital NHS Foundation Trust, Dorchester, United Kingdom, congratulated Dr. Mohta on her “very interesting” presentation, highlighting their “extensive experience in such a large cohort of patients.”

He asked what type of COVID-19 vaccines the patients had received, and whether Dr. Mohta could provide any “insights into which patients you can safely give the vaccine again to, and those [to whom] you may avoid giving further doses.”

Dr. Mohta said that the majority of the patients in the study received the AstraZeneca COVID-19 vaccine, as that was the one most commonly used in India at the time, with around 30 patients receiving the Indian Covishield version of the AstraZeneca vaccine. (The two-dose AstraZeneca vaccine, which is cheaper to manufacture and easier to store at typical refrigerated temperatures than mRNA-based vaccines, has been authorized by the World Health Organization, the European Medicines Agency, and over 50 countries but has not been authorized in the United States.)

She added that none of the patients in the study with mild-to-moderate skin reactions were advised against receiving further doses” but that those with severe reactions “were advised not to take any further doses.”

Consequently, in the case of mild reactions, “further doses are not a contraindication,” Dr. Mohta said, but patients with more severe reactions should be considered on a “case by case basis.”

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

A large case-control study finds the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than previously determined from prior analyses showing associations with breast, ovarian, prostate, and pancreatic cancers. The finding, published in JAMA Oncology suggests a possible broader clinical relevance for BRCA1 and BRCA2 genetic testing.

Pathogenic variants in BRCA1 were found to be associated with biliary tract cancer, in BRCA2 with esophageal cancer, and in BRCA1/2 with gastric cancer.

“The results suggest the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is likely broader than that determined from previous analysis of largely European ancestry cohorts,” wrote authors who were led by Yukihide Momozawa, DVM, PhD, RIKEN Center for Integrative Medical Sciences, Japan.

“These risk association findings, together with our analysis of an association with family history of cancer and clinical phenotypes, are relevant for developing and adapting guidelines about genetic testing, treatment options, and treatability with PARP [poly adenosine diphosphate-ribose polymerase] inhibitors for each cancer type,” the authors wrote.

Dr. Momozawa and associates conducted a large-scale sequencing study across 14 common cancer types in 63,828 patients (mean age 64 years, 42% female) and 37,086 controls on data drawn from a Japanese nationwide biobank between April 2003 and March 2018. They estimated the risk of each cancer type and determined clinical characteristics associated with pathogenic variant carrier status, while also investigating the utility of family history in detecting patients with pathogenic variants.

Three hundred fifteen pathogenic variants were identified. An odds ratios of greater than 4.0 (with P < 1 × 10−4 as the threshold of significance) for the pathogenic variants were found for biliary tract cancer (OR, 17.4; 95% confidence interval, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2. Two other cancer types were found to be associated with BRCA1, and four other cancer types with BRCA2. Enrichment of carrier patients was shown in biliary tract, female breast, ovarian, and prostate cancers in accordance with increased numbers of reported cancer types in relatives.

Male patients with breast cancer had a very high carrier frequency of pathogenic variants in BRCA2 (18.9%), but not BRCA1 (1.89%). Patients with ovarian cancer showed the next highest proportion (BRCA1, 4.86%; BRCA2, 3.42%). Frequency exceeding 1% was seen for several other cancer types (two cancer types for BRCA1, four cancer types for BRCA2). More than one cancer types was identified in 4,128 patients (6.3%). Carrier frequency of pathogenic variants in BRCA1 was 0.44% with one cancer type, 0.85% with two cancer types, and 0.69% with three cancer types. It was 0.97%, 1.40%, and 1.74%, respectively, in BRCA2.

“The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of seven cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing,” the authors wrote.

PARP inhibitors were developed based on the mechanism in BRCA1 and BRCA2 of homologous recombination repair defects associated with pathogenic variants. PARP inhibitors have been found to have therapeutic efficacy also in pathogenic variants found to be enriched in prostate and pancreatic cancers. While risk for additional cancer types (for example, biliary tract cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, and stomach cancer) has been reported after analyzing family members for the presence of pathogenic variants and performing case-control analyses, evidence for an association with these cancer types has not been considered sufficient for them to be adopted into clinical management guidelines, the authors wrote.

In an interview, Dr. Momozawa said that BRCA1 and BRCA2 genetic testing should be expanded in Japan. “But further studies are needed to reveal how much. If a clinical trial of a PARP inhibitor for these three cancer types reveals its clinical utility, the importance of this expansion will increase.”

Dr. Momozawa and associates state that while their selection of controls without a family history of cancer affects the generalizability of the study results, the estimated cumulative risks were comparable with those based on prospective cohorts, suggesting the study design did not greatly affect the results.

A large case-control study finds the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than previously determined from prior analyses showing associations with breast, ovarian, prostate, and pancreatic cancers. The finding, published in JAMA Oncology suggests a possible broader clinical relevance for BRCA1 and BRCA2 genetic testing.

Pathogenic variants in BRCA1 were found to be associated with biliary tract cancer, in BRCA2 with esophageal cancer, and in BRCA1/2 with gastric cancer.

“The results suggest the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is likely broader than that determined from previous analysis of largely European ancestry cohorts,” wrote authors who were led by Yukihide Momozawa, DVM, PhD, RIKEN Center for Integrative Medical Sciences, Japan.

“These risk association findings, together with our analysis of an association with family history of cancer and clinical phenotypes, are relevant for developing and adapting guidelines about genetic testing, treatment options, and treatability with PARP [poly adenosine diphosphate-ribose polymerase] inhibitors for each cancer type,” the authors wrote.

Dr. Momozawa and associates conducted a large-scale sequencing study across 14 common cancer types in 63,828 patients (mean age 64 years, 42% female) and 37,086 controls on data drawn from a Japanese nationwide biobank between April 2003 and March 2018. They estimated the risk of each cancer type and determined clinical characteristics associated with pathogenic variant carrier status, while also investigating the utility of family history in detecting patients with pathogenic variants.

Three hundred fifteen pathogenic variants were identified. An odds ratios of greater than 4.0 (with P < 1 × 10−4 as the threshold of significance) for the pathogenic variants were found for biliary tract cancer (OR, 17.4; 95% confidence interval, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2. Two other cancer types were found to be associated with BRCA1, and four other cancer types with BRCA2. Enrichment of carrier patients was shown in biliary tract, female breast, ovarian, and prostate cancers in accordance with increased numbers of reported cancer types in relatives.

Male patients with breast cancer had a very high carrier frequency of pathogenic variants in BRCA2 (18.9%), but not BRCA1 (1.89%). Patients with ovarian cancer showed the next highest proportion (BRCA1, 4.86%; BRCA2, 3.42%). Frequency exceeding 1% was seen for several other cancer types (two cancer types for BRCA1, four cancer types for BRCA2). More than one cancer types was identified in 4,128 patients (6.3%). Carrier frequency of pathogenic variants in BRCA1 was 0.44% with one cancer type, 0.85% with two cancer types, and 0.69% with three cancer types. It was 0.97%, 1.40%, and 1.74%, respectively, in BRCA2.

“The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of seven cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing,” the authors wrote.

PARP inhibitors were developed based on the mechanism in BRCA1 and BRCA2 of homologous recombination repair defects associated with pathogenic variants. PARP inhibitors have been found to have therapeutic efficacy also in pathogenic variants found to be enriched in prostate and pancreatic cancers. While risk for additional cancer types (for example, biliary tract cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, and stomach cancer) has been reported after analyzing family members for the presence of pathogenic variants and performing case-control analyses, evidence for an association with these cancer types has not been considered sufficient for them to be adopted into clinical management guidelines, the authors wrote.

In an interview, Dr. Momozawa said that BRCA1 and BRCA2 genetic testing should be expanded in Japan. “But further studies are needed to reveal how much. If a clinical trial of a PARP inhibitor for these three cancer types reveals its clinical utility, the importance of this expansion will increase.”

Dr. Momozawa and associates state that while their selection of controls without a family history of cancer affects the generalizability of the study results, the estimated cumulative risks were comparable with those based on prospective cohorts, suggesting the study design did not greatly affect the results.

A large case-control study finds the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than previously determined from prior analyses showing associations with breast, ovarian, prostate, and pancreatic cancers. The finding, published in JAMA Oncology suggests a possible broader clinical relevance for BRCA1 and BRCA2 genetic testing.

Pathogenic variants in BRCA1 were found to be associated with biliary tract cancer, in BRCA2 with esophageal cancer, and in BRCA1/2 with gastric cancer.

“The results suggest the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is likely broader than that determined from previous analysis of largely European ancestry cohorts,” wrote authors who were led by Yukihide Momozawa, DVM, PhD, RIKEN Center for Integrative Medical Sciences, Japan.

“These risk association findings, together with our analysis of an association with family history of cancer and clinical phenotypes, are relevant for developing and adapting guidelines about genetic testing, treatment options, and treatability with PARP [poly adenosine diphosphate-ribose polymerase] inhibitors for each cancer type,” the authors wrote.

Dr. Momozawa and associates conducted a large-scale sequencing study across 14 common cancer types in 63,828 patients (mean age 64 years, 42% female) and 37,086 controls on data drawn from a Japanese nationwide biobank between April 2003 and March 2018. They estimated the risk of each cancer type and determined clinical characteristics associated with pathogenic variant carrier status, while also investigating the utility of family history in detecting patients with pathogenic variants.

Three hundred fifteen pathogenic variants were identified. An odds ratios of greater than 4.0 (with P < 1 × 10−4 as the threshold of significance) for the pathogenic variants were found for biliary tract cancer (OR, 17.4; 95% confidence interval, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2. Two other cancer types were found to be associated with BRCA1, and four other cancer types with BRCA2. Enrichment of carrier patients was shown in biliary tract, female breast, ovarian, and prostate cancers in accordance with increased numbers of reported cancer types in relatives.

Male patients with breast cancer had a very high carrier frequency of pathogenic variants in BRCA2 (18.9%), but not BRCA1 (1.89%). Patients with ovarian cancer showed the next highest proportion (BRCA1, 4.86%; BRCA2, 3.42%). Frequency exceeding 1% was seen for several other cancer types (two cancer types for BRCA1, four cancer types for BRCA2). More than one cancer types was identified in 4,128 patients (6.3%). Carrier frequency of pathogenic variants in BRCA1 was 0.44% with one cancer type, 0.85% with two cancer types, and 0.69% with three cancer types. It was 0.97%, 1.40%, and 1.74%, respectively, in BRCA2.

“The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of seven cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing,” the authors wrote.

PARP inhibitors were developed based on the mechanism in BRCA1 and BRCA2 of homologous recombination repair defects associated with pathogenic variants. PARP inhibitors have been found to have therapeutic efficacy also in pathogenic variants found to be enriched in prostate and pancreatic cancers. While risk for additional cancer types (for example, biliary tract cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, and stomach cancer) has been reported after analyzing family members for the presence of pathogenic variants and performing case-control analyses, evidence for an association with these cancer types has not been considered sufficient for them to be adopted into clinical management guidelines, the authors wrote.

In an interview, Dr. Momozawa said that BRCA1 and BRCA2 genetic testing should be expanded in Japan. “But further studies are needed to reveal how much. If a clinical trial of a PARP inhibitor for these three cancer types reveals its clinical utility, the importance of this expansion will increase.”

Dr. Momozawa and associates state that while their selection of controls without a family history of cancer affects the generalizability of the study results, the estimated cumulative risks were comparable with those based on prospective cohorts, suggesting the study design did not greatly affect the results.

In the United States, the cost of brand-name medications for treating epilepsy soared during the period 2010-2018, while the cost of generic antiseizure medications (ASMs) decreased, a new analysis shows.

After adjustment for inflation, the cost of a 1-year supply of brand-name ASMs grew 277%, while generics became 42% less expensive.

“Our study makes transparent striking trends in brand name prescribing patterns,” the study team wrote.

Since 2010, the costs for brand-name ASMs have “consistently” increased. Costs were particularly boosted by increases in prescriptions for lacosamide (Vimpat), in addition to a “steep increase in the cost per pill, with brand-name drugs costing 10 times more than their generic counterparts,” first author Samuel Waller Terman, MD, of the University of Michigan, Ann Arbor, added in a news release.

The study was published online  in Neurology.
 

Is a 10-fold increase in cost worth it?

To evaluate trends in ASM prescriptions and costs, the researchers used a random sample of 20% of Medicare beneficiaries with coverage from 2008 to 2018. There were 77,000 to 133,000 patients with epilepsy each year.

Over time, likely because of increasing availability of generics, brand-name ASMs made up a smaller proportion of pills prescribed, from 56% in 2008 to 14% in 2018, but still made up 79% of prescription drug costs in 2018.

The annual cost of brand-name ASMs rose from $2,800 in 2008 to $10,700 in 2018, while the cost of generic drugs decreased from $800 to $460 during that time.

An increased number of prescriptions for lacosamide was responsible for 45% of the total increase in brand-name costs.

As of 2018, lacosamide comprised 30% of all brand-name pill supply (followed by pregabalin, at 15%) and 30% of all brand-name costs (followed by clobazam and pregabalin, both at 9%), the investigators reported.

Brand-name antiepileptic drug costs decreased from 2008 to 2010, but after the introduction of lacosamide, total brand-name costs steadily rose from $72 million in 2010 (in 2018 dollars) to $256 million in 2018, they noted.

Because the dataset consists of a 20% random Medicare sample, total Medicare costs for brand-name ASMs for beneficiaries with epilepsy alone likely rose from roughly $360 million in 2010 to $1.3 billion in 2018, they added.

“Clinicians must remain cognizant of this societal cost magnitude when judging whether the 10-fold increased expense per pill for brand name medications is worth the possible benefits,” they wrote.

“While newer-generation drugs have potential advantages such as limited drug interactions and different side effect profiles, there have been conflicting studies on whether they are cost effective,” Dr. Terman noted in a news release.
 

A barrier to treatment

The authors of an accompanying editorial propose that the problem of prescription drug costs could be solved through a combination of competition and government regulation of prices. Patients and physicians are the most important stakeholders in this issue.

“When something represents 14% of the total use, but contributes 79% of the cost, it would be wise to consider alternatives, assuming that these alternatives are not of lower quality,” wrote Wyatt Bensken, with Case Western Reserve University, Cleveland, and Iván Sánchez Fernández, MD, with Boston Medical Center.

“When there are several ASMs with a similar mechanism of action, similar efficacy, similar safety and tolerability profile, and different costs, it would be unwise to choose the more expensive alternative just because it is newer,” they said.

This study, they added, provides data to “understand, and begin to act, on the challenging problem of the cost of prescription ASMs. After all, what is the point of having a large number of ASMs if their cost severely limits their use?”

A limitation of the study is that only Medicare prescription claims were included, so the results may not apply to younger patients with private insurance.

The study received no direct funding. The authors and editorialists have disclosed no relevant financial relationships.

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

In the United States, the cost of brand-name medications for treating epilepsy soared during the period 2010-2018, while the cost of generic antiseizure medications (ASMs) decreased, a new analysis shows.

After adjustment for inflation, the cost of a 1-year supply of brand-name ASMs grew 277%, while generics became 42% less expensive.

“Our study makes transparent striking trends in brand name prescribing patterns,” the study team wrote.

Since 2010, the costs for brand-name ASMs have “consistently” increased. Costs were particularly boosted by increases in prescriptions for lacosamide (Vimpat), in addition to a “steep increase in the cost per pill, with brand-name drugs costing 10 times more than their generic counterparts,” first author Samuel Waller Terman, MD, of the University of Michigan, Ann Arbor, added in a news release.

The study was published online  in Neurology.
 

Is a 10-fold increase in cost worth it?

To evaluate trends in ASM prescriptions and costs, the researchers used a random sample of 20% of Medicare beneficiaries with coverage from 2008 to 2018. There were 77,000 to 133,000 patients with epilepsy each year.

Over time, likely because of increasing availability of generics, brand-name ASMs made up a smaller proportion of pills prescribed, from 56% in 2008 to 14% in 2018, but still made up 79% of prescription drug costs in 2018.

The annual cost of brand-name ASMs rose from $2,800 in 2008 to $10,700 in 2018, while the cost of generic drugs decreased from $800 to $460 during that time.

An increased number of prescriptions for lacosamide was responsible for 45% of the total increase in brand-name costs.

As of 2018, lacosamide comprised 30% of all brand-name pill supply (followed by pregabalin, at 15%) and 30% of all brand-name costs (followed by clobazam and pregabalin, both at 9%), the investigators reported.

Brand-name antiepileptic drug costs decreased from 2008 to 2010, but after the introduction of lacosamide, total brand-name costs steadily rose from $72 million in 2010 (in 2018 dollars) to $256 million in 2018, they noted.

Because the dataset consists of a 20% random Medicare sample, total Medicare costs for brand-name ASMs for beneficiaries with epilepsy alone likely rose from roughly $360 million in 2010 to $1.3 billion in 2018, they added.

“Clinicians must remain cognizant of this societal cost magnitude when judging whether the 10-fold increased expense per pill for brand name medications is worth the possible benefits,” they wrote.

“While newer-generation drugs have potential advantages such as limited drug interactions and different side effect profiles, there have been conflicting studies on whether they are cost effective,” Dr. Terman noted in a news release.
 

A barrier to treatment

The authors of an accompanying editorial propose that the problem of prescription drug costs could be solved through a combination of competition and government regulation of prices. Patients and physicians are the most important stakeholders in this issue.

“When something represents 14% of the total use, but contributes 79% of the cost, it would be wise to consider alternatives, assuming that these alternatives are not of lower quality,” wrote Wyatt Bensken, with Case Western Reserve University, Cleveland, and Iván Sánchez Fernández, MD, with Boston Medical Center.

“When there are several ASMs with a similar mechanism of action, similar efficacy, similar safety and tolerability profile, and different costs, it would be unwise to choose the more expensive alternative just because it is newer,” they said.

This study, they added, provides data to “understand, and begin to act, on the challenging problem of the cost of prescription ASMs. After all, what is the point of having a large number of ASMs if their cost severely limits their use?”

A limitation of the study is that only Medicare prescription claims were included, so the results may not apply to younger patients with private insurance.

The study received no direct funding. The authors and editorialists have disclosed no relevant financial relationships.

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

In the United States, the cost of brand-name medications for treating epilepsy soared during the period 2010-2018, while the cost of generic antiseizure medications (ASMs) decreased, a new analysis shows.

After adjustment for inflation, the cost of a 1-year supply of brand-name ASMs grew 277%, while generics became 42% less expensive.

“Our study makes transparent striking trends in brand name prescribing patterns,” the study team wrote.

Since 2010, the costs for brand-name ASMs have “consistently” increased. Costs were particularly boosted by increases in prescriptions for lacosamide (Vimpat), in addition to a “steep increase in the cost per pill, with brand-name drugs costing 10 times more than their generic counterparts,” first author Samuel Waller Terman, MD, of the University of Michigan, Ann Arbor, added in a news release.

The study was published online  in Neurology.
 

Is a 10-fold increase in cost worth it?

To evaluate trends in ASM prescriptions and costs, the researchers used a random sample of 20% of Medicare beneficiaries with coverage from 2008 to 2018. There were 77,000 to 133,000 patients with epilepsy each year.

Over time, likely because of increasing availability of generics, brand-name ASMs made up a smaller proportion of pills prescribed, from 56% in 2008 to 14% in 2018, but still made up 79% of prescription drug costs in 2018.

The annual cost of brand-name ASMs rose from $2,800 in 2008 to $10,700 in 2018, while the cost of generic drugs decreased from $800 to $460 during that time.

An increased number of prescriptions for lacosamide was responsible for 45% of the total increase in brand-name costs.

As of 2018, lacosamide comprised 30% of all brand-name pill supply (followed by pregabalin, at 15%) and 30% of all brand-name costs (followed by clobazam and pregabalin, both at 9%), the investigators reported.

Brand-name antiepileptic drug costs decreased from 2008 to 2010, but after the introduction of lacosamide, total brand-name costs steadily rose from $72 million in 2010 (in 2018 dollars) to $256 million in 2018, they noted.

Because the dataset consists of a 20% random Medicare sample, total Medicare costs for brand-name ASMs for beneficiaries with epilepsy alone likely rose from roughly $360 million in 2010 to $1.3 billion in 2018, they added.

“Clinicians must remain cognizant of this societal cost magnitude when judging whether the 10-fold increased expense per pill for brand name medications is worth the possible benefits,” they wrote.

“While newer-generation drugs have potential advantages such as limited drug interactions and different side effect profiles, there have been conflicting studies on whether they are cost effective,” Dr. Terman noted in a news release.
 

A barrier to treatment

The authors of an accompanying editorial propose that the problem of prescription drug costs could be solved through a combination of competition and government regulation of prices. Patients and physicians are the most important stakeholders in this issue.

“When something represents 14% of the total use, but contributes 79% of the cost, it would be wise to consider alternatives, assuming that these alternatives are not of lower quality,” wrote Wyatt Bensken, with Case Western Reserve University, Cleveland, and Iván Sánchez Fernández, MD, with Boston Medical Center.

“When there are several ASMs with a similar mechanism of action, similar efficacy, similar safety and tolerability profile, and different costs, it would be unwise to choose the more expensive alternative just because it is newer,” they said.

This study, they added, provides data to “understand, and begin to act, on the challenging problem of the cost of prescription ASMs. After all, what is the point of having a large number of ASMs if their cost severely limits their use?”

A limitation of the study is that only Medicare prescription claims were included, so the results may not apply to younger patients with private insurance.

The study received no direct funding. The authors and editorialists have disclosed no relevant financial relationships.

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

The Diagnosis: Borrelial Lymphocytoma (Lymphocytoma Cutis)

A punch biopsy revealed an atypical lobular lymphoid infiltrate within the dermis and subcutaneous tissue with a mixed composition of CD3⁺ T cells and CD20⁺ B cells (quiz image, bottom). Immunohistochemical studies revealed a normal CD4:CD8 ratio with preservation of CD5 and CD7. CD30 was largely negative. CD21 failed to detect follicular dendritic cell networks, and κ/λ light chain staining confirmed a preserved ratio of polytypic plasma cells. There was limited staining with B-cell lymphoma (Bcl-2 and Bcl-6). Polymerase chain reaction studies for both T- and B-cell receptors were negative (polyclonal).

Lyme disease is the most frequently reported vectorborne infectious disease in the United States, and borrelial lymphocytoma (BL) is a rare clinical sequela. Borrelial lymphocytoma is a variant of lymphocytoma cutis (also known as benign reactive lymphoid hyperplasia), which is an inflammatory lesion that can mimic malignant lymphoma clinically and histologically. Lymphocytoma cutis is considered the prototypical example of cutaneous B-cell pseudolymphoma.¹ Due to suspicion for lymphocytoma cutis based on the histologic findings and characteristic location of the lesions in our patient, Lyme serologies were ordered and were positive for IgM antibodies against p23, p39, and p41 antigens in high titers. Our patient was treated with doxycycline 100 mg twice daily for 3 weeks with complete resolution of the lesions at 3-month follow-up.

Clinically, BL appears as erythematous papules, plaques, or nodules commonly on the lobules of the ears (quiz image, top). Most cases of lymphocytoma cutis are idiopathic but may be triggered by identifiable associated etiologies including Borrelia burgdorferi, Leishmania donovani, molluscum contagiosum, herpes zoster virus, vaccinations, tattoos, insect bites, and drugs. The main differential diagnosis of lymphocytoma cutis is cutaneous B-cell lymphoma. Pseudolymphoma of the skin can mimic nearly all immunohistochemical staining patterns of true B-cell lymphomas.²

Primary cutaneous follicle center lymphoma frequently occurs on the head and neck. This true lymphoma of the skin can demonstrate prominent follicle centers with centrocytes and fragmented germinal centers (Figure 1) or show a diffuse pattern.³ Most cases show conspicuous Bcl-6 staining, and IgH gene rearrangements can detect a clonal B-cell population in more than 50% of cases.⁴

Diffuse large B-cell lymphoma can occur as a primary cutaneous malignancy or as a manifestation of systemic disease.4 When arising in the skin, lesions tend to affect the extremities, and the disease is classified as diffuse large B-cell lymphoma, leg type. Histologically, sheets of large atypical lymphocytes with numerous mitoses are seen (Figure 2). These cells stain positively with Bcl-2 and frequently demonstrate Bcl-6 and MUM-1, none of which were seen in our case.4 Lymphomatoid papulosis (LyP) tends to present with relapsing erythematous papules. Patients occasionally develop LyP in association with mycosis fungoides or other lymphomas. Both LyP and primary cutaneous anaplastic large cell lymphoma demonstrate conspicuous CD30+ large cells that can be multinucleated or resemble the Reed-Sternberg cells seen in Hodgkin lymphoma (Figure 3).4 Arthropod bite reactions are common but may be confused with lymphomas and pseudolymphomas. The perivascular lymphocytic infiltrate seen in arthropod bite reactions may be dense and usually is associated with numerous eosinophils (Figure 4). Occasional plasma cells also can be seen, and if the infiltrate closely adheres to vascular structures, a diagnosis of erythema chronicum migrans also can be considered. Patients with chronic lymphocytic leukemia/lymphoma may demonstrate exaggerated or persistent arthropod bite reactions, and atypical lymphocytes can be detected admixed with the otherwise reactive infiltrate.⁴

Borrelia burgdorferi is primarily endemic to North America and Europe. It is a spirochete bacterium spread by the Ixodes tick that was first recognized as the etiologic agent in 1975 in Old Lyme, Connecticut, where it received its name.⁵ Most reported cases of Lyme disease occur in the northeastern United States, which correlates with this case given our patient’s place of residence.⁶ Borrelial lymphocytoma cutis occurs in areas endemic for the Ixodes tick in Europe and North America.⁷ When describing the genotyping of Borrelia seen in BL, the strain B burgdorferi previously was grouped with Borrelia afzelii and Borrelia garinii.² In the contemporary literature, however, B burgdorferi is referred to as sensu stricto when specifically talking about the strain B burgdorferi, and the term sensu lato is used when referencing the combination of strains (B burgdorferi, B afzelii, B garinii).

A 2016 study by Maraspin et al⁸ comprising 144 patients diagnosed with BL showed that the lesions mainly were located on the breast (106 patients [73.6%]) and the earlobe (27 patients [18.8%]), with the remaining cases occurring elsewhere on the body (11 patients [7.6%]). The Borrelia strains isolated from the BL lesions included B afzelii, Borrelia bissettii, and B garinii, with B afzelii being the most commonly identified (84.6% [11/13]).⁸

Borrelial lymphocytoma usually is categorized as a form of early disseminated Lyme disease and is treated as such. The treatment of choice for early disseminated Lyme disease is doxycycline 100 mg twice daily for 14 to 21 days. Ceftriaxone and azithromycin are reasonable treatment options for patients who have tetracycline allergies or who are pregnant.⁹

In conclusion, the presentation of red papules or nodules on the ears should prompt clinical suspicion of Lyme disease, particularly in endemic areas. Differentiating pseudolymphomas from true lymphomas and other reactive conditions can be challenging.

The Diagnosis: Borrelial Lymphocytoma (Lymphocytoma Cutis)

A punch biopsy revealed an atypical lobular lymphoid infiltrate within the dermis and subcutaneous tissue with a mixed composition of CD3⁺ T cells and CD20⁺ B cells (quiz image, bottom). Immunohistochemical studies revealed a normal CD4:CD8 ratio with preservation of CD5 and CD7. CD30 was largely negative. CD21 failed to detect follicular dendritic cell networks, and κ/λ light chain staining confirmed a preserved ratio of polytypic plasma cells. There was limited staining with B-cell lymphoma (Bcl-2 and Bcl-6). Polymerase chain reaction studies for both T- and B-cell receptors were negative (polyclonal).

Lyme disease is the most frequently reported vectorborne infectious disease in the United States, and borrelial lymphocytoma (BL) is a rare clinical sequela. Borrelial lymphocytoma is a variant of lymphocytoma cutis (also known as benign reactive lymphoid hyperplasia), which is an inflammatory lesion that can mimic malignant lymphoma clinically and histologically. Lymphocytoma cutis is considered the prototypical example of cutaneous B-cell pseudolymphoma.¹ Due to suspicion for lymphocytoma cutis based on the histologic findings and characteristic location of the lesions in our patient, Lyme serologies were ordered and were positive for IgM antibodies against p23, p39, and p41 antigens in high titers. Our patient was treated with doxycycline 100 mg twice daily for 3 weeks with complete resolution of the lesions at 3-month follow-up.

Clinically, BL appears as erythematous papules, plaques, or nodules commonly on the lobules of the ears (quiz image, top). Most cases of lymphocytoma cutis are idiopathic but may be triggered by identifiable associated etiologies including Borrelia burgdorferi, Leishmania donovani, molluscum contagiosum, herpes zoster virus, vaccinations, tattoos, insect bites, and drugs. The main differential diagnosis of lymphocytoma cutis is cutaneous B-cell lymphoma. Pseudolymphoma of the skin can mimic nearly all immunohistochemical staining patterns of true B-cell lymphomas.²

Primary cutaneous follicle center lymphoma frequently occurs on the head and neck. This true lymphoma of the skin can demonstrate prominent follicle centers with centrocytes and fragmented germinal centers (Figure 1) or show a diffuse pattern.³ Most cases show conspicuous Bcl-6 staining, and IgH gene rearrangements can detect a clonal B-cell population in more than 50% of cases.⁴

Diffuse large B-cell lymphoma can occur as a primary cutaneous malignancy or as a manifestation of systemic disease.4 When arising in the skin, lesions tend to affect the extremities, and the disease is classified as diffuse large B-cell lymphoma, leg type. Histologically, sheets of large atypical lymphocytes with numerous mitoses are seen (Figure 2). These cells stain positively with Bcl-2 and frequently demonstrate Bcl-6 and MUM-1, none of which were seen in our case.4 Lymphomatoid papulosis (LyP) tends to present with relapsing erythematous papules. Patients occasionally develop LyP in association with mycosis fungoides or other lymphomas. Both LyP and primary cutaneous anaplastic large cell lymphoma demonstrate conspicuous CD30+ large cells that can be multinucleated or resemble the Reed-Sternberg cells seen in Hodgkin lymphoma (Figure 3).4 Arthropod bite reactions are common but may be confused with lymphomas and pseudolymphomas. The perivascular lymphocytic infiltrate seen in arthropod bite reactions may be dense and usually is associated with numerous eosinophils (Figure 4). Occasional plasma cells also can be seen, and if the infiltrate closely adheres to vascular structures, a diagnosis of erythema chronicum migrans also can be considered. Patients with chronic lymphocytic leukemia/lymphoma may demonstrate exaggerated or persistent arthropod bite reactions, and atypical lymphocytes can be detected admixed with the otherwise reactive infiltrate.⁴

Borrelia burgdorferi is primarily endemic to North America and Europe. It is a spirochete bacterium spread by the Ixodes tick that was first recognized as the etiologic agent in 1975 in Old Lyme, Connecticut, where it received its name.⁵ Most reported cases of Lyme disease occur in the northeastern United States, which correlates with this case given our patient’s place of residence.⁶ Borrelial lymphocytoma cutis occurs in areas endemic for the Ixodes tick in Europe and North America.⁷ When describing the genotyping of Borrelia seen in BL, the strain B burgdorferi previously was grouped with Borrelia afzelii and Borrelia garinii.² In the contemporary literature, however, B burgdorferi is referred to as sensu stricto when specifically talking about the strain B burgdorferi, and the term sensu lato is used when referencing the combination of strains (B burgdorferi, B afzelii, B garinii).

A 2016 study by Maraspin et al⁸ comprising 144 patients diagnosed with BL showed that the lesions mainly were located on the breast (106 patients [73.6%]) and the earlobe (27 patients [18.8%]), with the remaining cases occurring elsewhere on the body (11 patients [7.6%]). The Borrelia strains isolated from the BL lesions included B afzelii, Borrelia bissettii, and B garinii, with B afzelii being the most commonly identified (84.6% [11/13]).⁸

Borrelial lymphocytoma usually is categorized as a form of early disseminated Lyme disease and is treated as such. The treatment of choice for early disseminated Lyme disease is doxycycline 100 mg twice daily for 14 to 21 days. Ceftriaxone and azithromycin are reasonable treatment options for patients who have tetracycline allergies or who are pregnant.⁹

In conclusion, the presentation of red papules or nodules on the ears should prompt clinical suspicion of Lyme disease, particularly in endemic areas. Differentiating pseudolymphomas from true lymphomas and other reactive conditions can be challenging.

The Diagnosis: Borrelial Lymphocytoma (Lymphocytoma Cutis)

A punch biopsy revealed an atypical lobular lymphoid infiltrate within the dermis and subcutaneous tissue with a mixed composition of CD3⁺ T cells and CD20⁺ B cells (quiz image, bottom). Immunohistochemical studies revealed a normal CD4:CD8 ratio with preservation of CD5 and CD7. CD30 was largely negative. CD21 failed to detect follicular dendritic cell networks, and κ/λ light chain staining confirmed a preserved ratio of polytypic plasma cells. There was limited staining with B-cell lymphoma (Bcl-2 and Bcl-6). Polymerase chain reaction studies for both T- and B-cell receptors were negative (polyclonal).

Lyme disease is the most frequently reported vectorborne infectious disease in the United States, and borrelial lymphocytoma (BL) is a rare clinical sequela. Borrelial lymphocytoma is a variant of lymphocytoma cutis (also known as benign reactive lymphoid hyperplasia), which is an inflammatory lesion that can mimic malignant lymphoma clinically and histologically. Lymphocytoma cutis is considered the prototypical example of cutaneous B-cell pseudolymphoma.¹ Due to suspicion for lymphocytoma cutis based on the histologic findings and characteristic location of the lesions in our patient, Lyme serologies were ordered and were positive for IgM antibodies against p23, p39, and p41 antigens in high titers. Our patient was treated with doxycycline 100 mg twice daily for 3 weeks with complete resolution of the lesions at 3-month follow-up.

Clinically, BL appears as erythematous papules, plaques, or nodules commonly on the lobules of the ears (quiz image, top). Most cases of lymphocytoma cutis are idiopathic but may be triggered by identifiable associated etiologies including Borrelia burgdorferi, Leishmania donovani, molluscum contagiosum, herpes zoster virus, vaccinations, tattoos, insect bites, and drugs. The main differential diagnosis of lymphocytoma cutis is cutaneous B-cell lymphoma. Pseudolymphoma of the skin can mimic nearly all immunohistochemical staining patterns of true B-cell lymphomas.²

Primary cutaneous follicle center lymphoma frequently occurs on the head and neck. This true lymphoma of the skin can demonstrate prominent follicle centers with centrocytes and fragmented germinal centers (Figure 1) or show a diffuse pattern.³ Most cases show conspicuous Bcl-6 staining, and IgH gene rearrangements can detect a clonal B-cell population in more than 50% of cases.⁴

Diffuse large B-cell lymphoma can occur as a primary cutaneous malignancy or as a manifestation of systemic disease.4 When arising in the skin, lesions tend to affect the extremities, and the disease is classified as diffuse large B-cell lymphoma, leg type. Histologically, sheets of large atypical lymphocytes with numerous mitoses are seen (Figure 2). These cells stain positively with Bcl-2 and frequently demonstrate Bcl-6 and MUM-1, none of which were seen in our case.4 Lymphomatoid papulosis (LyP) tends to present with relapsing erythematous papules. Patients occasionally develop LyP in association with mycosis fungoides or other lymphomas. Both LyP and primary cutaneous anaplastic large cell lymphoma demonstrate conspicuous CD30+ large cells that can be multinucleated or resemble the Reed-Sternberg cells seen in Hodgkin lymphoma (Figure 3).4 Arthropod bite reactions are common but may be confused with lymphomas and pseudolymphomas. The perivascular lymphocytic infiltrate seen in arthropod bite reactions may be dense and usually is associated with numerous eosinophils (Figure 4). Occasional plasma cells also can be seen, and if the infiltrate closely adheres to vascular structures, a diagnosis of erythema chronicum migrans also can be considered. Patients with chronic lymphocytic leukemia/lymphoma may demonstrate exaggerated or persistent arthropod bite reactions, and atypical lymphocytes can be detected admixed with the otherwise reactive infiltrate.⁴

Borrelia burgdorferi is primarily endemic to North America and Europe. It is a spirochete bacterium spread by the Ixodes tick that was first recognized as the etiologic agent in 1975 in Old Lyme, Connecticut, where it received its name.⁵ Most reported cases of Lyme disease occur in the northeastern United States, which correlates with this case given our patient’s place of residence.⁶ Borrelial lymphocytoma cutis occurs in areas endemic for the Ixodes tick in Europe and North America.⁷ When describing the genotyping of Borrelia seen in BL, the strain B burgdorferi previously was grouped with Borrelia afzelii and Borrelia garinii.² In the contemporary literature, however, B burgdorferi is referred to as sensu stricto when specifically talking about the strain B burgdorferi, and the term sensu lato is used when referencing the combination of strains (B burgdorferi, B afzelii, B garinii).

A 2016 study by Maraspin et al⁸ comprising 144 patients diagnosed with BL showed that the lesions mainly were located on the breast (106 patients [73.6%]) and the earlobe (27 patients [18.8%]), with the remaining cases occurring elsewhere on the body (11 patients [7.6%]). The Borrelia strains isolated from the BL lesions included B afzelii, Borrelia bissettii, and B garinii, with B afzelii being the most commonly identified (84.6% [11/13]).⁸

Borrelial lymphocytoma usually is categorized as a form of early disseminated Lyme disease and is treated as such. The treatment of choice for early disseminated Lyme disease is doxycycline 100 mg twice daily for 14 to 21 days. Ceftriaxone and azithromycin are reasonable treatment options for patients who have tetracycline allergies or who are pregnant.⁹

In conclusion, the presentation of red papules or nodules on the ears should prompt clinical suspicion of Lyme disease, particularly in endemic areas. Differentiating pseudolymphomas from true lymphomas and other reactive conditions can be challenging.

For many Americans – especially those too young to know much about the Cold War or Hiroshima – Russia’s invasion of Ukraine might mark the first time they’ve truly considered the dangers of nuclear weapons. But dozens of hematologists in the United States already know the drill and have placed themselves on the front lines. These physicians stand prepared to treat patients exposed to radiation caused by nuclear accidents or attacks on U.S. soil.

They work nationwide at 74 medical centers that make up the Radiation Injury Treatment Network, ready to manage cases of acute radiation syndrome (ARS) during disasters. While RITN keeps a low profile, it’s been in the news lately amid anxieties about the Ukraine conflict, nuclear plant accidents, and the potential launching of nuclear weapons by foreign adversaries.

Wikimedia Commons

“The Radiation Injury Treatment Network helps plan responses for disaster scenarios where a person’s cells would be damaged after having been exposed to ionizing radiation,” program director Cullen Case Jr., MPA, said in an interview.

A U.S. Army veteran who took part in hurricane response early in his career, Mr. Case now oversees preparedness activities among all RITN hospitals, blood donor centers, and cord blood banks, in readiness for a mass casualty radiological incident. He also serves as a senior manager of the National Marrow Donor Program/Be a Match Marrow Registry.

Intense preparation for nuclear attacks or accidents is necessary, Mr. Case said, despite the doomsday scenarios disseminated on television shows and movies.

“The most frequent misconception we hear is that a nuclear disaster will encompass the whole world and be so complete that preparedness isn’t useful. However, many planning scenarios include smaller-scale incidents where survivors will need prompt and expert care,” he said.

In the wake of 9/11, the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation established the RITN in 2006, with a mission to prepare for nuclear disaster and help manage the response if one occurs.

National Archives/Wikimedia commons

“The widespread availability of radioactive material has made future exposure events, accidental or intentional, nearly inevitable,” RITN leaders warned in a 2008 report. “Hematologists, oncologists, and HSCT [hematopoietic stem cell transplantation] physicians are uniquely suited to care for victims of radiation exposure, creating a collective responsibility to prepare for a variety of contingencies.”

RITN doesn’t just train physicians, Mr. Case noted. All medical centers within the RITN are required to conduct an annual tabletop exercise where a radiation disaster scenario and a set of discussion questions are presented to the team.
 

Hematologists specially equipped to treat radiation injuries

Why are hematologists involved in treating people exposed to dangerously high levels of radiation? The answer has to do with how radiation harms the body, said Dr. Ann A. Jakubowski, a hematologist/oncologist and transplant physician at Memorial Sloan Kettering Cancer Center, New York, who serves as a medical director for RITN.

“One of the most common toxicities from radiation exposure and a major player in acute radiation syndrome is hematologic toxicity– damage to the bone marrow by the radiation, with a resultant decrease in peripheral blood counts,” she said in an interview. “This is similar to what is often seen in the treatment of cancers with radiation and/or chemotherapy.”

In cases of severe and nonreversible radiation damage to the bone marrow, Dr. Jakubowski noted, “patients can be considered for a stem cell transplant to provide new healthy cells to repopulate the bone marrow, which provides recovery of peripheral blood counts. Hematologist/oncologists are the physicians who manage stem cell transplants.”

The crucial role of hematologists in radiation injuries is not new. In fact, these physicians have been closely intertwined with nuclear research since the dawn of the atomic age. The work of developing atomic bombs also led investigators to an understanding of the structure and processes of hematopoiesis and helped them to identify hematopoietic stem cells and prove their existence in humans.
 

Disaster response poses multiple challenges

As noted in a recent article in ASH Clinical News, the challenges of treating radiation injuries would be intense, especially in the event of a nuclear accident or attack that affects a wide area. For starters, how quickly can medical professionals be mobilized, and will there be enough physicians comfortable treating patients? Fortunately, irradiated patients should not pose a direct risk to medical professionals who treat them.

“The expectation is that the patients will all be decontaminated,” said Nelson Chao, MD, MBA, one of the founders of RITN and a hematologist/oncologist and transplant physician at Duke University, Durham, N.C.

Dr. Jakubowski questions whether there will be adequate resources to handle the influx of patients who need more intensive treatment, as well as outpatients who “received lower doses of radiation and may experience a period of low blood counts but are expected to eventually recover blood counts.”

AFP/Getty Images

And if many people are injured, Dr. Chao asks, how will physicians “adopt altered standards of care to treat large numbers of patients?”

There will also be a need for physicians who aren’t hematologists, Dr. Jakubowski said. “There may be many victims who have both radiation exposure and traumatic or burn injuries, which need to be addressed first, before the hematologist can start addressing the consequences of ARS. Traumatic and burn injuries will require surgical resources.”

In addition, ARS affects the gastrointestinal track and central nervous system/cardiovascular, and it has multiple stages, she noted.

“Although we have methods of supporting the hematopoietic system – transfusions and growth factors – and even replacing it with a stem cell transplant, this will not necessarily fix the badly damaged other organs, Dr. Jakubowski said. “Also, not all radioactive isotopes are equal in their effects, nor are the various types of radiation exposure.”
 

Training goes beyond transplants and drugs

RITN offers individual hematologists specialized education about treating radiation injuries through annual exercises, modules, and “just-in-time” training.

For example, the RITN webpage devoted to triage includes guidelines for transferring radiation injury patients, triage guidelines for cytokine administration in cases of ARS, an exposure and symptom triage tool, and more. The treatment page includes details about subjects such as when human leukocyte antigen typing of casualties is appropriate and how to keep yourself safe while treating patients.

Another focus is teaching hematologists to react quickly in disasters, Mr. Case said. “The vast majority of hematologists have little to no experience in responding to disasters and making decisions with imperfect or incomplete information, as emergency medicine practitioners must do regularly.”

“Some of the RITN tabletop exercises present physicians and advanced practitioners with an incomplete set of patient information and ask physicians to then determine and prioritize their care,” Mr. Case said. “The resulting discussions help to lay the groundwork for being able to shift to the crisis standards of care mindset that would be necessary during a radiological disaster.”
 

Here’s how hematologists can get involved

If you want to help improve the nation’s response to radiation injuries, Mr. Case suggests checking RITN’s list of participating hospitals. If your facility is already part of this network, he said, contact its bone marrow transplant unit for more information.

In such cases, Dr. Jakubowski suggests that you “consider periodically giving a presentation to staff on the basics of radiation injury and the center’s role in RITN.” And if you’re not part of RITN, she said, consider contacting the network about becoming a member.

Hematologists, Mr. Case said, can also take advantage of RITN’s free short overview courses, review the RITN Treatment Guidelines, or watch short videos on the RITN’s YouTube channel.

He highlighted the Radiation Emergency Medical Management website administered by the Department of Health & Human Services, the Center for Disease Control’s radiation emergencies webpage, and the Department of Energy’s Radiation Emergency Assistance Center/Training Site.

For many Americans – especially those too young to know much about the Cold War or Hiroshima – Russia’s invasion of Ukraine might mark the first time they’ve truly considered the dangers of nuclear weapons. But dozens of hematologists in the United States already know the drill and have placed themselves on the front lines. These physicians stand prepared to treat patients exposed to radiation caused by nuclear accidents or attacks on U.S. soil.

They work nationwide at 74 medical centers that make up the Radiation Injury Treatment Network, ready to manage cases of acute radiation syndrome (ARS) during disasters. While RITN keeps a low profile, it’s been in the news lately amid anxieties about the Ukraine conflict, nuclear plant accidents, and the potential launching of nuclear weapons by foreign adversaries.

Wikimedia Commons

“The Radiation Injury Treatment Network helps plan responses for disaster scenarios where a person’s cells would be damaged after having been exposed to ionizing radiation,” program director Cullen Case Jr., MPA, said in an interview.

A U.S. Army veteran who took part in hurricane response early in his career, Mr. Case now oversees preparedness activities among all RITN hospitals, blood donor centers, and cord blood banks, in readiness for a mass casualty radiological incident. He also serves as a senior manager of the National Marrow Donor Program/Be a Match Marrow Registry.

Intense preparation for nuclear attacks or accidents is necessary, Mr. Case said, despite the doomsday scenarios disseminated on television shows and movies.

“The most frequent misconception we hear is that a nuclear disaster will encompass the whole world and be so complete that preparedness isn’t useful. However, many planning scenarios include smaller-scale incidents where survivors will need prompt and expert care,” he said.

In the wake of 9/11, the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation established the RITN in 2006, with a mission to prepare for nuclear disaster and help manage the response if one occurs.

National Archives/Wikimedia commons

“The widespread availability of radioactive material has made future exposure events, accidental or intentional, nearly inevitable,” RITN leaders warned in a 2008 report. “Hematologists, oncologists, and HSCT [hematopoietic stem cell transplantation] physicians are uniquely suited to care for victims of radiation exposure, creating a collective responsibility to prepare for a variety of contingencies.”

RITN doesn’t just train physicians, Mr. Case noted. All medical centers within the RITN are required to conduct an annual tabletop exercise where a radiation disaster scenario and a set of discussion questions are presented to the team.
 

Hematologists specially equipped to treat radiation injuries

Why are hematologists involved in treating people exposed to dangerously high levels of radiation? The answer has to do with how radiation harms the body, said Dr. Ann A. Jakubowski, a hematologist/oncologist and transplant physician at Memorial Sloan Kettering Cancer Center, New York, who serves as a medical director for RITN.

“One of the most common toxicities from radiation exposure and a major player in acute radiation syndrome is hematologic toxicity– damage to the bone marrow by the radiation, with a resultant decrease in peripheral blood counts,” she said in an interview. “This is similar to what is often seen in the treatment of cancers with radiation and/or chemotherapy.”

In cases of severe and nonreversible radiation damage to the bone marrow, Dr. Jakubowski noted, “patients can be considered for a stem cell transplant to provide new healthy cells to repopulate the bone marrow, which provides recovery of peripheral blood counts. Hematologist/oncologists are the physicians who manage stem cell transplants.”

The crucial role of hematologists in radiation injuries is not new. In fact, these physicians have been closely intertwined with nuclear research since the dawn of the atomic age. The work of developing atomic bombs also led investigators to an understanding of the structure and processes of hematopoiesis and helped them to identify hematopoietic stem cells and prove their existence in humans.
 

Disaster response poses multiple challenges

As noted in a recent article in ASH Clinical News, the challenges of treating radiation injuries would be intense, especially in the event of a nuclear accident or attack that affects a wide area. For starters, how quickly can medical professionals be mobilized, and will there be enough physicians comfortable treating patients? Fortunately, irradiated patients should not pose a direct risk to medical professionals who treat them.

“The expectation is that the patients will all be decontaminated,” said Nelson Chao, MD, MBA, one of the founders of RITN and a hematologist/oncologist and transplant physician at Duke University, Durham, N.C.

Dr. Jakubowski questions whether there will be adequate resources to handle the influx of patients who need more intensive treatment, as well as outpatients who “received lower doses of radiation and may experience a period of low blood counts but are expected to eventually recover blood counts.”

AFP/Getty Images

And if many people are injured, Dr. Chao asks, how will physicians “adopt altered standards of care to treat large numbers of patients?”

There will also be a need for physicians who aren’t hematologists, Dr. Jakubowski said. “There may be many victims who have both radiation exposure and traumatic or burn injuries, which need to be addressed first, before the hematologist can start addressing the consequences of ARS. Traumatic and burn injuries will require surgical resources.”

In addition, ARS affects the gastrointestinal track and central nervous system/cardiovascular, and it has multiple stages, she noted.

“Although we have methods of supporting the hematopoietic system – transfusions and growth factors – and even replacing it with a stem cell transplant, this will not necessarily fix the badly damaged other organs, Dr. Jakubowski said. “Also, not all radioactive isotopes are equal in their effects, nor are the various types of radiation exposure.”
 

Training goes beyond transplants and drugs

RITN offers individual hematologists specialized education about treating radiation injuries through annual exercises, modules, and “just-in-time” training.

For example, the RITN webpage devoted to triage includes guidelines for transferring radiation injury patients, triage guidelines for cytokine administration in cases of ARS, an exposure and symptom triage tool, and more. The treatment page includes details about subjects such as when human leukocyte antigen typing of casualties is appropriate and how to keep yourself safe while treating patients.

Another focus is teaching hematologists to react quickly in disasters, Mr. Case said. “The vast majority of hematologists have little to no experience in responding to disasters and making decisions with imperfect or incomplete information, as emergency medicine practitioners must do regularly.”

“Some of the RITN tabletop exercises present physicians and advanced practitioners with an incomplete set of patient information and ask physicians to then determine and prioritize their care,” Mr. Case said. “The resulting discussions help to lay the groundwork for being able to shift to the crisis standards of care mindset that would be necessary during a radiological disaster.”
 

Here’s how hematologists can get involved

If you want to help improve the nation’s response to radiation injuries, Mr. Case suggests checking RITN’s list of participating hospitals. If your facility is already part of this network, he said, contact its bone marrow transplant unit for more information.

In such cases, Dr. Jakubowski suggests that you “consider periodically giving a presentation to staff on the basics of radiation injury and the center’s role in RITN.” And if you’re not part of RITN, she said, consider contacting the network about becoming a member.

Hematologists, Mr. Case said, can also take advantage of RITN’s free short overview courses, review the RITN Treatment Guidelines, or watch short videos on the RITN’s YouTube channel.

He highlighted the Radiation Emergency Medical Management website administered by the Department of Health & Human Services, the Center for Disease Control’s radiation emergencies webpage, and the Department of Energy’s Radiation Emergency Assistance Center/Training Site.

For many Americans – especially those too young to know much about the Cold War or Hiroshima – Russia’s invasion of Ukraine might mark the first time they’ve truly considered the dangers of nuclear weapons. But dozens of hematologists in the United States already know the drill and have placed themselves on the front lines. These physicians stand prepared to treat patients exposed to radiation caused by nuclear accidents or attacks on U.S. soil.

They work nationwide at 74 medical centers that make up the Radiation Injury Treatment Network, ready to manage cases of acute radiation syndrome (ARS) during disasters. While RITN keeps a low profile, it’s been in the news lately amid anxieties about the Ukraine conflict, nuclear plant accidents, and the potential launching of nuclear weapons by foreign adversaries.

Wikimedia Commons

“The Radiation Injury Treatment Network helps plan responses for disaster scenarios where a person’s cells would be damaged after having been exposed to ionizing radiation,” program director Cullen Case Jr., MPA, said in an interview.

A U.S. Army veteran who took part in hurricane response early in his career, Mr. Case now oversees preparedness activities among all RITN hospitals, blood donor centers, and cord blood banks, in readiness for a mass casualty radiological incident. He also serves as a senior manager of the National Marrow Donor Program/Be a Match Marrow Registry.

Intense preparation for nuclear attacks or accidents is necessary, Mr. Case said, despite the doomsday scenarios disseminated on television shows and movies.

“The most frequent misconception we hear is that a nuclear disaster will encompass the whole world and be so complete that preparedness isn’t useful. However, many planning scenarios include smaller-scale incidents where survivors will need prompt and expert care,” he said.

In the wake of 9/11, the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation established the RITN in 2006, with a mission to prepare for nuclear disaster and help manage the response if one occurs.

National Archives/Wikimedia commons

“The widespread availability of radioactive material has made future exposure events, accidental or intentional, nearly inevitable,” RITN leaders warned in a 2008 report. “Hematologists, oncologists, and HSCT [hematopoietic stem cell transplantation] physicians are uniquely suited to care for victims of radiation exposure, creating a collective responsibility to prepare for a variety of contingencies.”

RITN doesn’t just train physicians, Mr. Case noted. All medical centers within the RITN are required to conduct an annual tabletop exercise where a radiation disaster scenario and a set of discussion questions are presented to the team.
 

Hematologists specially equipped to treat radiation injuries

Why are hematologists involved in treating people exposed to dangerously high levels of radiation? The answer has to do with how radiation harms the body, said Dr. Ann A. Jakubowski, a hematologist/oncologist and transplant physician at Memorial Sloan Kettering Cancer Center, New York, who serves as a medical director for RITN.

“One of the most common toxicities from radiation exposure and a major player in acute radiation syndrome is hematologic toxicity– damage to the bone marrow by the radiation, with a resultant decrease in peripheral blood counts,” she said in an interview. “This is similar to what is often seen in the treatment of cancers with radiation and/or chemotherapy.”

In cases of severe and nonreversible radiation damage to the bone marrow, Dr. Jakubowski noted, “patients can be considered for a stem cell transplant to provide new healthy cells to repopulate the bone marrow, which provides recovery of peripheral blood counts. Hematologist/oncologists are the physicians who manage stem cell transplants.”

The crucial role of hematologists in radiation injuries is not new. In fact, these physicians have been closely intertwined with nuclear research since the dawn of the atomic age. The work of developing atomic bombs also led investigators to an understanding of the structure and processes of hematopoiesis and helped them to identify hematopoietic stem cells and prove their existence in humans.
 

Disaster response poses multiple challenges

As noted in a recent article in ASH Clinical News, the challenges of treating radiation injuries would be intense, especially in the event of a nuclear accident or attack that affects a wide area. For starters, how quickly can medical professionals be mobilized, and will there be enough physicians comfortable treating patients? Fortunately, irradiated patients should not pose a direct risk to medical professionals who treat them.

“The expectation is that the patients will all be decontaminated,” said Nelson Chao, MD, MBA, one of the founders of RITN and a hematologist/oncologist and transplant physician at Duke University, Durham, N.C.

Dr. Jakubowski questions whether there will be adequate resources to handle the influx of patients who need more intensive treatment, as well as outpatients who “received lower doses of radiation and may experience a period of low blood counts but are expected to eventually recover blood counts.”

AFP/Getty Images

And if many people are injured, Dr. Chao asks, how will physicians “adopt altered standards of care to treat large numbers of patients?”

There will also be a need for physicians who aren’t hematologists, Dr. Jakubowski said. “There may be many victims who have both radiation exposure and traumatic or burn injuries, which need to be addressed first, before the hematologist can start addressing the consequences of ARS. Traumatic and burn injuries will require surgical resources.”

In addition, ARS affects the gastrointestinal track and central nervous system/cardiovascular, and it has multiple stages, she noted.

“Although we have methods of supporting the hematopoietic system – transfusions and growth factors – and even replacing it with a stem cell transplant, this will not necessarily fix the badly damaged other organs, Dr. Jakubowski said. “Also, not all radioactive isotopes are equal in their effects, nor are the various types of radiation exposure.”
 

Training goes beyond transplants and drugs

RITN offers individual hematologists specialized education about treating radiation injuries through annual exercises, modules, and “just-in-time” training.

For example, the RITN webpage devoted to triage includes guidelines for transferring radiation injury patients, triage guidelines for cytokine administration in cases of ARS, an exposure and symptom triage tool, and more. The treatment page includes details about subjects such as when human leukocyte antigen typing of casualties is appropriate and how to keep yourself safe while treating patients.

Another focus is teaching hematologists to react quickly in disasters, Mr. Case said. “The vast majority of hematologists have little to no experience in responding to disasters and making decisions with imperfect or incomplete information, as emergency medicine practitioners must do regularly.”

“Some of the RITN tabletop exercises present physicians and advanced practitioners with an incomplete set of patient information and ask physicians to then determine and prioritize their care,” Mr. Case said. “The resulting discussions help to lay the groundwork for being able to shift to the crisis standards of care mindset that would be necessary during a radiological disaster.”
 

Here’s how hematologists can get involved

If you want to help improve the nation’s response to radiation injuries, Mr. Case suggests checking RITN’s list of participating hospitals. If your facility is already part of this network, he said, contact its bone marrow transplant unit for more information.

In such cases, Dr. Jakubowski suggests that you “consider periodically giving a presentation to staff on the basics of radiation injury and the center’s role in RITN.” And if you’re not part of RITN, she said, consider contacting the network about becoming a member.

Hematologists, Mr. Case said, can also take advantage of RITN’s free short overview courses, review the RITN Treatment Guidelines, or watch short videos on the RITN’s YouTube channel.

He highlighted the Radiation Emergency Medical Management website administered by the Department of Health & Human Services, the Center for Disease Control’s radiation emergencies webpage, and the Department of Energy’s Radiation Emergency Assistance Center/Training Site.

Disaster Response and Global Health Section

Physician response to Ukraine and beyond

Displaced persons, international refugee crises, gun violence, and other disasters remain prevalent in current news. Recent events highlight the need for continued civilian physician leadership and response to disasters.

Before the Ukraine crisis, the United Nations Refugee Agency estimated displaced persons more than doubled to greater than 82 million persons over the last decade (unhcr.org). Since that analysis, there have been over 6.5 million externally displaced persons, 7.5 million internally displaced persons, and significant numbers of injured patients from the Ukraine crisis alone. The Ukraine Ministry of Health has shown preparedness in its ability to handle significant patient surges with minimal assistance.

However, organizations like the Ukraine Medical Association of North America, Razom for Ukraine, Doctors Without Borders (MSF), MedGlobal, Samaritan’s Purse, Global Response Management, and many more have deployed to assist in Ukraine. These NGOs continue to help with medical care, fulfill critical supply needs, and provide training in cutting-edge medicine (POCUS, trauma updates).

Challenges posed by unstable environments, from wars to active shooter situations, further underscore the need for continued education, advances in technology, and preparedness. Providers responding to these events often treat vulnerable populations suffering from physical and mental violence, requiring physicians to step out of their comfort zone.

Opportunities remain plentiful to affect many lives as physicians respond through well-established and coordinated efforts with NGOs across the world. Physicians should continue to be leaders in the care of vulnerable displaced persons.

Christopher Miller, DO, MPH
Fellow-in-Training Member

Thomas Marston, MD
Member-at-Large

Disaster Response and Global Health Section

Physician response to Ukraine and beyond

Displaced persons, international refugee crises, gun violence, and other disasters remain prevalent in current news. Recent events highlight the need for continued civilian physician leadership and response to disasters.

Before the Ukraine crisis, the United Nations Refugee Agency estimated displaced persons more than doubled to greater than 82 million persons over the last decade (unhcr.org). Since that analysis, there have been over 6.5 million externally displaced persons, 7.5 million internally displaced persons, and significant numbers of injured patients from the Ukraine crisis alone. The Ukraine Ministry of Health has shown preparedness in its ability to handle significant patient surges with minimal assistance.

However, organizations like the Ukraine Medical Association of North America, Razom for Ukraine, Doctors Without Borders (MSF), MedGlobal, Samaritan’s Purse, Global Response Management, and many more have deployed to assist in Ukraine. These NGOs continue to help with medical care, fulfill critical supply needs, and provide training in cutting-edge medicine (POCUS, trauma updates).

Challenges posed by unstable environments, from wars to active shooter situations, further underscore the need for continued education, advances in technology, and preparedness. Providers responding to these events often treat vulnerable populations suffering from physical and mental violence, requiring physicians to step out of their comfort zone.

Opportunities remain plentiful to affect many lives as physicians respond through well-established and coordinated efforts with NGOs across the world. Physicians should continue to be leaders in the care of vulnerable displaced persons.

Christopher Miller, DO, MPH
Fellow-in-Training Member

Thomas Marston, MD
Member-at-Large

Disaster Response and Global Health Section

Physician response to Ukraine and beyond

Displaced persons, international refugee crises, gun violence, and other disasters remain prevalent in current news. Recent events highlight the need for continued civilian physician leadership and response to disasters.

Before the Ukraine crisis, the United Nations Refugee Agency estimated displaced persons more than doubled to greater than 82 million persons over the last decade (unhcr.org). Since that analysis, there have been over 6.5 million externally displaced persons, 7.5 million internally displaced persons, and significant numbers of injured patients from the Ukraine crisis alone. The Ukraine Ministry of Health has shown preparedness in its ability to handle significant patient surges with minimal assistance.

However, organizations like the Ukraine Medical Association of North America, Razom for Ukraine, Doctors Without Borders (MSF), MedGlobal, Samaritan’s Purse, Global Response Management, and many more have deployed to assist in Ukraine. These NGOs continue to help with medical care, fulfill critical supply needs, and provide training in cutting-edge medicine (POCUS, trauma updates).

Challenges posed by unstable environments, from wars to active shooter situations, further underscore the need for continued education, advances in technology, and preparedness. Providers responding to these events often treat vulnerable populations suffering from physical and mental violence, requiring physicians to step out of their comfort zone.

Opportunities remain plentiful to affect many lives as physicians respond through well-established and coordinated efforts with NGOs across the world. Physicians should continue to be leaders in the care of vulnerable displaced persons.

Christopher Miller, DO, MPH
Fellow-in-Training Member

Thomas Marston, MD
Member-at-Large

Young children with allergies may be more likely to develop attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) by the time they’re 18, according to a large retrospective study.

“Our study provides strong evidence for the association between allergic disorders in early childhood and the development of ADHD,” Shay Nemet, MD, of the Kaplan Medical Center, Rehovot, Israel, and colleagues write in Pediatric Allergy and Immunology. “The risk of those children to develop ASD was less significant.”

The researchers analyzed data from 117,022 consecutive children diagnosed with at least one allergic disorder – asthma, conjunctivitis, rhinitis, and drug, food, or skin allergy – and 116,968 children without allergies in the Clalit Health Services pediatric database. The children had been treated from 2000 to 2018; the mean follow-up period was 11 years.

The children who were diagnosed with one or more allergies (mean age, 4.5 years) were significantly more likely to develop ADHD (odds ratio, 2.45; 95% confidence interval, 2.39-2.51), ASD (OR, 1.17; 95% CI, 1.08-1.27), or both ADHD and ASD (OR, 1.56; 95% CI, 1.35-1.79) than were the control children who did not have allergies.

Children diagnosed with rhinitis (OR, 3.96; 95% CI, 3.80-4.12) and conjunctivitis (OR, 3.63; 95% CI, 3.53-3.74) were the most likely to develop ADHD.
 

Allergy correlation with ADHD and ASD

Cy B. Nadler, PhD, a clinical psychologist and the director of Autism Services at Children’s Mercy Kansas City, Missouri, told this news organization that children and adults with neurodevelopmental differences are also more likely to have other health problems.

“Clinicians practicing in subspecialties such as allergy and immunology may have opportunities to help psychologists identify developmental and behavioral concerns early in childhood,” he added.

“Studies like this can’t be accomplished without large health care databases, but this approach has drawbacks, too,” Dr. Nadler said in an email. “Without more information about these patients’ co-occurring medical and behavioral conditions, we are almost certainly missing important contributors to the observed associations.”

Dr. Nadler, who was not involved in the study, noted that in the multivariable analysis that controlled for age at study entry, gender, and number of annual visits, the link between allergy and ASD diagnosis was not significant.

“It is important to remember not to interpret these study results as causal,” he added.

Desha M. Jordan, MD, FAAP, an assistant professor of pediatrics at UPMC Children’s Hospital of Pittsburgh, called the study “an interesting new area that has been speculated about for some time” and “one of the first I have seen with statistically significant correlations found between ADHD, ASD, and allergic conditions.”
 

More questions for future studies

Health care providers need to understand the potential sequelae of allergic conditions so that they can manage their patients appropriately, she advised.

Although symptoms and diagnoses were confirmed for all patients, the study’s retrospective design and the possibility of recall bias were limitations, said Dr. Jordan in an email. She also was not involved in the study.

“For example, the family of a child diagnosed with ADHD or ASD may have been more mindful of anything out of the norm in that child’s past, while the family of a child without these conditions may not have recalled allergic symptoms as important,” she explained.

Another question that arises is whether some patients were treated and managed well while others were not and whether this disparity in care affected the development or severity of ADHD or ASD, she added.

“Is a patient with a well-controlled allergic condition less likely to develop ADHD or ASD than a patient with an uncontrolled allergic condition? Does a well-controlled patient ever return to the same probability of getting ADHD or ASD as a nonallergic patient?”

“While this study expands our understanding of these conditions and their interrelationships, it also brings up many additional questions and opens a new segment of research,” Dr. Jordan said. “More studies in this area are necessary to confirm the findings of this paper.”

The study was partially funded by the Israel Ambulatory Pediatric Association. The authors, Dr. Nadler, and Dr. Jordan report no relevant financial relationships.

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

Young children with allergies may be more likely to develop attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) by the time they’re 18, according to a large retrospective study.

“Our study provides strong evidence for the association between allergic disorders in early childhood and the development of ADHD,” Shay Nemet, MD, of the Kaplan Medical Center, Rehovot, Israel, and colleagues write in Pediatric Allergy and Immunology. “The risk of those children to develop ASD was less significant.”

The researchers analyzed data from 117,022 consecutive children diagnosed with at least one allergic disorder – asthma, conjunctivitis, rhinitis, and drug, food, or skin allergy – and 116,968 children without allergies in the Clalit Health Services pediatric database. The children had been treated from 2000 to 2018; the mean follow-up period was 11 years.

The children who were diagnosed with one or more allergies (mean age, 4.5 years) were significantly more likely to develop ADHD (odds ratio, 2.45; 95% confidence interval, 2.39-2.51), ASD (OR, 1.17; 95% CI, 1.08-1.27), or both ADHD and ASD (OR, 1.56; 95% CI, 1.35-1.79) than were the control children who did not have allergies.

Children diagnosed with rhinitis (OR, 3.96; 95% CI, 3.80-4.12) and conjunctivitis (OR, 3.63; 95% CI, 3.53-3.74) were the most likely to develop ADHD.
 

Allergy correlation with ADHD and ASD

Cy B. Nadler, PhD, a clinical psychologist and the director of Autism Services at Children’s Mercy Kansas City, Missouri, told this news organization that children and adults with neurodevelopmental differences are also more likely to have other health problems.

“Clinicians practicing in subspecialties such as allergy and immunology may have opportunities to help psychologists identify developmental and behavioral concerns early in childhood,” he added.

“Studies like this can’t be accomplished without large health care databases, but this approach has drawbacks, too,” Dr. Nadler said in an email. “Without more information about these patients’ co-occurring medical and behavioral conditions, we are almost certainly missing important contributors to the observed associations.”

Dr. Nadler, who was not involved in the study, noted that in the multivariable analysis that controlled for age at study entry, gender, and number of annual visits, the link between allergy and ASD diagnosis was not significant.

“It is important to remember not to interpret these study results as causal,” he added.

Desha M. Jordan, MD, FAAP, an assistant professor of pediatrics at UPMC Children’s Hospital of Pittsburgh, called the study “an interesting new area that has been speculated about for some time” and “one of the first I have seen with statistically significant correlations found between ADHD, ASD, and allergic conditions.”
 

More questions for future studies

Health care providers need to understand the potential sequelae of allergic conditions so that they can manage their patients appropriately, she advised.

Although symptoms and diagnoses were confirmed for all patients, the study’s retrospective design and the possibility of recall bias were limitations, said Dr. Jordan in an email. She also was not involved in the study.

“For example, the family of a child diagnosed with ADHD or ASD may have been more mindful of anything out of the norm in that child’s past, while the family of a child without these conditions may not have recalled allergic symptoms as important,” she explained.

Another question that arises is whether some patients were treated and managed well while others were not and whether this disparity in care affected the development or severity of ADHD or ASD, she added.

“Is a patient with a well-controlled allergic condition less likely to develop ADHD or ASD than a patient with an uncontrolled allergic condition? Does a well-controlled patient ever return to the same probability of getting ADHD or ASD as a nonallergic patient?”

“While this study expands our understanding of these conditions and their interrelationships, it also brings up many additional questions and opens a new segment of research,” Dr. Jordan said. “More studies in this area are necessary to confirm the findings of this paper.”

The study was partially funded by the Israel Ambulatory Pediatric Association. The authors, Dr. Nadler, and Dr. Jordan report no relevant financial relationships.

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

Young children with allergies may be more likely to develop attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) by the time they’re 18, according to a large retrospective study.

“Our study provides strong evidence for the association between allergic disorders in early childhood and the development of ADHD,” Shay Nemet, MD, of the Kaplan Medical Center, Rehovot, Israel, and colleagues write in Pediatric Allergy and Immunology. “The risk of those children to develop ASD was less significant.”

The researchers analyzed data from 117,022 consecutive children diagnosed with at least one allergic disorder – asthma, conjunctivitis, rhinitis, and drug, food, or skin allergy – and 116,968 children without allergies in the Clalit Health Services pediatric database. The children had been treated from 2000 to 2018; the mean follow-up period was 11 years.

The children who were diagnosed with one or more allergies (mean age, 4.5 years) were significantly more likely to develop ADHD (odds ratio, 2.45; 95% confidence interval, 2.39-2.51), ASD (OR, 1.17; 95% CI, 1.08-1.27), or both ADHD and ASD (OR, 1.56; 95% CI, 1.35-1.79) than were the control children who did not have allergies.

Children diagnosed with rhinitis (OR, 3.96; 95% CI, 3.80-4.12) and conjunctivitis (OR, 3.63; 95% CI, 3.53-3.74) were the most likely to develop ADHD.
 

Allergy correlation with ADHD and ASD

Cy B. Nadler, PhD, a clinical psychologist and the director of Autism Services at Children’s Mercy Kansas City, Missouri, told this news organization that children and adults with neurodevelopmental differences are also more likely to have other health problems.

“Clinicians practicing in subspecialties such as allergy and immunology may have opportunities to help psychologists identify developmental and behavioral concerns early in childhood,” he added.

“Studies like this can’t be accomplished without large health care databases, but this approach has drawbacks, too,” Dr. Nadler said in an email. “Without more information about these patients’ co-occurring medical and behavioral conditions, we are almost certainly missing important contributors to the observed associations.”

Dr. Nadler, who was not involved in the study, noted that in the multivariable analysis that controlled for age at study entry, gender, and number of annual visits, the link between allergy and ASD diagnosis was not significant.

“It is important to remember not to interpret these study results as causal,” he added.

Desha M. Jordan, MD, FAAP, an assistant professor of pediatrics at UPMC Children’s Hospital of Pittsburgh, called the study “an interesting new area that has been speculated about for some time” and “one of the first I have seen with statistically significant correlations found between ADHD, ASD, and allergic conditions.”
 

More questions for future studies

Health care providers need to understand the potential sequelae of allergic conditions so that they can manage their patients appropriately, she advised.

Although symptoms and diagnoses were confirmed for all patients, the study’s retrospective design and the possibility of recall bias were limitations, said Dr. Jordan in an email. She also was not involved in the study.

“For example, the family of a child diagnosed with ADHD or ASD may have been more mindful of anything out of the norm in that child’s past, while the family of a child without these conditions may not have recalled allergic symptoms as important,” she explained.

Another question that arises is whether some patients were treated and managed well while others were not and whether this disparity in care affected the development or severity of ADHD or ASD, she added.

“Is a patient with a well-controlled allergic condition less likely to develop ADHD or ASD than a patient with an uncontrolled allergic condition? Does a well-controlled patient ever return to the same probability of getting ADHD or ASD as a nonallergic patient?”

“While this study expands our understanding of these conditions and their interrelationships, it also brings up many additional questions and opens a new segment of research,” Dr. Jordan said. “More studies in this area are necessary to confirm the findings of this paper.”

The study was partially funded by the Israel Ambulatory Pediatric Association. The authors, Dr. Nadler, and Dr. Jordan report no relevant financial relationships.

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

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.