MDedge Dermatology

Bloodroot (Sanguinaria canadensis) is a member of the family Papaveraceae.¹ This North American plant commonly is found in widespread distribution from Nova Scotia, Canada, to Florida and from the Great Lakes to Mississippi.² Historically, Native Americans used bloodroot as a skin dye and as a medicine for many ailments.³

Bloodroot blooms for only a few days, starting in March, and fruits in June. The flowers comprise 8 to 10 white petals, surrounding a bed of yellow stamens (Figure). The plant thrives in wooded areas and grows to 12 inches tall. In its off-season, the plant remains dormant and can survive below-freezing temperatures.⁴

Chemical Constituents

Bloodroot gets its colloquial name from its red sap, which is released when the plant’s rhizome is cut. This sap contains a high concentration of alkaloids that are used for protection against predators. The rhizome itself has a rusty, red-brown color; the roots are a brighter red-orange.⁴

The rhizome of S canadensis contains the highest concentration of active alkaloids; the roots also contain these chemicals, though to a lesser degree; and the leaves, flowers, and fruits harvest approximately 1% of the alkaloids found in the roots.⁴ The concentration of alkaloids can vary from one plant to the next, depending on environmental conditions.^5,6

The major alkaloids in S canadensis include both quaternary benzophenanthridine alkaloids (eg, sanguinarine, chelerythrine, sanguilutine, chelilutine, sanguirubine, chelirubine) and protopin alkaloids (eg, protopine, allocryptopine).^3,7 Of these, sanguinarine and chelerythrine typically are the most potent.¹ Oral ingestion or topical application of these molecules can have therapeutic and toxic effects.⁸

Biophysiological Effects

Bloodroot has been shown to have remarkable antimicrobial effects.⁹ The plant produces hydrogen peroxide and superoxide anion.¹⁰ These mediators cause oxidative stress, thus inducing destruction of cellular DNA and the cell membrane.¹¹ Although these effects can be helpful when fighting infection, they are not necessarily selective against healthy cells.¹²

Alkaloids of bloodroot also have cardiovascular therapeutic effects. Sanguinarine blocks angiotensin II and causes vasodilation, thus helping treat hypertension.¹³ It also acts as an inotrope by blocking the Na⁺/K⁺ ATPase pump. These effects in a patient who is already taking digoxin can cause notable cardiotoxicity because the 2 drugs share a mechanism of action.¹⁴

Chelerythrine blocks production of cyclooxygenase 2 and prostaglandin E₂.¹⁵ This pathway modification results in anti-inflammatory effects that can help treat arthritis, edema, and other inflammatory conditions.¹⁶ Moreover, sanguinarine has demonstrated efficacy in numerous anticancer pathways,¹⁷ including downregulation of intercellular adhesion molecules, vascular cell adhesion molecules, and vascular endothelial growth factor (VEGF).^18-20 Blocking VEGF is one way to inhibit angiogenesis,²¹ which is upregulated in tumor formation, thus sanguinarine can have an antiproliferative anticancer effect.²² Sanguinarine also upregulates molecules such as nuclear factor–κB and the protease enzymes known as caspases to cause proapoptotic effects, furthering its antitumor potential.^23,24

Treatment of Dermatologic Conditions

The initial technique of Mohs micrographic surgery employed a chemopaste that utilized an extract of S canadensis to preserve tissue.²⁵ Outside the dermatologist’s office, bloodroot is used as a topical home remedy for a variety of cutaneous conditions, including cancer, skin tags, and warts.²⁶ Bloodroot is advertised as black salve, an alternative anticancer treatment.^27,28

As useful as this natural agent sounds, it has a pitfall: The alkaloids of S canadensis are nonspecific in their cytotoxicity, damaging neoplastic and healthy tissue.²⁹ This cytotoxic effect can cause escharification through diffuse tissue destruction and has been observed to result in formation of a keloid scar.³⁰ The alkaloids in black salve also have been shown to cause skin erosions and cellular atypia.^28,31 Therefore, the utility of this escharotic in medical treatment is limited.³² Fortuitously, oral antibiotics and wound care can help address this adverse effect.²⁸

Bloodroot was once used as a mouth rinse and toothpaste to treat gingivitis, but this application was later associated with oral leukoplakia, a premalignant condition.³³ Leukoplakia associated with S canadensis extract often is unremitting. Immediate discontinuation of the offending agent produces little regression, suggesting that cellular damage is irreversible.³⁴

Final Thoughts

Although bloodroot demonstrates efficacy as a phytotherapeutic, it does come with notable toxicity. Physicians should warn patients of the unwanted cosmetic effects of black salve, especially oral products that incorporate sanguinarine. Adverse effects on the oropharynx can be irreversible, though the eschar associated with black salve can be treated with a topical or oral corticosteroid.²⁹

Bloodroot (Sanguinaria canadensis) is a member of the family Papaveraceae.¹ This North American plant commonly is found in widespread distribution from Nova Scotia, Canada, to Florida and from the Great Lakes to Mississippi.² Historically, Native Americans used bloodroot as a skin dye and as a medicine for many ailments.³

Bloodroot blooms for only a few days, starting in March, and fruits in June. The flowers comprise 8 to 10 white petals, surrounding a bed of yellow stamens (Figure). The plant thrives in wooded areas and grows to 12 inches tall. In its off-season, the plant remains dormant and can survive below-freezing temperatures.⁴

Chemical Constituents

Bloodroot gets its colloquial name from its red sap, which is released when the plant’s rhizome is cut. This sap contains a high concentration of alkaloids that are used for protection against predators. The rhizome itself has a rusty, red-brown color; the roots are a brighter red-orange.⁴

The rhizome of S canadensis contains the highest concentration of active alkaloids; the roots also contain these chemicals, though to a lesser degree; and the leaves, flowers, and fruits harvest approximately 1% of the alkaloids found in the roots.⁴ The concentration of alkaloids can vary from one plant to the next, depending on environmental conditions.^5,6

The major alkaloids in S canadensis include both quaternary benzophenanthridine alkaloids (eg, sanguinarine, chelerythrine, sanguilutine, chelilutine, sanguirubine, chelirubine) and protopin alkaloids (eg, protopine, allocryptopine).^3,7 Of these, sanguinarine and chelerythrine typically are the most potent.¹ Oral ingestion or topical application of these molecules can have therapeutic and toxic effects.⁸

Biophysiological Effects

Bloodroot has been shown to have remarkable antimicrobial effects.⁹ The plant produces hydrogen peroxide and superoxide anion.¹⁰ These mediators cause oxidative stress, thus inducing destruction of cellular DNA and the cell membrane.¹¹ Although these effects can be helpful when fighting infection, they are not necessarily selective against healthy cells.¹²

Alkaloids of bloodroot also have cardiovascular therapeutic effects. Sanguinarine blocks angiotensin II and causes vasodilation, thus helping treat hypertension.¹³ It also acts as an inotrope by blocking the Na⁺/K⁺ ATPase pump. These effects in a patient who is already taking digoxin can cause notable cardiotoxicity because the 2 drugs share a mechanism of action.¹⁴

Chelerythrine blocks production of cyclooxygenase 2 and prostaglandin E₂.¹⁵ This pathway modification results in anti-inflammatory effects that can help treat arthritis, edema, and other inflammatory conditions.¹⁶ Moreover, sanguinarine has demonstrated efficacy in numerous anticancer pathways,¹⁷ including downregulation of intercellular adhesion molecules, vascular cell adhesion molecules, and vascular endothelial growth factor (VEGF).^18-20 Blocking VEGF is one way to inhibit angiogenesis,²¹ which is upregulated in tumor formation, thus sanguinarine can have an antiproliferative anticancer effect.²² Sanguinarine also upregulates molecules such as nuclear factor–κB and the protease enzymes known as caspases to cause proapoptotic effects, furthering its antitumor potential.^23,24

Treatment of Dermatologic Conditions

The initial technique of Mohs micrographic surgery employed a chemopaste that utilized an extract of S canadensis to preserve tissue.²⁵ Outside the dermatologist’s office, bloodroot is used as a topical home remedy for a variety of cutaneous conditions, including cancer, skin tags, and warts.²⁶ Bloodroot is advertised as black salve, an alternative anticancer treatment.^27,28

As useful as this natural agent sounds, it has a pitfall: The alkaloids of S canadensis are nonspecific in their cytotoxicity, damaging neoplastic and healthy tissue.²⁹ This cytotoxic effect can cause escharification through diffuse tissue destruction and has been observed to result in formation of a keloid scar.³⁰ The alkaloids in black salve also have been shown to cause skin erosions and cellular atypia.^28,31 Therefore, the utility of this escharotic in medical treatment is limited.³² Fortuitously, oral antibiotics and wound care can help address this adverse effect.²⁸

Bloodroot was once used as a mouth rinse and toothpaste to treat gingivitis, but this application was later associated with oral leukoplakia, a premalignant condition.³³ Leukoplakia associated with S canadensis extract often is unremitting. Immediate discontinuation of the offending agent produces little regression, suggesting that cellular damage is irreversible.³⁴

Final Thoughts

Although bloodroot demonstrates efficacy as a phytotherapeutic, it does come with notable toxicity. Physicians should warn patients of the unwanted cosmetic effects of black salve, especially oral products that incorporate sanguinarine. Adverse effects on the oropharynx can be irreversible, though the eschar associated with black salve can be treated with a topical or oral corticosteroid.²⁹

Bloodroot (Sanguinaria canadensis) is a member of the family Papaveraceae.¹ This North American plant commonly is found in widespread distribution from Nova Scotia, Canada, to Florida and from the Great Lakes to Mississippi.² Historically, Native Americans used bloodroot as a skin dye and as a medicine for many ailments.³

Bloodroot blooms for only a few days, starting in March, and fruits in June. The flowers comprise 8 to 10 white petals, surrounding a bed of yellow stamens (Figure). The plant thrives in wooded areas and grows to 12 inches tall. In its off-season, the plant remains dormant and can survive below-freezing temperatures.⁴

Chemical Constituents

Bloodroot gets its colloquial name from its red sap, which is released when the plant’s rhizome is cut. This sap contains a high concentration of alkaloids that are used for protection against predators. The rhizome itself has a rusty, red-brown color; the roots are a brighter red-orange.⁴

The rhizome of S canadensis contains the highest concentration of active alkaloids; the roots also contain these chemicals, though to a lesser degree; and the leaves, flowers, and fruits harvest approximately 1% of the alkaloids found in the roots.⁴ The concentration of alkaloids can vary from one plant to the next, depending on environmental conditions.^5,6

The major alkaloids in S canadensis include both quaternary benzophenanthridine alkaloids (eg, sanguinarine, chelerythrine, sanguilutine, chelilutine, sanguirubine, chelirubine) and protopin alkaloids (eg, protopine, allocryptopine).^3,7 Of these, sanguinarine and chelerythrine typically are the most potent.¹ Oral ingestion or topical application of these molecules can have therapeutic and toxic effects.⁸

Biophysiological Effects

Bloodroot has been shown to have remarkable antimicrobial effects.⁹ The plant produces hydrogen peroxide and superoxide anion.¹⁰ These mediators cause oxidative stress, thus inducing destruction of cellular DNA and the cell membrane.¹¹ Although these effects can be helpful when fighting infection, they are not necessarily selective against healthy cells.¹²

Alkaloids of bloodroot also have cardiovascular therapeutic effects. Sanguinarine blocks angiotensin II and causes vasodilation, thus helping treat hypertension.¹³ It also acts as an inotrope by blocking the Na⁺/K⁺ ATPase pump. These effects in a patient who is already taking digoxin can cause notable cardiotoxicity because the 2 drugs share a mechanism of action.¹⁴

Chelerythrine blocks production of cyclooxygenase 2 and prostaglandin E₂.¹⁵ This pathway modification results in anti-inflammatory effects that can help treat arthritis, edema, and other inflammatory conditions.¹⁶ Moreover, sanguinarine has demonstrated efficacy in numerous anticancer pathways,¹⁷ including downregulation of intercellular adhesion molecules, vascular cell adhesion molecules, and vascular endothelial growth factor (VEGF).^18-20 Blocking VEGF is one way to inhibit angiogenesis,²¹ which is upregulated in tumor formation, thus sanguinarine can have an antiproliferative anticancer effect.²² Sanguinarine also upregulates molecules such as nuclear factor–κB and the protease enzymes known as caspases to cause proapoptotic effects, furthering its antitumor potential.^23,24

Treatment of Dermatologic Conditions

The initial technique of Mohs micrographic surgery employed a chemopaste that utilized an extract of S canadensis to preserve tissue.²⁵ Outside the dermatologist’s office, bloodroot is used as a topical home remedy for a variety of cutaneous conditions, including cancer, skin tags, and warts.²⁶ Bloodroot is advertised as black salve, an alternative anticancer treatment.^27,28

As useful as this natural agent sounds, it has a pitfall: The alkaloids of S canadensis are nonspecific in their cytotoxicity, damaging neoplastic and healthy tissue.²⁹ This cytotoxic effect can cause escharification through diffuse tissue destruction and has been observed to result in formation of a keloid scar.³⁰ The alkaloids in black salve also have been shown to cause skin erosions and cellular atypia.^28,31 Therefore, the utility of this escharotic in medical treatment is limited.³² Fortuitously, oral antibiotics and wound care can help address this adverse effect.²⁸

Bloodroot was once used as a mouth rinse and toothpaste to treat gingivitis, but this application was later associated with oral leukoplakia, a premalignant condition.³³ Leukoplakia associated with S canadensis extract often is unremitting. Immediate discontinuation of the offending agent produces little regression, suggesting that cellular damage is irreversible.³⁴

Final Thoughts

Although bloodroot demonstrates efficacy as a phytotherapeutic, it does come with notable toxicity. Physicians should warn patients of the unwanted cosmetic effects of black salve, especially oral products that incorporate sanguinarine. Adverse effects on the oropharynx can be irreversible, though the eschar associated with black salve can be treated with a topical or oral corticosteroid.²⁹

A ccording to the US Census Bureau, more than half of all Americans are projected to belong to a minority group, defined as any group other than non-Hispanic White alone, by 2044. ¹ Consequently, the United States rapidly is becoming a country in which the majority of citizens will have skin of color. Individuals with skin of color are of diverse ethnic backgrounds and include people of African, Latin American, Native American, Pacific Islander, and Asian descent, as well as interethnic backgrounds. ² Throughout the country, dermatologists along with primary care practitioners may be confronted with certain cutaneous conditions that have varying disease presentations or processes in patients with skin of color. It also is important to note that racial categories are socially rather than biologically constructed, and the term skin of color includes a wide variety of diverse skin types. Nevertheless, the current literature thoroughly supports unique pathophysiologic differences in skin of color as well as variations in disease manifestation compared to White patients. ^3-5 For example, the increased lability of melanosomes in skin of color patients, which increases their risk for postinflammatory hyperpigmentation, has been well documented. ^5-7 There are various dermatologic conditions that also occur with higher frequency and manifest uniquely in people with darker, more pigmented skin, ^7-9 and dermatologists, along with primary care physicians, should feel prepared to recognize and address them.

Extensive evidence also indicates that there are unique aspects to consider while managing certain skin diseases in patients with skin of color.^8,10,11 Consequently, as noted on the Skin of Color Society (SOCS) website, “[a]n increase in the body of dermatological literature concerning skin of color as well as the advancement of both basic science and clinical investigational research is necessary to meet the needs of the expanding skin of color population.”² In the meantime, current knowledge regarding cutaneous conditions that diversely or disproportionately affect skin of color should be actively disseminated to physicians in training. Although patients with skin of color should always have access to comprehensive care and knowledgeable practitioners, the current changes in national and regional demographics further underscore the need for a more thorough understanding of skin of color with regard to disease pathogenesis, diagnosis, and treatment.

Several studies have found that medical students in the United States are minimally exposed to dermatology in general compared to other clinical specialties,^12-14 which can easily lead to the underrecognition of disorders that may uniquely or disproportionately affect individuals with pigmented skin. Recent data showed that medical schools typically required fewer than 10 hours of dermatology instruction,¹² and on average, dermatologic training made up less than 1% of a medical student’s undergraduate medical education.^13,15,16 Consequently, less than 40% of primary care residents felt that their medical school curriculum adequately prepared them to manage common skin conditions.¹⁴ Although not all physicians should be expected to fully grasp the complexities of skin of color and its diagnostic and therapeutic implications, both practicing and training dermatologists have acknowledged a lack of exposure to skin of color. In one study, approximately 47% of dermatologists and dermatology residents reported that their medical training (medical school and/or residency) was inadequate in training them on skin conditions in Black patients. Furthermore, many who felt their training was lacking in skin of color identified the need for greater exposure to Black patients and training materials.¹⁵ The absence of comprehensive medical education regarding skin of color ultimately can be a disadvantage for both practitioners and patients, resulting in poorer outcomes. Furthermore, underrepresentation of skin of color may persist beyond undergraduate and graduate medical education. There also is evidence to suggest that noninclusion of skin of color pervades foundational dermatologic educational resources, including commonly used textbooks as well as continuing medical education disseminated at national conferences and meetings.¹⁷ Taken together, these findings highlight the need for more diverse and representative exposure to skin of color throughout medical training, which begins with a diverse inclusive undergraduate medical education in dermatology.

The objective of this study was to determine if the preclinical dermatology curriculum at 3 US medical schools provided adequate representation of skin of color patients in their didactic presentation slides.

Methods

Participants—Three US medical schools, a blend of private and public medical schools located across different geographic boundaries, agreed to participate in the study. All 3 institutions were current members of the American Medical Association (AMA) Accelerating Change in Medical Education consortium, whose primary goal is to create the medical school of the future and transform physician training.¹⁸ All 32 member institutions of the AMA consortium were contacted to request their participation in the study. As part of the consortium, these institutions have vowed to collectively work to develop and share the best models for educational advancement to improve care for patients, populations, and communities¹⁸ and would expectedly provide a more racially and ethnically inclusive curriculum than an institution not accountable to a group dedicated to identifying the best ways to deliver care for increasingly diverse communities.

Data Collection—Lectures were included if they were presented during dermatology preclinical courses in the 2015 to 2016 academic year. An uninvolved third party removed the names and identities of instructors to preserve anonymity. Two independent coders from different institutions extracted the data—lecture title, total number of clinical and histologic images, and number of skin of color images—from each of the anonymized lectures using a standardized coding form. We documented differences in skin of color noted in lectures and the disease context for the discussed differences, such as variations in clinical presentation, disease process, epidemiology/risk, and treatment between different skin phenotypes or ethnic groups. Photographs in which the coders were unable to differentiate whether the patient had skin of color were designated as indeterminate or unclear. Photographs appearing to represent Fitzpatrick skin types IV, V, and VI¹⁹ were categorically designated as skin of color, and those appearing to represent Fitzpatrick skin types I and II were described as not skin of color; however, images appearing to represent Fitzpatrick skin type III often were classified as not skin of color or indeterminate and occasionally skin of color. The Figure shows examples of images classified as skin of color, indeterminate, and not skin of color. Photographs often were classified as indeterminate due to poor lighting, close-up view photographs, or highlighted pathology obscuring the surrounding skin. We excluded duplicate photographs and histologic images from the analyses.

We also reviewed 19 conditions previously highlighted by the SOCS as areas of importance to skin of color patients.²⁰ The coders tracked how many of these conditions were noted in each lecture. Duplicate discussion of these conditions was not included in the analyses. Any discrepancies between coders were resolved through additional slide review and discussion. The final coded data with the agreed upon changes were used for statistical analyses. Recent national demographic data from the US Census Bureau in 2019 describe approximately 39.9% of the population as belonging to racial/ethnic groups other than non-Hispanic/Latinx White.²¹ Consequently, the standard for adequate representation for skin of color photographs was set at 35% for the purpose of this study.

Across all 3 institutions included in the study, the proportion of the total number of clinical photographs showing skin of color was 16% (290/1812). Eight percent of the total photographs (145/1812) were noted to be indeterminate (Table). For institution 1, 23.6% of photographs (155/658) showed skin of color, and 12.6% (83/658) were indeterminate. For institution 2, 13.1% (76/578) showed skin of color and 7.8% (45/578) were indeterminate. For institution 3, 10.2% (59/576) showed skin of color and 3% (17/576) were indeterminate.

Institutions 1, 2, and 3 had 18, 8, and 17 total dermatology lectures, respectively. Of the 19 conditions designated as areas of importance to skin of color patients by the SOCS, 16 (84.2%) were discussed by institution 1, 11 (57.9%) by institution 2, and 9 (47.4%) by institution 3 (eTable 1). Institution 3 did not include photographs of skin of color patients in its acne, psoriasis, or cutaneous malignancy lectures. Institution 1 also did not include any skin of color patients in its malignancy lecture. Lectures that focused on pigmentary disorders, atopic dermatitis, infectious conditions, and benign cutaneous neoplasms were more likely to display photographs of skin of color patients; for example, lectures that discussed infectious conditions, such as superficial mycoses, herpes viruses, human papillomavirus, syphilis, and atypical mycobacterial infections, were consistently among those with higher proportions of photographs of skin of color patients.

Throughout the entire preclinical dermatology course at all 3 institutions, of 2945 lecture slides, only 24 (0.8%) unique differences were noted between skin color and non–skin of color patients, with 10 total differences noted by institution 1, 6 by institution 2, and 8 by institution 3 (Table). The majority of these differences (19/24) were related to epidemiologic differences in prevalence among varying racial/ethnic groups, with only 5 instances highlighting differences in clinical presentation. There was only a single instance that elaborated on the underlying pathophysiologic mechanisms of the discussed difference. Of all 24 unique differences discussed, 8 were related to skin cancer, 3 were related to dermatitis, and 2 were related to the difference in manifestation of erythema in patients with darker skin (eTable 2).

Comment

The results of this study demonstrated that skin of color is underrepresented in the preclinical dermatology curriculum at these 3 institutions. Although only 16% of all included clinical photographs were of skin of color, individuals with skin of color will soon represent more than half of the total US population within the next 2 decades.¹ To increase representation of skin of color patients, teaching faculty should consciously and deliberately include more photographs of skin of color patients for a wider variety of common conditions, including atopic dermatitis and psoriasis, in addition to those that tend to disparately affect skin of color patients, such as pseudofolliculitis barbae or melasma. Furthermore, they also can incorporate more detailed discussions about important differences seen in skin of color patients.

More Skin of Color Photographs in Psoriasis Lectures—At institution 3, there were no skin of color patients included in the psoriasis lecture, even though there is considerable data in the literature indicating notable differences in the clinical presentation, quality-of-life impact, and treatment of psoriasis in skin of color patients.^11,22 There are multiple nuances in psoriasis manifestation in patients with skin of color, including less-conspicuous erythema in darker skin, higher degrees of dyspigmentation, and greater body surface area involvement. For Black patients with scalp psoriasis, the impact of hair texture, styling practices, and washing frequency are additional considerations that may impact disease severity and selection of topical therapy.¹¹ The lack of inclusion of any skin of color patients in the psoriasis lecture at one institution further underscores the pressing need to prioritize communities of color in medical education.

More Skin of Color Photographs in Cutaneous Malignancy Lectures—Similarly, while a lecturer at institution 2 noted that acral lentiginous melanoma accounts for a considerable proportion of melanoma among skin of color patients,²³ there was no mention of how melanoma generally is substantially more deadly in this population, potentially due to decreased awareness and inconsistent screening.²⁴ Furthermore, at institutions 1 and 3, there were no photographs or discussion of skin of color patients during the cutaneous malignancy lectures. Evidence shows that more emphasis is needed for melanoma screening and awareness in skin of color populations to improve survival outcomes,²⁴ and this begins with educating not only future dermatologists but all future physicians as well. The failure to include photographs of skin of color patients in discussions or lectures regarding cutaneous malignancies may serve to further perpetuate the harmful misperception that individuals with skin of color are unaffected by skin cancer.^25,26

Analysis of Skin of Color Photographs in Infectious Disease Lectures—In addition, lectures discussing infectious etiologies were among those with the highest proportion of skin of color photographs. This relatively disproportionate representation of skin of color compared to the other lectures may contribute to the development of harmful stereotypes or the stigmatization of skin of color patients. Although skin of color should continue to be represented in similar lectures, teaching faculty should remain mindful of the potential unintended impact from lectures including relatively disproportionate amounts of skin of color, particularly when other lectures may have sparse to absent representation of skin of color.

More Photographs Available for Education—Overall, our findings may help to inform changes to preclinical dermatology medical education at other institutions to create more inclusive and representative curricula for skin of color patients. The ability of instructors to provide visual representation of various dermatologic conditions may be limited by the photographs available in certain textbooks with few examples of patients with skin of color; however, concerns regarding the lack of skin of color representation in dermatology training is not a novel discussion.¹⁷ Although it is the responsibility of all dermatologists to advocate for the inclusion of skin of color, many dermatologists of color have been leading the way in this movement for decades, publishing several textbooks to document various skin conditions in those with darker skin types and discuss unique considerations for patients with skin of color.^27-29 Images from these textbooks can be utilized by programs to increase representation of skin of color in dermatology training. There also are multiple expanding online dermatologic databases, such as VisualDx, with an increasing focus on skin of color patients, some of which allow users to filter images by degree of skin pigmentation.³⁰ Moreover, instructors also can work to diversify their curricula by highlighting more of the SOCS conditions of importance to skin of color patients, which have since been renamed and highlighted on the Patient Dermatology Education section of the SOCS website.²⁰ These conditions, while not completely comprehensive, provide a useful starting point for medical educators to reevaluate for potential areas of improvement and inclusion.

There are several potential strategies that can be used to better represent skin of color in dermatologic preclinical medical education, including increasing awareness, especially among dermatology teaching faculty, of existing disparities in the representation of skin of color in the preclinical curricula. Additionally, all dermatology teaching materials could be reviewed at the department level prior to being disseminated to medical students to assess for instances in which skin of color could be prioritized for discussion or varying disease presentations in skin of color could be demonstrated. Finally, teaching faculty may consider photographing more clinical images of their skin of color patients to further develop a catalog of diverse images that can be used to teach students.

Study Limitations—Our study was unable to account for verbal discussion of skin of color not otherwise denoted or captured in lecture slides. Additional limitations include the utilization of Fitzpatrick skin types to describe and differentiate varying skin tones, as the Fitzpatrick scale originally was developed as a method to describe an individual’s response to UV exposure.¹⁹ The inability to further delineate the representation of darker skin types, such as those that may be classified as Fitzpatrick skin types V or VI,¹⁹ compared to those with lighter skin of color also was a limiting factor. This study was unable to assess for discussion of other common conditions affecting skin of color patients that were not listed as one of the priority conditions by SOCS. Photographs that were designated as indeterminate were difficult to elucidate as skin of color; however, it is possible that instructors may have verbally described these images as skin of color during lectures. Nonetheless, it may be beneficial for learners if teaching faculty were to clearly label instances where skin of color patients are shown or when notable differences are present.

Future studies would benefit from the inclusion of audio data from lectures, syllabi, and small group teaching materials from preclinical courses to more accurately assess representation of skin of color in dermatology training. Additionally, future studies also may expand to include images from lectures of overlapping clinical specialties, particularly infectious disease and rheumatology, to provide a broader assessment of skin of color exposure. Furthermore, repeat assessment may be beneficial to assess the longitudinal effectiveness of curricular changes at the institutions included in this study, comparing older lectures to more recent, updated lectures. This study also may be replicated at other medical schools to allow for wider comparison of curricula.

Acknowledgment—The authors wish to thank the institutions that offered and agreed to participate in this study with the hopes of improving medical education.

A ccording to the US Census Bureau, more than half of all Americans are projected to belong to a minority group, defined as any group other than non-Hispanic White alone, by 2044. ¹ Consequently, the United States rapidly is becoming a country in which the majority of citizens will have skin of color. Individuals with skin of color are of diverse ethnic backgrounds and include people of African, Latin American, Native American, Pacific Islander, and Asian descent, as well as interethnic backgrounds. ² Throughout the country, dermatologists along with primary care practitioners may be confronted with certain cutaneous conditions that have varying disease presentations or processes in patients with skin of color. It also is important to note that racial categories are socially rather than biologically constructed, and the term skin of color includes a wide variety of diverse skin types. Nevertheless, the current literature thoroughly supports unique pathophysiologic differences in skin of color as well as variations in disease manifestation compared to White patients. ^3-5 For example, the increased lability of melanosomes in skin of color patients, which increases their risk for postinflammatory hyperpigmentation, has been well documented. ^5-7 There are various dermatologic conditions that also occur with higher frequency and manifest uniquely in people with darker, more pigmented skin, ^7-9 and dermatologists, along with primary care physicians, should feel prepared to recognize and address them.

Extensive evidence also indicates that there are unique aspects to consider while managing certain skin diseases in patients with skin of color.^8,10,11 Consequently, as noted on the Skin of Color Society (SOCS) website, “[a]n increase in the body of dermatological literature concerning skin of color as well as the advancement of both basic science and clinical investigational research is necessary to meet the needs of the expanding skin of color population.”² In the meantime, current knowledge regarding cutaneous conditions that diversely or disproportionately affect skin of color should be actively disseminated to physicians in training. Although patients with skin of color should always have access to comprehensive care and knowledgeable practitioners, the current changes in national and regional demographics further underscore the need for a more thorough understanding of skin of color with regard to disease pathogenesis, diagnosis, and treatment.

Several studies have found that medical students in the United States are minimally exposed to dermatology in general compared to other clinical specialties,^12-14 which can easily lead to the underrecognition of disorders that may uniquely or disproportionately affect individuals with pigmented skin. Recent data showed that medical schools typically required fewer than 10 hours of dermatology instruction,¹² and on average, dermatologic training made up less than 1% of a medical student’s undergraduate medical education.^13,15,16 Consequently, less than 40% of primary care residents felt that their medical school curriculum adequately prepared them to manage common skin conditions.¹⁴ Although not all physicians should be expected to fully grasp the complexities of skin of color and its diagnostic and therapeutic implications, both practicing and training dermatologists have acknowledged a lack of exposure to skin of color. In one study, approximately 47% of dermatologists and dermatology residents reported that their medical training (medical school and/or residency) was inadequate in training them on skin conditions in Black patients. Furthermore, many who felt their training was lacking in skin of color identified the need for greater exposure to Black patients and training materials.¹⁵ The absence of comprehensive medical education regarding skin of color ultimately can be a disadvantage for both practitioners and patients, resulting in poorer outcomes. Furthermore, underrepresentation of skin of color may persist beyond undergraduate and graduate medical education. There also is evidence to suggest that noninclusion of skin of color pervades foundational dermatologic educational resources, including commonly used textbooks as well as continuing medical education disseminated at national conferences and meetings.¹⁷ Taken together, these findings highlight the need for more diverse and representative exposure to skin of color throughout medical training, which begins with a diverse inclusive undergraduate medical education in dermatology.

The objective of this study was to determine if the preclinical dermatology curriculum at 3 US medical schools provided adequate representation of skin of color patients in their didactic presentation slides.

Methods

Participants—Three US medical schools, a blend of private and public medical schools located across different geographic boundaries, agreed to participate in the study. All 3 institutions were current members of the American Medical Association (AMA) Accelerating Change in Medical Education consortium, whose primary goal is to create the medical school of the future and transform physician training.¹⁸ All 32 member institutions of the AMA consortium were contacted to request their participation in the study. As part of the consortium, these institutions have vowed to collectively work to develop and share the best models for educational advancement to improve care for patients, populations, and communities¹⁸ and would expectedly provide a more racially and ethnically inclusive curriculum than an institution not accountable to a group dedicated to identifying the best ways to deliver care for increasingly diverse communities.

Data Collection—Lectures were included if they were presented during dermatology preclinical courses in the 2015 to 2016 academic year. An uninvolved third party removed the names and identities of instructors to preserve anonymity. Two independent coders from different institutions extracted the data—lecture title, total number of clinical and histologic images, and number of skin of color images—from each of the anonymized lectures using a standardized coding form. We documented differences in skin of color noted in lectures and the disease context for the discussed differences, such as variations in clinical presentation, disease process, epidemiology/risk, and treatment between different skin phenotypes or ethnic groups. Photographs in which the coders were unable to differentiate whether the patient had skin of color were designated as indeterminate or unclear. Photographs appearing to represent Fitzpatrick skin types IV, V, and VI¹⁹ were categorically designated as skin of color, and those appearing to represent Fitzpatrick skin types I and II were described as not skin of color; however, images appearing to represent Fitzpatrick skin type III often were classified as not skin of color or indeterminate and occasionally skin of color. The Figure shows examples of images classified as skin of color, indeterminate, and not skin of color. Photographs often were classified as indeterminate due to poor lighting, close-up view photographs, or highlighted pathology obscuring the surrounding skin. We excluded duplicate photographs and histologic images from the analyses.

We also reviewed 19 conditions previously highlighted by the SOCS as areas of importance to skin of color patients.²⁰ The coders tracked how many of these conditions were noted in each lecture. Duplicate discussion of these conditions was not included in the analyses. Any discrepancies between coders were resolved through additional slide review and discussion. The final coded data with the agreed upon changes were used for statistical analyses. Recent national demographic data from the US Census Bureau in 2019 describe approximately 39.9% of the population as belonging to racial/ethnic groups other than non-Hispanic/Latinx White.²¹ Consequently, the standard for adequate representation for skin of color photographs was set at 35% for the purpose of this study.

Across all 3 institutions included in the study, the proportion of the total number of clinical photographs showing skin of color was 16% (290/1812). Eight percent of the total photographs (145/1812) were noted to be indeterminate (Table). For institution 1, 23.6% of photographs (155/658) showed skin of color, and 12.6% (83/658) were indeterminate. For institution 2, 13.1% (76/578) showed skin of color and 7.8% (45/578) were indeterminate. For institution 3, 10.2% (59/576) showed skin of color and 3% (17/576) were indeterminate.

Institutions 1, 2, and 3 had 18, 8, and 17 total dermatology lectures, respectively. Of the 19 conditions designated as areas of importance to skin of color patients by the SOCS, 16 (84.2%) were discussed by institution 1, 11 (57.9%) by institution 2, and 9 (47.4%) by institution 3 (eTable 1). Institution 3 did not include photographs of skin of color patients in its acne, psoriasis, or cutaneous malignancy lectures. Institution 1 also did not include any skin of color patients in its malignancy lecture. Lectures that focused on pigmentary disorders, atopic dermatitis, infectious conditions, and benign cutaneous neoplasms were more likely to display photographs of skin of color patients; for example, lectures that discussed infectious conditions, such as superficial mycoses, herpes viruses, human papillomavirus, syphilis, and atypical mycobacterial infections, were consistently among those with higher proportions of photographs of skin of color patients.

Throughout the entire preclinical dermatology course at all 3 institutions, of 2945 lecture slides, only 24 (0.8%) unique differences were noted between skin color and non–skin of color patients, with 10 total differences noted by institution 1, 6 by institution 2, and 8 by institution 3 (Table). The majority of these differences (19/24) were related to epidemiologic differences in prevalence among varying racial/ethnic groups, with only 5 instances highlighting differences in clinical presentation. There was only a single instance that elaborated on the underlying pathophysiologic mechanisms of the discussed difference. Of all 24 unique differences discussed, 8 were related to skin cancer, 3 were related to dermatitis, and 2 were related to the difference in manifestation of erythema in patients with darker skin (eTable 2).

Comment

The results of this study demonstrated that skin of color is underrepresented in the preclinical dermatology curriculum at these 3 institutions. Although only 16% of all included clinical photographs were of skin of color, individuals with skin of color will soon represent more than half of the total US population within the next 2 decades.¹ To increase representation of skin of color patients, teaching faculty should consciously and deliberately include more photographs of skin of color patients for a wider variety of common conditions, including atopic dermatitis and psoriasis, in addition to those that tend to disparately affect skin of color patients, such as pseudofolliculitis barbae or melasma. Furthermore, they also can incorporate more detailed discussions about important differences seen in skin of color patients.

More Skin of Color Photographs in Psoriasis Lectures—At institution 3, there were no skin of color patients included in the psoriasis lecture, even though there is considerable data in the literature indicating notable differences in the clinical presentation, quality-of-life impact, and treatment of psoriasis in skin of color patients.^11,22 There are multiple nuances in psoriasis manifestation in patients with skin of color, including less-conspicuous erythema in darker skin, higher degrees of dyspigmentation, and greater body surface area involvement. For Black patients with scalp psoriasis, the impact of hair texture, styling practices, and washing frequency are additional considerations that may impact disease severity and selection of topical therapy.¹¹ The lack of inclusion of any skin of color patients in the psoriasis lecture at one institution further underscores the pressing need to prioritize communities of color in medical education.

More Skin of Color Photographs in Cutaneous Malignancy Lectures—Similarly, while a lecturer at institution 2 noted that acral lentiginous melanoma accounts for a considerable proportion of melanoma among skin of color patients,²³ there was no mention of how melanoma generally is substantially more deadly in this population, potentially due to decreased awareness and inconsistent screening.²⁴ Furthermore, at institutions 1 and 3, there were no photographs or discussion of skin of color patients during the cutaneous malignancy lectures. Evidence shows that more emphasis is needed for melanoma screening and awareness in skin of color populations to improve survival outcomes,²⁴ and this begins with educating not only future dermatologists but all future physicians as well. The failure to include photographs of skin of color patients in discussions or lectures regarding cutaneous malignancies may serve to further perpetuate the harmful misperception that individuals with skin of color are unaffected by skin cancer.^25,26

Analysis of Skin of Color Photographs in Infectious Disease Lectures—In addition, lectures discussing infectious etiologies were among those with the highest proportion of skin of color photographs. This relatively disproportionate representation of skin of color compared to the other lectures may contribute to the development of harmful stereotypes or the stigmatization of skin of color patients. Although skin of color should continue to be represented in similar lectures, teaching faculty should remain mindful of the potential unintended impact from lectures including relatively disproportionate amounts of skin of color, particularly when other lectures may have sparse to absent representation of skin of color.

More Photographs Available for Education—Overall, our findings may help to inform changes to preclinical dermatology medical education at other institutions to create more inclusive and representative curricula for skin of color patients. The ability of instructors to provide visual representation of various dermatologic conditions may be limited by the photographs available in certain textbooks with few examples of patients with skin of color; however, concerns regarding the lack of skin of color representation in dermatology training is not a novel discussion.¹⁷ Although it is the responsibility of all dermatologists to advocate for the inclusion of skin of color, many dermatologists of color have been leading the way in this movement for decades, publishing several textbooks to document various skin conditions in those with darker skin types and discuss unique considerations for patients with skin of color.^27-29 Images from these textbooks can be utilized by programs to increase representation of skin of color in dermatology training. There also are multiple expanding online dermatologic databases, such as VisualDx, with an increasing focus on skin of color patients, some of which allow users to filter images by degree of skin pigmentation.³⁰ Moreover, instructors also can work to diversify their curricula by highlighting more of the SOCS conditions of importance to skin of color patients, which have since been renamed and highlighted on the Patient Dermatology Education section of the SOCS website.²⁰ These conditions, while not completely comprehensive, provide a useful starting point for medical educators to reevaluate for potential areas of improvement and inclusion.

There are several potential strategies that can be used to better represent skin of color in dermatologic preclinical medical education, including increasing awareness, especially among dermatology teaching faculty, of existing disparities in the representation of skin of color in the preclinical curricula. Additionally, all dermatology teaching materials could be reviewed at the department level prior to being disseminated to medical students to assess for instances in which skin of color could be prioritized for discussion or varying disease presentations in skin of color could be demonstrated. Finally, teaching faculty may consider photographing more clinical images of their skin of color patients to further develop a catalog of diverse images that can be used to teach students.

Study Limitations—Our study was unable to account for verbal discussion of skin of color not otherwise denoted or captured in lecture slides. Additional limitations include the utilization of Fitzpatrick skin types to describe and differentiate varying skin tones, as the Fitzpatrick scale originally was developed as a method to describe an individual’s response to UV exposure.¹⁹ The inability to further delineate the representation of darker skin types, such as those that may be classified as Fitzpatrick skin types V or VI,¹⁹ compared to those with lighter skin of color also was a limiting factor. This study was unable to assess for discussion of other common conditions affecting skin of color patients that were not listed as one of the priority conditions by SOCS. Photographs that were designated as indeterminate were difficult to elucidate as skin of color; however, it is possible that instructors may have verbally described these images as skin of color during lectures. Nonetheless, it may be beneficial for learners if teaching faculty were to clearly label instances where skin of color patients are shown or when notable differences are present.

Future studies would benefit from the inclusion of audio data from lectures, syllabi, and small group teaching materials from preclinical courses to more accurately assess representation of skin of color in dermatology training. Additionally, future studies also may expand to include images from lectures of overlapping clinical specialties, particularly infectious disease and rheumatology, to provide a broader assessment of skin of color exposure. Furthermore, repeat assessment may be beneficial to assess the longitudinal effectiveness of curricular changes at the institutions included in this study, comparing older lectures to more recent, updated lectures. This study also may be replicated at other medical schools to allow for wider comparison of curricula.

Acknowledgment—The authors wish to thank the institutions that offered and agreed to participate in this study with the hopes of improving medical education.

A ccording to the US Census Bureau, more than half of all Americans are projected to belong to a minority group, defined as any group other than non-Hispanic White alone, by 2044. ¹ Consequently, the United States rapidly is becoming a country in which the majority of citizens will have skin of color. Individuals with skin of color are of diverse ethnic backgrounds and include people of African, Latin American, Native American, Pacific Islander, and Asian descent, as well as interethnic backgrounds. ² Throughout the country, dermatologists along with primary care practitioners may be confronted with certain cutaneous conditions that have varying disease presentations or processes in patients with skin of color. It also is important to note that racial categories are socially rather than biologically constructed, and the term skin of color includes a wide variety of diverse skin types. Nevertheless, the current literature thoroughly supports unique pathophysiologic differences in skin of color as well as variations in disease manifestation compared to White patients. ^3-5 For example, the increased lability of melanosomes in skin of color patients, which increases their risk for postinflammatory hyperpigmentation, has been well documented. ^5-7 There are various dermatologic conditions that also occur with higher frequency and manifest uniquely in people with darker, more pigmented skin, ^7-9 and dermatologists, along with primary care physicians, should feel prepared to recognize and address them.

Extensive evidence also indicates that there are unique aspects to consider while managing certain skin diseases in patients with skin of color.^8,10,11 Consequently, as noted on the Skin of Color Society (SOCS) website, “[a]n increase in the body of dermatological literature concerning skin of color as well as the advancement of both basic science and clinical investigational research is necessary to meet the needs of the expanding skin of color population.”² In the meantime, current knowledge regarding cutaneous conditions that diversely or disproportionately affect skin of color should be actively disseminated to physicians in training. Although patients with skin of color should always have access to comprehensive care and knowledgeable practitioners, the current changes in national and regional demographics further underscore the need for a more thorough understanding of skin of color with regard to disease pathogenesis, diagnosis, and treatment.

Several studies have found that medical students in the United States are minimally exposed to dermatology in general compared to other clinical specialties,^12-14 which can easily lead to the underrecognition of disorders that may uniquely or disproportionately affect individuals with pigmented skin. Recent data showed that medical schools typically required fewer than 10 hours of dermatology instruction,¹² and on average, dermatologic training made up less than 1% of a medical student’s undergraduate medical education.^13,15,16 Consequently, less than 40% of primary care residents felt that their medical school curriculum adequately prepared them to manage common skin conditions.¹⁴ Although not all physicians should be expected to fully grasp the complexities of skin of color and its diagnostic and therapeutic implications, both practicing and training dermatologists have acknowledged a lack of exposure to skin of color. In one study, approximately 47% of dermatologists and dermatology residents reported that their medical training (medical school and/or residency) was inadequate in training them on skin conditions in Black patients. Furthermore, many who felt their training was lacking in skin of color identified the need for greater exposure to Black patients and training materials.¹⁵ The absence of comprehensive medical education regarding skin of color ultimately can be a disadvantage for both practitioners and patients, resulting in poorer outcomes. Furthermore, underrepresentation of skin of color may persist beyond undergraduate and graduate medical education. There also is evidence to suggest that noninclusion of skin of color pervades foundational dermatologic educational resources, including commonly used textbooks as well as continuing medical education disseminated at national conferences and meetings.¹⁷ Taken together, these findings highlight the need for more diverse and representative exposure to skin of color throughout medical training, which begins with a diverse inclusive undergraduate medical education in dermatology.

The objective of this study was to determine if the preclinical dermatology curriculum at 3 US medical schools provided adequate representation of skin of color patients in their didactic presentation slides.

Methods

Participants—Three US medical schools, a blend of private and public medical schools located across different geographic boundaries, agreed to participate in the study. All 3 institutions were current members of the American Medical Association (AMA) Accelerating Change in Medical Education consortium, whose primary goal is to create the medical school of the future and transform physician training.¹⁸ All 32 member institutions of the AMA consortium were contacted to request their participation in the study. As part of the consortium, these institutions have vowed to collectively work to develop and share the best models for educational advancement to improve care for patients, populations, and communities¹⁸ and would expectedly provide a more racially and ethnically inclusive curriculum than an institution not accountable to a group dedicated to identifying the best ways to deliver care for increasingly diverse communities.

Data Collection—Lectures were included if they were presented during dermatology preclinical courses in the 2015 to 2016 academic year. An uninvolved third party removed the names and identities of instructors to preserve anonymity. Two independent coders from different institutions extracted the data—lecture title, total number of clinical and histologic images, and number of skin of color images—from each of the anonymized lectures using a standardized coding form. We documented differences in skin of color noted in lectures and the disease context for the discussed differences, such as variations in clinical presentation, disease process, epidemiology/risk, and treatment between different skin phenotypes or ethnic groups. Photographs in which the coders were unable to differentiate whether the patient had skin of color were designated as indeterminate or unclear. Photographs appearing to represent Fitzpatrick skin types IV, V, and VI¹⁹ were categorically designated as skin of color, and those appearing to represent Fitzpatrick skin types I and II were described as not skin of color; however, images appearing to represent Fitzpatrick skin type III often were classified as not skin of color or indeterminate and occasionally skin of color. The Figure shows examples of images classified as skin of color, indeterminate, and not skin of color. Photographs often were classified as indeterminate due to poor lighting, close-up view photographs, or highlighted pathology obscuring the surrounding skin. We excluded duplicate photographs and histologic images from the analyses.

We also reviewed 19 conditions previously highlighted by the SOCS as areas of importance to skin of color patients.²⁰ The coders tracked how many of these conditions were noted in each lecture. Duplicate discussion of these conditions was not included in the analyses. Any discrepancies between coders were resolved through additional slide review and discussion. The final coded data with the agreed upon changes were used for statistical analyses. Recent national demographic data from the US Census Bureau in 2019 describe approximately 39.9% of the population as belonging to racial/ethnic groups other than non-Hispanic/Latinx White.²¹ Consequently, the standard for adequate representation for skin of color photographs was set at 35% for the purpose of this study.

Across all 3 institutions included in the study, the proportion of the total number of clinical photographs showing skin of color was 16% (290/1812). Eight percent of the total photographs (145/1812) were noted to be indeterminate (Table). For institution 1, 23.6% of photographs (155/658) showed skin of color, and 12.6% (83/658) were indeterminate. For institution 2, 13.1% (76/578) showed skin of color and 7.8% (45/578) were indeterminate. For institution 3, 10.2% (59/576) showed skin of color and 3% (17/576) were indeterminate.

Institutions 1, 2, and 3 had 18, 8, and 17 total dermatology lectures, respectively. Of the 19 conditions designated as areas of importance to skin of color patients by the SOCS, 16 (84.2%) were discussed by institution 1, 11 (57.9%) by institution 2, and 9 (47.4%) by institution 3 (eTable 1). Institution 3 did not include photographs of skin of color patients in its acne, psoriasis, or cutaneous malignancy lectures. Institution 1 also did not include any skin of color patients in its malignancy lecture. Lectures that focused on pigmentary disorders, atopic dermatitis, infectious conditions, and benign cutaneous neoplasms were more likely to display photographs of skin of color patients; for example, lectures that discussed infectious conditions, such as superficial mycoses, herpes viruses, human papillomavirus, syphilis, and atypical mycobacterial infections, were consistently among those with higher proportions of photographs of skin of color patients.

Throughout the entire preclinical dermatology course at all 3 institutions, of 2945 lecture slides, only 24 (0.8%) unique differences were noted between skin color and non–skin of color patients, with 10 total differences noted by institution 1, 6 by institution 2, and 8 by institution 3 (Table). The majority of these differences (19/24) were related to epidemiologic differences in prevalence among varying racial/ethnic groups, with only 5 instances highlighting differences in clinical presentation. There was only a single instance that elaborated on the underlying pathophysiologic mechanisms of the discussed difference. Of all 24 unique differences discussed, 8 were related to skin cancer, 3 were related to dermatitis, and 2 were related to the difference in manifestation of erythema in patients with darker skin (eTable 2).

Comment

The results of this study demonstrated that skin of color is underrepresented in the preclinical dermatology curriculum at these 3 institutions. Although only 16% of all included clinical photographs were of skin of color, individuals with skin of color will soon represent more than half of the total US population within the next 2 decades.¹ To increase representation of skin of color patients, teaching faculty should consciously and deliberately include more photographs of skin of color patients for a wider variety of common conditions, including atopic dermatitis and psoriasis, in addition to those that tend to disparately affect skin of color patients, such as pseudofolliculitis barbae or melasma. Furthermore, they also can incorporate more detailed discussions about important differences seen in skin of color patients.

More Skin of Color Photographs in Psoriasis Lectures—At institution 3, there were no skin of color patients included in the psoriasis lecture, even though there is considerable data in the literature indicating notable differences in the clinical presentation, quality-of-life impact, and treatment of psoriasis in skin of color patients.^11,22 There are multiple nuances in psoriasis manifestation in patients with skin of color, including less-conspicuous erythema in darker skin, higher degrees of dyspigmentation, and greater body surface area involvement. For Black patients with scalp psoriasis, the impact of hair texture, styling practices, and washing frequency are additional considerations that may impact disease severity and selection of topical therapy.¹¹ The lack of inclusion of any skin of color patients in the psoriasis lecture at one institution further underscores the pressing need to prioritize communities of color in medical education.

More Skin of Color Photographs in Cutaneous Malignancy Lectures—Similarly, while a lecturer at institution 2 noted that acral lentiginous melanoma accounts for a considerable proportion of melanoma among skin of color patients,²³ there was no mention of how melanoma generally is substantially more deadly in this population, potentially due to decreased awareness and inconsistent screening.²⁴ Furthermore, at institutions 1 and 3, there were no photographs or discussion of skin of color patients during the cutaneous malignancy lectures. Evidence shows that more emphasis is needed for melanoma screening and awareness in skin of color populations to improve survival outcomes,²⁴ and this begins with educating not only future dermatologists but all future physicians as well. The failure to include photographs of skin of color patients in discussions or lectures regarding cutaneous malignancies may serve to further perpetuate the harmful misperception that individuals with skin of color are unaffected by skin cancer.^25,26

Analysis of Skin of Color Photographs in Infectious Disease Lectures—In addition, lectures discussing infectious etiologies were among those with the highest proportion of skin of color photographs. This relatively disproportionate representation of skin of color compared to the other lectures may contribute to the development of harmful stereotypes or the stigmatization of skin of color patients. Although skin of color should continue to be represented in similar lectures, teaching faculty should remain mindful of the potential unintended impact from lectures including relatively disproportionate amounts of skin of color, particularly when other lectures may have sparse to absent representation of skin of color.

More Photographs Available for Education—Overall, our findings may help to inform changes to preclinical dermatology medical education at other institutions to create more inclusive and representative curricula for skin of color patients. The ability of instructors to provide visual representation of various dermatologic conditions may be limited by the photographs available in certain textbooks with few examples of patients with skin of color; however, concerns regarding the lack of skin of color representation in dermatology training is not a novel discussion.¹⁷ Although it is the responsibility of all dermatologists to advocate for the inclusion of skin of color, many dermatologists of color have been leading the way in this movement for decades, publishing several textbooks to document various skin conditions in those with darker skin types and discuss unique considerations for patients with skin of color.^27-29 Images from these textbooks can be utilized by programs to increase representation of skin of color in dermatology training. There also are multiple expanding online dermatologic databases, such as VisualDx, with an increasing focus on skin of color patients, some of which allow users to filter images by degree of skin pigmentation.³⁰ Moreover, instructors also can work to diversify their curricula by highlighting more of the SOCS conditions of importance to skin of color patients, which have since been renamed and highlighted on the Patient Dermatology Education section of the SOCS website.²⁰ These conditions, while not completely comprehensive, provide a useful starting point for medical educators to reevaluate for potential areas of improvement and inclusion.

There are several potential strategies that can be used to better represent skin of color in dermatologic preclinical medical education, including increasing awareness, especially among dermatology teaching faculty, of existing disparities in the representation of skin of color in the preclinical curricula. Additionally, all dermatology teaching materials could be reviewed at the department level prior to being disseminated to medical students to assess for instances in which skin of color could be prioritized for discussion or varying disease presentations in skin of color could be demonstrated. Finally, teaching faculty may consider photographing more clinical images of their skin of color patients to further develop a catalog of diverse images that can be used to teach students.

Study Limitations—Our study was unable to account for verbal discussion of skin of color not otherwise denoted or captured in lecture slides. Additional limitations include the utilization of Fitzpatrick skin types to describe and differentiate varying skin tones, as the Fitzpatrick scale originally was developed as a method to describe an individual’s response to UV exposure.¹⁹ The inability to further delineate the representation of darker skin types, such as those that may be classified as Fitzpatrick skin types V or VI,¹⁹ compared to those with lighter skin of color also was a limiting factor. This study was unable to assess for discussion of other common conditions affecting skin of color patients that were not listed as one of the priority conditions by SOCS. Photographs that were designated as indeterminate were difficult to elucidate as skin of color; however, it is possible that instructors may have verbally described these images as skin of color during lectures. Nonetheless, it may be beneficial for learners if teaching faculty were to clearly label instances where skin of color patients are shown or when notable differences are present.

Future studies would benefit from the inclusion of audio data from lectures, syllabi, and small group teaching materials from preclinical courses to more accurately assess representation of skin of color in dermatology training. Additionally, future studies also may expand to include images from lectures of overlapping clinical specialties, particularly infectious disease and rheumatology, to provide a broader assessment of skin of color exposure. Furthermore, repeat assessment may be beneficial to assess the longitudinal effectiveness of curricular changes at the institutions included in this study, comparing older lectures to more recent, updated lectures. This study also may be replicated at other medical schools to allow for wider comparison of curricula.

Acknowledgment—The authors wish to thank the institutions that offered and agreed to participate in this study with the hopes of improving medical education.

Dermatology is an often-underutilized resource in the hospital setting. As the health care landscape has evolved, so has the role of the inpatient dermatologist.^1-3 Structural changes in the health system and advances in therapies have shifted dermatology from an admitting service to an almost exclusively outpatient practice. Improved treatment modalities led to decreases in the number of patients requiring admission for chronic dermatoses, and outpatient clinics began offering therapies once limited to hospitals.^1,4 Inpatient dermatology consultations emerged and continue to have profound effects on hospitalized patients regardless of their reason for admission.^1-11

Inpatient dermatologists supply knowledge in areas primary medical teams lack, and there is evidence that dermatology consultations improve the quality of care while decreasing cost.^2,5-7 Establishing correct diagnoses, preventing exposure to unnecessary medications, and reducing hospitalization duration and readmission rates are a few ways dermatology consultations positively impact hospitalized patients.^2,5-7,9,10 This study highlights the role of the dermatologist in the care of hospitalized patients at a large academic medical center in an urban setting and reveals how consultation supports the efficiency and efficacy of other services.

Materials and Methods

Study Design—This single-institution, cross-sectional retrospective study included all hospitalized patients at the Thomas Jefferson University Hospital (Philadelphia, Pennsylvania), who received an inpatient dermatology consultation completed by physicians of Jefferson Dermatology Associates between January 1, 2019, and December 31, 2019. The institutional review board at Thomas Jefferson University approved this study.

Data Collection—A list of all inpatient dermatology consultations in 2019 was provided by Jefferson Dermatology Associates. Through a retrospective chart review, data regarding the consultations were collected from the electronic medical record (Epic Systems) and recorded into the Research Electronic Data Capture system. Data on patient demographics, the primary medical team, the dermatology evaluation, and the hospital course of the patient were collected.

Results

Patient Characteristics—Dermatology received 253 inpatient consultation requests during this time period; 53% of patients were female and 47% were male, with a mean age of 55 years. Most patients were White (57%), while 34% were Black. Five percent and 4% of patients were Asian and Hispanic or Latino, respectively (Table 1). The mean duration of hospitalization for all patients was 15 days, and the average number of days to discharge following the first encounter with dermatology was 10 days.

Requesting Team and Reason for Consultation—Internal medicine consulted dermatology most frequently (34% of all consultations), followed by emergency medicine (14%) and a variety of other services (Table 1). Most dermatology consultations were placed to assist in achieving a diagnosis of a cutaneous condition (77%), while a minority were to assist in the management of a previously diagnosed disease (22%). A small fraction of consultations (5%) were to complete full-body skin examinations (FBSEs) to rule out infection or malignancy in candidates for organ transplantation, left ventricular assist devices, or certain chemotherapies. One FBSE was conducted to search for a primary tumor in a patient diagnosed with metastatic melanoma.

Most Common Final Diagnoses and Consultation Impact—Table 2 lists the most common final diagnosis categories, as well as the effects of the consultation on diagnosis, management, biopsies, hospitalization, and clinical improvement as documented by the primary medical provider. The most common final diagnoses were inflammatory and autoimmune (39%), such as contact dermatitis and seborrheic dermatitis; infectious (23%), such as varicella (primary or zoster) and bacterial furunculosis; drug reactions (20%), such as morbilliform drug eruptions; vascular (8%), such as vasculitis and calciphylaxis; neoplastic (7%), such as keratinocyte carcinomas and leukemia cutis; and other (15%), such as xerosis, keratosis pilaris, and miliaria rubra.

Impact on Diagnosis—Fifty-six percent of all consultations resulted in a change in diagnosis. When dermatology was consulted specifically to assist in the diagnosis of a patient (195 consultations), the working diagnosis of the primary team was changed 69% of the time. Thirty-five of these consultation requests had no preliminary diagnosis, and the primary team listed the working diagnosis as either rash or a morphologic description of the lesion(s). Sixty-three percent of suspected drug eruptions ended with a diagnosis of a form of drug eruption, while 20% of consultations for suspected cellulitis or bacterial infections were confirmed to be cellulitis or soft tissue infections.

Impact on Management—Regardless of the reason for the consultation, most consultations (86%) resulted in a change in management. The remaining 14% consisted of FBSEs with benign findings; cases of cutaneous metastases and leukemia cutis managed by oncology; as well as select cases of purpura fulminans, postfebrile desquamation, and postinflammatory hyperpigmentation.

Changes in management included alterations in medications, requests for additional laboratory work or imaging, additional consultation requests, biopsies, or specific wound care instructions. Seventy-five percent of all consultations were given specific medication recommendations by dermatology. Most (61%) were recommended to be given a topical steroid, antibiotic, or both. However, 45% of all consultations were recommended to initiate a systemic medication, most commonly antihistamines, antibiotics, steroids, antivirals, or immunomodulators. Dermatology recommended discontinuing specific medications in 16% of all consultations, with antibiotics being the most frequent culprit (17 antibiotics discontinued), owing to drug eruptions or misdiagnosed infections. Vancomycin, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole were the most frequently discontinued antibiotics.

Dermatology was consulted for assistance in management of previously diagnosed cutaneous conditions 56 times (22% of all consultations), often regarding complicated cases of hidradenitis suppurativa (9 cases), pyoderma gangrenosum (5 cases), bullous pemphigoid (4 cases), or erythroderma (4 cases). Most of these cases required a single dermatology encounter to provide recommendations (71%), and 21% required 1 additional follow-up. Sixty-three percent of patients consulted for management assistance were noted to have improvement in their cutaneous condition by time of discharge, as documented by the primary provider in the medical record.

Twenty-eight percent of all consultations required at least 1 biopsy. Seventy-two percent of all biopsies were consistent with the dermatologist’s working diagnosis or highest-ranked differential diagnosis, and 16% of biopsy results were consistent with the second- or third-ranked diagnosis. The primary teams requested a biopsy 38 times to assist in diagnosis, as documented in the progress note or consultation request. Only 21 of these consultations (55% of requests) received at least 1 biopsy, as the remaining consultations did not require a biopsy to establish a diagnosis. The most common final diagnoses of consultations receiving biopsies included drug eruptions (5), leukemia cutis (4), vasculopathies (4), vasculitis (4), and calciphylaxis (3).

Impact on Hospitalization and Efficacy—Dermatology performed 217 consultations regarding patients already admitted to the hospital, and 92% remained hospitalized either due to comorbidities or complicated cutaneous conditions following the consultation. The remaining 8% were cleared for discharge. Dermatology received 36 consultation requests from emergency medicine physicians. Fifty-three percent of these patients were admitted, while the remaining 47% were discharged from the emergency department or its observation unit following evaluation.

Fifty-one percent of all consultations were noted to have improvement in their cutaneous condition by the time of discharge, as noted in the physical examination, progress note, or discharge summary of the primary team. Thirty percent of cases remained stable, where improvement was not noted in in the medical record. Most of these cases involved keratinocyte carcinomas scheduled for outpatient excision, benign melanocytic nevi found on FBSE, and benign etiologies that led to immediate discharge following consultation. Three percent of all consultations were noted to have worsened following consultation, including cases of calciphylaxis, vasculopathies, and purpura fulminans, as well as patients who elected for palliative care and hospice. The cutaneous condition by the time of discharge could not be determined from the medical record in 16% of all consultations.

Eighty-five percent of all consultations required a single encounter with dermatology. An additional 10% required a single follow-up with dermatology, while only 5% of patients required 3 or more encounters. Notably, these cases included patients with 1 or more severe cutaneous diseases, such as Sweet syndrome, calciphylaxis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and hidradenitis suppurativa.

Comment

Although dermatology often is viewed as an outpatient specialty, this study provides a glimpse into the ways inpatient dermatology consultations optimize the care of hospitalized patients. Most consultations involved assistance in diagnosing an unknown condition, but several regarded pre-existing skin disorders requiring management aid. As a variety of medical specialties requested consultations, dermatology was able to provide care to a diverse group of patients with conditions varying in complexity and severity. Several specialties benefited from niche dermatologic expertise: hematology and oncology frequently requested dermatology to assist in diagnosis and management of the toxic effects of chemotherapy, cutaneous metastasis, or suspected cutaneous infections in immunocompromised patients. Cardiology patients were frequently evaluated for potential malignancy or infection prior to heart transplantation and initiation of antirejection immunosuppressants. Dermatology was consulted to differentiate cutaneous manifestations of critical illness from underlying systemic disease in the intensive care unit, and patients presenting to the emergency department often were examined to determine if hospital admission was necessary, with 47% of these consultations resulting in a discharge following evaluation by a dermatologist.

Our results were consistent with prior studies^1,5,6 that have reported frequent changes in final diagnosis following dermatology consultation, with 69% of working diagnoses changed in this study when consultation was requested for diagnostic assistance. When dermatology was consulted for diagnostic assistance, several of these cases lacked a preliminary differential diagnosis. Although the absence of a documented differential diagnosis may not necessarily reflect a lack of suspicion for a particular etiology, 86% of all consultations included a ranked differential or working diagnosis either in the consultation request or progress note prior to consultation. The final diagnoses of consultations without a preliminary diagnosis varied from the mild and localized to systemic and severe, further suggesting these cases reflected knowledge gaps of the primary medical team.

Integration of dermatology into the care of hospitalized patients could provide an opportunity for education of primary medical teams. With frequent consultation, primary medical teams may become more comfortable diagnosing and managing common cutaneous conditions specific to their specialty or extended hospitalizations.

Several consultations were requested to aid in management of cases of hidradenitis suppurativa, pyoderma gangrenosum, or bullous pemphigoid that either failed outpatient therapy or were complicated by superinfections. Despite the ranges in complexity, the majority of all consultations required a single encounter and led to improvement by the time of discharge, demonstrating the efficacy and efficiency of inpatient dermatologists.

Dermatology consultations often led to changes in management involving medications and additional workup. Changes in management also extended to specific wound care instructions provided by dermatology, as expected for cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, Sweet syndrome, hidradenitis suppurativa, and pyoderma gangrenosum. However, patients with the sequelae of extended hospitalizations, such as chronic wounds, pressure ulcers, and edema bullae, also benefited from this expertise.

When patients required a biopsy, the final diagnoses were consistent with the dermatologist’s number one differential diagnosis or top 3 differential diagnoses 72% and 88% of the time, respectively. Only 55% of cases where the primary team requested a biopsy ultimately required a biopsy, as many involved clinical diagnoses such as urticaria. Not only was dermatology accurate in their preliminary diagnoses, but they decreased cost and morbidity by avoiding unnecessary procedures.

This study provided additional evidence to support the integration of dermatology into the hospital setting for the benefit of patients, primary medical teams, and hospital systems. Dermatology offers high-value care through the efficient diagnosis and management of hospitalized patients, which contributes to decreased cost and improved outcomes.^2,5-7,9,10 This study highlighted lesser-known areas of impact, such as the various specialty-specific services dermatology provides as well as the high rates of reported improvement following consultation. Future studies should continue to explore the field’s unique impact on hospitalized medicine as well as other avenues of care delivery, such as telemedicine, that may encourage dermatologists to participate in consultations and increase the volume of patients who may benefit from their care.

Dermatology is an often-underutilized resource in the hospital setting. As the health care landscape has evolved, so has the role of the inpatient dermatologist.^1-3 Structural changes in the health system and advances in therapies have shifted dermatology from an admitting service to an almost exclusively outpatient practice. Improved treatment modalities led to decreases in the number of patients requiring admission for chronic dermatoses, and outpatient clinics began offering therapies once limited to hospitals.^1,4 Inpatient dermatology consultations emerged and continue to have profound effects on hospitalized patients regardless of their reason for admission.^1-11

Inpatient dermatologists supply knowledge in areas primary medical teams lack, and there is evidence that dermatology consultations improve the quality of care while decreasing cost.^2,5-7 Establishing correct diagnoses, preventing exposure to unnecessary medications, and reducing hospitalization duration and readmission rates are a few ways dermatology consultations positively impact hospitalized patients.^2,5-7,9,10 This study highlights the role of the dermatologist in the care of hospitalized patients at a large academic medical center in an urban setting and reveals how consultation supports the efficiency and efficacy of other services.

Materials and Methods

Study Design—This single-institution, cross-sectional retrospective study included all hospitalized patients at the Thomas Jefferson University Hospital (Philadelphia, Pennsylvania), who received an inpatient dermatology consultation completed by physicians of Jefferson Dermatology Associates between January 1, 2019, and December 31, 2019. The institutional review board at Thomas Jefferson University approved this study.

Data Collection—A list of all inpatient dermatology consultations in 2019 was provided by Jefferson Dermatology Associates. Through a retrospective chart review, data regarding the consultations were collected from the electronic medical record (Epic Systems) and recorded into the Research Electronic Data Capture system. Data on patient demographics, the primary medical team, the dermatology evaluation, and the hospital course of the patient were collected.

Results

Patient Characteristics—Dermatology received 253 inpatient consultation requests during this time period; 53% of patients were female and 47% were male, with a mean age of 55 years. Most patients were White (57%), while 34% were Black. Five percent and 4% of patients were Asian and Hispanic or Latino, respectively (Table 1). The mean duration of hospitalization for all patients was 15 days, and the average number of days to discharge following the first encounter with dermatology was 10 days.

Requesting Team and Reason for Consultation—Internal medicine consulted dermatology most frequently (34% of all consultations), followed by emergency medicine (14%) and a variety of other services (Table 1). Most dermatology consultations were placed to assist in achieving a diagnosis of a cutaneous condition (77%), while a minority were to assist in the management of a previously diagnosed disease (22%). A small fraction of consultations (5%) were to complete full-body skin examinations (FBSEs) to rule out infection or malignancy in candidates for organ transplantation, left ventricular assist devices, or certain chemotherapies. One FBSE was conducted to search for a primary tumor in a patient diagnosed with metastatic melanoma.

Most Common Final Diagnoses and Consultation Impact—Table 2 lists the most common final diagnosis categories, as well as the effects of the consultation on diagnosis, management, biopsies, hospitalization, and clinical improvement as documented by the primary medical provider. The most common final diagnoses were inflammatory and autoimmune (39%), such as contact dermatitis and seborrheic dermatitis; infectious (23%), such as varicella (primary or zoster) and bacterial furunculosis; drug reactions (20%), such as morbilliform drug eruptions; vascular (8%), such as vasculitis and calciphylaxis; neoplastic (7%), such as keratinocyte carcinomas and leukemia cutis; and other (15%), such as xerosis, keratosis pilaris, and miliaria rubra.

Impact on Diagnosis—Fifty-six percent of all consultations resulted in a change in diagnosis. When dermatology was consulted specifically to assist in the diagnosis of a patient (195 consultations), the working diagnosis of the primary team was changed 69% of the time. Thirty-five of these consultation requests had no preliminary diagnosis, and the primary team listed the working diagnosis as either rash or a morphologic description of the lesion(s). Sixty-three percent of suspected drug eruptions ended with a diagnosis of a form of drug eruption, while 20% of consultations for suspected cellulitis or bacterial infections were confirmed to be cellulitis or soft tissue infections.

Impact on Management—Regardless of the reason for the consultation, most consultations (86%) resulted in a change in management. The remaining 14% consisted of FBSEs with benign findings; cases of cutaneous metastases and leukemia cutis managed by oncology; as well as select cases of purpura fulminans, postfebrile desquamation, and postinflammatory hyperpigmentation.

Changes in management included alterations in medications, requests for additional laboratory work or imaging, additional consultation requests, biopsies, or specific wound care instructions. Seventy-five percent of all consultations were given specific medication recommendations by dermatology. Most (61%) were recommended to be given a topical steroid, antibiotic, or both. However, 45% of all consultations were recommended to initiate a systemic medication, most commonly antihistamines, antibiotics, steroids, antivirals, or immunomodulators. Dermatology recommended discontinuing specific medications in 16% of all consultations, with antibiotics being the most frequent culprit (17 antibiotics discontinued), owing to drug eruptions or misdiagnosed infections. Vancomycin, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole were the most frequently discontinued antibiotics.

Dermatology was consulted for assistance in management of previously diagnosed cutaneous conditions 56 times (22% of all consultations), often regarding complicated cases of hidradenitis suppurativa (9 cases), pyoderma gangrenosum (5 cases), bullous pemphigoid (4 cases), or erythroderma (4 cases). Most of these cases required a single dermatology encounter to provide recommendations (71%), and 21% required 1 additional follow-up. Sixty-three percent of patients consulted for management assistance were noted to have improvement in their cutaneous condition by time of discharge, as documented by the primary provider in the medical record.

Twenty-eight percent of all consultations required at least 1 biopsy. Seventy-two percent of all biopsies were consistent with the dermatologist’s working diagnosis or highest-ranked differential diagnosis, and 16% of biopsy results were consistent with the second- or third-ranked diagnosis. The primary teams requested a biopsy 38 times to assist in diagnosis, as documented in the progress note or consultation request. Only 21 of these consultations (55% of requests) received at least 1 biopsy, as the remaining consultations did not require a biopsy to establish a diagnosis. The most common final diagnoses of consultations receiving biopsies included drug eruptions (5), leukemia cutis (4), vasculopathies (4), vasculitis (4), and calciphylaxis (3).

Impact on Hospitalization and Efficacy—Dermatology performed 217 consultations regarding patients already admitted to the hospital, and 92% remained hospitalized either due to comorbidities or complicated cutaneous conditions following the consultation. The remaining 8% were cleared for discharge. Dermatology received 36 consultation requests from emergency medicine physicians. Fifty-three percent of these patients were admitted, while the remaining 47% were discharged from the emergency department or its observation unit following evaluation.

Fifty-one percent of all consultations were noted to have improvement in their cutaneous condition by the time of discharge, as noted in the physical examination, progress note, or discharge summary of the primary team. Thirty percent of cases remained stable, where improvement was not noted in in the medical record. Most of these cases involved keratinocyte carcinomas scheduled for outpatient excision, benign melanocytic nevi found on FBSE, and benign etiologies that led to immediate discharge following consultation. Three percent of all consultations were noted to have worsened following consultation, including cases of calciphylaxis, vasculopathies, and purpura fulminans, as well as patients who elected for palliative care and hospice. The cutaneous condition by the time of discharge could not be determined from the medical record in 16% of all consultations.

Eighty-five percent of all consultations required a single encounter with dermatology. An additional 10% required a single follow-up with dermatology, while only 5% of patients required 3 or more encounters. Notably, these cases included patients with 1 or more severe cutaneous diseases, such as Sweet syndrome, calciphylaxis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and hidradenitis suppurativa.

Comment

Although dermatology often is viewed as an outpatient specialty, this study provides a glimpse into the ways inpatient dermatology consultations optimize the care of hospitalized patients. Most consultations involved assistance in diagnosing an unknown condition, but several regarded pre-existing skin disorders requiring management aid. As a variety of medical specialties requested consultations, dermatology was able to provide care to a diverse group of patients with conditions varying in complexity and severity. Several specialties benefited from niche dermatologic expertise: hematology and oncology frequently requested dermatology to assist in diagnosis and management of the toxic effects of chemotherapy, cutaneous metastasis, or suspected cutaneous infections in immunocompromised patients. Cardiology patients were frequently evaluated for potential malignancy or infection prior to heart transplantation and initiation of antirejection immunosuppressants. Dermatology was consulted to differentiate cutaneous manifestations of critical illness from underlying systemic disease in the intensive care unit, and patients presenting to the emergency department often were examined to determine if hospital admission was necessary, with 47% of these consultations resulting in a discharge following evaluation by a dermatologist.

Our results were consistent with prior studies^1,5,6 that have reported frequent changes in final diagnosis following dermatology consultation, with 69% of working diagnoses changed in this study when consultation was requested for diagnostic assistance. When dermatology was consulted for diagnostic assistance, several of these cases lacked a preliminary differential diagnosis. Although the absence of a documented differential diagnosis may not necessarily reflect a lack of suspicion for a particular etiology, 86% of all consultations included a ranked differential or working diagnosis either in the consultation request or progress note prior to consultation. The final diagnoses of consultations without a preliminary diagnosis varied from the mild and localized to systemic and severe, further suggesting these cases reflected knowledge gaps of the primary medical team.

Integration of dermatology into the care of hospitalized patients could provide an opportunity for education of primary medical teams. With frequent consultation, primary medical teams may become more comfortable diagnosing and managing common cutaneous conditions specific to their specialty or extended hospitalizations.

Several consultations were requested to aid in management of cases of hidradenitis suppurativa, pyoderma gangrenosum, or bullous pemphigoid that either failed outpatient therapy or were complicated by superinfections. Despite the ranges in complexity, the majority of all consultations required a single encounter and led to improvement by the time of discharge, demonstrating the efficacy and efficiency of inpatient dermatologists.

Dermatology consultations often led to changes in management involving medications and additional workup. Changes in management also extended to specific wound care instructions provided by dermatology, as expected for cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, Sweet syndrome, hidradenitis suppurativa, and pyoderma gangrenosum. However, patients with the sequelae of extended hospitalizations, such as chronic wounds, pressure ulcers, and edema bullae, also benefited from this expertise.

When patients required a biopsy, the final diagnoses were consistent with the dermatologist’s number one differential diagnosis or top 3 differential diagnoses 72% and 88% of the time, respectively. Only 55% of cases where the primary team requested a biopsy ultimately required a biopsy, as many involved clinical diagnoses such as urticaria. Not only was dermatology accurate in their preliminary diagnoses, but they decreased cost and morbidity by avoiding unnecessary procedures.

This study provided additional evidence to support the integration of dermatology into the hospital setting for the benefit of patients, primary medical teams, and hospital systems. Dermatology offers high-value care through the efficient diagnosis and management of hospitalized patients, which contributes to decreased cost and improved outcomes.^2,5-7,9,10 This study highlighted lesser-known areas of impact, such as the various specialty-specific services dermatology provides as well as the high rates of reported improvement following consultation. Future studies should continue to explore the field’s unique impact on hospitalized medicine as well as other avenues of care delivery, such as telemedicine, that may encourage dermatologists to participate in consultations and increase the volume of patients who may benefit from their care.

Dermatology is an often-underutilized resource in the hospital setting. As the health care landscape has evolved, so has the role of the inpatient dermatologist.^1-3 Structural changes in the health system and advances in therapies have shifted dermatology from an admitting service to an almost exclusively outpatient practice. Improved treatment modalities led to decreases in the number of patients requiring admission for chronic dermatoses, and outpatient clinics began offering therapies once limited to hospitals.^1,4 Inpatient dermatology consultations emerged and continue to have profound effects on hospitalized patients regardless of their reason for admission.^1-11

Inpatient dermatologists supply knowledge in areas primary medical teams lack, and there is evidence that dermatology consultations improve the quality of care while decreasing cost.^2,5-7 Establishing correct diagnoses, preventing exposure to unnecessary medications, and reducing hospitalization duration and readmission rates are a few ways dermatology consultations positively impact hospitalized patients.^2,5-7,9,10 This study highlights the role of the dermatologist in the care of hospitalized patients at a large academic medical center in an urban setting and reveals how consultation supports the efficiency and efficacy of other services.

Materials and Methods

Study Design—This single-institution, cross-sectional retrospective study included all hospitalized patients at the Thomas Jefferson University Hospital (Philadelphia, Pennsylvania), who received an inpatient dermatology consultation completed by physicians of Jefferson Dermatology Associates between January 1, 2019, and December 31, 2019. The institutional review board at Thomas Jefferson University approved this study.

Data Collection—A list of all inpatient dermatology consultations in 2019 was provided by Jefferson Dermatology Associates. Through a retrospective chart review, data regarding the consultations were collected from the electronic medical record (Epic Systems) and recorded into the Research Electronic Data Capture system. Data on patient demographics, the primary medical team, the dermatology evaluation, and the hospital course of the patient were collected.

Results

Patient Characteristics—Dermatology received 253 inpatient consultation requests during this time period; 53% of patients were female and 47% were male, with a mean age of 55 years. Most patients were White (57%), while 34% were Black. Five percent and 4% of patients were Asian and Hispanic or Latino, respectively (Table 1). The mean duration of hospitalization for all patients was 15 days, and the average number of days to discharge following the first encounter with dermatology was 10 days.

Requesting Team and Reason for Consultation—Internal medicine consulted dermatology most frequently (34% of all consultations), followed by emergency medicine (14%) and a variety of other services (Table 1). Most dermatology consultations were placed to assist in achieving a diagnosis of a cutaneous condition (77%), while a minority were to assist in the management of a previously diagnosed disease (22%). A small fraction of consultations (5%) were to complete full-body skin examinations (FBSEs) to rule out infection or malignancy in candidates for organ transplantation, left ventricular assist devices, or certain chemotherapies. One FBSE was conducted to search for a primary tumor in a patient diagnosed with metastatic melanoma.

Most Common Final Diagnoses and Consultation Impact—Table 2 lists the most common final diagnosis categories, as well as the effects of the consultation on diagnosis, management, biopsies, hospitalization, and clinical improvement as documented by the primary medical provider. The most common final diagnoses were inflammatory and autoimmune (39%), such as contact dermatitis and seborrheic dermatitis; infectious (23%), such as varicella (primary or zoster) and bacterial furunculosis; drug reactions (20%), such as morbilliform drug eruptions; vascular (8%), such as vasculitis and calciphylaxis; neoplastic (7%), such as keratinocyte carcinomas and leukemia cutis; and other (15%), such as xerosis, keratosis pilaris, and miliaria rubra.

Impact on Diagnosis—Fifty-six percent of all consultations resulted in a change in diagnosis. When dermatology was consulted specifically to assist in the diagnosis of a patient (195 consultations), the working diagnosis of the primary team was changed 69% of the time. Thirty-five of these consultation requests had no preliminary diagnosis, and the primary team listed the working diagnosis as either rash or a morphologic description of the lesion(s). Sixty-three percent of suspected drug eruptions ended with a diagnosis of a form of drug eruption, while 20% of consultations for suspected cellulitis or bacterial infections were confirmed to be cellulitis or soft tissue infections.

Impact on Management—Regardless of the reason for the consultation, most consultations (86%) resulted in a change in management. The remaining 14% consisted of FBSEs with benign findings; cases of cutaneous metastases and leukemia cutis managed by oncology; as well as select cases of purpura fulminans, postfebrile desquamation, and postinflammatory hyperpigmentation.

Changes in management included alterations in medications, requests for additional laboratory work or imaging, additional consultation requests, biopsies, or specific wound care instructions. Seventy-five percent of all consultations were given specific medication recommendations by dermatology. Most (61%) were recommended to be given a topical steroid, antibiotic, or both. However, 45% of all consultations were recommended to initiate a systemic medication, most commonly antihistamines, antibiotics, steroids, antivirals, or immunomodulators. Dermatology recommended discontinuing specific medications in 16% of all consultations, with antibiotics being the most frequent culprit (17 antibiotics discontinued), owing to drug eruptions or misdiagnosed infections. Vancomycin, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole were the most frequently discontinued antibiotics.

Dermatology was consulted for assistance in management of previously diagnosed cutaneous conditions 56 times (22% of all consultations), often regarding complicated cases of hidradenitis suppurativa (9 cases), pyoderma gangrenosum (5 cases), bullous pemphigoid (4 cases), or erythroderma (4 cases). Most of these cases required a single dermatology encounter to provide recommendations (71%), and 21% required 1 additional follow-up. Sixty-three percent of patients consulted for management assistance were noted to have improvement in their cutaneous condition by time of discharge, as documented by the primary provider in the medical record.

Twenty-eight percent of all consultations required at least 1 biopsy. Seventy-two percent of all biopsies were consistent with the dermatologist’s working diagnosis or highest-ranked differential diagnosis, and 16% of biopsy results were consistent with the second- or third-ranked diagnosis. The primary teams requested a biopsy 38 times to assist in diagnosis, as documented in the progress note or consultation request. Only 21 of these consultations (55% of requests) received at least 1 biopsy, as the remaining consultations did not require a biopsy to establish a diagnosis. The most common final diagnoses of consultations receiving biopsies included drug eruptions (5), leukemia cutis (4), vasculopathies (4), vasculitis (4), and calciphylaxis (3).

Impact on Hospitalization and Efficacy—Dermatology performed 217 consultations regarding patients already admitted to the hospital, and 92% remained hospitalized either due to comorbidities or complicated cutaneous conditions following the consultation. The remaining 8% were cleared for discharge. Dermatology received 36 consultation requests from emergency medicine physicians. Fifty-three percent of these patients were admitted, while the remaining 47% were discharged from the emergency department or its observation unit following evaluation.

Fifty-one percent of all consultations were noted to have improvement in their cutaneous condition by the time of discharge, as noted in the physical examination, progress note, or discharge summary of the primary team. Thirty percent of cases remained stable, where improvement was not noted in in the medical record. Most of these cases involved keratinocyte carcinomas scheduled for outpatient excision, benign melanocytic nevi found on FBSE, and benign etiologies that led to immediate discharge following consultation. Three percent of all consultations were noted to have worsened following consultation, including cases of calciphylaxis, vasculopathies, and purpura fulminans, as well as patients who elected for palliative care and hospice. The cutaneous condition by the time of discharge could not be determined from the medical record in 16% of all consultations.

Eighty-five percent of all consultations required a single encounter with dermatology. An additional 10% required a single follow-up with dermatology, while only 5% of patients required 3 or more encounters. Notably, these cases included patients with 1 or more severe cutaneous diseases, such as Sweet syndrome, calciphylaxis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and hidradenitis suppurativa.

Comment

Although dermatology often is viewed as an outpatient specialty, this study provides a glimpse into the ways inpatient dermatology consultations optimize the care of hospitalized patients. Most consultations involved assistance in diagnosing an unknown condition, but several regarded pre-existing skin disorders requiring management aid. As a variety of medical specialties requested consultations, dermatology was able to provide care to a diverse group of patients with conditions varying in complexity and severity. Several specialties benefited from niche dermatologic expertise: hematology and oncology frequently requested dermatology to assist in diagnosis and management of the toxic effects of chemotherapy, cutaneous metastasis, or suspected cutaneous infections in immunocompromised patients. Cardiology patients were frequently evaluated for potential malignancy or infection prior to heart transplantation and initiation of antirejection immunosuppressants. Dermatology was consulted to differentiate cutaneous manifestations of critical illness from underlying systemic disease in the intensive care unit, and patients presenting to the emergency department often were examined to determine if hospital admission was necessary, with 47% of these consultations resulting in a discharge following evaluation by a dermatologist.

Our results were consistent with prior studies^1,5,6 that have reported frequent changes in final diagnosis following dermatology consultation, with 69% of working diagnoses changed in this study when consultation was requested for diagnostic assistance. When dermatology was consulted for diagnostic assistance, several of these cases lacked a preliminary differential diagnosis. Although the absence of a documented differential diagnosis may not necessarily reflect a lack of suspicion for a particular etiology, 86% of all consultations included a ranked differential or working diagnosis either in the consultation request or progress note prior to consultation. The final diagnoses of consultations without a preliminary diagnosis varied from the mild and localized to systemic and severe, further suggesting these cases reflected knowledge gaps of the primary medical team.

Integration of dermatology into the care of hospitalized patients could provide an opportunity for education of primary medical teams. With frequent consultation, primary medical teams may become more comfortable diagnosing and managing common cutaneous conditions specific to their specialty or extended hospitalizations.

Several consultations were requested to aid in management of cases of hidradenitis suppurativa, pyoderma gangrenosum, or bullous pemphigoid that either failed outpatient therapy or were complicated by superinfections. Despite the ranges in complexity, the majority of all consultations required a single encounter and led to improvement by the time of discharge, demonstrating the efficacy and efficiency of inpatient dermatologists.

Dermatology consultations often led to changes in management involving medications and additional workup. Changes in management also extended to specific wound care instructions provided by dermatology, as expected for cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, Sweet syndrome, hidradenitis suppurativa, and pyoderma gangrenosum. However, patients with the sequelae of extended hospitalizations, such as chronic wounds, pressure ulcers, and edema bullae, also benefited from this expertise.

When patients required a biopsy, the final diagnoses were consistent with the dermatologist’s number one differential diagnosis or top 3 differential diagnoses 72% and 88% of the time, respectively. Only 55% of cases where the primary team requested a biopsy ultimately required a biopsy, as many involved clinical diagnoses such as urticaria. Not only was dermatology accurate in their preliminary diagnoses, but they decreased cost and morbidity by avoiding unnecessary procedures.

This study provided additional evidence to support the integration of dermatology into the hospital setting for the benefit of patients, primary medical teams, and hospital systems. Dermatology offers high-value care through the efficient diagnosis and management of hospitalized patients, which contributes to decreased cost and improved outcomes.^2,5-7,9,10 This study highlighted lesser-known areas of impact, such as the various specialty-specific services dermatology provides as well as the high rates of reported improvement following consultation. Future studies should continue to explore the field’s unique impact on hospitalized medicine as well as other avenues of care delivery, such as telemedicine, that may encourage dermatologists to participate in consultations and increase the volume of patients who may benefit from their care.

The US Department of Defense maintains a presence in several cold weather environments such as North Dakota, Alaska, and South Korea. Although much is known about preventing and caring for cold weather injuries, many of these ailments continue to occur. Therefore, it is vital that both military and civilian physicians who care for patients who are exposed to cold weather conditions have a thorough understanding of the prevention, clinical presentation, and treatment of cold weather injuries.

Although the focus of this article is on cutaneous cold weather injuries that occur in military service, these types of injuries are not limited to this population. Civilians who live, work, or seek recreation in cold climates also may experience these injuries. Classically, cold injuries are classified as freezing and nonfreezing injuries. For the purpose of this article, we also consider a third category: dermatologic conditions that flare upon cold exposure. Specifically, we discuss frostbite, cold-weather immersion foot, pernio, Raynaud phenomenon (RP), and cold urticaria. We also present a case of pernio in an active-duty military service member.

Frostbite

For centuries, frostbite has been well documented as a cold weather injury in military history.¹ Napoleon’s catastrophic invasion of Russia in 1812 started with 612,000 troops and ended with fewer than 10,000 effective soldiers; while many factors contributed to this attrition, exposure to cold weather and frostbite is thought to have been a major factor. The muddy trench warfare of World War I was no kinder to the poorly equipped soldiers across the European theater. Decades later during World War II, frostbite was a serious source of noncombat injuries, as battles were fought in frigid European winters. From 1942 to 1945, there were 13,196 reported cases of frostbite in the European theater, with most of these injuries occurring in 1945.¹

Despite advancements in cold weather clothing and increased knowledge about the causes of and preventative measures for frostbite, cold weather injuries continue to be a relevant topic in today’s military. From 2015 to 2020, there were 1120 reported cases of frostbite in the US military.² When skin is exposed to cold temperatures, the body peripherally vasoconstricts to reduce core heat loss. This autoregulatory vasoconstriction is part of a normal physiologic response that preserves the core body temperature, often at the expense of the extremities; for instance, the hands and feet are equipped with arteriovenous shunts, known as glomus bodies, which consist of vascular smooth muscle centers that control the flow of blood in response to changing external temperatures.³ This is partially mitigated by cold-induced vasodilation of the digits, also known as the Hunting reaction, which generally occurs 5 to 10 minutes after the start of local cold exposure.⁴ Additionally, discomfort from cold exposure warrants behavioral modifications such as going indoors, putting on warmer clothing, or building a fire. If an individual is unable to seek shelter in the face of cold exposure, the cold will inevitably cause injury.

Frostbite is caused by both direct and indirect cellular injury. Direct injury results from the crystallization of intracellular and interstitial fluids, cellular dehydration, and electrolyte disturbances. Indirect cellular injury is the result of a progressive microvascular insult and is caused by microvascular thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, and reperfusion injury.⁵

Frostnip is a more superficial injury that does not involve freezing of the skin or underlying tissue and typically does not leave any long-term damage. As severity of injury increases, frostbite is characterized by the depth of injury, presence of tissue loss, and radiotracer uptake on bone scan. There are 2 main classification systems for frostbite: one is based on the severity of the injury outcome, categorized by 4 degrees (1–4), and the other is designed as a predictive model, categorized by 4 grades (1–4).⁶ The first classification system is similar to the system for the severity of burns and ranges from partial-thickness injury (first degree) to full-thickness skin, subcutaneous tissue, muscle, tendon, and bone (fourth degree). The latter classification system uses the presence and characteristics of blisters after rewarming on days 0 and 2 and radiotracer uptake on bone scan on day 2. Severity ranges from no blistering, no indicated bone scan, and no long-term sequelae in grade 1 to hemorrhagic blisters overlying the carpal or tarsal bones and absence of radiotracer uptake with predicted extensive amputation, risk for thrombosis or sepsis, and long-term functional sequelae in grade 4.⁶

Male sex and African descent are associated with increased risk for sustaining frostbite. The ethnic predisposition may be explained by a less robust Hunting reaction in individuals of African descent.^4,7 Other risk factors include alcohol use, smoking, homelessness, history of cold-related injury, use of beta-blockers, and working with equipment that uses nitrogen dioxide or CO₂.⁵ Additionally, a history of systemic lupus erythematosus has been reported as a risk factor for frostbite.⁸

Clinically, frostbite initially may appear pale, blue, or erythematous, and patients may report skin numbness. In severe cases, necrosis can be seen.⁹ The most commonly affected anatomic locations include the fingers, toes, ears, and nose. Prevention is key for frostbite injuries. Steps to avoid injury include wearing appropriate clothing, minimizing the duration of time the skin is exposed to cold temperatures, avoiding alcohol consumption, and avoiding physical exhaustion in cold weather. These steps can help mitigate the effects of wind chill and low temperatures and decrease the risk of frostbite.¹⁰

Management of this condition includes prevention, early diagnosis, prehospital management, hospital management, and long-term sequelae management. Leadership and medical personnel for military units assigned to cold climates should be vigilant in looking for symptoms of frostbite. If any one individual is found to have frostbite or any other cold injury, all other team members should be evaluated.⁵

After identification of frostbite, seeking shelter and evacuation to a treatment facility are vital next steps. Constrictive clothing or jewelry should be removed. Depending on the situation, rewarming can be attempted in the prehospital setting, but it is imperative to avoid refreezing, as this may further damage the affected tissue due to intracellular ice formation with extensive cell destruction.⁶ Gentle warming can be attempted by placing the affected extremity in another person’s armpit or groin for up to 10 minutes or by immersing the affected limb in water that is 37° C to 39° C (98.6° F to 102.2° F). Rubbing the affected area and dry heat should be avoided. It should be noted that the decision to thaw in the field introduces the challenge of dealing with the severe pain associated with thawing in a remote or hostile environment. Ibuprofen (400 mg) can be given as an anti-inflammatory and analgesic agent in the prehospital setting.⁵ Once safely evacuated to the hospital, treatment options expand dramatically, including warming without concern of refreezing, wound care, thrombolytic therapy, and surgical intervention. If local frostbite expertise is not available, there are telemedicine services available.^5,6

Frostbite outcomes range from complete recovery to amputation. Previously frostbitten tissue has increased cold sensitivity and is more susceptible to similar injury in the future. Additionally, there can be functional loss, chronic pain, chronic ulceration, and arthritis.^5,6 As such, a history of frostbite can be disqualifying for military service and requires a medical waiver.¹¹ If a service member experiences frostbite and does not have any residual effects, they can expect to continue their military service, but if there are sequelae, it may prove to be career limiting.^12-14

Immersion Foot

Although frostbite represents a freezing injury, immersion foot (or trench foot) represents a nonfreezing cold injury. It should be noted that in addition to immersion foot associated with cold water exposure, there also are warm-water and tropical variants. For the purpose of this article, we are referring to immersion foot associated with exposure to cold water. Trench foot was described for the first time during Napoleon’s invasion of Russia in 1812 but came to prominence during World War I, where it is thought to have contributed to the deaths of 75,000 British soldiers. During World War II, there were 25,016 cases of immersion foot reported in the US military.¹ More recently, 590 cases of immersion foot were reported in the US military from 2015 to 2020.²

Classically, this condition was seen in individuals whose feet were immersed in cold but not freezing water or mud in trenches or on boats, hence the terms immersion foot and trench foot. The pathogenesis is thought to be related to overhydration of the stratum corneum and repetitive cycles of cold-induced, thermoprotective vasoconstriction, leading to cyclical hypoxic and reperfusion injuries, which eventually damage nerves, muscle, subcutaneous fat, and blood vessels.^9,15

A recent case series of 100 military service members in the United Kingdom showed that cold-induced extremity numbness for more than 30 minutes and painful rewarming after cold exposure were highly correlated with the development of immersion foot. Additionally, this case series showed that patients with repeated cycles of cooling and rewarming were more likely to have long-term symptoms.¹⁶ As with frostbite, prior cold injury and African descent increases the risk for developing immersion foot, possibly due to a less-pronounced Hunting reaction.^4,7

Early reports suggested prehyperemic, hyperemic, and posthyperemic stages. The prehyperemic stage lasts from hours to days and is characterized by cold extremities, discoloration, edema, stocking- or glove-distributed anesthesia, blisters, necrosis, and potential loss of palpable pulses.¹⁷ Of note, in Kuht et al’s¹⁶ more recent case series, edema was not seen as frequently as in prior reports. The hyperemic stage can last for 6 to 10 weeks and is characterized by vascular disturbances. In addition, the affected extremity typically remains warm and red even when exposed to cold temperatures. Sensory disturbances such as paresthesia and hyperalgesia may be seen, as well as motor disturbances, anhidrosis, blisters, ulcers, and gangrene. The posthyperemic stage can last from months to years and is characterized by cold sensitivity, possible digital blanching, edema, hyperhidrosis, and persistent peripheral neuropathy.¹⁶

Prevention is the most important treatment for immersion foot. The first step in preventing this injury is avoiding prolonged cold exposure. When this is not possible due to the demands of training or actual combat conditions, regular hand and foot inspections, frequent sock changes, and regularly rotating out of cold wet conditions can help prevent this injury.¹⁵ Vasodilators also have been considered as a possible treatment modality. Iloprost and nicotinyl alcohol tartrate showed some improvement, while aminophylline and papaverine were ineffective.¹⁵

As with frostbite, a history of immersion foot may be disqualifying for military service.¹¹ If it occurs during military service and there are no residual effects that limit the service member’s capabilities, they may expect to continue their career; however, if there are residual effects that limit activity or deployment, medical retirement may be indicated.

Pernio

Pernio is another important condition that is related to cold exposure; however, unlike the previous 2 conditions, it is not necessarily caused by cold exposure but rather flares with cold exposure.

Case Presentation—A 39-year-old active-duty male service member presented to the dermatology clinic for intermittent painful blistering on the toes of both feet lasting approximately 10 to 14 days about 3 to 4 times per year for the last several years. The patient reported that his symptoms started after spending 2 days in the snow with wet nonwinterized boots while stationed in Germany 10 years prior. He reported cold weather as his only associated trigger and denied other associated symptoms. Physical examination revealed mildly cyanotic toes containing scattered bullae, with the dorsal lesions appearing more superficial compared to the deeper plantar bullae (Figure 1). A complete blood cell count, serum protein electrophoresis, and antinuclear and autoimmune antibodies were within reference range. A punch biopsy was obtained from a lesion on the right dorsal great toe. Hematoxylin and eosin–stained sections revealed lichenoid and vacuolar dermatitis with scattered dyskeratosis and subtle papillary edema (Figure 2). Minimal interstitial mucin was seen on Alcian blue–stained sections. The histologic and clinical findings were most compatible with a diagnosis of chronic pernio. Nifedipine 20 mg once daily was initiated, and he had minimal improvement after a few months of treatment. His condition continued to limit his functionality in cold conditions due to pain. Without improvement of the symptoms, the patient likely will require medical separation from military service, as this condition limits the performance of his duties and his deployability.

Clinical Discussion—Pernio, also known as chilblains, is characterized by cold-induced erythematous patches and plaques, pain, and pruritus on the affected skin.¹⁸ Bullae and ulceration can be seen in more severe and chronic cases.¹⁹ Pernio most commonly is seen in young women but also can be seen in children, men, and older adults. It usually occurs on the tips of toes but also may affect the fingers, nose, and ears. It typically is observed in cold and damp conditions and is thought to be caused by an inflammatory response to vasospasms in the setting of nonfreezing cold. Acute pernio typically resolves after a few weeks; however, it also can persist in a chronic form after repeated cold exposure.¹⁸

Predisposing factors include excessive cold exposure, connective tissue disease, hematologic malignancy, antiphospholipid antibodies in adults, and anorexia nervosa in children.^18,20,21 More recently, perniolike lesions have been associated with prior SARS-CoV-2 infection.²² Histologically, pernio is characterized by a perivascular lymphocytic infiltrate and dermal edema.²³ Cold avoidance, warming, drying, and smoking cessation are primary treatments, while vasodilating medications such as nifedipine have been used with success in more resistant cases.^20,24

Although the prognosis generally is excellent, this condition also can be career limiting for military service members. If it resolves with no residual effects, patients can expect to continue their service; however, if it persists and limits their activity or ability to deploy, a medical retirement may be indicated.^11-14

Raynaud Phenomenon

Raynaud phenomenon (also known as Raynaud’s) is characterized by cold-induced extremity triphasic color changes—initial blanching and pallor that transitions to cyanosis and finally erythema with associated pain during the recovery stage. The fingers are the most commonly involved appendages and can have a symmetric distribution, but RP also has been observed on the feet, lips, nose, and ears. In severe cases, it can cause ulceration.²⁵ The prevalence of RP may be as high as 5% in the general population.²⁶ It more commonly is primary or idiopathic with no underlying cause or secondary with an associated underlying systemic disease.

Cold-induced vasoconstriction is a normal physiologic response, but in RP, the response becomes a vasospasm and is pathological. Autoimmune and connective tissue diseases often are associated with secondary RP. Other risk factors include female sex, smoking, family history in a first-degree relative, and certain medications.²⁵ A study in northern Sweden also identified a history of frostbite as a risk factor for the development of RP.²⁷ This condition can notably restrict mobility and deployability of affected service members as well as the types of manual tasks that they may be required to perform. As such, this condition can be disqualifying for military service.¹¹

Many patients improve with conservative treatment consisting of cold avoidance, smoking cessation, and avoidance of medications that worsen the vasospasm; however, some patients develop pain and chronic disease, which can become so severe and ischemic that digital loss is threatened.²⁵ When needed, calcium channel blockers commonly are used for treatment and can be used prophylactically to reduce flare rates and severity of disease. If this class of medications is ineffective or is not tolerated, there are other medications and treatments to consider, which are beyond the scope of this article.²⁵

Cold Urticaria

Cold urticaria is a subset of physical urticaria in which symptoms occur in response to a cutaneous cold stimulus. It can be primary or secondary, with potential underlying causes including cryoglobulinemia, infections, and some medications. Systemic involvement is possible with extensive cold contact and can include severe anaphylaxis. This condition is diagnosed using a cold stimulation test. Cold exposure avoidance and second-generation antihistamines are considered first-line treatment. Because anaphylaxis is possible, patients should be given an epinephrine pen and should be instructed to avoid swimming in cold water.²⁸ Cold urticaria is disqualifying for military service.¹¹

A 2013 case report described a 29-year-old woman on active duty in the US Air Force whose presenting symptoms included urticaria on the exposed skin on the arms when doing physical training in the rain.²⁹ In this case, secondary causes were eliminated, and she was diagnosed with primary acquired cold urticaria. This patient was eventually medically discharged from the air force because management with antihistamines failed, and her symptoms limited her ability to function in even mildly cold environments.²⁹

Final Thoughts

An understanding of cold weather injuries and other dermatologic conditions that may be flared by cold exposure is important for a medically ready military force, as there are implications for accession, training, and combat operations. Although the focus of this article has been on the military, these conditions also are seen in civilian medicine in patient populations routinely exposed to cold weather. This becomes especially pertinent in high-risk patients such as extreme athletes, homeless individuals, or those who have other predisposing characteristics such as chronic alcohol use. Appropriate cold weather gear, training, and deliberate mission or activity planning are important interventions in preventing cutaneous cold weather injuries within the military.

The US Department of Defense maintains a presence in several cold weather environments such as North Dakota, Alaska, and South Korea. Although much is known about preventing and caring for cold weather injuries, many of these ailments continue to occur. Therefore, it is vital that both military and civilian physicians who care for patients who are exposed to cold weather conditions have a thorough understanding of the prevention, clinical presentation, and treatment of cold weather injuries.

Although the focus of this article is on cutaneous cold weather injuries that occur in military service, these types of injuries are not limited to this population. Civilians who live, work, or seek recreation in cold climates also may experience these injuries. Classically, cold injuries are classified as freezing and nonfreezing injuries. For the purpose of this article, we also consider a third category: dermatologic conditions that flare upon cold exposure. Specifically, we discuss frostbite, cold-weather immersion foot, pernio, Raynaud phenomenon (RP), and cold urticaria. We also present a case of pernio in an active-duty military service member.

Frostbite

For centuries, frostbite has been well documented as a cold weather injury in military history.¹ Napoleon’s catastrophic invasion of Russia in 1812 started with 612,000 troops and ended with fewer than 10,000 effective soldiers; while many factors contributed to this attrition, exposure to cold weather and frostbite is thought to have been a major factor. The muddy trench warfare of World War I was no kinder to the poorly equipped soldiers across the European theater. Decades later during World War II, frostbite was a serious source of noncombat injuries, as battles were fought in frigid European winters. From 1942 to 1945, there were 13,196 reported cases of frostbite in the European theater, with most of these injuries occurring in 1945.¹

Despite advancements in cold weather clothing and increased knowledge about the causes of and preventative measures for frostbite, cold weather injuries continue to be a relevant topic in today’s military. From 2015 to 2020, there were 1120 reported cases of frostbite in the US military.² When skin is exposed to cold temperatures, the body peripherally vasoconstricts to reduce core heat loss. This autoregulatory vasoconstriction is part of a normal physiologic response that preserves the core body temperature, often at the expense of the extremities; for instance, the hands and feet are equipped with arteriovenous shunts, known as glomus bodies, which consist of vascular smooth muscle centers that control the flow of blood in response to changing external temperatures.³ This is partially mitigated by cold-induced vasodilation of the digits, also known as the Hunting reaction, which generally occurs 5 to 10 minutes after the start of local cold exposure.⁴ Additionally, discomfort from cold exposure warrants behavioral modifications such as going indoors, putting on warmer clothing, or building a fire. If an individual is unable to seek shelter in the face of cold exposure, the cold will inevitably cause injury.

Frostbite is caused by both direct and indirect cellular injury. Direct injury results from the crystallization of intracellular and interstitial fluids, cellular dehydration, and electrolyte disturbances. Indirect cellular injury is the result of a progressive microvascular insult and is caused by microvascular thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, and reperfusion injury.⁵

Frostnip is a more superficial injury that does not involve freezing of the skin or underlying tissue and typically does not leave any long-term damage. As severity of injury increases, frostbite is characterized by the depth of injury, presence of tissue loss, and radiotracer uptake on bone scan. There are 2 main classification systems for frostbite: one is based on the severity of the injury outcome, categorized by 4 degrees (1–4), and the other is designed as a predictive model, categorized by 4 grades (1–4).⁶ The first classification system is similar to the system for the severity of burns and ranges from partial-thickness injury (first degree) to full-thickness skin, subcutaneous tissue, muscle, tendon, and bone (fourth degree). The latter classification system uses the presence and characteristics of blisters after rewarming on days 0 and 2 and radiotracer uptake on bone scan on day 2. Severity ranges from no blistering, no indicated bone scan, and no long-term sequelae in grade 1 to hemorrhagic blisters overlying the carpal or tarsal bones and absence of radiotracer uptake with predicted extensive amputation, risk for thrombosis or sepsis, and long-term functional sequelae in grade 4.⁶

Male sex and African descent are associated with increased risk for sustaining frostbite. The ethnic predisposition may be explained by a less robust Hunting reaction in individuals of African descent.^4,7 Other risk factors include alcohol use, smoking, homelessness, history of cold-related injury, use of beta-blockers, and working with equipment that uses nitrogen dioxide or CO₂.⁵ Additionally, a history of systemic lupus erythematosus has been reported as a risk factor for frostbite.⁸

Clinically, frostbite initially may appear pale, blue, or erythematous, and patients may report skin numbness. In severe cases, necrosis can be seen.⁹ The most commonly affected anatomic locations include the fingers, toes, ears, and nose. Prevention is key for frostbite injuries. Steps to avoid injury include wearing appropriate clothing, minimizing the duration of time the skin is exposed to cold temperatures, avoiding alcohol consumption, and avoiding physical exhaustion in cold weather. These steps can help mitigate the effects of wind chill and low temperatures and decrease the risk of frostbite.¹⁰

Management of this condition includes prevention, early diagnosis, prehospital management, hospital management, and long-term sequelae management. Leadership and medical personnel for military units assigned to cold climates should be vigilant in looking for symptoms of frostbite. If any one individual is found to have frostbite or any other cold injury, all other team members should be evaluated.⁵

After identification of frostbite, seeking shelter and evacuation to a treatment facility are vital next steps. Constrictive clothing or jewelry should be removed. Depending on the situation, rewarming can be attempted in the prehospital setting, but it is imperative to avoid refreezing, as this may further damage the affected tissue due to intracellular ice formation with extensive cell destruction.⁶ Gentle warming can be attempted by placing the affected extremity in another person’s armpit or groin for up to 10 minutes or by immersing the affected limb in water that is 37° C to 39° C (98.6° F to 102.2° F). Rubbing the affected area and dry heat should be avoided. It should be noted that the decision to thaw in the field introduces the challenge of dealing with the severe pain associated with thawing in a remote or hostile environment. Ibuprofen (400 mg) can be given as an anti-inflammatory and analgesic agent in the prehospital setting.⁵ Once safely evacuated to the hospital, treatment options expand dramatically, including warming without concern of refreezing, wound care, thrombolytic therapy, and surgical intervention. If local frostbite expertise is not available, there are telemedicine services available.^5,6

Frostbite outcomes range from complete recovery to amputation. Previously frostbitten tissue has increased cold sensitivity and is more susceptible to similar injury in the future. Additionally, there can be functional loss, chronic pain, chronic ulceration, and arthritis.^5,6 As such, a history of frostbite can be disqualifying for military service and requires a medical waiver.¹¹ If a service member experiences frostbite and does not have any residual effects, they can expect to continue their military service, but if there are sequelae, it may prove to be career limiting.^12-14

Immersion Foot

Although frostbite represents a freezing injury, immersion foot (or trench foot) represents a nonfreezing cold injury. It should be noted that in addition to immersion foot associated with cold water exposure, there also are warm-water and tropical variants. For the purpose of this article, we are referring to immersion foot associated with exposure to cold water. Trench foot was described for the first time during Napoleon’s invasion of Russia in 1812 but came to prominence during World War I, where it is thought to have contributed to the deaths of 75,000 British soldiers. During World War II, there were 25,016 cases of immersion foot reported in the US military.¹ More recently, 590 cases of immersion foot were reported in the US military from 2015 to 2020.²

Classically, this condition was seen in individuals whose feet were immersed in cold but not freezing water or mud in trenches or on boats, hence the terms immersion foot and trench foot. The pathogenesis is thought to be related to overhydration of the stratum corneum and repetitive cycles of cold-induced, thermoprotective vasoconstriction, leading to cyclical hypoxic and reperfusion injuries, which eventually damage nerves, muscle, subcutaneous fat, and blood vessels.^9,15

A recent case series of 100 military service members in the United Kingdom showed that cold-induced extremity numbness for more than 30 minutes and painful rewarming after cold exposure were highly correlated with the development of immersion foot. Additionally, this case series showed that patients with repeated cycles of cooling and rewarming were more likely to have long-term symptoms.¹⁶ As with frostbite, prior cold injury and African descent increases the risk for developing immersion foot, possibly due to a less-pronounced Hunting reaction.^4,7

Early reports suggested prehyperemic, hyperemic, and posthyperemic stages. The prehyperemic stage lasts from hours to days and is characterized by cold extremities, discoloration, edema, stocking- or glove-distributed anesthesia, blisters, necrosis, and potential loss of palpable pulses.¹⁷ Of note, in Kuht et al’s¹⁶ more recent case series, edema was not seen as frequently as in prior reports. The hyperemic stage can last for 6 to 10 weeks and is characterized by vascular disturbances. In addition, the affected extremity typically remains warm and red even when exposed to cold temperatures. Sensory disturbances such as paresthesia and hyperalgesia may be seen, as well as motor disturbances, anhidrosis, blisters, ulcers, and gangrene. The posthyperemic stage can last from months to years and is characterized by cold sensitivity, possible digital blanching, edema, hyperhidrosis, and persistent peripheral neuropathy.¹⁶

Prevention is the most important treatment for immersion foot. The first step in preventing this injury is avoiding prolonged cold exposure. When this is not possible due to the demands of training or actual combat conditions, regular hand and foot inspections, frequent sock changes, and regularly rotating out of cold wet conditions can help prevent this injury.¹⁵ Vasodilators also have been considered as a possible treatment modality. Iloprost and nicotinyl alcohol tartrate showed some improvement, while aminophylline and papaverine were ineffective.¹⁵

As with frostbite, a history of immersion foot may be disqualifying for military service.¹¹ If it occurs during military service and there are no residual effects that limit the service member’s capabilities, they may expect to continue their career; however, if there are residual effects that limit activity or deployment, medical retirement may be indicated.

Pernio

Pernio is another important condition that is related to cold exposure; however, unlike the previous 2 conditions, it is not necessarily caused by cold exposure but rather flares with cold exposure.

Case Presentation—A 39-year-old active-duty male service member presented to the dermatology clinic for intermittent painful blistering on the toes of both feet lasting approximately 10 to 14 days about 3 to 4 times per year for the last several years. The patient reported that his symptoms started after spending 2 days in the snow with wet nonwinterized boots while stationed in Germany 10 years prior. He reported cold weather as his only associated trigger and denied other associated symptoms. Physical examination revealed mildly cyanotic toes containing scattered bullae, with the dorsal lesions appearing more superficial compared to the deeper plantar bullae (Figure 1). A complete blood cell count, serum protein electrophoresis, and antinuclear and autoimmune antibodies were within reference range. A punch biopsy was obtained from a lesion on the right dorsal great toe. Hematoxylin and eosin–stained sections revealed lichenoid and vacuolar dermatitis with scattered dyskeratosis and subtle papillary edema (Figure 2). Minimal interstitial mucin was seen on Alcian blue–stained sections. The histologic and clinical findings were most compatible with a diagnosis of chronic pernio. Nifedipine 20 mg once daily was initiated, and he had minimal improvement after a few months of treatment. His condition continued to limit his functionality in cold conditions due to pain. Without improvement of the symptoms, the patient likely will require medical separation from military service, as this condition limits the performance of his duties and his deployability.

Clinical Discussion—Pernio, also known as chilblains, is characterized by cold-induced erythematous patches and plaques, pain, and pruritus on the affected skin.¹⁸ Bullae and ulceration can be seen in more severe and chronic cases.¹⁹ Pernio most commonly is seen in young women but also can be seen in children, men, and older adults. It usually occurs on the tips of toes but also may affect the fingers, nose, and ears. It typically is observed in cold and damp conditions and is thought to be caused by an inflammatory response to vasospasms in the setting of nonfreezing cold. Acute pernio typically resolves after a few weeks; however, it also can persist in a chronic form after repeated cold exposure.¹⁸

Predisposing factors include excessive cold exposure, connective tissue disease, hematologic malignancy, antiphospholipid antibodies in adults, and anorexia nervosa in children.^18,20,21 More recently, perniolike lesions have been associated with prior SARS-CoV-2 infection.²² Histologically, pernio is characterized by a perivascular lymphocytic infiltrate and dermal edema.²³ Cold avoidance, warming, drying, and smoking cessation are primary treatments, while vasodilating medications such as nifedipine have been used with success in more resistant cases.^20,24

Although the prognosis generally is excellent, this condition also can be career limiting for military service members. If it resolves with no residual effects, patients can expect to continue their service; however, if it persists and limits their activity or ability to deploy, a medical retirement may be indicated.^11-14

Raynaud Phenomenon

Raynaud phenomenon (also known as Raynaud’s) is characterized by cold-induced extremity triphasic color changes—initial blanching and pallor that transitions to cyanosis and finally erythema with associated pain during the recovery stage. The fingers are the most commonly involved appendages and can have a symmetric distribution, but RP also has been observed on the feet, lips, nose, and ears. In severe cases, it can cause ulceration.²⁵ The prevalence of RP may be as high as 5% in the general population.²⁶ It more commonly is primary or idiopathic with no underlying cause or secondary with an associated underlying systemic disease.

Cold-induced vasoconstriction is a normal physiologic response, but in RP, the response becomes a vasospasm and is pathological. Autoimmune and connective tissue diseases often are associated with secondary RP. Other risk factors include female sex, smoking, family history in a first-degree relative, and certain medications.²⁵ A study in northern Sweden also identified a history of frostbite as a risk factor for the development of RP.²⁷ This condition can notably restrict mobility and deployability of affected service members as well as the types of manual tasks that they may be required to perform. As such, this condition can be disqualifying for military service.¹¹

Many patients improve with conservative treatment consisting of cold avoidance, smoking cessation, and avoidance of medications that worsen the vasospasm; however, some patients develop pain and chronic disease, which can become so severe and ischemic that digital loss is threatened.²⁵ When needed, calcium channel blockers commonly are used for treatment and can be used prophylactically to reduce flare rates and severity of disease. If this class of medications is ineffective or is not tolerated, there are other medications and treatments to consider, which are beyond the scope of this article.²⁵

Cold Urticaria

Cold urticaria is a subset of physical urticaria in which symptoms occur in response to a cutaneous cold stimulus. It can be primary or secondary, with potential underlying causes including cryoglobulinemia, infections, and some medications. Systemic involvement is possible with extensive cold contact and can include severe anaphylaxis. This condition is diagnosed using a cold stimulation test. Cold exposure avoidance and second-generation antihistamines are considered first-line treatment. Because anaphylaxis is possible, patients should be given an epinephrine pen and should be instructed to avoid swimming in cold water.²⁸ Cold urticaria is disqualifying for military service.¹¹

A 2013 case report described a 29-year-old woman on active duty in the US Air Force whose presenting symptoms included urticaria on the exposed skin on the arms when doing physical training in the rain.²⁹ In this case, secondary causes were eliminated, and she was diagnosed with primary acquired cold urticaria. This patient was eventually medically discharged from the air force because management with antihistamines failed, and her symptoms limited her ability to function in even mildly cold environments.²⁹

Final Thoughts

An understanding of cold weather injuries and other dermatologic conditions that may be flared by cold exposure is important for a medically ready military force, as there are implications for accession, training, and combat operations. Although the focus of this article has been on the military, these conditions also are seen in civilian medicine in patient populations routinely exposed to cold weather. This becomes especially pertinent in high-risk patients such as extreme athletes, homeless individuals, or those who have other predisposing characteristics such as chronic alcohol use. Appropriate cold weather gear, training, and deliberate mission or activity planning are important interventions in preventing cutaneous cold weather injuries within the military.

The US Department of Defense maintains a presence in several cold weather environments such as North Dakota, Alaska, and South Korea. Although much is known about preventing and caring for cold weather injuries, many of these ailments continue to occur. Therefore, it is vital that both military and civilian physicians who care for patients who are exposed to cold weather conditions have a thorough understanding of the prevention, clinical presentation, and treatment of cold weather injuries.

Although the focus of this article is on cutaneous cold weather injuries that occur in military service, these types of injuries are not limited to this population. Civilians who live, work, or seek recreation in cold climates also may experience these injuries. Classically, cold injuries are classified as freezing and nonfreezing injuries. For the purpose of this article, we also consider a third category: dermatologic conditions that flare upon cold exposure. Specifically, we discuss frostbite, cold-weather immersion foot, pernio, Raynaud phenomenon (RP), and cold urticaria. We also present a case of pernio in an active-duty military service member.

Frostbite

For centuries, frostbite has been well documented as a cold weather injury in military history.¹ Napoleon’s catastrophic invasion of Russia in 1812 started with 612,000 troops and ended with fewer than 10,000 effective soldiers; while many factors contributed to this attrition, exposure to cold weather and frostbite is thought to have been a major factor. The muddy trench warfare of World War I was no kinder to the poorly equipped soldiers across the European theater. Decades later during World War II, frostbite was a serious source of noncombat injuries, as battles were fought in frigid European winters. From 1942 to 1945, there were 13,196 reported cases of frostbite in the European theater, with most of these injuries occurring in 1945.¹

Despite advancements in cold weather clothing and increased knowledge about the causes of and preventative measures for frostbite, cold weather injuries continue to be a relevant topic in today’s military. From 2015 to 2020, there were 1120 reported cases of frostbite in the US military.² When skin is exposed to cold temperatures, the body peripherally vasoconstricts to reduce core heat loss. This autoregulatory vasoconstriction is part of a normal physiologic response that preserves the core body temperature, often at the expense of the extremities; for instance, the hands and feet are equipped with arteriovenous shunts, known as glomus bodies, which consist of vascular smooth muscle centers that control the flow of blood in response to changing external temperatures.³ This is partially mitigated by cold-induced vasodilation of the digits, also known as the Hunting reaction, which generally occurs 5 to 10 minutes after the start of local cold exposure.⁴ Additionally, discomfort from cold exposure warrants behavioral modifications such as going indoors, putting on warmer clothing, or building a fire. If an individual is unable to seek shelter in the face of cold exposure, the cold will inevitably cause injury.

Frostbite is caused by both direct and indirect cellular injury. Direct injury results from the crystallization of intracellular and interstitial fluids, cellular dehydration, and electrolyte disturbances. Indirect cellular injury is the result of a progressive microvascular insult and is caused by microvascular thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, and reperfusion injury.⁵

Frostnip is a more superficial injury that does not involve freezing of the skin or underlying tissue and typically does not leave any long-term damage. As severity of injury increases, frostbite is characterized by the depth of injury, presence of tissue loss, and radiotracer uptake on bone scan. There are 2 main classification systems for frostbite: one is based on the severity of the injury outcome, categorized by 4 degrees (1–4), and the other is designed as a predictive model, categorized by 4 grades (1–4).⁶ The first classification system is similar to the system for the severity of burns and ranges from partial-thickness injury (first degree) to full-thickness skin, subcutaneous tissue, muscle, tendon, and bone (fourth degree). The latter classification system uses the presence and characteristics of blisters after rewarming on days 0 and 2 and radiotracer uptake on bone scan on day 2. Severity ranges from no blistering, no indicated bone scan, and no long-term sequelae in grade 1 to hemorrhagic blisters overlying the carpal or tarsal bones and absence of radiotracer uptake with predicted extensive amputation, risk for thrombosis or sepsis, and long-term functional sequelae in grade 4.⁶

Male sex and African descent are associated with increased risk for sustaining frostbite. The ethnic predisposition may be explained by a less robust Hunting reaction in individuals of African descent.^4,7 Other risk factors include alcohol use, smoking, homelessness, history of cold-related injury, use of beta-blockers, and working with equipment that uses nitrogen dioxide or CO₂.⁵ Additionally, a history of systemic lupus erythematosus has been reported as a risk factor for frostbite.⁸

Clinically, frostbite initially may appear pale, blue, or erythematous, and patients may report skin numbness. In severe cases, necrosis can be seen.⁹ The most commonly affected anatomic locations include the fingers, toes, ears, and nose. Prevention is key for frostbite injuries. Steps to avoid injury include wearing appropriate clothing, minimizing the duration of time the skin is exposed to cold temperatures, avoiding alcohol consumption, and avoiding physical exhaustion in cold weather. These steps can help mitigate the effects of wind chill and low temperatures and decrease the risk of frostbite.¹⁰

Management of this condition includes prevention, early diagnosis, prehospital management, hospital management, and long-term sequelae management. Leadership and medical personnel for military units assigned to cold climates should be vigilant in looking for symptoms of frostbite. If any one individual is found to have frostbite or any other cold injury, all other team members should be evaluated.⁵

After identification of frostbite, seeking shelter and evacuation to a treatment facility are vital next steps. Constrictive clothing or jewelry should be removed. Depending on the situation, rewarming can be attempted in the prehospital setting, but it is imperative to avoid refreezing, as this may further damage the affected tissue due to intracellular ice formation with extensive cell destruction.⁶ Gentle warming can be attempted by placing the affected extremity in another person’s armpit or groin for up to 10 minutes or by immersing the affected limb in water that is 37° C to 39° C (98.6° F to 102.2° F). Rubbing the affected area and dry heat should be avoided. It should be noted that the decision to thaw in the field introduces the challenge of dealing with the severe pain associated with thawing in a remote or hostile environment. Ibuprofen (400 mg) can be given as an anti-inflammatory and analgesic agent in the prehospital setting.⁵ Once safely evacuated to the hospital, treatment options expand dramatically, including warming without concern of refreezing, wound care, thrombolytic therapy, and surgical intervention. If local frostbite expertise is not available, there are telemedicine services available.^5,6

Frostbite outcomes range from complete recovery to amputation. Previously frostbitten tissue has increased cold sensitivity and is more susceptible to similar injury in the future. Additionally, there can be functional loss, chronic pain, chronic ulceration, and arthritis.^5,6 As such, a history of frostbite can be disqualifying for military service and requires a medical waiver.¹¹ If a service member experiences frostbite and does not have any residual effects, they can expect to continue their military service, but if there are sequelae, it may prove to be career limiting.^12-14

Immersion Foot

Although frostbite represents a freezing injury, immersion foot (or trench foot) represents a nonfreezing cold injury. It should be noted that in addition to immersion foot associated with cold water exposure, there also are warm-water and tropical variants. For the purpose of this article, we are referring to immersion foot associated with exposure to cold water. Trench foot was described for the first time during Napoleon’s invasion of Russia in 1812 but came to prominence during World War I, where it is thought to have contributed to the deaths of 75,000 British soldiers. During World War II, there were 25,016 cases of immersion foot reported in the US military.¹ More recently, 590 cases of immersion foot were reported in the US military from 2015 to 2020.²

Classically, this condition was seen in individuals whose feet were immersed in cold but not freezing water or mud in trenches or on boats, hence the terms immersion foot and trench foot. The pathogenesis is thought to be related to overhydration of the stratum corneum and repetitive cycles of cold-induced, thermoprotective vasoconstriction, leading to cyclical hypoxic and reperfusion injuries, which eventually damage nerves, muscle, subcutaneous fat, and blood vessels.^9,15

A recent case series of 100 military service members in the United Kingdom showed that cold-induced extremity numbness for more than 30 minutes and painful rewarming after cold exposure were highly correlated with the development of immersion foot. Additionally, this case series showed that patients with repeated cycles of cooling and rewarming were more likely to have long-term symptoms.¹⁶ As with frostbite, prior cold injury and African descent increases the risk for developing immersion foot, possibly due to a less-pronounced Hunting reaction.^4,7

Early reports suggested prehyperemic, hyperemic, and posthyperemic stages. The prehyperemic stage lasts from hours to days and is characterized by cold extremities, discoloration, edema, stocking- or glove-distributed anesthesia, blisters, necrosis, and potential loss of palpable pulses.¹⁷ Of note, in Kuht et al’s¹⁶ more recent case series, edema was not seen as frequently as in prior reports. The hyperemic stage can last for 6 to 10 weeks and is characterized by vascular disturbances. In addition, the affected extremity typically remains warm and red even when exposed to cold temperatures. Sensory disturbances such as paresthesia and hyperalgesia may be seen, as well as motor disturbances, anhidrosis, blisters, ulcers, and gangrene. The posthyperemic stage can last from months to years and is characterized by cold sensitivity, possible digital blanching, edema, hyperhidrosis, and persistent peripheral neuropathy.¹⁶

Prevention is the most important treatment for immersion foot. The first step in preventing this injury is avoiding prolonged cold exposure. When this is not possible due to the demands of training or actual combat conditions, regular hand and foot inspections, frequent sock changes, and regularly rotating out of cold wet conditions can help prevent this injury.¹⁵ Vasodilators also have been considered as a possible treatment modality. Iloprost and nicotinyl alcohol tartrate showed some improvement, while aminophylline and papaverine were ineffective.¹⁵

As with frostbite, a history of immersion foot may be disqualifying for military service.¹¹ If it occurs during military service and there are no residual effects that limit the service member’s capabilities, they may expect to continue their career; however, if there are residual effects that limit activity or deployment, medical retirement may be indicated.

Pernio

Pernio is another important condition that is related to cold exposure; however, unlike the previous 2 conditions, it is not necessarily caused by cold exposure but rather flares with cold exposure.

Case Presentation—A 39-year-old active-duty male service member presented to the dermatology clinic for intermittent painful blistering on the toes of both feet lasting approximately 10 to 14 days about 3 to 4 times per year for the last several years. The patient reported that his symptoms started after spending 2 days in the snow with wet nonwinterized boots while stationed in Germany 10 years prior. He reported cold weather as his only associated trigger and denied other associated symptoms. Physical examination revealed mildly cyanotic toes containing scattered bullae, with the dorsal lesions appearing more superficial compared to the deeper plantar bullae (Figure 1). A complete blood cell count, serum protein electrophoresis, and antinuclear and autoimmune antibodies were within reference range. A punch biopsy was obtained from a lesion on the right dorsal great toe. Hematoxylin and eosin–stained sections revealed lichenoid and vacuolar dermatitis with scattered dyskeratosis and subtle papillary edema (Figure 2). Minimal interstitial mucin was seen on Alcian blue–stained sections. The histologic and clinical findings were most compatible with a diagnosis of chronic pernio. Nifedipine 20 mg once daily was initiated, and he had minimal improvement after a few months of treatment. His condition continued to limit his functionality in cold conditions due to pain. Without improvement of the symptoms, the patient likely will require medical separation from military service, as this condition limits the performance of his duties and his deployability.

Clinical Discussion—Pernio, also known as chilblains, is characterized by cold-induced erythematous patches and plaques, pain, and pruritus on the affected skin.¹⁸ Bullae and ulceration can be seen in more severe and chronic cases.¹⁹ Pernio most commonly is seen in young women but also can be seen in children, men, and older adults. It usually occurs on the tips of toes but also may affect the fingers, nose, and ears. It typically is observed in cold and damp conditions and is thought to be caused by an inflammatory response to vasospasms in the setting of nonfreezing cold. Acute pernio typically resolves after a few weeks; however, it also can persist in a chronic form after repeated cold exposure.¹⁸

Predisposing factors include excessive cold exposure, connective tissue disease, hematologic malignancy, antiphospholipid antibodies in adults, and anorexia nervosa in children.^18,20,21 More recently, perniolike lesions have been associated with prior SARS-CoV-2 infection.²² Histologically, pernio is characterized by a perivascular lymphocytic infiltrate and dermal edema.²³ Cold avoidance, warming, drying, and smoking cessation are primary treatments, while vasodilating medications such as nifedipine have been used with success in more resistant cases.^20,24

Although the prognosis generally is excellent, this condition also can be career limiting for military service members. If it resolves with no residual effects, patients can expect to continue their service; however, if it persists and limits their activity or ability to deploy, a medical retirement may be indicated.^11-14

Raynaud Phenomenon

Raynaud phenomenon (also known as Raynaud’s) is characterized by cold-induced extremity triphasic color changes—initial blanching and pallor that transitions to cyanosis and finally erythema with associated pain during the recovery stage. The fingers are the most commonly involved appendages and can have a symmetric distribution, but RP also has been observed on the feet, lips, nose, and ears. In severe cases, it can cause ulceration.²⁵ The prevalence of RP may be as high as 5% in the general population.²⁶ It more commonly is primary or idiopathic with no underlying cause or secondary with an associated underlying systemic disease.

Cold-induced vasoconstriction is a normal physiologic response, but in RP, the response becomes a vasospasm and is pathological. Autoimmune and connective tissue diseases often are associated with secondary RP. Other risk factors include female sex, smoking, family history in a first-degree relative, and certain medications.²⁵ A study in northern Sweden also identified a history of frostbite as a risk factor for the development of RP.²⁷ This condition can notably restrict mobility and deployability of affected service members as well as the types of manual tasks that they may be required to perform. As such, this condition can be disqualifying for military service.¹¹

Many patients improve with conservative treatment consisting of cold avoidance, smoking cessation, and avoidance of medications that worsen the vasospasm; however, some patients develop pain and chronic disease, which can become so severe and ischemic that digital loss is threatened.²⁵ When needed, calcium channel blockers commonly are used for treatment and can be used prophylactically to reduce flare rates and severity of disease. If this class of medications is ineffective or is not tolerated, there are other medications and treatments to consider, which are beyond the scope of this article.²⁵

Cold Urticaria

Cold urticaria is a subset of physical urticaria in which symptoms occur in response to a cutaneous cold stimulus. It can be primary or secondary, with potential underlying causes including cryoglobulinemia, infections, and some medications. Systemic involvement is possible with extensive cold contact and can include severe anaphylaxis. This condition is diagnosed using a cold stimulation test. Cold exposure avoidance and second-generation antihistamines are considered first-line treatment. Because anaphylaxis is possible, patients should be given an epinephrine pen and should be instructed to avoid swimming in cold water.²⁸ Cold urticaria is disqualifying for military service.¹¹

A 2013 case report described a 29-year-old woman on active duty in the US Air Force whose presenting symptoms included urticaria on the exposed skin on the arms when doing physical training in the rain.²⁹ In this case, secondary causes were eliminated, and she was diagnosed with primary acquired cold urticaria. This patient was eventually medically discharged from the air force because management with antihistamines failed, and her symptoms limited her ability to function in even mildly cold environments.²⁹

Final Thoughts

An understanding of cold weather injuries and other dermatologic conditions that may be flared by cold exposure is important for a medically ready military force, as there are implications for accession, training, and combat operations. Although the focus of this article has been on the military, these conditions also are seen in civilian medicine in patient populations routinely exposed to cold weather. This becomes especially pertinent in high-risk patients such as extreme athletes, homeless individuals, or those who have other predisposing characteristics such as chronic alcohol use. Appropriate cold weather gear, training, and deliberate mission or activity planning are important interventions in preventing cutaneous cold weather injuries within the military.

Hidradenitis suppurativa (HS) is a debilitating chronic condition that often is recalcitrant to first-line treatments, and mechanisms underlying its pathology remain unclear. Existing data suggest a multifactorial etiology with different pathophysiologic contributors, including genetic, hormonal, and immune dysregulation factors. At this time, only one medication (adalimumab) is US Food and Drug Administration approved for HS, but multiple medical and procedural therapies are available.¹ Herein, we discuss the concept of treatment stacking, or the combination of unique therapeutic modalities—an approach we believe is key to optimizing management of HS patients.

Stacking Treatments for HS

Unlike psoriasis, in which a single biologic agent may provide 100% clearance (psoriasis area and severity index 100 [PASI 100]) without adjuvant treatment,^2,3 the field of HS currently lacks medications that are efficacious to that degree of success as monotherapy. In HS, the benchmark for a positive treatment outcome is Hidradenitis Suppurativa Clinical Response 50 (HiSCR50),⁴ a 50% reduction in inflammatory lesion count—a far less stringent marker for disease improvement. Thus, providers should design HS treatment regimens with a model of combining therapies and shift away from monotherapy. Targeting different pathophysiologic pathways by stacking multiple treatments may provide synergistic benefits for HS patients. Treatment stacking is a familiar concept in acne; for instance, patients who benefit tremendously from isotretinoin may still require a hormone-modulating treatment (eg, spironolactone) to attain optimal results.

Adherence to a rigid treatment algorithm based on disease severity limits the potential to create comprehensive regimens that account for unique patient characteristics and clinical manifestations. When evaluating an HS patient, providers should systematically consider each pathophysiologic factor and target the ones that appear to be most involved in that particular patient. The North American HS guidelines illustrate this point by supporting use of several treatments across different Hurley stages, such as recommending hormonal treatment in patients with Hurley stages 1, 2, or 3.¹ Of note, treatment stacking also includes procedural therapies. Surgeons typically prefer a patient’s disease management to be optimized prior to surgery, including reduced drainage and inflammation. In addition, even after surgery, patients often still require medical management to prevent continued disease worsening.

Treatment Pathways for HS

A multimodal approach with treatment stacking (Figure) can be useful to all HS patients, from those with the mildest to the most severe disease. Modifiable pathophysiologic factors and examples of their targeted treatments include (1) follicular occlusion (eg, oral retinoids), (2) metabolic dysfunction (eg, metformin), (3) hormones (eg, oral contraceptive pills, spironolactone, finasteride), (4) dysbiosis (eg, antibiotics such as clindamycin and rifampin combination therapy), (5) immune dysregulation (eg, biologic agents), and (6) friction/irritation (eg, weight loss, clothing recommendations).

Combining treatments from different pathways enables potentiation of individual treatment efficacies. A female patient with only a few HS nodules that flare with menses may be well controlled with spironolactone as her only systemic agent; however, she still may benefit from use of an antiseptic wash, topical clindamycin, and lifestyle changes such as weight loss and reduction of mechanical irritation. A patient with severe recalcitrant HS could notably benefit from concomitant biologic, systemic antibiotic, and hormonal/metabolic treatments. If disease control is still inadequate, agents within the same class can be switched (eg, choosing a different biologic) or other disease-modifying agents such as colchicine also can be added. The goal is to create an effective treatment toolbox with therapies targeting different pathophysiologic arms of HS and working together in synergy. Each tool can be refined by modifying dosing frequency and duration of use to strive for optimal response. At this time, the literature on HS combination therapy is sparse. A retrospective study of 31 patients reported promising combinations, including isotretinoin with spironolactone for mild disease, isotretinoin or doxycycline with adalimumab for moderate disease, and cyclosporine with adalimumab for severe disease.⁵ Larger prospective studies on clinical response to different combination regimens are warranted.

Optimizing Therapy for HS and Its Comorbidities

Additional considerations may further optimize treatment plans. Some therapies benefit all patients; for example, providers should counsel all HS patients on healthy weight management, optimized clothing choices,⁶ and friction reduction in the intertriginous folds. Providers also may consider adding therapies with faster onset of efficacy as a bridge to long-term, slower-onset therapies. For instance, female HS patients with menstrual flares who are prescribed spironolactone also may benefit from a course of systemic antibiotics, which typically provides more prompt relief. Treatment regimens also can concomitantly treat HS and its comorbidities.⁷ For example, metformin serves a dual purpose in HS patients with diabetes mellitus, and adalimumab in patients with both HS and inflammatory bowel disease.

Final Thoughts

The last decade has seen tremendous growth in HS research⁸ coupled with a remarkable expansion in the therapeutic pipeline.⁹ However, currently no single therapy for HS can guarantee satisfactory disease remission or durability of remission. The contrast between clinical trials and real-world practice should be acknowledged; the former often is restrictive in design with monotherapy and allowance of very limited concomitant treatments, such as topical or oral antibiotics. This limits our ability to draw conclusions regarding the additive synergistic potential of different therapeutics in combination. In clinical practice, we are not restricted by monotherapy trial protocols. As we await new tools, treatment stacking allows for creating a framework to best utilize the tools that are available to us.

Although HS has continued to affect the lives of many patients, improved understanding of underlying pathophysiology and a well-placed sense of urgency from all stakeholders (ie, patients, clinicians, researchers, industry partners) has pushed this field forward. Until our therapeutic armamentarium has expanded to include highly efficacious monotherapy options, providers should consider treatment stacking for every HS patient.

Hidradenitis suppurativa (HS) is a debilitating chronic condition that often is recalcitrant to first-line treatments, and mechanisms underlying its pathology remain unclear. Existing data suggest a multifactorial etiology with different pathophysiologic contributors, including genetic, hormonal, and immune dysregulation factors. At this time, only one medication (adalimumab) is US Food and Drug Administration approved for HS, but multiple medical and procedural therapies are available.¹ Herein, we discuss the concept of treatment stacking, or the combination of unique therapeutic modalities—an approach we believe is key to optimizing management of HS patients.

Stacking Treatments for HS

Unlike psoriasis, in which a single biologic agent may provide 100% clearance (psoriasis area and severity index 100 [PASI 100]) without adjuvant treatment,^2,3 the field of HS currently lacks medications that are efficacious to that degree of success as monotherapy. In HS, the benchmark for a positive treatment outcome is Hidradenitis Suppurativa Clinical Response 50 (HiSCR50),⁴ a 50% reduction in inflammatory lesion count—a far less stringent marker for disease improvement. Thus, providers should design HS treatment regimens with a model of combining therapies and shift away from monotherapy. Targeting different pathophysiologic pathways by stacking multiple treatments may provide synergistic benefits for HS patients. Treatment stacking is a familiar concept in acne; for instance, patients who benefit tremendously from isotretinoin may still require a hormone-modulating treatment (eg, spironolactone) to attain optimal results.

Adherence to a rigid treatment algorithm based on disease severity limits the potential to create comprehensive regimens that account for unique patient characteristics and clinical manifestations. When evaluating an HS patient, providers should systematically consider each pathophysiologic factor and target the ones that appear to be most involved in that particular patient. The North American HS guidelines illustrate this point by supporting use of several treatments across different Hurley stages, such as recommending hormonal treatment in patients with Hurley stages 1, 2, or 3.¹ Of note, treatment stacking also includes procedural therapies. Surgeons typically prefer a patient’s disease management to be optimized prior to surgery, including reduced drainage and inflammation. In addition, even after surgery, patients often still require medical management to prevent continued disease worsening.

Treatment Pathways for HS

A multimodal approach with treatment stacking (Figure) can be useful to all HS patients, from those with the mildest to the most severe disease. Modifiable pathophysiologic factors and examples of their targeted treatments include (1) follicular occlusion (eg, oral retinoids), (2) metabolic dysfunction (eg, metformin), (3) hormones (eg, oral contraceptive pills, spironolactone, finasteride), (4) dysbiosis (eg, antibiotics such as clindamycin and rifampin combination therapy), (5) immune dysregulation (eg, biologic agents), and (6) friction/irritation (eg, weight loss, clothing recommendations).

Combining treatments from different pathways enables potentiation of individual treatment efficacies. A female patient with only a few HS nodules that flare with menses may be well controlled with spironolactone as her only systemic agent; however, she still may benefit from use of an antiseptic wash, topical clindamycin, and lifestyle changes such as weight loss and reduction of mechanical irritation. A patient with severe recalcitrant HS could notably benefit from concomitant biologic, systemic antibiotic, and hormonal/metabolic treatments. If disease control is still inadequate, agents within the same class can be switched (eg, choosing a different biologic) or other disease-modifying agents such as colchicine also can be added. The goal is to create an effective treatment toolbox with therapies targeting different pathophysiologic arms of HS and working together in synergy. Each tool can be refined by modifying dosing frequency and duration of use to strive for optimal response. At this time, the literature on HS combination therapy is sparse. A retrospective study of 31 patients reported promising combinations, including isotretinoin with spironolactone for mild disease, isotretinoin or doxycycline with adalimumab for moderate disease, and cyclosporine with adalimumab for severe disease.⁵ Larger prospective studies on clinical response to different combination regimens are warranted.

Optimizing Therapy for HS and Its Comorbidities

Additional considerations may further optimize treatment plans. Some therapies benefit all patients; for example, providers should counsel all HS patients on healthy weight management, optimized clothing choices,⁶ and friction reduction in the intertriginous folds. Providers also may consider adding therapies with faster onset of efficacy as a bridge to long-term, slower-onset therapies. For instance, female HS patients with menstrual flares who are prescribed spironolactone also may benefit from a course of systemic antibiotics, which typically provides more prompt relief. Treatment regimens also can concomitantly treat HS and its comorbidities.⁷ For example, metformin serves a dual purpose in HS patients with diabetes mellitus, and adalimumab in patients with both HS and inflammatory bowel disease.

Final Thoughts

The last decade has seen tremendous growth in HS research⁸ coupled with a remarkable expansion in the therapeutic pipeline.⁹ However, currently no single therapy for HS can guarantee satisfactory disease remission or durability of remission. The contrast between clinical trials and real-world practice should be acknowledged; the former often is restrictive in design with monotherapy and allowance of very limited concomitant treatments, such as topical or oral antibiotics. This limits our ability to draw conclusions regarding the additive synergistic potential of different therapeutics in combination. In clinical practice, we are not restricted by monotherapy trial protocols. As we await new tools, treatment stacking allows for creating a framework to best utilize the tools that are available to us.

Although HS has continued to affect the lives of many patients, improved understanding of underlying pathophysiology and a well-placed sense of urgency from all stakeholders (ie, patients, clinicians, researchers, industry partners) has pushed this field forward. Until our therapeutic armamentarium has expanded to include highly efficacious monotherapy options, providers should consider treatment stacking for every HS patient.

Hidradenitis suppurativa (HS) is a debilitating chronic condition that often is recalcitrant to first-line treatments, and mechanisms underlying its pathology remain unclear. Existing data suggest a multifactorial etiology with different pathophysiologic contributors, including genetic, hormonal, and immune dysregulation factors. At this time, only one medication (adalimumab) is US Food and Drug Administration approved for HS, but multiple medical and procedural therapies are available.¹ Herein, we discuss the concept of treatment stacking, or the combination of unique therapeutic modalities—an approach we believe is key to optimizing management of HS patients.

Stacking Treatments for HS

Unlike psoriasis, in which a single biologic agent may provide 100% clearance (psoriasis area and severity index 100 [PASI 100]) without adjuvant treatment,^2,3 the field of HS currently lacks medications that are efficacious to that degree of success as monotherapy. In HS, the benchmark for a positive treatment outcome is Hidradenitis Suppurativa Clinical Response 50 (HiSCR50),⁴ a 50% reduction in inflammatory lesion count—a far less stringent marker for disease improvement. Thus, providers should design HS treatment regimens with a model of combining therapies and shift away from monotherapy. Targeting different pathophysiologic pathways by stacking multiple treatments may provide synergistic benefits for HS patients. Treatment stacking is a familiar concept in acne; for instance, patients who benefit tremendously from isotretinoin may still require a hormone-modulating treatment (eg, spironolactone) to attain optimal results.

Adherence to a rigid treatment algorithm based on disease severity limits the potential to create comprehensive regimens that account for unique patient characteristics and clinical manifestations. When evaluating an HS patient, providers should systematically consider each pathophysiologic factor and target the ones that appear to be most involved in that particular patient. The North American HS guidelines illustrate this point by supporting use of several treatments across different Hurley stages, such as recommending hormonal treatment in patients with Hurley stages 1, 2, or 3.¹ Of note, treatment stacking also includes procedural therapies. Surgeons typically prefer a patient’s disease management to be optimized prior to surgery, including reduced drainage and inflammation. In addition, even after surgery, patients often still require medical management to prevent continued disease worsening.

Treatment Pathways for HS

A multimodal approach with treatment stacking (Figure) can be useful to all HS patients, from those with the mildest to the most severe disease. Modifiable pathophysiologic factors and examples of their targeted treatments include (1) follicular occlusion (eg, oral retinoids), (2) metabolic dysfunction (eg, metformin), (3) hormones (eg, oral contraceptive pills, spironolactone, finasteride), (4) dysbiosis (eg, antibiotics such as clindamycin and rifampin combination therapy), (5) immune dysregulation (eg, biologic agents), and (6) friction/irritation (eg, weight loss, clothing recommendations).

Combining treatments from different pathways enables potentiation of individual treatment efficacies. A female patient with only a few HS nodules that flare with menses may be well controlled with spironolactone as her only systemic agent; however, she still may benefit from use of an antiseptic wash, topical clindamycin, and lifestyle changes such as weight loss and reduction of mechanical irritation. A patient with severe recalcitrant HS could notably benefit from concomitant biologic, systemic antibiotic, and hormonal/metabolic treatments. If disease control is still inadequate, agents within the same class can be switched (eg, choosing a different biologic) or other disease-modifying agents such as colchicine also can be added. The goal is to create an effective treatment toolbox with therapies targeting different pathophysiologic arms of HS and working together in synergy. Each tool can be refined by modifying dosing frequency and duration of use to strive for optimal response. At this time, the literature on HS combination therapy is sparse. A retrospective study of 31 patients reported promising combinations, including isotretinoin with spironolactone for mild disease, isotretinoin or doxycycline with adalimumab for moderate disease, and cyclosporine with adalimumab for severe disease.⁵ Larger prospective studies on clinical response to different combination regimens are warranted.

Optimizing Therapy for HS and Its Comorbidities

Additional considerations may further optimize treatment plans. Some therapies benefit all patients; for example, providers should counsel all HS patients on healthy weight management, optimized clothing choices,⁶ and friction reduction in the intertriginous folds. Providers also may consider adding therapies with faster onset of efficacy as a bridge to long-term, slower-onset therapies. For instance, female HS patients with menstrual flares who are prescribed spironolactone also may benefit from a course of systemic antibiotics, which typically provides more prompt relief. Treatment regimens also can concomitantly treat HS and its comorbidities.⁷ For example, metformin serves a dual purpose in HS patients with diabetes mellitus, and adalimumab in patients with both HS and inflammatory bowel disease.

Final Thoughts

The last decade has seen tremendous growth in HS research⁸ coupled with a remarkable expansion in the therapeutic pipeline.⁹ However, currently no single therapy for HS can guarantee satisfactory disease remission or durability of remission. The contrast between clinical trials and real-world practice should be acknowledged; the former often is restrictive in design with monotherapy and allowance of very limited concomitant treatments, such as topical or oral antibiotics. This limits our ability to draw conclusions regarding the additive synergistic potential of different therapeutics in combination. In clinical practice, we are not restricted by monotherapy trial protocols. As we await new tools, treatment stacking allows for creating a framework to best utilize the tools that are available to us.

Although HS has continued to affect the lives of many patients, improved understanding of underlying pathophysiology and a well-placed sense of urgency from all stakeholders (ie, patients, clinicians, researchers, industry partners) has pushed this field forward. Until our therapeutic armamentarium has expanded to include highly efficacious monotherapy options, providers should consider treatment stacking for every HS patient.

Cutaneous amyloidosis encompasses a variety of clinical presentations. Primary localized cutaneous amyloidosis comprises lichen amyloidosis, macular amyloidosis, and nodular amyloidosis.¹ Macular and lichen amyloidosis result from keratin deposits, while nodular amyloidosis results from cutaneous infiltration of plasma cells.² Primary systemic amyloidosis is due to a plasma cell dyscrasia, particularly multiple myeloma, while secondary systemic amyloidosis occurs in the setting of restrictive cardiomyopathy, congestive heart failure, renal dysfunction, or chronic inflammation, as seen with rheumatoid arthritis, tuberculosis, and various autoinflammatory disorders.² Plasma cell proliferative disorders are associated with various skin disorders, which may result from aggregated misfolded monoclonal immunoglobulins, indicating light chain–related systemic amyloidosis. Mucocutaneous lesions can occur in 30% to 40% of cases of primary systemic amyloidosis and may present as purpura, ecchymoses, waxy thickening, plaques, subcutaneous nodules, and/or bullae.^3,4 When blistering is present, the differential diagnosis is broad and includes autoimmune bullous disease, drug eruptions, enoxaparin-induced bullous hemorrhagic dermatosis, deposition diseases, allergic contact dermatitis, bullous cellulitis, bullous bite reactions, neutrophilic dermatosis, and bullous lichen sclerosus.⁵ Herein, we present a case of a woman with a bullous skin eruption who eventually was diagnosed with bullous amyloidosis subsequent to a diagnosis of multiple myeloma.

Case Report

A 70-year-old woman presented to our dermatology clinic for evaluation of well-demarcated, hemorrhagic, flaccid vesicles and focal erosions with a rim of erythema on the distal forearms and hands. A shave biopsy from the right forearm showed cell-poor subepidermal vesicular dermatitis. Enzyme-linked immunosorbent assays for bullous pemphigoid antigens 1 and 2 as well as urinary porphyrins were negative. Direct immunofluorescence showed granular IgM at the basement membrane zone around vessels and cytoid bodies. At this time, a preliminary diagnosis of pseudoporphyria was suspected, though no classic medications (eg, nonsteroidal anti-inflammatory drugs, furosemide, antibiotics) or exogenous trigger factors (eg, UV light exposure, dialysis) were temporally related. Three months later, the patient presented with a large hemorrhagic bulla on the distal left forearm (Figure 1) and healing erosions on the dorsal fingers and upper back. Clobetasol ointment was initiated, as an autoimmune bullous dermatosis was suspected.

Approximately 1 year after she was first seen in our outpatient clinic, the patient was hospitalized for induction of chemotherapy—cyclophosphamide, bortezomib, and dexamethasone—for a new diagnosis of stage III multiple myeloma. A workup for back pain revealed multiple compression fractures and a plasma cell neoplasm with elevated λ light chains, which was confirmed with a bone marrow biopsy. During an inpatient dermatology consultation, we noted the development of intraoral hemorrhagic vesicles and worsening generalization of the hemorrhagic bullae, with healing erosions and intact hemorrhagic bullae on the dorsal hands, fingers (Figure 2), and upper back.

A repeat biopsy displayed bullous amyloidosis. Histopathologic examination revealed an ulcerated subepidermal blister with fibrin deposition at the ulcer base. A periadnexal, scant, eosinophilic deposition with extravasated red blood cells was appreciated. Amorphous eosinophilic deposits were found within the detached fragment of the epidermis and inflammatory infiltrate. A Congo red stain highlighted these areas with a salmon pink–colored material. Congo red staining showed a moderate amount of pale, apple green, birefringent deposit within these areas on polarized light examination.

A few months later, the patient was re-admitted, and the amount of skin detachment prompted the primary team to ask for another consultation. Although the extensive skin sloughing resembled toxic epidermal necrolysis, a repeat biopsy confirmed bullous amyloidosis.

Comment

Amyloidosis Histopathology—Amyloidoses represent a wide array of disorders with deposition of β-pleated sheets or amyloid fibrils, often with cutaneous manifestations.^2,3 Primary systemic amyloidosis has been associated with underlying dyscrasia or multiple myeloma.⁶ In such cases, the skin lesions of multiple myeloma may result from a collection of misfolded monoclonal immunoglobulins or their fragments, as in light chain–related systemic amyloidosis.³ Histopathologically, both systemic and cutaneous amyloidosis appear similar and display deposition of amorphous, eosinophilic, fissured amyloid material in the dermis. Congo red stains the material orange-red and will display a characteristic apple green birefringence under polarized light.⁴ Although bullous amyloid lesions are rare, the cutaneous forms of these lesions can be an important sign of plasma cell dyscrasia.⁷

Presentation of Bullous Amyloidosis—Bullous manifestations rarely have been noted in the primary cutaneous forms of amyloidosis.^5,8,9 Importantly, cutaneous blistering more often is linked to systemic forms of amyloidosis with multiorgan involvement, including primary systemic and myeloma-associated amyloidosis.^5,10 However, patients with localized bullous cutaneous amyloidosis without systemic involvement also have been seen.^10,11 Bullae may occur at any time, with contents that frequently are hemorrhagic due to capillary fragility.^12,13 Bullous manifestations raise the differential diagnoses of bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, porphyria cutanea tarda, pseudoporphyria, bullous drug eruption, bullous eruption of renal dialysis, or bullous lupus erythematosus.^5,13-17

In our patient, the acral distribution of bullae, presence of hemorrhage, chronicity of symptoms, and negative enzyme-linked immunosorbent assay initially suggested a diagnosis of pseudoporphyria. However, the presence of intraoral hemorrhagic vesicles and subsequent confirmatory pathology aided in differentiating bullous amyloidosis from pseudoporphyria. Nodular localized primary cutaneous amyloidosis, a rare form of skin-restricted amyloidoses, can coexist with bullous lesions. Of note, reported cases of nodular localized primary cutaneous amyloidosis did not result in development of multiple myeloma.^5,10

Bullae are located either subepidermally or intradermally, and bullous lesions of cutaneous amyloidosis typically demonstrate subepidermal or superficial intradermal clefting on light microscopy.^5,10,12 Histopathology of bullous amyloidosis shows intradermal or subepidermal blister formation and amorphous eosinophilic material showing apple green birefringence with Congo red staining deposited in the dermis and/or around the adipocytes and blood vessel walls.^12,18-20 In prior cases, direct immunofluorescence of bullous amyloidosis revealed absent immunoglobulin (IgG, IgA, IgM) or complement (C3 and C9) deposits in the basement membrane zone or dermis.^13,21,22 In these cases, electron microscopy was useful in diagnosis, as it showed the presence of amyloid deposits.^21,22

Cause of Bullae—Various mechanisms are thought to trigger the blister formation in amyloidosis. Bullae created from trauma or friction often present as tense painful blisters that commonly are hemorrhagic.^10,23 Amyloid deposits in the walls of blood vessels and the affinity of dermal amyloid in blood vessel walls to surrounding collagen likely leads to increased fragility of capillaries and the dermal matrix, hemorrhagic tendency, and infrapapillary blisters, thus creating hemorrhagic bullous eruptions.^24,25 Specifically, close proximity of immunoglobulin-derived amyloid oligomers to epidermal keratinocytes may be toxic and therefore could trigger subepidermal bullous change.⁵ Additionally, alteration in the physicochemical properties of the amyloidal protein might explain bullous eruption.⁹ Trauma or rubbing of the hands and feet may precipitate the acral blister formation in bullous amyloidosis.^5,11

Due to deposition of these amyloid fibrils, skin bleeding in these patients is called amyloid or pinch purpura. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal tract bleeding.²⁶ Destruction of the lamina densa and widening of the intercellular space between keratinocytes by amyloid globules induce skin fragility.¹¹

Although uncommon, various cases of bullous amyloidosis have been reported in the literature. Multiple myeloma patients represent the majority of those reported to have bullous amyloidosis.^{6,7,13,24,27-30} Plasmacytoma-associated bullous amyloid purpura and paraproteinemia also have been noted.²⁵ Multiple myeloma with secondary AL amyloidosis has been seen with amyloid purpura and atraumatic ecchymoses of the face, highlighting the hemorrhage noted in these patients.²⁶

Management of Amyloidosis—Various treatment options have been attempted for primary cutaneous amyloidosis, including oral retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D₃ analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser treatment, and phototherapy.¹ There is no clear consensus for therapeutic modalities except for treating the underlying plasma cell dyscrasia in primary systemic amyloidosis.

Conclusion

We report the case of a patient displaying signs of pseudoporphyria that ultimately proved to be bullous amyloidosis, or what we termed pseudopseudoporphyria. Bullous amyloidosis should be considered in the differential diagnoses of hemorrhagic bullous skin eruptions. Particular attention should be given to a systemic workup for multiple myeloma when hemorrhagic vesicles/bullae are chronic and coexist with purpura, angina bullosa hemorrhagica, fatigue/weight loss, and/or macroglossia.

Cutaneous amyloidosis encompasses a variety of clinical presentations. Primary localized cutaneous amyloidosis comprises lichen amyloidosis, macular amyloidosis, and nodular amyloidosis.¹ Macular and lichen amyloidosis result from keratin deposits, while nodular amyloidosis results from cutaneous infiltration of plasma cells.² Primary systemic amyloidosis is due to a plasma cell dyscrasia, particularly multiple myeloma, while secondary systemic amyloidosis occurs in the setting of restrictive cardiomyopathy, congestive heart failure, renal dysfunction, or chronic inflammation, as seen with rheumatoid arthritis, tuberculosis, and various autoinflammatory disorders.² Plasma cell proliferative disorders are associated with various skin disorders, which may result from aggregated misfolded monoclonal immunoglobulins, indicating light chain–related systemic amyloidosis. Mucocutaneous lesions can occur in 30% to 40% of cases of primary systemic amyloidosis and may present as purpura, ecchymoses, waxy thickening, plaques, subcutaneous nodules, and/or bullae.^3,4 When blistering is present, the differential diagnosis is broad and includes autoimmune bullous disease, drug eruptions, enoxaparin-induced bullous hemorrhagic dermatosis, deposition diseases, allergic contact dermatitis, bullous cellulitis, bullous bite reactions, neutrophilic dermatosis, and bullous lichen sclerosus.⁵ Herein, we present a case of a woman with a bullous skin eruption who eventually was diagnosed with bullous amyloidosis subsequent to a diagnosis of multiple myeloma.

Case Report

A 70-year-old woman presented to our dermatology clinic for evaluation of well-demarcated, hemorrhagic, flaccid vesicles and focal erosions with a rim of erythema on the distal forearms and hands. A shave biopsy from the right forearm showed cell-poor subepidermal vesicular dermatitis. Enzyme-linked immunosorbent assays for bullous pemphigoid antigens 1 and 2 as well as urinary porphyrins were negative. Direct immunofluorescence showed granular IgM at the basement membrane zone around vessels and cytoid bodies. At this time, a preliminary diagnosis of pseudoporphyria was suspected, though no classic medications (eg, nonsteroidal anti-inflammatory drugs, furosemide, antibiotics) or exogenous trigger factors (eg, UV light exposure, dialysis) were temporally related. Three months later, the patient presented with a large hemorrhagic bulla on the distal left forearm (Figure 1) and healing erosions on the dorsal fingers and upper back. Clobetasol ointment was initiated, as an autoimmune bullous dermatosis was suspected.

Approximately 1 year after she was first seen in our outpatient clinic, the patient was hospitalized for induction of chemotherapy—cyclophosphamide, bortezomib, and dexamethasone—for a new diagnosis of stage III multiple myeloma. A workup for back pain revealed multiple compression fractures and a plasma cell neoplasm with elevated λ light chains, which was confirmed with a bone marrow biopsy. During an inpatient dermatology consultation, we noted the development of intraoral hemorrhagic vesicles and worsening generalization of the hemorrhagic bullae, with healing erosions and intact hemorrhagic bullae on the dorsal hands, fingers (Figure 2), and upper back.

A repeat biopsy displayed bullous amyloidosis. Histopathologic examination revealed an ulcerated subepidermal blister with fibrin deposition at the ulcer base. A periadnexal, scant, eosinophilic deposition with extravasated red blood cells was appreciated. Amorphous eosinophilic deposits were found within the detached fragment of the epidermis and inflammatory infiltrate. A Congo red stain highlighted these areas with a salmon pink–colored material. Congo red staining showed a moderate amount of pale, apple green, birefringent deposit within these areas on polarized light examination.

A few months later, the patient was re-admitted, and the amount of skin detachment prompted the primary team to ask for another consultation. Although the extensive skin sloughing resembled toxic epidermal necrolysis, a repeat biopsy confirmed bullous amyloidosis.

Comment

Amyloidosis Histopathology—Amyloidoses represent a wide array of disorders with deposition of β-pleated sheets or amyloid fibrils, often with cutaneous manifestations.^2,3 Primary systemic amyloidosis has been associated with underlying dyscrasia or multiple myeloma.⁶ In such cases, the skin lesions of multiple myeloma may result from a collection of misfolded monoclonal immunoglobulins or their fragments, as in light chain–related systemic amyloidosis.³ Histopathologically, both systemic and cutaneous amyloidosis appear similar and display deposition of amorphous, eosinophilic, fissured amyloid material in the dermis. Congo red stains the material orange-red and will display a characteristic apple green birefringence under polarized light.⁴ Although bullous amyloid lesions are rare, the cutaneous forms of these lesions can be an important sign of plasma cell dyscrasia.⁷

Presentation of Bullous Amyloidosis—Bullous manifestations rarely have been noted in the primary cutaneous forms of amyloidosis.^5,8,9 Importantly, cutaneous blistering more often is linked to systemic forms of amyloidosis with multiorgan involvement, including primary systemic and myeloma-associated amyloidosis.^5,10 However, patients with localized bullous cutaneous amyloidosis without systemic involvement also have been seen.^10,11 Bullae may occur at any time, with contents that frequently are hemorrhagic due to capillary fragility.^12,13 Bullous manifestations raise the differential diagnoses of bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, porphyria cutanea tarda, pseudoporphyria, bullous drug eruption, bullous eruption of renal dialysis, or bullous lupus erythematosus.^5,13-17

In our patient, the acral distribution of bullae, presence of hemorrhage, chronicity of symptoms, and negative enzyme-linked immunosorbent assay initially suggested a diagnosis of pseudoporphyria. However, the presence of intraoral hemorrhagic vesicles and subsequent confirmatory pathology aided in differentiating bullous amyloidosis from pseudoporphyria. Nodular localized primary cutaneous amyloidosis, a rare form of skin-restricted amyloidoses, can coexist with bullous lesions. Of note, reported cases of nodular localized primary cutaneous amyloidosis did not result in development of multiple myeloma.^5,10

Bullae are located either subepidermally or intradermally, and bullous lesions of cutaneous amyloidosis typically demonstrate subepidermal or superficial intradermal clefting on light microscopy.^5,10,12 Histopathology of bullous amyloidosis shows intradermal or subepidermal blister formation and amorphous eosinophilic material showing apple green birefringence with Congo red staining deposited in the dermis and/or around the adipocytes and blood vessel walls.^12,18-20 In prior cases, direct immunofluorescence of bullous amyloidosis revealed absent immunoglobulin (IgG, IgA, IgM) or complement (C3 and C9) deposits in the basement membrane zone or dermis.^13,21,22 In these cases, electron microscopy was useful in diagnosis, as it showed the presence of amyloid deposits.^21,22

Cause of Bullae—Various mechanisms are thought to trigger the blister formation in amyloidosis. Bullae created from trauma or friction often present as tense painful blisters that commonly are hemorrhagic.^10,23 Amyloid deposits in the walls of blood vessels and the affinity of dermal amyloid in blood vessel walls to surrounding collagen likely leads to increased fragility of capillaries and the dermal matrix, hemorrhagic tendency, and infrapapillary blisters, thus creating hemorrhagic bullous eruptions.^24,25 Specifically, close proximity of immunoglobulin-derived amyloid oligomers to epidermal keratinocytes may be toxic and therefore could trigger subepidermal bullous change.⁵ Additionally, alteration in the physicochemical properties of the amyloidal protein might explain bullous eruption.⁹ Trauma or rubbing of the hands and feet may precipitate the acral blister formation in bullous amyloidosis.^5,11

Due to deposition of these amyloid fibrils, skin bleeding in these patients is called amyloid or pinch purpura. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal tract bleeding.²⁶ Destruction of the lamina densa and widening of the intercellular space between keratinocytes by amyloid globules induce skin fragility.¹¹

Although uncommon, various cases of bullous amyloidosis have been reported in the literature. Multiple myeloma patients represent the majority of those reported to have bullous amyloidosis.^{6,7,13,24,27-30} Plasmacytoma-associated bullous amyloid purpura and paraproteinemia also have been noted.²⁵ Multiple myeloma with secondary AL amyloidosis has been seen with amyloid purpura and atraumatic ecchymoses of the face, highlighting the hemorrhage noted in these patients.²⁶

Management of Amyloidosis—Various treatment options have been attempted for primary cutaneous amyloidosis, including oral retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D₃ analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser treatment, and phototherapy.¹ There is no clear consensus for therapeutic modalities except for treating the underlying plasma cell dyscrasia in primary systemic amyloidosis.

Conclusion

We report the case of a patient displaying signs of pseudoporphyria that ultimately proved to be bullous amyloidosis, or what we termed pseudopseudoporphyria. Bullous amyloidosis should be considered in the differential diagnoses of hemorrhagic bullous skin eruptions. Particular attention should be given to a systemic workup for multiple myeloma when hemorrhagic vesicles/bullae are chronic and coexist with purpura, angina bullosa hemorrhagica, fatigue/weight loss, and/or macroglossia.

Cutaneous amyloidosis encompasses a variety of clinical presentations. Primary localized cutaneous amyloidosis comprises lichen amyloidosis, macular amyloidosis, and nodular amyloidosis.¹ Macular and lichen amyloidosis result from keratin deposits, while nodular amyloidosis results from cutaneous infiltration of plasma cells.² Primary systemic amyloidosis is due to a plasma cell dyscrasia, particularly multiple myeloma, while secondary systemic amyloidosis occurs in the setting of restrictive cardiomyopathy, congestive heart failure, renal dysfunction, or chronic inflammation, as seen with rheumatoid arthritis, tuberculosis, and various autoinflammatory disorders.² Plasma cell proliferative disorders are associated with various skin disorders, which may result from aggregated misfolded monoclonal immunoglobulins, indicating light chain–related systemic amyloidosis. Mucocutaneous lesions can occur in 30% to 40% of cases of primary systemic amyloidosis and may present as purpura, ecchymoses, waxy thickening, plaques, subcutaneous nodules, and/or bullae.^3,4 When blistering is present, the differential diagnosis is broad and includes autoimmune bullous disease, drug eruptions, enoxaparin-induced bullous hemorrhagic dermatosis, deposition diseases, allergic contact dermatitis, bullous cellulitis, bullous bite reactions, neutrophilic dermatosis, and bullous lichen sclerosus.⁵ Herein, we present a case of a woman with a bullous skin eruption who eventually was diagnosed with bullous amyloidosis subsequent to a diagnosis of multiple myeloma.

Case Report

A 70-year-old woman presented to our dermatology clinic for evaluation of well-demarcated, hemorrhagic, flaccid vesicles and focal erosions with a rim of erythema on the distal forearms and hands. A shave biopsy from the right forearm showed cell-poor subepidermal vesicular dermatitis. Enzyme-linked immunosorbent assays for bullous pemphigoid antigens 1 and 2 as well as urinary porphyrins were negative. Direct immunofluorescence showed granular IgM at the basement membrane zone around vessels and cytoid bodies. At this time, a preliminary diagnosis of pseudoporphyria was suspected, though no classic medications (eg, nonsteroidal anti-inflammatory drugs, furosemide, antibiotics) or exogenous trigger factors (eg, UV light exposure, dialysis) were temporally related. Three months later, the patient presented with a large hemorrhagic bulla on the distal left forearm (Figure 1) and healing erosions on the dorsal fingers and upper back. Clobetasol ointment was initiated, as an autoimmune bullous dermatosis was suspected.

Approximately 1 year after she was first seen in our outpatient clinic, the patient was hospitalized for induction of chemotherapy—cyclophosphamide, bortezomib, and dexamethasone—for a new diagnosis of stage III multiple myeloma. A workup for back pain revealed multiple compression fractures and a plasma cell neoplasm with elevated λ light chains, which was confirmed with a bone marrow biopsy. During an inpatient dermatology consultation, we noted the development of intraoral hemorrhagic vesicles and worsening generalization of the hemorrhagic bullae, with healing erosions and intact hemorrhagic bullae on the dorsal hands, fingers (Figure 2), and upper back.

A repeat biopsy displayed bullous amyloidosis. Histopathologic examination revealed an ulcerated subepidermal blister with fibrin deposition at the ulcer base. A periadnexal, scant, eosinophilic deposition with extravasated red blood cells was appreciated. Amorphous eosinophilic deposits were found within the detached fragment of the epidermis and inflammatory infiltrate. A Congo red stain highlighted these areas with a salmon pink–colored material. Congo red staining showed a moderate amount of pale, apple green, birefringent deposit within these areas on polarized light examination.

A few months later, the patient was re-admitted, and the amount of skin detachment prompted the primary team to ask for another consultation. Although the extensive skin sloughing resembled toxic epidermal necrolysis, a repeat biopsy confirmed bullous amyloidosis.

Comment

Amyloidosis Histopathology—Amyloidoses represent a wide array of disorders with deposition of β-pleated sheets or amyloid fibrils, often with cutaneous manifestations.^2,3 Primary systemic amyloidosis has been associated with underlying dyscrasia or multiple myeloma.⁶ In such cases, the skin lesions of multiple myeloma may result from a collection of misfolded monoclonal immunoglobulins or their fragments, as in light chain–related systemic amyloidosis.³ Histopathologically, both systemic and cutaneous amyloidosis appear similar and display deposition of amorphous, eosinophilic, fissured amyloid material in the dermis. Congo red stains the material orange-red and will display a characteristic apple green birefringence under polarized light.⁴ Although bullous amyloid lesions are rare, the cutaneous forms of these lesions can be an important sign of plasma cell dyscrasia.⁷

Presentation of Bullous Amyloidosis—Bullous manifestations rarely have been noted in the primary cutaneous forms of amyloidosis.^5,8,9 Importantly, cutaneous blistering more often is linked to systemic forms of amyloidosis with multiorgan involvement, including primary systemic and myeloma-associated amyloidosis.^5,10 However, patients with localized bullous cutaneous amyloidosis without systemic involvement also have been seen.^10,11 Bullae may occur at any time, with contents that frequently are hemorrhagic due to capillary fragility.^12,13 Bullous manifestations raise the differential diagnoses of bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, porphyria cutanea tarda, pseudoporphyria, bullous drug eruption, bullous eruption of renal dialysis, or bullous lupus erythematosus.^5,13-17

In our patient, the acral distribution of bullae, presence of hemorrhage, chronicity of symptoms, and negative enzyme-linked immunosorbent assay initially suggested a diagnosis of pseudoporphyria. However, the presence of intraoral hemorrhagic vesicles and subsequent confirmatory pathology aided in differentiating bullous amyloidosis from pseudoporphyria. Nodular localized primary cutaneous amyloidosis, a rare form of skin-restricted amyloidoses, can coexist with bullous lesions. Of note, reported cases of nodular localized primary cutaneous amyloidosis did not result in development of multiple myeloma.^5,10

Bullae are located either subepidermally or intradermally, and bullous lesions of cutaneous amyloidosis typically demonstrate subepidermal or superficial intradermal clefting on light microscopy.^5,10,12 Histopathology of bullous amyloidosis shows intradermal or subepidermal blister formation and amorphous eosinophilic material showing apple green birefringence with Congo red staining deposited in the dermis and/or around the adipocytes and blood vessel walls.^12,18-20 In prior cases, direct immunofluorescence of bullous amyloidosis revealed absent immunoglobulin (IgG, IgA, IgM) or complement (C3 and C9) deposits in the basement membrane zone or dermis.^13,21,22 In these cases, electron microscopy was useful in diagnosis, as it showed the presence of amyloid deposits.^21,22

Cause of Bullae—Various mechanisms are thought to trigger the blister formation in amyloidosis. Bullae created from trauma or friction often present as tense painful blisters that commonly are hemorrhagic.^10,23 Amyloid deposits in the walls of blood vessels and the affinity of dermal amyloid in blood vessel walls to surrounding collagen likely leads to increased fragility of capillaries and the dermal matrix, hemorrhagic tendency, and infrapapillary blisters, thus creating hemorrhagic bullous eruptions.^24,25 Specifically, close proximity of immunoglobulin-derived amyloid oligomers to epidermal keratinocytes may be toxic and therefore could trigger subepidermal bullous change.⁵ Additionally, alteration in the physicochemical properties of the amyloidal protein might explain bullous eruption.⁹ Trauma or rubbing of the hands and feet may precipitate the acral blister formation in bullous amyloidosis.^5,11

Due to deposition of these amyloid fibrils, skin bleeding in these patients is called amyloid or pinch purpura. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal tract bleeding.²⁶ Destruction of the lamina densa and widening of the intercellular space between keratinocytes by amyloid globules induce skin fragility.¹¹

Although uncommon, various cases of bullous amyloidosis have been reported in the literature. Multiple myeloma patients represent the majority of those reported to have bullous amyloidosis.^{6,7,13,24,27-30} Plasmacytoma-associated bullous amyloid purpura and paraproteinemia also have been noted.²⁵ Multiple myeloma with secondary AL amyloidosis has been seen with amyloid purpura and atraumatic ecchymoses of the face, highlighting the hemorrhage noted in these patients.²⁶

Management of Amyloidosis—Various treatment options have been attempted for primary cutaneous amyloidosis, including oral retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D₃ analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser treatment, and phototherapy.¹ There is no clear consensus for therapeutic modalities except for treating the underlying plasma cell dyscrasia in primary systemic amyloidosis.

Conclusion

We report the case of a patient displaying signs of pseudoporphyria that ultimately proved to be bullous amyloidosis, or what we termed pseudopseudoporphyria. Bullous amyloidosis should be considered in the differential diagnoses of hemorrhagic bullous skin eruptions. Particular attention should be given to a systemic workup for multiple myeloma when hemorrhagic vesicles/bullae are chronic and coexist with purpura, angina bullosa hemorrhagica, fatigue/weight loss, and/or macroglossia.

To the Editor:

Kikuchi-Fujimoto Disease, also called histiocytic necrotizing lymphadenitis, was described in 1972 by both Kikuchi¹ and Fujimoto et al.² Most cases are reported in Asia, with limited reports in the United States.^3-5 Kikuchi-Fujimoto disease is a rare, self-limiting condition consisting of benign lymphadenopathy and oftentimes fever and systemic symptoms. Lymph node involvement may mimic non-Hodgkin lymphoma or other reactive lymphadenopathy, rendering diagnostic accuracy challenging.⁵ Cutaneous manifestations are reported in only 16% to 40% of patients.^6,7 Herein, we describe the clinical and pathologic features of a case of Kikuchi-Fujimoto disease with cutaneous involvement in an adolescent boy.

A 13-year-old adolescent boy with no notable medical history presented to the pediatric emergency department with cervical lymphadenopathy, weight loss, intermittent fever, and an evolving rash on the face, ears, arms, and thighs of 6 weeks’ duration. The illness began with enlarged lymph nodes and erythematous macules on the face and was diagnosed by his primary care physician as lymphadenitis that was unresponsive to clindamycin. Over the subsequent weeks, the rash worsened, and he developed intermittent fevers, night sweats, abdominal pain, and nausea with a 20-pound weight loss. He presented to the emergency department 3 weeks prior to the current admission and was noted to have elevated cytomegalovirus (CMV) IgM and IgG in addition to lymphopenia and anemia. He was discharged with outpatient follow-up. The rash progressed to involve the face, ears, arms, and thighs. One day prior to the current admission, the patient’s abdominal pain worsened acutely, and he experienced several episodes of emesis. He presented to the pediatric emergency department for further evaluation, and a dermatology consultation was requested at that time.

The patient’s rash was asymptomatic. In addition to the above symptoms, he also noted frequent nosebleeds, gingival bleeding, and diffuse myalgia that was most prominent on the hands and feet; he denied diarrhea, sick contacts, recent travel, or insect bites. His vital signs were normal, and he remained afebrile throughout the hospitalization. Physical examination revealed an ill-appearing patient with sunken eyes and dry lips. He had pink, oval, scaly plaques on the cheeks, ears, and arms (Figure 1). The thighs exhibited folliculocentric erythematous papules. The ocular conjunctivae were clear, but white exudative plaques were noted on the tongue. Tender, bilateral, cervical lymphadenopathy and diffuse abdominal tenderness with guarding and hepatosplenomegaly also were present. The fingers and toes were tender upon palpation.

Laboratory workup at admission revealed the following: low white blood cell count, 2700/μL (reference range, 4500–11,000/μL); low hemoglobin, 9.6 g/dL (reference range, 14.0–17.5 g/dL); elevated aspartate aminotransferase, 91 U/L (reference range, 10–30 U/L); and elevated alanine aminotransferase, 118 U/L (reference range, 10–40 U/L). Lactate dehydrogenase (582 U/L [reference range, 100–200 U/L]), ferritin (1681 ng/mL [reference range, 15–200 ng/mL]), and C-reactive protein (6.0 mg/L [reference range, 0.08–3.1 mg/L]) also were elevated. A respiratory viral panel was unremarkable. Blood cultures were negative, and an HIV 1/2 assay was nonreactive. A chest radiograph demonstrated clear lung fields. Computed tomography of the abdomen and pelvis showed prominent mesenteric, ileocolic, and retroperitoneal lymph nodes.

The differential diagnoses at this time included acute connective tissue disease, a paraneoplastic phenomenon, cutaneous lymphoma, or an infectious etiology. A punch biopsy of the skin as well as tissue cultures were performed from a lesion on the right arm. Quantitative immunoglobulin (IgA, IgG, IgM) levels were checked, all of which were within reference range. An antinuclear antibody (ANA) assay and rheumatoid factor were normal.

The tissue cultures were negative for bacteria, fungi, and mycobacteria. Microscopic examination of the skin biopsy revealed a moderate perivascular and interstitial infiltrate of predominantly histiocytes and lymphocytes with prominent karyorrhectic debris (nuclear dust) in the upper dermis as well as focal vacuolar interface changes with scattered necrotic keratinocytes in the epidermis (Figure 2). Based on these histopathologic findings, a diagnosis of Kikuchi-Fujimoto disease was considered. To confirm the diagnosis and to rule out the possibility of lymphoma, an excisional biopsy of the cervical lymph node was performed, which showed typical histopathologic features of histiocytic necrotizing lymphadenitis.

Given the patient’s clinical presentation with arthralgia, anorexia, lymphadenitis, and hepatosplenomegaly along with histopathologic findings from both the skin and lymph node biopsies, a diagnosis of Kikuchi-Fujimoto disease was made. The patient was conservatively managed with acetaminophen and was discharged with improvement in his appetite and systemic symptoms.

He was seen for follow-up 3 months later in the outpatient clinic. He denied any recurrence of systemic symptoms but endorsed a recent shedding of hair consistent with telogen effluvium. The rash had substantially improved, though residual asymptomatic erythematous plaques remained on the right forehead and right cheek (Figure 3). He was prescribed triamcinolone acetonide cream 0.1% to apply to the active area twice daily for the following 2 to 3 weeks.

Kikuchi-Fujimoto disease presents with a wide clinical spectrum, classically with benign lymphadenopathy and fever of unknown etiology.^5,6 Lymphadenopathy most often is cervical (55%–99%)⁸ and unilateral,^4,7 but patients can present with polyadenopathy (52%).^7,8 Constitutional signs commonly include fever (35%–76%), weight loss, arthritis (5%–34%), and leukopenia (25%–74%).^4,8,9

Cutaneous findings have been described in up to 40% of cases, of which clinical presentation is variable.⁶ Lesions may include blanchable, erythematous, painful, and/or indurated plaques, nodules, or maculopapules with confluence into patches, urticaria, morbilliform lesions, erythema multiforme, eyelid edema, leukocytoclastic vasculitis, papulopustules, ulcerated gingivae, and mucositis.^6,7,10-13 Patients with skin lesions may be at an increased risk for developing systemic lupus erythematosus (SLE).⁸ Our patient presented with erythematous scaly plaques with a predominance of lesions in photodistributed locations, which clinically mimicked an underlying connective tissue disease process such as SLE.

Infectious agents such as CMV, parvovirus B19, human herpesvirus 6, human herpesvirus 8 and human T-cell lymphotropic virus 1, HIV, Yersinia enterocolitica, and Toxoplasma have all been implicated as possible causes of Kikuchi-Fujimoto disease, but studies have failed to provide convincing causal evidence.^9,14,15 Our patient had positive IgM and IgG for CMV, which may have incited his disease.

Definitive diagnosis of Kikuchi-Fujimoto disease is made by lymph node excisional biopsy, which histologically exhibits a histiocytic cell proliferation with paracortical foci of necrosis and abundant karyorrhectic debris.⁵ Cutaneous histologic findings that support the diagnosis are variable and may include a dermal histiocytic infiltrate, epidermal change with necrotic keratinocytes, non-neutrophilic karyorrhectic debris, basal vacuolar change, papillary dermal edema, a nonspecific superficial and deep perivascular infiltrate, and a patchy infiltration of histiocytes and lymphocytes.^6,13

Clinical and histopathological features of this disease can mimic other diseases, specifically SLE or lymphoma.⁷ An association with SLE has been suspected, though it is not well defined and more frequently is associated with cases from Asia than from Europe (28% and 9%, respectively).⁹ Patients presenting concomitantly with positive ANA, weight loss, arthralgia, and skin lesions are more likely to develop SLE.⁸ Furthermore, the cutaneous histologic finding of interface change suggests a link between the two diseases. As such, recommendations have been made for ANA screenings and follow-up of patients diagnosed with Kikuchi-Fujimoto disease for clinical evidence of autoimmune disease, particularly SLE.⁶ Although our patient did not have a positive ANA, his biopsy did demonstrate interface change, and he should be monitored for possible progression of disease in the future.

Kikuchi-Fujimoto disease differs from lymphoma, as it initially presents with rapid lymph node enlargement as opposed to the gradual enlargement seen in lymphoma. The lymph nodes in Kikuchi-Fujimoto disease often are firm and moveable compared to hard and immobile in lymphoma.³ Excisional lymph node biopsy is necessary for both confirming the diagnosis of Kikuchi-Fujimoto disease and ruling out lymphoma.⁵

Spontaneous resolution usually occurs in 1 to 4 months.^3,6 As such, observation is the most common approach to management. When patients have symptoms that limit activities or cause undue distress such as fevers, joint pains, or abdominal pain, systemic treatment options may be desired. Symptomatic treatment can be managed with a short duration of oral corticosteroids,^10,11 nonsteroidal anti-inflammatory drugs, antimalarials, and/or antipyretics.^8-15 There are no guidelines regarding systemic steroid regimens, and various treatment schedules have been successful. Systemic therapy was considered for our patient for his weight loss and abdominal pain; however, by the time of discharge the patient was tolerating oral intake and his abdominal pain had improved.

To the Editor:

Kikuchi-Fujimoto Disease, also called histiocytic necrotizing lymphadenitis, was described in 1972 by both Kikuchi¹ and Fujimoto et al.² Most cases are reported in Asia, with limited reports in the United States.^3-5 Kikuchi-Fujimoto disease is a rare, self-limiting condition consisting of benign lymphadenopathy and oftentimes fever and systemic symptoms. Lymph node involvement may mimic non-Hodgkin lymphoma or other reactive lymphadenopathy, rendering diagnostic accuracy challenging.⁵ Cutaneous manifestations are reported in only 16% to 40% of patients.^6,7 Herein, we describe the clinical and pathologic features of a case of Kikuchi-Fujimoto disease with cutaneous involvement in an adolescent boy.

A 13-year-old adolescent boy with no notable medical history presented to the pediatric emergency department with cervical lymphadenopathy, weight loss, intermittent fever, and an evolving rash on the face, ears, arms, and thighs of 6 weeks’ duration. The illness began with enlarged lymph nodes and erythematous macules on the face and was diagnosed by his primary care physician as lymphadenitis that was unresponsive to clindamycin. Over the subsequent weeks, the rash worsened, and he developed intermittent fevers, night sweats, abdominal pain, and nausea with a 20-pound weight loss. He presented to the emergency department 3 weeks prior to the current admission and was noted to have elevated cytomegalovirus (CMV) IgM and IgG in addition to lymphopenia and anemia. He was discharged with outpatient follow-up. The rash progressed to involve the face, ears, arms, and thighs. One day prior to the current admission, the patient’s abdominal pain worsened acutely, and he experienced several episodes of emesis. He presented to the pediatric emergency department for further evaluation, and a dermatology consultation was requested at that time.

The patient’s rash was asymptomatic. In addition to the above symptoms, he also noted frequent nosebleeds, gingival bleeding, and diffuse myalgia that was most prominent on the hands and feet; he denied diarrhea, sick contacts, recent travel, or insect bites. His vital signs were normal, and he remained afebrile throughout the hospitalization. Physical examination revealed an ill-appearing patient with sunken eyes and dry lips. He had pink, oval, scaly plaques on the cheeks, ears, and arms (Figure 1). The thighs exhibited folliculocentric erythematous papules. The ocular conjunctivae were clear, but white exudative plaques were noted on the tongue. Tender, bilateral, cervical lymphadenopathy and diffuse abdominal tenderness with guarding and hepatosplenomegaly also were present. The fingers and toes were tender upon palpation.

Laboratory workup at admission revealed the following: low white blood cell count, 2700/μL (reference range, 4500–11,000/μL); low hemoglobin, 9.6 g/dL (reference range, 14.0–17.5 g/dL); elevated aspartate aminotransferase, 91 U/L (reference range, 10–30 U/L); and elevated alanine aminotransferase, 118 U/L (reference range, 10–40 U/L). Lactate dehydrogenase (582 U/L [reference range, 100–200 U/L]), ferritin (1681 ng/mL [reference range, 15–200 ng/mL]), and C-reactive protein (6.0 mg/L [reference range, 0.08–3.1 mg/L]) also were elevated. A respiratory viral panel was unremarkable. Blood cultures were negative, and an HIV 1/2 assay was nonreactive. A chest radiograph demonstrated clear lung fields. Computed tomography of the abdomen and pelvis showed prominent mesenteric, ileocolic, and retroperitoneal lymph nodes.

The differential diagnoses at this time included acute connective tissue disease, a paraneoplastic phenomenon, cutaneous lymphoma, or an infectious etiology. A punch biopsy of the skin as well as tissue cultures were performed from a lesion on the right arm. Quantitative immunoglobulin (IgA, IgG, IgM) levels were checked, all of which were within reference range. An antinuclear antibody (ANA) assay and rheumatoid factor were normal.

The tissue cultures were negative for bacteria, fungi, and mycobacteria. Microscopic examination of the skin biopsy revealed a moderate perivascular and interstitial infiltrate of predominantly histiocytes and lymphocytes with prominent karyorrhectic debris (nuclear dust) in the upper dermis as well as focal vacuolar interface changes with scattered necrotic keratinocytes in the epidermis (Figure 2). Based on these histopathologic findings, a diagnosis of Kikuchi-Fujimoto disease was considered. To confirm the diagnosis and to rule out the possibility of lymphoma, an excisional biopsy of the cervical lymph node was performed, which showed typical histopathologic features of histiocytic necrotizing lymphadenitis.

Given the patient’s clinical presentation with arthralgia, anorexia, lymphadenitis, and hepatosplenomegaly along with histopathologic findings from both the skin and lymph node biopsies, a diagnosis of Kikuchi-Fujimoto disease was made. The patient was conservatively managed with acetaminophen and was discharged with improvement in his appetite and systemic symptoms.

He was seen for follow-up 3 months later in the outpatient clinic. He denied any recurrence of systemic symptoms but endorsed a recent shedding of hair consistent with telogen effluvium. The rash had substantially improved, though residual asymptomatic erythematous plaques remained on the right forehead and right cheek (Figure 3). He was prescribed triamcinolone acetonide cream 0.1% to apply to the active area twice daily for the following 2 to 3 weeks.

Kikuchi-Fujimoto disease presents with a wide clinical spectrum, classically with benign lymphadenopathy and fever of unknown etiology.^5,6 Lymphadenopathy most often is cervical (55%–99%)⁸ and unilateral,^4,7 but patients can present with polyadenopathy (52%).^7,8 Constitutional signs commonly include fever (35%–76%), weight loss, arthritis (5%–34%), and leukopenia (25%–74%).^4,8,9

Cutaneous findings have been described in up to 40% of cases, of which clinical presentation is variable.⁶ Lesions may include blanchable, erythematous, painful, and/or indurated plaques, nodules, or maculopapules with confluence into patches, urticaria, morbilliform lesions, erythema multiforme, eyelid edema, leukocytoclastic vasculitis, papulopustules, ulcerated gingivae, and mucositis.^6,7,10-13 Patients with skin lesions may be at an increased risk for developing systemic lupus erythematosus (SLE).⁸ Our patient presented with erythematous scaly plaques with a predominance of lesions in photodistributed locations, which clinically mimicked an underlying connective tissue disease process such as SLE.

Infectious agents such as CMV, parvovirus B19, human herpesvirus 6, human herpesvirus 8 and human T-cell lymphotropic virus 1, HIV, Yersinia enterocolitica, and Toxoplasma have all been implicated as possible causes of Kikuchi-Fujimoto disease, but studies have failed to provide convincing causal evidence.^9,14,15 Our patient had positive IgM and IgG for CMV, which may have incited his disease.

Definitive diagnosis of Kikuchi-Fujimoto disease is made by lymph node excisional biopsy, which histologically exhibits a histiocytic cell proliferation with paracortical foci of necrosis and abundant karyorrhectic debris.⁵ Cutaneous histologic findings that support the diagnosis are variable and may include a dermal histiocytic infiltrate, epidermal change with necrotic keratinocytes, non-neutrophilic karyorrhectic debris, basal vacuolar change, papillary dermal edema, a nonspecific superficial and deep perivascular infiltrate, and a patchy infiltration of histiocytes and lymphocytes.^6,13

Clinical and histopathological features of this disease can mimic other diseases, specifically SLE or lymphoma.⁷ An association with SLE has been suspected, though it is not well defined and more frequently is associated with cases from Asia than from Europe (28% and 9%, respectively).⁹ Patients presenting concomitantly with positive ANA, weight loss, arthralgia, and skin lesions are more likely to develop SLE.⁸ Furthermore, the cutaneous histologic finding of interface change suggests a link between the two diseases. As such, recommendations have been made for ANA screenings and follow-up of patients diagnosed with Kikuchi-Fujimoto disease for clinical evidence of autoimmune disease, particularly SLE.⁶ Although our patient did not have a positive ANA, his biopsy did demonstrate interface change, and he should be monitored for possible progression of disease in the future.

Kikuchi-Fujimoto disease differs from lymphoma, as it initially presents with rapid lymph node enlargement as opposed to the gradual enlargement seen in lymphoma. The lymph nodes in Kikuchi-Fujimoto disease often are firm and moveable compared to hard and immobile in lymphoma.³ Excisional lymph node biopsy is necessary for both confirming the diagnosis of Kikuchi-Fujimoto disease and ruling out lymphoma.⁵

Spontaneous resolution usually occurs in 1 to 4 months.^3,6 As such, observation is the most common approach to management. When patients have symptoms that limit activities or cause undue distress such as fevers, joint pains, or abdominal pain, systemic treatment options may be desired. Symptomatic treatment can be managed with a short duration of oral corticosteroids,^10,11 nonsteroidal anti-inflammatory drugs, antimalarials, and/or antipyretics.^8-15 There are no guidelines regarding systemic steroid regimens, and various treatment schedules have been successful. Systemic therapy was considered for our patient for his weight loss and abdominal pain; however, by the time of discharge the patient was tolerating oral intake and his abdominal pain had improved.

To the Editor:

Kikuchi-Fujimoto Disease, also called histiocytic necrotizing lymphadenitis, was described in 1972 by both Kikuchi¹ and Fujimoto et al.² Most cases are reported in Asia, with limited reports in the United States.^3-5 Kikuchi-Fujimoto disease is a rare, self-limiting condition consisting of benign lymphadenopathy and oftentimes fever and systemic symptoms. Lymph node involvement may mimic non-Hodgkin lymphoma or other reactive lymphadenopathy, rendering diagnostic accuracy challenging.⁵ Cutaneous manifestations are reported in only 16% to 40% of patients.^6,7 Herein, we describe the clinical and pathologic features of a case of Kikuchi-Fujimoto disease with cutaneous involvement in an adolescent boy.

A 13-year-old adolescent boy with no notable medical history presented to the pediatric emergency department with cervical lymphadenopathy, weight loss, intermittent fever, and an evolving rash on the face, ears, arms, and thighs of 6 weeks’ duration. The illness began with enlarged lymph nodes and erythematous macules on the face and was diagnosed by his primary care physician as lymphadenitis that was unresponsive to clindamycin. Over the subsequent weeks, the rash worsened, and he developed intermittent fevers, night sweats, abdominal pain, and nausea with a 20-pound weight loss. He presented to the emergency department 3 weeks prior to the current admission and was noted to have elevated cytomegalovirus (CMV) IgM and IgG in addition to lymphopenia and anemia. He was discharged with outpatient follow-up. The rash progressed to involve the face, ears, arms, and thighs. One day prior to the current admission, the patient’s abdominal pain worsened acutely, and he experienced several episodes of emesis. He presented to the pediatric emergency department for further evaluation, and a dermatology consultation was requested at that time.

The patient’s rash was asymptomatic. In addition to the above symptoms, he also noted frequent nosebleeds, gingival bleeding, and diffuse myalgia that was most prominent on the hands and feet; he denied diarrhea, sick contacts, recent travel, or insect bites. His vital signs were normal, and he remained afebrile throughout the hospitalization. Physical examination revealed an ill-appearing patient with sunken eyes and dry lips. He had pink, oval, scaly plaques on the cheeks, ears, and arms (Figure 1). The thighs exhibited folliculocentric erythematous papules. The ocular conjunctivae were clear, but white exudative plaques were noted on the tongue. Tender, bilateral, cervical lymphadenopathy and diffuse abdominal tenderness with guarding and hepatosplenomegaly also were present. The fingers and toes were tender upon palpation.

Laboratory workup at admission revealed the following: low white blood cell count, 2700/μL (reference range, 4500–11,000/μL); low hemoglobin, 9.6 g/dL (reference range, 14.0–17.5 g/dL); elevated aspartate aminotransferase, 91 U/L (reference range, 10–30 U/L); and elevated alanine aminotransferase, 118 U/L (reference range, 10–40 U/L). Lactate dehydrogenase (582 U/L [reference range, 100–200 U/L]), ferritin (1681 ng/mL [reference range, 15–200 ng/mL]), and C-reactive protein (6.0 mg/L [reference range, 0.08–3.1 mg/L]) also were elevated. A respiratory viral panel was unremarkable. Blood cultures were negative, and an HIV 1/2 assay was nonreactive. A chest radiograph demonstrated clear lung fields. Computed tomography of the abdomen and pelvis showed prominent mesenteric, ileocolic, and retroperitoneal lymph nodes.

The differential diagnoses at this time included acute connective tissue disease, a paraneoplastic phenomenon, cutaneous lymphoma, or an infectious etiology. A punch biopsy of the skin as well as tissue cultures were performed from a lesion on the right arm. Quantitative immunoglobulin (IgA, IgG, IgM) levels were checked, all of which were within reference range. An antinuclear antibody (ANA) assay and rheumatoid factor were normal.

The tissue cultures were negative for bacteria, fungi, and mycobacteria. Microscopic examination of the skin biopsy revealed a moderate perivascular and interstitial infiltrate of predominantly histiocytes and lymphocytes with prominent karyorrhectic debris (nuclear dust) in the upper dermis as well as focal vacuolar interface changes with scattered necrotic keratinocytes in the epidermis (Figure 2). Based on these histopathologic findings, a diagnosis of Kikuchi-Fujimoto disease was considered. To confirm the diagnosis and to rule out the possibility of lymphoma, an excisional biopsy of the cervical lymph node was performed, which showed typical histopathologic features of histiocytic necrotizing lymphadenitis.

Given the patient’s clinical presentation with arthralgia, anorexia, lymphadenitis, and hepatosplenomegaly along with histopathologic findings from both the skin and lymph node biopsies, a diagnosis of Kikuchi-Fujimoto disease was made. The patient was conservatively managed with acetaminophen and was discharged with improvement in his appetite and systemic symptoms.

He was seen for follow-up 3 months later in the outpatient clinic. He denied any recurrence of systemic symptoms but endorsed a recent shedding of hair consistent with telogen effluvium. The rash had substantially improved, though residual asymptomatic erythematous plaques remained on the right forehead and right cheek (Figure 3). He was prescribed triamcinolone acetonide cream 0.1% to apply to the active area twice daily for the following 2 to 3 weeks.

Kikuchi-Fujimoto disease presents with a wide clinical spectrum, classically with benign lymphadenopathy and fever of unknown etiology.^5,6 Lymphadenopathy most often is cervical (55%–99%)⁸ and unilateral,^4,7 but patients can present with polyadenopathy (52%).^7,8 Constitutional signs commonly include fever (35%–76%), weight loss, arthritis (5%–34%), and leukopenia (25%–74%).^4,8,9

Cutaneous findings have been described in up to 40% of cases, of which clinical presentation is variable.⁶ Lesions may include blanchable, erythematous, painful, and/or indurated plaques, nodules, or maculopapules with confluence into patches, urticaria, morbilliform lesions, erythema multiforme, eyelid edema, leukocytoclastic vasculitis, papulopustules, ulcerated gingivae, and mucositis.^6,7,10-13 Patients with skin lesions may be at an increased risk for developing systemic lupus erythematosus (SLE).⁸ Our patient presented with erythematous scaly plaques with a predominance of lesions in photodistributed locations, which clinically mimicked an underlying connective tissue disease process such as SLE.

Infectious agents such as CMV, parvovirus B19, human herpesvirus 6, human herpesvirus 8 and human T-cell lymphotropic virus 1, HIV, Yersinia enterocolitica, and Toxoplasma have all been implicated as possible causes of Kikuchi-Fujimoto disease, but studies have failed to provide convincing causal evidence.^9,14,15 Our patient had positive IgM and IgG for CMV, which may have incited his disease.

Definitive diagnosis of Kikuchi-Fujimoto disease is made by lymph node excisional biopsy, which histologically exhibits a histiocytic cell proliferation with paracortical foci of necrosis and abundant karyorrhectic debris.⁵ Cutaneous histologic findings that support the diagnosis are variable and may include a dermal histiocytic infiltrate, epidermal change with necrotic keratinocytes, non-neutrophilic karyorrhectic debris, basal vacuolar change, papillary dermal edema, a nonspecific superficial and deep perivascular infiltrate, and a patchy infiltration of histiocytes and lymphocytes.^6,13

Clinical and histopathological features of this disease can mimic other diseases, specifically SLE or lymphoma.⁷ An association with SLE has been suspected, though it is not well defined and more frequently is associated with cases from Asia than from Europe (28% and 9%, respectively).⁹ Patients presenting concomitantly with positive ANA, weight loss, arthralgia, and skin lesions are more likely to develop SLE.⁸ Furthermore, the cutaneous histologic finding of interface change suggests a link between the two diseases. As such, recommendations have been made for ANA screenings and follow-up of patients diagnosed with Kikuchi-Fujimoto disease for clinical evidence of autoimmune disease, particularly SLE.⁶ Although our patient did not have a positive ANA, his biopsy did demonstrate interface change, and he should be monitored for possible progression of disease in the future.

Kikuchi-Fujimoto disease differs from lymphoma, as it initially presents with rapid lymph node enlargement as opposed to the gradual enlargement seen in lymphoma. The lymph nodes in Kikuchi-Fujimoto disease often are firm and moveable compared to hard and immobile in lymphoma.³ Excisional lymph node biopsy is necessary for both confirming the diagnosis of Kikuchi-Fujimoto disease and ruling out lymphoma.⁵

Spontaneous resolution usually occurs in 1 to 4 months.^3,6 As such, observation is the most common approach to management. When patients have symptoms that limit activities or cause undue distress such as fevers, joint pains, or abdominal pain, systemic treatment options may be desired. Symptomatic treatment can be managed with a short duration of oral corticosteroids,^10,11 nonsteroidal anti-inflammatory drugs, antimalarials, and/or antipyretics.^8-15 There are no guidelines regarding systemic steroid regimens, and various treatment schedules have been successful. Systemic therapy was considered for our patient for his weight loss and abdominal pain; however, by the time of discharge the patient was tolerating oral intake and his abdominal pain had improved.

Northwell Health, the largest hospital system in New York state, fired 1,400 employees Oct. 3 for not complying with the state’s COVID-19 vaccine mandate.

The employees represented less than 2% of Northwell’s 76,000 employees, who are now all fully vaccinated against COVID-19, Joe Kemp, the assistant vice president of public relations for the company, told The Hill.

“Northwell Health is proud to announce that our workforce -- the largest in New York State -- is 100% vaccinated,” the company said in a statement to several news outlets.

“This allows us to continue to provide exceptional care at all of our facilities, without interruption and remain open and fully operational,” Northwell Health said.

Having a fully vaccinated workforce is part of the health system’s duty to protect others, the company said. Northwell Health includes 23 hospitals and more than 830 outpatient facilities, according to ABC News.

“Northwell regrets losing any employee under such circumstances,” the company said. “We owe it to our staff, our patients, and the communities we serve to be 100% vaccinated against COVID-19.”

Former New York Gov. Andrew Cuomo announced in August that the state would require health care workers to receive at least one COVID-19 vaccine shot by Sept. 27. Employees didn’t have the option for weekly testing or religious exemptions, which is being challenged in several lawsuits, according to The New York Times.

The order went into effect last week, prompting tens of thousands of employees to get vaccinated. As of last week, 87% of hospital staff were fully vaccinated, and 92% of hospital and retirement home workers had received at least one dose, according to state health data.

Northwell announced its own vaccine mandate in August as well, which sparked protests among some workers. The order applied to both clinical and non-clinical staff.

A few thousand Northwell employees got vaccinated as the deadline approached, Mr. Kemp told The New York Times. Some who lost their jobs at first were able to return to work, and those who have been terminated can interview for reinstatement for 30 days. The hospital system is also “openly recruiting” for the vacant positions.

“The goal was to get people vaccinated, not to get people terminated,” Mr. Kemp said.

Hospitalized COVID-19 patients in New York hit a low of 350 in mid-July, according to state hospitalization data. Now, about 2,200 people are hospitalized throughout the state, most of whom are unvaccinated.

As of Oct. 3, nearly 72% of New York residents had received at least one vaccine dose, according to the latest state data. About 64% are fully vaccinated.

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

Northwell Health, the largest hospital system in New York state, fired 1,400 employees Oct. 3 for not complying with the state’s COVID-19 vaccine mandate.

The employees represented less than 2% of Northwell’s 76,000 employees, who are now all fully vaccinated against COVID-19, Joe Kemp, the assistant vice president of public relations for the company, told The Hill.

“Northwell Health is proud to announce that our workforce -- the largest in New York State -- is 100% vaccinated,” the company said in a statement to several news outlets.

“This allows us to continue to provide exceptional care at all of our facilities, without interruption and remain open and fully operational,” Northwell Health said.

Having a fully vaccinated workforce is part of the health system’s duty to protect others, the company said. Northwell Health includes 23 hospitals and more than 830 outpatient facilities, according to ABC News.

“Northwell regrets losing any employee under such circumstances,” the company said. “We owe it to our staff, our patients, and the communities we serve to be 100% vaccinated against COVID-19.”

Former New York Gov. Andrew Cuomo announced in August that the state would require health care workers to receive at least one COVID-19 vaccine shot by Sept. 27. Employees didn’t have the option for weekly testing or religious exemptions, which is being challenged in several lawsuits, according to The New York Times.

The order went into effect last week, prompting tens of thousands of employees to get vaccinated. As of last week, 87% of hospital staff were fully vaccinated, and 92% of hospital and retirement home workers had received at least one dose, according to state health data.

Northwell announced its own vaccine mandate in August as well, which sparked protests among some workers. The order applied to both clinical and non-clinical staff.

A few thousand Northwell employees got vaccinated as the deadline approached, Mr. Kemp told The New York Times. Some who lost their jobs at first were able to return to work, and those who have been terminated can interview for reinstatement for 30 days. The hospital system is also “openly recruiting” for the vacant positions.

“The goal was to get people vaccinated, not to get people terminated,” Mr. Kemp said.

Hospitalized COVID-19 patients in New York hit a low of 350 in mid-July, according to state hospitalization data. Now, about 2,200 people are hospitalized throughout the state, most of whom are unvaccinated.

As of Oct. 3, nearly 72% of New York residents had received at least one vaccine dose, according to the latest state data. About 64% are fully vaccinated.

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

Northwell Health, the largest hospital system in New York state, fired 1,400 employees Oct. 3 for not complying with the state’s COVID-19 vaccine mandate.

The employees represented less than 2% of Northwell’s 76,000 employees, who are now all fully vaccinated against COVID-19, Joe Kemp, the assistant vice president of public relations for the company, told The Hill.

“Northwell Health is proud to announce that our workforce -- the largest in New York State -- is 100% vaccinated,” the company said in a statement to several news outlets.

“This allows us to continue to provide exceptional care at all of our facilities, without interruption and remain open and fully operational,” Northwell Health said.

Having a fully vaccinated workforce is part of the health system’s duty to protect others, the company said. Northwell Health includes 23 hospitals and more than 830 outpatient facilities, according to ABC News.

“Northwell regrets losing any employee under such circumstances,” the company said. “We owe it to our staff, our patients, and the communities we serve to be 100% vaccinated against COVID-19.”

Former New York Gov. Andrew Cuomo announced in August that the state would require health care workers to receive at least one COVID-19 vaccine shot by Sept. 27. Employees didn’t have the option for weekly testing or religious exemptions, which is being challenged in several lawsuits, according to The New York Times.

The order went into effect last week, prompting tens of thousands of employees to get vaccinated. As of last week, 87% of hospital staff were fully vaccinated, and 92% of hospital and retirement home workers had received at least one dose, according to state health data.

Northwell announced its own vaccine mandate in August as well, which sparked protests among some workers. The order applied to both clinical and non-clinical staff.

A few thousand Northwell employees got vaccinated as the deadline approached, Mr. Kemp told The New York Times. Some who lost their jobs at first were able to return to work, and those who have been terminated can interview for reinstatement for 30 days. The hospital system is also “openly recruiting” for the vacant positions.

“The goal was to get people vaccinated, not to get people terminated,” Mr. Kemp said.

Hospitalized COVID-19 patients in New York hit a low of 350 in mid-July, according to state hospitalization data. Now, about 2,200 people are hospitalized throughout the state, most of whom are unvaccinated.

As of Oct. 3, nearly 72% of New York residents had received at least one vaccine dose, according to the latest state data. About 64% are fully vaccinated.

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

The Diagnosis: Drug-Induced Hyperpigmentation

Additional history provided by the patient’s caretaker elucidated an extensive list of medications including chlorpromazine and minocycline, among several others. The caretaker revealed that the patient began treatment for acne vulgaris 2 years prior; despite the acne resolving, therapy was not discontinued. The blue-gray and brown pigmentation on our patient’s shins likely was attributed to a medication he was taking.

Both chlorpromazine and minocycline, among many other medications, are known to cause abnormal pigmentation of the skin.¹ Minocycline is a tetracycline antibiotic prescribed for acne and other inflammatory cutaneous conditions. It is highly lipophilic, allowing it to reach high drug concentrations in the skin and nail unit.² Patients taking minocycline long term and at high doses are at greatest risk for pigment deposition.^3,4

Minocycline-induced hyperpigmentation is classified into 3 types. Type I describes blue-black deposition of pigment in acne scars and areas of inflammation, typically on facial skin.^1,5 Histologically, type I stains positive for Perls Prussian blue, indicating an increased deposition of iron as hemosiderin,¹ which likely occurs because minocycline is thought to play a role in defective clearance of hemosiderin from the dermis of injured tissue.⁵ Type II hyperpigmentation presents as bluegray pigment on the lower legs and occasionally the arms.^6,7 Type II stains positive for both Perls Prussian blue and Fontana-Masson, demonstrating hemosiderin and melanin, respectively.⁶ The third form of hyperpigmentation results in diffuse, dark brown to gray pigmentation with a predilection for sun-exposed areas.⁸ Histology of type III shows increased pigment in the basal portion of the epidermis and brown-black pigment in macrophages of the dermis. Type III stains positive for Fontana-Masson and negative for Perls Prussian blue. The etiology of hyperpigmentation has been suspected to be caused by minocycline stimulating melanin production and/or deposition of minocycline-melanin complexes in dermal macrophages after a certain drug level; this largely is seen in patients receiving 100 to 200 mg daily as early as 1 year into treatment.⁸

Chlorpromazine is a typical antipsychotic that causes abnormal skin pigmentation in sun-exposed areas due to increased melanogenesis.⁹ Similar to type III minocyclineinduced hyperpigmentation, a histologic specimen may stain positive for Fontana-Masson yet negative for Perls Prussian blue. Lal et al10 demonstrated complete resolution of abnormal skin pigmentation within 5 years after stopping chlorpromazine. In contrast, minocyclineinduced hyperpigmentation may be permanent in some cases. There is substantial clinical and histologic overlap for drug-induced hyperpigmentation etiologies; it would behoove the clinician to focus on the most common locations affected and the generalized coloration.

Treatment of minocycline-induced hyperpigmentation includes the use of Q-switched lasers, specifically Q-switched ruby and Q-switched alexandrite.¹¹ The use of the Q-switched Nd:YAG laser appears to be ineffective at clearing minocycline-induced pigmentation.^7,11 In our patient, minocycline was discontinued immediately. Due to the patient’s critical condition, he deferred all other therapy. Erythema dyschromicum perstans, also referred to as ashy dermatosis, is an idiopathic form of hyperpigmentation.¹² Lesions start as blue-gray to ashy gray macules, occasionally surrounded by a slightly erythematous, raised border.

Erythema dyschromicum perstans typically presents on the trunk, face, and arms of patients with Fitzpatrick skin types III and IV; it is considered a variant of lichen planus actinicus.¹² Histologically, erythema dyschromicum perstans may mimic lichen planus pigmentosus (LPP); however, subtle differences exist to distinguish the 2 conditions. Erythema dyschromicum perstans demonstrates a mild lichenoid infiltrate, focal basal vacuolization at the dermoepidermal junction, and melanophage deposition.¹³ In contrast, LPP demonstrates pigmentary incontinence and a more severe inflammatory infiltrate. A perifollicular infiltrate and fibrosis also can be seen in LPP, which may explain the frontal fibrosing alopecia that often precedes LPP.¹³

Addison disease, also known as primary adrenal insufficiency, can cause diffuse hyperpigmentation in the skin, mucosae, and nail beds. The pigmentation is prominent in regions of naturally increased pigmentation, such as the flexural surfaces and intertriginous areas.¹⁴ Patients with adrenal insufficiency will have accompanying weight loss, hypotension, and fatigue, among other symptoms related to deficiency of cortisol and aldosterone. Skin biopsy shows acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin deposition, and superficial dermal macrophages.¹⁵

Confluent and reticulated papillomatosis is an uncommon dermatosis that presents with multiple hyperpigmented macules and papules that coalesce to form patches and plaques centrally with reticulation in the periphery.¹⁶ Confluent and reticulated papillomatosis commonly presents on the upper trunk, axillae, and neck, though involvement can include flexural surfaces as well as the lower trunk and legs.^16,17 Biopsy demonstrates undulating hyperkeratosis, papillomatosis, acanthosis, and negative fungal staining.¹⁶

Pretibial myxedema most commonly is associated with Graves disease and presents as well-defined thickening and induration with overlying pink or purple-brown papules in the pretibial region.¹⁸ An acral surface and mucin deposition within the entire dermis may be appreciated on histology with staining for colloidal iron or Alcian blue.

The Diagnosis: Drug-Induced Hyperpigmentation

Additional history provided by the patient’s caretaker elucidated an extensive list of medications including chlorpromazine and minocycline, among several others. The caretaker revealed that the patient began treatment for acne vulgaris 2 years prior; despite the acne resolving, therapy was not discontinued. The blue-gray and brown pigmentation on our patient’s shins likely was attributed to a medication he was taking.

Both chlorpromazine and minocycline, among many other medications, are known to cause abnormal pigmentation of the skin.¹ Minocycline is a tetracycline antibiotic prescribed for acne and other inflammatory cutaneous conditions. It is highly lipophilic, allowing it to reach high drug concentrations in the skin and nail unit.² Patients taking minocycline long term and at high doses are at greatest risk for pigment deposition.^3,4

Minocycline-induced hyperpigmentation is classified into 3 types. Type I describes blue-black deposition of pigment in acne scars and areas of inflammation, typically on facial skin.^1,5 Histologically, type I stains positive for Perls Prussian blue, indicating an increased deposition of iron as hemosiderin,¹ which likely occurs because minocycline is thought to play a role in defective clearance of hemosiderin from the dermis of injured tissue.⁵ Type II hyperpigmentation presents as bluegray pigment on the lower legs and occasionally the arms.^6,7 Type II stains positive for both Perls Prussian blue and Fontana-Masson, demonstrating hemosiderin and melanin, respectively.⁶ The third form of hyperpigmentation results in diffuse, dark brown to gray pigmentation with a predilection for sun-exposed areas.⁸ Histology of type III shows increased pigment in the basal portion of the epidermis and brown-black pigment in macrophages of the dermis. Type III stains positive for Fontana-Masson and negative for Perls Prussian blue. The etiology of hyperpigmentation has been suspected to be caused by minocycline stimulating melanin production and/or deposition of minocycline-melanin complexes in dermal macrophages after a certain drug level; this largely is seen in patients receiving 100 to 200 mg daily as early as 1 year into treatment.⁸

Chlorpromazine is a typical antipsychotic that causes abnormal skin pigmentation in sun-exposed areas due to increased melanogenesis.⁹ Similar to type III minocyclineinduced hyperpigmentation, a histologic specimen may stain positive for Fontana-Masson yet negative for Perls Prussian blue. Lal et al10 demonstrated complete resolution of abnormal skin pigmentation within 5 years after stopping chlorpromazine. In contrast, minocyclineinduced hyperpigmentation may be permanent in some cases. There is substantial clinical and histologic overlap for drug-induced hyperpigmentation etiologies; it would behoove the clinician to focus on the most common locations affected and the generalized coloration.

Treatment of minocycline-induced hyperpigmentation includes the use of Q-switched lasers, specifically Q-switched ruby and Q-switched alexandrite.¹¹ The use of the Q-switched Nd:YAG laser appears to be ineffective at clearing minocycline-induced pigmentation.^7,11 In our patient, minocycline was discontinued immediately. Due to the patient’s critical condition, he deferred all other therapy. Erythema dyschromicum perstans, also referred to as ashy dermatosis, is an idiopathic form of hyperpigmentation.¹² Lesions start as blue-gray to ashy gray macules, occasionally surrounded by a slightly erythematous, raised border.

Erythema dyschromicum perstans typically presents on the trunk, face, and arms of patients with Fitzpatrick skin types III and IV; it is considered a variant of lichen planus actinicus.¹² Histologically, erythema dyschromicum perstans may mimic lichen planus pigmentosus (LPP); however, subtle differences exist to distinguish the 2 conditions. Erythema dyschromicum perstans demonstrates a mild lichenoid infiltrate, focal basal vacuolization at the dermoepidermal junction, and melanophage deposition.¹³ In contrast, LPP demonstrates pigmentary incontinence and a more severe inflammatory infiltrate. A perifollicular infiltrate and fibrosis also can be seen in LPP, which may explain the frontal fibrosing alopecia that often precedes LPP.¹³

Addison disease, also known as primary adrenal insufficiency, can cause diffuse hyperpigmentation in the skin, mucosae, and nail beds. The pigmentation is prominent in regions of naturally increased pigmentation, such as the flexural surfaces and intertriginous areas.¹⁴ Patients with adrenal insufficiency will have accompanying weight loss, hypotension, and fatigue, among other symptoms related to deficiency of cortisol and aldosterone. Skin biopsy shows acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin deposition, and superficial dermal macrophages.¹⁵

Confluent and reticulated papillomatosis is an uncommon dermatosis that presents with multiple hyperpigmented macules and papules that coalesce to form patches and plaques centrally with reticulation in the periphery.¹⁶ Confluent and reticulated papillomatosis commonly presents on the upper trunk, axillae, and neck, though involvement can include flexural surfaces as well as the lower trunk and legs.^16,17 Biopsy demonstrates undulating hyperkeratosis, papillomatosis, acanthosis, and negative fungal staining.¹⁶

Pretibial myxedema most commonly is associated with Graves disease and presents as well-defined thickening and induration with overlying pink or purple-brown papules in the pretibial region.¹⁸ An acral surface and mucin deposition within the entire dermis may be appreciated on histology with staining for colloidal iron or Alcian blue.

The Diagnosis: Drug-Induced Hyperpigmentation

Additional history provided by the patient’s caretaker elucidated an extensive list of medications including chlorpromazine and minocycline, among several others. The caretaker revealed that the patient began treatment for acne vulgaris 2 years prior; despite the acne resolving, therapy was not discontinued. The blue-gray and brown pigmentation on our patient’s shins likely was attributed to a medication he was taking.

Both chlorpromazine and minocycline, among many other medications, are known to cause abnormal pigmentation of the skin.¹ Minocycline is a tetracycline antibiotic prescribed for acne and other inflammatory cutaneous conditions. It is highly lipophilic, allowing it to reach high drug concentrations in the skin and nail unit.² Patients taking minocycline long term and at high doses are at greatest risk for pigment deposition.^3,4

Minocycline-induced hyperpigmentation is classified into 3 types. Type I describes blue-black deposition of pigment in acne scars and areas of inflammation, typically on facial skin.^1,5 Histologically, type I stains positive for Perls Prussian blue, indicating an increased deposition of iron as hemosiderin,¹ which likely occurs because minocycline is thought to play a role in defective clearance of hemosiderin from the dermis of injured tissue.⁵ Type II hyperpigmentation presents as bluegray pigment on the lower legs and occasionally the arms.^6,7 Type II stains positive for both Perls Prussian blue and Fontana-Masson, demonstrating hemosiderin and melanin, respectively.⁶ The third form of hyperpigmentation results in diffuse, dark brown to gray pigmentation with a predilection for sun-exposed areas.⁸ Histology of type III shows increased pigment in the basal portion of the epidermis and brown-black pigment in macrophages of the dermis. Type III stains positive for Fontana-Masson and negative for Perls Prussian blue. The etiology of hyperpigmentation has been suspected to be caused by minocycline stimulating melanin production and/or deposition of minocycline-melanin complexes in dermal macrophages after a certain drug level; this largely is seen in patients receiving 100 to 200 mg daily as early as 1 year into treatment.⁸

Chlorpromazine is a typical antipsychotic that causes abnormal skin pigmentation in sun-exposed areas due to increased melanogenesis.⁹ Similar to type III minocyclineinduced hyperpigmentation, a histologic specimen may stain positive for Fontana-Masson yet negative for Perls Prussian blue. Lal et al10 demonstrated complete resolution of abnormal skin pigmentation within 5 years after stopping chlorpromazine. In contrast, minocyclineinduced hyperpigmentation may be permanent in some cases. There is substantial clinical and histologic overlap for drug-induced hyperpigmentation etiologies; it would behoove the clinician to focus on the most common locations affected and the generalized coloration.

Treatment of minocycline-induced hyperpigmentation includes the use of Q-switched lasers, specifically Q-switched ruby and Q-switched alexandrite.¹¹ The use of the Q-switched Nd:YAG laser appears to be ineffective at clearing minocycline-induced pigmentation.^7,11 In our patient, minocycline was discontinued immediately. Due to the patient’s critical condition, he deferred all other therapy. Erythema dyschromicum perstans, also referred to as ashy dermatosis, is an idiopathic form of hyperpigmentation.¹² Lesions start as blue-gray to ashy gray macules, occasionally surrounded by a slightly erythematous, raised border.

Erythema dyschromicum perstans typically presents on the trunk, face, and arms of patients with Fitzpatrick skin types III and IV; it is considered a variant of lichen planus actinicus.¹² Histologically, erythema dyschromicum perstans may mimic lichen planus pigmentosus (LPP); however, subtle differences exist to distinguish the 2 conditions. Erythema dyschromicum perstans demonstrates a mild lichenoid infiltrate, focal basal vacuolization at the dermoepidermal junction, and melanophage deposition.¹³ In contrast, LPP demonstrates pigmentary incontinence and a more severe inflammatory infiltrate. A perifollicular infiltrate and fibrosis also can be seen in LPP, which may explain the frontal fibrosing alopecia that often precedes LPP.¹³

Addison disease, also known as primary adrenal insufficiency, can cause diffuse hyperpigmentation in the skin, mucosae, and nail beds. The pigmentation is prominent in regions of naturally increased pigmentation, such as the flexural surfaces and intertriginous areas.¹⁴ Patients with adrenal insufficiency will have accompanying weight loss, hypotension, and fatigue, among other symptoms related to deficiency of cortisol and aldosterone. Skin biopsy shows acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin deposition, and superficial dermal macrophages.¹⁵

Confluent and reticulated papillomatosis is an uncommon dermatosis that presents with multiple hyperpigmented macules and papules that coalesce to form patches and plaques centrally with reticulation in the periphery.¹⁶ Confluent and reticulated papillomatosis commonly presents on the upper trunk, axillae, and neck, though involvement can include flexural surfaces as well as the lower trunk and legs.^16,17 Biopsy demonstrates undulating hyperkeratosis, papillomatosis, acanthosis, and negative fungal staining.¹⁶

Pretibial myxedema most commonly is associated with Graves disease and presents as well-defined thickening and induration with overlying pink or purple-brown papules in the pretibial region.¹⁸ An acral surface and mucin deposition within the entire dermis may be appreciated on histology with staining for colloidal iron or Alcian blue.

Johnson & Johnson asked the Food and Drug Administration (FDA) on Tuesday to authorize an extra dose of its COVID-19 vaccine as a booster shot.

The company said it filed a request for people ages 18 and older who have received the one-shot vaccine. Johnson & Johnson submitted data for several different booster intervals -- ranging from 2 months to 6 months -- but didn’t formally recommend one to the FDA, The Associated Press reported.

“We’re describing the data to them,” Mathai Mammen, MD, head of global research and development for Janssen, the company’s vaccine division, told CNN.

“The process is not that we asked for a very specific interval -- we’re providing them data and we’re going to be presenting to the committee,” he said. “They’ll take all that into consideration when they ultimately decide on an appropriate interval.”

The FDA’s independent vaccine advisory committee meets next week to review data on booster shots from both Johnson & Johnson and Moderna. It’s the first step in the review process, which then requires approval from leaders at the FDA and Centers for Disease Control and Prevention. If both agencies authorize the extra shots, Americans could receive boosters from Johnson & Johnson and Moderna later this month, the AP reported.

Johnson & Johnson previously released data that showed the vaccine remains highly effective against COVID-19 at least 5 months after vaccination, with 81% efficacy against hospitalizations in the United States.

Two weeks ago, the company reported that a booster dose at 2 months or 6 months further lifted immunity, with a booster at 2 months providing 94% protection against moderate and severe COVID-19. The company said the 6-month booster raised antibodies by 12 times but didn’t release additional data at that time.

In September, the FDA authorized booster shots of the Pfizer vaccine for ages 65 and older, those who live in long-term care facilities, and those with higher risks for contracting COVID-19. The Biden administration is supporting a booster campaign to address potential waning vaccine immunity and remaining surges of the more contagious Delta variant, the AP reported.

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

Johnson & Johnson asked the Food and Drug Administration (FDA) on Tuesday to authorize an extra dose of its COVID-19 vaccine as a booster shot.

The company said it filed a request for people ages 18 and older who have received the one-shot vaccine. Johnson & Johnson submitted data for several different booster intervals -- ranging from 2 months to 6 months -- but didn’t formally recommend one to the FDA, The Associated Press reported.

“We’re describing the data to them,” Mathai Mammen, MD, head of global research and development for Janssen, the company’s vaccine division, told CNN.

“The process is not that we asked for a very specific interval -- we’re providing them data and we’re going to be presenting to the committee,” he said. “They’ll take all that into consideration when they ultimately decide on an appropriate interval.”

The FDA’s independent vaccine advisory committee meets next week to review data on booster shots from both Johnson & Johnson and Moderna. It’s the first step in the review process, which then requires approval from leaders at the FDA and Centers for Disease Control and Prevention. If both agencies authorize the extra shots, Americans could receive boosters from Johnson & Johnson and Moderna later this month, the AP reported.

Johnson & Johnson previously released data that showed the vaccine remains highly effective against COVID-19 at least 5 months after vaccination, with 81% efficacy against hospitalizations in the United States.

Two weeks ago, the company reported that a booster dose at 2 months or 6 months further lifted immunity, with a booster at 2 months providing 94% protection against moderate and severe COVID-19. The company said the 6-month booster raised antibodies by 12 times but didn’t release additional data at that time.

In September, the FDA authorized booster shots of the Pfizer vaccine for ages 65 and older, those who live in long-term care facilities, and those with higher risks for contracting COVID-19. The Biden administration is supporting a booster campaign to address potential waning vaccine immunity and remaining surges of the more contagious Delta variant, the AP reported.

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

Johnson & Johnson asked the Food and Drug Administration (FDA) on Tuesday to authorize an extra dose of its COVID-19 vaccine as a booster shot.

The company said it filed a request for people ages 18 and older who have received the one-shot vaccine. Johnson & Johnson submitted data for several different booster intervals -- ranging from 2 months to 6 months -- but didn’t formally recommend one to the FDA, The Associated Press reported.

“We’re describing the data to them,” Mathai Mammen, MD, head of global research and development for Janssen, the company’s vaccine division, told CNN.

“The process is not that we asked for a very specific interval -- we’re providing them data and we’re going to be presenting to the committee,” he said. “They’ll take all that into consideration when they ultimately decide on an appropriate interval.”

The FDA’s independent vaccine advisory committee meets next week to review data on booster shots from both Johnson & Johnson and Moderna. It’s the first step in the review process, which then requires approval from leaders at the FDA and Centers for Disease Control and Prevention. If both agencies authorize the extra shots, Americans could receive boosters from Johnson & Johnson and Moderna later this month, the AP reported.

Johnson & Johnson previously released data that showed the vaccine remains highly effective against COVID-19 at least 5 months after vaccination, with 81% efficacy against hospitalizations in the United States.

Two weeks ago, the company reported that a booster dose at 2 months or 6 months further lifted immunity, with a booster at 2 months providing 94% protection against moderate and severe COVID-19. The company said the 6-month booster raised antibodies by 12 times but didn’t release additional data at that time.

In September, the FDA authorized booster shots of the Pfizer vaccine for ages 65 and older, those who live in long-term care facilities, and those with higher risks for contracting COVID-19. The Biden administration is supporting a booster campaign to address potential waning vaccine immunity and remaining surges of the more contagious Delta variant, the AP reported.

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