MDedge Dermatology

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis of unknown etiology characterized by erythematosquamous salmon-colored plaques with well-demarcated islands of unaffected skin and hyperkeratotic follicles.¹ In the United States, an incidence of 1 in 3500to 5000 patients presenting to dermatology clinics has been reported.² Pityriasis rubra pilaris has several subtypes and variability in presentation that can make accurate and timely diagnosis challenging.^3-5 Herein, we present a case of PRP with complex diagnostic and therapeutic challenges.

A 22-year-old woman presented with symmetrical, well-demarcated, hyperkeratotic, erythematous plaques with a carnauba wax–like appearance on the palms (Figure 1), soles, elbows, and trunk covering approximately 5% of the body surface area. Two weeks prior to presentation, she experienced an upper respiratory tract infection without any treatment and subsequently developed redness on the palms, which became very hard and scaly. The redness then spread to the elbows, soles, and trunk. She reported itching as well as pain in areas of fissuring. Hand mobility became restricted due to thick scale.

The patient’s medical history was notable for suspected psoriasis 9 years prior, but there were no records or biopsy reports that could be obtained to confirm the diagnosis. She also reported a similar skin condition in her father, which also was diagnosed as psoriasis, but this diagnosis could not be verified.

Although the morphology of the lesions was most consistent with localized PRP, atypical psoriasis, palmoplantar keratoderma (PPK), and erythroderma progressive symmetrica (EPS) also were considered given the personal and family history of suspected psoriasis. A biopsy could not be obtained due to an insurance issue. She was started on clobetasol cream 0.05% and ointment. At 2-week follow-up, her condition remained unchanged. Empiric systemic treatment was discussed, which would potentially work for diagnoses of both PRP and psoriasis. Due to the history of psoriasis and level of discomfort, cyclosporine 300 mg once daily was started to gain rapid control of the disease. Methotrexate also was considered due to its efficacy and economic considerations but was not selected due to patient concerns about the medication.

After 10 weeks of cyclosporine treatment, our patient showed some improvement of the skin with decreased scale and flattening of plaques but not complete resolution. At this point, a biopsy was able to be obtained with prior authorization. A 4-mm punch biopsy of the right flank demonstrated a psoriasiform and papillated epidermis with multifocally capped, compact parakeratosis and minimal lymphocytic infiltrate consistent with PRP. Although EPS also was on the histologic differential, clinical history was more consistent with a diagnosis of PRP. There was some minimal improvement with cyclosporine, but with the diagnosis of PRP confirmed, a systemic retinoid became the treatment of choice. Although acitretin is the preferred treatment for PRP, given that pregnancy would be contraindicated during and for 3 years following acitretin therapy, a trial of isotretinoin 40 mg once daily was started due to its shorter half-life compared to acitretin and was continued for 3 months (Figure 2).^6,7

The diagnosis of PRP often can be challenging given the variety of clinical presentations. This case was an atypical presentation of PRP with several learning points, as our patient’s condition did not fit perfectly into any of the 6 types of PRP. The age of onset was atypical at 22 years old. Pityriasis rubra pilaris typically presents with a bimodal age distribution, appearing either in the first decade or the fifth to sixth decades of life.^3,8 Her clinical presentation was atypical for adult-onset types I and II, which typically present with cephalocaudal progression or ichthyosiform dermatitis, respectively. Her presentation also was atypical for juvenile onset in types III, IV, and V, which tend to present in younger children and with different physical examination findings.^3,8

The morphology of our patient’s lesions also was atypical for PRP, PPK, EPS, and psoriasis. The clinical presentation had features of these entities with erythema, fissuring, xerosis, carnauba wax–like appearance, symmetric scale, and well-demarcated plaques. Although these findings are not mutually exclusive, their combined presentation is atypical. Coupled with the ambiguous family history of similar skin disease in the patient’s father, the discussion of genodermatoses, particularly PPK, further confounded the diagnosis.^4,9 When evaluating for PRP, especially with any family history of skin conditions, genodermatoses should be considered. Furthermore, our patient’s remote and unverifiable history of psoriasis serves as a cautionary reminder that prior diagnoses and medical history always should be reasonably scrutinized. Additionally, a drug-induced PRP eruption also should be considered. Although our patient received no medical treatment for the upper respiratory tract infection prior to the onset of PRP, there have been several reports of drug-induced PRP.^10-12

The therapeutic challenge in this case is one that often is encountered in clinical practice. The health care system often may pose a barrier to diagnosis by inhibiting particular services required for adequate patient care. For our patient, diagnosis was delayed by several weeks due to difficulties obtaining a diagnostic skin biopsy. When faced with challenges from health care infrastructure, creativity with treatment options, such as finding an empiric treatment option (cyclosporine in this case), must be considered.

Systemic retinoids have been found to be efficacious treatment options for PRP, but when dealing with a woman of reproductive age, reproductive preferences must be discussed before identifying an appropriate treatment regimen.^1,13-15 The half-life of acitretin compared to isotretinoin is 2 days vs 22 hours.^6,16 With alcohol consumption, acitretin can be metabolized to etretinate, which has a half-life of 120 days.¹⁷ In our patient, isotretinoin was a more manageable option to allow for greater reproductive freedom upon treatment completion.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis of unknown etiology characterized by erythematosquamous salmon-colored plaques with well-demarcated islands of unaffected skin and hyperkeratotic follicles.¹ In the United States, an incidence of 1 in 3500to 5000 patients presenting to dermatology clinics has been reported.² Pityriasis rubra pilaris has several subtypes and variability in presentation that can make accurate and timely diagnosis challenging.^3-5 Herein, we present a case of PRP with complex diagnostic and therapeutic challenges.

A 22-year-old woman presented with symmetrical, well-demarcated, hyperkeratotic, erythematous plaques with a carnauba wax–like appearance on the palms (Figure 1), soles, elbows, and trunk covering approximately 5% of the body surface area. Two weeks prior to presentation, she experienced an upper respiratory tract infection without any treatment and subsequently developed redness on the palms, which became very hard and scaly. The redness then spread to the elbows, soles, and trunk. She reported itching as well as pain in areas of fissuring. Hand mobility became restricted due to thick scale.

The patient’s medical history was notable for suspected psoriasis 9 years prior, but there were no records or biopsy reports that could be obtained to confirm the diagnosis. She also reported a similar skin condition in her father, which also was diagnosed as psoriasis, but this diagnosis could not be verified.

Although the morphology of the lesions was most consistent with localized PRP, atypical psoriasis, palmoplantar keratoderma (PPK), and erythroderma progressive symmetrica (EPS) also were considered given the personal and family history of suspected psoriasis. A biopsy could not be obtained due to an insurance issue. She was started on clobetasol cream 0.05% and ointment. At 2-week follow-up, her condition remained unchanged. Empiric systemic treatment was discussed, which would potentially work for diagnoses of both PRP and psoriasis. Due to the history of psoriasis and level of discomfort, cyclosporine 300 mg once daily was started to gain rapid control of the disease. Methotrexate also was considered due to its efficacy and economic considerations but was not selected due to patient concerns about the medication.

After 10 weeks of cyclosporine treatment, our patient showed some improvement of the skin with decreased scale and flattening of plaques but not complete resolution. At this point, a biopsy was able to be obtained with prior authorization. A 4-mm punch biopsy of the right flank demonstrated a psoriasiform and papillated epidermis with multifocally capped, compact parakeratosis and minimal lymphocytic infiltrate consistent with PRP. Although EPS also was on the histologic differential, clinical history was more consistent with a diagnosis of PRP. There was some minimal improvement with cyclosporine, but with the diagnosis of PRP confirmed, a systemic retinoid became the treatment of choice. Although acitretin is the preferred treatment for PRP, given that pregnancy would be contraindicated during and for 3 years following acitretin therapy, a trial of isotretinoin 40 mg once daily was started due to its shorter half-life compared to acitretin and was continued for 3 months (Figure 2).^6,7

The diagnosis of PRP often can be challenging given the variety of clinical presentations. This case was an atypical presentation of PRP with several learning points, as our patient’s condition did not fit perfectly into any of the 6 types of PRP. The age of onset was atypical at 22 years old. Pityriasis rubra pilaris typically presents with a bimodal age distribution, appearing either in the first decade or the fifth to sixth decades of life.^3,8 Her clinical presentation was atypical for adult-onset types I and II, which typically present with cephalocaudal progression or ichthyosiform dermatitis, respectively. Her presentation also was atypical for juvenile onset in types III, IV, and V, which tend to present in younger children and with different physical examination findings.^3,8

The morphology of our patient’s lesions also was atypical for PRP, PPK, EPS, and psoriasis. The clinical presentation had features of these entities with erythema, fissuring, xerosis, carnauba wax–like appearance, symmetric scale, and well-demarcated plaques. Although these findings are not mutually exclusive, their combined presentation is atypical. Coupled with the ambiguous family history of similar skin disease in the patient’s father, the discussion of genodermatoses, particularly PPK, further confounded the diagnosis.^4,9 When evaluating for PRP, especially with any family history of skin conditions, genodermatoses should be considered. Furthermore, our patient’s remote and unverifiable history of psoriasis serves as a cautionary reminder that prior diagnoses and medical history always should be reasonably scrutinized. Additionally, a drug-induced PRP eruption also should be considered. Although our patient received no medical treatment for the upper respiratory tract infection prior to the onset of PRP, there have been several reports of drug-induced PRP.^10-12

The therapeutic challenge in this case is one that often is encountered in clinical practice. The health care system often may pose a barrier to diagnosis by inhibiting particular services required for adequate patient care. For our patient, diagnosis was delayed by several weeks due to difficulties obtaining a diagnostic skin biopsy. When faced with challenges from health care infrastructure, creativity with treatment options, such as finding an empiric treatment option (cyclosporine in this case), must be considered.

Systemic retinoids have been found to be efficacious treatment options for PRP, but when dealing with a woman of reproductive age, reproductive preferences must be discussed before identifying an appropriate treatment regimen.^1,13-15 The half-life of acitretin compared to isotretinoin is 2 days vs 22 hours.^6,16 With alcohol consumption, acitretin can be metabolized to etretinate, which has a half-life of 120 days.¹⁷ In our patient, isotretinoin was a more manageable option to allow for greater reproductive freedom upon treatment completion.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis of unknown etiology characterized by erythematosquamous salmon-colored plaques with well-demarcated islands of unaffected skin and hyperkeratotic follicles.¹ In the United States, an incidence of 1 in 3500to 5000 patients presenting to dermatology clinics has been reported.² Pityriasis rubra pilaris has several subtypes and variability in presentation that can make accurate and timely diagnosis challenging.^3-5 Herein, we present a case of PRP with complex diagnostic and therapeutic challenges.

A 22-year-old woman presented with symmetrical, well-demarcated, hyperkeratotic, erythematous plaques with a carnauba wax–like appearance on the palms (Figure 1), soles, elbows, and trunk covering approximately 5% of the body surface area. Two weeks prior to presentation, she experienced an upper respiratory tract infection without any treatment and subsequently developed redness on the palms, which became very hard and scaly. The redness then spread to the elbows, soles, and trunk. She reported itching as well as pain in areas of fissuring. Hand mobility became restricted due to thick scale.

The patient’s medical history was notable for suspected psoriasis 9 years prior, but there were no records or biopsy reports that could be obtained to confirm the diagnosis. She also reported a similar skin condition in her father, which also was diagnosed as psoriasis, but this diagnosis could not be verified.

Although the morphology of the lesions was most consistent with localized PRP, atypical psoriasis, palmoplantar keratoderma (PPK), and erythroderma progressive symmetrica (EPS) also were considered given the personal and family history of suspected psoriasis. A biopsy could not be obtained due to an insurance issue. She was started on clobetasol cream 0.05% and ointment. At 2-week follow-up, her condition remained unchanged. Empiric systemic treatment was discussed, which would potentially work for diagnoses of both PRP and psoriasis. Due to the history of psoriasis and level of discomfort, cyclosporine 300 mg once daily was started to gain rapid control of the disease. Methotrexate also was considered due to its efficacy and economic considerations but was not selected due to patient concerns about the medication.

After 10 weeks of cyclosporine treatment, our patient showed some improvement of the skin with decreased scale and flattening of plaques but not complete resolution. At this point, a biopsy was able to be obtained with prior authorization. A 4-mm punch biopsy of the right flank demonstrated a psoriasiform and papillated epidermis with multifocally capped, compact parakeratosis and minimal lymphocytic infiltrate consistent with PRP. Although EPS also was on the histologic differential, clinical history was more consistent with a diagnosis of PRP. There was some minimal improvement with cyclosporine, but with the diagnosis of PRP confirmed, a systemic retinoid became the treatment of choice. Although acitretin is the preferred treatment for PRP, given that pregnancy would be contraindicated during and for 3 years following acitretin therapy, a trial of isotretinoin 40 mg once daily was started due to its shorter half-life compared to acitretin and was continued for 3 months (Figure 2).^6,7

The diagnosis of PRP often can be challenging given the variety of clinical presentations. This case was an atypical presentation of PRP with several learning points, as our patient’s condition did not fit perfectly into any of the 6 types of PRP. The age of onset was atypical at 22 years old. Pityriasis rubra pilaris typically presents with a bimodal age distribution, appearing either in the first decade or the fifth to sixth decades of life.^3,8 Her clinical presentation was atypical for adult-onset types I and II, which typically present with cephalocaudal progression or ichthyosiform dermatitis, respectively. Her presentation also was atypical for juvenile onset in types III, IV, and V, which tend to present in younger children and with different physical examination findings.^3,8

The morphology of our patient’s lesions also was atypical for PRP, PPK, EPS, and psoriasis. The clinical presentation had features of these entities with erythema, fissuring, xerosis, carnauba wax–like appearance, symmetric scale, and well-demarcated plaques. Although these findings are not mutually exclusive, their combined presentation is atypical. Coupled with the ambiguous family history of similar skin disease in the patient’s father, the discussion of genodermatoses, particularly PPK, further confounded the diagnosis.^4,9 When evaluating for PRP, especially with any family history of skin conditions, genodermatoses should be considered. Furthermore, our patient’s remote and unverifiable history of psoriasis serves as a cautionary reminder that prior diagnoses and medical history always should be reasonably scrutinized. Additionally, a drug-induced PRP eruption also should be considered. Although our patient received no medical treatment for the upper respiratory tract infection prior to the onset of PRP, there have been several reports of drug-induced PRP.^10-12

The therapeutic challenge in this case is one that often is encountered in clinical practice. The health care system often may pose a barrier to diagnosis by inhibiting particular services required for adequate patient care. For our patient, diagnosis was delayed by several weeks due to difficulties obtaining a diagnostic skin biopsy. When faced with challenges from health care infrastructure, creativity with treatment options, such as finding an empiric treatment option (cyclosporine in this case), must be considered.

Systemic retinoids have been found to be efficacious treatment options for PRP, but when dealing with a woman of reproductive age, reproductive preferences must be discussed before identifying an appropriate treatment regimen.^1,13-15 The half-life of acitretin compared to isotretinoin is 2 days vs 22 hours.^6,16 With alcohol consumption, acitretin can be metabolized to etretinate, which has a half-life of 120 days.¹⁷ In our patient, isotretinoin was a more manageable option to allow for greater reproductive freedom upon treatment completion.

Soon after Merck announced on Oct. 1 that it would ask federal regulators for emergency use authorization (EUA) for its auspicious new COVID-19 pill, the accolades began.

Former Food and Drug Administration chief Scott Gottlieb, MD, told CNBC the drug was “a profound game changer.” Top infectious disease expert Anthony S. Fauci, MD, called the early data “impressive.” The World Health Organization termed it “certainly good news,” while saying it awaits more data.

Merck, partnering with Ridgeback Biotherapeutics on the investigational oral antiviral medicine molnupiravir, plans to submit applications to regulatory agencies worldwide, hoping to deliver the first oral antiviral medication for COVID-19. 

Interim clinical trial results show that the drug may slash the risk for hospitalization or death by 50% in those with mild to moderate COVID-19.

When the results were found to be so favorable, the study was halted at the recommendation of an independent data-monitoring committee and in consultation with the FDA.

That initial enthusiasm is now tempered with some perspective on the pros and cons. “This anticipated drug has gotten a little more hype than it deserves,” said William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tenn. He and others suggest a reality check.

“It’s not exactly a home run, like penicillin for strep throat,” agreed Carl Fichtenbaum, MD, professor of infectious diseases at the University of Cincinnati, who is investigating a similar pill for a rival company, Atea, partnering with Roche. 

“But it is encouraging,” he said. “It will probably be an incremental improvement on what we have.” The fact that it can be taken at home is a plus: “Anything we can do to keep people from getting sicker is a good thing.”

“The data show in this higher risk group [those who were studied had at least one risk factor for severe COVID-19, such as age or a medical condition], it reduces the risk of advancing to severe disease by 50%,” Dr. Schaffner said. While that’s a clear benefit for half, it of course leaves the other half without benefit, he said.

Others critiqued the predicted cost of the drug. The U.S. government has already agreed to pay about $700 per patient, according to a new report from Harvard T. H. Chan School of Public Health, Boston, and King’s College Hospital, London. That analysis concluded that the actual cost of production for the 5-day course is $17.74.

“We fully expect that having an oral treatment that reduces the risk of hospitalizations will be significantly cost effective for society,” Melissa Moody, a Merck spokesperson, told this news organization. “We are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”

Merck expects to produce 10 million courses of treatment by the end of the year, with additional doses expected to be produced in 2022, according to a company press release. Earlier in 2021, Merck finalized its agreement with the U.S. government to supply about 1.7 million courses of the drug at the $700 price, once an EUA or FDA approval is given.

Merck also has supply and purchase agreements with other governments worldwide, pending regulatory approval.
 

Study details

Details about the study findings came from a Merck press release. In the planned interim analysis, Merck and Ridgeback evaluated data from 775 patients initially enrolled in the phase 3 MOVe-OUT trial.

All adults had lab-confirmed mild to moderate COVID-19, and reported onset of symptoms within 5 days of being randomly assigned to the drug or placebo. All had at least one risk factor linked with poor disease outcome (such as older age or obesity).

The drug is a ribonucleoside and works by creating mutations in the virus’s genome, halting the ability of the virus to replicate.

Through day 29 of the study, the drug reduced the risk or hospitalization or death by about 50%. While 7.3% of those who received the drug either died or were hospitalized by day 29, 14.1% of those on placebo did, a statistically significant difference (P = .0012).

Side effects were similar in both groups, with 35% of the drug-treated and 40% of the placebo group reporting some side effect, Merck reported. Adverse drug-related events were 12% in the drug group and 11% in the placebo group. While 1.3% of the drug-treated group quit the study because of an adverse event, 3.4% of the placebo group quit.
 

Pros, cons, and unknowns

The ability to take the drug orally, and at home, is a definite plus, Dr. Schaffner said,  compared with the monoclonal antibody treatment currently approved that must be given intravenously or subcutaneously and in certain locations.

More people could be reached and helped with the option of an at-home, oral medicine, he and others agreed.

The regimen for molnupiravir is four pills, two times daily, for 5 days, even if symptoms are mild. As with other prescription drugs, “there will always be folks who don’t comply completely” with the prescribed regimen, Dr. Schaffner said. With this pill, that might be especially true if the symptoms are very mild.

The 50% reduction is not as effective as the benefit often quoted for monoclonal antibody treatment. In clinical trials of Regeneron’s monoclonal antibody treatment, the regimen reduced COVID-19–related hospitalization or death in high-risk patients by 70%.

Even so, the new pill could change the pandemic’s course, others say. “I think molnupiravir has the potential to change how we take care of people who have COVID and risk factors for developing severe disease,” Rajesh Tim Gandhi, MD, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization. 

“What we’ll need to do, however, is make sure that people get tested quickly after they develop symptoms and, if they’re confirmed to have COVID, start on the pills within 5 days of developing symptoms,” he said, while warning that more data are needed about the drug and the trial results.

Another concern is that the promise of a pill will stall vaccination rates, with some people figuring why get vaccinated when they can obtain the pill if they do get sick.

Relying on treatment alone won’t work, Dr. Schaffner said. “Let’s [also] focus on prevention, which is the vaccine. We have to keep working both sides of the street.”

Dr. Gandhi added: “It’s important to remember that even though molnupiravir reduced the likelihood of hospitalization and death, a number of people who received the drug still got sick enough to end up in the hospital.”

Also unknown, he said, is how severe their disease was and whether they will develop long COVID.

The Merck study included only unvaccinated people. Might it work for those vaccinated people who get a breakthrough infection? “From a purely scientific perspective, there is no reason to believe molnupiravir would not work in people who are vaccinated, but the overall efficacy on top of the vaccine is likely dependent on how well they were able to mount a protective immune response to the vaccine,” Ms. Moody said. Still, Merck believes the pill could be of benefit for these infections too, she added.

As for the expected cost, Ms. Moody said that the company takes into account a number of factors in setting pricing, “but fundamentally we look at the impact of the disease, the benefits that the drug delivers to patients and to society, and at supporting ongoing drug development.”
 

On Merck’s heels: Pfizer, Roche, Atea

Pfizer is studying an antiviral pill, PF-07321332, a protease inhibitor that blocks the protease enzymes and halts replication of the virus.

In addition to studying the drug in infected patients at high risk of severe illness and in those at typical risk, Pfizer launched a phase 2-3 study in late September that will enroll people who live in the same household as a person with a confirmed, symptomatic COVID-19 infection to see if the drug can prevent disease in those who have been exposed.

Atea and Roche’s COVID pill, AT527, is in phase 3 trials as well. AT527 is an inhibitor of polymerase, an enzyme many viruses have, to stop replications. Atea is evaluating the drug to reduce disease “burden” and for both pre- and postexposure prevention.
 

Big picture: Role of COVID-19 pills

It may be necessary to target the coronavirus with more than one antiviral agent, said Dr. Fichtenbaum, a principal investigator for the AT527 trials. 

“Sometimes viruses require two or three active agents to control their replication,” he said, citing information gleaned from other viral research, such as HIV. For control of HIV infection, a cocktail or combination of antivirals is often recommended.

That may well be the case for COVID-19, Dr. Fichtenbaum said. The goal would be to attack the virus at more than one pathway.

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

Soon after Merck announced on Oct. 1 that it would ask federal regulators for emergency use authorization (EUA) for its auspicious new COVID-19 pill, the accolades began.

Former Food and Drug Administration chief Scott Gottlieb, MD, told CNBC the drug was “a profound game changer.” Top infectious disease expert Anthony S. Fauci, MD, called the early data “impressive.” The World Health Organization termed it “certainly good news,” while saying it awaits more data.

Merck, partnering with Ridgeback Biotherapeutics on the investigational oral antiviral medicine molnupiravir, plans to submit applications to regulatory agencies worldwide, hoping to deliver the first oral antiviral medication for COVID-19. 

Interim clinical trial results show that the drug may slash the risk for hospitalization or death by 50% in those with mild to moderate COVID-19.

When the results were found to be so favorable, the study was halted at the recommendation of an independent data-monitoring committee and in consultation with the FDA.

That initial enthusiasm is now tempered with some perspective on the pros and cons. “This anticipated drug has gotten a little more hype than it deserves,” said William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tenn. He and others suggest a reality check.

“It’s not exactly a home run, like penicillin for strep throat,” agreed Carl Fichtenbaum, MD, professor of infectious diseases at the University of Cincinnati, who is investigating a similar pill for a rival company, Atea, partnering with Roche. 

“But it is encouraging,” he said. “It will probably be an incremental improvement on what we have.” The fact that it can be taken at home is a plus: “Anything we can do to keep people from getting sicker is a good thing.”

“The data show in this higher risk group [those who were studied had at least one risk factor for severe COVID-19, such as age or a medical condition], it reduces the risk of advancing to severe disease by 50%,” Dr. Schaffner said. While that’s a clear benefit for half, it of course leaves the other half without benefit, he said.

Others critiqued the predicted cost of the drug. The U.S. government has already agreed to pay about $700 per patient, according to a new report from Harvard T. H. Chan School of Public Health, Boston, and King’s College Hospital, London. That analysis concluded that the actual cost of production for the 5-day course is $17.74.

“We fully expect that having an oral treatment that reduces the risk of hospitalizations will be significantly cost effective for society,” Melissa Moody, a Merck spokesperson, told this news organization. “We are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”

Merck expects to produce 10 million courses of treatment by the end of the year, with additional doses expected to be produced in 2022, according to a company press release. Earlier in 2021, Merck finalized its agreement with the U.S. government to supply about 1.7 million courses of the drug at the $700 price, once an EUA or FDA approval is given.

Merck also has supply and purchase agreements with other governments worldwide, pending regulatory approval.
 

Study details

Details about the study findings came from a Merck press release. In the planned interim analysis, Merck and Ridgeback evaluated data from 775 patients initially enrolled in the phase 3 MOVe-OUT trial.

All adults had lab-confirmed mild to moderate COVID-19, and reported onset of symptoms within 5 days of being randomly assigned to the drug or placebo. All had at least one risk factor linked with poor disease outcome (such as older age or obesity).

The drug is a ribonucleoside and works by creating mutations in the virus’s genome, halting the ability of the virus to replicate.

Through day 29 of the study, the drug reduced the risk or hospitalization or death by about 50%. While 7.3% of those who received the drug either died or were hospitalized by day 29, 14.1% of those on placebo did, a statistically significant difference (P = .0012).

Side effects were similar in both groups, with 35% of the drug-treated and 40% of the placebo group reporting some side effect, Merck reported. Adverse drug-related events were 12% in the drug group and 11% in the placebo group. While 1.3% of the drug-treated group quit the study because of an adverse event, 3.4% of the placebo group quit.
 

Pros, cons, and unknowns

The ability to take the drug orally, and at home, is a definite plus, Dr. Schaffner said,  compared with the monoclonal antibody treatment currently approved that must be given intravenously or subcutaneously and in certain locations.

More people could be reached and helped with the option of an at-home, oral medicine, he and others agreed.

The regimen for molnupiravir is four pills, two times daily, for 5 days, even if symptoms are mild. As with other prescription drugs, “there will always be folks who don’t comply completely” with the prescribed regimen, Dr. Schaffner said. With this pill, that might be especially true if the symptoms are very mild.

The 50% reduction is not as effective as the benefit often quoted for monoclonal antibody treatment. In clinical trials of Regeneron’s monoclonal antibody treatment, the regimen reduced COVID-19–related hospitalization or death in high-risk patients by 70%.

Even so, the new pill could change the pandemic’s course, others say. “I think molnupiravir has the potential to change how we take care of people who have COVID and risk factors for developing severe disease,” Rajesh Tim Gandhi, MD, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization. 

“What we’ll need to do, however, is make sure that people get tested quickly after they develop symptoms and, if they’re confirmed to have COVID, start on the pills within 5 days of developing symptoms,” he said, while warning that more data are needed about the drug and the trial results.

Another concern is that the promise of a pill will stall vaccination rates, with some people figuring why get vaccinated when they can obtain the pill if they do get sick.

Relying on treatment alone won’t work, Dr. Schaffner said. “Let’s [also] focus on prevention, which is the vaccine. We have to keep working both sides of the street.”

Dr. Gandhi added: “It’s important to remember that even though molnupiravir reduced the likelihood of hospitalization and death, a number of people who received the drug still got sick enough to end up in the hospital.”

Also unknown, he said, is how severe their disease was and whether they will develop long COVID.

The Merck study included only unvaccinated people. Might it work for those vaccinated people who get a breakthrough infection? “From a purely scientific perspective, there is no reason to believe molnupiravir would not work in people who are vaccinated, but the overall efficacy on top of the vaccine is likely dependent on how well they were able to mount a protective immune response to the vaccine,” Ms. Moody said. Still, Merck believes the pill could be of benefit for these infections too, she added.

As for the expected cost, Ms. Moody said that the company takes into account a number of factors in setting pricing, “but fundamentally we look at the impact of the disease, the benefits that the drug delivers to patients and to society, and at supporting ongoing drug development.”
 

On Merck’s heels: Pfizer, Roche, Atea

Pfizer is studying an antiviral pill, PF-07321332, a protease inhibitor that blocks the protease enzymes and halts replication of the virus.

In addition to studying the drug in infected patients at high risk of severe illness and in those at typical risk, Pfizer launched a phase 2-3 study in late September that will enroll people who live in the same household as a person with a confirmed, symptomatic COVID-19 infection to see if the drug can prevent disease in those who have been exposed.

Atea and Roche’s COVID pill, AT527, is in phase 3 trials as well. AT527 is an inhibitor of polymerase, an enzyme many viruses have, to stop replications. Atea is evaluating the drug to reduce disease “burden” and for both pre- and postexposure prevention.
 

Big picture: Role of COVID-19 pills

It may be necessary to target the coronavirus with more than one antiviral agent, said Dr. Fichtenbaum, a principal investigator for the AT527 trials. 

“Sometimes viruses require two or three active agents to control their replication,” he said, citing information gleaned from other viral research, such as HIV. For control of HIV infection, a cocktail or combination of antivirals is often recommended.

That may well be the case for COVID-19, Dr. Fichtenbaum said. The goal would be to attack the virus at more than one pathway.

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

Soon after Merck announced on Oct. 1 that it would ask federal regulators for emergency use authorization (EUA) for its auspicious new COVID-19 pill, the accolades began.

Former Food and Drug Administration chief Scott Gottlieb, MD, told CNBC the drug was “a profound game changer.” Top infectious disease expert Anthony S. Fauci, MD, called the early data “impressive.” The World Health Organization termed it “certainly good news,” while saying it awaits more data.

Merck, partnering with Ridgeback Biotherapeutics on the investigational oral antiviral medicine molnupiravir, plans to submit applications to regulatory agencies worldwide, hoping to deliver the first oral antiviral medication for COVID-19. 

Interim clinical trial results show that the drug may slash the risk for hospitalization or death by 50% in those with mild to moderate COVID-19.

When the results were found to be so favorable, the study was halted at the recommendation of an independent data-monitoring committee and in consultation with the FDA.

That initial enthusiasm is now tempered with some perspective on the pros and cons. “This anticipated drug has gotten a little more hype than it deserves,” said William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center in Nashville, Tenn. He and others suggest a reality check.

“It’s not exactly a home run, like penicillin for strep throat,” agreed Carl Fichtenbaum, MD, professor of infectious diseases at the University of Cincinnati, who is investigating a similar pill for a rival company, Atea, partnering with Roche. 

“But it is encouraging,” he said. “It will probably be an incremental improvement on what we have.” The fact that it can be taken at home is a plus: “Anything we can do to keep people from getting sicker is a good thing.”

“The data show in this higher risk group [those who were studied had at least one risk factor for severe COVID-19, such as age or a medical condition], it reduces the risk of advancing to severe disease by 50%,” Dr. Schaffner said. While that’s a clear benefit for half, it of course leaves the other half without benefit, he said.

Others critiqued the predicted cost of the drug. The U.S. government has already agreed to pay about $700 per patient, according to a new report from Harvard T. H. Chan School of Public Health, Boston, and King’s College Hospital, London. That analysis concluded that the actual cost of production for the 5-day course is $17.74.

“We fully expect that having an oral treatment that reduces the risk of hospitalizations will be significantly cost effective for society,” Melissa Moody, a Merck spokesperson, told this news organization. “We are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic.”

Merck expects to produce 10 million courses of treatment by the end of the year, with additional doses expected to be produced in 2022, according to a company press release. Earlier in 2021, Merck finalized its agreement with the U.S. government to supply about 1.7 million courses of the drug at the $700 price, once an EUA or FDA approval is given.

Merck also has supply and purchase agreements with other governments worldwide, pending regulatory approval.
 

Study details

Details about the study findings came from a Merck press release. In the planned interim analysis, Merck and Ridgeback evaluated data from 775 patients initially enrolled in the phase 3 MOVe-OUT trial.

All adults had lab-confirmed mild to moderate COVID-19, and reported onset of symptoms within 5 days of being randomly assigned to the drug or placebo. All had at least one risk factor linked with poor disease outcome (such as older age or obesity).

The drug is a ribonucleoside and works by creating mutations in the virus’s genome, halting the ability of the virus to replicate.

Through day 29 of the study, the drug reduced the risk or hospitalization or death by about 50%. While 7.3% of those who received the drug either died or were hospitalized by day 29, 14.1% of those on placebo did, a statistically significant difference (P = .0012).

Side effects were similar in both groups, with 35% of the drug-treated and 40% of the placebo group reporting some side effect, Merck reported. Adverse drug-related events were 12% in the drug group and 11% in the placebo group. While 1.3% of the drug-treated group quit the study because of an adverse event, 3.4% of the placebo group quit.
 

Pros, cons, and unknowns

The ability to take the drug orally, and at home, is a definite plus, Dr. Schaffner said,  compared with the monoclonal antibody treatment currently approved that must be given intravenously or subcutaneously and in certain locations.

More people could be reached and helped with the option of an at-home, oral medicine, he and others agreed.

The regimen for molnupiravir is four pills, two times daily, for 5 days, even if symptoms are mild. As with other prescription drugs, “there will always be folks who don’t comply completely” with the prescribed regimen, Dr. Schaffner said. With this pill, that might be especially true if the symptoms are very mild.

The 50% reduction is not as effective as the benefit often quoted for monoclonal antibody treatment. In clinical trials of Regeneron’s monoclonal antibody treatment, the regimen reduced COVID-19–related hospitalization or death in high-risk patients by 70%.

Even so, the new pill could change the pandemic’s course, others say. “I think molnupiravir has the potential to change how we take care of people who have COVID and risk factors for developing severe disease,” Rajesh Tim Gandhi, MD, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization. 

“What we’ll need to do, however, is make sure that people get tested quickly after they develop symptoms and, if they’re confirmed to have COVID, start on the pills within 5 days of developing symptoms,” he said, while warning that more data are needed about the drug and the trial results.

Another concern is that the promise of a pill will stall vaccination rates, with some people figuring why get vaccinated when they can obtain the pill if they do get sick.

Relying on treatment alone won’t work, Dr. Schaffner said. “Let’s [also] focus on prevention, which is the vaccine. We have to keep working both sides of the street.”

Dr. Gandhi added: “It’s important to remember that even though molnupiravir reduced the likelihood of hospitalization and death, a number of people who received the drug still got sick enough to end up in the hospital.”

Also unknown, he said, is how severe their disease was and whether they will develop long COVID.

The Merck study included only unvaccinated people. Might it work for those vaccinated people who get a breakthrough infection? “From a purely scientific perspective, there is no reason to believe molnupiravir would not work in people who are vaccinated, but the overall efficacy on top of the vaccine is likely dependent on how well they were able to mount a protective immune response to the vaccine,” Ms. Moody said. Still, Merck believes the pill could be of benefit for these infections too, she added.

As for the expected cost, Ms. Moody said that the company takes into account a number of factors in setting pricing, “but fundamentally we look at the impact of the disease, the benefits that the drug delivers to patients and to society, and at supporting ongoing drug development.”
 

On Merck’s heels: Pfizer, Roche, Atea

Pfizer is studying an antiviral pill, PF-07321332, a protease inhibitor that blocks the protease enzymes and halts replication of the virus.

In addition to studying the drug in infected patients at high risk of severe illness and in those at typical risk, Pfizer launched a phase 2-3 study in late September that will enroll people who live in the same household as a person with a confirmed, symptomatic COVID-19 infection to see if the drug can prevent disease in those who have been exposed.

Atea and Roche’s COVID pill, AT527, is in phase 3 trials as well. AT527 is an inhibitor of polymerase, an enzyme many viruses have, to stop replications. Atea is evaluating the drug to reduce disease “burden” and for both pre- and postexposure prevention.
 

Big picture: Role of COVID-19 pills

It may be necessary to target the coronavirus with more than one antiviral agent, said Dr. Fichtenbaum, a principal investigator for the AT527 trials. 

“Sometimes viruses require two or three active agents to control their replication,” he said, citing information gleaned from other viral research, such as HIV. For control of HIV infection, a cocktail or combination of antivirals is often recommended.

That may well be the case for COVID-19, Dr. Fichtenbaum said. The goal would be to attack the virus at more than one pathway.

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

To the Editor:

A 40-year-old Somalian man presented to the dermatology clinic with lesions on the eyelids, tongue, lips, and hands of 8 years’ duration. He was a former refugee who had faced considerable stigma from his community due to his appearance. A review of systems was remarkable for decreased appetite but no weight loss. He reported no abdominal distention, early satiety, or urinary symptoms, and he had no personal history of diabetes mellitus or obesity. Physical examination demonstrated hyperpigmented velvety plaques in all skin folds and on the genitalia. Massive papillomatosis of the eyelid margins, tongue, and lips also was noted (Figure 1A). Flesh-colored papules also were scattered across the face. Punctate, flesh-colored papules were present on the volar and palmar hands (Figure 2A). Histopathology demonstrated pronounced papillomatous epidermal hyperplasia with negative human papillomavirus (HPV) type 16 and HPV-18 DNA studies. Given the appearance of malignant acanthosis nigricans with oral and conjunctival features, cutaneous papillomatosis, and tripe palms, concern for underlying malignancy was high. Malignancy workup, including upper and lower endoscopy as well as serial computed tomography scans of the chest, abdomen, and pelvis, was unrevealing.

Laboratory investigation revealed a positive Schistosoma IgG antibody (0.38 geometric mean egg count) and peripheral eosinophilia (1.09 ×10³/μL), which normalized after praziquantel therapy. With no malignancy identified over the preceding 6-month period, treatment with acitretin 50 mg daily was initiated based on limited literature support.^1-3 Treatment led to reduction in the size and number of papillomas (Figure 1B) and tripe palms (Figure 2B) with increased mobility of hands, lips, and tongue. The patient underwent oculoplastic surgery to reduce the papilloma burden along the eyelid margins. Subsequent cystoscopy 9 months after the initial presentation revealed low-grade transitional cell carcinoma of the bladder. Intraoperative mitomycin C led to tumor shrinkage and, with continued treatment with daily acitretin, dramatic improvement of all cutaneous and mucosal symptoms (Figure 1C and Figure 2C). To date, his cutaneous symptoms have resolved.

This case demonstrated a unique presentation of multiple paraneoplastic signs in bladder transitional cell carcinoma. The presence of malignant acanthosis nigricans (including oral and conjunctival involvement), cutaneous papillomatosis, and tripe palms have been individually documented in various types of gastric malignancies.⁴ Acanthosis nigricans often is secondary to diabetes and obesity, presenting with diffuse, thickened, velvety plaques in the flexural areas. Malignant acanthosis nigricans is a rare, rapidly progressive condition that often presents over a period of weeks to months; it almost always is associated with internal malignancies. It often has more extensive involvement, extending beyond the flexural areas, than typical acanthosis nigricans.⁴ Oral involvement can be either hypertrophic or papillomatous; papillomatosis of the oral mucosa was reported in over 40% of malignant acanthosis nigricans cases (N=200).⁵ Cases with conjunctival involvement are less common.⁶ Although malignant acanthosis nigricans often is codiagnosed with a malignancy, it can precede the cancer diagnosis in some cases.^7,8 A majority of cases are associated with adenocarcinomas of the gastrointestinal tract.⁴ Progressive mucocutaneous papillomatosis also is a rare paraneoplastic condition that most commonly is associated with gastric adenocarcinomas. Progressive mucocutaneous papillomatosis often presents rapidly as verrucous growths on cutaneous surfaces (including the hands and face) but also can affect mucosal surfaces such as the mouth and conjunctiva.^9-11 Tripe palms are characterized by exaggerated dermatoglyphics with diffuse palmar ridging and hyperkeratosis. Tripe palms most often are associated with pulmonary malignancies. When tripe palms are present with malignant acanthosis nigricans, they reflect up to a one-third incidence of gastrointestinal malignancy.^12,13

Despite the individual presentation of these paraneoplastic signs in a variety of malignancies, synchronous presentation is rare. A brief literature review only identified 6 cases of concurrent acanthosis nigricans, tripe palms, and progressive mucocutaneous papillomatosis with an underlying gastrointestinal malignancy.^1,11,14-17 Two additional reports described tripe palms with oral acanthosis nigricans and progressive mucocutaneous papillomatosis in metastatic gastric adenocarcinoma and renal urothelial carcinoma.^2,18 An additional case of all 3 paraneoplastic conditions was reported in the setting of metastatic cervical cancer (HPV positive).¹⁹ Per a recent case report and literature review,²⁰ there have only been 8 cases of acanthosis nigricans reported in bladder transitional cell carcinoma,^20-27 half of which have included oral malignant acanthosis nigricans.^20-23 Only one report of concurrent cutaneous and oral malignant acanthosis nigricans and triple palms in the setting of bladder cancer has been reported.²⁰ Given the extensive conjunctival involvement and cutaneous papillomatosis in our patient, ours is a rarely reported case of concurrent malignant mucocutaneous acanthosis nigricans, tripe palms, and progressive papillomatosis in transitional cell bladder carcinoma. We believe it is imperative to consider the role of this malignancy as a cause of these paraneoplastic conditions.

Although these paraneoplastic conditions rarely co-occur, our case further offers a common molecular pathway for these conditions.²⁸ In these paraneoplastic conditions, the stimulating factor is thought to be tumor growth factor α, which is structurally related to epidermal growth factor (EGF). Epidermal growth factor receptors (EGFRs) are found in the basal layer of the epidermis, where activation stimulates keratinocyte growth and leads to the cutaneous manifestation of symptoms.²⁸ Fibroblast growth factor receptor 3 mutations are found in most noninvasive transitional cell tumors of the bladder.²⁹ The fibroblast growth factor pathway is distinctly different from the tumor growth factor α and EGF pathways.³⁰ However, this association with transitional cell carcinoma suggests that fibroblast growth factor receptor 3 also may be implicated in these paraneoplastic conditions.

Our patient responded well to treatment with acitretin 50 mg daily. The mechanism of action of retinoids involves inducing mitotic activity and desmosomal shedding.³¹ Retinoids downregulate EGFR expression and activation in EGF-stimulated cells.³² We hypothesize that these oral retinoids decreased the growth stimulus and thereby improved cutaneous signs in the setting of our patient’s transitional cell cancer. Although definitive therapy is malignancy management, our case highlights the utility of adjunctive measures such as oral retinoids and surgical debulking. While previous cases have reported use of retinoids at a lower dosage than used in this case, oral lesions often have only been mildly improved with little impact on other cutaneous symptoms.^1,2 In one case of malignant acanthosis nigricans and oral papillomatosis, isotretinoin 25 mg once every 2 to 3 days led to a moderate decrease in hyperkeratosis and papillomas, but the patient was lost to follow-up.³ Our case highlights the use of higher daily doses of oral retinoids for over 9 months, resulting in marked improvement in both the mucosal and cutaneous symptoms of acanthosis nigricans, progressive mucocutaneous papillomatosis, and tripe palms. Therefore, oral acitretin should be considered as adjuvant therapy for these paraneoplastic conditions.

By reporting this case, we hope to demonstrate the importance of considering other forms of malignancies in the presence of paraneoplastic conditions. Although gastric malignancies more commonly are associated with these conditions, bladder carcinomas also can present with cutaneous manifestations. The presence of these paraneoplastic conditions alone or together rarely is reported in urologic cancers and generally is considered to be an indicator of poor prognosis. Paraneoplastic conditions often develop rapidly and occur in very advanced malignancies.⁴ The disfiguring presentation in our case also had unusual diagnostic challenges. The presence of these conditions for 8 years and nonmetastatic advanced malignancy suggest a more indolent process and that these signs are not always an indicator of poor prognosis. Future patients with these paraneoplastic conditions may benefit from both a thorough malignancy screen, including cystoscopy, and high daily doses of oral retinoids.

To the Editor:

A 40-year-old Somalian man presented to the dermatology clinic with lesions on the eyelids, tongue, lips, and hands of 8 years’ duration. He was a former refugee who had faced considerable stigma from his community due to his appearance. A review of systems was remarkable for decreased appetite but no weight loss. He reported no abdominal distention, early satiety, or urinary symptoms, and he had no personal history of diabetes mellitus or obesity. Physical examination demonstrated hyperpigmented velvety plaques in all skin folds and on the genitalia. Massive papillomatosis of the eyelid margins, tongue, and lips also was noted (Figure 1A). Flesh-colored papules also were scattered across the face. Punctate, flesh-colored papules were present on the volar and palmar hands (Figure 2A). Histopathology demonstrated pronounced papillomatous epidermal hyperplasia with negative human papillomavirus (HPV) type 16 and HPV-18 DNA studies. Given the appearance of malignant acanthosis nigricans with oral and conjunctival features, cutaneous papillomatosis, and tripe palms, concern for underlying malignancy was high. Malignancy workup, including upper and lower endoscopy as well as serial computed tomography scans of the chest, abdomen, and pelvis, was unrevealing.

Laboratory investigation revealed a positive Schistosoma IgG antibody (0.38 geometric mean egg count) and peripheral eosinophilia (1.09 ×10³/μL), which normalized after praziquantel therapy. With no malignancy identified over the preceding 6-month period, treatment with acitretin 50 mg daily was initiated based on limited literature support.^1-3 Treatment led to reduction in the size and number of papillomas (Figure 1B) and tripe palms (Figure 2B) with increased mobility of hands, lips, and tongue. The patient underwent oculoplastic surgery to reduce the papilloma burden along the eyelid margins. Subsequent cystoscopy 9 months after the initial presentation revealed low-grade transitional cell carcinoma of the bladder. Intraoperative mitomycin C led to tumor shrinkage and, with continued treatment with daily acitretin, dramatic improvement of all cutaneous and mucosal symptoms (Figure 1C and Figure 2C). To date, his cutaneous symptoms have resolved.

This case demonstrated a unique presentation of multiple paraneoplastic signs in bladder transitional cell carcinoma. The presence of malignant acanthosis nigricans (including oral and conjunctival involvement), cutaneous papillomatosis, and tripe palms have been individually documented in various types of gastric malignancies.⁴ Acanthosis nigricans often is secondary to diabetes and obesity, presenting with diffuse, thickened, velvety plaques in the flexural areas. Malignant acanthosis nigricans is a rare, rapidly progressive condition that often presents over a period of weeks to months; it almost always is associated with internal malignancies. It often has more extensive involvement, extending beyond the flexural areas, than typical acanthosis nigricans.⁴ Oral involvement can be either hypertrophic or papillomatous; papillomatosis of the oral mucosa was reported in over 40% of malignant acanthosis nigricans cases (N=200).⁵ Cases with conjunctival involvement are less common.⁶ Although malignant acanthosis nigricans often is codiagnosed with a malignancy, it can precede the cancer diagnosis in some cases.^7,8 A majority of cases are associated with adenocarcinomas of the gastrointestinal tract.⁴ Progressive mucocutaneous papillomatosis also is a rare paraneoplastic condition that most commonly is associated with gastric adenocarcinomas. Progressive mucocutaneous papillomatosis often presents rapidly as verrucous growths on cutaneous surfaces (including the hands and face) but also can affect mucosal surfaces such as the mouth and conjunctiva.^9-11 Tripe palms are characterized by exaggerated dermatoglyphics with diffuse palmar ridging and hyperkeratosis. Tripe palms most often are associated with pulmonary malignancies. When tripe palms are present with malignant acanthosis nigricans, they reflect up to a one-third incidence of gastrointestinal malignancy.^12,13

Despite the individual presentation of these paraneoplastic signs in a variety of malignancies, synchronous presentation is rare. A brief literature review only identified 6 cases of concurrent acanthosis nigricans, tripe palms, and progressive mucocutaneous papillomatosis with an underlying gastrointestinal malignancy.^1,11,14-17 Two additional reports described tripe palms with oral acanthosis nigricans and progressive mucocutaneous papillomatosis in metastatic gastric adenocarcinoma and renal urothelial carcinoma.^2,18 An additional case of all 3 paraneoplastic conditions was reported in the setting of metastatic cervical cancer (HPV positive).¹⁹ Per a recent case report and literature review,²⁰ there have only been 8 cases of acanthosis nigricans reported in bladder transitional cell carcinoma,^20-27 half of which have included oral malignant acanthosis nigricans.^20-23 Only one report of concurrent cutaneous and oral malignant acanthosis nigricans and triple palms in the setting of bladder cancer has been reported.²⁰ Given the extensive conjunctival involvement and cutaneous papillomatosis in our patient, ours is a rarely reported case of concurrent malignant mucocutaneous acanthosis nigricans, tripe palms, and progressive papillomatosis in transitional cell bladder carcinoma. We believe it is imperative to consider the role of this malignancy as a cause of these paraneoplastic conditions.

Although these paraneoplastic conditions rarely co-occur, our case further offers a common molecular pathway for these conditions.²⁸ In these paraneoplastic conditions, the stimulating factor is thought to be tumor growth factor α, which is structurally related to epidermal growth factor (EGF). Epidermal growth factor receptors (EGFRs) are found in the basal layer of the epidermis, where activation stimulates keratinocyte growth and leads to the cutaneous manifestation of symptoms.²⁸ Fibroblast growth factor receptor 3 mutations are found in most noninvasive transitional cell tumors of the bladder.²⁹ The fibroblast growth factor pathway is distinctly different from the tumor growth factor α and EGF pathways.³⁰ However, this association with transitional cell carcinoma suggests that fibroblast growth factor receptor 3 also may be implicated in these paraneoplastic conditions.

Our patient responded well to treatment with acitretin 50 mg daily. The mechanism of action of retinoids involves inducing mitotic activity and desmosomal shedding.³¹ Retinoids downregulate EGFR expression and activation in EGF-stimulated cells.³² We hypothesize that these oral retinoids decreased the growth stimulus and thereby improved cutaneous signs in the setting of our patient’s transitional cell cancer. Although definitive therapy is malignancy management, our case highlights the utility of adjunctive measures such as oral retinoids and surgical debulking. While previous cases have reported use of retinoids at a lower dosage than used in this case, oral lesions often have only been mildly improved with little impact on other cutaneous symptoms.^1,2 In one case of malignant acanthosis nigricans and oral papillomatosis, isotretinoin 25 mg once every 2 to 3 days led to a moderate decrease in hyperkeratosis and papillomas, but the patient was lost to follow-up.³ Our case highlights the use of higher daily doses of oral retinoids for over 9 months, resulting in marked improvement in both the mucosal and cutaneous symptoms of acanthosis nigricans, progressive mucocutaneous papillomatosis, and tripe palms. Therefore, oral acitretin should be considered as adjuvant therapy for these paraneoplastic conditions.

By reporting this case, we hope to demonstrate the importance of considering other forms of malignancies in the presence of paraneoplastic conditions. Although gastric malignancies more commonly are associated with these conditions, bladder carcinomas also can present with cutaneous manifestations. The presence of these paraneoplastic conditions alone or together rarely is reported in urologic cancers and generally is considered to be an indicator of poor prognosis. Paraneoplastic conditions often develop rapidly and occur in very advanced malignancies.⁴ The disfiguring presentation in our case also had unusual diagnostic challenges. The presence of these conditions for 8 years and nonmetastatic advanced malignancy suggest a more indolent process and that these signs are not always an indicator of poor prognosis. Future patients with these paraneoplastic conditions may benefit from both a thorough malignancy screen, including cystoscopy, and high daily doses of oral retinoids.

To the Editor:

A 40-year-old Somalian man presented to the dermatology clinic with lesions on the eyelids, tongue, lips, and hands of 8 years’ duration. He was a former refugee who had faced considerable stigma from his community due to his appearance. A review of systems was remarkable for decreased appetite but no weight loss. He reported no abdominal distention, early satiety, or urinary symptoms, and he had no personal history of diabetes mellitus or obesity. Physical examination demonstrated hyperpigmented velvety plaques in all skin folds and on the genitalia. Massive papillomatosis of the eyelid margins, tongue, and lips also was noted (Figure 1A). Flesh-colored papules also were scattered across the face. Punctate, flesh-colored papules were present on the volar and palmar hands (Figure 2A). Histopathology demonstrated pronounced papillomatous epidermal hyperplasia with negative human papillomavirus (HPV) type 16 and HPV-18 DNA studies. Given the appearance of malignant acanthosis nigricans with oral and conjunctival features, cutaneous papillomatosis, and tripe palms, concern for underlying malignancy was high. Malignancy workup, including upper and lower endoscopy as well as serial computed tomography scans of the chest, abdomen, and pelvis, was unrevealing.

Laboratory investigation revealed a positive Schistosoma IgG antibody (0.38 geometric mean egg count) and peripheral eosinophilia (1.09 ×10³/μL), which normalized after praziquantel therapy. With no malignancy identified over the preceding 6-month period, treatment with acitretin 50 mg daily was initiated based on limited literature support.^1-3 Treatment led to reduction in the size and number of papillomas (Figure 1B) and tripe palms (Figure 2B) with increased mobility of hands, lips, and tongue. The patient underwent oculoplastic surgery to reduce the papilloma burden along the eyelid margins. Subsequent cystoscopy 9 months after the initial presentation revealed low-grade transitional cell carcinoma of the bladder. Intraoperative mitomycin C led to tumor shrinkage and, with continued treatment with daily acitretin, dramatic improvement of all cutaneous and mucosal symptoms (Figure 1C and Figure 2C). To date, his cutaneous symptoms have resolved.

This case demonstrated a unique presentation of multiple paraneoplastic signs in bladder transitional cell carcinoma. The presence of malignant acanthosis nigricans (including oral and conjunctival involvement), cutaneous papillomatosis, and tripe palms have been individually documented in various types of gastric malignancies.⁴ Acanthosis nigricans often is secondary to diabetes and obesity, presenting with diffuse, thickened, velvety plaques in the flexural areas. Malignant acanthosis nigricans is a rare, rapidly progressive condition that often presents over a period of weeks to months; it almost always is associated with internal malignancies. It often has more extensive involvement, extending beyond the flexural areas, than typical acanthosis nigricans.⁴ Oral involvement can be either hypertrophic or papillomatous; papillomatosis of the oral mucosa was reported in over 40% of malignant acanthosis nigricans cases (N=200).⁵ Cases with conjunctival involvement are less common.⁶ Although malignant acanthosis nigricans often is codiagnosed with a malignancy, it can precede the cancer diagnosis in some cases.^7,8 A majority of cases are associated with adenocarcinomas of the gastrointestinal tract.⁴ Progressive mucocutaneous papillomatosis also is a rare paraneoplastic condition that most commonly is associated with gastric adenocarcinomas. Progressive mucocutaneous papillomatosis often presents rapidly as verrucous growths on cutaneous surfaces (including the hands and face) but also can affect mucosal surfaces such as the mouth and conjunctiva.^9-11 Tripe palms are characterized by exaggerated dermatoglyphics with diffuse palmar ridging and hyperkeratosis. Tripe palms most often are associated with pulmonary malignancies. When tripe palms are present with malignant acanthosis nigricans, they reflect up to a one-third incidence of gastrointestinal malignancy.^12,13

Despite the individual presentation of these paraneoplastic signs in a variety of malignancies, synchronous presentation is rare. A brief literature review only identified 6 cases of concurrent acanthosis nigricans, tripe palms, and progressive mucocutaneous papillomatosis with an underlying gastrointestinal malignancy.^1,11,14-17 Two additional reports described tripe palms with oral acanthosis nigricans and progressive mucocutaneous papillomatosis in metastatic gastric adenocarcinoma and renal urothelial carcinoma.^2,18 An additional case of all 3 paraneoplastic conditions was reported in the setting of metastatic cervical cancer (HPV positive).¹⁹ Per a recent case report and literature review,²⁰ there have only been 8 cases of acanthosis nigricans reported in bladder transitional cell carcinoma,^20-27 half of which have included oral malignant acanthosis nigricans.^20-23 Only one report of concurrent cutaneous and oral malignant acanthosis nigricans and triple palms in the setting of bladder cancer has been reported.²⁰ Given the extensive conjunctival involvement and cutaneous papillomatosis in our patient, ours is a rarely reported case of concurrent malignant mucocutaneous acanthosis nigricans, tripe palms, and progressive papillomatosis in transitional cell bladder carcinoma. We believe it is imperative to consider the role of this malignancy as a cause of these paraneoplastic conditions.

Although these paraneoplastic conditions rarely co-occur, our case further offers a common molecular pathway for these conditions.²⁸ In these paraneoplastic conditions, the stimulating factor is thought to be tumor growth factor α, which is structurally related to epidermal growth factor (EGF). Epidermal growth factor receptors (EGFRs) are found in the basal layer of the epidermis, where activation stimulates keratinocyte growth and leads to the cutaneous manifestation of symptoms.²⁸ Fibroblast growth factor receptor 3 mutations are found in most noninvasive transitional cell tumors of the bladder.²⁹ The fibroblast growth factor pathway is distinctly different from the tumor growth factor α and EGF pathways.³⁰ However, this association with transitional cell carcinoma suggests that fibroblast growth factor receptor 3 also may be implicated in these paraneoplastic conditions.

Our patient responded well to treatment with acitretin 50 mg daily. The mechanism of action of retinoids involves inducing mitotic activity and desmosomal shedding.³¹ Retinoids downregulate EGFR expression and activation in EGF-stimulated cells.³² We hypothesize that these oral retinoids decreased the growth stimulus and thereby improved cutaneous signs in the setting of our patient’s transitional cell cancer. Although definitive therapy is malignancy management, our case highlights the utility of adjunctive measures such as oral retinoids and surgical debulking. While previous cases have reported use of retinoids at a lower dosage than used in this case, oral lesions often have only been mildly improved with little impact on other cutaneous symptoms.^1,2 In one case of malignant acanthosis nigricans and oral papillomatosis, isotretinoin 25 mg once every 2 to 3 days led to a moderate decrease in hyperkeratosis and papillomas, but the patient was lost to follow-up.³ Our case highlights the use of higher daily doses of oral retinoids for over 9 months, resulting in marked improvement in both the mucosal and cutaneous symptoms of acanthosis nigricans, progressive mucocutaneous papillomatosis, and tripe palms. Therefore, oral acitretin should be considered as adjuvant therapy for these paraneoplastic conditions.

By reporting this case, we hope to demonstrate the importance of considering other forms of malignancies in the presence of paraneoplastic conditions. Although gastric malignancies more commonly are associated with these conditions, bladder carcinomas also can present with cutaneous manifestations. The presence of these paraneoplastic conditions alone or together rarely is reported in urologic cancers and generally is considered to be an indicator of poor prognosis. Paraneoplastic conditions often develop rapidly and occur in very advanced malignancies.⁴ The disfiguring presentation in our case also had unusual diagnostic challenges. The presence of these conditions for 8 years and nonmetastatic advanced malignancy suggest a more indolent process and that these signs are not always an indicator of poor prognosis. Future patients with these paraneoplastic conditions may benefit from both a thorough malignancy screen, including cystoscopy, and high daily doses of oral retinoids.

With the strong likelihood that dermatologists in the United States will have to resolve dermatologic issues created by cultural cosmetic practices originating elsewhere, strategies for an open nonjudgmental approach are instrumental, according to a dermatologist with expertise in these types of cases who spoke at the Skin of Color Update 2021.

“Instead of avoiding the discussion of cultural practices, we should discuss them and be open about them. It fosters a comfortable environment, trust, and better compliance,” reported Neelam Ajit Vashi, MD, founding director of the Boston University Center for Ethnic Skin.

Out of fear of causing offense, a desire to be discreet, or of personal discomfort with foreign cultural practices, some clinicians might elect to limit themselves to the information that the patient volunteers, which is a mistake, according to Dr. Vashi.

“The avoidance of topics around culture actually limits the ability to have a successful relationship,” she maintained.

Successful encounters are not just based on a willingness to listen, Dr. Vashi said. Clinicians should be seeking a base of knowledge. With growing globalization and widespread immigration, “it is increasingly important for dermatologists in the U.S. to understand the role of cultural practices [in creating skin problems] and recognize the sequelae,” Dr. Vashi said.

Taking some common examples of dermatologic complaints created by cosmetic practices originating elsewhere, Dr. Vashi described key clinical points in addressing complications related to henna, hair removal through threading, and placement of decorative adornments on the forehead, called bindi. In addition, she pointed out common issues with facial and body marking created with kumkum powder, hair oils, and skin lightening agents.
 

Black henna

For cosmetic enhancement, henna is relatively benign. It is also no longer confined to the south Asian communities where it originated. However, Dr. Vashi pointed out that patients of south Asian origin or descent might be more likely to use black henna, a variety with more risks.

Black henna contains additives, such as diaminobenzenes and p-phenylenediamine (PPD), to darken the tone of the product as well as provide other desired characteristics, such as an accelerated drying time. While some patients do develop reactions to conventional henna, the risks of black henna are greater.

“The acute contact dermatitis reactions can include dyspigmentation, leukoderma, and keloids,” Dr. Vashi said. Other complications include erythema multiforme, temporary hypertrichosis, and systemic allergic reactions, such as angioedema.

While those who have had a reaction to henna should avoid further contact, Dr. Vashi warned that sequelae can include cross reactions with latex and rubber as well as some pharmaceutical agents, such as sulfonamides. When taking a patient history, she noted, be aware that risks of henna extend to the hairdressers and cosmeticians who sometimes apply these products on others.

Hair threading, bindi, and kumkum

Hair threading, another practice popularized in south Asia and now growing in popularity globally, involves capturing hairs between cotton threads for removal of both the hair and its follicle. It is a relatively rapid and efficient method of permanent depilation. In addition to pain and erythema, Dr. Vashi reported that the complications associated with hair threading include pigmentary changes, infections such as bullous impetigo, and lesions of koebnerization – such as vitiligo and lichen planus.

Bindi, a Hindi tradition that involves placing adornments between the eyebrows, and kumkum, a powder typically made from turmeric to be employed for decorative markings, have also spread to use outside of their cultural context, according to Dr. Vashi. She said that the complications of these two cosmetic practices are shared, and stem largely from contact dermatitis.

Veena Nair/Moment/Getty Images

Hair oils, skin-lightening agents

Culturally-linked hair oils among patients from south Asia or Africa – or descendants from these areas – can damage hair in a variety of ways as well as cause contact dermatitis. The oils can also exacerbate existing skin diseases.

“Oils with high oleic acid, such as coconut or olive oils or shea butter, can worsen seborrheic dermatitis,” Dr. Vashi cautioned.

Of this list of dermatologic issues induced by culturally linked cosmetic practices, skin lightening agents might pose the most risk for permanent and irreversible complications. Dr. Vashi said that up to 70% of patients using lighteners develop complications, and there is a relationship between the severity of side effects as duration of use increases.

“The problem is that ingredients of many of these products, which are imported illegally and sold on the black market, are often not disclosed,” Dr. Vashi said. Some contain a high content of metals such as lead, copper, and iron, whether they are added intentionally or end up in the product because of poor quality control. For those developing adverse events associated with the products, the obvious treatment is discontinuation.

When patients are unwilling to discontinue any of the products that have led to dermatologic issues, Dr. Vashi encouraged physicians “to take a middle ground.” Simple avoidance can be challenging for practices that are culturally meaningful. In respecting cultural differences, she encouraged tolerance and compromise.

“Often these patients will be doing an alternative medication or intervention, but this does not mean that they are not accepting what we have to offer,” she said. She indicated that mutual respect will lead to better solutions.

The awareness of common cultural practices that can have a harmful impact on the skin is an area of practice that deserves more attention, Andrew F. Alexis, MD, vice-chair for diversity and inclusion in the department of dermatology at Weill Cornell Medical Center, New York, said in an interview.

With the strong likelihood that dermatologists in the United States will have to resolve dermatologic issues created by cultural cosmetic practices originating elsewhere, strategies for an open nonjudgmental approach are instrumental, according to a dermatologist with expertise in these types of cases who spoke at the Skin of Color Update 2021.

“Instead of avoiding the discussion of cultural practices, we should discuss them and be open about them. It fosters a comfortable environment, trust, and better compliance,” reported Neelam Ajit Vashi, MD, founding director of the Boston University Center for Ethnic Skin.

Out of fear of causing offense, a desire to be discreet, or of personal discomfort with foreign cultural practices, some clinicians might elect to limit themselves to the information that the patient volunteers, which is a mistake, according to Dr. Vashi.

“The avoidance of topics around culture actually limits the ability to have a successful relationship,” she maintained.

Successful encounters are not just based on a willingness to listen, Dr. Vashi said. Clinicians should be seeking a base of knowledge. With growing globalization and widespread immigration, “it is increasingly important for dermatologists in the U.S. to understand the role of cultural practices [in creating skin problems] and recognize the sequelae,” Dr. Vashi said.

Taking some common examples of dermatologic complaints created by cosmetic practices originating elsewhere, Dr. Vashi described key clinical points in addressing complications related to henna, hair removal through threading, and placement of decorative adornments on the forehead, called bindi. In addition, she pointed out common issues with facial and body marking created with kumkum powder, hair oils, and skin lightening agents.
 

Black henna

For cosmetic enhancement, henna is relatively benign. It is also no longer confined to the south Asian communities where it originated. However, Dr. Vashi pointed out that patients of south Asian origin or descent might be more likely to use black henna, a variety with more risks.

Black henna contains additives, such as diaminobenzenes and p-phenylenediamine (PPD), to darken the tone of the product as well as provide other desired characteristics, such as an accelerated drying time. While some patients do develop reactions to conventional henna, the risks of black henna are greater.

“The acute contact dermatitis reactions can include dyspigmentation, leukoderma, and keloids,” Dr. Vashi said. Other complications include erythema multiforme, temporary hypertrichosis, and systemic allergic reactions, such as angioedema.

While those who have had a reaction to henna should avoid further contact, Dr. Vashi warned that sequelae can include cross reactions with latex and rubber as well as some pharmaceutical agents, such as sulfonamides. When taking a patient history, she noted, be aware that risks of henna extend to the hairdressers and cosmeticians who sometimes apply these products on others.

Hair threading, bindi, and kumkum

Hair threading, another practice popularized in south Asia and now growing in popularity globally, involves capturing hairs between cotton threads for removal of both the hair and its follicle. It is a relatively rapid and efficient method of permanent depilation. In addition to pain and erythema, Dr. Vashi reported that the complications associated with hair threading include pigmentary changes, infections such as bullous impetigo, and lesions of koebnerization – such as vitiligo and lichen planus.

Bindi, a Hindi tradition that involves placing adornments between the eyebrows, and kumkum, a powder typically made from turmeric to be employed for decorative markings, have also spread to use outside of their cultural context, according to Dr. Vashi. She said that the complications of these two cosmetic practices are shared, and stem largely from contact dermatitis.

Veena Nair/Moment/Getty Images

Hair oils, skin-lightening agents

Culturally-linked hair oils among patients from south Asia or Africa – or descendants from these areas – can damage hair in a variety of ways as well as cause contact dermatitis. The oils can also exacerbate existing skin diseases.

“Oils with high oleic acid, such as coconut or olive oils or shea butter, can worsen seborrheic dermatitis,” Dr. Vashi cautioned.

Of this list of dermatologic issues induced by culturally linked cosmetic practices, skin lightening agents might pose the most risk for permanent and irreversible complications. Dr. Vashi said that up to 70% of patients using lighteners develop complications, and there is a relationship between the severity of side effects as duration of use increases.

“The problem is that ingredients of many of these products, which are imported illegally and sold on the black market, are often not disclosed,” Dr. Vashi said. Some contain a high content of metals such as lead, copper, and iron, whether they are added intentionally or end up in the product because of poor quality control. For those developing adverse events associated with the products, the obvious treatment is discontinuation.

When patients are unwilling to discontinue any of the products that have led to dermatologic issues, Dr. Vashi encouraged physicians “to take a middle ground.” Simple avoidance can be challenging for practices that are culturally meaningful. In respecting cultural differences, she encouraged tolerance and compromise.

“Often these patients will be doing an alternative medication or intervention, but this does not mean that they are not accepting what we have to offer,” she said. She indicated that mutual respect will lead to better solutions.

The awareness of common cultural practices that can have a harmful impact on the skin is an area of practice that deserves more attention, Andrew F. Alexis, MD, vice-chair for diversity and inclusion in the department of dermatology at Weill Cornell Medical Center, New York, said in an interview.

With the strong likelihood that dermatologists in the United States will have to resolve dermatologic issues created by cultural cosmetic practices originating elsewhere, strategies for an open nonjudgmental approach are instrumental, according to a dermatologist with expertise in these types of cases who spoke at the Skin of Color Update 2021.

“Instead of avoiding the discussion of cultural practices, we should discuss them and be open about them. It fosters a comfortable environment, trust, and better compliance,” reported Neelam Ajit Vashi, MD, founding director of the Boston University Center for Ethnic Skin.

Out of fear of causing offense, a desire to be discreet, or of personal discomfort with foreign cultural practices, some clinicians might elect to limit themselves to the information that the patient volunteers, which is a mistake, according to Dr. Vashi.

“The avoidance of topics around culture actually limits the ability to have a successful relationship,” she maintained.

Successful encounters are not just based on a willingness to listen, Dr. Vashi said. Clinicians should be seeking a base of knowledge. With growing globalization and widespread immigration, “it is increasingly important for dermatologists in the U.S. to understand the role of cultural practices [in creating skin problems] and recognize the sequelae,” Dr. Vashi said.

Taking some common examples of dermatologic complaints created by cosmetic practices originating elsewhere, Dr. Vashi described key clinical points in addressing complications related to henna, hair removal through threading, and placement of decorative adornments on the forehead, called bindi. In addition, she pointed out common issues with facial and body marking created with kumkum powder, hair oils, and skin lightening agents.
 

Black henna

For cosmetic enhancement, henna is relatively benign. It is also no longer confined to the south Asian communities where it originated. However, Dr. Vashi pointed out that patients of south Asian origin or descent might be more likely to use black henna, a variety with more risks.

Black henna contains additives, such as diaminobenzenes and p-phenylenediamine (PPD), to darken the tone of the product as well as provide other desired characteristics, such as an accelerated drying time. While some patients do develop reactions to conventional henna, the risks of black henna are greater.

“The acute contact dermatitis reactions can include dyspigmentation, leukoderma, and keloids,” Dr. Vashi said. Other complications include erythema multiforme, temporary hypertrichosis, and systemic allergic reactions, such as angioedema.

While those who have had a reaction to henna should avoid further contact, Dr. Vashi warned that sequelae can include cross reactions with latex and rubber as well as some pharmaceutical agents, such as sulfonamides. When taking a patient history, she noted, be aware that risks of henna extend to the hairdressers and cosmeticians who sometimes apply these products on others.

Hair threading, bindi, and kumkum

Hair threading, another practice popularized in south Asia and now growing in popularity globally, involves capturing hairs between cotton threads for removal of both the hair and its follicle. It is a relatively rapid and efficient method of permanent depilation. In addition to pain and erythema, Dr. Vashi reported that the complications associated with hair threading include pigmentary changes, infections such as bullous impetigo, and lesions of koebnerization – such as vitiligo and lichen planus.

Bindi, a Hindi tradition that involves placing adornments between the eyebrows, and kumkum, a powder typically made from turmeric to be employed for decorative markings, have also spread to use outside of their cultural context, according to Dr. Vashi. She said that the complications of these two cosmetic practices are shared, and stem largely from contact dermatitis.

Veena Nair/Moment/Getty Images

Hair oils, skin-lightening agents

Culturally-linked hair oils among patients from south Asia or Africa – or descendants from these areas – can damage hair in a variety of ways as well as cause contact dermatitis. The oils can also exacerbate existing skin diseases.

“Oils with high oleic acid, such as coconut or olive oils or shea butter, can worsen seborrheic dermatitis,” Dr. Vashi cautioned.

Of this list of dermatologic issues induced by culturally linked cosmetic practices, skin lightening agents might pose the most risk for permanent and irreversible complications. Dr. Vashi said that up to 70% of patients using lighteners develop complications, and there is a relationship between the severity of side effects as duration of use increases.

“The problem is that ingredients of many of these products, which are imported illegally and sold on the black market, are often not disclosed,” Dr. Vashi said. Some contain a high content of metals such as lead, copper, and iron, whether they are added intentionally or end up in the product because of poor quality control. For those developing adverse events associated with the products, the obvious treatment is discontinuation.

When patients are unwilling to discontinue any of the products that have led to dermatologic issues, Dr. Vashi encouraged physicians “to take a middle ground.” Simple avoidance can be challenging for practices that are culturally meaningful. In respecting cultural differences, she encouraged tolerance and compromise.

“Often these patients will be doing an alternative medication or intervention, but this does not mean that they are not accepting what we have to offer,” she said. She indicated that mutual respect will lead to better solutions.

The awareness of common cultural practices that can have a harmful impact on the skin is an area of practice that deserves more attention, Andrew F. Alexis, MD, vice-chair for diversity and inclusion in the department of dermatology at Weill Cornell Medical Center, New York, said in an interview.

The Diagnosis: Acquired Acrodermatitis Enteropathica

A punch biopsy of an elevated scaly border of the rash on the thigh revealed parakeratosis, absence of the granular layer, and epidermal pallor with psoriasiform and spongiotic dermatitis (Figure). Serum zinc levels were 60.1 μg/dL (reference range, 75.0–120.0 μg/dL), suggestive of a nutritional deficiency dermatitis. Laboratory and histopathologic findings were most consistent with a diagnosis of acquired acrodermatitis enteropathica (AE).

Acrodermatitis enteropathica has been associated with Roux-en-Y gastric bypass and alcohol use disorder working synergistically to cause malabsorption and malnutrition, respectively.¹ Zinc functions in the structural integrity, wound healing, and anti-inflammatory properties of the skin. There is a 17.3% risk for hypozincemia worldwide; in developed nations there is an estimated 3% to 10% occurrence rate.² Acrodermatitis enteropathica can be classified as either acquired or hereditary. Both classically present as a triad of acral dermatitis, diarrhea, and alopecia, though the complete triad is seen in 20% of cases.^3,4

Hereditary AE is an autosomal-recessive disorder presenting in infancy that results in the loss of a zinc transporter. In contrast, acquired AE occurs later in life and usually is seen in patients who have decreased intake, malabsorption, or excessive loss of zinc.⁴ Acrodermatitis enteropathica is observed in individuals with conditions such as anorexia nervosa, pancreatic insufficiency, celiac disease, Crohn disease, or gastric bypass surgery (as in our case) and alcohol recidivism. In early disease, AE often presents with angular cheilitis and paronychia, but if left untreated, it can progress to mental status changes, hypogonadism, and depression.4 Acrodermatitis enteropathica presents as erythematous, erosive, scaly plaques or a papulosquamous psoriasiform rash with well-demarcated borders typically involving the orificial, acral, and intertriginous areas of the body.^1,4

Acrodermatitis enteropathica belongs to a family of deficiency dermatoses that includes pellagra, necrolytic acral erythema (NAE), and necrolytic migratory erythema (NME).⁵ It is important to distinguish AE from NAE, as they can present similarly with well-defined and tender psoriasiform lesions peripherally. Histologically, NAE mimics AE with psoriasiform hyperplasia with parakeratosis.⁶ Necrolytic acral erythema characteristically is associated with active hepatitis C infection, which was absent in our patient.⁷

Similar to AE, NME affects the perineal and intertriginous surfaces.⁸ However, necrolytic migratory erythema has cutaneous manifestations in up to 70% of patients with glucagonoma syndrome, which classically presents as a triad of NME, weight loss, and diabetes mellitus.⁵ Laboratory studies show marked hyperglucagonemia, and imaging reveals enteropancreatic neoplasia. Necrolytic migratory erythema will rapidly resolve once the glucagonoma has been surgically removed.⁵ Bazex syndrome, or acrokeratosis paraneoplastica, is a paraneoplastic skin disease that is linked to underlying aerodigestive tract malignancies.

Bazex syndrome clinically is characterized by hyperkeratotic and psoriasiform lesions favoring the ears, nails, and nose.⁹

Psoriasis vulgaris is a common chronic inflammatory skin condition that usually presents as well-demarcated plaques with silvery scale and observed pinpoint bleeding when layers of scale are removed (Auspitz sign). Lesions typically are found on the extensor surfaces of the body in addition to the neck, feet, hands, and trunk. Treatment of psoriasis vulgaris ranges from topical steroids for mild cases to systemic biologics for moderate to severe circumstances.¹⁰ In our patient, topical triamcinolone offered little relief.

Acrodermatitis enteropathica displays clinical and histologic characteristics analogous to many deficiency dermatoses and may represent a spectrum of disease. Because the clinicopathologic findings are nonspecific, it is critical to obtain a comprehensive history and maintain a high index of suspicion in patients with risk factors for malnutrition. The treatment for AE is supplemental oral zinc usually initiated at 0.5 to 1 mg/kg daily in children and 30 to 45 mg daily in adults.³ Our patient initially was prescribed oral zinc supplementation; however, at 1-month follow-up, the rash had not improved. Failure of zinc monotherapy supports a multifactorial nutritional deficiency, which necessitated comprehensive nutritional appraisal and supplementation in our patient. Due to the steatorrhea, fecal pancreatic elastase levels were evaluated and were less than 15 μg/g (reference range, ≥201 μg/g), confirming pancreatic exocrine insufficiency, a known complication of Roux-en-Y gastric bypass.¹¹ Pancrelipase 500 U/kg per meal was added in addition to zinc oxide 40% paste to apply to the rash twice daily, with more frequent applications to the anogenital regions after bowel movements. The patient had substantial clinical improvement after 2 months.

The Diagnosis: Acquired Acrodermatitis Enteropathica

A punch biopsy of an elevated scaly border of the rash on the thigh revealed parakeratosis, absence of the granular layer, and epidermal pallor with psoriasiform and spongiotic dermatitis (Figure). Serum zinc levels were 60.1 μg/dL (reference range, 75.0–120.0 μg/dL), suggestive of a nutritional deficiency dermatitis. Laboratory and histopathologic findings were most consistent with a diagnosis of acquired acrodermatitis enteropathica (AE).

Acrodermatitis enteropathica has been associated with Roux-en-Y gastric bypass and alcohol use disorder working synergistically to cause malabsorption and malnutrition, respectively.¹ Zinc functions in the structural integrity, wound healing, and anti-inflammatory properties of the skin. There is a 17.3% risk for hypozincemia worldwide; in developed nations there is an estimated 3% to 10% occurrence rate.² Acrodermatitis enteropathica can be classified as either acquired or hereditary. Both classically present as a triad of acral dermatitis, diarrhea, and alopecia, though the complete triad is seen in 20% of cases.^3,4

Hereditary AE is an autosomal-recessive disorder presenting in infancy that results in the loss of a zinc transporter. In contrast, acquired AE occurs later in life and usually is seen in patients who have decreased intake, malabsorption, or excessive loss of zinc.⁴ Acrodermatitis enteropathica is observed in individuals with conditions such as anorexia nervosa, pancreatic insufficiency, celiac disease, Crohn disease, or gastric bypass surgery (as in our case) and alcohol recidivism. In early disease, AE often presents with angular cheilitis and paronychia, but if left untreated, it can progress to mental status changes, hypogonadism, and depression.4 Acrodermatitis enteropathica presents as erythematous, erosive, scaly plaques or a papulosquamous psoriasiform rash with well-demarcated borders typically involving the orificial, acral, and intertriginous areas of the body.^1,4

Acrodermatitis enteropathica belongs to a family of deficiency dermatoses that includes pellagra, necrolytic acral erythema (NAE), and necrolytic migratory erythema (NME).⁵ It is important to distinguish AE from NAE, as they can present similarly with well-defined and tender psoriasiform lesions peripherally. Histologically, NAE mimics AE with psoriasiform hyperplasia with parakeratosis.⁶ Necrolytic acral erythema characteristically is associated with active hepatitis C infection, which was absent in our patient.⁷

Similar to AE, NME affects the perineal and intertriginous surfaces.⁸ However, necrolytic migratory erythema has cutaneous manifestations in up to 70% of patients with glucagonoma syndrome, which classically presents as a triad of NME, weight loss, and diabetes mellitus.⁵ Laboratory studies show marked hyperglucagonemia, and imaging reveals enteropancreatic neoplasia. Necrolytic migratory erythema will rapidly resolve once the glucagonoma has been surgically removed.⁵ Bazex syndrome, or acrokeratosis paraneoplastica, is a paraneoplastic skin disease that is linked to underlying aerodigestive tract malignancies.

Bazex syndrome clinically is characterized by hyperkeratotic and psoriasiform lesions favoring the ears, nails, and nose.⁹

Psoriasis vulgaris is a common chronic inflammatory skin condition that usually presents as well-demarcated plaques with silvery scale and observed pinpoint bleeding when layers of scale are removed (Auspitz sign). Lesions typically are found on the extensor surfaces of the body in addition to the neck, feet, hands, and trunk. Treatment of psoriasis vulgaris ranges from topical steroids for mild cases to systemic biologics for moderate to severe circumstances.¹⁰ In our patient, topical triamcinolone offered little relief.

Acrodermatitis enteropathica displays clinical and histologic characteristics analogous to many deficiency dermatoses and may represent a spectrum of disease. Because the clinicopathologic findings are nonspecific, it is critical to obtain a comprehensive history and maintain a high index of suspicion in patients with risk factors for malnutrition. The treatment for AE is supplemental oral zinc usually initiated at 0.5 to 1 mg/kg daily in children and 30 to 45 mg daily in adults.³ Our patient initially was prescribed oral zinc supplementation; however, at 1-month follow-up, the rash had not improved. Failure of zinc monotherapy supports a multifactorial nutritional deficiency, which necessitated comprehensive nutritional appraisal and supplementation in our patient. Due to the steatorrhea, fecal pancreatic elastase levels were evaluated and were less than 15 μg/g (reference range, ≥201 μg/g), confirming pancreatic exocrine insufficiency, a known complication of Roux-en-Y gastric bypass.¹¹ Pancrelipase 500 U/kg per meal was added in addition to zinc oxide 40% paste to apply to the rash twice daily, with more frequent applications to the anogenital regions after bowel movements. The patient had substantial clinical improvement after 2 months.

The Diagnosis: Acquired Acrodermatitis Enteropathica

A punch biopsy of an elevated scaly border of the rash on the thigh revealed parakeratosis, absence of the granular layer, and epidermal pallor with psoriasiform and spongiotic dermatitis (Figure). Serum zinc levels were 60.1 μg/dL (reference range, 75.0–120.0 μg/dL), suggestive of a nutritional deficiency dermatitis. Laboratory and histopathologic findings were most consistent with a diagnosis of acquired acrodermatitis enteropathica (AE).

Acrodermatitis enteropathica has been associated with Roux-en-Y gastric bypass and alcohol use disorder working synergistically to cause malabsorption and malnutrition, respectively.¹ Zinc functions in the structural integrity, wound healing, and anti-inflammatory properties of the skin. There is a 17.3% risk for hypozincemia worldwide; in developed nations there is an estimated 3% to 10% occurrence rate.² Acrodermatitis enteropathica can be classified as either acquired or hereditary. Both classically present as a triad of acral dermatitis, diarrhea, and alopecia, though the complete triad is seen in 20% of cases.^3,4

Hereditary AE is an autosomal-recessive disorder presenting in infancy that results in the loss of a zinc transporter. In contrast, acquired AE occurs later in life and usually is seen in patients who have decreased intake, malabsorption, or excessive loss of zinc.⁴ Acrodermatitis enteropathica is observed in individuals with conditions such as anorexia nervosa, pancreatic insufficiency, celiac disease, Crohn disease, or gastric bypass surgery (as in our case) and alcohol recidivism. In early disease, AE often presents with angular cheilitis and paronychia, but if left untreated, it can progress to mental status changes, hypogonadism, and depression.4 Acrodermatitis enteropathica presents as erythematous, erosive, scaly plaques or a papulosquamous psoriasiform rash with well-demarcated borders typically involving the orificial, acral, and intertriginous areas of the body.^1,4

Acrodermatitis enteropathica belongs to a family of deficiency dermatoses that includes pellagra, necrolytic acral erythema (NAE), and necrolytic migratory erythema (NME).⁵ It is important to distinguish AE from NAE, as they can present similarly with well-defined and tender psoriasiform lesions peripherally. Histologically, NAE mimics AE with psoriasiform hyperplasia with parakeratosis.⁶ Necrolytic acral erythema characteristically is associated with active hepatitis C infection, which was absent in our patient.⁷

Similar to AE, NME affects the perineal and intertriginous surfaces.⁸ However, necrolytic migratory erythema has cutaneous manifestations in up to 70% of patients with glucagonoma syndrome, which classically presents as a triad of NME, weight loss, and diabetes mellitus.⁵ Laboratory studies show marked hyperglucagonemia, and imaging reveals enteropancreatic neoplasia. Necrolytic migratory erythema will rapidly resolve once the glucagonoma has been surgically removed.⁵ Bazex syndrome, or acrokeratosis paraneoplastica, is a paraneoplastic skin disease that is linked to underlying aerodigestive tract malignancies.

Bazex syndrome clinically is characterized by hyperkeratotic and psoriasiform lesions favoring the ears, nails, and nose.⁹

Psoriasis vulgaris is a common chronic inflammatory skin condition that usually presents as well-demarcated plaques with silvery scale and observed pinpoint bleeding when layers of scale are removed (Auspitz sign). Lesions typically are found on the extensor surfaces of the body in addition to the neck, feet, hands, and trunk. Treatment of psoriasis vulgaris ranges from topical steroids for mild cases to systemic biologics for moderate to severe circumstances.¹⁰ In our patient, topical triamcinolone offered little relief.

Acrodermatitis enteropathica displays clinical and histologic characteristics analogous to many deficiency dermatoses and may represent a spectrum of disease. Because the clinicopathologic findings are nonspecific, it is critical to obtain a comprehensive history and maintain a high index of suspicion in patients with risk factors for malnutrition. The treatment for AE is supplemental oral zinc usually initiated at 0.5 to 1 mg/kg daily in children and 30 to 45 mg daily in adults.³ Our patient initially was prescribed oral zinc supplementation; however, at 1-month follow-up, the rash had not improved. Failure of zinc monotherapy supports a multifactorial nutritional deficiency, which necessitated comprehensive nutritional appraisal and supplementation in our patient. Due to the steatorrhea, fecal pancreatic elastase levels were evaluated and were less than 15 μg/g (reference range, ≥201 μg/g), confirming pancreatic exocrine insufficiency, a known complication of Roux-en-Y gastric bypass.¹¹ Pancrelipase 500 U/kg per meal was added in addition to zinc oxide 40% paste to apply to the rash twice daily, with more frequent applications to the anogenital regions after bowel movements. The patient had substantial clinical improvement after 2 months.

Music plus mushrooms equals therapy

Magic mushrooms have been used recreationally and medicinally for thousands of years, but researchers have found adding music could be a game changer in antidepressant treatment.

chrissmith12/Pixabay

The ingredient that makes these mushrooms so magical is psilocybin. It works well for the clinical treatment of mental health conditions and some forms of depression because the “trip” can be contained to one work day, making it easy to administer under supervision. With the accompaniment of music, scientists have found that psilocybin evokes emotion.

This recent study, presented at the European College of Neuropsychopharmacology Congress in Lisbon, tested participants’ emotional response to music before and after the psilocybin. Ketanserin, an antihypertensive drug, was used to test against the effects of psilocybin. The scientist played Mozart and Elgar and found that participants on psilocybin had an emotional response increase of 60%. That response was even greater, compared with ketanserin, which actually lessened the emotional response to music.

“This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use,” said lead researcher Dea Siggaard Stenbæk of the University of Copenhagen.

Professor David J. Nutt of Imperial College in London, who was not involved in the study, said that it supports the use of music for treatment efficacy with psychedelics and suggested that the next step is to “optimise this approach probably through individualising and personalising music tracks in therapy.”

Cue the 1960s LSD music montage.
 

Chicken ‘white striping is not a disease’

Have you ever sliced open a new pack of chicken breasts to start dinner and noticed white fatty lines running through the chicken? Maybe you thought it was just some extra fat to trim off, but the Humane League calls it “white striping disease.”

rawpixel

Chicken is the No. 1 meat consumed by Americans, so it’s not surprising that chickens are factory farmed and raised to be ready for slaughter quickly, according to CBSNews.com, which reported that the Humane League claims white striping is found in 70% of the chicken in popular grocery stores. The league expressed concern for the chickens’ welfare as they are bred to grow bigger quickly, which is causing the white striping and increasing the fat content of the meat by as much as 224%.

The National Chicken Council told CBS that the league’s findings were unscientific. A spokesperson said, “White striping is not a disease. It is a quality factor in chicken breast meat caused by deposits of fat in the muscle during the bird’s growth and development.” He went on to say that severe white striping happens in 3%-6% of birds, which are mostly used in further processed products, not in chicken breast packages.

Somehow, that’s not making us feel any better.
 

The itsy bitsy spider lets us all down

Most people do not like spiders. That’s too bad, because spiders are generally nothing but helpful little creatures that prey upon annoying flies and other pests. Then there’s the silk they produce. The ancient Romans used it to treat conditions such as warts and skin lesions. Spiders wrap their eggs in silk to protect them from harmful bacteria.

Simon Fruergaard

Of course, we can hardly trust the medical opinions of people from 2,000 years ago, but modern-day studies have not definitively proved whether or not spider silk has any antimicrobial properties.

To settle the matter once and for all, researchers from Denmark built a silk-harvesting machine using the most famous of Danish inventions: Legos. The contraption, sort of a paddle wheel, pulled the silk from several different species of spider pinned down by the researchers. The silk was then tested against three different bacteria species, including good old Escherichia coli.

Unfortunately for our spider friends, their silk has no antimicrobial activity. The researchers suspected that any such activity seen in previous studies was actually caused by improper control for the solvents used to extract the silk; those solvents can have antimicrobial properties on their own. As for protecting their eggs, rather than killing bacteria, the silk likely provides a physical barrier alone.

It is bad news for spiders on the benefit-to-humanity front, but look at the bright side: If their silk had antimicrobial activity, we’d have to start farming them to acquire more silk. And that’s no good. Spiders deserve to roam free, hunt as they please, and drop down on your head from the ceiling.
 

Anxiety and allergies: Cause, effect, confusion

We’re big fans of science, but as longtime, totally impartial (Science rules!) observers of science’s medical realm, we can see that the day-to-day process of practicing the scientific method occasionally gets a bit messy. And no, we’re not talking about COVID-19.

pxfuel

We’re talking allergies. We’re talking mental health. We’re talking allergic disease and mental health.

We’re talking about a pair of press releases we came across during our never-ending search for material to educate, entertain, and astound our fabulously wonderful and loyal readers. (We say that, of course, in the most impartial way possible.)

The first release was titled, “Allergies including asthma and hay fever not linked to mental health traits” and covered research from the University of Bristol (England). The investigators were trying to determine if “allergic diseases actually causes mental health traits including anxiety, depression, bipolar disorder, and schizophrenia, or vice versa,” according to the release.

What they found, however, was “little evidence of a causal relationship between the onset of allergic disease and mental health.” Again, this is the press release talking.

The second release seemed to suggest the exact opposite: “Study uncovers link between allergies and mental health conditions.” That got our attention. A little more reading revealed that “people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism.”

One of the investigators was quoted as saying, “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”

Did you notice the “vice versa”? Did you notice that it appeared in quotes from both releases? We did, so we took a closer look at the source. The second release covered a group of investigators from the University of Bristol – the same group, and the same study, in fact, as the first one.

So there you have it. One study, two press releases, and one confused journalist. Thank you, science.

Music plus mushrooms equals therapy

Magic mushrooms have been used recreationally and medicinally for thousands of years, but researchers have found adding music could be a game changer in antidepressant treatment.

chrissmith12/Pixabay

The ingredient that makes these mushrooms so magical is psilocybin. It works well for the clinical treatment of mental health conditions and some forms of depression because the “trip” can be contained to one work day, making it easy to administer under supervision. With the accompaniment of music, scientists have found that psilocybin evokes emotion.

This recent study, presented at the European College of Neuropsychopharmacology Congress in Lisbon, tested participants’ emotional response to music before and after the psilocybin. Ketanserin, an antihypertensive drug, was used to test against the effects of psilocybin. The scientist played Mozart and Elgar and found that participants on psilocybin had an emotional response increase of 60%. That response was even greater, compared with ketanserin, which actually lessened the emotional response to music.

“This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use,” said lead researcher Dea Siggaard Stenbæk of the University of Copenhagen.

Professor David J. Nutt of Imperial College in London, who was not involved in the study, said that it supports the use of music for treatment efficacy with psychedelics and suggested that the next step is to “optimise this approach probably through individualising and personalising music tracks in therapy.”

Cue the 1960s LSD music montage.
 

Chicken ‘white striping is not a disease’

Have you ever sliced open a new pack of chicken breasts to start dinner and noticed white fatty lines running through the chicken? Maybe you thought it was just some extra fat to trim off, but the Humane League calls it “white striping disease.”

rawpixel

Chicken is the No. 1 meat consumed by Americans, so it’s not surprising that chickens are factory farmed and raised to be ready for slaughter quickly, according to CBSNews.com, which reported that the Humane League claims white striping is found in 70% of the chicken in popular grocery stores. The league expressed concern for the chickens’ welfare as they are bred to grow bigger quickly, which is causing the white striping and increasing the fat content of the meat by as much as 224%.

The National Chicken Council told CBS that the league’s findings were unscientific. A spokesperson said, “White striping is not a disease. It is a quality factor in chicken breast meat caused by deposits of fat in the muscle during the bird’s growth and development.” He went on to say that severe white striping happens in 3%-6% of birds, which are mostly used in further processed products, not in chicken breast packages.

Somehow, that’s not making us feel any better.
 

The itsy bitsy spider lets us all down

Most people do not like spiders. That’s too bad, because spiders are generally nothing but helpful little creatures that prey upon annoying flies and other pests. Then there’s the silk they produce. The ancient Romans used it to treat conditions such as warts and skin lesions. Spiders wrap their eggs in silk to protect them from harmful bacteria.

Simon Fruergaard

Of course, we can hardly trust the medical opinions of people from 2,000 years ago, but modern-day studies have not definitively proved whether or not spider silk has any antimicrobial properties.

To settle the matter once and for all, researchers from Denmark built a silk-harvesting machine using the most famous of Danish inventions: Legos. The contraption, sort of a paddle wheel, pulled the silk from several different species of spider pinned down by the researchers. The silk was then tested against three different bacteria species, including good old Escherichia coli.

Unfortunately for our spider friends, their silk has no antimicrobial activity. The researchers suspected that any such activity seen in previous studies was actually caused by improper control for the solvents used to extract the silk; those solvents can have antimicrobial properties on their own. As for protecting their eggs, rather than killing bacteria, the silk likely provides a physical barrier alone.

It is bad news for spiders on the benefit-to-humanity front, but look at the bright side: If their silk had antimicrobial activity, we’d have to start farming them to acquire more silk. And that’s no good. Spiders deserve to roam free, hunt as they please, and drop down on your head from the ceiling.
 

Anxiety and allergies: Cause, effect, confusion

We’re big fans of science, but as longtime, totally impartial (Science rules!) observers of science’s medical realm, we can see that the day-to-day process of practicing the scientific method occasionally gets a bit messy. And no, we’re not talking about COVID-19.

pxfuel

We’re talking allergies. We’re talking mental health. We’re talking allergic disease and mental health.

We’re talking about a pair of press releases we came across during our never-ending search for material to educate, entertain, and astound our fabulously wonderful and loyal readers. (We say that, of course, in the most impartial way possible.)

The first release was titled, “Allergies including asthma and hay fever not linked to mental health traits” and covered research from the University of Bristol (England). The investigators were trying to determine if “allergic diseases actually causes mental health traits including anxiety, depression, bipolar disorder, and schizophrenia, or vice versa,” according to the release.

What they found, however, was “little evidence of a causal relationship between the onset of allergic disease and mental health.” Again, this is the press release talking.

The second release seemed to suggest the exact opposite: “Study uncovers link between allergies and mental health conditions.” That got our attention. A little more reading revealed that “people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism.”

One of the investigators was quoted as saying, “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”

Did you notice the “vice versa”? Did you notice that it appeared in quotes from both releases? We did, so we took a closer look at the source. The second release covered a group of investigators from the University of Bristol – the same group, and the same study, in fact, as the first one.

So there you have it. One study, two press releases, and one confused journalist. Thank you, science.

Music plus mushrooms equals therapy

Magic mushrooms have been used recreationally and medicinally for thousands of years, but researchers have found adding music could be a game changer in antidepressant treatment.

chrissmith12/Pixabay

The ingredient that makes these mushrooms so magical is psilocybin. It works well for the clinical treatment of mental health conditions and some forms of depression because the “trip” can be contained to one work day, making it easy to administer under supervision. With the accompaniment of music, scientists have found that psilocybin evokes emotion.

This recent study, presented at the European College of Neuropsychopharmacology Congress in Lisbon, tested participants’ emotional response to music before and after the psilocybin. Ketanserin, an antihypertensive drug, was used to test against the effects of psilocybin. The scientist played Mozart and Elgar and found that participants on psilocybin had an emotional response increase of 60%. That response was even greater, compared with ketanserin, which actually lessened the emotional response to music.

“This shows that combination of psilocybin and music has a strong emotional effect, and we believe that this will be important for the therapeutic application of psychedelics if they are approved for clinical use,” said lead researcher Dea Siggaard Stenbæk of the University of Copenhagen.

Professor David J. Nutt of Imperial College in London, who was not involved in the study, said that it supports the use of music for treatment efficacy with psychedelics and suggested that the next step is to “optimise this approach probably through individualising and personalising music tracks in therapy.”

Cue the 1960s LSD music montage.
 

Chicken ‘white striping is not a disease’

Have you ever sliced open a new pack of chicken breasts to start dinner and noticed white fatty lines running through the chicken? Maybe you thought it was just some extra fat to trim off, but the Humane League calls it “white striping disease.”

rawpixel

Chicken is the No. 1 meat consumed by Americans, so it’s not surprising that chickens are factory farmed and raised to be ready for slaughter quickly, according to CBSNews.com, which reported that the Humane League claims white striping is found in 70% of the chicken in popular grocery stores. The league expressed concern for the chickens’ welfare as they are bred to grow bigger quickly, which is causing the white striping and increasing the fat content of the meat by as much as 224%.

The National Chicken Council told CBS that the league’s findings were unscientific. A spokesperson said, “White striping is not a disease. It is a quality factor in chicken breast meat caused by deposits of fat in the muscle during the bird’s growth and development.” He went on to say that severe white striping happens in 3%-6% of birds, which are mostly used in further processed products, not in chicken breast packages.

Somehow, that’s not making us feel any better.
 

The itsy bitsy spider lets us all down

Most people do not like spiders. That’s too bad, because spiders are generally nothing but helpful little creatures that prey upon annoying flies and other pests. Then there’s the silk they produce. The ancient Romans used it to treat conditions such as warts and skin lesions. Spiders wrap their eggs in silk to protect them from harmful bacteria.

Simon Fruergaard

Of course, we can hardly trust the medical opinions of people from 2,000 years ago, but modern-day studies have not definitively proved whether or not spider silk has any antimicrobial properties.

To settle the matter once and for all, researchers from Denmark built a silk-harvesting machine using the most famous of Danish inventions: Legos. The contraption, sort of a paddle wheel, pulled the silk from several different species of spider pinned down by the researchers. The silk was then tested against three different bacteria species, including good old Escherichia coli.

Unfortunately for our spider friends, their silk has no antimicrobial activity. The researchers suspected that any such activity seen in previous studies was actually caused by improper control for the solvents used to extract the silk; those solvents can have antimicrobial properties on their own. As for protecting their eggs, rather than killing bacteria, the silk likely provides a physical barrier alone.

It is bad news for spiders on the benefit-to-humanity front, but look at the bright side: If their silk had antimicrobial activity, we’d have to start farming them to acquire more silk. And that’s no good. Spiders deserve to roam free, hunt as they please, and drop down on your head from the ceiling.
 

Anxiety and allergies: Cause, effect, confusion

We’re big fans of science, but as longtime, totally impartial (Science rules!) observers of science’s medical realm, we can see that the day-to-day process of practicing the scientific method occasionally gets a bit messy. And no, we’re not talking about COVID-19.

pxfuel

We’re talking allergies. We’re talking mental health. We’re talking allergic disease and mental health.

We’re talking about a pair of press releases we came across during our never-ending search for material to educate, entertain, and astound our fabulously wonderful and loyal readers. (We say that, of course, in the most impartial way possible.)

The first release was titled, “Allergies including asthma and hay fever not linked to mental health traits” and covered research from the University of Bristol (England). The investigators were trying to determine if “allergic diseases actually causes mental health traits including anxiety, depression, bipolar disorder, and schizophrenia, or vice versa,” according to the release.

What they found, however, was “little evidence of a causal relationship between the onset of allergic disease and mental health.” Again, this is the press release talking.

The second release seemed to suggest the exact opposite: “Study uncovers link between allergies and mental health conditions.” That got our attention. A little more reading revealed that “people with asthma, atopic dermatitis, and hay fever also had a higher likelihood of having depression, anxiety, bipolar disorder, or neuroticism.”

One of the investigators was quoted as saying, “Establishing whether allergic disease causes mental health problems, or vice versa, is important to ensure that resources and treatment strategies are targeted appropriately.”

Did you notice the “vice versa”? Did you notice that it appeared in quotes from both releases? We did, so we took a closer look at the source. The second release covered a group of investigators from the University of Bristol – the same group, and the same study, in fact, as the first one.

So there you have it. One study, two press releases, and one confused journalist. Thank you, science.

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.

 

 

Results

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.

 

 

Conclusion

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.

 

 

Results

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.

 

 

Conclusion

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.

 

 

Results

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.

 

 

Conclusion

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.