A Maryland woman came down with a severe tropical infection called melioidosis from her freshwater home aquarium, says a report in Emerging Infectious Diseases describing a new route of transmission. Melioidosis is caused by the bacteria Burkholderia pseudomallei in soil or water.

Until last year, almost all U.S. cases of melioidosis were from people who lived or traveled to disease-endemic areas. It has been a rare infection in the United States.

But this is not the first case of melioidosis from an unusual source. Earlier in 2021, CDC and state epidemiologists traced an outbreak of melioidosis in Georgia, Kansas, Minnesota, and Texas to B pseudomallei in a bottle of “Better Homes & Gardens Lavender & Chamomile Essential Oil Infused Aromatherapy Room Spray with Gemstones.”

In the aquarium case, the patient was a 56-year-old woman with diabetes and rheumatologic disease. She had been on immunosuppressives (methotrexate, azathioprine, and prednisone) until 1 month before she became symptomatic. She was hospitalized for fever and pneumonia.

Multiple blood cultures obtained on days 1-4 grew B. pseudomallei, but she had no evidence of endocarditis or intravascular seeding. Despite weeks of meropenem (Merrem), she developed evidence of a lung abscess, and trimethoprim/sulfamethoxazole (Bactrim) was added. Ultimately, the patient required a 12-week course of antibiotics.

CDC epidemiologist Patrick Dawson, PhD, first author of the report, told this news organization that although outbreak investigators always ask about pet ownership, they have not explicitly asked about fish. In this case, the patient did not volunteer exposure to the fish.

When state epidemiologists visited the patient’s home, “one of the first things they saw was a few aquariums,” Dr. Dawson said. Seeing the water and knowing “that most freshwater tropical fish in the U.S. are imported from Southeast Asia” led them to culture specifically for B. pseudomallei, which can be difficult for the microbiology lab to identify.

From there, Dr. Dawson explained, “The Maryland Department of Health sent a team to the local pet store” but did not find any of the bacteria there. (The patient had bought her fish 6 months earlier.) The investigators then worked with the national brand “to identify where they had actually sourced the fish from.”

Two retailers supply almost all of U.S. guppies and plants. While investigators could not find an exact matching isolate after so many months had elapsed, they found a positive PCR for B. pseudomallei in a water sample from imported fish in Los Angeles.

Dr. Dawson said tropical fish are imported from southeast Asia and typically come from small family fish farms. The fish import industry has “certain products that they add to the water to hopefully kill any bacteria.” He was unaware whether this included antibiotics but suggested, “we would have seen many more cases [of antibiotic resistance] by now” if it did.

In general advice for the public, Dr. Dawson said, “I would recommend washing hands before and after contact with the aquarium. If you have cuts or wounds on your hands, it’s really important to wear gloves if you have to go clean or maintain the aquarium and you’re putting your hands in the water, just for that extra layer of protection. It’s probably a strong idea to just avoid that altogether if someone’s immunocompromised. And not letting young children under 5 years old clean aquariums.” These are the “simplest things to do to protect yourself.”

Stephen A. Smith, DVM, PhD, a professor in the Aquatic Medicine Program at Virginia-Maryland College of Veterinary Medicine, Blacksburg, also stressed the importance of careful hand hygiene when caring for aquariums. He said that the filter, filter floss, biofilm, charcoal, and gravel might have exceptionally high concentrations of bacteria. Dr. Smith also recommended gloves when cleaning aquariums and not doing this task if immunocompromised.

Dr. Smith, who was not involved in the CDC study, shared a broader perspective, noting that “the reason why it’s important to federal regulators is that [B. pseudomallei] is a tier 1 select agent. And so, when that was isolated, it sent up all the red flags.” The far more common Mycobacterium marinum, or fish handler’s disease, is not reportable.

Mycobacterium marinum is another pathogen of concern that can be acquired from aquariums. These infections typically occur as nodular lesions on the arms and require months of therapy.

Dr. Smith stressed the importance of physicians eliciting a careful exposure history as the key to diagnosing zoonoses. For most exotic aquarium animals, he noted, “They’re caught in the wild wherever they are. They’re transported to a major hub to transport to the U.S., and a lot of times, we don’t have quarantine for those animals.”

Aquatic zoonoses (infections from water) are important because an estimated 11.5 million U.S. households have pet fish, totaling about 139 million freshwater fish, Dr. Smith said.

Many infections also occur in the course of water sports – or even hiking and getting a cut or abrasion wet from a stream or lake. Aeromonas hydrophila can cause life-threatening infections. Vibrio vulnificus infections from salt-water injuries can cause sepsis and characteristic hemorrhagic bullae – large, discolored blisters filled with body fluid – during the summer. And eating contaminated shellfish has a 50%-60% death rate.

Other exposures to water-loving bacteria happen during fishing or cleaning/preparing fish. For example, Streptococcus iniae has caused cellulitis, arthritis, endocarditis, and meningitis following superficial or puncture injuries, notably from cleaning tilapia.

Other infections from contact with fish include Erysipelothrix rhusiopathiae (primarily skin infections) and gastroenteritis from Plesiomonas shigelloides, Campylobacter spp, and Salmonella spp.

Each of these zoonoses illustrates the importance of a careful exposure history when there’s an atypical presentation or an infection that is not responding promptly to empiric treatment. The aquarium case broadens the differential to include melioidosis, a serious disease from southeast Asia.

Dr. Dawson and Dr. Smith have disclosed no relevant financial relationships.

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

A Maryland woman came down with a severe tropical infection called melioidosis from her freshwater home aquarium, says a report in Emerging Infectious Diseases describing a new route of transmission. Melioidosis is caused by the bacteria Burkholderia pseudomallei in soil or water.

Until last year, almost all U.S. cases of melioidosis were from people who lived or traveled to disease-endemic areas. It has been a rare infection in the United States.

But this is not the first case of melioidosis from an unusual source. Earlier in 2021, CDC and state epidemiologists traced an outbreak of melioidosis in Georgia, Kansas, Minnesota, and Texas to B pseudomallei in a bottle of “Better Homes & Gardens Lavender & Chamomile Essential Oil Infused Aromatherapy Room Spray with Gemstones.”

In the aquarium case, the patient was a 56-year-old woman with diabetes and rheumatologic disease. She had been on immunosuppressives (methotrexate, azathioprine, and prednisone) until 1 month before she became symptomatic. She was hospitalized for fever and pneumonia.

Multiple blood cultures obtained on days 1-4 grew B. pseudomallei, but she had no evidence of endocarditis or intravascular seeding. Despite weeks of meropenem (Merrem), she developed evidence of a lung abscess, and trimethoprim/sulfamethoxazole (Bactrim) was added. Ultimately, the patient required a 12-week course of antibiotics.

CDC epidemiologist Patrick Dawson, PhD, first author of the report, told this news organization that although outbreak investigators always ask about pet ownership, they have not explicitly asked about fish. In this case, the patient did not volunteer exposure to the fish.

When state epidemiologists visited the patient’s home, “one of the first things they saw was a few aquariums,” Dr. Dawson said. Seeing the water and knowing “that most freshwater tropical fish in the U.S. are imported from Southeast Asia” led them to culture specifically for B. pseudomallei, which can be difficult for the microbiology lab to identify.

From there, Dr. Dawson explained, “The Maryland Department of Health sent a team to the local pet store” but did not find any of the bacteria there. (The patient had bought her fish 6 months earlier.) The investigators then worked with the national brand “to identify where they had actually sourced the fish from.”

Two retailers supply almost all of U.S. guppies and plants. While investigators could not find an exact matching isolate after so many months had elapsed, they found a positive PCR for B. pseudomallei in a water sample from imported fish in Los Angeles.

Dr. Dawson said tropical fish are imported from southeast Asia and typically come from small family fish farms. The fish import industry has “certain products that they add to the water to hopefully kill any bacteria.” He was unaware whether this included antibiotics but suggested, “we would have seen many more cases [of antibiotic resistance] by now” if it did.

In general advice for the public, Dr. Dawson said, “I would recommend washing hands before and after contact with the aquarium. If you have cuts or wounds on your hands, it’s really important to wear gloves if you have to go clean or maintain the aquarium and you’re putting your hands in the water, just for that extra layer of protection. It’s probably a strong idea to just avoid that altogether if someone’s immunocompromised. And not letting young children under 5 years old clean aquariums.” These are the “simplest things to do to protect yourself.”

Stephen A. Smith, DVM, PhD, a professor in the Aquatic Medicine Program at Virginia-Maryland College of Veterinary Medicine, Blacksburg, also stressed the importance of careful hand hygiene when caring for aquariums. He said that the filter, filter floss, biofilm, charcoal, and gravel might have exceptionally high concentrations of bacteria. Dr. Smith also recommended gloves when cleaning aquariums and not doing this task if immunocompromised.

Dr. Smith, who was not involved in the CDC study, shared a broader perspective, noting that “the reason why it’s important to federal regulators is that [B. pseudomallei] is a tier 1 select agent. And so, when that was isolated, it sent up all the red flags.” The far more common Mycobacterium marinum, or fish handler’s disease, is not reportable.

Mycobacterium marinum is another pathogen of concern that can be acquired from aquariums. These infections typically occur as nodular lesions on the arms and require months of therapy.

Dr. Smith stressed the importance of physicians eliciting a careful exposure history as the key to diagnosing zoonoses. For most exotic aquarium animals, he noted, “They’re caught in the wild wherever they are. They’re transported to a major hub to transport to the U.S., and a lot of times, we don’t have quarantine for those animals.”

Aquatic zoonoses (infections from water) are important because an estimated 11.5 million U.S. households have pet fish, totaling about 139 million freshwater fish, Dr. Smith said.

Many infections also occur in the course of water sports – or even hiking and getting a cut or abrasion wet from a stream or lake. Aeromonas hydrophila can cause life-threatening infections. Vibrio vulnificus infections from salt-water injuries can cause sepsis and characteristic hemorrhagic bullae – large, discolored blisters filled with body fluid – during the summer. And eating contaminated shellfish has a 50%-60% death rate.

Other exposures to water-loving bacteria happen during fishing or cleaning/preparing fish. For example, Streptococcus iniae has caused cellulitis, arthritis, endocarditis, and meningitis following superficial or puncture injuries, notably from cleaning tilapia.

Other infections from contact with fish include Erysipelothrix rhusiopathiae (primarily skin infections) and gastroenteritis from Plesiomonas shigelloides, Campylobacter spp, and Salmonella spp.

Each of these zoonoses illustrates the importance of a careful exposure history when there’s an atypical presentation or an infection that is not responding promptly to empiric treatment. The aquarium case broadens the differential to include melioidosis, a serious disease from southeast Asia.

Dr. Dawson and Dr. Smith have disclosed no relevant financial relationships.

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

A Maryland woman came down with a severe tropical infection called melioidosis from her freshwater home aquarium, says a report in Emerging Infectious Diseases describing a new route of transmission. Melioidosis is caused by the bacteria Burkholderia pseudomallei in soil or water.

Until last year, almost all U.S. cases of melioidosis were from people who lived or traveled to disease-endemic areas. It has been a rare infection in the United States.

But this is not the first case of melioidosis from an unusual source. Earlier in 2021, CDC and state epidemiologists traced an outbreak of melioidosis in Georgia, Kansas, Minnesota, and Texas to B pseudomallei in a bottle of “Better Homes & Gardens Lavender & Chamomile Essential Oil Infused Aromatherapy Room Spray with Gemstones.”

In the aquarium case, the patient was a 56-year-old woman with diabetes and rheumatologic disease. She had been on immunosuppressives (methotrexate, azathioprine, and prednisone) until 1 month before she became symptomatic. She was hospitalized for fever and pneumonia.

Multiple blood cultures obtained on days 1-4 grew B. pseudomallei, but she had no evidence of endocarditis or intravascular seeding. Despite weeks of meropenem (Merrem), she developed evidence of a lung abscess, and trimethoprim/sulfamethoxazole (Bactrim) was added. Ultimately, the patient required a 12-week course of antibiotics.

CDC epidemiologist Patrick Dawson, PhD, first author of the report, told this news organization that although outbreak investigators always ask about pet ownership, they have not explicitly asked about fish. In this case, the patient did not volunteer exposure to the fish.

When state epidemiologists visited the patient’s home, “one of the first things they saw was a few aquariums,” Dr. Dawson said. Seeing the water and knowing “that most freshwater tropical fish in the U.S. are imported from Southeast Asia” led them to culture specifically for B. pseudomallei, which can be difficult for the microbiology lab to identify.

From there, Dr. Dawson explained, “The Maryland Department of Health sent a team to the local pet store” but did not find any of the bacteria there. (The patient had bought her fish 6 months earlier.) The investigators then worked with the national brand “to identify where they had actually sourced the fish from.”

Two retailers supply almost all of U.S. guppies and plants. While investigators could not find an exact matching isolate after so many months had elapsed, they found a positive PCR for B. pseudomallei in a water sample from imported fish in Los Angeles.

Dr. Dawson said tropical fish are imported from southeast Asia and typically come from small family fish farms. The fish import industry has “certain products that they add to the water to hopefully kill any bacteria.” He was unaware whether this included antibiotics but suggested, “we would have seen many more cases [of antibiotic resistance] by now” if it did.

In general advice for the public, Dr. Dawson said, “I would recommend washing hands before and after contact with the aquarium. If you have cuts or wounds on your hands, it’s really important to wear gloves if you have to go clean or maintain the aquarium and you’re putting your hands in the water, just for that extra layer of protection. It’s probably a strong idea to just avoid that altogether if someone’s immunocompromised. And not letting young children under 5 years old clean aquariums.” These are the “simplest things to do to protect yourself.”

Stephen A. Smith, DVM, PhD, a professor in the Aquatic Medicine Program at Virginia-Maryland College of Veterinary Medicine, Blacksburg, also stressed the importance of careful hand hygiene when caring for aquariums. He said that the filter, filter floss, biofilm, charcoal, and gravel might have exceptionally high concentrations of bacteria. Dr. Smith also recommended gloves when cleaning aquariums and not doing this task if immunocompromised.

Dr. Smith, who was not involved in the CDC study, shared a broader perspective, noting that “the reason why it’s important to federal regulators is that [B. pseudomallei] is a tier 1 select agent. And so, when that was isolated, it sent up all the red flags.” The far more common Mycobacterium marinum, or fish handler’s disease, is not reportable.

Mycobacterium marinum is another pathogen of concern that can be acquired from aquariums. These infections typically occur as nodular lesions on the arms and require months of therapy.

Dr. Smith stressed the importance of physicians eliciting a careful exposure history as the key to diagnosing zoonoses. For most exotic aquarium animals, he noted, “They’re caught in the wild wherever they are. They’re transported to a major hub to transport to the U.S., and a lot of times, we don’t have quarantine for those animals.”

Aquatic zoonoses (infections from water) are important because an estimated 11.5 million U.S. households have pet fish, totaling about 139 million freshwater fish, Dr. Smith said.

Many infections also occur in the course of water sports – or even hiking and getting a cut or abrasion wet from a stream or lake. Aeromonas hydrophila can cause life-threatening infections. Vibrio vulnificus infections from salt-water injuries can cause sepsis and characteristic hemorrhagic bullae – large, discolored blisters filled with body fluid – during the summer. And eating contaminated shellfish has a 50%-60% death rate.

Other exposures to water-loving bacteria happen during fishing or cleaning/preparing fish. For example, Streptococcus iniae has caused cellulitis, arthritis, endocarditis, and meningitis following superficial or puncture injuries, notably from cleaning tilapia.

Other infections from contact with fish include Erysipelothrix rhusiopathiae (primarily skin infections) and gastroenteritis from Plesiomonas shigelloides, Campylobacter spp, and Salmonella spp.

Each of these zoonoses illustrates the importance of a careful exposure history when there’s an atypical presentation or an infection that is not responding promptly to empiric treatment. The aquarium case broadens the differential to include melioidosis, a serious disease from southeast Asia.

Dr. Dawson and Dr. Smith have disclosed no relevant financial relationships.

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

A real-world analysis of tofacitinib, presented at the annual Advances in Inflammatory Bowel Disease conference, confirms that long-term use of the selective immunosuppressant agent tofacitinib is associated with high rates of steroid-free remission in patients with ulcerative colitis (UC). These findings, along with clinical practice observations made during another session at the conference, further validate the efficacy of tofacitinib beyond that currently reported in specific clinical trial populations.

Tofacitinib is a small-molecule Janus kinase inhibitor that interferes with the intracellular JAK/signal transducer and activators of transcription pathway. Compared with other biologic agents, tofacitinib simultaneously acts on several cytokines and exerts broader effects on gastrointestinal inflammation.

Tofacitinib’s approval for moderate to severe UC was based on data from the OCTAVE clinical trial program. Although the phase 3 OCTAVE trial showed the JAK inhibitor features dose-dependent efficacy in inducing and maintaining remission in UC, stringent inclusion and exclusion criteria limit the generalizability of the trial’s findings across the broader, real-world UC population.

Findings from the recent analysis on tofacitinib were presented at AIBD 2021 by Knyazev Oleg, MD, who is the head of department of inflammatory bowel diseases at A.S. Loginov Moscow Clinical Scientific and Practical Center.

Dr. Oleg and colleagues reported on real-world treatment observations of 58 tofacitinib-treated patients with UC. Treatment efficacy was evaluated using the Mayo index (score <2), erythrocyte sedimentation rate, C-reactive protein, hemoglobin, fecal calprotectin, and the need for glucocorticoids (GCS).

At the time of tofacitinib initiation, all patients received GCS, with a mean therapeutic dose of 40 mg. In all 49 patients who responded to therapy, corticosteroids were discontinued after induction.

Only 15.5% (n = 9) of the study cohort did not respond to the JAK inhibitor during the follow-up period. A total of 14 patients (24.1%) who previously received anti-TNF therapies required a prolonged induction course of 20 mg tofacitinib. More than one out of five patients (22.4%) required repeated corticosteroids to manage exacerbations or dwindled tofacitinib response.

During another session, which discussed prescription treatment for moderate to severe UC, Bincy Abraham, MD, a professor of clinical medicine at Houston Methodist Academic Institute, summarized currently available clinical trial data on tofacitinib and discussed her own observations in her practice regarding the efficacy of the JAK inhibitor in the UC population.

The current data show the oral JAK inhibitor allows patients to reach remission as early as 8 weeks, with corresponding reductions observed in rectal bleeding and stool frequency as early as 2 weeks after therapy initiation. While the efficacy findings are corroborated by her own clinical practice, Dr. Abraham largely discussed the safety implications of the treatment.

Dr. Abraham emphasized the need for risk-mitigation strategies before initiating tofacitinib in appropriately selected patients with UC. In particular, Dr. Abraham explained that clinicians should be alerted to the possibility of tuberculosis as an opportunistic infection in tofacitinib-treated patients. “Before starting, I always liked to make sure that patients are getting checked for tuberculosis,” she said, adding that she performs annual monitoring for patients treated with the agent.

When considering tofacitinib, Dr. Abraham added that clinicians should ultimately consider discussing the risks of therapy versus the benefits in eligible patients.

During the question-and-answer portion of her session, Dr. Abraham noted that she has observed mixed findings in regard to tofacitinib’s effects on lipid levels. Specifically, only a small number of patients with UC in her practice have had to initiate cholesterol therapy while taking tofacitinib, but these patients typically have high-risk factors for hyperlipidemia, including family history and elevated body mass index.

On a question regarding the risk of shingles, Dr. Abraham noted that, if a patient does indeed develop the condition while taking tofacitinib, the therapy should be halted until shingles is resolved. In her practice, Dr. Abraham explained shingles vaccination is a priority before starting tofacitinib, suggesting this strategy has thus far prevented her tofacitinib-treated patients from developing the condition.

In patients with flares, Dr. Abraham noted that “we don’t have any specific clinical trial data specifically looking at” how to manage tofacitinib doses to further manage difficult-to-treat disease. She stated that, in her practice, she increases the dose of tofacitinib in patients who experience flares, as this often improves response. Subsequent dose reductions should be based on an individualized basis, with many patients requiring higher doses at varying periods.

Dr. Oleg has no relevant financial disclosures. Dr. Abraham reported conflicts of interest with Pfizer, which sponsored her discussion.
 

A real-world analysis of tofacitinib, presented at the annual Advances in Inflammatory Bowel Disease conference, confirms that long-term use of the selective immunosuppressant agent tofacitinib is associated with high rates of steroid-free remission in patients with ulcerative colitis (UC). These findings, along with clinical practice observations made during another session at the conference, further validate the efficacy of tofacitinib beyond that currently reported in specific clinical trial populations.

Tofacitinib is a small-molecule Janus kinase inhibitor that interferes with the intracellular JAK/signal transducer and activators of transcription pathway. Compared with other biologic agents, tofacitinib simultaneously acts on several cytokines and exerts broader effects on gastrointestinal inflammation.

Tofacitinib’s approval for moderate to severe UC was based on data from the OCTAVE clinical trial program. Although the phase 3 OCTAVE trial showed the JAK inhibitor features dose-dependent efficacy in inducing and maintaining remission in UC, stringent inclusion and exclusion criteria limit the generalizability of the trial’s findings across the broader, real-world UC population.

Findings from the recent analysis on tofacitinib were presented at AIBD 2021 by Knyazev Oleg, MD, who is the head of department of inflammatory bowel diseases at A.S. Loginov Moscow Clinical Scientific and Practical Center.

Dr. Oleg and colleagues reported on real-world treatment observations of 58 tofacitinib-treated patients with UC. Treatment efficacy was evaluated using the Mayo index (score <2), erythrocyte sedimentation rate, C-reactive protein, hemoglobin, fecal calprotectin, and the need for glucocorticoids (GCS).

At the time of tofacitinib initiation, all patients received GCS, with a mean therapeutic dose of 40 mg. In all 49 patients who responded to therapy, corticosteroids were discontinued after induction.

Only 15.5% (n = 9) of the study cohort did not respond to the JAK inhibitor during the follow-up period. A total of 14 patients (24.1%) who previously received anti-TNF therapies required a prolonged induction course of 20 mg tofacitinib. More than one out of five patients (22.4%) required repeated corticosteroids to manage exacerbations or dwindled tofacitinib response.

During another session, which discussed prescription treatment for moderate to severe UC, Bincy Abraham, MD, a professor of clinical medicine at Houston Methodist Academic Institute, summarized currently available clinical trial data on tofacitinib and discussed her own observations in her practice regarding the efficacy of the JAK inhibitor in the UC population.

The current data show the oral JAK inhibitor allows patients to reach remission as early as 8 weeks, with corresponding reductions observed in rectal bleeding and stool frequency as early as 2 weeks after therapy initiation. While the efficacy findings are corroborated by her own clinical practice, Dr. Abraham largely discussed the safety implications of the treatment.

Dr. Abraham emphasized the need for risk-mitigation strategies before initiating tofacitinib in appropriately selected patients with UC. In particular, Dr. Abraham explained that clinicians should be alerted to the possibility of tuberculosis as an opportunistic infection in tofacitinib-treated patients. “Before starting, I always liked to make sure that patients are getting checked for tuberculosis,” she said, adding that she performs annual monitoring for patients treated with the agent.

When considering tofacitinib, Dr. Abraham added that clinicians should ultimately consider discussing the risks of therapy versus the benefits in eligible patients.

During the question-and-answer portion of her session, Dr. Abraham noted that she has observed mixed findings in regard to tofacitinib’s effects on lipid levels. Specifically, only a small number of patients with UC in her practice have had to initiate cholesterol therapy while taking tofacitinib, but these patients typically have high-risk factors for hyperlipidemia, including family history and elevated body mass index.

On a question regarding the risk of shingles, Dr. Abraham noted that, if a patient does indeed develop the condition while taking tofacitinib, the therapy should be halted until shingles is resolved. In her practice, Dr. Abraham explained shingles vaccination is a priority before starting tofacitinib, suggesting this strategy has thus far prevented her tofacitinib-treated patients from developing the condition.

In patients with flares, Dr. Abraham noted that “we don’t have any specific clinical trial data specifically looking at” how to manage tofacitinib doses to further manage difficult-to-treat disease. She stated that, in her practice, she increases the dose of tofacitinib in patients who experience flares, as this often improves response. Subsequent dose reductions should be based on an individualized basis, with many patients requiring higher doses at varying periods.

Dr. Oleg has no relevant financial disclosures. Dr. Abraham reported conflicts of interest with Pfizer, which sponsored her discussion.
 

A real-world analysis of tofacitinib, presented at the annual Advances in Inflammatory Bowel Disease conference, confirms that long-term use of the selective immunosuppressant agent tofacitinib is associated with high rates of steroid-free remission in patients with ulcerative colitis (UC). These findings, along with clinical practice observations made during another session at the conference, further validate the efficacy of tofacitinib beyond that currently reported in specific clinical trial populations.

Tofacitinib is a small-molecule Janus kinase inhibitor that interferes with the intracellular JAK/signal transducer and activators of transcription pathway. Compared with other biologic agents, tofacitinib simultaneously acts on several cytokines and exerts broader effects on gastrointestinal inflammation.

Tofacitinib’s approval for moderate to severe UC was based on data from the OCTAVE clinical trial program. Although the phase 3 OCTAVE trial showed the JAK inhibitor features dose-dependent efficacy in inducing and maintaining remission in UC, stringent inclusion and exclusion criteria limit the generalizability of the trial’s findings across the broader, real-world UC population.

Findings from the recent analysis on tofacitinib were presented at AIBD 2021 by Knyazev Oleg, MD, who is the head of department of inflammatory bowel diseases at A.S. Loginov Moscow Clinical Scientific and Practical Center.

Dr. Oleg and colleagues reported on real-world treatment observations of 58 tofacitinib-treated patients with UC. Treatment efficacy was evaluated using the Mayo index (score <2), erythrocyte sedimentation rate, C-reactive protein, hemoglobin, fecal calprotectin, and the need for glucocorticoids (GCS).

At the time of tofacitinib initiation, all patients received GCS, with a mean therapeutic dose of 40 mg. In all 49 patients who responded to therapy, corticosteroids were discontinued after induction.

Only 15.5% (n = 9) of the study cohort did not respond to the JAK inhibitor during the follow-up period. A total of 14 patients (24.1%) who previously received anti-TNF therapies required a prolonged induction course of 20 mg tofacitinib. More than one out of five patients (22.4%) required repeated corticosteroids to manage exacerbations or dwindled tofacitinib response.

During another session, which discussed prescription treatment for moderate to severe UC, Bincy Abraham, MD, a professor of clinical medicine at Houston Methodist Academic Institute, summarized currently available clinical trial data on tofacitinib and discussed her own observations in her practice regarding the efficacy of the JAK inhibitor in the UC population.

The current data show the oral JAK inhibitor allows patients to reach remission as early as 8 weeks, with corresponding reductions observed in rectal bleeding and stool frequency as early as 2 weeks after therapy initiation. While the efficacy findings are corroborated by her own clinical practice, Dr. Abraham largely discussed the safety implications of the treatment.

Dr. Abraham emphasized the need for risk-mitigation strategies before initiating tofacitinib in appropriately selected patients with UC. In particular, Dr. Abraham explained that clinicians should be alerted to the possibility of tuberculosis as an opportunistic infection in tofacitinib-treated patients. “Before starting, I always liked to make sure that patients are getting checked for tuberculosis,” she said, adding that she performs annual monitoring for patients treated with the agent.

When considering tofacitinib, Dr. Abraham added that clinicians should ultimately consider discussing the risks of therapy versus the benefits in eligible patients.

During the question-and-answer portion of her session, Dr. Abraham noted that she has observed mixed findings in regard to tofacitinib’s effects on lipid levels. Specifically, only a small number of patients with UC in her practice have had to initiate cholesterol therapy while taking tofacitinib, but these patients typically have high-risk factors for hyperlipidemia, including family history and elevated body mass index.

On a question regarding the risk of shingles, Dr. Abraham noted that, if a patient does indeed develop the condition while taking tofacitinib, the therapy should be halted until shingles is resolved. In her practice, Dr. Abraham explained shingles vaccination is a priority before starting tofacitinib, suggesting this strategy has thus far prevented her tofacitinib-treated patients from developing the condition.

In patients with flares, Dr. Abraham noted that “we don’t have any specific clinical trial data specifically looking at” how to manage tofacitinib doses to further manage difficult-to-treat disease. She stated that, in her practice, she increases the dose of tofacitinib in patients who experience flares, as this often improves response. Subsequent dose reductions should be based on an individualized basis, with many patients requiring higher doses at varying periods.

Dr. Oleg has no relevant financial disclosures. Dr. Abraham reported conflicts of interest with Pfizer, which sponsored her discussion.
 

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

For uncomplicated chlamydia infection in a pregnant woman, what is the most appropriate treatment?

Continue to the answer...

Uncomplicated chlamydia infection in a pregnant woman should be treated with a single 1,000-mg oral dose of azithromycin. An acceptable alternative is amoxicillin 500 mg orally 3 times daily for 7 days.

In a nonpregnant patient, doxycycline 100 mg orally twice daily for 7 days is also an appropriate alternative. However, doxycycline is relatively expensive and may not be well tolerated because of gastrointestinal adverse effects. (Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Morbid Mortal Wkly Rep. 2015;64[RR3]:1-137.)

For uncomplicated chlamydia infection in a pregnant woman, what is the most appropriate treatment?

Continue to the answer...

Uncomplicated chlamydia infection in a pregnant woman should be treated with a single 1,000-mg oral dose of azithromycin. An acceptable alternative is amoxicillin 500 mg orally 3 times daily for 7 days.

In a nonpregnant patient, doxycycline 100 mg orally twice daily for 7 days is also an appropriate alternative. However, doxycycline is relatively expensive and may not be well tolerated because of gastrointestinal adverse effects. (Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Morbid Mortal Wkly Rep. 2015;64[RR3]:1-137.)

For uncomplicated chlamydia infection in a pregnant woman, what is the most appropriate treatment?

Continue to the answer...

Uncomplicated chlamydia infection in a pregnant woman should be treated with a single 1,000-mg oral dose of azithromycin. An acceptable alternative is amoxicillin 500 mg orally 3 times daily for 7 days.

In a nonpregnant patient, doxycycline 100 mg orally twice daily for 7 days is also an appropriate alternative. However, doxycycline is relatively expensive and may not be well tolerated because of gastrointestinal adverse effects. (Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Morbid Mortal Wkly Rep. 2015;64[RR3]:1-137.)

Updated guidelines from the American Academy of Neurology advise against prescribing opioids for painful diabetic neuropathy – but note that several other oral and topical therapies may help ease pain.

Painful diabetic neuropathy is very common and can greatly affect an individual’s quality of life, guideline author Brian Callaghan, MD, University of Michigan, Ann Arbor, noted in a news release.

“This guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Dr. Callaghan said.

The recommendations update the 2011 AAN guideline on the treatment of painful diabetic neuropathy. The new guidance was published online Dec. 27, 2021, in Neurology and has been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
 

Multiple options

To update the guideline, an expert panel reviewed data from more than 100 randomized controlled trials published from January 2008 to April 2020.

The panel noted that more than 16% of individuals with diabetes experience painful diabetic neuropathy, but it often goes unrecognized and untreated. The guideline recommends clinicians assess patients with diabetes for peripheral neuropathic pain and its effect on their function and quality of life.

Before prescribing treatment, health providers should determine if the patient also has mood or sleep problems as both can influence pain perception.

The guideline recommends offering one of four classes of oral medications found to be effective for neuropathic pain: tricyclic antidepressants such as amitriptyline, nortriptyline, or imipramine; serotonin norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, or desvenlafaxine; gabapentinoids such as gabapentin or pregabalin; and/or sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide.

All four classes of medications have “comparable effect sizes just above or just below our cutoff for a medium effect size” (standardized median difference, 0.5), the panel noted.

In addition, “new studies on sodium channel blockers published since the last guideline have resulted in these drugs now being recommended and considered as effective at providing pain relief as the other drug classes recommended in this guideline,” said Dr. Callaghan.

When an initial medication fails to provide meaningful improvement in pain, or produces significant side effects, a trial of another medication from a different class is recommended.
 

Pain reduction, not elimination

Opioids are not recommended for painful diabetic neuropathy. Not only do they come with risks, there is also no strong evidence they are effective for painful diabetic neuropathy in the long term, the panel wrote. Tramadol and tapentadol are also not recommended for the treatment of painful diabetic neuropathy.

“Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed,” Dr. Callaghan said.

For patients interested in trying topical, nontraditional, or nondrug interventions to reduce pain, the guideline recommends a number of options including capsaicin, glyceryl trinitrate spray, and Citrullus colocynthis. Ginkgo biloba, exercise, mindfulness, cognitive-behavioral therapy, and tai chi are also suggested.

“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Dr. Callaghan said. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”

Along with the updated guideline, the AAN has also published a new Polyneuropathy Quality Measurement Set to assist neurologists and other health care providers in treating patients with painful diabetic neuropathy.

The updated guideline was developed with financial support from the AAN.

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

Updated guidelines from the American Academy of Neurology advise against prescribing opioids for painful diabetic neuropathy – but note that several other oral and topical therapies may help ease pain.

Painful diabetic neuropathy is very common and can greatly affect an individual’s quality of life, guideline author Brian Callaghan, MD, University of Michigan, Ann Arbor, noted in a news release.

“This guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Dr. Callaghan said.

The recommendations update the 2011 AAN guideline on the treatment of painful diabetic neuropathy. The new guidance was published online Dec. 27, 2021, in Neurology and has been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
 

Multiple options

To update the guideline, an expert panel reviewed data from more than 100 randomized controlled trials published from January 2008 to April 2020.

The panel noted that more than 16% of individuals with diabetes experience painful diabetic neuropathy, but it often goes unrecognized and untreated. The guideline recommends clinicians assess patients with diabetes for peripheral neuropathic pain and its effect on their function and quality of life.

Before prescribing treatment, health providers should determine if the patient also has mood or sleep problems as both can influence pain perception.

The guideline recommends offering one of four classes of oral medications found to be effective for neuropathic pain: tricyclic antidepressants such as amitriptyline, nortriptyline, or imipramine; serotonin norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, or desvenlafaxine; gabapentinoids such as gabapentin or pregabalin; and/or sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide.

All four classes of medications have “comparable effect sizes just above or just below our cutoff for a medium effect size” (standardized median difference, 0.5), the panel noted.

In addition, “new studies on sodium channel blockers published since the last guideline have resulted in these drugs now being recommended and considered as effective at providing pain relief as the other drug classes recommended in this guideline,” said Dr. Callaghan.

When an initial medication fails to provide meaningful improvement in pain, or produces significant side effects, a trial of another medication from a different class is recommended.
 

Pain reduction, not elimination

Opioids are not recommended for painful diabetic neuropathy. Not only do they come with risks, there is also no strong evidence they are effective for painful diabetic neuropathy in the long term, the panel wrote. Tramadol and tapentadol are also not recommended for the treatment of painful diabetic neuropathy.

“Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed,” Dr. Callaghan said.

For patients interested in trying topical, nontraditional, or nondrug interventions to reduce pain, the guideline recommends a number of options including capsaicin, glyceryl trinitrate spray, and Citrullus colocynthis. Ginkgo biloba, exercise, mindfulness, cognitive-behavioral therapy, and tai chi are also suggested.

“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Dr. Callaghan said. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”

Along with the updated guideline, the AAN has also published a new Polyneuropathy Quality Measurement Set to assist neurologists and other health care providers in treating patients with painful diabetic neuropathy.

The updated guideline was developed with financial support from the AAN.

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

Updated guidelines from the American Academy of Neurology advise against prescribing opioids for painful diabetic neuropathy – but note that several other oral and topical therapies may help ease pain.

Painful diabetic neuropathy is very common and can greatly affect an individual’s quality of life, guideline author Brian Callaghan, MD, University of Michigan, Ann Arbor, noted in a news release.

“This guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Dr. Callaghan said.

The recommendations update the 2011 AAN guideline on the treatment of painful diabetic neuropathy. The new guidance was published online Dec. 27, 2021, in Neurology and has been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
 

Multiple options

To update the guideline, an expert panel reviewed data from more than 100 randomized controlled trials published from January 2008 to April 2020.

The panel noted that more than 16% of individuals with diabetes experience painful diabetic neuropathy, but it often goes unrecognized and untreated. The guideline recommends clinicians assess patients with diabetes for peripheral neuropathic pain and its effect on their function and quality of life.

Before prescribing treatment, health providers should determine if the patient also has mood or sleep problems as both can influence pain perception.

The guideline recommends offering one of four classes of oral medications found to be effective for neuropathic pain: tricyclic antidepressants such as amitriptyline, nortriptyline, or imipramine; serotonin norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, or desvenlafaxine; gabapentinoids such as gabapentin or pregabalin; and/or sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide.

All four classes of medications have “comparable effect sizes just above or just below our cutoff for a medium effect size” (standardized median difference, 0.5), the panel noted.

In addition, “new studies on sodium channel blockers published since the last guideline have resulted in these drugs now being recommended and considered as effective at providing pain relief as the other drug classes recommended in this guideline,” said Dr. Callaghan.

When an initial medication fails to provide meaningful improvement in pain, or produces significant side effects, a trial of another medication from a different class is recommended.
 

Pain reduction, not elimination

Opioids are not recommended for painful diabetic neuropathy. Not only do they come with risks, there is also no strong evidence they are effective for painful diabetic neuropathy in the long term, the panel wrote. Tramadol and tapentadol are also not recommended for the treatment of painful diabetic neuropathy.

“Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed,” Dr. Callaghan said.

For patients interested in trying topical, nontraditional, or nondrug interventions to reduce pain, the guideline recommends a number of options including capsaicin, glyceryl trinitrate spray, and Citrullus colocynthis. Ginkgo biloba, exercise, mindfulness, cognitive-behavioral therapy, and tai chi are also suggested.

“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Dr. Callaghan said. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”

Along with the updated guideline, the AAN has also published a new Polyneuropathy Quality Measurement Set to assist neurologists and other health care providers in treating patients with painful diabetic neuropathy.

The updated guideline was developed with financial support from the AAN.

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

A traumatic brain injury (TBI), even a mild type, can lead to posttraumatic epilepsy up to 1 year after the head injury occurs, new research suggests.

Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.

“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.

Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”

The findings were published online Dec. 29 in JAMA Network Open.
 

Novel study

Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.

To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.

The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.

The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.

The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
 

Confirmatory data

Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.

Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.

The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).

This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.

Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.

“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.

The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.

“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
 

Universal screening?

The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.

Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.

Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.

What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.

The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.

The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.

A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.

The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.

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

A traumatic brain injury (TBI), even a mild type, can lead to posttraumatic epilepsy up to 1 year after the head injury occurs, new research suggests.

Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.

“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.

Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”

The findings were published online Dec. 29 in JAMA Network Open.
 

Novel study

Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.

To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.

The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.

The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.

The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
 

Confirmatory data

Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.

Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.

The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).

This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.

Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.

“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.

The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.

“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
 

Universal screening?

The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.

Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.

Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.

What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.

The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.

The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.

A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.

The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.

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

A traumatic brain injury (TBI), even a mild type, can lead to posttraumatic epilepsy up to 1 year after the head injury occurs, new research suggests.

Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.

“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.

Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”

The findings were published online Dec. 29 in JAMA Network Open.
 

Novel study

Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.

To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.

The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.

The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.

The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
 

Confirmatory data

Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.

Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.

The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).

This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.

Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.

“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.

The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.

“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
 

Universal screening?

The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.

Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.

Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.

What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.

The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.

The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.

A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.

The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.

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

An obesity prevention program targeted at parents of infants benefited not only firstborn infants but their second-born siblings as well, a new study suggests.

According to a statement from the National Institutes of Health, who funded the study, it is the first such infant obesity intervention to show the spillover effect. Findings were published online Dec. 21, 2021, in Obesity.

The program is called Infants Growing on Healthy Trajectories (INSIGHT) responsive parenting (RP) intervention, and it included guidance on feeding, sleep, interactive play, and regulating emotion.

Parents were given guidance by nurses who came to their homes on how to respond when their child is drowsy, sleeping, fussy, and alert. They also learned how to put infants to bed drowsy, but awake, and avoid feeding infants to get them to sleep; how to respond to infants waking up at night; when to start solid foods; how to limit inactive time; and how to use growth charts.

The control group program focused on safety and matched the guidance categories. For example, early visits included information on prevention of sudden infant death syndrome for sleep, breast milk storage and formula for feeding, and safe bathing.

Jennifer S. Savage, Center for Childhood Obesity Research, Penn State University, University Park, led the study that enrolled 117 infants in a randomized controlled trial. Mother and firstborn children were randomized to the RP or home safety intervention (control) group 10-14 days after delivery. Their second-born siblings were enrolled in an observation-only ancillary study.

Second-born children were delivered 2.5 (standard deviation, 0.9) years after firstborns. Anthropometrics were measured in both siblings at ages 3, 16, 28, and 52 weeks.

Firstborn children at 1 year had a body mass index (BMI) that was 0.44 kg/m² lower than the control group (95% confidence interval, −0.82 to −0.06), and second-born children whose parents received the RP intervention with their first child had BMI that was 0.36 kg/m² lower.

“What we saw here is that it worked again,” coauthor Ian Paul, MD, MSc, professor of pediatrics and public health sciences at Penn State University, Hershey, said in an interview.

“Once we imprint them with a certain approach to parenting with the first child, they’re doing the same thing with the second child, which is wonderful to see,” he said.

He noted that this happened with second children without any reinforcements or booster information.

Dr. Paul said it’s still not clear which of the interventions – whether related to feeding techniques or sleeping or activity – helps most. And for each family the problematic behaviors may be different.

Responsive parenting programs have shown success previously among firstborns, the authors wrote, but 80% of those children grow up with younger siblings, so an intervention that also benefits them is important.

Weighing the costs of the intervention

The intervention was extensive. It involved four hour-plus nurse visits a year, often by the same nurse who built a relationship with the family.

But Ms. Savage said that it is possible to replicate INSIGHT on a larger scale in the United States with the dozens of home visitation models.

“Currently, 21 home visitation models meet the U.S. Department of Health & Human Services criteria for evidence of effectiveness, such as Nurse Family Partnership, Family Check-up, and Early Head Start Home Based Option. There is an opportunity to use home visitation models at the national scale to potentially interrupt the cycle of poor multigenerational outcomes such as obesity,” she said.

Dr. Paul said the initial investment “can save money in the long term,” given what’s at stake. “We know that 20%-25% of 2- to 5-year-olds are already overweight or obese and if they are already overweight or obese at that age, that;’s likely to persist.”

However, he acknowledged that staff shortages and costs are a challenge.

“Other countries have made that investment in their health care system,” he said. “In the U.S. only a fraction of new mothers and babies get home visitation. The kind of work that we did for obesity prevention has not yet been incorporated into evidence-based models of home visitation, though it certainly could be.”

Dr. Paul said his team is hoping to collaborate with others in the near future on expanding this program to such models of home visitation.

Telehealth, though a less desirable option, compared with in-home visits, could also be utilized, he said.

Short of the comprehensive intervention, he said, many of the concepts can be put into practice by pediatricians and parents.

Dr. Paul noted that the Robert Wood Johnson Foundation has endorsed “responsive feeding” as the preferred approach to feeding infants and toddlers. Responsive feeding – helping parents recognize hunger and satiety cues as opposed to other distress cues – is a big part of the intervention.

“Feeding to soothe is not the preferred approach,” he said. “Food and milk and formula should be used for hunger.” That’s something pediatricians may not be stressing to parents, he said.

Pediatricians can also counsel parents on not using food as a reward. “We shouldn’t be giving kids M&Ms to teach them how to potty train,” he said.
 

‘Promising’ findings

Charles Wood, MD, a childhood obesity specialist at Duke University, Durham, N.C., who was not part of the study, called the findings “very promising.”

It also makes sense that the “aha moments” of first-time parents learning from the INSIGHT intervention would carry over to the second sibling, he said.

Dr. Wood agreed costs are a big factor. However, he said, the potential downstream costs of not preventing obesity are worse. And this study indicates the benefits may keep spreading with future siblings.

Dr. Wood said accessing obesity interventions outside the pediatrician visit can also help. Connecting patients with support groups or dietitians or with a counselor from Women, Infants, and Children can help. However, consistent messaging among the providers is key, he noted.

Dr. Wood’s research group is investigating text messaging platforms so parents can get answer to real-time questions, such as those about feeding behaviors.

He pointed to a limitation the authors mention, which is that the study was done in mostly White, highly educated, higher-income families.

“There’s a big problem with racial disparities and obesity,” Dr. Wood noted. “We definitely need solutions that address disparities as well.”

Mothers included in the study had given birth for the first time and their infants were enrolled after birth from a single maternity ward between January 2012 and March 2014. Major eligibility criteria were that the babies were full term (at least 37 weeks’ gestation), single births, and delivered to English-speaking mothers at least 20 years of age. Infants who weighed less than 2,500 g at birth were excluded.

The paper’s authors and Dr. Wood declared no relevant financial relationships.

This research was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases; and the Department of Agriculture.

An obesity prevention program targeted at parents of infants benefited not only firstborn infants but their second-born siblings as well, a new study suggests.

According to a statement from the National Institutes of Health, who funded the study, it is the first such infant obesity intervention to show the spillover effect. Findings were published online Dec. 21, 2021, in Obesity.

The program is called Infants Growing on Healthy Trajectories (INSIGHT) responsive parenting (RP) intervention, and it included guidance on feeding, sleep, interactive play, and regulating emotion.

Parents were given guidance by nurses who came to their homes on how to respond when their child is drowsy, sleeping, fussy, and alert. They also learned how to put infants to bed drowsy, but awake, and avoid feeding infants to get them to sleep; how to respond to infants waking up at night; when to start solid foods; how to limit inactive time; and how to use growth charts.

The control group program focused on safety and matched the guidance categories. For example, early visits included information on prevention of sudden infant death syndrome for sleep, breast milk storage and formula for feeding, and safe bathing.

Jennifer S. Savage, Center for Childhood Obesity Research, Penn State University, University Park, led the study that enrolled 117 infants in a randomized controlled trial. Mother and firstborn children were randomized to the RP or home safety intervention (control) group 10-14 days after delivery. Their second-born siblings were enrolled in an observation-only ancillary study.

Second-born children were delivered 2.5 (standard deviation, 0.9) years after firstborns. Anthropometrics were measured in both siblings at ages 3, 16, 28, and 52 weeks.

Firstborn children at 1 year had a body mass index (BMI) that was 0.44 kg/m² lower than the control group (95% confidence interval, −0.82 to −0.06), and second-born children whose parents received the RP intervention with their first child had BMI that was 0.36 kg/m² lower.

“What we saw here is that it worked again,” coauthor Ian Paul, MD, MSc, professor of pediatrics and public health sciences at Penn State University, Hershey, said in an interview.

“Once we imprint them with a certain approach to parenting with the first child, they’re doing the same thing with the second child, which is wonderful to see,” he said.

He noted that this happened with second children without any reinforcements or booster information.

Dr. Paul said it’s still not clear which of the interventions – whether related to feeding techniques or sleeping or activity – helps most. And for each family the problematic behaviors may be different.

Responsive parenting programs have shown success previously among firstborns, the authors wrote, but 80% of those children grow up with younger siblings, so an intervention that also benefits them is important.

Weighing the costs of the intervention

The intervention was extensive. It involved four hour-plus nurse visits a year, often by the same nurse who built a relationship with the family.

But Ms. Savage said that it is possible to replicate INSIGHT on a larger scale in the United States with the dozens of home visitation models.

“Currently, 21 home visitation models meet the U.S. Department of Health & Human Services criteria for evidence of effectiveness, such as Nurse Family Partnership, Family Check-up, and Early Head Start Home Based Option. There is an opportunity to use home visitation models at the national scale to potentially interrupt the cycle of poor multigenerational outcomes such as obesity,” she said.

Dr. Paul said the initial investment “can save money in the long term,” given what’s at stake. “We know that 20%-25% of 2- to 5-year-olds are already overweight or obese and if they are already overweight or obese at that age, that;’s likely to persist.”

However, he acknowledged that staff shortages and costs are a challenge.

“Other countries have made that investment in their health care system,” he said. “In the U.S. only a fraction of new mothers and babies get home visitation. The kind of work that we did for obesity prevention has not yet been incorporated into evidence-based models of home visitation, though it certainly could be.”

Dr. Paul said his team is hoping to collaborate with others in the near future on expanding this program to such models of home visitation.

Telehealth, though a less desirable option, compared with in-home visits, could also be utilized, he said.

Short of the comprehensive intervention, he said, many of the concepts can be put into practice by pediatricians and parents.

Dr. Paul noted that the Robert Wood Johnson Foundation has endorsed “responsive feeding” as the preferred approach to feeding infants and toddlers. Responsive feeding – helping parents recognize hunger and satiety cues as opposed to other distress cues – is a big part of the intervention.

“Feeding to soothe is not the preferred approach,” he said. “Food and milk and formula should be used for hunger.” That’s something pediatricians may not be stressing to parents, he said.

Pediatricians can also counsel parents on not using food as a reward. “We shouldn’t be giving kids M&Ms to teach them how to potty train,” he said.
 

‘Promising’ findings

Charles Wood, MD, a childhood obesity specialist at Duke University, Durham, N.C., who was not part of the study, called the findings “very promising.”

It also makes sense that the “aha moments” of first-time parents learning from the INSIGHT intervention would carry over to the second sibling, he said.

Dr. Wood agreed costs are a big factor. However, he said, the potential downstream costs of not preventing obesity are worse. And this study indicates the benefits may keep spreading with future siblings.

Dr. Wood said accessing obesity interventions outside the pediatrician visit can also help. Connecting patients with support groups or dietitians or with a counselor from Women, Infants, and Children can help. However, consistent messaging among the providers is key, he noted.

Dr. Wood’s research group is investigating text messaging platforms so parents can get answer to real-time questions, such as those about feeding behaviors.

He pointed to a limitation the authors mention, which is that the study was done in mostly White, highly educated, higher-income families.

“There’s a big problem with racial disparities and obesity,” Dr. Wood noted. “We definitely need solutions that address disparities as well.”

Mothers included in the study had given birth for the first time and their infants were enrolled after birth from a single maternity ward between January 2012 and March 2014. Major eligibility criteria were that the babies were full term (at least 37 weeks’ gestation), single births, and delivered to English-speaking mothers at least 20 years of age. Infants who weighed less than 2,500 g at birth were excluded.

The paper’s authors and Dr. Wood declared no relevant financial relationships.

This research was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases; and the Department of Agriculture.

An obesity prevention program targeted at parents of infants benefited not only firstborn infants but their second-born siblings as well, a new study suggests.

According to a statement from the National Institutes of Health, who funded the study, it is the first such infant obesity intervention to show the spillover effect. Findings were published online Dec. 21, 2021, in Obesity.

The program is called Infants Growing on Healthy Trajectories (INSIGHT) responsive parenting (RP) intervention, and it included guidance on feeding, sleep, interactive play, and regulating emotion.

Parents were given guidance by nurses who came to their homes on how to respond when their child is drowsy, sleeping, fussy, and alert. They also learned how to put infants to bed drowsy, but awake, and avoid feeding infants to get them to sleep; how to respond to infants waking up at night; when to start solid foods; how to limit inactive time; and how to use growth charts.

The control group program focused on safety and matched the guidance categories. For example, early visits included information on prevention of sudden infant death syndrome for sleep, breast milk storage and formula for feeding, and safe bathing.

Jennifer S. Savage, Center for Childhood Obesity Research, Penn State University, University Park, led the study that enrolled 117 infants in a randomized controlled trial. Mother and firstborn children were randomized to the RP or home safety intervention (control) group 10-14 days after delivery. Their second-born siblings were enrolled in an observation-only ancillary study.

Second-born children were delivered 2.5 (standard deviation, 0.9) years after firstborns. Anthropometrics were measured in both siblings at ages 3, 16, 28, and 52 weeks.

Firstborn children at 1 year had a body mass index (BMI) that was 0.44 kg/m² lower than the control group (95% confidence interval, −0.82 to −0.06), and second-born children whose parents received the RP intervention with their first child had BMI that was 0.36 kg/m² lower.

“What we saw here is that it worked again,” coauthor Ian Paul, MD, MSc, professor of pediatrics and public health sciences at Penn State University, Hershey, said in an interview.

“Once we imprint them with a certain approach to parenting with the first child, they’re doing the same thing with the second child, which is wonderful to see,” he said.

He noted that this happened with second children without any reinforcements or booster information.

Dr. Paul said it’s still not clear which of the interventions – whether related to feeding techniques or sleeping or activity – helps most. And for each family the problematic behaviors may be different.

Responsive parenting programs have shown success previously among firstborns, the authors wrote, but 80% of those children grow up with younger siblings, so an intervention that also benefits them is important.

Weighing the costs of the intervention

The intervention was extensive. It involved four hour-plus nurse visits a year, often by the same nurse who built a relationship with the family.

But Ms. Savage said that it is possible to replicate INSIGHT on a larger scale in the United States with the dozens of home visitation models.

“Currently, 21 home visitation models meet the U.S. Department of Health & Human Services criteria for evidence of effectiveness, such as Nurse Family Partnership, Family Check-up, and Early Head Start Home Based Option. There is an opportunity to use home visitation models at the national scale to potentially interrupt the cycle of poor multigenerational outcomes such as obesity,” she said.

Dr. Paul said the initial investment “can save money in the long term,” given what’s at stake. “We know that 20%-25% of 2- to 5-year-olds are already overweight or obese and if they are already overweight or obese at that age, that;’s likely to persist.”

However, he acknowledged that staff shortages and costs are a challenge.

“Other countries have made that investment in their health care system,” he said. “In the U.S. only a fraction of new mothers and babies get home visitation. The kind of work that we did for obesity prevention has not yet been incorporated into evidence-based models of home visitation, though it certainly could be.”

Dr. Paul said his team is hoping to collaborate with others in the near future on expanding this program to such models of home visitation.

Telehealth, though a less desirable option, compared with in-home visits, could also be utilized, he said.

Short of the comprehensive intervention, he said, many of the concepts can be put into practice by pediatricians and parents.

Dr. Paul noted that the Robert Wood Johnson Foundation has endorsed “responsive feeding” as the preferred approach to feeding infants and toddlers. Responsive feeding – helping parents recognize hunger and satiety cues as opposed to other distress cues – is a big part of the intervention.

“Feeding to soothe is not the preferred approach,” he said. “Food and milk and formula should be used for hunger.” That’s something pediatricians may not be stressing to parents, he said.

Pediatricians can also counsel parents on not using food as a reward. “We shouldn’t be giving kids M&Ms to teach them how to potty train,” he said.
 

‘Promising’ findings

Charles Wood, MD, a childhood obesity specialist at Duke University, Durham, N.C., who was not part of the study, called the findings “very promising.”

It also makes sense that the “aha moments” of first-time parents learning from the INSIGHT intervention would carry over to the second sibling, he said.

Dr. Wood agreed costs are a big factor. However, he said, the potential downstream costs of not preventing obesity are worse. And this study indicates the benefits may keep spreading with future siblings.

Dr. Wood said accessing obesity interventions outside the pediatrician visit can also help. Connecting patients with support groups or dietitians or with a counselor from Women, Infants, and Children can help. However, consistent messaging among the providers is key, he noted.

Dr. Wood’s research group is investigating text messaging platforms so parents can get answer to real-time questions, such as those about feeding behaviors.

He pointed to a limitation the authors mention, which is that the study was done in mostly White, highly educated, higher-income families.

“There’s a big problem with racial disparities and obesity,” Dr. Wood noted. “We definitely need solutions that address disparities as well.”

Mothers included in the study had given birth for the first time and their infants were enrolled after birth from a single maternity ward between January 2012 and March 2014. Major eligibility criteria were that the babies were full term (at least 37 weeks’ gestation), single births, and delivered to English-speaking mothers at least 20 years of age. Infants who weighed less than 2,500 g at birth were excluded.

The paper’s authors and Dr. Wood declared no relevant financial relationships.

This research was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases; and the Department of Agriculture.

Since the end of 2019, COVID-19 infection caused by SARS-CoV-2 has spread in a worldwide pandemic. The first cutaneous manifestations possibly linked to COVID-19 were reported in spring 2020.¹ Herpes zoster (HZ) was suspected as a predictive cutaneous manifestation of COVID-19 with a debated prognostic significance.² The end of 2020 was marked with the beginning of vaccination against COVID-19, and safety studies reported few side effects after vaccination with nucleoside-modified messenger RNA (mRNA) COVID-19 vaccines.³ Real-life use of vaccines could lead to the occurrence of potential side effects (or fortuitous medical events) that were not observed in these studies. We report a series of 5 cases of HZ occurring after vaccination with a nucleoside-modified mRNA COVID-19 vaccine extracted from a declarative cohort of cutaneous reactions in our vaccination center.

Case Series

We identified 2 men and 3 women (Table) who experienced HZ after vaccination with a nucleoside-modified mRNA COVID-19 vaccine (Comirnaty, Pfizer-BioNTech). Patients fulfilled French governmental criteria for vaccination at the time of the report—older than 75 years or a health care professional—and they were vaccinated at the vaccination center of a French university hospital. The median age of the patients was 56 years (interquartile range [IQR], 51–82 years). One patient was diagnosed with COVID-19 in February 2020. A medical history of HZ was found in 1 patient. No medical history of immunosuppression was noted. Herpes zoster was observed on the same side of the body as the vaccination site in 4 patients. The median delay before the onset of symptoms was 6 days (IQR, 1–15 days) after injection. The median duration of the symptoms was 13 days (IQR, 11.5–16.5 days). Clinical signs of HZ were mild with few vesicles in 4 patients, and we observed a notably long delay between the onset of pain and the eruption of vesicles in 2 cases (4 and 10 days, respectively). The clinical diagnosis of HZ was confirmed by a dermatologist for all patients (Figures 1 and 2). Polymerase chain reaction assays for the detection of the varicella-zoster virus were performed in 2 cases and were positive. A complete blood cell count was performed in 1 patient, and we observed isolated lymphopenia (500/mm³ [reference range, 1000–4000/mm³]). Herpes zoster occurred after the first dose of vaccine in 4 patients and after the second dose for 1 patient. Three patients were treated with antiviral therapy (acyclovir) for 7 days. Three patients recovered from symptoms within 2 weeks and 2 patients within 1 week.

Comment

We report a series of HZ cases occurring after vaccination with a nucleoside-modified mRNA COVID-19 vaccine. We did not observe complicated HZ, and most of the time, HZ lesions were located on the same side of the body as the vaccine injection. One case of HZ after COVID-19 vaccination was reported by Bostan and Yalici-Armagan,⁴ but it followed injection with an inactivated vaccine, which is different from our series. Herpes zoster remains rarely reported, mainly following mRNA COVID-19 vaccination.⁵

Cases of HZ after vaccination have been reported after the live attenuated zoster or yellow fever vaccines, but HZ should not appear as a concomitant effect after any type of vaccines.^6,7 Kawai et al⁸ reported that the incidence rate of HZ ranged from 3 to 5 cases per 1000 person-years in North America, Europe, and Asia-Pacific. The risk for recurrence of HZ ranged from 1% to 6% depending on the type of study design, age distribution of studied populations, and definition.⁸ In another retrospective database analysis in Israel, the incidence density rate of HZ was 3.46 cases per 1000 person-years in the total population and 12.8 cases per 1000 person-years in immunocompromised patients, therefore the immunocompromised status is important to consider.⁹

In our declarative cohort of skin eruptions before vaccination, we recorded 11 cases of HZ among 148 skin eruptions (7.43%) at the time of the study, but the design of the study did not allow us to estimate the exact incidence of HZ in the global COVID-19–vaccinated population because our study was not based on a systematic and prospective analysis of all vaccinated patients. The comparison between the prevalence of HZ in the COVID-19–vaccinated population and the nonvaccinated population is difficult owing to the lack of data about HZ in the nonvaccinated population at the time of our analysis. Furthermore, we did not include all vaccinated patients in a prospective follow-up. We highlight the importance of medical history of patients that differed between vaccinated patients (at the time of our analysis) and the global population due to French governmental access criteria to vaccination. The link to prior SARS-CoV-2 infection was uncertain because a medical history of COVID-19 was found in only 1 patient. Only 1 patient had a history of HZ, which is not a contraindication of COVID-19 vaccination.

Postinjection pains are frequent with COVID-19 vaccines, but clinical signs such as extension of pain, burning sensation, and eruption of vesicles should lead the physician to consider the diagnosis of HZ, regardless of the delay between the injection and the symptoms. Indeed, the onset of symptoms could be late, and the clinical presentation initially may be mistaken for an injection-site reaction, which is a frequent known side effect of vaccines. These new cases do not prove causality between COVID-19 vaccination and HZ. Varicella-zoster virus remains latent in dorsal-root or ganglia after primary infection, and HZ caused by reactivation of varicella-zoster virus may occur spontaneously or be triggered. In our series, we did not observe medical history of immunosuppression, and no other known risk factors of HZ (eg, radiation therapy, physical trauma, fever after vaccination) were recorded. The pathophysiologic mechanism remains elusive, but local vaccine-induced immunomodulation or an inflammatory state may be involved.

Conclusion

Our case series highlights that clinicians must remain vigilant to diagnose HZ early to prevent potential complications, such as postherpetic neuralgia. Also, vaccination should not be contraindicated in patients with medical history of HZ; the occurrence of HZ does not justify avoiding the second injection of the vaccine due to the benefit of vaccination.

Since the end of 2019, COVID-19 infection caused by SARS-CoV-2 has spread in a worldwide pandemic. The first cutaneous manifestations possibly linked to COVID-19 were reported in spring 2020.¹ Herpes zoster (HZ) was suspected as a predictive cutaneous manifestation of COVID-19 with a debated prognostic significance.² The end of 2020 was marked with the beginning of vaccination against COVID-19, and safety studies reported few side effects after vaccination with nucleoside-modified messenger RNA (mRNA) COVID-19 vaccines.³ Real-life use of vaccines could lead to the occurrence of potential side effects (or fortuitous medical events) that were not observed in these studies. We report a series of 5 cases of HZ occurring after vaccination with a nucleoside-modified mRNA COVID-19 vaccine extracted from a declarative cohort of cutaneous reactions in our vaccination center.

Case Series

We identified 2 men and 3 women (Table) who experienced HZ after vaccination with a nucleoside-modified mRNA COVID-19 vaccine (Comirnaty, Pfizer-BioNTech). Patients fulfilled French governmental criteria for vaccination at the time of the report—older than 75 years or a health care professional—and they were vaccinated at the vaccination center of a French university hospital. The median age of the patients was 56 years (interquartile range [IQR], 51–82 years). One patient was diagnosed with COVID-19 in February 2020. A medical history of HZ was found in 1 patient. No medical history of immunosuppression was noted. Herpes zoster was observed on the same side of the body as the vaccination site in 4 patients. The median delay before the onset of symptoms was 6 days (IQR, 1–15 days) after injection. The median duration of the symptoms was 13 days (IQR, 11.5–16.5 days). Clinical signs of HZ were mild with few vesicles in 4 patients, and we observed a notably long delay between the onset of pain and the eruption of vesicles in 2 cases (4 and 10 days, respectively). The clinical diagnosis of HZ was confirmed by a dermatologist for all patients (Figures 1 and 2). Polymerase chain reaction assays for the detection of the varicella-zoster virus were performed in 2 cases and were positive. A complete blood cell count was performed in 1 patient, and we observed isolated lymphopenia (500/mm³ [reference range, 1000–4000/mm³]). Herpes zoster occurred after the first dose of vaccine in 4 patients and after the second dose for 1 patient. Three patients were treated with antiviral therapy (acyclovir) for 7 days. Three patients recovered from symptoms within 2 weeks and 2 patients within 1 week.

Comment

We report a series of HZ cases occurring after vaccination with a nucleoside-modified mRNA COVID-19 vaccine. We did not observe complicated HZ, and most of the time, HZ lesions were located on the same side of the body as the vaccine injection. One case of HZ after COVID-19 vaccination was reported by Bostan and Yalici-Armagan,⁴ but it followed injection with an inactivated vaccine, which is different from our series. Herpes zoster remains rarely reported, mainly following mRNA COVID-19 vaccination.⁵

Cases of HZ after vaccination have been reported after the live attenuated zoster or yellow fever vaccines, but HZ should not appear as a concomitant effect after any type of vaccines.^6,7 Kawai et al⁸ reported that the incidence rate of HZ ranged from 3 to 5 cases per 1000 person-years in North America, Europe, and Asia-Pacific. The risk for recurrence of HZ ranged from 1% to 6% depending on the type of study design, age distribution of studied populations, and definition.⁸ In another retrospective database analysis in Israel, the incidence density rate of HZ was 3.46 cases per 1000 person-years in the total population and 12.8 cases per 1000 person-years in immunocompromised patients, therefore the immunocompromised status is important to consider.⁹

In our declarative cohort of skin eruptions before vaccination, we recorded 11 cases of HZ among 148 skin eruptions (7.43%) at the time of the study, but the design of the study did not allow us to estimate the exact incidence of HZ in the global COVID-19–vaccinated population because our study was not based on a systematic and prospective analysis of all vaccinated patients. The comparison between the prevalence of HZ in the COVID-19–vaccinated population and the nonvaccinated population is difficult owing to the lack of data about HZ in the nonvaccinated population at the time of our analysis. Furthermore, we did not include all vaccinated patients in a prospective follow-up. We highlight the importance of medical history of patients that differed between vaccinated patients (at the time of our analysis) and the global population due to French governmental access criteria to vaccination. The link to prior SARS-CoV-2 infection was uncertain because a medical history of COVID-19 was found in only 1 patient. Only 1 patient had a history of HZ, which is not a contraindication of COVID-19 vaccination.

Postinjection pains are frequent with COVID-19 vaccines, but clinical signs such as extension of pain, burning sensation, and eruption of vesicles should lead the physician to consider the diagnosis of HZ, regardless of the delay between the injection and the symptoms. Indeed, the onset of symptoms could be late, and the clinical presentation initially may be mistaken for an injection-site reaction, which is a frequent known side effect of vaccines. These new cases do not prove causality between COVID-19 vaccination and HZ. Varicella-zoster virus remains latent in dorsal-root or ganglia after primary infection, and HZ caused by reactivation of varicella-zoster virus may occur spontaneously or be triggered. In our series, we did not observe medical history of immunosuppression, and no other known risk factors of HZ (eg, radiation therapy, physical trauma, fever after vaccination) were recorded. The pathophysiologic mechanism remains elusive, but local vaccine-induced immunomodulation or an inflammatory state may be involved.

Conclusion

Our case series highlights that clinicians must remain vigilant to diagnose HZ early to prevent potential complications, such as postherpetic neuralgia. Also, vaccination should not be contraindicated in patients with medical history of HZ; the occurrence of HZ does not justify avoiding the second injection of the vaccine due to the benefit of vaccination.

Since the end of 2019, COVID-19 infection caused by SARS-CoV-2 has spread in a worldwide pandemic. The first cutaneous manifestations possibly linked to COVID-19 were reported in spring 2020.¹ Herpes zoster (HZ) was suspected as a predictive cutaneous manifestation of COVID-19 with a debated prognostic significance.² The end of 2020 was marked with the beginning of vaccination against COVID-19, and safety studies reported few side effects after vaccination with nucleoside-modified messenger RNA (mRNA) COVID-19 vaccines.³ Real-life use of vaccines could lead to the occurrence of potential side effects (or fortuitous medical events) that were not observed in these studies. We report a series of 5 cases of HZ occurring after vaccination with a nucleoside-modified mRNA COVID-19 vaccine extracted from a declarative cohort of cutaneous reactions in our vaccination center.

Case Series

We identified 2 men and 3 women (Table) who experienced HZ after vaccination with a nucleoside-modified mRNA COVID-19 vaccine (Comirnaty, Pfizer-BioNTech). Patients fulfilled French governmental criteria for vaccination at the time of the report—older than 75 years or a health care professional—and they were vaccinated at the vaccination center of a French university hospital. The median age of the patients was 56 years (interquartile range [IQR], 51–82 years). One patient was diagnosed with COVID-19 in February 2020. A medical history of HZ was found in 1 patient. No medical history of immunosuppression was noted. Herpes zoster was observed on the same side of the body as the vaccination site in 4 patients. The median delay before the onset of symptoms was 6 days (IQR, 1–15 days) after injection. The median duration of the symptoms was 13 days (IQR, 11.5–16.5 days). Clinical signs of HZ were mild with few vesicles in 4 patients, and we observed a notably long delay between the onset of pain and the eruption of vesicles in 2 cases (4 and 10 days, respectively). The clinical diagnosis of HZ was confirmed by a dermatologist for all patients (Figures 1 and 2). Polymerase chain reaction assays for the detection of the varicella-zoster virus were performed in 2 cases and were positive. A complete blood cell count was performed in 1 patient, and we observed isolated lymphopenia (500/mm³ [reference range, 1000–4000/mm³]). Herpes zoster occurred after the first dose of vaccine in 4 patients and after the second dose for 1 patient. Three patients were treated with antiviral therapy (acyclovir) for 7 days. Three patients recovered from symptoms within 2 weeks and 2 patients within 1 week.

Comment

We report a series of HZ cases occurring after vaccination with a nucleoside-modified mRNA COVID-19 vaccine. We did not observe complicated HZ, and most of the time, HZ lesions were located on the same side of the body as the vaccine injection. One case of HZ after COVID-19 vaccination was reported by Bostan and Yalici-Armagan,⁴ but it followed injection with an inactivated vaccine, which is different from our series. Herpes zoster remains rarely reported, mainly following mRNA COVID-19 vaccination.⁵

Cases of HZ after vaccination have been reported after the live attenuated zoster or yellow fever vaccines, but HZ should not appear as a concomitant effect after any type of vaccines.^6,7 Kawai et al⁸ reported that the incidence rate of HZ ranged from 3 to 5 cases per 1000 person-years in North America, Europe, and Asia-Pacific. The risk for recurrence of HZ ranged from 1% to 6% depending on the type of study design, age distribution of studied populations, and definition.⁸ In another retrospective database analysis in Israel, the incidence density rate of HZ was 3.46 cases per 1000 person-years in the total population and 12.8 cases per 1000 person-years in immunocompromised patients, therefore the immunocompromised status is important to consider.⁹

In our declarative cohort of skin eruptions before vaccination, we recorded 11 cases of HZ among 148 skin eruptions (7.43%) at the time of the study, but the design of the study did not allow us to estimate the exact incidence of HZ in the global COVID-19–vaccinated population because our study was not based on a systematic and prospective analysis of all vaccinated patients. The comparison between the prevalence of HZ in the COVID-19–vaccinated population and the nonvaccinated population is difficult owing to the lack of data about HZ in the nonvaccinated population at the time of our analysis. Furthermore, we did not include all vaccinated patients in a prospective follow-up. We highlight the importance of medical history of patients that differed between vaccinated patients (at the time of our analysis) and the global population due to French governmental access criteria to vaccination. The link to prior SARS-CoV-2 infection was uncertain because a medical history of COVID-19 was found in only 1 patient. Only 1 patient had a history of HZ, which is not a contraindication of COVID-19 vaccination.

Postinjection pains are frequent with COVID-19 vaccines, but clinical signs such as extension of pain, burning sensation, and eruption of vesicles should lead the physician to consider the diagnosis of HZ, regardless of the delay between the injection and the symptoms. Indeed, the onset of symptoms could be late, and the clinical presentation initially may be mistaken for an injection-site reaction, which is a frequent known side effect of vaccines. These new cases do not prove causality between COVID-19 vaccination and HZ. Varicella-zoster virus remains latent in dorsal-root or ganglia after primary infection, and HZ caused by reactivation of varicella-zoster virus may occur spontaneously or be triggered. In our series, we did not observe medical history of immunosuppression, and no other known risk factors of HZ (eg, radiation therapy, physical trauma, fever after vaccination) were recorded. The pathophysiologic mechanism remains elusive, but local vaccine-induced immunomodulation or an inflammatory state may be involved.

Conclusion

Our case series highlights that clinicians must remain vigilant to diagnose HZ early to prevent potential complications, such as postherpetic neuralgia. Also, vaccination should not be contraindicated in patients with medical history of HZ; the occurrence of HZ does not justify avoiding the second injection of the vaccine due to the benefit of vaccination.

To the Editor:

Securing a dermatology residency position is extraordinarily competitive. The match rate for US allopathic seniors for dermatology is 84.7%, among the lowest of all medical specialties. Matched dermatology applicants boast a mean US Medical Licensing Examination (USMLE) Step 1 score of 248, the second highest of all specialties.¹ To gain an edge, applicants are faced with decisions regarding pursuit of dedicated research time and additional professional degrees.

We conducted a cross-sectional study to determine how many dermatology residency applicants pursue additional years of training and how this decision relates to USMLE scores and other metrics. This study was approved by the University of Michigan institutional review board. Using Electronic Residency Application Service applicant data, all applicants to the University of Michigan Medical School (Ann Arbor, Michigan) dermatology residency program for the 2018-2019 application cycle were included.

Analysis of variance was performed to determine differences in mean USMLE Step 1 scores, Step 2 Clinical Knowledge scores, and number of research experiences (eg, presentations, publications) between groups. A 2-tailed z test of independent samples was performed for individual pairwise subgroup analyses.

There were 608 (377 female, 231 male; mean age, 27.9 years) applicants from 199 different medical schools; 550 graduated with an MD degree, 40 with a DO degree, and 18 were international medical graduates (IMGs)(eg, MBBS, MBBCh, BAO, MBChB). One hundred eighty-four applicants (30.2%) pursued either a second professional degree or a dedicated research period lasting at least 12 months. Twenty-eight applicants (4.6%) obtained a master’s degree, 21 (3.5%) obtained a doctorate, and 135 (22.2%) pursued dedicated research.

Of the 40 DO applicants, 1 (2.5%) pursued dedicated research time; 0 (zero) completed a dual degree. None (zero) of the 18 IMGs pursued a dual degree or dedicated research time. When the scores of applicants who pursued additional training and the scores of applicants who did not were compared, neither mean USMLE Step 1 scores nor mean USMLE Step 2 Clinical Knowledge scores were statistically different (P=.31 and P=.44, respectively). Applicants who completed medical school in 4 years had fewer research experiences (mean [SD] experiences, 13.9 [13.2]) than students with a master’s degree (18.5 [8.4]), doctorate (24.5 [17.5]), or dedicated research time (23.9 [14.9])(P<.001).

Utilizing US News & World Report rankings (2019 Best Medical Schools: Research), we determined that 146 applicants (24.0%) attended a top 25 medical school in 2019.² Of those 146 applicants, 77 (52.7%) pursued additional training through dedicated research or a second professional degree. Only 107 of the 462 applicants (23.2%) from medical schools that were not in the top 25 as determined by the US News & World Report pursued additional training (P<.0001)(Figure).

There is sentiment among applicants that a weaker dermatology residency application can be bolstered through a dedicated research year or a second professional degree. Whether this additional training has an impact on an applicant’s chances of matching is unclear and requires further investigation. Our data showed that applicants from the top 25 medical schools were more likely to pursue additional training than graduates at other institutions. These highly ranked academic institutions might encourage students to pursue a dual degree or research fellowship. In addition, year-long research opportunities might be more available through top medical schools; these schools might be more likely to offer dual-degree programs or provide funding to support student research opportunities.

It is important to comment on the potential importance of funding to support research years; the unpaid nature of many research fellowships in dermatology tends to favor applicants from a higher socioeconomic background. In that respect, the pervasive trend of encouraging research years in dermatology might widen already apparent disparities in our field, likely impacting underrepresented minorities disproportionately.³ Importantly, students with an MD degree represent nearly all applicants who completed a dual degree or dedicated research time. This might be due to fewer opportunities available to IMGs and DO students or secondary to incentivization by MD institutions.

Our data also suggest that students who pursue additional training have academic achievement metrics similar to those who do not. Additional training might increase medical students’ debt burden, thus catering to more affluent applicants, which, in turn, might have an impact on the diversity of the dermatology residency applicant pool.

Our data come from a single institution during a single application cycle, comprising 608 applicants. Nationwide, there were 701 dermatology residency applicants for the 2018-2019 application cycle; our pool therefore represents most (86.7%) but not all applicants.

We decided to use the US News & World Report 2019 rankings to identify top medical schools. Although this ranking system is imperfect and inherently subjective, it is widely utilized by prospective applicants and administrative faculty; we deemed it the best ranking that we could utilize to identify top medical schools. Because the University of Michigan Medical School was in the top 25 of Best Medical Schools: Research, according to the US News & World Report 2019 rankings, our applicant pool might be skewed to applicants interested in a more academic, research-focused residency program.

Our study revealed that 30% (n=184) of dermatology residency applicants pursued a second professional degree or dedicated research time. There was no difference in UMLE Step 1 and Step 2 scores for those who pursued additional training compared to those who did not.

To the Editor:

Securing a dermatology residency position is extraordinarily competitive. The match rate for US allopathic seniors for dermatology is 84.7%, among the lowest of all medical specialties. Matched dermatology applicants boast a mean US Medical Licensing Examination (USMLE) Step 1 score of 248, the second highest of all specialties.¹ To gain an edge, applicants are faced with decisions regarding pursuit of dedicated research time and additional professional degrees.

We conducted a cross-sectional study to determine how many dermatology residency applicants pursue additional years of training and how this decision relates to USMLE scores and other metrics. This study was approved by the University of Michigan institutional review board. Using Electronic Residency Application Service applicant data, all applicants to the University of Michigan Medical School (Ann Arbor, Michigan) dermatology residency program for the 2018-2019 application cycle were included.

Analysis of variance was performed to determine differences in mean USMLE Step 1 scores, Step 2 Clinical Knowledge scores, and number of research experiences (eg, presentations, publications) between groups. A 2-tailed z test of independent samples was performed for individual pairwise subgroup analyses.

There were 608 (377 female, 231 male; mean age, 27.9 years) applicants from 199 different medical schools; 550 graduated with an MD degree, 40 with a DO degree, and 18 were international medical graduates (IMGs)(eg, MBBS, MBBCh, BAO, MBChB). One hundred eighty-four applicants (30.2%) pursued either a second professional degree or a dedicated research period lasting at least 12 months. Twenty-eight applicants (4.6%) obtained a master’s degree, 21 (3.5%) obtained a doctorate, and 135 (22.2%) pursued dedicated research.

Of the 40 DO applicants, 1 (2.5%) pursued dedicated research time; 0 (zero) completed a dual degree. None (zero) of the 18 IMGs pursued a dual degree or dedicated research time. When the scores of applicants who pursued additional training and the scores of applicants who did not were compared, neither mean USMLE Step 1 scores nor mean USMLE Step 2 Clinical Knowledge scores were statistically different (P=.31 and P=.44, respectively). Applicants who completed medical school in 4 years had fewer research experiences (mean [SD] experiences, 13.9 [13.2]) than students with a master’s degree (18.5 [8.4]), doctorate (24.5 [17.5]), or dedicated research time (23.9 [14.9])(P<.001).

Utilizing US News & World Report rankings (2019 Best Medical Schools: Research), we determined that 146 applicants (24.0%) attended a top 25 medical school in 2019.² Of those 146 applicants, 77 (52.7%) pursued additional training through dedicated research or a second professional degree. Only 107 of the 462 applicants (23.2%) from medical schools that were not in the top 25 as determined by the US News & World Report pursued additional training (P<.0001)(Figure).

There is sentiment among applicants that a weaker dermatology residency application can be bolstered through a dedicated research year or a second professional degree. Whether this additional training has an impact on an applicant’s chances of matching is unclear and requires further investigation. Our data showed that applicants from the top 25 medical schools were more likely to pursue additional training than graduates at other institutions. These highly ranked academic institutions might encourage students to pursue a dual degree or research fellowship. In addition, year-long research opportunities might be more available through top medical schools; these schools might be more likely to offer dual-degree programs or provide funding to support student research opportunities.

It is important to comment on the potential importance of funding to support research years; the unpaid nature of many research fellowships in dermatology tends to favor applicants from a higher socioeconomic background. In that respect, the pervasive trend of encouraging research years in dermatology might widen already apparent disparities in our field, likely impacting underrepresented minorities disproportionately.³ Importantly, students with an MD degree represent nearly all applicants who completed a dual degree or dedicated research time. This might be due to fewer opportunities available to IMGs and DO students or secondary to incentivization by MD institutions.

Our data also suggest that students who pursue additional training have academic achievement metrics similar to those who do not. Additional training might increase medical students’ debt burden, thus catering to more affluent applicants, which, in turn, might have an impact on the diversity of the dermatology residency applicant pool.

Our data come from a single institution during a single application cycle, comprising 608 applicants. Nationwide, there were 701 dermatology residency applicants for the 2018-2019 application cycle; our pool therefore represents most (86.7%) but not all applicants.

We decided to use the US News & World Report 2019 rankings to identify top medical schools. Although this ranking system is imperfect and inherently subjective, it is widely utilized by prospective applicants and administrative faculty; we deemed it the best ranking that we could utilize to identify top medical schools. Because the University of Michigan Medical School was in the top 25 of Best Medical Schools: Research, according to the US News & World Report 2019 rankings, our applicant pool might be skewed to applicants interested in a more academic, research-focused residency program.

Our study revealed that 30% (n=184) of dermatology residency applicants pursued a second professional degree or dedicated research time. There was no difference in UMLE Step 1 and Step 2 scores for those who pursued additional training compared to those who did not.

To the Editor:

Securing a dermatology residency position is extraordinarily competitive. The match rate for US allopathic seniors for dermatology is 84.7%, among the lowest of all medical specialties. Matched dermatology applicants boast a mean US Medical Licensing Examination (USMLE) Step 1 score of 248, the second highest of all specialties.¹ To gain an edge, applicants are faced with decisions regarding pursuit of dedicated research time and additional professional degrees.

We conducted a cross-sectional study to determine how many dermatology residency applicants pursue additional years of training and how this decision relates to USMLE scores and other metrics. This study was approved by the University of Michigan institutional review board. Using Electronic Residency Application Service applicant data, all applicants to the University of Michigan Medical School (Ann Arbor, Michigan) dermatology residency program for the 2018-2019 application cycle were included.

Analysis of variance was performed to determine differences in mean USMLE Step 1 scores, Step 2 Clinical Knowledge scores, and number of research experiences (eg, presentations, publications) between groups. A 2-tailed z test of independent samples was performed for individual pairwise subgroup analyses.

There were 608 (377 female, 231 male; mean age, 27.9 years) applicants from 199 different medical schools; 550 graduated with an MD degree, 40 with a DO degree, and 18 were international medical graduates (IMGs)(eg, MBBS, MBBCh, BAO, MBChB). One hundred eighty-four applicants (30.2%) pursued either a second professional degree or a dedicated research period lasting at least 12 months. Twenty-eight applicants (4.6%) obtained a master’s degree, 21 (3.5%) obtained a doctorate, and 135 (22.2%) pursued dedicated research.

Of the 40 DO applicants, 1 (2.5%) pursued dedicated research time; 0 (zero) completed a dual degree. None (zero) of the 18 IMGs pursued a dual degree or dedicated research time. When the scores of applicants who pursued additional training and the scores of applicants who did not were compared, neither mean USMLE Step 1 scores nor mean USMLE Step 2 Clinical Knowledge scores were statistically different (P=.31 and P=.44, respectively). Applicants who completed medical school in 4 years had fewer research experiences (mean [SD] experiences, 13.9 [13.2]) than students with a master’s degree (18.5 [8.4]), doctorate (24.5 [17.5]), or dedicated research time (23.9 [14.9])(P<.001).

Utilizing US News & World Report rankings (2019 Best Medical Schools: Research), we determined that 146 applicants (24.0%) attended a top 25 medical school in 2019.² Of those 146 applicants, 77 (52.7%) pursued additional training through dedicated research or a second professional degree. Only 107 of the 462 applicants (23.2%) from medical schools that were not in the top 25 as determined by the US News & World Report pursued additional training (P<.0001)(Figure).

There is sentiment among applicants that a weaker dermatology residency application can be bolstered through a dedicated research year or a second professional degree. Whether this additional training has an impact on an applicant’s chances of matching is unclear and requires further investigation. Our data showed that applicants from the top 25 medical schools were more likely to pursue additional training than graduates at other institutions. These highly ranked academic institutions might encourage students to pursue a dual degree or research fellowship. In addition, year-long research opportunities might be more available through top medical schools; these schools might be more likely to offer dual-degree programs or provide funding to support student research opportunities.

It is important to comment on the potential importance of funding to support research years; the unpaid nature of many research fellowships in dermatology tends to favor applicants from a higher socioeconomic background. In that respect, the pervasive trend of encouraging research years in dermatology might widen already apparent disparities in our field, likely impacting underrepresented minorities disproportionately.³ Importantly, students with an MD degree represent nearly all applicants who completed a dual degree or dedicated research time. This might be due to fewer opportunities available to IMGs and DO students or secondary to incentivization by MD institutions.

Our data also suggest that students who pursue additional training have academic achievement metrics similar to those who do not. Additional training might increase medical students’ debt burden, thus catering to more affluent applicants, which, in turn, might have an impact on the diversity of the dermatology residency applicant pool.

Our data come from a single institution during a single application cycle, comprising 608 applicants. Nationwide, there were 701 dermatology residency applicants for the 2018-2019 application cycle; our pool therefore represents most (86.7%) but not all applicants.

We decided to use the US News & World Report 2019 rankings to identify top medical schools. Although this ranking system is imperfect and inherently subjective, it is widely utilized by prospective applicants and administrative faculty; we deemed it the best ranking that we could utilize to identify top medical schools. Because the University of Michigan Medical School was in the top 25 of Best Medical Schools: Research, according to the US News & World Report 2019 rankings, our applicant pool might be skewed to applicants interested in a more academic, research-focused residency program.

Our study revealed that 30% (n=184) of dermatology residency applicants pursued a second professional degree or dedicated research time. There was no difference in UMLE Step 1 and Step 2 scores for those who pursued additional training compared to those who did not.

To the Editor:

Pityriasis lichenoides is a papulosquamous dermatologic disorder that is characterized by recurrent papules.¹ There is a spectrum of disease in pityriasis lichenoides that includes pityriasis lichenoides et varioliformis acuta (PLEVA) at one end and pityriasis lichenoides chronica at the other. Pityriasis lichenoides et varioliformis acuta is more common in younger individuals and is characterized by erythematous papules that often crust; these lesions resolve over weeks. The lesions of pityriasis lichenoides chronica are characteristically scaly, pink to red-brown papules that tend to resolve over months.¹

Histologically, PLEVA exhibits parakeratosis, interface dermatitis, and a wedge-shaped infiltrate.¹ Necrotic keratinocytes and extravasated erythrocytes also are common features. Additionally, monoclonal T cells may be present in the infiltrate.¹

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe variant of PLEVA. Febrile ulceronecrotic Mucha-Habermann disease is characterized by ulceronecrotic lesions, fever, and systemic symptoms.² Herein, we present a case of FUMHD.

A 57-year-old man presented with an eruption of painful lesions involving the face, trunk, arms, legs, and genitalia of 1 month’s duration. The patient denied oral and ocular involvement. He had soreness and swelling of the arms and legs. A prior 12-day course of prednisone prescribed by a community dermatologist failed to improve the rash. A biopsy performed by a community dermatologist was nondiagnostic. The patient denied fever but did report chills. He had no preceding illness and was not taking new medications. On physical examination, the patient was afebrile and normotensive with innumerable deep-seated pustules and crusted ulcerations on the face, palms, soles, trunk, extremities, and penis (Figures 1 and 2). There was a background morbilliform eruption on the trunk. The ocular and oral mucosae were spared. The upper and lower extremities had pitting edema.

The patient’s alanine aminotransaminase and aspartate aminotransaminase levels were elevated at 55 and 51 U/L, respectively. His white blood cell count was within reference range; however, there was an elevated absolute neutrophil count (8.7×10³/μL). No eosinophilia was noted. Laboratory evaluation showed a positive antimitochondrial antibody, and magnetic resonance imaging showed evidence of steatohepatitis. Punch biopsies from both the morbilliform eruption and a deep-seated pustule showed epidermal necrosis, parakeratosis, necrotic keratinocytes, and a lichenoid infiltrate of lymphocytes at the dermoepidermal interface. In the dermis, there was a wedge-shaped superficial and deep, perivascular infiltrate with extravasated erythrocytes (Figures 3 and 4). Tissue Gram stain was negative for bacteria. Varicella-zoster virus and herpes simplex virus immunostains were negative. Direct immunofluorescence showed colloid bodies, as can be seen in lichenoid dermatitis.

At the next clinic visit, the patient reported a fever of 39.4 °C. After reviewing the patient’s histopathology and clinical picture, along with the presence of fever, a final diagnosis of FUMHD was made. The patient was started on an oral regimen of prednisone 80 mg once daily, minocycline 100 mg twice daily, and methotrexate 15 mg weekly. Unna boots (specialized compression wraps) with triamcinolone acetonide ointment 0.1% were placed weekly until the leg edema and ulcerations healed. He was maintained on methotrexate 15 mg weekly and 5 to 10 mg of prednisone once daily. The patient demonstrated residual scarring, with only rare new papulonodules that did not ulcerate when attempts were made to taper his medications. He was followed for nearly 3 years, with a recurrence of symptoms 2 years and 3 months after initial presentation to the academic dermatology clinic.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of PLEVA that can present with the rapid appearance of necrotic skin lesions, fever, and systemic manifestations, including pulmonary, gastrointestinal, central nervous system, cardiac, hematologic, and rheumatologic symptoms.^2-4 The evolution from PLEVA to FUMHD ranges from days to weeks, and patientsrarely can have an initial presentation of FUMHD.² The duration of illness has been reported to be 1 to 24 months⁵; however, the length of illness still remains unclear, as many studies of FUMHD are case reports with limited follow-up. Our patient had a disease duration of at least 27 months. The lesions of FUMHD usually are generalized with flexural prominence, and mucosal involvement occurs in approximately one-quarter of cases. Hypertrophic scarring may be seen after the ulcerated lesions heal.² The incidence of FUMHD is higher in men than in women, and it is more common in younger individuals.^2,6 There have been reported fatalities associated with FUMHD, mostly in adults.^2,4

The clinical differential diagnosis for PLEVA includes disseminated herpes zoster, varicella-zoster virus or coxsackievirus infections, lymphomatoid papulosis, angiodestructive lymphoma such as extranodal natural killer/T-cell lymphoma, drug eruption, arthropod bite, erythema multiforme, ecthyma, ecthyma gangrenosum, necrotic folliculitis, and cutaneous small vessel vasculitis. To differentiate between these diagnoses and PLEVA or FUMHD, it is important to take a strong clinical history. For example, for varicella-zoster virus and coxsackievirus infections, exposure history to the viruses and vaccination history for varicella-zoster virus can help elucidate the diagnosis.

Skin biopsy can help differentiate between these entities and PLEVA or FUMHD. The histopathology of a nonulcerated lesion of FUMHD shows parakeratosis, spongiosis, and lymphocyte exocytosis, as well as lymphocytic vasculitis—findings commonly seen in PLEVA. With the ulceronecrotic lesions of FUMHD, epidermal necrosis and ulceration can be seen microscopically.² Although skin biopsy is not absolutely necessary for making the diagnosis of PLEVA, it can be helpful.³ However, given the dramatic and extreme clinical impression with an extensive differential diagnosis that includes disorders ranging from infectious to neoplastic, biopsy of FUMHD with clinicopathologic correlation often is required.

It is important to avoid biopsying ulcerated lesions of FUMHD, as the histopathologic findings are more likely to be nonspecific. Additionally, nonspecific features often are seen with immunohistochemistry; abnormal laboratory testing may be seen in FUMHD, but there is no specific test to diagnose FUMHD.² Finally, a predominantly CD8⁺ cell infiltrate was seen in 4 of 6 cases of FUMHD, with 2 cases showing a mixed infiltrate of CD8⁺ and CD4⁺ cells.^5,7-10

Although no unified diagnostic criterion exists for FUMHD, Nofal et al² proposed criteria comprised of constant features, which are found in every case of FUMHD and can confirm the diagnosis alone, and variable features to help ensure that cases of FUMHD are not missed. The constant features include fever, acute onset of generalized ulceronecrotic papules and plaques, a course that is rapid and progressive (without a tendency for spontaneous resolution), and histopathology that is consistent with PLEVA. The variable features include history of PLEVA, involvement of mucous membranes, and systemic involvement.²

No single unifying treatment modality for all cases of FUMHD has been described. Immunosuppressive drugs (eg, systemic steroids, methotrexate), antibiotics, antivirals, phototherapy, intravenous immunoglobulin, and dapsone have been tried in patients with FUMHD.² Combination therapy with an oral medication such as erythromycin or methotrexate and psoralen plus UVA may be effective for FUMHD.³ Additionally, some authors believe that patients with FUMHD should be treated similar to burn victims with intensive supportive care.²

The etiology of PLEVA is unknown, but it is presumed to be associated with an effector cytotoxic T-cell response to either an infectious agent or a drug.¹¹Three studies have shown that most PLEVA cases (100% [3/3]; 65% [13/20]; and 57% [8/14]) demonstrate T-cell clonality,^12-14 and some have suggested that PLEVA may be a T-cell lymphoproliferative disorder.^12,13 Additionally, in a case report of 2 children with PLEVA who progressed to cutaneous T-cell lymphoma, the authors suggested that PLEVA may be related to nonaggressive cutaneous T-cell lymphoma.¹⁵ Of note, T-cell clonality, often found through the analysis of T-cell receptor gene rearrangement, is not an absolute criterion for determining malignancy, as some benign conditions may have clonality.¹⁶ However, in another study, clonality was found in only 1 of 10 cases of PLEVA, suggesting that PLEVA stems from an inflammatory reaction to infectious or other triggering agents.¹⁷

Four cases of FUMHD with monoclonality have been reported,^4,7,8 and some researchers propose that FUMHD may be a subset of cutaneous T-cell lymphoma.⁷ However, 2 other cases of FUMHD did not show monoclonality of T cells,^5,18 suggesting that FUMHD may represent an inflammatory disorder, rather than a lymphoproliferative process of T cells.¹⁸ Given the controversy surrounding the clonality of FUMHD, T-cell gene rearrangement studies were not performed in our case.

To the Editor:

Pityriasis lichenoides is a papulosquamous dermatologic disorder that is characterized by recurrent papules.¹ There is a spectrum of disease in pityriasis lichenoides that includes pityriasis lichenoides et varioliformis acuta (PLEVA) at one end and pityriasis lichenoides chronica at the other. Pityriasis lichenoides et varioliformis acuta is more common in younger individuals and is characterized by erythematous papules that often crust; these lesions resolve over weeks. The lesions of pityriasis lichenoides chronica are characteristically scaly, pink to red-brown papules that tend to resolve over months.¹

Histologically, PLEVA exhibits parakeratosis, interface dermatitis, and a wedge-shaped infiltrate.¹ Necrotic keratinocytes and extravasated erythrocytes also are common features. Additionally, monoclonal T cells may be present in the infiltrate.¹

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe variant of PLEVA. Febrile ulceronecrotic Mucha-Habermann disease is characterized by ulceronecrotic lesions, fever, and systemic symptoms.² Herein, we present a case of FUMHD.

A 57-year-old man presented with an eruption of painful lesions involving the face, trunk, arms, legs, and genitalia of 1 month’s duration. The patient denied oral and ocular involvement. He had soreness and swelling of the arms and legs. A prior 12-day course of prednisone prescribed by a community dermatologist failed to improve the rash. A biopsy performed by a community dermatologist was nondiagnostic. The patient denied fever but did report chills. He had no preceding illness and was not taking new medications. On physical examination, the patient was afebrile and normotensive with innumerable deep-seated pustules and crusted ulcerations on the face, palms, soles, trunk, extremities, and penis (Figures 1 and 2). There was a background morbilliform eruption on the trunk. The ocular and oral mucosae were spared. The upper and lower extremities had pitting edema.

The patient’s alanine aminotransaminase and aspartate aminotransaminase levels were elevated at 55 and 51 U/L, respectively. His white blood cell count was within reference range; however, there was an elevated absolute neutrophil count (8.7×10³/μL). No eosinophilia was noted. Laboratory evaluation showed a positive antimitochondrial antibody, and magnetic resonance imaging showed evidence of steatohepatitis. Punch biopsies from both the morbilliform eruption and a deep-seated pustule showed epidermal necrosis, parakeratosis, necrotic keratinocytes, and a lichenoid infiltrate of lymphocytes at the dermoepidermal interface. In the dermis, there was a wedge-shaped superficial and deep, perivascular infiltrate with extravasated erythrocytes (Figures 3 and 4). Tissue Gram stain was negative for bacteria. Varicella-zoster virus and herpes simplex virus immunostains were negative. Direct immunofluorescence showed colloid bodies, as can be seen in lichenoid dermatitis.

At the next clinic visit, the patient reported a fever of 39.4 °C. After reviewing the patient’s histopathology and clinical picture, along with the presence of fever, a final diagnosis of FUMHD was made. The patient was started on an oral regimen of prednisone 80 mg once daily, minocycline 100 mg twice daily, and methotrexate 15 mg weekly. Unna boots (specialized compression wraps) with triamcinolone acetonide ointment 0.1% were placed weekly until the leg edema and ulcerations healed. He was maintained on methotrexate 15 mg weekly and 5 to 10 mg of prednisone once daily. The patient demonstrated residual scarring, with only rare new papulonodules that did not ulcerate when attempts were made to taper his medications. He was followed for nearly 3 years, with a recurrence of symptoms 2 years and 3 months after initial presentation to the academic dermatology clinic.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of PLEVA that can present with the rapid appearance of necrotic skin lesions, fever, and systemic manifestations, including pulmonary, gastrointestinal, central nervous system, cardiac, hematologic, and rheumatologic symptoms.^2-4 The evolution from PLEVA to FUMHD ranges from days to weeks, and patientsrarely can have an initial presentation of FUMHD.² The duration of illness has been reported to be 1 to 24 months⁵; however, the length of illness still remains unclear, as many studies of FUMHD are case reports with limited follow-up. Our patient had a disease duration of at least 27 months. The lesions of FUMHD usually are generalized with flexural prominence, and mucosal involvement occurs in approximately one-quarter of cases. Hypertrophic scarring may be seen after the ulcerated lesions heal.² The incidence of FUMHD is higher in men than in women, and it is more common in younger individuals.^2,6 There have been reported fatalities associated with FUMHD, mostly in adults.^2,4

The clinical differential diagnosis for PLEVA includes disseminated herpes zoster, varicella-zoster virus or coxsackievirus infections, lymphomatoid papulosis, angiodestructive lymphoma such as extranodal natural killer/T-cell lymphoma, drug eruption, arthropod bite, erythema multiforme, ecthyma, ecthyma gangrenosum, necrotic folliculitis, and cutaneous small vessel vasculitis. To differentiate between these diagnoses and PLEVA or FUMHD, it is important to take a strong clinical history. For example, for varicella-zoster virus and coxsackievirus infections, exposure history to the viruses and vaccination history for varicella-zoster virus can help elucidate the diagnosis.

Skin biopsy can help differentiate between these entities and PLEVA or FUMHD. The histopathology of a nonulcerated lesion of FUMHD shows parakeratosis, spongiosis, and lymphocyte exocytosis, as well as lymphocytic vasculitis—findings commonly seen in PLEVA. With the ulceronecrotic lesions of FUMHD, epidermal necrosis and ulceration can be seen microscopically.² Although skin biopsy is not absolutely necessary for making the diagnosis of PLEVA, it can be helpful.³ However, given the dramatic and extreme clinical impression with an extensive differential diagnosis that includes disorders ranging from infectious to neoplastic, biopsy of FUMHD with clinicopathologic correlation often is required.

It is important to avoid biopsying ulcerated lesions of FUMHD, as the histopathologic findings are more likely to be nonspecific. Additionally, nonspecific features often are seen with immunohistochemistry; abnormal laboratory testing may be seen in FUMHD, but there is no specific test to diagnose FUMHD.² Finally, a predominantly CD8⁺ cell infiltrate was seen in 4 of 6 cases of FUMHD, with 2 cases showing a mixed infiltrate of CD8⁺ and CD4⁺ cells.^5,7-10

Although no unified diagnostic criterion exists for FUMHD, Nofal et al² proposed criteria comprised of constant features, which are found in every case of FUMHD and can confirm the diagnosis alone, and variable features to help ensure that cases of FUMHD are not missed. The constant features include fever, acute onset of generalized ulceronecrotic papules and plaques, a course that is rapid and progressive (without a tendency for spontaneous resolution), and histopathology that is consistent with PLEVA. The variable features include history of PLEVA, involvement of mucous membranes, and systemic involvement.²

No single unifying treatment modality for all cases of FUMHD has been described. Immunosuppressive drugs (eg, systemic steroids, methotrexate), antibiotics, antivirals, phototherapy, intravenous immunoglobulin, and dapsone have been tried in patients with FUMHD.² Combination therapy with an oral medication such as erythromycin or methotrexate and psoralen plus UVA may be effective for FUMHD.³ Additionally, some authors believe that patients with FUMHD should be treated similar to burn victims with intensive supportive care.²

The etiology of PLEVA is unknown, but it is presumed to be associated with an effector cytotoxic T-cell response to either an infectious agent or a drug.¹¹Three studies have shown that most PLEVA cases (100% [3/3]; 65% [13/20]; and 57% [8/14]) demonstrate T-cell clonality,^12-14 and some have suggested that PLEVA may be a T-cell lymphoproliferative disorder.^12,13 Additionally, in a case report of 2 children with PLEVA who progressed to cutaneous T-cell lymphoma, the authors suggested that PLEVA may be related to nonaggressive cutaneous T-cell lymphoma.¹⁵ Of note, T-cell clonality, often found through the analysis of T-cell receptor gene rearrangement, is not an absolute criterion for determining malignancy, as some benign conditions may have clonality.¹⁶ However, in another study, clonality was found in only 1 of 10 cases of PLEVA, suggesting that PLEVA stems from an inflammatory reaction to infectious or other triggering agents.¹⁷

Four cases of FUMHD with monoclonality have been reported,^4,7,8 and some researchers propose that FUMHD may be a subset of cutaneous T-cell lymphoma.⁷ However, 2 other cases of FUMHD did not show monoclonality of T cells,^5,18 suggesting that FUMHD may represent an inflammatory disorder, rather than a lymphoproliferative process of T cells.¹⁸ Given the controversy surrounding the clonality of FUMHD, T-cell gene rearrangement studies were not performed in our case.

To the Editor:

Pityriasis lichenoides is a papulosquamous dermatologic disorder that is characterized by recurrent papules.¹ There is a spectrum of disease in pityriasis lichenoides that includes pityriasis lichenoides et varioliformis acuta (PLEVA) at one end and pityriasis lichenoides chronica at the other. Pityriasis lichenoides et varioliformis acuta is more common in younger individuals and is characterized by erythematous papules that often crust; these lesions resolve over weeks. The lesions of pityriasis lichenoides chronica are characteristically scaly, pink to red-brown papules that tend to resolve over months.¹

Histologically, PLEVA exhibits parakeratosis, interface dermatitis, and a wedge-shaped infiltrate.¹ Necrotic keratinocytes and extravasated erythrocytes also are common features. Additionally, monoclonal T cells may be present in the infiltrate.¹

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe variant of PLEVA. Febrile ulceronecrotic Mucha-Habermann disease is characterized by ulceronecrotic lesions, fever, and systemic symptoms.² Herein, we present a case of FUMHD.

A 57-year-old man presented with an eruption of painful lesions involving the face, trunk, arms, legs, and genitalia of 1 month’s duration. The patient denied oral and ocular involvement. He had soreness and swelling of the arms and legs. A prior 12-day course of prednisone prescribed by a community dermatologist failed to improve the rash. A biopsy performed by a community dermatologist was nondiagnostic. The patient denied fever but did report chills. He had no preceding illness and was not taking new medications. On physical examination, the patient was afebrile and normotensive with innumerable deep-seated pustules and crusted ulcerations on the face, palms, soles, trunk, extremities, and penis (Figures 1 and 2). There was a background morbilliform eruption on the trunk. The ocular and oral mucosae were spared. The upper and lower extremities had pitting edema.

The patient’s alanine aminotransaminase and aspartate aminotransaminase levels were elevated at 55 and 51 U/L, respectively. His white blood cell count was within reference range; however, there was an elevated absolute neutrophil count (8.7×10³/μL). No eosinophilia was noted. Laboratory evaluation showed a positive antimitochondrial antibody, and magnetic resonance imaging showed evidence of steatohepatitis. Punch biopsies from both the morbilliform eruption and a deep-seated pustule showed epidermal necrosis, parakeratosis, necrotic keratinocytes, and a lichenoid infiltrate of lymphocytes at the dermoepidermal interface. In the dermis, there was a wedge-shaped superficial and deep, perivascular infiltrate with extravasated erythrocytes (Figures 3 and 4). Tissue Gram stain was negative for bacteria. Varicella-zoster virus and herpes simplex virus immunostains were negative. Direct immunofluorescence showed colloid bodies, as can be seen in lichenoid dermatitis.

At the next clinic visit, the patient reported a fever of 39.4 °C. After reviewing the patient’s histopathology and clinical picture, along with the presence of fever, a final diagnosis of FUMHD was made. The patient was started on an oral regimen of prednisone 80 mg once daily, minocycline 100 mg twice daily, and methotrexate 15 mg weekly. Unna boots (specialized compression wraps) with triamcinolone acetonide ointment 0.1% were placed weekly until the leg edema and ulcerations healed. He was maintained on methotrexate 15 mg weekly and 5 to 10 mg of prednisone once daily. The patient demonstrated residual scarring, with only rare new papulonodules that did not ulcerate when attempts were made to taper his medications. He was followed for nearly 3 years, with a recurrence of symptoms 2 years and 3 months after initial presentation to the academic dermatology clinic.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of PLEVA that can present with the rapid appearance of necrotic skin lesions, fever, and systemic manifestations, including pulmonary, gastrointestinal, central nervous system, cardiac, hematologic, and rheumatologic symptoms.^2-4 The evolution from PLEVA to FUMHD ranges from days to weeks, and patientsrarely can have an initial presentation of FUMHD.² The duration of illness has been reported to be 1 to 24 months⁵; however, the length of illness still remains unclear, as many studies of FUMHD are case reports with limited follow-up. Our patient had a disease duration of at least 27 months. The lesions of FUMHD usually are generalized with flexural prominence, and mucosal involvement occurs in approximately one-quarter of cases. Hypertrophic scarring may be seen after the ulcerated lesions heal.² The incidence of FUMHD is higher in men than in women, and it is more common in younger individuals.^2,6 There have been reported fatalities associated with FUMHD, mostly in adults.^2,4

The clinical differential diagnosis for PLEVA includes disseminated herpes zoster, varicella-zoster virus or coxsackievirus infections, lymphomatoid papulosis, angiodestructive lymphoma such as extranodal natural killer/T-cell lymphoma, drug eruption, arthropod bite, erythema multiforme, ecthyma, ecthyma gangrenosum, necrotic folliculitis, and cutaneous small vessel vasculitis. To differentiate between these diagnoses and PLEVA or FUMHD, it is important to take a strong clinical history. For example, for varicella-zoster virus and coxsackievirus infections, exposure history to the viruses and vaccination history for varicella-zoster virus can help elucidate the diagnosis.

Skin biopsy can help differentiate between these entities and PLEVA or FUMHD. The histopathology of a nonulcerated lesion of FUMHD shows parakeratosis, spongiosis, and lymphocyte exocytosis, as well as lymphocytic vasculitis—findings commonly seen in PLEVA. With the ulceronecrotic lesions of FUMHD, epidermal necrosis and ulceration can be seen microscopically.² Although skin biopsy is not absolutely necessary for making the diagnosis of PLEVA, it can be helpful.³ However, given the dramatic and extreme clinical impression with an extensive differential diagnosis that includes disorders ranging from infectious to neoplastic, biopsy of FUMHD with clinicopathologic correlation often is required.

It is important to avoid biopsying ulcerated lesions of FUMHD, as the histopathologic findings are more likely to be nonspecific. Additionally, nonspecific features often are seen with immunohistochemistry; abnormal laboratory testing may be seen in FUMHD, but there is no specific test to diagnose FUMHD.² Finally, a predominantly CD8⁺ cell infiltrate was seen in 4 of 6 cases of FUMHD, with 2 cases showing a mixed infiltrate of CD8⁺ and CD4⁺ cells.^5,7-10

Although no unified diagnostic criterion exists for FUMHD, Nofal et al² proposed criteria comprised of constant features, which are found in every case of FUMHD and can confirm the diagnosis alone, and variable features to help ensure that cases of FUMHD are not missed. The constant features include fever, acute onset of generalized ulceronecrotic papules and plaques, a course that is rapid and progressive (without a tendency for spontaneous resolution), and histopathology that is consistent with PLEVA. The variable features include history of PLEVA, involvement of mucous membranes, and systemic involvement.²

No single unifying treatment modality for all cases of FUMHD has been described. Immunosuppressive drugs (eg, systemic steroids, methotrexate), antibiotics, antivirals, phototherapy, intravenous immunoglobulin, and dapsone have been tried in patients with FUMHD.² Combination therapy with an oral medication such as erythromycin or methotrexate and psoralen plus UVA may be effective for FUMHD.³ Additionally, some authors believe that patients with FUMHD should be treated similar to burn victims with intensive supportive care.²

The etiology of PLEVA is unknown, but it is presumed to be associated with an effector cytotoxic T-cell response to either an infectious agent or a drug.¹¹Three studies have shown that most PLEVA cases (100% [3/3]; 65% [13/20]; and 57% [8/14]) demonstrate T-cell clonality,^12-14 and some have suggested that PLEVA may be a T-cell lymphoproliferative disorder.^12,13 Additionally, in a case report of 2 children with PLEVA who progressed to cutaneous T-cell lymphoma, the authors suggested that PLEVA may be related to nonaggressive cutaneous T-cell lymphoma.¹⁵ Of note, T-cell clonality, often found through the analysis of T-cell receptor gene rearrangement, is not an absolute criterion for determining malignancy, as some benign conditions may have clonality.¹⁶ However, in another study, clonality was found in only 1 of 10 cases of PLEVA, suggesting that PLEVA stems from an inflammatory reaction to infectious or other triggering agents.¹⁷

Four cases of FUMHD with monoclonality have been reported,^4,7,8 and some researchers propose that FUMHD may be a subset of cutaneous T-cell lymphoma.⁷ However, 2 other cases of FUMHD did not show monoclonality of T cells,^5,18 suggesting that FUMHD may represent an inflammatory disorder, rather than a lymphoproliferative process of T cells.¹⁸ Given the controversy surrounding the clonality of FUMHD, T-cell gene rearrangement studies were not performed in our case.